FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kawa, S Onda, M Ho, M Kreitman, RJ Bera, TK Pastan, I AF Kawa, Seiji Onda, Masanori Ho, Mitchell Kreitman, Robert J. Bera, Tapan K. Pastan, Ira TI The improvement of an anti-CD22 immunotoxin Conversion to single-chain and disulfide stabilized form and affinity maturation by alanine scan SO MABS LA English DT Article DE immunotoxin; HA22; affinity-maturation; alanine scan; V-H/V-L interface AB HA22-LR is a recombinant immunotoxin for the treatment of B-cell malignancies that contains the Fv portion of an anti-CD22 antibody fused to a functional portion of Pseudomonas exotoxin A. In the present study, we attempted to improve this molecule. First, we produced a single-chain version of HA22-LR (scdsFv-HA22-LR) in which a peptide linker was introduced between the disulfide-linked light and heavy chains to enable production via single fermentation. No difference in cytotoxic activity was observed between scdsFv-HA22-LR and prototype HA22-LR. Next, we attempted to increase the affinity of scdsFv-HA22-LR by using alanine scanning mutagenesis of complementarity determining regions (CDRs) to assess the specific contribution of each CDR residue to the antigen binding. We found that mutation of asparagine 34 in V(L)CDR1, which is located at the V-L/V-H interface, to alanine (N34A) caused a substantial increase in affinity and activity. Estimated K-D values measured by fluorescence-activated cell sorting were lowered by 10-fold: 0.056 nM in the N34A mutant compared to 0.58 nM in wild type (WT). Cell viability assays of CD22-positive B-cell lymphoma and leukemia cell lines showed that the N34A mutant had increased cytotoxicity ranging from similar to 2 (HAL-1, IC50(WT): 2.37 +/- 0.62 ng/ml, IC50(N34A): 1.32 +/- 0.41 ng/ml) to 10 (SUDHL-6, IC50(WT): 0.47 +/- 0.090 ng/ml, IC50(N34A): 0.048 +/- 0.018 ng/ml)-fold compared to WT immunotoxin. The present study suggests that the N34A mutant of scdsFv-HA22-LR could have important consequences in a clinical setting. C1 [Kawa, Seiji; Onda, Masanori; Ho, Mitchell; Kreitman, Robert J.; Bera, Tapan K.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov RI Ho, Mitchell/F-5059-2015 FU NIH, National Cancer Institute, Center for Cancer Research; JSPS FX We thank Dr. Louis M. Staudt for providing SUDHL-5 and SUDHL-6 cells, and Dr. Alan Wayne for HAL-1 and Nalm-19 cells. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and in part by JSPS Research Fellowship to S.K. for Japanese Biomedical and Behavioral Research, Japan Society for the Promotion of Science. NR 41 TC 7 Z9 8 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1942-0862 J9 MABS-AUSTIN JI mAbs PD SEP-OCT PY 2011 VL 3 IS 5 BP 479 EP 486 DI 10.4161/mabs.3.5.17228 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA V29HX UT WOS:000208740600009 PM 22048691 ER PT J AU Dvir-Ginzberg, M Gabay, O Oppenhiemer, H Meir, H Gagarina, V Lee, E Haze, A Kandel, L Liebergall, M AF Dvir-Ginzberg, M. Gabay, O. Oppenhiemer, H. Meir, H. Gagarina, V. Lee, E. Haze, A. Kandel, L. Liebergall, M. TI TNFa INDUCES SIRT1 CLEAVAGE IN HUMAN OSTEOARTHRITIC CHONDROCYTES SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract C1 [Dvir-Ginzberg, M.; Oppenhiemer, H.; Meir, H.; Haze, A.] Hebrew Univ Jerusalem, Jerusalem, Israel. [Gabay, O.; Gagarina, V.; Lee, E.] NIAMS, Bethesda, MD USA. [Kandel, L.; Liebergall, M.] Hadassah Mt Scopus Hosp, Jerusalem, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD SEP PY 2011 VL 19 SU 1 MA 198 BP S98 EP S98 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA V33EH UT WOS:000209001600221 ER PT J AU Gabay, OH Sanchez, C Dvir-Ginzberg, M Gagarina, V Lee, E Zaal, KJ McBurney, MW Hall, DJ AF Gabay, O. H. Sanchez, C. Dvir-Ginzberg, M. Gagarina, V. Lee, E. Zaal, K. J. McBurney, M. W. Hall, D. J. TI SIRT1-DEFICIENT MICE EXHIBIT AN ALTERED CARTILAGE PHENOTYPE AND UNDERGO INCREASED CARTILAGE BREAKDOWN AND APOPTOSIS SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract C1 [Gabay, O. H.; Gagarina, V.; Lee, E.; Zaal, K. J.; Hall, D. J.] NIH, Bethesda, MD 20892 USA. [Sanchez, C.] Univ Liege, Inst Pathol B23, Bone & Cartilage Res Unit, Liege, Belgium. [Dvir-Ginzberg, M.] Hebrew Univ Hadassah Kerem, Fac Med Dent, Inst Dent Sci, Lab Cartilage Biol, Jerusalem, Israel. [McBurney, M. W.] Ottawa Hosp Res Inst, Ottawa, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD SEP PY 2011 VL 19 SU 1 MA 60 BP S33 EP S33 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA V33EH UT WOS:000209001600083 ER PT J AU Hicks, CW Cui, XZ Sweeney, DA Li, Y Barochia, A Eichacker, PQ AF Hicks, Caitlin W. Cui, Xizhong Sweeney, Daniel A. Li, Yan Barochia, Amisha Eichacker, Peter Q. TI The Potential Contributions of Lethal and Edema Toxins to the Pathogenesis of Anthrax Associated Shock SO TOXINS LA English DT Review DE anthrax; lethal toxin; edema toxin; shock; myocardial function ID BACILLUS-ANTHRACIS; PROTECTIVE ANTIGEN; INHALATIONAL ANTHRAX; CYCLIC-AMP; ADENYLATE-CYCLASE; IN-VIVO; CAPILLARY MORPHOGENESIS; ESCHERICHIA-COLI; CHOLERA TOXIN; UNITED-STATES AB Outbreaks of Bacillus anthracis in the US and Europe over the past 10 years have emphasized the health threat this lethal bacteria poses even for developed parts of the world. In contrast to cutaneous anthrax, inhalational disease in the US during the 2001 outbreaks and the newly identified injectional drug use form of disease in the UK and Germany have been associated with relatively high mortality rates. One notable aspect of these cases has been the difficulty in supporting patients once shock has developed. Anthrax bacilli produce several different components which likely contribute to this shock. Growing evidence indicates that both major anthrax toxins may produce substantial cardiovascular dysfunction. Lethal toxin (LT) can alter peripheral vascular function; it also has direct myocardial depressant effects. Edema toxin (ET) may have even more pronounced peripheral vascular effects than LT, including the ability to interfere with the actions of conventional vasopressors. Additionally, ET also appears capable of interfering with renal sodium and water retention. Importantly, the two toxins exert their actions via quite different mechanisms and therefore have the potential to worsen shock and outcome in an additive fashion. Finally, both toxins have the ability to inhibit host defense and microbial clearance, possibly contributing to the very high bacterial loads noted in patients dying with anthrax. This last point is clinically relevant since emerging data has begun to implicate other bacterial components such as anthrax cell wall in the shock and organ injury observed with infection. Taken together, accumulating evidence regarding the potential contribution of LT and ET to anthrax-associated shock supports efforts to develop adjunctive therapies that target both toxins in patients with progressive shock. C1 [Cui, Xizhong; Li, Yan; Barochia, Amisha; Eichacker, Peter Q.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Hicks, Caitlin W.] Cleveland Clin Lerner Coll Med, Cleveland, OH 44195 USA. [Hicks, Caitlin W.] Natl Inst Hlth Res Scholar, Howard Hughes Med Inst, NIH, Bethesda, MD 20814 USA. [Sweeney, Daniel A.] Washington Hosp, Med Intensivist Program, Fremont, CA 94538 USA. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. EM caitlin.hicks@gmail.com; cxizhong@mail.cc.nih.gov; danielasweeney@yahoo.com; yli@mail.cc.nih.gov; braochiaav@mail.cc.nih.gov; peichacker@mail.cc.nih.gov OI Hicks, Caitlin/0000-0001-7638-1936 NR 86 TC 12 Z9 15 U1 0 U2 5 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6651 J9 TOXINS JI Toxins PD SEP PY 2011 VL 3 IS 9 BP 1185 EP 1202 DI 10.3390/toxins3091185 PG 18 WC Toxicology SC Toxicology GA 995AW UT WOS:000307979300007 PM 22069762 ER PT J AU Toobert, DJ Strycker, LA King, DK Barrera, M Osuna, D Glasgow, RE AF Toobert, Deborah J. Strycker, Lisa A. King, Diane K. Barrera, Manuel, Jr. Osuna, Diego Glasgow, Russell E. TI Long-term outcomes from a multiple-risk-factor diabetes trial for Latinas: Viva Bien! SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Latina; Diabetes; Multiple behavior change Self-management; Randomized controlled trial AB Latinas with type 2 diabetes are in need of culturally sensitive interventions to make recommended long-term lifestyle changes and reduce heart disease risk. To test the longer-term (24-month) effects of a previously successful, culturally adapted, multiple-health-behavior-change program, Viva Bien!, 280 Latinas were randomly assigned to usual care or Viva Bien!. Treatment included group meetings to promote a culturally adapted Mediterranean diet, physical activity, supportive resources, problem solving, stress-management practices, and smoking cessation. Viva Bien! participants achieved and maintained some lifestyle improvements from baseline through 24 months, including significant improvements for psychosocial outcomes, fat intake, social-environmental support, body mass index, and hemoglobin A1c. Effects tended to diminish over time. The Viva Bien! multiple-behavior program was effective in improving and maintaining some psychosocial, behavioral, and biological outcomes related to heart health across 24 months for Latinas with type 2 diabetes, a high-risk, underserved population (ClinicalTrials.gov number, NCT00233259). C1 [Toobert, Deborah J.; Strycker, Lisa A.] Oregon Res Inst, Eugene, OR 97403 USA. [King, Diane K.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO 80237 USA. [Barrera, Manuel, Jr.] Arizona State Univ, Dept Psychol, Tempe, AZ 85287 USA. [Osuna, Diego] Univ Colorado, Hlth Sci Ctr, Inst Hlth Res, Kaiser Permanente Colorado, Denver, CO 80237 USA. [Glasgow, Russell E.] NCI, Disseminat & Implementat Sci, 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 National Heart, Lung, and Blood Institute [R01-HL077120] FX This research was supported by grant number R01-HL077120 from the National Heart, Lung, and Blood Institute. NR 71 TC 20 Z9 20 U1 4 U2 4 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD SEP PY 2011 VL 1 IS 3 BP 416 EP 426 DI 10.1007/s13142-010-0011-1 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V39LI UT WOS:000209412100011 PM 22022345 ER PT J AU Thomas, DG Klaessig, F Harper, SL Fritts, M Hoover, MD Gaheen, S Stokes, TH Reznik-Zellen, R Freund, ET Klemm, JD Paik, DS Baker, NA AF Thomas, Dennis G. Klaessig, Fred Harper, Stacey L. Fritts, Martin Hoover, Mark D. Gaheen, Sharon Stokes, Todd H. Reznik-Zellen, Rebecca Freund, Elaine T. Klemm, Juli D. Paik, David S. Baker, Nathan A. TI Informatics and standards for nanomedicine technology SO WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY LA English DT Review ID MEDICAL INFORMATICS; DRUG-DELIVERY; BIOMEDICAL INFORMATICS; IMAGING INFORMATICS; BIOLOGICAL INTEREST; CHEMICAL ENTITIES; CANCER-THERAPY; ONTOLOGY; NANOTECHNOLOGY; NANOPARTICLES AB There are several issues to be addressed concerning the management and effective use of information (or data), generated from nanotechnology studies in biomedical research and medicine. These data are large in volume, diverse in content, and are beset with gaps and ambiguities in the description and characterization of nanomaterials. In this work, we have reviewed three areas of nanomedicine informatics: information resources; taxonomies, controlled vocabularies, and ontologies; and information standards. Informatics methods and standards in each of these areas are critical for enabling collaboration; data sharing; unambiguous representation and interpretation of data; semantic (meaningful) search and integration of data; and for ensuring data quality, reliability, and reproducibility. In particular, we have considered four types of information standards in this article, which are standard characterization protocols, common terminology standards, minimum information standards, and standard data communication (exchange) formats. Currently, because of gaps and ambiguities in the data, it is also difficult to apply computational methods and machine learning techniques to analyze, interpret, and recognize patterns in data that are high dimensional in nature, and also to relate variations in nanomaterial properties to variations in their chemical composition, synthesis, characterization protocols, and so on. Progress toward resolving the issues of information management in nanomedicine using informatics methods and standards discussed in this article will be essential to the rapidly growing field of nanomedicine informatics. (C) 2011 JohnWiley & Sons, Inc. WIREs Nanomed Nanobiotechnol 2011 3 511-532 DOI: 10.1002/wnan.152 C1 [Thomas, Dennis G.; Baker, Nathan A.] Pacific NW Natl Lab, Knowledge Discovery & Informat Grp, Richland, WA 99352 USA. [Klaessig, Fred] Penn Bio Nano Syst LLC, Doylestown, PA USA. [Harper, Stacey L.] Oregon State Univ, Sch Chem Biol & Environm Engn, Corvallis, OR 97331 USA. [Fritts, Martin] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Hoover, Mark D.] NIOSH, Morgantown, WV USA. [Gaheen, Sharon] SAIC, Hlth Solut Business Unit, Rockville, MD USA. [Stokes, Todd H.] Emory Univ, Dept Biomed Engn, Atlanta, GA 30322 USA. [Stokes, Todd H.] Georgia Tech, Atlanta, GA USA. [Reznik-Zellen, Rebecca] Univ Massachusetts, Ctr Hierarch Mfg, Amherst, MA 01003 USA. [Freund, Elaine T.] 3rd Millenium Inc, Waltham, MA USA. [Klemm, Juli D.] NCI, Ctr Biomed Informat & Informat Technol, Bethesda, MD 20892 USA. [Paik, David S.] Stanford Univ, Radiol Sci Lab, Stanford, CA 94305 USA. RP Baker, NA (reprint author), Pacific NW Natl Lab, Knowledge Discovery & Informat Grp, Richland, WA 99352 USA. EM nathan.baker@pnl.gov RI Hoover, Mark/I-4201-2012; Baker, Nathan/A-8605-2010; OI Hoover, Mark/0000-0002-8726-8127; Baker, Nathan/0000-0002-5892-6506; Reznik-Zellen, Rebecca/0000-0001-9321-8284 FU NIH NCI caBIG(R) Working Group; Pacific Northwest National Laboratory; NIH [U54 HG004028, U54 CA11934205, U01 NS073457]; Environmental Health and Sciences Center [P30 ES03850]; EPA [STAR RD-833320]; Safer Nanomaterials and Nanomanufacturing Initiative of the Oregon Nanoscience and Microtechnologies Institute [FA8650-05-1-5041] FX We are grateful to the participants of the caBIG (R) Nanotechnology Working Group for their comments and contributions to the working group activities as well as the National Center for Biomedical Ontology for their support of nanomedicine informatics through the NCBO Bioportal, Resource Index, and caOBR (R) N.A.B. and D.G.T. acknowledge support from the NIH NCI caBIG (R) Working Group, Pacific Northwest National Laboratory HHS sector LDRD funds, as well as NIH grants U54 HG004028, U54 CA11934205, and U01 NS073457. S.L.H. acknowledges support from NIH NCI caBIG (R) Working Group, Environmental Health and Sciences Center P30 ES03850, EPA STAR RD-833320, and the Safer Nanomaterials and Nanomanufacturing Initiative of the Oregon Nanoscience and Microtechnologies Institute FA8650-05-1-5041. The views, opinions, and content in this article are those of the authors and do not necessarily represent the views, opinions, or policies of their respective employers or organizations. Mention of company names or products does not constitute endorsement. NR 93 TC 17 Z9 17 U1 1 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1939-5116 EI 1939-0041 J9 WIRES NANOMED NANOBI JI Wiley Interdiscip. Rev.-Nanomed. Nanobiotechnol. PD SEP-OCT PY 2011 VL 3 IS 5 BP 511 EP 532 DI 10.1002/wnan.152 PG 22 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA 864RX UT WOS:000298258800007 PM 21721140 ER PT J AU Reedy, J Kirkpatrick, SI AF Reedy, Jill Kirkpatrick, Sharon I. TI The ONQI Is Not a Black Box Author Response SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Letter C1 [Reedy, Jill; Kirkpatrick, Sharon I.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. RP Reedy, J (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. EM reedyj@mail.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2011 VL 41 IS 3 BP E16 EP E16 DI 10.1016/j.amepre.2011.06.023 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 808TW UT WOS:000294002700002 ER PT J AU Carney, JA Young, WF Stratakis, CA AF Carney, J. Aidan Young, William F., Jr. Stratakis, Constantine A. TI Primary Bimorphic Adrenocortical Disease: Cause of Hypercortisolism in McCune-Albright Syndrome SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE adrenal cortical atrophy; adrenal cortical hyperplasia; Cushing syndrome; GNAS1 mutation; McCune-Albright syndrome ID NODULAR ADRENAL-HYPERPLASIA; STIMULATORY G-PROTEIN; CUSHINGS-SYNDROME; ACTIVATING MUTATIONS; PRECOCIOUS PUBERTY; HYPERTHYROIDISM; MANIFESTATIONS; PIGMENTATION; DISCORDANT; ENDOCRINE AB McCune-Albright syndrome (polyostotic fibrous dysplasia, cafe-au-lait skin spots, and precocious puberty) is a genetically mosaic disorder with populations of mutant and normal cells in affected organs. Cushing syndrome, a rare feature of the condition, usually affects infants and is the result of corticotropin-independent primary bilateral adrenal disease, usually interpreted as nodular adrenocortical hyperplasia. In this study of 9 patients with Cushing syndrome and McCune-Albright syndrome, light microscopy revealed a characteristic bimorphic pattern of diffuse and nodular hyperplasia and a distinctive form of cortical atrophy with apparent zona glomerulosa hyperplasia in 8 patients, all very young. The pattern could be explained by the presence of a mosaic distribution of mutant and normal cells in the adrenal glands. The findings are different from those in inherited or other forms of genetically caused Cushing syndrome. The ninth patient, aged 17 years, had an adrenal adenoma and diffuse cortical hyperplasia in each adrenal gland. C1 [Carney, J. Aidan] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Young, William F., Jr.] Mayo Clin, Div Endocrinol Diabet Nutr & Metab, Rochester, MN 55905 USA. [Stratakis, Constantine A.] NICHD, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. RP Carney, JA (reprint author), Mayo Clin, Dept Lab Med & Pathol, 200 SW 1st St, Rochester, MN 55905 USA. EM carney.aidan@mayo.edu FU Mayo Foundation; NIH [Z01HD00064204] FX J.A.C. received funding from the Mayo Foundation and the Intramural Program, NIH project Z01HD00064204. NR 35 TC 22 Z9 25 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD SEP PY 2011 VL 35 IS 9 BP 1311 EP 1326 DI 10.1097/PAS.0b013e31821ec4ce PG 16 WC Pathology; Surgery SC Pathology; Surgery GA 806TG UT WOS:000293834400007 PM 21836496 ER PT J AU Lago, CU Sung, HJ Ma, WZ Wang, PY Hwang, PM AF Lago, Cory U. Sung, Ho Joong Ma, Wenzhe Wang, Ping-Yuan Hwang, Paul M. TI p53, Aerobic Metabolism, and Cancer SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID MITOCHONDRIAL TRANSCRIPTION FACTOR; TUMOR-SUPPRESSOR P53; LI-FRAUMENI-SYNDROME; RAT SKELETAL-MUSCLE; PHYSICAL-ACTIVITY; DNA-BINDING; ENERGY-METABOLISM; OXIDATIVE STRESS; CARDIORESPIRATORY FITNESS; P53-INDUCIBLE REGULATOR AB p53 regulates the cell cycle and deoxyribonucleic acid (DNA) repair pathways as part of its unequivocally important function to maintain genomic stability. Intriguingly, recent studies show that p53 can also transactivate genes involved in coordinating the two major pathways of energy generation to promote aerobic metabolism, but how this serves to maintain genomic stability is less clear. In an attempt to understand the biology, this review presents human epidemiologic data on the inverse relationship between aerobic capacity and cancer incidence that appears to be mirrored by the impact of p53 on aerobic capacity in mouse models. The review summarizes mechanisms by which p53 regulates mitochondrial respiration and proposes how this might contribute to maintaining genomic stability. Although disparate in nature, the data taken together suggest that the promotion of aerobic metabolism by p53 serves as an important tumor suppressor activity and may provide insights for cancer prevention strategies in the future. Antioxid. Redox Signal. 15, 1739-1748. C1 [Lago, Cory U.; Sung, Ho Joong; Ma, Wenzhe; Wang, Ping-Yuan; Hwang, Paul M.] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Sung, Ho Joong] Eulji Univ, Coll Hlth Sci, Dept Biomed Lab Sci, Gyeonggi Do, South Korea. RP Hwang, PM (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10-CRC,Rm 5-5330, Bethesda, MD 20892 USA. EM hwangp@mail.nih.gov NR 123 TC 20 Z9 20 U1 0 U2 6 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 SEP PY 2011 VL 15 IS 6 BP 1739 EP 1748 DI 10.1089/ars.2010.3650 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 803JA UT WOS:000293576400017 PM 20919942 ER PT J AU Motegi, S Leitner, WW Lu, M Tada, Y Sardy, M Wu, CJ Chavakis, T Udey, MC AF Motegi, Sei-ichiro Leitner, Wolfgang W. Lu, Michael Tada, Yayoi Sardy, Miklos Wu, Chuanjin Chavakis, Triantafyllos Udey, Mark C. TI Pericyte-Derived MFG-E8 Regulates Pathologic Angiogenesis SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE angiogenesis; MFG-E8; melanoma; oxygen-induced retinopathy; pericyte ID EPIDERMAL-GROWTH FACTOR-8; DISCOIDIN-DOMAIN PROTEIN; APOPTOTIC CELLS; RETINAL NEOVASCULARIZATION; INDUCED RETINOPATHY; ENDOTHELIAL-CELLS; TUMOR VASCULATURE; DENDRITIC CELLS; 10T1/2 CELLS; MOUSE MODEL AB Objective-MFG-E8 (also called lactadherin and SED1) is a secreted glycoprotein that has been previously implicated in enhancement of vascular endothelial growth factor-dependent angiogenesis. Major sources of MFG-E8 in vivo and precise mechanisms of MFG-E8 action remain undetermined. The objective of this study was to identify important sources of MFG-E8 in vivo and further elucidate the role(s) of MFG-E8 in the regulation of angiogenesis. Methods and Results-We used knockout mice and anti-MFG-E8 antibodies to study MFG-E8 function in vivo. In melanomas and in retinas of mice with oxygen-induced retinopathy, MFG-E8 colocalized with pericytes rather than endothelial cells, and platelet-derived growth factor receptor beta+ pericytes/pericyte precursors purified from tumors contained large amounts of MFG-E8 mRNA. Tumor-and retinopathy-associated angiogenesis was diminished in MFG-E8 knockout mice, and pericyte coverage of neovessels was reduced. Inhibition of MFG-E8 production by 10T1/2 cells (surrogate pericyte/pericyte precursors) using small interfering RNAs and short hairpin RNAs, or inhibition of MFG-E8 action with some anti-MFG-E8 antibodies, selectively attenuated migration in vitro. Significantly, the anti-MFG-E8 antibodies that inhibited 10T1/2 cell migration in vitro also inhibited pathological angiogenesis in vivo. Conclusion-These studies strongly implicate MFG-E8 in pericyte/pericyte precursor function and indicate that MFG-E8-directed therapeutics may merit further development. (Arterioscler Thromb Vasc Biol. 2011;31:2024-2034.) C1 [Motegi, Sei-ichiro; Leitner, Wolfgang W.; Lu, Michael; Tada, Yayoi; Sardy, Miklos; Wu, Chuanjin; Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20802 USA. [Chavakis, Triantafyllos] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20802 USA. RP Udey, MC (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Rm 12N238, Bethesda, MD 20802 USA. EM udeym@mail.nih.gov RI Leitner, Wolfgang/F-5741-2011 OI Leitner, Wolfgang/0000-0003-3125-5922 FU National Institutes of Health, Center for Cancer Research, National Cancer Institute; Japan Foundation for Aging and Health; Japan Society for Promotion of Science at the National Institutes of Health FX This work was supported by the Intramural Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (to M.C.U.). Dr Motegi was supported, in part, by project grants from the Japan Foundation for Aging and Health and a Japan Society for Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health. NR 55 TC 19 Z9 19 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD SEP PY 2011 VL 31 IS 9 BP 2024 EP U281 DI 10.1161/ATVBAHA.111.232587 PG 33 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 808DF UT WOS:000293955200021 PM 21737783 ER PT J AU Hiranita, T Soto, PL Tanda, G Katz, JL AF Hiranita, Takato Soto, Paul L. Tanda, Gianluigi Katz, Jonathan L. TI Lack of cocaine-like discriminative-stimulus effects of sigma-receptor agonists in rats SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE sigma receptor; 1,3-di-o-tolylguanidine; cocaine; discriminative-stimulus effects; dopamine-uptake inhibitor; methylphenidate; PRE-084; WIN 35 428 ID CONDITIONED PLACE PREFERENCE; DOPAMINE; MICE; METHAMPHETAMINE; BLOCKADE; LIGANDS; INVOLVEMENT; ACTIVATION; MORPHINE AB Previous studies demonstrated the effectiveness of selective sigma-receptor (sigma R) agonists [1,3-di-o-tolylguanidine (DTG), PRE-084] as reinforcers in rats trained to self-administer cocaine. Similar to cocaine, these drugs increased nucleus accumbens shell dopamine levels, and effects of DTG, but not PRE-084, on dopamine seemed to be mediated by sigma Rs. In addition, sigma R antagonists blocked self-administration of sigma R agonists, but were inactive against reinforcing and neurochemical effects of cocaine. Thus, pharmacologically distinct mechanisms likely underlie the reinforcing and neurochemical effects of sigma R agonists and cocaine. This study further examined the cocaine-like effects of sigma R agonists in rats trained to discriminate injections of cocaine from saline to assess the similarity of their subjective effects. Standard dopamine-uptake inhibitors (WIN 35 428, methylphenidate), but neither sigma R agonist (PRE-084, DTG), produced full cocaine-like discriminative-stimulus effects. The lack of effects of sigma R agonists was obtained regardless of route of administration (intraperitoneal, subcutaneous, or intravenous) or pretreatment time (5 or 30 min before sessions). The present results demonstrate differences in the discriminative-stimulus effects of cocaine and selective sigma R agonists, indicating that an overlap of subjective effects is not necessary for sigma R agonist self-administration. The previously found differences in neurochemical effects of cocaine and sigma R agonists may contribute to their different subjective effects. Behavioural Pharmacology 22:525-530 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Hiranita, Takato; Tanda, Gianluigi; Katz, Jonathan L.] NIDA, Psychobiol Sect, Medicat Discovery Res Branch, Intramural Res Program,Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. [Soto, Paul L.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Medicat Discovery Res Branch, Intramural Res Program,Dept Hlth & Human Serv,NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov RI Tanda, Gianluigi/B-3318-2009; Hiranita, Takato/G-6567-2011 OI Tanda, Gianluigi/0000-0001-9526-9878; FU National Institute on Drug Abuse FX The authors thank Patty Ballerstadt for administrative assistance and Bettye Campbell for technical assistance. This study was supported by the Intramural Research Program of the National Institute on Drug Abuse. The animal housing facilities are fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International and all procedures were conducted in accordance with the guidelines of the Institutional Care and Use Committee of the NIDA Intramural Research Program and the 1996 National Research Council and Guide for Care and Use of Laboratory Animals. NR 30 TC 9 Z9 9 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2011 VL 22 IS 5-6 BP 525 EP 530 DI 10.1097/FBP.0b013e328349ab22 PG 6 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 806QM UT WOS:000293825000017 PM 21808192 ER PT J AU Yum, S Choi, J Hong, S Park, MH Lee, J Ha, NC Jung, Y AF Yum, Soohwan Choi, Jeongyoun Hong, Sungchae Park, Myung Hee Lee, Jaewon Ha, Nam-Chul Jung, Yunjin TI Hyperoxia attenuates the inhibitory effect of nitric oxide donors on HIF prolyl-4-hydroxylase-2: Implication on discriminative effect of nitric oxide on HIF prolyl-4-hydroxylase-2 and collagen prolyl-4-hydroxylase SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Nitric oxide; Hyperoxia; HIF polyl-4-hydroxylase; Collagen prolyl-4-hydroxylase; Hypoxia inducible factor ID HYPOXIA-INDUCIBLE FACTOR; PROLYL 4-HYDROXYLASES; KEY ENZYMES; HYDROXYLATION; ALPHA; FIBROBLASTS; HIF-1-ALPHA; ACTIVATION; STABILITY; PATHWAY AB Prolyl 4-hydroxylases (P4Hs), such as collagen prolyl-4-hydroxylases (CPHs) and hypoxia inducible factor prolyl-4-hydroxylases (HPHs), have recently been recognized as promising drug targets for the treatment of fibrotic and ischemic diseases. CPHs and HPHs catalyze identical metabolic reactions, yet lead to quite different physiological consequences, collagen synthesis and the regulation of oxygen homeostasis. Selective modulation of the two enzymes should provide a therapeutic benefit upon pharmacotherapy. In an in vitro VHL capture assay, hydroxylation of the 19mer HIF peptide (corresponding to HIF-1 alpha residues 556-574) by HPH-2 was effectively prevented by nitric oxide (NO) donors, (+/-)-S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione. The NO donors also caused inhibition of HPHs and accumulation of nonhydroxylated HIF-1 alpha protein in A549 human lung adenocarcinoma cells. Hyperoxia (100% O(2)) attenuated both NO donor-induced accumulation of HIF-1 alpha and inhibition of HPH-mediated hydroxylation. In the presence of a proteasome inhibitor, MG132, the hyperoxia-mediated degradation of HIF-1 alpha was deterred and hydroxylated HIF-1 alpha was detected. SNAP, while being an effective inhibitor of proline 4-hydroxylation of HIF-1 alpha by HPH-2, did not diminish praline hydroxylation of collagen by CPHs. Our data suggest that NO inhibits HPH-2 via competing with dioxygen and that the discriminative effect of NO on CPHs and HPH-2 is attributable to the difference in the affinity of the two enzymes toward dioxygen. (C) 2011 Elsevier Inc. All rights reserved. C1 [Yum, Soohwan; Choi, Jeongyoun; Hong, Sungchae; Park, Myung Hee; Lee, Jaewon; Ha, Nam-Chul; Jung, Yunjin] Pusan Natl Univ, Coll Pharm, Pusan 609735, South Korea. [Park, Myung Hee] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Jung, Y (reprint author), Pusan Natl Univ, Coll Pharm, Pusan 609735, South Korea. EM jungy@pusan.ac.kr RI Lee, Jaewon/N-9064-2013 FU Ministry of Education, Science and Technology [2009-0071594]; Ministry for Health, Welfare and Family Affairs, Republic of Korea [A080640] FX This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No: 2009-0071594) and a grant of the Korea Healthcare technology R and D Project (A080640), Ministry for Health, Welfare and Family Affairs, Republic of Korea. NR 23 TC 0 Z9 0 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD SEP 1 PY 2011 VL 82 IS 5 BP 485 EP 490 DI 10.1016/j.bcp.2011.05.033 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 806PR UT WOS:000293820600007 PM 21723853 ER PT J AU Giano, MC Pochan, DJ Schneider, JP AF Giano, Michael C. Pochan, Darrin J. Schneider, Joel P. TI Controlled biodegradation of Self-assembling beta-hairpin Peptide hydrogels by proteolysis with matrix metalloproteinase-13 SO BIOMATERIALS LA English DT Article DE Biodegradation; Matrix metalloproteinase; Peptide; Self assembly; Hydrogel; Extracellular matrix ID ENGINEERED PEG HYDROGELS; BIOMEDICAL APPLICATIONS; SUBSTRATE-SPECIFICITY; SCAFFOLD DESIGN; CELL-MIGRATION; NETWORKS; BIOMATERIALS; DEGRADATION; TISSUE; CARTILAGE AB Controlled biodegradation specific to matrix metalloproteinase-13 was incorporated into the design of self-assembling beta-hairpin peptide hydrogels. Degrading Peptides (DP peptides) are a series of five peptides that have varying proteolytic susceptibilities toward MMP-13. These peptides undergo environmentally triggered folding and self-assembly under physiologically relevant conditions (150 mm NaCl. pH 7.6) to form self-supporting hydrogels. In the presence of enzyme, gels prepared from distinct peptides are degraded at rates that differ according to the primary sequence of the single peptide comprising the gel. Material degradation was monitored by oscillatory shear rheology over the course of 14 days, where overall degradation of the gels vary from 5% to 70%. Degradation products were analyzed by HPLC and identified by electrospray-ionization mass spectrometry. This data shows that proteolysis of the parent peptides constituting each gel occurs at the intended sequence location. DP hydrogels show specificity to MMP-13 and are only minimally cleaved by matrix metalloproteinase-3 (MMP-3), another common enzyme present during tissue injury. In vitro migration assays performed with SW1353 cells show that migration rates through each gel differs according to peptide sequence, which is consistent with the proteolysis studies using exogenous MMP-13. Published by Elsevier Ltd. C1 [Giano, Michael C.; Schneider, Joel P.] NCI, Canc Res Ctr, Frederick, MD 21701 USA. [Giano, Michael C.] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. [Pochan, Darrin J.] Univ Delaware, Dept Mat Sci & Engn, Newark, DE 19716 USA. RP Schneider, JP (reprint author), NCI, Canc Res Ctr, Frederick, MD 21701 USA. EM Joel.Schneider@nih.gov RI Schneider, Joel/N-2610-2014 FU National Cancer Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute of the National Institutes of Health. I would personally like to thank Daphne A. Salick and Monica C. Branco for intellectual conversations. NR 60 TC 42 Z9 42 U1 3 U2 79 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 SEP PY 2011 VL 32 IS 27 BP 6471 EP 6477 DI 10.1016/j.biomaterials.2011.05.052 PG 7 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 801HR UT WOS:000293429700012 PM 21683437 ER PT J AU Domire, JS Green, JA Lee, KG Johnson, AD Askwith, CC Mykytyn, K AF Domire, Jacqueline S. Green, Jill A. Lee, Kirsten G. Johnson, Andrew D. Askwith, Candice C. Mykytyn, Kirk TI Dopamine receptor 1 localizes to neuronal cilia in a dynamic process that requires the Bardet-Biedl syndrome proteins SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE Ciliopathy; Neuronal cilia; Dopamine receptor 1; Bardet-Biedl syndrome ID INTRAFLAGELLAR TRANSPORT; COUPLED-RECEPTORS; PLASMA-MEMBRANE; RHODOPSIN; COMPLEX; MICE; ACTIVATION; FLAGELLA; AMYGDALA; BRAIN AB Primary cilia are nearly ubiquitous cellular appendages that provide important sensory and signaling functions. Ciliary dysfunction underlies numerous human diseases, collectively termed ciliopathies. Primary cilia have distinct functions on different cell types and these functions are defined by the signaling proteins that localize to the ciliary membrane. Neurons throughout the mammalian brain possess primary cilia upon which certain G protein-coupled receptors localize. Yet, the precise signaling proteins present on the vast majority of neuronal cilia are unknown. Here, we report that dopamine receptor 1 (D1) localizes to cilia on mouse central neurons, thereby implicating neuronal cilia in dopamine signaling. Interestingly, ciliary localization of D1 is dynamic, and the receptor rapidly translocates to and from cilia in response to environmental cues. Notably, the translocation of D1 from cilia requires proteins mutated in the ciliopathy Bardet-Biedl syndrome (BBS), and we find that one of the BBS proteins, Bbs5, specifically interacts with D1. C1 [Domire, Jacqueline S.; Green, Jill A.; Mykytyn, Kirk] Ohio State Univ, Coll Med, Dept Pharmacol, Columbus, OH 43210 USA. [Lee, Kirsten G.; Askwith, Candice C.] Ohio State Univ, Coll Med, Dept Neurosci, Columbus, OH 43210 USA. [Johnson, Andrew D.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Ctr Populat Studies, Framingham, MA 01702 USA. RP Mykytyn, K (reprint author), Ohio State Univ, Coll Med, Dept Pharmacol, 5034 Graves Hall,333 W 10th Ave, Columbus, OH 43210 USA. EM mykytyn.1@osu.edu RI Johnson, Andrew/G-6520-2013; Mykytyn, Kirk/E-3723-2011 OI Mykytyn, Kirk/0000-0002-0158-4592 FU NIH/National Institute of General Medical Sciences [T32 GM068412, R01 GM083120] FX We are grateful to Joshua Stowell for technical assistance and David Sibley (NINDS) for providing D1 WT and KO brains. This work was supported in part by the Systems and Integrative Biology Training Grant T32 GM068412(J.G.) and R01 GM083120 from the NIH/National Institute of General Medical Sciences (K.M.). NR 42 TC 55 Z9 56 U1 1 U2 9 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD SEP PY 2011 VL 68 IS 17 BP 2951 EP 2960 DI 10.1007/s00018-010-0603-4 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 808DS UT WOS:000293957400010 PM 21152952 ER PT J AU Tomasi, D Volkow, ND AF Tomasi, Dardo Volkow, Nora D. TI Association between Functional Connectivity Hubs and Brain Networks SO CEREBRAL CORTEX LA English DT Article DE functional connectivity; 1000 functional connectomes ID RESTING-STATE NETWORKS; VISUAL-ATTENTION TASKS; DEFAULT NETWORK; ALZHEIMERS-DISEASE; WORKING-MEMORY; SMALL-WORLD; ACTIVATION PATTERNS; MOTOR CORTEX; IMAGES; MRI AB Functional networks are usually accessed with "resting-state" functional magnetic resonance imaging using preselected "seeds" regions. Frequently, however, the selection of the seed locations is arbitrary. Recently, we proposed local functional connectivity density mapping (FCDM), an ultrafast data-driven to locate highly connected brain regions (functional hubs). Here, we used the functional hubs obtained from local FCDM to determine the functional networks of the resting state in 979 healthy subjects without a priori hypotheses on seed locations. In addition, we computed the global functional connectivity hubs. Seven networks covering 80% of the gray matter volume were identified. Four major cortical hubs (ventral precuneus/posterior cingulate, inferior parietal cortex, cuneus, and postcentral gyrus) were linked to 4 cortical networks (default mode, dorsal attention, visual, and somatosensory). Three subcortical networks were associated to the major subcortical hubs (cerebellum, thalamus, and amygdala). The networks differed in their resting activity and topology. The higher coupling and overlap of subcortical networks was associated to higher contribution of short-range functional connectivity in thalamus and cerebellum. Whereas cortical local FCD hubs were also hubs of long-range connectivity, which corroborates the key role of cortical hubs in network architecture, subcortical hubs had minimal long-range connectivity. The significant variability among functional networks may underlie their sensitivity/resilience to neuropathology. C1 [Tomasi, Dardo; Volkow, Nora D.] NIAAA, Bethesda, MD 20892 USA. [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. RP Tomasi, D (reprint author), Brookhaven Natl Lab, Lab Neuroimaging LNI NIAAA, Dept Med, Bldg 490,30 Bell Ave, Upton, NY 11973 USA. EM tomasi@bnl.gov RI Tomasi, Dardo/J-2127-2015 FU National Institutes of Alcohol Abuse and Alcoholism [2RO1AA09481] FX National Institutes of Alcohol Abuse and Alcoholism (2RO1AA09481). NR 63 TC 114 Z9 117 U1 3 U2 19 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD SEP PY 2011 VL 21 IS 9 BP 2003 EP 2013 DI 10.1093/cercor/bhq268 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 807PH UT WOS:000293911700005 PM 21282318 ER PT J AU Markowitz, JT Laffel, LMB Volkening, LK Anderson, BJ Nansel, TR Weissberg-Benchell, J Wysocki, T AF Markowitz, J. T. Laffel, L. M. B. Volkening, L. K. Anderson, B. J. Nansel, T. R. Weissberg-Benchell, J. Wysocki, T. TI Validation of an abbreviated adherence measure for young people with Type 1 diabetes SO DIABETIC MEDICINE LA English DT Article DE adherence; paediatrics; Type 1 diabetes ID STRUCTURED INTERVIEW; SELF-MANAGEMENT; INTERVENTION; RELIABILITY; VALIDITY; SCALE AB Aims Adherence to diabetes-related tasks is an important construct. The Diabetes Self-Management Profile is a validated, semi-structured interview assessing adherence in paediatric patients with Type 1 diabetes. We created and validated a brief questionnaire version of the Diabetes Self-Management Profile called the Diabetes Self-Management Questionnaire. Methods Young people with Type 1 diabetes, ages 9-15 years (n = 338) and their parents provided data from chart review, interview and questionnaires. Results Diabetes Self-Management Questionnaire scores correlated significantly with Diabetes Self-Management Profile scores, HbA(1c), blood glucose monitoring frequency and other measures associated with adherence and/or glycaemic control (P <= 0.01 for all). Young people and parent scores were correlated (r = 0.55, P < 0.0001). The Diabetes Self-Management Questionnaire demonstrated modest internal consistency (Cronbach's alpha = 0.59), adequate for a brief measure of multidimensional adherence. In addition, factor analysis confirmed one factor. Conclusions This brief adherence questionnaire demonstrated construct validity in young people 9-15 years old and their parents and may have utility in clinical and research settings. C1 [Laffel, L. M. B.] Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Boston, MA 02215 USA. [Anderson, B. J.] Baylor Coll Med, Houston, TX 77030 USA. [Nansel, T. R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Weissberg-Benchell, J.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Wysocki, T.] Nemours Childrens Clin, Jacksonville, FL USA. RP Laffel, LMB (reprint author), Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, 1 Joslin Pl, Boston, MA 02215 USA. EM lori.laffel@joslin.harvard.edu OI Nansel, Tonja/0000-0002-8298-7595 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); NIH [T32 DK007260]; National Institute of Diabetes and Digestive and Kidney Diseases [DK-46887]; Charles H. Hood Foundation; Maria Griffin Drury Pediatric Fund; Katherine Adler Astrove Youth Education Fund; [N01-HD-4-3363]; [N01-HD-4-3362]; [N01-HD-4-3361]; [N01-HD-4-3364]; [N01-HD-3-3360] FX This research was supported in part by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The following investigators and institutions made up the steering committee of the Family Management of Childhood Diabetes multi-site trial: Jill Weissberg-Benchell PhD, Grayson Holmbeck PhD (Children's Memorial Hospital, Chicago, Contract N01-HD-4-3363); Barbara Anderson PhD (Texas Children's Hospital, Houston, Contract N01-HD-4-3362); Tim Wysocki PhD, Amanda Lochrie PhD (Nemours Children's Clinic, Jacksonville, FL, Contract N01-HD-4-3361); Lori Laffel MD MPH, Deborah Butler MSW, Lisa Volkening MA (Joslin Diabetes Center, Boston, Contract N01-HD-4-3364); Tonja Nansel PhD, Ronald Iannotti PhD (NICHD, Bethesda, MD); Cheryl McDonnell PhD, MaryAnn D'Elio (James Bell Associates, Arlington, VA, Contract N01-HD-3-3360). This work was also supported in part by NIH Training Grant No. T32 DK007260, a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-46887), the Charles H. Hood Foundation, the Maria Griffin Drury Pediatric Fund and the Katherine Adler Astrove Youth Education Fund. NR 12 TC 10 Z9 10 U1 2 U2 4 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 SEP PY 2011 VL 28 IS 9 BP 1113 EP 1117 DI 10.1111/j.1464-5491.2011.03321.x PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 807NG UT WOS:000293905000018 PM 21843307 ER PT J AU Cheng, YF Martinez-Guerrero, LJ Wright, SH Kuester, RK Hooth, MJ Sipes, IG AF Cheng, Yaofeng Martinez-Guerrero, Lucy J. Wright, Stephen H. Kuester, Robert K. Hooth, Michelle J. Sipes, I. Glenn TI Characterization of the Inhibitory Effects of N-Butylpyridinium Chloride and Structurally Related Ionic Liquids on Organic Cation Transporters 1/2 and Human Toxic Extrusion Transporters 1/2-K In Vitro and In Vivo SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID FEMALE B6C3F1 MICE; MALE F344 RATS; TETRAALKYLAMMONIUM COMPOUNDS; PROXIMAL TUBULES; RENAL SECRETION; METFORMIN; PHARMACOKINETICS; MULTIDRUG; KIDNEY; MATE1 AB Ionic liquids (ILs) are a class of salts that are expected to be used as a new source of solvents and for many other applications. Our previous studies revealed that selected ILs, structurally related organic cations, are eliminated exclusively in urine as the parent compound, partially mediated by renal transporters. This study investigated the inhibitory effects of N-butylpyridinium chloride (NBuPy-Cl) and structurally related ILs on organic cation transporters (OCTs) and multidrug and toxic extrusion transporters (MATEs) in vitro and in vivo. After Chinese hamster ovary cells expressing rat (r) OCT1, rOCT2, human (h) OCT2, hMATE1, or hMATE2-K were constructed, the ability of NBuPy-Cl, 1-methyl-3-butylimidazolium chloride (Bmim-Cl), N-butyl-N-methylpyrrolidinium chloride (BmPy-Cl), and alkyl substituted pyridinium ILs to inhibit these transporters was determined in vitro. NBuPy-Cl (0, 0.5, or 2 mg/kg per hour) was also infused into rats to assess its effect on the pharmacokinetics of metformin, a substrate of OCTs and MATEs. NBuPy-Cl, Bmim-Cl, and BmPy-Cl displayed strong inhibitory effects on these transporters (IC50 = 0.2-8.5 mu M). In addition, the inhibitory effects of alkyl-substituted pyridinium ILs on OCTs increased dramatically as the length of the alkyl chain increased. The IC50 values were 0.1, 3.8, 14, and 671 mu M (hexyl-, butyl-, and ethyl-pyridinium and pyridinium chloride) for rOCT2-mediated metformin transport. Similar structurally related inhibitory kinetics were also observed for rOCT1 and hOCT2. The in vivo coadministration study revealed that NBuPy-Cl reduced the renal clearance of metformin in rats. These results demonstrate that ILs compete with other substrates of OCTs and MATEs and could alter the in vivo pharmacokinetics of such substrates. C1 [Cheng, Yaofeng; Kuester, Robert K.; Sipes, I. Glenn] Univ Arizona, Dept Pharmacol, Coll Med, Tucson, AZ 85724 USA. [Martinez-Guerrero, Lucy J.; Wright, Stephen H.] Univ Arizona, Dept Physiol, Coll Med, Tucson, AZ 85724 USA. [Hooth, Michelle J.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Sipes, IG (reprint author), Univ Arizona, Dept Pharmacol, Coll Med, POB 245050, Tucson, AZ 85724 USA. EM sipes@email.arizona.edu FU National Institutes of Health National Institute of Environmental Health Sciences [N01-ES45529, ES06694]; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [DK58251] FX This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Contract N01-ES45529] (National Toxicology Program); the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK58251]; and the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES06694]. NR 42 TC 7 Z9 7 U1 0 U2 14 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD SEP PY 2011 VL 39 IS 9 BP 1755 EP 1761 DI 10.1124/dmd.110.035865 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 809JV UT WOS:000294050900033 PM 21646436 ER PT J AU Schirren, J Donges, T Melzer, M Schonmayr, R Eberlein, M Bolukbas, S Walsh, G Weder, W Turna, A Cassivi, S Athanassiadi, K AF Schirren, Joachim Doenges, Tina Melzer, Michael Schoenmayr, Robert Eberlein, Michael Boeluekbas, Servet Walsh, G. Weder, W. Turna, A. Cassivi, S. Athanassiadi, K. TI En bloc resection of non-small-cell lung cancer invading the spine 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 Spine; NSCLC; Surgery; Multimodality Treatment; Vertebrectomy ID SUPERIOR SULCUS TUMORS; SURGICAL RESECTION; INDUCTION CHEMORADIATION; THORACIC INLET; MANAGEMENT; INVOLVEMENT; STAGE; THERAPY; TRENDS AB Objective: To describe our surgical en bloc approach and to assess the outcome and survival of non-small-cell lung cancer (NSCLC) invading the spine. Methods: We retrospectively reviewed our prospective database of all patients, who underwent lung resection with en bloc hemivertebrectomy or total vertebrectomy for NSCLC between January 2003 and December 2008 in an individualized multimodality treatment concept. Survival was estimated by the Kaplan-Meier method. Log-rank analyses were used to compare groups. Results: Twenty-eight patients (age 58.9 +/- 12.9 years) were diagnosed with NSCLC invading the spine at a single center. Eight of those patients were inoperable. Twenty patients proceeded to surgery with en bloc hemivertebrectomy (n = 16) or total vertebrectomy (n = 4). Six patients had induction chemotherapy (30%). Complete resection could be achieved in 16 patients (80%). Morbidity was observed in eight patients (40%); no mortality occurred. Adjuvant radiation (n = 14) or chemoradiation (n = 6) was administered with 66 Gy. The mean survival and 5-year survival for patients, who underwent surgery (n = 20), were 46.0 months and 47%, respectively. Inoperable patients had poorer survival (14.0 months; p = 0.004). Sublobar resections (p = 0.002) and incomplete resections (p = 0.02) were associated with inferior survival. Adjuvant chemoradiation (p = 0.088), hemivertebrectomy (p = 0.062), and age < 70 years (p = 0.076) trended toward prolonged survival. Conclusions: Multimodality treatment including en bloc lung resections with hemivertebrectomy or total vertebrectomy offer promising long-term survival in highly selected patients with NSCLC invading the spine. These extended resections can be performed with acceptable morbidity and mortality in specialized centers. Patients aged >= 70 years should be selected very carefully for radical resection. Sublobar resections should be avoided. (C) 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B. V. All rights reserved. C1 [Schirren, Joachim; Doenges, Tina; Boeluekbas, Servet] Dr Horst Schmidt Klin, Dept Thorac Surg, D-65199 Wiesbaden, Germany. [Melzer, Michael; Schoenmayr, Robert] Dr Horst Schmidt Klin, Dept Neurosurg, 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 23 TC 9 Z9 9 U1 1 U2 3 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 SEP PY 2011 VL 40 IS 3 BP 647 EP 654 DI 10.1016/j.ejcts.2010.12.046 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 806QF UT WOS:000293824000031 PM 21334220 ER PT J AU Janssens, ACJW Ioannidis, JPA Bedrosian, S Boffetta, P Dolan, SM Dowling, N Fortier, I Freedman, AN Grimshaw, JM Gulcher, J Gwinn, M Hlatky, MA Janes, H Kraft, P Melillo, S O'Donnell, CJ Pencina, MJ Ransohoff, D Schully, SD Seminara, D Winn, DM Wright, CF van Duijn, CM Little, J Khoury, MJ AF Janssens, A. Cecile J. W. Ioannidis, John P. A. Bedrosian, Sara Boffetta, Paolo Dolan, Siobhan M. Dowling, Nicole Fortier, Isabel Freedman, Andrew N. Grimshaw, Jeremy M. Gulcher, Jeffrey Gwinn, Marta Hlatky, Mark A. Janes, Holly Kraft, Peter Melillo, Stephanie O'Donnell, Christopher J. Pencina, Michael J. Ransohoff, David Schully, Sheri D. Seminara, Daniela Winn, Deborah M. Wright, Caroline F. van Duijn, Cornelia M. Little, Julian Khoury, Muin J. TI Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GENOME-WIDE ASSOCIATION; HEART-DISEASE RISK; OPERATING CHARACTERISTIC CURVE; TYPE-2 DIABETES RISK; COMMON DISEASES; RECLASSIFICATION MEASURES; MACULAR DEGENERATION; DIAGNOSTIC-ACCURACY; CARDIOVASCULAR RISK; RANDOMIZED-TRIALS AB The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis. C1 [Janssens, A. Cecile J. W.; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Ioannidis, John P. A.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Ioannidis, John P. A.] Fdn Res & Technol, Biomed Res Inst, Ioannina, Greece. [Ioannidis, John P. A.] Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. [Ioannidis, John P. A.] Tufts Med Ctr, Ctr Genet Epidemiol & Modeling, Boston, MA USA. [Ioannidis, John P. A.] Tufts Med Ctr, Tufts CTSI, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Stanford Prevent Res Ctr, Stanford, CA USA. [Bedrosian, Sara; Dowling, Nicole; Gwinn, Marta; Melillo, Stephanie; Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Dolan, Siobhan M.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10467 USA. [Fortier, Isabel] Publ Populat Project Genom P3G, Montreal, PQ, Canada. [Freedman, Andrew N.; Kraft, Peter; Schully, Sheri D.; Seminara, Daniela; Winn, Deborah M.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Grimshaw, Jeremy M.] Ottawa Hosp, Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. [Grimshaw, Jeremy M.] Univ Ottawa, Dept Med, Ottawa, ON, Canada. [Gulcher, Jeffrey] DeCODE Genet, Reykjavik, Iceland. [Hlatky, Mark A.] Stanford Univ, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. [Janes, Holly] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Inst, Seattle, WA 98104 USA. [Janes, Holly] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Div Cardiol, Sch Med, Boston, MA USA. [Pencina, Michael J.] Boston Univ, Dept Biostat, Harvard Clin Res Inst, Boston, MA 02215 USA. [Ransohoff, David] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Wright, Caroline F.] PHG Fdn, Cambridge, England. [Little, Julian] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON, Canada. RP Janssens, ACJW (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM a.janssens@erasmusmc.nl RI Ioannidis, John/G-9836-2011; Grimshaw, Jeremy/D-8726-2013; janssens, cecile/L-1075-2015; Wright, Caroline/N-5355-2015; OI Janssens, A Cecile/0000-0002-6153-4976; Wright, Caroline/0000-0003-2958-5076; Grimshaw, Jeremy/0000-0001-8015-8243 FU National Heart, Lung, and Blood Institute; National Cancer Institute, National Institutes of Health; Donald W. Reynolds Foundation; Leducq Foundation FX This study was supported by grants from the National Heart, Lung, and Blood Institute and National Cancer Institute, National Institutes of Health; the Donald W. Reynolds Foundation; and the Leducq Foundation. Additional support for DNA extraction, reagents, and data analysis was provided by Roche Diagnostics and Amgen. Genotyping of the 9p21.3 variant was performed by Celera. The funding sources had no role in the design, conduct, or reporting of this study or the decision to submit the manuscript for publication' [53]. NR 92 TC 16 Z9 17 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD SEP PY 2011 VL 41 IS 9 BP 1010 EP 1035 DI 10.1111/j.1365-2362.2011.02493.x PG 26 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 802KJ UT WOS:000293509200013 PM 21434890 ER PT J AU Sanu, O Lamont, RF AF Sanu, Olaleye Lamont, Ronald F. TI Hyperemesis gravidarum: pathogenesis and the use of antiemetic agents reply SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Letter C1 [Sanu, Olaleye] Hillingdon Hosp NHS Fdn Trust, Dept Obstet & Gynaecol, Uxbridge, Middx, England. [Lamont, Ronald F.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 48201 USA. RP Sanu, O (reprint author), Hillingdon Hosp NHS Fdn Trust, Dept Obstet & Gynaecol, Pield Heath Rd, Uxbridge, Middx, England. NR 3 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-6566 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD SEP PY 2011 VL 12 IS 13 BP 2140 EP 2140 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 803RZ UT WOS:000293599700015 ER PT J AU Huang, SYN Pommier, Y Marchand, C AF Huang, Shar-yin N. Pommier, Yves Marchand, Christophe TI Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) inhibitors SO EXPERT OPINION ON THERAPEUTIC PATENTS LA English DT Editorial Material DE bleomycin; DNA repair; furamidine; topoisomerase ID TOPOISOMERASE-I INHIBITORS; STRAND BREAK REPAIR; CELL LUNG-CANCER; SPINOCEREBELLAR ATAXIA; COVALENT COMPLEXES; AXONAL NEUROPATHY; DAMAGE; PATHWAYS; IDENTIFICATION; CAMPTOTHECIN AB Inhibitors of topoisomerase I (Top1) that result in stalled Top1 cleavage complexes (Top1cc) are commonly employed against cancer. Combination chemotherapy with DNA repair inhibitors can potentially improve response to these widely used chemotherapeutics. One line of inquiry focuses on inhibitors of tyrosyl-DNA phosphodiesterase 1 (Tdp1), a repair enzyme for Top1cc. Tdp1 catalyzes the hydrolysis of DNA adducts covalently linked to the 3'-phosphate of DNA, including Top1-derived peptides and also 3'-phosphoglycolates. Tdp1 inhibitors should synergize not only with Top1-targeting drugs (camptothecins, indenoisoquinolines), but also with bleomycin, topoisomerase II (Top2) inhibitors (etoposide, doxorubicin) and DNA alkylating agents. Here, we summarize the structure-activity relationship obtained from the reported Tdp1 inhibitors. Better understanding of Top1cc repair in vivo coupled with detailed structural studies on Tdp1-inhibitor interaction will be crucial in guiding the rational design of Tdp1 inhibitors. C1 [Huang, Shar-yin N.; Pommier, Yves; Marchand, Christophe] NCI, Ctr Canc Res, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Ctr Canc Res, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. EM Pommier@nih.gov FU Intramural NIH HHS [Z01 BC006150-26] NR 47 TC 26 Z9 26 U1 1 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-3776 J9 EXPERT OPIN THER PAT JI Expert Opin. Ther. Patents PD SEP PY 2011 VL 21 IS 9 BP 1285 EP 1292 DI 10.1517/13543776.2011.604314 PG 8 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 807SK UT WOS:000293919800001 PM 21843105 ER PT J AU Grace, MB Cliffer, KD Moyer, BR Coleman, CN Prasher, JM Hatchett, R Mercier, J Manning, RG Bader, JL Disbrow, GL Kovacs, GR AF Grace, Marcy B. Cliffer, Kenneth D. Moyer, Brian R. Coleman, C. Norman Prasher, Joanna M. Hatchett, Richard Mercier, John Manning, Ronald G. Bader, Judith L. Disbrow, Gary L. Kovacs, Gerald R. TI THE US GOVERNMENT'S MEDICAL COUNTERMEASURE PORTFOLIO MANAGEMENT FOR NUCLEAR AND RADIOLOGICAL EMERGENCIES: SYNERGY FROM INTERAGENCY COOPERATION SO HEALTH PHYSICS LA English DT Article AB Following the attacks of 11 September 2001, emergency preparedness within the U. S. Department of Health and Human Services, as well as at the Department of Defense and other federal agencies, received higher visibility, new mandates and increased funding. Emergency deployment teams increased the frequency of drills to enable better response to the health consequences of mass-casualty incidents. Interagency coordination has also continued to increase to more efficiently and effectively leverage federal resources toward emergency medical preparedness for both civilian and military populations. Health Phys. 101(3):238-247; 2011 C1 [Grace, Marcy B.; Manning, Ronald G.; Disbrow, Gary L.; Kovacs, Gerald R.] Dept Hlth & Human Serv, Div CBRN Countermeasures, Off Secretary,BARDA, Off Assistant Secretary Preparedness & Response, Washington, DC 20201 USA. [Cliffer, Kenneth D.; Prasher, Joanna M.] Dept Hlth & Human Serv, Div Med Countermeasure Strategy & Requirements, Off Policy & Planning,Off Secretary, Off Assistant Secretary Preparedness & Response, Washington, DC 20201 USA. [Moyer, Brian R.] Tunnell Consulting Inc, King Of Prussia, PA 19406 USA. [Coleman, C. Norman; Bader, Judith L.] Dept Hlth & Human Serv, Off Preparedness & Emergency Operat, Off Assistant Secretary Preparedness & Response, Off Secretary, Washington, DC 20201 USA. [Coleman, C. Norman; Bader, Judith L.] NCI, NIH, Bethesda, MD 20892 USA. [Mercier, John] Uniformed Serv Univ Hlth Sci, Armed Forces Radiobiol Res Inst, Bethesda, MD 20889 USA. RP Grace, MB (reprint author), Dept Hlth & Human Serv, Div CBRN Countermeasures, Off Secretary,BARDA, Off Assistant Secretary Preparedness & Response, 330 Independence Ave SW,Room 644G, Washington, DC 20201 USA. EM marcy.grace@hhs.gov NR 31 TC 6 Z9 6 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD SEP PY 2011 VL 101 IS 3 BP 238 EP 247 DI 10.1097/HP.0b013e3182135fba PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 799EH UT WOS:000293266100003 PM 21799340 ER PT J AU Bouville, A AF Bouville, Andre TI NCRP Report No. 163, Radiation Dose Reconstruction: Principles and Practices SO HEALTH PHYSICS LA English DT Book Review C1 NCI, Bethesda, MD 20892 USA. RP Bouville, A (reprint author), NCI, 6120 Execut Blvd,Room EPS-7094, Bethesda, MD 20892 USA. EM BouvillA@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD SEP PY 2011 VL 101 IS 3 BP 321 EP 321 DI 10.1097/HP.0b013e31820f8e30 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 799EH UT WOS:000293266100011 ER PT J AU Taylor, KC Lange, LA Zabaneh, D Lange, E Keating, BJ Tang, W Smith, NL Delaney, JA Kumari, M Hingorani, A North, KE Kivimaki, M Tracy, RP O'Donnell, CJ Folsom, AR Green, D Humphries, SE Reiner, AP AF Taylor, Kira C. Lange, Leslie A. Zabaneh, Delilah Lange, Ethan Keating, Brendan J. Tang, Weihong Smith, Nicholas L. Delaney, Joseph A. Kumari, Meena Hingorani, Aroon North, Kari E. Kivimaki, Mika Tracy, Russell P. O'Donnell, Christopher J. Folsom, Aaron R. Green, David Humphries, Steve E. Reiner, Alexander P. TI A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; VON-WILLEBRAND-FACTOR; CLOTTING FACTOR-VII; F7 GENE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; ISCHEMIC-STROKE; ARTERY-DISEASE; PLASMA-LEVELS AB Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50 000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2 000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16 324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12-13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors. C1 [Taylor, Kira C.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27514 USA. [Lange, Leslie A.; Lange, Ethan] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27514 USA. [Zabaneh, Delilah] UCL, Genet Inst, Dept Genet Environm & Evolut, London WC1E 6JJ, England. [Humphries, Steve E.] UCL, Inst Cardiovasc Sci, BHF Labs, Ctr Cardiovasc Genet, London WC1E 6JJ, England. [Keating, Brendan J.] Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Tang, Weihong; Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Smith, Nicholas L.; Reiner, Alexander P.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Delaney, Joseph A.] Univ Florida, Dept Pharmaceut Outcomes & Pharm, Coll Pharm, Gainesville, FL 32610 USA. [Kumari, Meena; Kivimaki, Mika] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1E 7HT, England. [Hingorani, Aroon] UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London WC1E 6BT, England. [Tracy, Russell P.] Univ Vermont, Dept Pathol & Lab Med, Coll Med, Burlington, VT 05405 USA. [O'Donnell, Christopher J.] NHLBI, NIH, Bethesda, MD 20824 USA. [Green, David] Northwestern Univ, Div Hematol Oncol, Feinberg Sch Med, Chicago, IL 60611 USA. RP Taylor, KC (reprint author), Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, 137 E Franklin St,Suite 306, Chapel Hill, NC 27514 USA. EM kirat@email.unc.edu RI Kivimaki, Mika/B-3607-2012; OI Kivimaki, Mika/0000-0002-4699-5627; Humphries, Stephen E/0000-0002-8221-6547 FU National Heart, Lung and Blood Institute of the National Institutes of Health [5T32HL007055-34]; Heart Lung and Blood Institute of the National Institutes of Health [HL36310, HL71862-06]; National Institutes of Health [HHSN268200625226C, N01HC65226-6-0-0]; National Institute of Aging of the National Institutes of Health [AG032136, AG034454, AG13196]; Agency for Health Care Policy Research [HS06516]; Medical Research Council; Health and Safety Executive; John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health; BUPA Foundation; UCL Genetics Institute; British Heart Foundation FX This work was supported by the National Heart, Lung and Blood Institute of the National Institutes of Health (#5T32HL007055-34); the Heart Lung and Blood Institute of the National Institutes of Health (HL36310, HL71862-06); the National Institutes of Health (HHSN268200625226C, N01HC65226-6-0-0); the National Institute of Aging of the National Institutes of Health (AG032136, AG034454, AG13196); the Agency for Health Care Policy Research (HS06516); the Medical Research Council; the Health and Safety Executive; and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health and the BUPA Foundation. D.Z. is funded by the UCL Genetics Institute and S.E.H. by the British Heart Foundation. NR 53 TC 8 Z9 8 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 1 PY 2011 VL 20 IS 17 BP 3525 EP 3534 DI 10.1093/hmg/ddr264 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 807NZ UT WOS:000293907500018 PM 21676895 ER PT J AU Roman, MJ Howard, BV Howard, WJ Mete, M Fleg, JL Lee, ET Devereux, RB AF Roman, Mary J. Howard, Barbara V. Howard, Wm. James Mete, Mihriye Fleg, Jerome L. Lee, Elisa T. Devereux, Richard B. TI Differential Impacts of Blood Pressure and Lipid Lowering on Regression of Ventricular and Arterial Mass The Stop Atherosclerosis in Native Diabetics Trial SO HYPERTENSION LA English DT Article DE hypertrophy/remodeling; atherosclerosis; target organ damage ID INTIMA-MEDIA THICKNESS; ASYMPTOMATIC CAROTID ATHEROSCLEROSIS; DENSITY-LIPOPROTEIN CHOLESTEROL; EXTENDED-RELEASE NIACIN; CORONARY-HEART-DISEASE; DOUBLE-BLIND; REDUCING CHOLESTEROL; VASCULAR HYPERTROPHY; AMERICAN-SOCIETY; RANDOMIZED-TRIAL AB The relative impacts of lowering blood pressure versus lowering low-density lipoprotein (LDL) cholesterol on regression of ventricular and arterial mass have not been systematically examined. Changes in left ventricular mass and arterial mass (common carotid artery cross-sectional area) after 36 months of simultaneous lowering of systolic blood pressure and LDL cholesterol were examined in the Stop Atherosclerosis in Native Diabetics Trial of standard versus aggressive LDL cholesterol and blood pressure targets in American Indians with type 2 diabetes mellitus. The 2 treatment groups were combined to examine changes in left ventricular and arterial mass over a spectrum of achieved blood pressure and lipid levels. Among the combined group of 413 Stop Atherosclerosis in Native Diabetics Trials participants, systolic blood pressure, LDL cholesterol, and left ventricular mass were all significantly reduced, whereas arterial mass significantly increased, after 36 months of therapy (P<0.001 for all). In linear regression models, a decrease in arterial mass was significantly related to achieved systolic blood pressure and, to a lesser extent, achieved LDL cholesterol, after adjustment for important covariates. Left ventricular mass progressively decreased with lower achieved levels of systolic blood pressure, independent of baseline levels of left ventricular mass. In conclusion, achieved levels of systolic blood pressure are important determinants of the extent of regression of arterial and ventricular mass during prolonged therapy in diabetic individuals. Achieved levels of LDL cholesterol influence regression of arterial but not ventricular mass. Our findings suggest that there is no threshold of systolic blood pressure below which regression of cardiovascular target organ damage cannot be achieved. (Hypertension. 2011;58:367-371.) C1 [Roman, Mary J.; Devereux, Richard B.] Weill Cornell Med Coll, Div Cardiol, New York, NY 10021 USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Lee, Elisa T.] Univ Oklahoma, Hlth Sci Ctr, Ctr Amer Indian Hlth Res, Oklahoma City, OK USA. [Howard, Barbara V.; Howard, Wm. James; Mete, Mihriye] Medstar Res Inst, Washington, DC USA. RP Roman, MJ (reprint author), Weill Cornell Med Coll, Div Cardiol, 525 E 68th St, New York, NY 10021 USA. EM mroman@med.cornell.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health [1U01 HL67031-01A1] FX Funding was provided by the National Heart, Lung, and Blood Institute, National Institutes of Health, grant 1U01 HL67031-01A1. Medications were donated by First Horizon Pharmacy (Triglide); Merck and Co (Cozaar/Hyzaar); and Pfizer, Inc (Lipitor). NR 37 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2011 VL 58 IS 3 BP 367 EP 371 DI 10.1161/HYPERTENSIONAHA.111.172486 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 808CN UT WOS:000293952500014 PM 21788602 ER PT J AU Dulebohn, DP Bestor, A Rego, ROM Stewart, PE Rosa, PA AF Dulebohn, Daniel P. Bestor, Aaron Rego, Ryan O. M. Stewart, Philip E. Rosa, Patricia A. TI Borrelia burgdorferi Linear Plasmid 38 Is Dispensable for Completion of the Mouse-Tick Infectious Cycle SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE SPIROCHETE; OUTER SURFACE PROTEIN; CIRCULAR PLASMIDS; GENE-EXPRESSION; SENSU-STRICTO; RESERVOIR COMPETENCE; MOLECULAR-BIOLOGY; NORTH-AMERICA; GENOME; DNA AB Borrelia burgdorferi, the causative agent of Lyme disease, exists in a complex enzootic cycle, transiting between its vector, Ixodes ticks, and a diverse range of vertebrate hosts. B. burgdorferi linear plasmid 38 (lp38) contains several genes that are differentially regulated in response to conditions mimicking the tick or mouse environments, suggesting that these plasmid-borne genes may encode proteins important for the B. burgdorferi infectious cycle. Some of these genes encode potential virulence factors, including hypothetical lipoproteins as well as a putative membrane transport system. To characterize the role of lp38 in the B. burgdorferi infectious cycle, we constructed a shuttle vector to selectively displace lp38 from the B. burgdorferi genome and analyzed the resulting clones to confirm the loss of lp38. We found that, in vitro, clones lacking lp38 were similar to isogenic wild-type bacteria, both in growth rate and in antigenic protein production. We analyzed these strains in an experimental mouse-tick infectious cycle, and our results demonstrate that clones lacking lp38 are fully infectious in a mouse, can efficiently colonize the tick vector, and are readily transmitted to a naive host. C1 [Dulebohn, Daniel P.; Bestor, Aaron; Rego, Ryan O. M.; Stewart, Philip E.; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT 59840 USA. RP Dulebohn, DP (reprint author), Natl Inst Infect Dis, Lab Zoonot Pathogens, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT 59840 USA. EM dulebohnd@niaid.nih.gov RI Rego, Ryan/G-9773-2014 OI Rego, Ryan/0000-0001-6932-0940 FU NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. NR 66 TC 12 Z9 12 U1 0 U2 0 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 SEP PY 2011 VL 79 IS 9 BP 3510 EP 3517 DI 10.1128/IAI.05014-11 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 807IV UT WOS:000293891000004 PM 21708994 ER PT J AU Kalil, AC Sun, JF AF Kalil, Andre C. Sun, Junfeng TI Reply to Sprung et al: steroid treatment for patients with severe sepsis and septic shock SO INTENSIVE CARE MEDICINE LA English DT Letter ID CORTICOSTEROIDS C1 [Kalil, Andre C.] Univ Nebraska Med Ctr, Omaha, NE 68198 USA. [Sun, Junfeng] NIH, Bethesda, MD 20892 USA. RP Kalil, AC (reprint author), Univ Nebraska Med Ctr, Omaha, NE 68198 USA. EM akalil@unmc.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 J9 INTENS CARE MED JI Intensive Care Med. PD SEP PY 2011 VL 37 IS 9 BP 1567 EP 1568 DI 10.1007/s00134-011-2294-1 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 807OI UT WOS:000293908600031 ER PT J AU Kweon, O Kim, SJ Holland, RD Chen, HY Kim, DW Gao, Y Yu, LR Baek, S Baek, DH Ahn, H Cerniglia, CE AF Kweon, Ohgew Kim, Seong-Jae Holland, Ricky D. Chen, Hongyan Kim, Dae-Wi Gao, Yuan Yu, Li-Rong Baek, Songjoon Baek, Dong-Heon Ahn, Hongsik Cerniglia, Carl E. TI Polycyclic Aromatic Hydrocarbon Metabolic Network in Mycobacterium vanbaalenii PYR-1 SO JOURNAL OF BACTERIOLOGY LA English DT Article ID SP STRAIN PYR-1; RING-HYDROXYLATING OXYGENASES; DEGRADING MYCOBACTERIUM; SYSTEMS-BIOLOGY; MOLECULAR CHARACTERIZATION; DEGRADATION PATHWAY; PYRENE DEGRADATION; FUNCTIONAL MODULES; GROWTH SUBSTRATE; ORGANIZATION AB This study investigated a metabolic network (MN) from Mycobacterium vanbaalenii PYR-1 for polycyclic aromatic hydrocarbons (PAHs) from the perspective of structure, behavior, and evolution, in which multilayer omics data are integrated. Initially, we utilized a high-throughput proteomic analysis to assess the protein expression response of M. vanbaalenii PYR-1 to seven different aromatic compounds. A total of 3,431 proteins (57.38% of the genome-predicted proteins) were identified, which included 160 proteins that seemed to be involved in the degradation of aromatic hydrocarbons. Based on the proteomic data and the previous metabolic, biochemical, physiological, and genomic information, we reconstructed an experiment-based system-level PAH-MN. The structure of PAH-MN, with 183 metabolic compounds and 224 chemical reactions, has a typical scale-free nature. The behavior and evolution of the PAH-MN reveals a hierarchical modularity with funnel effects in structure/function and intimate association with evolutionary modules of the functional modules, which are the ring cleavage process (RCP), side chain process (SCP), and central aromatic process (CAP). The 189 commonly upregulated proteins in all aromatic hydrocarbon treatments provide insights into the global adaptation to facilitate the PAH metabolism. Taken together, the findings of our study provide the hierarchical viewpoint from genes/proteins/metabolites to the network via functional modules of the PAH-MN equipped with the engineering-driven approaches of modularization and rationalization, which may expand our understanding of the metabolic potential of M. vanbaalenii PYR-1 for bioremediation applications. C1 [Kweon, Ohgew; Kim, Seong-Jae; Kim, Dae-Wi; Cerniglia, Carl E.] Natl Ctr Toxicol Res FDA, Div Microbiol, Jefferson, AR 72079 USA. [Kweon, Ohgew; Kim, Seong-Jae; Kim, Dae-Wi; Cerniglia, Carl E.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Holland, Ricky D.; Gao, Yuan; Yu, Li-Rong] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chen, Hongyan; Ahn, Hongsik] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. [Baek, Songjoon] USN Hosp, NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20814 USA. [Baek, Dong-Heon] Dankook Univ, Dept Oral Microbiol & Immunol, Sch Dent, Cheonan 330714, South Korea. RP Cerniglia, CE (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM carl.cerniglia@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration FX This work was supported in part by an appointment to the Postgraduate Research Fellowship Program (D.K.) at the National Center for Toxicological Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The views presented in this article do not necessarily reflect those of the U.S. FDA. NR 49 TC 32 Z9 34 U1 4 U2 49 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD SEP PY 2011 VL 193 IS 17 BP 4326 EP 4337 DI 10.1128/JB.00215-11 PG 12 WC Microbiology SC Microbiology GA 806EE UT WOS:000293788300003 PM 21725022 ER PT J AU Preston, KL Riley, P Reamer, D Schmittner, JP Epstein, DH Phillips, KA AF Preston, Kenzie L. Riley, Peter Reamer, David Schmittner, John P. Epstein, David H. Phillips, Karran A. TI Effect of Methadone Maintenance on Body Mass Index and Lipid Profile in a Cocaine- and Heroin-Using Population SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Meeting Abstract C1 [Preston, Kenzie L.; Riley, Peter; Reamer, David; Schmittner, John P.; Epstein, David H.; Phillips, Karran A.] NIDA Intramural Res Program, Clin Pharmacol & Therapeut Res Branch, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD SEP PY 2011 VL 51 IS 9 BP 1329 EP 1329 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 806EM UT WOS:000293789100020 ER PT J AU Harunaga, J Hsu, JC Yamada, KM AF Harunaga, J. Hsu, J. C. Yamada, K. M. TI Dynamics of Salivary Gland Morphogenesis SO JOURNAL OF DENTAL RESEARCH LA English DT Review DE developmental biology; cell-matrix interactions; microscopy; gene expression; cell signaling; tissue engineering ID MOUSE SUBMANDIBULAR-GLAND; ADENOVIRAL-MEDIATED TRANSFER; INCREASED FLUID SECRETION; BRANCHING MORPHOGENESIS; DEVELOPING KIDNEY; AQUAPORIN-1 CDNA; SYSTEMS-ANALYSIS; GENE-EXPRESSION; MYOSIN-II; CELL AB Salivary glands form during embryonic development by a complex process that creates compact, highly organized secretory organs with functions essential for oral health. The architecture of these glands is generated by branching morphogenesis, revealed by recent research to involve unexpectedly dynamic cell motility and novel regulatory pathways. Numerous growth factors, extracellular matrix molecules, gene regulatory pathways, and mechanical forces contribute to salivary gland morphogenesis, but local gene regulation and morphological changes appear to play particularly notable roles. Here we review these recent advances and their potential application to salivary gland tissue engineering. C1 [Harunaga, J.; Hsu, J. C.; Yamada, K. M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Yamada, KM (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bldg 30,Room 426,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM kenneth.yamada@nih.gov OI Yamada, Kenneth/0000-0003-1512-6805 FU National Institute of Dental and Craniofacial Research FX The authors acknowledge support from the Intramural Research Program of the National Institute of Dental and Craniofacial Research. They declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 52 TC 26 Z9 26 U1 2 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD SEP PY 2011 VL 90 IS 9 BP 1070 EP 1077 DI 10.1177/0022034511405330 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 807FT UT WOS:000293882400005 PM 21487116 ER PT J AU Musselmann, K Green, JA Sone, K Hsu, JC Bothwell, IR Johnson, SA Harunaga, JS Wei, Z Yamada, KM AF Musselmann, K. Green, J. A. Sone, K. Hsu, J. C. Bothwell, I. R. Johnson, S. A. Harunaga, J. S. Wei, Z. Yamada, K. M. TI Salivary Gland Gene Expression Atlas Identifies a New Regulator of Branching Morphogenesis SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE microarray; laser microdissection; branching morphogenesis; GSK3beta; organ morphogenesis; gene expression ID GLYCOGEN-SYNTHASE KINASE-3; SUBMANDIBULAR-GLAND; EMBRYONIC LUNG; BETA-CATENIN; MOUSE; CELL; WNT; FIBRONECTIN; PHOSPHORYLATION; ELONGATION AB During organ development, local changes in gene expression govern morphogenesis and cell fate. We have generated a microanatomical atlas of epithelial gene expression of embryonic salivary glands. The mouse submandibular salivary gland first appears as a single mass of epithelial cells surrounded by mesenchyme, and it undergoes rapid branching morphogenesis to form a complex secretory organ with acini connected to an extensive ductal system. Using laser capture microdissection, we collected samples from 14 distinct epithelial locations at embryonic days 12.5, 13.5, 14, and 15, and characterized their gene expression by microarray analysis. These microarray results were evaluated by qPCR of biological replicates and by comparisons of the gene expression dataset with published expression data. Using this gene expression atlas to search for novel regulators of branching morphogenesis, we found a substantial reduction in mRNA levels of GSK3 beta at the base of forming clefts. This unexpected finding was confirmed by immunostaining, and inhibition of GSK3 beta activity enhanced salivary gland branching. This first microanatomical expression atlas of a developing gland characterizes changes in local gene expression during salivary gland development and differentiation, which should facilitate the identification of key genes involved in tissue morphogenesis. C1 [Musselmann, K.; Green, J. A.; Sone, K.; Hsu, J. C.; Bothwell, I. R.; Johnson, S. A.; Harunaga, J. S.; Yamada, K. M.] Natl Inst Dent & Craniofacial Res, Cell Biol Sect, Lab Cell & Dev Biol, Div Intramural Res, Bethesda, MD 20892 USA. [Wei, Z.] Natl Inst Dent & Craniofacial Res, Dev Mech Sect, Div Intramural Res, Bethesda, MD 20892 USA. RP Musselmann, K (reprint author), Natl Inst Dent & Craniofacial Res, Cell Biol Sect, Lab Cell & Dev Biol, Div Intramural Res, 30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM kurt.musselmann@gmail.com; kenneth.yamada@nih.gov OI Yamada, Kenneth/0000-0003-1512-6805 FU Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health (Bethesda, MD, USA) FX This work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health (Bethesda, MD, USA). The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 30 TC 12 Z9 12 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD SEP PY 2011 VL 90 IS 9 BP 1078 EP 1084 DI 10.1177/0022034511413131 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 807FT UT WOS:000293882400006 PM 21709141 ER PT J AU Wang, EA McGinnis, KA Fiellin, DA Goulet, JL Bryant, K Gibert, CL Leaf, DA Mattocks, K Sullivan, LE Vogenthaler, N Justice, AC AF Wang, Emily A. McGinnis, Kathleen A. Fiellin, David A. Goulet, Joseph L. Bryant, Kendall Gibert, Cynthia L. Leaf, David A. Mattocks, Kristin Sullivan, Lynn E. Vogenthaler, Nicholas Justice, Amy C. CA VACS Project Team TI Food Insecurity is Associated with Poor Virologic Response among HIV-Infected Patients Receiving Antiretroviral Medications SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE food insecurity; HIV; patients; antiretrovirals ID HOUSING INSTABILITY; ALCOHOL-CONSUMPTION; WELFARE RECIPIENTS; PHARMACY RECORDS; MENTAL-HEALTH; SAN-FRANCISCO; WEIGHT-LOSS; ADHERENCE; HIV/AIDS; INSUFFICIENCY AB BACKGROUND AND OBJECTIVE: Food insecurity negatively impacts HIV disease outcomes in international settings. No large scale U.S. studies have investigated the association between food insecurity and severity of HIV disease or the mechanism of this possible association. The objective of this study was to examine the impact of food insecurity on HIV disease outcomes in a large cohort of HIV-infected patients receiving antiretroviral medications. DESIGN: This is a cross-sectional study. PARTICIPANTS AND SETTING: Participants were HIV-infected patients enrolled in the Veterans Aging Cohort Study between 2002-2008 who were receiving antiretroviral medications. MAIN MEASUREMENTS: Participants reporting "concern about having enough food for you or your family in the past 30 days" were defined as food insecure. Using multivariable logistic regression, we explored the association between food insecurity and both low CD4 counts (< 200 cells/mu L) and unsuppressed HIV-1 RNA (> 500 copies/mL). We then performed mediation analysis to examine whether antiretroviral adherence or body mass index mediates the observed associations. KEY RESULTS: Among 2353 HIV-infected participants receiving antiretroviral medications, 24% reported food insecurity. In adjusted analyses, food insecure participants were more likely to have an unsuppressed HIV-1 RNA (AOR 1.37, 95% CI 1.09, 1.73) compared to food secure participants. Mediation analysis revealed that neither antiretroviral medication adherence nor body mass index contributes to the association between food insecurity and unsuppressed HIV-1 RNA. Food insecurity was not independently associated with low CD4 counts. CONCLUSIONS: Among HIV-infected participants receiving antiretroviral medications, food insecurity is associated with unsuppressed viral load and may render treatment less effective. Longitudinal studies are needed to test the potential causal association between food insecurity, lack of virologic suppression, and additional HIV outcomes. C1 [Wang, Emily A.; Fiellin, David A.; Goulet, Joseph L.; Mattocks, Kristin; Sullivan, Lynn E.; Justice, Amy C.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [McGinnis, Kathleen A.] Pittsburgh VA Healthcare Syst, Pittsburgh, PA USA. [Goulet, Joseph L.; Justice, Amy C.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Bryant, Kendall] NIAAA, NIH, Rockville, MD 20852 USA. [Gibert, Cynthia L.] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Gibert, Cynthia L.] VA Med Ctr, Washington, DC USA. [Leaf, David A.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Vogenthaler, Nicholas] Emory Univ, Sch Med, Div Infect Dis, Atlanta, GA USA. RP Wang, EA (reprint author), Yale Univ, Sch Med, Dept Internal Med, Harkness Hall Bldg A 367 Cedar St,Suite 410A, New Haven, CT 06510 USA. EM emily.wang@yale.edu RI Nguyen, Giang/D-9027-2016; OI Goulet, Joseph/0000-0002-0842-804X; Fiellin, David/0000-0002-4006-010X FU National Institute on Alcohol and Alcohol Abuse [U01 AA 13566, U10 AA 13566]; National Institute of Aging [K23 AG00826]; Robert Wood Johnson Generalist Faculty Scholar Award; NIA; National Institute of Mental Health; VA HSR&D Research Enhancement Award Program (REAP) PRIME Project [REA 08-266] FX This work was funded by National Institute on Alcohol and Alcohol Abuse (U01 AA 13566 and U10 AA 13566), National Institute of Aging (K23 AG00826), Robert Wood Johnson Generalist Faculty Scholar Award, an Inter-agency Agreement between NIA, National Institute of Mental Health, and VA HSR&D Research Enhancement Award Program (REAP) PRIME Project (REA 08-266). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. NR 36 TC 41 Z9 41 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2011 VL 26 IS 9 BP 1012 EP 1018 DI 10.1007/s11606-011-1723-8 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 808WW UT WOS:000294013700015 PM 21573882 ER PT J AU Zeremski, M Hooker, G Shu, MA Winkelstein, E Brown, Q Des Jarlais, DC Tobler, LH Rehermann, B Busch, MP Edlin, BR Talal, AH AF Zeremski, Marija Hooker, Giles Shu, Marla A. Winkelstein, Emily Brown, Queenie Des Jarlais, Don C. Tobler, Leslie H. Rehermann, Barbara Busch, Michael P. Edlin, Brian R. Talal, Andrew H. TI Induction of CXCR3-and CCR5-associated chemokines during acute hepatitis C virus infection SO JOURNAL OF HEPATOLOGY LA English DT Article DE CXCL9; CXCL10; CXCL11; CCL3; CCL4; Inflammation ID INJECTION-DRUG USERS; IMMUNOLOGICAL DETERMINANTS; IMMUNE-RESPONSES; PERSISTENCE; CHIMPANZEES; EVASION; DISEASE; INNATE; LIVER AB Background & Aims: Characterization of inflammatory mediators, such as chemokines, during acute hepatitis C virus (HCV) infection might shed some light on viral clearance mechanisms. Methods: Plasma levels of CXCR3 (CXCL9-11)- and CCR5 (CCL3-4)-associated chemokines, ALT, and HCV RNA were measured in nine injection drug users (median 26 samples/patient) before and during 10 acute (eight primary and two secondary) HCV infections. Using functional data analysis, we estimated smooth long-term trends in chemokine expression levels to obtain the magnitude and timing of overall changes. Residuals were analyzed to characterize short-term fluctuations. Results: CXCL9-11 induction began 38-53 days and peaked 7283 days after virus acquisition. Increases in ALT levels followed a similar pattern. Substantial negative auto-correlations of chemokine levels at 1 week lags suggested substantial week-to-week oscillations. Significant correlations were observed between CXCL10 and HCV RNA as well as ALT and CXCR3-associated chemokines measured in the preceding week, CCL3-4 expression levels did not change appreciably during acute HCV infection. Conclusions: Elevation of CXCR3-associated chemokines late during acute HCV infection suggests a role for cellular immune responses in chemokine induction. Week-to-week oscillations of HCV RNA, chemokines, and ALT suggest frequent, repeated cycles of gain and loss of immune control during acute hepatitis C. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Zeremski, Marija; Shu, Marla A.; Winkelstein, Emily; Brown, Queenie; Edlin, Brian R.; Talal, Andrew H.] Weill Cornell Med Coll, Ctr Study Hepatitis C, New York, NY 10065 USA. [Zeremski, Marija; Shu, Marla A.; Winkelstein, Emily; Brown, Queenie; Edlin, Brian R.; Talal, Andrew H.] Weill Cornell Med Coll, Div Gastroenterol & Hepatol, New York, NY 10065 USA. [Hooker, Giles] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY USA. [Shu, Marla A.; Winkelstein, Emily; Edlin, Brian R.] State Univ New York Downstate Coll Med, Dept Med, Brooklyn, NY USA. [Des Jarlais, Don C.] Beth Israel Deaconess Med Ctr, Baron Edmond Rothschild Chem Dependency Inst, New York, NY 10003 USA. [Tobler, Leslie H.] Blood Syst Res Inst, San Francisco, CA USA. [Rehermann, Barbara; Busch, Michael P.] NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, Bethesda, MD USA. [Busch, Michael P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Talal, AH (reprint author), Weill Cornell Med Coll, Ctr Study Hepatitis C, 525 E 68th St,Box 319, New York, NY 10065 USA. EM aht2002@med.cornell.edu OI Edlin, Brian/0000-0001-8172-8797 FU NIH [R01-DA16159, R01-DA021550, UL1-RR024996]; Greenberg Foundation for Medical Research; NIDDK, National Institutes of Health FX We are grateful to the staff of the Lower East Side Harm Reduction Coalition, and Kelly Szott for assistance with data and sample collection, Lynn Mubita, Leeanne Stratton, Jessica Noack, Hanna Alemayehu, and Queenie Brown for assistance with sample processing, and Jihad Obeid, MD for assistance with data management. We also thank our study participants for making this work possible. This work was supported by NIH Grants R01-DA16159, R01-DA021550, UL1-RR024996, the Greenberg Foundation for Medical Research, and the intramural research program of NIDDK, National Institutes of Health. NR 28 TC 20 Z9 21 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD SEP PY 2011 VL 55 IS 3 BP 545 EP 553 DI 10.1016/j.jhep.2010.12.033 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 807VH UT WOS:000293930600009 PM 21256906 ER PT J AU He, J Gu, DF Kelly, TN Hixson, JE Rao, DC Jaquish, CE Chen, J Zhao, Q Gu, C Huang, JF Shimmin, LC Chen, JC Mu, JJ Ji, X Liu, DP Whelton, PK AF He, Jiang Gu, Dongfeng Kelly, Tanika N. Hixson, James E. Rao, Dabeeru C. Jaquish, Cashell E. Chen, Jing Zhao, Qi Gu, Chi Huang, Jianfeng Shimmin, Lawrence C. Chen, Ji-Chun Mu, Jianjun Ji, Xu Liu, De-Pei Whelton, Paul K. CA GenSalt Collaborative Res Grp TI Genetic variants in the renin-angiotensin-aldosterone system and blood pressure responses to potassium intake SO JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; dietary potassium; genetic variants; renin-angiotensin-aldosterone system ID MINERALOCORTICOID RECEPTOR GENE; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-2; ESSENTIAL-HYPERTENSION; SALT SENSITIVITY; MOLECULAR-BASIS; DIETARY-SODIUM; ASSOCIATION; POLYMORPHISMS; POPULATION; MECHANISMS AB Objective Observational epidemiologic studies and clinical trials have documented that dietary potassium intake lowers blood pressure (BP). We examined the association between genetic variants in the renin-angiotensinaldosterone system and BP responses to potassium intervention. Methods A 7-day high-sodium followed by a 7-day high-sodium plus 60 mmol/day potassium-supplementation feeding study was conducted among 1906 participants from rural northern China. Nine BP measurements were obtained at each intervention phase using a random-zero sphygmomanometer and 181 single-nucleotide polymorphisms (SNPs) in 11 candidate genes of the renin-angiotensin-aldosterone system were used for analyses. Results Several SNPs in nuclear receptor subfamily 3, group C, member 2 (NR3C2), angiotensin II type 1 receptor (AGTR1), hydroxysteroid (11-beta) dehydrogenase 1 (HSD11B1), and hydroxysteroid (11-beta) dehydrogenase 2 (HSD11B2) genes were significantly associated with BP responses to potassium intervention. For example, the number of G alleles of the N554S missense mutation (rs5527) of NR3C2 was significantly associated with greater SBP responses to potassium intervention; mean [95% confidence interval (CI)] responses (mmHg) were -3.33 (-3.65 to -3.02) for genotype A/A and -5.47 (-6.64 to -4.29) for A/G, respectively (P value = 0.0004). In addition, the number of C alleles of the A1166C variant (rs5186) in AGTR1 was significantly and inversely associated with SBP responses to potassium intervention; mean (95% CI) responses were -3.55 (-3.87 to -3.24) for genotype A/A, -2.45 (-3.27 to -1.62) for A/C, and 3.25 (-5.73 to 12.23) for CC (P value = 0.003). Conclusion These novel findings indicated that genetic variants in the renin-angiotensin-aldosterone system may play an important role in determining an individual's BP responses to dietary potassium intake. J Hypertens 29:1719-1730 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [He, Jiang; Kelly, Tanika N.; Zhao, Qi] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA. [He, Jiang; Chen, Ji-Chun] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Gu, Dongfeng; Gu, Chi; Huang, Jianfeng; Chen, Ji-Chun] Chinese Acad Med Sci, Fuwai Hosp, Beijing 100730, Peoples R China. [Gu, Dongfeng; Gu, Chi; Huang, Jianfeng; Chen, Ji-Chun] Chinese Acad Med Sci, Cardiovasc Inst, Beijing 100730, Peoples R China. [Gu, Dongfeng; Gu, Chi; Huang, Jianfeng; Chen, Ji-Chun] Peking Union Med Coll, Natl Ctr Cardiovasc Dis, Beijing 100021, Peoples R China. [Hixson, James E.; Shimmin, Lawrence C.] Univ Texas Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX USA. [Rao, Dabeeru C.; Gu, Chi] Washington Univ, Sch Med, Dept Biostat, St Louis, MO USA. [Jaquish, Cashell E.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Mu, Jianjun] Xi An Jiao Tong Univ, Sch Med, Dept Med, Xian, Shanxi, Peoples R China. [Liu, De-Pei] Chinese Acad Med Sci, Natl Lab Med Mol Biol, Inst Basic Med Sci, Beijing 100730, Peoples R China. [Liu, De-Pei] Peking Union Med Coll, Beijing 100021, Peoples R China. [Whelton, Paul K.] Loyola Univ, Med Ctr, Off President, Maywood, IL 60153 USA. RP He, J (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, 1440 Canal St,Suite 2000, New Orleans, LA 70112 USA. EM jhe@tulane.edu RI Gu, Charles/A-7934-2010 OI Gu, Charles/0000-0002-8527-8145 FU National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland [U01HL072507, R01HL087263, R01HL090682] FX The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) is supported by research grants (U01HL072507, R01HL087263, and R01HL090682) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. The GenSalt investigators acknowledge Upsher-Smith Laboratories Inc. for providing potassium chloride tablets (Klor-ConM20). NR 30 TC 10 Z9 12 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD SEP PY 2011 VL 29 IS 9 BP 1719 EP 1730 DI 10.1097/HJH.0b013e32834a4d1f PG 12 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 806QS UT WOS:000293825600008 PM 21799445 ER PT J AU Sachs, DH Cone, JL AF Sachs, David H. Cone, James L. TI A MOUSE B-CELL ALLOANTIGEN DETERMINED BY GENE(S) LINKED TO THE MAJOR HISTOCOMPATIBILITY COMPLEX SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LYMPHOID-CELLS; BONE MARROW; ANTIGENS; IMMUNOGLOBULIN; LYMPHOCYTES; SURFACE; MICE; THETA AB The humoral response to transplantation across species includes the production of antibodies specific for the major histocompatibility alloantigens of the donor animal (1-3). In particular, rats immunized with mouse tissues have been shown to produce antibodies reactive against a number of individual H-2 specificities (1). One possible advantage of this method of production of cytotoxic antisera is the possibility that rats may respond to histocompatibility alloantigens not detected by other mice, thus providing new genetic markers. In the course of analyzing antisera from a series of cross-species immunizations, and unexpected cytotoxic reaction with C57Bl/10 lymph node cells was observed with an antiserum which, according to the current H-2 chart, should have contained only specificity for H-2.31. The results of additional studies indicate: (a) that immunizations between appropriate congenic mouse strains produce alloimmune antisera which likewise detect this new specificity, (b) that these cytotoxic antisera (hereafter called anti-"beta") detect a cell-surface antigens(s) (hereafter called "beta") expressed preferentially on B cells, and (c) that tests of recombinant strains indicate that the gene(s) determining beta are linked to the K-end of the H-2 complex; i.e., in or to the left of the Ir-1 region. C1 [Sachs, David H.; Cone, James L.] NCI, Immunol Branch, NIH, Bethesda, MD 20014 USA. RP Sachs, DH (reprint author), NCI, Immunol Branch, NIH, Bethesda, MD 20014 USA. NR 34 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2011 VL 187 IS 5 BP 1289 EP 1304 PG 16 WC Immunology SC Immunology GA 809MD UT WOS:000294059500005 ER PT J AU Gibbons, DL Abeler-Dorner, L Raine, T Hwang, IY Jandke, A Wencker, M Deban, L Rudd, CE Irving, PM Kehrl, JH Hayday, AC AF Gibbons, Deena L. Abeler-Doerner, Lucie Raine, Tim Hwang, Il-Young Jandke, Anett Wencker, Melanie Deban, Livija Rudd, Christopher E. Irving, Peter M. Kehrl, John H. Hayday, Adrian C. TI Cutting Edge: Regulator of G Protein Signaling-1 Selectively Regulates Gut T Cell Trafficking and Colitic Potential SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTRAEPITHELIAL LYMPHOCYTES; CELIAC-DISEASE; B-LYMPHOCYTES; RESPONSES; RGS1; MICE; INFLAMMATION; MIGRATION; VARIANTS AB The RGS1 gene is associated with celiac disease, multiple sclerosis, and type I diabetes, which are all T cell-mediated pathologies, yet there is no reported analysis of regulator of G protein signaling (RGS)1 biology in human T cells. This study shows that RGS1 expression is substantially higher in T cells from human gut versus peripheral blood and that this can be exaggerated in intestinal inflammation. Elevated RGS1 levels profoundly reduce T cell migration to lymphoid-homing chemokines, whereas RGS1 depletion selectively enhances such chemotaxis in gut T cells and impairs their colitogenic potential. These findings provide a revised framework in which to view the linkage of RGS1 to inflammatory disease. The Journal of Immunology, 2011, 187: 2067-2071. C1 [Hayday, Adrian C.] Kings Coll London, Sch Med, Guys Hosp, Natl Inst Hlth Res,Biomed Res Ctr, London SE1 9RT, England. [Gibbons, Deena L.; Abeler-Doerner, Lucie; Raine, Tim; Wencker, Melanie; Deban, Livija; Hayday, Adrian C.] Kings Coll London, Peter Gorer Dept Immunobiol, London SE1 9RT, England. [Raine, Tim; Rudd, Christopher E.] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Hwang, Il-Young; Kehrl, John H.] NIH, Bethesda, MD 20892 USA. [Jandke, Anett; Wencker, Melanie; Deban, Livija; Hayday, Adrian C.] London Res Inst, London WC2A 3LY, England. RP Hayday, AC (reprint author), Kings Coll London, Sch Med, Guys Hosp, Natl Inst Hlth Res,Biomed Res Ctr, 2nd Floor,Borough Wing, London SE1 9RT, England. EM adrian.hayday@kcl.ac.uk RI Wencker, Melanie/M-3849-2014; OI Wencker, Melanie/0000-0003-4200-0079; Kehrl, John/0000-0002-6526-159X FU National Institute for Health Research Comprehensive Biomedical Research Centre; Wellcome Trust; Marie Curie fellowship programme; National Institutes of Health FX This work was supported by the National Institute for Health Research Comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service Foundation Trust in partnership with King's College London and King's College Hospital National Health Service Foundation Trust; The Wellcome Trust; the Marie Curie fellowship programme; and the National Institutes of Health. NR 19 TC 18 Z9 18 U1 0 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 SEP 1 PY 2011 VL 187 IS 5 BP 2067 EP 2071 DI 10.4049/jimmunol.1100833 PG 5 WC Immunology SC Immunology GA 809MD UT WOS:000294059500007 PM 21795595 ER PT J AU O'Connor, GM Yamada, E Rampersaud, A Thomas, R Carrington, M McVicar, DW AF O'Connor, Geraldine M. Yamada, Eriko Rampersaud, Andy Thomas, Rasmi Carrington, Mary McVicar, Daniel W. TI Analysis of Binding of KIR3DS1*014 to HLA Suggests Distinct Evolutionary History of KIR3DS1 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELL INHIBITORY RECEPTOR; MHC CLASS-I; IMMUNOGLOBULIN-LIKE RECEPTORS; NK-CELLS; PERIPHERAL-BLOOD; CUTTING EDGE; RECOGNITION; MOLECULES; GENE; KIR AB NK cell activity is regulated by the integration of positive and negative signals. One important source of these signals for human NK cells is the killer Ig-like receptor (KIR) family, which includes both members that transduce positive and those that generate negative signals. KIR3DL1 inhibits NK cell activity upon engagement by its ligand HLA-Bw4. The highly homologous KIR3DS1 is an activating receptor, which is implicated in the outcome of a variety of pathological situations. However, unlike KIR3DL1, direct binding of KIR3DS1(+) cells to HLA has not been demonstrated. We analyzed four key amino acid differences between KIR3DL1*01502 and KIR3DS1*013 to determine their role in KIR binding to HLA. Single substitutions of these residues dramatically reduced binding by KIR3DL1. In the reciprocal experiment, we found that the rare KIR3DS1 allotype KIR3DS1*014 binds HLA-Bw4 even though it differs from KIR3DS1*013 at only one of these positions (position 138). This reactivity was unexpectedly dependent on residues at other variable positions, as HLA-Bw4 binding was lost in receptors with KIR3DL1-like residues at both positions 199 and 138. These data provide the first evidence, to our knowledge, for the direct binding of KIR3DS1(+) cells to HLA-Bw4 and highlight the key role for position 138 in determining ligand specificity of KIR3DS1. They also reveal that KIR3DS1 reactivity and specificity is dictated by complex interactions between the residues in this region, suggesting a unique functional evolution of KIR3DS1 within the activating KIR family. The Journal of Immunology, 2011, 187: 2162-2171. C1 [Thomas, Rasmi; Carrington, Mary; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick, Frederick, MD 21702 USA. [Thomas, Rasmi; Carrington, Mary] Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. RP McVicar, DW (reprint author), NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick, Bldg 560,Room 31-50, Frederick, MD 21702 USA. EM mcvicard@mail.nih.gov RI McVicar, Daniel/G-1970-2015 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. This work has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. NR 37 TC 16 Z9 16 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 SEP 1 PY 2011 VL 187 IS 5 BP 2162 EP 2171 DI 10.4049/jimmunol.1002906 PG 10 WC Immunology SC Immunology GA 809MD UT WOS:000294059500020 PM 21804024 ER PT J AU Sharda, DR Yu, S Ray, M Squadrito, ML De Palma, M Wynn, TA Morris, SM Hankey, PA AF Sharda, Daniel R. Yu, Shan Ray, Manujendra Squadrito, Mario Leonardo De Palma, Michele Wynn, Thomas A. Morris, Sidney M., Jr. Hankey, Pamela A. TI Regulation of Macrophage Arginase Expression and Tumor Growth by the Ron Receptor Tyrosine Kinase SO JOURNAL OF IMMUNOLOGY LA English DT Article ID STIMULATING PROTEIN; NITRIC-OXIDE; IFN-GAMMA; DIFFERENTIAL REGULATION; PERITONEAL-MACROPHAGES; ARGININE METABOLISM; ALTERED EXPRESSION; SUPPRESSOR-CELLS; DENDRITIC CELLS; INNATE IMMUNITY AB M1 activation of macrophages promotes inflammation and immunity to intracellular pathogens, whereas M2 macrophage activation promotes resolution of inflammation, wound healing, and tumor growth. These divergent phenotypes are characterized, in part, by the expression of inducible NO synthase and arginase I (Arg1) in M1 versus M2 activated macrophages, respectively. In this study, we demonstrate that the Ron receptor tyrosine kinase tips the balance of macrophage activation by attenuating the M1 phenotype while promoting expression of Arg1 through a Stat6-independent mechanism. Induction of the Arg1 promoter by Ron is mediated by an AP-1 site located 433 bp upstream of the transcription start site. Treatment of primary macrophages with macrophage stimulating protein, the ligand for Ron, induces potent MAPK activation, upregulates Fos, and enhances binding of Fos to the AP-1 site in the Arg1 promoter. In vivo, Arg1 expression in tumor-associated macrophages (TAMs) from Ron(-/-) mice was significantly reduced compared with that in TAMs from control animals. Furthermore, we show that Ron is expressed specifically by Tie2-expressing macrophages, a TAM subset that exhibits a markedly skewed M2 and protumoral phenotype. Decreased Arg1 in TAMs from Ron(-/-) mice was associated with reduced syngeneic tumor growth in these animals. These findings indicate that Ron induces Arg1 expression in macrophages through a previously uncharacterized AP-1 site in the Arg1 promoter and that Ron could be therapeutically targeted in the tumor microenvironment to inhibit tumor growth by targeting expression of Arg1. The Journal of Immunology, 2011, 187: 2181-2192. C1 [Sharda, Daniel R.; Hankey, Pamela A.] Penn State Univ, Dept Vet & Biomed Sci, Grad Program Pathobiol, University Pk, PA 16802 USA. [Yu, Shan; Hankey, Pamela A.] Penn State Univ, Dept Vet & Biomed Sci, Grad Program Physiol, University Pk, PA 16802 USA. [Ray, Manujendra] Penn State Univ, Dept Vet & Biomed Sci, Grad Program Immunol & Infect Dis, University Pk, PA 16802 USA. [Squadrito, Mario Leonardo; De Palma, Michele] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy, Angiogenesis & Tumor Targeting Unit, I-20132 Milan, Italy. [Squadrito, Mario Leonardo; De Palma, Michele] Univ Vita Salute San Raffaele, I-20132 Milan, Italy. [Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Morris, Sidney M., Jr.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15219 USA. RP Hankey, PA (reprint author), Penn State Univ, Dept Vet & Biomed Sci, Grad Program Pathobiol, 115 Henning Bldg, University Pk, PA 16802 USA. EM phc7@psu.edu RI Wynn, Thomas/C-2797-2011; Morris, Sidney/I-3440-2015; De Palma, Michele/L-5350-2016 FU American Heart Association [09GRNT2390164]; National Institutes of Health [R01 GM57384] FX This work was supported by Grant 09GRNT2390164 from the American Heart Association and Grant R01 GM57384 from the National Institutes of Health. NR 45 TC 46 Z9 49 U1 0 U2 11 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2011 VL 187 IS 5 BP 2181 EP 2192 DI 10.4049/jimmunol.1003460 PG 12 WC Immunology SC Immunology GA 809MD UT WOS:000294059500022 PM 21810604 ER PT J AU Novikov, A Cardone, M Thompson, R Shenderov, K Kirschman, KD Mayer-Barber, KD Myers, TG Rabin, RL Trinchieri, G Sher, A Feng, CG AF Novikov, Aleksey Cardone, Marco Thompson, Robert Shenderov, Kevin Kirschman, Kevin D. Mayer-Barber, Katrin D. Myers, Timothy G. Rabin, Ronald L. Trinchieri, Giorgio Sher, Alan Feng, Carl G. TI Mycobacterium tuberculosis Triggers Host Type I IFN Signaling To Regulate IL-1 beta Production in Human Macrophages SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PEGYLATED INTERFERON-ALPHA; INFLAMMASOME ACTIVATION; PULMONARY TUBERCULOSIS; INFECTED MACROPHAGES; GENE-EXPRESSION; DENDRITIC CELLS; IMMUNE-SYSTEM; BOVIS BCG; INDUCTION; GAMMA AB Mycobacterium tuberculosis is a virulent intracellular pathogen that survives in macrophages even in the presence of an intact adaptive immune response. Type I IFNs have been shown to exacerbate tuberculosis in mice and to be associated with disease progression in infected humans. Nevertheless, the mechanisms by which type I IFNs regulate the host response to M. tuberculosis infection are poorly understood. In this study, we show that M. tuberculosis induces an IFN-related gene expression signature in infected primary human macrophages, which is dependent on host type I IFN signaling as well as the mycobacterial virulence factor, region of difference-1. We further demonstrate that type I IFNs selectively limit the production of IL-1 beta, a critical mediator of immunity to M. tuberculosis. This regulation occurs at the level of IL1B mRNA expression, rather than caspase-1 activation or autocrine IL-1 amplification and appears to be preferentially used by virulent mycobacteria since avirulent M. bovis bacillus Calmette-Guerin (BCG) fails to trigger significant expression of type I IFNs or release of mature IL-1 beta protein. The latter property is associated with decreased caspase-1-dependent IL-1 beta maturation in the BCG-infected macrophages. Interestingly, human monocytes in contrast to macrophages produce comparable levels of IL-1 beta in response to either M. tuberculosis or BCG. Taken together, these findings demonstrate that virulent and avirulent mycobacteria employ distinct pathways for regulating IL-1 beta production in human macrophages and reveal that in the case of M. tuberculosis infection the induction of type I IFNs is a major mechanism used for this purpose. The Journal of Immunology, 2011, 187:2540-2547. C1 [Novikov, Aleksey; Thompson, Robert; Shenderov, Kevin; Mayer-Barber, Katrin D.; Trinchieri, Giorgio; Sher, Alan; Feng, Carl G.] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Novikov, Aleksey] Howard Hughes Med Inst, Howard Hughes Med Inst Natl Inst Hlth Res Scholar, Chevy Chase, MD 20892 USA. [Novikov, Aleksey] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Cardone, Marco; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shenderov, Kevin; Rabin, Ronald L.] US FDA, Lab Immunobiochem, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Myers, Timothy G.] NIAID, Res & Technol Branch, NIH, Bethesda, MD 20892 USA. RP Feng, CG (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Room 6142,Bldg 50,50 South Dr,MSC 8003, Bethesda, MD 20892 USA. EM cfeng@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services. NR 49 TC 86 Z9 87 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 SEP 1 PY 2011 VL 187 IS 5 BP 2540 EP 2547 DI 10.4049/jimmunol.1100926 PG 8 WC Immunology SC Immunology GA 809MD UT WOS:000294059500057 PM 21784976 ER PT J AU Kang, JG Amar, MJ Remaley, AT Kwon, J Blackshear, PJ Wang, PY Hwang, PM AF Kang, Ju-Gyeong Amar, Marcelo J. Remaley, Alan T. Kwon, Jaeyul Blackshear, Perry J. Wang, Ping-yuan Hwang, Paul M. TI Zinc Finger Protein Tristetraprolin Interacts with CCL3 mRNA and Regulates Tissue Inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; RHEUMATOID-ARTHRITIS; GENE-EXPRESSION; DEFICIENT MICE; TNF-ALPHA; ATHEROSCLEROSIS; CHEMOKINES; DISEASE; CELLS; STABILITY AB Zinc finger protein tristetraprolin (TTP) modulates macrophage inflammatory activity by destabilizing cytokine mRNAs. In this study, through a screen of TTP-bound mRNAs in activated human macrophages, we have identified CCL3 mRNA as the most abundantly bound TTP target mRNA and have characterized this interaction via conserved AU-rich elements. Compared to the wild-type cells, TTP(-/-) macrophages produced higher levels of LPS-induced CCL3. In addition, the plasma level of CCL3 in TTP(-/-) mice was markedly higher than that in wild-type mice. To determine the in vivo significance of TTP-regulated CCL3, we generated CCL3(-/-) TTP(-/-) double-knockout mice. Along with decreased proinflammatory cytokines in their paw joints, there were significant functional and histologic improvements in the inflammatory arthritis of TTP(-/-) mice when CCL3 was absent, although cachexia, reflecting systemic inflammation, was notably unaffected. Furthermore, the marked exacerbation of aortic plaque formation caused by TTP deficiency in the APOE(-/-) mouse model of atherosclerosis was also rescued by disrupting CCL3. Taken together, our data indicate that the interaction between TTP and CCL3 mRNA plays an important role in modulating localized inflammatory processes in tissues that are dissociated from the systemic manifestations of chronic inflammation. The Journal of Immunology, 2011, 187: 2696-2701. C1 [Kang, Ju-Gyeong; Wang, Ping-yuan; Hwang, Paul M.] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Amar, Marcelo J.; Remaley, Alan T.] NHLBI, Cardiopulm Branch, NIH, Bethesda, MD 20892 USA. [Kwon, Jaeyul] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Hwang, PM (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10 CRC,Room 5-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM hwangp@mail.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by funds from the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. NR 43 TC 17 Z9 17 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 SEP 1 PY 2011 VL 187 IS 5 BP 2696 EP 2701 DI 10.4049/jimmunol.1101149 PG 6 WC Immunology SC Immunology GA 809MD UT WOS:000294059500073 PM 21784977 ER PT J AU Falkenburg, WJJ Melenhorst, JJ van de Meent, M Kester, MGD Hombrink, P Heemskerk, MHM Hagedoorn, RS Gostick, E Price, DA Falkenburg, JHF Barrett, AJ Jedema, I AF Falkenburg, Willem J. J. Melenhorst, J. Joseph van de Meent, Marian Kester, Michel G. D. Hombrink, Pleun Heemskerk, Mirjam H. M. Hagedoorn, Renate S. Gostick, Emma Price, David A. Falkenburg, J. H. Frederik Barrett, A. John Jedema, Inge TI Allogeneic HLA-A*02-Restricted WT1-Specific T Cells from Mismatched Donors Are Highly Reactive but Show Off-Target Promiscuity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR GENE WT1; ACUTE MYELOID-LEUKEMIA; HLA CLASS-I; HIGH-AVIDITY; PEPTIDE VACCINATION; DENDRITIC CELLS; MYELODYSPLASTIC SYNDROME; ANTITUMOR-ACTIVITY; COMPLETE REMISSION; HEALTHY DONORS AB T cells recognizing tumor-associated Ags such as Wilms tumor protein (WT1) are thought to exert potent antitumor reactivity. However, no consistent high-avidity T cell responses have been demonstrated in vaccination studies with WT1 as target in cancer immunotherapy. The aim of this study was to investigate the possible role of negative thymic selection on the avidity and specificity of T cells directed against self-antigens. T cell clones directed against the HLA-A*0201-binding WT1(126-134) peptide were generated from both HLA-A*02-positive (self-HLA-restricted) and HLA-A*02-negative [nonself (allogeneic) HLA [allo-HLA]-restricted] individuals by direct ex vivo isolation using tetramers or after in vitro priming and selection. The functional avidity and specificity of these T cell clones was analyzed in-depth. Self-HLA-restricted WT1-specific clones only recognized WT1(126-134) with low avidities. In contrast, allo-HLA-restricted WT1 clones exhibited profound functional reactivity against a multitude of HLAA*02-positive targets, even in the absence of exogenously loaded WT1 peptide, indicative of Ag-binding promiscuity. To characterize this potential promiscuity, reactivity of the T cell clones against 400 randomly selected HLA-A*0201-binding peptides was investigated. The self-HLA-restricted WT1-specific T cell clones only recognized the WT1 peptide. In contrast, the allo-HLA-restricted WT1-reactive clones recognized besides WT1 various other HLA-A*0201-binding peptides. In conclusion, allogeneic HLA-A*02-restricted WT1-specific T cells isolated from mismatched donors may be more tumor-reactive than their autologous counterparts but can show specific off-target promiscuity of potential clinical importance. As a result of this, administration of WT1-specific T cells generated from HLA-mismatched donors should be performed with appropriate precautions against potential off-target effects. The Journal of Immunology, 2011, 187: 2824-2833. C1 [van de Meent, Marian; Kester, Michel G. D.; Hombrink, Pleun; Heemskerk, Mirjam H. M.; Hagedoorn, Renate S.; Falkenburg, J. H. Frederik; Jedema, Inge] Leiden Univ, Med Ctr, Dept Hematol, NL-2300 RC Leiden, Netherlands. [Falkenburg, Willem J. J.; Melenhorst, J. Joseph; Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Gostick, Emma; Price, David A.] Cardiff Univ, Sch Med, Dept Infect Immun & Biochem, Cardiff CF14 4XN, S Glam, Wales. RP Jedema, I (reprint author), Univ Med Ctr, Dept Hematol, C2R-140,POB 9600, NL-2300 RC Leiden, Netherlands. EM i.jedema@lumc.nl RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Medical Research Council [G0501963] NR 59 TC 21 Z9 22 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 SEP 1 PY 2011 VL 187 IS 5 BP 2824 EP 2833 DI 10.4049/jimmunol.1100852 PG 10 WC Immunology SC Immunology GA 809MD UT WOS:000294059500087 PM 21821799 ER PT J AU Bottalico, D Chen, ZG Dunne, A Ostoloza, J McKinney, S Sun, C Schlecht, NF Fatahzadeh, M Herrero, R Schiffman, M Burk, RD AF Bottalico, Danielle Chen, Zigui Dunne, Anne Ostoloza, Janae McKinney, Sharod Sun, Chang Schlecht, Nicolas F. Fatahzadeh, Mahnaz Herrero, Rolando Schiffman, Mark Burk, Robert D. TI The Oral Cavity Contains Abundant Known and Novel Human Papillomaviruses From the Betapapillomavirus and Gammapapillomavirus Genera SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SQUAMOUS-CELL CARCINOMA; SEXUAL-BEHAVIOR; NATURAL-HISTORY; CERVICAL-CANCER; HEALTHY SKIN; RISK-FACTORS; INFECTION; PREVALENCE; ADULTS AB Background. Human papillomaviruses (HPVs) primarily sort into 3 genera: Alphapapillomavirus (alpha-HPV), predominantly isolated from mucosa, and Betapapillomavirus (beta-HPV) and Gammapapillomavirus (gamma-HPV), predominantly isolated from skin. HPV types might infect body sites that are different from those from which they were originally isolated. Methods. We investigated the spectrum of HPV type distribution in oral rinse samples from 2 populations: 52 human immunodeficiency virus (HIV)-positive men and women and 317 men who provided a sample for genomic DNA for a prostate cancer study. HPV types were detected with the MY09/MY11 and FAP59/64 primer systems and identified by dot blot hybridization and/or direct sequencing. Results. Oral rinse specimens from 35 (67%) of 52 HIV-positive individuals and 117 (37%) of 317 older male participants tested positive for HPV DNA. We found 117 type-specific HPV infections from the HIV-positive individuals, including 73 alpha-HPV, 33 beta-HPV, and 11 gamma-HPV infections; whereas, the distribution was 46 alpha-HPV, 108 beta-HPV, and 14 gamma-HPV infections from 168 type-specific infections from the 317 male participants. Conclusions. The oral cavity contains a wide spectrum of HPV types predominantly from the beta-HPV and gamma-HPV genera, which were previously considered to be cutaneous types. These results could have significant implications for understanding the biology of HPV and the epidemiological associations of HPV with oral and skin neoplasia. C1 [Burk, Robert D.] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USA. [Bottalico, Danielle; Chen, Zigui; Dunne, Anne; Ostoloza, Janae; McKinney, Sharod; Burk, Robert D.] Univ Med & Dent New Jersey, New Jersey Dent Sch, Dept Pediat, Newark, NJ 07103 USA. [Chen, Zigui; Sun, Chang; Burk, Robert D.] Univ Med & Dent New Jersey, New Jersey Dent Sch, Dept Microbiol & Immunol, Newark, NJ 07103 USA. [Schlecht, Nicolas F.; Burk, Robert D.] Univ Med & Dent New Jersey, New Jersey Dent Sch, Dept Epidemiol & Populat Hlth, Newark, NJ 07103 USA. [Fatahzadeh, Mahnaz] Univ Med & Dent New Jersey, New Jersey Dent Sch, Dept Diagnost Sci, Newark, NJ 07103 USA. [Herrero, Rolando] Fdn INCIENSA, San Jose, Costa Rica. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Burk, RD (reprint author), Albert Einstein Coll Med, Albert Einstein Canc Ctr, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM robert.burk@einstein.yu.edu RI Sun, Chang/I-6326-2012; Chen, Zigui/E-8490-2017 FU National Cancer Institute [CA78527, P30CA013330]; National Institutes of Health [AI-51519] FX This work was supported by the National Cancer Institute (grant CA78527 to R. D. B.); the Einstein-Montefiore Center for AIDS, funded by the National Institutes of Health (grant AI-51519); and the Einstein Cancer Research Center, funded by the National Cancer Institute (grant P30CA013330). NR 30 TC 68 Z9 68 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 1 PY 2011 VL 204 IS 5 BP 787 EP 792 DI 10.1093/infdis/jir383 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 809QB UT WOS:000294070700017 PM 21844305 ER PT J AU Thu, KL Pikor, LA Chari, R Wilson, IM MacAulay, CE English, JC Tsao, MS Gazdar, AF Lam, S Lam, WL Lockwood, WW AF Thu, Kelsie L. Pikor, Larissa A. Chari, Raj Wilson, Ian M. MacAulay, Calum E. English, John C. Tsao, Ming-Sound Gazdar, Adi F. Lam, Stephen Lam, Wan L. Lockwood, William W. TI Genetic Disruption of KEAP1/CUL3 E3 Ubiquitin Ligase Complex Components is a Key Mechanism of NF-KappaB Pathway Activation in Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE KEAP1; CUL3; RBX1; IKBKB; NF-kappa B signaling; Genetic disruption ID OXIDATIVE STRESS; CELL-LINES; HUMAN GENOME; NRF2; REQUIREMENT; MUTATIONS; CATALOG; TARGETS; PROTEIN; ADAPTER AB Introduction: Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKBKB) (IKK-beta/IKK-2), which activates NF-kappa B, is a substrate of the KEAP1-CUL3-RBX1 E3-ubiquitin ligase complex, implicating this complex in NF-kappa B pathway regulation. We investigated complex component gene disruption as a novel genetic mechanism of NF-kappa B activation in non-small cell lung cancer. Methods: A total of 644 tumor-and 90 cell-line genomes were analyzed for gene dosage status of the individual complex components and IKBKB. Gene expression of these genes and NF-kappa B target genes were analyzed in 48 tumors. IKBKB protein levels were assessed in tumors with and without complex or IKBKB genetic disruption. Complex component knockdown was performed to assess effects of the E3-ligase complex on IKBKB and NF-kappa B levels, and phenotypic importance of IKBKB expression was measured by pharmacological inhibition. Results: We observed strikingly frequent genetic disruption (42%) and aberrant expression (63%) of the E3-ligase complex and IKBKB in the samples examined. Although both adenocarcinomas and squamous cell carcinomas showed complex disruption, the patterns of gene disruption differed. IKBKB levels were elevated with complex disruption, knockdown of complex components increased activated forms of IKBKB and NF-kappa B proteins, and IKBKB inhibition detriments cell viability, highlighting the biological significance of complex disruption. NF-kappa B target genes were overex-pressed in samples with complex disruption, further demonstrating the effect of complex disruption on NF-kappa B activity. Conclusions: Gene dosage alteration is a prominent mechanism that disrupts each component of the KEAP1-CUL3-RBX1 complex and its NF-kappa B stimulating substrate, IKBKB. Herein, we show that, multiple component disruption of this complex represents a novel mechanism of NF-kappa B activation in non-small cell lung cancer. C1 [Thu, Kelsie L.; Pikor, Larissa A.; Chari, Raj; Wilson, Ian M.; MacAulay, Calum E.; Lam, Stephen; Lam, Wan L.; Lockwood, William W.] BC Canc Res Ctr, Integrat Oncol Dept, Vancouver, BC V5Z 1L3, Canada. [English, John C.] Vancouver Gen Hosp, Dept Pathol, Vancouver, BC V5Z 1M9, Canada. [Tsao, Ming-Sound] Princess Margaret Hosp, Ontario Canc Inst, Univ Hlth Network, Toronto, ON M4X 1K9, Canada. [Tsao, Ming-Sound] Univ Toronto, Toronto, ON, Canada. [Gazdar, Adi F.] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. [Lockwood, William W.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Thu, KL (reprint author), BC Canc Res Ctr, Integrat Oncol Dept, 675 W 10th Ave, Vancouver, BC V5Z 1L3, Canada. EM kthu@bccrc.ca RI MacAulay, Calum/K-1795-2016 FU Canadian Institutes for Health Research (CIHR) [MOP 86731, MOP 94867]; Canadian Cancer Society [CCS20485, CCS20527]; NCI Early Detection Research Network (EDRN) [5U01, CA84971-10]; Canary Foundation; Michael Smith Foundation for Health Research; Vanier Canada Graduate Scholarship; University of British Columbia Interdisciplinary Oncology Program FX Supported by funds from the Canadian Institutes for Health Research (CIHR; MOP 86731 and MOP 94867), Canadian Cancer Society (CCS20485 and CCS20527), NCI Early Detection Research Network (EDRN; 5U01 CA84971-10), and the Canary Foundation. K.L.T., L.A.P., R.C., I.M.W., and W.W.L. are supported by scholarships from the CIHR, the Michael Smith Foundation for Health Research, Vanier Canada Graduate Scholarship, and the University of British Columbia Interdisciplinary Oncology Program. NR 31 TC 26 Z9 27 U1 0 U2 2 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 SEP PY 2011 VL 6 IS 9 BP 1521 EP 1529 DI 10.1097/JTO.0b013e3182289479 PG 9 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 808VB UT WOS:000294008000013 PM 21795997 ER PT J AU Thu, KL Chari, R Lockwood, WW Lam, S Lam, WL AF Thu, Kelsie L. Chari, Raj Lockwood, William W. Lam, Stephen Lam, Wan L. TI miR-101 DNA Copy Loss is a Prominent Subtype Specific Event in Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Non-small cell lung cancer; miR-101; Deletion ID GASTRIC-CANCER; GENOMIC LOSS; MICRORNA-101; EXPRESSION; CARCINOMA; EZH2 AB Introduction: MicroRNA-101 (miR-101) is frequently downregulated in cancer and exhibits antitumorigenic properties, suggesting that miR-101 is a putative tumor suppressor. miR-101 is encoded at two loci in the human genome: 1p31.3 (miR-101-1) and 9p24.1 (miR-101-2). We sought to investigate miR-101 locus-specific deletions and genomic loss in the major subtypes of lung cancer. Methods: Analyses of high-resolution array comparative genomic hybridization and single-nucleotide polymorphism array data were performed to determine the DNA copy number status and deletion boundaries of miR-101-1 and miR-101-2 in seven independent cohorts that comprised 1236 lung cancer specimens and 20 lung carcinoma in situ samples. miR-101 expression was also investigated in lung cancer cell lines and tumors. Results: miR-101 loss at either genomic locus was identified in 29% of lung cancers analyzed and was associated with reduced miR-101 expression. Loss was more frequent at the 9p locus and occurred more often in NSCLC as opposed to small cell lung cancer. Lung carcinoma in situ also harbored miR-101 deletions, suggesting that genomic loss may be an early event in lung cancer development. Finally, miR-101 deletions on 9p were exclusive of CDKN2A deletions in several cases, providing evidence that loss of miR-101 is not merely a passenger of CDKN2A deletion. Conclusions: miR-101 genomic loss occurs frequently in NSCLC and may be an early event in lung tumorigenesis. DNA deletions likely represent a prominent molecular mechanism of miR-101 downregulation in NSCLC but not in small cell lung cancer. C1 [Thu, Kelsie L.; Chari, Raj; Lockwood, William W.; Lam, Stephen; Lam, Wan L.] BC Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada. [Lockwood, William W.] NIH, Bethesda, MD 20892 USA. RP Thu, KL (reprint author), BC Canc Res Ctr, 675 W 10th Ave, Vancouver, BC V5Z 1L3, Canada. EM kthu@bccrc.ca FU Michael Smith Foundation for Health Research; Vanier Canada Graduate Scholarship; Canadian Institutes for Health Research (CIHR) [MOP 86731, MOP 94867]; Canadian Cancer Society [CCS20485]; NCI Early Detection Research Network (EDRN) [5U01 CA84971-10]; Canary Foundation FX Thu, Chari, and Lockwood were supported by scholarships from the CIHR, the Michael Smith Foundation for Health Research, and Vanier Canada Graduate Scholarship.; Supported by the Canadian Institutes for Health Research (CIHR; MOP 86731, MOP 94867), Canadian Cancer Society (CCS20485), NCI Early Detection Research Network (EDRN; 5U01 CA84971-10), and the Canary Foundation. NR 19 TC 16 Z9 21 U1 0 U2 7 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 SEP PY 2011 VL 6 IS 9 BP 1594 EP 1598 DI 10.1097/JTO.0b013e3182217d81 PG 5 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 808VB UT WOS:000294008000022 PM 21849855 ER PT J AU Crawford, ED Hirst, K Kusek, JW Donnell, RF Kaplan, SA McVary, KT Mynderse, LA Roehrborn, CG Smith, CP Bruskewitz, R AF Crawford, E. David Hirst, Kathryn Kusek, John W. Donnell, Robert F. Kaplan, Steven A. McVary, Kevin T. Mynderse, Lance A. Roehrborn, Claus G. Smith, Christopher P. Bruskewitz, Reginald TI Effects of 100 and 300 Units of Onabotulinum Toxin A on Lower Urinary Tract Symptoms of Benign Prostatic Hyperplasia: A Phase II Randomized Clinical Trial SO JOURNAL OF UROLOGY LA English DT Article DE prostatic hyperplasia; onabotulinum toxin A ID BOTULINUM TOXIN; DETRUSOR OVERACTIVITY; INNERVATION; INJECTIONS; RELIEF AB Purpose: We conducted a 2-stage, multicenter, double-blind, randomized phase II clinical trial of 100 and 300 unit doses of onabotulinum toxin A to treat the lower urinary tract symptoms of benign prostatic hyperplasia. Materials and Methods: Men 50 years old or older with clinically diagnosed benign prostatic hyperplasia, American Urological Association symptom index 8 or greater, maximum urinary flow rate less than 15 ml per second, voided volume 125 ml or greater, and post-void residual 350 ml or less were randomized to prostatic transrectal injection of 100 or 300 units of onabotulinum toxin A. The primary outcome was at least 30% improvement from baseline to 3 months in American Urological Association symptom index and/or maximum urinary flow rate and safety. The men were followed for 12 months. Results: A total of 134 men were randomized and treated (68 with 100 units, 66 with 300 units), with 131 assessed at 3 months and 108 assessed at 12 months. Each dose met the 3-month primary outcome criteria. In the 100 unit arm the mean baseline American Urological Association symptom index of 18.8 decreased by 7.1 and 6.9 at 3 and 12 months, respectively. In the 300 unit arm the baseline of 19.5 decreased by 8.9 and 7.1, respectively. In the 100 unit arm the mean baseline maximum urinary flow rate of 10.0 ml per second increased by 2.5 and 2.2, respectively, and in the 300 unit arm the baseline of 9.6 increased by 2.6 and 2.3, respectively. Conclusions: The intraprostatic injection of 100 or 300 units of onabotulinum toxin A passed predetermined criteria for treatment efficacy and safety, and a randomized trial with either dose is warranted. The 100 unit dose may be preferable due to similar efficacy with reduced costs and adverse effects. C1 [Hirst, Kathryn] George Washington Univ, Ctr Biostat, Rockville, MD 20852 USA. [Crawford, E. David] Univ Colorado Denver, Sect Urol Oncol, Sch Med, Aurora, CO USA. [Kusek, John W.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. [Donnell, Robert F.] Med Coll Wisconsin, Dept Urol, Milwaukee, WI 53226 USA. [Bruskewitz, Reginald] Univ Wisconsin, Dept Urol, Madison, WI USA. [Kaplan, Steven A.] Cornell Univ, Dept Urol, New York, NY 10021 USA. [McVary, Kevin T.] Northwestern Univ, Sch Med, Dept Urol, Chicago, IL 60611 USA. [Mynderse, Lance A.] Mayo Clin, Dept Urol, Rochester, MN USA. [Roehrborn, Claus G.] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. [Smith, Christopher P.] Baylor Coll Med, Dept Urol, Houston, TX 77030 USA. RP Hirst, K (reprint author), George Washington Univ, Ctr Biostat, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM khirst@bsc.gwu.edu FU NIDDK/NIH [U01 DK60791, U01 DK60795, U01 DK60799, U01 DK60803, U01 DK60804, U01 DK060810, U01 DK60813, U01 DK60817] FX Supported by NIDDK/NIH Grants U01 DK60791 (University of Colorado Denver), U01 DK60795 (Northwestern University), U01 DK60799 (University of Texas Southwestern Medical Center), U01 DK60803 (Medical College of Wisconsin), U01 DK60804 (Cornell University), U01 DK060810 (Baylor College of Medicine), U01 DK60813 (Mayo Clinic) and U01 DK60817 (George Washington University). NR 18 TC 26 Z9 26 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD SEP PY 2011 VL 186 IS 3 BP 965 EP 970 DI 10.1016/j.juro.2011.04.062 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 804XL UT WOS:000293688300062 PM 21791356 ER PT J AU Yang, HP Walmer, DK Merisier, D Gage, JC Bell, L Rangwala, S Shrestha, N Kobayashi, L Eder, PS Castle, PE AF Yang, Hannah P. Walmer, David K. Merisier, Delson Gage, Julia C. Bell, Laura Rangwala, Sameera Shrestha, Niwashin Kobayashi, Lori Eder, Paul S. Castle, Philip E. TI A pilot analytic study of a research-level, lower-cost human papillomavirus 16, 18, and 45 test SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Human papillomavirus (HPV); HPV test; Cervical cancer; HPV genotypes ID CERVICAL-CANCER; WOMEN; RISK; DNA; PREVALENCE; PRIMERS; PCR AB The analytic performance of a low-cost, research-stage DNA test for the most carcinogenic human papillomavirus (HPV) genotypes (HPV16. HPV18. and HPV45) in aggregate was evaluated among carcinogenic HPV-positive women, which might be used to decide who needs immediate colposcopy in low-resource settings ("triage test"). We found that HPV16/18/45 test agreed well with two DNA tests, a GP5+/6+ genotyping assay (Kappa = 0.77) and a quantitative PCR assay (at a cutpoint of 5000 viral copies) (Kappa = 0.87). DNA sequencing on a subset of 16 HPV16/18/45 positive and 16 HPV16/18/45 negative verified the analytic specificity of the research test. It is concluded that the HPV16/18/45 assay is a promising triage test with a minimum detection of approximately 5000 viral copies, the clinically relevant threshold. Published by Elsevier B.V. C1 [Yang, Hannah P.; Gage, Julia C.] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Walmer, David K.; Merisier, Delson] Family Hlth Minist, Durham, NC 27705 USA. [Walmer, David K.; Merisier, Delson] Duke Univ, Duke Global Hlth Inst, Durham, NC 27710 USA. [Bell, Laura; Rangwala, Sameera; Shrestha, Niwashin; Kobayashi, Lori; Eder, Paul S.] QIAGEN Inc, Gaithersburg, MD 20878 USA. [Castle, Philip E.] Amer Soc Clin Pathol Inst, Washington, DC 20005 USA. RP Yang, HP (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 5102,MSC 7234, Bethesda, MD 20892 USA. EM yanghan@mail.nih.gov FU NIH/NCI FX The evaluation of the HPV16/18/45 triage test data was conducted for research purposes and was supported in part by the intramural research program of the NIH/NCI. The authors would like to recognize Adam Mallonee of QIAGEN for his contribution to performing the genotyping tests. NR 19 TC 4 Z9 4 U1 0 U2 1 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 SEP PY 2011 VL 176 IS 1-2 BP 112 EP 114 DI 10.1016/j.jviromet.2011.05.024 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 809ED UT WOS:000294033700017 PM 21640138 ER PT J AU Radoshitzky, SR Warfield, KL Chi, XL Dong, L Kota, K Bradfute, SB Gearhart, JD Retterer, C Kranzusch, PJ Misasi, JN Hogenbirk, MA Wahl-Jensen, V Volchkov, VE Cunningham, JM Jahrling, PB Aman, MJ Bavari, S Farzan, M Kuhn, JH AF Radoshitzky, Sheli R. Warfield, Kelly L. Chi, Xiaoli Dong, Lian Kota, Krishna Bradfute, Steven B. Gearhart, Jacqueline D. Retterer, Cary Kranzusch, Philip J. Misasi, John N. Hogenbirk, Marc A. Wahl-Jensen, Victoria Volchkov, Viktor E. Cunningham, James M. Jahrling, Peter B. Aman, M. Javad Bavari, Sina Farzan, Michael Kuhn, Jens H. TI Ebolavirus Delta-Peptide Immunoadhesins Inhibit Marburgvirus and Ebolavirus Cell Entry SO JOURNAL OF VIROLOGY LA English DT Article ID ANGIOTENSIN-CONVERTING ENZYME-2; SMALL GLYCOPROTEIN SGP; VIRUS GLYCOPROTEIN; ENDOSOMAL CATHEPSINS; ELECTRON-MICROSCOPY; SARS CORONAVIRUS; VIRAL ENTRY; RECEPTOR; SEQUENCE; MEMBRANE AB With the exception of Reston and Lloviu viruses, filoviruses (marburgviruses, ebolaviruses, and "cuevaviruses") cause severe viral hemorrhagic fevers in humans. Filoviruses use a class I fusion protein, GP(1,2), to bind to an unknown, but shared, cell surface receptor to initiate virus-cell fusion. In addition to GP(1,2), ebolaviruses and cuevaviruses, but not marburgviruses, express two secreted glycoproteins, soluble GP (sGP) and small soluble GP (ssGP). All three glycoproteins have identical N termini that include the receptor-binding region (RBR) but differ in their C termini. We evaluated the effect of the secreted ebolavirus glycoproteins on marburgvirus and ebolavirus cell entry, using Fc-tagged recombinant proteins. Neither sGP-Fc nor ssGP-Fc bound to filovirus-permissive cells or inhibited GP(1,2)-mediated cell entry of pseudotyped retroviruses. Surprisingly, several Fc-tagged Delta-peptides, which are small C-terminal cleavage products of sGP secreted by ebolavirus-infected cells, inhibited entry of retroviruses pseudotyped with Marburg virus GP(1,2), as well as Marburg virus and Ebola virus infection in a dose-dependent manner and at low molarity despite absence of sequence similarity to filovirus RBRs. Fc-tagged Delta-peptides from three ebolaviruses (Ebola virus, Sudan virus, and Ta Forest virus) inhibited GP(1,2)-mediated entry and infection of viruses comparably to or better than the Fc-tagged RBRs, whereas the Delta-peptide-Fc of an ebolavirus nonpathogenic for humans (Reston virus) and that of an ebolavirus with lower lethality for humans (Bundibugyo virus) had little effect. These data indicate that Delta-peptides are functional components of ebolavirus proteomes. They join cathepsins and integrins as novel modulators of filovirus cell entry, might play important roles in pathogenesis, and could be exploited for the synthesis of powerful new antivirals. C1 [Wahl-Jensen, Victoria; Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. [Radoshitzky, Sheli R.; Warfield, Kelly L.; Chi, Xiaoli; Dong, Lian; Kota, Krishna; Bradfute, Steven B.; Gearhart, Jacqueline D.; Retterer, Cary; Aman, M. Javad; Bavari, Sina] USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Radoshitzky, Sheli R.; Kranzusch, Philip J.; Hogenbirk, Marc A.; Farzan, Michael; Kuhn, Jens H.] Harvard Univ, New England Primate Res Ctr, Sch Med, Southborough, MA 01772 USA. [Warfield, Kelly L.; Aman, M. Javad] Integrated BioTherapeut Inc, Germantown, MD 20876 USA. [Misasi, John N.; Cunningham, James M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Hogenbirk, Marc A.] Univ Utrecht, Eijkman Grad Sch Immunol & Infect Dis, NL-3508 TC Utrecht, Netherlands. [Volchkov, Viktor E.] Univ Lyon 1, Ecole Normale Super Lyon, INSERM, U758, F-69365 Lyon, France. [Kuhn, Jens H.] Free Univ Berlin, Dept Biol, D-14195 Berlin, Germany. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick, NIH, B-8200 Res Plaza, Frederick, MD 21702 USA. EM kuhnjens@mail.nih.gov RI Kuhn, Jens H./B-7615-2011; Volchkov, Viktor/M-7846-2014 OI Kuhn, Jens H./0000-0002-7800-6045; Volchkov, Viktor/0000-0001-7896-8706 FU NIAID [HHSN272200200016I]; NERCE/BEID, Boston, MA [AI057159]; Agence Nationale de la Recherche [ANR-07-MIME-006-01] FX J.H.K. and V.W.-J. performed part of this work as employees of Tunnell Consulting, Inc., a subcontractor to Battelle Memorial Institute, under its prime contract with NIAID (contract HHSN272200200016I). NERCE/BEID, Boston, MA, provided a Career Development Fellowship to J.H.K. (grant AI057159). Agence Nationale de la Recherche supported V. E. V. (ANR-07-MIME-006-01). NR 60 TC 22 Z9 25 U1 0 U2 15 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 SEP PY 2011 VL 85 IS 17 BP 8502 EP 8513 DI 10.1128/JVI.02600-10 PG 12 WC Virology SC Virology GA 804AO UT WOS:000293626100005 PM 21697477 ER PT J AU Pak, V Heidecker, G Pathak, VK Derse, D AF Pak, Vladimir Heidecker, Gisela Pathak, Vinay K. Derse, David TI The Role of Amino-Terminal Sequences in Cellular Localization and Antiviral Activity of APOBEC3B SO JOURNAL OF VIROLOGY LA English DT Article ID LEUKEMIA-VIRUS TYPE-1; CYTIDINE DEAMINASE DOMAINS; ANTIRETROVIRAL FACTOR; POTENT INHIBITORS; HIV-1 VIF; DNA; RNA; RETROTRANSPOSITION; RESTRICTION; PROTEINS AB Human APOBEC3B (A3B) has been described as a potent inhibitor of retroviral infection and retrotransposition. However, we found that the predominantly nuclear A3B only weakly restricted infection by HIV-1, HIV-1 Delta vif, and human T-cell leukemia virus type 1 (HTLV-1), while significantly inhibiting LINE-1 retrotransposition. The chimeric construct A3G/B, in which the first 60 amino acids of A3B were replaced with those of A3G, restricted HIV-1, HIV-1 Delta vif, and HTLV-1 infection, as well as LINE-1 retrotransposition. In contrast to the exclusively cytoplasmic A3G, which is inactive against LINE-1 retrotransposition, the A3G/B protein, while localized mainly to the cytoplasm, was also present in the nucleus. Further mutational analysis revealed that residues 18, 19, 22, and 24 in A3B were the major determinants for nuclear versus cytoplasmic localization and antiretroviral activity. HIV-1 Delta vif packages A3G, A3B, and A3G/B into particles with close-to-equal efficiencies. Mutation E68Q or E255Q in the active centers of A3G/B resulted in loss of the inhibitory activity against HIV-1 Delta vif, while not affecting activity against LINE-1 retrotransposition. The low inhibition of HIV-1 Delta vif by A3B correlated with a low rate of G-to-A hypermutation. In contrast, viruses that had been exposed to A3G/B showed a high number of G-to-A transitions. The mutation pattern was similar to that previously reported for A3B, with a preference for the GA context. In summary, these observations suggest that changing 4 residues in the amino terminus of A3B not only retargets the protein from the nucleus to the cytoplasm but also enhances its ability to restrict HIV while retaining inhibition of retrotransposition. C1 [Pak, Vladimir; Heidecker, Gisela; Pathak, Vinay K.; Derse, David] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Heidecker, G (reprint author), NCI, HIV Drug Resistance Program, POB B,Bldg 535,Rm 111, Frederick, MD 21702 USA. EM heidecke@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 48 TC 19 Z9 20 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 SEP PY 2011 VL 85 IS 17 BP 8538 EP 8547 DI 10.1128/JVI.02645-10 PG 10 WC Virology SC Virology GA 804AO UT WOS:000293626100008 PM 21715505 ER PT J AU Kim, SH Subbiah, M Samuel, AS Collins, PL Samal, SK AF Kim, Shin-Hee Subbiah, Madhuri Samuel, Arthur S. Collins, Peter L. Samal, Siba K. TI Roles of the Fusion and Hemagglutinin-Neuraminidase Proteins in Replication, Tropism, and Pathogenicity of Avian Paramyxoviruses SO JOURNAL OF VIROLOGY LA English DT Article ID NEWCASTLE-DISEASE VIRUS; COMPLETE GENOME SEQUENCE; RESPIRATORY SYNCYTIAL VIRUS; CELL-FUSION; HN PROTEIN; MUTATIONAL ANALYSIS; CLEAVAGE SITE; FOREIGN GENE; CLONED CDNA; F-PROTEIN AB Virulent and moderately virulent strains of Newcastle disease virus (NDV), representing avian paramyxovirus serotype 1 (APMV-1), cause respiratory and neurological disease in chickens and other species of birds. In contrast, APMV-2 is avirulent in chickens. We investigated the role of the fusion (F) and hemagglutinin-neuraminidase (HN) envelope glycoproteins in these contrasting phenotypes by designing chimeric viruses in which the F and HN glycoproteins or their ectodomains were exchanged individually or together between the moderately virulent, neurotropic NDV strain Beaudette C (BC) and the avirulent APMV-2 strain Yucaipa. When we attempted to exchange the complete F and HN glycoproteins individually and together between the two viruses, the only construct that could be recovered was recombinant APMV-2 strain Yucaipa (rAPMV-2), containing the NDV F glycoprotein in place of its own. This substitution of NDV F into APMV-2 was sufficient to confer the neurotropic, neuroinvasive, and neurovirulent phenotypes, in spite of all being at reduced levels compared to what was seen for NDV-BC. When the ectodomains of F and HN were exchanged individually and together, two constructs could be recovered: NDV, containing both the F and HN ectodomains of APMV-2; and APMV-2, containing both ectodomains of NDV. This supported the idea that homologous cytoplasmic tails and matched F and HN ectodomains are important for virus replication. Analysis of these viruses for replication in vitro, syncytium formation, mean embryo death time, intracerebral pathogenicity index, and replication and tropism in 1-day-old chicks and 2-week-old chickens showed that the two contrasting phenotypes of NDV and APMV-2 could largely be transferred between the two backbones by transfer of homotypic F and HN ectodomains. Further analysis provided evidence that the homologous stalk domain of NDV HN is essential for virus replication, while the globular head domain of NDV HN could be replaced with that of APMV-2 with only a minimal attenuating effect. These results demonstrate that the F and HN ectodomains together determine the cell fusion, tropism, and virulence phenotypes of NDV and APMV-2 and that the regions of HN that are critical to replication and the species-specific phenotypes include the cytoplasmic tail and stalk domain but not the globular head domain. C1 [Kim, Shin-Hee; Subbiah, Madhuri; Samuel, Arthur S.; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, 8075 Greenmead Dr, College Pk, MD 20742 USA. EM ssamal@umd.edu FU National Institute of Allergy and Infectious Diseases (NIAID) [N01A060009]; NIAID, National Institutes of Health (NIH) FX This research was supported by National Institute of Allergy and Infectious Diseases (NIAID) contract no. N01A060009 (85% support) and NIAID, National Institutes of Health (NIH) Intramural Research Program (15% support). NR 57 TC 19 Z9 23 U1 1 U2 5 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 SEP PY 2011 VL 85 IS 17 BP 8582 EP 8596 DI 10.1128/JVI.00652-11 PG 15 WC Virology SC Virology GA 804AO UT WOS:000293626100012 PM 21680512 ER PT J AU Boon, D Mahar, JE Abente, EJ Kirkwood, CD Purcell, RH Kapikian, AZ Green, KY Bok, K AF Boon, Denali Mahar, Jackie E. Abente, Eugenio J. Kirkwood, Carl D. Purcell, Robert H. Kapikian, Albert Z. Green, Kim Y. Bok, Karin TI Comparative Evolution of GII.3 and GII.4 Norovirus over a 31-Year Period SO JOURNAL OF VIROLOGY LA English DT Article ID LINKED IMMUNOSORBENT ASSAYS; AUTOMATED PROTEIN-STRUCTURE; I-TASSER; ACUTE GASTROENTERITIS; STRUCTURE PREDICTION; HUMAN-POPULATIONS; SEQUENCE-ANALYSIS; NORWALK VIRUS; P2 DOMAIN; INFECTION AB Noroviruses are the most common cause of epidemic gastroenteritis. Genotype II.3 is one of the most frequently detected noroviruses associated with sporadic infections. We studied the evolution of the major capsid gene from seven archival GII.3 noroviruses collected during a cross-sectional study at the Children's Hospital in Washington, DC, from 1975 through 1991, together with capsid sequence from 56 strains available in GenBank. Evolutionary analysis concluded that GII.3 viruses evolved at a rate of 4.16 x 10(-3) nucleotide substitutions/site/year (strict clock), which is similar to that described for the more prevalent GII.4 noroviruses. The analysis of the amino acid changes over the 31-year period found that GII.3 viruses evolve at a relatively steady state, maintaining 4% distance, and have a tendency to revert back to previously used residues while preserving the same carbohydrate binding profile. In contrast, GII.4 viruses demonstrate increasing rates of distance over time because of the continued integration of new amino acids and changing HBGA binding patterns. In GII.3 strains, seven sites acting under positive selection were predicted to be surface-exposed residues in the P2 domain, in contrast to GII.4 positively selected sites located primarily in the shell domain. Our study suggests that GII.3 noroviruses caused disease as early as 1975 and that they evolve via a specific pattern, responding to selective pressures induced by the host rather than presenting a nucleotide evolution rate lower than that of GII.4 noroviruses, as previously proposed. Understanding the evolutionary dynamics of prevalent noroviruses is relevant to the development of effective prevention and control strategies. C1 [Bok, Karin] NIAID, Caliciviruses Sect, Infect Dis Lab, NIH,DHHS, Bethesda, MD 20892 USA. [Mahar, Jackie E.; Kirkwood, Carl D.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic, Australia. [Mahar, Jackie E.] La Trobe Univ, Bundoora, Vic 3086, Australia. RP Bok, K (reprint author), NIAID, Caliciviruses Sect, Infect Dis Lab, NIH,DHHS, 50 South Dr,Bldg 50,Room 6316, Bethesda, MD 20892 USA. EM bokk@niaid.nih.gov OI Abente, Eugenio/0000-0002-3390-2786 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 48 TC 56 Z9 58 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2011 VL 85 IS 17 BP 8656 EP 8666 DI 10.1128/JVI.00472-11 PG 11 WC Virology SC Virology GA 804AO UT WOS:000293626100019 PM 21715504 ER PT J AU Vinton, C Klatt, NR Harris, LD Briant, JA Sanders-Beer, BE Herbert, R Woodward, R Silvestri, G Pandrea, I Apetrei, C Hirsch, VM Brenchley, JM AF Vinton, Carol Klatt, Nichole R. Harris, Levelle D. Briant, Judith A. Sanders-Beer, Brigitte E. Herbert, Richard Woodward, Ruth Silvestri, Guido Pandrea, Ivona Apetrei, Cristian Hirsch, Vanessa M. Brenchley, Jason M. TI CD4-Like Immunological Function by CD4(-) T Cells in Multiple Natural Hosts of Simian Immunodeficiency Virus SO JOURNAL OF VIROLOGY LA English DT Article ID SOOTY MANGABEYS; SIVAGM INFECTION; AIDS; PATTERNS; SUBSETS; HISTORY; WILD AB Many species of African nonhuman primates are natural hosts for individual strains of simian immunodeficiency virus (SIV). These infected animals do not, however, develop AIDS. Here we show that multiple species of African nonhuman primate species characteristically have low frequencies of CD4(+) T cells and high frequencies of both T cells that express only the alpha-chain of CD8 and double-negative T cells. These subsets of T cells are capable of eliciting functions generally associated with CD4(+) T cells, yet these cells lack surface expression of the CD4 protein and are, therefore, poor targets for SIV in vivo. These data demonstrate that coevolution with SIV has, in several cases, involved downregulation of receptors for the virus by otherwise-susceptible host target cells. Understanding the genetic factors that lead to downregulation of these receptors may lead to therapeutic interventions that mimic this modulation in progressive infections. C1 [Vinton, Carol; Klatt, Nichole R.; Harris, Levelle D.; Briant, Judith A.; Hirsch, Vanessa M.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Sanders-Beer, Brigitte E.] Bioqual, Rockville, MD 20850 USA. [Herbert, Richard] NIAID, Expt Primate Virol Sect, NIH, Bethesda, MD 20892 USA. [Woodward, Ruth] NICHD, NIH, Bethesda, MD 20892 USA. [Silvestri, Guido] Emory Univ, Div Microbiol & Immunol, Atlanta, GA 30322 USA. [Pandrea, Ivona; Apetrei, Cristian] Univ Pittsburgh, Ctr Vaccine Res, Pittsburgh, PA 15261 USA. RP Brenchley, JM (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM jbrenchl@mail.nih.gov OI Anesi, Judith/0000-0001-6671-4557 FU NIAID, NIH; Tulane National Primate Research Center [R01 AI064066, R01 AI065325, R01 AI66998, RR-00168] FX These studies were supported by the intramural NIAID, NIH program and by R01 AI064066 (I. P.), R01 AI065325 (C. A.), R01 AI66998 (G. S.), and RR-00168 (Tulane National Primate Research Center). NR 30 TC 28 Z9 28 U1 0 U2 0 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 SEP PY 2011 VL 85 IS 17 BP 8702 EP 8708 DI 10.1128/JVI.00332-11 PG 7 WC Virology SC Virology GA 804AO UT WOS:000293626100023 PM 21715501 ER PT J AU Li, YX O'Dell, S Walker, LM Wu, XL Guenaga, J Feng, Y Schmidt, SD McKee, K Louder, MK Ledgerwood, JE Graham, BS Haynes, BF Burton, DR Wyatt, RT Mascola, JR AF Li, Yuxing O'Dell, Sijy Walker, Laura M. Wu, Xueling Guenaga, Javier Feng, Yu Schmidt, Stephen D. McKee, Krisha Louder, Mark K. Ledgerwood, Julie E. Graham, Barney S. Haynes, Barton F. Burton, Dennis R. Wyatt, Richard T. Mascola, John R. TI Mechanism of Neutralization by the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01 SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROXIMAL EXTERNAL REGION; ENVELOPE GLYCOPROTEIN; SOLUBLE CD4; OLIGOMERIC STRUCTURE; T4 MOLECULE; GP120; GP41; RECEPTOR; BINDING AB The structure of VRC01 in complex with the HIV-1 gp120 core reveals that this broadly neutralizing CD4 binding site (CD4bs) antibody partially mimics the interaction of the primary virus receptor, CD4, with gp120. Here, we extended the investigation of the VRC01-gp120 core interaction to the biologically relevant viral spike to better understand the mechanism of VRC01-mediated neutralization and to define viral elements associated with neutralization resistance. In contrast to the interaction of CD4 or the CD4bs monoclonal antibody (MAb) b12 with the HIV-1 envelope glycoprotein (Env), occlusion of the VRC01 epitope by quaternary constraints was not a major factor limiting neutralization. Mutagenesis studies indicated that VRC01 contacts within the gp120 loop D, the CD4 binding loop, and the V5 region were necessary for optimal VRC01 neutralization, as suggested by the crystal structure. In contrast to interactions with the soluble gp120 monomer, VRC01 interaction with the native viral spike did not occur in a CD4-like manner; VRC01 did not induce gp120 shedding from the Env spike or enhance gp41 membrane proximal external region (MPER)-directed antibody binding to the Env spike. Finally, VRC01 did not display significant reactivity with human antigens, boding well for potential in vivo applications. The data indicate that VRC01 interacts with gp120 in the context of the functional spike in a manner distinct from that of CD4. It achieves potent neutralization by precisely targeting the CD4bs without requiring alterations of Env spike configuration and by avoiding steric constraints imposed by the quaternary structure of the functional Env spike. C1 [Li, Yuxing; O'Dell, Sijy; Wu, Xueling; Schmidt, Stephen D.; McKee, Krisha; Louder, Mark K.; Ledgerwood, Julie E.; Graham, Barney S.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Walker, Laura M.; Guenaga, Javier; Feng, Yu; Burton, Dennis R.; Wyatt, Richard T.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr TSRI, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Haynes, Barton F.] Duke Univ, Med Ctr, Durham, NC 27710 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM wyatt@scripps.edu; jmascola@nih.gov RI Feng, Yu/A-3396-2012; Schmidt, Stephen/B-5398-2012 FU Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health; International AIDS Vaccine Initiative FX This study was supported by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the International AIDS Vaccine Initiative. NR 76 TC 107 Z9 108 U1 0 U2 19 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 SEP PY 2011 VL 85 IS 17 BP 8954 EP 8967 DI 10.1128/JVI.00754-11 PG 14 WC Virology SC Virology GA 804AO UT WOS:000293626100046 PM 21715490 ER PT J AU Sakakibara, N Mitra, R McBride, AA AF Sakakibara, Nozomi Mitra, Ruchira McBride, Alison A. TI The Papillomavirus E1 Helicase Activates a Cellular DNA Damage Response in Viral Replication Foci SO JOURNAL OF VIROLOGY LA English DT Article ID TYPE-16 E7 ONCOPROTEIN; LARGE T-ANTIGEN; BOVINE PAPILLOMAVIRUS; IN-VIVO; E2 PROTEIN; GENOME INTEGRITY; GROWTH ARREST; S-PHASE; PHOSPHORYLATION; CHECKPOINT AB The papillomavirus E1 and E2 proteins are essential for viral genome replication. E1 is a helicase that unwinds the viral origin and recruits host cellular factors to replicate the viral genome. E2 is a transcriptional regulator that helps recruit the E1 helicase to the origin and also plays a role in genome partitioning. We find that when coexpressed, the E1 and E2 proteins from several papillomavirus types localize to defined nuclear foci and result in growth suppression of the host cells. Growth suppression was due primarily to E1 protein function, and nuclear expression of E1 was accompanied by activation of a DNA damage response, resulting in phosphorylation of ATM, Chk2, and H2AX. Growth suppression and ATM activation required the ATPase and origin-specific binding functions of the E1 protein and resulted in active DNA repair, as evidenced by incorporation of nucleotide analogs and detection of free DNA ends. In the presence of the E2 protein, these activities became localized to nuclear foci. We postulate that these foci represent viral replication factories and that a cellular DNA damage response is activated to facilitate replication of viral DNA. C1 [Sakakibara, Nozomi; Mitra, Ruchira; McBride, Alison A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0455, Bethesda, MD 20892 USA. EM amcbride@nih.gov OI McBride, Alison/0000-0001-5607-5157 FU NIAID, NIH FX This work was funded by the Intramural Research Program of the NIAID, NIH. NR 51 TC 69 Z9 70 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 SEP PY 2011 VL 85 IS 17 BP 8981 EP 8995 DI 10.1128/JVI.00541-11 PG 15 WC Virology SC Virology GA 804AO UT WOS:000293626100048 PM 21734054 ER PT J AU Alexandre, KB Gray, ES Pantophlet, R Moore, PL McMahon, JB Chakauya, E O'Keefe, BR Chikwamba, R Morris, L AF Alexandre, Kabamba Bankoledi Gray, Elin S. Pantophlet, Ralph Moore, Penny L. McMahon, James B. Chakauya, Ereck O'Keefe, Barry R. Chikwamba, Rachel Morris, Lynn TI Binding of the Mannose-Specific Lectin, Griffithsin, to HIV-1 gp120 Exposes the CD4-Binding Site SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; N-LINKED GLYCOSYLATION; ENVELOPE GLYCOPROTEIN GP120; ENTRY INHIBITOR GRIFFITHSIN; SUBTYPE-C; CD4 BINDING; TYPE-1 HIV-1; IN-VITRO; NEUTRALIZING ANTIBODIES AB The glycans on HIV-1 gp120 play an important role in shielding neutralization-sensitive epitopes from antibody recognition. They also serve as targets for lectins that bind mannose-rich glycans. In this study, we investigated the interaction of the lectin griffithsin (GRFT) with HIV-1 gp120 and its effects on exposure of the CD4-binding site (CD4bs). We found that GRFT enhanced the binding of HIV-1 to plates coated with anti-CD4bs antibodies b12 and b6 or the CD4 receptor mimetic CD4-IgG2. The average enhancement of b12 or b6 binding was higher for subtype B viruses than for subtype C, while for CD4-IgG2, it was similar for both subtypes, although lower than observed with antibodies. This GRFT-mediated enhancement of HIV-1 binding to b12 was reflected in synergistic neutralization for 2 of the 4 viruses tested. The glycan at position 386, which shields the CD4bs, was involved in both GRFT-mediated enhancement of binding and neutralization synergism between GRFT and b12. Although GRFT enhanced CD4bs exposure, it simultaneously inhibited ligand binding to the coreceptor binding site, suggesting that GRFT-dependent enhancement and neutralization utilize independent mechanisms. This study shows for the first time that GRFT interaction with gp120 exposes the CD4bs through binding the glycan at position 386, which may have implications for how to access this conserved site. C1 [Alexandre, Kabamba Bankoledi; Gray, Elin S.; Moore, Penny L.; Morris, Lynn] Natl Inst Communicable Dis, AIDS Virus Res Unit, ZA-2131 Johannesburg, South Africa. [Pantophlet, Ralph] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. [Pantophlet, Ralph] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada. [McMahon, James B.; O'Keefe, Barry R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Chakauya, Ereck; Chikwamba, Rachel] Ctr Sci & Ind Res, Pretoria, South Africa. RP Morris, L (reprint author), Natl Inst Communicable Dis, AIDS Virus Res Unit, Private Bag X4, ZA-2131 Johannesburg, South Africa. EM lynnm@nicd.ac.za OI Moore, Penny/0000-0001-8719-4028; Gray, Elin/0000-0002-8613-3570 FU NEPAD; South African AIDS Vaccine Initiative (SAAVI); Fogarty International Center, NIH [D43TW00231]; NIH, National Cancer Institute, Center for Cancer Research FX This work was funded by a Biofisa grant from NEPAD, the South African AIDS Vaccine Initiative (SAAVI), and a training fellowship to K. B. A. from Columbia University-Southern African Fogarty AIDS International Training and Research Programme (AITRP) funded by the Fogarty International Center, NIH (AITRP grant D43TW00231). This research was also supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (B.R.O. and J.B.M.). NR 67 TC 20 Z9 20 U1 4 U2 10 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 SEP PY 2011 VL 85 IS 17 BP 9039 EP 9050 DI 10.1128/JVI.02675-10 PG 12 WC Virology SC Virology GA 804AO UT WOS:000293626100053 PM 21697467 ER PT J AU Race, B Meade-White, K Miller, MW Fox, KA Chesebro, B AF Race, Brent Meade-White, Kimberly Miller, Michael W. Fox, Karen A. Chesebro, Bruce TI In Vivo Comparison of Chronic Wasting Disease Infectivity from Deer with Variation at Prion Protein Residue 96 SO JOURNAL OF VIROLOGY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; WHITE-TAILED DEER; BOVINE SPONGIFORM ENCEPHALOPATHY; TRANSGENIC MICE; INFLUENCE SUSCEPTIBILITY; ODOCOILEUS SPP.; MULE DEER; SCRAPIE; VARIANT; ELK AB Chronic wasting disease (CWD) is a prion disease of cervids that causes neurodegeneration and death. Susceptibility to prion infections, including CWD, can be dependent on the amino acid sequence of the host prion protein (PrP). Here, CWD agent obtained from a deer expressing the 96SS genotype, associated with partial resistance to CWD, was used to infect transgenic (tg) mice expressing either 96GG or 96SS deer PrP. Transgenic mice expressing 96GG deer PrP succumbed to this agent, but tg mice expressing 96SS deer PrP did not. Additional studies using inocula from 96GG deer showed no transmission to 96SS PrP mice and delayed disease in 96GS mice. Thus, 96S PrP played an inhibitory role in disease progression in tg mice. C1 [Race, Brent] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. [Miller, Michael W.; Fox, Karen A.] Colorado Div Wildlife, Ft Collins, CO 80526 USA. RP Race, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM raceb@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, Division of Intramural Research FX Funding for this work was provided by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research. NR 28 TC 6 Z9 6 U1 0 U2 13 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 SEP PY 2011 VL 85 IS 17 BP 9235 EP 9238 DI 10.1128/JVI.00790-11 PG 4 WC Virology SC Virology GA 804AO UT WOS:000293626100072 PM 21697479 ER PT J AU Berger, CT Frahm, N Price, DA Mothe, B Ghebremichael, M Hartman, KL Henry, LM Brenchley, JM Ruff, LE Venturi, V Pereyra, F Sidney, J Sette, A Douek, DC Walker, BD Kaufmann, DE Brander, C AF Berger, Christoph T. Frahm, Nicole Price, David A. Mothe, Beatriz Ghebremichael, Musie Hartman, Kari L. Henry, Leah M. Brenchley, Jason M. Ruff, Laura E. Venturi, Vanessa Pereyra, Florencia Sidney, John Sette, Alessandro Douek, Daniel C. Walker, Bruce D. Kaufmann, Daniel E. Brander, Christian TI High-Functional-Avidity Cytotoxic T Lymphocyte Responses to HLA-B-Restricted Gag-Derived Epitopes Associated with Relative HIV Control SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; HEPATITIS-C VIRUS; CELL RESPONSES; INFECTED-CELLS; VIRAL LOAD; SELECTION PRESSURE; CONSERVED REGIONS; CROSS-RECOGNITION; PERIPHERAL-BLOOD AB Virus-specific cytotoxic T lymphocytes (CTL) with high levels of functional avidity have been associated with viral clearance in hepatitis C virus infection and with enhanced antiviral protective immunity in animal models. However, the role of functional avidity as a determinant of HIV-specific CTL efficacy remains to be assessed. Here we measured the functional avidities of HIV-specific CTL responses targeting 20 different, optimally defined CTL epitopes restricted by 13 different HLA class I alleles in a cohort comprising 44 HIV controllers and 68 HIV noncontrollers. Responses restricted by HLA-B alleles and responses targeting epitopes located in HIV Gag exhibited significantly higher functional avidities than responses restricted by HLA-A or HLA-C molecules (P = 0.0003) or responses targeting epitopes outside Gag (P < 0.0001). The functional avidities of Gag-specific and HLA-B-restricted responses were higher in HIV controllers than in noncontrollers (P = 0.014 and P = 0.018) and were not restored in HIV noncontrollers initiating antiretroviral therapy. T-cell receptor (TCR) analyses revealed narrower TCR repertoires in higher-avidity CTL populations, which were dominated by public TCR sequences in HIV controllers. Together, these data link the presence of high-avidity Gag-specific and HLA-B-restricted CTL responses with viral suppression in vivo and provide new insights into the immune parameters that mediate spontaneous control of HIV infection. C1 [Berger, Christoph T.; Ghebremichael, Musie; Hartman, Kari L.; Henry, Leah M.; Pereyra, Florencia; Walker, Bruce D.; Kaufmann, Daniel E.; Brander, Christian] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Berger, Christoph T.; Ghebremichael, Musie; Hartman, Kari L.; Henry, Leah M.; Pereyra, Florencia; Walker, Bruce D.; Kaufmann, Daniel E.; Brander, Christian] Harvard Univ, Boston, MA 02115 USA. [Frahm, Nicole] Fred Hutchinson Canc Res Ctr, NIAID HIV Vaccine Trials Network HVTN, Seattle, WA 98104 USA. [Price, David A.; Brenchley, Jason M.; Ruff, Laura E.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Price, David A.] Cardiff Univ, Sch Med, Dept Infect Immun & Biochem, Cardiff, S Glam, Wales. [Mothe, Beatriz] Univ Autonoma Badalona, Hosp Germans Trias & Pujol, Lluita Sida Fdn, Barcelona, Spain. [Mothe, Beatriz; Brander, Christian] Hosp Badalona Germans Trias & Pujol, IrsiCaixa AIDS Res Inst HIVACAT, Barcelona, Spain. [Ghebremichael, Musie] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Venturi, Vanessa] Univ New S Wales, Ctr Vasc Res, Computat Biol Grp, Kensington, NSW 2033, Australia. [Sidney, John; Sette, Alessandro] La Jolla Inst Allergy & Immunol, La Jolla, CA USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Brander, Christian] ICREA, Barcelona, Spain. RP Brander, C (reprint author), Hosp Badalona Germans Trias & Pujol, Fdn IrsiCaixa HIVACAT, AIDS Res Inst, Ctra Canyet S-N, Barcelona 08916, Catalonia, Spain. EM cbrander@irsicaixa.es RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Brander, Christian/0000-0002-0548-5778 FU National Institutes of Health [R01 067 077]; Spanish FIPSE [36-0737-09]; University of Basel, Basel, Switzerland; Janggen-Pohn Foundation, Switzerland; FIS, Madrid, Spain [CM08/00020] FX This work was funded by a National Institutes of Health grant to C. B. and D. E. K. (R01 067 077) and in part by the Spanish FIPSE grant 36-0737-09. C. T. B. is supported by a research grant from the University of Basel, Basel, Switzerland, and the Janggen-Pohn Foundation, Switzerland. D. A. P. is a Medical Research Council (United Kingdom) senior clinical fellow. B. M. holds a research fellowship grant from the FIS (Rio Hortega; CM08/00020), Madrid, Spain. C. B. is a senior ICREA research professor. NR 87 TC 64 Z9 65 U1 0 U2 10 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 SEP PY 2011 VL 85 IS 18 BP 9334 EP 9345 DI 10.1128/JVI.00460-11 PG 12 WC Virology SC Virology GA 808DM UT WOS:000293956400008 PM 21752903 ER PT J AU Chen, WZ Feng, Y Gong, R Zhu, ZY Wang, YP Zhao, Q Dimitrov, DS AF Chen, Weizao Feng, Yang Gong, Rui Zhu, Zhongyu Wang, Yanping Zhao, Qi Dimitrov, Dimiter S. TI Engineered Single Human CD4 Domains as Potent HIV-1 Inhibitors and Components of Vaccine Immunogens SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; AIDS-RELATED COMPLEX; HUMAN SOLUBLE CD4; CLASS-II MHC; HUMAN-ANTIBODY; PHASE-I; ENVELOPE GLYCOPROTEIN; MONOCLONAL-ANTIBODY; CRYSTAL-STRUCTURE; FUSION PROTEIN AB Soluble forms of the HIV-1 receptor CD4 (sCD4) have been extensively characterized for more than 2 decades as promising inhibitors and components of vaccine immunogens. However, they were mostly based on the first two CD4 domains (D1D2), and numerous attempts to develop functional, high-affinity, stable soluble one-domain sCD4 (D1) have not been successful because of the strong interactions between the two domains. We have hypothesized that combining the power of structure-based design with sequential panning of large D1 mutant libraries against different HIV-1 envelope glycoproteins (Envs) and screening for soluble mutants could not only help solve the fundamental stability problem of isolated D1, but may also allow improvement of D1 affinity while preserving its cross-reactivity. By using this strategy, we identified two stable monomeric D1 mutants, mD1.1 and mD1.2, which were significantly more soluble and bound Env gp120s more strongly (50-fold) than D1D2, neutralized a panel of HIV-1 primary isolates from different clades more potently than D1D2, induced conformational changes in gp120, and sensitized HIV-1 for neutralization by CD4-induced antibodies. mD1.1 and mD1.2 exhibited much lower binding to human blood cell lines than D1D2; moreover, they preserved a beta-strand secondary structure and stability against thermally induced unfolding, trypsin digestion, and degradation by human serum. Because of their superior properties, mD1.1 and mD1.2 could be potentially useful as candidate therapeutics, components of vaccine immunogens, and research reagents for exploration of HIV-1 entry and immune responses. Our approach could be applied to other cases where soluble isolated protein domains are needed. C1 [Chen, Weizao; Feng, Yang; Gong, Rui; Zhu, Zhongyu; Wang, Yanping; Zhao, Qi; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. [Wang, Yanping] NCI, Basic Res Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. RP Dimitrov, DS (reprint author), Miller Dr,Bldg 469,Room 150B, Frederick, MD 21702 USA. EM dimiter.dimitrov@nih.gov FU National Institutes of Health (NIH); NIH, National Cancer Institute, Center for Cancer Research; Gates Foundation FX This project was supported by the Intramural AIDS Targeted Antiviral Program of the National Institutes of Health (NIH); by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; and by the Gates Foundation (D.S.D.). NR 42 TC 13 Z9 13 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 SEP PY 2011 VL 85 IS 18 BP 9395 EP 9405 DI 10.1128/JVI.05119-11 PG 11 WC Virology SC Virology GA 808DM UT WOS:000293956400014 PM 21715496 ER PT J AU Winstone, N Wilson, AJ Morrow, G Boggiano, C Chiuchiolo, MJ Lopez, M Kemelman, M Ginsberg, AA Mullen, K Coleman, JW Wu, CD Narpala, S Ouellette, I Dean, HJ Lin, F Sardesai, NY Cassamasa, H McBride, D Felber, BK Pavlakis, GN Schultz, A Hudgens, MG King, CR Zamb, TJ Parks, CL McDermott, AB AF Winstone, Nicola Wilson, Aaron J. Morrow, Gavin Boggiano, Cesar Chiuchiolo, Maria J. Lopez, Mary Kemelman, Marina Ginsberg, Arielle A. Mullen, Karl Coleman, John W. Wu, Chih-Da Narpala, Sandeep Ouellette, Ian Dean, Hansi J. Lin, Feng Sardesai, Niranjan Y. Cassamasa, Holly McBride, Dawn Felber, Barbara K. Pavlakis, George N. Schultz, Alan Hudgens, Michael G. King, C. Richter Zamb, Timothy J. Parks, Christopher L. McDermott, Adrian B. TI Enhanced Control of Pathogenic Simian Immunodeficiency Virus SIVmac239 Replication in Macaques Immunized with an Interleukin-12 Plasmid and a DNA Prime-Viral Vector Boost Vaccine Regimen SO JOURNAL OF VIROLOGY LA English DT Article ID IN-VIVO ELECTROPORATION; LOW-DOSE CHALLENGE; T-CELL RESPONSES; RHESUS MACAQUES; DISEASE PROGRESSION; ADENOVIRUS VECTOR; SIV CHALLENGE; HIV-1; EFFECTOR; MONKEYS AB DNA priming has previously been shown to elicit augmented immune responses when administered by electroporation (EP) or codelivered with a plasmid encoding interleukin-12 (pIL-12). We hypothesized that the efficacy of a DNA prime and recombinant adenovirus 5 boost vaccination regimen (DNA/rAd5) would be improved when incorporating these vaccination strategies into the DNA priming phase, as determined by pathogenic simian immunodeficiency virus SIVmac239 challenge outcome. The whole SIVmac239 proteome was delivered in 5 separate DNA plasmids (pDNA-SIV) by EP with or without pIL-12, followed by boosting 4 months later with corresponding rAd5-SIV vaccine vectors. Remarkably, after repeated low-dose SIVmac239 mucosal challenge, we demonstrate 2.6 and 4.4 log reductions of the median SIV peak and set point viral loads in rhesus macaques (RMs) that received pDNA-SIV by EP with pIL-12 compared to the median peak and set point viral loads in mock-immunized controls (P < 0.01). In 5 out of 6 infected RMs, strong suppression of viremia was observed, with intermittent "blips" in virus replication. In 2 RMs, we could not detect the presence of SIV RNA in tissue and lymph nodes, even after 13 viral challenges. RMs immunized without pIL-12 demonstrated a typical maximum of 1.5 log reduction in virus load. There was no significant difference in the overall magnitude of SIV-specific antibodies or CD8 T-cell responses between groups; however, pDNA delivery by EP with pIL-12 induced a greater magnitude of SIV-specific CD4 T cells that produced multiple cytokines. This vaccine strategy is relevant for existing vaccine candidates entering clinical evaluation, and this model may provide insights into control of retrovirus replication. C1 [Winstone, Nicola; Wilson, Aaron J.; Morrow, Gavin; Boggiano, Cesar; Chiuchiolo, Maria J.; Lopez, Mary; Kemelman, Marina; Ginsberg, Arielle A.; Mullen, Karl; Coleman, John W.; Narpala, Sandeep; Ouellette, Ian; Dean, Hansi J.; Schultz, Alan; King, C. Richter; Zamb, Timothy J.; Parks, Christopher L.; McDermott, Adrian B.] Brooklyn Army Terminal, Int AIDS Vaccine Initiat, Design & Dev Lab, Brooklyn, NY 11220 USA. [Wu, Chih-Da; Hudgens, Michael G.] UNC, Gillings Sch Global Publ Hlth, Dept Biostat, Chapel Hill, NC USA. [Lin, Feng; Sardesai, Niranjan Y.] Inovio Pharmaceut, Blue Bell, PA USA. [Cassamasa, Holly; McBride, Dawn] Univ Pittsburgh, RIDC, Pittsburgh, PA USA. [Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. RP Winstone, N (reprint author), Brooklyn Army Terminal, Int AIDS Vaccine Initiat, Design & Dev Lab, 140 58th St, Brooklyn, NY 11220 USA. EM nwinstone@iavi.org FU NIH NIAID [AI054165-08]; NIH, National Cancer Institute, Center for Cancer Research; NIH [5R24RR016038] FX Statistical analyses were partially funded by NIH NIAID R01 grant no. AI054165-08. This research was supported in part by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. Typing for major histocompatibility type I alleles was performed with support from NIH grant 5R24RR016038 awarded to David Watkins. NR 66 TC 45 Z9 46 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 SEP PY 2011 VL 85 IS 18 BP 9578 EP 9587 DI 10.1128/JVI.05060-11 PG 10 WC Virology SC Virology GA 808DM UT WOS:000293956400031 PM 21734035 ER PT J AU Holmes, EC AF Holmes, Edward C. TI What Does Virus Evolution Tell Us About Virus Origins? (vol 85, pg 5247, 2011) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Holmes, Edward C.] Penn State Univ, Mueller Lab, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Mueller Lab, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16802 USA. NR 1 TC 0 Z9 0 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 SEP PY 2011 VL 85 IS 18 BP 9655 EP 9655 DI 10.1128/JVI.05689-11 PG 1 WC Virology SC Virology GA 808DM UT WOS:000293956400040 ER PT J AU Merkle, H Murphy-Boesch, J van Gelderen, P Wang, SM Li, TQ Koretsky, AP Duyn, JH AF Merkle, Hellmut Murphy-Boesch, Joseph van Gelderen, Peter Wang, Shumin Li, Tie-Qiang Koretsky, Alan P. Duyn, Josef H. TI Transmit B-1-Field Correction at 7T Using Actively Tuned Coupled Inner Elements SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE 7T MRI; B-1 field correction; passive B-1 shimming; 7T head phantom ID ARRAYS; COIL; HEAD; EXCITATION; RESONANCE; IMAGES; POWER AB When volume coils are used for H-1 imaging of the human head at 7T, wavelength effects in tissue cause a variation in intensity, that is typically brighter at the center of the head and darker in the periphery. Much of this image nonuniformity can be attributed to variation in the effective transmit B-1 field, which falls by similar to 50% to the left and right of center at mid-elevation in the brain. Because most of this B-1 loss occurs in the periphery of the brain, we have explored use of actively controlled, off-resonant loop elements to locally enhance the transmit B-1 field in these regions. When tuned to frequencies above the NMR frequency, these elements provide strong local enhancement of the B-1 field of the transmit coil. Because they are tuned off-resonance, some volume coil detuning results, but resistive loading of the coil mode remains dominated by the sample. By digitally controlling their frequency offsets, the field enhancement of each inner element can be placed under active control. Using an array of eight digitally controlled elements placed around a custom-built head phantom, we demonstrate the feasibility of improving the B-1 homogeneity of a transmit/receive volume coil without the need for multiple radio frequency transmit channels. Magn Reson Med 66:901-910, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Merkle, Hellmut; Murphy-Boesch, Joseph; van Gelderen, Peter; Wang, Shumin; Li, Tie-Qiang; Koretsky, Alan P.; Duyn, Josef H.] Natl Inst Neurol Disorders & Stroke, NIH, Lab Funct & Mol Imaging, Bethesda, MD USA. [Wang, Shumin] Auburn Univ, Dept Elect & Comp Engn, Auburn, AL 36849 USA. [Li, Tie-Qiang] Karolinska Univ Hosp Huddinge, Dept Med Phys, Stockholm, Sweden. RP Murphy-Boesch, J (reprint author), NINDS, NIH, LFMI, Rm B1D728,10 Ctr Dr, Bethesda, MD 20892 USA. EM murphyboeschj@mail.nih.gov RI Koretsky, Alan/C-7940-2015; OI Koretsky, Alan/0000-0002-8085-4756; Li, Tieqiang/0000-0002-6636-8938; Li, Tie-Qiang/0000-0002-4866-5904 FU National Institute of Neurological Disorders and Stroke, NIH FX This research was supported by the National Institute of Neurological Disorders and Stroke (Intramural Research Program of the NIH). NR 25 TC 4 Z9 4 U1 0 U2 3 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 SEP PY 2011 VL 66 IS 3 BP 901 EP 910 DI 10.1002/mrm.22864 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 808OJ UT WOS:000293988000032 PM 21437974 ER PT J AU Strober, W Watanabe, T AF Strober, W. Watanabe, T. TI NOD2, an intracellular innate immune sensor involved in host defense and Crohn's disease SO MUCOSAL IMMUNOLOGY LA English DT Review ID TOLL-LIKE-RECEPTOR; KAPPA-B ACTIVATION; INFLAMMATORY-BOWEL-DISEASE; MURAMYL DIPEPTIDE; DENDRITIC CELLS; ADAPTIVE IMMUNITY; MYCOBACTERIUM-TUBERCULOSIS; NEGATIVE REGULATION; CYTOKINE PRODUCTION; KINASE-ACTIVITY AB Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular sensor for small peptides derived from the bacterial cell wall component, peptidoglycan. Recent studies have uncovered unexpected functions of NOD2 in innate immune responses such as induction of type I interferon and facilitation of autophagy; moreover, they have disclosed extensive cross-talk between NOD2 and Toll-like receptors, which has an indispensable role both in host defense against microbial infection and in the development of autoimmunity. Of particular interest, polymorphisms of CARD15 encoding NOD2 are associated with Crohn's disease and other autoimmune states such as graft vs. host disease. In this review, we summarize recent findings regarding normal functions of NOD2 and discuss the mechanisms by which NOD2 polymorphisms associated with Crohn's disease lead to intestinal inflammation. C1 [Strober, W.] NIAID, Host Def Lab, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. [Watanabe, T.] Kyoto Univ, Dept Gastroenterol, Kyoto, Japan. RP Strober, W (reprint author), NIAID, Host Def Lab, Mucosal Immun Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Wstrober@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 77 TC 60 Z9 63 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD SEP PY 2011 VL 4 IS 5 BP 484 EP 495 DI 10.1038/mi.2011.29 PG 12 WC Immunology SC Immunology GA 809HC UT WOS:000294041400002 PM 21750585 ER PT J AU Levin, HL Moran, JV AF Levin, Henry L. Moran, John V. TI Dynamic interactions between transposable elements and their hosts SO NATURE REVIEWS GENETICS LA English DT Review ID RNA-POLYMERASE-III; HUMAN L1 RETROTRANSPOSITION; INDEPENDENT LINE-1 RETROTRANSPOSITION; TERMINAL REPEAT RETROTRANSPOSON; POSITION-SPECIFIC INTEGRATION; YEAST TY5 RETROTRANSPOSON; MAMMALIAN GERM-CELLS; EMBRYONIC STEM-CELLS; VIRUS-LIKE PARTICLES; HUMAN GENOME AB Transposable elements (TEs) have a unique ability to mobilize to new genomic locations, and the major advance of second-generation DNA sequencing has provided insights into the dynamic relationship between TEs and their hosts. It now is clear that TEs have adopted diverse strategies - such as specific integration sites or patterns of activity - to thrive in host environments that are replete with mechanisms, such as small RNAs or epigenetic marks, that combat TE amplification. Emerging evidence suggests that TE mobilization might sometimes benefit host genomes by enhancing genetic diversity, although TEs are also implicated in diseases such as cancer. Here, we discuss recent findings about how, where and when TEs insert in diverse organisms. C1 [Levin, Henry L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Eukaryot Transposable Elements, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Moran, John V.] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA. [Moran, John V.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Moran, John V.] Univ Michigan, Sch Med, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. RP Levin, HL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Eukaryot Transposable Elements, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM henry_levin@nih.gov; moranj@umich.edu FU US National Institutes of Health (NIH) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development; Intramural AIDS Targeted Antiviral Program; NIH [GM060518, GM082970] FX We thank J. Kim, J. Garcia-Perez and members of the Moran laboratory for critical reading of the manuscript. H.L.L. was supported in part by the Intramural Research Program of the US National Institutes of Health (NIH) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. He received additional support from the Intramural AIDS Targeted Antiviral Program. J.V.M. was supported in part by grants from the NIH (GM060518 and GM082970) and is an Investigator of the Howard Hughes Medical Institute. NR 192 TC 191 Z9 195 U1 7 U2 51 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD SEP PY 2011 VL 12 IS 9 BP 615 EP 627 DI 10.1038/nrg3030 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 808UH UT WOS:000294004100008 PM 21850042 ER PT J AU Li, YT Li, SC Buck, WR Haskins, ME Wu, SW Khoo, KH Sidransky, E Bunnell, BA AF Li, Yu-Teh Li, Su-Chen Buck, Wayne R. Haskins, Mark E. Wu, Sz-Wei Khoo, Kay-Hooi Sidransky, Ellen Bunnell, Bruce A. TI Selective Extraction and Effective Separation of Galactosylsphingosine (Psychosine) and Glucosylsphingosine from Other Glycosphingolipids in Pathological Tissue Samples SO NEUROCHEMICAL RESEARCH LA English DT Article DE Galactosylsphingosine; Psychosine; Glucosylsphingosine; Krabbe disease; Gaucher disease ID GLOBOID-CELL LEUKODYSTROPHY; TYPE-2 GAUCHER-DISEASE; KRABBE-DISEASE; ACCUMULATION; QUANTIFICATION; CHROMATOGRAPHY; BRAIN; LIVER AB To facilitate the study of the chemical pathology of galactosylsphingosine (psychosine, GalSph) in Krabbe disease and glucosylsphingosine (GlcSph) in Gaucher disease, we have devised a facile method for the effective separation of these two glycosylsphingosines from other glycosphingolipids (GSLs) in Krabbe brain and Gaucher spleen samples. The procedure involves the use of acetone to selectively extract GalSph and GlcSph, respectively, from Krabbe brain and Gaucher spleen samples. Since acetone does not extract other GSLs except modest amounts of galactosylceramide, sulfatide, and glucosylceramide, the positively charged GalSph or GlcSph in the acetone extract can be readily separated from other GSLs by batchwise cation-exchange chromatography using a Waters Accell Plus CM Cartridge. GalSph or GlcSph enriched by this simple procedure can be readily analyzed by thin-layer chromatography or high-performance liquid chromatography. C1 [Li, Yu-Teh; Li, Su-Chen] Tulane Univ, Sch Med, Dept Biochem, New Orleans, LA 70112 USA. [Buck, Wayne R.] Tulane Natl Primate Res Ctr, Dept Pathol, Covington, LA USA. [Haskins, Mark E.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Wu, Sz-Wei; Khoo, Kay-Hooi] Acad Sinica, Inst Biol Chem, Taipei, Taiwan. [Sidransky, Ellen] Natl Genome Res Inst, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD USA. [Bunnell, Bruce A.] Tulane Univ, Sch Med, Ctr Gene Therapy, New Orleans, LA 70112 USA. [Bunnell, Bruce A.] Tulane Natl Primate Res Ctr, Div Gene Therapy, Covington, LA USA. [Bunnell, Bruce A.] Tulane Univ, Sch Med, Dept Pharmacol, New Orleans, LA 70112 USA. RP Li, YT (reprint author), Tulane Univ, Sch Med, Dept Biochem, 1430 Tulane Ave,SL-43, New Orleans, LA 70112 USA. EM yli1@tulane.edu FU NIH [R01 NS09626, RR02512, NCRR R24RR022826]; Louisiana Gene Therapy Research Consortium Tulane University; NSC [NSC98-3112-B-001-023] FX This study was supported by NIH grant R01 NS09626 (to YT Li), NIH grant RR02512 (to ME Haskins), NIH grant NCRR R24RR022826 and Louisiana Gene Therapy Research Consortium Tulane University (to B. Bunnell). The human brain samples from Krabbe patients and the age matched control subjects were obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD. MALDI-MS analyses were performed at the NRPGM Core Facilities for Proteomics and Glycomics, Institute of Biological Chemistry, Academia Sinica, Taiwan, supported by an NSC grant NSC98-3112-B-001-023. NR 19 TC 6 Z9 6 U1 0 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD SEP PY 2011 VL 36 IS 9 SI SI BP 1612 EP 1622 DI 10.1007/s11064-010-0348-3 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 808DO UT WOS:000293956800006 PM 21136152 ER PT J AU Chefer, VI Wang, RZ Shippenberg, TS AF Chefer, Vladimir I. Wang, Ruizhong Shippenberg, Toni S. TI Basolateral Amygdala-Driven Augmentation of Medial Prefrontal Cortex GABAergic Neurotransmission in Response to Environmental Stimuli Associated with Cocaine Administration SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE basolateral amygdala; cocaine; drug-associated environment; glutamate; GABA; medial prefrontal cortex ID VENTRAL TEGMENTAL AREA; ELICITED DRUG SEEKING; BEHAVIORAL SENSITIZATION; GABA TRANSMISSION; RAT; NEURONS; HIPPOCAMPUS; ACTIVATION; ADDICTION; GLUTAMATE AB Basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) interactions have been implicated in cue-elicited craving and drug seeking. However, the neurochemical mechanisms underlying drug/environment associations are ill-defined. We used in vivo microdialysis and pharmacological inactivation techniques to identify alterations in mPFC glutamate (GLU) and gamma-aminobutyric acid (GABA) transmission in response to cues previously associated with experimenter-administered cocaine (COC) and the BLA contribution to these effects. Rats received alternate day injections of COC and saline (SAL) paired with a distinct environment for 6 days. Behavioral, neurochemical and immunohistochemical studies were conducted, in drug-free animals, 24 h after the last conditioning session. Animals exposed to a COC-paired environment demonstrated an augmented locomotor activity (LMA) relative to those exposed to the SAL-paired environment. mPFC GABA neurotransmission in the COC-paired environment was significantly increased, whereas GLU overflow was unaltered. Dual labeling of cFos and glutamic acid decarboxylase 67 immunoreactivity in mPFC neurons revealed significantly greater colocalization of these proteins following exposure to the COC-associated environment (CAE) relative to pseudo-conditioned rats or rats exposed to the SAL-associated environment indicating that the conditioned neurochemical response to the COC-paired environment is associated with activation of intrinsic mPFC GABA neurons. BLA inactivation prevented the increase in LMA and the augmentation of mPFC GABA transmission produced by cue exposure. Intra-mPFC application of the AMPA/KA receptor antagonist, NBQX, produced similar effects. These findings indicate that exposure to a CAE increases mPFC GABA transmission by enhancing excitatory drive from the BLA and activation of AMPA/KA receptors on mPFC GABA neurons. Neuropsychopharmacology (2011) 36, 2018-2029; doi: 10.1038/npp.2011.89; published online 1 June 2011 C1 [Chefer, Vladimir I.; Wang, Ruizhong; Shippenberg, Toni S.] Natl Inst Drug Abuse, Integrat Neurosci Sect, Integrat Neurosci Branch, NIH,Intramural Res Program, Baltimore, MD 21224 USA. RP Chefer, VI (reprint author), Natl Inst Drug Abuse, Integrat Neurosci Sect, Integrat Neurosci Branch, NIH,Intramural Res Program, 333 Cassell Dr, Baltimore, MD 21224 USA. EM vchefer@intra.nida.nih.gov FU US National Institutes of Health; National Institute on Drug Abuse FX This work was supported by the US National Institutes of Health, the National Institute on Drug Abuse Intramural Research Program. NR 42 TC 8 Z9 8 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2011 VL 36 IS 10 BP 2018 EP 2029 DI 10.1038/npp.2011.89 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 807JM UT WOS:000293893100007 PM 21633339 ER PT J AU Lenoir, M Kiyatkin, EA AF Lenoir, Magalie Kiyatkin, Eugene A. TI Critical Role of Peripheral Actions of Intravenous Nicotine in Mediating Its Central Effects SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE electroencephalography; electromyography; field potentials; peripheral nicotinic receptors; sensory signal; learning ID SENSORY NERVE-ENDINGS; ACETYLCHOLINE-RECEPTORS; EEG DESYNCHRONIZATION; NEURONS; RAT; ADDICTION; RESPONSES; BRAIN; CHEMORECEPTORS; MONOMETHIODIDE AB In addition to its direct action on central neurons, nicotine (NIC) activates multiple nicotinic acetylcholine receptors localized on afferent terminals of sensory nerves at the sites of its administration. Although the activation of these receptors is important in mediating the primary sensory and cardiovascular effects of NIC, their role in triggering and maintaining the neural effects of NIC remains unclear. Using high-speed electroencephalography (EEG) and electromyography (EMG) recordings in freely moving rats, we showed that NIC at low intravenous (i.v.) doses (10-30 mu g/kg) induced rapid, strong, and prolonged EEG desynchronization both in the cortex and ventral tegmental area (with decreases in alpha and robust increases in beta and gamma frequencies) and neck EMG activation that began during the injection (similar to 5 s). EEG and EMG effects of NIC were drastically reduced by pre-treatment with hexamethonium, a peripherally acting NIC antagonist, and the immediate EEG effects of NIC were strongly inhibited during urethane anesthesia. Although NIC pyrrolidine methiodide, a quaternary NIC analog that cannot enter the brain, also induced rapid EEG desynchronization, its effects were much shorter and weaker than those of NIC. Therefore, NIC by acting on peripheral nicotinic receptors provides a major contribution to its rapid, excitatory effects following i.v. administration. Since this action creates a sensory signal that rapidly reaches the brain via neural pathways and precedes the slower and more prolonged direct actions of NIC on brain cells, it could have a major role in associative learning and changes in the behavioral and physiological effects of NIC following its repeated use. Neuropsychopharmacology (2011) 36, 2125-2138; doi: 10.1038/npp.2011.104; published online 8 June 2011 C1 [Kiyatkin, Eugene A.] Natl Inst Drug Abuse, In Vivo Electrophysiol Unit, Behav Neurosci Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), Natl Inst Drug Abuse, In Vivo Electrophysiol Unit, Behav Neurosci Branch, Intramural Res Program,NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov FU NIH, NIDA FX The research described in this manuscript was supported by the Intramural Research Program of the NIH, NIDA. We thank Drs Charles Spivak, Serge Ahmed, and Alexey Mukhin for valuable comments regarding scientific issues and Jeremy Tang for assistance in editing of this manuscript. NR 43 TC 9 Z9 9 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2011 VL 36 IS 10 BP 2125 EP 2138 DI 10.1038/npp.2011.104 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 807JM UT WOS:000293893100017 PM 21654739 ER PT J AU Stamatelli, A Saetta, AA Bei, T Kavantzas, N Michalopoulos, NV Patsouris, E Aroni, K AF Stamatelli, Angeliki Saetta, Angelica A. Bei, Thaleia Kavantzas, Nicolaos Michalopoulos, Nicolaos V. Patsouris, Efstratios Aroni, Kiriaki TI B-Raf Mutations, Microsatellite Instability and p53 Protein Expression in Sporadic Basal Cell Carcinomas SO PATHOLOGY & ONCOLOGY RESEARCH LA English DT Article DE Basal cell carcinoma; B-Raf; Microsatellite instability; p53; Skin ID P53-PROTEIN EXPRESSION; HISTOLOGIC VARIANTS; SKIN TUMORS; BRAF GENE; CANCER; TARGETS; DNA AB Basal Cell Carcinoma (BCC) is the most common skin malignancy. Genes related to the Ras/Raf signalling pathway have been implicated in the pathogenesis of skin cancer. The objective of this study was to investigate the presence of B-Raf mutations in sporadic BCCs as well as its correlation with the phenotype of microsatellite instability (MSI), the clinicopathological parameters of the tumours and p53 protein expression. 83 BCC specimens were screened for B-Raf mutations, applying polymerase chain reaction, single-stranded conformation polymorphism (PCR-SSCP) and DNA sequencing. MSI status was examined using mononucleotide microsatellite markers and p53 protein expression was demonstrated by immunohistochemical staining. A C to T transition at 1790 nucleotide leading to a silent mutation L597L; and a T to A transversion causing an amino acid change (F610I) have been found. MSI was detected in 5% of the cases and p53 accumulation was present in 37/83 samples studied. Although rare B-Raf alterations have been observed in BCC, none of them harboured the hot-spot mutation T1799A commonly present in melanomas and colon carcinomas. Consequently, no correlation could be determined between B-Raf alterations, MSI status, the clinicopathological features and p53 protein expression. Our results are in favour of a secondary importance for Ras signalling cascade genes in BCC pathogenesis. C1 [Stamatelli, Angeliki; Saetta, Angelica A.; Kavantzas, Nicolaos; Michalopoulos, Nicolaos V.; Patsouris, Efstratios; Aroni, Kiriaki] Univ Athens, Sch Med, Dept Pathol 1, GR-11527 Athens, Greece. [Bei, Thaleia] NICHHD, Sect Endocrinol & Genet, DEB, NIH, Bethesda, MD 20892 USA. RP Stamatelli, A (reprint author), Univ Athens, Sch Med, Dept Pathol 1, 75 Mikras Asias Str, GR-11527 Athens, Greece. EM agstam@med.uoa.gr NR 29 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1219-4956 J9 PATHOL ONCOL RES JI Pathol. Oncol. Res. PD SEP PY 2011 VL 17 IS 3 BP 633 EP 637 DI 10.1007/s12253-011-9363-1 PG 5 WC Oncology; Pathology SC Oncology; Pathology GA 809OY UT WOS:000294067800024 PM 21274671 ER PT J AU Lin, FYC Weisman, LE Azimi, P Young, AE Chang, K Cielo, M Moyer, P Troendle, JF Schneerson, R Robbins, JB AF Lin, Feng-Ying C. Weisman, Leonard E. Azimi, Parvin Young, Amy E. Chang, Kathleen Cielo, Mikhaela Moyer, Patricia Troendle, James F. Schneerson, Rachel Robbins, John B. TI Assessment of Intrapartum Antibiotic Prophylaxis for the Prevention of Early-onset Group B Streptococcal Disease SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE group B Streptococcus; early onset disease; predictive values; prenatal cultures; intrapartum antibiotic prophylaxis ID POLYMERASE-CHAIN-REACTION; PREDICTIVE VALUE; COLONIZATION; CULTURES; WOMEN; ACCURACY; ERA AB Background: Most early-onset group B streptococcal (GBS) disease in recent years has occurred in newborns of prenatally GBS-negative mothers who missed intrapartum antibiotic prophylaxis (IAP). We aimed to assess the accuracy of prenatal culture in predicting GBS carriage during labor, the IAP use, and occurrence of early-onset GBS disease. Methods: We obtained vaginal-rectal swabs at labor for GBS culture from 5497 women of >= 32 weeks' gestation and surface cultures at birth from newborns between February 5, 2008 and February 4, 2009 at 3 hospitals in Houston, TX and Oakland, CA. Prenatal cultures were performed by a healthcare provider during routine care, and culture results were obtained from medical records. The accuracy of prenatal culture in predicting intrapartum GBS carriage was assessed by positive and negative predictive values. Mother-to-newborn transmission of GBS was assessed. Newborns were monitored for early-onset GBS disease. Results: GBS carriage was 24.5% by prenatal and 18.8% by labor cultures. Comparing prenatal with labor GBS cultures of 4696 women, the positive predictive value was 50.5% and negative predictive value was 91.7%. IAP, administered to 93.3% of prenatally GBS-positive women, was 83.7% effective in preventing newborn's GBS colonization. Mother-to-newborn transmission of GBS occurred in 2.6% of elective cesarean deliveries. Two newborns developed early-onset GBS disease (0.36/1000 births); the prenatal GBS culture of one was negative, the other's was unknown. Conclusions: IAP was effective in interrupting mother-to-newborn transmission of GBS. However, approximately 10% of prenatally GBS-negative women were positive during labor and missed IAP, whereas approximately 50% of prenatally GBS-positive women were negative during labor and received IAP. These findings emphasize the need for rapid diagnostics during labor. C1 [Lin, Feng-Ying C.; Moyer, Patricia; Schneerson, Rachel; Robbins, John B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Lin, Feng-Ying C.; Moyer, Patricia; Schneerson, Rachel; Robbins, John B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. [Weisman, Leonard E.; Young, Amy E.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Weisman, Leonard E.; Young, Amy E.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Azimi, Parvin; Chang, Kathleen; Cielo, Mikhaela] Childrens Hosp & Res Ctr, Oakland, CA USA. [Troendle, James F.] NHLBI, Div Cardiovasc Sci, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Lin, FYC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Res, NIH, 31 Ctr Dr,Rm 2A25, Bethesda, MD 20892 USA. EM Link@mail.nih.gov FU Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX Supported by the Intramural Research Program, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 31 TC 23 Z9 25 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD SEP PY 2011 VL 30 IS 9 BP 759 EP 763 DI 10.1097/INF.0b013e31821dc76f PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 809IF UT WOS:000294044400010 PM 21540758 ER PT J AU Mirochnick, M Nielsen-Saines, K Pilotto, JH Pinto, J Veloso, VG Rossi, S Moye, J Bryson, Y Mofenson, L Camarca, M Watts, DH AF Mirochnick, Mark Nielsen-Saines, Karin Pilotto, Jose Henrique Pinto, Jorge Veloso, Valdilea Goncalves Rossi, Steven Moye, Jack Bryson, Yvonne Mofenson, Lynne Camarca, Margaret Heather Watts, D. CA NICHD HPTN 040-PACTG 1043 PROTOCO TI Nelfinavir and Lamivudine Pharmacokinetics During the First Two Weeks of Life SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE nelfinavir; lamivudine; pharmacokinetics; newborns ID IMMUNODEFICIENCY-VIRUS TYPE-1; HYDROXY-TERT-BUTYLAMIDE; ACTIVE METABOLITE; INFECTED INFANTS; SAFETY; ZIDOVUDINE; INHIBITOR; CHILDREN; AGE AB Background: There are no previous data describing nelfinavir and lamivudine pharmacokinetics in neonates treated with weight-band dosing regimens. Design: Pharmacokinetic study of nelfinavir and lamivudine pharmacokinetics in infants during the first 2 weeks of life treated with weight-band dosing regimens. Methods: Intensive 12-hour pharmacokinetic profiles were performed between either days 4-7 or days 10-14 of life in 26 Brazilian infants. Results: Pharmacokinetic data were obtained from 26 infants who received median (range) per kg doses of 58.8 (48.4-79.0) mg/kg for nelfinavir and 2.0 (1.5-3.2) mg/kg for lamivudine. Median nelfinavir 12-hour AUC (AUC0-12) was 25.5 (1.7-183.5) mu g*h/mL and median 12-hour concentration (C12h) was 1.09 (< 0.04-14.44) mu g/mL. AUC0-12 was less than 15 mu g*h/mL (the 10% for adults) in 12 infants (46%). Median lamivudine AUC0-12 was 7.8 (2.7-15.6) mu g*h/mL and median C12h was 0.23 (< 0.04-0.74) mu g/mL. Conclusions: Lamivudine pharmacokinetic parameters observed in this study were consistent with those seen in other studies of neonates. While median nelfinavir AUC and C12h in these neonates were above the exposure targets, interindividual variability in nelfinavir exposure was large and nelfinavir exposure failed to meet the exposure targets in 46% of infants. C1 [Mirochnick, Mark] Boston Univ, Sch Med, Dept Pediat, Boston Med Ctr, Boston, MA 02118 USA. [Nielsen-Saines, Karin; Bryson, Yvonne] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Pilotto, Jose Henrique] Hosp Geral de Nova Iguacu, Dept Infect Dis, Nova Iguacu, Brazil. [Pilotto, Jose Henrique] Fiocruz MS, Lab AIDS & Imunol Mol, BR-21045900 Rio De Janeiro, Brazil. [Pinto, Jorge] Univ Fed Minas Gerais, Dept Pediat, Div Immunol, Belo Horizonte, MG, Brazil. [Veloso, Valdilea Goncalves] Fiocruz Inst, Inst Pesquias Clin Evandro Chagas, Rio De Janeiro, Brazil. [Rossi, Steven] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA. [Moye, Jack] NICHD, Natl Childrens Study, NIH, DHHS, Bethesda, MD USA. [Mofenson, Lynne; Heather Watts, D.] NICHD, Adolescent & Maternal AIDS Branch, NIH, DHHS, Bethesda, MD USA. [Camarca, Margaret] Westat Corp, Clin Trials Area, Rockville, MD USA. RP Mirochnick, M (reprint author), Boston Univ, Sch Med, Dept Pediat, Boston Med Ctr, 771 Albany St,Dowling 4N,Room 4111, Boston, MA 02118 USA. EM markm@bu.edu RI Goncalves Veloso, Valdilea/J-6189-2012; OI Mofenson, Lynne/0000-0002-2818-9808; moye, john/0000-0001-9976-8586 FU NICHD [HHSN267200800001C, N01-HD-8-0001]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [NO1-HD33345]; HIV Prevention Trials Network (HPTN); (IMPAACT) Group FX Supported by NICHD Contract HHSN267200800001C (NICHD Control N01-HD-8-0001) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract NO1-HD33345), and co-sponsored by the HIV Prevention Trials Network (HPTN) and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group. NR 16 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD SEP PY 2011 VL 30 IS 9 BP 769 EP 772 DI 10.1097/INF.0b013e3182242950 PG 4 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 809IF UT WOS:000294044400012 PM 21666540 ER PT J AU Freeman, AF Marciano, BE Anderson, VL Uzel, G Costas, C Holland, SM AF Freeman, Alexandra F. Marciano, Beatriz E. Anderson, Victoria L. Uzel, Gulbu Costas, Christ Holland, Steven M. TI CORTICOSTEROIDS IN THE TREATMENT OF SEVERE NOCARDIA PNEUMONIA IN CHRONIC GRANULOMATOUS DISEASE SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE chronic granulomatous disease; Nocardia pneumonia ID INFECTION; THERAPY AB Nocardia is 1 of the 5 main pathogens that infect chronic granulomatous disease patients. Despite aggressive antimicrobial therapy, medical treatment is not always successful and surgical resection of infected tissue has been intermittently required. We present 2 chronic granulomatous disease patients with severe Nocardia pneumonia whose pulmonary status worsened despite appropriate antimicrobials, but then improved clinically and radiographically with the addition of corticosteroids. C1 [Freeman, Alexandra F.; Marciano, Beatriz E.; Anderson, Victoria L.; Uzel, Gulbu; Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Costas, Christ] St Francis Hosp, Evanston, IL USA. RP Freeman, AF (reprint author), NIH Bldg 10,Room 11N234,10 Ctr Dr, Bethesda, MD 20892 USA. EM freemaal@niaid.nih.gov FU Division of Intramural Research of the NIAID, NIH, Bethesda, MD FX Supported by the Division of Intramural Research of the NIAID, NIH, Bethesda, MD 20892. NR 11 TC 7 Z9 7 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD SEP PY 2011 VL 30 IS 9 BP 806 EP 808 DI 10.1097/INF.0b013e318218181d PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 809IF UT WOS:000294044400024 PM 21412179 ER PT J AU Mattoo, T Carpenter, M Chesney, R Greenfield, S Hoberman, A Keren, R Mathews, R Moxey-Mims, M AF Mattoo, T. Carpenter, M. Chesney, R. Greenfield, S. Hoberman, A. Keren, R. Mathews, R. Moxey-Mims, M. TI Screening and enrolling children with vesicoureteral reflux: preliminary data from the RIVUR trial SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 [Mattoo, T.] Childrens Hosp Michigan, Detroit, MI USA. [Carpenter, M.] Univ N Carolina, Chapel Hill, NC 27515 USA. [Chesney, R.] Univ Tennessee, Knoxville, TN 37996 USA. [Greenfield, S.] Womens & Childrens Hosp Buffalo, Buffalo, NY USA. [Hoberman, A.; Keren, R.] Childrens Hosp Pittsburgh, Pittsburgh, PA USA. [Mathews, R.] Johns Hopkins Sch Med, Baltimore, MD USA. [Moxey-Mims, M.] NIDDK, NIH, Bethesda, MD USA. 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 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD SEP PY 2011 VL 26 IS 9 BP 1729 EP 1730 PG 2 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 798YT UT WOS:000293248800531 ER PT J AU Bindewald, E Wendeler, M Legiewicz, M Bona, MK Wang, Y Pritt, MJ Le Grice, SFJ Shapiro, BA AF Bindewald, Eckart Wendeler, Michaela Legiewicz, Michal Bona, Marion K. Wang, Yi Pritt, Mark J. Le Grice, Stuart F. J. Shapiro, Bruce A. TI Correlating SHAPE signatures with three-dimensional RNA structures SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE 3D structures; RNA; SHAPE signatures; context sensitivity; probabilistic models ID SELECTIVE 2'-HYDROXYL ACYLATION; SINGLE NUCLEOTIDE RESOLUTION; PRIMER EXTENSION SHAPE; SECONDARY STRUCTURE; RIBOSWITCHES; QUANTIFICATION; CLASSIFICATION; INFORMATION; SOFTWARE AB Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) is a facile technique for quantitative analysis of RNA secondary structure. In general, low SHAPE signal values indicate Watson-Crick base-pairing, and high values indicate positions that are single-stranded within the RNA structure. However, the relationship of SHAPE signals to structural properties such as non-Watson-Crick base-pairing or stacking has thus far not been thoroughly investigated. Here, we present results of SHAPE experiments performed on several RNAs with published three-dimensional structures. This strategy allows us to analyze the results in terms of correlations between chemical reactivities and structural properties of the respective nucleotide, such as different types of base-pairing, stacking, and phosphate-backbone interactions. We find that the RNA SHAPE signal is strongly correlated with cis-Watson-Crick/Watson-Crick base-pairing and is to a remarkable degree not dependent on other structural properties with the exception of stacking. We subsequently generated probabilistic models that estimate the likelihood that a residue with a given SHAPE score participates in base-pairing. We show that several models that take SHAPE scores of adjacent residues into account perform better in predicting base-pairing compared with individual SHAPE scores. This underscores the context sensitivity of SHAPE and provides a framework for an improved interpretation of the response of RNA to chemical modification. C1 [Pritt, Mark J.; Shapiro, Bruce A.] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Bindewald, Eckart; Bona, Marion K.] NCI, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Wendeler, Michaela; Legiewicz, Michal; Wang, Yi; Le Grice, Stuart F. J.] NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Shapiro, BA (reprint author), NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. EM shapirbr@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This work 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 US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 19 Z9 19 U1 0 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 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD SEP PY 2011 VL 17 IS 9 BP 1688 EP 1696 DI 10.1261/rna.2640111 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 808GF UT WOS:000293964600008 PM 21752927 ER PT J AU Hong, SH Osborne, T Ren, L Briggs, J Mazcko, C Burkett, SS Khanna, C AF Hong, S. -H. Osborne, T. Ren, L. Briggs, J. Mazcko, C. Burkett, S. S. Khanna, C. TI Protein kinase C regulates ezrin-radixin-moesin phosphorylation in canine osteosarcoma cells SO VETERINARY AND COMPARATIVE ONCOLOGY LA English DT Article DE dog; ezrin; metastasis; osteosarcoma; PKC ID GENE-EXPRESSION; CARCINOMA-CELLS; LINKER EZRIN; METASTASIS; TUMORS; MODEL; MELANOMA; SURVIVAL; BIOLOGY; DOG AB The development of metastasis is the most significant cause of death for both canine and human patients with osteosarcoma (OS). Ezrin has been associated with tumour progression and metastasis in human, canine and murine OS. Ezrin activation is dynamically regulated by protein kinase C (PKC) during metastatic progression in human and murine OS. To include the dog in the development of therapeutics that target ezrin biology, we characterized four new canine OS cell lines and confirmed the relationship between PKC and ezrin in these cells. Three of four cell lines formed tumours in mice that were histologically consistent with OS. All cell lines were markedly aneuploid and expressed ezrin and PKC. Finally, both ezrin phosphorylation and cell migration were inhibited using a PKC inhibitor. These data suggest that an association between PKC-mediated activation of ezrin and the metastatic phenotype in canine OS cells. C1 [Hong, S. -H.; Osborne, T.; Ren, L.; Briggs, J.; Khanna, C.] NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Mazcko, C.; Khanna, C.] NCI, Comparat Oncol Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Burkett, S. S.] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21701 USA. RP Hong, SH (reprint author), NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM hongsu@mail.nih.gov FU American Kennel Club Canine Health Foundation [1046-A] FX This project was supported by a grant (1046-A) from the American Kennel Club Canine Health Foundation. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the views of the Foundation. NR 29 TC 15 Z9 15 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1476-5810 J9 VET COMP ONCOL JI Vet. Comp. Oncol. PD SEP PY 2011 VL 9 IS 3 BP 207 EP 218 DI 10.1111/j.1476-5829.2010.00249.x PG 12 WC Veterinary Sciences SC Veterinary Sciences GA 808ZH UT WOS:000294020000005 PM 21848623 ER PT J AU Shmulewitz, D Keyes, KM Wall, MM Aharonovich, E Aivadyan, C Greenstein, E Spivak, B Weizman, A Frisch, A Grant, BF Hasin, D AF Shmulewitz, Dvora Keyes, Katherine M. Wall, Melanie M. Aharonovich, Efrat Aivadyan, Christina Greenstein, Eliana Spivak, Baruch Weizman, Abraham Frisch, Amos Grant, Bridget F. Hasin, Deborah TI Nicotine dependence, abuse and craving: dimensionality in an Israeli sample SO ADDICTION LA English DT Article DE DSM-IV; DSM-5; Israel; item response theory; nicotine dependence; nicotine use disorders ID ALCOHOL-USE DISORDERS; ITEM RESPONSE THEORY; NATIONAL EPIDEMIOLOGIC SURVEY; RECENT RUSSIAN IMMIGRANTS; GENERAL-POPULATION SAMPLE; DSM-IV; DIAGNOSTIC-CRITERIA; DRINKING PATTERNS; UNITED-STATES; DRUG-ABUSE AB Aims Evidence-based changes planned for Diagnostic and Statistical Manual 5th edition (DSM-5) substance use disorders (SUDs) include combining dependence and three of the abuse criteria into one disorder and adding a criterion indicating craving. Because DSM-IV did not include a category for nicotine abuse, little empirical support is available for aligning the nicotine use disorder criteria with the DSM-5 criteria for other SUDs. Design Latent variable analyses, bootstrap tests and likelihood ratio tests were used to explore the unidimensionality, psychometric properties and information of the nicotine criteria. Setting and participants A sample of household residents selected from the Israeli population register yielded 727 life-time cigarette smokers. Measurements DSM-IV nicotine dependence criteria and proposed abuse and craving criteria, assessed with a structured interview. Findings Three abuse criteria (hazardous use, social/interpersonal problems and neglect roles) were prevalent among smokers, formed a unidimensional latent trait with nicotine dependence criteria, were intermixed with dependence criteria across the severity spectrum and significantly increased the diagnostic information over the dependence-only model. A craving criterion was shown to fit well with the other criteria. Conclusion Similar to findings from research on other substances, nicotine dependence, abuse and craving criteria appear to derive from a common underlying dimension. The results support alignment of nicotine criteria with those for alcohol and drug use disorders in Diagnostic and Statistical Manual 5th edition. C1 [Shmulewitz, Dvora; Wall, Melanie M.; Aharonovich, Efrat; Hasin, Deborah] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY 10032 USA. [Shmulewitz, Dvora; Keyes, Katherine M.; Wall, Melanie M.; Aharonovich, Efrat; Aivadyan, Christina; Greenstein, Eliana; Hasin, Deborah] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Keyes, Katherine M.; Hasin, Deborah] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Wall, Melanie M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY 10032 USA. [Spivak, Baruch; Weizman, Abraham; Frisch, Amos] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Weizman, Abraham; Frisch, Amos] Felsenstein Med Res Ctr, Petah Tiqwa, Israel. [Weizman, Abraham] Geha Mental Hlth Ctr, Res Unit, Petah Tiqwa, Israel. [Grant, Bridget F.] Natl Inst Alcohol Abuse & Alcoholism, Lab Epidemiol & Biometry, Bethesda, MD USA. RP Hasin, D (reprint author), Columbia Univ, Dept Psychiat, Coll Phys & Surg, 1051 Riverside Dr 123, New York, NY 10032 USA. EM dsh2@columbia.edu FU National Institutes of Health [R01AA013654, R01DA018652, K05AA014223, F31DA026689, K23DA016743]; New York State Psychiatric Institute FX This research was funded by National Institutes of Health grants R01AA013654, R01DA018652, K05AA014223 (Hasin), F31DA026689 (Keyes), K23DA016743 (Aharonovich) and the New York State Psychiatric Institute (Hasin). We would like to acknowledge the helpful consultations of Rachel Bar-Hamburger PhD, Rina Meyer and Zalman Shoval in collecting the data in Israel, and extensive input from the DSM-5 Substance Disorders Work-group, who reviewed and approved the questions included in the analyses, and discussed earlier versions of the analyses and text in a series of conference calls. NR 67 TC 13 Z9 13 U1 6 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD SEP PY 2011 VL 106 IS 9 BP 1675 EP 1686 DI 10.1111/j.1360-0443.2011.03484.x PG 12 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 803YP UT WOS:000293619300022 PM 21545668 ER PT J AU Dawson, DA AF Dawson, Deborah A. TI RISKY SINGLE-OCCASION DRINKING SO ADDICTION LA English DT Letter C1 NIAAA, NIH, Bethesda, MD USA. RP Dawson, DA (reprint author), NIAAA, NIH, Bethesda, MD USA. EM ddawson@willco.niaaa.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD SEP PY 2011 VL 106 IS 9 BP 1709 EP 1710 DI 10.1111/j.1360-0443.2011.03530.x PG 3 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 803YP UT WOS:000293619300028 PM 21714824 ER PT J AU Sanders-Beer, BE Hirsch, VM AF Sanders-Beer, B. E. Hirsch, V. M. TI EVOLUTIONARY HISTORY OF PRIMATE LENTIVIRUSES IN OLD WORLD MONKEYS (CERCOPITHECIDAE) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the American-Society-of-Primatologists CY SEP 16-19, 2011 CL Austin, TX SP Amer Soc Primatol C1 [Sanders-Beer, B. E.] BIOQUAL Inc, Rockville, MD 20850 USA. [Hirsch, V. M.] NIAID, Mol Microbiol Lab, NIH, 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2011 VL 73 SU 1 MA 48 BP 46 EP 46 PG 1 WC Zoology SC Zoology GA 805XO UT WOS:000293764600043 ER PT J AU Hipps, A Maxwell, WF Page, H Suomi, SJ Barr, CS Schwandt, ML Higley, JD AF Hipps, A. Maxwell, W. F. Page, H. Suomi, S. J. Barr, C. S. Schwandt, M. L. Higley, J. D. TI EFFECT OF SOCIAL SEPARATION ON MOTHER-DAUGHTER RELATIONSHIPS IN INFANT RHESUS MACAQUES SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the American-Society-of-Primatologists CY SEP 16-19, 2011 CL Austin, TX SP Amer Soc Primatol C1 [Hipps, A.; Maxwell, W. F.; Page, H.; Higley, J. D.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Barr, C. S.; Schwandt, M. L.] NIAAA, NIH, LCS, Bethesda, MD USA. [Suomi, S. J.] NICHD, NIH, LCE, 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2011 VL 73 SU 1 MA 92 BP 61 EP 61 PG 1 WC Zoology SC Zoology GA 805XO UT WOS:000293764600087 ER PT J AU Jensen, MB Chaffin, AC Barr, CS Schwandt, ML Suomi, SJ Higley, JD AF Jensen, M. B. Chaffin, A. C. Barr, C. S. Schwandt, M. L. Suomi, S. J. Higley, J. D. TI MOTHER-INFANT SEPARATION IS ASSOCIATED WITH LATER PATHOLOGICAL BEHAVIORS SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the American-Society-of-Primatologists CY SEP 16-19, 2011 CL Austin, TX SP Amer Soc Primatol C1 [Jensen, M. B.; Chaffin, A. C.; Higley, J. D.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Barr, C. S.; Schwandt, M. L.; Suomi, S. J.] NICHD, NIH, Bethesda, MD USA. [Barr, C. S.; Schwandt, M. L.; Suomi, S. J.] NIAAA, 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2011 VL 73 SU 1 MA 94 BP 62 EP 62 PG 1 WC Zoology SC Zoology GA 805XO UT WOS:000293764600089 ER PT J AU Paukner, A Suomi, SJ AF Paukner, A. Suomi, S. J. TI FUR RUBBING AFFECTS SUBSEQUENT SOCIAL BEHAVIOR IN CAPTIVE CAPUCHIN MONKEYS (CEBUS APELLA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the American-Society-of-Primatologists CY SEP 16-19, 2011 CL Austin, TX SP Amer Soc Primatol C1 [Paukner, A.; Suomi, S. J.] NIH Anim Ctr, Comparat Ethol Lab, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 1 U2 5 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 SEP PY 2011 VL 73 SU 1 MA 108 BP 66 EP 66 PG 1 WC Zoology SC Zoology GA 805XO UT WOS:000293764600103 ER PT J AU Bower, S Ferrari, PF Vanderwert, R Paukner, A Suomi, SJ Fox, NA AF Bower, S. Ferrari, P. F. Vanderwert, R. Paukner, A. Suomi, S. J. Fox, N. A. TI NEUROPHYSIOLOGICAL EVIDENCE FOR A MIRROR NEURON SYSTEM IN NEWBORN RHESUS MACAQUES SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the American-Society-of-Primatologists CY SEP 16-19, 2011 CL Austin, TX SP Amer Soc Primatol C1 [Bower, S.; Paukner, A.; Suomi, S. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH Anim Ctr, Dickerson, MD 20842 USA. [Ferrari, P. F.] Univ Parma, Dipartimento Biol Evolut & Funz, I-43100 Parma, Italy. [Ferrari, P. F.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. [Ferrari, P. F.] Italian Inst Technol, IIT, Parma, Italy. [Vanderwert, R.; Fox, N. A.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2011 VL 73 SU 1 MA 178 BP 91 EP 91 PG 1 WC Zoology SC Zoology GA 805XO UT WOS:000293764600179 ER PT J AU Chaffin, AC Blocker, DJ Barr, C Schwandt, ML Chefer, S Stein, E Suomi, SJ Higley, JD AF Chaffin, A. C. Blocker, D. J. Barr, C. Schwandt, M. L. Chefer, S. Stein, E. Suomi, S. J. Higley, J. D. TI BRAIN STRUCTURES ASSOCIATED WITH TEMPERAMENT AND SOCIAL BEHAVIOR IN RHESUS MONKEYS SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the American-Society-of-Primatologists CY SEP 16-19, 2011 CL Austin, TX SP Amer Soc Primatol C1 [Chaffin, A. C.; Blocker, D. J.; Higley, J. D.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Barr, C.; Schwandt, M. L.; Chefer, S.; Stein, E.; Suomi, S. J.] NICHD, NIH, NIAAA, Bethesda, MD USA. [Barr, C.; Schwandt, M. L.; Chefer, S.; Stein, E.; Suomi, S. J.] NIDA, 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2011 VL 73 SU 1 MA 179 BP 92 EP 92 PG 1 WC Zoology SC Zoology GA 805XO UT WOS:000293764600180 ER PT J AU Orgad, K Gibson, MS Chaffin, AC Suomi, SJ Barr, CS Schwandt, ML Higley, JD AF Orgad, K. Gibson, M. S. Chaffin, A. C. Suomi, S. J. Barr, C. S. Schwandt, M. L. Higley, J. D. TI EARLY TEMPERAMENT PREDICTS ALCOHOL INTAKE IN GROUP-HOUSED RHESUS MACAQUES SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the American-Society-of-Primatologists CY SEP 16-19, 2011 CL Austin, TX SP Amer Soc Primatol C1 [Orgad, K.; Gibson, M. S.; Chaffin, A. C.; Higley, J. D.] Brigham Young Univ, Dept Psychol & Neurosci, Provo, UT 84602 USA. [Barr, C. S.; Schwandt, M. L.] NIAAA, NIH Anim Ctr, LCTS, Bethesda, MD USA. [Suomi, S. J.] NICHD, NIH Anim Ctr, LCE, 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2011 VL 73 SU 1 MA 180 BP 92 EP 92 PG 1 WC Zoology SC Zoology GA 805XO UT WOS:000293764600181 ER PT J AU Suarez-Jimenez, B Hathaway, A Waters, C Vaughan, K Suomi, SJ Noble, P Nelson, E AF Suarez-Jimenez, B. Hathaway, A. Waters, C. Vaughan, K. Suomi, S. J. Noble, P. Nelson, E. TI EFFECT OF MOTHER'S DOMINANCE RANK ON OFFSPRING TEMPERAMENT IN INFANT RHESUS MONKEYS (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the American-Society-of-Primatologists CY SEP 16-19, 2011 CL Austin, TX SP Amer Soc Primatol C1 [Suarez-Jimenez, B.; Hathaway, A.; Waters, C.; Vaughan, K.; Noble, P.; Nelson, E.] NIMH, NIH, Bethesda, MD 20892 USA. [Suomi, S. J.] NICHD, 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD SEP PY 2011 VL 73 SU 1 MA 182 BP 93 EP 93 PG 1 WC Zoology SC Zoology GA 805XO UT WOS:000293764600183 ER PT J AU Songrady, JC Suomi, SJ Egan, LC Paukner, A AF Songrady, J. C. Suomi, S. J. Egan, L. C. Paukner, A. TI THE EFFECTS OF EXTRINSIC REWARD ON INTRINSIC MOTIVATION IN INFANT RHESUS MACAQUES (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the American-Society-of-Primatologists CY SEP 16-19, 2011 CL Austin, TX SP Amer Soc Primatol C1 [Songrady, J. C.; Suomi, S. J.; Paukner, A.] NIH, Anim Ctr, Dickerson, MD 20842 USA. [Songrady, J. C.; Suomi, S. J.; Paukner, A.] NICHHD, Bethesda, MD USA. [Egan, L. C.] Northwestern Univ, Kellogg Sch Management, Evanston, IL 60208 USA. NR 0 TC 0 Z9 0 U1 1 U2 6 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 SEP PY 2011 VL 73 SU 1 MA 188 BP 95 EP 95 PG 1 WC Zoology SC Zoology GA 805XO UT WOS:000293764600189 ER PT J AU Pilkonis, PA Choi, SW Reise, SP Stover, AM Riley, WT Cella, D AF Pilkonis, Paul A. Choi, Seung W. Reise, Steven P. Stover, Angela M. Riley, William T. Cella, David CA PROMIS Cooperative Grp TI Item Banks for Measuring Emotional Distress From the Patient-Reported Outcomes Measurement Information System (PROMIS (R)): Depression, Anxiety, and Anger SO ASSESSMENT LA English DT Article DE depression; anxiety; anger; item response theory; measurement ID COMPUTERIZED ADAPTIVE ASSESSMENT; QUALITY-OF-LIFE; RESPONSE THEORY; TRIPARTITE MODEL; SHORT-FORMS; BIFACTOR ANALYSIS; SYMPTOM STRUCTURE; MENTAL-DISORDERS; BECK DEPRESSION; MOOD DISORDERS AB The authors report on the development and calibration of item banks for depression, anxiety, and anger as part of the Patient-Reported Outcomes Measurement Information System (PROMIS (R)). Comprehensive literature searches yielded an initial bank of 1,404 items from 305 instruments. After qualitative item analysis (including focus groups and cognitive interviewing), 168 items (56 for each construct) were written in a first person, past tense format with a 7-day time frame and five response options reflecting frequency. The calibration sample included nearly 15,000 respondents. Final banks of 28, 29, and 29 items were calibrated for depression, anxiety, and anger, respectively, using item response theory. Test information curves showed that the PROMIS item banks provided more information than conventional measures in a range of severity from approximately -1 to +3 standard deviations (with higher scores indicating greater distress). Short forms consisting of seven to eight items provided information comparable to legacy measures containing more items. C1 [Pilkonis, Paul A.; Stover, Angela M.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Choi, Seung W.; Cella, David] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Reise, Steven P.] Univ Calif Los Angeles, Los Angeles, CA USA. [Riley, William T.] NHLBI, Bethesda, MD 20892 USA. RP Pilkonis, PA (reprint author), Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA USA. EM pilkonispa@upmc.edu FU NCATS NIH HHS [UL1 TR000005]; NIAMS NIH HHS [U01AR52171, U01 AR052155, U01 AR052155-06, U01 AR052158, U01 AR052170, U01 AR052171, U01 AR052177, U01 AR052181, U01 AR052186, U01AR52155, U01AR52158, U01AR52170, U01AR52177, U01AR52181, U01AR52186] NR 110 TC 189 Z9 189 U1 12 U2 25 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-1911 J9 ASSESSMENT JI Assessment PD SEP PY 2011 VL 18 IS 3 BP 263 EP 283 DI 10.1177/1073191111411667 PG 21 WC Psychology, Clinical SC Psychology GA 804AF UT WOS:000293624700001 PM 21697139 ER PT J AU Wang, YY Xiang, J Vannest, J Holroyd, T Narmoneva, D Horn, P Liu, YH Rose, D deGrauw, T Holland, S AF Wang, Yingying Xiang, Jing Vannest, Jennifer Holroyd, Tom Narmoneva, Daria Horn, Paul Liu, Yinhong Rose, Douglas deGrauw, Ton Holland, Scott TI Neuromagnetic measures of word processing in bilinguals and monolinguals SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Magnetoencephalography; Word processing; Bilinguals; Monolinguals; Frequency; Oscillation ID 2ND-LANGUAGE LEARNERS; FREQUENCY DIFFERENCES; CEREBRAL ASYMMETRY; LEXICAL DECISION; BRAIN ACTIVITY; LANGUAGE; CHINESE; OSCILLATIONS; ENGLISH; MAGNETOENCEPHALOGRAPHY AB Objective: This study aimed to use magnetoencephalography (MEG) to examine the question of whether Mandarin-English bilingual speakers recruit the same cortical areas or develop distinct language-specific networks without overlaps for word processing. Methods: Eight healthy Mandarin-English bilingual adults and eight healthy English monolingual adults were scanned while single-word paradigms were audio-visually presented. Results: Our results showed significantly stronger beta-band power suppression in the right inferior parietal lobe (IPL) covering the supramarginal gyrus (BA 40) and angular gyrus (BA 39) for bilinguals when processing Mandarin versus English. Moreover, there were no significant differences between bilinguals and monolinguals in the left inferior frontal cortex (LIFC, BA 44/45) when both were processing their first language. Conclusions: These results support the view that Mandarin-English bilinguals have a shared neural system for word processing in both the first and second language, which is highly similar to monolinguals', but with stronger right hemisphere involvement. Significance: To our knowledge, this is the first MEG study to investigate the spatio-temporal and frequency characteristics between bilinguals and monolinguals, which provides us a new angle to better understand the language system in bilinguals' and monolingual's brain. (C) 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Wang, Yingying; Narmoneva, Daria] Univ Cincinnati, Dept Biomed Engn, Cincinnati, OH USA. [Wang, Yingying; Xiang, Jing; Vannest, Jennifer; Horn, Paul; Rose, Douglas; deGrauw, Ton] Cincinnati Childrens Hosp Med Ctr, Div Neurol, Cincinnati, OH USA. [Wang, Yingying; Vannest, Jennifer; Holland, Scott] Cincinnati Childrens Hosp Res Fdn, Pediat Neuroimaging Res Consortium, Cincinnati, OH USA. [Holroyd, Tom] NIMH, MEG Core Facil, Bethesda, MD 20892 USA. [Horn, Paul] Univ Cincinnati, Dept Math Sci, Cincinnati, OH 45221 USA. [Liu, Yinhong] Beijing Hosp, Minist Hlth, Dept Neurol, Beijing, Peoples R China. RP Wang, YY (reprint author), MLC 5033,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM yingying.wang@cchmc.org RI Wang, Yingying/A-4694-2011; OI Holland, Scott/0000-0003-3719-0875 FU Cincinnati Children's Hospital Medical Centre, Cincinnati, OH, USA FX This study was supported by a Trustee Grant to Dr. Jing Xiang from Cincinnati Children's Hospital Medical Centre, Cincinnati, OH, USA. We would like to thank Dr. David Brown for his help in audio recording and Ms. Akhila Rajagopal for her help in statistical analysis. Also we would like to thank Mr. Kendall O'Brien for his technical help in performing all the MRI scans. NR 66 TC 11 Z9 11 U1 3 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD SEP PY 2011 VL 122 IS 9 BP 1706 EP 1717 DI 10.1016/j.clinph.2011.02.008 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 799EU UT WOS:000293267800005 PM 21414839 ER PT J AU Angerer, LM Yaguchi, S Angerer, RC Burke, RD AF Angerer, Lynne M. Yaguchi, Shunsuke Angerer, Robert C. Burke, Robert D. TI The evolution of nervous system patterning: insights from sea urchin development SO DEVELOPMENT LA English DT Review DE Wnt; TGF beta; Nodal; BMP; Dorsal-ventral axis; Anterior-posterior axis; Lefty; Chordin; Six3; FoxQ2; Ciliary band; Apical organ; Ectoderm patterning; Neural development; Neural patterning ID ORAL-ABORAL AXIS; NUCLEAR BETA-CATENIN; EMBRYONIC STEM-CELLS; ANIMAL-VEGETAL AXIS; STRONGYLOCENTROTUS-PURPURATUS; NEURAL INDUCTION; GENE NETWORK; REGULATORY ANALYSIS; FATE SPECIFICATION; MESODERM INDUCTION AB Recent studies of the sea urchin embryo have elucidated the mechanisms that localize and pattern its nervous system. These studies have revealed the presence of two overlapping regions of neurogenic potential at the beginning of embryogenesis, each of which becomes progressively restricted by separate, yet linked, signals, including Wnt and subsequently Nodal and BMP. These signals act to specify and localize the embryonic neural fields - the anterior neuroectoderm and the more posterior ciliary band neuroectoderm - during development. Here, we review these conserved nervous system patterning signals and consider how the relationships between them might have changed during deuterostome evolution. C1 [Angerer, Lynne M.; Angerer, Robert C.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Yaguchi, Shunsuke] Univ Tsukuba, Shimoda Marine Res Ctr, Shimoda 4150025, Japan. [Burke, Robert D.] Univ Victoria, Biochem Microbiol Dept, Victoria, BC V3P 5C2, Canada. RP Angerer, LM (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. EM langerer@mail.nih.gov OI Yaguchi, Shunsuke/0000-0002-8326-5762; Burke, Robert/0000-0001-5527-4410 FU Division of Intramural Research in the National Institute for Dental and Craniofacial Research, National Institutes of Health; Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (MEXT); NSERC FX We thank Adi Sethi, Diane Adams and Ryan Range for discussions and especially Zheng Wei for experimental and bioinformatic contributions. Support for this work was provided by the Division of Intramural Research in the National Institute for Dental and Craniofacial Research, National Institutes of Health (L.M.A. and R.C.A.), Special Coordination Funds for Promoting Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (MEXT), by a Grant-in Aid for Young Scientists (Start-up) (S.Y.) and NSERC (R.D.B.). Deposited in PMC for release after 12 months. NR 105 TC 44 Z9 44 U1 3 U2 35 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP 1 PY 2011 VL 138 IS 17 BP 3613 EP 3623 DI 10.1242/dev.058172 PG 11 WC Developmental Biology SC Developmental Biology GA 804XG UT WOS:000293687700002 PM 21828090 ER PT J AU Lim, AH Suli, A Yaniv, K Weinstein, B Li, DY Chien, CB AF Lim, Amy H. Suli, Arminda Yaniv, Karina Weinstein, Brant Li, Dean Y. Chien, Chi-Bin TI Motoneurons are essential for vascular pathfinding SO DEVELOPMENT LA English DT Article DE Netrin; DCC; Lymphatic; Parachordal chain; Motoneuron; Axon guidance; Vascular guidance; Angiogenesis; Zebrafish ID INHIBITS SPROUTING ANGIOGENESIS; NETRIN RECEPTOR; ZEBRAFISH EMBRYO; IN-VIVO; LYMPHATIC DEVELOPMENT; GUIDANCE CUES; AXON GUIDANCE; UNC5B; DCC; EXPRESSION AB The neural and vascular systems share common guidance cues that have direct and independent signaling effects on nerves and endothelial cells. Here, we show that zebrafish Netrin 1a directs Dcc-mediated axon guidance of motoneurons and that this neural guidance function is essential for lymphangiogenesis. Specifically, Netrin 1a secreted by the muscle pioneers at the horizontal myoseptum (HMS) is required for the sprouting of dcc-expressing rostral primary motoneuron (RoP) axons and neighboring axons along the HMS, adjacent to the future trajectory of the parachordal chain (PAC). These axons are required for the formation of the PAC and, subsequently, the thoracic duct. The failure to form the PAC in netrin 1a or dcc morphants is phenocopied by laser ablation of motoneurons and is rescued both by cellular transplants and overexpression of dcc mRNA. These results provide a definitive example of the requirement of axons in endothelial guidance leading to the parallel patterning of nerves and vessels in vivo. C1 [Lim, Amy H.; Li, Dean Y.] Univ Utah, Program Mol Med, Salt Lake City, UT 84112 USA. [Lim, Amy H.; Suli, Arminda; Chien, Chi-Bin] Univ Utah, Dept Neurobiol & Anat, Salt Lake City, UT 84132 USA. [Yaniv, Karina] Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel. [Weinstein, Brant] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Li, Dean Y.] Univ Utah, Dept Med, Div Cardiol, Salt Lake City, UT 84132 USA. [Li, Dean Y.] Univ Utah, Dept Oncol Sci, Salt Lake City, UT 84112 USA. RP Li, DY (reprint author), Univ Utah, Program Mol Med, 15 N 2030 East,Room 4140, Salt Lake City, UT 84112 USA. EM dean.li@u2m2.utah.edu OI Suli, Arminda/0000-0003-2690-8407 FU NHLBI; NIH (NICHD) FX We thank D. Lim for graphical assistance; Hideo Otsuna for help with FluoRender; K. Thomas, F. Poulain, N. London, K. Kwan and A. Chan for critical reading of this manuscript; S. Hutchinson, L. Hale and J. Eisen for helpful discussions; G. King and the Centralized Zebrafish Animal Resource Facility; C. Rodesch, K. Carney and the Cell Imaging Core; Xiaoming Sheng at the Biostatistics Core for help with statistical analysis; M. Granato, J. Yost and N. Lawson for fish; L. Hale and J. Eisen for isl1 morpholinos; B. Appel for olig2 morpholino; Uwe Strahle for a partial netrin 1a clone; and M. Jurynec and D. Grunwald for the 4D9 antibody and cyclopamine. Funding: D.Y.L. and C.-B.C., NHLBI; B.W., Intramural Research Program of the NIH (NICHD). Deposited in PMC for release after 12 months. NR 58 TC 24 Z9 24 U1 0 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP 1 PY 2011 VL 138 IS 17 BP 3847 EP 3857 DI 10.1242/dev.068403 PG 11 WC Developmental Biology SC Developmental Biology GA 804XG UT WOS:000293687700023 PM 21828101 ER PT J AU Lauer, MS Hodes, R AF Lauer, Michael S. Hodes, Richard TI Epidemiology, Comparative Effectiveness Research, and the National Institutes of Health Forces for Health SO EPIDEMIOLOGY LA English DT Editorial Material ID CORONARY HEART-DISEASE; IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; TYPE-2 DIABETES-MELLITUS; OUTCOMES; PREVENTION; MORTALITY; TRIAL; RISK; INTERVENTION; PROGRAM C1 [Lauer, Michael S.] NHLBI, Off Director, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Hodes, Richard] NIA, Off Director, NIH, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 FU Intramural NIH HHS [Z99 HL999999] NR 25 TC 3 Z9 4 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2011 VL 22 IS 5 BP 625 EP 628 DI 10.1097/EDE.0b013e3182262ac6 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 801NT UT WOS:000293447500005 PM 21811109 ER PT J AU Saha-Chaudhuri, P Umbach, DM Weinberg, CR AF Saha-Chaudhuri, Paramita Umbach, David M. Weinberg, Clarice R. TI Pooled Exposure Assessment for Matched Case-control Studies SO EPIDEMIOLOGY LA English DT Article ID POPULATIONS; BIOMARKERS; COHORTS; BLOOD; SERA; RISK AB Exposure assessment using biologic specimens is important for epidemiology but may become impracticable if assays are expensive, specimen volumes are marginally adequate, or analyte levels fall below the limit of detection. Pooled exposure assessment can provide an effective remedy for these problems in unmatched case-control studies. We extend pooled exposure strategies to handle specimens collected in a matched case-control study. We show that if a logistic model applies to individuals, then a logistic model also applies to an analysis using pooled exposures. Consequently, the individual-level odds ratio can be estimated while conserving both cost and specimen. We discuss appropriate pooling strategies for a single exposure, with adjustment for multiple, possibly continuous, covariates (confounders) and assessment of effect modification by a categorical variable. We assess the performance of the approach via simulations and conclude that pooled strategies can markedly improve efficiency for matched as well as unmatched case-control studies. (Epidemiology 2011; 22: 704-712) C1 [Saha-Chaudhuri, Paramita; Umbach, David M.; Weinberg, Clarice R.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Saha-Chaudhuri, P (reprint author), NIEHS, Biostat Branch, POB 12233,Mail Drop A3-03,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM sahap@niehs.nih.gov RI Saha Chaudhuri, Paramita/F-3835-2010; OI Saha Chaudhuri, Paramita/0000-0003-1987-320X FU NIH, National Institute of Environmental Health Sciences [ES040006-14] FX Supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (project ES040006-14). NR 20 TC 6 Z9 6 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2011 VL 22 IS 5 BP 704 EP 712 DI 10.1097/EDE.0b013e318227af1a PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 801NT UT WOS:000293447500016 PM 21747285 ER PT J AU Schoonjans, F De Bacquer, D Schmid, P AF Schoonjans, Frank De Bacquer, Dirk Schmid, Pirmin TI Estimation of Population Percentiles SO EPIDEMIOLOGY LA English DT Letter C1 [Schoonjans, Frank] Ghent Univ Hosp, Dept Endocrinol, B-9000 Ghent, Belgium. [Schoonjans, Frank] MedCalc Software Bvba, Mariakerke, Belgium. [De Bacquer, Dirk] Univ Ghent, Dept Publ Hlth, B-9000 Ghent, Belgium. [Schmid, Pirmin] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Schoonjans, F (reprint author), Ghent Univ Hosp, Dept Endocrinol, B-9000 Ghent, Belgium. EM frank.schoonjans@ugent.be FU Intramural NIH HHS [Z99 CL999999] NR 6 TC 8 Z9 9 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2011 VL 22 IS 5 BP 750 EP 751 DI 10.1097/EDE.0b013e318225c1de PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 801NT UT WOS:000293447500027 PM 21811118 ER PT J AU Noureddin, M Kleiner, DE Gharib, AM Bratslavsky, G Heller, T AF Noureddin, Mazen Kleiner, David E. Gharib, Ahmed M. Bratslavsky, Gennady Heller, Theo TI To resect or not to resect? That is the question SO GUT LA English DT Editorial Material ID LIVER C1 [Noureddin, Mazen; Heller, Theo] NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Gharib, Ahmed M.] NIDDK, Integrat Cardiovasc Imaging Sect, NIH, Bethesda, MD 20892 USA. [Bratslavsky, Gennady] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Noureddin, M (reprint author), NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. EM noureddinm@niddk.nih.gov RI Gharib, Ahmed/O-2629-2016; OI Gharib, Ahmed/0000-0002-2476-481X; Kleiner, David/0000-0003-3442-4453 FU Intramural NIH HHS [Z99 DK999999, ZIA DK075083-01] NR 4 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 0017-5749 J9 GUT JI Gut PD SEP PY 2011 VL 60 IS 9 BP 1177 EP + DI 10.1136/gut.2010.221440 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 803NS UT WOS:000293588600005 PM 20965874 ER PT J AU Vogel-Claussen, J Shehata, ML Lossnitzer, D Skrok, J Singh, S Boyce, D Lechtzin, N Girgis, RE Mathai, SC Lima, JA Bluemke, DA Hassoun, PM AF Vogel-Claussen, Jens Shehata, Monda L. Lossnitzer, Dirk Skrok, Jan Singh, Sukhminder Boyce, Danielle Lechtzin, Noah Girgis, Reda E. Mathai, Stephen C. Lima, Joao A. Bluemke, David A. Hassoun, Paul M. TI Increased Right Ventricular Septomarginal Trabeculation Mass is a Novel Marker for Pulmonary Hypertension Comparison With Ventricular Mass Index and Right Ventricular Mass SO INVESTIGATIVE RADIOLOGY LA English DT Article DE cardiac MRI; pulmonary hypertension; ventricular mass index; right ventricular septomarginal trabeculation ID CARDIOVASCULAR MAGNETIC-RESONANCE; ARTERIAL-HYPERTENSION; CLINICAL CLASSIFICATION; DOPPLER ULTRASOUND; PRESSURE; REGURGITATION; EPIDEMIOLOGY; EXPERIENCE; ACCURACY; SURVIVAL AB Objective: To prospectively evaluate the cardiac magnetic resonance (MR) imaging-derived measurement of right ventricular (RV) septomarginal trabeculation (SMT) mass as a noninvasive marker for pulmonary hypertension (PH), compared with the ventricular mass index (VMI = RV mass/left ventricular mass) and RV mass. Materials and Methods: A total of 49 patients (60 +/- 12 years; 35 female) with suspected PH underwent cardiac MR and right heart catheterization on the same day. Eighteen normal volunteers were also included. The performance of SMT mass, VMI and RV mass measurement, with regard to PH detection, was analyzed using receiver operating characteristic curves. Logistic regression analysis was used to assess the association between SMT mass, RV mass, VMI, and PH. Results: The area under the receiver operating characteristic curve for SMT mass/body surface area (BSA), VMI, and RV mass/BSA in diagnosing the presence or absence of PH was 0.88, 0.87, and 0.73 respectively. In multivariable models, both SMT mass/BSA (P = 0.005, odds ratio: 8.6) and VMI (P = 0. 012, odds ratio: 1.1) were found to be significant, independent predictors of PH. Conclusion: Compared with right heart catheterization measurement, SMT mass and VMI are reproducible and noninvasive MR imaging markers for the diagnosis of PH. C1 [Vogel-Claussen, Jens; Shehata, Monda L.; Skrok, Jan] Johns Hopkins Univ, Dept Radiol, Sch Med, Baltimore, MD 21287 USA. [Vogel-Claussen, Jens] Univ Tubingen Hosp, Dept Diagnost & Intervent Radiol, Tubingen, Germany. [Vogel-Claussen, Jens] Hannover Med Sch, Dept Radiol, D-3000 Hannover, Germany. [Lossnitzer, Dirk] Univ Heidelberg Hosp, Dept Cardiol, Heidelberg, Germany. [Singh, Sukhminder; Boyce, Danielle; Lechtzin, Noah; Girgis, Reda E.; Mathai, Stephen C.; Hassoun, Paul M.] Johns Hopkins Univ, Sch Med, Dept Med, Div Pulm & Crit Care Med, Baltimore, MD 21287 USA. [Lima, Joao A.] Johns Hopkins Univ, Div Cardiol, Sch Med, Baltimore, MD 21287 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Biomed Engn, Dept Radiol & Imaging Sci, NIH, Bethesda, MD USA. RP Vogel-Claussen, J (reprint author), Johns Hopkins Univ, Dept Radiol, Sch Med, Nelson Basement MRI 143,600 N Wolfe St, Baltimore, MD 21287 USA. EM jclauss1@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU NIH [1P50HL08946] FX NIH 1P50HL08946. DAB supported by the NIH intramural research program. NR 29 TC 14 Z9 15 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD SEP PY 2011 VL 46 IS 9 BP 567 EP 575 DI 10.1097/RLI.0b013e31821b7041 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 804XK UT WOS:000293688200005 PM 21577127 ER PT J AU Condon, TP Jacobs, P Tai, B Pintello, D Miner, L Elcano, JC AF Condon, Timothy P. Jacobs, Petra Tai, Betty Pintello, Denise Miner, Lucinda Elcano, Jennifer C. TI Patient Relapse in the Context of Drug Abuse Treatment SO JOURNAL OF ADDICTION MEDICINE LA English DT Editorial Material DE addiction; discharge policies; drug abuse treatment; relapse ID ADAPTIVE TREATMENT MODEL; FOLLOW-UP OUTCOMES; MAINTENANCE TREATMENT; CONTROLLED-TRIAL; ALCOHOL DEPENDENCE; OPIOID DEPENDENCE; SUBSTANCE-ABUSE; CHRONIC PAIN; METHADONE; RETENTION AB How do addiction treatment programs integrate the expectation of relapse into drug abuse treatment? This article serves as a thought piece to pose questions rather than definitive solutions. It reflects a distillation of discussions that occurred at the National Institute on Drug Abuse meeting titled "Program Response to Patient Relapse," held on July 15, 2009, along with quantitative and qualitative information about the patterns and types of discharge policies, which factors influence them, and how the culture of drug abuse treatment and the personnel interact with this issue. Some existing data on the discharging of relapsed patients are identified. A program's response to relapse is usually guided by its setting (level of care), philosophy (abstinence vs risk behavior reduction), and associated patient behavior ("benign" vs program disruptive). Key questions examined in this context include the following: Can different discharge policies impact a patient's access to treatment, and what are the implications of incorporating a medical model of addiction into discharge policies? C1 [Condon, Timothy P.; Jacobs, Petra; Tai, Betty; Pintello, Denise; Miner, Lucinda; Elcano, Jennifer C.] Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. RP Elcano, JC (reprint author), Natl Inst Drug Abuse, NIH, 6001 Execut Blvd,Suite 5230,MSC 9591, Bethesda, MD 20892 USA. EM elcanoj@nida.nih.gov NR 36 TC 2 Z9 2 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1932-0620 J9 J ADDICT MED JI J. Addict. Med. PD SEP PY 2011 VL 5 IS 3 BP 157 EP 162 DI 10.1097/ADM.0b013e31820497ae PG 6 WC Substance Abuse SC Substance Abuse GA 806ST UT WOS:000293832500001 PM 21844830 ER PT J AU Kloner, RA Longacre, LS AF Kloner, Robert A. Longacre, Lisa Schwartz TI Introduction to Proceedings of the NHLBI Workshop: New Horizons in Cardioprotection-A Focused Issue of Journal of Cardiovascular Pharmacology and Therapeutics SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Editorial Material C1 [Kloner, Robert A.] Univ So Calif, Inst Heart, Keck Sch Med, Good Samaritan Hosp, Los Angeles, CA 90017 USA. [Longacre, Lisa Schwartz] NHLBI, NIH, Bethesda, MD 20892 USA. RP Kloner, RA (reprint author), Univ So Calif, Inst Heart, Keck Sch Med, Good Samaritan Hosp, 1225 Wilshire Blvd, Los Angeles, CA 90017 USA. EM rkloner@goodsam.org RI Kloner, Robert/B-2971-2012 NR 0 TC 2 Z9 2 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1074-2484 J9 J CARDIOVASC PHARM T JI J. Cardiovasc. Pharmacol. Ther. PD SEP-DEC PY 2011 VL 16 IS 3-4 BP 222 EP 222 DI 10.1177/1074248411413547 PG 1 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 803QJ UT WOS:000293595500001 PM 21821519 ER PT J AU Kloner, RA Longacre, LS AF Kloner, Robert A. Longacre, Lisa Schwartz TI State of the Science of Cardioprotection: Challenges and Opportunities-Proceedings of the 2010 NHLBI Workshop on Cardioprotection SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Article; Proceedings Paper CT Workshop on New Horizons in Cardioprotection CY SEP 20-21, 2010 CL Rockville, MD DE acute myocardial infarction; cardioactive agents; experimental cardiology; acute coronary syndromes; heart disease ID ACUTE MYOCARDIAL-INFARCTION; PERCUTANEOUS CORONARY INTERVENTION; ISCHEMIA-REPERFUSION; REGIONAL HYPOTHERMIA; SIZE; PROTECTION; ADENOSINE; THERAPY; RABBIT; INJURY AB The National Heart, Lung, and Blood Institute convened a Workshop on September 20-21, 2010, "New Horizons in Cardioprotection," to identify future research directions for cardioprotection against ischemia and reperfusion injury. Since the early 1970s, there has been evidence that the size of a myocardial infarction could be altered by various interventions. Early coronary artery reperfusion has been an intervention that consistently reduces myocardial infarct size in animal models as well as humans. Most cardiologists agree that the best way to treat acute ST-segment elevation myocardial infarction is to reperfuse the infarct artery as soon as possible and to keep the infarct artery patent. In general, stenting is superior to angioplasty, which is superior to thrombolysis. There is no accepted adjunctive therapy to acutely limit myocardial infarct size along with reperfusion that is routinely used in clinical practice. In the Kloner experimental laboratory, some adjunctive therapies have reproducibly limited infarct size (regional hypothermia, preconditioning, cariporide, combinations of the above, remote preconditioning, certain adenosine agonists, and late sodium current blockade). In clinical trials, a host of pharmacologic adjunctive therapies have failed to either reduce infarct size or improve clinical outcome. Potential reasons for the failure of these trials are discussed. However, some adjunctive therapies have shown promise in data subanalyses or subpopulations of clinical trials (adenosine, therapeutic hypothermia, and hyperoxemic reperfusion) or in small clinical trials (atrial natriuretic peptide, ischemic postconditioning, and cyclosporine, the mitochondrial permeability transition pore inhibitor). A recent clinical trial with remote conditioning induced by repetitive inflation of a brachial artery cuff begun prior to hospitalization showed promise in improving myocardial salvage and there are several reports in the cardiothoracic literature, suggesting that remote preconditioning protects hearts during surgery. Thus, in 2011, there is hope that applying some of the body's own conditioning mechanisms may provide protection against ischemic damage. C1 [Kloner, Robert A.] Univ So Calif, Good Samaritan Hosp, Inst Heart, Los Angeles, CA 90017 USA. [Longacre, Lisa Schwartz] NHLBI, Bethesda, MD 20892 USA. RP Kloner, RA (reprint author), Univ So Calif, Good Samaritan Hosp, Inst Heart, 1225 Wilshire Blvd, Los Angeles, CA 90017 USA. EM rkloner@goodsam.org RI Kloner, Robert/B-2971-2012 NR 42 TC 31 Z9 31 U1 0 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1074-2484 J9 J CARDIOVASC PHARM T JI J. Cardiovasc. Pharmacol. Ther. PD SEP-DEC PY 2011 VL 16 IS 3-4 BP 223 EP 232 DI 10.1177/1074248411402501 PG 10 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 803QJ UT WOS:000293595500002 PM 21821520 ER PT J AU Sack, MN Murphy, E AF Sack, Michael N. Murphy, Elizabeth TI The Role of Comorbidities in Cardioprotection SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Article; Proceedings Paper CT Workshop on New Horizons in Cardioprotection CY SEP 20-21, 2010 CL Rockville, MD DE metabolic syndrome; ischemia-reperfusion injury; heart disease ID NITRIC-OXIDE SYNTHASE; DIABETES-MELLITUS; ISCHEMIA/REPERFUSION INJURY; CALORIC RESTRICTION; INFARCT SIZE; TETRAHYDROBIOPTERIN BH4; ENDOTHELIAL DYSFUNCTION; MYOCARDIAL-INFARCTION; ISCHEMIA-REPERFUSION; CONSCIOUS RABBITS AB Cardioprotective strategies such as pre- and postconditioning result in a robust reduction in infarct size in young, healthy male animals. However, there are data suggesting that the protection is diminished in animals with comorbidities such as hypertension, hypercholesterolemia, and diabetes. It is important to understand at a mechanistic level the reasons for these differences. The effects of sex and diseases need to be considered in design of cardioprotective interventions in animal studies and clinical trials. C1 [Sack, Michael N.] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), Bld 10,Room 8N202,10 Ctr Dr, Bethesda, MD 20892 USA. EM Tish.Murphy@nih.hhs.gov FU Intramural NIH HHS [ZIA HL006059-02, ZIA HL002065-04, ZIA HL002066-04, ZIA HL005102-07] NR 54 TC 14 Z9 14 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1074-2484 J9 J CARDIOVASC PHARM T JI J. Cardiovasc. Pharmacol. Ther. PD SEP-DEC PY 2011 VL 16 IS 3-4 BP 267 EP 272 DI 10.1177/1074248411408313 PG 6 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 803QJ UT WOS:000293595500009 PM 21821527 ER PT J AU Arai, AE AF Arai, Andrew E. TI Magnetic Resonance Imaging for Area at Risk, Myocardial Infarction, and Myocardial Salvage SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Article; Proceedings Paper CT Workshop on New Horizons in Cardioprotection CY SEP 20-21, 2010 CL Rockville, MD DE acute myocardial infarction; area at risk; myocardial salvage; magnetic resonance imaging; ischemia ID EMISSION-COMPUTED-TOMOGRAPHY; DELAYED CONTRAST-ENHANCEMENT; ISCHEMIC CELL-DEATH; CORONARY INTERVENTION; WAVEFRONT PHENOMENON; IRREVERSIBLE INJURY; T2 QUANTIFICATION; STIMULATED ECHOES; RELAXATION TIMES; EDEMA AB Almost all published preclinical studies of cardioprotective agents include a measurement of area at risk, infarct size, and thus allow determination of myocardial salvage as an indicator of therapeutic benefit. Until recently, single-photon emission tomography (SPECT) imaging with injection of sestamibi prior to intervention was the only clinical method suitable for making similar assessments in patients. Over the past 5 years, a large number of articles have documented that magnetic resonance imaging (MRI) can noninvasively determine area at risk, infarct size, and myocardial salvage. While T2-weighted imaging has been the method used most commonly, precontrast T1-weighted images and early gadolinium enhancement (EGE) images can also determine the size of the area at risk. All 3 of these MRI methods detect the area at risk based on myocardial edema resulting from ischemia. Late gadolinium enhancement (LGE) images provide a well-accepted reference standard for infarct size in all of those methods. Finally, LGE images can also provide a single modality measure of myocardial salvage based on the "wave front" of myocardial injury associated with the progressively more severe damage associated with acute myocardial infarction (MI). Essentially, the LGE images can provide an endocardial-based snap shot of infarct size and salvaged myocardium is estimated as the viable myocardium within the circumferential extent of the infarct. Thus, the purpose of this review is to provide an overview of how MRI can determine the area at risk, infarct size, and thus measure myocardial salvage. C1 NHLBI, Dept Hlth & Human Serv, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, Dept Hlth & Human Serv, Cardiovasc & Pulm Branch, NIH, Bldg 10,RM B1D416,MSC1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov FU Intramural NIH HHS [ZIA HL006136-02, Z99 HL999999, ZIA HL006136-01]; NHLBI NIH HHS [Z01 HL004607-08] NR 56 TC 20 Z9 20 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1074-2484 J9 J CARDIOVASC PHARM T JI J. Cardiovasc. Pharmacol. Ther. PD SEP-DEC PY 2011 VL 16 IS 3-4 BP 313 EP 320 DI 10.1177/1074248411412378 PG 8 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 803QJ UT WOS:000293595500016 PM 21821534 ER PT J AU Becker, MR Choi, YS Millar, SE Udey, MC AF Becker, Maria R. Choi, Yeon S. Millar, Sarah E. Udey, Mark C. TI Wnt Signaling Influences the Development of Murine Epidermal Langerhans Cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID HEMATOPOIETIC STEM-CELL; DENDRITIC CELLS; BETA-CATENIN; IN-VIVO; CONTACT HYPERSENSITIVITY; E-CADHERIN; MICE; SKIN; DICKKOPF-1; INHIBITION AB Langerhans cells (LCs) are distinct dendritic cells (DCs) that populate stratified squamous epithelia. Despite extensive studies, our understanding of LC development is incomplete. Transforming growth factor beta 1 (TGF beta 1) is required for LC development, but other epidermis-derived influences may also be important. Recently, EpCAM (CD326) has been identified as a cell surface protein discriminating LCs from Langerin(+) dermal DCs and other DCs in the skin. EpCAM is a known transcriptional target of the Wnt signaling pathway. We hypothesized that intraepidermal Wnt signaling might influence LC development. Addition of Wnt3A into cultures of bone-marrow-derived cells in combination with TGF beta 1, GM-CSF, and M-CSF resulted in increased (33%; P<0.05) accumulation of EpCAM(+) DCs. In contrast, addition of the Wnt antagonist dickkopf-related protein 1 (Dkk1) decreased the number of EpCAM(+) DCs (21%; P<0.05). We used K14-KRM1; K5-rtTA; tetO-Dkk1 triple-transgenic and K5-rtTA; tetO-Dkk1 double-transgenic mice to test the in vivo relevance of our in vitro findings. Feeding doxycycline to nursing mothers induced expression of Dkk1 in the skin of transgenic pups, causing an obvious hair phenotype. Expression of Dkk1 reduced LC proliferation (40%; P<0.01) on P7, decreased LC densities (26%; P<0.05) on P14, and decreased EpCAM expression intensities on LCs as well (33%). In aggregate, these data suggest that Wnt signaling in skin influences LC development. C1 [Becker, Maria R.; Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Choi, Yeon S.; Millar, Sarah E.] Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. RP Udey, MC (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N238, Bethesda, MD 20892 USA. EM udey@helix.nih.gov FU Center for Cancer Research, National Cancer Institute, The National Institutes of Health FX We thank Dr William Telford for his advice and assistance with flow and laser scanning cytometer-related experiments. We also thank Jay Linton, Michael Lu, and Dr Sei-ichiro Motegi for advice and assistance with other experimental procedures. This work was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, The National Institutes of Health encompasses the preceding items (program, center, institute). NR 45 TC 7 Z9 8 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2011 VL 131 IS 9 BP 1861 EP 1868 DI 10.1038/jid.jid2011.131 PG 8 WC Dermatology SC Dermatology GA 808BO UT WOS:000293948600014 PM 21614016 ER PT J AU Camargos, ST Gurgel-Giannetti, J Lees, A Hardy, J Singleton, A Cardoso, F AF Camargos, S. T. Gurgel-Giannetti, J. Lees, A. Hardy, J. Singleton, A. Cardoso, F. TI Low prevalence of PANK2 mutations in Brazilian patients with early onset generalised dystonia and basal ganglia abnormalities on MRI SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Letter ID HALLERVORDEN-SPATZ-SYNDROME; THE-TIGER SIGN C1 [Camargos, S. T.; Gurgel-Giannetti, J.; Cardoso, F.] Univ Fed Minas Gerais, Movement Disorders Clin, Belo Horizonte, MG, Brazil. [Lees, A.; Hardy, J.] Reta Lila Weston Inst, London, England. [Singleton, A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Cardoso, F (reprint author), Univ Fed Minas Gerais, Movement Disorders Clin, Ave Pasteur 89-1107, Belo Horizonte, MG, Brazil. EM cardosofe@terra.com.br RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Lees, Andrew/A-6605-2009; Cardoso, Francisco/A-2285-2014; CAMARGOS, SARAH/O-4670-2014 OI Cardoso, Francisco/0000-0003-0808-0116; CAMARGOS, SARAH/0000-0001-9829-6783 FU Intramural NIH HHS [ZIA AG000932-08]; Medical Research Council [G0701075]; NIA NIH HHS [Z01 AG000957]; Parkinson's UK [G-0907] NR 5 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 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD SEP PY 2011 VL 82 IS 9 BP 1059 EP + DI 10.1136/jnnp.2009.200808 PG 2 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 803PN UT WOS:000293593300056 PM 20551478 ER PT J AU Williams-Brown, MY Salih, SM Xu, X Veenstra, TD Saeed, M Theiler, SK Diaz-Arrastia, CR Salama, SA AF Williams-Brown, Marian Y. Salih, Sana M. Xu, Xia Veenstra, Timothy D. Saeed, Muhammad Theiler, Shaleen K. Diaz-Arrastia, Concepcion R. Salama, Salama A. TI The effect of tamoxifen and raloxifene on estrogen metabolism and endometrial cancer risk SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Endometrial cancer; Estrogen metabolism; Tamoxifen; Raloxifene ID PROTEIN-COUPLED RECEPTOR; PREGNANE-X-RECEPTOR; BREAST-CANCER; DNA-ADDUCTS; 17-BETA-HYDROXYSTEROID DEHYDROGENASE; AROMATASE INHIBITORS; ANTIESTROGEN EM-800; MASS-SPECTROMETRY; GLANDULAR CELLS; UP-REGULATION AB Selective estrogen receptor modulators (SERMs) demonstrate differential endometrial cancer (EC) risk. While tamoxifen (TAM) use increases the risk of endometrial hyperplasia and malignancy, raloxifene (RAL) has neutral effects on the uterus. How TAM increases the risk of EC and why TAM and RAL differentially modulate the risk for EC, however, remain elusive. Here, we tested the hypothesis that TAM increases the risk for EC, at least in part, by enhancing the local estrogen biosynthesis and directing estrogen metabolism towards the formation of genotoxic and hormonally active estrogen metabolites. In addition, the differential effects of TAM and RAL in EC risk are attributed to their differential effect on estrogen metabolism/metabolites. The endometrial cancer cell line (Ishikawa cells) and the nonmalignant immortalized human endometrial glandular cell line (EM1) were used for the study. The profile of estrogen/estrogen metabolites (EM), depurinating estrogen-DNA adducts, and the expression of estrogen-metabolizing enzymes in cells treated with 17 beta-estradiol (E2) alone or in combination with TAM or RAL were investigated using high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS(2)), ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS), and Western blot analysis, respectively. TAM significantly increased the total EM and enhanced the formation of hormonally active and carcinogenic estrogen metabolites, 4-hydroxestrone (4-OHE1) and 16 alpha-hydroxyestrone, with concomitant reduction in the formation of antiestrogenic and anticarcinogenic 2-hydroxyestradiol and 2-methoxyestradiol. Furthermore, TAM increased the formation of depurinating estrogen-DNA adducts 4-OHE1 [2]-1-N7Guanine and 4-OHE1 [2]-1-N3 Adenine. TAM-induced alteration in EM and depurinating DNA adduct formation is associated with altered expression of estrogen metabolizing enzymes CYP1A1, CYP1B1, COMT, NQO1, and SF-1 as revealed by Western blot analysis. In contrast to TAM, RAL has minimal effect on EM, estrogen-DNA adduct formation, or estrogen-metabolizing enzymes expression. These data show that TAM perturbs the balance of estrogen-metabolizing enzymes and alters the disposition of estrogen metabolites, which can explain, at least in part, the mechanism for TAM-induced EC. These results also implicate the differential effect of TAM and RAL on estrogen metabolism/metabolites as a potential mechanism for their disparate effects on the endometrium. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Theiler, Shaleen K.; Diaz-Arrastia, Concepcion R.; Salama, Salama A.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Williams-Brown, Marian Y.; Theiler, Shaleen K.; Diaz-Arrastia, Concepcion R.; Salama, Salama A.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Salih, Sana M.] Univ Wisconsin, Dept Obstet & Gynecol, Madison, WI 53792 USA. [Xu, Xia; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Saeed, Muhammad] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. RP Salama, SA (reprint author), Baylor Coll Med, Dept Obstet & Gynecol, 1 Baylor Plaza MS BCM 610, Houston, TX 77030 USA. EM mywillia@utmb.edu; salih@wisc.edu; XuX@mail.nih.gov; veenstrat@mail.nih.gov; msaeed@unmc.edu; shaleen.theiler@yahoo.com; arrastia@bcm.tmc.edu; salama@bcm.edu OI theiler, shaleen/0000-0002-6881-6319; Williams-Brown, Marian/0000-0001-5034-5152 FU NICHD NIH HHS [K12 HD055894] NR 55 TC 22 Z9 24 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD SEP PY 2011 VL 126 IS 3-5 BP 78 EP 86 DI 10.1016/j.jsbmb.2011.05.001 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 797FQ UT WOS:000293110300004 PM 21600284 ER PT J AU Sullivan, JM Landoure, G Martinez, TL Burnett, B Kong, L Sahin, B Gaudet, R Lloyd, TE Sumner, CJ AF Sullivan, J. M. Landoure, G. Martinez, T. L. Burnett, B. Kong, L. Sahin, B. Gaudet, R. Lloyd, T. E. Sumner, C. J. TI DOMINANT TRPV4 MUTATIONS IN HEREDITARY NEUROPATHIES SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Meeting Abstract CT Meeting of the Peripheral-Nerve-Society CY JUN 25-29, 2011 CL Potomac, MD SP Peripheral Nerve Soc C1 [Sullivan, J. M.; Martinez, T. L.; Kong, L.; Sahin, B.; Lloyd, T. E.; Sumner, C. J.] Johns Hopkins Univ, Baltimore, MD USA. [Landoure, G.; Burnett, B.] NIH, Bethesda, MD 20892 USA. [Martinez, T. L.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Gaudet, R.] Harvard Univ, Cambridge, MA 02138 USA. RI Gaudet, Rachelle/I-4133-2014 OI Gaudet, Rachelle/0000-0002-9177-054X 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 1085-9489 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD SEP PY 2011 VL 16 SU 3 BP S133 EP S133 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 802KS UT WOS:000293510300288 ER PT J AU Louis, GMB Schisterman, EF Sweeney, AM Wilcosky, TC Gore-Langton, RE Lynch, CD Barr, DB Schrader, SM Kim, S Chen, Z Sundaram, R AF Louis, Germaine M. Buck Schisterman, Enrique F. Sweeney, Anne M. Wilcosky, Timothy C. Gore-Langton, Robert E. Lynch, Courtney D. Barr, Dana Boyd Schrader, Steven M. Kim, Sungduk Chen, Zhen Sundaram, Rajeshwari CA LIFE Study TI Designing prospective cohort studies for assessing reproductive and developmental toxicity during sensitive windows of human reproduction and development - the LIFE Study SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE cohort; environment; fecundity; fertility; LIFE Study; preconception; pregnancy; study design; enrolment ID EARLY-PREGNANCY LOSS; SPONTANEOUS-ABORTION; DYSGENESIS SYNDROME; RECRUITMENT; FERTILITY; FECUNDITY; OBESITY; STYLE; TIME; RISK AB The relationship between the environment and human fecundity and fertility remains virtually unstudied from a couple-based perspective in which longitudinal exposure data and biospecimens are captured across sensitive windows. In response, we completed the LIFE Study with methodology that intended to empirically evaluate a priori purported methodological challenges: implementation of population-based sampling frameworks suitable for recruiting couples planning pregnancy; obtaining environmental data across sensitive windows of reproduction and development; home-based biospecimen collection; and development of a data management system for hierarchical exposome data. We used two sampling frameworks (i.e. fish/wildlife licence registry and a direct marketing database) for 16 targeted counties with presumed environmental exposures to persistent organochlorine chemicals to recruit 501 couples planning pregnancies for prospective longitudinal follow-up while trying to conceive and throughout pregnancy. Enrolment rates varied from <1% of the targeted population (n = 424 423) to 42% of eligible couples who were successfully screened; 84% of the targeted population could not be reached, while 36% refused screening. Among enrolled couples, similar to 85% completed daily journals while trying; 82% of pregnant women completed daily early pregnancy journals, and 80% completed monthly pregnancy journals. All couples provided baseline blood/urine samples; 94% of men provided one or more semen samples and 98% of women provided one or more saliva samples. Women successfully used urinary fertility monitors for identifying ovulation and home pregnancy test kits. Couples can be recruited for preconception cohorts and will comply with intensive data collection across sensitive windows. However, appropriately sized sampling frameworks are critical, given the small percentage of couples contacted found eligible and reportedly planning pregnancy at any point in time. C1 [Louis, Germaine M. Buck; Schisterman, Enrique F.; Kim, Sungduk; Chen, Zhen; Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Sweeney, Anne M.] Texas A&M Hlth Sci Ctr, Sch Rural Publ Hlth, College Stn, TX USA. [Wilcosky, Timothy C.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Gore-Langton, Robert E.] EMMES Corp, Rockville, MD USA. [Lynch, Courtney D.] Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Barr, Dana Boyd] Emory Univ, Rollins Sch Publ Hlth, Dept Environm & Occupat Hlth, Atlanta, GA 30322 USA. [Schrader, Steven M.] NIOSH, Div Appl Res & Technol, Cincinnati, OH 45226 USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM louisg@mail.nih.gov RI Barr, Dana/E-6369-2011; Barr, Dana/E-2276-2013; 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 [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358). The authors acknowledge the support of the Texas Parks and Wildlife Department in providing the database for study purposes. The authors have no competing interests. NR 22 TC 69 Z9 69 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD SEP PY 2011 VL 25 IS 5 BP 413 EP 424 DI 10.1111/j.1365-3016.2011.01205.x PG 12 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 804MV UT WOS:000293658800002 ER PT J AU Parker, CB Hogue, CJR Koch, MA Willinger, M Reddy, UM Thorsten, VR Dudley, DJ Silver, RM Coustan, D Saade, GR Conway, D Varner, MW Stoll, B Pinar, H Bukowski, R Carpenter, M Goldenberg, R AF Parker, Corette B. Hogue, Carol J. R. Koch, Matthew A. Willinger, Marian Reddy, Uma M. Thorsten, Vanessa R. Dudley, Donald J. Silver, Robert M. Coustan, Donald Saade, George R. Conway, Deborah Varner, Michael W. Stoll, Barbara Pinar, Halit Bukowski, Radek Carpenter, Marshall Goldenberg, Robert CA Stillbirth Collaborative Res Netwo TI Stillbirth Collaborative Research Network: design, methods and recruitment experience SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE SCRN; stillbirth; study methodology ID MATERNAL ANXIETY; LATE PREGNANCY; RISK-FACTORS; BIRTH; VARIABLES; STRESS; RATES AB The Stillbirth Collaborative Research Network (SCRN) has conducted a multisite, population-based, case-control study, with prospective enrolment of stillbirths and livebirths at the time of delivery. This paper describes the general design, methods and recruitment experience. The SCRN attempted to enrol all stillbirths and a representative sample of livebirths occurring to residents of pre-defined geographical catchment areas delivering at 59 hospitals associated with five clinical sites. Livebirths <32 weeks gestation and women of African descent were oversampled. The recruitment hospitals were chosen to ensure access to at least 90% of all stillbirths and livebirths to residents of the catchment areas. Participants underwent a standardised protocol including maternal interview, medical record abstraction, placental pathology, biospecimen testing and, in stillbirths, post-mortem examination. Recruitment began in March 2006 and was completed in September 2008 with 663 women with a stillbirth and 1932 women with a livebirth enrolled, representing 69% and 63%, respectively, of the women identified. Additional surveillance for stillbirths continued until June 2009 and a follow-up of the case-control study participants was completed in December 2009. Among consenting women, there were high consent rates for the various study components. For the women with stillbirths, 95% agreed to a maternal interview, chart abstraction and a placental pathological examination; 91% of the women with a livebirth agreed to all of these components. Additionally, 84% of the women with stillbirths agreed to a fetal post-mortem examination. This comprehensive study is poised to systematically study a wide range of potential causes of, and risk factors for, stillbirths and to better understand the scope and incidence of the problem. C1 [Parker, Corette B.; Koch, Matthew A.; Thorsten, Vanessa R.] RTI Int, Res Triangle Pk, NC 27709 USA. [Hogue, Carol J. R.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Willinger, Marian; Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. [Dudley, Donald J.; Conway, Deborah] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Silver, Robert M.; Varner, Michael W.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Coustan, Donald; Pinar, Halit; Carpenter, Marshall] Brown Univ, Sch Med, Providence, RI 02912 USA. [Saade, George R.; Bukowski, Radek] Univ Texas Med Branch Galveston, Galveston, TX USA. [Stoll, Barbara] Emory Univ, Sch Med, Atlanta, GA USA. [Goldenberg, Robert] Drexel Univ, Sch Med, Philadelphia, PA 19104 USA. RP Parker, CB (reprint author), RTI Int, 3040 E Cornwallis Rd, Res Triangle Pk, NC 27709 USA. EM rette@rti.org RI Bukowski, Radek/B-6976-2013; Hogue, Carol/H-5442-2012; Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01-HD045954, U10-HD045953, U10-HD045925, U10-HD045952, U10-HD045955, U10-HD045944] FX The authors gratefully acknowledge the cooperation of the study participants, the staff members of the participating hospitals and the members of the NICHD Scientific Advisory and Safety Monitoring Board: Reverend Phillip Cato, PhD; James W. Collins, Jr, MD, MPH; Terry Dwyer, MD, MPH; William P. Fifer, PhD; John Ilekis, PhD; Marc Incerpi, MD; George Macones, MD, MSCE; Jeff Murray, MD; Richard M. Pauli, MD, PhD; Raymond W. Redline, MD; Elizabeth Thom, PhD (chair). A list of participating hospitals is given in Appendix S1. This study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Cooperative Agreement mechanism (U01-HD045954, U10-HD045953, U10-HD045925, U10-HD045952, U10-HD045955, U10-HD045944). NR 29 TC 19 Z9 19 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD SEP PY 2011 VL 25 IS 5 BP 425 EP 435 DI 10.1111/j.1365-3016.2011.01218.x PG 11 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 804MV UT WOS:000293658800003 PM 21819424 ER PT J AU Mumford, SL Schisterman, EF Gaskins, AJ Pollack, AZ Perkins, NJ Whitcomb, BW Ye, AJ Wactawski-Wende, J AF Mumford, Sunni L. Schisterman, Enrique F. Gaskins, Audrey J. Pollack, Anna Z. Perkins, Neil J. Whitcomb, Brian W. Ye, Aijun Wactawski-Wende, Jean TI Realignment and multiple imputation of longitudinal data: an application to menstrual cycle data SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE menstrual cycle; multiple imputation; statistical methodology; oestradiol 2; luteinising hormone; diet; fibre; missing data ID SERUM ESTROGEN CONCENTRATIONS; HIGH-FIBER DIET; PREMENOPAUSAL WOMEN; FERTILITY MONITOR; HORMONE-LEVELS; BREAST-CANCER; FAT; VARIABILITY; OVULATION; BIOCYCLE AB Reproductive hormone levels are highly variable among premenopausal women during the menstrual cycle. Accurate timing of hormone measurement is essential, especially when investigating day-or phase-specific effects. The BioCycle Study used daily urine home fertility monitors to help detect the luteinising hormone (LH) surge in order to schedule visits with biologically relevant windows of hormonal variability. However, as the LH surge is brief and cycles vary in length, relevant hormonal changes may not align with scheduled visits even when fertility monitors are used. Using monitor data, measurements were reclassified according to biological phase of the menstrual cycle to more accurate cycle phase categories. Longitudinal multiple imputation methods were applied after reclassification if no visit occurred during a given menstrual cycle phase. Reclassified cycles had more clearly defined hormonal profiles, with higher mean peak hormones (up to 141%) and reduced variability (up to 71%). We demonstrate the importance of realigning visits to biologically relevant windows when assessing phase-or day-specific effects and the feasibility of applying longitudinal multiple imputation methods. Our method has applications in settings where missing data may occur over time, where daily blood sampling for hormonal measurements is not feasible, and in other areas where timing is essential. C1 [Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Whitcomb, Brian W.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,7B03M, Rockville, MD 20852 USA. EM mumfords@mail.nih.gov RI Pollack, Anna/F-2021-2011; OI Perkins, Neil/0000-0002-6802-4733; Pollack, Anna/0000-0002-4313-3298; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 28 TC 16 Z9 16 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD SEP PY 2011 VL 25 IS 5 BP 448 EP 459 DI 10.1111/j.1365-3016.2011.01204.x PG 12 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 804MV UT WOS:000293658800005 PM 21819426 ER PT J AU McLain, AC Sundaram, R Cooney, MA Gollenberg, AL Louis, GMB AF McLain, Alexander C. Sundaram, Rajeshwari Cooney, Maureen A. Gollenberg, Audra L. Louis, Germaine M. Buck TI Clustering of fecundability within women SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE conception delay; fecundity; fertility; time to pregnancy; CPP ID LOW-BIRTH-WEIGHT; PREGNANCY OUTCOMES; TIME; RISK; CONCEPTION; RECURRENCE; FECUNDITY; VALIDITY; DEFECTS; IMPACT AB Adverse pregnancy outcomes have long been observed to cluster within women resulting in the inclusion of past reproductive history in clinical assessments and perinatal scoring systems. However, limited study has focused on the clustering of fecundability as measured by time to pregnancy (TTP), despite growing evidence suggestive of a possible association with adverse pregnancy outcomes known to cluster within women. We sought to empirically evaluate the clustering of conception delay, and TTP more globally, in one of the few existing prospective pregnancy cohort studies that captured women's successive pregnancies. The study cohort comprised 544 women who contributed 1119 pregnancies in the US Collaborative Perinatal Project. We used a discrete Cox frailty model to estimate the degree and significance of within-woman clustering of TTP. Women with an initial conception delay (TTP > 6 months) were older, less educated and had higher body mass indices than women not experiencing delays (TTP <= 6 months). Our analysis indicates that there is significant within-woman clustering of TTP (variance of the frailty = 0.80, [95% confidence interval 0.49, 1.11]) after adjusting for baseline maternal age, body mass index and education level. Similar to many other reproductive and perinatal outcomes, our findings suggest that TTP clusters within women. Identifying exposures or behaviours that affect TTP may offer strategies for reducing conception delay in future pregnancy attempts. C1 [McLain, Alexander C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Gollenberg, Audra L.] Shenandoah Univ, Dept Publ Hlth, Winchester, VA USA. RP McLain, AC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Rm 7B05K, Rockville, MD 20852 USA. EM mclaina@mail.nih.gov OI McLain, Alexander/0000-0002-5475-0670; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 37 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD SEP PY 2011 VL 25 IS 5 BP 460 EP 465 DI 10.1111/j.1365-3016.2011.01219.x PG 6 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 804MV UT WOS:000293658800006 PM 21819427 ER PT J AU Zhu, JL Obel, C Basso, O Henriksen, TB Bech, BH Hvidtjorn, D Olsen, J AF Zhu, Jin Liang Obel, Carsten Basso, Olga Henriksen, Tine B. Bech, Bodil H. Hvidtjorn, Dorte Olsen, Jorn TI Infertility, infertility treatment and behavioural problems in the offspring SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE childhood behaviour; child development; infertility; infertility treatment; Strengths and Difficulties Questionnaire (SDQ) ID DIFFICULTIES QUESTIONNAIRE SDQ; IN-VITRO FERTILIZATION; ASSISTED REPRODUCTION FAMILIES; PARENT-CHILD RELATIONSHIPS; AUTISM SPECTRUM DISORDERS; NATIONAL BIRTH COHORT; PSYCHOMETRIC PROPERTIES; PSYCHIATRIC-DISORDERS; COMMUNITY SAMPLE; SWEDISH VERSION AB Behavioural patterns in children of infertile couples may be influenced by both the underlying causes of infertility and stress in the couples. Treatment procedures, such as culture media and manipulation of gametes and embryos, may also result in developmental problems. We examined behavioural problems in children as a function of infertility and infertility treatment, using data from three population-based birth cohorts in Denmark (Aalborg-Odense Birth Cohort, Aarhus Birth Cohort and Danish National Birth Cohort). Information on time to pregnancy and infertility treatment was collected during pregnancy. Children aged between 7 and 21 years were assessed using the Strengths and Difficulties Questionnaire (SDQ). The SDQ was completed by mothers in all cohorts and, in addition, by teachers in the Aarhus cohort and by children themselves in the Aalborg-Odense cohort. Children born after a time to pregnancy of > 12 months and no infertility treatment had a behavioural pattern similar to children of fertile parents. Teachers reported a higher total difficulties score for children born after infertility treatment, but no significant differences were seen on any subscales of the teachers' report, and neither the mothers nor the children reported any differences on the total difficulties score and the prosocial behaviour score. Our results are thus overall reassuring regarding behavioural problems in children born to infertile couples, regardless of infertility treatment. C1 [Zhu, Jin Liang] Univ Aarhus, Danish Epidemiol Sci Ctr, Sch Publ Hlth, Dept Epidemiol, DK-8000 Aarhus C, Denmark. [Obel, Carsten; Henriksen, Tine B.] Aarhus Univ Hosp, Dept Paediat, DK-8000 Aarhus, Denmark. [Basso, Olga] NIEHS, Epidemiol Branch, NIH, Durham, NC USA. [Olsen, Jorn] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Basso, Olga] McGill Univ, Dept Obstet & Gynecol, Montreal, PQ H3A 2T5, Canada. RP Zhu, JL (reprint author), Univ Aarhus, Danish Epidemiol Sci Ctr, Sch Publ Hlth, Dept Epidemiol, Bartholins Alle 2, DK-8000 Aarhus C, Denmark. EM zjl@soci.au.dk RI Basso, Olga/E-5384-2010; Olsen, Jorn/F-8801-2015; Bech, Bodil Hammer/B-9646-2016 OI Basso, Olga/0000-0001-9298-4921; Olsen, Jorn/0000-0001-7462-5140; FU Danish Medical Research Council [271-05-0115, 271-07-0402, 09-063477]; NIH, National Institute of Environmental Health Sciences [Z01 ES044003]; Danish National Research Foundation FX The authors thank Matthew P. Longnecker and two anonymous reviewers for providing valuable comments on an earlier version of this paper. This work was supported by grants from the Danish Medical Research Council (271-05-0115, 271-07-0402 and 09-063477) and, in part, by the Intramural Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES044003). The Danish National Research Foundation has established the Danish Epidemiology Science Centre, which initiated and created the Danish National Birth Cohort. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the Danish National Birth Cohort is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Foundation. NR 54 TC 8 Z9 9 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD SEP PY 2011 VL 25 IS 5 BP 466 EP 477 DI 10.1111/j.1365-3016.2011.01220.x PG 12 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 804MV UT WOS:000293658800007 PM 21819428 ER PT J AU Vasudevan, K Sztein, JM AF Vasudevan, Kuzhalini Sztein, Jorge M. TI Treatment of sperm with extracellular adenosine 5 '-triphosphate improves the in vitro fertility rate of inbred and genetically modified mice with low fertility SO THERIOGENOLOGY LA English DT Article DE Genetically modified mice; In vitro fertilization; Extracellular ATP; Fertility ID MALE FACTOR INFERTILITY; MOUSE SPERM; ACROSOME REACTION; BOVINE SPERMATOZOA; ACTIVATING-FACTOR; FERTILIZATION; MOTILITY; INVITRO; CAPACITATION; STRAINS AB In vitro fertilization (IVF) is one of the most important techniques used for assisted reproduction in mouse colony management. As with natural mating, where mice have varying fertility indices, fertility rates of genetically modified (GM) [transgenic (Tg), knock out (KO) and congenic (Cg)] mice are influenced by their genetic background. Lines of GM mice that have poor fertility have a concomitant poor IVF outcome. Treatment of mouse sperm with extracellular adenosine 5'-triphosphate (ATPe) enhanced in vitro fertilization rates in outbred and hybrid mice. The objective of this study was to analyze the effects of using extracellular adenosine 5'-triphosphate-treated sperm for IVF of inbred wild type, and genetically modified mouse lines, for which standard IVF did not work well. The IVF was performed using the GM mice on C57BL/10SnJ, C57BL/6J, BALB/cJ and NFS/N background strains and wild type (WT) mice such as C57BL/6N, BALB/cAnN, and B6129SF1 strains. Oocytes from superovulated females were fertilized in vitro with sperm from the same background strain, and either treated or not treated with ATPe. The ATPe treatment enhanced IVF outcome in most of the GM and some WT strains, as indicated by the percentage of embryos that progressed to the two-cell stage. There was no marked difference between ATPe treated and control groups for the development rate of two-cell embryos to blastocysts in culture, or in the number of pups born after transfer of two-cell embryos into recipient females. The observed improvement of the IVF results following ATPe treatment of transgenic and KO mouse sperm were a potential solution for improving the outcome of assisted reproduction techniques used for rederivation or for gamete banking. Published by Elsevier Inc. C1 [Vasudevan, Kuzhalini; Sztein, Jorge M.] NIAID, Assisted Reprod Technol & Cryopreservat Unit, CMB, NIH, Rockville, MD USA. RP Sztein, JM (reprint author), NIAID, Assisted Reprod Technol & Cryopreservat Unit, CMB, NIH, Rockville, MD USA. EM szteinj@niaid.nih.gov OI Sztein, Jorge Mario/0000-0001-7047-2634 FU Comparative Medicine Branch; National Institutes of Allergy and Infectious Diseases/National Institutes of Health FX The authors thank Chris McGregor for technical assistance and Dr. Kathy Perdue for critical reading of the manuscript. We also thank all scientists who allowed us to use their mice for this study. This research was supported by Comparative Medicine Branch and the Intramural Research Program of National Institutes of Allergy and Infectious Diseases/National Institutes of Health. NR 31 TC 5 Z9 7 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0093-691X J9 THERIOGENOLOGY JI Theriogenology PD SEP 1 PY 2011 VL 76 IS 4 BP 729 EP 736 DI 10.1016/j.theriogenology.2011.04.005 PG 8 WC Reproductive Biology; Veterinary Sciences SC Reproductive Biology; Veterinary Sciences GA 807CC UT WOS:000293870100017 PM 21601915 ER PT J AU Kuranov, AB Mukhamedyarov, DA Momynaliev, KT AF Kuranov, A. B. Mukhamedyarov, D. A. Momynaliev, K. T. TI Characterization of new HLA-A and -B alleles from Kazakhstan SO TISSUE ANTIGENS LA English DT Editorial Material DE DNA sequencing; human leukocyte antigen; new allele C1 [Momynaliev, K. T.] Res Inst Physicochem Med, Moscow 119992, Russia. [Kuranov, A. B.; Mukhamedyarov, D. A.; Momynaliev, K. T.] Natl Biotechnol Ctr, Astana, Kazakhstan. RP Momynaliev, KT (reprint author), Res Inst Physicochem Med, Malaya Pirogovskaya 1A, Moscow 119992, Russia. EM dhoroshun@gmail.com NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD SEP PY 2011 VL 78 IS 3 BP 217 EP 218 DI 10.1111/j.1399-0039.2011.01681.x PG 2 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 801BP UT WOS:000293411700009 PM 21732918 ER PT J AU Sherrill, J Mariappan, M Dominik, P Hegde, RS Keenan, RJ AF Sherrill, John Mariappan, Malaiyalam Dominik, Pawel Hegde, Ramanujan S. Keenan, Robert J. TI A Conserved Archaeal Pathway for Tail-Anchored Membrane Protein Insertion SO TRAFFIC LA English DT Article DE archaea; ArsA; Get3; insertion; posttranslational; targeting; tail-anchored membrane proteins; TRC40 ID ENDOPLASMIC-RETICULUM; ER MEMBRANE; GET3; BINDING; COMPLEX AB Eukaryotic tail-anchored ( TA) membrane proteins are inserted into the endoplasmic reticulum by a posttranslational TRC40 pathway, but no comparable pathway is known in other domains of life. The crystal structure of an archaebacterial TRC40 sequence homolog bound to ADP.AlF(4)(-) reveals characteristic features of eukaryotic TRC40, including a zinc-mediated dimer and a large hydrophobic groove. Moreover, archaeal TRC40 interacts with the transmembrane domain of TA substrates and directs their membrane insertion. Thus, the TRC40 pathway is more broadly conserved than previously recognized. C1 [Sherrill, John; Dominik, Pawel; Keenan, Robert J.] Univ Chicago, Dept Biochem & Mol Biol, Gordon Ctr Integrat Sci, Chicago, IL 60637 USA. [Mariappan, Malaiyalam; Hegde, Ramanujan S.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Keenan, RJ (reprint author), Univ Chicago, Dept Biochem & Mol Biol, Gordon Ctr Integrat Sci, Room W238, Chicago, IL 60637 USA. EM bkeenan@uchicago.edu RI mariappan, malaiyalam/K-9024-2012; OI Hegde, Ramanujan/0000-0001-8338-852X FU US DOE [DE-AC02-06CH11357]; NIH [T32 GM008720]; Edward Mallinckrodt, Jr Foundation FX Data were collected at beamline 21-IDF at the Advanced Photon Source (APS), Argonne National Laboratory, and we thank the beamline staff for support. Use of the Advanced Photon Source, an Office of Science User Facility operated for the US Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the US DOE under Contract No. DE-AC02-06CH11357. We thank Maureen Downing for cloning the M. thermautotrophicus TRC40 homolog, and Agnieszka Mateja andMalgorzata Dobosz for help with data collection. This work was supported by the Intramural Research Program of the NIH (to RSH), NIH grant T32 GM008720 (to JS), an Edward Mallinckrodt, Jr Foundation Grant (to RJK) and NIH Grant R01 GM086487 (to RJK). JS and PD carried out cloning, protein purification and crystallization. JS, PD and RJK performed data collection and JS carried out the structure determination and model building. MM and RSH performed the substrate-binding and membrane insertion assays. RJK conceived the project, guided experiments and wrote the article. All authors discussed the results and commented on the manuscript. The X-ray structure of Mg2+ADP.AlF4- bound M. thermautotrophicus TRC40 is deposited in the Protein Data Bank under ID code 3zq6. NR 23 TC 6 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD SEP PY 2011 VL 12 IS 9 BP 1119 EP 1123 DI 10.1111/j.1600-0854.2011.01229.x PG 5 WC Cell Biology SC Cell Biology GA 806HP UT WOS:000293797200003 PM 21658170 ER PT J AU Mathews, JA Ford, J Norton, S Kang, D Dellinger, A Gibb, DR Ford, AQ Massay, H Kepley, CL Scherle, P Keegan, AD Conrad, DH AF Mathews, J. A. Ford, J. Norton, S. Kang, D. Dellinger, A. Gibb, D. R. Ford, A. Q. Massay, H. Kepley, C. L. Scherle, P. Keegan, A. D. Conrad, D. H. TI A potential new target for asthma therapy: A Disintegrin and Metalloprotease 10 (ADAM10) involvement in murine experimental asthma SO ALLERGY LA English DT Article DE ADAM10; asthma; CD23; IgE; Th2 ID INDUCED AIRWAY HYPERREACTIVITY; IGE PRODUCTION; ALLERGIC DISEASE; IN-VIVO; CD23; INFLAMMATION; CELLS; INHIBITION; MODEL; LUNG AB Background: Elevated levels of CD23, a natural regulator of IgE production, have been shown to decrease the signs of lung inflammation in mice. The aim of this study was to study the involvement of ADAM10, the primary CD23 sheddase, in experimental asthma. Methods: ADAM10 was blocked either by using mice with a B-cell-specific deletion of the protease or pharmacologically by intranasal administration of selective ADAM10 inhibitors. Airway hypersensitivity (AHR) and bronchoaveolar lavage fluid (BALF) eosinophilia and select BALF cytokine/chemokine levels were then determined. Results: Using an IgE and mast cell-dependent mouse model, B-cell-specific ADAM10(-/-) mice (C57B/6 background) exhibited decreased eosinophilia and AHR when compared with littermate (LM) controls. Treatment of C57B/6 mice with selective inhibitors of ADAM10 resulted in an even further decrease in BALF eosinophilia, as compared with the ADAM10(-/-) animals. Even in the Th2 selective strain, Balb/c, BALF eosinophilia was reduced from 60% to 23% respectively. In contrast, when an IgE/mast cell-independent model of lung inflammation was used, the B-cell ADAM10(-/-) animals and ADAM10 inhibitor treated animals had lung inflammation levels that were similar to the controls. Conclusions: These results thus show that ADAM10 is important in the progression of IgE-dependent lung inflammation. The use of the inhibitor further suggested that ADAM10 was important for maintaining Th2 levels in the lung. These results thus suggest that decreasing ADAM10 activity could be beneficial in controlling asthma and possibly other IgE-dependent diseases. C1 [Mathews, J. A.; Norton, S.; Kang, D.; Gibb, D. R.; Conrad, D. H.] Virginia Commonwealth Univ, Sch Med, Dept Microbiol & Immunol, Richmond, VA 23298 USA. [Ford, J.] NCI, Canc & Inflammatory Program, Frederick, MD 21701 USA. [Dellinger, A.; Kepley, C. L.] NanoImmunol Luna Innovat, Danville, VA USA. [Ford, A. Q.] Board Populat Hlth Inst Med, Washington, DC USA. [Massay, H.] Virginia Commonwealth Univ, Sch Med, Dept Pathol, Richmond, VA 23298 USA. [Scherle, P.] Incyte Corp, Wilmington, DE USA. [Keegan, A. D.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Conrad, DH (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Microbiol & Immunol, POB 980678, Richmond, VA 23298 USA. EM dconrad@vcu.edu RI Gung, Amber/D-9842-2011 FU NIH-NINDS Center [5P30NSD4763-02]; NIH [RO1AI18697, 1U19AI077435] FX We thank John Tew and Keith Brooks for their review and comments on the manuscript. Also we thank Drew Jones for his help in developing the IgE/mast cell-independent model and Jorge Almenara for his help in sectioning of the lungs. Microscopy was performed at the VCU Department of Anatomy and Neurobiology Microscopy Facility, supported, in part, with funding from NIH-NINDS Center core grand (5P30NSD4763-02). Support for this work came from the NIH grants RO1AI18697 and 1U19AI077435. NR 32 TC 21 Z9 21 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-4538 J9 ALLERGY JI Allergy PD SEP PY 2011 VL 66 IS 9 BP 1193 EP 1200 DI 10.1111/j.1398-9995.2011.02614.x PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 800EQ UT WOS:000293343000008 PM 21557750 ER PT J AU Nair, V Dai, ZL Khan, M Ciolino, HP AF Nair, Vidhya Dai, Zhaoli Khan, Maruf Ciolino, Henry P. TI Pomegranate Extract Induces Cell Cycle Arrest and Alters Cellular Phenotype of Human Pancreatic Cancer Cells SO ANTICANCER RESEARCH LA English DT Article DE Pomegranate; pancreatic cancer cells; phytochemicals; cell cycle arrest ID PUNICA-GRANATUM L.; IN-VITRO; STEM-CELLS; ANTIOXIDANT; CHEMOPREVENTION; CHEMOTHERAPY; POLYPHENOLS; PACLITAXEL; GROWTH; LINES AB Background: Pomegranate extract (PE) is a standardized whole-fruit extract of pomegranate, a fruit with known anticancer properties. Materials and Methods: PANC-1 and AsPC-1 human pancreatic cancer cells were used as in vitro models to test the effects of PE. Results: PE treatment induced cell cycle arrest and inhibited cell proliferation in PANC-1 cells. PE treatment increased the proportion of cells lacking CD44 and CD24 expression, which are associated with increased tumor-initiating ability, demonstrating that PE altered cell phenotype. PE was more effective in inhibiting the proliferation of PANC-1 cells than the clinically used dose of paclitaxel. Similar results were obtained in the AsPC-1 cell line. Individual pomegranate phytochemicals were only modestly effective in inhibiting cell proliferation, suggesting that unidentified phytochemicals are responsible for the inhibitory effect of PE. Conclusion: These data suggest that PE is a promising candidate for further preclinical testing for treatment of human pancreatic cancer. C1 [Ciolino, Henry P.] NCI, Off Canc Ctr, Rockville, MD 20892 USA. [Nair, Vidhya; Dai, Zhaoli; Khan, Maruf] Univ Texas Austin, Dept Nutr Sci, Austin, TX 78712 USA. RP Ciolino, HP (reprint author), NCI, Off Canc Ctr, Bldg 6116,Room 7002, Rockville, MD 20892 USA. EM ciolinoh@mail.nih.gov NR 25 TC 5 Z9 5 U1 1 U2 5 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD SEP PY 2011 VL 31 IS 9 BP 2699 EP 2704 PG 6 WC Oncology SC Oncology GA 800KG UT WOS:000293357700003 PM 21868510 ER PT J AU Cai, T Hirai, H Zhang, G Zhang, M Takahashi, N Kasai, H Satin, LS Leapman, RD Notkins, AL AF Cai, T. Hirai, H. Zhang, G. Zhang, M. Takahashi, N. Kasai, H. Satin, L. S. Leapman, R. D. Notkins, A. L. TI Deletion of Ia-2 and/or Ia-2 beta in mice decreases insulin secretion by reducing the number of dense core vesicles SO DIABETOLOGIA LA English DT Article DE Autophagy; Capacitance; Dense core vesicle; Diabetes; Electron microscopy; Gene knockout; Insulin; Pancreatic islet; Protein tyrosine phosphates; Two-photon microscopy ID PROTEIN-TYROSINE-PHOSPHATASE; PANCREATIC BETA-CELLS; DEPENDENT DIABETES-MELLITUS; TARGETED DISRUPTION; DOUBLE KNOCKOUT; CA2+ CHANNELS; ISLET CELLS; GLUCOSE; GRANULES; EXOCYTOSIS AB Islet antigen 2 (IA-2) and IA-2 beta are dense core vesicle (DCV) transmembrane proteins and major autoantigens in type 1 diabetes. The present experiments were initiated to test the hypothesis that the knockout of the genes encoding these proteins impairs the secretion of insulin by reducing the number of DCV. Insulin secretion, content and DCV number were evaluated in islets from single knockout (Ia-2 [also known as Ptprn] KO, Ia-2 beta [also known as Ptprn2] KO) and double knockout (DKO) mice by a variety of techniques including electron and two-photon microscopy, membrane capacitance, Ca(2+) currents, DCV half-life, lysosome number and size and autophagy. Islets from single and DKO mice all showed a significant decrease in insulin content, insulin secretion and the number and half-life of DCV (p < 0.05 to 0.001). Exocytosis as evaluated by two-photon microscopy, membrane capacitance and Ca(2+) currents supports these findings. Electron microscopy of islets from KO mice revealed a marked increase (p < 0.05 to 0.001) in the number and size of lysosomes and enzymatic studies showed an increase in cathepsin D activity (p < 0.01). LC3 protein, an indicator of autophagy, also was increased in islets of KO compared with wild-type mice (p < 0.05 to 0.01) suggesting that autophagy might be involved in the deletion of DCV. We conclude that the decrease in insulin content and secretion, resulting from the deletion of Ia-2 and/or Ia-2 beta, is due to a decrease in the number of DCV. C1 [Cai, T.; Hirai, H.; Notkins, A. L.] NIDCR, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Zhang, G.; Leapman, R. D.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. [Zhang, M.; Satin, L. S.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA USA. [Takahashi, N.; Kasai, H.] Univ Tokyo, Ctr Dis Biol & Integrat Med, Lab Struct Physiol, Tokyo, Japan. [Satin, L. S.] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Satin, L. S.] Univ Michigan, Sch Med, Brehm Diabet Ctr, Ann Arbor, MI 48109 USA. RP Cai, T (reprint author), NIDCR, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. EM tcai@mail.nih.gov; anotkins@dir.nidcr.nih.gov FU NIH (NIDCR and NIBIB); NIH [RO1 DK46409] FX We thank C. Wohlenberg (NIDCR/NIH, Bethesda, MD, USA) for technical help. This research was supported in part by the Intramural Research Program of the NIH (NIDCR and NIBIB) and grant NIH RO1 DK46409 for the Satin laboratory. The authors thank A. Sherman (NIDDK/NIH, Bethesda, MD, USA) and M. Merrins (L. S. Satin's lab) for helpful discussions. NR 43 TC 28 Z9 31 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2011 VL 54 IS 9 BP 2347 EP 2357 DI 10.1007/s00125-011-2221-6 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 802XS UT WOS:000293544900020 PM 21732083 ER PT J AU Chaves, LF Keogh, CL Nguyen, AM Decker, GM Vazquez-Prokopec, GM Kitron, UD AF Chaves, L. F. Keogh, C. L. Nguyen, A. M. Decker, G. M. Vazquez-Prokopec, G. M. Kitron, U. D. TI Combined sewage overflow accelerates immature development and increases body size in the urban mosquito Culex quinquefasciatus SO JOURNAL OF APPLIED ENTOMOLOGY LA English DT Article DE density dependence; phenotypic plasticity; sewage ID AEDES-AEGYPTI DIPTERA; WEST-NILE-VIRUS; TREE-HOLE ECOSYSTEMS; CULICIDAE; LARVAL; INFECTION; TRANSMISSION; TRITAENIORHYNCHUS; SUSCEPTIBILITY; OVIPOSITION AB In urban landscapes the crowding of humans and their waste products may alleviate intra-specific interactions of common mosquitoes. Here, we present the results of a semi-natural experiment addressing the effects of water from a sewage overflow stream on density dependent fitness components and phenotypic traits of a common tropical and subtropical urban mosquito, Culex quinquefasciatus Say (Diptera: Culicidae). This semi-natural experiment was designed to quantify the relative importance of density dependence, weather forces and water quality on larval mortality, sex ratio and size at adult emergence. Results showed that mortality hazards were independent of larval density, decreased in sewage overflow water and increased with minimum temperatures. Under all rearing conditions adult mosquito size decreased with density. Mosquitoes from sewage overflow water emerged faster, were bigger and had an increased ratio of females to males. All these traits may contribute to the regulation of mosquito populations. C1 [Chaves, L. F.; Decker, G. M.; Vazquez-Prokopec, G. M.; Kitron, U. D.] Emory Univ, Dept Environm Studies, Atlanta, GA 30322 USA. [Keogh, C. L.] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. [Nguyen, A. M.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Kitron, U. D.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Chaves, LF (reprint author), Emory Univ, Dept Environm Studies, 400 Dowman Dr,Suite E510, Atlanta, GA 30322 USA. EM lfchave@emory.edu RI Chaves, Luis Fernando/F-3448-2010 OI Chaves, Luis Fernando/0000-0002-5301-2764 FU Emory University; Department of Environmental Studies; NSF FX This work was funded by Emory University and the Lester fund - Department of Environmental Studies. Alexandra Van Nostrand and Will Galvin provided technical support. LFC and UK also thank the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate and the Fogarty International Center, National Institutes of Health program on mosquito borne diseases, for helpful discussions in the context of this manuscript. CLK was supported by a NSF Pre-Doctoral Fellowship. NR 42 TC 15 Z9 15 U1 5 U2 26 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0931-2048 J9 J APPL ENTOMOL JI J. Appl. Entomol. PD SEP PY 2011 VL 135 IS 8 BP 611 EP 620 DI 10.1111/j.1439-0418.2010.01580.x PG 10 WC Entomology SC Entomology GA 801MT UT WOS:000293444200005 ER PT J AU Massilamany, C Gangaplara, A Gardner, DJ Musser, JM Steffen, D Somerville, GA Reddy, J AF Massilamany, Chandirasegaran Gangaplara, Arunakumar Gardner, Donald J. Musser, James M. Steffen, David Somerville, Greg A. Reddy, Jay TI TCA cycle inactivation in Staphylococcus aureus alters nitric oxide production in RAW 264.7 cells SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE Staphylococcus aureus; Aconitase; Nitric oxide; RAW 264.7 cells; Immune evasion ID INNATE IMMUNITY; HOST-DEFENSE; KAPPA-B; SYNTHASE; EXPRESSION; MACROPHAGES; ACTIVATION; INDUCTION; VIRULENCE; DEHYDROGENASE AB Inactivation of the Staphylococcus aureus tricarboxylic acid (TCA) cycle delays the resolution of cutaneous ulcers in a mouse soft tissue infection model. In this study, it was observed that cutaneous lesions in mice infected with wild-type or isogenic aconitase mutant S. aureus strains contained comparable inflammatory infiltrates, suggesting the delayed resolution was independent of the recruitment of immune cells. These observations led us to hypothesize that staphylococcal metabolism can modulate the host immune response. Using an in vitro model system involving RAW 264.7 cells, the authors observed that cells cultured with S. aureus aconitase mutant strains produced significantly lower amounts of nitric oxide (NO(aEuro cent)) and an inducible nitric oxide synthase as compared to those cells exposed to wild-type bacteria. Despite the decrease in NO(aEuro cent) synthesis, the expression of antigen-presentation and costimulatory molecules was similar in cells cultured with wild-type and those cultured with aconitase mutant bacteria. The data suggest that staphylococci can evade innate immune responses and potentially enhance their ability to survive in infected hosts by altering their metabolism. This may also explain the occurrence of TCA cycle mutants in clinical S. aureus isolates. C1 [Massilamany, Chandirasegaran; Gangaplara, Arunakumar; Steffen, David; Somerville, Greg A.; Reddy, Jay] Univ Nebraska, Sch Vet Med & Biomed Sci, Lincoln, NE 68583 USA. [Gardner, Donald J.] NIAID, Rocky Mt Vet Branch, Lab Human Bacterial Pathogenesis, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Reddy, J (reprint author), Univ Nebraska, Sch Vet Med & Biomed Sci, Room 202,Bldg VBS, Lincoln, NE 68583 USA. EM nreddy2@unl.edu RI Somerville, Greg/B-1326-2013; Reddy, Jay/K-7200-2014; Massilamany, Chandirasegaran/D-9305-2016; OI Somerville, Greg/0000-0002-0991-8737; Reddy, Jay/0000-0003-4082-9254; Massilamany, Chandirasegaran/0000-0002-0205-282X; Gangaplara, Arunakumar/0000-0001-6307-9391 FU Hatch Act; National Center for Research Resources (NIH) [P20-RR-17675]; Redox Biology Center, University of Nebraska-Lincoln; National Institutes of Health [AI087668]; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This manuscript is a contribution of the University of Nebraska Agricultural Research Division, supported in part by funds provided through the Hatch Act and by the COBRE Program from the National Center for Research Resources (P20-RR-17675, NIH), Redox Biology Center, University of Nebraska-Lincoln. Additional funding was provided by the National Institutes of Health to GAS (AI087668) and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 39 TC 6 Z9 6 U1 0 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD SEP PY 2011 VL 355 IS 1-2 BP 75 EP 82 DI 10.1007/s11010-011-0840-3 PG 8 WC Cell Biology SC Cell Biology GA 800ZD UT WOS:000293405300009 PM 21519920 ER PT J AU Leoni, RF Paiva, FF Henning, EC Nascimento, GC Tannus, A de Araujo, DB Silva, AC AF Leoni, Renata F. Paiva, Fernando F. Henning, Erica C. Nascimento, George C. Tannus, Alberto de Araujo, Draulio B. Silva, Afonso C. TI Magnetic resonance imaging quantification of regional cerebral blood flow and cerebrovascular reactivity to carbon dioxide in normotensive and hypertensive rats SO NEUROIMAGE LA English DT Article DE Arterial spin labeling; Hypercapnia; Magnetic resonance imaging; Perfusion; Spontaneously hypertensive rat ID FUNCTIONAL MRI; ANESTHETIZED RATS; AUTO-REGULATION; ISOFLURANE; ISCHEMIA; HYPERCAPNIA; RESPONSES; ARTERY; AUTOREGULATION; STIMULATION AB Hypertension afflicts 25% of the general population and over 50% of the elderly. In the present work, arterial spin labeling MRI was used to non-invasively quantify regional cerebral blood flow (CBE), cerebrovascular resistance and CO(2) reactivity in spontaneously hypertensive rats (SHR) and in normotensive Wistar Kyoto rats (WKY), at two different ages (3 months and 10 months) and under the effects of two anesthetics, alpha-chloralose and 2% isoflurane (1.5 MAC). Repeated CBE measurements were highly consistent, differing by less than 10% and 18% within and across animals, respectively. Under alpha-chloralose, whole brain CBE at normocapnia did not differ between groups (young WKY: 61 3 ml/100 g/min; adult WKY: 62 +/- 4 ml/100 g/min; young SHR: 70 +/- 9 ml/100 g/min: adult SHR: 69 8 ml/100 g/min), indicating normal cerebral autoregulation in SHR. At hypercapnia, CBE values increased significantly, and a linear relationship between CBE and PaCO(2) levels was observed. In contrast, 2% isoflurane impaired cerebral autoregulation. Whole brain CBE in SHR was significantly higher than in WKY rats at normocapnia (young SHR: 139 +/- 25 ml/100 g/min; adult SHR: 104 +/- 23 ml/100 g/min; young WKY: 55 +/- 9 ml/100 g/min; adult WKY: 71 +/- 19 ml/100 g/min). CBE values increased significantly with increasing CO(2): however, there was a clear saturation of CBF at PaCO(2) levels greater than 70 mm Hg in both young and adult rats, regardless of absolute CBE values, suggesting that isoflurane interferes with the vasoclilatory mechanisms of CO(2). This behavior was observed for both cortical and subcortical structures. Under either anesthetic, CO(2) reactivity values in adult SHR were decreased, confirming that hypertension, when combined with age, increases cerebrovascular resistance and reduces cerebrovascular compliance. Published by Elsevier Inc. C1 [Leoni, Renata F.; Paiva, Fernando F.; Nascimento, George C.; Silva, Afonso C.] Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Leoni, Renata F.; de Araujo, Draulio B.] Univ Sao Paulo, Dept Math & Phys, FFCLRP, BR-14040901 Ribeirao Preto, SP, Brazil. [Paiva, Fernando F.; Tannus, Alberto] Univ Sao Paulo, CIERMag Ctr Imagens & Espectroscopia Vivo Ressona, Inst Phys Sao Carlos, BR-13560970 Sao Carlos, SP, Brazil. [Henning, Erica C.] Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. [de Araujo, Draulio B.] Univ Fed Rio Grande do Norte, Hosp Univ Oliofre Lopes, BR-59012300 Natal, RN, Brazil. RP Silva, AC (reprint author), Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr MSC 1065,Bldg 10 Room 81D106, Bethesda, MD 20892 USA. EM SilvaA@ninds.nih.gov RI Paiva, Fernando/C-1429-2012; Araujo, Draulio/I-6038-2012; Sao Carlos Institute of Physics, IFSC/USP/M-2664-2016; Tannus, Alberto/B-9821-2012; OI Paiva, Fernando/0000-0002-8989-9707; Araujo, Draulio/0000-0002-6934-2485; Tannus, Alberto/0000-0002-1675-1971; Leoni, Renata/0000-0002-4568-0746 FU NIH; NINDS; FAPESP [2006/05706-5, 2003/13399-7, 2005/56663-1] FX This research was supported by the Intramural Research Program of the NIH, NINDS (Alan P. Koretsky, Scientific Director), and FAPESP (2006/05706-5, 2003/13399-7, 2005/56663-1). NR 42 TC 20 Z9 22 U1 1 U2 7 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 SEP 1 PY 2011 VL 58 IS 1 BP 75 EP 81 DI 10.1016/j.neuroimage.2011.06.030 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 802ZC UT WOS:000293548500010 PM 21708273 ER PT J AU Lubet, RA Heckman, BM De Flora, SL Steele, VE Crowell, JA Juliana, MM Grubbs, CJ AF Lubet, Ronald A. Heckman, Brandy M. De Flora, Silvio L. Steele, Vernon E. Crowell, James A. Juliana, M. Margaret Grubbs, Clinton J. TI Effects of 5,6-benzoflavone, indole-3-carbinol (I3C) and diindolyimethane (DIM) on chemically-induced mammary carcinogenesis: Is DIM a substitute for I3C? SO ONCOLOGY REPORTS LA English DT Article DE Ah receptors; 5,6-benzoflavone; indole-3-carbinol; diindolylmethane; mammary cancer ID DNA ADDUCT FORMATION; DIETARY INDOLE-3-CARBINOL; HYDROXYLASE-ACTIVITY; BETA-NAPHTHOFLAVONE; CANCER CELLS; CHEMOPREVENTION; INHIBITION; METABOLISM; MICE; RAT AB The abilities of 5,6-benzoflavone (5,6-BF, a synthetic flavonoid), indole-3-carbinol (I3C, a plant derived product) or diindolylmethane (DIM, a condensation product of I3C) to alter the induction of mammary cancers induced by the carcinogens 7,12-dimethylbenzanthracene (DMBA) or N-methyl-N-nitrosourea (M NU) were evaluated. Interestingly, the first two agents act as aryl hydrocarbon receptor (AhR) agonists, while DIM does not. The agents were initially examined for their ability to inhibit DM BA-induced mammary carcinogenesis. Agents were administered for 14 days starting 7 days prior to a single dose of the carcinogen. Evaluated over an extensive range of doses (165, 550 and 1650 ppm in the diet), 5,6-BF caused a dose-dependent decrease of mammary cancers. In addition, 5,6-BF at closes of 1650 and 165 ppm in the diet blocked the induction of DMBA-induced DNA adducts in the mammary gland by approximately 85% and 45%, respectively. In contrast, DIM (180 or 20 mg/kg BW/day) failed to block induction of DMBA tumors. The effect of these agents on the promotion/progression phase of carcinogenesis using the MNU mammary cancer model was also determined. 5,6-BF (1650 or 165 ppm in the diet), I3C (180 or 60 mg/kg BW/day administered by gavage), or DIM (180 or 60 mg/kg BW/day by gavage) were initiated 5 days after the administration of MNU, and continually thereafter. 5,6-BF decreased MNU-induced mammary tumor multiplicity by 40-60%. I3C reduced tumor multiplicity at the high dose, while DIM at either dose had minimal effects on tumor multiplicity. Thus, 5,6-BE and I3C were highly effective against initiation of DMBA-induced mammary carcinogenesis, and were also effective against MNU-induced tumors during the promotion/progression phase of carcinogenesis. In contrast, DIM had minimal effects in either model; arguing that administration of DIM is not analogous to administration of I3C. C1 [Lubet, Ronald A.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Crowell, James A.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [De Flora, Silvio L.] Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. [Juliana, M. Margaret] Univ Alabama, Chemoprevent Ctr, Birmingham, AL 35294 USA. RP Lubet, RA (reprint author), NCI, Canc Prevent Div, NIH, Executive Plaza N,Suite 2110,9000 Rockville Pike, Bethesda, MD 20892 USA. EM lubetr@mail.nih.gov FU NCI [N01-CN-75008, NO1-CN-43301] FX The authors wish to thank Jeanne Hale, Mary Jo Cagle and Julie Gray for editorial services. Also, thanks are expressed to Tom Morgan, Bonnie Dillon and Brittany Cornelius for assistance with the animal studies. This study was supported by NCI Master Agreements N01-CN-75008 and NO1-CN-43301. NR 32 TC 15 Z9 15 U1 0 U2 4 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD SEP PY 2011 VL 26 IS 3 BP 731 EP 736 DI 10.3892/or.2011.1316 PG 6 WC Oncology SC Oncology GA 801GI UT WOS:000293426100028 PM 21617870 ER PT J AU Schindler, CW Cogan, ES Thorndike, EB Panlilio, LV AF Schindler, Charles W. Cogan, Elizabeth S. Thorndike, Eric B. Panlilio, Leigh V. TI Rapid delivery of cocaine facilitates acquisition of self-administration in rats: An effect masked by paired stimuli SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Cocaine; Self-administration; Infusion duration; Acquisition; Rat ID INTRAVENOUS-INJECTION SPEED; DOPAMINE TRANSPORTER; RHESUS-MONKEYS; REINFORCING STRENGTH; HUMANS; NICOTINE; SENSITIZATION; MAINTENANCE; INFUSION; DEPEND AB In general, faster infusions of cocaine are more likely to support behavior related to abuse than are slower infusions. However, some studies of cocaine self-administration in rats have failed to support this finding, possibly because the effect was masked by other factors. One such factor may be the pairing of a stimulus with the infusion, a procedure that is known to facilitate acquisition of drug self-administration. We compared fast and slow infusions by allowing groups of rats to acquire cocaine self-administration at a dose of 1 mg/kg/infusion, delivered over different durations (1.8 or 100s). Two groups were trained with either short or long infusions paired with a visual stimulus change ( lights off), and two other groups were trained with short or long durations but with no stimulus change. Both groups trained with a paired stimulus acquired cocaine self-administration. With no stimulus change, the rats trained with the 1.8-s infusion acquired cocaine self-administration at a rate comparable to the two groups that were trained with a paired stimulus. However, most rats in the group trained with the 100-s infusion that was not accompanied by a stimulus change failed to acquire cocaine self-administration. The stimulus itself did not support responding. These results indicate that infusing a given dose of cocaine over a longer duration reduces its ability to support self-administration, but drug-paired stimuli can partially mask this effect by enhancing the effectiveness of slow infusions. Published by Elsevier Inc. C1 [Schindler, Charles W.; Cogan, Elizabeth S.; Thorndike, Eric B.; Panlilio, Leigh V.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, DHHS,NIH,Intramural Res Program, Baltimore, MD 21224 USA. RP Schindler, CW (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, DHHS,NIH,Intramural Res Program, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM cschindl@helix.nih.gov FU NIH, NIDA FX This research was supported by the Intramural Research Program of the NIH, NIDA. NR 43 TC 8 Z9 8 U1 0 U2 0 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 SEP PY 2011 VL 99 IS 3 BP 301 EP 306 DI 10.1016/j.pbb.2011.05.005 PG 6 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 800OL UT WOS:000293371100002 PM 21600912 ER PT J AU Winter, JC Amorosi, DJ Rice, KC Cheng, KJ Yu, AM AF Winter, J. C. Amorosi, D. J. Rice, Kenner C. Cheng, Kejun Yu, Ai-Ming TI Stimulus control by 5-methoxy-N,N-dimethyltryptamine in wild-type and CYP2D6-humanized mice SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Drug-induced stimulus control; Harmaline; 5-methoxy-N,N-dimethyltryptamine; Drug interact on; CYP2D6; Humanized mice ID DISCRIMINATIVE STIMULI; PHARMACOLOGICAL ACTIONS; CYTOCHROME-P450 2D6; MONOAMINE-OXIDASE; HUMANIZED MOUSE; BETA-CARBOLINES; LSD; HALLUCINOGENS; BUFOTENINE; N,N-DIMETHYLTRYPTAMINE AB In previous studies we have observed that, in comparison with wild type mice, Tg-CYP2D6 mice have increased serum levels of bufotenine [5-hydroxy-N,N-dimethyltryptamine] following the administration of 5-MeO-DMT. Furthermore, following the injection of 5-MeO-DMT, harmaline was observed to increase serum levels of bufotenine and 5-MeO-DMT in both wild-type and Tg-CYP2D6 mice. In the present investigation, 5-MeO-DMT-induced stimulus control was established in wild-type and Tg-CYP2D6 mice. The two groups did not differ in their rate of acquisition of stimulus control. When tested with bufotenine, no 5-MeO-DMT-appropriate responding was observed. In contrast, the more lipid soluble analog of bufotenine, acetylbufotenine, was followed by an intermediate level of responding. The combination of harmaline with 5-MeO-DMT yielded a statistically significant increase in 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice; a comparable increase occurred in wild-type mice. In addition, it was noted that harmaline alone was followed by a significant degree of 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice. It is concluded that wild-type and Tg-CYPD2D6 mice do not differ in terms of acquisition of stimulus control by 5-MeO-DMT or in their response to bufotenine and acetylbufotenine. In both groups of mice, harmaline was found to enhance the stimulus effects of 5-MeO-DMT. (C) 2011 Elsevier Inc. All rights reserved. C1 [Winter, J. C.; Amorosi, D. J.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Pharmacol & Toxicol, Buffalo, NY 14214 USA. [Yu, Ai-Ming] SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Buffalo, NY 14214 USA. [Rice, Kenner C.; Cheng, Kejun] NIDA, Chem Biol Res Branch, Rockville, MD 20892 USA. RP Winter, JC (reprint author), SUNY Buffalo, Sch Med & Biomed Sci, Dept Pharmacol & Toxicol, 102 Farber Hall, Buffalo, NY 14214 USA. EM jcwinter@buffalo.edu FU National Institute on Drug Abuse [DA03385, DA021172]; National Institutes of Health FX This study was supported in part by award number DA03385 [J.C. Winter] and DA021172 [A-M Yu] from the National Institute on Drug Abuse, and National Institutes of Health. NR 36 TC 6 Z9 7 U1 0 U2 8 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 SEP PY 2011 VL 99 IS 3 BP 311 EP 315 DI 10.1016/j.pbb.2011.05.015 PG 5 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 800OL UT WOS:000293371100004 PM 21624387 ER PT J AU Deveney, CM Kim, P Brotman, MA Pine, DS Leibenluft, E AF Deveney, Christen M. Kim, Pilyoung Brotman, Melissa A. Pine, Daniel S. Leibenluft, Ellen TI NEUROIMAGING EXAMINATIONS OF INHIBITORY PROCESSES IN YOUTHS WITH SEVERE MOOD DYSREGULATION AND BIPOLAR DISORDER SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-of-Psychophysiological-Research CY SEP 14-18, 2011 CL Boston, MA SP Soc Psychophysiol Res C1 [Deveney, Christen M.; Kim, Pilyoung; Brotman, Melissa A.; Pine, Daniel S.; Leibenluft, Ellen] NIMH, NIH, HHS, Bethesda, MD USA. RI Brotman, Melissa/H-7409-2013 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 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2011 VL 48 SU 1 SI SI BP S13 EP S13 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 800TE UT WOS:000293389200071 ER PT J AU Goldman, DJ Sponheim, SR Van Meerten, N Skorheim, MK Cuthbert, BN AF Goldman, Daniel J. Sponheim, Scott R. Van Meerten, Nicolaas Skorheim, Mallory K. Cuthbert, Bruce N. TI EMOTION-MODULATED STARTLE REACTIVITY IN COMBAT VETERANS WITH AND WITHOUT PTSD AND BLAST-RELATED MILD TRAUMATIC BRAIN INJURY SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-of-Psychophysiological-Research CY SEP 14-18, 2011 CL Boston, MA SP Soc Psychophysiol Res DE startle blink; PTSD; mtbi C1 [Goldman, Daniel J.; Sponheim, Scott R.] Univ Minnesota, Minneapolis, MN 55455 USA. [Sponheim, Scott R.; Van Meerten, Nicolaas; Skorheim, Mallory K.] Minneapolis VAHCS, Minneapolis, MN USA. [Cuthbert, Bruce N.] NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2011 VL 48 SU 1 SI SI BP S110 EP S110 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 800TE UT WOS:000293389200613 ER PT J AU Nielsen, L AF Nielsen, Lisbeth TI EMOTION REGULATION AND EMOTION-COGNITION INTERACTIONS IN NORMAL AGING SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-of-Psychophysiological-Research CY SEP 14-18, 2011 CL Boston, MA SP Soc Psychophysiol Res C1 [Nielsen, Lisbeth] NIA, 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 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2011 VL 48 SU 1 SI SI BP S2 EP S2 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 800TE UT WOS:000293389200002 ER PT J AU Robinson, OJ Overstreet, C Charney, DR Letkiewicz, A Vytal, K Grillon, C AF Robinson, Oliver J. Overstreet, Cassie Charney, Danielle R. Letkiewicz, Allison Vytal, Katherine Grillon, Christian TI THE EFFECTS OF THREAT OF SHOCK ON EMOTIONAL FACE PROCESSING SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-of-Psychophysiological-Research CY SEP 14-18, 2011 CL Boston, MA SP Soc Psychophysiol Res C1 [Robinson, Oliver J.; Overstreet, Cassie; Charney, Danielle R.; Letkiewicz, Allison; Vytal, Katherine; Grillon, Christian] NIMH, 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 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2011 VL 48 SU 1 SI SI BP S7 EP S8 PG 2 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 800TE UT WOS:000293389200037 ER PT J AU Vytal, K Cornwell, B Robinson, OJ Grillon, C AF Vytal, Katherine Cornwell, Brian Robinson, Oliver J. Grillon, Christian TI RECIPROCAL INTERACTIONS BETWEEN ANXIETY AND COGNITION SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-of-Psychophysiological-Research CY SEP 14-18, 2011 CL Boston, MA SP Soc Psychophysiol Res C1 [Vytal, Katherine; Cornwell, Brian; Robinson, Oliver J.; Grillon, Christian] NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2011 VL 48 SU 1 SI SI BP S8 EP S8 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 800TE UT WOS:000293389200039 ER PT J AU White, SF Marsh, AA Fowler, KA Schechter, JC Sinclair, S Pine, DS Blair, RJR AF White, Stuart F. Marsh, Abigail A. Fowler, Katherine A. Schechter, Julia C. Sinclair, Stephen Pine, Daniel S. Blair, R. J. R. TI A TEST OF CAUSAL HYPOTHESES OF PSYCHOPATHIC TRAITS: REDUCED EMOTIONAL RESPONSIVENESS OR ANOMALOUS ATTENTIONAL CONTROL? SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-of-Psychophysiological-Research CY SEP 14-18, 2011 CL Boston, MA SP Soc Psychophysiol Res C1 [White, Stuart F.; Fowler, Katherine A.; Sinclair, Stephen; Pine, Daniel S.; Blair, R. J. R.] NIMH, NIH, HHS, Bethesda, MD USA. [Marsh, Abigail A.] Georgetown Univ, Washington, DC 20057 USA. [Schechter, Julia C.] Emory Univ, Atlanta, GA 30322 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 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2011 VL 48 SU 1 SI SI BP S13 EP S13 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 800TE UT WOS:000293389200069 ER PT J AU Saradhi, UVRV Gupta, SV Chiu, M Wang, J Ling, YH Liu, ZF Newman, DJ Covey, JM Kinghorn, AD Marcucci, G Lucas, DM Grever, MR Phelps, MA Chan, KK AF Saradhi, U. V. R. Vijaya Gupta, Sneha V. Chiu, Ming Wang, Jiang Ling, Yonghua Liu, Zhongfa Newman, David J. Covey, Joseph M. Kinghorn, A. Douglas Marcucci, Guido Lucas, David M. Grever, Michael R. Phelps, Mitch A. Chan, Kenneth K. TI Characterization of Silvestrol Pharmacokinetics in Mice Using Liquid Chromatography-Tandem Mass Spectrometry SO AAPS JOURNAL LA English DT Article DE liquid chromatography-tandem mass spectrometry; mouse plasma; pharmacokinetics; silvestrol ID AGLAIA; (-)-SILVESTROL; (-)-EPISILVESTROL; ROCAGLAMIDE; DERIVATIVES AB A sensitive and specific liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of the plant natural product silvestrol in mice, using ansamitocin P-3 as the internal standard. The method was validated in plasma with a lower limit of quantification of 1 ng/mL, accuracy ranging from 87 to 114%, and precision (coefficient of variation) below 15%. The validated method was used to characterize pharmacokinetics in C57BL/6 mice and metabolism in mouse, human and rat plasma, and liver microsomes. Mice were dosed with silvestrol formulated in hydroxypropyl-beta-cyclodextrin via intravenous, intraperitoneal, and oral routes followed by blood sampling up to 24 h. Intraperitoneal systemic availability was 100%, but oral administration resulted in only 1.7% bioavailability. Gradual degradation of silvestrol was observed in mouse and human plasma, with approximately 60% of the parent drug remaining after 6 h. In rat plasma, however, silvestrol was completely converted to silvestric acid (SA) within 10 min. Evaluation in microsomes provided further evidence that the main metabolite formed was SA, which subsequently showed no cytotoxic or cytostatic activity in a silvestrol-sensitive lymphoblastic cell line. The ability of the analytical assay to measure tissue levels of silvestrol was evaluated in liver, brain, kidney, and spleen. Results indicated the method was capable of accurately measuring tissue levels of silvestrol and suggested it has a relatively low distribution to brain. Together, these data suggest an overall favorable pharmacokinetic profile of silvestrol in mice and provide crucial information for its continued development toward potential clinical testing. C1 [Saradhi, U. V. R. Vijaya; Gupta, Sneha V.; Chiu, Ming; Wang, Jiang; Ling, Yonghua; Liu, Zhongfa; Kinghorn, A. Douglas; Marcucci, Guido; Lucas, David M.; Phelps, Mitch A.; Chan, Kenneth K.] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. [Newman, David J.; Covey, Joseph M.] NCI, Rockville, MD USA. [Marcucci, Guido; Lucas, David M.; Grever, Michael R.; Phelps, Mitch A.; Chan, Kenneth K.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. RP Phelps, MA (reprint author), Ohio State Univ, Coll Pharm, 500 W 12th Ave, Columbus, OH 43210 USA. EM mitch.phelps@osumc.edu; chan.56@osu.edu RI Liu, Zhongfa/G-8549-2013; Phelps, Mitch/H-3941-2013; Lucas, David/E-3555-2011; OI Phelps, Mitch/0000-0002-1615-5280; Kinghorn, A. Douglas/0000-0002-6647-8707 FU U.S. National Cancer Institute [N01-CM-52205, P01-CA125066, P50-CA140158]; Ohio State University Comprehensive Cancer Center [P30-CA016058-35] FX This work was supported by the U.S. National Cancer Institute [Contract N01-CM-52205 to KKC, P01-CA125066 to ADK, SPORE P50-CA140158 to MRG, and The Ohio State University Comprehensive Cancer Center Core Grant (P30-CA016058-35) supporting the Experimental Therapeutics Program and Pharmacoanalytical Shared Resource]. NR 17 TC 18 Z9 18 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD SEP PY 2011 VL 13 IS 3 BP 347 EP 356 DI 10.1208/s12248-011-9273-x PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 798ES UT WOS:000293186000006 PM 21499689 ER PT J AU Lubin, JH Muscat, J Gaudet, MM Olshan, AF Curado, MP Dal Maso, L Wunsch, V Sturgis, EM Szeszenia-Dabrowska, N Castellsague, X Zhang, ZF Smith, E Fernandez, L Matos, E Franceschi, S Fabianova, E Rudnai, P Purdue, MP Mates, D Wei, QY Herrero, R Kelsey, K Morgenstern, H Shangina, O Koifman, S Lissowska, J Levi, F Daudt, AW Neto, JE Chen, C Lazarus, P Winn, DM Schwartz, SM Boffetta, P Brennan, P Menezes, A La Vecchia, C McClean, M Talamini, R Rajkumar, T Hayes, RB Hashibe, M AF Lubin, Jay H. Muscat, Joshua Gaudet, Mia M. Olshan, Andrew F. Curado, Maria Paula Dal Maso, Luigino Wuensch-Filho, Victor Sturgis, Erich M. Szeszenia-Dabrowska, Neonilia Castellsague, Xavier Zhang, Zuo-Feng Smith, Elaine Fernandez, Leticia Matos, Elena Franceschi, Silvia Fabianova, Eleonora Rudnai, Peter Purdue, Mark P. Mates, Dana Wei, Qingyi Herrero, Rolando Kelsey, Karl Morgenstern, Hal Shangina, Oxana Koifman, Sergio Lissowska, Jolanta Levi, Fabio Daudt, Alexander W. Eluf Neto, Jose Chen, Chu Lazarus, Philip Winn, Deborah M. Schwartz, Stephen M. Boffetta, Paolo Brennan, Paul Menezes, Ana La Vecchia, Carlo McClean, Michael Talamini, Renato Rajkumar, Thangarajan Hayes, Richard B. Hashibe, Mia TI An examination of male and female odds ratios by BMI, cigarette smoking, and alcohol consumption for cancers of the oral cavity, pharynx, and larynx in pooled data from 15 case-control studies SO CANCER CAUSES & CONTROL LA English DT Article DE Alcohol consumption; Cigarette smoking; Interactions; Odds ratio models ID BODY-MASS INDEX; HUMAN-PAPILLOMAVIRUS INFECTION; SQUAMOUS-CELL CARCINOMA; NECK-CANCER; OROPHARYNGEAL CANCER; UNITED-STATES; INTERNATIONAL HEAD; INHANCE CONSORTIUM; HPV INFECTION; RISK AB Greater tobacco smoking and alcohol consumption and lower body mass index (BMI) increase odds ratios (OR) for oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers; however, there are no comprehensive sex-specific comparisons of ORs for these factors. We analyzed 2,441 oral cavity (925 women and 1,516 men), 2,297 oropharynx (564 women and 1,733 men), 508 hypopharynx (96 women and 412 men), and 1,740 larynx (237 women and 1,503 men) cases from the INHANCE consortium of 15 head and neck cancer case-control studies. Controls numbered from 7,604 to 13,829 subjects, depending on analysis. Analyses fitted linear-exponential excess ORs models. ORs were increased in underweight (< 18.5 BMI) relative to normal weight (18.5-24.9) and reduced in overweight and obese categories (a parts per thousand yen25 BMI) for all sites and were homogeneous by sex. ORs by smoking and drinking in women compared with men were significantly greater for oropharyngeal cancer (p < 0.01 for both factors), suggestive for hypopharyngeal cancer (p = 0.05 and p = 0.06, respectively), but homogeneous for oral cavity (p = 0.56 and p = 0.64) and laryngeal (p = 0.18 and p = 0.72) cancers. The extent that OR modifications of smoking and drinking by sex for oropharyngeal and, possibly, hypopharyngeal cancers represent true associations, or derive from unmeasured confounders or unobserved sex-related disease subtypes (e.g., human papillomavirus-positive oropharyngeal cancer) remains to be clarified. C1 [Lubin, Jay H.; Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Muscat, Joshua; Lazarus, Philip] Penn State Coll Med, Hershey, PA USA. [Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Olshan, Andrew F.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Curado, Maria Paula; Franceschi, Silvia; Boffetta, Paolo; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Dal Maso, Luigino; Talamini, Renato] Aviano Canc Ctr, Epidemiol & Biostat Unit, I-33081 Aviano, Italy. [Wuensch-Filho, Victor; Eluf Neto, Jose] Univ Sao Paulo, Sao Paulo, Brazil. [Sturgis, Erich M.; Wei, Qingyi] UT MD Anderson Canc Ctr, Houston, TX USA. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Lodz, Poland. [Castellsague, Xavier] CIBER ESP, IDIBELL, ICO, Barcelona, Spain. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Smith, Elaine] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. [Fernandez, Leticia] Inst Oncol & Radiobiol, Havana, Cuba. [Matos, Elena] Univ Buenos Aires, Inst Oncol Angel H Roffo, Buenos Aires, DF, Argentina. [Fabianova, Eleonora] Specialized State Hlth Inst, Banska Bystrica, Slovakia. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Mates, Dana] Inst Publ Hlth, Dept Occupat Hlth, Bucharest, Romania. [Herrero, Rolando] Inst Invest Epidemiol, San Jose, Costa Rica. [Kelsey, Karl] Brown Univ, Bio Med Ctr Environm Hlth & Technol, Providence, RI 02912 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Shangina, Oxana] Russian Acad Med Sci, Canc Res Ctr, Moscow, Russia. [Koifman, Sergio] Fundacao Oswaldo Cruz, Escola Nacl Saude Publ, Rio De Janeiro, Brazil. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Levi, Fabio] Univ Lausanne, Inst Med Sociale & Prevent, Lausanne, Switzerland. [Daudt, Alexander W.] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Chen, Chu; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Winn, Deborah M.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Boffetta, Paolo] Mt Sinai Sch Med, New York, NY USA. [Menezes, Ana] Univ Fed Pelotas, Pelotas, Brazil. [La Vecchia, Carlo] Ist Ric Farmacol Mario Negri, Milan, Italy. [La Vecchia, Carlo] Univ Milan, Milan, Italy. [McClean, Michael] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Rajkumar, Thangarajan] Canc Inst WIA, Dept Mol Oncol, Madras, Tamil Nadu, India. [Hayes, Richard B.] NYU, Langone Med Ctr, Div Epidemiol, New York, NY USA. [Hashibe, Mia] Univ Utah, Huntsman Canc Inst, Dept Family & Prevent Med, Salt Lake City, UT USA. RP Lubin, JH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20852 USA. EM lubinj@mail.nih.gov RI Sriwisit, Sukhumaphorn/G-1405-2011; Wunsch Filho, Victor/C-4475-2012; Inca, Inct/K-2204-2013; Epidemiologicas, Centro de pesquisas /D-4561-2013; Menezes, Ana/G-7266-2012; Szeszenia-Dabrowska, Neonila/F-7190-2010; McClean, Michael/J-2934-2015; Castellsague Pique, Xavier/N-5795-2014; Eluf-Neto, Jose/B-2522-2009; Purdue, Mark/C-9228-2016; Curado, Maria Paula/M-6200-2013; OI Castellsague Pique, Xavier/0000-0002-0802-3595; Eluf-Neto, Jose/0000-0001-7504-2115; Purdue, Mark/0000-0003-1177-3108; Curado, Maria Paula/0000-0001-8172-2483; mates, dana/0000-0002-6219-9807; Lissowska, Jolanta/0000-0003-2695-5799; dal maso, luigino/0000-0001-6163-200X; La Vecchia, Carlo/0000-0003-1441-897X; Hayes, Richard/0000-0002-0918-661X FU National Institutes of Health; National Cancer Institute, Department of Health and Human Services; National Institute of Environmental Health Sciences [P30ES10126] FX This research was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute, Department of Health and Human Services and by a grant from the National Institute of Environmental Health Sciences (P30ES10126). NR 62 TC 14 Z9 14 U1 3 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2011 VL 22 IS 9 BP 1217 EP 1231 DI 10.1007/s10552-011-9792-x PG 15 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 799OO UT WOS:000293296200001 PM 21744095 ER PT J AU Andreotti, G Liu, EJ Gao, YT Safaeian, M Rashid, A Shen, MC Wang, BS Deng, J Han, TQ Zhang, BH Hsing, AW AF Andreotti, Gabriella Liu, Enju Gao, Yu-Tang Safaeian, Mahboobeh Rashid, Asif Shen, Ming-Chang Wang, Bin-Shen Deng, Jie Han, Tian-Quian Zhang, Bai-He Hsing, Ann W. TI Medical history and the risk of biliary tract cancers in Shanghai, China: implications for a role of inflammation SO CANCER CAUSES & CONTROL LA English DT Article DE Biliary tract cancer; Biliary stones; Medical history; Inflammation; China ID NITRIC-OXIDE; GALLBLADDER CARCINOGENESIS; CHRONIC CHOLECYSTITIS; INSULIN-RESISTANCE; GALL-BLADDER; CARCINOMA; LESIONS; EXPRESSION; GALLSTONES; INFECTION AB Several lines of evidence suggest that inflammation may play a role in the etiology of biliary tract cancers. To examine further the role of inflammation, we evaluated the associations between self-reported inflammatory-related medical conditions and the risk of biliary tract cancers in a population-based case-control study in Shanghai, China. Our analysis included 368 gallbladder cancer cases, 191 bile duct cancer cases, 68 ampulla of Vater cancer cases, and 959 healthy subjects. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for biliary tract cancers in relation to six inflammation-related conditions. Gallbladder cancer was significantly associated with cholecystitis occurring at least 5 years prior to interview (OR = 1.7, 95% CI 1.1-2.9). Even though biliary stones did not significantly modify the associations between cholecystitis and gallbladder cancer, 90% of the gallbladder cancer cases with cholecystitis also had biliary stones, indicating that stones likely play an important role in the link between cholecystitis and gallbladder cancer. Among subjects who smoked and drank alcohol, a history of gastric (OR = 4.3, 95% CI 1.2-15.0) or duodenal ulcers (OR = 3.7, 1.2-12.0) was associated with an excess risk of gallbladder cancer. Although the mechanisms are unclear, our results further support the role for inflammation in the etiology of biliary tract cancers. C1 [Andreotti, Gabriella; Safaeian, Mahboobeh; Hsing, Ann W.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Liu, Enju; Gao, Yu-Tang; Deng, Jie] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Rashid, Asif] Univ Texas Houston, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Shen, Ming-Chang] Fudan Univ, Shanghai Tumor Hosp, Shanghai 200433, Peoples R China. [Wang, Bin-Shen] Fudan Univ, Zhong Shan Hosp, Shanghai 200433, Peoples R China. [Han, Tian-Quian] Shanghai Med Univ 2, Rui Jin Hosp, Dept Surg, Shanghai, Peoples R China. [Zhang, Bai-He] Shanghai Second Mil Univ, Inst E Hepatobiliary Surg, Shanghai, Peoples R China. RP Andreotti, G (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8011,MSC 7240, Bethesda, MD 20892 USA. EM andreotg@mail.nih.gov RI liu, enju/F-4062-2010 FU National Institute of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, USA FX We thank the collaborating surgeons and pathologists in Shanghai for assistance in patient recruitment and pathology review; Chia-Rong Cheng, Lu Sun, and Kai Wu of the Shanghai Cancer Institute for coordinating data and specimen collection; and Shelley Niwa of Westat for support with study and data management. The study was funded by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, USA. NR 29 TC 8 Z9 9 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2011 VL 22 IS 9 BP 1289 EP 1296 DI 10.1007/s10552-011-9802-z PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 799OO UT WOS:000293296200007 PM 21744094 ER PT J AU Volpe, A Cadeddu, JA Cestari, A Gill, IS Jewett, MAS Joniau, S Kirkali, Z Marberger, M Patard, JJ Staehler, M Uzzo, RG AF Volpe, Alessandro Cadeddu, Jeffrey A. Cestari, Andrea Gill, Inderbir S. Jewett, Michael A. S. Joniau, Steven Kirkali, Ziya Marberger, Michael Patard, Jean Jacques Staehler, Michael Uzzo, Robert G. TI Contemporary Management of Small Renal Masses SO EUROPEAN UROLOGY LA English DT Review DE Carcinoma, renal cell; Cryoablation; Nephron-sparing surgery; Partial nephrectomy; Renal mass; Renal tumour biopsy; Surveillance; Thermal ablation ID LAPAROSCOPIC PARTIAL NEPHRECTOMY; NEPHRON-SPARING SURGERY; INTENSITY FOCUSED ULTRASOUND; NORMAL CONTRALATERAL KIDNEY; RADIO-FREQUENCY ABLATION; PERCUTANEOUS RADIOFREQUENCY ABLATION; WARM ISCHEMIA TIME; CELL CARCINOMA; ACTIVE SURVEILLANCE; NATURAL-HISTORY AB Context: An increasing number of small renal masses (SRMs) with heterogeneous histology and clinical behaviour are being detected with modern radiologic imaging. Although surgical removal is the standard of care for small renal tumours, alternative minimally invasive and conservative treatment options are possible in selected patients with shorter life expectancy. Objective: To systematically review indications, techniques, and outcomes of surgical and conservative treatments of SRMs. Evidence acquisition: A literature search of English-language publications was performed using the Medline database from January 2000 to February 2011 using the terms renal mass and renal carcinoma in conjunction with the evaluated management options. The articles that provided the highest level of evidence were selected with the consensus of all the authors and reviewed. Evidence synthesis: Only one randomised controlled trial comparing the results of elective nephron-sparing surgery and radical nephrectomy for low-stage renal tumours is available. Few comparative studies of different treatment options for SRMs have been published. The assessment of oncologic outcomes is therefore based mainly on observational studies. Most series of nonsurgical therapies have strong selection biases and relatively short follow-up. Treatment selection is based on the clinical and histologic characteristics of SRMs, on patient age and comorbidities, and on personal preferences and experience of the urologist. Conclusions: Partial nephrectomy (PN) is the standard treatment for solitary SRMs whenever it is technically feasible. Laparoscopic PN is an alternative to open PN in experienced hands. The rationale of ablative treatments is to treat incidental cortical SRMs in patients at high surgical risk with potentially reduced morbidity. Active surveillance is considered an appropriate strategy for the elderly or for patients with significant comorbidity who have a shorter life expectancy. Percutaneous biopsies are increasingly being used to establish histology of SRMs and support treatment decisions, especially for patients who are candidates for nonsurgical treatment. (C) 2011 Published by Elsevier B. V. on behalf of European Association of Urology. C1 [Volpe, Alessandro] Univ Piemonte Orientale, Maggiore Carita Hosp, Div Urol, I-28100 Novara, Italy. [Cadeddu, Jeffrey A.] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. [Cestari, Andrea] Univ Vita Salute, Hosp San Raffaele, Dept Urol, Milan, Italy. [Gill, Inderbir S.] Univ So Calif, Keck Sch Med, USC Inst Urol, Los Angeles, CA 90033 USA. [Jewett, Michael A. S.] Univ Toronto, Princess Margaret Hosp, Dept Surg & Surg Oncol, Div Urol, Toronto, ON M5S 1A1, Canada. [Jewett, Michael A. S.] Univ Toronto, Univ Hlth Network, Toronto, ON M5S 1A1, Canada. [Joniau, Steven] Katholieke Univ Leuven Hosp, Dept Urol, Louvain, Belgium. [Kirkali, Ziya] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. [Marberger, Michael] Med Univ Vienna, Dept Urol, Vienna, Austria. [Patard, Jean Jacques] Univ Paris 11, Bicetre Hosp, Dept Urol, Paris, France. [Staehler, Michael] Univ Munich, Klinikum Grosshadern, Dept Urol, D-8000 Munich, Germany. [Uzzo, Robert G.] Fox Chase Canc Ctr, Dept Urol Oncol, Philadelphia, PA 19111 USA. RP Volpe, A (reprint author), Univ Piemonte Orientale, Maggiore Carita Hosp, Div Urol, Corso Mazzini 18, I-28100 Novara, Italy. EM alessandro.volpe@med.unipmn.it RI Joniau, Steven/K-7655-2013 OI Joniau, Steven/0000-0003-3195-9890 NR 134 TC 90 Z9 92 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD SEP PY 2011 VL 60 IS 3 BP 501 EP 515 DI 10.1016/j.eururo.2011.05.044 PG 15 WC Urology & Nephrology SC Urology & Nephrology GA 799JN UT WOS:000293283100029 PM 21664040 ER PT J AU Nguyen, CM Levy, AJ AF Nguyen, Chien M. Levy, Alan J. TI Mechanics of interface failure in the trilayer elastic composite SO INTERNATIONAL JOURNAL OF SOLIDS AND STRUCTURES LA English DT Article DE Debonding; Layers; Interface; Integral equation; Cohesion; Imperfections; Bifurcation; Elasticity ID FRP-CONCRETE INTERFACE; RC BEAMS; DECOHESION; FRACTURE; DELAMINATION; SUBSTRATE; BEHAVIOR; CRACKING; CONTACT; PLATE AB An exact analysis of the mechanics of interface failure is presented for a trilayer composite system consisting of geometrically and materially distinct linear elastic layers separated by straight nonlinear, uniform and nonuniform decohesive interfaces. The technical significance of this system stems from its utility in representing two slabs joined together by a third adhesive layer whose thickness cannot be neglected. The formulation, based on exact infinitesimal strain elasticity solutions for rectangular domains, employs a methodology recently developed by the authors to investigate both solitary defect as well as multiple defect interaction problems in layered systems under arbitrary loading. Interfacial integral equations, governing the normal and tangential displacement jump components at the interfaces, are solved for the uniformly loaded trilayer system. Interfacial defects, taken in the form of interface perturbations and nonbonded portions of interface, are modeled by coordinate dependent interface strengths. They are examined in a variety of configurations chosen so as to shed light on the various interfacial failure mechanisms active in layered systems. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Levy, Alan J.] Syracuse Univ, Dept Mech & Aerosp Engn, Syracuse, NY 13244 USA. [Nguyen, Chien M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Levy, AJ (reprint author), Syracuse Univ, Dept Mech & Aerosp Engn, Syracuse, NY 13244 USA. EM ajlevy@syr.edu NR 30 TC 3 Z9 3 U1 4 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0020-7683 J9 INT J SOLIDS STRUCT JI Int. J. Solids Struct. PD SEP 1 PY 2011 VL 48 IS 18 BP 2467 EP 2484 DI 10.1016/j.ijsolstr.2011.04.018 PG 18 WC Mechanics SC Mechanics GA 798JN UT WOS:000293202100003 ER PT J AU Benson, JF Hostetler, JA Onorato, DP Johnson, WE Roelke, ME O'Brien, SJ Jansen, D Oli, MK AF Benson, John F. Hostetler, Jeffrey A. Onorato, David P. Johnson, Warren E. Roelke, Melody E. O'Brien, Stephen J. Jansen, Deborah Oli, Madan K. TI Intentional genetic introgression influences survival of adults and subadults in a small, inbred felid population SO JOURNAL OF ANIMAL ECOLOGY LA English DT Article DE admixture; AIC; Cox proportional hazard; demographic parameter; heterosis; hybridization; model averaging ID FLORIDA PANTHER; HYBRID VIGOR; CONSERVATION; HYBRIDIZATION; MANAGEMENT; EXTINCTION; DISPERSAL; MODELS; METAPOPULATION; RESTORATION AB 1. Inbreeding and low genetic diversity can cause reductions in individual fitness and increase extinction risk in animal populations. Intentional introgression, achieved by releasing genetically diverse individuals into inbred populations, has been used as a conservation tool to improve demographic performance in endangered populations. 2. By the 1980s, Florida panthers (Puma concolor coryi) had been reduced to a small, inbred population that appeared to be on the brink of extinction. In 1995, female pumas from Texas (P. c. stanleyana) were released in occupied panther range as part of an intentional introgression programme to restore genetic variability and improve demographic performance of panthers. 3. We used 25 years (1981-2006) of continuous radiotelemetry and genetic data to estimate and model subadult and adult panther survival and cause-specific mortality to provide rigorous sex and age class-specific survival estimates and evaluate the effect of the introgression programme on these parameters. 4. Genetic ancestry influenced annual survival of subadults and adults after introgression, as F-1 generation admixed panthers ((s) over cap = 0 98) survived better than pre-introgression type panthers ((s) over cap = 0 77) and other admixed individuals ((s) over cap = 0 82). Furthermore, heterozygosity was higher for admixed panthers relative to pre-introgression type panthers and positively influenced survival. 5. Our results are consistent with hybrid vigour; however, extrinsic factors such as low density of males in some areas of panther range may also have contributed to higher survival of F-1 panthers. Regardless, improved survival of F-1 subadults and adults likely contributed to the numerical increase in panthers following introgression, and our results indicate that intentional admixture, achieved here by releasing individuals from another population, appears to have been successful in improving demographic performance in this highly endangered population. C1 [Benson, John F.; Onorato, David P.] Florida Fish & Wildlife Conservat Commiss, US Fish & Wildlife Res Inst, Naples, FL 34114 USA. [Hostetler, Jeffrey A.; Oli, Madan K.] Univ Florida, Dept Wildlife Ecol & Conservat, Gainesville, FL 32611 USA. [Johnson, Warren E.; Roelke, Melody E.; O'Brien, Stephen J.] NCI, Lab Genom Div, Frederick, MD 21702 USA. [Roelke, Melody E.] NCI, SAIC Frederick, Frederick, MD 21702 USA. [Jansen, Deborah] Big Cypress Natl Preserve, Ochopee, FL 34141 USA. RP Hostetler, JA (reprint author), Smithsonian Conservat Biol Inst, Migratory Bird Ctr, Natl Zool Pk,MRC SS03, Washington, DC 20013 USA. EM hostetlerj@si.edu RI Hostetler, Jeffrey/A-3345-2011; Johnson, Warren/D-4149-2016 OI Hostetler, Jeffrey/0000-0003-3669-1758; Johnson, Warren/0000-0002-5954-186X FU Florida Panther Research and Management Trust; National Park Service; University of Florida; United States Fish and Wildlife Service FX We thank D. Land, M. Cunningham, Roy McBride, M. Lotz, D. Shindle, S. Schulze, D. Giardina, A. Johnson, S. Bass, L. Oberhofer, M. Alvarado, H. Fitting and Rocky McBride, Rowdy McBride, C. McBride and others for assistance with fieldwork. We also thank B. Bolker, D. Valle, J. White, J. Nichols and G. White for statistical assistance or advice and D. Land, Roy McBride, B. Bolker, J. Nichols, A. Singh, M. Lotz, M. Cunningham, T. O'Meara, J. Gore, P. Mahoney and two anonymous reviewers for reviewing earlier versions of this manuscript. This work was funded through the Florida Panther Research and Management Trust Fund, National Park Service, University of Florida, and a grant from the United States Fish and Wildlife Service. NR 70 TC 15 Z9 15 U1 1 U2 57 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-8790 J9 J ANIM ECOL JI J. Anim. Ecol. PD SEP PY 2011 VL 80 IS 5 BP 958 EP 967 DI 10.1111/j.1365-2656.2011.01809.x PG 10 WC Ecology; Zoology SC Environmental Sciences & Ecology; Zoology GA 798BN UT WOS:000293176400007 PM 21338353 ER PT J AU Pandya, A Yakel, JL AF Pandya, Anshul Yakel, Jerrel L. TI Allosteric Modulator Desformylflustrabromine Relieves the Inhibition of alpha 2 beta 2 and alpha 4 beta 2 Nicotinic Acetylcholine Receptors by beta-Amyloid(1-42) Peptide SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Alzheimer's disease (AD); Beta amyloid (A beta(1-42)); Desformylflustrabromine (dFBr); Electrophysiology; Nicotinic acetylcholine receptors (nAChRs); Positive allosteric modulators (PAMs) ID ALZHEIMERS-DISEASE; FLUSTRA-FOLIACEA; RAT HIPPOCAMPUS; XENOPUS OOCYTES; ACH RECEPTORS; BRAIN; NEURONS; SUBTYPE; INTERNEURONS; POTENTIATION AB Nicotinic acetylcholine receptors (nAChRs) are pentameric transmembrane proteins that belong to the cys-loop ligand-gated ion channel family. These receptors are widely expressed in the brain and implicated in the pathophysiology of many neurological conditions, including Alzheimer's disease (AD), where typical symptoms include the loss of cognitive function and dementia. The presence of extracellular neuritic plaques composed of beta amyloid (A beta(1-42)) peptide is a characteristic feature of AD. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) for alpha 4 beta 2 nAChRs since it increases peak ACh responses without inducing a response on its own. Previously, the effect of dFBr on the alpha 2 beta 2 nAChR subtype was not known. The action of dFBr was tested on alpha 2 beta 2 receptors expressed in Xenopus oocytes. It was found that dFBr is also a PAM for the alpha 2 beta 2 receptor. Next we tested whether dFBr had any effect on the previously known block of both the alpha 4 beta 2 and alpha 2 beta 2 receptors by A beta(1-42). We found that the functional blockade of ACh-induced currents in oocytes expressing alpha 4 beta 2 and alpha 2 beta 2 receptors by A beta(1-42) was prevented by dFBr. We conclude that dFBr is a positive allosteric modulator for both alpha 4 beta 2 and alpha 2 beta 2 subtypes of nAChRs and that it also relieves the blockade of these receptors by A beta(1-42). This study demonstrates that PAMs for the non-alpha 7 nAChRs have the potential to develop into clinically applicable drugs for AD and other disorders. C1 [Pandya, Anshul; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, MD F2-08,POB 12233, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov FU National Institute of Environmental Health Sciences, NIH FX We would like to thank Patricia Lamb for the synthesis of mRNA and other molecular biology work. We extend our appreciation to C. Erxleben and R. Saha for advice in preparing the manuscript. This research was supported by the Intramural Research Program of National Institute of Environmental Health Sciences, NIH. NR 34 TC 20 Z9 21 U1 2 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD SEP PY 2011 VL 45 IS 1 BP 42 EP 47 DI 10.1007/s12031-011-9509-3 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 798GT UT WOS:000293191300006 PM 21424792 ER PT J AU Houghton, PJ Lock, R Carol, H Morton, CL Phelps, D Gorlick, R Kolb, EA Keir, ST Reynolds, CP Kang, MH Maris, JM Wozniak, AW Gu, YC Wilson, WR Smith, MA AF Houghton, Peter J. Lock, Richard Carol, Hernan Morton, Christopher L. Phelps, Doris Gorlick, Richard Kolb, E. Anders Keir, Stephen T. Reynolds, C. Patrick Kang, Min H. Maris, John M. Wozniak, Amy W. Gu, Yongchuan Wilson, William R. Smith, Malcolm A. TI Initial Testing of the Hypoxia-Activated Prodrug PR-104 by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; preclinical testing; PR-104 ID MARROW HEMATOPOIETIC COMPARTMENT; MODELING PO(2) DISTRIBUTIONS; KETO REDUCTASE 1C3; SOLID TUMORS; IN-VIVO; CANCER MODELS; SYSTEMIC EXPOSURE; DRUG DEVELOPMENT; CELL-LINES; XENOGRAFTS AB Background. PR-104 is rapidly hydrolyzed to PR-104A in vivo, which is activated by reduction to the corresponding 5-hydroxylamine (PR-104H) and amine (PR-104M) to produce DNA interstrand cross-links. PR-104 activation can occur via hypoxia-dependent reductases and also independently of hypoxia by aldo-keto reductase (AKR) 1C3. Procedures. PR-104A was tested against the PPTP in vitropanel(10 nM to 100 mu M), and PR-104 in vivo using a weekly x 6 schedule at its maximum tolerated dose (MTD) of 550 mg/kg. Subsequently PR-104 was tested at 270 and 110 mg/kg. Pharmacokinetics for PR-104 and its metabolites were determined, as were levels of AKR1C3 RNA and protein in xenografts. Results. In vitro, the leukemia models were most sensitive to PR-104A. In vivo, PR-104 induced objective responses at its MTD in 21/34 solid tumor models and maintained complete responses against 7/7 acute lymphoblastic leukemia (ALL) models. At 270 mg/kg and lower dose levels, PR-104 did not induce solid tumor regressions, suggesting a steep dose-response relationship. Pharmacokinetic analysis suggests higher systemic exposures to PR-104A and its metabolites in mice compared to those achievable in patients. Levels of AKR1C3 protein did not correlate with tumor responsiveness. Conclusions. As monotherapy, PR-104 demonstrated a high level of activity against both solid tumor and ALL models at its MTD, but the activity was almost completely lost at half the MTD dose for solid tumors. Pharmacokinetic data at the PR-104 MTD from human trials suggest that PR-104 metabolites may not reach the plasma exposures in children that were associated with high-level preclinical activity. Pediatr Blood Cancer 2011; 57: 443-453. (C) 2010 Wiley-Liss, Inc. C1 [Houghton, Peter J.] Nationwide Childrens Hosp, Ctr Childhood Canc, Res Inst, Columbus, OH 43205 USA. [Lock, Richard; Carol, Hernan; Wozniak, Amy W.] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Morton, Christopher L.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Gu, Yongchuan; Wilson, William R.] Univ Auckland, Auckland Canc Soc Res Ctr, Auckland 1, New Zealand. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Houghton, PJ (reprint author), Nationwide Childrens Hosp, Ctr Childhood Canc, Res Inst, 700 Childrens Dr, Columbus, OH 43205 USA. EM peter.houghton@nationwidechildrens.org RI Houghton, Peter/E-3265-2011; Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786]; Health Research Council of New Zealand [HRC08/103] FX Grant sponsor: National Cancer Institute; Grant number: NO1-CM-42216; Grant number: CA21765; Grant number: CA108786; Grant sponsor: Health Research Council of New Zealand; Grant number: HRC08/103. NR 40 TC 13 Z9 14 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2011 VL 57 IS 3 BP 443 EP 453 DI 10.1002/pbc.22921 PG 11 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 799GD UT WOS:000293272800015 PM 21744473 ER PT J AU Kamdar, KY Krull, KR El-Zein, RA Brouwers, P Potter, BS Harris, LL Holm, S Dreyer, Z Scaglia, F Etzel, CJ Bondy, M Okcu, MF AF Kamdar, Kala Y. Krull, Kevin R. El-Zein, Randa A. Brouwers, Pim Potter, Brian S. Harris, Lynnette L. Holm, Suzanne Dreyer, ZoAnn Scaglia, Fernando Etzel, Carol J. Bondy, Melissa Okcu, M. Fatih TI Folate Pathway Polymorphisms Predict Deficits in Attention and Processing Speed After Childhood Leukemia Therapy SO PEDIATRIC BLOOD & CANCER LA English DT Article DE folate; leukemia; neurocognitive; survivor ID ACUTE LYMPHOBLASTIC-LEUKEMIA; LONG-TERM SURVIVORS; THYMIDYLATE SYNTHASE; METHYLENETETRAHYDROFOLATE REDUCTASE; INTRAVENOUS METHOTREXATE; PLASMA HOMOCYSTEINE; CRANIAL RADIATION; CANCER; CHEMOTHERAPY; CHILDREN AB Background. Neurocognitive impairment occurs in 20-40% of childhood acute lymphoblastic leukemia (ALL) survivors, possibly mediated by folate depletion and homocysteine elevation following methotrexate treatment. We evaluated the relationship between folate pathway polymorphisms and neurocognitive impairment after childhood ALL chemotherapy. Procedure. Seventy-two childhood ALL survivors treated with chemotherapy alone underwent a neurocognitive battery consisting of: Trail Making Tests A (TMTA) and B (TMTB), Grooved Pegboard Test Dominant-Hand and Nondominant-Hand, Digit Span subtest, and Verbal Fluency Test. We performed genotyping for: 10-methylenetetrahydrofolate reductase (MTHFR 677C>T and MTHFR 1298A>C), serine hydroxymethyltransferase (SHMT 1420C>T), methionine synthase (MS 2756 A>G), methionine synthase reductase (MTRR 66A>G), and thymidylate synthase (TSER). Student's two sample t-test and analysis of covariance were used to compare test scores by genotype. Results. General impairment on the neurocognitive battery was related to MTHFR 1298A>C (P = 0.03) and MS 2756A>G (P = 0.05). Specifically, survivors with MTHFR 1298AC/CC genotypes scored, on average, 13 points lower on TMTB than those with MTHFR 1298AA genotype (P = 0.001). The MS 2756AA genotype was associated with a 12.2 point lower mean TMTA score, compared to MS 2756 AG/GG genotypes (P = 0.01). The TSER 2R/3R and 3R/3R genotypes were associated with an 11.4 point lower mean score on TMTB, compared to the TSER 2R/2R genotype (P = 0.03). Survivors with >= 6 folate pathway risk alleles demonstrated a 9.5 point lower mean TMTA score (P = 0.06) and 14.5 point lower TMTB score (P = 0.002) than survivors with <6 risk alleles. Conclusions. Folate pathway polymorphisms are associated with deficits in attention and processing speed after childhood ALL therapy. Pediatr Blood Cancer 2011; 57: 454-460. (C) 2011 Wiley-Liss, Inc. C1 [Kamdar, Kala Y.; Brouwers, Pim; Harris, Lynnette L.; Holm, Suzanne; Dreyer, ZoAnn; Okcu, M. Fatih] Texas Childrens Canc Ctr, Dept Pediat, Baylor Coll Med, Houston, TX 77030 USA. [Kamdar, Kala Y.; El-Zein, Randa A.; Bondy, Melissa; Okcu, M. Fatih] Childhood Canc Epidemiol & Prevent Ctr, Houston, TX USA. [Krull, Kevin R.] St Jude Childrens Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [El-Zein, Randa A.; Etzel, Carol J.; Bondy, Melissa] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Brouwers, Pim] NIMH, Div AIDS Res, Rockville, MD 20857 USA. [Potter, Brian S.] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA. [Scaglia, Fernando] Texas Childrens Hosp, Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Kamdar, KY (reprint author), Texas Childrens Canc Ctr, Dept Pediat, Baylor Coll Med, 1102 Bates St,Suite 1220, Houston, TX 77030 USA. EM kykamdar@txccc.org FU NCI [R25T CA57730] FX Grant sponsor: M.D. Anderson Education Program in Cancer Prevention (NCI Training, PI: Robert M. Chamberlain); Grant number: R25T CA57730. NR 43 TC 19 Z9 20 U1 3 U2 7 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2011 VL 57 IS 3 BP 454 EP 460 DI 10.1002/pbc.23162 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 799GD UT WOS:000293272800016 PM 21618410 ER PT J AU Jagoda, EM Lang, LX Mccullough, K Contoreggi, C Kim, BM Ma, Y Rice, KC Szajek, LP Eckelman, WC Kiesewetter, DO AF Jagoda, Elaine M. Lang, Lixin Mccullough, Karen Contoreggi, Carlo Kim, B. Moon Ma, Ying Rice, Kenner C. Szajek, Lawrence P. Eckelman, William C. Kiesewetter, Dale O. TI [Br-76]BMK-152, a Nonpeptide Analogue, With High Affinity and Low Nonspecific Binding for the Corticotropin-Releasing Factor Type 1 Receptor SO SYNAPSE LA English DT Article DE corticotropin-releasing factor type 1 receptors; CRF1 receptor; Br-76 BMK; PET ID CENTRAL-NERVOUS-SYSTEM; FACTOR CRF RECEPTORS; ANTAGONIST ANTALARMIN; AUTORADIOGRAPHIC LOCALIZATION; P-GLYCOPROTEIN; PRIMATE BRAIN; I RECEPTOR; RAT-BRAIN; G-PROTEIN; HORMONE AB Corticotropin-releasing factor (CRF), a neuropeptide, regulates endocrine and autonomic responses to stress through G-protein coupled receptors, CRF1 or CRF2. A PET ligand able to monitor changes in CRF1 receptor occupancy in vivo would aid in understanding the pathophysiology of stress-related diseases as well as in the clinical development of nonpeptide antagonists with therapeutic value. We have radiolabeled the CRF1 receptor ligand, [8-(4-bromo-2,6-dimethoxyphenyl)-2,7-dimethylpyrazolo[1,5-alpha][1,3,5]triazin-4-yl]-N,N-bis-(2-methoxyethyl)amine (BMK-152) (ClogP = 2.6), at both the 3 and 4 position with [Br-76]. Using in vitro autoradiography saturation studies the 4-[Br-76]BMK-152 exhibited high affinity binding to both rat (K-d = 0.23 +/- 0.07 nM; n = 3) and monkey frontal cortex (K-d = 0.31 +/- 0.08 nM; n = 3) consistent with CRF1 receptor regional distribution whereas with the 3-[Br-76]BMK-152, the K(d)s could not be determined due to high nonspecific binding. In vitro autoradiography competition studies using [I-125]Tyr(0)-o-CRF confirmed that 3-Br-BMK-152 (K-i = 24.4 +/- 4.9 nM; n = 3) had lower affinity (70-fold) than 4-Br-BMK-152 (K-i = 0.35 +/- 0.07 nM; n 5 3) in monkey frontal cortex and similiar studies using [I-125] Sauvagine confirmed CRF1 receptor selectivity. In vivo studies with P-glycoprotein (PGP) knockout mice ( KO) and their wild-type littermates (WT) showed that the brain uptake of 3-[Br-76]BMK/4-[Br-76]BMK was increased less than twofold in KO versus WT indicating that 3-[Br-76]BMK-152/4-[Br-76]BMK was not a Pgp substrate. Rat brain uptakes of 4-[Br-76]BMK-152 from ex vivo autoradiography studies showed regional localization consistent with known published CRF1 receptor distribution and potential as a PET ligand for in vivo imaging of CRF1 receptors. Synapse 65:910-918, 2011. Published 2011 Wiley-Liss, Inc. C1 [Jagoda, Elaine M.; Lang, Lixin; Ma, Ying; Kiesewetter, Dale O.] NIBIB, PET Radiochem Grp, NIH, Bethesda, MD USA. [Mccullough, Karen; Contoreggi, Carlo] NIDA, IRP, NIH, Baltimore, MD USA. [Kim, B. Moon] Seoul Natl Univ, Coll Nat Sci, Dept Chem, Seoul 151747, South Korea. [Rice, Kenner C.] NIDDK, LMC, NIH, Bethesda, MD USA. [Szajek, Lawrence P.] NIH, PET Dept CC, Bethesda, MD 20892 USA. [Eckelman, William C.] Mol Tracer LLC, Bethesda, MD USA. RP Jagoda, EM (reprint author), NCI, Mol Imaging Program, 10 Ctr Dr MSC1088,BLG 10-RM B3B69, Bethesda, MD 20892 USA. EM ejagoda@mail.nih.gov FU Intramural NIH HHS [Z01 EB000001-03] NR 50 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0887-4476 J9 SYNAPSE JI Synapse PD SEP PY 2011 VL 65 IS 9 BP 910 EP 918 DI 10.1002/syn.20919 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 799GU UT WOS:000293275200007 PM 21308801 ER PT J AU Thanos, PK Bermeo, C Wang, GJ Volkow, ND AF Thanos, Panayotis K. Bermeo, Carlos Wang, Gene-Jack Volkow, Nora D. TI D-Cycloserine Facilitates Extinction of Cocaine Self-Administration in Rats SO SYNAPSE LA English DT Article DE learning; glutamate; withdrawal; abstinence; drug abuse; NMDA; addiction; substance abuse ID CONDITIONED PLACE PREFERENCE; FEAR EXTINCTION; NUCLEUS-ACCUMBENS; RECEPTORS; REINSTATEMENT; PSYCHOTHERAPY; POTENTIATION; ADDICTION; BEHAVIOR; SEEKING AB Previous research has indicated that D-cycloserine [DCS; a N-methyl-D-aspartate (NMDA) partial agonist] facilitates the extinction of conditioned fear as well as the extinction of cocaine conditioned place preference. Sprague Dawley rats were first trained to self-administer cocaine and then we compared their extinction behavior (lever pressing) following treatment with vehicle; 15 mg/kg DCS; or 30 mg/kg DCS. We showed that 30 mg/kg DCS, but not 15 mg/kg significantly accelerated extinction of cocaine self-administration behavior when compared with saline by almost half (4 days vs. 9 days). At 2 weeks when all animals had extinguished, there were no longer differences between the groups. The present findings support of the potential of NMDA partial agonists as prospectively valuable in facilitating the extinction of cocaine-seeking behavior. More specifically, we demonstrate that 30 mg/kg DCS was effective at significantly accelerating the extinction of cocaine self-administration behavior in rats. These results provide further support for the potential of DCS as a treatment strategy for addiction. Synapse 65:938-944, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Thanos, Panayotis K.; Volkow, Nora D.] NIAAA, Neuroimaging Lab, Intramural Program, NIH, Bethesda, MD USA. [Thanos, Panayotis K.; Bermeo, Carlos; Wang, Gene-Jack] Brookhaven Natl Lab, Dept Med, Behav Pharmacol & Neuroimaging Lab, Upton, NY 11973 USA. RP Thanos, PK (reprint author), NIAAA, Neuroimaging Lab, Intramural Program, NIH, Bethesda, MD USA. EM thanos@bnl.gov9Z FU NIAAA at the National Institute of Health (NIH); NIDA FX Contract grant sponsor: The Intramural Research Program of NIAAA at the National Institute of Health (NIH); Contract grant sponsor: The NIDA summer research program to C.B. NR 33 TC 21 Z9 22 U1 2 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0887-4476 J9 SYNAPSE JI Synapse PD SEP PY 2011 VL 65 IS 9 BP 938 EP 944 DI 10.1002/syn.20922 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 799GU UT WOS:000293275200010 PM 21360592 ER PT J AU Kerridge, BT Saha, TD Smith, S Chou, PS Pickering, RP Huang, B Ruan, JW Pulay, AJ AF Kerridge, Bradley T. Saha, Tulshi D. Smith, Sharon Chou, Patricia S. Pickering, Roger P. Huang, Boji Ruan, June W. Pulay, Attila J. TI Dimensionality of hallucinogen and inhalant/solvent abuse and dependence criteria: Implications for the diagnostic and statistical manual of mental disorders-Fifth edition SO ADDICTIVE BEHAVIORS LA English DT Article DE Hallucinogen use disorder; Inhalant/solvent use disorder; DSM-V; Item response theory; Dimensionality ID ITEM RESPONSE THEORY; NATIONAL EPIDEMIOLOGIC SURVEY; ALCOHOL-USE DISORDERS; DSM-IV CRITERIA; CANNABIS; CONSUMPTION; ADOLESCENTS; PSYCHOPATHY; COMMUNITY; CONTINUUM AB Background: Prior research has demonstrated the dimensionality of Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) alcohol, nicotine, cannabis, cocaine and amphetamine abuse and dependence criteria. The purpose of this study was to examine the dimensionality of hallucinogen and inhalant/solvent abuse and dependence criteria. In addition, we assessed the impact of elimination of the legal problems abuse criterion on the information value of the aggregate abuse and dependence criteria, another proposed change for DSM-IV currently lacking empirical justification. Methods: Factor analyses and item response theory (IRT) analyses were used to explore the unidimisionality and psychometric properties of hallucinogen and inhalant/solvent abuse and dependence criteria using a large representative sample of the United States (U.S.) general population. Results: Hallucinogen and inhalant/solvent abuse and dependence criteria formed unidimensional latent traits. For both substances, IRT models without the legal problems abuse criterion demonstrated better fit than the corresponding model with the legal problem abuse criterion. Further, there were no differences in the information value of the IRT models with and without the legal problems abuse criterion, supporting the elimination of that criterion. No bias in the new diagnoses was observed by sex, age and race-ethnicity. Conclusion: Consistent with findings for alcohol, nicotine, cannabis, cocaine and amphetamine abuse and dependence criteria, hallucinogen and inhalant/solvent criteria reflect underlying dimensions of severity. The legal problems criterion associated with each of these substance use disorders can be eliminated with no loss in informational value and an advantage of parsimony. Taken together, these findings support the changes to substance use disorder diagnoses recommended by the DSM-V Substance and Related Disorders Workgroup, that is, combining DSM-IV abuse and dependence criteria and eliminating the legal problems abuse criterion. Published by Elsevier Ltd. C1 [Saha, Tulshi D.; Smith, Sharon; Chou, Patricia S.; Pickering, Roger P.; Huang, Boji; Ruan, June W.; Pulay, Attila J.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. [Kerridge, Bradley T.] Univ Maryland, Dept Epidemiol & Biostat, Sch Publ Hlth, College Pk, MD 20740 USA. RP Saha, TD (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Lane,Room 3083, Bethesda, MD 20892 USA. EM sahatd@mail.nih.gov OI Kerridge, Bradley/0000-0003-0459-9439 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Drug Abuse (NIDA); National Institutes of Health (NIH), NIAAA; NIH/NIDA [5F31DA025377] FX The National Institute on Alcohol Abuse and Alcoholism (NIAAA) funded the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) with supplemental funding from the National Institute on Drug Abuse (NIDA). Funding was also from the International Program of the National Institutes of Health (NIH), NIAAA. Support for Mr. Kerridge, NIH/NIDA Fellowship 5F31DA025377 is acknowledged. NR 34 TC 11 Z9 11 U1 3 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD SEP PY 2011 VL 36 IS 9 BP 912 EP 918 DI 10.1016/j.addbeh.2011.04.006 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 793GO UT WOS:000292808600003 PM 21621334 ER PT J AU Soria, JA Arroyo, DS Gaviglio, EA Rodriguez-Galan, MC Wang, JM Iribarren, P AF Soria, Javier A. Arroyo, Daniela S. Gaviglio, Emilia A. Rodriguez-Galan, Maria C. Wang, Ji Ming Iribarren, Pablo TI Interleukin 4 induces the apoptosis of mouse microglial cells by a caspase-dependent mechanism SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Microglia; Interleukin 4; Apoptosis; Caspases; Neuroinflammation ID FORMYL PEPTIDE RECEPTOR-2; ACTIVATED MICROGLIA; ALTERNATIVE ACTIVATION; REACTIVE MICROGLIOSIS; POPULATION-CONTROL; DENDRITIC CELLS; IN-VIVO; IL-4; EXPRESSION; PROTEIN AB Microglial cells are resident macrophages in the central nervous system (CNS) and become activated in many pathological conditions. Activation of microglial cells results in reactive microgliosis, manifested by an increase in cell number in the affected CNS regions. The control of microgliosis may be important to prevent pathological damage to the brain. The type 2 cytokine IL-4 has been reported to be protective in brain inflammation. However, its effect on microglial cell survival was not well understood. In this study, we report a dual effect of IL-4 on the survival of mouse microglial cells. In a 6 h short term culture. IL-4 reduced the death of microglial cells induced by staurosporine. In contrast, in long term treatment (more than 48 h), IL-4 increased the apoptotic death of both primary mouse microglial cells and a microglial cell line N9. Mechanistic studies revealed that, in microglial cells, IL-4 increased the levels of cleaved caspase 3 and PARP, which is down-stream of activated caspase 3. In addition, IL-4 down regulated the autophagy and the antiapoptotic protein Bcl-xL in microglial cells. On the other hand, the pre-incubation of microglial cells with IL-4 for 24 h, attenuated the cell death induced by the neurotoxic peptide amyloid beta 1-42 (A beta 42). Our observations demonstrate a novel function of IL-4 in regulating the survival of microglial cells, which may have important significance in reduction of undesired inflammatory responses in the CNS. (C) 2011 Elsevier Inc. All rights reserved. C1 [Soria, Javier A.; Arroyo, Daniela S.; Gaviglio, Emilia A.; Rodriguez-Galan, Maria C.; Iribarren, Pablo] Univ Nacl Cordoba, Fac Ciencias Quim, Dept Bioquim Clin, Ctr Invest Bioquim Clin & Inmunol CIBICI CONICET, RA-5000 Cordoba, Argentina. [Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Iribarren, P (reprint author), Univ Nacl Cordoba, Fac Ciencias Quim, Dept Bioquim Clin, Ctr Invest Bioquim Clin & Inmunol CIBICI CONICET, Ciudad Univ,X5000HUA, RA-5000 Cordoba, Argentina. EM piribarr@fcq.unc.edu.ar FU Fogarty International Center, NIH, USA [1R01TW007621-01A2]; CONICET; SECyT-UNC, Argentina FX This work was supported by grant number 1R01TW007621-01A2 from Fogarty International Center, NIH, USA, CONICET and SECyT-UNC, Argentina. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Fogarty International Center (FIC), NIH, USA. NR 55 TC 15 Z9 15 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD SEP PY 2011 VL 43 IS 3 BP 616 EP 624 DI 10.1016/j.nbd.2011.05.010 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 796GX UT WOS:000293040900010 PM 21624466 ER PT J AU Coddou, C Yan, ZH Obsil, T Huidobro-Toro, JP Stojilkovic, SS AF Coddou, Claudio Yan, Zonghe Obsil, Tomas Pablo Huidobro-Toro, J. Stojilkovic, Stanko S. TI Activation and Regulation of Purinergic P2X Receptor Channels SO PHARMACOLOGICAL REVIEWS LA English DT Review ID GATED ION CHANNELS; ROOT GANGLION NEURONS; PROTEIN-KINASE-C; AMINO-ACID-RESIDUES; PIG URINARY-BLADDER; MESSENGER-RNA EXPRESSION; ANTERIOR-PITUITARY-CELLS; ATP-INDUCED CURRENTS; NEGATIVELY CHARGED RESIDUES; FIRST TRANSMEMBRANE DOMAIN AB Mammalian ATP-gated nonselective cation channels (P2XRs) can be composed of seven possible subunits, denoted P2X1 to P2X7. Each subunit contains a large ectodomain, two transmembrane domains, and intracellular N and C termini. Functional P2XRs are organized as homomeric and heteromeric trimers. This review focuses on the binding sites involved in the activation (orthosteric) and regulation (allosteric) of P2XRs. The ectodomains contain three ATP binding sites, presumably located between neighboring subunits and formed by highly conserved residues. The detection and coordination of three ATP phosphate residues by positively charged amino acids are likely to play a dominant role in determining agonist potency, whereas an AsnPheArg motif may contribute to binding by coordinating the adenine ring. Nonconserved ectodomain histidines provide the binding sites for trace metals, divalent cations, and protons. The transmembrane domains account not only for the formation of the channel pore but also for the binding of ivermectin (a specific P2X4R allosteric regulator) and alcohols. The N- and C-domains provide the structures that determine the kinetics of receptor desensitization and/or pore dilation and are critical for the regulation of receptor functions by intracellular messengers, kinases, reactive oxygen species and mercury. The recent publication of the crystal structure of the zebrafish P2X4.1R in a closed state provides a major advance in the understanding of this family of receptor channels. We will discuss data obtained from numerous site-directed mutagenesis experiments accumulated during the last 15 years with reference to the crystal structure, allowing a structural interpretation of the molecular basis of orthosteric and allosteric ligand actions. C1 [Coddou, Claudio; Yan, Zonghe; Stojilkovic, Stanko S.] NICHHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Obsil, Tomas] Charles Univ Prague, Dept Phys & Macromol Chem, Fac Sci, Prague, Czech Republic. [Pablo Huidobro-Toro, J.] Pontificia Univ Catolica Chile, Ctr Envejecimiento & Regenerac, Ctr Regulac Celular & Patol Prof JV Luco,Fac Cien, Inst Milenio Biol Fundamental & Aplicada,Dept Fis, Santiago, Chile. RP Stojilkovic, SS (reprint author), NICHD, Sect Cellular Signaling, PDN, NIH, Bldg 49,Room 6A36, Bethesda, MD 20892 USA. EM stojilks@mail.nih.gov RI Obsil, Tomas/B-7142-2012 OI Obsil, Tomas/0000-0003-4602-1272 FU National Institutes of Health National Institute of Child Health and Human Development; Internal Grant Agency of the Academy of Sciences; Fondo de Financiamiento de Centros de Excelencia en Investigacion [13980001]; Instituto Milenio de Biologia Fundamental y Aplicada; PFB [12/2007] FX This research was funded in part by the Intramural Research Program of the National Institutes of Health National Institute of Child Health and Human Development (to C. C., Z.Y., S. S. S.); the Internal Grant Agency of the Academy of Sciences (to T.O.); the Fondo de Financiamiento de Centros de Excelencia en Investigacion [Grant 13980001], and the Instituto Milenio de Biologia Fundamental y Aplicada and PFB 12/2007 (to J.P.H.-T.). NR 548 TC 198 Z9 201 U1 18 U2 58 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD SEP PY 2011 VL 63 IS 3 BP 641 EP 683 DI 10.1124/pr.110.003129 PG 43 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 793ZK UT WOS:000292862800005 PM 21737531 ER PT J AU Stutzmann, GE Mattson, MP AF Stutzmann, Grace E. Mattson, Mark P. TI Endoplasmic Reticulum Ca2+ Handling in Excitable Cells in Health and Disease SO PHARMACOLOGICAL REVIEWS LA English DT Review ID AMYLOID-BETA-PEPTIDE; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; CALCIUM-RELEASE CHANNEL; CULTURED HIPPOCAMPAL-NEURONS; CARDIAC RYANODINE RECEPTOR; LONG-TERM POTENTIATION; KNOCK-IN MICE; POLYMORPHIC VENTRICULAR-TACHYCARDIA; AMYOTROPHIC-LATERAL-SCLEROSIS; ISCHEMIA-REPERFUSION INJURY AB The endoplasmic reticulum (ER) is a morphologically and functionally diverse organelle capable of integrating multiple extracellular and internal signals and generating adaptive cellular responses. It plays fundamental roles in protein synthesis and folding and in cellular responses to metabolic and proteotoxic stress. In addition, the ER stores and releases Ca2+ in sophisticated scenarios that regulate a range of processes in excitable cells throughout the body, including muscle contraction and relaxation, endocrine regulation of metabolism, learning and memory, and cell death. One or more Ca2+ ATPases and two types of ER membrane Ca2+ channels (inositol trisphosphate and ryanodine receptors) are the major proteins involved in ER Ca2+ uptake and release, respectively. There are also direct and indirect interactions of ER Ca2+ stores with plasma membrane and mitochondrial Ca2+-regulating systems. Pharmacological agents that selectively modify ER Ca2+ release or uptake have enabled studies that revealed many different physiological roles for ER Ca2+ signaling. Several inherited diseases are caused by mutations in ER Ca2+-regulating proteins, and perturbed ER Ca2+ homeostasis is implicated in a range of acquired disorders. Preclinical investigations suggest a therapeutic potential for use of agents that target ER Ca2+ handling systems of excitable cells in disorders ranging from cardiac arrhythmias and skeletal muscle myopathies to Alzheimer disease. C1 [Stutzmann, Grace E.] Rosalind Franklin Univ, Chicago Med Sch, Dept Neurosci, N Chicago, IL 60064 USA. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Stutzmann, GE (reprint author), Rosalind Franklin Univ, Chicago Med Sch, Dept Neurosci, 3333 Green Bay Rd, N Chicago, IL 60064 USA. EM grace.stutzmann@rosalindfranklin.edu RI Mattson, Mark/F-6038-2012 FU National Institutes of Health National Institute on Aging [AG030205] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health National Institute on Aging (to M. M.); and by the National Institutes of Health National Institute on Aging [Grant AG030205] (to G. E. S.). We thank K. C. Alexander for assistance in the preparation of figures and Corinne Schneider for editorial assistance. NR 338 TC 94 Z9 100 U1 2 U2 22 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD SEP PY 2011 VL 63 IS 3 BP 700 EP 727 DI 10.1124/pr.110.003814 PG 28 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 793ZK UT WOS:000292862800007 PM 21737534 ER PT J AU Hutchinson, MR Shavit, Y Grace, PM Rice, KC Maier, SF Watkins, LR AF Hutchinson, Mark R. Shavit, Yehuda Grace, Peter M. Rice, Kenner C. Maier, Steven F. Watkins, Linda R. TI Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia SO PHARMACOLOGICAL REVIEWS LA English DT Review ID ROSTRAL VENTROMEDIAL MEDULLA; ACTIVATED PROTEIN-KINASE; TOLL-LIKE RECEPTOR; MORPHINE ANTINOCICEPTIVE TOLERANCE; PERIPHERAL-NERVE INJURY; BLOOD-BRAIN-BARRIER; MONOCYTE CHEMOATTRACTANT PROTEIN-1; DORSAL-ROOT GANGLIA; FIBRILLARY ACIDIC PROTEIN; MOUSE MICROGLIAL CELLS AB Vastly stimulated by the discovery of opioid receptors in the early 1970s, preclinical and clinical research was directed at the study of stereo-selective neuronal actions of opioids, especially those played in their crucial analgesic role. However, during the past decade, a new appreciation of the non-neuronal actions of opioids has emerged from preclinical research, with specific appreciation for the nonclassic and nonstereoselective sites of action. Opioid activity at Toll-like receptors, newly recognized innate immune pattern recognition receptors, adds substantially to this unfolding story. It is now apparent from molecular and rodent data that these newly identified signaling events significantly modify the pharmacodynamics of opioids by eliciting proinflammatory reactivity from glia, the immunocompetent cells of the central nervous system. These central immune signaling events, including the release of cytokines and chemokines and the associated disruption of glutamate homeostasis, cause elevated neuronal excitability, which subsequently decreases opioid analgesic efficacy and leads to heightened pain states. This review will examine the current preclinical literature of opioid-induced central immune signaling mediated by classic and nonclassic opioid receptors. A unification of the preclinical pharmacology, neuroscience, and immunology of opioids now provides new insights into common mechanisms of chronic pain, naive tolerance, analgesic tolerance, opioid-induced hyperalgesia, and allodynia. Novel pharmacological targets for future drug development are discussed in the hope that disease-modifying chronic pain treatments arising from the appreciation of opioid-induced central immune signaling may become practical. C1 [Hutchinson, Mark R.; Grace, Peter M.] Univ Adelaide, Sch Med Sci, Discipline Physiol, S Australia, SA 5005, Australia. [Hutchinson, Mark R.] Univ Adelaide, Sch Med Sci, Discipline Physiol, S Australia, SA 5005, Australia. [Hutchinson, Mark R.; Maier, Steven F.; Watkins, Linda R.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Shavit, Yehuda] Hebrew Univ Jerusalem, Dept Psychol, IL-91905 Jerusalem, Israel. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Rockville, MD 90034 USA. [Rice, Kenner C.] NIAAA, Rockville, MD 20852 USA. RP Hutchinson, MR (reprint author), Univ Adelaide, Sch Med Sci, Discipline Physiol, S Australia, SA 5005, Australia. EM mark.hutchinson@adelaide.edu.au RI Grace, Peter/I-5507-2013; Shavit, Yehuda/A-1219-2010; Hutchinson, Mark/G-4147-2014 OI Grace, Peter/0000-0002-8999-1220; Hutchinson, Mark/0000-0003-2154-5950 FU National Institutes of Health National Institute on Drug Abuse; National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [K05-DA024044]; National Health and Medical Research Council [ID 465423]; Australian Research Council [DP110100297]; Faculty of Health Sciences Divisional Scholarship; Israel Science Foundation [512/08]; Leon and Clara Sznajderman Chair of Psychology FX This work was supported in part by the Intramural Research Programs of the National Institutes of Health National Institute on Drug Abuse and the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism (to K. C. R.); the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant K05-DA024044] (to L. R. W.); the National Health and Medical Research Council CJ Martin Fellowship [ID 465423, 2010] (to M. R. H.); the Australian Research Council Australian Research Fellowship [DP110100297, 2011] (to M. R. H.); a Faculty of Health Sciences Divisional Scholarship (to P. M. G.); the Israel Science Foundation [Grant 512/08] (to Y.S.); and the Leon and Clara Sznajderman Chair of Psychology (to Y.S.). Thanks to Tavik Morgenstern for assistance inpreparing the figures. NR 488 TC 123 Z9 129 U1 5 U2 32 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD SEP PY 2011 VL 63 IS 3 BP 772 EP 810 DI 10.1124/pr.110.004135 PG 39 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 793ZK UT WOS:000292862800010 PM 21752874 ER PT J AU Feng, Y Gong, R Dimitrov, DS AF Feng, Yang Gong, Rui Dimitrov, Dimiter S. TI Design, expression and characterization of a soluble single-chain functional human neonatal Fc receptor SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE Neonatal Fc receptor; FcRn; IgG half-life ID I-RELATED RECEPTOR; SERUM HALF-LIFE; HUMAN IGG1; EPITHELIAL-CELLS; IMMUNOGLOBULIN-G; AFFINITY; BINDING; ANTIBODY; STOICHIOMETRY; SITE AB The neonatal Fc receptor (FcRn) is responsible for transporting maternal IgGs to fetus/newborns and maintaining the homeostasis of IgGs in adults. FcRn resembles class I major histocompatibility complex in structure, and is composed of a transmembrane heavy chain and an invariant beta 2 microglobulin. Changes in the affinity of IgGs to FcRn lead to changes in the half-life of engineered IgGs and Fc fusion proteins. Longer half-life of therapeutic antibodies means lower dose and longer interval between administering. For some diagnostic agents including imaging or radio-labeled agents a shorter half life in circulation results in lower non-specific binding and decreased side effects. Therefore, studying the interaction of FcRn and therapeutic antibodies has direct clinical implications. A reliable method to prepare soluble and functional FcRn protein is essential for such studies. In this study, we describe a new method to express in mammalian cells soluble human FcRn (sFcRn) as a single-chain soluble fusion protein. The highly hydrophilic beta 2 microglobulin was joined with the hydrophobic heavy chain via a 15 amino acid linker. The single-chain fusion protein format not only improved the expression level of the heavy chain but also simplified the purification process. The sFcRn maintained its pH-dependent binding to IgG. This method typically yielded similar to 1 mg/100 ml culture without optimization, and is easy to scale up for production of large quantities. Published by Elsevier Inc. C1 [Feng, Yang; Gong, Rui; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, CCR Nanobiol Program, NIH, Frederick, MD 21702 USA. RP Feng, Y (reprint author), NCI, Prot Interact Grp, CCR Nanobiol Program, NIH, Bldg 469,Rm 140, Frederick, MD 21702 USA. EM fengya@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We thank members of our groups for helpful discussions. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This Research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 23 TC 15 Z9 15 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 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD SEP PY 2011 VL 79 IS 1 BP 66 EP 71 DI 10.1016/j.pep.2011.03.012 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 795SM UT WOS:000292996100009 PM 21453773 ER PT J AU Yang, MH Sun, S Kostov, Y Rasooly, A AF Yang, Minghui Sun, Steven Kostov, Yordan Rasooly, Avraham TI An automated point-of-care system for immunodetection of staphylococcal enterotoxin B SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Point of care; ELISA; Lab-on-a-chip; Open platform; CCD; Microfabrication; Staphylococcal enterotoxins; Food safety ID ENHANCED CHEMILUMINESCENCE IMMUNOASSAY; ON-A-CHIP; ATOPIC-DERMATITIS; RHEUMATOID-ARTHRITIS; CARBON NANOTUBES; SUPERANTIGENS; ANTIBODIES; FOOD; SEB; IMMUNOSENSOR AB An automated point-of-care (POC) immunodetection system for immunological detection of staphylococcal enterotoxin B (SEB) was designed, fabricated, and tested. The system combines several elements: (i) enzyme-linked immunosorbent assay-lab-on-a-chip (ELISA-LOC) with fluidics, (ii) a charge-coupled device (CCD) camera detector, (iii) pumps and valves for fluid delivery to the ELISA-LOC, (iv) a computer interface board, and (v) a computer for controlling the fluidics, logging, and data analysis of the CCD data. The ELISA-LOC integrates a simple microfluidic system into a miniature 96-well sample plate, allowing the user to carry out immunological assays without a laboratory. The analyte is measured in a sandwich ELISA assay format combined with a sensitive electrochemiluminescence (ECL) detection method. Using the POC system, SEB, a major foodborne toxin, was detected at concentrations as low as 0.1 ng/ml. This is similar to the reported sensitivity of conventional ELISA. The open platform with simple modular fluid delivery automation design described here is interchangeable between detection systems, and because of its versatility it can also be used to automate many other LOC systems, simplifying LOC development. This new POC system is useful for carrying out various immunological and other complex medical assays without a laboratory and can easily be adapted for high-throughput biological screening in remote and resource-poor areas. Published by Elsevier Inc. C1 [Yang, Minghui; Sun, Steven; Kostov, Yordan] Univ Maryland Baltimore Cty, Ctr Adv Sensor Technol, Baltimore, MD 21250 USA. [Yang, Minghui] Univ Jinan, Sch Chem & Chem Engn, Jinan 250022, Peoples R China. [Sun, Steven; Rasooly, Avraham] Food & Drug Adm, Off Sci & Engn, Div Biol, Silver Spring, MD 20993 USA. [Rasooly, Avraham] NCI, Bethesda, MD 20892 USA. RP Rasooly, A (reprint author), NCI, 6130 Executive Blvd, Rockville, MD 20852 USA. EM rasoolya@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 51 TC 25 Z9 25 U1 1 U2 35 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 1 PY 2011 VL 416 IS 1 BP 74 EP 81 DI 10.1016/j.ab.2011.05.014 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 790XG UT WOS:000292623500010 PM 21640067 ER PT J AU Adhikari, S Karmahapatra, SK Elias, H Dhopeshwarkar, P Williams, RS Byers, S Uren, A Roy, R AF Adhikari, Sanjay Karmahapatra, Soumendra K. Elias, Hadi Dhopeshwarkar, Priyanka Williams, R. Scott Byers, Stephen Uren, Aykut Roy, Rabindra TI Development of a novel assay for human tyrosyl DNA phosphodiesterase 2 SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE DNA repair; Enzyme assay; Kinetics; TDP2; High-throughput screening ID TOPOISOMERASE-II; ANTITUMOR DRUGS; DAMAGE; REPAIR; CELLS; NUCLEI; ENZYME AB Tyrosyl DNA phosphodiesterase 2 (TDP2), a newly discovered enzyme that cleaves 5'-phosphotyrosyl bonds, is a potential target for chemotherapy. TDP2 possesses both 3'- and 5'-tyrosyl-DNA phosphodiesterase activity, which is generally measured in a gel-based assay using 3'- and 5'-phosphotyrosyl linkage at the 3' and 5' ends of an oligonucleotide. To understand the enzymatic mechanism of this novel enzyme, the gel-based assay is useful, but this technique is cumbersome for TDP2 inhibitor screening. For this reason, we have designed a novel assay using p-nitrophenyl-thymidine-5'-phosphate (T5PNP) as a substrate. This assay can be used in continuous colorimetric assays in a 96-well format. We compared the salt and pH effect on product formation with the colorimetric and gel-based assays and showed that they behave similarly. Steady-state kinetic studies showed that the 5' activity of TDP2 is 1000-fold more efficient than T5PNP. Tyrosyl DNA phosphodiesterase 1 (TDP1) and human AP-endonuclease 1 (APE1) could not hydrolyze T5PNP. Sodium orthovanadate, a known inhibitor of TDP2, inhibits product formation from T5PNP by TDP2 (IC(50) = 40 mM). Our results suggest that this novel assay system with this new TDP2 substrate can be used for inhibitor screening in a high-throughput manner. (C) 2011 Elsevier Inc. All rights reserved. C1 [Adhikari, Sanjay; Karmahapatra, Soumendra K.; Elias, Hadi; Dhopeshwarkar, Priyanka; Byers, Stephen; Uren, Aykut; Roy, Rabindra] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Med Ctr, Washington, DC 20057 USA. [Williams, R. Scott] Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Adhikari, S (reprint author), Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Med Ctr, Washington, DC 20057 USA. EM sa354@georgetown.edu RI Williams, Robert/A-6059-2015 FU American Cancer Society [IRG-92-152-17]; National Institutes of Health [RO1 CA 92306] FX This work was supported by American Cancer Society Grant IRG-92-152-17 (American Cancer Society Institutional Research Grant to S.A.) and National Institutes of Health Grant RO1 CA 92306 (to R.R.). We thank Elsevier Language Editing Services for editing the manuscript. We also thank Jordan Woodrick for critically reading the manuscript. NR 22 TC 12 Z9 12 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 1 PY 2011 VL 416 IS 1 BP 112 EP 116 DI 10.1016/j.ab.2011.05.008 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 790XG UT WOS:000292623500015 PM 21620793 ER PT J AU Altunbas, A Lee, SJ Rajasekaran, SA Schneider, JP Pochan, DJ AF Altunbas, Aysegul Lee, Seung J. Rajasekaran, Sigrid A. Schneider, Joel P. Pochan, Darrin J. TI Encapsulation of curcumin in self-assembling peptide hydrogels as injectable drug delivery vehicles SO BIOMATERIALS LA English DT Article DE Peptide; Self-assembly; Curcumin; Hydrogel ID CANCER-CELLS; BIOMEDICAL APPLICATIONS; REVERSIBLE HYDROGELS; CONTROLLED-RELEASE; DESIGNED PEPTIDE; APOPTOSIS; NANOCARRIER; ANTITUMOR; PROTEINS; MEDICINE AB Curcumin, a hydrophobic polyphenol, is an extract of turmeric root with antioxidant, anti-inflammatory and anti-tumorigenic properties. Its lack of water solubility and relatively low bioavailability set major limitations for its therapeutic use. In this study, a self-assembling peptide hydrogel is demonstrated to be an effective vehicle for the localized delivery of curcumin over sustained periods of time. The curcumin-hydrogel is prepared in-situ where curcumin encapsulation within the hydrogel network is accomplished concurrently with peptide self-assembly. Physical and in vitro biological studies were used to demonstrate the effectiveness of curcumin-loaded beta-hairpin hydrogels as injectable agents for localized curcumin delivery. Notably, theological characterization of the curcumin-loaded hydrogel before and after shear flow have indicated solid-like properties even at high curcumin payloads. In vitro experiments with a medulloblastoma cell line confirm that the encapsulation of the curcumin within the hydrogel does not have an adverse effect on its bioactivity. Most importantly, the rate of curcumin release and its consequent therapeutic efficacy can be conveniently modulated as a function of the concentration of the MAX8 peptide. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Altunbas, Aysegul; Pochan, Darrin J.] Univ Delaware, Dept Mat Sci & Engn, Newark, DE 19716 USA. [Altunbas, Aysegul; Pochan, Darrin J.] Univ Delaware, Delaware Biotechnol Inst, Newark, DE 19716 USA. [Lee, Seung J.; Rajasekaran, Sigrid A.] Alfred I DuPont Hosp Children, Nemours Ctr Childhood Canc Res, Canc Epigenet Lab, Wilmington, DE 19803 USA. [Schneider, Joel P.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Pochan, DJ (reprint author), Univ Delaware, Dept Mat Sci & Engn, 201 DuPont Hall, Newark, DE 19716 USA. EM pochan@udel.edu RI Osorio Tobon, Juan Felipe/G-6877-2012; Schneider, Joel/N-2610-2014 FU NIH COBRE [P20 RR017716]; American Cancer Society [RSG-09-021-01-CNE]; Nemours Foundation; College of Engineering at the University of Delaware FX AA and SJL have contributed equally to this work. This work was supported by the NIH COBRE P20 RR017716, American Cancer Society Research Grant RSG-09-021-01-CNE and funds from the Nemours Foundation to Sigrid A. Rajasekaran. We thank C. Ni, F. Kriss and the College of Engineering at the University of Delaware, for partial funding of W.M. Keck Electron Microscopy Facility. NR 68 TC 170 Z9 176 U1 22 U2 217 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 SEP PY 2011 VL 32 IS 25 BP 5906 EP 5914 DI 10.1016/j.biomaterials.2011.04.069 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 792BE UT WOS:000292714700019 PM 21601921 ER PT J AU Furusato, E Shen, DF Cao, XG Furusato, B Nussenblatt, RB Rushing, EJ Chan, CC AF Furusato, Emiko Shen, DeFen Cao, Xiaoguang Furusato, Bungo Nussenblatt, Robert B. Rushing, Elisabeth J. Chan, Chi-Chao TI Inflammatory cytokine and chemokine expression in sympathetic ophthalmia: a pilot study SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Article DE Chemokines; Cytokines; Macrophages; Sympathetic ophthalmia; Uveitis ID KOYANAGI-HARADA SYNDROME; T-CELLS; MACROPHAGE ACTIVATION; ALVEOLAR MACROPHAGES; ELECTRON-MICROSCOPY; LUNG INFLAMMATION; CXC CHEMOKINE; POLARIZATION; DISEASE; GENE AB Sympathetic ophthalmia is a bilateral uveitis that develops after penetrating injury to one eye. This study aimed to identify the inflammatory cellular sub-phenotypes and expression of pertinent inflammatory cytokines/chemokines in sympathetic ophthalmia (SO). Dalen-Fuchs nodules (DFN), granulomas, and non-granulomatous foci of inflammation were micro-dissected from 15 cases. RNA was extracted, and quantitative PCR was performed to measure IL-17, IL-18, IL-23, IFN-gamma, CCL19, CXCL11, CCL17, and CCL22 transcripts. Immunohistochemical methods were used to characterize CD3, CD4, CD8, CD20, CD68, and CD163 expression. Non-granulomatous lymphocytes were predominantly CD3-positive and expressed more IFN-gamma than cells within granulomas, consistent with Th1 cells. In contrast, granulomas and DFN contained mainly CD68+, CD163+/- and expressed more IL-17, IL-18, IL-23, CCL19, and CXCL11 than non-granulomatous cells. Our data indicate for the first time that M1 macrophages are the predominant inflammatory cells within granulomas and DFN of SO. We further observed high levels of IL-17 within granulomas and the presence of Th1 and M1 cells. C1 [Furusato, Emiko; Shen, DeFen; Cao, Xiaoguang; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Furusato, Emiko; Rushing, Elisabeth J.] NEI, Clin Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Furusato, Bungo; Nussenblatt, Robert B.] Armed Forces Inst Pathol, Washington, DC 20306 USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov OI Furusato, Bungo/0000-0003-4614-9882 FU NEI FX This study was supported by the NEI Intramural Research Program. NR 41 TC 8 Z9 8 U1 1 U2 1 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD SEP PY 2011 VL 26 IS 9 BP 1145 EP 1151 PG 7 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 791RZ UT WOS:000292683600005 PM 21751146 ER PT J AU Liang, HS Zhong, YH Zhou, SB Li, QQ AF Liang, Huasheng Zhong, Yuhua Zhou, Shaobi Li, Qingdi Quentin TI Palmitic Acid-induced Apoptosis in Pancreatic beta-Cells Is Increased by Liver X Receptor Agonist and Attenuated by Eicosapentaenoate SO IN VIVO LA English DT Article DE Liver X receptors; palmitic acid; apoptosis; INS-1 cells; SREBP-1; eicosapentaenoate ID INSULIN-SECRETION; CANCER CELLS; DIABETIC-NEPHROPATHY; LIPID-METABOLISM; SKELETAL-MUSCLE; GENE-EXPRESSION; CYCLE ARREST; TUMOR-CELLS; FATTY-ACIDS; LXR-ALPHA AB Saturated fatty acids are implicated in the development of diabetes via the impairment of pancreatic islet beta-cell viability and function. Liver X receptors (LXRs) and eicosapentaenoate (EPA) are known regulators of fatty acid metabolism. However, their roles in the pathogenesis of diabetes remain incompletely understood. The aim of this study was to determine the effects of EPA and the LXR agonist T0901317 on saturated fatty acid (palmitic acid)-induced apoptosis in the insulinoma beta-cell line INS-1, a model for insulin-secreting beta-cells. T0901317 significantly promoted palmitic acid-induced apoptotic cell death in the INS-1 cells. Consistent with these results, caspase-3 activity and BAX and sterol regulatory element binding protein-1c (SREBP-1c) mRNA levels were markedly increased in INS-1 cells co-administered palmitic acid and T0901317. The production of reactive oxygen species was considerably higher in the cells cultured concurrently with T0901317 and palmitic acid than in the cells incubated with either agent alone. EPA treatment attenuated the cellular death promoted by palmitic acid and T0901317 in the INS-1 cells, disclosing a possible mediating mechanism involving the inhibition of SREBP-1c. Finally, T0901317 up-regulated the palmitic acid-induced expression of p27(KIP1), transforming growth factor beta 1, and SMAD3 proteins in INS-1 cells. These results demonstrate that palmitic acid-induced apoptosis in beta-cells is enhanced by T0901317 via the activation of LXRs and is blocked by EPA via the inhibition of SREBP-1c, suggesting that the regulation of lipogenesis and lipotoxicity affecting pancreatic beta-cell viability and insulin production may be a unique strategy for diabetes therapy. C1 [Liang, Huasheng; Zhong, Yuhua; Zhou, Shaobi] Guangxi Med Univ, Hosp 9, Beihai Inst Endocrine & Metab Dis, Beihai 536000, Guangxi, Peoples R China. [Li, Qingdi Quentin] NIAID, NIH, Bethesda, MD 20892 USA. RP Zhong, YH (reprint author), Guangxi Med Univ, Hosp 9, Beihai Inst Endocrine & Metab Dis, Beihai 536000, Guangxi, Peoples R China. EM zhongyh111@163.com; liquenti@niaid.nih.gov FU Science and Technology Commission Foundation of Guangxi Province [0991294] FX This study was supported by a grant from the Applied Basic Research Programs of Science and Technology Commission Foundation of Guangxi Province (No. 0991294). NR 51 TC 12 Z9 13 U1 0 U2 6 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0258-851X J9 IN VIVO JI In Vivo PD SEP-OCT PY 2011 VL 25 IS 5 BP 711 EP 718 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 792MY UT WOS:000292752400001 PM 21753123 ER PT J AU Evans, S Fleming, SM Dolan, RJ Averbeck, BB AF Evans, Simon Fleming, Stephen M. Dolan, Raymond J. Averbeck, Bruno B. TI Effects of Emotional Preferences on Value-based Decision-making Are Mediated by Mentalizing and Reward Networks SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID VENTROMEDIAL PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; BEHAVIORAL-CONTROL; BRAIN; VALUATION; ATTENTION; SYSTEMS; HUMANS; METAANALYSIS; COGNITION AB Real-world decision-making often involves social considerations. Consequently, the social value of stimuli can induce preferences in choice behavior. However, it is unknown how financial and social values are integrated in the brain. Here, we investigated how smiling and angry face stimuli interacted with financial reward feedback in a stochastically rewarded decision-making task. Subjects reliably preferred the smiling faces despite equivalent reward feedback, demonstrating a socially driven bias. We fit a Bayesian reinforcement learning model to factor the effects of financial rewards and emotion preferences in individual subjects, and regressed model predictions on the trial-by-trial fMRI signal. Activity in the subcallosal cingulate and the ventral striatum, both involved in reward learning, correlated with financial reward feedback, whereas the differential contribution of social value activated dorsal temporo-parietal junction and dorsal anterior cingulate cortex, previously proposed as components of a mentalizing network. We conclude that the impact of social stimuli on value-based decision processes is mediated by effects in brain regions partially separable from classical reward circuitry. C1 [Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Evans, Simon; Fleming, Stephen M.; Dolan, Raymond J.; Averbeck, Bruno B.] UCL Inst Neurol, London, England. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Room 1B80,49 Convent Dr,MSC 4415, Bethesda, MD 20892 USA. EM bruno.averbeck@nih.gov OI Dolan, Ray/0000-0001-9356-761X FU Wellcome Trust; MRC within UCL; NIH, National Institute of Mental Health FX We thank all the volunteers who participated in this study. This work was supported by a Wellcome Trust Programme Grant to R. J. D., MRC funding within the UCL 4-Year PhD in Neuroscience to S. M. F. This work was supported in part by the Intramural Program of the NIH, National Institute of Mental Health. NR 43 TC 11 Z9 11 U1 4 U2 18 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD SEP PY 2011 VL 23 IS 9 BP 2197 EP 2210 DI 10.1162/jocn.2010.21584 PG 14 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 789IK UT WOS:000292508900009 PM 20946058 ER PT J AU Maldonado, H Ramirez, E Utreras, E Pando, ME Kettlun, AM Chiong, M Kulkarni, AB Collados, L Puente, J Cartier, L Valenzuela, MA AF Maldonado, Horacio Ramirez, Eugenio Utreras, Elias Pando, Maria E. Kettlun, Ana M. Chiong, Mario Kulkarni, Ashok B. Collados, Lucia Puente, Javier Cartier, Luis Valenzuela, Maria A. TI Inhibition of Cyclin-Dependent Kinase 5 but Not of Glycogen Synthase Kinase 3-beta Prevents Neurite Retraction and Tau Hyperphosphorylation Caused by Secretable Products of Human T-Cell Leukemia Virus Type I-Infected Lymphocytes SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE HAM/TSP; MT-2; SH-SY5Y; CDK5-siRNA; Tax ID HTLV-I; LYSOPHOSPHATIDIC ACID; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; NEURODEGENERATIVE DISEASES; SH-SY5Y CELLS; PHOSPHORYLATION; PROTEIN; DEGENERATION; PATHOLOGY AB Human T-cell leukemia virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease characterized by selective loss of axons and myelin in the corticospinal tracts. This central axonopathy may originate from the impairment of anterograde axoplasmic transport. Previous work showed tau hyperphosphorylation at T(181) in cerebrospinal fluid of HAM/TSP patients. Similar hyperphosphorylation occurs in SH-SY5Y cells incubated with supernatant from MT-2 cells (HTLV-I-infected lymphocytes secreting viral proteins, including Tax) that produce neurite shortening. Tau phosphorylation at T 181 is attributable to glycogen synthase kinase 3-beta (GSK3-beta) and cyclin-dependent kinase 5 (CDK5) activation. Here we investigate whether neurite retraction in the SH-SY5Y model associates with concurrent changes in other tau hyperphosphorylable residues. Threonine 181 turned out to be the only tau hyperphosphorylated residue. We also evaluate the role of GSK3-beta and CDK5 in this process by using specific kinase inhibitors (LiCl, TDZD-8, and roscovitine). Changes in both GSK3-beta active and inactive forms were followed by measuring the regulatory phosphorylable sites (S(9) and Y(216), inactivating and activating phosphorylation, respectively) together with changes in beta-catenin protein levels. Our results showed that LiCl and TDZD-8 were unable to prevent MT-2 supernatant-mediated neurite retraction and also that neither Y(216) nor S(9) phosphorylations were changed in GSK3-beta. Thus, GSK3-beta seems not to play a role in T 181 hyperphosphorylation. On the other hand, the CDK5 involvement in tau phosphorylation was confirmed by both the increase in its enzymatic activity and the absence of MT-2 neurite retraction in the presence of roscovitine or CDK5 siRNA transfection. (C) 2011 Wiley-Liss, Inc. C1 [Maldonado, Horacio; Pando, Maria E.; Kettlun, Ana M.; Chiong, Mario; Collados, Lucia; Puente, Javier; Valenzuela, Maria A.] Univ Chile, Fac Ciencias Quim & Farmaceut, Dept Bioquim & Biol Mol, Santiago, Chile. [Ramirez, Eugenio] Univ Chile, Fac Med, Dept Virol, Programa Virol, Santiago 7, Chile. [Utreras, Elias; Kulkarni, Ashok B.] NIDCR, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. [Cartier, Luis] Univ Chile, Fac Med, Dept Ciencias Neurol, Santiago 7, Chile. RP Valenzuela, MA (reprint author), Univ Chile, Fac Ciencias Quim & Farmaceut, Dept Bioquim & Biol Mol, Casilla 233, Santiago, Chile. EM mavalenz@uchile.cl RI utreras, elias/I-1038-2013; Chiong, Mario/I-1043-2013 OI utreras, elias/0000-0002-1004-0466; Chiong, Mario/0000-0002-5174-6545 FU FONDECYT [108-0396] FX Contract grant sponsor: FONDECYT; Contract grant number: 108-0396. NR 48 TC 13 Z9 14 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD SEP PY 2011 VL 89 IS 9 BP 1489 EP 1498 DI 10.1002/jnr.22678 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 790QM UT WOS:000292604300016 PM 21671254 ER PT J AU Roth, BL AF Roth, Bryan L. TI Irving Page Lecture: 5-HT2A serotonin receptor biology: Interacting proteins, kinases and paradoxical regulation SO NEUROPHARMACOLOGY LA English DT Review DE PDZ domain; Functional selectivity; Antipsychotic; Psychoactive; RSK2; Caveolin ID RAT CEREBRAL-CORTEX; KETANSERIN RECOGNITION SITES; SMOOTH-MUSCLE-CELLS; 5-HYDROXYTRYPTAMINE(2A) RECEPTOR; FUNCTIONAL SELECTIVITY; ACID DIETHYLAMIDE; BINDING-SITES; IN-VITRO; SIGNAL-TRANSDUCTION; PREFRONTAL CORTEX AB 5-hydroxytryptamine(2A) (5-HT2A) serotonin receptors are important pharmacological targets for a large number of central nervous system and peripheral serotonergic medications. In this review article I summarize work mainly from my lab regarding serotonin receptor anatomy, pharmacology, signaling and regulation. I highlight the role of serotonin receptor interacting proteins and the emerging paradigm of G-protein coupled receptor functional selectivity. This article is part of a Special Issue entitled 'Serotonin: The New Wave'. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Sch Med, Program Neurosci,Lineberger Canc Ctr,NIMH Psychoa, Chapel Hill, NC 27514 USA. [Roth, Bryan L.] Univ N Carolina, Div Med Chem & Nat Prod, Sch Med, Chapel Hill, NC 27514 USA. RP Roth, BL (reprint author), Univ N Carolina, Dept Pharmacol, Sch Med, Program Neurosci,Lineberger Canc Ctr,NIMH Psychoa, Room 4072,Genet Med Bldg, Chapel Hill, NC 27514 USA. EM bryan_roth@med.unc.edu RI Roth, Bryan/F-3928-2010 FU NIH [RO1MH61887, U19MH82441]; Michael Hooker Distinguished Chair of Pharmacology; NARSAD FX This work was supported in part by grants and contracts from the NIH (RO1MH61887, U19MH82441, the NIMH Psychoactive Drug Screening Program), the Michael Hooker Distinguished Chair of Pharmacology and a NARSAD Distinguished Investigator Award. NR 120 TC 21 Z9 21 U1 2 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2011 VL 61 IS 3 SI SI BP 348 EP 354 DI 10.1016/j.neuropharm.2011.01.012 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 791OD UT WOS:000292673600002 PM 21288474 ER PT J AU Peterson, KM Guo, XT Elkahloun, AG Mondal, D Bardhan, PK Sugawara, A Duggal, P Haque, R Petri, WA AF Peterson, Kristine M. Guo, Xiaoti Elkahloun, Abdel G. Mondal, Dinesh Bardhan, Pradip K. Sugawara, Akira Duggal, Priya Haque, Rashidul Petri, William A., Jr. TI The expression of REG 1A and REG 1B is increased during acute amebic colitis SO PARASITOLOGY INTERNATIONAL LA English DT Article DE Entamoeba histolytica; Regenerating gene (REG) 1; Apoptosis ID I-ALPHA PROTEIN; INFLAMMATORY-BOWEL-DISEASE; ENTAMOEBA-HISTOLYTICA; ULCERATIVE-COLITIS; GENE-EXPRESSION; GASTRIC-CANCER; UP-REGULATION; CELLS; MUCOSA; PROLIFERATION AB Entamoeba histolytica, a protozoan parasite, is an important cause of diarrhea and colitis in the developing world. Amebic colitis is characterized by ulceration of the intestinal mucosa. We performed microarray analysis of intestinal biopsies during acute and convalescent amebiasis in order to identify genes potentially involved in tissue injury or repair. Colonic biopsy samples were obtained from 8 patients during acute E. histolytica colitis and again 60 days after recovery. Gene expression in the biopsies was evaluated using microarray, and confirmed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). REG 1A and REG 1B were the most upregulated of all genes in the human intestine in acute versus convalescent E. histolytica disease: as determined by microarray, the levels of induction were 7.4-fold and 10.7 fold for REG 1A and B; p = 0.003 and p = 0.006 respectively. Increased expression of REG 1A and REG 1B protein in the colonic crypt epithelial cells during acute amebiasis was similarly observed by immunohistochemistry. Because REG 1 protein is anti-apoptotic and pro-proliferative, and since E. histolytica induces apoptosis of the intestinal epithelium as part of its disease process, we next tested if REG 1 might be protective during amebiasis by preventing parasite-induced apoptosis. Intestinal epithelial cells from REG 1 -/- mice were found to be more susceptible to spontaneous, and parasite-induced, apoptosis in vitro (p = 0.03). We concluded that REG 1A and REG 1B were upregulated during amebiasis and may function to protect the intestinal epithelium from parasite-induced apoptosis. Published by Elsevier Ireland Ltd. C1 [Peterson, Kristine M.; Guo, Xiaoti; Petri, William A., Jr.] Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA USA. [Elkahloun, Abdel G.] Natl Human Genome Inst, NIH, Baltimore, MD USA. [Mondal, Dinesh; Bardhan, Pradip K.; Haque, Rashidul] ICDDR B, Dhaka, Bangladesh. [Sugawara, Akira] Tohoku Univ, Grad Sch Med, Sendai, Miyagi 980, Japan. [Duggal, Priya] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Peterson, KM (reprint author), Univ Virginia Hlth Syst, POB 801340,Bldg MR6,Crispell Dr, Charlottesville, VA 22908 USA. EM kmp5v@virginia.edu FU National Institutes of Health [AI-43596, K08A1072470]; intramural division of the National Human Genome Research Institute, National Institutes of Health FX We thank Patcharin Pramoonjago for her assistance with immunohistochemistry. This work was supported by grant AI-43596 (to WP) and K08A1072470 (to KP) from the National Institutes of Health, and also funded in part by the intramural division of the National Human Genome Research Institute, National Institutes of Health. NR 29 TC 16 Z9 16 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1383-5769 J9 PARASITOL INT JI Parasitol. Int. PD SEP PY 2011 VL 60 IS 3 BP 296 EP 300 DI 10.1016/j.parint.2011.04.005 PG 5 WC Parasitology SC Parasitology GA 791OF UT WOS:000292673800010 PM 21586335 ER PT J AU Zheng, G Yuan, A Jeffries, N AF Zheng, Gang Yuan, Ao Jeffries, Neal TI Hybrid Bayes factors for genome-wide association studies when a robust test is used SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article DE Bayesian model averaging; Bayes factors; Genetic models; Genome-wide scan and ranking; Posterior weighted likelihood; Profile likelihood ID GENETIC ASSOCIATION; SAMPLE-SIZE; RISK LOCI; MODELS; SCANS AB Bayes factor (BF) is often used to measure evidence against the null hypothesis in Bayesian hypothesis testing. In the analysis of genome-wide association (GWA) studies, extreme BF values support the associations detected based on significant p-values. Results from recent GWA studies are presented, which show that existing BFs may not be consistent with p-values when a robust test is used due to using different genetic models in the BF and p-value approaches and this may result in misleading conclusions. Two hybrid BFs, which combine the advantages of both the frequentist and Bayesian methods, are then proposed for the markers showing at least moderate associations (p-value < 10(-5)) based on a robust test. One is Bayesian model averaging using a posterior weighted likelihood and the other is the maximum BF using a profile likelihood. The proposed hybrid BFs and p-values of robust tests do not depend on a single genetic model, but instead, consolidate information over a set of models. We compare the hybrid BFs with two existing BF approaches, including an existing Bayesian model averaging method, in terms of false and true positive rates by simulations. The results show that, for markers showing at least moderate associations, both the hybrid BFs have higher true positive rates than the two existing BFs, while all false positive rates are similar. Applications of the two hybrid BFs to the markers associated with bipolar disorder, type 2 diabetes and age-related macular degeneration are presented. Our hybrid BFs provide better and more robust measures to compare significantly associated markers within and across GWA studies. Published by Elsevier B.V. C1 [Zheng, Gang; Jeffries, Neal] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Yuan, Ao] Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM zhengg@nhlbi.nih.gov NR 16 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 EI 1872-7352 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD SEP 1 PY 2011 VL 55 IS 9 BP 2698 EP 2711 DI 10.1016/j.csda.2011.03.021 PG 14 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA 781FN UT WOS:000291916100013 ER PT J AU Oh, U Fujita, M Ikonomidou, VN Evangelou, IE Matsuura, E Harberts, E Ohayon, J Pike, VW Zhang, Y Zoghbi, SS Innis, RB Jacobson, S AF Oh, Unsong Fujita, Masahiro Ikonomidou, Vasiliki N. Evangelou, Iordanis E. Matsuura, Eiji Harberts, Erin Ohayon, Joan Pike, Victor W. Zhang, Yi Zoghbi, Sami S. Innis, Robert B. Jacobson, Steven TI Translocator Protein PET Imaging for Glial Activation in Multiple Sclerosis SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Article DE Multiple sclerosis; Translocator protein; PET; Glial activation ID POSITRON-EMISSION-TOMOGRAPHY; BENZODIAZEPINE-RECEPTOR; IN-VIVO; BRAIN; BINDING; INFLAMMATION; RADIOLIGAND; MICROGLIA; BIOMARKER; LESIONS AB Glial activation in the setting of central nervous system inflammation is a key feature of the multiple sclerosis (MS) pathology. Monitoring glial activation in subjects with MS, therefore, has the potential to be informative with respect to disease activity. The translocator protein 18 kDa (TSPO) is a promising biomarker of glial activation that can be imaged by positron emission tomography (PET). To characterize the in vivo TSPO expression in MS, we analyzed brain PET scans in subjects with MS and healthy volunteers in an observational study using [(11)C]PBR28, a newly developed translocator protein-specific radioligand. The [(11)C]PBR28 PET showed altered compartmental distribution of TSPO in the MS brain compared to healthy volunteers (p = 0.019). Focal increases in [(11)C]PBR28 binding corresponded to areas of active inflammation as evidenced by significantly greater binding in regions of gadolinium contrast enhancement compared to contralateral normal-appearing white matter (p = 0.0039). Furthermore, increase in [(11)C]PBR28 binding preceded the appearance of contrast enhancement on magnetic resonance imaging in some lesions, suggesting a role for early glial activation in MS lesion formation. Global [(11)C]PBR28 binding showed correlation with disease duration (p = 0.041), but not with measures of clinical disability. These results further define TSPO as an informative marker of glial activation in MS. C1 [Oh, Unsong; Evangelou, Iordanis E.; Harberts, Erin; Ohayon, Joan; Jacobson, Steven] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Fujita, Masahiro; Pike, Victor W.; Zhang, Yi; Zoghbi, Sami S.; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Ikonomidou, Vasiliki N.] George Mason Univ, Dept Elect & Comp Engn, Volgenau Sch Informat Technol & Engn, Fairfax, VA 22030 USA. [Matsuura, Eiji] Kagoshima Univ Grad Sch Med & Dent Sci, Dept Neurol & Geriatr, Kagoshima, Japan. RP Jacobson, S (reprint author), Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, 10 Ctr Dr,Bldg 10 Rm 5C103, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov RI MATSUURA, EIJI/E-1231-2013 OI MATSUURA, EIJI/0000-0001-8215-8853 FU NIH (NINDS and NIMH) FX We thank Maria Ferraris Araneta (MIB/NIMH) and Kaylan Fenton (NIB/NINDS) for clinical support. This research was supported by the Intramural Research Program of the NIH (NINDS and NIMH). NR 17 TC 42 Z9 42 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD SEP PY 2011 VL 6 IS 3 BP 354 EP 361 DI 10.1007/s11481-010-9243-6 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 786MQ UT WOS:000292312900004 PM 20872081 ER PT J AU Cohen, S Stemmer, SM Zozulya, G Ochaion, A Patoka, R Barer, F Bar-Yehuda, S Rath-Wolfson, L Jacobson, KA Fishman, P AF Cohen, S. Stemmer, S. M. Zozulya, G. Ochaion, A. Patoka, R. Barer, F. Bar-Yehuda, S. Rath-Wolfson, L. Jacobson, K. A. Fishman, P. TI CF102 an A(3) Adenosine Receptor Agonist Mediates Anti-Tumor and Anti-Inflammatory Effects in the Liver SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID NF-KAPPA-B; ADJUVANT-INDUCED ARTHRITIS; TUMOR-NECROSIS-FACTOR; HUMAN-MELANOMA CELLS; IB-MECA; RHEUMATOID-ARTHRITIS; HEPATOCELLULAR-CARCINOMA; CONCANAVALIN-A; CANCER-THERAPY; GROWTH INHIBITION AB The Gi protein-associated A(3) adenosine receptor (A(3)AR) is a member of the adenosine receptor family. Selective agonists at the A(3)AR, such as CF101 and CF102 were found to induce anti-inflammatory and anti-cancer effects. In this study, we examined the differential effect of CF102 in pathological conditions of the liver. The anti-inflammatory protective effect of CF101 was tested in a model of liver inflammation induced by Concanavalin A (Con. A) and the anti-cancer effect of CF102 was examined in vitro and in a xenograft animal model utilizing Hep-3B hepatocellular carcinoma (HCC) cells. The mechanism of action was explored by following the expression levels of key signaling proteins in the inflamed and tumor liver tissues, utilizing Western blot (WB) analysis. In the liver inflammation model, CF102 (100 mu g/kg) markedly reduced the secretion of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase in comparison to the vehicle-treated group. Mechanistically, CF102 treatment decreased the expression level of phosphorylated glycogen synthase kinase-3 beta, NF-kappa B, and TNF-alpha and prevented apoptosis in the liver. This was demonstrated by decreased expression levels of Fas receptor (FasR) and of the pro-apoptotic proteins Bax and Bad in liver tissues. In addition, CF102-induced apoptosis of Hep-3B cells both in vitro and in vivo via de-regulation of the PI3K-NF-kappa B signaling pathway, resulting in up-regulation of pro-apoptotic proteins. Taken together, CF102 acts as a protective agent in liver inflammation and inhibits HCC tumor growth. These results suggest that CF102 through its differential effect is a potential drug candidate to treat various pathological liver conditions. J. Cell. Physiol. 226: 2438-2447, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Cohen, S.; Zozulya, G.; Ochaion, A.; Patoka, R.; Barer, F.; Bar-Yehuda, S.; Fishman, P.] Can Fite BioPharma Ltd, IL-49170 Kiryat Matalon, Petach Tikva, Israel. [Stemmer, S. M.] Tel Aviv Univ, Davidoff Ctr, Rabin Med Ctr, Inst Oncol,Sackler Sch Med, Petah Tiqwa, Israel. [Rath-Wolfson, L.] Tel Aviv Univ, Dept Pathol, Rabin Med Ctr, Sackler Fac Med, Petah Tiqwa, Israel. [Jacobson, K. A.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Fishman, P (reprint author), Can Fite BioPharma Ltd, 10 Bareket St,POB 7537, IL-49170 Kiryat Matalon, Petach Tikva, Israel. EM pnina@canfite.co.il RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z99 DK999999, ZIA DK031117-23] NR 57 TC 21 Z9 22 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD SEP PY 2011 VL 226 IS 9 BP 2438 EP 2447 DI 10.1002/jcp.22593 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 778FY UT WOS:000291689700026 PM 21660967 ER PT J AU McCarthy, J Lochner, A Opie, LH Sack, MN Essop, MF AF McCarthy, Joy Lochner, Amanda Opie, Lionel H. Sack, Michael N. Essop, M. Faadiel TI PKC epsilon Promotes Cardiac Mitochondrial and Metabolic Adaptation to Chronic Hypobaric Hypoxia by GSK3 beta Idnhibition SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID PROTEIN-KINASE-C; GLYCOGEN-SYNTHASE KINASE-3-BETA; RIGHT-VENTRICULAR HYPERTROPHY; PERMEABILITY TRANSITION PORE; HIGH-ALTITUDE HYPOXIA; INDUCED HEART-FAILURE; ISCHEMIA-REPERFUSION; GENE-EXPRESSION; FATTY-ACID; RAT-HEART AB PKC epsilon is central to cardioprotection. Sub-proteome analysis demonstrated co-localization of activated cardiac PKC epsilon (aPKC epsilon) with metabolic, mitochondrial, and cardioprotective modulators like hypoxia-inducible factor 1 alpha (HIF-1 alpha). aPKC epsilon relocates to the mitochondrion, inactivating glycogen synthase kinase 3 beta (GSK3 beta) to modulate glycogen metabolism, hypertrophy and HIF-1 alpha. However, there is no established mechanistic link between PKC epsilon, p-GSK3 beta and HIF1-alpha. Here we hypothesized that cardiac-restricted aPKC epsilon improves mitochondrial response to hypobaric hypoxia by altered substrate fuel selection via a GSK3 beta/HIF-1 alpha-dependent mechanism. aPKC epsilon and wild-type (WT) mice were exposed to 14 days of hypobaric hypoxia (45 kPa, 11% O(2)) and cardiac metabolism, functional parameters, p-GSK3 beta/HIF-1 alpha expression, mitochondrial function and ultrastructure analyzed versus normoxic controls. Mitochondrial ADP-dependent respiration, ATP production and membrane potential were attenuated in hypoxic WT but maintained in hypoxic aPKC epsilon mitochondria (P < 0.005, n = 8). Electron microscopy revealed a hypoxia-associated increase in mitochondrial number with ultrastructural disarray in WT versus aPKCe hearts. Concordantly, left ventricular work was diminished in hypoxic WT but not aPKC epsilon mice (glucose only perfusions). However, addition of palmitate abrogated this (P < 0.05 vs. WT). aPKC epsilon hearts displayed increased glucose utilization at baseline and with hypoxia. In parallel, p-GSK3 beta and HIF1-alpha peptide levels were increased in hypoxic aPKC epsilon hearts versus WT. Our study demonstrates that modest, sustained PKC epsilon activation blunts cardiac pathophysiologic responses usually observed in response to chronic hypoxia. Moreover, we propose that preferential glucose utilization by PKC epsilon hearts is orchestrated by a p-GSK3 beta/HIF-1 alpha-mediated mechanism, playing a crucial role to sustain contractile function in response to chronic hypobaric hypoxia. J. Cell. Physiol. 226: 2457-2468, 2011. (C) 2010 Wiley-Liss, Inc. C1 [McCarthy, Joy; Opie, Lionel H.] Univ Cape Town, Sch Med, Hatter Inst Cardiovasc Res, ZA-7925 Cape Town, South Africa. [Lochner, Amanda] Univ Stellenbosch, Fac Hlth Sci, Dept Med Physiol, ZA-7505 Tygerberg, South Africa. [Sack, Michael N.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Essop, M. Faadiel] CMRG, Dept Physiol Sci, Stellenbosch, South Africa. RP McCarthy, J (reprint author), Univ Cape Town, Sch Med, Hatter Inst Cardiovasc Res, ZA-7925 Cape Town, South Africa. EM joy.mccarthy@uct.ac.za FU South African MRC; South African National Research Foundation FX The University of Cape Town Electron Microscopy Unit for assistance, Ms Sonia Genade for the working mouse heart perfusions and Dr. Heinrich Taegtmeyer (Houston, TX, USA) for quantitative RT-PCR analysis performed in his laboratory. We further acknowledge the South African MRC and the South African National Research Foundation for financial support, and Dr. Uthra Rajamani for formatting of the figures. NR 69 TC 11 Z9 11 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD SEP PY 2011 VL 226 IS 9 BP 2457 EP 2468 DI 10.1002/jcp.22592 PG 12 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 778FY UT WOS:000291689700028 PM 21660969 ER PT J AU Hu, ZH Follmann, DA Qin, J AF Hu, Zonghui Follmann, Dean A. Qin, Jing TI Dimension reduced kernel estimation for distribution function with incomplete data SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE Curse of dimensionality; Dimension reduction; Distribution function; Ignorable missingness; Kernel regression; Quantile ID AUXILIARY INFORMATION AB This work focuses on the estimation of distribution functions with incomplete data, where the variable of interest Y has ignorable missingness but the covariate X is always observed. When X is high dimensional, parametric approaches to incorporate X-information is encumbered by the risk of model misspecification and nonparametric approaches by the curse of dimensionality. We propose a semiparametric approach, which is developed under a nonparametric kernel regression framework, but with a parametric working index to condense the high dimensional X-information for reduced dimension. This kernel dimension reduction estimator has double robustness to model misspecification and is most efficient if the working index adequately conveys the X-information about the distribution of Y. Numerical studies indicate better performance of the semiparametric estimator over its parametric and nonparametric counterparts. We apply the kernel dimension reduction estimation to an HIV study for the effect of antiretroviral therapy on HIV virologic suppression. Published by Elsevier B.V. C1 [Hu, Zonghui; Follmann, Dean A.; Qin, Jing] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Hu, ZH (reprint author), NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM huzo@niaid.nih.gov; dfollmann@niaid.nih.gov; jqin@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 18 TC 3 Z9 3 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD SEP PY 2011 VL 141 IS 9 BP 3084 EP 3093 DI 10.1016/j.jspi.2011.03.030 PG 10 WC Statistics & Probability SC Mathematics GA 776GS UT WOS:000291523100009 PM 21731174 ER PT J AU Liu, Y AF Liu, Yuan TI The DIADEM and Beyond SO NEUROINFORMATICS LA English DT Editorial Material C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Liu, Y (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM liuyuan@ninds.nih.gov NR 19 TC 18 Z9 18 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1539-2791 J9 NEUROINFORMATICS JI Neuroinformatics PD SEP PY 2011 VL 9 IS 2-3 SI SI BP 99 EP 102 DI 10.1007/s12021-011-9102-5 PG 4 WC Computer Science, Interdisciplinary Applications; Neurosciences SC Computer Science; Neurosciences & Neurology GA 771OS UT WOS:000291171200002 PM 21431331 ER PT J AU Gillette, TA Brown, KM Svoboda, K Liu, Y Ascoli, GA AF Gillette, Todd A. Brown, Kerry M. Svoboda, Karel Liu, Yuan Ascoli, Giorgio A. TI DIADEMchallenge.Org: A Compendium of Resources Fostering the Continuous Development of Automated Neuronal Reconstruction SO NEUROINFORMATICS LA English DT Editorial Material C1 [Gillette, Todd A.; Brown, Kerry M.; Ascoli, Giorgio A.] George Mason Univ, Ctr Neural Informat Struct & Plast, Krasnow Inst Adv Study, Fairfax, VA 22030 USA. [Svoboda, Karel] Howard Hughes Med Inst, Ashburn, VA USA. [Liu, Yuan] NINDS, NIH, Bethesda, MD 20892 USA. RP Ascoli, GA (reprint author), George Mason Univ, Ctr Neural Informat Struct & Plast, Krasnow Inst Adv Study, Fairfax, VA 22030 USA. EM ascoli@gmu.edu OI Gillette, Todd/0000-0001-6896-4824 NR 2 TC 13 Z9 13 U1 1 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1539-2791 J9 NEUROINFORMATICS JI Neuroinformatics PD SEP PY 2011 VL 9 IS 2-3 SI SI BP 303 EP 304 DI 10.1007/s12021-011-9104-3 PG 2 WC Computer Science, Interdisciplinary Applications; Neurosciences SC Computer Science; Neurosciences & Neurology GA 771OS UT WOS:000291171200019 ER PT J AU Barry, CS Backus, KM Barry, CE Davis, BG AF Barry, Conor S. Backus, Keriann M. Barry, Clifton E., III Davis, Benjamin G. TI ESI-MS Assay of M. tuberculosis Cell Wall Antigen 85 Enzymes Permits Substrate Profiling and Design of a Mechanism-Based Inhibitor SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; GLYCOSYLTRANSFERASES; INACTIVATION; PURIFICATION; GLYCOSIDES; SMEGMATIS; ENVELOPE; SYNTHASE; ANALOGS AB Mycobacterium tuberculosis Antigen 85 enzymes are vital to the integrity of the highly impermeable cell envelope and are potential therapeutic targets. Kinetic analysis using a label-free assay revealed both mechanistic details and a substrate profile that allowed the design and construction of a selective in vitro mechanism-based inhibitor. C1 [Backus, Keriann M.; Barry, Clifton E., III] US Natl Inst Allergy & Infect Dis, TB Res Sect, Lab Clin Infect Dis, Bethesda, MD USA. [Barry, Conor S.; Backus, Keriann M.; Davis, Benjamin G.] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England. RP Barry, CE (reprint author), US Natl Inst Allergy & Infect Dis, TB Res Sect, Lab Clin Infect Dis, Bethesda, MD USA. EM cbarry@niaid.nih.gov; Ben.Davis@chem.ox.ac.uk RI Barry, III, Clifton/H-3839-2012; Davis, Benjamin/C-5281-2011 OI Davis, Benjamin/0000-0002-5056-407X FU National Institutes of Health, National Institute of Allergy and Infectious Disease; Rhodes Trust; Biotechnology and Biological Sciences Research Council; Bill and Melinda Gates Foundation; Royal Society FX This work was funded by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Disease (C.E.B.), the Rhodes Trust (K.M.B.), the Biotechnology and Biological Sciences Research Council (C.S.B.), and the Bill and Melinda Gates Foundation through the TB Drug Accelerator Program (C.E.B, B.G.D.). B.G.D. is a Royal Society Wolfson Research Merit Award recipient. We thank Colorado State "TB Vaccine Testing and Research Materials" contract for providing Antigen 85 plasmids. NR 27 TC 13 Z9 13 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD AUG 31 PY 2011 VL 133 IS 34 BP 13232 EP 13235 DI 10.1021/ja204249p PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 829BZ UT WOS:000295551600007 PM 21776980 ER PT J AU Goldova, J Ulrych, A Hercik, K Branny, P AF Goldova, Jana Ulrych, Ales Hercik, Kamil Branny, Pavel TI A eukaryotic-type signalling system of Pseudomonas aeruginosa contributes to oxidative stress resistance, intracellular survival and virulence SO BMC GENOMICS LA English DT Article ID SERINE/THREONINE PROTEIN-KINASE; SER/THR KINASE; MYCOBACTERIUM-TUBERCULOSIS; TRANSCRIPTOME ANALYSIS; HYDROGEN-PEROXIDE; BIOFILM FORMATION; ESCHERICHIA-COLI; GENE-EXPRESSION; FUNCTIONAL-CHARACTERIZATION; ALLOSTERIC ACTIVATION AB Background: The genome of Pseudomonas aeruginosa contains at least three genes encoding eukaryotic-type Ser/Thr protein kinases, one of which, ppkA, has been implicated in P. aeruginosa virulence. Together with the adjacent pppA phosphatase gene, they belong to the type VI secretion system (H1-T6SS) locus, which is important for bacterial pathogenesis. To determine the biological function of this protein pair, we prepared a pppA-ppkA double mutant and characterised its phenotype and transcriptomic profiles. Results: Phenotypic studies revealed that the mutant grew slower than the wild-type strain in minimal media and exhibited reduced secretion of pyoverdine. In addition, the mutant had altered sensitivity to oxidative and hyperosmotic stress conditions. Consequently, mutant cells had an impaired ability to survive in murine macrophages and an attenuated virulence in the plant model of infection. Whole-genome transcriptome analysis revealed that pppA-ppkA deletion affects the expression of oxidative stress-responsive genes, stationary phase sigma-factor RpoS-regulated genes, and quorum-sensing regulons. The transcriptome of the pppA-ppkA mutant was also analysed under conditions of oxidative stress and showed an impaired response to the stress, manifested by a weaker induction of stress adaptation genes as well as the genes of the SOS regulon. In addition, expression of either RpoS-regulated genes or quorum-sensing-dependent genes was also affected. Complementation analysis confirmed that the transcription levels of the differentially expressed genes were specifically restored when the pppA and ppkA genes were expressed ectopically. Conclusions: Our results suggest that in addition to its crucial role in controlling the activity of P. aeruginosa H1-T6SS at the post-translational level, the PppA-PpkA pair also affects the transcription of stress-responsive genes. Based on these data, it is likely that the reduced virulence of the mutant strain results from an impaired ability to survive in the host due to the limited response to stress conditions. C1 [Goldova, Jana; Ulrych, Ales; Hercik, Kamil; Branny, Pavel] Acad Sci Czech Republic, Inst Microbiol, Cell & Mol Microbiol Div, Vvi, CR-14220 Prague 4, Czech Republic. [Hercik, Kamil] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Branny, P (reprint author), Acad Sci Czech Republic, Inst Microbiol, Cell & Mol Microbiol Div, Vvi, Videnska 1083, CR-14220 Prague 4, Czech Republic. EM branny@biomed.cas.cz RI Branny, Pavel/H-2490-2014; Ulrych, Ales/J-8048-2014; Goldova, Jana/J-8258-2014 FU Czech Science Foundation [204/08/0783]; Grant Agency of the Charles University in Prague [161/2006/B-BIO/PrF]; [AV0Z50200510] FX We are grateful to Thilo Kohler (University of Geneva) for the gift of P. aeruginosa PAO1 wild type strain and Herbert P. Schweizer (Colorado State University) for the gift of plasmids pEX18Ap, pFLP2, pPS858, pUC18-mini-Tn7T-LAC and pTNS2. This work was supported by the Czech Science Foundation (grant no. 204/08/0783 to PB), the Grant Agency of the Charles University in Prague (Project no. 161/2006/B-BIO/PrF to JG) and by Institutional Research Concept grant AV0Z50200510. NR 83 TC 17 Z9 18 U1 1 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 31 PY 2011 VL 12 AR 437 DI 10.1186/1471-2164-12-437 PG 21 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 827GC UT WOS:000295415500001 PM 21880152 ER PT J AU Alves, G Yu, YK AF Alves, Gelio Yu, Yi-Kuo TI Combining Independent, Weighted P-Values: Achieving Computational Stability by a Systematic Expansion with Controllable Accuracy SO PLOS ONE LA English DT Article ID MULTIPLE END-POINTS; SIGNIFICANCE TESTS; CLINICAL-TRIALS; COMBINATION; PROBABILITIES; DISTRIBUTIONS; VARIABLES; STATISTICS; SEARCHES; EVENTS AB Given the expanding availability of scientific data and tools to analyze them, combining different assessments of the same piece of information has become increasingly important for social, biological, and even physical sciences. This task demands, to begin with, a method-independent standard, such as the P-value, that can be used to assess the reliability of a piece of information. Good's formula and Fisher's method combine independent P-values with respectively unequal and equal weights. Both approaches may be regarded as limiting instances of a general case of combining P-values from m groups; P-values within each group are weighted equally, while weight varies by group. When some of the weights become nearly degenerate, as cautioned by Good, numeric instability occurs in computation of the combined P-values. We deal explicitly with this difficulty by deriving a controlled expansion, in powers of differences in inverse weights, that provides both accurate statistics and stable numerics. We illustrate the utility of this systematic approach with a few examples. In addition, we also provide here an alternative derivation for the probability distribution function of the general case and show how the analytic formula obtained reduces to both Good's and Fisher's methods as special cases. A C++ program, which computes the combined P-values with equal numerical stability regardless of whether weights are (nearly) degenerate or not, is available for download at our group website http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/downloads/CoinedPValues.html. C1 [Alves, Gelio; Yu, Yi-Kuo] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Alves, G (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM yyu@ncbi.nlm.nih.gov FU National Library of Medicine at the National Institutes of Health/DHHS FX This work was supported by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health/DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 3 Z9 3 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 31 PY 2011 VL 6 IS 8 AR e22647 DI 10.1371/journal.pone.0022647 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817NM UT WOS:000294680800003 PM 21912585 ER PT J AU Gao, JJ Huang, XM Park, Y Hollenbeck, A Chen, HL AF Gao, Jianjun Huang, Xuemei Park, YikYung Hollenbeck, Albert Chen, Honglei TI An Exploratory Study on CLU, CR1 and PICALM and Parkinson Disease SO PLOS ONE LA English DT Article ID APOLIPOPROTEIN-E GENOTYPE; GENOME-WIDE ASSOCIATION; ALZHEIMERS-DISEASE; CLUSTERIN/APOLIPOPROTEIN-J; IDENTIFIES VARIANTS; RISK; DEMENTIA; AGGREGATION; CHOLESTEROL; RELATIVES AB Background: Recent GWAS and subsequent confirmation studies reported several single-nucleotide polymorphisms (SNPs) at the CLU, CR1 and PICALM loci in association with late-onset Alzheimer's disease (AD). Parkinson disease (PD) shares several clinical and pathologic characteristics with AD; we therefore explored whether these SNPs were also associated with PD risk. Methodology/Principal Findings: 791 non-Hispanic Whites cases and 1,580 matched controls were included in the study. Odds ratios (OR) and 95% confidence intervals (CI) were obtained from logistic regression models. rs11136000 at the CLU locus was associated with PD risk under the recessive model (comparing TT versus CC+CT: OR = 0.71, 95% CI: 0.55-0.92, p = 0.008) after adjusting for year of birth, gender, smoking, and caffeine intake. Further adjustment for family history of PD and ApoE epsilon 4 status did not change the result. In addition, we did not find evidence for effect modification by ApoE or known PD risk factors. The association, however, appeared to be stronger for PD with dementia (OR = 0.49, 95% CI: 0.27-0.91) than for PD without dementia (OR = 0.81, 95% CI: 0.61-1.06). The two other SNPs, rs6656401 from CR1, and rs3851179 from PICALM region were not associated with PD (p > 0.05). Conclusion: Our exploratory analysis suggests an association of CLU with PD. This exploratory finding and the role of dementia in explaining this finding needs further investigation. C1 [Gao, Jianjun; Chen, Honglei] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Park, YikYung] NCI, Nutr Epidemiol Branch, Rockville, MD USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Gao, JJ (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, Res Triangle Pk, NC 27709 USA. EM chenh2@niehs.nih.gov OI Chen, Honglei/0000-0003-3446-7779; Park, Yikyung/0000-0002-6281-489X FU NIH; National Institute of Environmental Health Sciences [Z01-ES-101986]; National Cancer Institute [Z01 CP010196-02] FX This study was supported by the intramural research program of the NIH, the National Institute of Environmental Health Sciences (Z01-ES-101986) and the National Cancer Institute (Z01 CP010196-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the authors have financial conflict of interest. NR 34 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 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 30 PY 2011 VL 6 IS 8 AR e24211 DI 10.1371/journal.pone.0024211 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817MS UT WOS:000294678300031 PM 21912625 ER PT J AU Pecsi, I Szabo, JE Adams, SD Simon, I Sellers, JR Vertessy, BG Toth, J AF Pecsi, Ildiko Szabo, Judit E. Adams, Scott D. Simon, Istvan Sellers, James R. Vertessy, Beata G. Toth, Judit TI Nucleotide pyrophosphatase employs a P-loop-like motif to enhance catalytic power and NDP/NTP discrimination SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE NTP hydrolysis; nucleotide discrimination; dUTP pyrophosphatase; Walker A motif; evolutionary adaptation ID BIFUNCTIONAL DCTP DEAMINASE; PHOSPHATE ESTER HYDROLYSIS; DIMERIC DUTPASE-DUDPASE; INFECTIOUS-ANEMIA VIRUS; MYOSIN MOTOR DOMAIN; X-RAY STRUCTURES; ESCHERICHIA-COLI; ACTIVE-SITE; CRYSTAL-STRUCTURE; C-TERMINUS AB We investigated the potential (d)NDP/(d)NTP discrimination mechanisms in nucleotide pyrophosphatases. Here, we report that dUTPase, an essential nucleotide pyrophosphatase, uses a C-terminal P-loop-like sequence in a unique mechanism for substrate discrimination and efficient hydrolysis. Our spectroscopy and transient kinetics results on human dUTPase mutants combined with previous structural studies indicate that (i) H-bond interactions between the gamma-phosphate and the P-loop-like motif V promote the catalytically competent conformation of the reaction center at the alpha-phosphate group; (ii) these interactions accelerate the chemical step of the kinetic cycle and that (iii) hydrolysis occurs very slowly or not at all in the absence of the gamma-phosphate-motif V interactions, i.e., in dUDP, dUDP.BeFx, or in the motif V-deleted mutant. The physiological role of dUTPase is to set cellular dUTP: dTTP ratios and prevent injurious uracil incorporation into DNA. Based upon comparison with related pyrophosphate generating (d)NTPases, we propose that the unusual use of a P-loop-like motif enables dUTPases to achieve efficient catalysis of dUTP hydrolysis and efficient discrimination against dUDP at the same time. These specifics might have been advantageous on the appearance of uracil-DNA repair. The similarities and differences between dUTPase motif V and the P-loop (or Walker A sequence) commonly featured by ATP- and GTPases offer insight into functional adaptation to various nucleotide hydrolysis tasks. C1 [Pecsi, Ildiko; Szabo, Judit E.; Adams, Scott D.; Simon, Istvan; Vertessy, Beata G.; Toth, Judit] Hungarian Acad Sci, Biol Res Ctr, Inst Enzymol, H-1113 Budapest, Hungary. [Adams, Scott D.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Sellers, James R.; Toth, Judit] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Vertessy, Beata G.] Budapest Univ Technol & Econ, Dept Appl Biotechnol, H-1111 Budapest, Hungary. RP Vertessy, BG (reprint author), Hungarian Acad Sci, Biol Res Ctr, Inst Enzymol, Karolina Ut 29, H-1113 Budapest, Hungary. EM vertessy@enzim.hu; tothj@enzim.hu RI Vertessy, Beata/H-6202-2012; Simon, Istvan/A-2868-2008 FU US National Institutes of Health [1R01TW008130-01]; Hungarian Academy of Sciences; Howard Hughes Medical Institutes [55000342]; Hungarian Scientific Research Funds [PD72008, CK-78646, K68229, K72973, NI68466]; National Office for Research and Technology, Hungary [JAP_TSZ_071128_TB_INTER]; EU [SPINE2c LSHG-CT-2006-031220, TEACH-SG LSSG-CT-2007-037198]; Alexander von Humboldt Foundation FX This work was supported by the US National Institutes of Health (Grant number 1R01TW008130-01); the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences, the Howard Hughes Medical Institutes (Grant number 55000342); the Hungarian Scientific Research Funds (Grant numbers PD72008, CK-78646, K68229, K72973, and NI68466); the National Office for Research and Technology, Hungary (Grant number JAP_TSZ_071128_TB_INTER) and the EU FP6 (Grant numbers SPINE2c LSHG-CT-2006-031220, TEACH-SG LSSG-CT-2007-037198) and the Alexander von Humboldt Foundation. NR 34 TC 16 Z9 16 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 30 PY 2011 VL 108 IS 35 BP 14437 EP 14442 DI 10.1073/pnas.1013872108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 814DH UT WOS:000294425900021 PM 21831832 ER PT J AU Feng, HQ Zhou, Z Zhou, BR Bai, YW AF Feng, Hanqiao Zhou, Zheng Zhou, Bing-Rui Bai, Yawen TI Structure of the budding yeast Saccharomyces cerevisiae centromeric histones Cse4-H4 complexed with the chaperone Scm3 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter ID RECOGNITION C1 [Feng, Hanqiao; Zhou, Zheng; Zhou, Bing-Rui; Bai, Yawen] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov RI Zhou, Bing-Rui/D-4766-2009 NR 2 TC 8 Z9 8 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 30 PY 2011 VL 108 IS 35 BP E596 EP E596 DI 10.1073/pnas.1109548108 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 814DH UT WOS:000294425900002 PM 21844330 ER PT J AU Ascierto, ML De Giorgi, V Liu, QZ Bedognetti, D Spivey, TL Murtas, D Uccellini, L Ayotte, BD Stroncek, DF Chouchane, L Manjili, MH Wang, E Marincola, FM AF Ascierto, Maria Libera De Giorgi, Valeria Liu, Qiuzhen Bedognetti, Davide Spivey, Tara L. Murtas, Daniela Uccellini, Lorenzo Ayotte, Ben D. Stroncek, David F. Chouchane, Lotfi Manjili, Masoud H. Wang, Ena Marincola, Francesco M. TI An immunologic portrait of cancer SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID TUMOR-INFILTRATING LYMPHOCYTES; REGULATORY T-CELLS; NF-KAPPA-B; SEROUS OVARIAN-CANCER; INDEPENDENT PROGNOSTIC-FACTOR; HUMAN COLORECTAL-CANCER; PROSTATE-CANCER; BREAST-CANCER; MALIGNANT-MELANOMA; IMMUNE-RESPONSES AB The advent of high-throughput technology challenges the traditional histopathological classification of cancer, and proposes new taxonomies derived from global transcriptional patterns. Although most of these molecular reclassifications did not endure the test of time, they provided bulk of new information that can reframe our understanding of human cancer biology. Here, we focus on an immunologic interpretation of cancer that segregates oncogenic processes independent from their tissue derivation into at least two categories of which one bears the footprints of immune activation. Several observations describe a cancer phenotype where the expression of interferon stimulated genes and immune effector mechanisms reflect patterns commonly observed during the inflammatory response against pathogens, which leads to elimination of infected cells. As these signatures are observed in growing cancers, they are not sufficient to entirely clear the organism of neoplastic cells but they sustain, as in chronic infections, a self-perpetuating inflammatory process. Yet, several studies determined an association between this inflammatory status and a favorable natural history of the disease or a better responsiveness to cancer immune therapy. Moreover, these signatures overlap with those observed during immune-mediated cancer rejection and, more broadly, immune-mediated tissue-specific destruction in other immune pathologies. Thus, a discussion concerning this cancer phenotype is warranted as it remains unknown why it occurs in immune competent hosts. It also remains uncertain whether a genetically determined response of the host to its own cancer, the genetic makeup of the neoplastic process or a combination of both drives the inflammatory process. Here we reflect on commonalities and discrepancies among studies and on the genetic or somatic conditions that may cause this schism in cancer behavior. C1 [Ascierto, Maria Libera; De Giorgi, Valeria; Liu, Qiuzhen; Bedognetti, Davide; Spivey, Tara L.; Murtas, Daniela; Uccellini, Lorenzo; Stroncek, David F.; Wang, Ena; Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Ascierto, Maria Libera; De Giorgi, Valeria; Liu, Qiuzhen; Bedognetti, Davide; Spivey, Tara L.; Murtas, Daniela; Uccellini, Lorenzo; Stroncek, David F.; Wang, Ena; Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. [Ascierto, Maria Libera] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Ascierto, Maria Libera; Bedognetti, Davide] CEBR, Genoa, Italy. [Bedognetti, Davide] Natl Canc Res Inst Genoa, Genoa, Italy. [Ayotte, Ben D.] No Michigan Univ, Dept Biol, Marquette, MI 49855 USA. [Manjili, Masoud H.] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Microbiol & Immunol, Richmond, VA 23298 USA. RP Marincola, FM (reprint author), NIH, IDIS, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM fmarincola@mail.cc.nih.gov RI duan, hf/F-9166-2011; Bedognetti, Davide/A-9090-2012; Ascierto, Maria Libera/A-9239-2012; De Giorgi, Valeria/D-4582-2017; OI Bedognetti, Davide/0000-0002-5857-773X NR 131 TC 45 Z9 45 U1 2 U2 19 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 AUG 29 PY 2011 VL 9 AR 146 DI 10.1186/1479-5876-9-146 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 822NI UT WOS:000295054700001 PM 21875439 ER PT J AU Blanford, S Shi, WP Christian, R Marden, JH Koekemoer, LL Brooke, BD Coetzee, M Read, AF Thomas, MB AF Blanford, Simon Shi, Wangpeng Christian, Riann Marden, James H. Koekemoer, Lizette L. Brooke, Basil D. Coetzee, Maureen Read, Andrew F. Thomas, Matthew B. TI Lethal and Pre-Lethal Effects of a Fungal Biopesticide Contribute to Substantial and Rapid Control of Malaria Vectors SO PLOS ONE LA English DT Article ID CELLULAR DEFENSE RESPONSE; ANOPHELES-GAMBIAE-S.S.; ADULT AEDES-AEGYPTI; ANISOPLIAE IP 46; METARHIZIUM-ANISOPLIAE; ENTOMOPATHOGENIC FUNGUS; BEAUVERIA-BASSIANA; INSECTICIDE RESISTANCE; SCHISTOCERCA-GREGARIA; MOSQUITO RESISTANCE AB Rapidly emerging insecticide resistance is creating an urgent need for new active ingredients to control the adult mosquitoes that vector malaria. Biopesticides based on the spores of entomopathogenic fungi have shown considerable promise by causing very substantial mortality within 7-14 days of exposure. This mortality will generate excellent malaria control if there is a high likelihood that mosquitoes contact fungi early in their adult lives. However, where contact rates are lower, as might result from poor pesticide coverage, some mosquitoes will contact fungi one or more feeding cycles after they acquire malaria, and so risk transmitting malaria before the fungus kills them. Critics have argued that 'slow acting' fungal biopesticides are, therefore, incapable of delivering malaria control in real-world contexts. Here, utilizing standard WHO laboratory protocols, we demonstrate effective action of a biopesticide much faster than previously reported. Specifically, we show that transient exposure to clay tiles sprayed with a candidate biopesticide comprising spores of a natural isolate of Beauveria bassiana, could reduce malaria transmission potential to zero within a feeding cycle. The effect resulted from a combination of high mortality and rapid fungal-induced reduction in feeding and flight capacity. Additionally, multiple insecticide-resistant lines from three key African malaria vector species were completely susceptible to fungus. Thus, fungal biopesticides can block transmission on a par with chemical insecticides, and can achieve this where chemical insecticides have little impact. These results support broadening the current vector control paradigm beyond fast-acting chemical toxins. C1 [Blanford, Simon; Read, Andrew F.] Penn State Univ, Dept Biol, Mueller Lab, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Blanford, Simon; Shi, Wangpeng; Read, Andrew F.; Thomas, Matthew B.] Penn State Univ, Dept Entomol, Merkle Lab, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Shi, Wangpeng] China Agr Univ, Minist Agr, Key Lab Biol Control, Beijing 100094, Peoples R China. [Christian, Riann; Koekemoer, Lizette L.; Brooke, Basil D.; Coetzee, Maureen] Natl Inst Communicable Dis, Natl Hlth Lab Serv, Vector Control Reference Unit, Johannesburg, South Africa. [Christian, Riann; Koekemoer, Lizette L.; Brooke, Basil D.; Coetzee, Maureen] Univ Witwatersrand, Fac Hlth Sci, Sch Pathol, Malaria Entomol Res Unit, Johannesburg, South Africa. [Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Blanford, S (reprint author), Penn State Univ, Dept Biol, Mueller Lab, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM mbt13@psu.edu FU Gates Grand Challenges Explorations [53066]; National Institutes of Health [AI088094-01]; Innovative Vector Control Consortium; China Scholarship Council; Pennsylvania Department of Health FX This research was part-funded by grants from Gates Grand Challenges Explorations (No. 53066), the National Institutes of Health (AI088094-01), the Innovative Vector Control Consortium, and a China Scholarship Council Grant to WP. This project was also funded, in part, under a grant with the Pennsylvania Department of Health using Tobacco Settlement Funds. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 31 Z9 31 U1 2 U2 28 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 AUG 29 PY 2011 VL 6 IS 8 AR e23591 DI 10.1371/journal.pone.0023591 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817MF UT WOS:000294676900009 PM 21897846 ER PT J AU Austin, C AF Austin, Christopher TI Translational therapeutics development at NIH SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Austin, Christopher] NIH, NIH Ctr Translat Therapeut, Bethesda, MD 20892 USA. EM austinc@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 166-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304468 ER PT J AU Betzig, E Planchon, T Gao, L Davidson, M Galbraith, J Galbraith, C AF Betzig, Eric Planchon, Thomas Gao, Liang Davidson, Michael Galbraith, James Galbraith, Catherine TI Rapid 3D isotropic imaging of living cells using Bessel beam plane illumination SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Betzig, Eric; Planchon, Thomas; Gao, Liang; Davidson, Michael] Janelia Farm HHMI, Ashburn, VA 20147 USA. [Galbraith, James] NINDS, Bethesda, MD 20892 USA. [Galbraith, Catherine] NICHHD, Bethesda, MD 20892 USA. EM betzige@janelia.hhmi.org NR 0 TC 0 Z9 0 U1 0 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 297-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378306074 ER PT J AU Bienstock, RJ Wang, JL Tomer, KB Deterding, LJ AF Bienstock, Rachelle J. Wang, Jinglan Tomer, Kenneth B. Deterding, Leesa J. TI Structure prediction of the RNA binding La autoantigen protein through computational docking of protein domain structures with Mass Spectrometry (MS) experimental constraints SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Bienstock, Rachelle J.; Wang, Jinglan; Tomer, Kenneth B.; Deterding, Leesa J.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. EM rachelleb1@gmail.com NR 4 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 354-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378302291 ER PT J AU Bryant, S AF Bryant, Stephen TI Open repository for chemical structure and biological activity information SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Bryant, Stephen] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM bryant@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 54-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378302313 ER PT J AU Chan, M DeVito, MJ Shafer, T Hughes, MF AF Chan, Melissa DeVito, Michael J. Shafer, Timothy Hughes, Michael F. TI Evaluating tools and models used for quantitative extrapolation of in vitro to in vivo data for neurotoxicants SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Chan, Melissa; DeVito, Michael J.] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Shafer, Timothy; Hughes, Michael F.] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. EM chanp2@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 236-AGRO PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378300353 ER PT J AU Chung, HS Eaton, WA AF Chung, Hoi Sung Eaton, William A. TI Single-molecule FRET and transition paths in protein folding SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Chung, Hoi Sung; Eaton, William A.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM chunghoi@niddk.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 400-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378306180 ER PT J AU Collins, F Austin, CP AF Collins, Francis Austin, Christopher P. TI Catalyzing opportunities in translational research SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Collins, Francis; Austin, Christopher P.] NIH, Bethesda, MD 20892 USA. EM austinc@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 223-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304531 ER PT J AU Deflorian, F Jacobson, KA AF Deflorian, Francesca Jacobson, Kenneth A. TI Comparison of three GPCR structural templates for modeling of the P2Y(12) nucleotide receptor SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Deflorian, Francesca; Jacobson, Kenneth A.] NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. EM deflorianf@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 197-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378302129 ER PT J AU Fritz, J Arora, K Boshoff, HIM Plotkin, BJ Green, J Konaklieva, M AF Fritz, Juliana Arora, Kriti Boshoff, Helena I. M. Plotkin, Balbina J. Green, Jacalyn Konaklieva, Monika TI Effect of the aryl ring heteroatom attached at C4 on the antimicrobial activity of N-carbamylated b-Lactams SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Fritz, Juliana; Konaklieva, Monika] American Univ, Dept Chem, Washington, DC 20016 USA. [Arora, Kriti; Boshoff, Helena I. M.] NIAID, Dept TB Res, NIH, LCID, Bethesda, MD 20892 USA. [Plotkin, Balbina J.; Green, Jacalyn] Midwestern Univ, Dept Microbiol & Immunol, Chicago, IL 60515 USA. EM jf9075a@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 308-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304619 ER PT J AU Ganesan, V Liang, FT Shock, D Beard, W Wilson, S Cho, B AF Ganesan, Vaidyanathan Liang, Fengting Shock, David Beard, William Wilson, Samuel Cho, Bongsup TI Solution structure studies of aminofluorene-DNA adduct complexed with Klenow fragment and DNA polymerase beta SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Ganesan, Vaidyanathan; Liang, Fengting; Cho, Bongsup] Univ Rhode Isl, Dept Biomed & Pharmaceut Sci, Kingston, RI 02881 USA. [Shock, David; Beard, William; Wilson, Samuel] NIEHS, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. EM vaidychem@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 51-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378307517 ER PT J AU Gangjee, A Zaware, N Mooberry, SL Hamel, E AF Gangjee, Aleem Zaware, Nilesh Mooberry, Susan L. Hamel, Ernest TI Synthesis and biological evaluation of N-4-(substitutedphenyl)-N-4-methyl/desmethyl-9H-pyrimido[4,5-b]indole-2, 4-diamines as antimitotic agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Gangjee, Aleem; Zaware, Nilesh] Duquesne Univ, Grad Sch Pharmaceut Sci, Pittsburgh, PA 15217 USA. [Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Hamel, Ernest] NIH, Screening Technol Branch, Frederick, MD 21702 USA. EM nileshpharm@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 52-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304713 ER PT J AU Gangjee, A Zaware, N Devambatla, RKV Mooberry, SL Hamel, E AF Gangjee, Aleem Zaware, Nilesh Devambatla, Ravi Kumar Vyas Mooberry, Susan L. Hamel, Ernest TI Synthesis and biological evaluation of 5-chloro-N-4-substituted-N-4-methyl-9H-pyrimido[4,5-b]indole-2,4-diamine s as antimitotic agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Gangjee, Aleem; Zaware, Nilesh; Devambatla, Ravi Kumar Vyas] Duquesne Univ, Div Med Chem, Pittsburgh, PA 15282 USA. [Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Hamel, Ernest] NCI, Div Canc Treatment & Diag, Frederick, MD 21702 USA. EM drk_vyas@yahoo.co.in NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 53-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304714 ER PT J AU Gangjee, A Zhao, Y Raghavan, S Mooberry, SL Hamel, E AF Gangjee, Aleem Zhao, Ying Raghavan, Sudhir Mooberry, Susan L. Hamel, Ernest TI Synthesis and biological evaluation of the R- and S-enantiomers of the antitubulin 6-methyl cyclopenta[d]pyrimidines as cytotoxic agents that parallel predicted antitubulin activities SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Gangjee, Aleem; Zhao, Ying; Raghavan, Sudhir] Duquesne Univ, Grad Sch Pharmaceut Sci, Pittsburgh, PA 15282 USA. [Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Hamel, Ernest] NCI, NIH, Frederick, MD 21702 USA. EM gangjee@duq.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 269-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304580 ER PT J AU Gerhold, D Dieterle, F Ozer, J Holder, D Troth, S Glaab, W Bailey, W Sistare, F AF Gerhold, David Dieterle, Frank Ozer, Josef Holder, Daniel Troth, Sean Glaab, Warren Bailey, Wendy Sistare, Frank TI Kidney injury biomarkers in urine: From rats to regulatory approvals SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Gerhold, David] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Gerhold, David; Ozer, Josef; Troth, Sean; Glaab, Warren; Bailey, Wendy; Sistare, Frank] Merck & Co Inc, Safety Assessment Mol & Investigat Toxicol, West Point, PA 19486 USA. [Dieterle, Frank] Novartis Pharmaceut, Global Program Diagnost, Basel, Switzerland. [Holder, Daniel] Merck Co Inc, Dept Biometr, West Point, PA 19486 USA. EM david.gerhold@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 36-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378307502 ER PT J AU Horkay, F Basser, PJ Hecht, AM Geissler, E AF Horkay, Ferenc Basser, Peter J. Hecht, Anne-Marie Geissler, Erik TI Biological self-assembly and nanoscale interactions in aggrecan solutions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Horkay, Ferenc; Basser, Peter J.] NIH, Sect Tissue Biophys & Biomimet, Bethesda, MD 20892 USA. [Hecht, Anne-Marie; Geissler, Erik] Univ J Fourier Grenoble, Spectrometrie Phys Lab, St Martin Dheres, France. EM horkay@helix.nih.gov RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 165-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378306748 ER PT J AU Horkay, F Horkayne-Szakaly, I Dimitriadis, EK Silva, C Basser, PJ AF Horkay, Ferenc Horkayne-Szakaly, Iren Dimitriadis, Emilios K. Silva, Candida Basser, Peter J. TI Molecular biomechanics of cartilage SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Horkay, Ferenc; Horkayne-Szakaly, Iren; Silva, Candida; Basser, Peter J.] NIH, Sect Tissue Biophys & Biomimet, Bethesda, MD 20892 USA. [Dimitriadis, Emilios K.] NIBIB, NIH, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 151-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378300703 ER PT J AU Hughes, MF Starr, JM Scollon, EJ DeVito, MJ AF Hughes, Michael F. Starr, James M. Scollon, Edward J. DeVito, Michael J. TI In vitro and in vivo experimental data for pyrethroid pharmacokinetic models: The case of bifenthrin SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Hughes, Michael F.] US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Starr, James M.] US EPA, Off Res & Dev, Natl Exposure Res Lab, Res Triangle Pk, NC 27711 USA. [Scollon, Edward J.] US EPA, Off Pesticide Programs, Div Hlth Effects, Washington, DC 20460 USA. [DeVito, Michael J.] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. EM hughes.michaelf@epa.gov NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 214-AGRO PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378300330 ER PT J AU Iyer, MR Dersch, CM Rothman, RB Jacobson, AE Rice, KC AF Iyer, Malliga R. Dersch, Christina M. Rothman, Richard B. Jacobson, Arthur E. Rice, Kenner C. TI Probes for narcotic receptor mediated phenomena: Effect of C4a alkyl and ar-alkyl chain length on the opioid receptor affinity of N-methyl cis-4a-substituted 1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Iyer, Malliga R.; Jacobson, Arthur E.; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Rockville, MD 20852 USA. [Dersch, Christina M.; Rothman, Richard B.] NIDA, Clin Psychopharmacol Sect, Chem Biol Res Branch, Addict Res Ctr, Baltimore, MD 21224 USA. EM iyerma@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 281-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304593 ER PT J AU Iyer, MR Dersch, CM Rothman, RB Jacobson, AE Rice, KC AF Iyer, Malliga R. Dersch, Christina M. Rothman, Richard B. Jacobson, Arthur E. Rice, Kenner C. TI Probes for narcotic receptor mediated phenomena: Effect of C4a ar-alkyl and alkyl chain length on the opioid receptor affinity of N-methyl cis-4a-substituted 1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Iyer, Malliga R.; Jacobson, Arthur E.; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Rockville, MD 20852 USA. [Dersch, Christina M.; Rothman, Richard B.] NIDA, Clin Psychopharmacol Sect, Chem Biol Res Branch, Addict Res Ctr, Baltimore, MD 21224 USA. EM iyerma@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 33-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378300025 ER PT J AU Jacobson, KA IJzerman, AP Auchampach, JA Gao, ZG AF Jacobson, Kenneth A. IJzerman, Adriaan P. Auchampach, John A. Gao, Zhan-Guo TI Allosteric modulators of the A(3) adenosine receptor SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Jacobson, Kenneth A.; Gao, Zhan-Guo] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [IJzerman, Adriaan P.] Leiden Univ, Leiden Amsterdam Ctr Drug Res, Leiden, Netherlands. [Auchampach, John A.] Med Coll Wisconsin, Dept Pharmacol, Milwaukee, WI 53226 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 210-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304517 ER PT J AU Jimenez, JL Cubison, MJ Ortega, AM Hayes, PL Farmer, DK Day, DA Lechner, MJ Brune, WH Apel, E Diskin, GS Fisher, JA Fuelberg, HA Hecobian, A Knapp, DJ Mikoviny, T Riemer, D Sachse, GW Sessions, W Weber, RJ Weinheimer, AJ Wisthaler, A AF Jimenez, Jose L. Cubison, Michael J. Ortega, Amber M. Hayes, Patrick L. Farmer, Delphine K. Day, Douglas A. Lechner, Michael J. Brune, William H. Apel, Eric Diskin, Glenn S. Fisher, Jenny A. Fuelberg, Henry A. Hecobian, Arsineh Knapp, David J. Mikoviny, Tomas Riemer, Daniel Sachse, Glen W. Sessions, Walter Weber, Rodney J. Weinheimer, Andrew J. Wisthaler, Armin TI Effects of aging on organic aerosol from open biomass burning smoke in aircraft & lab studies SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Jimenez, Jose L.; Cubison, Michael J.; Ortega, Amber M.; Hayes, Patrick L.; Farmer, Delphine K.; Day, Douglas A.; Lechner, Michael J.] Univ Colorado, Dept Chem & Biochem, CIRES, Boulder, CO 80309 USA. [Jimenez, Jose L.; Cubison, Michael J.; Ortega, Amber M.; Hayes, Patrick L.; Farmer, Delphine K.; Day, Douglas A.; Lechner, Michael J.] Univ Colorado, Dept Atmospher & Ocean Sci, Boulder, CO 80309 USA. [Brune, William H.] Penn State Univ, University Pk, PA 16802 USA. [Diskin, Glenn S.] NASA Langley Res Ctr, Washington, DC USA. [Fisher, Jenny A.] Harvard Univ, Cambridge, MA 02138 USA. [Fuelberg, Henry A.; Sessions, Walter] Florida State Univ, Tallahassee, FL 32306 USA. [Hecobian, Arsineh; Weber, Rodney J.] Georgia Inst Technol, Atlanta, GA 30332 USA. [Mikoviny, Tomas; Wisthaler, Armin] Univ Innsbruck, A-6020 Innsbruck, Austria. [Riemer, Daniel] Univ Miami, Coral Gables, FL 33124 USA. [Sachse, Glen W.] NIA, Bethesda, MD 20892 USA. EM jose.jimenez@colorado.edu RI Jimenez, Jose/A-5294-2008 OI Jimenez, Jose/0000-0001-6203-1847 NR 0 TC 0 Z9 0 U1 0 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 106-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378305764 ER PT J AU Jun, JH Malhotra, SV AF Jun, Jung Ho Malhotra, Sanjay V. TI Application of microwave chemistry in the etherification of heterocyclic compounds by nucleophilic aromatic substitutions reactions (SNAr) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Jun, Jung Ho; Malhotra, Sanjay V.] NCI, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 117-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378305008 ER PT J AU Kang, D Luecke, H AF Kang, Dongwook Luecke, Hans TI Development of clickable small molecule inhibitors of histone acetyltransferases SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Kang, Dongwook; Luecke, Hans] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kangdongwook@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 266-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304577 ER PT J AU Klausmeyer, P Shipley, S McCloud, TG Zuck, K Newman, DJ AF Klausmeyer, Paul Shipley, Suzanne McCloud, Thomas G. Zuck, Karina Newman, David J. TI Spiruchostatin C, an HDAC inhibitory compound isolated from Burkholderia thailandensis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Klausmeyer, Paul; Shipley, Suzanne; McCloud, Thomas G.; Zuck, Karina] SAIC Frederick Inc, Nat Prod Support Grp, Frederick, MD 21702 USA. [Newman, David J.] NCI, DTP, DCTD, Frederick, MD 21702 USA. EM klausmeyerp@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 272-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304584 ER PT J AU Kumar, A Kumar, V Alegria, AE Malhotra, SV AF Kumar, Ajay Kumar, Vineet Alegria, Antonio E. Malhotra, Sanjay V. TI Syntheses and antitumor activities on NCI-60 human tumor cell line protocol of N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Kumar, Ajay; Alegria, Antonio E.] Univ Puerto Rico, Dept Chem, Humacao, PR 00791 USA. [Kumar, Vineet; Malhotra, Sanjay V.] NCI, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21702 USA. EM drajay_ipu@yahoo.co.in NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 54-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304715 ER PT J AU Kumar, A Kumar, V Alegria, AE Malhotra, SV AF Kumar, Ajay Kumar, Vineet Alegria, Antonio E. Malhotra, Sanjay V. TI Syntheses and antitumor activity of N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Kumar, Ajay; Alegria, Antonio E.] Univ Puerto Rico, Dept Chem, Humacao, PR 00791 USA. [Kumar, Vineet; Malhotra, Sanjay V.] NCI, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21702 USA. EM drajaybhati@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 249-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304559 ER PT J AU Kumar, V Kim, YS Lee, S Trepel, J Malhotra, SV AF Kumar, Vineet Kim, Yeong Sang Lee, Sunmin Trepel, Jane Malhotra, Sanjay V. TI Synthesis and evaluation of novel androgen receptor inhibitors: Potential candidates for castrate-resistant prostate cancer treatment SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Kumar, Vineet; Malhotra, Sanjay V.] NCI, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21702 USA. [Kim, Yeong Sang; Lee, Sunmin; Trepel, Jane] NCI, Med Oncol Branch, CCR, Bethesda, MD 20892 USA. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 247-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304557 ER PT J AU Kuskovsky, R Arora, K Boshoff, HIM AF Kuskovsky, Rostislav Arora, Kriti Boshoff, Helena I. M. TI Synthesis of biotin-tagged b-lactams: Probes for identification of the molecular target SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Kuskovsky, Rostislav] American Univ, Dept Chem, Washington, DC 20016 USA. [Arora, Kriti; Boshoff, Helena I. M.] NIAID, TB Res Sect, LCID, NIH, Bethesda, MD 20892 USA. EM rostislav4@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 387-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378305279 ER PT J AU Lloyd, D Plotkin, BJ Arora, K Boshoff, HI Konaklieva, MI AF Lloyd, Dina Plotkin, Balbina J. Arora, Kriti Boshoff, Helena I. Konaklieva, Monika I. TI Effect of aryl ring fluorination on the antibacterial properties of C4 aryl-substituted b-Lactams SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Lloyd, Dina; Konaklieva, Monika I.] American Univ, Dept Chem, Washington, DC 20016 USA. [Plotkin, Balbina J.] Midwestern Univ, Dept Microbiol & Immunol, Chicago, IL 60515 USA. [Arora, Kriti; Boshoff, Helena I.] NIAID, TB Res Sect, LCID, NIH, Bethesda, MD 20892 USA. EM dina.lloyd@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 604-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378305507 ER PT J AU Marriner, GA Kiesewetter, DO Mukherjee, T Weiner, DM Schimel, DM Dayao, EK Via, LE Barry, CE AF Marriner, Gwendolyn A. Kiesewetter, Dale O. Mukherjee, Tathagatha Weiner, Danielle M. Schimel, Daniel M. Dayao, Emmanuel K. Via, Laura E. Barry, Clifton E. TI Development of PET radiotracers based on small molecule antitubercular drugs SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Marriner, Gwendolyn A.; Mukherjee, Tathagatha; Weiner, Danielle M.; Schimel, Daniel M.; Dayao, Emmanuel K.; Via, Laura E.; Barry, Clifton E.] NIAID, NIH, Rockville, MD 20892 USA. [Kiesewetter, Dale O.] Natl Inst Biomed Imaging & Bioengn, NIH, Rockville, MD 20892 USA. EM marrinerga@mail.nih.gov RI Barry, III, Clifton/H-3839-2012 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 310-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304622 ER PT J AU Mott, BT Su, XZ Yuan, J Chang, CC Maloney, DJ Rai, G Jadhav, A Simeonov, A Williams, DL Thomas, CJ Posner, GH AF Mott, Bryan T. Su, Xinzhuan Yuan, Jing Chang, Chin-Chien Maloney, David J. Rai, Ganesha Jadhav, Ajit Simeonov, Anton Williams, David L. Thomas, Craig J. Posner, Gary H. TI Molecules containing reactive peroxide or nitric oxide species for the treatment of malaria SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Mott, Bryan T.; Posner, Gary H.] Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. [Mott, Bryan T.; Chang, Chin-Chien; Maloney, David J.; Rai, Ganesha; Jadhav, Ajit; Simeonov, Anton; Thomas, Craig J.] NHGRI, NIH, Chem Genom Ctr, Rockville, MD 20850 USA. [Su, Xinzhuan; Yuan, Jing] NIAID, Lab Malaria & Vector Res, Bethesda, MD 20810 USA. [Williams, David L.] Rush Univ, Sch Med, Dept Immunol Microbiol, Chicago, IL 60612 USA. EM mottb@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 90-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304753 ER PT J AU Nguyen, TM Zhu, L Kim, S Lee, S Chen, XY Lee, SB AF Nguyen, Thao M. Zhu, Lei Kim, Sungkyoung Lee, Seulki Chen, Xiaoyuan Lee, Sang Bok TI Conductive polymer nanotubes patch as an enhanced controlled transdermal delivery system SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Nguyen, Thao M.; Kim, Sungkyoung; Lee, Sang Bok] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Lee, Sang Bok] Korea Adv Inst Sci & Technol, Grad Sch Nanosci & Technol, Taejon 305701, South Korea. [Zhu, Lei; Lee, Seulki; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM nguyent@umd.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 425-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378301843 ER PT J AU Nussinov, R AF Nussinov, Ruth TI Allostery and conformational control in signaling: The ubiquitin E3 ligases SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Nussinov, Ruth] NCI, Computat Struct Biol Grp, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. EM ruthnu@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 263-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378302196 ER PT J AU Okur, A Lee, J Brooks, BR AF Okur, Asim Lee, Jooyoung Brooks, Bernard R. TI Generating reservoir conformations for replica exchange through the use of conformational space annealing method SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Okur, Asim; Brooks, Bernard R.] NIH, Bethesda, MD USA. [Lee, Jooyoung] Korea Adv Inst Sci & Technol, Seoul, South Korea. EM okura@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 123-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378302052 ER PT J AU Pamment, M Malhotra, SV AF Pamment, Michael Malhotra, Sanjay V. TI Novel syntheses of substituted dihydropyridones SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Pamment, Michael; Malhotra, Sanjay V.] NCI, Lab Synthet Chem, SIAC Frederick Inc, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 118-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378305009 ER PT J AU Patterson, AD Shah, YM Gonzalez, FJ AF Patterson, Andrew D. Shah, Yatrik M. Gonzalez, Frank J. TI Mechanism and protection against acetaminophen-induced hepatotoxicity SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Patterson, Andrew D.; Shah, Yatrik M.; Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov RI Patterson, Andrew/G-3852-2012 OI Patterson, Andrew/0000-0003-2073-0070 NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 13-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378307478 ER PT J AU Pavana, RK Gangjee, A Hamel, E Mooberry, SL AF Pavana, Roheeth K. Gangjee, Aleem Hamel, Ernest Mooberry, Susan L. TI Design, synthesis and biological evaluation of novel, conformationally restricted, water soluble, substituted pyrrolo[3,2-d]pyrimidines as antitubulin antitumor agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Pavana, Roheeth K.; Gangjee, Aleem] Duquesne Univ, Div Med Chem, Grad Sch Pharmaceut Sci, Pittsburgh, PA 15282 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. EM kp.roheeth@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 48-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304709 ER PT J AU San Jose, G Kehn-Hall, K Boshoff, HI Kashanchi, F Dowd, CS AF San Jose, Geraldine Kehn-Hall, Kylene Boshoff, Helena I. Kashanchi, Fatah Dowd, Cynthia S. TI Design, synthesis, and biological evaluation of novel Mtb-specific Dxr inhibitors as potential antitubercular agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [San Jose, Geraldine; Dowd, Cynthia S.] George Washington Univ, Dept Chem, Washington, DC 20052 USA. [Kehn-Hall, Kylene; Kashanchi, Fatah] George Mason Univ, Dept Mol & Microbiol, Manassa, VA 20110 USA. [Boshoff, Helena I.] NIAID, NIH, Bethesda, MD 20892 USA. EM gsanjose@gwu.edu RI Kehn-Hall, Kylene/I-5752-2013 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 110-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304414 ER PT J AU Sengupta, P Talisman, T Veatch, S Lippincott-Schwartz, J AF Sengupta, Prabuddha Talisman, Tijana Veatch, Sarah Lippincott-Schwartz, Jennifer TI Nano-scale spatial organization of plasma membrane revealed by pair-correlation analysis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Sengupta, Prabuddha; Talisman, Tijana; Lippincott-Schwartz, Jennifer] NICHD, CBMP, NIH, Bethesda, MD 20892 USA. [Veatch, Sarah] Univ Michigan, Dept Biophys, Ann Arbor, MI 48109 USA. EM prabuddha.sengupta@nih.gov NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 114-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378305772 ER PT J AU Talisman, IJ Malhotra, SV AF Talisman, Ian Jamie Malhotra, Sanjay V. TI Evaluation of glycosidated ginsenoside mimics as anticancer agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Talisman, Ian Jamie; Malhotra, Sanjay V.] NCI, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 253-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304564 ER PT J AU Topczewski, JJ Beutler, JA Wiemer, DF AF Topczewski, Joeseph J. Beutler, John A. Wiemer, David F. TI Schweinfurthins: Development of their antiproliferative activity SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Topczewski, Joeseph J.; Wiemer, David F.] Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. [Beutler, John A.] NCI, Mol Targets Dev Program, Frederick, MD 21702 USA. EM joseph-topczewski@uiowa.edu RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 195-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304499 ER PT J AU Tosh, DK Chanyshev, B Isak, A Chepurko, Y Phan, K Hochhauser, E Shainberg, A Jacobson, KA AF Tosh, Dilip K. Chanyshev, Bella Isak, Ahuva Chepurko, Yelena Phan, Khai Hochhauser, Edith Shainberg, Asher Jacobson, Kenneth A. TI Discovery of novel polyamidoamine (PAMAM) dendrimer conjugated A(3) adenosine receptor agonist ligand as a cardioprotective agent SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Tosh, Dilip K.; Phan, Khai; Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Chanyshev, Bella; Isak, Ahuva; Shainberg, Asher] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel. [Chepurko, Yelena; Hochhauser, Edith] Tel Aviv Univ, Felsenstein Med Res Ctr, Cardiac Res Lab, Petah Tiqwa, Israel. EM toshd@mail.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 355-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304669 ER PT J AU Tsai, DH Elzey, S DelRio, F Keene, A Tyner, K Clogston, J Zheng, JW MacCuspie, R Cho, TJ Guha, S Zachariah, M Hackley, V AF Tsai, De-Hao Elzey, Sherrie DelRio, Frank Keene, Athena Tyner, Katherine Clogston, Jeffrey Zheng, Jiwen MacCuspie, Robert Cho, Tae Joon Guha, Suvajyoti Zachariah, Michael Hackley, Vincent TI Characterization of tumor necrosis factor (TNF) protein conjugation on gold nanoparticles SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Tsai, De-Hao; Elzey, Sherrie; DelRio, Frank; MacCuspie, Robert; Cho, Tae Joon; Guha, Suvajyoti; Zachariah, Michael; Hackley, Vincent] Natl Inst Stand & Technol, Mat Measurement Lab, Gaithersburg, MD 20899 USA. [Keene, Athena; Tyner, Katherine] Ctr Drug Evaluat & Res Food & Drug Adm, Silver Spring, MD 20993 USA. [Clogston, Jeffrey; Zheng, Jiwen] SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, NCI Frederick, Frederick, MD 21702 USA. [Guha, Suvajyoti; Zachariah, Michael] Univ Maryland, Dept Mech Engn, College Pk, MD 20742 USA. [Guha, Suvajyoti; Zachariah, Michael] Univ Maryland, Dept Chem, College Pk, MD 20742 USA. EM sherrie.elzey@nist.gov RI Tsai, De-Hao/K-6702-2012 OI Tsai, De-Hao/0000-0002-2669-3007 NR 0 TC 0 Z9 0 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 249-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378301664 ER PT J AU Tsai, WXL Forbes, JG Wang, K AF Tsai, Wanxia L. Forbes, Jeffrey G. Wang, Kuan TI Elastic scaffolding protein engineered from a SH3 binding Titin PEVK module SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Tsai, Wanxia L.; Forbes, Jeffrey G.; Wang, Kuan] NIAMS DHHS, Muscle Biol Lab, Bethesda, MD 20892 USA. [Wang, Kuan] Acad Sinica, Nanomed Program, Taipei 115, Taiwan. EM liwan@exchange.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 173-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378300725 ER PT J AU Urick, A Chuppa, S Riordon, DR Tarasova, Y Boheler, KR Gundry, RL AF Urick, Amanda Chuppa, Sandra Riordon, Daniel R. Tarasova, Yelena Boheler, Kenneth R. Gundry, Rebekah L. TI Cell surface capturing & mass spectrometry reveal new markers for immunophenotyping pluripotent stem cells and cardiac progenitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Urick, Amanda; Chuppa, Sandra; Gundry, Rebekah L.] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA. [Chuppa, Sandra; Gundry, Rebekah L.] Med Coll Wisconsin, Biotechnol & Bioengn Ctr, Milwaukee, WI 53226 USA. [Riordon, Daniel R.; Tarasova, Yelena; Boheler, Kenneth R.] NIA, NIH, Baltimore, MD 21224 USA. EM rgundry@mcw.edu NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 154-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378300511 ER PT J AU Weisz, A Mazzola, EP Ito, Y AF Weisz, Adrian Mazzola, Eugene P. Ito, Yoichiro TI Preparative separation of 1,3,6-pyrenetrisulfonic acid from the color additive D&C Green No. 8 using pH-zone-refining counter-current chromatography SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Weisz, Adrian; Mazzola, Eugene P.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Ito, Yoichiro] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. EM adrian.weisz@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 73-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378300178 ER PT J AU White, JK Hodoscek, M Brooks, BR Woodcock, HL AF White, Justin K. Hodoscek, Milan Brooks, Bernard R. Woodcock, H. Lee TI Off-path simulations: A new chain-of-replica method to compute reaction free energies SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [White, Justin K.; Woodcock, H. Lee] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. [Hodoscek, Milan] Natl Inst Chem, Ctr Mol Modeling, SI-1000 Ljubljana, Slovenia. [Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM hlw@mail.usf.edu NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 119-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378302047 ER PT J AU Yan, CQ Schneider, JP Pochan, DJ AF Yan, Congqi Schneider, Joel P. Pochan, Darrin J. TI Injectable solid hydrogels as cell carriers: Mechanism of b-hairpin hydrogel shear thinning/immediate recovery and effects on cell payload SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Yan, Congqi; Pochan, Darrin J.] Univ Delaware, Dept Mat Sci & Engn, Newark, DE 19716 USA. [Schneider, Joel P.] NCI, Ctr Canc Res, Frederick, MD 21702 USA. EM cqyan@udel.edu NR 0 TC 0 Z9 0 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 104-PMSE PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378306395 ER PT J AU Waidyanatha, S Johnson, JD Hong, SP Godfrey-Robinson, VD Graves, SW Cristy, T Dunnick, JK Smith, CS AF Waidyanatha, S. Johnson, J. D. Hong, S. P. Godfrey-Robinson, V. D. Graves, S. W. Cristy, T. Dunnick, J. K. Smith, C. S. TI Toxicokinetics of bis(2-chloroethoxy)methane following intravenous administration and dermal application in male and female F344/N rats and B6C3F1 mice SO TOXICOLOGY LETTERS LA English DT Article DE Bis(2-chloroethoxy)methane; Thiodiglycolic acid; Bioavailability; Toxicokinetics; Metabolism ID THIODIGLYCOLIC ACID; POLLUTANTS; HUMANS; CYCLOPHOSPHAMIDE; IFOSFAMIDE; EXCRETION; METHANE; RIVER AB In the National Toxicology Program's toxicity studies, rats were more sensitive than mice to Bis(2-chloroethoxy)methane (CEM) - induced cardiac toxicity following dermal application to male and female F344/N rats and B6C3F1 mice. Thiodiglycolic acid (TOGA) is a major metabolite of CEM in rats. It has been implicated that chemicals metabolized to TOGA cause cardiac toxicity in humans. Therefore, the toxicokinetics of CEM and TOGA were investigated in male and female F344/N rats and B6C3F1 mice following a single intravenous administration or dermal application of CEM to aid in the interpretation of the toxicity data. Absorption of CEM following dermal application was rapid in both species and genders. Bioavailability following dermal application was low but was higher in rats than in mice with females of both species showing higher bioavailability than males. CEM was rapidly distributed to the heart, thymus, and liver following both routes of administration. Plasma CEM C(max) and AUc(infinity) increased proportionally with dose, although at the dermal dose of 400 mg/kg in rats and 600 mg/kg in mice non-linear kinetics were apparent. Following dermal application, dose-normalized plasma CEM C(max) and AUC(infinity) was significantly higher in rats than in mice (p-value <0.0001 for all comparisons except for Cmax in the highest dose groups where p-value = 0.053). In rats, dose-normalized plasma CEM C(max) and AUC(infinity) was higher in females than in males: however, the difference was significant only at the lowest dose (p-value = 0.009 for C(max) and 0.056 for AUC(infinity)). Similar to rats, female mice also showed higher C(max) and AUC(infinity) in females than in male: the difference was significant only for C(max) at the lowest dose (p-value = 0.002). Dose-normalized heart CEM C(max) was higher in rats than in mice and in females than their male counterparts. The liver CEM C(max) was lower compared to that of heart and thymus in both rats and mice following intravenous administration and in rats following dermal application. This is likely due to the rapid metabolism of CEM in the liver as evidenced by the high concentration of TDGA measured in the liver. Dose-normalized plasma and heart TDGA C(max) values were higher in rats compared to mice. In rats, females had higher plasma and heart TDGA C. than males; however, there was no gender difference in plasma or heart TOGA C(max) in mice. These findings support the increased sensitivity of rats compared to mice to CEM-induced cardiac toxicity. Data also suggest that, either CEM C(max) or AUC can be used to predict the CEM-induced cardiac toxicity. Although, both plasma and heart TDGA C(max) was consistent with the observed species difference and the gender difference in rats, the gender difference in mice to cardiac toxicity could not be explained based on the TDGA data. This animal study suggests that toxicologically significant concentrations of CEM and TOGA could possibly be achieved in the systemic circulation and/or target tissues in humans as a result of dermal exposure to CEM. Published by Elsevier Ireland Ltd. C1 [Waidyanatha, S.; Godfrey-Robinson, V. D.; Dunnick, J. K.; Smith, C. S.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Johnson, J. D.; Hong, S. P.; Graves, S. W.; Cristy, T.] Battelle Mem Inst, Columbus, OH 43201 USA. RP Waidyanatha, S (reprint author), NIEHS, Natl Toxicol Program, 111 Alexander Dr,POB 12233,MD K2-07, Res Triangle Pk, NC 27709 USA. EM waidyanathas@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Department of Health and Human Services [N01-ES-55551] FX This study was conducted for the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Department of Health and Human Services, under Contract No. N01-ES-55551. NR 22 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2011 VL 205 IS 2 BP 215 EP 226 DI 10.1016/j.toxlet.2011.06.012 PG 12 WC Toxicology SC Toxicology GA 809CO UT WOS:000294029600016 PM 21708233 ER PT J AU Englund, EE Neumann, S Eliseeva, E McCoy, J Titus, S Zheng, W Southall, N Marugan, J Thomas, C Austin, C Gerhsngorn, M Huang, WW AF Englund, Erika E. Neumann, Susanne Eliseeva, Elena McCoy, Josh Titus, Steve Zheng, Wei Southall, Noel Marugan, Juan Thomas, Craig Austin, Christopher Gerhsngorn, Marvin Huang, Wenwei TI Synthesis and SAR analysis of a library of TSHR modulators SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Englund, Erika E.; McCoy, Josh; Titus, Steve; Zheng, Wei; Southall, Noel; Marugan, Juan; Thomas, Craig; Austin, Christopher; Huang, Wenwei] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Neumann, Susanne; Eliseeva, Elena; Gerhsngorn, Marvin] NIDDK, Bethesda, MD 20892 USA. RI Southall, Noel/H-8991-2012 OI Southall, Noel/0000-0003-4500-880X NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 374-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304687 ER PT J AU Bogoslovsky, T Spatz, M Chaudhry, A Maric, D Luby, M Frank, J Warach, S AF Bogoslovsky, Tanya Spatz, Maria Chaudhry, Aneeka Maric, Dragan Luby, Marie Frank, Joseph Warach, Steven TI Circulating CD133+CD34+progenitor cells inversely correlate with soluble ICAM-1 in early ischemic stroke patients SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID ENDOTHELIAL PROGENITOR CELLS; INTERCELLULAR-ADHESION MOLECULE-1; MATRIX-METALLOPROTEINASE EXPRESSION; ACUTE MYOCARDIAL-INFARCTION; CARDIOEMBOLIC STROKE; BRAIN ISCHEMIA; RECRUITMENT; NEOVASCULARIZATION; ANGIOGENESIS; MOBILIZATION AB Background and Purpose: Both endothelial progenitor cells (EPC) and markers of neuroinflammation are candidate biomarkers for stroke severity and outcome prediction. A relationship between EPC and neuroinflammatory markers in early stroke is not fully elucidated. The objectives were to investigate correlations between EPC and neuroinflammation markers (adhesion molecules ICAM-1, VCAM-1, E-selectin, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, endothelin (ET)-1, markers of tissue injury (matrix metalloproteinases (MMP)-9 and tissue inhibitor of matrix metalloproteinases (TIMP)-1) in early stroke patients. Methods: We prospectively recruited symptomatic patients with ischemic cerebrovascular disease. We assessed stroke severity by using of acute (diffusion-weighted imaging (DWI) and final lesion volumes (fluid attenuated inversion recovery (FLAIR). We measured serum soluble ICAM-1, VCAM-1, E-selectin, MMP-9, TIMP-1 and plasma TNF-alpha, IL-6, ET-1 by ELISA, and quantified EPC in mononuclear fraction of peripheral blood on days 1 and 3 in 17 patients (mean(SD) age 62(14), with admission National Institutes of Health Stroke Scale (NIHSS) 10(8)) selected from 175 patients with imaging confirmed ischemic stroke. Non-parametric statistics, univariate and multivariate analysis were used. Results: Only ICAM-1 inversely correlated with EPC subset CD133+CD34+ on day 1 (Spearman r = -0.6, p < 0.01) and on day 3 (r = -0.967, p < 0.001). This correlation remained significant after adjustment for age and NIHSS (beta -0.992, p < 0.004), for glucose and systolic blood pressure (beta -0.86, p < 0.005), and for white blood cells and hematocrit (beta -1.057, p < 0.0001) on day 3. MMP-9 (r = 0.509, p < 0.04) and MMP-9/TIMP-1 (r = 0.59, p < 0.013) on day 1 correlated with acute lesion volume. Both IL-6 (r = 0.624, p < 0.01) and MMP-9/TIMP-1 (r = 0.56, p < 0.02) correlated with admission NIHSS. Conclusion: Our study showed that high ICAM-1 is associated with low CD133+CD34+ subset of EPC. Biomarkers of neuroinflammation may predict tissue injury and stroke severity in early ischemia. C1 [Bogoslovsky, Tanya; Luby, Marie; Warach, Steven] Natl Inst Neurol Disorders & Stroke, Stroke Diagnost & Therapeut Sect, NIH, Bethesda, MD 20892 USA. [Spatz, Maria] Natl Inst Neurol Disorders & Stroke, Stroke Branch, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] Natl Inst Neurol Disorders & Stroke, NINDS Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. [Chaudhry, Aneeka; Frank, Joseph] Natl Inst Biomed Imaging & Bioengn, Frank Lab, Ctr Clin, NIH, Bethesda, MD 20892 USA. RP Bogoslovsky, T (reprint author), Natl Inst Neurol Disorders & Stroke, Stroke Diagnost & Therapeut Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM Tanya.Bogoslovsky.CTR@usuhs.mil FU Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, National Institutes of Health; CNRM, Uniformed Services University of Health Sciences FX This research was supported by the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, National Institutes of Health and by CNRM, Uniformed Services University of Health Sciences. NR 34 TC 9 Z9 12 U1 0 U2 5 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 AUG 26 PY 2011 VL 9 AR 145 DI 10.1186/1479-5876-9-145 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 828QR UT WOS:000295517800001 PM 21871109 ER PT J AU Plaza, L Jimeno-Yepes, AJ Diaz, A Aronson, AR AF Plaza, Laura Jimeno-Yepes, Antonio J. Diaz, Alberto Aronson, Alan R. TI Studying the correlation between different word sense disambiguation methods and summarization effectiveness in biomedical texts SO BMC BIOINFORMATICS LA English DT Article ID DOMAIN; DOCUMENTS AB Background: Word sense disambiguation (WSD) attempts to solve lexical ambiguities by identifying the correct meaning of a word based on its context. WSD has been demonstrated to be an important step in knowledge-based approaches to automatic summarization. However, the correlation between the accuracy of the WSD methods and the summarization performance has never been studied. Results: We present three existing knowledge-based WSD approaches and a graph-based summarizer. Both the WSD approaches and the summarizer employ the Unified Medical Language System (UMLS) Metathesaurus as the knowledge source. We first evaluate WSD directly, by comparing the prediction of the WSD methods to two reference sets: the NLM WSD dataset and the MSH WSD collection. We next apply the different WSD methods as part of the summarizer, to map documents onto concepts in the UMLS Metathesaurus, and evaluate the summaries that are generated. The results obtained by the different methods in both evaluations are studied and compared. Conclusions: It has been found that the use of WSD techniques has a positive impact on the results of our graph-based summarizer, and that, when both the WSD and summarization tasks are assessed over large and homogeneous evaluation collections, there exists a correlation between the overall results of the WSD and summarization tasks. Furthermore, the best WSD algorithm in the first task tends to be also the best one in the second. However, we also found that the improvement achieved by the summarizer is not directly correlated with the WSD performance. The most likely reason is that the errors in disambiguation are not equally important but depend on the relative salience of the different concepts in the document to be summarized. C1 [Plaza, Laura; Diaz, Alberto] Univ Complutense Madrid, E-28040 Madrid, Spain. [Jimeno-Yepes, Antonio J.; Aronson, Alan R.] Natl Lib Med, Bethesda, MD 20894 USA. RP Plaza, L (reprint author), Univ Complutense Madrid, Calle Prof Jose Garcia Santesmases S-N, E-28040 Madrid, Spain. EM lplazam@fdi.ucm.es OI Diaz, Alberto/0000-0002-7641-8919; Jimeno Yepes, Antonio Jose/0000-0002-6581-094X; DIAZ ESTEBAN, ALBERTO/0000-0003-1966-3421 FU Spanish Government; NIH, National Library of Medicine; National Library of Medicine; [TIN2009-14659-C03-01] FX This research was supported by the Spanish Government through the FPU program and the project TIN2009-14659-C03-01.; 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 46 TC 5 Z9 5 U1 0 U2 3 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 AUG 26 PY 2011 VL 12 AR 355 DI 10.1186/1471-2105-12-355 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 823SH UT WOS:000295145000001 PM 21871110 ER PT J AU Alberobello, AT Congedo, V Liu, H Cochran, C Skarulis, MC Forrest, D Celi, FS AF Alberobello, Anna Teresa Congedo, Valentina Liu, Hong Cochran, Craig Skarulis, Monica C. Forrest, Douglas Celi, Francesco S. TI An intronic SNP in the thyroid hormone receptor beta gene is associated with pituitary cell-specific over-expression of a mutant thyroid hormone receptor beta 2 (R338W) in the index case of pituitary-selective resistance to thyroid hormone SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID BINDING DOMAIN; MUTATION; IDENTIFICATION; SECRETION; KINDREDS; TSH; SEX AB Background: The syndrome of resistance to thyroid hormone (RTH) is caused by mutations in the thyroid hormone receptor beta gene (THRB). The syndrome varies from asymptomatic to diffuse hypothyroidism, to pituitary-selective resistance with predominance of hyperthyroid signs and symptoms. The wide spectrum of clinical presentation is not completely attributable to specific THRB mutations. The THRB gene encodes two main isoforms, TR beta 1 which is widely distributed, and TR beta 2, whose expression is limited to the cochlea, retina, hypothalamus, and pituitary. Recent data demonstrated that in mice an intron enhancer region plays a critical role in the pituitary expression of the beta 2 isoform of the receptor. We thus hypothesized that polymorphisms in the human homologous region could modulate the pituitary expression of the mutated gene contributing to the clinical presentation of RTH. Methods: Screening and in vitro characterization of polymorphisms of the intron enhancer region of the THRB gene in the index case of pituitary-selective RTH. Results: The index case of pituitary-selective resistance is characterized by the missense R338W exon 9 mutation in cis with two common SNPs, rs2596623T and rs2596622C, located in the intron enhancer region of the THRB gene. Reporter gene assay experiments in GH3 pituitary-derived cells indicate that rs2596623T generates an increased pituitary cell-specific activity of the TR beta 2 promoter suggesting that rs2596623T leads to pituitary over-expression of the mutant allele. Conclusions: The combined coding mutation and non-coding SNP therefore generate a tissue-specific dominant-negative condition recapitulating the patient's peculiar phenotype. This case illustrates the role of regulatory regions in modifying the clinical presentation of genetic diseases. C1 [Alberobello, Anna Teresa; Congedo, Valentina; Cochran, Craig; Skarulis, Monica C.; Celi, Francesco S.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Congedo, Valentina] Univ G DAnnunzio, Dept Med & Sci Aging, Chieti, Italy. [Liu, Hong; Forrest, Douglas] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD USA. RP Celi, FS (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM fc93a@nih.gov FU NIDDK [Z01-DK047057-01, DK 047037-04] FX This research could have not been accomplished without the selfless participation of the patients enrolled in the NIH RTH cohort. This work was supported by the Intramural Research Program of the NIDDK, programs Z01-DK047057-01, and DK 047037-04. NR 24 TC 14 Z9 14 U1 0 U2 3 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 AUG 26 PY 2011 VL 9 AR 144 DI 10.1186/1479-5876-9-144 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 819QN UT WOS:000294844100001 PM 21871106 ER PT J AU Mashayekhi, M Sandau, MM Dunay, IR Frickel, EM Khan, A Goldszmid, RS Sher, A Ploegh, HL Murphy, TL Sibley, LD Murphy, KM AF Mashayekhi, Mona Sandau, Michelle M. Dunay, Ildiko R. Frickel, Eva M. Khan, Asis Goldszmid, Romina S. Sher, Alan Ploegh, Hidde L. Murphy, Theresa L. Sibley, L. David Murphy, Kenneth M. TI CD8 alpha(+) Dendritic Cells Are the Critical Source of Interleukin-12 that Controls Acute Infection by Toxoplasma gondii Tachyzoites SO IMMUNITY LA English DT Article ID CUTTING EDGE; IFN-GAMMA; INFLAMMATORY MONOCYTES; IL-12 PRODUCTION; RESISTANCE; MICE; PARASITE; IMMUNITY; STIMULATION; NEUTROPHILS AB CD8 alpha(+) dendritic cells (DCs) are important in vivo for cross-presentation of antigens derived from intracellular pathogens and tumors. Additionally, secretion of interleukin-12 (IL-12) by CD8 alpha(+) DCs suggests a role for these cells in response to Toxoplasma gondii antigens, although it remains unclear whether these cells are required for protection against T. gondii infection. Toward this goal, we examined T. gondii infection of Batf3(-/-) mice, which selectively lack only lymphoid-resident CD8 alpha(+) DCs and related peripheral CD103(+) DCs. Batf3(-/-) mice were extremely susceptible to T. gondii infection, with decreased production of IL-12 and interferon-gamma. IL-12 administration restored resistance in Batf3(-/-) mice, and mice in which IL-12 production was ablated only from CD8 alpha(+) DCs failed to control infection. These results reveal that the function of CD8 alpha(+) DCs extends beyond a role in cross-presentation and includes a critical role for activation of innate immunity through IL-12 production during T. gondii infection. C1 [Mashayekhi, Mona; Sandau, Michelle M.; Murphy, Theresa L.; Murphy, Kenneth M.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Dunay, Ildiko R.; Khan, Asis; Sibley, L. David] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Murphy, Kenneth M.] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. [Frickel, Eva M.; Ploegh, Hidde L.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Goldszmid, Romina S.; Sher, Alan] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Goldszmid, Romina S.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Murphy, KM (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. EM kmurphy@pathology.wustl.edu FU Howard Hughes Medical Institute; American Heart Association; [AI059176] FX This work was supported by the Howard Hughes Medical Institute (K.M.M.), the American Heart Association Midwest Affiliate Predoctoral Fellowship Program (M.M.), and AI059176 (L.D.S.). NR 31 TC 126 Z9 129 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 26 PY 2011 VL 35 IS 2 BP 249 EP 259 DI 10.1016/j.immuni.2011.08.008 PG 11 WC Immunology SC Immunology GA 813SC UT WOS:000294387900014 PM 21867928 ER PT J AU Wei, G Abraham, BJ Yagi, R Jothi, R Cui, KR Sharma, S Narlikar, L Northrup, DL Tang, QS Paul, WE Zhu, JF Zhao, KJ AF Wei, Gang Abraham, Brian J. Yagi, Ryoji Jothi, Raja Cui, Kairong Sharma, Suveena Narlikar, Leelavati Northrup, Daniel L. Tang, Qingsong Paul, William E. Zhu, Jinfang Zhao, Keji TI Genome-wide Analyses of Transcription Factor GATA3-Mediated Gene Regulation in Distinct T Cell Types SO IMMUNITY LA English DT Article ID FACTOR GATA-3; CHROMATIN OCCUPANCY; LINEAGE COMMITMENT; DNA-BINDING; EXPRESSION; DIFFERENTIATION; CD4; FINGER; TH1; IDENTIFICATION AB The transcription factor GATA3 plays an essential role during T cell development and T helper 2 (Th2) cell differentiation. To understand GATA3-mediated gene regulation, we identified genome-wide GATA3 binding sites in ten well-defined developmental and effector T lymphocyte lineages. In the thymus, GATA3 directly regulated many critical factors, including Th-POK, Notch1, and T cell receptor subunits. In the periphery, GATA3 induced a large number of Th2 cell-specific as well as Th2 cell-nonspecific genes, including several transcription factors. Our data also indicate that GATA3 regulates both active and repressive histone modifications of many target genes at their regulatory elements near GATA3 binding sites. Overall, although GATA3 binding exhibited both shared and cell-specific patterns among various T cell lineages, many genes were either positively or negatively regulated by GATA3 in a cell type-specific manner, suggesting that GATA3-mediated gene regulation depends strongly on cofactors existing in different T cells. C1 [Yagi, Ryoji; Sharma, Suveena; Paul, William E.; Zhu, Jinfang] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wei, Gang; Abraham, Brian J.; Cui, Kairong; Northrup, Daniel L.; Tang, Qingsong; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Jothi, Raja; Narlikar, Leelavati] Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Zhu, JF (reprint author), NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM jfzhu@niaid.nih.gov; zhaok@nhlbi.nih.gov RI Zhu, Jinfang/B-7574-2012; cheng, yong/I-4270-2012; Jothi, Raja/G-3780-2015 FU Division of Intramural Research, National Institute of Environmental Health Sciences [Z01ES102625]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases; Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, USA FX We thank W. Leonard for critical reading of the manuscript. We thank I. Chepelev, G. Hu, and D. Schones for helpful discussions on data analysis. This work was supported by the Division of Intramural Research, National Institute of Environmental Health Sciences (R.J.; Project Number Z01ES102625), Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, USA. NR 43 TC 124 Z9 127 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 26 PY 2011 VL 35 IS 2 BP 299 EP 311 DI 10.1016/j.immuni.2011.08.007 PG 13 WC Immunology SC Immunology GA 813SC UT WOS:000294387900018 PM 21867929 ER PT J AU Vojnov, L Martins, MA Almeida, JR Ende, Z Rakasz, EG Reynolds, MR Leon, EJ Weisgrau, KL Burwitz, BJ Folkvord, JM de Santana, MGV Neves, PCC Connick, E Skinner, PJ Gostick, E O'Connor, DH Wilson, NA Bonaldo, MC Galler, R Price, DA Douek, DC Watkins, DI AF Vojnov, Lara Martins, Mauricio A. Almeida, Jorge R. Ende, Zachary Rakasz, Eva G. Reynolds, Matthew R. Leon, Enrique J. Weisgrau, Kim L. Burwitz, Benjamin J. Folkvord, Joy M. Veloso de Santana, Marlon G. Costa Neves, Patricia C. Connick, Elizabeth Skinner, Pamela J. Gostick, Emma O'Connor, David H. Wilson, Nancy A. Bonaldo, Myrna C. Galler, Ricardo Price, David A. Douek, Danny C. Watkins, David I. TI GagCM9-Specific CD8(+) T Cells Expressing Limited Public TCR Clonotypes Do Not Suppress SIV Replication In Vivo SO PLOS ONE LA English DT Article ID SIMIAN-IMMUNODEFICIENCY-VIRUS; CELLULAR IMMUNE-RESPONSES; RHESUS-MONKEYS; LYMPHOCYTE RESPONSE; HIV-1 INFECTION; MAMU-B-ASTERISK-08-POSITIVE MACAQUES; GASTROINTESTINAL-TRACT; SIVMAC239 REPLICATION; VIRAL REPLICATION; ESCAPE MUTATIONS AB Several lines of evidence suggest that HIV/SIV-specific CD8(+) T cells play a critical role in the control of viral replication. Recently we observed high levels of viremia in Indian rhesus macaques vaccinated with a segment of SIVmac239 Gag (Gag(45-269)) that were subsequently infected with SIVsmE660. These seven Mamu-A*01(+) animals developed CD8(+) T cell responses against an immunodominant epitope in Gag, GagCM9, yet failed to control virus replication. We carried out a series of immunological and virological assays to understand why these Gag-specific CD8(+) T cells could not control virus replication in vivo. GagCM9-specific CD8(+) T cells from all of the animals were multifunctional and were found in the colonic mucosa. Additionally, GagCM9-specific CD8(+) T cells accessed B cell follicles, the primary residence of SIV-infected cells in lymph nodes, with effector to target ratios between 20-250 GagCM9-specific CD8(+) T cells per SIV-producing cell. Interestingly, vaccinated animals had few public TCR clonotypes within the GagCM9-specific CD8(+) T cell population pre- and post-infection. The number of public TCR clonotypes expressed by GagCM9-specific CD8(+) T cells post-infection significantly inversely correlated with chronic phase viral load. It is possible that these seven animals failed to control viral replication because of the narrow TCR repertoire expressed by the GagCM9-specific CD8(+) T cell population elicited by vaccination and infection. C1 [Vojnov, Lara; Martins, Mauricio A.; Rakasz, Eva G.; Reynolds, Matthew R.; Burwitz, Benjamin J.; O'Connor, David H.; Wilson, Nancy A.; Watkins, David I.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. [Almeida, Jorge R.; Ende, Zachary; Douek, Danny C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Rakasz, Eva G.; Leon, Enrique J.; Weisgrau, Kim L.; Watkins, David I.] Wisconsin Natl Primate Res Ctr, Madison, WI USA. [Folkvord, Joy M.; Connick, Elizabeth] Univ Colorado, Sch Med, Denver, CO USA. [Veloso de Santana, Marlon G.; Costa Neves, Patricia C.; Bonaldo, Myrna C.] Inst Oswaldo Cruz FIOCRUZ, Lab Biol Mol Flavivirus, Rio De Janeiro, Brazil. [Skinner, Pamela J.] Univ Minnesota, Dept Vet & Biomed Sci, St Paul, MN 55108 USA. [Galler, Ricardo] Fundacao Oswaldo Cruz, Inst Tecnol Imunobiol, Rio De Janeiro, Brazil. [Gostick, Emma; Price, David A.] Cardiff Univ, Dept Infect Immun & Biochem, Cardiff, S Glam, Wales. RP Vojnov, L (reprint author), Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. EM Watkins@primate.wisc.edu RI Bonaldo, Myrna/D-9494-2013; Vacinas, Inct/J-9431-2013; Galler, Ricardo/B-3280-2014; Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Ramos de Almeida, Jorge/0000-0002-5009-8478; Martins, Mauricio/0000-0001-8336-216X; o'connor, david/0000-0003-2139-470X FU National Institutes of Health (NIH)/National Institute of Allergy and Infectious Disease [R01 AI076114, R01 AI049120, R24 RR015371, R24 RR016038]; National Center for Research Resources (NCRR) [R51 RR000167] FX This research was supported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Disease grants R01 AI076114, R01 AI049120, R24 RR015371, and R24 RR016038 and in part by grant R51 RR000167 from the National Center for Research Resources (NCRR) awarded to the WNPRC, University of Wisconsin-Madison. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 8 Z9 8 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 26 PY 2011 VL 6 IS 8 AR e23515 DI 10.1371/journal.pone.0023515 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 812MY UT WOS:000294298800011 PM 21887264 ER PT J AU Shchedrina, VA Kabil, H Vorbruggen, G Lee, BC Turanov, AA Hirosawa-Takamori, M Kim, HY Harshman, LG Hatfield, DL Gladyshev, VN AF Shchedrina, Valentina A. Kabil, Hadise Vorbruggen, Gerd Lee, Byung Cheon Turanov, Anton A. Hirosawa-Takamori, Mitsuko Kim, Hwa-Young Harshman, Lawrence G. Hatfield, Dolph L. Gladyshev, Vadim N. TI Analyses of Fruit Flies That Do Not Express Selenoproteins or Express the Mouse Selenoprotein, Methionine Sulfoxide Reductase B1, Reveal a Role of Selenoproteins in Stress Resistance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LIFE-SPAN; DROSOPHILA-MELANOGASTER; OXIDATIVE DAMAGE; SELENOPHOSPHATE SYNTHETASE; SELENOCYSTEINE INCORPORATION; ANTIOXIDANT DEFENSE; BINDING-PROTEIN; GENE; LONGEVITY; OVEREXPRESSION AB Selenoproteins are essential in vertebrates because of their crucial role in cellular redox homeostasis, but some invertebrates that lack selenoproteins have recently been identified. Genetic disruption of selenoprotein biosynthesis had no effect on lifespan and oxidative stress resistance of Drosophila melanogaster. In the current study, fruit flies with knock-out of the selenocysteine-specific elongation factor were metabolically labeled with Se-75; they did not incorporate selenium into proteins and had the same lifespan on a chemically defined diet with or without selenium supplementation. These flies were, however, more susceptible to starvation than controls, and this effect could be ascribed to the function of selenoprotein K. We further expressed mouse methionine sulfoxide reductase B1 (MsrB1), a selenoenzyme that catalyzes the reduction of oxidized methionine residues and has protein repair function, in the whole body or the nervous system of fruit flies. This exogenous selenoprotein could only be expressed when the Drosophila selenocysteine insertion sequence element was used, whereas the corresponding mouse element did not support selenoprotein synthesis. Ectopic expression of MsrB1 in the nervous system led to an increase in the resistance against oxidative stress and starvation, but did not affect lifespan and reproduction, whereas ubiquitous MsrB1 expression had no effect. Dietary selenium did not influence lifespan of MsrB1-expressing flies. Thus, in contrast to vertebrates, fruit flies preserve only three selenoproteins, which are not essential and play a role only under certain stress conditions, thereby limiting the use of the micronutrient selenium by these organisms. C1 [Shchedrina, Valentina A.; Lee, Byung Cheon; Turanov, Anton A.; Gladyshev, Vadim N.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Shchedrina, Valentina A.; Lee, Byung Cheon; Turanov, Anton A.; Gladyshev, Vadim N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kabil, Hadise; Harshman, Lawrence G.] Univ Nebraska, Sch Biol Sci, Lincoln, NE 68588 USA. [Vorbruggen, Gerd; Hirosawa-Takamori, Mitsuko] Max Planck Inst Biophys Chem, Abt Mol Entwicklungsbiol, D-37077 Gottingen, Germany. [Kim, Hwa-Young] Yeungnam Univ, Coll Med, Dept Biochem & Mol Biol, Taegu 705717, South Korea. [Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), New Res Bldg,77 Ave Louis Pasteur,Rm 435, Boston, MA 02115 USA. EM vgladyshev@rics.bwh.harvard.edu RI Gladyshev, Vadim/A-9894-2013 FU National Institutes of Health [AG021518, GM061603, DK074136]; Center for Cancer Research, NCI; National Research Foundation of Korea [2010-0001240] FX This work was supported, in whole or in part, by National Institutes of Health Grants AG021518, GM061603 (to V. N. G.), and DK074136 (to L. G. H.), the Intramural Research Program at the Center for Cancer Research, NCI (to D. L. H.), and National Research Foundation of Korea Grant 2010-0001240 (to H. Y. K.). NR 59 TC 12 Z9 13 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 AUG 26 PY 2011 VL 286 IS 34 BP 29449 EP 29461 DI 10.1074/jbc.M111.257600 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809IU UT WOS:000294046600002 PM 21622567 ER PT J AU Zhang, YX Bonzo, JA Gonzalez, FJ Wang, L AF Zhang, Yuxia Bonzo, Jessica A. Gonzalez, Frank J. Wang, Li TI Diurnal Regulation of the Early Growth Response 1 (Egr-1) Protein Expression by Hepatocyte Nuclear Factor 4 alpha (HNF4 alpha) and Small Heterodimer Partner (SHP) Cross-talk in Liver Fibrosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BILE-ACID BIOSYNTHESIS; RECEPTOR-SHP; GENE-EXPRESSION; TARGET GENES; INJURY; CELLS; IDENTIFICATION; STIMULATION; FIBROBLASTS; METABOLISM AB Early growth response 1 (Egr-1) protein is a critical regulator of genes contributing to liver fibrosis; however, little is known about the upstream transcriptional factors that control its expression. Here we show that Egr-1 expression is tightly regulated by nuclear receptor signaling. Hepatocyte nuclear factor 4 alpha (HNF4 alpha) activated the Egr-1 promoter through three DR1 response elements as identified by trans-activation assays. Deletion of these response elements or knockdown of HNF4 alpha using siRNA largely abrogated Egr-1 promoter activation. HNF4 alpha activity, as well as its enrichment on the Egr-1 promoter, were markedly repressed by small heterodimer partner (SHP) co-expression. Egr-1 mRNA and protein were transiently induced by HNF4 alpha. On the contrary, HNF4 alpha siRNA reduced Egr-1 expression at both the mRNA and protein levels, and overexpression of SHP reversed these effects. Conversely, knockdown of SHP by siRNA elevated Egr-1 protein. Interestingly, Egr-1 mRNA exhibited diurnal fluctuation, which was synchronized to the cyclic expression of SHP and HNF4 alpha after cells were released from serum shock. Unexpectedly, the levels of Egr-1 mRNA and protein were highly up-regulated in Hnf4 alpha(-/-) mice. Both HNF4 alpha and Egr-1 expression were dramatically increased in SHP-/- mice with bile duct ligation and in human cirrhotic livers, which was inversely correlated with diminished SHP expression. In conclusion, our study revealed control network for Egr-1 expression through a feedback loop between SHP and HNF4 alpha. C1 [Zhang, Yuxia; Wang, Li] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Med, Salt Lake City, UT 84132 USA. [Zhang, Yuxia; Wang, Li] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84132 USA. [Bonzo, Jessica A.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wang, L (reprint author), 30 North 1900 East,SOM 3C310, Salt Lake City, UT 84132 USA. EM l.wang@hsc.utah.edu FU National Institutes of Health [DK080440, N01-DK-7-0004/HHSN267200700004C]; Multidisciplinary Cancer Research Training Program [T32CA092347] FX This work was supported, in whole or in part, by National Institutes of Health Grant DK080440 (to L. W.).; Supported by Multidisciplinary Cancer Research Training Program Grant T32CA092347.; We thank Dr. Scott Friedman for the LX2 cells and Drs. Frances Sladek and Akiyoshi Fukamizu for the HNF4 alpha constructs. Normal human liver and cirrhotic liver specimens were obtained through the Liver Tissue Cell Distribution System (Minneapolis, MN), which is funded by National Institutes of Health Contract N01-DK-7-0004/HHSN267200700004C. NR 40 TC 16 Z9 18 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 AUG 26 PY 2011 VL 286 IS 34 BP 29635 EP 29643 DI 10.1074/jbc.M111.253039 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809IU UT WOS:000294046600022 PM 21725089 ER PT J AU Chung, YW Kim, HK Kim, IY Yim, MB Chock, PB AF Chung, Youn Wook Kim, Ha Kun Kim, Ick Young Yim, Moon B. Chock, P. Boon TI Dual Function of Protein Kinase C (PKC) in 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced Manganese Superoxide Dismutase (MnSOD) Expression ACTIVATION OF CREB AND FOXO3a BY PKC-alpha PHOSPHORYLATION AND BY PKC-MEDIATED INACTIVATION OF Akt, RESPECTIVELY SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; FORKHEAD TRANSCRIPTION FACTOR; GENE-EXPRESSION; SIGNAL-TRANSDUCTION; OXIDATIVE STRESS; PROMOTER REVEAL; PHORBOL ESTER; CANCER-CELLS; FACTOR-ALPHA AB 12-O-tetradecanoylphorbol-13-acetate (TPA) has been shown to induce transcriptional activation of human manganese superoxide dismutase (MnSOD) mRNA in human lung carcinoma cells, A549, mediated by a protein kinase C (PKC)-dependent activation of cAMP-responsive element-binding protein (CREB)-1/ATF-1-like factors. In this study, we showed that MnSOD protein expression was elevated in response to TPA or TNF-alpha, but not to hydrogen peroxide treatment. TPA-induced generation of reactive oxygen species (ROS) was blocked by pretreatment of the PKC inhibitor BIM and NADPH oxidase inhibitor DPI. Small interfering RNA (siRNA) experiments indicated that knocking down the NADPH oxidase components e.g. Rac1, p22(phox), p67(phox), and NOXO1 in A549 cells impaired TPA-induced MnSOD expression. To identify the PKC isozyme involved, we used a sod2 gene response reporter plasmid, pSODLUC-3340-I2E-C, capable of sensing the effect of TNF-alpha and TPA, to monitor the effects of PKC isozyme-specific inhibitors and siRNA-induced knockdown of specific PKC isozyme. Our data indicate that TPA-induced MnSOD expression was independent of p53 and most likely mediated by PKC-alpha-, and -epsilon-dependent signaling pathways. Furthermore, siRNA-induced knock-down of CREB and Forkhead box class O (FOXO) 3a led to a reduction in TPA-induced MnSOD gene expression. Together, our results revealed that TPA up-regulates, in part, two PKC-dependent transcriptional pathways to induce MnSOD expression. One pathway involves PKC-alpha catalyzed phosphorylation of CREB and the other involves a PKC-mediated the PP2A catalyzed dephosphorylation of Akt at Ser(473) which in turn leads to FOXO3a Ser(253) dephosphorylation and its activation. C1 [Chung, Youn Wook; Kim, Ha Kun; Yim, Moon B.; Chock, P. Boon] NHLBI, Biochim Lab, NIH, Bethesda, MD 20892 USA. [Kim, Ick Young] Korea Univ, Sch Life Sci & Biotechnol, Lab Cellular & Mol Biochem, Seoul 136701, South Korea. RP Yim, MB (reprint author), NHLBI, Biochim Lab, NIH, Bldg 50,Room 2134,MSC 8012, Bethesda, MD 20892 USA. EM bchock@nih.gov FU NHLBI, National Institutes of Health FX This work was supported, in whole or in part, by the Intramural Research Program of NHLBI, National Institutes of Health. NR 55 TC 22 Z9 23 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 26 PY 2011 VL 286 IS 34 BP 29681 EP 29690 DI 10.1074/jbc.M111.264945 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809IU UT WOS:000294046600027 PM 21705328 ER PT J AU White, CD Li, ZG Dillon, DA Sacks, DB AF White, Colin D. Li, Zhigang Dillon, Deborah A. Sacks, David B. TI IQGAP1 Protein Binds Human Epidermal Growth Factor Receptor 2 (HER2) and Modulates Trastuzumab Resistance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER CELLS; DEPENDENT KINASE INHIBITOR; ERBB RECEPTORS; METASTATIC BREAST; SYNERGISTICALLY INHIBIT; MONOCLONAL-ANTIBODY; SIGNALING PATHWAYS; SCAFFOLD PROTEINS; NEU ONCOGENE; PROLIFERATION AB Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20-25% of breast cancers. Increased HER2 expression is an adverse prognostic factor and correlates with decreased patient survival. HER2-positive (HER2(+)) breast cancer is treated with trastuzumab. Unfortunately, some patients are intrinsically refractory to therapy, and many who do respond initially become resistant within 1 year. Understanding the molecular mechanisms underlying HER2 signaling and trastuzumab resistance is essential to reduce breast cancer mortality. IQGAP1 is a ubiquitously expressed scaffold protein that contains multiple protein interaction domains. By regulating its binding partners IQGAP1 integrates signaling pathways, several of which contribute to breast tumorigenesis. We show here that IQGAP1 is overexpressed in HER2(+) breast cancer tissue and binds directly to HER2. Knockdown of IQGAP1 decreases HER2 expression, phosphorylation, signaling, and HER2-stimulated cell proliferation, effects that are all reversed by reconstituting cells with IQGAP1. Reducing IQGAP1 up-regulates p27, and blocking this increase attenuates the growth inhibitory effects of IQGAP1 knockdown. Importantly, IQGAP1 is overexpressed in trastuzumab-resistant breast epithelial cells, and reducing IQGAP1 both augments the inhibitory effects of trastuzumab and restores trastuzumab sensitivity to trastuzumab-resistant SkBR3 cells. These data suggest that inhibiting IQGAP1 function may represent a rational strategy for treating HER2(+) breast carcinoma. C1 [White, Colin D.] Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [White, Colin D.; Li, Zhigang; Dillon, Deborah A.; Sacks, David B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [White, Colin D.; Li, Zhigang; Dillon, Deborah A.; Sacks, David B.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Li, Zhigang; Sacks, David B.] NIH, Bethesda, MD 20892 USA. RP White, CD (reprint author), Beth Israel Deaconess Med Ctr, 3 Blackfan Circle, Boston, MA 02115 USA. EM cdwhite@bidmc.harvard.edu OI Sacks, David/0000-0003-3100-0735 FU National Institutes of Health [R01CA075205-09]; Department of Defense [BC087504] FX This work was supported, in whole or in part, by National Institutes of Health Grant R01CA075205-09 (to D. B. S.). This work was also funded by the Department of Defense Breast Cancer Research Program (BC087504; to C. D. W.). NR 70 TC 19 Z9 19 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 26 PY 2011 VL 286 IS 34 BP 29734 EP 29747 DI 10.1074/jbc.M111.220939 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809IU UT WOS:000294046600033 PM 21724847 ER PT J AU Joshi, A Garg, H Ablan, SD Freed, EO AF Joshi, Anjali Garg, Himanshu Ablan, Sherimay D. Freed, Eric O. TI Evidence of a Role for Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor (SNARE) Machinery in HIV-1 Assembly and Release SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; INFECTIOUS-ANEMIA VIRUS; GAG-MEMBRANE-BINDING; PLASMA-MEMBRANE; INTRACELLULAR TRAFFICKING; CELL-SURFACE; PARTICLE-PRODUCTION; PRIMARY MACROPHAGES; FUSION PROTEIN; MATRIX DOMAIN AB Retrovirus assembly is a complex process that requires the orchestrated participation of viral components and host-cell factors. The concerted movement of different viral proteins to specific sites in the plasma membrane allows for virus particle assembly and ultimately budding and maturation of infectious virions. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins constitute the minimal machinery that catalyzes the fusion of intracellular vesicles with the plasma membrane, thus regulating protein trafficking. Using siRNA and dominant negative approaches we demonstrate here that generalized disruption of the host SNARE machinery results in a significant reduction in human immunodeficiency virus type 1 (HIV-1) and equine infectious anemia virus particle production. Further analysis of the mechanism involved revealed a defect at the level of HIV-1 Gag localization to the plasma membrane. Our findings demonstrate for the first time a role of SNARE proteins in HIV-1 assembly and release, likely by affecting cellular trafficking pathways required for Gag transport and association with the plasma membrane. C1 [Joshi, Anjali; Garg, Himanshu] Texas Tech Univ, Hlth Sci Ctr, Dept Biomed Sci, Ctr Excellence Infect Dis, El Paso, TX 79905 USA. [Joshi, Anjali; Garg, Himanshu] Texas Tech Univ, Hlth Sci Ctr, Paul L Foster Sch Med, Dept Pediat, El Paso, TX 79905 USA. [Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. RP Joshi, A (reprint author), 5001 El Paso Dr,MSB-1, El Paso, TX 79905 USA. EM anjali.joshi@ttuhsc.edu FU Center for Cancer Research, NCI, National Institutes of Health; Intramural AIDS Targeted Antiviral Program FX This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health. This work was also supported by the Intramural AIDS Targeted Antiviral Program. NR 86 TC 13 Z9 14 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 26 PY 2011 VL 286 IS 34 BP 29861 EP 29871 DI 10.1074/jbc.M111.241521 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809IU UT WOS:000294046600045 PM 21680744 ER PT J AU Fukushima, M Villar, J Tsai-Morris, CH Dufau, ML AF Fukushima, Masato Villar, Joaquin Tsai-Morris, Chon-Hwa Dufau, Maria L. TI Gonadotropin-regulated Testicular RNA Helicase (GRTH/DDX25), a Negative Regulator of Luteinizing/Chorionic Gonadotropin Hormone-induced Steroidogenesis in Leydig Cells CENTRAL ROLE OF STEROIDOGENIC ACUTE REGULATORY PROTEIN (StAR) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MEDIATED STEROIDOGENESIS; RAT TESTIS; SPERMATOGENESIS; GENE; CHOLESTEROL; TRANSLATION; MODULATION AB Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) is a testis-specific gonadotropin-regulated RNA helicase that is present in Leydig cells (LCs) and germ cells and is essential for spermatid development and completion of spermatogenesis. Normal basal levels of testosterone in serum and LCs were observed in GRTH null (GRTH(-/-)) mice. However, testosterone production was enhanced in LCs of GRTH(-/-) mice compared with WT mice by both in vivo and in vitro human chorionic gonadotropin stimulation. LCs of GRTH(-/-) mice had swollen mitochondria with a significantly increased cholesterol content in the inner mitochondrial membrane. Basal protein levels of SREBP2, HMG-CoAreductase, and steroidogenic acute regulatory protein (StAR; a protein that transports cholesterol to the inner mitochondrial membrane) were markedly increased in LCs of GRTH(-/-) mice compared with WT mice. Gonadotropin stimulation caused an increase in StAR mRNA levels and protein expression inGRTH(-/-) mice versus WT mice, with no further increase in SREBP2 and down-regulation of HMG-CoA reductase protein. The half-life of StAR mRNA was significantly increased in GRTH(-/-) mice. Moreover, association of StAR mRNA with GRTH protein was observed in WT mice. Human chorionic gonadotropin increased GRTH gene expression and its associated StAR protein at cytoplasmic sites. Taken together, these findings indicate that, through its negative role in StAR message stability, GRTH regulates cholesterol availability at the mitochondrial level. The finding of an inhibitory action of GRTH associated with gonadotropin-mediated steroidogenesis has provided insights into a novel negative autocrine molecular control mechanism of this helicase in the regulation of steroid production in the male. C1 [Fukushima, Masato; Villar, Joaquin; Tsai-Morris, Chon-Hwa; Dufau, Maria L.] Eunice Kennedy Shriver NICHD, Sect Mol Endocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), Eunice Kennedy Shriver NICHD, Sect Mol Endocrinol, Program Dev Endocrinol & Genet, NIH, Bldg 49,Rm 6A-36, Bethesda, MD 20892 USA. EM dufaum@mail.nih.gov FU NICHD, National Institutes of Health FX This work was supported by the NICHD Intramural Research Program, National Institutes of Health. NR 23 TC 8 Z9 8 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 26 PY 2011 VL 286 IS 34 BP 29932 EP 29940 DI 10.1074/jbc.M111.236083 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809IU UT WOS:000294046600052 PM 21719703 ER PT J AU Merikangas, KR Cui, LH Richardson, AK Isler, H Khoromi, S Nakamura, E Lamers, F Rossler, W Ajdacic-Gross, V Gamma, A Angst, J AF Merikangas, Kathleen R. Cui, Lihong Richardson, Amanda Kalaydjian Isler, Hansruedi Khoromi, Suzan Nakamura, Erin Lamers, Femke Roessler, Wulf Ajdacic-Gross, Vladeta Gamma, Alex Angst, Jules TI Magnitude, impact, and stability of primary headache subtypes: 30 year prospective Swiss cohort study SO BRITISH MEDICAL JOURNAL LA English DT Article ID TENSION-TYPE HEADACHE; POPULATION-BASED TWIN; FOLLOW-UP; YOUNG-ADULTS; ZURICH COHORT; MIGRAINE HEADACHES; MENTAL-DISORDERS; UNITED-STATES; PREVALENCE; EPIDEMIOLOGY AB Objective To determine the prevalence, impact, and stability of different subtypes of headache in a 30 year prospective follow-up study of a general population sample. Design Prospective cohort study. Setting Canton of Zurich, Switzerland. Participants 591 people aged 19-20 from a cohort of 4547 residents of Zurich, Switzerland, interviewed seven times across 30 years of follow-up. Main outcome measures Prevalence of headache; stability of the predominant subtype of headache over time; and age of onset, severity, impact, family history, use of healthcare services, and drugs for headache subtypes. Results The average one year prevalences of subtypes of headache were 0.9% (female: male ratio of 2.8) for migraine with aura, 10.9% (female: male ratio of 2.2) for migraine without aura, and 11.5% (female: male ratio of 1.2) for tension-type headache. Cumulative 30 year prevalences of headache subtypes were 3.0% for migraine with aura, 36.0% for migraine without aura, and 29.3% for tension-type headache. Despite the high prevalence of migraine without aura, most cases were transient and only about 20% continued to have migraine for more than half of the follow-up period. 69% of participants with migraine and 58% of those with tension-type headache manifested the same predominant subtype over time. However, the prospective stability of the predominant headache subtypes was quite low, with substantial crossover among the subtypes and no specific ordinal pattern of progression. A gradient of severity of clinical correlates and service use was present across headache subtypes; the greatest effect was for migraine with aura followed by migraine without aura, and then tension-type headache and unclassified headaches. Conclusions These findings highlight the importance of prospective follow-up of people with headache. The substantial longitudinal overlap among subtypes of headache shows the developmental heterogeneity of headache syndromes. Studies of the causes of headache that apply diagnostic nomenclature based on distinctions between discrete headache subtypes may not capture the true nature of headache in the general population. C1 [Merikangas, Kathleen R.; Cui, Lihong; Richardson, Amanda Kalaydjian; Khoromi, Suzan; Nakamura, Erin; Lamers, Femke] NIMH, NIH, Intramural Res Program, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [Isler, Hansruedi] Hochhaus Schanze, CH-8032 Zurich, Switzerland. [Roessler, Wulf; Ajdacic-Gross, Vladeta; Gamma, Alex; Angst, Jules] Univ Zurich, Hosp Psychiat, Zurich, Switzerland. RP Merikangas, KR (reprint author), NIMH, NIH, Intramural Res Program, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. EM Kathleen.Merikangas@nih.gov RI Lamers, Femke/G-5161-2012; OI Ajdacic-Gross, Vladeta/0000-0002-7032-9237 FU Swiss National Science Foundation [3200-050881.97/1]; National Institute of Mental Health [ZIAMH002807-07]; Netherlands Organisation for Scientific Research (NWO) FX This work was supported by grant 3200-050881.97/1 of the Swiss National Science Foundation and National Institute of Mental Health, Intramural Research Program grant No ZIAMH002807-07 for collaborative analyses of the Zurich Cohort Study. FL is supported by a Rubicon fellowship from the Netherlands Organisation for Scientific Research (NWO). 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 organisations, agencies, or US government. NR 42 TC 12 Z9 12 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD AUG 25 PY 2011 VL 343 AR d5076 DI 10.1136/bmj.d5076 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 813ZQ UT WOS:000294410400003 PM 21868455 ER PT J AU Belgard, TG Marques, AC Oliver, PL Abaan, HO Sirey, TM Hoerder-Suabedissen, A Garcia-Moreno, F Molnar, Z Margulies, EH Ponting, CP AF Belgard, T. Grant Marques, Ana C. Oliver, Peter L. Abaan, Hatice Ozel Sirey, Tamara M. Hoerder-Suabedissen, Anna Garcia-Moreno, Fernando Molnar, Zoltan Margulies, Elliott H. Ponting, Chris P. TI A Transcriptomic Atlas of Mouse Neocortical Layers SO NEURON LA English DT Article ID LONG NONCODING RNAS; CAT VISUAL-CORTEX; GENE-EXPRESSION; CEREBRAL-CORTEX; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; NMDA RECEPTORS; HUMAN BRAIN; CELL-TYPES; NEURONS AB In the mammalian cortex, neurons and glia form a patterned structure across six layers whose complex cytoarchitectonic arrangement is likely to contribute to cognition. We sequenced transcriptomes from layers 1-6b of different areas (primary and secondary) of the adult (postnatal day 56) mouse somatosensory cortex to understand the transcriptional levels and functional repertoires of coding and noncoding loci for cells constituting these layers. A total of 5,835 protein-coding genes and 66 noncoding RNA loci are differentially expressed ("patterned") across the layers, on the basis of a machine-learning model (naive Bayes) approach. Layers 2-6b are each associated with specific functional and disease annotations that provide insights into their biological roles. This new resource (http://genserv.anat.ox.ac.uk/layers) greatly extends currently available resources, such as the Allen Mouse Brain Atlas and microarray data sets, by providing quantitative expression levels, by being genome-wide, by including novel loci, and by identifying candidate alternatively spliced transcripts that are differentially expressed across layers. C1 [Belgard, T. Grant; Sirey, Tamara M.; Hoerder-Suabedissen, Anna; Garcia-Moreno, Fernando; Molnar, Zoltan] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. [Belgard, T. Grant; Marques, Ana C.; Oliver, Peter L.; Sirey, Tamara M.; Ponting, Chris P.] Univ Oxford, MRC Funct Genom Unit, Oxford OX1 3QX, England. [Belgard, T. Grant; Abaan, Hatice Ozel; Margulies, Elliott H.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Molnar, Z (reprint author), Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. EM zoltan.molnar@dpag.ox.ac.uk; emargulies@illumina.com; chris.ponting@dpag.ox.ac.uk RI Hoerder-Suabedissen, Anna/G-7053-2011; OI Marques, Ana Claudia/0000-0001-5174-8092; Hoerder-Suabedissen, Anna/0000-0003-1953-7871; Molnar, Zoltan/0000-0002-6852-6004; Belgard, Tildon/0000-0002-6962-7894; Ponting, Chris/0000-0003-0202-7816; Garcia-Moreno, Fernando/0000-0001-9048-4237 FU Marshall Scholarship; New College, Oxford; NIH-Oxford-Cambridge; Marie Curie Fellowship; National Human Genome Research Institute; MRC; BBSRC; MAC; Wellcome Trust; St. John's College, Oxford; ERC FX We thank W.Z. Wang, A.F. Cheung, and the NIH Intramural Sequencing Center for technical assistance; R.A. Chodroff, E.D. Green, A. Heger, L. Goodstadt, M. Goodson, C. Webber and J. Becker for helpful discussions. T.G.B. was supported by a Marshall Scholarship; New College, Oxford; and the NIH-Oxford-Cambridge Scholars Program. A.C.M. was supported by a Marie Curie Fellowship. E.H.M. and H.O.A. were supported by the Intramural Research Program of the National Human Genome Research Institute. A.H-S. was supported by a MRC Programme Grant to ZM. T.M.S. was supported by a BBSRC Project Grant to ZM and C.P.P. Z.M. was supported by MAC, BBSRC, Wellcome Trust and St. John's College, Oxford. P.L.O. was supported by the MRC and C.P.P. was supported by the MRC, BBSRC and ERC. NR 76 TC 116 Z9 121 U1 1 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 25 PY 2011 VL 71 IS 4 BP 605 EP 616 DI 10.1016/j.neuron.2011.06.039 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 815JJ UT WOS:000294521600007 PM 21867878 ER PT J AU Ciraci, E Della Bella, S Salvucci, O Rofani, C Segarra, M Bason, C Molinari, A Maric, D Tosato, G Berardi, AC AF Ciraci, Elisa Della Bella, Silvia Salvucci, Ombretta Rofani, Cristina Segarra, Marta Bason, Caterina Molinari, Agnese Maric, Dragan Tosato, Giovanna Berardi, Anna C. TI Adult human circulating CD34(-)Lin(-)CD45(-)CD133(-) cells can differentiate into hematopoietic and endothelial cells SO BLOOD LA English DT Article ID HUMAN CORD BLOOD; BONE MARROW INJECTION; STEM-CELLS; PROGENITOR CELLS; IN-VITRO; IDENTIFICATION; PRECURSORS; EXPRESSION; HEMANGIOBLAST; MICE AB A precise identification of adult human hemangioblast is still lacking. To identify circulating precursors having the developmental potential of the hemangioblast, we established a new ex vivo long-term culture model supporting the differentiation of both hematopoietic and endothelial cell lineages. We identified from peripheral blood a population lacking the expression of CD34, lineage markers, CD45 and CD133 (CD34(-)Lin(-)CD45(-)CD133(-) cells), endowed with the ability to differentiate after a 6-week culture into both hematopoietic and endothelial lineages. The bilineage potential of CD34(-)Lin(-)CD45(-)CD133(-) cells was determined at the single-cell level in vitro and was confirmed by transplantation into NOD/SCID mice. In vivo, CD34(-)Lin(-)CD45(-)CD133(-) cells showed the ability to reconstitute hematopoietic tissue and to generate functional endothelial cells that contribute to new vessel formation during tumor angiogenesis. Molecular characterization of CD34(-)Lin(-)CD45(-)CD133(-) cells unveiled a stem cell profile compatible with both hematopoietic and endothelial potentials, characterized by the expression of c-Kit and CXCR4 as well as EphB4, EphB2, and ephrinB2. Further molecular and functional characterization of CD34(-)Lin(-)CD45(-)CD133(-) cells will help dissect their physiologic role in blood and blood vessel maintenance and repair in adult life. (Blood. 2011;118(8):2105-2115) C1 [Ciraci, Elisa; Berardi, Anna C.] Spirito Santo Hosp, Dept Transfus Med, Lab Stem Cells, I-65100 Pescara, Italy. [Della Bella, Silvia] Univ Milan, Dept Translat Med, Clin & Expt Immunol Lab, Milan, Italy. [Della Bella, Silvia] IRCCS Ist Clin Humanitas, Milan, Italy. [Salvucci, Ombretta; Segarra, Marta; Tosato, Giovanna] NCI, Ctr Canc Res, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Rofani, Cristina] Univ Roma La Sapienza, Dept Histol & Med Embryol, Rome, Italy. [Bason, Caterina] Univ Verona, Dept Med, Sect Internal Med B, I-37100 Verona, Italy. [Molinari, Agnese] Ist Super Sanita, Dept Technol & Hlth, I-00161 Rome, Italy. [Maric, Dragan] Natl Inst Neurol Disorders & Stroke, Neurophysiol Lab, NIH, Bethesda, MD USA. RP Berardi, AC (reprint author), Spirito Santo Hosp, Res Stem Cells Lab Transfus Med, Via Circuito, I-65100 Pescara, Italy. EM annacberardi@yahoo.it RI Molinari, Agnese/E-7588-2015; OI Molinari, Agnese/0000-0002-9592-5465; Berardi, Anna C./0000-0002-5078-6158; Della Bella, Silvia/0000-0003-0818-5049 FU "Associazione Italiana contro le Leucemie" (AIL) Pescara FX This work was partially supported by "Associazione Italiana contro le Leucemie" (AIL) Pescara. NR 50 TC 14 Z9 14 U1 0 U2 9 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 AUG 25 PY 2011 VL 118 IS 8 BP 2105 EP 2115 DI 10.1182/blood-2010-10-316596 PG 11 WC Hematology SC Hematology GA 811ZR UT WOS:000294258000013 PM 21715308 ER PT J AU Iglesias, MC Almeida, JR Fastenackels, S van Bockel, DJ Hashimoto, M Venturi, V Gostick, E Urrutia, A Wooldridge, L Clement, M Gras, S Wilmann, PG Autran, B Moris, A Rossjohn, J Davenport, MP Takiguchi, M Brander, C Douek, DC Kelleher, AD Price, DA Appay, V AF Iglesias, Maria Candela Almeida, Jorge R. Fastenackels, Solene van Bockel, David J. Hashimoto, Masao Venturi, Vanessa Gostick, Emma Urrutia, Alejandra Wooldridge, Linda Clement, Mathew Gras, Stephanie Wilmann, Pascal G. Autran, Brigitte Moris, Arnaud Rossjohn, Jamie Davenport, Miles P. Takiguchi, Masafumi Brander, Christian Douek, Daniel C. Kelleher, Anthony D. Price, David A. Appay, Victor TI Escape from highly effective public CD8(+) T-cell clonotypes by HIV SO BLOOD LA English DT Article ID LYMPHOCYTE RESPONSE; PEPTIDE-MHC; CONVERGENT RECOMBINATION; ANTIGEN SENSITIVITY; SIV INFECTION; REPERTOIRE; RECEPTOR; CTL; ACTIVATION; VIRUS AB Mapping the precise determinants of T-cell efficacy against viruses in humans is a public health priority with crucial implications for vaccine design. To inform this effort, we performed a comprehensive analysis of the effective CD8(+) T-cell clonotypes that constitute responses specific for the HIV p24 Gag-derived KK10 epitope (KRWIILGLNK; residues 263-272) restricted by HLA-B*2705, which are known to confer superior control of viral replication in HIV-infected individuals. Particular KK10-specific CD8(+) T-cell clonotypes, characterized by TRBV4-3/TRBJ1-3 gene rearrangements, were found to be preferentially selected in vivo and shared between individuals. These "public" clonotypes exhibit high levels of TCR avidity and Ag sensitivity, which impart functional advantages and enable effective suppression of HIV replication. The early L268M mutation at position 6 of the KK10 epitope enables the virus to avoid recognition by these highly effective CD8(+) T-cell clonotypes. However, alternative clonotypes with variant reactivity provide flexibility within the overall KK10-specific response. These findings provide refined mechanistic insights into the workings of an effective CD8(+) T-cell response against HIV. (Blood. 2011;118(8):2138-2149) C1 [Iglesias, Maria Candela; Almeida, Jorge R.; Fastenackels, Solene; Urrutia, Alejandra; Autran, Brigitte; Moris, Arnaud; Appay, Victor] Univ Paris 06, Hop La Pitie Salpetriere, Avenir Grp, Inserm UMR S 945, Paris, France. [Almeida, Jorge R.; Douek, Daniel C.; Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [van Bockel, David J.; Kelleher, Anthony D.] Univ New S Wales, St Vincents Ctr Appl Med Res, Darlinghurst, NSW, Australia. [van Bockel, David J.; Kelleher, Anthony D.] Univ New S Wales, Kirby Inst, Darlinghurst, NSW, Australia. [Hashimoto, Masao; Takiguchi, Masafumi] Kumamoto Univ, Ctr AIDS Res, Div Viral Immunol, Kumamoto, Japan. [Venturi, Vanessa] Univ New S Wales, Ctr Vasc Res, Computat Biol Grp, Kensington, NSW 2033, Australia. [Gostick, Emma; Wooldridge, Linda; Clement, Mathew; Price, David A.] Cardiff Univ, Sch Med, Dept Infect Immun & Biochem, Cardiff, S Glam, Wales. [Gras, Stephanie; Wilmann, Pascal G.; Rossjohn, Jamie] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. [Appay, Victor] Grp Hosp Pitie Salpetriere, AP HP, Lab Immunol Cellulaire & Tissulaire, F-75634 Paris, France. [Davenport, Miles P.] Univ New S Wales, Ctr Vasc Res, Complex Syst Biol Grp, Kensington, NSW 2033, Australia. [Brander, Christian] Hosp Univ Germans Trias & Pujol Ctra Canyet, AIDS Res Inst IrsiCaixa HIVACAT, Barcelona, Spain. [Brander, Christian] ICREA, Barcelona, Spain. RP Appay, V (reprint author), Univ Paris 06, Hop La Pitie Salpetriere, Avenir Grp, Inserm UMR S 945, Paris, France. EM victor.appay@upmc.fr RI gras, stephanie/C-8307-2013; Takiguchi, Masafumi/E-7468-2013; Rossjohn, Jamie/F-9032-2013; Kumamoto University, CAIDS/G-8446-2013; Price, David/C-7876-2013; OI Rossjohn, Jamie/0000-0002-2020-7522; Price, David/0000-0001-9416-2737; Ramos de Almeida, Jorge/0000-0002-5009-8478; Brander, Christian/0000-0002-0548-5778; Moris, Arnaud/0000-0002-5052-1678 FU ANR [ANR-09-JCJC-0114-01]; Sidaction; Inserm; French ANRS; National Institutes of Health via Vaccine Research Center (National Institute of Allergy and Infectious Diseases [NIAID]) [R01 067077]; Australian Research Council (ARC); Australian National Health and Medical Research Council (NHMRC); UK Medical Research Council (MRC); Fundacao para a Ciencia e Tecnologia FX This work was supported by the ANR (project ANR-09-JCJC-0114-01), Sidaction, the Inserm AVENIR grant, the French ANRS, the National Institutes of Health via the Intramural Program of the Vaccine Research Center (National Institute of Allergy and Infectious Diseases [NIAID]) and R01 067077 (C. B.), the Australian Research Council (ARC), the Australian National Health and Medical Research Council (NHMRC), and the UK Medical Research Council (MRC). M. C. I. is supported by a Sidaction Fellowship. J.R.A. is supported by a Fundacao para a Ciencia e Tecnologia Fellowship. NR 50 TC 62 Z9 63 U1 0 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 AUG 25 PY 2011 VL 118 IS 8 BP 2138 EP 2149 DI 10.1182/blood-2011-01-328781 PG 12 WC Hematology SC Hematology GA 811ZR UT WOS:000294258000016 PM 21734237 ER PT J AU Walker, T Johnson, PH Moreira, LA Iturbe-Ormaetxe, I Frentiu, FD McMeniman, CJ Leong, YS Dong, Y Axford, J Kriesner, P Lloyd, AL Ritchie, SA O'Neill, SL Hoffmann, AA AF Walker, T. Johnson, P. H. Moreira, L. A. Iturbe-Ormaetxe, I. Frentiu, F. D. McMeniman, C. J. Leong, Y. S. Dong, Y. Axford, J. Kriesner, P. Lloyd, A. L. Ritchie, S. A. O'Neill, S. L. Hoffmann, A. A. TI The wMel Wolbachia strain blocks dengue and invades caged Aedes aegypti populations SO NATURE LA English DT Article ID UNITED-STATES; VIRUS; INFECTION; MOSQUITO; DROSOPHILA; AUSTRALIA; CULICIDAE; DIPTERA; MODELS; SPREAD AB Dengue fever is the most important mosquito-borne viral disease of humans with more than 50 million cases estimated annually in more than 100 countries(1,2). Disturbingly, the geographic range of dengue is currently expanding and the severity of outbreaks is increasing(2-4). Control options for dengue are very limited and currently focus on reducing population abundance of the major mosquito vector, Aedes aegypti(5,6). These strategies are failing to reduce dengue incidence in tropical communities and there is an urgent need for effective alternatives. It has been proposed that endosymbiotic bacterial Wolbachia infections of insects might be used in novel strategies for dengue control(7-9). For example, the wMelPop-CLA Wolbachia strain reduces the lifespan of adult A. aegypti mosquitoes in stably transinfected lines(8). This life-shortening phenotype was predicted to reduce the potential for dengue transmission. The recent discovery that several Wolbachia infections, including wMelPop-CLA, can also directly influence the susceptibility of insects to infection with a range of insect and human pathogens(9-11) has markedly changed the potential for Wolbachia infections to control human diseases. Here we describe the successful transinfection of A. aegypti with the avirulent wMel strain of Wolbachia, which induces the reproductive phenotype cytoplasmic incompatibility with minimal apparent fitness costs and high maternal transmission, providing optimal phenotypic effects for invasion. Under semi-field conditions, the wMel strain increased from an initial starting frequency of 0.65 to near fixation within a few generations, invading A. aegypti populations at an accelerated rate relative to trials with the wMelPop-CLA strain. We also show that wMel and wMelPop-CLA strains block transmission of dengue serotype 2 (DENV-2) in A. aegypti, forming the basis of a practical approach to dengue suppression(12). C1 [Walker, T.; Moreira, L. A.; Iturbe-Ormaetxe, I.; Frentiu, F. D.; McMeniman, C. J.; Leong, Y. S.; Dong, Y.; O'Neill, S. L.] Univ Queensland, Sch Biol Sci, Brisbane, Qld 4072, Australia. [Axford, J.; Kriesner, P.; Hoffmann, A. A.] Univ Melbourne, Dept Genet, Inst Bio21, Melbourne, Vic 3010, Australia. [Johnson, P. H.; Ritchie, S. A.] James Cook Univ, Sch Publ Hlth & Trop Med & Rehabil Sci, Cairns, Qld 4870, Australia. [Lloyd, A. L.] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. [Lloyd, A. L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Lloyd, A. L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [O'Neill, S. L.] Monash Univ, Sch Biol Sci, Clayton, Vic 3800, Australia. RP O'Neill, SL (reprint author), Univ Queensland, Sch Biol Sci, Brisbane, Qld 4072, Australia. EM scott.oneill@monash.edu RI Lloyd, Alun/H-4944-2012; Frentiu, Francesca/K-4561-2012; Walker, Thomas/F-6572-2013; Entomologiamolecular, Inct/J-8214-2013; Walker, Thomas/B-9198-2014; Hoffmann, Ary/C-2961-2011; O'Neill, Scott/B-3568-2009 OI Walker, Thomas/0000-0003-4475-5395; Walker, Thomas/0000-0002-3545-012X; O'Neill, Scott/0000-0002-4131-3615 FU Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative of the Bill and Melinda Gates Foundation; National Health and Medical Research Council, Australia; NIH; Climate and Health Cluster of the CSIRO; Australian Research Council FX We are grateful to N. Kenny for technical support and to members of the O'Neill laboratory for critical reading of the manuscript. We thank R. Silcock, M. Janes, S. Long, C. Paton and C. Omodei for their assistance in the semi-field cages and laboratory at James Cook University. We are very grateful for all of our volunteers who helped to blood-feed the mosquitoes in the cages and to P. Young for providing the anti-dengue antibodies. This research was supported by a grant from the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative of the Bill and Melinda Gates Foundation, The National Health and Medical Research Council, Australia, the RAPIDD program of the NIH, the Climate and Health Cluster of the CSIRO Flagship collaboration Fund and fellowships from the Australian Research Council. NR 36 TC 346 Z9 366 U1 30 U2 169 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 25 PY 2011 VL 476 IS 7361 BP 450 EP U101 DI 10.1038/nature10355 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811KT UT WOS:000294209400036 PM 21866159 ER PT J AU Snyder, JS Soumier, A Brewer, M Pickel, J Cameron, HA AF Snyder, Jason S. Soumier, Amelie Brewer, Michelle Pickel, James Cameron, Heather A. TI Adult hippocampal neurogenesis buffers stress responses and depressive behaviour SO NATURE LA English DT Article ID GLUCOCORTICOID-RECEPTOR; TRANSGENIC MICE; ANIMAL-MODEL; ASTROCYTES; NEURONS; ANTIDEPRESSANTS; FOREBRAIN; LESIONS; BRAIN; RATS AB Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness(1,2). In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis(3). Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking(4,5). Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to inhibit adult neurogenesis specifically, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis(6,7). Relative to controls, neurogenesis-deficient mice also showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness. C1 [Snyder, Jason S.; Soumier, Amelie; Brewer, Michelle; Pickel, James; Cameron, Heather A.] NIMH, NIH, Bethesda, MD 20892 USA. RP Cameron, HA (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM heathercameron@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 National Institute of Mental Health, National Institutes of Health, USA [ZIA MH002784] FX We thank A. Sowers and J. Mitchell for help with irradiation, M. Brenner for providing the plasmid construct, GlaxoSmithKline for providing the antibody against HSV-TK, and K. Sanzone, F. Kamhi, L. Glover, S. Ferrante and L. Grigereit for assisting with mouse breeding and treatment. This research was supported by the Intramural Program of the National Institute of Mental Health, National Institutes of Health, USA, ZIA MH002784 (to H.A.C.). NR 30 TC 458 Z9 478 U1 28 U2 161 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 25 PY 2011 VL 476 IS 7361 BP 458 EP U112 DI 10.1038/nature10287 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811KT UT WOS:000294209400038 PM 21814201 ER PT J AU Marom, M Birnbaumer, L Atlas, D AF Marom, M. Birnbaumer, L. Atlas, D. TI MEMBRANE DEPOLARIZATION COMBINED WITH Gq-ACTIVATED G-PROTEIN-COUPLED RECEPTORS INDUCE TRANSIENT RECEPTOR POTENTIAL CHANNEL 1 (TRPC1)- DEPENDENT POTENTIATION OF CATECHOLAMINE RELEASE SO NEUROSCIENCE LA English DT Article DE Ca(2+) channel; TRPC channel; Gq/11 GPCR; PLC beta; depolarization-evoked secretion; LTP ID ADRENAL CHROMAFFIN CELLS; RAT HIPPOCAMPAL-NEURONS; PIG CORONARY MYOCYTES; GATED CALCIUM-CHANNEL; CA2+ SENSOR PROTEIN; NEUROTRANSMITTER RELEASE; GUINEA-PIG; INTRACELLULAR CALCIUM; TRANSMITTER RELEASE; CEREBELLAR NUCLEI AB Agonists of the G(q/11)-activated G-protein-coupled receptors (GPCRs) combined with strong membrane depolarization (high KCI) induce a synergistic amplification of transmitter release. The molecular basis for the synergy is unknown. Here, we investigated this potentiated transmitter release (PTR) phenomenon at the single cell level by monitoring catecholamine (CA) release in chromaffin cells using amperometry. We found that the 60 mM KCI (K60)-triggered release in bovine chromaffin cells synergizes with bradykinin (BK) or histamine (Hist) to potentiate CA release. PTR was independent of Ca(2+) influx through voltage-gated calcium channels (VGCC), but required Ca(2+) at the extracellular medium and was abolished by inhibitors of phospholipase C beta (PLC beta). The similar to four-fold PTR induced in mouse chromaffin cells by BK and K60, was not observed in chromaffin cells prepared from TRPC1 KO mice and was restored by expressing hTRPC1. The synergy between strong voltage perturbation (K60) in the presence of VGCC blockers, and the activation of the G(q/11)-PLC beta signal-transduction cascade generates unique and fundamental amplified signaling machinery. The concerted activation of two independent cellular pathways could reinforce physiological signals that impinge on regulation of secretory events during repeated sequence of high-frequency excitation, hyperpolarization, and relief of inhibition such as long-term potentiation (LTP), that lead to neuronal synaptic plasticity. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Marom, M.; Atlas, D.] Hebrew Univ Jerusalem, Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel. [Birnbaumer, L.] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Atlas, D (reprint author), Hebrew Univ Jerusalem, Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel. EM datlas@vms.huji.ac.il FU Betty Feffer foundation; H.L Lauterbach foundation FX The authors thank Dr. B. Minke and M Peters for discussions, suggestions and critically commenting on the work. This study was supported by The Betty Feffer and The H.L Lauterbach foundations for D.A. NR 68 TC 2 Z9 2 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD AUG 25 PY 2011 VL 189 BP 132 EP 145 DI 10.1016/j.neuroscience.2011.05.007 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 809XT UT WOS:000294090700013 PM 21621591 ER PT J AU Huskins, WC O'Grady, NP Goldmann, DA AF Huskins, W. Charles O'Grady, Naomi P. Goldmann, Donald A. TI Transmission of Resistant Bacteria in Intensive Care REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Huskins, W. Charles] Mayo Clin, Rochester, MN 55905 USA. [O'Grady, Naomi P.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Goldmann, Donald A.] Harvard Univ, Sch Med, Boston, MA USA. RP Huskins, WC (reprint author), Mayo Clin, Rochester, MN 55905 USA. EM huskins.charles@mayo.edu NR 1 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 AUG 25 PY 2011 VL 365 IS 8 BP 764 EP 765 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 811JM UT WOS:000294205300024 ER PT J AU Cherian, J Choi, I Nayyar, A Manjunatha, UH Mukherjee, T Lee, YS Boshoff, HI Singh, R Ha, YH Goodwin, M Lakshminarayana, SB Niyomrattanakit, P Jiricek, J Rayindran, S Dick, T Keller, TH Dartois, V Barry, CE AF Cherian, Joseph Choi, Inhee Nayyar, Arnit Manjunatha, Ujjini H. Mukherjee, Tathagata Lee, Yong Sok Boshoff, Helena I. Singh, Ramandeep Ha, Young Hwan Goodwin, Michael Lakshminarayana, Suresh B. Niyomrattanakit, Pornwaratt Jiricek, Jan Rayindran, Sindhu Dick, Thomas Keller, Thomas H. Dartois, Veronique Barry, Clifton E., III TI Structure-Activity Relationships of Antitubercular Nitroimidazoles. 3. Exploration of the Linker and Lipophilic Tail of ((S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)-(4-trifluoro methoxybenzyl)amine (6-Amino PA-824). SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MURINE MODEL; BACTERICIDAL ACTIVITY; MYCOBACTERIUM-TUBERCULOSIS; IN-VITRO; PYRAZINAMIDE; ANALOGS; DRUG AB The (S)-2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine named PA-824 (1) has demonstrated antitubercular activity in vitro and in animal models and is currently in clinical trials. We synthesized derivatives at three positions of the 4-(trifluoromethoxy)benzylamino tail, and these were tested for whole-cell activity against both replicating and nonreplicating Mycobacterium tuberculosis (Mtb). In addition, we determined their kinetic parameters as substrates of the deazaflavin-dependent nitroreductase (Ddn) from Mtb that reductively activates these pro-drugs. These studies yielded multiple compounds with 40 nM aerobic whole cell activity and 1.6 mu M anaerobic whole cell activity: 10-fold improvements over both characteristics from the parent molecule. Some of these compounds exhibited enhanced solubility with acceptable stability to microsomal and in vivo metabolism. Analysis of the conformational preferences of these analogues using quantum chemistry suggests a preference for a pseudoequatorial orientation of the linker and lipophilic tail. C1 [Cherian, Joseph; Manjunatha, Ujjini H.; Lakshminarayana, Suresh B.; Niyomrattanakit, Pornwaratt; Jiricek, Jan; Rayindran, Sindhu; Dick, Thomas; Keller, Thomas H.; Dartois, Veronique] Novartis Inst Trop Dis, Singapore 138670, Singapore. [Choi, Inhee; Nayyar, Arnit; Mukherjee, Tathagata; Boshoff, Helena I.; Singh, Ramandeep; Ha, Young Hwan; Goodwin, Michael; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Lee, Yong Sok] NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Barry, CE (reprint author), CEB3, Room 2W20D,Bldg 33,9000 Rockville Pike, Bethesda, MD 20892 USA. EM cbarry@mail.nih.gov RI Barry, III, Clifton/H-3839-2012; Cherian, Joseph/Q-2522-2016; OI Keller, Thomas/0000-0002-7553-6235 FU NIH, NIAID; NITD; Bill and Melinda Gates Foundation; Wellcome Trust; NIH through the Center for Information Technology FX This work was funded, in part, by the intramural research program of NIH, NIAID, by NITD, and by a grant from the Bill and Melinda Gates Foundation and the Wellcome Trust through the Grand Challenges in Global Health Initiative. We thank Anne Goh and the bioanalytical team of NITD for the determination of compound concentrations in microsomal and plasma samples and Dr. Noel Whittaker, NIDDK, for HRMS of some of the compounds. The quantum chemical study utilized PC/LINUX clusters at the Center for Molecular Modeling of the NIH (http://cit.nih.gov), and this research was also supported in part by the NIH Intramural Research Program through the Center for Information Technology. NR 25 TC 17 Z9 17 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 25 PY 2011 VL 54 IS 16 BP 5639 EP 5659 DI 10.1021/jm1010644 PG 21 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 809SP UT WOS:000294077300002 PM 21755942 ER PT J AU Hall, MD Brimacombe, KR Varonka, MS Pluchino, KM Monda, JK Li, JY Walsh, MJ Boxer, MB Warren, TH Fales, HM Gottesman, MM AF Hall, Matthew D. Brimacombe, Kyle R. Varonka, Matthew S. Pluchino, Kristen M. Monda, Julie K. Li, Jiayang Walsh, Martin J. Boxer, Matthew B. Warren, Timothy H. Fales, Henry M. Gottesman, Michael M. TI Synthesis and Structure-Activity Evaluation of Isatin-beta-thiosemicarbazones with Improved Selective Activity toward Multidrug-Resistant Cells Expressing P-Glycoprotein SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CARCINOMA-CELLS; CANCER-CELLS; PHASE-I; TRANSPORTER; COMPLEXES; TOXICITY; AGENTS; LINES; HYPERSENSITIVITY; 2-DEOXYGLUCOSE AB Cancer multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters presents a significant unresolved clinical challenge. One strategy to resolve MDR is to develop compounds that selectively kill cells overexpressing the efflux transporter P-glycoprotein (MDR1, P-gp, ABCB1). We have previously reported structure-activity studies based around the lead compound NSC73306 (1, 1-isatin-4-(4'-methoxyphenyl)-3-thiosemicarbazone, 4.3-fold selective). Here we sought to extend this work on MDR1-selective analogues by establishing whether 1 showed "robust" activity against a range of cell lines expressing P-gp. We further aimed to synthesize and test analogues with varied substitution at the N4-position, and substitution around the N4-phenyl ring of isatin-beta-thiosemicarbazones (IBTs), to identify compounds with increased MDR1-selectivity. Compound 1 demonstrated MDR1-selectivity against all P-gp-expressing cell lines examined. This selectivity was reversed by inhibitors of P-gp ATPase activity. Structural variation at the 4'-phenyl position of 1 yielded compounds of greater MDR1-selectivity. Two of these analogues, 1-isatin-4-(4'-nitrophenyl)-3-thiosemicarbazone (22, 8.3-fold selective) and 1-isatin-4-(4'-tert-butyl phenyl)-3-thiosemicarbazone (32, 14.8-fold selective), were selected for further testing and were found to retain the activity profile of 1. These compounds are the most active IBTs identified to date. C1 [Hall, Matthew D.; Brimacombe, Kyle R.; Pluchino, Kristen M.; Monda, Julie K.; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Varonka, Matthew S.; Warren, Timothy H.] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. [Li, Jiayang; Fales, Henry M.] NHLBI, Lab Appl Mass Spectrometry, NIH, Bethesda, MD 20892 USA. [Walsh, Martin J.; Boxer, Matthew B.] NIH, NIH Chem Genom Ctr, NIH Ctr Translat Therapeut, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM gottesnun@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. We thank George Leiman for editorial assistance. NR 50 TC 43 Z9 43 U1 2 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 25 PY 2011 VL 54 IS 16 BP 5878 EP 5889 DI 10.1021/jm2006047 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 809SP UT WOS:000294077300019 PM 21721528 ER PT J AU Ghosh, AK Chapsal, BD Parham, GL Steffey, M Agniswamy, J Wang, YF Amano, M Weber, IT Mitsuya, H AF Ghosh, Arun K. Chapsal, Bruno D. Parham, Garth L. Steffey, Melinda Agniswamy, Johnson Wang, Yuan-Fang Amano, Masayuki Weber, Irene T. Mitsuya, Hiroaki TI Design of HIV-1 Protease Inhibitors with C3-Substituted Hexahydrocyclopentafuranyl Urethanes as P2-Ligands: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Crystal Structure SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DRUG-RESISTANT MUTANTS; ANTIRETROVIRAL THERAPY; IN-VITRO; COMPLEXES; BACKBONE; TMC114; POTENT; PI AB We report the design, synthesis, biological evaluation, and the X-ray crystal structure of a novel inhibitor bound to the HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed to interact with the flap Gly48 carbonyl or amide NH in the S2-subsite of the HIV-1 protease. We investigated the potential of those functionalized ligands in combination with hydroxyethylsulfonamide isosteres. Inhibitor 26 containing a 3-(R)-hydroxyl group on the Cp-THF core displayed the most potent enzyme inhibitory and antiviral activity. Our studies revealed a preference for the 3-(R)-configuration over the corresponding 3-(S)-derivative. Inhibitor 26 exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray structure of 26-bound HIV-1 protease revealed important molecular insight into the ligand-binding site interactions. C1 [Ghosh, Arun K.; Chapsal, Bruno D.; Parham, Garth L.; Steffey, Melinda] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Ghosh, Arun K.; Chapsal, Bruno D.; Parham, Garth L.; Steffey, Melinda] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Agniswamy, Johnson; Wang, Yuan-Fang; Weber, Irene T.] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. [Amano, Masayuki; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, Dept Hematol, Kumamoto 8608556, Japan. [Amano, Masayuki; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, Dept Infect Dis, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Ghosh, AK (reprint author), Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. EM akghosh@purdue.edu RI Amano, Masayuki/N-7407-2016 OI Amano, Masayuki/0000-0003-0516-9502 FU National Institutes of Health [GM53386, GM62920]; Center for Cancer Research, National Cancer Institute, National Institutes of Health; Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho); Ministry of Health, Welfare, and Labor of Japan; Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo) of Monbu-Kagakusho FX This research was supported by the National Institutes of Health (Grant GM53386 to A.K.G. and Grant GM62920 to IT. W.). This work was also supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and in part by a Grant-in-Aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho), a Grant for Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan, and the Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo) of Monbu-Kagakusho. NR 33 TC 16 Z9 17 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 25 PY 2011 VL 54 IS 16 BP 5890 EP 5901 DI 10.1021/jm200649p PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 809SP UT WOS:000294077300020 PM 21800876 ER PT J AU Lee, KH Shim, MS Kim, JY Jung, HK Lee, E Carlson, BA Xu, XM Park, JM Hatfield, DL Park, T Lee, BJ AF Lee, Kwang Hee Shim, Myoung Sup Kim, Jin Young Jung, Hee Kyoung Lee, Eunji Carlson, Bradley A. Xu, Xue-Ming Park, Jin Mo Hatfield, Dolph L. Park, Taesung Lee, Byeong Jae TI Drosophila selenophosphate synthetase 1 regulates vitamin B6 metabolism: prediction and confirmation SO BMC GENOMICS LA English DT Article ID SELENOCYSTEINE BIOSYNTHESIS; SELENOPROTEIN SYNTHESIS; 5'-PHOSPHATE OXIDASE; ESCHERICHIA-COLI; GENE ONTOLOGY; SELENIUM; SYNTHASE; HOMOLOG; PATHWAY; IDENTIFICATION AB Background: There are two selenophosphate synthetases (SPSs) in higher eukaryotes, SPS1 and SPS2. Of these two isotypes, only SPS2 catalyzes selenophosphate synthesis. Although SPS1 does not contain selenophosphate synthesis activity, it was found to be essential for cell growth and embryogenesis in Drosophila. The function of SPS1, however, has not been elucidated. Results: Differentially expressed genes in Drosophila SL2 cells were identified using two-way analysis of variance methods and clustered according to their temporal expression pattern. Gene ontology analysis was performed against differentially expressed genes and gene ontology terms related to vitamin B6 biosynthesis were found to be significantly affected at the early stage at which megamitochondria were not formed (day 3) after SPS1 knockdown. Interestingly, genes related to defense and amino acid metabolism were affected at a later stage (day 5) following knockdown. Levels of pyridoxal phosphate, an active form of vitamin B6, were decreased by SPS1 knockdown. Treatment of SL2 cells with an inhibitor of pyridoxal phosphate synthesis resulted in both a similar pattern of expression as that found by SPS1 knockdown and the formation of megamitochondria, the major phenotypic change observed by SPS1 knockdown. Conclusions: These results indicate that SPS1 regulates vitamin B6 synthesis, which in turn impacts various cellular systems such as amino acid metabolism, defense and other important metabolic activities. C1 [Lee, Kwang Hee; Shim, Myoung Sup; Kim, Jin Young; Jung, Hee Kyoung; Lee, Byeong Jae] Seoul Natl Univ, Dept Biol Sci, Seoul 151742, South Korea. [Lee, Kwang Hee; Lee, Eunji; Park, Taesung; Lee, Byeong Jae] Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul 151742, South Korea. [Lee, Eunji; Park, Taesung] Seoul Natl Univ, Dept Stat, Seoul 151742, South Korea. [Carlson, Bradley A.; Xu, Xue-Ming; Hatfield, Dolph L.] NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Park, Jin Mo] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Park, Jin Mo] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Lee, BJ (reprint author), Seoul Natl Univ, Dept Biol Sci, Seoul 151742, South Korea. EM imbglmg@snu.ac.kr FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2009-0094020, 2011-0012947]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Korea Ministry of Education and Human Resources Development FX This work was supported by the Priority Research Centers Program and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Grant Nos 2009-0094020 and 2011-0012947 to BJL) and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. MSS, JYK, KHL and HKJ were supported by Brain Korea 21 Research Fellowship from the Korea Ministry of Education and Human Resources Development. NR 45 TC 6 Z9 6 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 24 PY 2011 VL 12 AR 426 DI 10.1186/1471-2164-12-426 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 848KG UT WOS:000297049900001 PM 21864351 ER PT J AU Zhang, CY Elkahloun, AG Robertson, M Gills, JJ Tsurutani, J Shih, JH Fukuoka, J Hollander, MC Harris, CC Travis, WD Jen, J Dennis, PA AF Zhang, Chunyu Elkahloun, Abdel G. Robertson, Matthew Gills, Joell J. Tsurutani, Junji Shih, Joanna H. Fukuoka, Junya Hollander, M. Christine Harris, Curtis C. Travis, William D. Jen, Jin Dennis, Phillip A. TI Loss of Cytoplasmic CDK1 Predicts Poor Survival in Human Lung Cancer and Confers Chemotherapeutic Resistance SO PLOS ONE LA English DT Article ID BRONCHIAL EPITHELIAL-CELLS; CYCLIN-DEPENDENT KINASES; GENE-EXPRESSION; EPIGENETIC INACTIVATION; MAMMARY TUMORIGENESIS; AKT ACTIVATION; BREAST-CANCER; APOPTOSIS; CDC25A; PHOSPHORYLATION AB The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery. C1 [Zhang, Chunyu; Robertson, Matthew; Gills, Joell J.; Tsurutani, Junji; Hollander, M. Christine; Dennis, Phillip A.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Elkahloun, Abdel G.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Tsurutani, Junji] Kinki Univ, Sch Med, Dept Med Oncol, Osaka 589, Japan. [Shih, Joanna H.] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Fukuoka, Junya; Jen, Jin] NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. [Fukuoka, Junya] Toyama Univ Hosp, Dept Surg Pathol, Toyama, Japan. [Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Travis, William D.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Jen, Jin] Mayo Clin, Dept Pulm & Crit Care Med, Rochester, MN USA. RP Zhang, CY (reprint author), Lovelace Resp Res Inst, COPD program, Albuquerque, NM USA. EM dennisp@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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 14 Z9 15 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 24 PY 2011 VL 6 IS 8 AR e23849 DI 10.1371/journal.pone.0023849 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 832TW UT WOS:000295832000067 PM 21887332 ER PT J AU Salgado, MT Ramasamy, S Tsuneshige, A Manoharan, PT Rifkind, JM AF Salgado, Maria T. Ramasamy, Somasundararn Tsuneshige, Antonio Manoharan, Periakaruppan T. Rifkind, Joseph M. TI A New Paramagnetic Intermediate Formed during the Reaction of Nitrite with Deoxyhemoglobin SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PROTEIN THIYL RADICALS; HYPOXIC CONDITIONS; HUMAN HEMOGLOBIN; S-NITROSOHEMOGLOBIN; QUATERNARY STRUCTURE; BETA-93 CYSTEINE; VASCULAR CONTROL; PLASMA NITRITE; OXIDE; REDUCTASE AB The reduction of nitrite by deoxygenated hemoglobin chains has been implicated in red cell-induced vasodilation, although the mechanism for this process has not been established. We have previously demonstrated that the reaction of nitrite with deoxyhemoglobin produces a hybrid intermediate with properties of Hb(II)NO+ and Hb(III)NO that builds up during the reaction retaining potential NO bioactivity. To explain the unexpected stability of this intermediate, which prevents NO release from the Hb(III)NO component, we had implicated the transfer of an electron from the beta-93 thiol to NO+ producing center dot SHb(II)NO. To determine if this species is formed and to characterize its properties, we have investigated the electron paramagnetic resonance (EPR) changes taking place during the nitrite reaction. The EPR effects of blocking the thiol group with N-ethyl-maleimide and using carboxypeptidase-A to stabilize the R-quaternary conformation have demonstrated that center dot SHb(II)NO is formed and that it has the EPR spectrum expected for NO bound to the heme in the beta-chain plus that of a thiyl radical. This new NO-related paramagnetic species is in equilibrium with the hybrid intermediate "Hb(II)NO+ <-> Hb(III)NO", thereby further inhibiting the release of NO from Hb(II)NO. The formation of an NO-related paramagnetic species other than the tightly bound NO in Hb(II)NO was also confirmed by a decrease in the EPR signal by -20 degrees C incubation, which shifts the equilibrium back to the "Hb(II)NO+ <-> Hb(III)NO" intermediate. This previously unrecognized NO hemoglobin species explains the stability of the intermediates and the buildup of a pool of potentially bioactive NO during nitrite reduction. It also provides a pathway for the formation of beta-93 cysteine S-nitrosylated hemoglobin [SNOHb:S-nitrosohemoglobin], which has been shown to induce vasodilation, by a rapid radical radical-reaction of any free NO with the thiyl radical of this new paramagnetic intermediate. C1 [Salgado, Maria T.; Ramasamy, Somasundararn; Rifkind, Joseph M.] NIA, Mol Dynam Sect, NIH, Baltimore, MD 21224 USA. [Tsuneshige, Antonio] Hosei Univ, Fac Biosci & Appl Chem, Dept Frontier Biosci, Tokyo 1848584, Japan. [Manoharan, Periakaruppan T.] IIT Madras, Dept Chem SAIF, Madras 600036, Tamil Nadu, India. RP Rifkind, JM (reprint author), NIA, Mol Dynam Sect, NIH, Baltimore, MD 21224 USA. EM rifkindj@mail.nih.gov FU NIH, National Institute on Aging; DST, Government of India [SR/S1/RFIC-02-2006]; India Gandhi National Open University, New Delhi FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. We thank Dr. Antonio Tsuneshige for providing the semihemoglobins samples for this study and Dr. Manoharan for providing the spectra of T-state Hb(II)alpha NO and Hb(II)beta NO. Dr. Manoharan acknowledges the Ramanna Fellowship (SR/S1/RFIC-02-2006) from the DST, Government of India, and Sir C.V. Raman Chair Professorship from India Gandhi National Open University, New Delhi. NR 60 TC 12 Z9 13 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD AUG 24 PY 2011 VL 133 IS 33 BP 13010 EP 13022 DI 10.1021/ja1115088 PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA 816IG UT WOS:000294591300031 PM 21755997 ER PT J AU Kleykamp, BA Heishman, SJ AF Kleykamp, Bethea A. Heishman, Stephen J. TI The Older Smoker SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID SMOKING-CESSATION; UNITED-STATES; ADULTS C1 [Kleykamp, Bethea A.] NIDA, Intramural Res Program, Nicotine Psychopharmacol Sect, NIH, Baltimore, MD 21224 USA. RP Kleykamp, BA (reprint author), NIDA, Intramural Res Program, Nicotine Psychopharmacol Sect, NIH, 251 Bayview Blvd,Ste 200, Baltimore, MD 21224 USA. EM annie.kleykamp@nih.gov FU Intramural NIH HHS [ZIA DA000483-08] NR 10 TC 9 Z9 9 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 AUG 24 PY 2011 VL 306 IS 8 BP 876 EP 877 DI 10.1001/jama.2011.1221 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 810VY UT WOS:000294157300027 PM 21862749 ER PT J AU Bell, AH Malecek, NJ Morin, EL Hadj-Bouziane, F Tootell, RBH Ungerleider, LG AF Bell, Andrew H. Malecek, Nicholas J. Morin, Elyse L. Hadj-Bouziane, Fadila Tootell, Roger B. H. Ungerleider, Leslie G. TI Relationship between Functional Magnetic Resonance Imaging-Identified Regions and Neuronal Category Selectivity SO JOURNAL OF NEUROSCIENCE LA English DT Article ID INFERIOR TEMPORAL CORTEX; POSTERIOR INFEROTEMPORAL CORTEX; DISTRIBUTED ORGANIZATION; OBJECT REPRESENTATIONS; BEHAVING MONKEYS; NEURAL RESPONSES; CONTRAST AGENT; BODY PARTS; MACAQUE; FACE AB Functional magnetic resonance imaging (fMRI) has been used extensively to identify regions in the inferiortemporal (IT) cortex that are selective for categories of visual stimuli. However, comparatively little is known about the neuronal responses relative to these fMRI-defined regions. Here, we compared in nonhuman primates the distribution and response properties of IT neurons recorded within versus outside fMRI regions selective for four different visual categories: faces, body parts, objects, and places. Although individual neurons that preferred each of the four categories were found throughout the sampled regions, they were most concentrated within the corresponding fMRI region, decreasing significantly within 1-4 mm from the edge of these regions. Furthermore, the correspondence between fMRI and neuronal distributions was specific to neurons that increased their firing rates in response to the visual stimuli but not to neurons suppressed by visual stimuli, suggesting that the processes associated with inhibiting neuronal activity did not contribute strongly to the fMRI signal in this experiment. C1 [Bell, Andrew H.; Malecek, Nicholas J.; Morin, Elyse L.; Hadj-Bouziane, Fadila; Tootell, Roger B. H.; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Tootell, Roger B. H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Tootell, Roger B. H.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Bell, AH (reprint author), MRC, Cognit & Brain Sci Unit, 15 Chaucer Rd, Cambridge CB2 7EF, England. EM andrew.bell@mrc-cbu.cam.ac.uk RI Hadj-Bouziane, Fadila/A-1180-2013; OI Bell, Andrew/0000-0001-8420-4622 FU National Institutes of Health [R01 MH67529, R01 EY017081]; Athinoula A. Martinos Center for Biomedical Imaging; National Center for Research Resources; National Institute of Mental Health FX This work was supported by National Institutes of Health Grants R01 MH67529 and R01 EY017081 (R.B.H.T.), the Athinoula A. Martinos Center for Biomedical Imaging, the National Center for Research Resources, and the National Institute of Mental Health Intramural Research Program (A.H.B., N.J.M., E.L.M., F.H-B., and L.G.U.). We thank the following individuals: Wim Vanduffel, Hauke Kolster, and Leeland Ekstrom for their invaluable assistance with the imaging experiments conducted while at Massachusetts General Hospital, and Lucy Guillory for her assistance with animal training and collection of the imaging data. NR 51 TC 47 Z9 47 U1 0 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 24 PY 2011 VL 31 IS 34 BP 12229 EP 12240 DI 10.1523/JNEUROSCI.5865-10.2011 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 811IU UT WOS:000294202900018 PM 21865466 ER PT J AU Steigelman, KA Lelli, A Wu, XD Gao, JG Lin, S Piontek, K Wodarczyk, C Boletta, A Kim, H Qian, F Germino, G Geleoc, GSG Holt, JR Zuo, J AF Steigelman, Katherine A. Lelli, Andrea Wu, Xudong Gao, Jiangang Lin, Susan Piontek, Klaus Wodarczyk, Claas Boletta, Alessandra Kim, Hyunho Qian, Feng Germino, Gregory Geleoc, Gwenaelle S. G. Holt, Jeffrey R. Zuo, Jian TI Polycystin-1 Is Required for Stereocilia Structure But Not for Mechanotransduction in Inner Ear Hair Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article ID KIDNEY-DISEASE; TRP CHANNELS; PKD1 GENE; IN-VIVO; TRANSDUCTION CHANNEL; SENSORY TRANSDUCTION; EPITHELIAL-CELLS; CYST FORMATION; TIP-LINK; PROTEIN AB The polycystic kidney disease-1 (Pkd1) gene encodes a large transmembrane protein (polycystin-1, or PC-1) that is reported to function as a fluid flow sensor in the kidney. As a member of the transient receptor potential family, PC-1 has also been hypothesized to play a role in the elusive mechanoelectrical transduction (MET) channel in inner ear hair cells. Here, we analyze two independent mouse models of PC-1, a knock-in (KI) mutant line and a hair cell-specific inducible Cre-mediated knock-out line. Both models exhibit normal MET channel function at neonatal ages despite hearing loss and ultrastructural abnormalities of sterecilia that remain properly polarized at adult ages. These findings demonstrate that PC-1 plays an essential role in stereocilia structure and maintenance but not directly in MET channel function or planar cell polarity. We also demonstrate that PC-1 is colocalized with F-actin in hair cell stereocilia in vivo, using a hemagglutinin-tagged PC-1 KI mouse model, and in renal epithelial cell microvilli in vitro. These results not only demonstrate a novel role for PC-1 in the cochlea, but also suggest insight into the development of polycystic kidney disease. C1 [Steigelman, Katherine A.; Wu, Xudong; Gao, Jiangang; Lin, Susan; Zuo, Jian] St Jude Childrens Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. [Steigelman, Katherine A.] Univ Tennessee, Ctr Hlth Sci, Dept Anat & Neurobiol, Memphis, TN 38163 USA. [Lelli, Andrea; Geleoc, Gwenaelle S. G.; Holt, Jeffrey R.] Univ Virginia, Dept Neurosci, Charlottesville, VA 22908 USA. [Piontek, Klaus; Kim, Hyunho; Qian, Feng; Germino, Gregory] Johns Hopkins Univ, Div Nephrol, Baltimore, MD 21205 USA. [Wodarczyk, Claas; Boletta, Alessandra] Dibit San Raffaele Sci Inst, Dulbecco Telethon Inst, I-20132 Milan, Italy. [Germino, Gregory] NIDDK, NIH, Bethesda, MD 20892 USA. RP Zuo, J (reprint author), St Jude Childrens Hosp, Dept Dev Biol, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM jian.zuo@stjude.org OI Germino, Gregory/0000-0002-3609-5588 FU NIH [1F31DC009393, DC06471, DC08800, CA21765, 5R25CA023944, DC006183, DC05439, DK062199, DK090868, DK48006]; American Lebanese Syrian Associated Charities; Hartwell Foundation; NIDDK; Johns Hopkins Polycystic Kidney Disease Research; Office of Naval Research [N000140911014]; Fondazione Telethon FX This work was supported by NIH Grants 1F31DC009393 (K.S.), DC06471 (J.Z.), DC08800 (J.Z.), CA21765 (J.Z.), 5R25CA023944 (S.L.), DC006183 (G.S.G.G.), DC05439 (J.R.H.), DK062199 (Q.F.), DK090868 (Q.F.), and DK48006 (G.G.), as well as the American Lebanese Syrian Associated Charities, The Hartwell Foundation (J.Z.), the Intramural Research Program of the NIDDK (G.G.), Johns Hopkins Polycystic Kidney Disease Research, and Office of Naval Research Grant N000140911014 (J.Z.). We thank Sharon Frase (St. Jude Children's Research Hospital, Memphis, TN), Rich Martens (University of Alabama, Tuscaloosa, AL), and Lou Boykins (University of Memphis, Memphis, TN) for their help and guidance with scanning electron microscopy images; Stefan Heller (Stanford University, Stanford, CA), Ulrich Mueller (Scripps Research Institute, La Jolla, CA), James Bartles (Northwestern, Evanston, IL), and Peter Gillespie (Oregon Hearing Research Center, Portland, OR) for sharing valuable reagents (antibodies and constructs); Stanislav S. Zakharenko (St. Jude Children's Research Hospital) for his discussion on protein colocalization; and the Zuo lab, especially Dr. Brandon C. Cox, for their helpful comments and suggestions. NR 60 TC 14 Z9 14 U1 0 U2 6 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 AUG 24 PY 2011 VL 31 IS 34 BP 12241 EP 12250 DI 10.1523/JNEUROSCI.6531-10.2011 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 811IU UT WOS:000294202900019 PM 21865467 ER PT J AU Abouyannis, M Menten, J Kiragga, A Lynen, L Robertson, G Castelnuovo, B Manabe, YC Reynolds, SJ Roberts, L AF Abouyannis, Michael Menten, Joris Kiragga, Agnes Lynen, Lutgarde Robertson, Gavin Castelnuovo, Barbara Manabe, Yukari C. Reynolds, Steven J. Roberts, Lesley TI Development and validation of systems for rational use of viral load testing in adults receiving first-line ART in sub-Saharan Africa SO AIDS LA English DT Article DE antiretroviral therapy; HIV; resource-constrained settings; treatment failure; Uganda; viral load ID RESOURCE-LIMITED SETTINGS; ANTIRETROVIRAL TREATMENT FAILURE; HIV-INFECTED ADULTS; IMMUNOLOGICAL CRITERIA; HIV-1-INFECTED ADULTS; DISCORDANT RESPONSES; VIROLOGICAL FAILURE; THERAPY FAILURE; CELL COUNT; MISCLASSIFICATION AB Background: World Health Organization (WHO) immunological and clinical criteria for monitoring first-line antiretroviral treatment (ART) offer low accuracy for predicting viral failure. Targeting viral load assays to those at high risk has been recommended and a system to do this has been developed in Cambodia. Systems for use in sub-Saharan African populations were evaluated. Methods: A new Ugandan-based scoring system for targeting viral load assays was developed from data from the first 4 years of a Ugandan cohort (N - 559) receiving first-line ART. The accuracy of this, the Cambodian system and the WHO criteria to predict viral failure, through targeting viral load assays, were compared in a separate population of 496 Ugandans. Results: The new Ugandan scoring system included CD4 cell count, mean cell volume, adherence, and HIV-associated clinical events as predictors of viral failure. In the validation population, the Ugandan system undertook viral load assays in 61 (12.3%) cases offering 20.5% sensitivity and 100% positive predictive value (PPV) to predict viral failure. The Cambodian system undertook viral load assays in 33 (6.7%) cases producing 23.1% sensitivity and 90.0% PPV. WHO criteria recommended viral load assays in 72 (14.5%) cases offering 30.8% sensitivity and 100% PPV. Conclusion: Locally developed algorithms based on clinical and immunological criteria may offer little additional accuracy over WHO criteria for targeting viral load assays. When possible, confirming viral load before switching therapy is recommended. Scoring systems are more flexible than WHO criteria in allowing ART providers to choose the proportion of the population that undergo targeted viral load testing. (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Abouyannis, Michael; Roberts, Lesley] Univ Birmingham, Birmingham B15 2TT, W Midlands, England. [Menten, Joris; Lynen, Lutgarde] Inst Trop Med, B-2000 Antwerp, Belgium. [Kiragga, Agnes; Robertson, Gavin; Castelnuovo, Barbara; Manabe, Yukari C.] Infect Dis Inst, Kampala, Uganda. [Manabe, Yukari C.; Reynolds, Steven J.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Reynolds, Steven J.] NIAID, NIH, Bethesda, MD 20892 USA. RP Roberts, L (reprint author), Univ Birmingham, Birmingham B15 2TT, W Midlands, England. EM l.m.roberts@bham.ac.uk RI Lynen, Lutgarde/A-1212-2014 OI Lynen, Lutgarde/0000-0001-7183-4895 FU College of Medical and Dental Sciences, University of Birmingham; Infectious Diseases Institute, Kampala, Uganda; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The study was undertaken in part-fulfilment of an intercalated BmedSc and M. A. was financially supported by the College of Medical and Dental Sciences, University of Birmingham in this work. Funding was also provided by the Infectious Diseases Institute, Kampala, Uganda and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. All other authors are employees of the institutions listed above and undertook activity as part of their core role or as an additional activity. NR 47 TC 18 Z9 18 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD AUG 24 PY 2011 VL 25 IS 13 BP 1627 EP 1635 DI 10.1097/QAD.0b013e328349a414 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 801MB UT WOS:000293441900008 PM 21673555 ER PT J AU Cadavid-Restrepo, G Gastardelo, TS Faudry, E de Almeida, H Bastos, IMD Negreiros, RS Lima, MM Assumpcao, TC Almeida, KC Ragno, M Ebel, C Ribeiro, BM Felix, CR Santana, JM AF Cadavid-Restrepo, Gloria Gastardelo, Thiago S. Faudry, Eric de Almeida, Hugo Bastos, Izabela M. D. Negreiros, Raquel S. Lima, Meire M. Assumpcao, Teresa C. Almeida, Keyla C. Ragno, Michel Ebel, Christine Ribeiro, Bergmann M. Felix, Carlos R. Santana, Jaime M. TI The major leucyl aminopeptidase of Trypanosoma cruzi (LAPTc) assembles into a homohexamer and belongs to the M17 family of metallopeptidases SO BMC BIOCHEMISTRY LA English DT Article ID MAMMALIAN-CELL INVASION; LEUCINE AMINOPEPTIDASE; PROLYL OLIGOPEPTIDASE; PARASITIC PROTOZOA; SEQUENCE ALIGNMENT; PROTEINASE; BRUCEI; PURIFICATION; PEPTIDASES; INFECTION AB Background: Pathogens depend on peptidase activities to accomplish many physiological processes, including interaction with their hosts, highlighting parasitic peptidases as potential drug targets. In this study, a major leucyl aminopeptidolytic activity was identified in Trypanosoma cruzi, the aetiological agent of Chagas disease. Results: The enzyme was isolated from epimastigote forms of the parasite by a two-step chromatographic procedure and associated with a single 330-kDa homohexameric protein as determined by sedimentation velocity and light scattering experiments. Peptide mass fingerprinting identified the enzyme as the predicted T. cruzi aminopeptidase EAN97960. Molecular and enzymatic analysis indicated that this leucyl aminopeptidase of T. cruzi (LAPTc) belongs to the peptidase family M17 or leucyl aminopeptidase family. LAPTc has a strong dependence on neutral pH, is mesophilic and retains its oligomeric form up to 80 degrees C. Conversely, its recombinant form is thermophilic and requires alkaline pH. Conclusions: LAPTc is a 330-kDa homohexameric metalloaminopeptidase expressed by all T. cruzi forms and mediates the major parasite leucyl aminopeptidolytic activity. Since biosynthetic pathways for essential amino acids, including leucine, are lacking in T. cruzi, LAPTc could have a function in nutritional supply. C1 [Cadavid-Restrepo, Gloria; Gastardelo, Thiago S.; de Almeida, Hugo; Negreiros, Raquel S.; Lima, Meire M.; Assumpcao, Teresa C.; Almeida, Keyla C.; Ribeiro, Bergmann M.; Felix, Carlos R.; Santana, Jaime M.] Univ Brasilia, Dept Cell Biol, BR-70910900 Brasilia, DF, Brazil. [Cadavid-Restrepo, Gloria] Univ Nacl Colombia, Dept Biosci, Nucleo El Volador, Medellin, Colombia. [Faudry, Eric; Ragno, Michel] INSERM, Biol Canc & Infect IRTSV CEA, UMR1036, Grenoble, France. [Faudry, Eric; Ragno, Michel] CNRS, Bacterial Pathogenesis & Cellular Responses ERL5, Grenoble, France. [Faudry, Eric; Ragno, Michel; Ebel, Christine] Univ Grenoble 1, Grenoble, France. [Bastos, Izabela M. D.] Univ Brasilia, Fac Ceilandia, BR-70910900 Brasilia, DF, Brazil. [Assumpcao, Teresa C.] NIH, Lab Malaria & Vector Res, Rockville, MD 20852 USA. [Ebel, Christine] CEA, Inst Biol Struct, F-38027 Grenoble, France. [Ebel, Christine] CNRS, UMR 5075, Inst Biol Struct, F-38027 Grenoble, France. RP Santana, JM (reprint author), Univ Brasilia, Dept Cell Biol, BR-70910900 Brasilia, DF, Brazil. EM jsantana@unb.br RI Faudry, Eric/I-9154-2014; RIBEIRO, BERGMANN/C-7114-2015; Santana, Jaime/H-5319-2013; OI de Almeida Silva, Hugo/0000-0003-3773-3251; Ribeiro, Bergmann/0000-0002-1061-196X FU CNPq; FINEP; FAP-DF; PRONEX; CAPES; UnB, Brazil FX We thank Dr Marcelo Valle de Sousa from The University of Brasilia for mass spectrometry analysis, and Aline Le Roy from the AUC and Protein Analysis On Line (PAOL) platforms of the Partnership for Structural Biology and the Institut de Biologie Structurale in Grenoble (PSB/IBS) for performing experiments and analysis. This work was supported by grants from CNPq, FINEP, FAP-DF, PRONEX, CAPES and UnB, Brazil. NR 48 TC 10 Z9 10 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2091 J9 BMC BIOCHEM JI BMC Boichem. PD AUG 23 PY 2011 VL 12 AR 46 DI 10.1186/1471-2091-12-46 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 824SL UT WOS:000295222300002 PM 21861921 ER PT J AU Key, TJ Appleby, PN Reeves, GK Roddam, AW Helzlsouer, KJ Alberg, AJ Rollison, DE Dorgan, JF Brinton, LA Overvad, K Kaaks, R Trichopoulou, A Clavel-Chapelon, F Panico, S Duell, EJ Peeters, PHM Rinaldi, S Riboli, E Fentiman, IS Dowsett, M Manjer, J Lenner, P Hallmans, G Baglietto, L English, DR Giles, GG Hopper, JL Severi, G Morris, HA Koenig, K Zeleniuch-Jacquotte, A Arslan, AA Toniolo, P Shore, RE Krogh, V Micheli, A Berrino, F Muti, P Barrett-Connor, E Laughlin, GA Kabuto, M Akiba, S Stevens, RG Neriishi, K Land, CE Cauley, JA Lui, LY Cummings, SR Gunter, MJ Rohan, TE Strickler, HD AF Key, T. J. Appleby, P. N. Reeves, G. K. Roddam, A. W. Helzlsouer, K. J. Alberg, A. J. Rollison, D. E. Dorgan, J. F. Brinton, L. A. Overvad, K. Kaaks, R. Trichopoulou, A. Clavel-Chapelon, F. Panico, S. Duell, E. J. Peeters, P. H. M. Rinaldi, S. Riboli, E. Fentiman, I. S. Dowsett, M. Manjer, J. Lenner, P. Hallmans, G. Baglietto, L. English, D. R. Giles, G. G. Hopper, J. L. Severi, G. Morris, H. A. Koenig, K. Zeleniuch-Jacquotte, A. Arslan, A. A. Toniolo, P. Shore, R. E. Krogh, V. Micheli, A. Berrino, F. Muti, P. Barrett-Connor, E. Laughlin, G. A. Kabuto, M. Akiba, S. Stevens, R. G. Neriishi, K. Land, C. E. Cauley, J. A. Lui, Li Yung Cummings, Steven R. Gunter, M. J. Rohan, T. E. Strickler, H. D. CA Endogenous Hormones Breast Canc TI Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; hormones; oestrogens; androgens; sex hormone-binding globulin ID LIFE-STYLE FACTORS; GROWTH-FACTOR-I; DEHYDROEPIANDROSTERONE-SULFATE; CIGARETTE-SMOKING; ESTRADIOL LEVELS; SERUM CONCENTRATIONS; ADRENAL ANDROGENS; BINDING GLOBULIN; STEROID-HORMONES; FAT DISTRIBUTION AB BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk. British Journal of Cancer (2011) 105, 709-722. doi:10.1038/bjc.2011.254 www.bjcancer.com Published online 19 July 2011 (C) 2011 Cancer Research UK C1 [Key, T. J.; Appleby, P. N.; Reeves, G. K.; Roddam, A. W.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Helzlsouer, K. J.; Alberg, A. J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Helzlsouer, K. J.] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Alberg, A. J.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Rollison, D. E.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Interdisciplinary Oncol, Tampa, FL 33682 USA. [Dorgan, J. F.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Dorgan, J. F.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Overvad, K.] Aarhus Univ Hosp, Dept Clin Epidemiol, DK-8000 Aarhus, Denmark. [Kaaks, R.] DKFZ, Heidelberg, Germany. [Trichopoulou, A.] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, WHO Collaborating Ctr Food & Nutr Policies, GR-11527 Athens, Greece. [Trichopoulou, A.] Hellen Hlth Fdn, Athens, Greece. [Clavel-Chapelon, F.] INSERM, Ctr Res Epidemiol & Populat, U1018, Villejuif, France. [Clavel-Chapelon, F.] Paris S Univ, UMRS1018, IGR, Villejuif, France. [Panico, S.] Univ Naples Federico II, Dept Clin & Expt Med, Naples, Italy. [Duell, E. J.] Catalan Inst Oncol, Unit Nutr Environm & Canc, Barcelona, Spain. [Peeters, P. H. M.] Univ Med Ctr, Julius Ctr, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Peeters, P. H. M.; Riboli, E.] Univ London Imperial Coll Sci Technol & Med, London, England. [Rinaldi, S.] Int Agcy Res Canc, F-69372 Lyon, France. [Fentiman, I. S.] Guys Hosp, London SE1 9RT, England. [Fentiman, I. S.] Inst Canc Res, Dept Biochem, London SW3 6JB, England. [Manjer, J.] Malmo Univ Hosp, Dept Surg, Malmo, Sweden. [Lenner, P.] Umea Univ, Dept Radiat Sci, Umea, Sweden. [Hallmans, G.] Umea Univ Hosp, Dept Clin Med & Publ Hlth, Umea, Sweden. [Baglietto, L.; English, D. R.; Giles, G. G.; Hopper, J. L.; Severi, G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Koenig, K.; Zeleniuch-Jacquotte, A.] NYU, Sch Med, Dept Environm Med, New York, NY USA. [Toniolo, P.] NYU, Sch Med, Dept Obstet & Gynecol, New York, NY USA. [Shore, R. E.] Radiat Effects Res Fdn, Hiroshima, Japan. [Krogh, V.; Micheli, A.; Berrino, F.] Fdn Ist Nazl Tumori, Milan, Italy. [Muti, P.] Ist Nazl Tumori Regina Elena, Rome, Italy. [Barrett-Connor, E.; Laughlin, G. A.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Kabuto, M.] Natl Inst Environm Studies, Environm Risk Res Div, Ibaraki, Japan. [Akiba, S.] Kagoshima Univ, Fac Med, Dept Publ Hlth, Kagoshima 890, Japan. [Stevens, R. G.] Univ Connecticut, Ctr Hlth, Dept Community Med, Farmington, CT USA. [Neriishi, K.] Radiat Effects Res Fdn, Dept Clin Studies, Hiroshima, Japan. [Land, C. E.] NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. [Cauley, J. A.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Lui, Li Yung; Cummings, Steven R.] Calif Pacific Med Ctr, San Francisco Coordinating Ctr, San Francisco, CA USA. [Lui, Li Yung; Cummings, Steven R.] San Francisco Coordinating Ctr, Study Osteoporot Fractures Res Grp, San Francisco, CA USA. [Gunter, M. J.; Rohan, T. E.; Strickler, H. D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. RP Key, TJ (reprint author), Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. EM tim.key@ceu.ox.ac.uk RI Morris, Howard/G-4564-2010; Perez , Claudio Alejandro/F-8310-2010; Clavel-Chapelon, Francoise/G-6733-2014; Brinton, Louise/G-7486-2015; Krogh, Vittorio/K-2628-2016; Panico, Salvatore/K-6506-2016; OI Giles, Graham/0000-0003-4946-9099; English, Dallas/0000-0001-7828-8188; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Tworoger, Shelley/0000-0002-6986-7046; Cauley, Jane A/0000-0003-0752-4408; Perez , Claudio Alejandro/0000-0001-9688-184X; Brinton, Louise/0000-0003-3853-8562; Krogh, Vittorio/0000-0003-0122-8624; Panico, Salvatore/0000-0002-5498-8312; Duell, Eric J/0000-0001-5256-0163; Micheli, Andrea/0000-0002-4558-4754 FU Cancer Research, UK [C570/A5028] FX We thank the women who participated, the research staff and the collaborating laboratories in each of the studies. This work was supported by Cancer Research, UK (C570/A5028) for the central pooling and analysis of the data; details of funding for the original studies are in the relevant publications. The funders of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report. The authors had full access to all the data and had final responsibility for the decision to submit the manuscript. NR 80 TC 116 Z9 118 U1 3 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD AUG 23 PY 2011 VL 105 IS 5 BP 709 EP 722 DI 10.1038/bjc.2011.254 PG 14 WC Oncology SC Oncology GA 811KG UT WOS:000294207800017 ER PT J AU Barsov, EV Trivett, MT Minang, JT Sun, HS Ohlen, C Ott, DE AF Barsov, Eugene V. Trivett, Matthew T. Minang, Jacob T. Sun, Haosi Ohlen, Claes Ott, David E. TI Transduction of SIV-Specific TCR Genes into Rhesus Macaque CD8(+) T Cells Conveys the Ability to Suppress SIV Replication SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RECEPTOR GENES; VIRAL ESCAPE; RETROVIRAL TRANSFER; CANCER REGRESSION; ADOPTIVE IMMUNOTHERAPY; EFFECTOR FUNCTIONS; IMMUNE ESCAPE; LYMPHOCYTES; THERAPY AB Background: The SIV/rhesus macaque model for HIV/AIDS is a powerful system for examining the contribution of T cells in the control of AIDS viruses. To better our understanding of CD8(+) T-cell control of SIV replication in CD4(+) T cells, we asked whether TCRs isolated from rhesus macaque CD8(+) T-cell clones that exhibited varying abilities to suppress SIV replication could convey their suppressive properties to CD8(+) T cells obtained from an uninfected/unvaccinated animal. Principal Findings: We transferred SIV-specific TCR genes isolated from rhesus macaque CD8(+) T-cell clones with varying abilities to suppress SIV replication in vitro into CD8(+) T cells obtained from an uninfected animal by retroviral transduction. After sorting and expansion, transduced CD8(+) T-cell lines were obtained that specifically bound their cognate SIV tetramer. These cell lines displayed appropriate effector function and specificity, expressing intracellular IFN gamma upon peptide stimulation. Importantly, the SIV suppression properties of the transduced cell lines mirrored those of the original TCR donor clones: cell lines expressing TCRs transferred from highly suppressive clones effectively reduced wild-type SIV replication, while expression of a non-suppressing TCR failed to reduce the spread of virus. However, all TCRs were able to suppress the replication of an SIV mutant that did not downregulate MHC-I, recapitulating the properties of their donor clones. Conclusions: Our results show that antigen-specific SIV suppression can be transferred between allogenic T cells simply by TCR gene transfer. This advance provides a platform for examining the contributions of TCRs versus the intrinsic effector characteristics of T-cell clones in virus suppression. Additionally, this approach can be applied to develop non-human primate models to evaluate adoptive T-cell transfer therapy for AIDS and other diseases. C1 [Barsov, Eugene V.; Trivett, Matthew T.; Minang, Jacob T.; Sun, Haosi; Ohlen, Claes; Ott, David E.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Barsov, EV (reprint author), NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21701 USA. EM ottde@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded 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 organization imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 12 Z9 12 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 23 PY 2011 VL 6 IS 8 AR e23703 DI 10.1371/journal.pone.0023703 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811YA UT WOS:000294253500025 PM 21886812 ER PT J AU Hwang, CI Matoso, A Corney, DC Flesken-Nikitin, A Korner, S Wang, W Boccaccio, C Thorgeirsson, SS Comoglio, PM Hermeking, H Nikitin, AY AF Hwang, Chang-Il Matoso, Andres Corney, David C. Flesken-Nikitin, Andrea Koerner, Stefanie Wang, Wei Boccaccio, Carla Thorgeirsson, Snorri S. Comoglio, Paolo M. Hermeking, Heiko Nikitin, Alexander Yu. TI Wild-type p53 controls cell motility and invasion by dual regulation of MET expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID OVARIAN-CANCER; MUTANT P53; C-MET; TRANSCRIPTIONAL ACTIVATION; SEROUS CARCINOMA; GENE-EXPRESSION; DOWN-REGULATION; SP1; GROWTH; MUTATIONS AB Recent observations suggest that p53 mutations are responsible not only for growth of primary tumors but also for their dissemination. However, mechanisms involved in p53-mediated control of cell motility and invasion remain poorly understood. By using the primary ovarian surface epithelium cell culture, we show that conditional inactivation of p53 or expression of its mutant forms results in overexpression of MET receptor tyrosine kinase, a crucial regulator of invasive growth. At the same time, cells acquire increased MET-dependent motility and invasion. Wild-type p53 negatively regulates MET expression by two mechanisms: (i) trans-activation of MET-targeting miR-34, and (ii) inhibition of SP1 binding to MET promoter. Both mechanisms are not functional in p53 absence, but mutant p53 proteins retain partial MET promoter suppression. Accordingly, MET overexpression, cell motility, and invasion are particularly high in p53-null cells. These results identify MET as a critical effector of p53 and suggest that inhibition of MET may be an effective antimetastatic approach to treat cancers with p53 mutations. These results also show that the extent of advanced cancer traits, such as invasion, may be determined by alterations in individual components of p53/MET regulatory network. C1 [Hwang, Chang-Il; Matoso, Andres; Corney, David C.; Flesken-Nikitin, Andrea; Nikitin, Alexander Yu.] Cornell Univ, Dept Biomed Sci, Ithaca, NY 14853 USA. [Wang, Wei] Cornell Univ, Microarray Core Facil, Ithaca, NY 14853 USA. [Koerner, Stefanie; Hermeking, Heiko] Univ Munich, Inst Pathol, D-80337 Munich, Germany. [Boccaccio, Carla; Comoglio, Paolo M.] Univ Turin, Sch Med, Div Mol Oncol, Inst Canc Res & Treatment, I-10060 Candiolo, Italy. [Thorgeirsson, Snorri S.] NCI, NIH, Expt Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Nikitin, AY (reprint author), Cornell Univ, Dept Biomed Sci, Ithaca, NY 14853 USA. EM an58@cornell.edu OI Hwang, Chang-il/0000-0002-5710-7672; Boccaccio, Carla/0000-0003-2620-9083; Comoglio, Paolo/0000-0002-7056-5328 FU National Institutes of Health [R01 CA96823, R01 CA112354]; Marsha Rivkin Center for Ovarian Cancer; College of Veterinary Medicine, Cornell University; Ovarian Cancer Research Fund FX We thank Dr. Elena N. Shmidt, Dr. Irina N. Trofimova, Jessica Eng, and Jane Ann for their technical help at the early stages of this project; Dr. Stephen J. Weiss for critical reading of this manuscript; and Dr. Anton Berns, Dr. Bert Vogelstein, and Dr. Samuel Mok for the generous gifts of the p53fl/fl and Rbfl/fl mice, CMV-mutant p53 constructs and plasmids PG13-luc and MG15-luc, and OVCA432 and OVCA433 cell lines, respectively. This work was supported by National Institutes of Health Grants R01 CA96823, R01 CA112354 and The Marsha Rivkin Center for Ovarian Cancer funding (to A.Y.N.); a Graduate Research Assistantship awarded by the College of Veterinary Medicine, Cornell University (to C.-I.H.); and a Postdoctoral Fellowship awarded by the Ovarian Cancer Research Fund (to A.M.). NR 49 TC 66 Z9 68 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 AUG 23 PY 2011 VL 108 IS 34 BP 14240 EP 14245 DI 10.1073/pnas.1017536108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 810XO UT WOS:000294163500074 PM 21831840 ER PT J AU Klepac, P Laxminarayan, R Grenfell, BT AF Klepac, Petra Laxminarayan, Ramanan Grenfell, Bryan T. TI Synthesizing epidemiological and economic optima for control of immunizing infections SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE eradication threshold; transboundary model; resource allocation ID QUANTITATIVE GUIDELINES; MEASLES ERADICATION; DISEASE; VACCINATION; EPIDEMICS; POLIO; SMALLPOX; METAPOPULATIONS; ELIMINATION; STRATEGIES AB Epidemic theory predicts that the vaccination threshold required to interrupt local transmission of an immunizing infection like measles depends only on the basic reproductive number R 0 and hence transmission rates. When the search for optimal strategies is expanded to incorporate economic constraints, the optimum for disease control in a single population is determined by relative costs of infection and control, rather than transmission rates. Adding a spatial dimension, which precludes local elimination unless it can be achieved globally, can reduce or increase optimal vaccination levels depending on the balance of costs and benefits. For weakly coupled populations, local optimal strategies agree with the global cost-effective strategy; however, asymmetries in costs can lead to divergent control optima in more strongly coupled systems-in particular, strong regional differences in costs of vaccination can preclude local elimination even when elimination is locally optimal. Under certain conditions, it is locally optimal to share vaccination resources with other populations. C1 [Klepac, Petra; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Laxminarayan, Ramanan] Princeton Univ, Princeton Environm Inst, Princeton, NJ 08544 USA. [Grenfell, Bryan T.] Princeton Univ, Woodrow Wilson Sch Publ & Int Affairs, Princeton, NJ 08544 USA. [Laxminarayan, Ramanan] Ctr Dis Dynam Econ & Policy, Washington, DC 20036 USA. [Laxminarayan, Ramanan] Publ Hlth Fdn India, New Delhi 110070, India. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Klepac, P (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM pklepac@alum.mit.edu FU Bill and Melinda Gates Foundation; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; United Nations Educational, Scientific, and Cultural Organization-L'Oreal for Women in Science Program FX This research was supported by the Bill and Melinda Gates Foundation, the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (B.G.). P. K. acknowledges support from the United Nations Educational, Scientific, and Cultural Organization-L'Oreal for Women in Science Program. NR 48 TC 29 Z9 30 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 23 PY 2011 VL 108 IS 34 BP 14366 EP 14370 DI 10.1073/pnas.1101694108 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 810XO UT WOS:000294163500095 PM 21825129 ER PT J AU Dulyaninova, NG Hite, KM Zencheck, WD Scudiero, DA Almo, SC Shoemaker, RH Bresnick, AR AF Dulyaninova, Natalya G. Hite, Karen M. Zencheck, Wendy D. Scudiero, Dominic A. Almo, Steven C. Shoemaker, Robert H. Bresnick, Anne R. TI Cysteine 81 Is Critical for the Interaction of S100A4 and Myosin-IIA SO BIOCHEMISTRY LA English DT Article ID METASTASIS-ASSOCIATED PROTEIN; CDC25 PHOSPHATASE INHIBITORS; CALCIUM-BINDING PROTEIN; CRYSTAL-STRUCTURE; HEAVY-CHAIN; VITAMIN-K; TARGET; PEPTIDE; FAMILY; POTENT AB Overexpression of S100A4, a member of the S100 family of Ca2+-binding proteins, is associated with a number of human pathologies, including fibrosis, inflammatory disorders, and metastatic disease. The identification of small molecules that disrupt S100A4/target interactions provides a mechanism for inhibiting S100A4-mediated cellular activities and their associated pathologies. Using an anisotropy assay that monitors the Ca2+-dependent binding of myosin-IIA to S100A4, NSC 95397 was identified as an inhibitor that disrupts the S100A4/myosin-IIA interaction and inhibits S100A4-mediated depolymerization of myosin-ILA filaments. Mass spectrometry demonstrated that NSC 95397 forms covalent adducts with Cys81 and Cys86, which are located in the canonical target binding cleft. Mutagenesis studies showed that covalent modification of just Cys81 is sufficient to inhibit S100A4 function with respect to myosin-IIA binding and depolymerization. Remarkably, substitution of Cys81 with serine or alanine significantly impaired the ability of S100A4 to promote myosin-IIA filament disassembly. As reversible covalent cysteine modifications have been observed for several S100 proteins, we propose that modification of Cys81 may provide an additional regulatory mechanism for mediating the binding of S100A4 to myosin-IIA. C1 [Dulyaninova, Natalya G.; Zencheck, Wendy D.; Almo, Steven C.; Bresnick, Anne R.] Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA. [Hite, Karen M.; Scudiero, Dominic A.] Natl Canc Inst Frederick, SAIC Frederick, Frederick, MD 21702 USA. [Shoemaker, Robert H.] Natl Canc Inst Frederick, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Natl Inst Hlth, Frederick, MD 21702 USA. RP Bresnick, AR (reprint author), Albert Einstein Coll Med, Dept Biochem, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM anne.bresnick@einstein.yu.edu FU National Institutes of Health [CA129598]; National Cancer Institute, National Institutes of Health [HHSN26120080001E] FX This work was supported in part with grants from the National Institutes of Health grant CA129598 (A.R.B.) and in part with funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN26120080001E. NR 46 TC 10 Z9 10 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 23 PY 2011 VL 50 IS 33 BP 7218 EP 7227 DI 10.1021/bi200853y PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809SD UT WOS:000294076100015 PM 21749055 ER PT J AU Nestorovich, EM Karginov, VA Popoff, MR Bezrukov, SM Barth, H AF Nestorovich, Ekaterina M. Karginov, Vladimir A. Popoff, Michel R. Bezrukov, Sergey M. Barth, Holger TI Tailored beta-Cyclodextrin Blocks the Translocation Pores of Binary Exotoxins from C. Botulinum and C. Perfringens and Protects Cells from Intoxication SO PLOS ONE LA English DT Article ID LIPID BILAYER-MEMBRANES; ANTHRAX TOXIN CHANNELS; SYMMETRICAL TETRAALKYLAMMONIUM IONS; FLUORESCENCE-ACTIVATED CYTOMETRY; VOLTAGE-DEPENDENT BLOCK; CURRENT NOISE-ANALYSIS; CLOSTRIDIUM-BOTULINUM; C2 TOXIN; IOTA-TOXIN; ADP-RIBOSYLTRANSFERASE AB Background: Clostridium botulinum C2 toxin and Clostridium perfringens iota toxin are binary exotoxins, which ADP-ribosylate actin in the cytosol of mammalian cells and thereby destroy the cytoskeleton. C2 and iota toxin consists of two individual proteins, an enzymatic active (A-) component and a separate receptor binding and translocation (B-) component. The latter forms a complex with the A-component on the surface of target cells and after receptor-mediated endocytosis, it mediates the translocation of the A-component from acidified endosomal vesicles into the cytosol. To this end, the B-components form heptameric pores in endosomal membranes, which serve as translocation channels for the A-components. Methodology/Principal Findings: Here we demonstrate that a 7-fold symmetrical positively charged beta-cyclodextrin derivative, per-6-S-(3-aminomethyl) benzylthio-beta-cyclodextrin, protects cultured cells from intoxication with C2 and iota toxins in a concentration-dependent manner starting at low micromolar concentrations. We discovered that the compound inhibited the pH-dependent membrane translocation of the A-components of both toxins in intact cells. Consistently, the compound strongly blocked transmembrane channels formed by the B-components of C2 and iota toxin in planar lipid bilayers in vitro. With C2 toxin, we consecutively ruled out all other possible inhibitory mechanisms showing that the compound did not interfere with the binding of the toxin to the cells or with the enzyme activity of the A-component. Conclusions/Significance: The described beta-cyclodextrin derivative was previously identified as one of the most potent inhibitors of the binary lethal toxin of Bacillus anthracis both in vitro and in vivo, implying that it might represent a broad-spectrum inhibitor of binary pore-forming exotoxins from pathogenic bacteria. C1 [Nestorovich, Ekaterina M.] Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. [Nestorovich, Ekaterina M.; Bezrukov, Sergey M.] NIH, Program Phys Biol, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Karginov, Vladimir A.] Innovat Biol Inc, Herndon, VA USA. [Popoff, Michel R.] Inst Pasteur, Dept Host Pathogen Interact, Paris, France. [Barth, Holger] Univ Ulm, Inst Pharmacol & Toxicol, Med Ctr, Ulm, Germany. RP Nestorovich, EM (reprint author), Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. EM holger.barth@uni-ulm.de RI Barth, Holger/E-7920-2013; Popoff, Michel/O-7719-2016 OI Popoff, Michel/0000-0001-9305-8989 FU Deutsche Forschungsgemeinschaft DFG [BA 2087/2-1]; Catholic University of America; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH; NIAID (National Institute of Allergy and Infectious Diseases) FX HB was financially supported by the Deutsche Forschungsgemeinschaft DFG (http://www.dfg.de/) (grant BA 2087/2-1). EMN was supported by startup funds from The Catholic University of America. EMN and SMB were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (http://www.nih.gov/) and NIAID (National Institute of Allergy and Infectious Diseases; http://www.niaid.nih.gov) Intramural Biodefense Research Grant for institutes other than NIAID (National Institute of Allergy and Infectious Diseases; http://www.niaid.nih.gov). VAK is an employee and shareholder of Innovative Biologics, Inc.; VAK provided the substance (beta-cyclodextrin derivative) for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 78 TC 18 Z9 18 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 22 PY 2011 VL 6 IS 8 AR e23927 DI 10.1371/journal.pone.0023927 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811XK UT WOS:000294251800041 PM 21887348 ER PT J AU Berezhkovskii, A Szabo, A AF Berezhkovskii, Alexander Szabo, Attila TI Time scale separation leads to position-dependent diffusion along a slow coordinate SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE diffusion; Markov processes; statistical mechanics ID DYNAMICS; BARRIER; FLUID AB When there is a separation of time scales, an effective description of the dynamics of the slow variables can be obtained by adiabatic elimination of fast ones. For example, for anisotropic Langevin dynamics in two dimensions, the conventional procedure leads to a Langevin equation for the slow coordinate that involves the potential of the mean force. The friction constant along this coordinate remains unchanged. Here, we show that a more accurate, but still Markovian, description of the slow dynamics can be obtained by using position-dependent friction that is related to the time integral of the autocorrelation function of the difference between the actual force and the mean force by a Kirkwood-like formula. The result is generalized to many dimensions, where the slow or reaction coordinate is an arbitrary function of the Cartesian coordinates. When the fast variables are effectively one-dimensional, the additional friction along the slow coordinate can be expressed in closed form for an arbitrary potential. For a cylindrically symmetric channel of varying cross section with winding centerline, our analytical expression immediately yields the multidimensional version of the Zwanzig-Bradley formula for the position-dependent diffusion coefficient. [doi:10.1063/1.3626215] C1 [Berezhkovskii, Alexander] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Szabo, Attila] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Berezhkovskii, A (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM berezh@mail.nih.gov RI Szabo, Attila/H-3867-2012 FU NIH, Center for Information Technology; National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Gerhard Hummer for his comments on the manuscript. This study was supported by the Intramural Research Program of the NIH, Center for Information Technology and National Institute of Diabetes and Digestive and Kidney Diseases. NR 18 TC 43 Z9 43 U1 1 U2 30 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 AUG 21 PY 2011 VL 135 IS 7 AR 074108 DI 10.1063/1.3626215 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 809NY UT WOS:000294065200012 PM 21861557 ER PT J AU Berezhkovskii, AM Szabo, A Zhou, HX AF Berezhkovskii, Alexander M. Szabo, Attila Zhou, Huan-Xiang TI Diffusion-influenced ligand binding to buried sites in macromolecules and transmembrane channels SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE biochemistry; biodiffusion; biomembranes; enzymes; macromolecules; molecular biophysics ID TIME-DEPENDENT RATE; ACTIVE-SITE; ORIENTATION CONSTRAINTS; PROTON CHANNEL; ASSOCIATION; MECHANISM; KINETICS; RECEPTORS; SURFACE AB We consider diffusion-influenced binding to a buried binding site that is connected to the surface by a narrow tunnel. Under the single assumption of an equilibrium distribution of ligands over the tunnel cross section, we reduce the calculation of the time-dependent rate coefficient to the solution of a one-dimensional diffusion equation with appropriate boundary conditions. We obtain a simple analytical expression for the steady-state rate that depends on the potential of mean force in the tunnel and the diffusion-controlled rate of binding to the tunnel entrance. Potential applications of our theory include substrate binding to a buried active site of an enzyme and permeant ion binding to an internal site in a transmembrane channel. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3609973] C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Szabo, Attila] Natl Inst Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Zhou, Huan-Xiang] Florida State Univ, Dept Phys, Tallahassee, FL 32306 USA. [Zhou, Huan-Xiang] Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM berezh@mail.nih.gov RI Szabo, Attila/H-3867-2012; Zhou, Huan-Xiang/M-5170-2016 OI Zhou, Huan-Xiang/0000-0001-9020-0302 FU NIH, Center for Information Technology; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health (NIH) [GM58187, AI23007] FX This study was supported by the Intramural Research Program of the NIH, Center for Information Technology and National Institute of Diabetes and Digestive and Kidney Diseases, and by grants GM58187 and AI23007 from the National Institutes of Health (NIH). NR 28 TC 11 Z9 11 U1 1 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 AUG 21 PY 2011 VL 135 IS 7 AR 075103 DI 10.1063/1.3609973 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 809NY UT WOS:000294065200041 PM 21861586 ER PT J AU Berezhkovskii, AM AF Berezhkovskii, Alexander M. TI Ordinary differential equation for local accumulation time SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE biochemistry; biological tissues; cellular biophysics; macromolecules; molecular biophysics; partial differential equations; reaction-diffusion systems ID MORPHOGEN GRADIENT; DIFFUSION AB Cell differentiation in a developing tissue is controlled by the concentration fields of signaling molecules called morphogens. Formation of these concentration fields can be described by the reaction-diffusion mechanism in which locally produced molecules diffuse through the patterned tissue and are degraded. The formation kinetics at a given point of the patterned tissue can be characterized by the local accumulation time, defined in terms of the local relaxation function. Here, we show that this time satisfies an ordinary differential equation. Using this equation one can straightforwardly determine the local accumulation time, i.e., without preliminary calculation of the relaxation function by solving the partial differential equation, as was done in previous studies. We derive this ordinary differential equation together with the accompanying boundary conditions and demonstrate that the earlier obtained results for the local accumulation time can be recovered by solving this equation. [doi:10.1063/1.3624898] C1 NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. FU National Institutes of Health (NIH), Center for Information Technology FX The author is grateful to Stas Shvartsman for numerous illuminating discussions of different aspects of the problem. This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), Center for Information Technology. NR 18 TC 8 Z9 8 U1 0 U2 3 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 AUG 21 PY 2011 VL 135 IS 7 AR 074112 DI 10.1063/1.3624898 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 809NY UT WOS:000294065200016 PM 21861561 ER PT J AU Woody, GE Metzger, DS AF Woody, George E. Metzger, David S. TI Injectable extended-release naltrexone for opioid dependence SO LANCET LA English DT Letter ID PHARMACOTHERAPIES C1 [Woody, George E.] Univ Penn, Philadelphia, PA 19106 USA. NIDA Clin Trials Network, Philadelphia, PA 19106 USA. RP Woody, GE (reprint author), Univ Penn, Philadelphia, PA 19106 USA. EM woody@tresearch.org NR 5 TC 5 Z9 5 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD AUG 20 PY 2011 VL 378 IS 9792 BP 664 EP 665 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 815EW UT WOS:000294509900022 PM 21856476 ER PT J AU Oza, AM Elit, L Tsao, MS Kamel-Reid, S Biagi, J Provencher, DM Gotlieb, WH Hoskins, PJ Ghatage, P Tonkin, KS Mackay, HJ Mazurka, J Sederias, J Ivy, P Dancey, JE Eisenhauer, EA AF Oza, Amit M. Elit, Laurie Tsao, Ming-Sound Kamel-Reid, Suzanne Biagi, Jim Provencher, Diane Michele Gotlieb, Walter H. Hoskins, Paul J. Ghatage, Prafull Tonkin, Katia S. Mackay, Helen J. Mazurka, John Sederias, Joana Ivy, Percy Dancey, Janet E. Eisenhauer, Elizabeth A. TI Phase II Study of Temsirolimus in Women With Recurrent or Metastatic Endometrial Cancer: A Trial of the NCIC Clinical Trials Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; MEDROXYPROGESTERONE ACETATE; MAMMALIAN TARGET; PTEN EXPRESSION; CARCINOMA; TAMOXIFEN; ADENOCARCINOMA; PACLITAXEL; MUTATIONS; TUMORS AB Purpose Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting. Patients and Methods Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles. Results In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome. Conclusion mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs. J Clin Oncol 29:3278-3285. (C) 2011 by American Society of Clinical Oncology C1 [Oza, Amit M.; Tsao, Ming-Sound; Kamel-Reid, Suzanne; Mackay, Helen J.] Univ Toronto, Princess Margaret Hosp, Univ Hlth Network, Toronto, ON M5G 2M9, Canada. [Sederias, Joana; Dancey, Janet E.; Eisenhauer, Elizabeth A.] Queens Univ, NCIC Clin Trials Grp, Kingston, ON, Canada. [Provencher, Diane Michele] Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Gotlieb, Walter H.] McGill Univ, Segal Canc Ctr, Montreal, PQ, Canada. [Hoskins, Paul J.] British Columbia Canc Agcy Vancouver Clin, Vancouver, BC, Canada. [Ghatage, Prafull] Tom Baker Canc Clin, Calgary, AB, Canada. [Tonkin, Katia S.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Ivy, Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Oza, AM (reprint author), Univ Toronto, Princess Margaret Hosp, Univ Hlth Network, 610 Univ Ave,Suite 5-700, Toronto, ON M5G 2M9, Canada. EM amit.oza@uhn.on.ca FU Canadian Cancer Society [021039] FX Supported by Grant No. 021039 from the Canadian Cancer Society to the NCIC Clinical Trials Group. Drugs were supplied by the Cancer Therapeutics Evaluation Program, National Cancer Institute, Bethesda, MD. NR 36 TC 136 Z9 140 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2011 VL 29 IS 24 BP 3278 EP 3285 DI 10.1200/JCO.2010.34.1578 PG 8 WC Oncology SC Oncology GA 808VD UT WOS:000294008500021 PM 21788564 ER PT J AU Pinsky, PF AF Pinsky, Paul F. TI Point Estimates of Number Needed to Treat/Screen Are Insufficient Without Characterization of Their Uncertainty SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 NCI, NIH, Bethesda, MD 20892 USA. RP Pinsky, PF (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 1 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2011 VL 29 IS 24 BP 3336 EP 3336 DI 10.1200/JCO.2011.36.4554 PG 1 WC Oncology SC Oncology GA 808VD UT WOS:000294008500034 PM 21768452 ER PT J AU Loeb, S Vonesh, EF Metter, EJ Carter, HB Gann, PH Catalona, WJ AF Loeb, Stacy Vonesh, Edward F. Metter, E. Jeffrey Carter, H. Ballentine Gann, Peter H. Catalona, William J. TI Point Estimates of Number Needed to Treat/Screen Are Insufficient Without Characterization of Their Uncertainty Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID MORTALITY C1 [Loeb, Stacy; Carter, H. Ballentine] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Vonesh, Edward F.; Catalona, William J.] NW Feinberg Sch Med, Chicago, IL USA. [Metter, E. Jeffrey] NIA, Baltimore, MD 21224 USA. [Gann, Peter H.] Univ Illinois, Chicago, IL USA. RP Loeb, S (reprint author), Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2011 VL 29 IS 24 BP 3337 EP 3337 DI 10.1200/JCO.2011.36.5395 PG 1 WC Oncology SC Oncology GA 808VD UT WOS:000294008500035 ER PT J AU Joo, JH Dorsey, FC Joshi, A Hennessy-Walters, KM Rose, KL McCastlain, K Zhang, J Iyengar, R Jung, CH Suen, DF Steeves, MA Yang, CY Prater, SM Kim, DH Thompson, CB Youle, RJ Ney, PA Cleveland, JL Kundu, M AF Joo, Joung Hyuck Dorsey, Frank C. Joshi, Aashish Hennessy-Walters, Kristin M. Rose, Kristie L. McCastlain, Kelly Zhang, Ji Iyengar, Rekha Jung, Chang Hwa Suen, Der-Fen Steeves, Meredith A. Yang, Chia-Ying Prater, Stephanie M. Kim, Do-Hyung Thompson, Craig B. Youle, Richard J. Ney, Paul A. Cleveland, John L. Kundu, Mondira TI Hsp90-Cdc37 Chaperone Complex Regulates Ulk1-and Atg13-Mediated Mitophagy SO MOLECULAR CELL LA English DT Article ID AUTOPHAGY INHIBITION; CANCER-TREATMENT; MOUSE MODELS; HSP90; MITOCHONDRIA; PARKIN; DEGRADATION; MUTATIONS; MECHANISM; DISEASE AB Autophagy, the primary recycling pathway of cells, plays a critical role in mitochondrial quality control under normal growth conditions and in the response to cellular stress. The Hsp90-Cdc37 chaperone complex coordinately regulates the activity of select kinases to orchestrate many facets of the stress response. Although both maintain mitochondrial integrity, the relationship between Hsp90-Cdc37 and autophagy has not been well characterized. Ulk1, one of the mammalian homologs of yeast Atg1, is a serine-threonine kinase required for mitophagy. Here we show that the interaction between Ulk1 and Hsp90-Cdc37 stabilizes and activates Ulk1, which in turn is required for the phosphorylation and release of Atg13 from Ulk1, and for the recruitment of Atg13 to damaged mitochondria. Hsp90-Cdc37, Ulk1, and Atg13 phosphorylation are all required for efficient mitochondrial clearance. These findings establish a direct pathway that integrates Ulk1- and Atg13-directed mitophagy with the stress response coordinated by Hsp90 and Cdc37. C1 [Joo, Joung Hyuck; Joshi, Aashish; Hennessy-Walters, Kristin M.; McCastlain, Kelly; Iyengar, Rekha; Kundu, Mondira] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA. [Zhang, Ji; Ney, Paul A.] St Jude Childrens Hosp, Dept Biochem, Memphis, TN 38105 USA. [Dorsey, Frank C.; Rose, Kristie L.; Steeves, Meredith A.; Prater, Stephanie M.; Cleveland, John L.] Scripps Res Inst Florida, Dept Canc Biol, Jupiter, FL 33458 USA. [Jung, Chang Hwa; Kim, Do-Hyung] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Suen, Der-Fen; Youle, Richard J.] NINDS, NIH, Bethesda, MD 20892 USA. [Yang, Chia-Ying; Thompson, Craig B.] Univ Penn, Abramson Family Canc Res Inst, Dept Canc Biol, Sch Med, Philadelphia, PA 19104 USA. RP Kundu, M (reprint author), St Jude Childrens Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM mondira.kundu@stjude.org OI Kim, Do-Hyung/0000-0002-2924-4370 FU National Institutes of Health [HL084199, CA123777, CA076379, DK074519, GM097057, CA099179]; NINDS; Burroughs Welcome Fund; American Society of Hematology; American Diabetes Association [ADA 7-07-CD-08]; monies from the State of Florida; monies from the American Lebanese Syrian Associated Charities (ALSAC) FX We are grateful to Charles J. Sherr (St. Jude Children's Research Hospital [SJCRH], Memphis, TN) for providing Cdc37 antibody; Emily Tresse (SJCRH) for the LPC-mCherry-EGFP-LC3b construct; Toshifumi Tomoda (Beckman Research Institute of City of Hope, Duarte, CA) for Flag-Ulk1 deletion constructs; Sharon Tooze (London Research Institute, Cancer Research UK, London, UK) for providing an Atg13 antibody; Mark Hall (The Scripps Research Institute [TSRI], Jupiter, Florida) for providing the MSCV-Gateway-IRES-GFP vector; Reuben Shaw (The Salk Institute for Biological Studies, La Jolla, CA) for providing ulk1-/- MEFs stably expressing ulk2 shRNA; Jennifer Moore (SJCRH) for assistance with generation of MEFs; Aaron Poole (SJCRH), Valerie Cavett (TSRI), Chunying Yang (TSRI), and Laura Alsina (TSRI) for technical support; the Proteomics Core facilities of Scripps Florida (TSRI) and the University of Pennsylvania; the Biomedical Imaging Core facilities at SJCRH (Samuel Connell, Jennifer Peters, and Sharon Erase) and University of Pennsylvania (Neelima Shaw and Ray Meade); and Robert Matts (Oklahoma State University) for helpful discussions. This research was partially supported by grants from the National Institutes of Health to M.K. (HL084199), F.C.D. (CA123777), J.L.C. (CA076379), P.A.N. (DK074519), D.-H.K. (GM097057), and C.B.T. (CA099179); the NINDS intramural program to R.Y; the Burroughs Welcome Fund to M.K.; the American Society of Hematology to M.K.; and the American Diabetes Association to D.-H.K. (ADA 7-07-CD-08); by monies from the State of Florida to J.L.C. at Scripps Florida; and by monies from the American Lebanese Syrian Associated Charities (ALSAC) to P.A.N. and M.K. NR 59 TC 79 Z9 82 U1 3 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 19 PY 2011 VL 43 IS 4 BP 572 EP 585 DI 10.1016/j.molcel.2011.06.018 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 810TW UT WOS:000294151000010 PM 21855797 ER PT J AU Acuna-Soto, R Viboud, C Chowell, G AF Acuna-Soto, Rodolfo Viboud, Cecile Chowell, Gerardo TI Influenza and Pneumonia Mortality in 66 Large Cities in the United States in Years Surrounding the 1918 Pandemic SO PLOS ONE LA English DT Article ID INCREASED SUSCEPTIBILITY; PNEUMOCOCCAL SURFACE; BACTERIAL PNEUMONIA; SPANISH INFLUENZA; EPIDEMIC; WAVE; SUPERINFECTION; INFECTION; PATTERNS; IMPACT AB The 1918 influenza pandemic was a major epidemiological event of the twentieth century resulting in at least twenty million deaths worldwide; however, despite its historical, epidemiological, and biological relevance, it remains poorly understood. Here we examine the relationship between annual pneumonia and influenza death rates in the pre-pandemic (1910-17) and pandemic (1918-20) periods and the scaling of mortality with latitude, longitude and population size, using data from 66 large cities of the United States. The mean pre-pandemic pneumonia death rates were highly associated with pneumonia death rates during the pandemic period (Spearman rho = 0.64-0.72; P < 0.001). By contrast, there was a weak correlation between pre-pandemic and pandemic influenza mortality rates. Pneumonia mortality rates partially explained influenza mortality rates in 1918 (rho = 0.34, P = 0.005) but not during any other year. Pneumonia death counts followed a linear relationship with population size in all study years, suggesting that pneumonia death rates were homogeneous across the range of population sizes studied. By contrast, influenza death counts followed a power law relationship with a scaling exponent of similar to 0.81 (95% CI: 0.71, 0.91) in 1918, suggesting that smaller cities experienced worst outcomes during the pandemic. A linear relationship was observed for all other years. Our study suggests that mortality associated with the 1918-20 influenza pandemic was in part predetermined by pre-pandemic pneumonia death rates in 66 large US cities, perhaps through the impact of the physical and social structure of each city. Smaller cities suffered a disproportionately high per capita influenza mortality burden than larger ones in 1918, while city size did not affect pneumonia mortality rates in the pre-pandemic and pandemic periods. C1 [Acuna-Soto, Rodolfo] Univ Nacl Autonoma Mexico, Fac Med, Dept Microbiol & Parasitol, Mexico City 04510, DF, Mexico. [Viboud, Cecile; Chowell, Gerardo] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Computat & Modeling Sci Ctr, Tempe, AZ USA. RP Acuna-Soto, R (reprint author), Univ Nacl Autonoma Mexico, Fac Med, Dept Microbiol & Parasitol, Mexico City 04510, DF, Mexico. EM acunasoto.rodolfo@gmail.com RI Chowell, Gerardo/F-5038-2012 OI Chowell, Gerardo/0000-0003-2194-2251 NR 31 TC 5 Z9 5 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 19 PY 2011 VL 6 IS 8 AR e23467 DI 10.1371/journal.pone.0023467 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 810LZ UT WOS:000294128100014 PM 21886792 ER PT J AU Zimmerberg, J Hess, ST AF Zimmerberg, Joshua Hess, Samuel T. TI Elongated Membrane Zones Boost Interactions of Diffusing Proteins SO CELL LA English DT Editorial Material C1 [Zimmerberg, Joshua] Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Hess, Samuel T.] Univ Maine, Dept Phys & Astron, Orono, ME 04469 USA. RP Zimmerberg, J (reprint author), Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM joshz@mail.nih.gov; sam.hess@umit.maine.edu NR 8 TC 2 Z9 2 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 19 PY 2011 VL 146 IS 4 BP 501 EP 503 DI 10.1016/j.cell.2011.08.003 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 809HY UT WOS:000294043600004 PM 21854976 ER PT J AU Voss, TC Schiltz, RL Sung, MH Yen, PM Stamatoyannopoulos, JA Biddie, SC Johnson, TA Miranda, TB John, S Hager, GL AF Voss, Ty C. Schiltz, R. Louis Sung, Myong-Hee Yen, Paul M. Stamatoyannopoulos, John A. Biddie, Simon C. Johnson, Thomas A. Miranda, Tina B. John, Sam Hager, Gordon L. TI Dynamic Exchange at Regulatory Elements during Chromatin Remodeling Underlies Assisted Loading Mechanism SO CELL LA English DT Article ID TRANSCRIPTION-FACTOR-BINDING; PROTEIN-DNA INTERACTIONS; CHIP-SEQ DATA; GLUCOCORTICOID-RECEPTOR; IN-VIVO; LIVING CELLS; ESTROGEN-RECEPTOR; GENE-EXPRESSION; SITES; ASSOCIATION AB The glucocorticoid receptor (GR), like other eukaryotic transcription factors, regulates gene expression by interacting with chromatinized DNA response elements. Photobleaching experiments in living cells indicate that receptors transiently interact with DNA on the time scale of seconds and predict that the response elements may be sparsely occupied on average. Here, we show that the binding of one receptor at the glucocorticoid response element (GRE) does not reduce the steady-state binding of another receptor variant to the same GRE. Mathematical simulations reproduce this noncompetitive state using short GR/GRE residency times and relatively long times between DNA binding events. At many genomic sites where GR binding causes increased chromatin accessibility, concurrent steady-state binding levels for the variant receptor are actually increased, a phenomenon termed assisted loading. Temporally sparse transcription factor-DNA interactions induce local chromatin reorganization, resulting in transient access for binding of secondary regulatory factors. C1 [Voss, Ty C.; Schiltz, R. Louis; Sung, Myong-Hee; Biddie, Simon C.; Johnson, Thomas A.; Miranda, Tina B.; John, Sam; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Yen, Paul M.] Duke Natl Univ Singapore, Cardiovasc & Metab Disorders Program, Lab Hormonal Regulat, Singapore 169857, Singapore. [Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,B602,41 Lib Dr, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov OI Biddie, Simon/0000-0002-8253-0253 FU NIH, National Cancer Institute, Center for Cancer Research; D.O.D.'s U.S. [W81XWH-06-1-0776] FX The authors thank Anindya Indrawan for general technical support of these experiments. Tatiana Karpova, manager of the NCI Fluorescence Imaging Core Facility), provided expert assistance for epifluorescence microscopy experiments. The resources of the NCI High-Throughput Imaging Facility (HiTIF) were also essential for the rapid completion of this study. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the D.O.D.'s U.S. Congressionally Directed Medical Research Programs Grant W81XWH-06-1-0776. NR 38 TC 122 Z9 122 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 19 PY 2011 VL 146 IS 4 BP 544 EP 554 DI 10.1016/j.cell.2011.07.006 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 809HY UT WOS:000294043600010 PM 21835447 ER PT J AU Lee, B Park, I Jin, S Choi, H Kwon, JT Kim, J Jeong, J Cho, BN Eddy, EM Cho, C AF Lee, Boyeon Park, Inju Jin, Sora Choi, Heejin Kwon, Jun Tae Kim, Jihye Jeong, Juri Cho, Byung-Nam Eddy, Edward M. Cho, Chunghee TI Impaired Spermatogenesis and Fertility in Mice Carrying a Mutation in the Spink2 Gene Expressed Predominantly in Testes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SERINE-PROTEASE INHIBITOR; PANCREATIC ACINAR-CELLS; TRYPSIN-INHIBITOR; MATRIX METALLOPROTEINASES; NETHERTON-SYNDROME; MOLECULAR-CLONING; AMINO-ACID; HUSI-II; KAZAL; APOPTOSIS AB Spermatogenesis is a complex process involving an intrinsic genetic program composed of germ cell-specific and -predominant genes. In this study, we investigated the mouse Spink2 (serine protease inhibitor Kazal-type 2) gene, which belongs to the SPINK family of proteins characterized by the presence of a Kazal-type serine protease inhibitor-pancreatic secretory trypsin inhibitor domain. We showed that recombinant mouse SPINK2 has trypsin-inhibitory activity. Distribution analyses revealed that Spink2 is transcribed strongly in the testis and weakly in the epididymis, but is not detected in other mouse tissues. Expression of Spink2 is specific to germ cells in the testis and is first evident at the pachytene spermatocyte stage. Immunoblot analyses demonstrated that SPINK2 protein is present in male germ cells at all developmental stages, including in testicular spermatogenic cells, testicular sperm, and mature sperm. To elucidate the functional role of SPINK2 in vivo, we generated mutant mice with diminished levels of SPINK2 using a gene trap mutagenesis approach. Mutant male mice exhibit significantly impaired fertility; further phenotypic analyses revealed that testicular integrity is disrupted, resulting in a reduction in sperm number. Moreover, we found that testes from mutant mice exhibit abnormal spermatogenesis and germ cell apoptosis accompanied by elevated serine protease activity. Our studies thus provide the first demonstration that SPINK2 is required for maintaining normal spermatogenesis and potentially regulates serine protease-mediated apoptosis in male germ cells. C1 [Lee, Boyeon; Park, Inju; Jin, Sora; Choi, Heejin; Kwon, Jun Tae; Kim, Jihye; Jeong, Juri; Cho, Chunghee] Gwangju Inst Sci & Technol, Sch Life Sci, Kwangju 500712, South Korea. [Cho, Byung-Nam] Catholic Univ Korea, Dept Sci, Puchon 420743, South Korea. [Eddy, Edward M.] NIEHS, Gamete Biol Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Cho, C (reprint author), Gwangju Inst Sci & Technol, Sch Life Sci, Kwangju 500712, South Korea. EM choch@gist.ac.kr FU Korea Science and Engineering Foundation [2010-0028776]; Korea Research Foundation [KRF-2008-313-C00736]; Gwangju Institute of Science and Technology Systems Biology Infrastructure Establishment FX This work was supported by Korea Science and Engineering Foundation Grant 2010-0028776, a Korea Research Foundation Grant KRF-2008-313-C00736, and a Gwangju Institute of Science and Technology Systems Biology Infrastructure Establishment Grant. NR 36 TC 12 Z9 14 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 19 PY 2011 VL 286 IS 33 BP 29108 EP 29117 DI 10.1074/jbc.M111.244905 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 806TY UT WOS:000293837000047 PM 21705336 ER PT J AU Van Duyne, R Guendel, I Narayanan, A Gregg, E Shafagati, N Tyagi, M Easley, R Klase, Z Nekhai, S Kehn-Hall, K Kashanchi, F AF Van Duyne, Rachel Guendel, Irene Narayanan, Aarthi Gregg, Edward Shafagati, Nazly Tyagi, Mudit Easley, Rebecca Klase, Zachary Nekhai, Sergei Kehn-Hall, Kylene Kashanchi, Fatah TI Varying Modulation of HIV-1 LTR Activity by BAF Complexes SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE chromatin remodeling; retrovirus; infection; phosphorylation; transcription ID CHROMATIN-REMODELING COMPLEX; TAT-ACTIVATED TRANSCRIPTION; ACTIN-RELATED PROTEIN; ESSENTIAL COFACTOR; P-TEFB; I TAT; C-MYC; PHOSPHORYLATION; IDENTIFICATION; TRANSFORMATION AB The human immunodeficiency virus type 1 (HIV-1) long terminal repeat is present on both ends of the integrated viral genome and contains regulatory elements needed for transcriptional initiation and elongation. Post-integration, a highly ordered chromatin structure consisting of at least five nucleosomes, is found at the 5' long terminal repeat, the location and modification state of which control the state of active viral replication as well as silencing of the latent HIV-1 provirus. In this context, the chromatin remodeling field rapidly emerges as having a critical role in the control of viral gene expression. In the current study, we focused on unique Baf subunits that are common to the most highly recognized of chromatin remodeling proteins, the SWI/SNF (switching-defective-sucrose non-fermenting) complexes. We find that at least two Baf proteins, Baf53 and Baf170, are highly regulated in HIV-1-infected cells. Previously, studies have shown that the depletion of Baf53 in uninfected cells leads to the expansion of chromosomal territories and the decompaction of the chromatin. Baf53, in the presence of HIV-1 infection, co-elutes off of a chromatographic column as a different-sized complex when compared to uninfected cells and appears to be predominantly phosphorylated. The innate function of Baf53-containing complexes appears to be transcriptionally suppressive, in that knocking down Baf53 increases viral gene expression from cells both transiently and chronically infected with HIV-1. Additionally, cdk9/cyclin T in the presence of Tat is able to phosphorylate Baf53 in vitro, implying that this posttranslationally modified form relieves the suppressive effect and allows for viral transcription to proceed. (c) 2011 Elsevier Ltd. All rights reserved. C1 [Van Duyne, Rachel; Guendel, Irene; Narayanan, Aarthi; Gregg, Edward; Shafagati, Nazly; Tyagi, Mudit; Easley, Rebecca; Kehn-Hall, Kylene; Kashanchi, Fatah] George Mason Univ, Natl Ctr Biodef & Infect Dis, Dept Mol & Microbiol, Manassas, VA 20110 USA. [Van Duyne, Rachel; Kashanchi, Fatah] George Washington Univ, Med Ctr, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA. [Klase, Zachary] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Nekhai, Sergei] Howard Univ, Dept Microbiol, Dept Med, Ctr Sickle Cell Dis, Washington, DC 20060 USA. RP Kashanchi, F (reprint author), George Mason Univ, Natl Ctr Biodef & Infect Dis, Dept Mol & Microbiol, Discovery Hall,Room 306,10900 Univ Blvd,MS 1H8, Manassas, VA 20110 USA. EM fkashanc@gmu.edu RI Kehn-Hall, Kylene/I-5752-2013 FU National Institutes of Health [AI078859, AI074410, AI043894] FX We would like to thank the members of the Kashanchi laboratory for experiments and assistance with the manuscript. Also, we are grateful to Dr. Lee Ratner for the HTLV-1 infectious clone and Dr. David Price for the generous gift of cdk9/cyclin T and cdk9/cyclin T and Tat. Most of the data on the manuscript were generated using funds from National Institutes of Health grants AI078859, AI074410, and AI043894. R.V.D. is a predoctoral student in the Microbiology and Immunology Program of the Institute for Biomedical Sciences at the George Washington University. NR 38 TC 17 Z9 17 U1 0 U2 1 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 AUG 19 PY 2011 VL 411 IS 3 BP 581 EP 596 DI 10.1016/j.jmb.2011.06.001 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 807YI UT WOS:000293938500007 PM 21699904 ER PT J AU Zhao, HY Brown, PH Magone, MT Schuck, P AF Zhao, Huaying Brown, Patrick H. Magone, M. Teresa Schuck, Peter TI The Molecular Refractive Function of Lens gamma-Crystallins SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE crystallin; protein structure function; protein refractive index; excluded volume ID GLUTATHIONE-S-TRANSFERASE; VERTEBRATE EYE LENS; SPORE COAT PROTEIN; X-RAY-ANALYSIS; STRUCTURAL PROTEIN; ALPHA-CRYSTALLIN; OCTOPUS LENS; AMINO-ACIDS; LACTATE-DEHYDROGENASE; GENE RECRUITMENT AB gamma-Crystallins constitute the major protein component in the nucleus of the vertebrate eye lens. Present at very high concentrations, they exhibit extreme solubility and thermodynamic stability to prevent scattering of light and formation of cataracts. However, functions beyond this structural role have remained mostly unclear. Here, we calculate molecular refractive index increments of crystallins. We show that all lens gamma-crystallins have evolved a significantly elevated molecular refractive index increment, which is far above those of most proteins, including nonlens members of the beta gamma-crystallin family from different species. The same trait has evolved in parallel in crystallins of different phyla, including S-crystallins of cephalopods. A high refractive index increment can lower the crystallin concentration required to achieve a suitable refractive power of the lens and thereby reduce their propensity to aggregate and form cataracts. To produce a significant increase in the refractive index increment, a substantial global shift in amino acid composition is required, which can naturally explain the highly unusual amino acid composition of gamma-crystallins and their functional homologues. This function provides a new perspective for interpreting their molecular structure. (c) 2011 Published by Elsevier Ltd. C1 [Zhao, Huaying; Magone, M. Teresa; Schuck, Peter] NIH, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, Bethesda, MD 20892 USA. [Brown, Patrick H.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Schuck, P (reprint author), NIH, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, Bldg 13,Room 3N17,13 South Dr, Bethesda, MD 20892 USA. EM schuckp@mail.nih.gov RI Zhao, Huaying/F-5716-2012; OI Schuck, Peter/0000-0002-8859-6966 FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX We thank Dr. Cu-Gang Chang for providing the coordinates from the homology model of octopus S-crystallin, Dr. Andor Kiss for providing some protein sequences, and Dr. Graeme Wistow for critically reading an initial draft of the manuscript. This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 126 TC 16 Z9 16 U1 2 U2 31 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 AUG 19 PY 2011 VL 411 IS 3 BP 680 EP 699 DI 10.1016/j.jmb.2011.06.007 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 807YI UT WOS:000293938500013 PM 21684289 ER PT J AU Tabak, LA Collins, FS AF Tabak, Lawrence A. Collins, Francis S. TI Weaving a Richer Tapestry in Biomedical Science SO SCIENCE LA English DT Editorial Material C1 [Tabak, Lawrence A.; Collins, Francis S.] NIH, Bethesda, MD 20892 USA. RP Tabak, LA (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM tabakl@mail.nih.gov; colllinsf@mail.nih.gov FU Intramural NIH HHS [Z99 OD999999] NR 12 TC 28 Z9 29 U1 0 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 19 PY 2011 VL 333 IS 6045 BP 940 EP 941 DI 10.1126/science.1211704 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 808TD UT WOS:000294000400030 PM 21852476 ER PT J AU Metcalf, CJE Graham, AL Huijben, S Barclay, VC Long, GH Grenfell, BT Read, AF Bjornstad, ON AF Metcalf, C. J. E. Graham, A. L. Huijben, S. Barclay, V. C. Long, G. H. Grenfell, B. T. Read, A. F. Bjornstad, O. N. TI Partitioning Regulatory Mechanisms of Within-Host Malaria Dynamics Using the Effective Propagation Number SO SCIENCE LA English DT Article ID BLOOD-STAGE MALARIA; PLASMODIUM-CHABAUDI; IMMUNE-RESPONSES; PARASITES; INFECTIONS; MODEL; ALPHA(+)-THALASSEMIA; COMPETITION; CHILDREN; ANEMIA AB Immune clearance and resource limitation (via red blood cell depletion) shape the peaks and troughs of malaria parasitemia, which in turn affect disease severity and transmission. Quantitatively partitioning the relative roles of these effects through time is challenging. Using data from rodent malaria, we estimated the effective propagation number, which reflects the relative importance of contrasting within-host control mechanisms through time and is sensitive to the inoculating parasite dose. Our analysis showed that the capacity of innate responses to restrict initial parasite growth saturates with parasite dose and that experimentally enhanced innate immunity can affect parasite density indirectly via resource depletion. Such a statistical approach offers a tool to improve targeting of drugs or vaccines for human therapy by revealing the dynamics and interactions of within-host regulatory mechanisms. C1 [Metcalf, C. J. E.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Graham, A. L.; Grenfell, B. T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Huijben, S.; Barclay, V. C.; Read, A. F.; Bjornstad, O. N.] Penn State Univ, Ctr Infect Dis Dynam, State Coll, PA USA. [Long, G. H.] Univ Sheffield, Dept Anim & Plant Sci, Western Bank, Sheffield S10 2TN, S Yorkshire, England. [Grenfell, B. T.; Read, A. F.; Bjornstad, O. N.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Metcalf, CJE (reprint author), Univ Oxford, Dept Zool, S Parks Rd, Oxford OX1 3PS, England. EM charlotte.metcalf@zoo.ox.ac.uk RI Graham, Andrea/A-8808-2010; Long, Grainne/B-3635-2012; Bjornstad, Ottar/I-4518-2012 OI Graham, Andrea/0000-0002-6580-2755; Long, Grainne/0000-0001-5080-9885; FU Wellcome Trust; Darwin Trust of the University of Edinburgh; UK Biotechnology and Biological Sciences Research Council; National Institute of General Medical Sciences [R01GM089932] FX Our empirical work was funded by the Wellcome Trust (A.F.R., V.C.B., G.H.L.), the Darwin Trust of the University of Edinburgh (S.H.), and the UK Biotechnology and Biological Sciences Research Council (A.L.G., G.H.L.), and the theoretical work by the Bill and Melinda Gates Foundation (C.J.E.M., B.T.G., O.N.B.), the RAPIDD program of the Science and Technology Directorate (B.T.G., A.L.G., A.F.R.), and National Institute of General Medical Sciences grant R01GM089932 (B.G., O.N.B., A.F.R.). We thank N. Mideo and P. Klepac for extensive discussion. All authors discussed the results and implications and commented on the manuscript at all stages. C.J.E.M. and O.N.B. developed the statistical approach; A.F.R., V.B., and S.H. designed and performed the dose-dependent and CD4+ T cell-depleted mice experiments; A.L.G. and G.H.L. designed and performed the innate immunity experiments. The authors declare no competing interests. NR 43 TC 36 Z9 36 U1 6 U2 28 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 19 PY 2011 VL 333 IS 6045 BP 984 EP 988 DI 10.1126/science.1204588 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 808TD UT WOS:000294000400047 PM 21852493 ER PT J AU Ginther, DK Schaffer, WT Schnell, J Masimore, B Liu, FY Haak, LL Kington, R AF Ginther, Donna K. Schaffer, Walter T. Schnell, Joshua Masimore, Beth Liu, Faye Haak, Laurel L. Kington, Raynard TI Race, Ethnicity, and NIH Research Awards SO SCIENCE LA English DT Article AB We investigated the association between a U. S. National Institutes of Health (NIH) R01 applicant's self-identified race or ethnicity and the probability of receiving an award by using data from the NIH IMPAC II grant database, the Thomson Reuters Web of Science, and other sources. Although proposals with strong priority scores were equally likely to be funded regardless of race, we find that Asians are 4 percentage points and black or African-American applicants are 13 percentage points less likely to receive NIH investigator-initiated research funding compared with whites. After controlling for the applicant's educational background, country of origin, training, previous research awards, publication record, and employer characteristics, we find that black applicants remain 10 percentage points less likely than whites to be awarded NIH research funding. Our results suggest some leverage points for policy intervention. C1 [Ginther, Donna K.] Univ Kansas, Inst Policy & Social Res, Dept Econ, Lawrence, KS 66045 USA. [Ginther, Donna K.] Univ Kansas, Inst Policy & Social Res, Ctr Sci Technol & Econ Policy, Lawrence, KS 66045 USA. [Schaffer, Walter T.; Kington, Raynard] NIH, Bethesda, MD 20892 USA. [Schnell, Joshua; Masimore, Beth; Liu, Faye; Haak, Laurel L.] Thomson Reuters, Discovery Log, Rockville, MD 20850 USA. RP Ginther, DK (reprint author), Univ Kansas, Inst Policy & Social Res, Dept Econ, Lawrence, KS 66045 USA. EM dginther@ku.edu RI Schaffer, Walter/E-5982-2010; Haak, Laurel/C-4986-2008; Schnell, Joshua/J-4000-2012; Ginther, Donna/F-7317-2016 OI Schaffer, Walter/0000-0002-2276-4656; Haak, Laurel/0000-0001-5109-3700; Schnell, Joshua/0000-0001-9241-7441; Ginther, Donna/0000-0002-0881-7969 FU NSF [SES-0353703]; NIH [1R01AG36820-01, HHSN276200800458U, HHSN276200900100U, 07-6008 OD OER] FX D.K.G. acknowledges financial support from NSF grant SES-0353703 and NIH grant 1R01AG36820-01. D. K. G. and Discovery Logic, a Thomson Reuters company, acknowledge support from NIH contracts HHSN276200800458U and HHSN276200900100U, made possible through an NIH Evaluation Set-Aside Award to W. T. S. (07-6008 OD OER). We thank C. Bollinger, S. Kahn, and W. McGarvey for helpful discussions. The analytical files used in the studies described here contain personal information from individuals who have submitted applications and in some cases have received awards from NIH. Many of these application records have been matched to records included in the Survey of Earned Doctorates as maintained by the National Science Foundation and to records included in the Faculty Roster maintained by the Association of American Medical Colleges. The information is therefore protected by the Privacy Act of 1974 as amended (5 U. S. C. 552a) and the National Science Foundation Act of 1950 as amended (42 U. S. C. 1873(i). More complete information can be found in the NSF/SRS Restricted-Use Data Procedures Guide available at www.nsf.gov/statistics/license/forms/pdf/srs_license_guide_august_2008.p df and the NSF Data and Tools Web site at www.nsf.gov/statistics/database.cfm. Researchers interested in access should call W. T. S. at 301-402-2725 to discuss the security clearance requirements necessary for using the data. A de-identified version of the data files will be posted at http://report.nih.gov/investigators_and_trainees/index.aspx and archived by Science. NR 9 TC 123 Z9 123 U1 3 U2 42 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 19 PY 2011 VL 333 IS 6045 BP 1015 EP 1019 DI 10.1126/science.1196783 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 808TD UT WOS:000294000400055 PM 21852498 ER PT J AU Solomon, DA Kim, T Diaz-Martinez, LA Fair, J Elkahloun, AG Harris, BT Toretsky, JA Rosenberg, SA Shukla, N Ladanyi, M Samuels, Y James, CD Yu, HT Kim, JS Waldman, T AF Solomon, David A. Kim, Taeyeon Diaz-Martinez, Laura A. Fair, Joshlean Elkahloun, Abdel G. Harris, Brent T. Toretsky, Jeffrey A. Rosenberg, Steven A. Shukla, Neerav Ladanyi, Marc Samuels, Yardena James, C. David Yu, Hongtao Kim, Jung-Sik Waldman, Todd TI Mutational Inactivation of STAG2 Causes Aneuploidy in Human Cancer SO SCIENCE LA English DT Article ID TUMOR-SUPPRESSOR GENE; GLIOBLASTOMA-MULTIFORME; CHROMOSOME INSTABILITY; COPY NUMBER; COHESIN; HETEROZYGOSITY; TUMORIGENESIS; OVEREXPRESSION; EXPRESSION; GENOMES AB Most cancer cells are characterized by aneuploidy, an abnormal number of chromosomes. We have identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors. A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer. C1 [Solomon, David A.; Kim, Taeyeon; Fair, Joshlean; Toretsky, Jeffrey A.; Kim, Jung-Sik; Waldman, Todd] Georgetown Univ, Sch Med, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Diaz-Martinez, Laura A.; Yu, Hongtao] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. [Diaz-Martinez, Laura A.; Yu, Hongtao] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Elkahloun, Abdel G.; Samuels, Yardena] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Harris, Brent T.] Georgetown Univ, Sch Med, Dept Neurol, Washington, DC 20057 USA. [Harris, Brent T.] Georgetown Univ, Sch Med, Dept Pathol, Washington, DC 20057 USA. [Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Shukla, Neerav; Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [James, C. David] Univ Calif San Francisco, Helen Diller Comprehens Canc Ctr, Brain Tumor Res Ctr, Dept Neurol Surg, San Francisco, CA 94143 USA. RP Waldman, T (reprint author), Georgetown Univ, Sch Med, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. EM waldmant@georgetown.edu RI James, Charles/E-2721-2012; OI James, Charles/0000-0002-1027-203X; Diaz-Martinez, Laura/0000-0002-7226-7068 FU NIH [R01CA115699, R21CA143282]; SPORE grant [CA097257]; American Cancer Society [RSG0619101]; National Human Genome Research Institute, NIH FX We thank K. Creswell, S. Sen, and Applied Genetics Laboratories for technical assistance; and M. White and the Brain Tumor Tissue Bank of Canada, S. Baker, F. Bunz, J.-M. Peters, and the Children's Oncology Group for reagents and tumor samples. This research was supported by NIH grants R01CA115699 (T. W.), R21CA143282 (T. W.), SPORE grant CA097257 (C.D.J.), and American Cancer Society grant RSG0619101 (T. W.). Georgetown University has filed a patent application relating to the application of the mutations described in this work to the diagnosis and treatment of cancer. Y.S. is supported by the Intramural Research Programs of the National Human Genome Research Institute, NIH. Primer sequences are in table S6. For copy number arrays: the scanned array images and processed data sets have been deposited in the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo, dataset GSE13021). For expression microarrays: the scanned array images and processed data sets have been deposited in the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo, dataset GSE28214) NR 25 TC 187 Z9 188 U1 2 U2 14 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 19 PY 2011 VL 333 IS 6045 BP 1039 EP 1043 DI 10.1126/science.1203619 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 808TD UT WOS:000294000400062 PM 21852505 ER PT J AU Minor, RK Baur, JA Gomes, AP Ward, TM Csiszar, A Mercken, EM Abdelmohsen, K Shin, YK Canto, C Scheibye-Knudsen, M Krawczyk, M Irusta, PM Martin-Montalvo, A Hubbard, BP Zhang, YQ Lehrmann, E White, AA Price, NL Swindell, WR Pearson, KJ Becker, KG Bohr, VA Gorospe, M Egan, JM Talan, MI Auwerx, J Westphal, CH Ellis, JL Ungvari, Z Vlasuk, GP Elliott, PJ Sinclair, DA de Cabo, R AF Minor, Robin K. Baur, Joseph A. Gomes, Ana P. Ward, Theresa M. Csiszar, Anna Mercken, Evi M. Abdelmohsen, Kotb Shin, Yu-Kyong Canto, Carles Scheibye-Knudsen, Morten Krawczyk, Melissa Irusta, Pablo M. Martin-Montalvo, Alejandro Hubbard, Basil P. Zhang, Yongqing Lehrmann, Elin White, Alexa A. Price, Nathan L. Swindell, William R. Pearson, Kevin J. Becker, Kevin G. Bohr, Vilhelm A. Gorospe, Myriam Egan, Josephine M. Talan, Mark I. Auwerx, Johan Westphal, Christoph H. Ellis, James L. Ungvari, Zoltan Vlasuk, George P. Elliott, Peter J. Sinclair, David A. de Cabo, Rafael TI SRT1720 improves survival and healthspan of obese mice SO SCIENTIFIC REPORTS LA English DT Article ID SMALL-MOLECULE ACTIVATORS; SIRT1 ACTIVATION; MITOCHONDRIAL BIOGENESIS; LIFE-SPAN; CALORIE RESTRICTION; INSULIN SENSITIVITY; BILE-ACIDS; RESVERATROL; PROTECTS; PGC-1-ALPHA AB Sirt1 is an NAD1-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1a-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals. C1 [Minor, Robin K.; Ward, Theresa M.; Mercken, Evi M.; Irusta, Pablo M.; Martin-Montalvo, Alejandro; Pearson, Kevin J.; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Baur, Joseph A.] Univ Penn, Sch Med, Dept Physiol, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Gomes, Ana P.; Hubbard, Basil P.; Price, Nathan L.; Sinclair, David A.] Harvard Univ, Sch Med, Dept Pathol, Paul F Glenn Labs Biol Mech Aging, Boston, MA 02115 USA. [Csiszar, Anna; Ungvari, Zoltan] Univ Oklahoma, Hlth Sci Ctr, Dept Geriatr Med, Reynolds Oklahoma Ctr Aging, Oklahoma City, OK 73104 USA. [Abdelmohsen, Kotb; Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. [Shin, Yu-Kyong; White, Alexa A.; Egan, Josephine M.] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Canto, Carles; Auwerx, Johan] Ecole Polytech Fed Lausanne, LISP, CH-1015 Lausanne, Switzerland. [Scheibye-Knudsen, Morten; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Krawczyk, Melissa; Talan, Mark I.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Zhang, Yongqing; Lehrmann, Elin; Becker, Kevin G.] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA. [Irusta, Pablo M.] Georgetown Univ, Med Ctr, Dept Human Sci, Washington, DC 20007 USA. [Swindell, William R.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Pearson, Kevin J.] Univ Kentucky, Grad Ctr Nutr Sci, Lexington, KY 40536 USA. [Westphal, Christoph H.; Ellis, James L.; Vlasuk, George P.; Elliott, Peter J.] Sirtris, Cambridge, MA 02139 USA. RP de Cabo, R (reprint author), NIA, Lab Expt Gerontol, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM decabora@mail.nih.gov RI de Cabo, Rafael/J-5230-2016; Martin-Montalvo, Alejandro/C-2031-2017; OI Canto, Carles/0000-0002-5167-7922; de Cabo, Rafael/0000-0002-3354-2442; Martin-Montalvo, Alejandro/0000-0002-3886-5355; Lehrmann, Elin/0000-0002-9869-9475; Baur, Joseph/0000-0001-8262-6549; Scheibye-Knudsen, Morten/0000-0002-6637-1280; abdelmohsen, Kotb/0000-0001-6240-5810; Becker, Kevin/0000-0002-6794-6656; Sinclair, David/0000-0002-9936-436X; , rafael/0000-0003-2830-5693 FU NIH [R00AG031182]; NIA/NIH; Swiss National Science Foundation; ERC; Glenn Foundation for Medical Research FX This research was conducted under a Cooperative Research and Development Agreement (CRADA) between Sirtris, a GSK Company, and the National Institute on Aging, National Institutes of Health (NIA/NIH). Microarray data are archived under the accession number GSE19102. JAB is supported by NIH Pathway to Independence Award R00AG031182. We are grateful to Dawn Nines, Dawn Phillips and Justine Lucas for their excellent animal care. We also thank Larry Brant for help with data analyses and Olga Carlson for technical assistance. Funding was provided by the Intramural Research Program of the NIA/NIH, the Swiss National Science Foundation and the ERC Ideas program. Funding to DAS was provided by the NIH/NIA Extramural Research Program and the Glenn Foundation for Medical Research. NR 49 TC 91 Z9 94 U1 1 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD AUG 18 PY 2011 VL 1 AR 70 DI 10.1038/srep00070 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 835QT UT WOS:000296051600001 PM 22355589 ER PT J AU Crispino, G Di Pasquale, G Scimemi, P Rodriguez, L Ramirez, FG De Siati, RD Santarelli, RM Arslan, E Bortolozzi, M Chiorini, JA Mammano, F AF Crispino, Giulia Di Pasquale, Giovanni Scimemi, Pietro Rodriguez, Laura Ramirez, Fabian Galindo De Siati, Romolo Daniele Santarelli, Rosa Maria Arslan, Edoardo Bortolozzi, Mario Chiorini, John A. Mammano, Fabio TI BAAV Mediated GJB2 Gene Transfer Restores Gap Junction Coupling in Cochlear Organotypic Cultures from Deaf Cx26Sox10Cre Mice SO PLOS ONE LA English DT Article ID BOVINE ADENOASSOCIATED VIRUS; MAMMALIAN INNER-EAR; CONNEXIN 26; HEARING-LOSS; HEREDITARY DEAFNESS; DOMINANT DEAFNESS; STRIA VASCULARIS; ATP RELEASE; NULL MICE; EXPRESSION AB The deafness locus DFNB1 contains GJB2, the gene encoding connexin26 and GJB6, encoding connexin30, which appear to be coordinately regulated in the inner ear. In this work, we investigated the expression and function of connexin26 and connexin30 from postnatal day 5 to adult age in double transgenic Cx26(Sox10Cre) mice, which we obtained by crossing connexin26 floxed mice with a deleter Sox10-Cre line. Cx26(Sox10Cre) mice presented with complete connexin26 ablation in the epithelial gap junction network of the cochlea, whereas connexin30 expression was developmentally delayed; immunolabeling patterns for both connexins were normal in the cochlear lateral wall. In vivo electrophysiological measurements in Cx26(Sox10Cre) mice revealed profound hearing loss accompanied by reduction of endocochlear potential, and functional experiments performed in postnatal cochlear organotypic cultures showed impaired gap junction coupling. Transduction of these cultures with a bovine adeno associated virus vector restored connexin26 protein expression and rescued gap junction coupling. These results suggest that restoration of normal connexin levels by gene delivery via recombinant adeno associated virus could be a way to rescue hearing function in DFNB1 mouse models and, in future, lead to the development of therapeutic interventions in humans. C1 [Crispino, Giulia; Rodriguez, Laura; Ramirez, Fabian Galindo; Bortolozzi, Mario; Mammano, Fabio] Ist Veneto Med Mol, Fdn Ric Biomed Avanzata, Padua, Italy. [Crispino, Giulia; Rodriguez, Laura; Bortolozzi, Mario; Mammano, Fabio] Univ Padua, Dipartimento Fis G Galilei, Padua, Italy. [Di Pasquale, Giovanni; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Scimemi, Pietro; De Siati, Romolo Daniele; Santarelli, Rosa Maria; Arslan, Edoardo] Univ Padua, Dipartimento Specialita Med Chirurg, Padua, Italy. [Scimemi, Pietro; De Siati, Romolo Daniele; Santarelli, Rosa Maria; Arslan, Edoardo] Univ Padua, Serv Audiol, Padua, Italy. [Bortolozzi, Mario; Mammano, Fabio] Ist CNR Neurosci, Padua, Italy. RP Crispino, G (reprint author), Ist Veneto Med Mol, Fdn Ric Biomed Avanzata, Padua, Italy. EM fabio.mammano@unipd.it RI Mammano, Fabio/I-5064-2012; Bortolozzi, Mario/H-6872-2015; OI Mammano, Fabio/0000-0003-3751-1691; Bortolozzi, Mario/0000-0001-7198-9838; SCIMEMI, PIETRO/0000-0001-5273-1938 FU European Commission [LSHGCT20054512063]; Fondazione Cariparo; Telethon Italy [GGP09137]; Italian Ministry of Research [2007BZ4RX3_003] FX Supported by grants to FM from: The European Commission [FP6 Integrated Project EuroHear, grant number LSHGCT20054512063]; Fondazione Cariparo [Progetti di Eccellenza 2006-2007], Telethon Italy [grant number GGP09137], Italian Ministry of Research [PRIN 2007, grant number 2007BZ4RX3_003]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 17 Z9 18 U1 3 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 AUG 18 PY 2011 VL 6 IS 8 AR e23279 DI 10.1371/journal.pone.0023279 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 810LN UT WOS:000294126900016 PM 21876744 ER PT J AU Lindhurst, MJ Sapp, JC Teer, JK Johnston, JJ Finn, EM Peters, K Turner, J Cannons, JL Bick, D Blakemore, L Blumhorst, C Brockmann, K Calder, P Cherman, N Deardorff, MA Everman, DB Golas, G Greenstein, RM Kato, BM Keppler-Noreuil, KM Kuznetsov, SA Miyamoto, RT Newman, K Ng, D O'Brien, K Rothenberg, S Schwartzentruber, DJ Singhal, V Tirabosco, R Upton, J Wientroub, S Zackai, EH Hoag, K Whitewood-Neal, T Robey, PG Schwartzberg, PL Darling, TN Tosi, LL Mullikin, JC Biesecker, LG AF Lindhurst, Marjorie J. Sapp, Julie C. Teer, Jamie K. Johnston, Jennifer J. Finn, Erin M. Peters, Kathryn Turner, Joyce Cannons, Jennifer L. Bick, David Blakemore, Laurel Blumhorst, Catherine Brockmann, Knut Calder, Peter Cherman, Natasha Deardorff, Matthew A. Everman, David B. Golas, Gretchen Greenstein, Robert M. Kato, B. Maya Keppler-Noreuil, Kim M. Kuznetsov, Sergei A. Miyamoto, Richard T. Newman, Kurt Ng, David O'Brien, Kevin Rothenberg, Steven Schwartzentruber, Douglas J. Singhal, Virender Tirabosco, Roberto Upton, Joseph Wientroub, Shlomo Zackai, Elaine H. Hoag, Kimberly Whitewood-Neal, Tracey Robey, Pamela G. Schwartzberg, Pamela L. Darling, Thomas N. Tosi, Laura L. Mullikin, James C. Biesecker, Leslie G. TI A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MCCUNE-ALBRIGHT SYNDROME; TUMOR-SUPPRESSOR PTEN; GERMLINE MUTATION; LETHAL GENES; MICE; CELLS; LIPOMATOSIS; CHALLENGES; DEFECTS; GROWTH AB BACKGROUND The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. METHODS We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots. RESULTS Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G -> A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation. CONCLUSIONS The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.) C1 [Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Cherman, Natasha; Kuznetsov, Sergei A.; Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. [Schwartzentruber, Douglas J.] NCI, Bethesda, MD 20892 USA. [Darling, Thomas N.] Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. [Mullikin, James C.; Biesecker, Leslie G.] Natl Inst Hlth Intramural Sequencing Ctr, Rockville, MD USA. [Bick, David] Med Coll Wisconsin, Dept Pediat, Div Genet, Milwaukee, WI 53226 USA. [Blakemore, Laurel; Tosi, Laura L.] Childrens Natl Med Ctr, Div Orthopaed & Sports Med, Washington, DC 20010 USA. [Newman, Kurt] Childrens Natl Med Ctr, Dept Surg, Washington, DC 20010 USA. [Brockmann, Knut] Univ Gottingen, Dept Pediat & Pediat Neurol, Gottingen, Germany. [Calder, Peter; Tirabosco, Roberto] Royal Natl Orthopaed Hosp, Stanmore HA7 4LP, Middx, England. [Deardorff, Matthew A.; Zackai, Elaine H.] Childrens Hosp Philadelphia, Div Genet, Philadelphia, PA 19104 USA. [Everman, David B.] Greenwood Genet Ctr, Greenwood, SC 29646 USA. [Greenstein, Robert M.] Univ Connecticut, Dept Genet & Dev Biol, Hartford, CT USA. [Kato, B. Maya] Ear Inst, Palm Desert, CA USA. [Keppler-Noreuil, Kim M.] Univ Iowa, Dept Pediat, Div Genet, Iowa City, IA 52242 USA. [Miyamoto, Richard T.] Indiana Univ Purdue Univ, Dept Otolaryngol, Indianapolis, IN 46202 USA. [Rothenberg, Steven] Rocky Mt Hosp Children, Dept Pediat Surg, Denver, CO USA. [Singhal, Virender] Childrens Mercy Hosp & Clin, Dept Pediat Plast & Craniofacial Surg, Kansas City, MO USA. [Upton, Joseph] Childrens Hosp, Div Plast Surg, Boston, MA 02115 USA. [Wientroub, Shlomo] Tel Aviv Univ, Tel Aviv Med Ctr, Dana Childrens Hosp, Dept Pediat Orthopaed, IL-69978 Tel Aviv, Israel. [Hoag, Kimberly] Proteus Syndrome Fdn, Colorado Springs, CO USA. [Whitewood-Neal, Tracey] Proteus Syndrome Fdn UK, Bexhill On Sea, England. RP Biesecker, LG (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bldg 49,Rm 4A56, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov RI Robey, Pamela/H-1429-2011; OI Robey, Pamela/0000-0002-5316-5576; Darling, Thomas/0000-0002-5161-1974 FU National Human Genome Research Institute; Proteus Syndrome Foundation in the United States; Proteus Syndrome Foundation in the United Kingdom FX Supported by the Intramural Research Program of the National Human Genome Research Institute. The Proteus Syndrome Foundations in the United States and the United Kingdom contributed financial support for the sequencing. NR 35 TC 296 Z9 305 U1 2 U2 22 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 AUG 18 PY 2011 VL 365 IS 7 BP 611 EP 619 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 808ER UT WOS:000293960500008 PM 21793738 ER PT J AU Weiss, SA Bassett, DS Rubinstein, D Holroyd, T Apud, J Dickinson, D Coppola, R AF Weiss, Shennan Aibel Bassett, Danielle S. Rubinstein, Daniel Holroyd, Tom Apud, Jose Dickinson, Dwight Coppola, Richard TI Functional brain network characterization and adaptivity during task practice in healthy volunteers and people with schizophrenia SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE cognitive remediation; schizophrenia; magnetoencephalography; graph theory; synthetic aperture magnetometry; practice; beta band; high gamma ID SMALL-WORLD NETWORKS; COGNITIVE REMEDIATION; PITCH MEMORY; CORTICAL PLASTICITY; AUDITORY-STIMULI; CONTROLLED-TRIAL; WORKING-MEMORY; GAMMA-BAND; EEG DATA; CORTEX AB Cognitive remediation involves task practice and may improve deficits in people suffering from schizophrenia, but little is known about underlying neurophysiological mechanisms. In people with schizophrenia and controls, we used magnetoencephalography (MEG) to examine accuracy and practice-related changes in parameters indexing neural network structure and activity, to determine whether these might be useful assays of the efficacy of cognitive remediation. Two MEG recordings were acquired during performance of a tone discrimination task used to improve the acuity of auditory processing, before and after similar to 2.5 h of task practice. Accuracy before practice was negatively correlated with beta-band cost efficiency, a graph theoretical measure of network organization. Synthetic aperture magnetometry was used to localize brain oscillations with high spatial accuracy; results demonstrated sound and sensorimotor modulations of the beta band in temporo-parietal regions and the sensorimotor cortex respectively. High-gamma activity also correlated with sensorimotor processing during the task, with activation of auditory regions following sound stimulation, and activation of the left sensorimotor cortex preceding the button press. High-gamma power in the left frontal cortex was also found to correlate with accuracy. Following practice, sound-induced broad-band power in the left angular gyri increased. Accuracy improved and was found to correlate with increased mutual information (MI) between sensors in temporal-parietal regions in the beta band but not global cost efficiency. Based on these results, we conclude that hours of task practice can induce meso-scale changes such as increased power in relevant brain regions as well as changes in MI that correlate with improved accuracy. C1 [Weiss, Shennan Aibel] Columbia Univ, Dept Neurol, New York, NY 10027 USA. [Bassett, Danielle S.] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA. [Rubinstein, Daniel; Holroyd, Tom] NIMH, MEG Core Facil, Bethesda, MD 20892 USA. [Apud, Jose; Dickinson, Dwight; Coppola, Richard] NIMH, Clin Brain Disorder Branch, Bethesda, MD 20892 USA. RP Weiss, SA (reprint author), Columbia Univ, Dept Neurol, New York, NY 10027 USA. EM saw2164@columbia.edu FU NIMH FX This research was supported by the Intramural Research Program of the NIMH. NR 61 TC 6 Z9 7 U1 2 U2 11 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD AUG 17 PY 2011 VL 5 AR 81 DI 10.3389/fnhum.2011.00081 PG 14 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 814QO UT WOS:000294472200001 PM 21887140 ER PT J AU Cortini, R Kornyshev, AA Lee, DJ Leikin, S AF Cortini, Ruggero Kornyshev, Alexei A. Lee, Dominic J. Leikin, Sergey TI Electrostatic Braiding and Homologous Pairing of DNA Double Helices SO BIOPHYSICAL JOURNAL LA English DT Article ID COLI TOPOISOMERASE-IV; SUPERCOILED DNA; SINGLE-MOLECULE; II TOPOISOMERASES; FORCES; AGGREGATION; RECOMBINATION; SIMULATIONS; STABILITY; MECHANISM AB Homologous pairing and braiding (supercoiling) have crucial effects on genome organization, maintenance, and evolution. Generally, the pairing and braiding processes are discussed in different contexts, independently of each other. However, analysis of electrostatic interactions between DNA double helices suggests that in some situations these processes may be related. Here we present a theory of DNA braiding that accounts for the elastic energy of DNA double helices as well as for the chiral nature of the discrete helical patterns of DNA charges. This theory shows that DNA braiding may be affected, stabilized, or even driven by chiral electrostatic interactions. For example, electrostatically driven braiding may explain the surprising recent observation of stable pairing of homologous double-stranded DNA in solutions containing only monovalent salt. Electrostatic stabilization of left-handed braids may stand behind the chiral selectivity of type II topoisomerases and positive plasmid supercoiling in hyperthermophilic bacteria and archea. C1 [Cortini, Ruggero; Kornyshev, Alexei A.; Lee, Dominic J.] Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AY, England. [Leikin, Sergey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Phys Biochem, NIH, Bethesda, MD USA. RP Cortini, R (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AY, England. EM ruggero.cortini@gmail.com; a.kornyshev@imperial.ac.uk; domolee@hotmail.com; leikins@mail.nih.gov RI Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU United Kingdom Engineering and Physical Sciences Research Council [EP/H004319/1]; Human Frontiers Science Program [RGP0049/2010-C102]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the United Kingdom Engineering and Physical Sciences Research Council (grant No. EP/H004319/1), the Human Frontiers Science Program (grant No. RGP0049/2010-C102), and the Intramural research program of The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 55 TC 17 Z9 18 U1 2 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG 17 PY 2011 VL 101 IS 4 BP 875 EP 884 DI 10.1016/j.bpj.2011.06.058 PG 10 WC Biophysics SC Biophysics GA 810CS UT WOS:000294103600017 PM 21843478 ER PT J AU Piknova, B Kocharyan, A Schechter, AN Silva, AC AF Piknova, Barbora Kocharyan, Ara Schechter, Alan N. Silva, Afonso C. TI The role of nitrite in neurovascular coupling SO BRAIN RESEARCH LA English DT Article DE Cerebral blood flow; Functional hyperemia; Nitrite; Nitric oxide; Neurovascular coupling; nNOS inhibition ID CEREBRAL-BLOOD-FLOW; OXIDE SYNTHASE; NORMAL BRAIN; STIMULATION; RAT; HYPERCAPNIA; INHIBITION; HYPOXIA; DISEASE AB Nitric oxide (NO), a potent vasodilator and nontraditional neurotransmitter, is an important mediator of the changes in cerebral blood flow (CBF) associated with increased neuronal activity (neurovascular coupling). In the present work, we investigated the role of NO and of its newly recognized precursor, nitrite, in neurovascular coupling using a well-established rat model of somatosensory stimulation. Biological synthesis of NO of neuronal origin was inhibited pharmacologically. Following the initial uncoupling of neuronal and hemodynamic responses to somatosensory stimulation, the NO donor sodium nitroprusside, added within the range of physiological concentrations, significantly increased, but did not fully restore the functional CBF response. In contrast, nitrite at its physiological concentration fully recovered neurovascular coupling to its original magnitude. The magnitude of the effect is, however, dose-dependent. Sub-physiological concentrations of nitrite were not enough to entirely restore neurovascular coupling and supra-physiological concentrations acted more as a local vasodilator that changed resting CBF and interfered with the functional CBF response. These results suggest that nitrite can be efficiently converted into NO and utilized to support normal cerebrovascular physiology. Published by Elsevier B.V. C1 [Piknova, Barbora; Schechter, Alan N.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Kocharyan, Ara; Silva, Afonso C.] NINDS, NIH, Bethesda, MD 20892 USA. RP Piknova, B (reprint author), NIDDKD, NIH, 9000 Rockville Pike,Bldg 10,Rm 9N318, Bethesda, MD 20892 USA. EM piknovab@mail.nih.gov OI Schechter, Alan N/0000-0002-5235-9408 FU NIH; NINDS; NIDDK FX Authors would like to thank Xianfeng (Lisa) Zhang for her excellent technical assistance. This research was supported by the Intramural Research Program of the NIH, NINDS and NIDDK. NR 31 TC 15 Z9 15 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD AUG 17 PY 2011 VL 1407 BP 62 EP 68 DI 10.1016/j.brainres.2011.06.045 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 810QO UT WOS:000294142400006 PM 21764040 ER PT J AU Goldfeder, RL Parker, SCJ Ajay, SS Abaan, HO Margulies, EH AF Goldfeder, Rachel L. Parker, Stephen C. J. Ajay, Subramanian S. Abaan, Hatice Ozel Margulies, Elliott H. TI A Bioinformatics Approach for Determining Sample Identity from Different Lanes of High-Throughput Sequencing Data SO PLOS ONE LA English DT Article ID MAP AB The ability to generate whole genome data is rapidly becoming commoditized. For example, a mammalian sized genome (similar to 3Gb) can now be sequenced using approximately ten lanes on an Illumina HiSeq 2000. Since lanes from different runs are often combined, verifying that each lane in a genome's build is from the same sample is an important quality control. We sought to address this issue in a post hoc bioinformatic manner, instead of using upstream sample or "barcode" modifications. We rely on the inherent small differences between any two individuals to show that genotype concordance rates can be effectively used to test if any two lanes of HiSeq 2000 data are from the same sample. As proof of principle, we use recent data from three different human samples generated on this platform. We show that the distributions of concordance rates are non-overlapping when comparing lanes from the same sample versus lanes from different samples. Our method proves to be robust even when different numbers of reads are analyzed. Finally, we provide a straightforward method for determining the gender of any given sample. Our results suggest that examining the concordance of detected genotypes from lanes purported to be from the same sample is a relatively simple approach for confirming that combined lanes of data are of the same identity and quality. C1 [Goldfeder, Rachel L.; Parker, Stephen C. J.; Ajay, Subramanian S.; Abaan, Hatice Ozel; Margulies, Elliott H.] NHGRI, Genome Informat Sect, Technol Branch, NIH, Bethesda, MD 20892 USA. RP Goldfeder, RL (reprint author), NHGRI, Genome Informat Sect, Technol Branch, NIH, Bethesda, MD 20892 USA. EM emargulies@illumina.com FU National Human Genome Research Institute at the National Institutes of Health, USA FX This work was funded by the intramural research program of the National Human Genome Research Institute at the National Institutes of Health, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 11 TC 2 Z9 2 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 17 PY 2011 VL 6 IS 8 AR e23683 DI 10.1371/journal.pone.0023683 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 810JJ UT WOS:000294121300083 PM 21858207 ER PT J AU Lu, Y Ji, YY Ganesan, S Schloesser, R Martinowich, K Sun, M Mei, F Chao, MV Lu, B AF Lu, Yuan Ji, Yuanyuan Ganesan, Sundar Schloesser, Robert Martinowich, Keri Sun, Mu Mei, Fan Chao, Moses V. Lu, Bai TI TrkB as a Potential Synaptic and Behavioral Tag SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; PROTEIN-SYNTHESIS; LATE-PHASE; HIPPOCAMPAL-NEURONS; TYROSINE KINASE; MESSENGER-RNAS; RECEPTOR TRKB; BDNF; PLASTICITY; LTP AB Late-phase long-term potentiation (L-LTP), a cellular model for long-term memory (LTM), requires de novo protein synthesis. An attractive hypothesis for synapse specificity of long-term memory is "synaptic tagging": synaptic activity generates a tag, which "captures" the PRPs (plasticity-related proteins) derived outside of synapses. Here we provide evidence that TrkB, the receptor of BDNF (brain-derived neurotrophic factor), may serve as a "synaptic tag." TrkB is transiently activated by weak theta-burst stimulation (TBS) that induces only early-phase LTP (E-LTP). This TrkB activation is independent of protein synthesis, and confined to stimulated synapses. Induction of L-LTP by strong stimulation in one synaptic pathway converts weak TBS-induced E-LTP to L-LTP in a second, independent pathway. Transient inhibition of TrkB around the time of weak TBS to the second pathway diminished L-LTP in that pathway without affecting the first one. Behaviorally, weak training, which induces short-term memory (STM) but not LTM, can be consolidated into LTM by exposing animals to novel but not familiar environment 1 h before training. Inhibition of TrkB during STM training blocked such consolidation. These results suggest TrkB as a potential tag for synapse-specific expression of L-LTP and LTM. C1 [Ji, Yuanyuan; Sun, Mu; Lu, Bai] GlaxoSmithKline Inc, R&D China, Shanghai 201203, Peoples R China. [Lu, Yuan; Martinowich, Keri; Lu, Bai] NIMH, Gene Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Ji, Yuanyuan; Ganesan, Sundar; Mei, Fan; Lu, Bai] NICHD, Sect Neural Dev & Plast, NIH, Bethesda, MD 20892 USA. [Schloesser, Robert; Martinowich, Keri] NIMH, Mood & Anxiety Program, NIH, Bethesda, MD 20892 USA. [Chao, Moses V.] NYU Med Ctr, Skirball Inst, New York, NY 10016 USA. RP Lu, B (reprint author), GlaxoSmithKline Inc, R&D China, Bldg 3,898 Halei Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China. EM bai.b.lu@gsk.com RI Lu, Bai/A-4018-2012; Mei, Fan/H-2665-2012; Sun, Mu/A-6772-2008; Martinowich, Keri/F-9841-2012; OI Sun, Mu/0000-0001-8261-3705; Martinowich, Keri/0000-0002-5237-0789; Chao, Moses/0000-0002-6969-3744 FU NIMH; NICHD; GSK RD China FX This work was supported by the Intramural Research Programs of NIMH and NICHD and by GSK R&D China. We thank Dr. David D. Ginty for providing the TrkBF616A knock-in mice. We also thank Drs. Kimberly M. Christian and KuanHong Wang for critical comments and constructive suggestions for this manuscript, and Shiyi Jin for assistance with the confocal microscopy. NR 43 TC 45 Z9 45 U1 0 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 17 PY 2011 VL 31 IS 33 BP 11762 EP 11771 DI 10.1523/JNEUROSCI.2707-11.2011 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 808CB UT WOS:000293950300004 PM 21849537 ER PT J AU Cheng, K Bai, L Belluscio, L AF Cheng, Kai Bai, Li Belluscio, Leonardo TI Fas-Associated Factor 1 as a Regulator of Olfactory Axon Guidance SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PROTEIN GAMMA-SUBUNIT; PARKINSONS-DISEASE; CASPASE ACTIVATION; SENSORY NEURONS; MARKER PROTEIN; APOPTOSIS; SYSTEM; MOUSE; FAF1; MAP AB Axon guidance is a crucial part of neural circuit formation. While precise axonal targeting forms the basis of accurate information delivery, the mechanisms that regulate this process are still unclear. Apoptotic signaling molecules have been identified in the axon terminal, but their specific role in axon guidance is not well understood. Here we use the mouse olfactory system as an in vivo model to demonstrate that by modulating Fas-associated factor 1 (FAF1), an apoptosis regulatory molecule, we can rewire axonal projections. Interestingly, FAF1 is highly expressed in the developing mouse olfactory system, but its expression is downregulated postnatally. Using a tetracycline-inducible promoter Tet-Off system, we generated transgenic mice in which FAF1 is specifically expressed in immature olfactory sensory neurons (OSNs) and show that overexpression of FAF1 not only misroutes OSN axons to deep layers of the olfactory bulb but also leads to widespread disruption of the glomerular layer. In addition, we also demonstrate that the specific convergence of P2 receptor OSN axons is completely distorted in the FAF1 mice. Strikingly, all of the mutant phenotypes can be recovered by shutting down FAF1 expression through the administration of doxycycline. Together, our study provides clear in vivo evidence that an apoptotic molecule can indeed regulate axon targeting and that OSNs can restore their organization even after broad disruption. C1 [Belluscio, Leonardo] Natl Inst Neurol Disorders & Stroke, Dev Neural Plast Unit, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Belluscio, L (reprint author), Natl Inst Neurol Disorders & Stroke, Dev Neural Plast Unit, Porter Neurosci Res Ctr, NIH, Bldg 35,Room 3A-116,35 Convent Dr,MSC 3703, Bethesda, MD 20892 USA. EM belluscl@ninds.nih.gov FU National Institutes of Health [1ZIANS003116-01] FX This work was supported by the National Institutes of Health, Intramural Research Program, Project 1ZIANS003116-01. We thank the Ryba laboratory for their generosity with transgenic lines, James Pickel at the National Institute of Mental Health Transgenic Facility for pronuclear injection and generation of TetO-FAF1 mice, and members of the Belluscio laboratory for helpful comments on the manuscript. NR 41 TC 5 Z9 6 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 AUG 17 PY 2011 VL 31 IS 33 BP 11905 EP 11913 DI 10.1523/JNEUROSCI.0053-11.2011 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 808CB UT WOS:000293950300018 PM 21849551 ER PT J AU Freedman, ND Silverman, DT Hollenbeck, AR Schatzkin, A Abnet, CC AF Freedman, Neal D. Silverman, Debra T. Hollenbeck, Albert R. Schatzkin, Arthur Abnet, Christian C. TI Association Between Smoking and Risk of Bladder Cancer Among Men and Women SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ACTIVE CIGARETTE-SMOKING; HONOLULU HEART PROGRAM; LUNG-CANCER; UNITED-STATES; REPRODUCTIVE FACTORS; PROSPECTIVE COHORT; PANCREATIC-CANCER; ADVENTIST HEALTH; HISTOLOGIC TYPE; POOLED ANALYSIS AB Context Previous studies indicate that the population attributable risk (PAR) of bladder cancer for tobacco smoking is 50% to 65% in men and 20% to 30% in women and that current cigarette smoking triples bladder cancer risk relative to never smoking. During the last 30 years, incidence rates have remained stable in the United States in men (123.8 per 100 000 person-years to 142.2 per 100 000 person-years) and women (32.5 per 100 000 person-years to 33.2 per 100 000 person-years); however, changing smoking prevalence and cigarette composition warrant revisiting risk estimates for smoking and bladder cancer. Objective To evaluate the association between tobacco smoking and bladder cancer. Design, Setting, and Participants Men (n=281 394) and women (n=186 134) of the National Institutes of Health-AARP (NIH-AARP) Diet and Health Study cohort completed a lifestyle questionnaire and were followed up between October 25, 1995, and December 31, 2006. Previous prospective cohort studies of smoking and incident bladder cancer were identified by systematic review and relative risks were estimated from fixed-effects models with heterogeneity assessed by the I-2 statistic. Main Outcome Measures Hazard ratios (HRs), PARs, and number needed to harm (NNH). Results During 4 518 941 person-years of follow-up, incident bladder cancer occurred in 3896 men (144.0 per 100 000 person-years) and 627 women (34.5 per 100 000 person-years). Former smokers (119.8 per 100 000 person-years; HR, 2.22; 95% confidence interval [CI], 2.03-2.44; NNH, 1250) and current smokers (177.3 per 100 000 person-years; HR, 4.06; 95% CI, 3.66-4.50; NNH, 727) had higher risks of bladder cancer than never smokers (39.8 per 100 000 person-years). In contrast, the summary risk estimate for current smoking in 7 previous studies (initiated between 1963 and 1987) was 2.94 (95% CI, 2.45-3.54; I-2=0.0%). The PAR for ever smoking in our study was 0.50 (95% CI, 0.45-0.54) in men and 0.52 (95% CI, 0.45-0.59) in women. Conclusion Compared with a pooled estimate of US data from cohorts initiated between 1963 and 1987, relative risks for smoking in the more recent NIH-AARP Diet and Health Study cohort were higher, with PARs for women comparable with those for men. C1 [Freedman, Neal D.; Silverman, Debra T.; Schatzkin, Arthur; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD 20852 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Freedman, ND (reprint author), NCI, 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 Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Florida Department of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry; from Georgia by the Georgia Center for Cancer Statistics; from California by the California Department of Health Services, Cancer Surveillance Section; from Michigan by the Michigan Cancer Surveillance Program; from Florida by the Florida Cancer Data System under contract to the Florida Department of Health; from Louisiana by the Louisiana Tumor Registry; from New Jersey by the New Jersey State Cancer Registry; from North Carolina by the North Carolina Central Cancer Registry; from Pennsylvania by the Division of Health Statistics and Research, Pennsylvania Department of Health; and from Texas by the Texas Cancer Registry. NR 57 TC 200 Z9 201 U1 2 U2 18 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 AUG 17 PY 2011 VL 306 IS 7 BP 737 EP 745 DI 10.1001/jama.2011.1142 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 807LP UT WOS:000293900000023 PM 21846855 ER PT J AU Thomas, JD Burke, TR AF Thomas, Joshua D. Burke, Terrence R., Jr. TI Application of a water-soluble pyridyl disulfide amine linker for use in Cu-free click bioconjugation SO TETRAHEDRON LETTERS LA English DT Article DE Bioconjugation; Cleavable linker; Cu-free click reaction; Pyridyl disulfide ID DELIVERY; GLUTATHIONE; PEPTIDE; CANCER; CELLS; LIGATION; CHAINS AB Described herein is the design and synthesis of a discrete heterobifunctional PEG-based pyridyl disulfide/amine-containing linker that can be used in the Cu-free click preparation of bioconjugates. The title PEG-based pyridyl disulfide amine linker is a potentially useful reagent for preparing water-soluble disulfide-linked cargos, and that it may be particularly valuable in expanding the field of Cu-free click-based bioconjugations to include reductively labile antibody, polymer, or nanoparticle-based drug conjugates. Published by Elsevier Ltd. C1 [Thomas, Joshua D.; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 FU NIH, Center for Cancer Research, NCI-Frederick; National Cancer Institute, National Institutes of Health FX This work was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick and the National Cancer Institute, National Institutes of Health. 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 26 TC 5 Z9 5 U1 1 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD AUG 17 PY 2011 VL 52 IS 33 BP 4316 EP 4319 DI 10.1016/j.tetlet.2011.06.042 PG 4 WC Chemistry, Organic SC Chemistry GA 801JX UT WOS:000293436100019 PM 21826118 ER PT J AU Rao, JS Kim, HW Kellom, M Greenstein, D Chen, M Kraft, AD Harry, GJ Rapoport, SI Basselin, M AF Rao, Jagadeesh Sridhara Kim, Hyung-Wook Kellom, Matthew Greenstein, Dede Chen, Mei Kraft, Andrew David Harry, Gaylia Jean Rapoport, Stanley Isaac Basselin, Mireille TI Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in brain of HIV-1 transgenic rats SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; CENTRAL-NERVOUS-SYSTEM; CYTOSOLIC PHOSPHOLIPASE A(2); EXPRESSING TNF-ALPHA; NEURONAL CELL-DEATH; ALZHEIMERS-DISEASE; NITRIC-OXIDE; NEUROCOGNITIVE IMPAIRMENT; COGNITIVE IMPAIRMENT AB Background: Cognitive impairment has been reported in human immune deficiency virus-1- (HIV-1-) infected patients as well as in HIV-1 transgenic (Tg) rats. This impairment has been linked to neuroinflammation, disturbed brain arachidonic acid (AA) metabolism, and synapto-dendritic injury. We recently reported upregulated brain AA metabolism in 7- to 9-month-old HIV-1 Tg rats. We hypothesized that these HIV-1 Tg rats also would show upregulated brain inflammatory and AA cascade markers and a deficit of synaptic proteins. Methods: We measured protein and mRNA levels of markers of neuroinflammation and the AA cascade, as well as pro-apoptotic factors and synaptic proteins, in brains from 7- to 9-month-old HIV-1 Tg and control rats. Results: Compared with control brain, HIV-1 Tg rat brain showed immunoreactivity to glycoprotein 120 and tat HIV-1 viral proteins, and significantly higher protein and mRNA levels of (1) the inflammatory cytokines interleukin-1 beta and tumor necrosis factor alpha, (2) the activated microglial/macrophage marker CD11b, (3) AA cascade enzymes: AA-selective Ca(2+)-dependent cytosolic phospholipase A(2) (cPLA(2))-IVA, secretory sPLA(2)-IIA, cyclooxygenase (COX)-2, membrane prostaglandin E(2) synthase, 5-lipoxygenase (LOX) and 15-LOX, cytochrome p450 epoxygenase, and (4) transcription factor NF-kappa Bp50 DNA binding activity. HIV-1 Tg rat brain also exhibited signs of cell injury, including significantly decreased levels of brain-derived neurotrophic factor (BDNF) and drebrin, a marker of post-synaptic excitatory dendritic spines. Expression of Ca(2+)-independent iPLA(2)-VIA and COX-1 was unchanged. Conclusions: HIV-1 Tg rats show elevated brain markers of neuroinflammation and AA metabolism, with a deficit in several synaptic proteins. These changes are associated with viral proteins and may contribute to cognitive impairment. The HIV-1 Tg rat may be a useful model for understanding progression and treatment of cognitive impairment in HIV-1 patients. C1 [Rao, Jagadeesh Sridhara; Kim, Hyung-Wook; Kellom, Matthew; Chen, Mei; Rapoport, Stanley Isaac; Basselin, Mireille] NIA, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. [Greenstein, Dede] NIMH, NIH, Bethesda, MD 20892 USA. [Kraft, Andrew David; Harry, Gaylia Jean] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Rao, JS (reprint author), NIA, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. EM jrao@mail.nih.gov FU National Institute on Aging; National Institute of Mental Health National Institutes of Health, Bethesda, MD; National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC FX This research was entirely supported by the Intramural Research Programs of the National Institute on Aging and the National Institute of Mental Health National Institutes of Health, Bethesda, MD, and the National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. We thank the NIH Fellows Editorial Board for editing the manuscript. NR 80 TC 39 Z9 40 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD AUG 16 PY 2011 VL 8 AR 101 DI 10.1186/1742-2094-8-101 PG 13 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 822MZ UT WOS:000295053500001 PM 21846384 ER PT J AU Solomon, BD AF Solomon, Benjamin D. TI VACTERL/VATER Association SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Review ID RESPIRATORY-CHAIN DEFICIENCY; GENOTYPE-PHENOTYPE CORRELATIONS; PRENATAL SONOGRAPHIC DIAGNOSIS; MULTIPLE CONGENITAL-ANOMALIES; RIGHT PULMONARY AGENESIS; PALLISTER-HALL-SYNDROME; TOWNES-BROCKS-SYNDROME; ACID RECEPTORS RARS; HOLT-ORAM-SYNDROME; VATER-ASSOCIATION AB VACTERL/VATER association is typically defined by the presence of at least three of the following congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. In addition to these core component features, patients may also have other congenital anomalies. Although diagnostic criteria vary, the incidence is estimated at approximately 1 in 10,000 to 1 in 40,000 live-born infants. The condition is ascertained clinically by the presence of the above-mentioned malformations; importantly, there should be no clinical or laboratory-based evidence for the presence of one of the many similar conditions, as the differential diagnosis is relatively large. This differential diagnosis includes (but is not limited to) Baller-Gerold syndrome, CHARGE syndrome, Currarino syndrome, deletion 22q11.2 syndrome, Fanconi anemia, Feingold syndrome, Fryns syndrome, MURCS association, oculo-auriculo-vertebral syndrome, Opitz G/BBB syndrome, Pallister-Hall syndrome, Townes-Brocks syndrome, and VACTERL with hydrocephalus. Though there are hints regarding causation, the aetiology has been identified only in a small fraction of patients to date, likely due to factors such as a high degree of clinical and causal heterogeneity, the largely sporadic nature of the disorder, and the presence of many similar conditions. New genetic research methods offer promise that the causes of VACTERL association will be better defined in the relatively near future. Antenatal diagnosis can be challenging, as certain component features can be difficult to ascertain prior to birth. The management of patients with VACTERL/VATER association typically centers around surgical correction of the specific congenital anomalies (typically anal atresia, certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae of the congenital malformations. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life. Importantly, patients with VACTERL association do not tend to have neurocognitive impairment. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Solomon, BD (reprint author), NHGRI, Med Genet Branch, NIH, Bldg 35,Room 1B-207, Bethesda, MD 20892 USA. EM solomonb@mail.nih.gov FU Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health and Human Services, United States of America FX This work 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 author would like to thank Dr. Maximilian Muenke for his support and mentorship, and would like to extend his deepest gratitude to the patients and families who have participated in research on VACTERL association. NR 114 TC 87 Z9 92 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD AUG 16 PY 2011 VL 6 AR 56 DI 10.1186/1750-1172-6-56 PG 12 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 817NC UT WOS:000294679500001 PM 21846383 ER PT J AU Peluso, CE Umulis, D Kim, YJ O'Connor, MB Serpe, M AF Peluso, Carolyn E. Umulis, David Kim, Young-Jun O'Connor, Michael B. Serpe, Mihaela TI Shaping BMP Morphogen Gradients through Enzyme-Substrate Interactions SO DEVELOPMENTAL CELL LA English DT Article ID SHORT GASTRULATION GENE; DROSOPHILA EMBRYO; TWISTED GASTRULATION; SOG; DPP; ANTAGONIST; PROTEINS; CHORDIN; TLD AB Bone morphogenetic proteins (BMPs) regulate dorsal/ventral (D/V) patterning across the animal kingdom; however, the biochemical properties of certain pathway components can vary according to species-specific developmental requirements. For example, Tolloid (Tld)-like metalloproteases cleave vertebrate BMP-binding proteins called Chordins constitutively, while the Drosophila Chordin ortholog, Short gastrulation (Sog), is only cleaved efficiently when bound to BMPs. We identified Sog characteristics responsible for making its cleavage dependent on BMP binding. "Chordin-like" variants that are processed independently of BMPs changed the steep BM P gradient found in Drosophila embryos to a shallower profile, analogous to that observed in some vertebrate embryos. This change ultimately affected cell fate allocation and tissue size and resulted in increased variability of patterning. Thus, the acquisition of BMP-dependent Sog processing during evolution appears to facilitate long-range ligand diffusion and formation of a robust morphogen gradient, enabling the bistable BMP signaling outputs required for early Drosophila patterning. C1 [Peluso, Carolyn E.; Kim, Young-Jun; Serpe, Mihaela] NICHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. [Umulis, David] Purdue Univ, Dept Agr & Biol Engn, W Lafayette, IN 47907 USA. [O'Connor, Michael B.] Univ Minnesota, Howard Hughes Med Inst, Minneapolis, MN 55455 USA. [O'Connor, Michael B.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. RP Serpe, M (reprint author), NICHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. EM serpemih@mail.nih.gov FU NIH; Showalter Trust FX We thank Osamu Shimmi for communicating unpublished information and Stuart Newfeld for comments on the manuscript. We thank Chi-Hon Lee and Alan Hinnebusch for helpful discussions and suggestions. We are grateful to Mary Jane Shimell for help in constructing the sog-HA transgene and to Seth Blair for Sog antibodies. We thank Peter Nguyen, Gabriel Peal, Jeremy Swan, and David Zhitomirsky for technical assistance. This work was supported in part by the Intramural Research Program at NIH. D.U. is supported by a grant from the Showalter Trust. M.B.O. is an Investigator with the Howard Hughes Medical Institute. NR 25 TC 20 Z9 20 U1 2 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD AUG 16 PY 2011 VL 21 IS 2 BP 375 EP 383 DI 10.1016/j.devcel.2011.06.025 PG 9 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 813RW UT WOS:000294387300017 PM 21839924 ER PT J AU Lamb, JS Chadwick, RS AF Lamb, Jessica S. Chadwick, Richard S. TI Dual Traveling Waves in an Inner Ear Model with Two Degrees of Freedom SO PHYSICAL REVIEW LETTERS LA English DT Article ID TECTORIAL MEMBRANE; COCHLEAR MECHANICS; DISTORTION; GAIN; 2ND AB We calculate traveling waves in the mammalian cochlea, which transduces acoustic vibrations into neural signals. We use a WKB-based mechanical model with both the tectorial membrane (TM) and basilar membrane (BM) coupled to the fluid to calculate motions along the length of the cochlea. This approach generates two wave numbers that manifest as traveling waves with different modes of motion between the BM and TM. The waves add differently on each mass, producing distinct tuning curves and different characteristic frequencies (CFs) for the TM and the BM. We discuss the effect of TM stiffness and coupling on the waves and tuning curves. We also consider how the differential motions between the masses could influence the cochlear amplifier and how mode conversion could take place in the cochlea. C1 [Lamb, Jessica S.; Chadwick, Richard S.] NIDCD, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. RP Lamb, JS (reprint author), NIDCD, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. FU National Institute on Deafness and other Communication Disorders [DC00033-15] FX This work was supported by the intramural program project DC00033-15 in the National Institute on Deafness and other Communication Disorders. We thank E. Dimitriadis and S. Smith for critical comments, and A. Hoofring for creating the illustration in Fig. 1(c). NR 20 TC 23 Z9 23 U1 0 U2 10 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD AUG 16 PY 2011 VL 107 IS 8 AR 088101 DI 10.1103/PhysRevLett.107.088101 PG 4 WC Physics, Multidisciplinary SC Physics GA 807SW UT WOS:000293921000026 PM 21929207 ER PT J AU Masedunskas, A Sramkova, M Parente, L Sales, KU Amornphimoltham, P Bugge, TH Weigert, R AF Masedunskas, Andrius Sramkova, Monika Parente, Laura Sales, Katiuchia Uzzun Amornphimoltham, Panomwat Bugge, Thomas H. Weigert, Roberto TI Role for the actomyosin complex in regulated exocytosis revealed by intravital microscopy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE in vivo imaging; cytoskeleton ID PAROTID ACINAR-CELLS; SECRETORY GRANULES; FUSION PORE; MYOSIN-II; COMPOUND EXOCYTOSIS; SALIVARY SECRETION; PROTEIN SECRETION; PANCREATIC ACINI; EPITHELIAL-CELLS; PLASMA-MEMBRANE AB The regulation and the dynamics of membrane trafficking events have been studied primarily in in vitro models that often do not fully reflect the functional complexity found in a living multicellular organism. Here we used intravital microscopy in the salivary glands of live rodents to investigate regulated exocytosis, a fundamental process in all of the secretory organs. We found that beta-adrenergic stimulation elicits exocytosis of large secretory granules, which gradually collapse with the apical plasma membrane without any evidence of compound exocytosis, as was previously described. Furthermore, we show that the driving force required to complete the collapse of the granules is provided by the recruitment of F-actin and nonmuscle myosin II on the granule membranes that is triggered upon fusion with the plasma membrane. Our results provide information on the machinery controlling regulated secretion and show that intravital microscopy provides unique opportunities to address fundamental questions in cell biology under physiological conditions. C1 [Masedunskas, Andrius; Sramkova, Monika; Parente, Laura; Amornphimoltham, Panomwat; Weigert, Roberto] Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, NIH, Bethesda, MD 20892 USA. [Sales, Katiuchia Uzzun; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Masedunskas, Andrius] Univ N Carolina, Dept Biol, Chapel Hill, NC 27514 USA. RP Weigert, R (reprint author), Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, NIH, Bethesda, MD 20892 USA. EM weigertr@mail.nih.gov OI Masedunskas, Andrius/0000-0002-4533-5467 FU National Institutes of Health, National Institute of Dental and Craniofacial Research FX We thank Drs. J. S. Gutkind, J. Donaldson, P. Randazzo, and M. J. Danton for critical reading of the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research. NR 45 TC 45 Z9 45 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 AUG 16 PY 2011 VL 108 IS 33 BP 13552 EP 13557 DI 10.1073/pnas.1016778108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 807KC UT WOS:000293895100043 PM 21808006 ER PT J AU Carbone, M Baris, YI Bertino, P Brass, B Comertpay, S Dogan, AU Gaudino, G Jube, S Kanodia, S Partridge, CR Pass, HI Rivera, ZS Steele, I Tuncer, M Way, S Yang, HN Miller, A AF Carbone, Michele Baris, Y. Izzettin Bertino, Pietro Brass, Brian Comertpay, Sabahattin Dogan, A. Umran Gaudino, Giovanni Jube, Sandro Kanodia, Shreya Partridge, Charles R. Pass, Harvey I. Rivera, Zeyana S. Steele, Ian Tuncer, Murat Way, Steven Yang, Haining Miller, Aubrey TI Erionite exposure in North Dakota and Turkish villages with mesothelioma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE asbestosis; cancer; carcinogenesis; environmental carcinogenesis; mineral fiber carcinogenesis ID MALIGNANT PLEURAL MESOTHELIOMA; ASBESTOS; TURKEY; CELLS; TRANSFORMATION; VERMICULITE; CONTACTS; MONTANA; ZEOLITE; WORKERS AB Exposure to erionite, an asbestos-like mineral, causes unprecedented rates of malignant mesothelioma (MM) mortality in some Turkish villages. Erionite deposits are present in at least 12 US states. We investigated whether increased urban development has led to erionite exposure in the United States and after preliminary exploration, focused our studies on Dunn County, North Dakota (ND). In Dunn County, ND, we discovered that over the past three decades, more than 300 miles of roads were surfaced with erionite-containing gravel. To determine potential health implications, we compared erionite from the Turkish villages to that from ND. Our study evaluated airborne point exposure concentrations, examined the physical and chemical properties of erionite, and examined the hallmarks of mesothelial cell transformation in vitro and in vivo. Airborne erionite concentrations measured in ND along roadsides, indoors, and inside vehicles, including school buses, equaled or exceeded concentrations in Boyali, where 6.25% of all deaths are caused by MM. With the exception of outdoor samples along roadsides, ND concentrations were lower than those measured in Turkish villages with MM mortality ranging from 20 to 50%. The physical and chemical properties of erionite from Turkey and ND are very similar and they showed identical biological activities. Considering the known 30- to 60-y latency for MM development, there is reason for concern for increased risk in ND in the future. Our findings indicate that implementation of novel preventive and early detection programs in ND and other erionite-rich areas of the United States, similar to efforts currently being undertaken in Turkey, is warranted. C1 [Carbone, Michele; Bertino, Pietro; Comertpay, Sabahattin; Gaudino, Giovanni; Jube, Sandro; Kanodia, Shreya; Rivera, Zeyana S.; Yang, Haining] Univ Hawaii, Ctr Canc, Honolulu, HI 96813 USA. [Baris, Y. Izzettin; Tuncer, Murat] Hacettepe Univ, TR-06500 Ankara, Turkey. [Brass, Brian; Partridge, Charles R.; Way, Steven] US EPA, Denver, CO 80202 USA. [Dogan, A. Umran] King Fahd Univ Petr & Minerals, Dept Earth Sci, Dhahran 31261, Saudi Arabia. [Dogan, A. Umran] Univ Iowa, Dept Chem & Biochem Engn, Iowa City, IA 52242 USA. [Pass, Harvey I.] NYU, Langone Med Ctr, New York, NY 10016 USA. [Pass, Harvey I.] NYU, Ctr Canc, New York, NY 10016 USA. [Rivera, Zeyana S.] Univ Hawaii, Dept Mol Biosci & Bioengn, Honolulu, HI 96813 USA. [Steele, Ian] Univ Chicago, Dept Geophys Sci, Chicago, IL 60637 USA. [Tuncer, Murat] Turkish Minist Hlth, TR-06434 Ankara, Turkey. [Yang, Haining] Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96813 USA. [Miller, Aubrey] NIEHS, NIH, Bethesda, MD USA. RP Carbone, M (reprint author), Univ Hawaii, Ctr Canc, Honolulu, HI 96813 USA. EM mcarbone@cc.hawaii.edu RI Dogan, Ahmet/B-4087-2010 FU National Cancer Institute at the National Institutes of Health [P01 114047]; American Association for Cancer Research; Butitta Mesothelioma Foundation; Mesothelioma Applied Research Foundation; Riviera Foundation; Aramec Foundation; Hawaii Community Foundation FX This work was supported in part by the National Cancer Institute at the National Institutes of Health (P01 114047 to M. C.), the American Association for Cancer Research Landon Innovator Award, and a grant from the Butitta Mesothelioma Foundation (to M. C.). This work was also supported by grants from Mesothelioma Applied Research Foundation, Riviera Foundation, Aramec Foundation (to H.Y.), and the Hawaii Community Foundation (to H.Y. and G. G.). For B. B., C. R. P., S. W. (USEPA), and A. M. (NIEHS), this research does not represent policies or positions of the respective agencies. NR 38 TC 61 Z9 61 U1 1 U2 22 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 AUG 16 PY 2011 VL 108 IS 33 BP 13618 EP 13623 DI 10.1073/pnas.1105887108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 807KC UT WOS:000293895100054 PM 21788493 ER PT J AU Sharma, D Masison, DC AF Sharma, Deepak Masison, Daniel C. TI Single methyl group determines prion propagation and protein degradation activities of yeast heat shock protein (Hsp)-70 chaperones Ssa1p and Ssa2p SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SACCHAROMYCES-CEREVISIAE; CELL-GROWTH; IN-VITRO; HEAT-SHOCK-PROTEIN-70 FAMILY; GUANIDINE-HYDROCHLORIDE; FUNCTIONAL SPECIFICITY; MOLECULAR CHAPERONES; CYTOSOLIC HSP70; TRANSGENIC MICE; URE3 AB Organisms encode multiple homologous heat shock protein (Hsp)-70s, which are essential protein chaperones that play the major role in cellular protein "quality control." Although Hsp70s are functionally redundant and highly homologous, many possess distinct functions. A regulatory motif underlying such distinctions, however, is unknown. The 98% identical cytoplasmic Hsp70s Ssa1p and Ssa2p function differently with regard to propagation of yeast [URE3] prions and in the vacuolar-mediated degradation of gluconeogenesis enzymes, such as FBPase. Here, we show that the Hsp70 nucleotide binding domain (NBD) regulates these functional specificities. We find little difference in ATPase, protein refolding, and amyloid inhibiting activities of purified Ssa1p and Ssa2p, but show that interchanging NBD residue alanine 83 (Ssa1p) and glycine 83 (Ssa2p) switched functions of Ssa1p and Ssa2p in [URE3] propagation and FBPase degradation. Disrupting the degradation pathway did not affect prion propagation, however, indicating these are two distinct processes where Ssa1/2p chaperones function differently. Our results suggest that the primary evolutionary pressure for Hsp70 functional distinctions is not to specify interactions of Hsp70 with substrate, but to specify the regulation of this activity. Our data suggest a rationale for maintaining multiple Hsp70s and suggest that subtle differences among Hsp70s evolved to provide functional specificity without affecting overall enzymatic activity. C1 [Sharma, Deepak; Masison, Daniel C.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Masison, DC (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM masisond@helix.nih.gov FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX We thank C. Randell Brown for antibodies and advice, R. Duden for antibodies, R. Wickner for plamids, and our National Institutes of Health (NIH) colleagues for insightful discussion and helpful comments on the manuscript. This work was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 39 TC 26 Z9 26 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 16 PY 2011 VL 108 IS 33 BP 13665 EP 13670 DI 10.1073/pnas.1107421108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 807KC UT WOS:000293895100062 PM 21808014 ER PT J AU Harberts, E Yao, K Wohler, JE Maric, D Ohayon, J Henkin, R Jacobson, S AF Harberts, Erin Yao, Karen Wohler, Jillian E. Maric, Dragan Ohayon, Joan Henkin, Robert Jacobson, Steven TI Human herpesvirus-6 entry into the central nervous system through the olfactory pathway SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE olfactory system; viral infection ID POLYMERASE-CHAIN-REACTION; HERPES-SIMPLEX-VIRUS; LIMBIC ENCEPHALITIS; CEREBROSPINAL-FLUID; MULTIPLE-SCLEROSIS; HUMAN ASTROCYTES; INFECTION; HUMAN-HERPESVIRUS-6; BRAIN; CELLS AB Viruses have been implicated in the development of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and multiple sclerosis. Human herpesvirus-6 (HHV-6) is a neurotropic virus that has been associated with a wide variety of neurologic disorders, including encephalitis, mesial temporal lobe epilepsy, and multiple sclerosis. Currently, the route of HHV-6 entry into the CNS is unknown. Using autopsy specimens, we found that the frequency of HHV-6 DNA in the olfactory bulb/tract region was among the highest in the brain regions examined. Given this finding, we investigated whether HHV-6 may infect the CNS via the olfactory pathway. HHV-6 DNA was detected in a total of 52 of 126 (41.3%) nasal mucous samples, showing the nasal cavity is a reservoir for HHV-6. Furthermore, specialized olfactory-ensheathing glial cells located in the nasal cavity were demonstrated to support HHV-6 replication in vitro. Collectively, these results support HHV-6 utilization of the olfactory pathway as a route of entry into the CNS. C1 [Harberts, Erin; Yao, Karen; Wohler, Jillian E.; Ohayon, Joan; Jacobson, Steven] NINDS, Viral Immunol Sect, Bethesda, MD 20892 USA. [Yao, Karen] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Maric, Dragan] NINDS, Flow Cytometry Core Facil, Bethesda, MD 20892 USA. [Henkin, Robert] Ctr Mol Nutr & Sensory Disorders, Washington, DC 20016 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov NR 37 TC 31 Z9 32 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 16 PY 2011 VL 108 IS 33 BP 13734 EP 13739 DI 10.1073/pnas.1105143108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 807KC UT WOS:000293895100074 PM 21825120 ER PT J AU Snitkin, ES Zelazny, AM Montero, CI Stock, F Mijares, L Murray, PR Segre, JA AF Snitkin, Evan S. Zelazny, Adrian M. Montero, Clemente I. Stock, Frida Mijares, Lilia Murray, Patrick R. Segre, Julie A. CA NISC Comparative Sequence Program TI Genome-wide recombination drives diversification of epidemic strains of Acinetobacter baumannii SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bacterial evolution; microbial genomics; clinical microbiology; hospital epidemiology; hospital infection ID GRAM-NEGATIVE BACILLI; OUTBREAK; RESISTANCE; EVOLUTION; IDENTIFICATION; INFECTIONS; HOSPITALS; SPREAD; GENES; CLONE AB Acinetobacter baumannii is an emerging human pathogen and a significant cause of nosocomial infections among hospital patients worldwide. The enormous increase in multidrug resistance among hospital isolates and the recent emergence of pandrug-resistant strains underscores the urgency to understand how A. baumannii evolves in hospital environments. To this end, we undertook a genomic study of a polyclonal outbreak of multidrug-resistant A. baumannii at the research-based National Institutes of Health Clinical Center. Comparing the complete genome sequences of the three dominant outbreak strain types enabled us to conclude that, despite all belonging to the same epidemic lineage, the three strains diverged before their arrival at the National Institutes of Health. The simultaneous presence of three divergent strains from this lineage supports its increasing prevalence in international hospitals and suggests an ongoing adaptation to the hospital environment. Further genomic comparisons uncovered that much of the diversification that occurred since the divergence of the three outbreak strains was mediated by homologous recombination across 20% of their genomes. Inspection of recombinant regions revealed that several regions were associated with either the loss or swapping out of genes encoding proteins that are exposed to the cell surface or that synthesize cell-surface molecules. Extending our analysis to a larger set of international clinical isolates revealed a previously unappreciated ability of A. baumannii to vary surface molecules through horizontal gene transfer, with subsequent intraspecies dissemination by homologous recombination. These findings have immediate implications in surveillance, prevention, and treatment of A. baumannii infections. C1 [Snitkin, Evan S.; Mijares, Lilia; Segre, Julie A.] NHGRI, Genet & Mol Biol Branch, Epithelial Biol Sect, Bethesda, MD 20892 USA. [Zelazny, Adrian M.; Montero, Clemente I.; Stock, Frida; Mijares, Lilia; Murray, Patrick R.] Natl Inst Hlth Clin Ctr, Dept Lab Med, NIH, Bethesda, MD 20892 USA. [NISC Comparative Sequence Program] Natl Inst Hlth Intramural Sequencing Ctr, NIH, Rockville, MD 20852 USA. RP Murray, PR (reprint author), BD Diagnost, Sparks, MD 21152 USA. EM Patrick_Murray@bd.com; jsegre@nhgri.nih.gov FU National Institute of General Medical Sciences; National Human Genome Research Institute; NIHCC FX We thank members of the J.A.S. laboratory and National Institutes of Health Intramural Sequencing Center (NISC) for critical reading of the manuscript; Jyoti Gupta for confirming SNPs; and Effie Nomicos for chart review. E.S.S. is supported by a Pharmacology Research Associate Training Fellowship, National Institute of General Medical Sciences. This work was supported by the National Human Genome Research Institute and NIHCC Intramural Research Programs. NR 39 TC 67 Z9 67 U1 2 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 16 PY 2011 VL 108 IS 33 BP 13758 EP 13763 DI 10.1073/pnas.1104404108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 807KC UT WOS:000293895100078 PM 21825119 ER PT J AU Poliakov, E Parikh, T Ayele, M Kuo, S Chander, P Gentleman, S Redmond, TM AF Poliakov, Eugenia Parikh, Toral Ayele, Michael Kuo, Stephanie Chander, Preethi Gentleman, Susan Redmond, T. Michael TI Aromatic Lipophilic Spin Traps Effectively Inhibit RPE65 Isomerohydrolase Activity SO BIOCHEMISTRY LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; VISUAL CYCLE; CONGENITAL AMAUROSIS; IN-VITRO; MUTATIONS; ISOMERIZATION; ISOMERASE; DEGENERATION; MECHANISM; RADICALS AB We previously showed that RPE65 does not specifically produce 11-cis-retinol only but also 13-cis-retinol, supporting a carbocation or radical cation mechanism of isomerization. The intrinsic properties of conjugated polyene chains result in facile formation of radical cations in oxidative conditions. We hypothesized that such radical intermediates, if involved in the mechanism of RPE65, could be stabilized by spin traps. We tested a variety of hydrophilic and lipophilic spin traps for their ability to inhibit RPE65 isomerohydrolase activity. We found that the aromatic lipophilic spin traps such as N-tert-butyl-alpha-phenylnitrone (PBN), 2,2-dimethyl-4-phenyl-2H-imidazole-1-oxide (DMPIO), and nitrosobenzene (NB) strongly inhibit RPE65 isomerohydrolase activity in vitro. C1 [Poliakov, Eugenia; Parikh, Toral; Ayele, Michael; Kuo, Stephanie; Chander, Preethi; Gentleman, Susan; Redmond, T. Michael] NEI, LRCMB, NIH, Bethesda, MD 20892 USA. RP Redmond, TM (reprint author), NEI, LRCMB, NIH, Bethesda, MD 20892 USA. EM redmond@helix.nih.gov OI Redmond, T. Michael/0000-0002-1813-5291 FU National Eye Institute, NIH; Howard Hughes Medical Institute (HHMI) FX This research was supported by the Intramural Research Program of the National Eye Institute, NIH. T.P. was supported by the Howard Hughes Medical Institute (HHMI), while MA. was a HHMI/Montgomery County (MD) Public Schools/NIH student intern when this work was performed. NR 23 TC 12 Z9 12 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 16 PY 2011 VL 50 IS 32 BP 6739 EP 6741 DI 10.1021/bi200532m PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 804PI UT WOS:000293665500001 PM 21736383 ER PT J AU Wang, HX Gillis, A Zhao, CY Lee, E Wu, J Zhang, FC Ye, F Zhang, DY AF Wang, Hongxia Gillis, Andrew Zhao, Chunyan Lee, Eugene Wu, Josephine Zhang, Fengchun Ye, Fei Zhang, David Y. TI Crocidolite asbestos-induced signal pathway dysregulation in mesothelial cells SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Immunoblot; Signaling network; Proteomics; Mesothelioma ID MALIGNANT PLEURAL MESOTHELIOMA; MOLECULAR-BIOLOGY; NETWORK; UPDATE; CANCER AB Background: Malignant mesothelioma is a rare cancer caused by exposure to asbestos. Current therapies have limited efficacy and the prognosis is dismal. A better understanding of the underlying mechanism of asbestos-induced malignant transformation will help to identify molecular markers that can be used for diagnosis, prognosis or therapeutic targets. Objectives: The objectives of this study are (1) to identify altered levels of proteins and phosphoproteins and (2) to establish the interactive network among those proteins in crocidolite-treated benign mesothelial cells and in malignant mesothelial cells. Methods: Total cellular proteins were extracted from benign mesothelial cells, crocidolite-treated mesothelial cells and malignant mesothelial cells. The expression levels of 112 proteins and phosphoproteins were analyzed using a multiplex immunoblot-based assay followed by computational analysis (Protein Pathway Array). Results: A total of 16 proteins/phosphoproteins (7 down-regulated and 9 up-regulated) were altered after exposure of benign mesothelial cells to crocidolite asbestos and the majority of them are involved in DNA damage repair and cell cycle regulation. In malignant mesothelial cells, 21 proteins/phosphoproteins (5 down-regulated and 16 up-regulated) were dysregulated and majority of them are involved in EGFR/ERK and PI3K/Akt pathways. Within the regulatory network affected by crocidolite, p53 and NF-kappa B complex are the most important regulators. There was substantial overlap in the regulatory networks between the asbestos-treated cells and malignant mesothelial cells. Conclusions: Asbestos exposure has extensive effects on regulatory pathways and networks. These altered proteins may be used in the future to identify those with a high risk for developing malignant mesothelioma and as targets for preventing this deadly malignancy. (C) 2011 Elsevier B.V All rights reserved. C1 [Ye, Fei] Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA. [Wang, Hongxia; Zhang, Fengchun] Shanghai Jiao Tong Univ, Sch Med, Shanghai Renji Hosp, Shanghai 200030, Peoples R China. [Zhao, Chunyan] Jilin Univ, Dept Pathogenobiol, Changchun 130023, Peoples R China. [Lee, Eugene] Natl Inst Biomed Imaging & Bioengn, Div Interdisciplinary Training, Bethesda, MD USA. RP Ye, F (reprint author), Mt Sinai Sch Med, Dept Pathol, 1425 Madison Ave,Box 1122, New York, NY 10029 USA. EM Feiyecc@gmail.com; David.zhang@mssm.edu FU National Institute for Occupational Safety and Health (NIOSH) Mountain and Plains Education and Research Center (MAP ERC); Shanghai Municipal Education Committee [J50208]; Shanghai Municipal Natural Science Foundation [09ZR1417900] FX The study was partially supported by the National Institute for Occupational Safety and Health (NIOSH) Mountain and Plains Education and Research Center (MAP ERC) to F. Ye, the leading academic discipline project of Shanghai Municipal Education Committee (Project Number: J50208) to H. Wang and Shanghai Municipal Natural Science Foundation (Project Number: 09ZR1417900) to H. Wang. NR 24 TC 11 Z9 12 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD AUG 16 PY 2011 VL 723 IS 2 BP 171 EP 176 DI 10.1016/j.mrgentox.2011.04.008 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 799VY UT WOS:000293315400015 PM 21570478 ER PT J AU Yang, JH Cisar, JO Bush, CA AF Yang, Jinghua Cisar, John O. Bush, C. Allen TI Structure of type 3Gn coaggregation receptor polysaccharide from Streptococcus cristatus LS4 SO CARBOHYDRATE RESEARCH LA English DT Article DE Oral bacteria; Polysaccharides; Structure; NMR spectroscopy ID CELL-SURFACE POLYSACCHARIDE; VIRIDANS GROUP STREPTOCOCCI; MOLECULAR CHARACTERIZATION; CAPSULAR POLYSACCHARIDE; WALL POLYSACCHARIDES; ORALIS; NMR; RECOGNITION; ACTINOMYCES; STRAINS AB The presence of a novel coaggregation receptor polysaccharide (RPS) on the dental plaque isolate Streptococcus cristatus LS4 was suggested by this strain's antigenic and coaggregation properties. Examination of RPS isolated from strain LS4 by a combination of 2-dimensional and pseudo 3-dimensional single quantum heteronuclear NMR methods that included detection of (13)C chemical shifts at high resolution revealed the following repeat unit structure: -> 6)-beta-D-Galf-(1 -> 6)-beta-D-GalpNAc-(1 -> 3)-alpha-D-Galp-(1 -> P -> 6)-alpha-D-Galp-(1 -> 3)-beta-L-Rhap-(1 -> 4)-beta-D-Glcp-(1 ->. The identification of this polysaccharide as RPS3Gn, a new structural type, was established by the alpha-D-Galp-containing epitope of RPS serotype 3 and Gn recognition motif (i.e., beta-D-GalpNAc (1 -> 3)-alpha-D-Galp) for coaggregation with other bacteria. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Bush, C. Allen] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. [Yang, Jinghua; Cisar, John O.] Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Bush, CA (reprint author), Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. EM bush@umbc.edu FU NIDCR, National Institutes of Health FX We thank Mogens Kilian for help in identification of S. cristatus and the Complex Carbohydrate Research Center at the University of Georgia for chemical analyses. This work was supported by the Intramural Research Program of the NIDCR, National Institutes of Health. NR 24 TC 3 Z9 3 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD AUG 16 PY 2011 VL 346 IS 11 BP 1342 EP 1346 DI 10.1016/j.carres.2011.04.035 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 793YA UT WOS:000292858600012 PM 21601178 ER PT J AU Chang, CM Wang, SS Dave, BJ Jain, S Vasef, MA Weisenburger, DD Cozen, W Davis, S Severson, RK Lynch, CF Rothman, N Cerhan, JR Hartge, P Morton, LM AF Chang, Cindy M. Wang, Sophia S. Dave, Bhavana J. Jain, Smrati Vasef, Mohammad A. Weisenburger, Dennis D. Cozen, Wendy Davis, Scott Severson, Richard K. Lynch, Charles F. Rothman, Nathaniel Cerhan, James R. Hartge, Patricia Morton, Lindsay M. TI Risk factors for non-Hodgkin lymphoma subtypes defined by histology and t(14;18) in a population-based case-control study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE lymphoma; non-Hodgkin; case-control studies; translocation; follicular lymphoma; diffuse large B-cell lymphoma; etiology ID EPIDEMIOLOGY CONSORTIUM INTERLYMPH; HAIR DYE USE; CIGARETTE-SMOKING; PHYSICAL-ACTIVITY; POOLED ANALYSIS; UNITED-STATES; ANTHROPOMETRIC CHARACTERISTICS; HEALTHY-INDIVIDUALS; ALCOHOL-CONSUMPTION; PERIPHERAL-BLOOD AB The t(14;18) chromosomal translocation is the most common cytogenetic abnormality in non-Hodgkin lymphoma (NHL), occurring in 70-90% of follicular lymphomas (FL) and 30-50% of diffuse large B-cell lymphomas (DLBCL). Previous t(14;18)-NHL studies have not evaluated risk factors for NHL defined by both t(14; 18) status and histology. In this population-based case-control study, t(14;18) status was determined in DLBCL cases using fluorescence in situ hybridization on paraffin-embedded tumor sections. Polytomous logistic regression was used to evaluate the association between a wide variety of exposures and t(14;18)-positive (N = 109) and -negative DLBCL (N = 125) and FL (N = 318), adjusting for sex, age, race, and study center. Taller height, more lifetime surgeries, and PCB180 exposure were associated with t(14;18)-positivity. Taller individuals (third tertile vs. first tertile) had elevated risks of t(14;18)-positive DLBCL (odds ratio [OR] = 1.8, 95% confidence interval [CI] 1.1-3.0) and FL (OR = 1.4, 95% CI 1.0-1.9) but not t(14;18)-negative DLBCL. Similar patterns were seen for individuals with more lifetime surgeries (131 vs. 0-12 surgeries; t(14;18)-positive DLBCL OR 5 1.4, 95% CI 0.7-2.7; FL OR = 1.6, 95% CI 1.1-2.5) and individuals exposed to PCB180 greater than 20.8 ng/g (t(14;18)-positive DLBCL OR = 1.3, 95% CI 0.6-2.9; FL OR = 1.7, 95% CI 1.0-2.8). In contrast, termite treatment and high alpha-chlordane levels were associated with t(14; 18)-negative DLBCL only, suggesting that these exposures do not act through t(14;18). Our findings suggest that putative associations between NHL and height, surgeries, and PCB180 may be t(14;18)-mediated and provide support for case-subtyping based on molecular and histologic subtypes. Future efforts should focus on pooling data to confirm and extend previous research on risk factors for t(14;18)-NHL subtypes. C1 [Chang, Cindy M.; Wang, Sophia S.; Rothman, Nathaniel; Hartge, Patricia; Morton, Lindsay M.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20892 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Dave, Bhavana J.; Jain, Smrati; Weisenburger, Dennis D.] Univ Nebraska Med Ctr, Omaha, NE USA. [Vasef, Mohammad A.] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Cozen, Wendy] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Davis, Scott] Univ Washington, Seattle, WA 98195 USA. [Davis, Scott] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Severson, Richard K.] Wayne State Univ, Dept Family Med, Detroit, MI USA. [Severson, Richard K.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Cerhan, James R.] Mayo Clin, Coll Med, Div Epidemiol, Rochester, MN USA. RP Chang, CM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Executive Blvd,EPS 7074, Rockville, MD 20892 USA. EM changcm@mail.nih.gov RI Chang, Cindy/G-4514-2010; Morton, Lindsay/B-5234-2015; OI Morton, Lindsay/0000-0001-9767-2310; Cerhan, James/0000-0002-7482-178X FU National Cancer Institute, National Institutes of Health, and Public Health Service (PHS) [N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105] FX Grant sponsor: Intramural Research Program of the National Cancer Institute, National Institutes of Health, and Public Health Service (PHS); Grant numbers: N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, and N02-PC-71105 NR 45 TC 10 Z9 10 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 15 PY 2011 VL 129 IS 4 BP 938 EP 947 DI 10.1002/ijc.25717 PG 10 WC Oncology SC Oncology GA 789IC UT WOS:000292508000019 PM 20949561 ER PT J AU Kranick, S Ekanayake, V Martinez, V Ameli, R Hallett, M Voon, V AF Kranick, Sarah Ekanayake, Vindhya Martinez, Valeria Ameli, Rezvan Hallett, Mark Voon, Valerie TI Psychopathology and Psychogenic Movement Disorders SO MOVEMENT DISORDERS LA English DT Article DE dystonia; movement disorders; psychogenic; psychological measures; trauma ID MOTOR CONVERSION DISORDER; CLINICAL CHARACTERISTICS; NONEPILEPTIC SEIZURES; CHILDHOOD TRAUMA; ABUSE; DEPRESSION; DISABILITY; LIFE AB Psychogenic movement disorder is defined as abnormal movements unrelated to a medical cause and presumed related to underlying psychological factors. Although psychological factors are of both clinical and pathophysiological relevance, very few studies to date have systematically assessed their role in psychogenic movement disorder. We sought to assess the role of previous life stress using validated quantitative measures in patients with psychogenic movement disorder compared with age- and sex-matched healthy volunteers as well as a convenience sample of patients with focal hand dystonia. Sixty-four patients with psychogenic movement disorder (72% female; mean age, 45.2 years [standard deviation, 15.2 years]), 38 healthy volunteers (74% female; mean age, 49 years [standard deviation, 13.7 years]), and 39 patients with focal hand dystonia (37% female; mean age, 48.7 years [standard deviation, 11.7 years]) were evaluated using a standardized psychological interview as well as validated quantitative scales to assess trauma and previous stressors, depression, anxiety, and personality traits. Patients with psychogenic movement disorder reported higher rates of childhood trauma, specifically greater emotional abuse and physical neglect, greater fear associated with traumatic events, and a greater number of traumatic episodes compared with healthy volunteers and patients with focal hand dystonia controlled for depressive symptoms and sex (Bonferroni corrected P < .005). There were no differences in categorical psychiatric diagnoses or scores on childhood physical or sexual abuse sub-scales, personality traits, or the dissociative experience scale. Our findings highlight a biopsychosocial approach toward the pathophysiology of psychogenic movement disorder, although the association with psychological issues is much less prominent than expected compared with the nonepileptic seizure population. A careful psychological assessment is indicated to optimize therapeutic modalities. (C)2011 Movement Disorder Society C1 [Voon, Valerie] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England. [Kranick, Sarah; Martinez, Valeria; Hallett, Mark; Voon, Valerie] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD USA. [Ekanayake, Vindhya] Purdue Univ, Dept Psychol Sci, W Lafayette, IN 47907 USA. [Ameli, Rezvan] NIMH, NIH, Bethesda, MD 20892 USA. RP Voon, V (reprint author), Univ Cambridge, Behav & Clin Neurosci Inst, Downing Site, Cambridge CB2 3EB, England. EM w247@cam.ac.uk FU Intramural NIH HHS [Z01 NS002667-23] NR 29 TC 51 Z9 51 U1 3 U2 18 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2011 VL 26 IS 10 BP 1844 EP 1850 DI 10.1002/mds.23830 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 822DS UT WOS:000295024700009 PM 21714007 ER PT J AU Virtanen, JO Pietilainen-Nicklen, J Uotila, L Farkkila, M Vaheri, A Koskiniemi, M AF Virtanen, Jussi O. Pietilainen-Nicklen, Jenna Uotila, Lasse Farkkila, Markus Vaheri, Antti Koskiniemi, Marjaleena TI Intrathecal human herpesvirus 6 antibodies in multiple sclerosis and other demyelinating diseases presenting as oligoclonal bands in cerebrospinal fluid SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Cerebrospinal fluid; Human herpesvirus 6; Intrathecal antibody; Multiple sclerosis; Demyelination; Oligoclonal IgG bands ID VIRUS-SPECIFIC IGG; DIAGNOSTIC-CRITERIA; IMMUNE-RESPONSE; IN-VITRO; INFECTION; GENOME; CELLS; VIVO; MS AB Demyelinating diseases of the central nervous system (CNS) often include elevated IgG production in intrathecal space presenting as oligoclonal bands (OCBs) in cerebrospinal fluid (CSF). In most demyelinating diseases, e.g. in multiple sclerosis (MS), the underlying cause is not known. We used isoelectric focusing and affinity immunoblot to study the specificity of CSF OCBs to human herpesvirus-6 (HHV-6) in patients with demyelinating diseases of the CNS including MS. Eighty patients with positive OCB finding were included in the study. The OCBs reacted with the HHV-6 antigen in 18 cases (23%). Twelve of 46 MS patients (26%), 5 of 24 other demyelinating diseases (21%) and 1 of 10 other neurological disorders (10%) had HHV-6 specific OCBs in CSF. A specific intrathecal HHV-6 A and B antibody production was shown in a proportion of patients with demyelinating diseases and might suggest a role in the pathogenesis of these diseases. (C) 2011 Elsevier B.V. All rights reserved. C1 [Virtanen, Jussi O.; Pietilainen-Nicklen, Jenna; Vaheri, Antti; Koskiniemi, Marjaleena] Univ Helsinki, Haartman Inst, Dept Virol, FIN-00014 Helsinki, Finland. [Virtanen, Jussi O.; Vaheri, Antti] HUSLAB Lab Serv, Dept Virol, Helsinki, Finland. [Pietilainen-Nicklen, Jenna; Farkkila, Markus] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. [Uotila, Lasse] HUSLAB Lab Serv, Dept Clin Chem, Helsinki, Finland. RP Virtanen, JO (reprint author), NINDS, Neuroimmunol Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM virtanenjo@ninds.nih.gov RI Virtanen, Jussi Oskari/D-3253-2013 FU Biomedicum Helsinki Foundation; Finnish MS Foundation; Orion-Farmos Foundation; Academy of Finland; Instrumentarium Foundation FX The authors are grateful to Kari Borchers from ILS Laboratories Scandinavia for providing Isofocusing gels and for technical help. Irina Suomalainen and Sari Parkkamaki are thanked for technical help. Biomedicum Helsinki Foundation, Finnish MS Foundation, Orion-Farmos Foundation, Academy of Finland and Instrumentarium Foundation partially funded the study. NR 25 TC 15 Z9 15 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG 15 PY 2011 VL 237 IS 1-2 BP 93 EP 97 DI 10.1016/j.jneuroim.2011.06.012 PG 5 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 820VI UT WOS:000294933800013 PM 21767883 ER PT J AU Laje, G McMahon, FJ AF Laje, Gonzalo McMahon, Francis J. TI Genome-wide association studies of antidepressant outcome: A brief review SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE Antidepressant treatment outcome; Genome-wide association; GWAS; Pharmacogenetics; Pharmacogenomics ID GENE PROMOTER POLYMORPHISM; STAR-ASTERISK-D; MAJOR DEPRESSION; PHARMACOGENETICS; METAANALYSIS; CITALOPRAM; IMPUTATION; EFFICACY AB Genome-wide association studies (GWAS) of antidepressant treatment outcome have been at the forefront of psychiatric pharmacogenetics. Such studies may ultimately help match medications with patients, maximizing efficacy while minimizing adverse effects. The hypothesis-free approach of the GWAS has the advantage of interrogating genes that otherwise would have not been considered as candidates due to our limited understanding of their function, and may also uncover important regulatory variation within the large regions of the genome that do not contain protein-coding genes. Three independent samples have so far been studied using a genome-wide approach: The Sequenced Treatment Alternatives to Relieve Depression sample (STAR*D) (n = 1953), the Munich Antidepressant Response Signature (MARS) sample (n = 339) and the Genome-based Therapeutic Drugs for Depression (GENDEP) sample (n = 706). None of the studies reported results that achieved genome-wide significance, suggesting that larger samples and better outcome measures will be needed. This review discusses the published GWAS studies, their strengths, limitations, and possible future directions. Published by Elsevier Inc. C1 [Laje, Gonzalo; McMahon, Francis J.] NIMH, Human Genet Branch, Intramural Res Program, NIH,US DHHS, Bethesda, MD 20892 USA. RP Laje, G (reprint author), 35 Convent Dr,Rm 1A207, Bethesda, MD 20892 USA. EM gonzalo.laje@nih.gov RI Laje, Gonzalo/L-2654-2014; OI Laje, Gonzalo/0000-0003-2763-3329; McMahon, Francis/0000-0002-9469-305X FU NIMH; NIH, US DHHS [K99MH085098] FX Drs. Laje and McMahon are listed as co-inventors in patent applications filed by the NIH related to genetic markers of antidepressant treatment outcome. Under federal law the NIH is required to pay inventors a portion of any royalties the NIH receives through licenses granted under patents. Funded by the Intramural Research Program of NIMH and K99MH085098 (GL), NIH, US DHHS. 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 26 TC 21 Z9 21 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD AUG 15 PY 2011 VL 35 IS 7 BP 1553 EP 1557 DI 10.1016/j.pnpbp.2010.11.031 PG 5 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 820YK UT WOS:000294941800004 PM 21115088 ER PT J AU Greer, YE Rubin, JS AF Greer, Yoshimi Endo Rubin, Jeffrey S. TI The role of centrosomal casein kinase 1 delta in neurite outgrowth and beyond SO CELL CYCLE LA English DT Editorial Material DE casein kinase 1 delta; centrosome; ciliogenesis; dishevelled; mitotic spindle; neurite outgrowth; Wnt signaling ID MITOTIC SPINDLE FORMATION; CELLS; INHIBITION; APOPTOSIS C1 [Greer, Yoshimi Endo; Rubin, Jeffrey S.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Rubin, JS (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM rubinj@mail.nih.gov NR 10 TC 2 Z9 2 U1 1 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD AUG 15 PY 2011 VL 10 IS 16 BP 2605 EP 2606 DI 10.4161/cc.10.16.16386 PG 2 WC Cell Biology SC Cell Biology GA 810VK UT WOS:000294155600001 PM 21785261 ER PT J AU Ebersole, T Kim, JH Samoshkin, A Kouprina, N Pavlicek, A White, RJ Larionov, V AF Ebersole, Thomas Kim, Jung-Hyun Samoshkin, Alexander Kouprina, Natalay Pavlicek, Adam White, Robert J. Larionov, Vladimir TI tRNA genes protect a reporter gene from epigenetic silencing in mouse cells SO CELL CYCLE LA English DT Article DE barrier elements; tRNA genes; Pol-III transcribed genes ID POLYMERASE III TRANSCRIPTION; CHROMATIN-STRUCTURE; HETEROCHROMATIN BARRIERS; SACCHAROMYCES-CEREVISIAE; CHROMOSOMAL INTEGRATION; TRANSPOSABLE ELEMENTS; MOBILE ELEMENTS; BINDING-SITES; FISSION YEAST; HUMAN GENOME AB It is a well-established fact that the tRNA genes in yeast can function as chromatin barrier elements. However, so far there is no experimental evidence that tRNA and other Pol-III-transcribed genes exhibit barrier activity in mammals. This study utilizes a recently developed reporter gene assay to test a set of Pol-III-transcribed genes and gene clusters with variable promoter and intergenic regions for their ability to prevent heterochromatin-mediated reporter gene silencing in mouse cells. The results show that functional copies of mouse tRNA genes are effective barrier elements. The number of tRNA genes as well as their orientation influence barrier function. Furthermore, the DNA sequence composition of intervening and flanking regions affects barrier activity of tRNA genes. Barrier activity was maintained for much longer time when the intervening and flanking regions of tRNA genes were replaced by AT-rich sequences, suggesting a negative role of DNA methylation in the establishment of a functional barrier. Thus, our results suggest that tRNA genes are essential elements in establishment and maintenance of chromatin domain architecture in mammalian cells. C1 [Ebersole, Thomas; Kim, Jung-Hyun; Samoshkin, Alexander; Kouprina, Natalay; Larionov, Vladimir] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Pavlicek, Adam] Pfizer Global Res & Dev, Oncol Res Unit, Computat Biol, San Diego, CA USA. [White, Robert J.] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland. RP Larionov, V (reprint author), NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. EM larionov@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX Thanks to Mark Batzer for the Alu-Yb data, general support and discussion. This research was supported by the intramural research program of the NIH, National Cancer Institute, Center for Cancer Research. NR 55 TC 21 Z9 21 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD AUG 15 PY 2011 VL 10 IS 16 BP 2779 EP 2791 DI 10.4161/cc.10.16.17092 PG 13 WC Cell Biology SC Cell Biology GA 810VK UT WOS:000294155600033 PM 21822054 ER PT J AU Bercovitch, RS Catanzaro, A Schwartz, BS Pappagianis, D Watts, D Ampel, NM AF Bercovitch, Robert S. Catanzaro, Antonino Schwartz, Brian S. Pappagianis, Demosthenes Watts, D. Heather Ampel, Neil M. TI Coccidioidomycosis During Pregnancy: A Review and Recommendations for Management SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID ANTLEY-BIXLER-SYNDROME; OF-THE-LITERATURE; CYTOCHROME-P450 OXIDOREDUCTASE; PULMONARY COCCIDIOIDOMYCOSIS; COMPLICATING PREGNANCY; VAGINAL CANDIDIASIS; IMMITIS INFECTION; BREAST-MILK; FLUCONAZOLE; MENINGITIS AB The severity and risk for dissemination of coccidioidomycosis are increased when infection is acquired during pregnancy. Azole antifungals are potentially teratogenic when given in the first trimester. These issues are reviewed and guidance regarding management of coccidioidomycosis during pregnancy is provided.Pregnancy is an established risk factor for the development of severe and disseminated coccidioidomycosis, particularly when infection is acquired during the later stages of gestation. Although recent studies suggest that the incidence of symptomatic coccidioidomycosis during pregnancy is decreasing and that outcome has improved, management is complicated by the observations that azole antifungal agents can be teratogenic when given to some women, particularly at high doses, early in pregnancy. This article summarizes the data on these issues and offers guidance on the management of coccidioidomycosis during pregnancy. C1 [Bercovitch, Robert S.; Catanzaro, Antonino] Univ Calif San Diego, San Diego, CA 92103 USA. [Schwartz, Brian S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Pappagianis, Demosthenes] Univ Calif Davis, Davis, CA 95616 USA. [Watts, D. Heather] Eunice Kennedy Shriver Natl Inst Child Hlth & Hu, Bethesda, MD USA. [Ampel, Neil M.] Univ Arizona, Valley Fever Ctr, Tucson, AZ USA. [Ampel, Neil M.] So Arizona Vet Affairs Hlth Care Syst, Tucson, AZ USA. RP Ampel, NM (reprint author), SAVAHCS, Med & Subspecialty Serv 1 111, 3601 S 6th Ave, Tucson, AZ 85745 USA. EM nampel@email.arizona.edu NR 72 TC 24 Z9 24 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2011 VL 53 IS 4 BP 363 EP 368 DI 10.1093/cid/cir410 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 804DW UT WOS:000293635500008 PM 21810749 ER PT J AU Taha, TE Hoover, DR Chen, S Kumwenda, NI Mipando, L Nkanaunena, K Thigpen, MC Taylor, A Fowler, MG Mofenson, LM AF Taha, Taha E. Hoover, Donald R. Chen, Shu Kumwenda, Newton I. Mipando, Linda Nkanaunena, Kondwani Thigpen, Michael C. Taylor, Allan Fowler, Mary Glenn Mofenson, Lynne M. TI Effects of Cessation of Breastfeeding in HIV-1-Exposed, Uninfected Children in Malawi SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HIV-INFECTED CHILDREN; INFANTS BORN; MORTALITY; TRANSMISSION; COTRIMOXAZOLE; PROPHYLAXIS; BOTSWANA; MOTHERS; UGANDA; ZAMBIA AB Background. We assessed morbidity rates during short intervals that accompanied weaning and cumulative mortality among HIV-exposed, uninfected infants enrolled in the postexposure prophylaxis of infants in Malawi (PEPI-Malawi) trial. Methods. Women were counseled to stop breastfeeding (BF) by 6 months in the PEPI-Malawi trial. HIV-uninfected infants were included in this analysis starting at age 6 months. Breastfeeding and morbidity (illness and/or hospital admission and malnutrition [weight-for-age Z-score, < 2]) were assessed during age intervals of 6-9, 9-12, and 12-15 months. BF was defined as any BF at the start and end of the interval and no breastfeeding (NBF) was defined as NBF at any time during the interval. The association of NBF with morbidity at each mutually exclusive interval was assessed using Poisson regression models controlling for other factors. Cumulative mortality among infants aged 6-15 months with BF and NBF was assessed using an extended Kaplan-Meier method. Results. At age 6 months, 1761 HIV-uninfected infants were included in the study. The adjusted rate ratios for illnesses and/or hospital admission for NBF, compared with BF, was 1.7 (P < .0001) at 6-9 months, 1.66 (P = .0001) at 9-12 months, and 1.75 (P = .0008) at 12-15 months. The rates of morbidity were consistently higher among NBF infants during each age interval, compared with BF infants. The 15 months cumulative mortality among BF and NBF children was 3.5% and 6.4% (P = .03), respectively. Conclusions. Cessation of BF is associated with acute morbidity events and cumulative mortality. Prolonged BF should be encouraged, in addition to close monitoring of infant health and provision of support services. C1 [Taha, Taha E.; Chen, Shu; Kumwenda, Newton I.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Hoover, Donald R.] Rutgers State Univ, Dept Stat, Piscataway, NJ USA. [Hoover, Donald R.] Rutgers State Univ, Inst Hlth Hlth Policy & Aging Res, Piscataway, NJ USA. [Mipando, Linda] Johns Hopkins Univ Res Project, Coll Med, Blantyre, Malawi. [Nkanaunena, Kondwani; Fowler, Mary Glenn] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Thigpen, Michael C.; Taylor, Allan] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Epidemiol Branch, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediatr Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, Bethesda, MD USA. RP Taha, TE (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Rm E7138,615 N Wolfe St, Baltimore, MD 21205 USA. EM ttaha@jhsph.edu OI Mofenson, Lynne/0000-0002-2818-9808 FU Centers for Disease Control and Prevention; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [U50 PS022061-05, U50/CC0222061] FX This work was supported by a Cooperative Agreement from the Centers for Disease Control and Prevention and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (U50 PS022061-05; U50/CC0222061). NR 28 TC 31 Z9 31 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2011 VL 53 IS 4 BP 388 EP 395 DI 10.1093/cid/cir413 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 804DW UT WOS:000293635500013 PM 21810754 ER PT J AU Sevy, S Robinson, DG Sunday, S Napolitano, B Miller, R McCormack, J Kane, J AF Sevy, Serge Robinson, Delbert G. Sunday, Suzanne Napolitano, Barbara Miller, Rachel McCormack, Joanne Kane, John TI Olanzapine vs. risperidone in patients with first-episode schizophrenia and a lifetime history of cannabis use disorders: 16-week clinical and substance use outcomes SO PSYCHIATRY RESEARCH LA English DT Article DE Psychosis; Marijuana; Atypicals; Alcohol; Negative symptoms; Positive symptoms ID PSYCHOSIS; CLOZAPINE; ONSET; MISUSE; TRIAL; ABUSE; HALOPERIDOL; ILLNESS; ALCOHOL; SMOKING AB The purpose of this study is to compare the efficacy of olanzapine and risperidone for the acute treatment of first-episode schizophrenia patients with cannabis use disorders. This secondary analysis of a previously published study included 49 first-episode patients with a diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder and a co-occurring lifetime diagnosis of cannabis use disorders randomly assigned to treatment with either olanzapine (n = 28) or risperidone (n = 21) for 16 weeks. The olanzapine group did not differ significantly from the risperidone group for initial response rates of positive symptoms, and rates of cannabis use or alcohol use during the study. Positive symptoms and the Scale for Assessment of Negative Symptoms (SANS) global asociality-anhedonia scores improved over time but did not differ between study medications. In both groups, cannabis use during the study was higher in patients who used cannabis within three months of the admission. Thus, our results suggest that olanzapine and risperidone had a similar initial efficacy on psychotic symptoms and substance use in first-episode patients with co-occurring cannabis use disorders. If clinicians are choosing between olanzapine versus risperidone treatment for this population, their decision should be based upon factors other than symptom response and short-term substance misuse. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Sevy, Serge; Robinson, Delbert G.; Sunday, Suzanne; Napolitano, Barbara; Kane, John] Feinstein Inst Med Res, Manhasset, NY 11030 USA. [Sevy, Serge; Robinson, Delbert G.; McCormack, Joanne; Kane, John] Zucker Hillside Hosp, Glen Oaks, NY 11004 USA. [Sevy, Serge; Robinson, Delbert G.; Kane, John] Albert Einstein Coll Med, Bronx, NY 10461 USA. [Sevy, Serge; Robinson, Delbert G.; Sunday, Suzanne; Kane, John] Hofstra N Shore LIJ Sch Med, Hempstead, NY 11549 USA. [Miller, Rachel] NIMH, Bethesda, MD 20892 USA. RP Sevy, S (reprint author), Feinstein Inst Med Res, 350 Community Dr, Manhasset, NY 11030 USA. EM sevy@lij.edu FU Bristol-Meyers Squibb; Eli Lilly; Janssen Pharmaceutica; NIH [K23 DA015541, MH60004, MH41960, RR018535] FX Dr. Robinson has received grant support from Bristol-Meyers Squibb, Eli Lilly, and Janssen Pharmaceutica. He has served as a speaker for Astra Zeneca and Janssen Pharmaceutica. Dr. Kane has served as a consultant or speaker for Astra Zeneca, Bristol-Myers Squibb. Cephalon, Eli Lilly, GSK, Janssen Pharmaceutica, Johnson and Johnson, Lundbeck, Organon, Otsuka, Pfizer Inc, PhXHealth, Proteus, Vanda, and Wyeth. He is a shareholder of MedAvante. Dr. Sevy has served as a consultant for Abbott. Dr. Sunday, Ms. Napolitano, Dr. Miller, and Ms. McCormack report no competing interests. This work was supported by NIH grants K23 DA015541 (SS), MH60004 (DR), MH41960, and RR018535. The NIH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 24 TC 13 Z9 13 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD AUG 15 PY 2011 VL 188 IS 3 BP 310 EP 314 DI 10.1016/j.psychres.2011.05.001 PG 5 WC Psychiatry SC Psychiatry GA 810QU UT WOS:000294143000002 PM 21636134 ER PT J AU Buydens-Branchey, L Branchey, M Hibbeln, JR AF Buydens-Branchey, Laure Branchey, Marc Hibbeln, Joseph R. TI Higher n-3 fatty acids are associated with more intense fenfluramine-induced ACTH and cortisol responses among cocaine-abusing men SO PSYCHIATRY RESEARCH LA English DT Article DE Serotonin probe; Hormonal responses; EPA; DHA ID DOCOSAHEXAENOIC ACID; SEROTONINERGIC NEUROTRANSMISSION; CEREBROSPINAL-FLUID; NERVOUS-SYSTEM; OMEGA-3-FATTY-ACIDS; BRAIN; DEPRESSION; TRYPTOPHAN; DISORDERS; ALPHA AB Preclinical studies have shown that diets supplemented with or deficient in n-3 polyunsaturated fatty acids (PUFAs) could influence serotonergic neurotransmission, but information about their effects on the serotonergic function of humans is scant. Therefore, simultaneous assessments of n-3 PUFAs and of the adrenocorticotropic hormone (ACTH) and cortisol responses to challenges with the serotonin (5-HT) probe d,l-fenfluramine (FEN) were performed in 25 cocaine-abusing men and 12 control subjects. Cocaine abusers were tested 18 days after their admission to a closed ward. ACTH and cortisol were measured in plasma samples collected on two testing days separated by 48 h following the random administration of 60 mg of FEN or placebo. Fatty acids were measured in the first test day samples. Patients' FEN-induced ACTH rises were significantly and positively correlated with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Patients' cortisol rises were positively and significantly correlated with EPA but not with DHA. There were no significant correlations between hormonal responses and pre-hospitalization cocaine use parameters. Control subjects' responses to FEN were not correlated with any PUFA. In conclusion, higher EPA and DHA levels were associated with a more intense FEN-induced ACTH response and higher EPA levels with a more intense cortisol response in cocaine-abusing men withdrawn from cocaine but not in control subjects. These findings support and expand existing evidence that EPA and DHA could influence 5-HT function in some human subgroups. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Buydens-Branchey, Laure] Narrows Inst Biomed Res, NYHHS, Brooklyn, NY 11209 USA. [Hibbeln, Joseph R.] NIAAA, Bethesda, MD USA. RP Buydens-Branchey, L (reprint author), Narrows Inst Biomed Res, NYHHS, Brooklyn Campus,800 Poly Pl, Brooklyn, NY 11209 USA. EM lbuydens@att.net FU National Institute on Drug Abuse [R01-DA15360]; National Institute on Alcohol Abuse and Alcoholism FX This work was supported by grant R01-DA15360 from the National Institute on Drug Abuse and by the National Institute on Alcohol Abuse and Alcoholism. NR 37 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD AUG 15 PY 2011 VL 188 IS 3 BP 422 EP 427 DI 10.1016/j.psychres.2011.05.027 PG 6 WC Psychiatry SC Psychiatry GA 810QU UT WOS:000294143000020 PM 21658782 ER PT J AU Atochina-Vasserman, EN Bates, SR Zhang, P Abramova, H Zhang, ZG Gonzales, L Tao, JQ Gochuico, BR Gahl, W Guo, CJ Gow, AJ Beers, MF Guttentag, S AF Atochina-Vasserman, Elena N. Bates, Sandra R. Zhang, Peggy Abramova, Helen Zhang, Zhenguo Gonzales, Linda Tao, Jian-Qin Gochuico, Bernadette R. Gahl, William Guo, Chang-Jiang Gow, Andrew J. Beers, Michael F. Guttentag, Susan TI Early Alveolar Epithelial Dysfunction Promotes Lung Inflammation in a Mouse Model of Hermansky-Pudlak Syndrome SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE Hermansky-Pudlak syndrome; S-nitrosylation; surfactant protein D; lung remodeling ID SURFACTANT-PROTEIN-D; IDIOPATHIC PULMONARY-FIBROSIS; INTERSTITIAL PNEUMONIA; COMPONENT EXPRESSION; S-NITROSYLATION; CELLS; INJURY; TYPE-2; MICE; COLLECTINS AB Rationale: The pulmonary phenotype of Hermansky-Pudlak syndrome (HPS) in adults includes foamy alveolar type 2 cells, inflammation, and lung remodeling, but there is no information about ontogeny or early disease mediators. Objectives: To establish the ontogeny of HPS lung disease in an animal model, examine disease mediators, and relate them to patients with HPS1. Methods: Mice with mutations in both HPS1/pale ear and HPS2/AP3B1/pearl (EPPE mice) were studied longitudinally. Total lung homogenate, lung tissue sections, and bronchoalveolar lavage (BAL) were examined for phospholipid, collagen, histology, cell counts, chemokines, surfactant protein D (SP-D), and S-nitrosylated SP-D. Isolated alveolar epithelial cells were examined for expression of inflammatory mediators, and chemotaxis assays were used to assess their importance. Pulmonary function test results and BAL from patients with HPS1 and normal volunteers were examined for clinical correlation. Measurements and Main Results: EPPE mice develop increased total lung phospholipid, followed by a macrophage-predominant pulmonary inflammation, and lung remodeling including fibrosis. BAL fluid from EPPE animals exhibited early accumulation of both SP-D and S-nitrosylated SP-D. BAL fluid from patients with HPS1 exhibited similar changes in SP-D that correlated inversely with pulmonary function. Alveolar epithelial cells demonstrated expression of both monocyte chemotactic protein (MCP)-1 and inducible nitric oxide synthase in juvenile EPPE mice. Last, BAL from EPPE mice and patients with HPS1 enhanced migration of RAW267.4 cells, which was attenuated by immunodepletion of SP-D and MCP-1. Conclusions: Inflammation is initiated from the abnormal alveolar epithelial cells in HPS, and S-nitrosylated SP-D plays a significant role in amplifying pulmonary inflammation. C1 [Atochina-Vasserman, Elena N.; Abramova, Helen; Beers, Michael F.] Univ Penn, Sch Med, Div Pulm & Crit Care Med, Philadelphia, PA 19104 USA. [Bates, Sandra R.; Tao, Jian-Qin] Univ Penn, Sch Med, Inst Environm Med, Philadelphia, PA 19104 USA. [Zhang, Peggy; Zhang, Zhenguo; Gonzales, Linda; Guttentag, Susan] Childrens Hosp Philadelphia, Dept Pediat, Div Neonatol, Philadelphia, PA 19104 USA. [Gochuico, Bernadette R.; Gahl, William] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Abramova, Helen; Guo, Chang-Jiang; Gow, Andrew J.] Rutgers State Univ, Ernest Mario Sch Pharm, Dept Pharmacol, Piscataway, NJ USA. RP Guttentag, S (reprint author), 416G Abramson Res Ctr, 3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM guttentag@email.chop.edu RI Guttentag, Susan/D-8705-2013; Gow, Andrew/N-8566-2013 OI Guttentag, Susan/0000-0003-4420-5879; Gow, Andrew/0000-0003-0876-5158 FU National Human Genome Research Institute, National Institutes of Health; National Institutes of Health [HL086621, HL019737, HL064520, ES013508, HL059959]; Mead Johnson; Abbott Nutritionals; American Heart Association FX Supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (B.R.G., W.G.), and by extramural funding from the National Institutes of Health through HL086621 (A.J.G.), HL019737 (S.R.B., M.F.B.), HL064520 (M.F.B.), ES013508 (M.F.B.), and HL059959 (S.G.).; E.N.A.-V., S.R.B., P.Z., H.A., Z.Z., L.G., J.-Q.T., B.R.G., W.G., C.-J.G., A.J.G., and M.F.B. do not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S. G. received lecture fees from Mead Johnson and Abbott Nutritionals, and received grant support from the American Heart Association. NR 46 TC 18 Z9 18 U1 0 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG 15 PY 2011 VL 184 IS 4 BP 449 EP 458 DI 10.1164/rccm.201011-1882OC PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 808EL UT WOS:000293959600015 PM 21616998 ER PT J AU Willett, M Brocard, M Davide, A Morley, SJ AF Willett, Mark Brocard, Michele Davide, Alexandre Morley, Simon J. TI Translation initiation factors and active sites of protein synthesis co-localize at the leading edge of migrating fibroblasts SO BIOCHEMICAL JOURNAL LA English DT Article DE Golgi apparatus; localization; membrane microdomain; translation initiation factor ID MESSENGER-RNA LOCALIZATION; ENDOPLASMIC-RETICULUM; MAMMALIAN-CELLS; POLY(A)-BINDING PROTEIN-1; HYPERTONIC STRESS; COMPLEX; GOLGI; MTOR; TRANSPORT; MECHANISMS AB Cell migration is a highly controlled essential cellular process, often dysregulated in tumour cells, dynamically controlled by the architecture of the cell. Studies involving cellular fractionation and microarray profiling have previously identified functionally distinct mRNA populations specific to cellular organelles and architectural compartments. However, the interaction between the translational machinery itself and cellular structures is relatively unexplored. To help understand the role for the compartmentalization and localized protein synthesis in cell migration, we have used scanning confocal microscopy, immunofluorescence and a novel ribopuromycylation method to visualize translating ribosomes. In the present study we show that eIFs (eukaryotic initiation factors) localize to the leading edge of migrating MRCS fibroblasts in a process dependent on TGN (trans-Golgi network) to plasma membrane vesicle transport. We show that eIF4E and eIF4GI are associated with the Golgi apparatus and membrane microdomains, and that a proportion of these proteins co-localize to sites of active translation at the leading edge of migrating cells. C1 [Willett, Mark; Brocard, Michele; Morley, Simon J.] Univ Sussex, Dept Biochem, Sch Life Sci, Brighton BN1 9QG, E Sussex, England. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Morley, SJ (reprint author), Univ Sussex, Dept Biochem, Sch Life Sci, Brighton BN1 9QG, E Sussex, England. EM s.j.morley@sussex.ac.uk OI David, Alexandre/0000-0003-3365-1339 FU Biotechnology and Biological Sciences Research Council (UK) [BB/H018956/1] FX This work was supported by the Biotechnology and Biological Sciences Research Council (UK) [grant number BB/H018956/1]. NR 67 TC 16 Z9 16 U1 0 U2 9 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD AUG 15 PY 2011 VL 438 BP 217 EP 227 DI 10.1042/BJ20110435 PN 1 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809UY UT WOS:000294083400021 PM 21539520 ER PT J AU May, KF Gulley, JL Drake, CG Dranoff, G Kantoff, PW AF May, Kenneth F., Jr. Gulley, James L. Drake, Charles G. Dranoff, Glenn Kantoff, Philip W. TI Prostate Cancer Immunotherapy SO CLINICAL CANCER RESEARCH LA English DT Article ID CD8(+) T-CELLS; CTLA-4 BLOCKADE; COMBINATION IMMUNOTHERAPY; ANDROGEN-DEPRIVATION; ANTITUMOR IMMUNITY; TUMOR; PD-1; EFFECTOR; THERAPY; MICE AB The interaction between the immune system and prostate cancer has been an area of research interest for several decades. The recent U. S. Food and Drug Administration approval of 2 first-in-class proof-of-concept immunotherapies (sipuleucel-T and ipilimumab) has stimulated broader interest in manipulating immunity to fight cancer. In the context of prostate cancer, the immunotherapy strategies that have garnered the most interest are the therapeutic vaccination strategies, exemplified by sipuleucel-T and PROSTVAC-VF, and immune checkpoint blockade of CTLA-4 and PD-1. Improved understanding of the immune responses generated by these strategies and development of predictive biomarkers for patient selection will guide rational combinations of these treatments and provide building blocks for future immunotherapies. Clin Cancer Res; 17(16); 5233-8. (C)2011 AACR. C1 [May, Kenneth F., Jr.; Dranoff, Glenn; Kantoff, Philip W.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [May, Kenneth F., Jr.; Dranoff, Glenn] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02215 USA. [May, Kenneth F., Jr.; Dranoff, Glenn; Kantoff, Philip W.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [May, Kenneth F., Jr.; Dranoff, Glenn; Kantoff, Philip W.] Harvard Univ, Sch Med, Boston, MA USA. [Gulley, James L.] NCI, Clin Trials Grp, Tumor Immunol & Biol Lab, Med Oncol Branch,Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Drake, Charles G.] Johns Hopkins Sch Med, James Buchanan Brady Urol Inst, Dept Urol,Dept Oncol, Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP May, KF (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Smith 353, Boston, MA 02215 USA. EM kmay1@partners.org RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Prostate Cancer Foundation; NIH, National Cancer Institute; Center for Cancer Research; NIH [R01 CA127153, 1P50CA58236-15, CA143083, CA78378, 5P01CA089021-10, 5P50CA090381-09]; Patrick C. Walsh Fund; OneInSix Foundation; Leukemia & Lymphoma Society; Melanoma Research Alliance; Alliance for Cancer Gene Therapy; Research Foundation for the Treatment of Ovarian Cancer; Department of Defense FX Prostate Cancer Foundation Young Investigator Award (K. F. May); Intramural Research Program of the NIH, National Cancer Institute, and Center for Cancer Research (J.L. Gulley); NIH R01 CA127153 and 1P50CA58236-15, the Patrick C. Walsh Fund, the OneInSix Foundation, and the Prostate Cancer Foundation (C. G. Drake); NIH CA143083 and CA78378, Leukemia & Lymphoma Society, Melanoma Research Alliance, Alliance for Cancer Gene Therapy, and Research Foundation for the Treatment of Ovarian Cancer (G. Dranoff); NIH 5P01CA089021-10 and 5P50CA090381-09, Prostate Cancer Foundation, and Department of Defense (P. W. Kantoff). NR 52 TC 35 Z9 35 U1 2 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2011 VL 17 IS 16 BP 5233 EP 5238 DI 10.1158/1078-0432.CCR-10-3402 PG 6 WC Oncology SC Oncology GA 806VN UT WOS:000293843700004 PM 21700764 ER PT J AU Klebanoff, CA Gattinoni, L Palmer, DC Muranski, P Ji, Y Hinrichs, CS Borman, ZA Kerkar, SP Scott, CD Finkelstein, SE Rosenberg, SA Restifo, NP AF Klebanoff, Christopher A. Gattinoni, Luca Palmer, Douglas C. Muranski, Pawel Ji, Yun Hinrichs, Christian S. Borman, Zachary A. Kerkar, Sid P. Scott, Christopher D. Finkelstein, Steven E. Rosenberg, Steven A. Restifo, Nicholas P. TI Determinants of Successful CD8(+) T-Cell Adoptive Immunotherapy for Large Established Tumors in Mice SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC MELANOMA PATIENTS; IN-VIVO; PHASE-I; INFILTRATING LYMPHOCYTES; CANCER REGRESSION; ANTITUMOR-ACTIVITY; TRANSFER THERAPY; GENE-THERAPY; STEM-CELLS; MEMORY AB Purpose: Adoptive cell transfer (ACT) of tumor infiltrating or genetically engineered T cells can cause durable responses in patients with metastatic cancer. Multiple clinically modifiable parameters can comprise this therapy, including cell dose and phenotype, in vivo antigen restimulation, and common gamma-chain (gamma(c)) cytokine support. However, the relative contributions of each these individual components to the magnitude of the antitumor response have yet to be quantified. Experimental Design: To systematically and quantitatively appraise each of these variables, we employed the Pmel-1 mouse model treating large, established B16 melanoma tumors. In addition to cell dose and magnitude of in vivo antigen restimulation, we also evaluated the relative efficacy of central memory (T(CM)), effector memory (T(EM)), and stem cell memory (T(SCM)) subsets on the strength of tumor regression as well as the dose and type of clinically available gamma(c) cytokines, including IL-2, IL-7, IL-15, and IL-21. Results: We found that cell dose, T-cell differentiation status, and viral vaccine titer each were correlated strongly and significantly with the magnitude of tumor regression. Surprisingly, although the total number of IL-2 doses was correlated with tumor regression, no significant benefit to prolonged (>= 6 doses) administration was observed. Moreover, the specific type and dose of gamma(c) cytokine only moderately correlated with response. Conclusion: Collectively, these findings elucidate some of the key determinants of successful ACT immunotherapy for the treatment of cancer in mice and further show that gamma(c) cytokines offer a similar ability to effectively drive antitumor T-cell function in vivo. Clin Cancer Res; 17(16); 5343-52. (C)2011 AACR. C1 [Klebanoff, Christopher A.; Gattinoni, Luca; Palmer, Douglas C.; Muranski, Pawel; Ji, Yun; Hinrichs, Christian S.; Borman, Zachary A.; Kerkar, Sid P.; Scott, Christopher D.; Finkelstein, Steven E.; Rosenberg, Steven A.; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Klebanoff, CA (reprint author), NCI, Ctr Canc Res, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM klebanoc@mail.nih.gov; NPR@nih.gov RI Gattinoni, Luca/A-2281-2008; Ji, Yun/B-7245-2009; Restifo, Nicholas/A-5713-2008; Palmer, Douglas/B-9454-2008; OI Gattinoni, Luca/0000-0003-2239-3282; Ji, Yun/0000-0001-6340-7009; Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580 FU NCI, Center for Cancer Research, NIH, Bethesda, MD FX This study was funded in part by the intramural research program of the NCI, Center for Cancer Research, NIH, Bethesda, MD. This article was written in partial fulfillment of a PhD degree for the George Washington University, Washington, DC (D.C. Palmer). NR 65 TC 100 Z9 103 U1 2 U2 27 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 AUG 15 PY 2011 VL 17 IS 16 BP 5343 EP 5352 DI 10.1158/1078-0432.CCR-11-0503 PG 10 WC Oncology SC Oncology GA 806VN UT WOS:000293843700015 PM 21737507 ER PT J AU Lim, WT Ng, QS Ivy, P Leong, SS Singh, O Chowbay, B Gao, F Thng, CH Goh, BC Tan, DSW Koh, TS Toh, CK Tan, EH AF Lim, Wan-Teck Ng, Quan-Sing Ivy, Percy Leong, Swan-Swan Singh, Onkar Chowbay, Balram Gao, Fei Thng, Choon Hua Goh, Boon-Cher Tan, Daniel Shao-Weng Koh, Tong San Toh, Chee-Keong Tan, Eng-Huat TI A Phase II Study of Pazopanib in Asian Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TUMOR ANGIOGENESIS; PROGNOSTIC-FACTORS; CELL CARCINOMA; FDG-PET; RECURRENT; THERAPY; TRIAL; CT; EXPRESSION AB Purpose: Nasopharyngeal carcinoma is endemic in Asia and angiogenesis is important for growth and progression. We hypothesized that pazopanib would have antiangiogenic activity in nasopharyngeal carcinoma. Experimental Design: A single arm monotherapy study of pazopanib in patients with WHO type II/III nasopharyngeal carcinoma who had metastatic/recurrent disease and failed at least one line of chemotherapy. A Simon's optimal 2-stage design was used. Patients with Eastern Cooperative Oncology Group (ECOG) 0-2 and adequate organ function were treated with pazopanib 800 mg daily on a 21-day cycle. The primary endpoint was clinical benefit rate (CR/PR/SD) achieved after 12 weeks of treatment. Secondary endpoints included toxicity and progression-free survival. Exploratory studies of dynamic-contrast enhanced computed tomography (DCE-CT) paired with pharmacokinetics (PK) of pazopanib was done. Results: Thirty-three patients were accrued. Patients were ECOG 0-1 with median age of 50 years (range 36-68). There were 2 (6.1%) partial responses, 16 (48.5%) stable disease, 11 (33.3%) progressive disease, 4 (12.1%) were not evaluable for response. The clinical benefit rate was 54.5% (95% CI: 38.0-70.2). Ten patients (30.3%) received more than 6 cycles (4 months) of treatment and 7 (21.2%) had PR/SD that lasted at least 6 months. One patient each died from epistaxis and myocardial infarction. Common grade 3/4 toxicities included fatigue (15.2%), hand-foot syndrome (15.2%), anorexia (9.1%), diarrhea (6.1%), and vomiting (6.1%). Serial DCE-CT scans show significant reductions in tumor blood flow, permeability surface area product, and fractional intravascular blood volume. Conclusion: Pazopanib showed encouraging activity in heavily pretreated nasopharyngeal carcinoma with an acceptable toxicity profile. Clin Cancer Res; 17(16); 5481-9. (C)2011 AACR. C1 [Lim, Wan-Teck; Ng, Quan-Sing; Leong, Swan-Swan; Tan, Daniel Shao-Weng; Toh, Chee-Keong; Tan, Eng-Huat] Natl Canc Ctr Singapore, Dept Med Oncol, Singapore 169610, Singapore. [Thng, Choon Hua; Koh, Tong San] Natl Canc Ctr Singapore, Dept Oncol Imaging, Singapore 169610, Singapore. [Gao, Fei] Natl Canc Ctr Singapore, Div Clin Trials & Epidemiol Sci, Singapore 169610, Singapore. [Ivy, Percy] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Lim, WT (reprint author), Natl Canc Ctr Singapore, Dept Med Oncol, 11 Hosp Dr, Singapore 169610, Singapore. EM dmolwt@nccs.com.sg RI KOH, TONG SAN/A-5027-2011 FU Singapore Cancer Syndicate [SCS-CS-0072]; Biomedical Research Council, Singapore [BMRC/08/1/31/19/577]; NCI CTEP FX This work was funded in part by the Singapore Cancer Syndicate (SCS-CS-0072) and Biomedical Research Council, Singapore (BMRC/08/1/31/19/577) research grants and supported by NCI CTEP. NR 41 TC 30 Z9 30 U1 0 U2 2 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 AUG 15 PY 2011 VL 17 IS 16 BP 5481 EP 5489 DI 10.1158/1078-0432.CCR-10-3409 PG 9 WC Oncology SC Oncology GA 806VN UT WOS:000293843700028 PM 21712450 ER PT J AU Stone, JE Kumar, D Binz, SK Inase, A Iwai, S Chabes, A Burgers, PM Kunkel, TA AF Stone, Jana E. Kumar, Dinesh Binz, Sara K. Inase, Aki Iwai, Shigenori Chabes, Andrei Burgers, Peter M. Kunkel, Thomas A. TI Lesion bypass by S-cerevisiae Pol zeta alone SO DNA REPAIR LA English DT Article DE DNA polymerase zeta; Translesion synthesis; UV photoproducts; Abasic sites ID DNA-POLYMERASE-ZETA; DEPENDENT TRANSLESION SYNTHESIS; THYMINE-THYMINE DIMER; STRAND-BREAK-REPAIR; EMBRYONIC LETHALITY; REV1 PROTEIN; ERROR-FREE; INDUCED MUTAGENESIS; CATALYTIC SUBUNIT; ABASIC SITES AB DNA polymerase zeta (Pol zeta) participates in translesion synthesis (TLS) of DNA adducts that stall replication fork progression. Previous studies have led to the suggestion that the primary role of Pol zeta in TLS is to extend primers created when another DNA polymerase inserts nucleotides opposite lesions. Here we test the non-exclusive possibility that Pol zeta can sometimes perform TLS in the absence of any other polymerase. To do so, we quantified the efficiency with which S. cerevisiae Pol zeta bypasses abasic sites, cis-syn cyclobutane pyrimidine dimers and (6-4) photoproducts. In reactions containing dNTP concentrations that mimic those induced by DNA damage, a Pol zeta derivative with phenylalanine substituted for leucine 979 at the polymerase active site bypasses all three lesions at efficiencies between 27 and 73%. Wild-type Pol zeta also bypasses these lesions, with efficiencies that are lower and depend on the sequence context in which the lesion resides. The results are consistent with the hypothesis that, in addition to extending aberrant termini created by other DNA polymerases, Pol zeta has the potential to be the sole DNA polymerase involved in TLS. Published by Elsevier B.V. C1 [Stone, Jana E.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Stone, Jana E.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Kumar, Dinesh; Chabes, Andrei] Umea Univ, Dept Med Biochem & Biophys, SE-90187 Umea, Sweden. [Kumar, Dinesh; Chabes, Andrei] Umea Univ, Lab Mol Infect Med Sweden MIMS, SE-90187 Umea, Sweden. [Binz, Sara K.; Burgers, Peter M.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Inase, Aki; Iwai, Shigenori] Osaka Univ, Grad Sch Engn Sci, Div Chem, Osaka 5608531, Japan. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health [Z01 ES065070]; Swedish Foundation for Strategic Research; Swedish Research Council; Swedish Cancer Society; National Institutes of Health [GM032431]; Ministry of Education, Culture, Sports, Science, and Technology, Japan FX We thank Mercedes Arana, Katarzyna Bebenek and Danielle Watt for helpful comments on the manuscript. This work was supported in part by the Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health [Project Z01 ES065070 to TAK], by the Swedish Foundation for Strategic Research, the Swedish Research Council and the Swedish Cancer Society [to AC], by National Institutes of Health [grant GM032431 to PMB] and by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan [to SI]. NR 60 TC 19 Z9 19 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD AUG 15 PY 2011 VL 10 IS 8 BP 826 EP 834 DI 10.1016/j.dnarep.2011.04.032 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 809EE UT WOS:000294033800005 PM 21622032 ER PT J AU Watt, DL Johansson, E Burgers, PM Kunkel, TA AF Watt, Danielle L. Johansson, Erik Burgers, Peter M. Kunkel, Thomas A. TI Replication of ribonucleotide-containing DNA templates by yeast replicative polymerases SO DNA REPAIR LA English DT Article DE DNA replication; Ribonucleotides; rNMP bypass; Translesion synthesis ID REVERSE-TRANSCRIPTASE; FIDELITY; RESIDUE; FAMILY; DISCRIMINATION; EFFICIENCY; INSERTION; MUTANTS; EPSILON; BYPASS AB The major replicative DNA polymerases of S. cerevisiae (Pots alpha, delta, and epsilon) incorporate substantial numbers of ribonucleotides into DNA during DNA synthesis. When these ribonucleotides are not removed in vivo, they reside in the template strand used for the next round of replication and could potentially reduce replication efficiency and fidelity. To examine if the presence of ribonucleotides in a DNA template impede DNA synthesis, we determined the efficiency with which Pols alpha, delta, and epsilon copy DNA templates containing a single ribonucleotide. All three polymerases can replicate past ribonucleotides. Relative to all-DNA templates, bypass of ribo-containing templates is slightly reduced, to extents that depend on the identity of the ribo and the sequence context in which it resides. Bypass efficiencies for Pols delta and epsilon were increased by increasing the dNTP concentrations to those induced by cellular stress, and in the case of Pol epsilon, by inactivating the 3'-exonuclease activity. Overall, ribonucleotide bypass efficiencies are comparable to, and usually exceed, those for the common oxidative stress-induced lesion 8-oxo-guanine. Published by Elsevier B.V. C1 [Watt, Danielle L.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Watt, Danielle L.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Johansson, Erik] Umea Univ, Dept Med Biochem & Biophys, SE-90187 Umea, Sweden. [Burgers, Peter M.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Division of Intramural Research of the NIH, NIEHS [Z01 ES065070]; Swedish Research Council; Swedish Cancer Society, Smartafonden; Medical Faculty of Umea University; NIH [GM032431] FX We thank Katarzyna Bebenek and Jessica Williams for helpful comments on the manuscript, Amy Abdulovic for providing purified Pol delta holoenzyme, and Else-Britt Lundstrom for providing purified Pol epsilon enzymes. This work was supported by Project Z01 ES065070 to T.A.K. from the Division of Intramural Research of the NIH, NIEHS, by the Swedish Research Council, the Swedish Cancer Society, Smartafonden and the fund for Basic Science-oriented Biotechnology, Medical Faculty of Umea University to E.J., and by NIH grant GM032431 to P.M.B. NR 41 TC 29 Z9 29 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD AUG 15 PY 2011 VL 10 IS 8 BP 897 EP 902 DI 10.1016/j.dnarep.2011.05.009 PG 6 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 809EE UT WOS:000294033800012 PM 21703943 ER PT J AU Moshkovich, N Nisha, P Boyle, PJ Thompson, BA Dale, RK Lei, EP AF Moshkovich, Nellie Nisha, Parul Boyle, Patrick J. Thompson, Brandi A. Dale, Ryan K. Lei, Elissa P. TI RNAi-independent role for Argonaute2 in CTCF/CP190 chromatin insulator function SO GENES & DEVELOPMENT LA English DT Article DE RNAi; chromatin; insulator; Drosophila; ChIP-seq; nuclear organization ID BITHORAX COMPLEX; HETEROCHROMATIN FORMATION; CHROMOSOME SEGREGATION; GENOME ORGANIZATION; RESPONSE ELEMENTS; BOUNDARY-ELEMENT; GENE-REGULATION; DISTINCT ROLES; GROUP PROTEINS; BINDING-SITES AB A major role of the RNAi pathway in Schizosaccharomyces pombe is to nucleate heterochromatin, but it remains unclear whether this mechanism is conserved. To address this question in Drosophila, we performed genome-wide localization of Argonaute2 (AGO2) by chromatin immunoprecipitation (ChIP)-seq in two different embryonic cell lines and found that AGO2 localizes to euchromatin but not heterochromatin. This localization pattern is further supported by immunofluorescence staining of polytene chromosomes and cell lines, and these studies also indicate that a substantial fraction of AGO2 resides in the nucleus. Intriguingly, AGO2 colocalizes extensively with CTCF/CP190 chromatin insulators but not with genomic regions corresponding to endogenous siRNA production. Moreover, AGO2, but not its catalytic activity or Dicer-2, is required for CTCF/CP190-dependent Fab-8 insulator function. AGO2 interacts physically with CTCF and CP190, and depletion of either CTCF or CP190 results in genome-wide loss of AGO2 chromatin association. Finally, mutation of CTCF, CP190, or AGO2 leads to reduction of chromosomal looping interactions, thereby altering gene expression. We propose that RNAi-independent recruitment of AGO2 to chromatin by insulator proteins promotes the definition of transcriptional domains throughout the genome. C1 [Moshkovich, Nellie; Nisha, Parul; Boyle, Patrick J.; Thompson, Brandi A.; Dale, Ryan K.; Lei, Elissa P.] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Moshkovich, Nellie] Univ Maryland, Grad Program Mol & Cell Biol, College Pk, MD 20742 USA. RP Lei, EP (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM leielissa@niddk.nih.gov OI Dale, Ryan/0000-0003-2664-3744 FU National Institute of Diabetes and Digestive and Kidney Diseases FX We thank A. Beyer for alpha-Pep; F. Fuller-Pace for alpha-p68; J. Kassis for alpha-Pho; Q. Liu, A. Mueller, and M. Siomi for alpha-AGO2; P. O'Farrell and D. Moazed for alpha-Pc; and C. Berg, J. Birchler, R. Carthew, G. Gavalli, V. Corces, G. Hannon, S. Hou, F. Karch, J. Kassis, E. Lai, G. Shanower, P. Schedl, and P. Zamore for strains. We are indebted to P. Murphy for antibody characterization; M. Emmett for primers; A. Dean for 3C protocols; S. Grewal, F. Karch, and B. Oliver for discussions; and J. Kassis and L. Matzat for critical reading of the manuscript. This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 65 TC 62 Z9 63 U1 1 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG 15 PY 2011 VL 25 IS 16 BP 1686 EP 1701 DI 10.1101/gad.16651211 PG 16 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 808UF UT WOS:000294003800005 PM 21852534 ER PT J AU Kulkarni, H Okulicz, JF Grandits, G Crum-Cianflone, NF Landrum, ML Hale, B Wortmann, G Tramont, E Polis, M Dolan, M Lifson, AR Agan, BK Ahuja, SK Marconi, VC AF Kulkarni, Hemant Okulicz, Jason F. Grandits, Greg Crum-Cianflone, Nancy F. Landrum, Michael L. Hale, Braden Wortmann, Glenn Tramont, Edmund Polis, Michael Dolan, Matthew Lifson, Alan R. Agan, Brian K. Ahuja, Sunil K. Marconi, Vincent C. TI Early Postseroconversion CD4 Cell Counts Independently Predict CD4 Cell Count Recovery in HIV-1-Postive Subjects Receiving Antiretroviral Therapy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE CD4 count; highly active antiretroviral therapy; outcomes; predictors; treatment response ID PLASMA HIV RNA; VIROLOGICAL RESPONSES; HIV-1-INFECTED PATIENTS; IMMUNOLOGICAL RESPONSE; DISEASE PROGRESSION; PROTEASE INHIBITOR; INFECTED PATIENTS; IMMUNODEFICIENCY; SUPPRESSION; INTERRUPTION AB Background: The relationship between CD4(+) T-cell counts determined soon after seroconversion with HIV-1 (baseline CD4), nadir CD4, and CD4 levels attained during highly active antiretroviral therapy (HAART) is unknown. Methods: Longitudinal, including baseline (at or soon after HIV diagnosis), intermediate (nadir), and distal (post-HAART) CD4(+) T-cell counts were assessed in 1085 seroconverting subjects who achieved viral load suppression from a large well-characterized cohort. The association of baseline with post-HAART CD4(+) T-cell count was determined after adjustment for other relevant covariates. Results: A higher baseline CD4(+) T-cell count predicted a greater postHAART CD4(+) T-cell count, independent of the nadir and other explanatory variables. Together, baseline and nadir strongly predicted the post-HAART CD4(+) count such that a high baseline and lower nadir were associated with a maximal immune recovery after HAART. Likelihood of recovery of the baseline count after HAART was significantly higher when the nadir/ baseline count ratio was consistently >= 0.6. Conclusions: Among viral load suppressing seroconverters, the absolute CD4(+) T-cell count attained post-HAART is highly dependent on both baseline and nadir CD4(+) T-cell counts. These associations further support the early diagnosis and initiation of HAART among HIV-infected persons. C1 [Kulkarni, Hemant; Ahuja, Sunil K.] S Texas Vet Hlth Care Syst, Vet Adm Res Ctr AIDS & HIV Infect 1, San Antonio, TX USA. [Kulkarni, Hemant; Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Okulicz, Jason F.; Grandits, Greg; Crum-Cianflone, Nancy F.; Landrum, Michael L.; Hale, Braden; Wortmann, Glenn; Tramont, Edmund; Polis, Michael; Agan, Brian K.; Marconi, Vincent C.] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20814 USA. [Okulicz, Jason F.; Landrum, Michael L.] Brooke Army Med Ctr, San Antonio Mil Med Ctr, Infect Dis Serv, Ft Sam Houston, TX 78234 USA. [Grandits, Greg] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Crum-Cianflone, Nancy F.; Hale, Braden] USN, Infect Dis Clin, San Diego Med Ctr, San Diego, CA 92152 USA. [Wortmann, Glenn] Walter Reed Army Med Ctr, Infect Dis Serv, Washington, DC 20307 USA. [Tramont, Edmund; Polis, Michael] NIAID, NIH, Bethesda, MD 20892 USA. [Dolan, Matthew] Wilford Hall USAF Med Ctr, Henry M Jackson Fdn, Lackland AFB, TX 78236 USA. [Lifson, Alan R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol & Biochem, San Antonio, TX 78229 USA. [Marconi, Vincent C.] Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA USA. RP Kulkarni, H (reprint author), 12023 Waterway Rdg, San Antonio, TX USA. EM kulkarnih@uthscsa.edu RI Marconi, Vincent/N-3210-2014; OI Marconi, Vincent/0000-0001-8409-4689; Polis, Michael/0000-0002-9151-2268; Agan, Brian/0000-0002-5114-1669 FU Infectious Disease Clinical Research Program (IDCRP) [IDCRP-000-03]; Department of Defense; National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) [Y1-AI-5072]; Veterans Administration Center on AIDS and HIV infection of the South Texas Veterans Health Care System; NIH [R37046326]; VA MERIT award; Elizabeth Glaser Scientist Award; Burroughs Wellcome Clinical Scientist Award in Translational Research; Doris Duke Distinguished Clinical Scientist Award FX Support for this work (IDCRP-000-03) was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense program executed through the Uniformed Services University of the Health Sciences. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), under Inter-Agency Agreement Y1-AI-5072. This work was also supported by the Veterans Administration Center on AIDS and HIV infection of the South Texas Veterans Health Care System, and a MERIT (R37046326) award from the NIH to S. K. A. S. K. A. is also supported by a VA MERIT award and is a recipient of the Elizabeth Glaser Scientist Award, the Burroughs Wellcome Clinical Scientist Award in Translational Research, and the Doris Duke Distinguished Clinical Scientist Award. The content of this publication is the sole responsibility of the authors and does not necessarily reflect the views or policies of the NIH or the Department of Health and Human Services, the Department of Defense or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government. NR 45 TC 9 Z9 9 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 AUG 15 PY 2011 VL 57 IS 5 BP 387 EP 395 DI 10.1097/QAI.0b013e3182219113 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 800RE UT WOS:000293381300013 PM 21546844 ER PT J AU Jacobson, DL Williams, P Tassiopoulos, K Melvin, A Hazra, R Farley, J AF Jacobson, Denise L. Williams, Paige Tassiopoulos, Katherine Melvin, Ann Hazra, Rohan Farley, John TI Clinical Management and Follow-up of Hypercholesterolemia Among Perinatally HIV-Infected Children Enrolled in the PACTG 219C Study SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; children; hypercholesterolemia; antiretroviral therapy; cohort study ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; CONTAINING ANTIRETROVIRAL THERAPY; PROTEASE INHIBITOR SUBSTITUTION; INSULIN-RESISTANCE; SERUM-LIPIDS; RISK-FACTORS; DYSLIPIDEMIA; HYPERLIPIDEMIA; IMPROVEMENT; ATAZANAVIR AB Background: Hypercholesterolemia is common in perinatally HIV-infected (HIV+) children, but little is known about the clinical course and management in this population. Methods: We studied HIV+ children in a multisite prospective cohort study (Pediatric AIDS Clinical Trials Group 219C) and considered follow-up for 2 years after development of hypercholesterolemia. We estimated the time and factors associated with resolution of hypercholesterolemia and described changes in antiretroviral regimen and use of lipid-lowering medications. We defined incident hypercholesterolemia as entry total cholesterol (cholesterol) <220 mg/dL and 2 subsequent consecutive cholesterol >= 220 mg/dL and defined resolution of hypercholesterolemia as 2 consecutive cholesterol <200 mg/dL after incident hypercholesterolemia. Results: Among 240 incident hypercholesterolemia cases, 81 (34%) had resolution to normal cholesterol within 2 years of follow-up (median follow-up = 1.9 years). The median age of cases was 10.3 years with 54% non-Hispanic black and 53% male. Resolution to normal cholesterol was more likely in children who changed antiretroviral regimen (adjusted hazard ratio = 2.37, 95% confidence interval: 1.45 to 3.88) and who were 13 years and older (aHR = 2.39, 95% confidence interval: 1.33 to 4.27). Types of regimen changes varied greatly, and 15 children began statins. Conclusion: The majority of children who develop hypercholesterolemia maintain elevated levels over time, potentially placing them at risk for premature cardiovascular morbidity. C1 [Jacobson, Denise L.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Williams, Paige] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Tassiopoulos, Katherine] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Melvin, Ann] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Farley, John] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. RP Jacobson, DL (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, 651 Huntington Ave, Boston, MA 02115 USA. EM jacobson@sdac.harvard.edu FU Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases [5 U01 AI41110]; PACTG; International Maternal Pediatric Adolescent AIDS Clinical Trials Group; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-DK-9-001/HHSN267200800001C]; [1 U01 AI068616] FX Supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement No. 5 U01 AI41110 with the PACTG and No. 1 U01 AI068616 with the International Maternal Pediatric Adolescent AIDS Clinical Trials Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract number N01-DK-9-001/HHSN267200800001C).; We thank the children and families for their participation in PACTG 219C and the individuals and institutions involved in the conduct of 219C and the leadership and participants of the P219/219C protocol team. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group was provided by the National Institute of Allergy and Infectious Diseases (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health (AI068632). We also thank the individual staff members and sites who have participated in the conduct of this study, as provided in Supplemental Digital Content 1 (see Appendix, http://links.lww.com/QAI/A191). We thank Todd Brown, MD, PhD, for clinical information used to develop this article. NR 35 TC 11 Z9 11 U1 0 U2 0 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 AUG 15 PY 2011 VL 57 IS 5 BP 413 EP 420 DI 10.1097/QAI.0b013e31822203f5 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 800RE UT WOS:000293381300016 PM 21602698 ER PT J AU Shinohara, RT Crainiceanu, CM Caffo, BS Gaitan, MI Reich, DS AF Shinohara, Russell T. Crainiceanu, Ciprian M. Caffo, Brian S. Gaitan, Maria Ines Reich, Daniel S. TI Population-wide principal component-based quantification of blood-brain-barrier dynamics in multiple sclerosis SO NEUROIMAGE LA English DT Article DE Blood-brain barrier; Multiple sclerosis; MRI; DCE-MRI; Gadolinium enhancement; Functional principal components analysis AB The processes by which new white matter lesions in multiple sclerosis (MS) develop are only partially understood. Much of this understanding has come through magnetic resonance imaging (MRI) of the human brain. One of the hallmarks of new lesion development in MS is enhancement on T-1-weighted MRI scans following the intravenous administration of a gadolinium-based contrast agent that shortens the longitudinal relaxation time of the tissue. Visible enhancement on the MRI results from the opening of the blood-brain barrier and reveals areas of active inflammation. The incidence and number of existing enhancing lesions are common outcome measures used in MS treatment clinical trials. Dynamic-contrast-enhanced MRI (DCE-MRI) can estimate the rate at which contrast agents pass from the plasma to MS lesions. In this paper, we develop a principal component-based framework for the analysis of these data that provides biologically meaningful quantification of blood-brain-barrier opening in new MS lesions. To accomplish this, we use functional principal components analysis to study directions of variation in the voxel-level time series of intensities both within and across subjects. The analysis reveals and allows quantification of typical spatiotemporal enhancement patterns in acute MS lesions, providing measures of magnitude, rate, shape (ring-like vs. nodular), and dynamics (centrifugal vs. centripetal). Across 10 subjects with relapsing-remitting and primary progressive MS, we found subjects to have between 0 and 12 gadolinium-enhancing lesions, the majority of which enhanced centripetally. We quantified the spatiotemporal behavior within each of these lesions using novel measures. Further application of these techniques will determine the extent to which these lesion measures can predict or track response to therapy or long-term prognosis in this disorder. (C) 2011 Elsevier Inc. All rights reserved. C1 [Shinohara, Russell T.; Crainiceanu, Ciprian M.; Caffo, Brian S.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Gaitan, Maria Ines; Reich, Daniel S.] Natl Inst Neurol Disorders & Stroke, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Shinohara, RT (reprint author), Johns Hopkins Univ, Dept Biostat, 615 N Wolfe St, Baltimore, MD 21205 USA. EM rshinoha@jhsph.edu RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU National Institute of Neurological Disorders and Stroke; National Institute of Neurological Disorders And Stroke [R01NS060910]; National Institute on Aging [T32AG000247]; NIH National Institute of Biomedical Imaging and Bioengineering [EB012547] FX The authors thank Bibiana Bielekova, Iordanis Evangelou, Colin Shea, Roger Stone, the Neuroimmunology Branch clinical group, and the NIH Functional Magnetic Resonance Imaging Facility technologists, who were instrumental in collecting and processing the data for this study. The research was partially supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. The research of Shinohara, Crainiceanu and Caffo was supported by Award Number R01NS060910 from the National Institute of Neurological Disorders And Stroke. Shinohara is supported by the Epidemiology and Biostatistics of Aging Training Grant T32AG000247 from the National Institute on Aging. Crainiceanu and Caffo are partially supported by EB012547 from the NIH National Institute of Biomedical Imaging and Bioengineering. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 18 TC 14 Z9 14 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 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2011 VL 57 IS 4 BP 1430 EP 1446 DI 10.1016/j.neuroimage.2011.05.038 PG 17 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 796LZ UT WOS:000293054100016 PM 21635955 ER PT J AU Raznahan, A Greenstein, D Lee, Y Long, R Clasen, L Gochman, P Addington, A Giedd, JN Rapoport, JL Gogtay, N AF Raznahan, Armin Greenstein, Deanna Lee, Yohan Long, Robert Clasen, Liv Gochman, Pete Addington, Anjene Giedd, Jay N. Rapoport, Judith L. Gogtay, Nitin TI Catechol-o-methyl transferase (COMT) val(158)met polymorphism and adolescent cortical development in patients with childhood-onset schizophrenia, their non-psychotic siblings, and healthy controls SO NEUROIMAGE LA English DT Article DE Neuroimaging; COMT; Schizophrenia; Siblings; Cortex; Maturation; Dopamine ID HUMAN CEREBRAL-CORTEX; BRAIN-DEVELOPMENT; YOUNG-ADULTS; VAL158MET POLYMORPHISM; INTELLECTUAL ABILITY; EXECUTIVE FUNCTION; GENETIC-VARIATION; BIPOLAR DISORDER; MRI DATA; METHYLTRANSFERASE AB Non-psychotic individuals at increased risk for schizophrenia show alterations in fronto-striatal dopamine signaling and cortical gray matter maturation reminiscent of those seen in schizophrenia. It remains unclear however if variations in dopamine signaling influence rates of structural cortical maturation in typically developing individuals, and whether such influences are disrupted in patients with schizophrenia and their non-psychotic siblings. We sought to address these issues by relating a functional Val -> Met polymorphism within the gene encoding catechol-o-methyltransferase (COMT)-a key enzymatic regulator of cortical dopamine levels-to longitudinal structural neuroimaging measures of cortical gray matter thickness. We included a total of 792 magnetic resonance imaging brain scans, acquired between ages 9 and 22 years from patients with childhood-onset schizophrenia (COS), their non-psychotic full siblings, and matched healthy controls. Whereas greater Val allele dose (which confers enhanced dopamine catabolism and is proposed to aggravate cortical deficits in schizophrenia) accelerated adolescent cortical thinning in both schizophrenia probands and their siblings, it attenuated cortical thinning in healthy controls. This similarity between COS patients and their siblings was accompanied by differences between the two groups in the timing and spatial distribution of disrupted COMT influences on cortical maturation. Consequently, whereas greater Val "dose" conferred persistent dorsolateral prefrontal cortical deficits amongst affected probands by adulthood, cortical thickness differences associated with varying Val dose in non-psychotic siblings resolved over the age-range studied. These findings suggest that cortical abnormalities in pedigrees affected by schizophrenia may be contributed to by a disruption of dopaminergic infleunces on cortical maturation. (C) 2011 Published by Elsevier Inc. C1 [Raznahan, Armin] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Raznahan, Armin] Kings Coll London, Dept Child & Adolescent Psychiat, Inst Psychiat, London, England. RP Raznahan, A (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM raznahan@mail.nih.gov RI Giedd, Jay/A-3080-2008; Gogtay, Nitin/A-3035-2008; Raznahan, Armin/F-4534-2012; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU National Institutes of Health, National Institute of Health Intramural Research; UK Medical Research Council [AR-G0701370] FX This study was funded through the National Institutes of Health, National Institute of Health Intramural Research, and a UK Medical Research Council Clinical Research Training Fellowship (Author AR-G0701370). The authors wish to thank the participants who took part in this study. NR 63 TC 30 Z9 31 U1 0 U2 6 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 AUG 15 PY 2011 VL 57 IS 4 BP 1517 EP 1523 DI 10.1016/j.neuroimage.2011.05.032 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 796LZ UT WOS:000293054100024 PM 21620981 ER PT J AU Lezin, G Kosaka, Y Yost, HJ Kuehn, MR Brunelli, L AF Lezin, George Kosaka, Yasuhiro Yost, H. Joseph Kuehn, Michael R. Brunelli, Luca TI A One-Step Miniprep for the Isolation of Plasmid DNA and Lambda Phage Particles SO PLOS ONE LA English DT Article ID ESCHERICHIA-COLI; DEOXYRIBONUCLEIC-ACID; BACTERIAL PLASMIDS; RAPID PREPARATION; CIRCULAR DNA; LYSIS; DETERGENTS AB Plasmid DNA minipreps are fundamental techniques in molecular biology. Current plasmid DNA minipreps use alkali and the anionic detergent SDS in a three-solution format. In addition, alkali minipreps usually require additional column-based purification steps and cannot isolate other extra-chromosomal elements, such as bacteriophages. Non-ionic detergents (NIDs) have been used occasionally as components of multiple-solution plasmid DNA minipreps, but a one-step approach has not been developed. Here, we have established a one-tube, one-solution NID plasmid DNA miniprep, and we show that this approach also isolates bacteriophage lambda particles. NID minipreps are more time-efficient than alkali minipreps, and NID plasmid DNA performs better than alkali DNA in many downstream applications. In fact, NID crude lysate DNA is sufficiently pure to be used in digestion and sequencing reactions. Microscopic analysis showed that the NID procedure fragments E. coli cells into small protoplast-like components, which may, at least in part, explain the effectiveness of this approach. This work demonstrates that one-step NID minipreps are a robust method to generate high quality plasmid DNA, and NID approaches can also isolate bacteriophage lambda particles, outperforming current standard alkali-based minipreps. C1 [Lezin, George; Kosaka, Yasuhiro; Brunelli, Luca] Univ Utah, Sch Med, Dept Pediat, Div Neonatol, Salt Lake City, UT 84112 USA. [Yost, H. Joseph] Univ Utah, Sch Med, Dept Neurobiol & Anat, Salt Lake City, UT USA. [Kuehn, Michael R.] NCI, Lab Prot Dynam & Signaling, NIH, Frederick, MD 21701 USA. RP Lezin, G (reprint author), Univ Utah, Sch Med, Dept Pediat, Div Neonatol, Salt Lake City, UT 84112 USA. EM mkuehn@mail.nih.gov; luca.brunelli@genetics.utah.edu RI Kuehn, Michael/A-4573-2014 OI Kuehn, Michael/0000-0002-7703-9160 FU Division of Neonatology, the Children's Health Research Center; Primary Children's Medical Center Foundation; Department of Pediatrics, The University of Utah School of Medicine; American Heart Association; Western States Affiliate [09BGIA2251076]; National Institutes of Health, National Cancer Institute, and Center for Cancer Research FX This work was supported by funds to L.B. from the Division of Neonatology, the Children's Health Research Center, and the Primary Children's Medical Center Foundation Innovative Grant, Department of Pediatrics, The University of Utah School of Medicine, and the American Heart Association, Beginning Grant-In-Aid, Western States Affiliate (09BGIA2251076); and by funds to M.R.K. from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services and nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 1 Z9 2 U1 4 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 15 PY 2011 VL 6 IS 8 AR e23457 DI 10.1371/journal.pone.0023457 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 808CV UT WOS:000293953700025 PM 21858126 ER PT J AU Deroo, LA Cummings, P Mueller, BA AF DeRoo, Lisa A. Cummings, Peter Mueller, Beth A. TI Smoking Before the First Pregnancy and the Risk of Breast Cancer: A Meta-Analysis SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE breast neoplasms; pregnancy; smoking ID PASSIVE CIGARETTE-SMOKING; NAT2 ACETYLATION GENOTYPE; UNITED-STATES; TOBACCO-SMOKE; YOUNG-WOMEN; NULL ASSOCIATION; NURSES HEALTH; REGISTRY DATA; EXPOSURE; BIAS AB The authors conducted a meta-analysis of the association between smoking before a first pregnancy, when undifferentiated breast tissue may be vulnerable to tobacco carcinogens, and the risk of breast cancer. A search of the published literature through August 2010 identified 23 papers reporting on associations between smoking before a first pregnancy and breast cancer. Odds ratios or hazard ratios and 95% confidence intervals, adjusted for known or suspected breast cancer risk factors, were abstracted from each study. Data were pooled using both fixed- and random-effects models. The fixed-effect summary risk ratio for breast cancer among the women who smoked before their first pregnancy versus women who had never smoked was 1.10 (95% confidence interval: 1.07, 1.14); the random-effects estimate was similar. The separate fixed-effect risk ratios for smoking only before the first pregnancy (5 studies) or only after the first pregnancy (16 studies) were both 1.07, providing no evidence that breast tissue is more susceptible to malignant transformation from smoking before the first pregnancy. While these small summary risk ratios may represent causal effects, residual confounding could readily produce estimates of this size in the absence of any causal effect. C1 [DeRoo, Lisa A.; Mueller, Beth A.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [DeRoo, Lisa A.; Cummings, Peter; Mueller, Beth A.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. RP Deroo, LA (reprint author), NIEHS, Epidemiol Branch, POB 12233,MD A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM DeRooL@niehs.nih.gov NR 49 TC 18 Z9 18 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2011 VL 174 IS 4 BP 390 EP 402 DI 10.1093/aje/kwr090 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 803QH UT WOS:000293595300002 PM 21719745 ER PT J AU Venzo, A Antonello, S Gascon, JA Guryanov, I Leapman, RD Perera, NV Sousa, A Zamuner, M Zanella, A Maran, F AF Venzo, Alfonso Antonello, Sabrina Gascon, Jose A. Guryanov, Ivan Leapman, Richard D. Perera, Neranjan V. Sousa, Alioscka Zamuner, Martina Zanella, Alessandro Maran, Flavio TI Effect of the Charge State (z =-1, 0,+1) on the Nuclear Magnetic Resonance of Monodisperse Au-25[S(CH2)(2)Ph](18)(z) Clusters SO ANALYTICAL CHEMISTRY LA English DT Article ID DISSOCIATIVE ELECTRON-TRANSFER; THIOLATE-PROTECTED AU-25; GOLD NANOPARTICLE; CRYSTAL-STRUCTURE; REDOX POTENTIALS; AU-38 CLUSTERS; SELF-EXCHANGE; ELECTROREDUCTION; RESOLUTION; ENERGIES AB Monodisperse Au25L180 (L = S(CH2)(2)Ph) and [n-Oct(4)N(+)][Au25L18,(-)]clusters were synthesized in tetrahydrofuran. An original strategy was then devised to oxidize them: in the presence of bis(pentafluorobenzoyl) peroxide, the neutral or the negatively charged dusters react as efficient electron donors in a dissociative electron-transfer (ET) process, in the former case yielding [Au25L18+][C6F5CO2-]. As opposed to, other reported redox methods, this dissociative ET approach is irreversible, easily controllable, and clean, particularly for NMR purposes, as no hydrogen atoms are introduced. By using this approach, the -1, 0, and +1 charge states of Au25L18 could be fully characterized by H-1 and C-13 NMR spectroscopy, using one- and two-dimensional techniques, in various solvents, and as a function of temperature. For all charge states, the NMR results and analysis nicely match recent structural findings about the presence of two different ligand populations in the capping monolayer, each resonance of the two ligand families displaying distinct NMR patterns. The radical nature of Au25L180 is particularly evident in the H-1 and C-13 NMR patterns" of the inner ligands. The NMR behavior of radical (AuL180)-L-25 was also simulated by DFT calculations, and the interplay between theory and experiments revealed a fundamental paramagnetic contribution coming from Fermi contact shifts. Interestingly, the NMR patterns of Au25L18- and Au25L18+ were found to be quite similar, pointing to the latter duster form as a diamagnetic species. C1 [Venzo, Alfonso; Antonello, Sabrina; Guryanov, Ivan; Zamuner, Martina; Zanella, Alessandro; Maran, Flavio] Univ Padua, Dept Chem, I-35131 Padua, Italy. [Venzo, Alfonso] ISTM CNR, I-35131 Padua, Italy. [Gascon, Jose A.; Perera, Neranjan V.] Univ Connecticut, Dept Chem, Storrs, CT 06269 USA. [Leapman, Richard D.; Sousa, Alioscka] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Maran, F (reprint author), Univ Padua, Dept Chem, Via Marzolo 1, I-35131 Padua, Italy. EM flavio.maran@unipd.it RI Guryanov, Ivan/A-6007-2012; Gascon, Joaquim/M-3598-2015; Guryanov, Ivan/N-3117-2016; Gascon, Jose /N-5702-2016 OI Gascon, Joaquim/0000-0002-5045-1585; Guryanov, Ivan/0000-0001-6897-3528; Gascon, Jose /0000-0002-4176-9030 FU Foundation CARIPARO FX This work was financially supported by the Foundation CARIPARO. NR 34 TC 55 Z9 55 U1 3 U2 57 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD AUG 15 PY 2011 VL 83 IS 16 BP 6355 EP 6362 DI 10.1021/ac2012653 PG 8 WC Chemistry, Analytical SC Chemistry GA 805WD UT WOS:000293758800035 PM 21718063 ER PT J AU Fonseca, CG Backhaus, M Bluemke, DA Britten, RD Chung, JD Cowan, BR Dinov, ID Finn, JP Hunter, PJ Kadish, AH Lee, DC Lima, JAC Medrano-Gracia, P Shivkumar, K Suinesiaputra, A Tao, WC Young, AA AF Fonseca, Carissa G. Backhaus, Michael Bluemke, David A. Britten, Randall D. Chung, Jae Do Cowan, Brett R. Dinov, Ivo D. Finn, J. Paul Hunter, Peter J. Kadish, Alan H. Lee, Daniel C. Lima, Joao A. C. Medrano-Gracia, Pau Shivkumar, Kalyanam Suinesiaputra, Avan Tao, Wenchao Young, Alistair A. TI The Cardiac Atlas Project-an imaging database for computational modeling and statistical atlases of the heart SO BIOINFORMATICS LA English DT Article ID HUMAN BRAIN; POPULATION; DESIGN; VOLUME AB Motivation: Integrative mathematical and statistical models of cardiac anatomy and physiology can play a vital role in understanding cardiac disease phenotype and planning therapeutic strategies. However, the accuracy and predictive power of such models is dependent upon the breadth and depth of noninvasive imaging datasets. The Cardiac Atlas Project (CAP) has established a large-scale database of cardiac imaging examinations and associated clinical data in order to develop a shareable, web-accessible, structural and functional atlas of the normal and pathological heart for clinical, research and educational purposes. A goal of CAP is to facilitate collaborative statistical analysis of regional heart shape and wall motion and characterize cardiac function among and within population groups. Results: Three main open-source software components were developed: (i) a database with web-interface; (ii) a modeling client for 3D + time visualization and parametric description of shape and motion; and (iii) open data formats for semantic characterization of models and annotations. The database was implemented using a three-tier architecture utilizing MySQL, JBoss and Dcm4chee, in compliance with the DICOM standard to provide compatibility with existing clinical networks and devices. Parts of Dcm4chee were extended to access image specific attributes as search parameters. To date, approximately 3000 de-identified cardiac imaging examinations are available in the database. All software components developed by the CAP are open source and are freely available under the Mozilla Public License Version 1.1 (http://www.mozilla.org/MPL/MPL-1.1.txt). C1 [Backhaus, Michael; Britten, Randall D.; Chung, Jae Do; Cowan, Brett R.; Hunter, Peter J.; Medrano-Gracia, Pau; Suinesiaputra, Avan; Young, Alistair A.] Univ Auckland, Auckland Bioengn Inst, Auckland 1, New Zealand. [Fonseca, Carissa G.; Finn, J. Paul; Tao, Wenchao] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol Sci, Los Angeles, CA 90095 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, Bethesda, MD 20814 USA. [Dinov, Ivo D.] Univ Calif Los Angeles, Lab Neuro Imaging, Los Angeles, CA 90095 USA. [Kadish, Alan H.; Lee, Daniel C.] Northwestern Univ, Div Cardiol, Feinberg Sch Med, Chicago, IL 60611 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Dept Radiol, Div Cardiol, Baltimore, MD 21205 USA. [Shivkumar, Kalyanam] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Cardiac Arrhythmia Ctr, Los Angeles, CA 90095 USA. RP Young, AA (reprint author), Univ Auckland, Auckland Bioengn Inst, 70 Symonds St, Auckland 1, New Zealand. EM a.young@auckland.ac.nz RI Trivedi, Kruti/E-7558-2015; OI Shivkumar, Kalyanam/0000-0002-4121-1766; Hunter, Peter/0000-0001-9665-4145; Dinov, Ivo/0000-0003-3825-4375; Bluemke, David/0000-0002-8323-8086; Suinesiaputra, Avan/0000-0003-1165-458X; Young, Alistair/0000-0001-5702-4220; Lee, Daniel/0000-0001-9447-4175; Medrano-Gracia, Pau/0000-0002-6255-4864 FU National Heart, Lung and Blood Institute, USA [R01HL087773]; National Institutes of Health/National Center for Research Resources [U54 RR021813, P41 RR013642]; St Jude Medical, Inc; National Heart, Lung and Blood Institute [R01HL91069, N01-HC-95169] FX National Heart, Lung and Blood Institute, USA (R01HL087773). Support from the Center for Computational Biology (LONI) was provided by National Institutes of Health/National Center for Research Resources (U54 RR021813, P41 RR013642). MESA was supported by the National Heart, Lung and Blood Institute (N01-HC-95159 through N01-HC-95169). A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. DETERMINE was supported by St Jude Medical, Inc; and the National Heart, Lung and Blood Institute (R01HL91069). A list of participating DETERMINE investigators can be found at http://www.clinicaltrials.gov. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung and Blood Institute or the National Institutes of Health. NR 31 TC 67 Z9 67 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD AUG 15 PY 2011 VL 27 IS 16 BP 2288 EP 2295 DI 10.1093/bioinformatics/btr360 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 803ZC UT WOS:000293620800016 PM 21737439 ER PT J AU Hagemann, AR Cadungog, M Hagemann, IS Hammond, R Adams, SF Chu, CS Rubin, SC Zhang, L Addya, K Birrer, MJ Gimotty, PA Coukos, G AF Hagemann, Andrea R. Cadungog, Mark Hagemann, Ian S. Hammond, Rachel Adams, Sarah F. Chu, Christina S. Rubin, Stephen C. Zhang, Lin Addya, Kathakali Birrer, Michael J. Gimotty, Phyllis A. Coukos, George TI Tissue-based immune monitoring I Tumor core needle biopsies allow in-depth interrogation of the tumor microenvironment SO CANCER BIOLOGY & THERAPY LA English DT Article DE ovarian neoplasms; lymphocytes; tumor-infiltrating; adoptive immunotherapy; gene expression profiling; immunohistochemistry ID INTRAEPITHELIAL T-CELLS; OVARIAN-CANCER; INFILTRATING LYMPHOCYTES; PROGNOSTIC-SIGNIFICANCE; COLORECTAL-CANCER; CARCINOMA; SURVIVAL; RESPONSES; STAGE; IMMUNOTHERAPY AB We sought to assess the feasibility and reproducibility of performing tissue-based immune characterization of the tumor microenvironment using CT-compatible needle biopsy material. Three independent biopsies were obtained intraoperatively from one metastatic epithelial ovarian cancer lesion of seven consecutive patients undergoing surgical cytoreduction using a 16-gauge core biopsy needle. Core specimens were snap-frozen and subjected to immunohistochemistry (IHC) against human CD3, CD4, CD8 and FoxP3. A portion of the cores was used to isolate RNA for (1) real-time quantitative (q) PCR for CD3, CD4, CD8, FoxP3, IL-10 and TGF beta, (2) multiplexed PCR-based T-cell receptor (TCR) CDR3 V-beta region spectratyping and (3) gene expression profiling. Pearson's correlations were examined for immunohistochemistry and PCR gene expression, as well as for gene expression array data obtained from different tumor biopsies. Needle biopsy yielded sufficient tissue for all assays in all patients. IHC was highly reproducible and informative. Significant correlations were seen between the frequency of CD3+, CD8+ and FoxP3+ T cells by IHC with CD3-epsilon, CD8A and FoxP3 gene expression, respectively, by qPCR (r = 0.61, 0.86 and 0.89; all p < 0.05). CDR3 spectratyping was feasible and highly reproducible in each tumor, and indicated a restricted repertoire for specific TCR V-beta chains in tumor-infiltrating T cells. Microarray gene expression revealed strong correlation between different biopsies collected from the same tumor. Our results demonstrate a feasible and reproducible method of immune monitoring using CT-compatible needle biopsies from tumor tissue, thereby paving the way for sophisticated translational studies during tumor biological therapy. C1 [Hagemann, Andrea R.; Cadungog, Mark; Adams, Sarah F.; Chu, Christina S.; Rubin, Stephen C.; Zhang, Lin; Coukos, George] Univ Penn, Ovarian Canc Res Ctr, Philadelphia, PA 19104 USA. [Hagemann, Andrea R.; Cadungog, Mark; Adams, Sarah F.; Chu, Christina S.; Rubin, Stephen C.; Zhang, Lin; Coukos, George] Univ Penn, Div Gynecol Oncol, Philadelphia, PA 19104 USA. [Hagemann, Ian S.; Addya, Kathakali] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Hammond, Rachel; Gimotty, Phyllis A.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Birrer, Michael J.] NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Coukos, G (reprint author), Univ Penn, Ovarian Canc Res Ctr, Philadelphia, PA 19104 USA. EM gcks@mail.med.upenn.edu FU Ovarian Cancer SPORE NIH [P50-CA083638]; Ovarian Cancer Research Foundation FX This work was supported by Ovarian Cancer SPORE NIH P50-CA083638 and the Ovarian Cancer Research Foundation. NR 29 TC 5 Z9 5 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG 15 PY 2011 VL 12 IS 4 BP 357 EP 366 DI 10.4161/cbt.12.4.16951 PG 10 WC Oncology SC Oncology GA 806WN UT WOS:000293847500012 PM 21785264 ER PT J AU Hagemann, AR Hagemann, IS Cadungog, M Hwang, WT Patel, P Lal, P Hammond, R Gimotty, PA Chu, CS Rubin, SC Birrer, MJ Powell, DJ Feldman, MD Coukos, G AF Hagemann, Andrea R. Hagemann, Ian S. Cadungog, Mark Hwang, Wei-Ting Patel, Priya Lal, Priti Hammond, Rachel Gimotty, Phyllis A. Chu, Christina S. Rubin, Stephen C. Birrer, Michael J. Powell, Daniel J., Jr. Feldman, Michael D. Coukos, George TI Tissue-based immune monitoring II Multiple tumor sites reveal immunologic homogeneity in serous ovarian carcinoma SO CANCER BIOLOGY & THERAPY LA English DT Article DE ovarian neoplasms; lymphocytes; tumor-infiltrating; adoptive immunotherapy; metastasis; microarray analysis ID REGULATORY T-CELLS; LYMPHOCYTE-ASSOCIATED ANTIGEN-4; DENDRITIC CELLS; INFILTRATING LYMPHOCYTES; ANTIBODY BLOCKADE; CANCER-PATIENTS; SURVIVAL; STAGE; IMMUNOTHERAPY; PROGNOSIS AB The presence of tumor-infiltrating lymphocytes (TILs) in epithelial ovarian cancer indicates a host antitumor response and is associated with improved survival. We wished to determine the extent to which TIL density differs from site to site within a given patient. We initially studied multiple paired metastases from serous ovarian carcinoma obtained at the time of primary debulking. The expression of genes in specific immune-related pathways was profiled on a pilot set of five patients. We then used immunohistochemistry and quantitative PCR to estimate the density of CD3(+), CD8(+) and FoxP3(+) TILs in these same tumors. To extend the findings to a larger cohort, we semiquantitatively measured intraepithelial and stromal TILs in a tissue microarray (TMA) containing both primary tumors and metastases from 50 patients. In the pilot group, genes related to antimicrobial signaling and TGF beta signaling showed between-site heterogeneity, whereas cytokines and antigen presentation transcripts were more homogeneous in any given patient. IHC and qPCR for T-cell markers were concordant. In the TMA cohort, two-way ANOVA showed that TIL heterogeneity between sites was present in some but not all patients. The stroma of extra-ovarian metastases showed significantly greater TIL infiltration than ovarian sites. A simulation showed that at clinically meaningful levels of precision, up to 3% of patients will be misclassified for intraepithelial TILs by a single biopsy. In conclusion, between-site heterogeneity exists in some patients with metastatic serous ovarian cancer. The predictive value of biopsies should be considered in clinical trial design. C1 [Hagemann, Andrea R.; Cadungog, Mark; Patel, Priya; Chu, Christina S.; Rubin, Stephen C.; Powell, Daniel J., Jr.; Coukos, George] Univ Penn, Ovarian Canc Res Ctr, Philadelphia, PA 19104 USA. [Hagemann, Andrea R.; Cadungog, Mark; Patel, Priya; Chu, Christina S.; Rubin, Stephen C.; Powell, Daniel J., Jr.; Coukos, George] Univ Penn, Div Gynecol Oncol, Philadelphia, PA 19104 USA. [Hagemann, Ian S.; Lal, Priti; Powell, Daniel J., Jr.; Feldman, Michael D.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Hwang, Wei-Ting; Hammond, Rachel; Gimotty, Phyllis A.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Birrer, Michael J.] NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Coukos, G (reprint author), Univ Penn, Ovarian Canc Res Ctr, Philadelphia, PA 19104 USA. EM gcks@mail.med.upenn.edu FU Ovarian Cancer SPORE NIH [P50-CA083638]; Ovarian Cancer Research Foundation; NCI [P30 CA016520-34] FX We thank Li-Ping Wang and Emma Hung for outstanding technical support with TMA construction and immunostaining. This work was supported by Ovarian Cancer SPORE NIH P50-CA083638, the Ovarian Cancer Research Foundation and a core grant (NCI P30 CA016520-34) to the Abramson Cancer Center of the University of Pennsylvania. NR 33 TC 7 Z9 7 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG 15 PY 2011 VL 12 IS 4 BP 367 EP 377 DI 10.4161/cbt.12.4.16908 PG 11 WC Oncology SC Oncology GA 806WN UT WOS:000293847500013 PM 21785280 ER PT J AU Dugan, VG Dunham, EJ Jin, GZ Sheng, ZM Kaser, E Nolting, JM Alexander, HL Slemons, RD Taubenberger, JK AF Dugan, Vivien G. Dunham, Eleca J. Jin, Guozhong Sheng, Zong-Mei Kaser, Emilee Nolting, Jacqueline M. Alexander, H. Lloyd, Jr. Slemons, Richard D. Taubenberger, Jeffery K. TI Phylogenetic analysis of low pathogenicity H5N1 and H7N3 influenza A virus isolates recovered from sentinel, free flying, wild mallards at one study site during 2006 SO VIROLOGY LA English DT Article DE Influenza A virus; Avian influenza; H5N1; H7N3; Phylogenetics ID AVIAN INFLUENZA; NORTH-AMERICA; PANDEMIC INFLUENZA; SEQUENCE-ANALYSIS; UNITED-STATES; BIRDS; EVOLUTION; POULTRY; DUCKS; EPIDEMIOLOGY AB From August 2 to October 11, 2006, clusters of low pathogenicity (LP) North American lineage H5N1 and H7N3 avian influenza A viruses (AIV), and other subtypes, were recovered from free-flying, resident, wild mallards used as sentinels at one site. The antigenic subtypes, pathogenicity potential, and Sanger sequencing of the isolates determined the H5N1 and H7N3 isolates were only recovered from samples collected on 8/2/2006 and 9/8/2006, respectively. However, subsequent efforts using next-generation sequencing (NGS) and additional Sanger sequencing found partial H7 segments in other HA-NA virus combinations on 8/2/2006, 9/8/2006 and 10/11/2006. It is well established that over larger geographic areas and years AIVs form transient genomic constellations; this sequential sampling data revealed that over a short period of time the dynamics of AIVs can be active and newer sequencing platforms increase recognition of mixed infections. Both findings provide further insight into the natural history of AIVs in natural reservoirs. Published by Elsevier Inc. C1 [Dugan, Vivien G.; Dunham, Eleca J.; Jin, Guozhong; Sheng, Zong-Mei; Kaser, Emilee; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Nolting, Jacqueline M.; Alexander, H. Lloyd, Jr.; Slemons, Richard D.] Ohio State Univ, Dept Vet Prevent Med, Columbus, OH 43210 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, 33 North Dr,Room 3E19A-2 MSC 3203, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov RI Nolting, Jacqueline/C-4464-2015 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases; USDA FX This work was supported by in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases and in part by the USDA CSREES (NIFA) Coordinated Agriculture Project (CAP) for the Prevention and Control of Avian Influenza in the USA, 2005-2007. JMN completed all initial virus isolations, identifications, and RNA extractions. We thank Seth Schobel at JCVI for help with submitting the AIV sequences to NCBI. A special thanks goes to the USDA, APHIS, National Veterinary Service Laboratory, Ames, Iowa for their excellent support of this investigation. We would also like to especially thank the conscientious private landowners and wildlife biologists who provided critical input, access, time and support for this project thus furthering our understanding of the natural history of type A influenza viruses in waterfowl. NR 36 TC 9 Z9 9 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD AUG 15 PY 2011 VL 417 IS 1 BP 98 EP 105 DI 10.1016/j.virol.2011.05.004 PG 8 WC Virology SC Virology GA 806PO UT WOS:000293820300012 PM 21658737 ER PT J AU Belanger, JM Raviv, Y Viard, M de la Cruz, MJ Nagashima, K Blumenthal, R AF Belanger, Julie M. Raviv, Yossef Viard, Mathias de la Cruz, M. Jason Nagashima, Kunio Blumenthal, Robert TI Effects of UVA irradiation, aryl azides, and reactive oxygen species on the orthogonal inactivation of the human immunodeficiency virus (HIV-1) SO VIROLOGY LA English DT Article DE HIV; Detergent; Vaccine; Triton; Hydrophobic; Azide; Reactive oxygen species (ROS); Viral membrane ID STRUCTURAL INTEGRITY; IMMUNE-RESPONSES; TYPE-1; PRESERVATION; ENVELOPE; VACCINES; PROTEIN; IMMUNOGENICITY; VACCINATION; EPITOPES AB Previously we reported that hydrophobic aryl azides partition into hydrophobic regions of the viral membrane of enveloped viruses and inactivate the virus upon UVA irradiation for 2 min. Prolonged irradiation (15 min) resulted in viral protein aggregation as visualized via Western blot analysis, due to reactive oxygen species (ROS) formation, with preservation of the surface antigenic epitopes. Herein, we demonstrate that these aggregates show detergent resistance and that this property may be useful towards the creation of a novel orthogonal virus inactivation strategy for use in preparing experimental vaccines. When ROS-modified HIV virus preparations were treated with 1% Triton X-100, there was an increase in the percent of viral proteins (gp41, p24) in the viral pellet after ultracentrifugation through sucrose. Transmission electron microscopy (TEM) of these detergent-resistant pellets shows some recognizable virus fragments, and immunoprecipitation studies of the gp41 aggregates suggest the aggregation is covalent in nature, involving short-range interactions. Published by Elsevier Inc. C1 [Belanger, Julie M.; Blumenthal, Robert] NCI, Ctr Canc Res, Nanobiol Program, Bethesda, MD 20892 USA. [Raviv, Yossef; Viard, Mathias] NCI Frederick, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [de la Cruz, M. Jason; Nagashima, Kunio] NCI Frederick, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI, Ctr Canc Res, Nanobiol Program, Bethesda, MD 20892 USA. EM blumenthalr@mail.nih.gov RI Belanger, Julie/A-5734-2009 OI Belanger, Julie/0000-0002-7236-2778 FU Intramural AIDS Targeted Antiviral Program; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN26120080001E] FX We thank ARRRP for reagents, and Jeff Lifson and the AIDS and Cancer Virus Program for generously providing purified virus and anti-p17 antibody. We thank Randall Johnson for his assistance with the statistics. We also thank Julian W. Bess, Jr. for many helpful discussions and his critical reading of the manuscript. This research was supported [in part] by federal funds from the Intramural AIDS Targeted Antiviral Program and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 26 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD AUG 15 PY 2011 VL 417 IS 1 BP 221 EP 228 DI 10.1016/j.virol.2011.06.007 PG 8 WC Virology SC Virology GA 806PO UT WOS:000293820300026 PM 21726886 ER PT J AU Parisi, MA Spong, CY Zajicek, A Guttmacher, AE AF Parisi, Melissa A. Spong, Catherine Y. Zajicek, Anne Guttmacher, Alan E. TI We Don't Know What We Don't Study: The Case for Research on Medication Effects in Pregnancy SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Editorial Material DE medication; exposure; pregnancy; teratogen; research ID SEROTONIN-REUPTAKE INHIBITORS; BIRTH-DEFECTS; WOMEN; RISK; DRUG; PHARMACOKINETICS; TRIMESTER AB This Commentary addresses issues related to exposures to teratogens and makes the case for increased research into the safety of medication usage during pregnancy for mothers and fetuses. Not only are medications commonly used during pregnancy, but evidence points to an increasing prevalence and number of drug exposures experienced by the embryo or fetus, particularly during the critical first trimester of pregnancy. Although the first trimester represents a particularly vulnerable period of organogenesis, exposures during other gestational time periods may also be associated with deleterious outcomes. In addition to the changing (and in many cases unknown) risks to a developing fetus, other challenges to studying medication exposures and their effects during pregnancy include the dramatic changes in physiology that occur in pregnant women and the ethical dilemmas posed by including this vulnerable population in randomized controlled trials of safety and efficacy. However, without adequate knowledge of the pharmacokinetics, pharmacodynamics, efficacy, and safety of medication use in pregnancy, women may be under-dosed to minimize exposure or not treated at all, resulting in inadequate treatment and potential harm to the mother and her baby. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is undertaking studies on medications and teratogenic exposures during pregnancy, including alcohol, maternal diabetes, oral hypoglycemic agents, and antiviral medications, through several of its research networks. Although this is a start, there is a critical need for further research on medications used during pregnancy, especially their effects on both the mother and her developing child. Published 2011 Wiley-Liss, Inc.(dagger) C1 [Parisi, Melissa A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intellectual & Dev Disabil Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD 20892 USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Bethesda, MD USA. [Zajicek, Anne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Obstet & Pediat Pharmacol Branch, Bethesda, MD USA. RP Parisi, MA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intellectual & Dev Disabil Branch, Ctr Dev Biol & Perinatal Med, NIH, 6100 Execut Blvd,Room 4B09,MSC 7510, Bethesda, MD 20892 USA. EM parisima@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 23 TC 21 Z9 24 U1 0 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4868 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD AUG 15 PY 2011 VL 157C IS 3 SI SI BP 247 EP 250 DI 10.1002/ajmg.c.30309 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 802VM UT WOS:000293539100013 PM 21766436 ER PT J AU Qu, W Cheng, LD Dill, AL Saavedra, JE Hong, SY Keefer, LK Waalkes, MP AF Qu, Wei Cheng, Lida Dill, Anna L. Saavedra, Joseph E. Hong, Sam Y. Keefer, Larry K. Waalkes, Michael P. TI Nitric oxide donor, V-PROLI/NO, provides protection against arsenical induced toxicity in rat liver cells: Requirement for Cyp1a1 SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE V-PROLI/NO; Arsenic; Rat liver cell; Cyp1a1 ID ACUTE PROMYELOCYTIC LEUKEMIA; EPITHELIAL-CELLS; METALLOTHIONEIN; APOPTOSIS; PRODRUG; CANCER; SENSITIVITY; METABOLISM; ACTIVATION; MECHANISMS AB Arsenic is a cancer chemotherapeutic but hepatotoxicity can be a limiting side effect. O(2)-vinyl 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (V-PROLI/NO) is a nitric oxide (NO) donor prodrug and metabolized by liver cytochromes P450 (CYP450) to release NO. The effects of V-PROLI/NO pretreatment on the toxicity of arsenic (as NaAsO(2)) were studied in a rat liver cell line (TRL 1215). The cells acted upon the prodrug to release NO, as assessed by nitrite levels, in a time-dependent fashion to maximal levels of 8-fold above basal levels. Pretreatment with V-PROLI/NO markedly reduced arsenic cytolethality which was directly related to the level of NO produced by V-PROLI/NO treatment. Cyp1a1 expression was directly related to the level of NO production and to reduced arsenic cytotoxicity. V-PROLI/NO pretreatment markedly reduced arsenic-induced apoptosis and suppressed phosphorylation of JNK1/2. V-PROLI/NO pretreatment facilitated additional increases in arsenic-induced metallothionein, a metal-binding protein important in arsenic tolerance. Thus, V-PROLI/NO protects against arsenic toxicity in rat liver cells, reducing cytolethality, apoptosis and dysregulation of MAPKs, through generation of NO formed after metabolism by liver cell enzymes, possibly including Cyp1a1. CYP450 required for NO production from V-PROLI/NO treatment in the rat and human appears to differ as we have previously studied the ability of V-PROLI/NO to prevent arsenic toxicity in human liver cells where it reduced toxicity apparently through a CYP2E1-mediated metabolic mechanism. None-the-less, it appears that both rat and human liver cells act upon V-PROLI/NO via a CYP450-related mechanism to produce NO and subsequently reduce arsenic toxicity. Published by Elsevier Ireland Ltd. C1 [Qu, Wei; Cheng, Lida; Dill, Anna L.; Waalkes, Michael P.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Qu, Wei; Cheng, Lida; Dill, Anna L.; Waalkes, Michael P.] NCI, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Saavedra, Joseph E.] NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA. [Hong, Sam Y.; Keefer, Larry K.] NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Waalkes, MP (reprint author), Natl Inst Environm Hlth Sci, Natl Toxicol Program, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU National Institute of Environmental Health Sciences (NIEHS); National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; SAIC Frederick, Inc. [HHSN261200800001E] FX The authors thank Drs. Erik Tokar and Yang Sun for critical review of this manuscript. This research was supported in part by the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS) and by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. Additional support came from Contract HHSN261200800001E with SAIC Frederick, Inc. This article may be the work product of an employee or a group of employees of the NIEHS, NIH, however, the statements contained herein do not necessarily represent the statements, opinions or conclusions of the NIEHS, NIH or the United States Government. The content of this publication does not necessarily reflect the views or the 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 40 TC 3 Z9 5 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD AUG 15 PY 2011 VL 193 IS 1 BP 88 EP 96 DI 10.1016/j.cbi.2011.05.005 PG 9 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 802EI UT WOS:000293491700012 PM 21621526 ER PT J AU Keembiyehetty, CN Krzeslak, A Love, DC Hanover, JA AF Keembiyehetty, Chithra N. Krzeslak, Anna Love, Dona C. Hanover, John A. TI A lipid-droplet-targeted O-GlcNAcase isoform is a key regulator of the proteasome SO JOURNAL OF CELL SCIENCE LA English DT Article DE O-GlcNAcase isoforms; O-GlcNAc cycling; Perilipin-2; Lipid droplets; Proteasome ID BETA-N-ACETYLGLUCOSAMINIDASE; CYTOSOLIC PROTEINS; MEXICAN-AMERICANS; GLYCOSYLATION; INHIBITION; NUCLEAR; PATHWAY; KINASE; GLUCOSAMINIDASE; PHOSPHORYLATION AB Protein-O-linked N-Acetyl-beta-D-glucosaminidase (O-GlcNAcase, OGA; also known as hexosaminidase C) participates in a nutrient-sensing, hexosamine signaling pathway by removing O-linked N-acetylglucosamine (O-GlcNAc) from key target proteins. Perturbations in O-GlcNAc signaling have been linked to Alzheimer's disease, diabetes and cancer. Mammalian O-GlcNAcase exists as two major spliced isoforms differing only by the presence (OGA-L) or absence (OGA-S) of a histone-acetyltransferase domain. Here we demonstrate that OGA-S accumulates on the surface of nascent lipid droplets with perilipin-2; both of these proteins are stabilized by proteasome inhibition. We show that selective downregulation of OGA-S results in global proteasome inhibition and the striking accumulation of ubiquitinylated proteins. OGA-S knockdown increased levels of perilipin-2 and perilipin-3 suggesting that O-GlcNAc-dependent regulation of proteasomes might occur on the surface of lipid droplets. By locally activating proteasomes during maturation of the nascent lipid droplet, OGA-S could participate in an O-GlcNAc-dependent feedback loop regulating lipid droplet surface remodeling. Our findings therefore suggest a mechanistic link between hexosamine signaling and lipid droplet assembly and mobilization. C1 [Keembiyehetty, Chithra N.; Krzeslak, Anna; Love, Dona C.; Hanover, John A.] Natl Inst Diabet & Kidney Dis, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Hanover, JA (reprint author), Natl Inst Diabet & Kidney Dis, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. EM jah@helix.nih.gov OI Krzeslak, Anna/0000-0002-4982-7901 FU National Institutes of Health, National Institute for Diabetes and Digestive and Kidney Diseases FX We are grateful to the Londos laboratory for providing us with antibodies to perilipins 1, 2 and 3, and assistance with the lipid droplet isolation. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute for Diabetes and Digestive and Kidney Diseases. Deposited in PMC for release after 12 months. NR 42 TC 29 Z9 30 U1 0 U2 10 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD AUG 15 PY 2011 VL 124 IS 16 BP 2851 EP 2860 DI 10.1242/jcs.083287 PG 10 WC Cell Biology SC Cell Biology GA 800IK UT WOS:000293352800019 PM 21807949 ER PT J AU Chen, X Oppenheim, JJ AF Chen, Xin Oppenheim, Joost J. TI Comment on "Interplay between TNF and Regulatory T Cells in a TNF-Driven Murine Model of Arthritis" SO JOURNAL OF IMMUNOLOGY LA English DT Letter ID EXPRESSION C1 [Chen, Xin] NCI, Basic Sci Program, Sci Applicat Int Corp Frederick Inc, Mol Immunoregulat Lab, Frederick, MD 21702 USA. [Oppenheim, Joost J.] NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Chen, X (reprint author), NCI, Basic Sci Program, Sci Applicat Int Corp Frederick Inc, Mol Immunoregulat Lab, POB B,Bldg 560,Room 31-19, Frederick, MD 21702 USA. EM chenxin@mail.nih.gov; oppenhej@mail.nih.gov RI Chen, Xin/I-6601-2015 OI Chen, Xin/0000-0002-2628-4027 NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2011 VL 187 IS 4 BP 1527 EP 1527 DI 10.4049/jimmunol.1190029 PG 1 WC Immunology SC Immunology GA 800RX UT WOS:000293384600001 PM 21810616 ER PT J AU Fessler, MB Parks, JS AF Fessler, Michael B. Parks, John S. TI Intracellular Lipid Flux and Membrane Microdomains as Organizing Principles in Inflammatory Cell Signaling SO JOURNAL OF IMMUNOLOGY LA English DT Review ID LOW-DENSITY-LIPOPROTEIN; LIGAND-INDEPENDENT ACTIVATION; TOLL-LIKE RECEPTOR-4; PHOSPHOLIPID OXIDATION-PRODUCTS; FREE-CHOLESTEROL ACCUMULATION; PLASMA-MEMBRANE; HOST-DEFENSE; ABCA1-DEFICIENT MACROPHAGES; PERITONEAL-MACROPHAGES; KINASE ACTIVATION AB Lipid rafts and caveolae play a pivotal role in organization of signaling by TLR4 and several other immune receptors. Beyond the simple cataloguing of signaling events compartmentalized by these membrane microdomains, recent studies have revealed the surprisingly central importance of dynamic remodeling of membrane lipid domains to immune signaling. Simple interventions upon membrane lipid, such as changes in cholesterol loading or crosslinking of raft lipids, are sufficient to induce micrometer-scale reordering of membranes and their protein cargo with consequent signal transduction. In this review, using TLR signaling in the macrophage as a central focus, we discuss emerging evidence that environmental and genetic perturbations of membrane lipid regulate protein signaling, illustrate how homeostatic flow of cholesterol and other lipids through rafts regulates the innate immune response, and highlight recent attempts to harness these insights toward therapeutic development. The Journal of Immunology, 2011, 187: 1529-1535. C1 [Fessler, Michael B.] Natl Inst Environm Hlth Sci, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Parks, John S.] Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol & Biochem, Sect Lipid Sci, Winston Salem, NC 27157 USA. RP Fessler, MB (reprint author), Natl Inst Environm Hlth Sci, Lab Resp Biol, NIH, 111 TW Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, NC 27709 USA. EM fesslerm@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES102005]; [HL094525]; [HL049373] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES102005) and by Grants HL094525 and HL049373 (to J.S.P.). NR 92 TC 98 Z9 100 U1 3 U2 15 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2011 VL 187 IS 4 BP 1529 EP 1535 DI 10.4049/jimmunol.1100253 PG 7 WC Immunology SC Immunology GA 800RX UT WOS:000293384600003 PM 21810617 ER PT J AU Lee, JH Kim, JW Kim, DK Kim, HS Park, HJ Park, DK Kim, AR Kim, B Beaven, MA Park, KL Kim, YM Choi, WS AF Lee, Jun Ho Kim, Jie Wan Kim, Do Kyun Kim, Hyuk Soon Park, Hye Jin Park, Dong Ki Kim, A-Ram Kim, Bokyung Beaven, Michael A. Park, Kui Lea Kim, Young Mi Choi, Wahn Soo TI The Src Family Kinase Fgr Is Critical for Activation of Mast Cells and IgE-Mediated Anaphylaxis in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FC-EPSILON-RI; TYROSINE KINASE; ALLERGIC INFLAMMATION; NEGATIVE REGULATION; IN-VIVO; RECEPTOR; LYN; RESPONSES; SYK; FYN AB Mast cells are critical for various allergic disorders. Mast cells express Src family kinases, which relay positive and negative regulatory signals by Ag. Lyn, for example, initiates activating signaling events, but it also induces inhibitory signals. Fyn and Hck are reported to be positive regulators, but little is known about the roles of other Src kinases, including Fgr, in mast cells. In this study, we define the role of Fgr. Endogenous Fgr associates with Fc epsilon RI and promotes phosphorylation of Syk, Syk substrates, which include linkers for activation of T cells, SLP76, and Gab2, and downstream targets such as Akt and the MAPKs in Ag-stimulated mast cells. As a consequence, Fgr positively regulates degranulation, production of eicosanoids, and cytokines. Fgr and Fyn appeared to act in concert, as phosphorylation of Syk and degranulation are enhanced by overexpression of Fgr and further augmented by overexpression of Fyn but are suppressed by overexpression of Lyn. Moreover, knockdown of Fgr by small interfering RNAs (siRNAs) further suppressed degranulation in Fyn-deficient bone marrow-derived mast cells. Overexpression of Fyn or Fgr restored phosphorylation of Syk and partially restored degranulation in Fyn-deficient cells. Additionally, knockdown of Fgr by siRNAs inhibited association of Syk with Fc epsilon RI gamma as well as the tyrosine phosphorylation of Fc epsilon RI gamma. Of note, the injection of Fgr siRNAs diminished the protein level of Fgr in mice and simultaneously inhibited IgE-mediated anaphylaxis. In conclusion, Fgr positively regulates mast cell through activation of Syk. These findings help clarify the interplay among Src family kinases and identify Fgr as a potential therapeutic target for allergic diseases. The Journal of Immunology, 2011, 187: 1807-1815. C1 [Lee, Jun Ho; Kim, Jie Wan; Kim, Do Kyun; Kim, Hyuk Soon; Kim, A-Ram; Kim, Bokyung; Choi, Wahn Soo] Konkuk Univ, Coll Med, Inst Biomed Sci & Technol, Chungju 380701, South Korea. [Park, Hye Jin; Park, Dong Ki] Konkuk Univ, Dept Biosci & Biotechnol, Seoul 143701, South Korea. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Park, Kui Lea] Korea Food & Drug Adm, Natl Inst Food Drug Safety Evaluat, Ctr Drug Dev Assistance, Cheongwon Gun 363951, South Korea. [Kim, Young Mi] Duksung Womens Univ, Coll Pharm, Seoul 132714, South Korea. RP Choi, WS (reprint author), Konkuk Univ, Coll Med, Inst Biomed Sci & Technol, Chungju 380701, South Korea. EM wahnchoi@kku.ac.kr FU Ministry for Health, Welfare and Family Affairs, Korea [A084847]; Regional Core Research Program/Chungbuk Biotech-Information Technology Research-Oriented University Consortium; Ministry of Knowledge Economy at Konkuk University, Korea; National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by a grant from the Korean Health Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Korea (A084847), and in part by a grant from the Regional Core Research Program/Chungbuk Biotech-Information Technology Research-Oriented University Consortium and the Regional Innovation Center Program of the Ministry of Knowledge Economy at Konkuk University, Korea. M. A. B. was supported by the Intramural Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 41 TC 23 Z9 27 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2011 VL 187 IS 4 BP 1807 EP 1815 DI 10.4049/jimmunol.1100296 PG 9 WC Immunology SC Immunology GA 800RX UT WOS:000293384600032 PM 21746961 ER PT J AU Bauler, TJ Chase, JC Bosio, CM AF Bauler, Timothy J. Chase, Jennifer C. Bosio, Catharine M. TI IFN-beta Mediates Suppression of IL-12p40 in Human Dendritic Cells following Infection with Virulent Francisella tularensis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-BETA; I INTERFERON; INTRACELLULAR SURVIVAL; PHAGOSOMAL ESCAPE; AIM2 INFLAMMASOME; MACROPHAGES; TULAREMIA; ACTIVATION; MATURATION; IMMUNITY AB Active suppression of inflammation is a strategy used by many viral and bacterial pathogens, including virulent strains of the bacterium Francisella tularensis, to enable colonization and infection in susceptible hosts. In this study, we demonstrated that virulent F. tularensis strain SchuS4 selectively inhibits production of IL-12p40 in primary human cells via induction of IFN-beta. In contrast to the attenuated live vaccine strain, infection of human dendritic cells with virulent SchuS4 failed to induce production of many cytokines associated with inflammation (e.g., TNF-alpha and IL-12p40). Furthermore, SchuS4 actively suppressed secretion of these cytokines. Assessment of changes in the expression of host genes associated with suppression of inflammatory responses revealed that SchuS4, but not live vaccine strain, induced IFN-beta following infection of human dendritic cells. Phagocytosis of SchuS4 and endosomal acidification were required for induction of IFN-beta. Further, using a defined mutant of SchuS4, we demonstrated that the presence of bacteria in the cytosol was required, but not sufficient, for induction of IFN-beta. Surprisingly, unlike previous reports, induction of IFN-beta by F. tularensis was not required for activation of the inflammasome, was not associated with exacerbation of inflammatory responses, and did not control SchuS4 replication when added exogenously. Rather, IFN-beta selectively suppressed the ability of SchuS4-infected dendritic cells to produce IL-12p40. Together, these data demonstrated a novel mechanism by which virulent bacteria, in contrast to attenuated strains, modulate human cells to cause disease. The Journal of Immunology, 2011, 187: 1845-1855. C1 [Bauler, Timothy J.; Chase, Jennifer C.; Bosio, Catharine M.] NIAID, Immun Pulm Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Bosio, CM (reprint author), LICP RML NIAID NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM bosioc@niaid.nih.gov RI Bosio, Catharine/D-7456-2015 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 56 TC 20 Z9 20 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 AUG 15 PY 2011 VL 187 IS 4 BP 1845 EP 1855 DI 10.4049/jimmunol.1100377 PG 11 WC Immunology SC Immunology GA 800RX UT WOS:000293384600036 PM 21753150 ER PT J AU Mattapallil, MJ Silver, PB Mattapallil, JJ Horai, R Karabekian, Z McDowell, JH Chan, CC James, EA Kwok, WW Sen, HN Nussenblatt, RB David, CS Caspi, RR AF Mattapallil, Mary J. Silver, Phyllis B. Mattapallil, Joseph J. Horai, Reiko Karabekian, Zaruhi McDowell, J. Hugh Chan, Chi-Chao James, Eddie A. Kwok, William W. Sen, H. Nida Nussenblatt, Robert B. David, Chella S. Caspi, Rachel R. TI Uveitis-Associated Epitopes of Retinal Antigens Are Pathogenic in the Humanized Mouse Model of Uveitis and Identify Autoaggressive T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CLASS-II TETRAMERS; HLA CLASS-II; EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; COLLAGEN-INDUCED ARTHRITIS; KOYANAGI-HARADA-DISEASE; TRANSGENIC MICE; S-ANTIGEN; BIRDSHOT RETINOCHOROIDOPATHY; BEHCETS-DISEASE; SYMPATHETIC OPHTHALMIA AB Noninfectious uveitis is a leading cause of blindness and thought to involve autoimmune T cell responses to retinal proteins (e. g., retinal arrestin [soluble-Ag (S-Ag)]). There are no known biomarkers for the disease. Susceptibility is associated with HLA, but little is known about susceptible class II alleles or the potentially pathogenic epitopes that they present. Using a humanized HLA-transgenic mouse model of S-Ag-induced autoimmune uveitis, we identified several susceptible and resistant alleles of HLA-DR and -DQ genes and defined pathogenic epitopes of S-Ag presented by the susceptible alleles. The sequences of these epitopes overlap with some previously identified peptides of S-Ag ("M" and "N"), known to elicit memory responses in lymphocytes of uveitis patients. HLA-DR-restricted, S-Ag-specific CD4(+) T cells could be detected in blood and draining lymph nodes of uveitic mice with HLA class II tetramers and transferred the disease to healthy mice. Importantly, tetramer-positive cells were detected in peripheral blood of a uveitis patient. To our knowledge, these findings provide the first tangible evidence that an autoimmune response to retina is causally involved in pathogenesis of human uveitis, demonstrating the feasibility of identifying and isolating retinal Ag-specific T cells from uveitis patients and may facilitate their development as biomarkers for the disease. The Journal of Immunology, 2011, 187: 1977-1985. C1 [Mattapallil, Mary J.; Silver, Phyllis B.; Horai, Reiko; Karabekian, Zaruhi; Chan, Chi-Chao; Sen, H. Nida; Nussenblatt, Robert B.; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Mattapallil, Joseph J.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [McDowell, J. Hugh] Univ Florida, Dept Ophthalmol, Gainesville, FL 32610 USA. [James, Eddie A.; Kwok, William W.] Benaroya Res Inst Virginia Mason, Seattle, WA 98101 USA. [David, Chella S.] Mayo Clin, Dept Immunol, Rochester, MN 55905 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM mattapallilm@nei.nih.gov; rcaspi@helix.nih.gov OI Caspi, Rachel/0000-0002-7140-7671; James, Eddie/0000-0002-7217-5729 FU National Eye Institute, National Institutes of Health; National Institutes of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research [K22AI07812, R21DE018339]; National Institutes of Health [EY014864, EY006225]; Research to Prevent Blindness FX This work was supported by an intramural research grant from the National Eye Institute, National Institutes of Health. This work was also supported in part by federal funds from the National Institutes of Allergy and Infectious Diseases and National Institute of Dental and Craniofacial Research under Grants K22AI07812 and R21DE018339 (to J.J.M.). J.H.M. was supported by National Institutes of Health Grants EY014864 and EY006225 and an unrestricted departmental grant from Research to Prevent Blindness. NR 62 TC 16 Z9 16 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 AUG 15 PY 2011 VL 187 IS 4 BP 1977 EP 1985 DI 10.4049/jimmunol.1101247 PG 9 WC Immunology SC Immunology GA 800RX UT WOS:000293384600050 PM 21765017 ER PT J AU Herold, KC Pescovitz, MD McGee, P Krause-Steinrauf, H Spain, LM Bourcier, K Asare, A Liu, ZG Lachin, JM Dosch, HM AF Herold, Kevan C. Pescovitz, Mark D. McGee, Paula Krause-Steinrauf, Heidi Spain, Lisa M. Bourcier, Kasia Asare, Adam Liu, Zhugong Lachin, John M. Dosch, H. Michael CA Type 1 Diabet TrialNet Anti-CD20 TI Increased T Cell Proliferative Responses to Islet Antigens Identify Clinical Responders to Anti-CD20 Monoclonal Antibody (Rituximab) Therapy in Type 1 Diabetes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MULTIPLE-SCLEROSIS; B-LYMPHOCYTES; MICE; DISEASE; PATHOGENESIS; INITIATION; PHENOTYPE; SUBSETS; INDUCE; ANERGY AB Type 1 diabetes mellitus is believed to be due to the autoimmune destruction of beta-cells by T lymphocytes, but a single course of rituximab, a monoclonal anti-CD20 B lymphocyte Ab, can attenuate C-peptide loss over the first year of disease. The effects of B cell depletion on disease-associated T cell responses have not been studied. We compare changes in lymphocyte subsets, T cell proliferative responses to disease-associated target Ags, and C-peptide levels of participants who did (responders) or did not (nonresponders) show signs of beta-cell preservation 1 y after rituximab therapy in a placebo-controlled TrialNet trial. Rituximab decreased B lymphocyte levels after four weekly doses of mAb. T cell proliferative responses to diabetes-associated Ags were present at baseline in 75% of anti-CD20- and 82% of placebo-treated subjects and were not different over time. However, in rituximab-treated subjects with significant C-peptide preservation at 6 mo (58%), the proliferative responses to diabetes-associated total (p = 0.032), islet-specific (p = 0.048), and neuronal autoantigens (p = 0.005) increased over the 12-mo observation period. This relationship was not seen in placebo-treated patients. We conclude that in patients with type 1 diabetes mellitus, anti-B cell mAb causes increased proliferative responses to diabetes Ags and attenuated beta-cell loss. The way in which these responses affect the disease course remains unknown. The Journal of Immunology, 2011, 187: 1998-2005. C1 [Herold, Kevan C.] Yale Univ, Dept Immunobiol, New Haven, CT 06511 USA. [Pescovitz, Mark D.] Indiana Univ, Dept Surg, Indianapolis, IN 46202 USA. [McGee, Paula; Krause-Steinrauf, Heidi; Lachin, John M.] George Washington Univ, Biostat Ctr, Washington, DC 20052 USA. [Spain, Lisa M.] NIDDK, Bethesda, MD 20892 USA. [Bourcier, Kasia; Asare, Adam; Liu, Zhugong] Immune Tolerance Network, Seattle, WA 98101 USA. [Dosch, H. Michael] Univ Toronto, Dept Pediat, Toronto, ON M5A 2N4, Canada. RP Herold, KC (reprint author), Yale Univ, Dept Immunobiol, 300 George St,353, New Haven, CT 06511 USA. EM kevan.herold@yale.edu OI Lachin, John/0000-0001-9838-2841 FU Genentech; National Institutes of Health [U01DK085466]; Type 1 Diabetes TrialNet Anti-CD20 Study Group; National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute for Child Health and Human Development; National Center for Research Resources; Juvenile Diabetes Research Foundation International; American Diabetes Association FX M.D.P. has been a speaker and consultant to Roche/Genentech and has received research support for a clinical trial from Genentech. The other authors have no financial conflicts of interest.; This work was supported by National Institutes of Health Grant U01DK085466. The sponsor of the trial was the Type 1 Diabetes TrialNet Anti-CD20 Study Group. TrialNet is a clinical trials network funded by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute for Child Health and Human Development, the National Center for Research Resources, the Juvenile Diabetes Research Foundation International, and the American Diabetes Association. NR 28 TC 30 Z9 32 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 AUG 15 PY 2011 VL 187 IS 4 BP 1998 EP 2005 DI 10.4049/jimmunol.1100539 PG 8 WC Immunology SC Immunology GA 800RX UT WOS:000293384600052 PM 21775681 ER PT J AU Quinn, TC AF Quinn, Thomas C. TI Viral Kinetics of Genital Herpes: A Molecular Probe Into Host-Viral Interactions SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID SIMPLEX-VIRUS TYPE-2; ACTIVE ANTIRETROVIRAL THERAPY; RAPIDLY CLEARED EPISODES; DYNAMICS IN-VIVO; HIV-1 INFECTION; PERINATAL TRANSMISSION; HSV-2 REACTIVATION; T-CELLS; LOAD; RNA C1 [Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Quinn, TC (reprint author), Johns Hopkins Univ, 855 N Wolfe St,Rangos 530, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu FU Intramural NIH HHS NR 49 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2011 VL 204 IS 4 BP 495 EP 498 DI 10.1093/infdis/jir317 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 799RS UT WOS:000293304400002 PM 21791649 ER PT J AU Morens, DM Holmes, EC Davis, AS Taubenberger, JK AF Morens, David M. Holmes, Edward C. Davis, A. Sally Taubenberger, Jeffery K. TI Global Rinderpest Eradication: Lessons Learned and Why Humans Should Celebrate Too SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID PHOCINE DISTEMPER VIRUS; MEASLES ERADICATION; GENOME SEQUENCE; DISEASE; CATTLE; PARAMYXOVIRUSES; MORBILLIVIRUSES; 18TH-CENTURY; TRANSMISSION; INFECTIONS C1 [Morens, David M.] NIAID, NIH, Off Director, Bethesda, MD 20892 USA. [Davis, A. Sally; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis Sect, Infect Dis Lab, Bethesda, MD 20892 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. RP Morens, DM (reprint author), NIAID, NIH, Off Director, 31 Ctr Dr,Room 7A-03,MSC 2520, Bethesda, MD 20892 USA. EM dm270q@nih.gov OI Davis, Anne/0000-0001-5711-3936; Holmes, Edward/0000-0001-9596-3552 FU Intramural NIH HHS NR 54 TC 22 Z9 24 U1 0 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2011 VL 204 IS 4 BP 502 EP 505 DI 10.1093/infdis/jir327 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 799RS UT WOS:000293304400004 PM 21653230 ER PT J AU Wei, Q Costanzi, S Liu, QZ Gao, ZG Jacobson, KA AF Wei, Qiang Costanzi, Stefano Liu, Qiu-Zhen Gao, Zhan-Guo Jacobson, Kenneth A. TI Activation of the P2Y(1) receptor induces apoptosis and inhibits proliferation of prostate cancer cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Prostate cancer; P2Y(1) receptor; Apoptosis; Nucleotide; GPCR ID EXTRACELLULAR ADENOSINE-TRIPHOSPHATE; PROTEIN-COUPLED RECEPTORS; NUCLEOTIDE RECEPTORS; HUMAN MELANOMAS; IN-VIVO; ASTROCYTES; ATP; MECHANISMS; EXPRESSION; SURVIVAL AB G protein-coupled receptors, the largest cell surface receptor family, have emerged as critical players in cell death and survival. High gene expression level of the G(q)-coupled P2Y(1) nucleotide receptor in PC-3 prostate cancer cells was demonstrated using real-time quantitative PCR and confirmed by Western blotting and confocal laser scanning microscopy. A selective P2Y(1) receptor agonist, the ADP analogue MRS2365, concentration-dependently induced intracellular calcium mobilization (EC50 5.28 nM), which was diminished by P2Y(1) receptor-selective antagonist MRS2500. P2Y(1) receptor activation by MRS2365 induced apoptosis in assays of Caspase-3. LDH release, and annexin-V staining. The pro-apoptotic effect of MRS2365 was blocked by MRS2500, P2Y(1) siRNA, and an inhibitor of the MAP kinase pathway PD98059. MRS2365 significantly inhibited the proliferation of PC-3 cells, examined using a MTT assay. Thus, activation of the P2Y(1) receptor induced cell death and inhibited growth of human prostatic carcinoma PC-3 cells. Activation of the P2Y(1) receptor should be a novel and promising therapeutic strategy for prostate cancer. Published by Elsevier Inc. C1 [Wei, Qiang; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Wei, Qiang] So Med Univ, Nan Fang Hosp, Guangdong Inst Kidney Dis, Guangzhou 510515, Guangdong, Peoples R China. [Costanzi, Stefano] NIDDKD, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Liu, Qiu-Zhen] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; Costanzi, Stefano/G-8990-2013; OI Jacobson, Kenneth/0000-0001-8104-1493; Costanzi, Stefano/0000-0003-3183-7332 FU NIDDK; National Institutes of Health, Bethesda, MD, USA; National Natural Science Foundation of China [30940072]; Nanfang Hospital, Southern Medical University, Guangzhou, China FX Supported by the NIDDK Intramural Research Program, National Institutes of Health, Bethesda, MD, USA, National Natural Science Foundation of China (No. 30940072) and Nanfang Hospital, Southern Medical University, Guangzhou, China. The authors thank Dr. Yafang Hu (Children's National Medical Center, Washington, DC) for assistance in Western blotting and confocal microscopy experiments. NR 33 TC 13 Z9 15 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 15 PY 2011 VL 82 IS 4 BP 418 EP 425 DI 10.1016/j.bcp.2011.05.013 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 799WF UT WOS:000293316100011 PM 21632028 ER PT J AU Cunningham, K Uchida, Y O'Donnell, E Claudio, E Li, WL Soneji, K Wang, HS Mukouyama, YS Siebenlist, U AF Cunningham, Kirk Uchida, Yutaka O'Donnell, Erin Claudio, Estefania Li, Wenling Soneji, Kosha Wang, Hongshan Mukouyama, Yoh-suke Siebenlist, Ulrich TI Conditional deletion of Ccm2 causes hemorrhage in the adult brain: a mouse model of human cerebral cavernous malformations SO HUMAN MOLECULAR GENETICS LA English DT Article ID KINASE KINASE 3; RECENT INSIGHTS; VASCULAR MALFORMATIONS; SPROUTING ANGIOGENESIS; ENDOTHELIAL-CELLS; 2-HIT MECHANISM; MUTATIONS; PROTEIN; GENE; MICE AB Cerebral cavernous malformations (CCM) are irregularly shaped and enlarged capillaries in the brain that are prone to hemorrhage, resulting in headaches, seizures, strokes and even death in patients. The disease affects up to 0.5% of the population and the inherited form has been linked to mutations in one of three genetic loci, CCM1, CCM2 and CCM3. To understand the pathophysiology underlying the vascular lesions in CCM, it is critical to develop a reproducible mouse genetic model of this disease. Here, we report that limited conditional ablation of Ccm2 in young adult mice induces observable neurological dysfunction and reproducibly results in brain hemorrhages whose appearance is highly reminiscent of the lesions observed in human CCM patients. We first demonstrate that conventional or endothelial-specific deletion of Ccm2 leads to fatal cardiovascular defects during embryogenesis, including insufficient vascular lumen formation as well as defective arteriogenesis and heart malformation. These findings confirm and extend prior studies. We then demonstrate that the inducible deletion of Ccm2 in adult mice recapitulates the CCM-like brain lesions in humans; the lesions display disrupted vascular lumens, enlarged capillary cavities, loss of proper neuro-vascular associations and an inflammatory reaction. The CCM lesions also exhibit damaged neuronal architecture, the likely cause of neurologic defects, such as ataxia and seizure. These mice represent the first CCM2 animal model for CCM and should provide the means to elucidate disease mechanisms and evaluate therapeutic strategies for human CCM. C1 [Uchida, Yutaka; O'Donnell, Erin; Li, Wenling; Soneji, Kosha; Mukouyama, Yoh-suke] NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [Cunningham, Kirk; Claudio, Estefania; Wang, Hongshan; Siebenlist, Ulrich] NIAID, Immune Activat Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Mukouyama, YS (reprint author), NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bldg 10,Rm 6C103, Bethesda, MD 20892 USA. EM mukoyamay@mail.nih.gov; ulrich.siebenlist@nih.gov FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA FX This work was supported by funding from the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. NR 38 TC 16 Z9 17 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2011 VL 20 IS 16 BP 3198 EP 3206 DI 10.1093/hmg/ddr225 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 796CF UT WOS:000293027100008 PM 21596842 ER PT J AU Broeks, A Schmidt, MK Sherman, ME Couch, FJ Hopper, JL Dite, GS Apicella, C Smith, LD Hammet, F Southey, MC Van 't Veer, LJ de Groot, R Smit, VTHBM Fasching, PA Beckmann, MW Jud, S Ekici, AB Hartmann, A Hein, A Schulz-Wendtland, R Burwinkel, B Marme, F Schneeweiss, A Sinn, HP Sohn, C Tchatchou, S Bojesen, SE Nordestgaard, BG Flyger, H Orsted, DD Kaur-Knudsen, D Milne, RL Perez, JIA Zamora, P Rodriguez, PM Benitez, J Brauch, H Justenhoven, C Ko, YD Hamann, U Fischer, HP Bruning, T Pesch, B Chang-Claude, J Wang-Gohrke, S Bremer, M Karstens, JH Hillemanns, P Dork, T Nevanlinna, HA Heikkinen, T Heikkila, P Blomqvist, C Aittomaki, K Aaltonen, K Lindblom, A Margolin, S Mannermaa, A Kosma, VM Kauppinen, JM Kataja, V Auvinen, P Eskelinen, M Soini, Y Chenevix-Trench, G Spurdle, AB Beesley, J Chen, XQ Holland, H Lambrechts, D Claes, B Vandorpe, T Neven, P Wildiers, H Flesch-Janys, D Hein, R Loning, T Kosel, M Fredericksen, ZS Wang, XS Giles, GG Baglietto, L Severi, G McLean, C Haiman, CA Henderson, BE Le Marchand, L Kolonel, LN Alnaes, GG Kristensen, V Borresen-Dale, AL Hunter, DJ Hankinson, SE Andrulis, IL Mulligan, AM O'Malley, FP Devilee, P Huijts, PEA Tollenaar, RAEM Van Asperen, CJ Seynaeve, CS Chanock, SJ Lissowska, J Brinton, L Peplonska, B Figueroa, J Yang, XHR Hooning, MJ Hollestelle, A Oldenburg, RA Jager, A Kriege, M Ozturk, B van Leenders, GJLH Hall, P Czene, K Humphreys, K Liu, JJ Cox, A Connley, D Cramp, HE Cross, SS Balasubramanian, SP Reed, MWR Dunning, AM Easton, DF Humphreys, MK Caldas, C Blows, F Driver, K Provenzano, E Lubinski, J Jakubowska, A Huzarski, T Byrski, T Cybulski, C Gorski, B Gronwald, J Brennan, P Sangrajrang, S Gaborieau, V Shen, CY Hsiung, CN Yu, JC Chen, ST Hsu, GC Hou, MF Huang, CS Anton-Culver, H Ziogas, A Pharoah, PDP Garcia-Closas, M AF Broeks, Annegien Schmidt, Marjanka K. Sherman, Mark E. Couch, Fergus J. Hopper, John L. Dite, Gillian S. Apicella, Carmel Smith, Letitia D. Hammet, Fleur Southey, Melissa C. Van 't Veer, Laura J. de Groot, Renate Smit, Vincent T. H. B. M. Fasching, Peter A. Beckmann, Matthias W. Jud, Sebastian Ekici, Arif B. Hartmann, Arndt Hein, Alexander Schulz-Wendtland, Ruediger Burwinkel, Barbara Marme, Frederik Schneeweiss, Andreas Sinn, Hans-Peter Sohn, Christof Tchatchou, Sandrine Bojesen, Stig E. Nordestgaard, Borge G. Flyger, Henrik Orsted, David D. Kaur-Knudsen, Diljit Milne, Roger L. Perez, Jose I. Arias Zamora, Pilar Menendez Rodriguez, Primitiva Benitez, Javier Brauch, Hiltrud Justenhoven, Christina Ko, Yon-Dschun Hamann, Ute Fischer, Hans-Peter Bruening, Thomas Pesch, Beate Chang-Claude, Jenny Wang-Gohrke, Shan Bremer, Michael Karstens, Johann H. Hillemanns, Peter Doerk, Thilo Nevanlinna, Heli A. Heikkinen, Tuomas Heikkila, Paeivi Blomqvist, Carl Aittomaki, Kristiina Aaltonen, Kirsimari Lindblom, Annika Margolin, Sara Mannermaa, Arto Kosma, Veli-Matti Kauppinen, Jaana M. Kataja, Vesa Auvinen, Paeivi Eskelinen, Matti Soini, Ylermi Chenevix-Trench, Georgia Spurdle, Amanda B. Beesley, Jonathan Chen, Xiaoqing Holland, Helene Lambrechts, Diether Claes, Bart Vandorpe, Thijs Neven, Patrick Wildiers, Hans Flesch-Janys, Dieter Hein, Rebecca Loening, Thomas Kosel, Matthew Fredericksen, Zachary S. Wang, Xianshu Giles, Graham G. Baglietto, Laura Severi, Gianluca McLean, Catriona Haiman, Christopher A. Henderson, Brian E. Le Marchand, Loic Kolonel, Laurence N. Alnaes, Grethe Grenaker Kristensen, Vessela Borresen-Dale, Anne-Lise Hunter, David J. Hankinson, Susan E. Andrulis, Irene L. Mulligan, Anna Marie O'Malley, Frances P. Devilee, Peter Huijts, Petra E. A. Tollenaar, Rob A. E. M. Van Asperen, Christi J. Seynaeve, Caroline S. Chanock, Stephen J. Lissowska, Jolanta Brinton, Louise Peplonska, Beata Figueroa, Jonine Yang, Xiaohong R. Hooning, Maartje J. Hollestelle, Antoinette Oldenburg, Rogier A. Jager, Agnes Kriege, Mieke Ozturk, Bahar van Leenders, Geert J. L. H. Hall, Per Czene, Kamila Humphreys, Keith Liu, Jianjun Cox, Angela Connley, Daniel Cramp, Helen E. Cross, Simon S. Balasubramanian, Sabapathy P. Reed, Malcolm W. R. Dunning, Alison M. Easton, Douglas F. Humphreys, Manjeet K. Caldas, Carlos Blows, Fiona Driver, Kristy Provenzano, Elena Lubinski, Jan Jakubowska, Anna Huzarski, Tomasz Byrski, Tomasz Cybulski, Cezary Gorski, Bohdan Gronwald, Jacek Brennan, Paul Sangrajrang, Suleeporn Gaborieau, Valerie Shen, Chen-Yang Hsiung, Chia-Ni Yu, Jyh-Cherng Chen, Shou-Tung Hsu, Giu-Cheng Hou, Ming-Feng Huang, Chiun-Sheng Anton-Culver, Hoda Ziogas, Argyrios Pharoah, Paul D. P. Garcia-Closas, Montserrat CA Genica Network KConFab AOCS TI Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium SO HUMAN MOLECULAR GENETICS LA English DT Article ID BRCA2 MUTATION CARRIERS; GENOME-WIDE ASSOCIATION; ESTROGEN-RECEPTOR; COMMON VARIANTS; CONFER SUSCEPTIBILITY; RISK PREDICTION; EXPRESSION; PATTERNS; ALLELES; POPULATION AB Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 x 10(-18)), rs3803662 (16q12) (P = 3.7 x 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 x 10(-6) and P = 4.1 x 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P <= 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P <= 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment. C1 [Broeks, Annegien; Schmidt, Marjanka K.; Van 't Veer, Laura J.] Netherlands Canc Inst, Dept Expt Therapy, NL-1066 CX Amsterdam, Netherlands. [Schmidt, Marjanka K.] Netherlands Canc Inst, Dept Epidemiol, NL-1066 CX Amsterdam, Netherlands. [Van 't Veer, Laura J.; de Groot, Renate] Netherlands Canc Inst, Dept Mol Pathol, NL-1066 CX Amsterdam, Netherlands. [Sherman, Mark E.; Figueroa, Jonine; Yang, Xiaohong R.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Couch, Fergus J.; Kosel, Matthew; Fredericksen, Zachary S.; Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. 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EM a.broeks@nki.nl RI Caldas, Carlos/A-7543-2008; Peplonska, Beata/F-6004-2010; Smith, Letitia /J-9035-2014; Hein, Alexander/F-6999-2010; BYRSKI, Tomasz/I-2844-2014; Jakubowska, Anna/O-8050-2014; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Shen, CY/F-6271-2010; Verdrengh, Evelien/H-4571-2012; Ekici, Arif/C-3971-2013; Andrulis, Irene/E-7267-2013; Dork, Thilo/J-8620-2012; Hartikainen, Jaana/E-6256-2015; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Gronwald, Jacek/A-4576-2017; Spurdle, Amanda/A-4978-2011; OI Hein, Alexander/0000-0003-2601-3398; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Gronwald, Jacek/0000-0002-3643-2871; Dite, Gillian/0000-0002-2448-2548; Czene, Kamila/0000-0002-3233-5695; Spurdle, Amanda/0000-0003-1337-7897; Dunning, Alison Margaret/0000-0001-6651-7166; Nevanlinna, Heli/0000-0002-0916-2976; Cox, Angela/0000-0002-5138-1099; Giles, Graham/0000-0003-4946-9099 FU European Community [223175, HEALTH-F2-2009-223175]; CR-UK [C1287/A10118, C1287/A7497, C1287/A12014, C8197/A10865]; European Union [BM0606, LSHC-CT-2003-503297]; National Health and Medical Research Council of Australia [199600]; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); National Cancer Institute, National Institutes of Health [RFA-CA-06-503, CA-06-503, CA-58860]; Dutch Cancer Society [NKI 2001-2423, 2007-3839, DDHK 2004-3124]; Dutch National Genomics Initiative; University of Erlangen; Dr Mildred Scheel Stiftung of the Deutsche Krebshilfe e.V; Dietmar-Hopp Foundation; Helmholtz Society; Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Copenhagen University Hospital, Herlev Hospital; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra Cancer; Fondo de Investigacion Sanitario [PI081120, PI081583]; Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114]; Deutsche Krebshilfe e.V [70492, 70-2892-BR I]; Hannover Medical School; Helsinki University Central Hospital; Academy of Finland [110663]; Finnish Cancer Society; Sigrid Juselius Foundation; Swedish Cancer Society; Gustav V Jubilee Foundation; Bert von Kantzow Foundation; Kuopio University; University of Kuopio; EVO research funding of Vaasa Hospital District; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC) [145684, 288704, 454508, 209057, 251533, 396414, 504711, 504715]; 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; US Army Medical Research and Material Command [DAMD17-01-1-0729]; Cancer Council Tasmania and Cancer Foundation of Western Australia; Stichting tegen Kanker [232-2008]; Hamburg Cancer Society; German Cancer Research Center; German Federal Ministry of Education and Research [01KH0402]; National Institutes of Health [R01 CA122340, R01-CA63464, R37-CA54281]; NCI Specialized Program of Research Excellence (SPORE) in breast cancer [P50 CA116201]; Cancer Council Victoria; Norwegian Research council [155218/V40, 175240/S10, 181600/V11]; Swizz Bridge Award; Cancer Care Ontario [U01 CA69467]; Northern California Cancer Center [U01 CA69417]; University of Melbourne [U01 CA69638]; National Cancer Institute, Department of Health and Human Services, USA; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Breast Cancer Campaign; Yorkshire Cancer Research; Cancer Research UK [C1287/A10118, C490/A1102, C8197/A10123, C490/A10119, C490/A11020]; NIHR Cambridge Biomedical Research Centre; Cambridge Experimental Cancer Medicine Centre; National Cancer Institute Thailand; Institute of Biomedical Sciences, Academia Sinica, National Sciences Counciland Taiwan Biobank; Lon V Smith Foundation [LVS-39420]; [PBZ_KBN_122/P05/2004] FX This work was supported by funding from the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175). The BCAC is funded by CR-UK (C1287/A10118, C1287/A7497, C1287/A12014). Meetings of the BCAC have been funded by the European Union COST program (BM0606). D.F.E. is a Principal Research Fellow of CR-UK. The ABCFS study was supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (CFR) and P.I.s. The ABCS study was supported by the Dutch Cancer Society (grants NKI 2001-2423; 2007-3839) and the Dutch National Genomics Initiative. The BBCC study was partly funded by a Grand of ELAN Funding of the University of Erlangen. P.A.F. is partly funded by Dr Mildred Scheel Stiftung of the Deutsche Krebshilfe e.V. The BSUCH study was supported by the Dietmar-Hopp Foundation and the Helmholtz Society. The CGPS study was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Copenhagen University Hospital, Herlev Hospital. The CNIO-BCS study was supported by the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra Cancer and the Fondo de Investigacion Sanitario (PI081120 to JB and PI081583 to RLM). The GENICA study was supported by the German Human Genome Project and funded by the Federal Ministry of Education and Research (BMBF) Germany (grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114). The Robert Bosch Foundation of Medical Research, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GESBC study was supported by the Deutsche Krebshilfe e.V. (70492) and GESBC genotyping in part by the state of Baden-Wurttemberg through the Medical Faculty of the University of Ulm (P.685). The HABCS study was supported by an intramural grant from Hannover Medical School. The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (110663), the Finnish Cancer Society and the Sigrid Juselius Foundation. The KARBAC study was supported by The Swedish Cancer Society, The Gustav V Jubilee Foundation And The Bert von Kantzow Foundation. The KBCP was supported by the Kuopio University Central EVO Research Fund, Academy of Finland, the Finnish Cancer Society, the University of Kuopio and EVO research funding of Vaasa Hospital District. The kConFab and its Clinical Follow-Up study were funded by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia and the Cancer Foundation of Western Australia, as well as by NHMRC (grants 145684, 288704 and 454508). The AOCS study was supported by the US Army Medical Research and Material Command (DAMD17-01-1-0729), the Cancer Council Tasmania and Cancer Foundation of Western Australia and The National Health and Medical Research Council of Australia (199600). Amanda B.; Spurdle is supported by an NHMRC Senior Research Fellowship, and Georgia Chenevx-Trench by an NHMRC Senior Principal Research Fellowship The LMBC stduy was supported by European Union Framework Programme 6 (Project LSHC-CT-2003-503297) and by the 'Stichting tegen Kanker' (232-2008). The MARIE study was supported by the Deutsche Krebshilfe e.V., (grant70-2892-BR I), the Hamburg Cancer Society, the German Cancer Research Center and the German Federal Ministry of Education and Research (01KH0402). The MCBCS was supported by National Institutes of Health (grant R01 CA122340), and an NCI Specialized Program of Research Excellence (SPORE) in breast cancer (P50 CA116201). The MCCS study was supported by Cancer Council Victoria and by NHMRC (grants 209057, 251533, 396414,504711, 504715). The MEC study was supported by National Institutes of Health (grants R01-CA63464, R37-CA54281). The NBCS study was supported by grants from the Norwegian Research council, (155218/V40, 175240/S10) to ALBD, FUGE-NFR (181600/V11) to VNK and a Swizz Bridge Award to ALBD. The OFBCR was supported by the National Cancer Institute, National Institutes of Health under (grant CA-06-503) and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Northern California Cancer Center (U01 CA69417), and University of Melbourne (U01 CA69638) and by Cancer Care Ontario. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR. The ORIGO study was supported by the Dutch Cancer Society. The PBCS was supported by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The RBCS study was supported by the Dutch Cancer Society (grant DDHK 2004-3124). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCS study was funded by the Breast Cancer Campaign (grant 2004Nov 49) and Yorkshire Cancer Research core funding. SEARCH study was supported by Cancer Research UK grants (C490/A1102, C8197/A10123, C490/A10119, C490/A11020, C1287/A10118) and AMD was funded by CR-UK grant (C8197/A10865). The pathology work in Cambridge was supported by the NIHR Cambridge Biomedical Research Centre and by the Cambridge Experimental Cancer Medicine Centre. The SZBCS was supported by Grant (PBZ_KBN_122/P05/2004). The TBCS was funded by The National Cancer Institute Thailand. The TWBCS study was supported by the Institute of Biomedical Sciences, Academia Sinica, National Sciences Counciland Taiwan Biobank. The UCIBCS study was supported by the National Institutes of Health, National Cancer Institute (grants CA-58860) and the Lon V Smith Foundation (grant LVS-39420). NR 39 TC 100 Z9 100 U1 1 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2011 VL 20 IS 16 BP 3289 EP 3303 DI 10.1093/hmg/ddr228 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 796CF UT WOS:000293027100016 PM 21596841 ER PT J AU Antoniou, AC Kartsonaki, C Sinilnikova, OM Soucy, P McGuffog, L Healey, S Lee, A Peterlongo, P Manoukian, S Peissel, B Zaffaroni, D Cattaneo, E Barile, M Pensotti, V Pasini, B Dolcetti, R Giannini, G Putignano, AL Varesco, L Radice, P Mai, PL Greene, MH Andrulis, IL Glendon, G Ozcelik, H Thomassen, M Gerdes, AM Kruse, TA Jensen, UB Cruger, DG Caligo, MA Laitman, Y Milgrom, R Kaufman, B Paluch-Shimon, S Friedman, E Loman, N Harbst, K Lindblom, A Arver, B Ehrencrona, H Melin, B Nathanson, KL Domchek, SM Rebbeck, T Jakubowska, A Lubinski, J Gronwald, J Huzarski, T Byrski, T Cybulski, C Gorski, B Osorio, A Cajal, TRY Fostira, F Andres, R Benitez, J Hamann, U Hogervorst, FB Rookus, MA Hooning, MJ Nelen, MR van der Luijt, RB van Os, TAM van Asperen, CJ Devilee, P Meijers-Heijboer, HEJ Garcia, EBG Peock, S Cook, M Frost, D Platte, R Leyland, J Evans, DG Lalloo, F Eeles, R Izatt, L Adlard, J Davidson, R Eccles, D Ong, KR Cook, J Douglas, F Paterson, J Kennedy, MJ Miedzybrodzka, Z Godwin, A Stoppa-Lyonnet, D Buecher, B Belotti, M Tirapo, C Mazoyer, S Barjhoux, L Lasset, C Leroux, D Faivre, L Bronner, M Prieur, F Nogues, C Rouleau, E Pujol, P Coupier, I Frenay, M Hopper, JL Daly, MB Terry, MB John, EM Buys, SS Yassin, Y Miron, A Goldgar, D Singer, CF Tea, MK Pfeiler, G Dressler, AC Hansen, TV Jonson, L Ejlertsen, B Barkardottir, RB Kirchhoff, T Offit, K Piedmonte, M Rodriguez, G Small, L Boggess, J Blank, S Basil, J Azodi, M Toland, AE Montagna, M Tognazzo, S Agata, S Imyanitov, E Janavicius, R Lazaro, C Blanco, I Pharoah, PDP Sucheston, L Karlan, BY Walsh, CS Olah, E Bozsik, A Teo, SH Seldon, JL Beattie, MS van Rensburg, EJ Sluiter, MD Diez, O Schmutzler, RK Wappenschmidt, B Engel, C Meindl, A Ruehl, I Varon-Mateeva, R Kast, K Deissler, H Niederacher, D Arnold, N Gadzicki, D Schonbuchner, I Caldes, T de la Hoya, M Nevanlinna, H Aittomaki, K Dumont, M Chiquette, J Tischkowitz, M Chen, XQ Beesley, J Spurdle, AB Neuhausen, SL Ding, YC Fredericksen, Z Wang, X Pankratz, VS Couch, F Simard, J Easton, DF Chenevix-Trench, G AF Antoniou, Antonis C. Kartsonaki, Christiana Sinilnikova, Olga M. Soucy, Penny McGuffog, Lesley Healey, Sue Lee, Andrew Peterlongo, Paolo Manoukian, Siranoush Peissel, Bernard Zaffaroni, Daniela Cattaneo, Elisa Barile, Monica Pensotti, Valeria Pasini, Barbara Dolcetti, Riccardo Giannini, Giuseppe Putignano, Anna Laura Varesco, Liliana Radice, Paolo Mai, Phuong L. Greene, Mark H. Andrulis, Irene L. Glendon, Gord Ozcelik, Hilmi Thomassen, Mads Gerdes, Anne-Marie Kruse, Torben A. Jensen, Uffe Birk Crueger, Dorthe G. Caligo, Maria A. Laitman, Yael Milgrom, Roni Kaufman, Bella Paluch-Shimon, Shani Friedman, Eitan Loman, Niklas Harbst, Katja Lindblom, Annika Arver, Brita Ehrencrona, Hans Melin, Beatrice Nathanson, Katherine L. Domchek, Susan M. Rebbeck, Timothy Jakubowska, Ania Lubinski, Jan Gronwald, Jacek Huzarski, Tomasz Byrski, Tomasz Cybulski, Cezary Gorski, Bohdan Osorio, Ana Ramon y Cajal, Teresa Fostira, Florentia Andres, Raquel Benitez, Javier Hamann, Ute Hogervorst, Frans B. Rookus, Matti A. Hooning, Maartje J. Nelen, Marcel R. van der Luijt, Rob B. van Os, Theo A. M. van Asperen, Christi J. Devilee, Peter Meijers-Heijboer, Hanne E. J. Garcia, Encarna B. Gomez Peock, Susan Cook, Margaret Frost, Debra Platte, Radka Leyland, Jean Evans, D. Gareth Lalloo, Fiona Eeles, Ros Izatt, Louise Adlard, Julian Davidson, Rosemarie Eccles, Diana Ong, Kai-ren Cook, Jackie Douglas, Fiona Paterson, Joan Kennedy, M. John Miedzybrodzka, Zosia Godwin, Andrew Stoppa-Lyonnet, Dominique Buecher, Bruno Belotti, Muriel Tirapo, Carole Mazoyer, Sylvie Barjhoux, Laure Lasset, Christine Leroux, Dominique Faivre, Laurence Bronner, Myriam Prieur, Fabienne Nogues, Catherine Rouleau, Etienne Pujol, Pascal Coupier, Isabelle Frenay, Marc Hopper, John L. Daly, Mary B. Terry, Mary B. John, Esther M. Buys, Saundra S. Yassin, Yosuf Miron, Alexander Goldgar, David Singer, Christian F. Tea, Muy-Kheng Pfeiler, Georg Dressler, Anne Catharina Hansen, Thomas v. O. Jonson, Lars Ejlertsen, Bent Barkardottir, Rosa Bjork Kirchhoff, Tomas Offit, Kenneth Piedmonte, Marion Rodriguez, Gustavo Small, Laurie Boggess, John Blank, Stephanie Basil, Jack Azodi, Masoud Toland, Amanda Ewart Montagna, Marco Tognazzo, Silvia Agata, Simona Imyanitov, Evgeny Janavicius, Ramunas Lazaro, Conxi Blanco, Ignacio Pharoah, Paul D. P. Sucheston, Lara Karlan, Beth Y. Walsh, Christine S. Olah, Edith Bozsik, Aniko Teo, Soo-Hwang Seldon, Joyce L. Beattie, Mary S. van Rensburg, Elizabeth J. Sluiter, Michelle D. Diez, Orland Schmutzler, Rita K. Wappenschmidt, Barbara Engel, Christoph Meindl, Alfons Ruehl, Ina Varon-Mateeva, Raymonda Kast, Karin Deissler, Helmut Niederacher, Dieter Arnold, Norbert Gadzicki, Dorothea Schoenbuchner, Ines Caldes, Trinidad de la Hoya, Miguel Nevanlinna, Heli Aittomaki, Kristiina Dumont, Martine Chiquette, Jocelyne Tischkowitz, Marc Chen, Xiaoqing Beesley, Jonathan Spurdle, Amanda B. Neuhausen, Susan L. Ding, Yuan Chun Fredericksen, Zachary Wang, Xianshu Pankratz, Vernon S. Couch, Fergus Simard, Jacques Easton, Douglas F. Chenevix-Trench, Georgia CA SWE-BRCA HEBON EMBRACE CEMO Study Collaborators Breast Canc Family Registry kConFab Investigators CIMBA TI Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; ESTROGEN-RECEPTOR; CONFER SUSCEPTIBILITY; GENETIC MODIFIERS; VARIANTS; LOCUS; POPULATION; 2Q35 AB Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [ hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women. C1 [Antoniou, Antonis C.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge CB1 8RN, England. [Sinilnikova, Olga M.; CEMO Study Collaborators] Ctr Hosp Univ Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. 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[Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Chiquette, Jocelyne] Univ Quebec, Ctr Hosp, Ctr Rech FRSQ, Unite Rech Sante Populat,Ctr Malad Sein Deschenes, Quebec City, PQ, Canada. [Tischkowitz, Marc] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada. [Tischkowitz, Marc] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Tischkowitz, Marc] McGill Univ, Jewish Gen Hosp, Segal Canc Ctr, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Neuhausen, Susan L.; Ding, Yuan Chun] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Fredericksen, Zachary; Pankratz, Vernon S.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Wang, Xianshu; Couch, Fergus] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. RP Antoniou, AC (reprint author), Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. EM antonis@srl.cam.ac.uk RI Ehrencrona, Hans/M-5619-2014; Jakubowska, Anna/O-8050-2014; GLADIEFF, Laurence/O-5129-2014; Nelen, Marcel/L-4542-2015; Dolcetti, Riccardo/O-3832-2015; Ligtenberg, Marjolijn/N-9666-2013; Gronwald, Jacek/A-4576-2017; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; Rahman, Nazneen/D-2802-2013; Arnold, Norbert/E-3012-2010; Toland, Amanda/E-4202-2011; montagna, marco/E-2225-2012; Giannini, Giuseppe/B-5672-2013; Hoogerbrugge, Nicoline/O-1016-2013; Radice, Paolo/O-3119-2013; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Blanco, Ignacio/D-2565-2013; Leroux, Dominique/G-7309-2014; Teo, Soo-hwang/H-2353-2014; Osorio, Ana/I-4324-2014; BYRSKI, Tomasz/I-2844-2014; Oosterwijk, Jan C./G-5770-2011; Spurdle, Amanda/A-4978-2011; OI Ehrencrona, Hans/0000-0002-5589-3622; GLADIEFF, Laurence/0000-0002-6980-9719; Dolcetti, Riccardo/0000-0003-1625-9853; Ligtenberg, Marjolijn/0000-0003-1290-1474; Gronwald, Jacek/0000-0002-3643-2871; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; Janavicius, Ramunas/0000-0002-3773-8485; Nordling, Margareta/0000-0002-4047-4994; Rahman, Nazneen/0000-0003-4376-0440; Arnold, Norbert/0000-0003-4523-8808; montagna, marco/0000-0002-4929-2150; Giannini, Giuseppe/0000-0003-0299-4056; Blanco, Ignacio/0000-0002-7414-7481; Osorio, Ana/0000-0001-8124-3984; Eeles, Rosalind/0000-0002-3698-6241; Barton, David E/0000-0002-2031-9719; Nathanson, Katherine/0000-0002-6740-0901; Spurdle, Amanda/0000-0003-1337-7897; PUTIGNANO, Anna Laura/0000-0001-9434-1612; Nevanlinna, Heli/0000-0002-0916-2976; Kirchhoff, Tomas/0000-0002-9055-2364; Evans, Gareth/0000-0002-8482-5784; Kruse, Inken/0000-0001-7176-6300 FU Cancer Research UK [C12292/A11174, C1287/A10118]; European Community [223175 (HEALTH-F22009-223175)]; Associazion