FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Klinman, DM Yamamoto, M Tross, D Tomaru, K AF Klinman, Dennis M. Yamamoto, Masaki Tross, Debra Tomaru, Koji TI Anthrax prevention and treatment: utility of therapy combining antibiotic plus vaccine SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE adjuvant; anthrax; vaccine ID RECOMBINANT PROTECTIVE ANTIGEN; EXPERIMENTAL INHALATIONAL ANTHRAX; CPG OLIGONUCLEOTIDES IMPROVE; BACILLUS-ANTHRACIS; IMMUNE-RESPONSE; POSTEXPOSURE PROPHYLAXIS; NASAL IMMUNIZATION; ANTIBODY-RESPONSE; RHESUS MACAQUES; COMPARATIVE EFFICACY AB The intentional release of anthrax spores in 2001 confirmed this pathogen's ability to cause widespread panic, morbidity and mortality. While individuals exposed to anthrax can be successfully treated with antibiotics, pre-exposure vaccination can reduce susceptibility to infection-induced illness. Concern over the safety and immunogenicity of the licensed US vaccine (Anthrax Vaccine Adsorbed (AVA)) has fueled research into alternatives. Second-generation anthrax vaccines based on purified recombinant protective antigen (rPA) have entered clinical trials. These rPA vaccines induce neutralizing antibodies that prevent illness, but the magnitude and duration of the resultant protective response is modest. Efforts are underway to bolster the immunogenicity of rPA by combining it with adjuvants and other immunostimulatory agents. Third generation vaccines are under development that utilize a wide variety of immunization platforms, antigens, adjuvants, delivery methods and routes of delivery to optimize the induction of a protective immunity. For the foreseeable future, vaccination will rely on first and second generation vaccines co-administered with immune adjuvants. Optimal post-exposure treatment of immunologically naive individuals should include a combination of vaccine plus antibiotic therapy. C1 [Klinman, Dennis M.; Yamamoto, Masaki; Tross, Debra; Tomaru, Koji] NCI, Frederick, MD 21702 USA. RP Klinman, DM (reprint author), NCI, Bldg 567,Room 205, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov NR 121 TC 3 Z9 3 U1 2 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD DEC PY 2009 VL 9 IS 12 BP 1477 EP 1486 DI 10.1517/14712590903307347 PG 10 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 532LJ UT WOS:000272749200003 PM 19769541 ER PT J AU Carter, CA Kelly, RJ Giaccone, G AF Carter, Corey A. Kelly, Ronan J. Giaccone, Giuseppe TI Small-molecule inhibitors of the human epidermal receptor family SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Review DE EGFR inhibitors; erbB1; erbB2; erbB3; erbB4; HER family; HER2 inhibitors ID CELL LUNG-CANCER; GROWTH-FACTOR RECEPTOR; PHASE-II TRIAL; TYROSINE KINASE INHIBITOR; K-RAS MUTATIONS; PREVIOUSLY TREATED PATIENTS; ADVANCED PANCREATIC-CANCER; HUMAN BREAST-CANCER; ACQUIRED-RESISTANCE; OPEN-LABEL AB Background: Small molecule inhibitors of human epidermal receptors (HER) have become an integral part of the armamentarium available to the medical oncologist in the treatment of solid tumor malignancies. At present, there are two small-molecule inhibitors (erlotinib and lapatinib) approved by the FDA in the USA, and a third inhibitor, gefitinib, is approved in other countries. Objective: To summarize the current standards of care for these new agents in solid tumors, and to discuss ongoing clinical trials; to review the known mechanisms of action of these inhibitors as well as to discuss both the known predictive markers for response and likely mechanisms of resistance. Methods: We reviewed key presentations and recent publications on small-molecule inhibitors targeting the HER family in solid tumors. Conclusions: Recent data have highlighted the importance of mutations and amplifications of receptors within the HER family. Amplification of HER2 often translates into responses in anti-HER2 therapy. Mutations either enhance sensitivity or confer resistance to small-molecule inhibitors. Other mechanisms of resistance are being elucidated which should lead to the ability to predict both responses and resistance to HER family inhibitors and should translate into improvements in patient care. C1 [Carter, Corey A.; Giaccone, Giuseppe] NCI, NIH, Bethesda Naval Hosp, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, NIH, Bethesda Naval Hosp, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 106 TC 22 Z9 22 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-3784 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD DEC PY 2009 VL 18 IS 12 BP 1829 EP 1842 DI 10.1517/13543780903373343 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 532LT UT WOS:000272750200004 PM 19938898 ER PT J AU Yang, SX AF Yang, Sherry X. TI Bevacizumab and breast cancer: current therapeutic progress and future perspectives SO EXPERT REVIEW OF ANTICANCER THERAPY LA English DT Review DE bevacizumab; breast cancer; chemotherapy clinical trials; first-line therapy; VEGF ID ENDOTHELIAL GROWTH-FACTOR; PACLITAXEL PLUS BEVACIZUMAB; METASTATIC COLORECTAL-CANCER; PHASE-II TRIAL; MONOCLONAL-ANTIBODY; FACTOR PROTEIN; FACTOR VEGF; ANGIOGENESIS; DOCETAXEL; CELLS AB Bevacizumab is a humanized monoclonal antibody to VEGF, and the incorporation of bevacizumab to chemotherapy is one of the rapidly evolving areas in the treatment of breast cancer. Bevacizumab in combination with chemotherapy versus chemotherapy alone improves progression-free survival and increases the response rate in first-line therapy for locally recurrent or metastatic breast cancer. This approach has been and is still being evaluated for early breast cancer in neoadjuvant and adjuvant settings. Bevacizumab is well tolerated and has an established tolerability profile. Both tumor- and host-related biomarkers of bevacizumab activity, response and benefit are emerging from Phase I, II and III clinical trials. The biomarkers of benefit will ultimately help identify the subgroups of patients who specifically benefit from anti-VEGF therapy with bevacizumab. C1 Natl Canc Inst, Natl Clin Target Validat Lab, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Yang, SX (reprint author), Natl Canc Inst, Natl Clin Target Validat Lab, Div Canc Treatment & Diag, NIH, Bldg 37 Room 1048,37 Convent Dr, Bethesda, MD 20892 USA. EM xy32m@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 70 TC 12 Z9 15 U1 0 U2 1 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7140 J9 EXPERT REV ANTICANC JI Expert Rev. Anticancer Ther PD DEC PY 2009 VL 9 IS 12 BP 1715 EP 1725 DI 10.1586/ERA.09.153 PG 11 WC Oncology SC Oncology GA 534WW UT WOS:000272929200009 PM 19954282 ER PT J AU Mai, PL Chen, BE Tucker, K Friedlander, M Phillips, KA Hogg, D Jewett, MAS Bodrogi, I Geczi, L Olah, E Heimdal, K Fossa, SD Nathanson, KL Korde, L Easton, DF Dudakia, D Huddart, R Stratton, MR Bishop, DT Rapley, EA Greene, MH AF Mai, Phuong L. Chen, Bingshu E. Tucker, Kathy Friedlander, Michael Phillips, Kelly-Anne Hogg, David Jewett, Michael A. S. Bodrogi, Istvan Geczi, Lajos Olah, Edith Heimdal, Ketil Fossa, Sophie D. Nathanson, Katherine L. Korde, Larissa Easton, Douglas F. Dudakia, Darshna Huddart, Robert Stratton, Michael R. Bishop, D. Timothy Rapley, Elizabeth A. Greene, Mark H. TI Younger age-at-diagnosis for familial malignant testicular germ cell tumor SO FAMILIAL CANCER LA English DT Article DE Age at diagnosis; Familial; Non-seminoma; Population-based testicular cancer; Seminoma; Testicular germ cell tumor ID SUSCEPTIBILITY GENES; CANCER; POPULATION; RISK AB One of the clinical hallmarks of hereditary cancer susceptibility disorders is a younger-than-usual age at diagnosis. Familial aggregation of testicular germ cell tumor (TGCT) has been reported, but data on whether familial TGCT cases are diagnosed at an earlier age are inconclusive. Here we compared the age at diagnosis of familial TGCT cases with that of population cases in several countries. Familial TGCT is defined as affected individuals from families with a parts per thousand yen2 cases of TGCT. Age at diagnosis of familial cases from the United States, Canada, United Kingdom, Australia and New Zealand, Norway, and Hungary was compared to cases identified in population-based cancer registries from the respective country, using the generalized estimation equation method. Age at diagnosis was statistically significantly younger for familial TGCT cases from North America (P = 0.024), the United Kingdom (P < 0.0001), and Australia and New Zealand (P = 0.0033) compared with population cases. When stratified by histology, the difference in age at diagnosis distribution between familial and population cases was observed for seminoma cases from North America (P = 0.002) and the United Kingdom (P < 0.0001) and non-seminoma cases from the United Kingdom (P = 0.029) and Australia and New Zealand (P = 0.0023). In summary, we found that the age at diagnosis for familial TGCT cases is, on the average, 2-3 years younger than that for the population cases in North America, United Kingdom, and Australia and New Zealand. The younger age at diagnosis might be suggestive of a genetic basis for familial TGCT. C1 [Mai, Phuong L.; Korde, Larissa; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Chen, Bingshu E.] Queens Univ, NCIC, Clin Trials Grp, Kingston, ON K7L 3N6, Canada. [Tucker, Kathy; Friedlander, Michael] Univ New S Wales, Prince Wales Hosp, Div Med, Dept Med Oncol, Randwick, NSW 2031, Australia. [Phillips, Kelly-Anne] Peter MacCallum Canc Ctr, Dept Haematol & Med Oncol, Melbourne, Vic 3002, Australia. [Hogg, David; Jewett, Michael A. S.] Univ Toronto, Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. [Bodrogi, Istvan; Geczi, Lajos; Olah, Edith] Natl Inst Oncol, Dept Chemotherapy & Mol Genet, H-1122 Budapest, Hungary. [Heimdal, Ketil; Fossa, Sophie D.] Radiumhosp Univ Hosp, Rikshosp, Dept Clin Canc Res, N-0027 Oslo, Norway. [Heimdal, Ketil; Fossa, Sophie D.] Radiumhosp Univ Hosp, Rikshosp, Dept Med Genet, N-0027 Oslo, Norway. [Nathanson, Katherine L.] Univ Penn, Sch Med, Div Med Genet, Dept Med, Philadelphia, PA 19104 USA. [Easton, Douglas F.] Strangeways Res Lab, CRC Genet Epidemiol Unit, Cambridge CB1 8RN, England. [Dudakia, Darshna; Stratton, Michael R.; Rapley, Elizabeth A.] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England. [Huddart, Robert] Inst Canc Res, Acad Radiotherapy Unit, Sutton SM2 5NG, Surrey, England. [Bishop, D. Timothy] St James Univ Hosp, Imperial Canc Res Fund Genet Epidemiol Lab, Leeds LS9 7TF, W Yorkshire, England. RP Mai, PL (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd EPS 7022, Rockville, MD 20852 USA. EM maip@mail.nih.gov RI friedlander, michael/G-3490-2013; OI friedlander, michael/0000-0002-6488-0604; Nathanson, Katherine/0000-0002-6740-0901; Phillips, Kelly-Anne/0000-0002-0475-1771; Bishop, Tim/0000-0002-8752-8785; Heimdal, Ketil/0000-0002-8911-3508 FU National Cancer Institute, National Institutes of Health [N02-CP-11019, N02-CP-65504] FX We would like to thank Dr. Parry Guilford for his contribution to the familial TGCT cases. We also thank Istvan Gaudi (Cancer Registry of National Institute of Oncology, Budapest, Hungary) and Sue Westlake (Social & Health Analysis & Reporting Division, Office for National Statistics, UK) for their contribution from the cancer registries. This research was funded in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, and supported by contracts N02-CP-11019 and N02-CP-65504 with Westat, Incorporated. The authors have no conflict of interest or financial disclosures to report. NR 22 TC 10 Z9 12 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 J9 FAM CANCER JI Fam. Cancer PD DEC PY 2009 VL 8 IS 4 BP 451 EP 456 DI 10.1007/s10689-009-9264-6 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 514MP UT WOS:000271399200023 PM 19609727 ER PT J AU Lindsey, EW Chambers, JC Frabutt, JM Mackinnon-Lewis, C AF Lindsey, Eric W. Chambers, Jessica Campbell Frabutt, James M. Mackinnon-Lewis, Carol TI Marital Conflict and Adolescents' Peer Aggression: The Mediating and Moderating Role of Mother-Child Emotional Reciprocity SO FAMILY RELATIONS LA English DT Article DE emotional reciprocity; marital conflict; mother-adolescent; overt aggression; relational aggression ID SOCIAL-PSYCHOLOGICAL ADJUSTMENT; AFRICAN-AMERICAN FAMILIES; INTERPARENTAL CONFLICT; RELATIONAL AGGRESSION; PHYSICAL AGGRESSION; BEHAVIOR PROBLEMS; IMPACT; MODEL; PARENTS; STRESS AB This study examined the role of mother-adolescent emotional reciprocity in connections between marital conflict and adolescent aggression with peers. Data were collected from a racially diverse community sample of 268 adolescents and their mothers. Adolescents reported on parents' marital conflict, and mother-adolescent positive and negative emotional reciprocity were coded from videotaped observations. Teachers provided assessments of adolescents' overt and relational aggression with peers. Structural equation modeling revealed both direct and indirect paths in connections between marital conflict and adolescents' peer aggression. Mother-adolescent emotional reciprocity both mediated and moderated the association between marital conflict and peer aggression. Patterns of association linking marital conflict to peer aggression were similar for African American and European American adolescents; however, differences were observed for men and women. C1 [Lindsey, Eric W.] Penn State Berks, Dept Appl Psychol, Reading, PA 19610 USA. [Chambers, Jessica Campbell] Natl Inst Drug Abuse, Ctr AIDS & Other Med Consequences Drug Abuse, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20852 USA. [Frabutt, James M.] Univ Notre Dame, ACE Leadership Program, Notre Dame, IN 46556 USA. [Mackinnon-Lewis, Carol] Univ S Florida, Dept Child & Family Studies, Tampa, FL 33612 USA. RP Lindsey, EW (reprint author), Penn State Berks, Dept Appl Psychol, 7009 Tulpehocken Rd, Reading, PA 19610 USA. EM EWL10@psu.edu NR 36 TC 2 Z9 2 U1 1 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0197-6664 J9 FAM RELAT JI Fam. Relat. PD DEC PY 2009 VL 58 IS 5 BP 593 EP 606 PG 14 WC Family Studies; Social Work SC Family Studies; Social Work GA 530EP UT WOS:000272572100008 ER PT J AU Clay, JR AF Clay, John R. TI Determining K+ channel activation curves from K+ channel currents often requires the Goldman-Hodgkin-Katz equation SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Review DE ion permeation; channel gating; membrane excitability ID SQUID GIANT-AXON; SUPRACHIASMATIC NUCLEUS NEURONS; MAMMALIAN CIRCADIAN CLOCK; VOLTAGE CLAMP DATA; POTASSIUM CURRENT; GATING CURRENTS; SODIUM-CHANNELS; XENOPUS LAEVIS; SINGLE-CHANNEL; NERVE FIBRE AB Potassium ion current in nerve membrane, I-K, has traditionally been described by I-K = g(K) (V - E-K), where g(K) is the K ion conductance, V is membrane potential and E-K is the K+ Nernst potential. This description has been unchallenged by most investigators in neuroscience since its introduction almost 60 years ago. The problem with the I-K similar to (V - E-K) proportionality is that it is inconsistent with the unequal distribution of K ions in the intra- and extracellular bathing media. Under physiological conditions the intracellular K+ concentration is significantly higher than the extracellular concentration. Consequently, the slope conductance at potentials positive to E-K cannot be the same as that for potentials negative to E-K, as the linear proportionality between I K and (V - E-K) requires. Instead I-K has a non-linear dependence on (V - E-K) which is well described by the Goldman-Hodgkin-Katz equation. The implications of this result for K+ channel gating and membrane excitability are reviewed in this report. C1 [Clay, John R.] NINDS, Ion Channel Biophys Grp, NIH, Bethesda, MD 20892 USA. RP Clay, JR (reprint author), TN 41,Twinbrook Bldg,5625 Fishers Lane, Bethesda, MD 20892 USA. EM jrclay@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. NR 47 TC 8 Z9 8 U1 0 U2 4 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD DEC PY 2009 VL 3 AR 20 DI 10.3389/neuro.03.020.2009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 674KW UT WOS:000283743200002 PM 20057933 ER PT J AU Gentsch, JR Parashar, UD Glass, RI AF Gentsch, Jon R. Parashar, Umesh D. Glass, Roger I. TI Impact of rotavirus vaccination: the importance of monitoring strains SO FUTURE MICROBIOLOGY LA English DT Editorial Material ID 1ST 2 YEARS; UNITED-STATES; DOUBLE-BLIND; GASTROENTERITIS; EFFICACY; SAFETY; POPULATION; DIVERSITY; DIARRHEA; CHILDREN C1 [Gentsch, Jon R.; Parashar, Umesh D.] Ctr Dis Control & Prevent, Div Viral Dis, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Gentsch, JR (reprint author), Ctr Dis Control & Prevent, Div Viral Dis, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. EM jrg4@cdc.gov; glassr@mail.nih.gov NR 28 TC 23 Z9 24 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0913 J9 FUTURE MICROBIOL JI Future Microbiol. PD DEC PY 2009 VL 4 IS 10 BP 1231 EP 1234 DI 10.2217/FMB.09.105 PG 4 WC Microbiology SC Microbiology GA 535RZ UT WOS:000272989700001 PM 19995181 ER PT J AU Day, PM Schiller, JT AF Day, Patricia M. Schiller, John T. TI The role of furin in papillomavirus infection SO FUTURE MICROBIOLOGY LA English DT Article DE basement membrane; extracellular matrix; furin; heparan sulfate proteoglycan; papillomavirus; proprotein convertase ID MINOR CAPSID PROTEIN; VIRUS-LIKE PARTICLES; CELL-SURFACE; PROPROTEIN CONVERTASES; HEPARAN-SULFATE; EXTRACELLULAR-MATRIX; HUMAN KERATINOCYTES; L2; NEUTRALIZATION; ACTIVATION AB Papillomaviruses represent a medically important virus family, Infection with a high-risk human papillomavirus type is a prerequisite for cervical carcinoma development. Infection by low-risk types may result in the generation of benign skin warts, It was recently found that infectious entry of these viruses is dependent upon a specific proteolytic event that occurs prior to viral endocytosis. Specifically, a proprotein convertase, furin or proprotein convertase 5/6, must cleave the minor capsid protein for infection to proceed. Here, an overview of what is currently known about this process is presented, and what we have learned about the papillomavirus lifecycle from these studies discussed. This work also has implications for further advances in papillomavirus vaccine development. C1 [Day, Patricia M.; Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Day, PM (reprint author), NCI, Cellular Oncol Lab, NIH, Room 4112,Bldg 37, Bethesda, MD 20892 USA. EM pmd@nih.gov; schillej@mail.nih.gov FU Intramural NIH HHS [ZIA BC009052-20, Z99 CA999999, Z01 BC009052-18, Z01 BC009052-19] NR 49 TC 24 Z9 28 U1 0 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0913 J9 FUTURE MICROBIOL JI Future Microbiol. PD DEC PY 2009 VL 4 IS 10 BP 1255 EP 1262 DI 10.2217/FMB.09.86 PG 8 WC Microbiology SC Microbiology GA 535RZ UT WOS:000272989700009 PM 19995186 ER PT J AU Shiffman, ML Morishima, C Dienstag, JL Lindsay, KL Hoefs, JC Lee, WM Wright, EC Naishadham, D Everson, GT Lok, AS Di Bisceglie, AM Bonkovsky, HL Ghany, MG AF Shiffman, Mitchell L. Morishima, Chihiro Dienstag, Jules L. Lindsay, Karen L. Hoefs, John C. Lee, William M. Wright, Elizabeth C. Naishadham, Deepa Everson, Gregory T. Lok, Anna S. Di Bisceglie, Adrian M. Bonkovsky, Herbert L. Ghany, Marc G. CA HALT-C Trial Grp TI Effect of HCV RNA Suppression During Peginterferon Alfa-2a Maintenance Therapy on Clinical Outcomes in the HALT-C Trial SO GASTROENTEROLOGY LA English DT Article ID CHRONIC HEPATITIS-C; LOW-DOSE PEGINTERFERON; ADVANCED FIBROSIS; PLUS RIBAVIRIN; COMPENSATED CIRRHOSIS; LIVER-TRANSPLANTATION; VIROLOGICAL RESPONSE; VIRUS-INFECTION; INTERFERON; TELAPREVIR AB BACKGROUND & AIMS: The Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial demonstrated that low-dose peginterferon maintenance therapy was ineffective in preventing clinical outcomes in patients with chronic hepatitis C, advanced fibrosis, and failure to achieve a sustained virologic response during lead-in phase treatment with standard dose peginterferon/ribavirin. This analysis was performed to determine whether suppressing HCV RNA during the trial was associated with a reduction in clinical outcomes. METHODS: Seven hundred sixty-four patients treated during the lead-in phase of HALT-C trial were randomized to either peginterferon alfa-2a (90 mu g/week) maintenance therapy or no treatment (control) for 3.5 years. Clinical outcomes included an increase in Child-Turcotte-Pugh score, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, hepatocellular carcinoma, and mortality. RESULTS: During the lead-in, >= 4 log(10) decline in serum HCV RNA occurred in 178 patients; 82% of whom lost detectable HCV RNA and later broke through or relapsed. These patients had significantly (P = .003) fewer clinical outcomes whether randomized to maintenance therapy or control. Following randomization, serum HCV RNA increased significantly in all 90 control patients and in 58 of 88 receiving maintenance therapy. Only 30 patients had persistent suppression of HCV RNA by >= 4 log(10) during maintenance therapy. No significant reduction in clinical out-comes was observed in these patients. CONCLUSIONS: Viral suppression by >= 4 log(10) with full-dose peginterferon/ribavirin is associated with a significant reduction in clinical outcomes. Continuing low-dose peginterferon maintenance therapy, even in patients with persistent viral suppression, does not lead to a further decline in clinical outcomes. C1 [Shiffman, Mitchell L.] Virginia Commonwealth Univ, Med Ctr, Hepatol Sect, Richmond, VA 23298 USA. [Morishima, Chihiro] Univ Washington, Dept Lab Med, Div Virol, Seattle, WA 98195 USA. [Dienstag, Jules L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Dienstag, Jules L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Med Serv, Boston, MA USA. [Lindsay, Karen L.] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Hoefs, John C.] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. [Lee, William M.] Univ Texas SW Med Ctr Dallas, Div Digest & Liver Dis, Dallas, TX 75390 USA. [Naishadham, Deepa] New England Res Inst, Watertown, MA 02172 USA. [Everson, Gregory T.] Univ Colorado Denver, Dept Internal Med, Div Gastroenterol & Hepatol, Sect Hepatol, Aurora, CO USA. [Lok, Anna S.] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. [Di Bisceglie, Adrian M.] St Louis Univ, Sch Med, Div Gastroenterol & Hepatol, St Louis, MO USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Mol & Struct Biol, Farmington, CT USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Liver Biliary Pancreat Ctr, Farmington, CT USA. [Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Shiffman, ML (reprint author), VCU Hlth Syst, Hepatol Sect, Box 980341, Richmond, VA 23298 USA. EM mshiffma@vcu.edu OI Yang, Shuman/0000-0002-9638-0890 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases (NIAID); National Cancer Institute; National Center for Minority Health and Health Disparities; National Center for Research Resources; National Institutes of Health; Hoffmann-La Roche, Inc FX Supported by the National Institute of Diabetes and Digestive and Kidney Diseases (contract numbers listed above), the National Institute of Allergy and Infectious Diseases (NIAID), the National Cancer Institute, the National Center for Minority Health and Health Disparities, and the General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, and National Institutes of Health (grant numbers are listed above). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc, through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health. NR 27 TC 27 Z9 27 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2009 VL 137 IS 6 BP 1986 EP 1994 DI 10.1053/j.gastro.2009.08.067 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 529TF UT WOS:000272539900023 PM 19747918 ER PT J AU Lafdil, F Wang, H Park, O Zhang, WC Moritoki, Y Yin, S Fu, XY Gershwin, ME Lian, ZX Gao, B AF Lafdil, Fouad Wang, Hua Park, Ogyi Zhang, Weici Moritoki, Yuki Yin, Shi Fu, Xin Yuan Gershwin, M. Eric Lian, Zhe-Xiong Gao, Bin TI Myeloid STAT3 Inhibits T Cell-Mediated Hepatitis by Regulating T Helper 1 Cytokine and Interleukin-17 Production SO GASTROENTEROLOGY LA English DT Article ID A-INDUCED HEPATITIS; TNF-INDUCED APOPTOSIS; INDUCED LIVER-INJURY; KEY PATHOGENIC ROLE; CONCANAVALIN-A; KUPFFER CELLS; ISCHEMIA/REPERFUSION INJURY; NEUTROPHIL RECRUITMENT; INFLAMMATORY RESPONSE; AUTOIMMUNE RESPONSES AB BACKGROUND & AIMS: T cell-mediated hepatitis is leading cause of acute liver failure; there is no treatment, and the mechanisms underlying its pathogenesis are obscure. The aim of this study was to investigate the immune cell-signaling pathways involved-specifically the role of signal transducer and activator transcription 3 (STAT3)-in T cell-mediated hepatitis in mice. METHODS: T cell-mediated hepatitis was induced in mice by injection of concanavalin A (Con A). Mice with myeloid cell-specific and T-cell-specific deletion STAT3 were generated. RESULTS: STAT3 was activated in myeloid and T cells following Con A injection. Deletion of STAT3 specifically from myeloid cells exacerbated T-cell hepatitis and induced STAT1-dependent production of a T helper cell (Th)1 cytokine (interferon [IFN]-gamma) and to a lesser extent of Th17 cytokines (interleukin [IL]-17 and IL-22) in a STAT1-independent manner. In contrast, deletion of STAT3 in T cells reduced T cell-mediated hepatitis and IL-17 production. Furthermore, deletion of IFN-gamma completely abolished Con A-induced T-cell hepatitis, whereas deletion of IL-17 slightly but significantly reduced such injury. In vitro experiments indicated that IL-17 promoted liver inflammation but inhibited hepatocyte apoptosis. CONCLUSIONS: Myeloid STAT3 activation inhibits T cell-mediated hepatitis via suppression of a Th1 cytokine (IFN-gamma) in a STAT1-dependent manner, whereas STAT3 activation in T cells promotes T-cell hepatitis to a lesser extent, via induction of IL-17. Therefore, activation of STAT3 in myeloid cells could be a novel therapeutic strategy for patients with T-cell hepatitis. C1 [Lafdil, Fouad; Wang, Hua; Park, Ogyi; Yin, Shi; Gao, Bin] NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Zhang, Weici; Moritoki, Yuki; Fu, Xin Yuan; Gershwin, M. Eric] Univ Calif Davis, Div Rheumatol, Davis, CA 95616 USA. [Fu, Xin Yuan] Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Fu, Xin Yuan] Indiana Univ, Sch Med, Walther Oncol Ctr, Indianapolis, IN 46202 USA. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov RI Ji, Haofeng/G-6206-2012 FU NIAAA; NIH FX Supported by the intramural program of NIAAA, NIH. NR 47 TC 56 Z9 59 U1 0 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2009 VL 137 IS 6 BP 2125 EP 2135 DI 10.1053/j.gastro.2009.08.004 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 529TF UT WOS:000272539900037 PM 19686746 ER PT J AU von Rosenvinge, EC Gopal, LD Heller, T Kohn, EC Yao, MD AF von Rosenvinge, Erik C. Gopal, Lakshmi D. Heller, Theo Kohn, Elise C. Yao, Michael D. TI Rectal fistulae resulting from treatment with sorafenib and bevacizumab SO GASTROINTESTINAL ENDOSCOPY LA English DT Editorial Material C1 [von Rosenvinge, Erik C.; Gopal, Lakshmi D.; Heller, Theo] NIDDK, Bethesda, MD 20892 USA. [Kohn, Elise C.] NCI, Bethesda, MD 20892 USA. [Yao, Michael D.] NIAID, NIH, Bethesda, MD 20892 USA. RP von Rosenvinge, EC (reprint author), NIDDK, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD DEC PY 2009 VL 70 IS 6 BP 1246 EP 1247 DI 10.1016/j.gie.2009.06.027 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 537KH UT WOS:000273111300036 PM 19683714 ER PT J AU Bigos, KL Pollock, BG Stankevich, BA Bies, RR AF Bigos, Kristin L. Pollock, Bruce G. Stankevich, Beth A. Bies, Robert R. TI Sex Differences in the Pharmacokinetics and Pharmacodynamics of Antidepressants: An Updated Review SO GENDER MEDICINE LA English DT Review DE sex; gender; pharmacokinetics; pharmacodynamics; antidepressant; SSRI ID SEROTONIN-REUPTAKE INHIBITORS; MAJOR DEPRESSIVE DISORDER; PERSISTENT PULMONARY-HYPERTENSION; N-DEMETHYL METABOLITE; GENDER-DIFFERENCES; CONGENITAL-MALFORMATIONS; POSTMENOPAUSAL WOMEN; MENSTRUAL-CYCLE; LUTEAL-PHASE; MATERNAL USE AB Background: An increasing number of studies have reported differences in the pharmacokinetics and/or pharmacodynamics of antidepressants between women and men. Objectives: This article updates previously published literature describing sex differences in the pharmacokinetics and pharmacodynamics of antidepressants, and examines specific issues that face women with psychiatric illness. Methods: An English-language literature search was performed with the PubMed database (March 2003-December 2008) using combinations of the search terms sex, gender, and antidepressants. In addition, each antidepressant was identified in the 63rd edition of the Physicians' Desk Reference. Results: The current data suggest that the pharmacokinetics of antidepressants can be substantially different between women and men. Likewise, the response to antidepressants can be quite variable, including sex differences in adverse effects and time to response. Conclusions: Despite the many sex differences reported, there is still little published work systematically evaluating potential sex differences in antidepressant pharmacokinetics and pharmacodynamics. More research is needed to guide the treatment of depression and other mental illnesses. (Gend Med. 2009;6:522-543) (C) 2009 Excerpta Medica Inc. C1 [Bigos, Kristin L.; Stankevich, Beth A.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Pollock, Bruce G.; Bies, Robert R.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Pollock, Bruce G.] Univ Toronto, Rotman Res Inst, Toronto, ON, Canada. [Pollock, Bruce G.; Bies, Robert R.] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Bies, Robert R.] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA USA. RP Bigos, KL (reprint author), NIMH, Clin Brain Disorders Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 3C101, Bethesda, MD 20892 USA. EM bigosk@mail.nih.gov RI Bigos, Kristin/E-9768-2010 NR 132 TC 39 Z9 44 U1 6 U2 19 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 1550-8579 J9 GENDER MED JI Gend. Med. PD DEC PY 2009 VL 6 IS 4 BP 522 EP 543 DI 10.1016/j.genm.2009.12.004 PG 22 WC Medicine, General & Internal SC General & Internal Medicine GA 550YQ UT WOS:000274171300003 PM 20114004 ER PT J AU Stanghellini, I Falco, G Lee, SL Monti, M Ko, MSH AF Stanghellini, Ilaria Falco, Geppino Lee, Sung-Lim Monti, Manuela Ko, Minoru S. H. TI Trim43a, Trim43b, and Trim43c: Novel mouse genes expressed specifically in mouse preimplantation embryos SO GENE EXPRESSION PATTERNS LA English DT Article DE Mouse preimplantation; Gene expression; 8-Cell; Morula; Fluorescent proteins; Asymmetric PCR; Promoter analysis ID TRANSGENIC MICE; FAMILY; PROTEINS; PCR AB We describe the identification and characterization of Trim43a, Trim43b, and Trim43c genes, whose expression are restricted to preimplantation stages and peak at the 8-cell to morula stage. We identified a 5 kb DNA fragment that covers upstream region of Trim43a as a putative promoter, which can drive the expression of mStrawberry fluorescent protein in a manner similar to endogenous Trim43 genes. Trim43 genes will be useful stage-specific markers for the study of preimplantation embryos. Published by Elsevier B.V. C1 [Stanghellini, Ilaria; Falco, Geppino; Lee, Sung-Lim; Monti, Manuela; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Ko, MSH (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. EM KoM@mail.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU National Institute on Aging, NIH FX We thank Dr. Toshio Hamatani for the initial contribution to the work, Dr. Yuhki Nakatake for the discussion, Ms. Donna Tignor and Dr. Suresh Poosala for help in mouse husbandry, and Mr. Dawood Dudekula for help in DNA sequence analysis. We also thank Dr. Gary Felsenfeld for a generous gift of the insulator DNA, Dr. Roger Tsien for a generous gift of mStrawberry, and Ms. Lois Maltais for help in assigning gene symbols. This work was supported entirely by the Intramural Research Program of the National Institute on Aging, NIH. NR 20 TC 7 Z9 10 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-133X J9 GENE EXPR PATTERNS JI Gene Expr. Patterns PD DEC PY 2009 VL 9 IS 8 BP 595 EP 602 DI 10.1016/j.gep.2009.08.002 PG 8 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 528IA UT WOS:000272435700006 PM 19703589 ER PT J AU Shulzhenko, N Morgun, A Matzinger, P AF Shulzhenko, N. Morgun, A. Matzinger, P. TI Spontaneous mutation in the Cd79b gene leads to a block in B-lymphocyte development at the C ' (early pre-B) stage SO GENES AND IMMUNITY LA English DT Article DE immunodeficiency; CD79b; B lymphocytes; mutation ID X-LINKED AGAMMAGLOBULINEMIA; ANTIGEN RECEPTOR COMPLEX; MOUSE BONE-MARROW; IG-BETA; CELLS; LINEAGE; B29; IMMUNODEFICIENCY; EXPRESSION; MEMBER AB We discovered B-lymphocyte-deficient mice within a group of B10.A-CD45.1 mice, and established that this deficiency was a recessively inherited trait. Gene mapping and sequence analysis showed a mutation in the third exon of the Cd79b gene (c.224G>A) that leads to the generation of a stop codon (W75X) in the mutant mouse. Fluorescent-activated cell sorting analysis of bone marrow cells showed that the mutant mice did not express the CD79B antigen. To establish where the block in development happens, we analyzed CD43(pos)B220(pos) B-lymphocyte precursors present in the mutant mice and found that the fraction C' (corresponding to early pre-B lymphocytes) was absent in the mutant mouse, whereas fractions B and C showed a relative accumulation. As expected, we found no IgG or IgA in mutant mice. These results suggest that this CD79b-mutant strain may be a useful tool for immunological research in human immunodeficiencies. Genes and Immunity (2009) 10, 722-726; doi: 10.1038/gene.2009.70; published online 3 September 2009 C1 [Shulzhenko, N.; Morgun, A.; Matzinger, P.] NIAID, Ghost lab, T Cell Memory & Tolerance Sect, LCMI,NIH, Bethesda, MD 20892 USA. RP Shulzhenko, N (reprint author), NIAID, Ghost lab, T Cell Memory & Tolerance Sect, LCMI,NIH, 9000 Rockville Pike,Bldg 4,Room 111, Bethesda, MD 20892 USA. EM shulzhenkon@niaid.nih.gov; anemorgun@hotmail.com FU NIAID; NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. We thank BJ Fowlkes and Xianyu Zhang for suggestions about staining of bone marrow samples, and for sharing antibodies; Andy Johnson for suggestions regarding gene mapping; Debbie Wagner for help in typing mice; LCMI/NIAID personnel, Stefan Muljo and Richard Hardy for comments and discussions; Alison Brown and Oleg Iartchouk from Partners HealthCare Center for Personalized Genetic Medicine for excellent service. NR 19 TC 2 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD DEC PY 2009 VL 10 IS 8 BP 722 EP 726 DI 10.1038/gene.2009.70 PG 5 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 525WL UT WOS:000272248000007 PM 19727123 ER PT J AU Julier, C Akolkar, B Concannon, P Morahan, G Nierras, C Pugliese, A AF Julier, C. Akolkar, B. Concannon, P. Morahan, G. Nierras, C. Pugliese, A. CA Type I Diabet Genetics Consortium TI The Type I Diabetes Genetics Consortium 'Rapid Response' family-based candidate gene study: strategy, genes selection, and main outcome SO GENES AND IMMUNITY LA English DT Article DE type I diabetes; candidate genes; T1DGC; SNP selection ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; LYMPHOID TYROSINE PHOSPHATASE; FUNCTIONAL VARIANT; INSULIN GENE; SUSCEPTIBILITY; LOCUS; REGION; MELLITUS; POPULATIONS AB Candidate gene studies have long been the principal method for identification of susceptibility genes for type I diabetes (T1D), resulting in the discovery of HLA, INS, PTPN22, CTLA4, and IL2RA. However, many of the initial studies that relied on this strategy were largely underpowered, because of the limitations in genomic information and genotyping technology, as well as the limited size of available cohorts. The Type I Diabetes Genetic Consortium (T1DGC) has established resources to re-evaluate earlier reported genes associated with T1D, using its collection of 2298 Caucasian affected sib-pair families (with 11 159 individuals). A total of 382 single-nucleotide polymorphisms (SNPs) located in 21 T1D candidate genes were selected for this study and genotyped in duplicate on two platforms, Illumina and Sequenom. The genes were chosen based on published literature as having been either 'confirmed' (replicated) or not (candidates). This study showed several important features of genetic association studies. First, it showed the major impact of small rates of genotyping errors on association statistics. Second, it confirmed associations at INS, PTPN22, IL2RA, IFIH1 (earlier confirmed genes), and CTLA4 (earlier confirmed, with distinct SNPs) loci. Third, it did not find evidence for an association with T1D at SUMO4, despite confirmed association in Asian populations, suggesting the potential for population-specific gene effects. Fourth, at PTPN22, there was evidence for a novel contribution to T1D risk, independent of the replicated effect of the R620W variant. Fifth, among the candidate genes selected for replication, the association of TCF7-P19T with T1D was newly replicated in this study. In summary, this study was able to replicate some genetic effects, reject others, and provide suggestions of association with several of the other candidate genes in stratified analyses (age at onset, HLA status, population of origin). These results have generated additional interesting functional hypotheses that will require further replication in independent cohorts. Genes and Immunity (2009) 10, S121-S127; doi:10.1038/gene.2009.99 C1 [Julier, C.] INSERM, Ctr Natl Genotypage, U958, F-91057 Evry, France. [Akolkar, B.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD USA. [Akolkar, B.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA USA. [Concannon, P.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Morahan, G.] Univ Western Australia, Ctr Diabet Res, Western Australian Inst Med Res, Perth, WA 6009, Australia. [Morahan, G.] Univ Western Australia, Ctr Diabet Res, Med Res Ctr, Perth, WA 6009, Australia. [Nierras, C.] Juvenile Diabet Res Fdn, New York, NY USA. [Pugliese, A.] Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA. RP Julier, C (reprint author), INSERM, Ctr Natl Genotypage, U958, 2 Rue Gaston Cremieux,CP 5721, F-91057 Evry, France. EM cjulier@cng.fr RI Boehm, Bernhard/F-8750-2015; OI Concannon, Patrick/0000-0002-5801-1859 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Allergy and Infectious Diseases (NIAID); National Human Genome Research Institute (NHGRI); National Institute of Child Health and Human Development (NICHD); Juvenile Diabetes Research Foundation International (JDRF); NIH [U01 DK062418]; National Center for Research Resources [U54 RR020278] FX This research uses resources provided by the Type I Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by NIH grant U01 DK062418. We are grateful to all the T1D patients and family members who contributed samples and to all the participating T1DGC investigators and sites, listed at http://www.t1dgc.org. Genotyping was performed at the Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. NR 48 TC 10 Z9 11 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD DEC PY 2009 VL 10 BP S121 EP S127 DI 10.1038/gene.2009.99 PG 7 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 528DA UT WOS:000272419900016 PM 19956109 ER PT J AU Rich, SS Akolkar, B Concannon, P Erlich, H Hilner, JE Julier, C Morahan, G Nerup, J Nierras, C Pociot, F Todd, JA AF Rich, S. S. Akolkar, B. Concannon, P. Erlich, H. Hilner, J. E. Julier, C. Morahan, G. Nerup, J. Nierras, C. Pociot, F. Todd, J. A. TI Current status and the future for the genetics of type I diabetes SO GENES AND IMMUNITY LA English DT Article DE type I diabetes; sequence analysis; HLA; structural variants; expression ID GENOME-WIDE ASSOCIATION; MULTIPLEX FAMILIES; LOCI; METAANALYSIS; LINKAGE; RISK AB The Type I Diabetes Genetics Consortium (T1DGC) is an international collaboration whose primary goal is to identify genes whose variants modify an individual's risk of type I diabetes (T1D). An integral part of the T1DGC's mission is the establishment of clinical and data resources that can be used by, and that are fully accessible to, the T1D research community (http://www.t1dgc.org). The T1DGC has organized the collection and analyses of study samples and conducted several major research projects focused on T1D gene discovery: a genome-wide linkage scan, an intensive evaluation of the human major histocompatibility complex, a detailed examination of published candidate genes, and a genome-wide association scan. These studies have provided important information to the scientific community regarding the function of specific genes or chromosomal regions on T1D risk. The results are continually being updated and displayed (http://www.t1dbase.org). The T1DGC welcomes all investigators interested in using these data for scientific endeavors on T1D. The T1DGC resources provide a framework for future research projects, including examination of structural variation, re-sequencing of candidate regions in a search for T1D-associated genes and causal variants, correlation of T1D risk genotypes with biomarkers obtained from T1DGC serum and plasma samples, and in-depth bioinformatics analyses. Genes and Immunity (2009) 10, S128-S131; doi:10.1038/gene.2009.100 C1 [Rich, S. S.; Concannon, P.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Rich, S. S.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Akolkar, B.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD USA. [Concannon, P.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. [Erlich, H.] Roche Mol Syst, Pleasanton, CA USA. [Hilner, J. E.] Univ Alabama, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [Julier, C.] INSERM, Ctr Natl Genotypage, U730, Evry, France. [Morahan, G.] Univ Western Australia, Ctr Diabet Res, Western Australian Inst Med Res, Perth, WA 6009, Australia. [Morahan, G.] Univ Western Australia, Ctr Diabet Res, Med Res Ctr, Perth, WA 6009, Australia. [Nerup, J.; Pociot, F.] Hagendorn Res Inst, Gentofte, Denmark. [Nerup, J.; Pociot, F.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Nierras, C.] Juvenile Diabet Res Fdn Int, New York, NY USA. [Todd, J. A.] Univ Cambridge, Addenbrookes Hosp, Diabet Res Fdn Wellcome Trust Diabet & Inflammat, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 2QQ, England. RP Rich, SS (reprint author), Univ Virginia, Ctr Publ Hlth Genom, POB 800717, Charlottesville, VA 22908 USA. EM ssr4n@virginia.edu RI Todd, John/A-3542-2010; OI Concannon, Patrick/0000-0002-5801-1859; Pociot, Flemming/0000-0003-3274-5448 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK46635]; National Institute of Allergy and Infectious Diseases (NIAID); National Human Genome Research Institute (NHGRI); National Institute of Child Health and Human Development (NICHD); Juvenile Diabetes Research Foundation International (JDRF); Wellcome Trust; National Institute for Health Research Cambridge Biomedical Research Centre; [U01 DK062418] FX This research uses resources provided by the Type I Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. Further support was provided by a grant from the NIDDK (DK46635) to PC and a joint JDRF and Wellcome Trust grant to the Diabetes and Inflammation Laboratory at Cambridge that also received support from the National Institute for Health Research Cambridge Biomedical Research Centre. NR 12 TC 3 Z9 3 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD DEC PY 2009 VL 10 BP S128 EP S131 DI 10.1038/gene.2009.100 PG 4 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 528DA UT WOS:000272419900017 PM 19956094 ER PT J AU Rich, SS Akolkar, B Concannon, P Erlich, H Hilner, JE Julier, C Morahan, G Nerup, J Nierras, C Pociot, F Todd, JA AF Rich, S. S. Akolkar, B. Concannon, P. Erlich, H. Hilner, J. E. Julier, C. Morahan, G. Nerup, J. Nierras, C. Pociot, F. Todd, J. A. TI Overview of the Type I Diabetes Genetics Consortium SO GENES AND IMMUNITY LA English DT Article DE type I diabetes; autoantibodies; HLA; families; linkage; association ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; MULTIPLEX FAMILIES; METAANALYSIS; LINKAGE AB The Type I Diabetes Genetics Consortium (T1DGC) is an international, multicenter research program with two primary goals. The first goal is to identify genomic regions and candidate genes whose variants modify an individual's risk of type I diabetes (T1D) and help explain the clustering of the disease in families. The second goal is to make research data available to the research community and to establish resources that can be used by, and that are fully accessible to, the research community. To facilitate the access to these resources, the T1DGC has developed a Consortium Agreement (http://www.t1dgc.org) that specifies the rights and responsibilities of investigators who participate in Consortium activities. The T1DGC has assembled a resource of affected sib-pair families, parent-child trios, and case-control collections with banks of DNA, serum, plasma, and EBV-transformed cell lines. In addition, both candidate gene and genome-wide (linkage and association) studies have been performed and displayed in T1DBase (http://www.t1dbase.org) for all researchers to use in their own investigations. In this supplement, a subset of the T1DGC collection has been used to investigate earlier published candidate genes for T1D, to confirm the results from a genome-wide association scan for T1D, and to determine associations with candidate genes for other autoimmune diseases or with type II diabetes that may be involved with beta-cell function. Genes and Immunity (2009) 10, S1-S4; doi: 10.1038/gene.2009.84 C1 [Rich, S. S.; Concannon, P.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Rich, S. S.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Akolkar, B.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD USA. [Concannon, P.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. [Erlich, H.] Roche Mol Syst, Pleasanton, CA USA. [Hilner, J. E.] Univ Alabama, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [Julier, C.] INSERM, Ctr Natl Genotypage, U730, Evry, France. [Morahan, G.] Univ Western Australia, Ctr Diabet Res, Western Australian Inst Med Res, Perth, WA 6009, Australia. [Morahan, G.] Univ Western Australia, Ctr Diabet Res, Med Res Ctr, Perth, WA 6009, Australia. [Nerup, J.; Pociot, F.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Nierras, C.] Juvenile Diabet Res Fdn Int, New York, NY USA. [Todd, J. A.] Univ Cambridge, Addenbrookes Hosp,Juvenile Diabet Res Fdn, Cambridge Inst Med Res,Dept Med Genet, Wellcome Trust Diabet & Inflammat Lab, Cambridge CB2 2QQ, England. RP Rich, SS (reprint author), Univ Virginia, Ctr Publ Hlth Genom, POB 800717, Charlottesville, VA 22908 USA. EM ssr4n@virginia.edu RI Todd, John/A-3542-2010; OI Concannon, Patrick/0000-0002-5801-1859; Pociot, Flemming/0000-0003-3274-5448 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK46635]; National Institute of Allergy and Infectious Diseases (NIAID); National Human Genome Research Institute (NHGRI); National Institute of Child Health and Human Development (NICHD); Juvenile Diabetes Research Foundation International (JDRF); Wellcome Trust; National Institute for Health Research Cambridge Biomedical Research Centre; National Institutes of Health [N01-HG-65403]; [U01 DK062418] FX This research uses resources provided by the Type I Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. Further support was provided by a grant from the NIDDK (DK46635) to PC and a joint JDRF and Wellcome Trust grant to the Diabetes and Inflammation Laboratory at Cambridge, which also received support from the National Institute for Health Research Cambridge Biomedical Research Centre. Genotyping was performed by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, contract no. N01-HG-65403. NR 25 TC 15 Z9 15 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD DEC PY 2009 VL 10 BP S1 EP S4 DI 10.1038/gene.2009.84 PG 4 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 528DA UT WOS:000272419900001 PM 19956093 ER PT J AU Yu, K Li, QZ Bergen, AW Pfeiffer, RM Rosenberg, PS Caporaso, N Kraft, P Chatterjee, N AF Yu, Kai Li, Qizhai Bergen, Andrew W. Pfeiffer, Ruth M. Rosenberg, Philip S. Caporaso, Neil Kraft, Peter Chatterjee, Nilanjan TI Pathway Analysis by Adaptive Combination of P-Values SO GENETIC EPIDEMIOLOGY LA English DT Article DE pathway analysis; genetic association study; permutation procedure ID GENOME-WIDE ASSOCIATION; HAPLOTYPE SIMILARITY; GENETIC ASSOCIATION; TRUNCATED PRODUCT; CANDIDATE GENE; BREAST-CANCER; DISEASE; TESTS; REGRESSION; POWERFUL AB It is increasingly recognized that pathway analyses-a joint test of association between the outcome and a group of single nucleotide polymorphisms (SNPs) within a biological pathway-could potentially complement single-SNP analysis and provide additional insights for the genetic architecture of complex diseases. Building upon existing P-value combining methods, we propose a class of highly flexible pathway analysis approaches based on an adaptive rank truncated product statistic that can effectively combine evidence of associations over different SNPs and genes within a pathway. The statistical significance of the pathway-level test statistics is evaluated using a highly efficient permutation algorithm that remains computationally feasible irrespective of the size of the pathway and complexity of the underlying test statistics for summarizing SNP- and gene-level associations. We demonstrate through simulation studies that a gene-based analysis that treats the underlying genes, as opposed to the underlying SNPs, as the basic units for hypothesis testing, is a very robust and powerful approach to pathway-based association testing. We also illustrate the advantage of the proposed methods using a study of the association between the nicotinic receptor pathway and cigarette smoking behaviors. Genet. Epidemiol. 33:700-709, 2009. Published 2009 Wiley-Liss, Inc.(dagger) C1 [Yu, Kai; Li, Qizhai; Pfeiffer, Ruth M.; Rosenberg, Philip S.; Caporaso, Neil; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Li, Qizhai] CAS, Acad Math & Syst Sci, Beijing, Peoples R China. [Bergen, Andrew W.] SRI Int, Mol Genet Program, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. RP Yu, K (reprint author), NCI, Div Canc Epidemiol & Genet, EPS 8050,MSC 7244,6120 Execut Blvd, Rockville, MD 20892 USA. EM yuka@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; OI Bergen, Andrew/0000-0002-1237-7644 FU NIH [U01 DA020830]; National Cancer Institute; National Science Foundation of China [10371126] FX Contract grant sponsor: Intramural Research Program of NIH and the National Cancer Institute; Contract grant sponsor: National Science Foundation of China; Contract grant number: 10371126; Contract grant sponsor: NIH; Contract grant number: U01 DA020830. NR 39 TC 154 Z9 158 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 BP 700 EP 709 DI 10.1002/gepi.20422 PG 10 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600005 PM 19333968 ER PT J AU Luo, S Mukherjee, B Chen, JB Chatterjee, N AF Luo, Sheng Mukherjee, Bhramar Chen, Jinbo Chatterjee, Nilanjan TI Shrinkage Estimation for Robust and Efficient Screening of Single-SNP Association from Case-Control Genome-Wide Association Studies SO GENETIC EPIDEMIOLOGY LA English DT Article DE association test; case-control studies; genome scan; Hardy-Weinberg Equilibrium; retrospective likelihood ID PROSTATE-CANCER; SAMPLE-SIZE; INFERENCE; GENES; TESTS; POWER AB Population-based case-control design has become one of the most popular approaches for conducting genome-wide association scans for rare diseases like cancer. In this article, we propose a novel method for improving the power of the widely used single-single-nucleotide polymorphism (SNP) two-degrees-of-freedom (2 d.f.) association test for case-control studies by exploiting the common assumption of Hardy-Weinberg Equilibrium (HWE) for the underlying population. A key feature of the method is that it can relax the assumed model constraints via a completely data-adaptive shrinkage estimation approach so that the number of false-positive results due to the departure of HWE is controlled. The method is computationally simple and is easily scalable to association tests involving hundreds of thousands or millions of genetic markers. Simulation studies as well as an application involving data from a real genome-wide association study illustrate that the proposed method is very robust for large-scale association studies and can improve the power for detecting susceptibility SNPs with recessive effects, when compared to existing methods. Implications of the general estimation strategy beyond the simple 2 d.f. association test are discussed. Genet. Epidemiol. 33:740-750, 2009. Published 2009 Wiley-Liss, Inc.(dagger) C1 [Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. [Luo, Sheng] Univ Texas Hlth Sci Ctr, Div Biostat, Houston, TX USA. [Mukherjee, Bhramar] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Chen, Jinbo] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Chatterjee, N (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS 8038, Rockville, MD 20852 USA. EM chattern@mail.nih.gov FU National Heart Lung and Blood Institute [R01 HL091172-01]; National Cancer Institute; NSF [DMS 07-06935]; NIH [R03 CA130045-01] FX Contract grant sponsor: National Heart Lung and Blood Institute; Contract grant number: R01 HL091172-01; Contract grant sponsors: National Cancer Institute; NSF; Contract grant number: DMS 07-06935; Contract grant sponsor: NIH; Contract grant number: R03 CA130045-01. NR 19 TC 2 Z9 2 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 BP 740 EP 750 DI 10.1002/gepi.20428 PG 11 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600009 PM 19434716 ER PT J AU Demenais, F Corda, E Barrett, J Iles, M Gillanders, EM Goldstein, AM Kanetsky, PA Bakker, E Bishop, T Newton-Bishop, JA Gruis, NA AF Demenais, Florence Corda, Eve Barrett, Jennifer Iles, Mark Gillanders, Elizabeth M. Goldstein, Alisa M. Kanetsky, Peter A. Bakker, Egbert Bishop, Timothy Newton-Bishop, Julia A. Gruis, Nelleke A. TI Importance of Sequencing Rare Variants After a Genome-Wide Association Study (GWAS): the MC1R Gene, 16q24 Region and Melanoma Story (the GenoMEL Consortium) SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Demenais, Florence] INSERM, U946, Paris, France. [Corda, Eve] Fdn Jean Dausset CEPH, Paris, France. [Barrett, Jennifer; Iles, Mark; Bishop, Timothy; Newton-Bishop, Julia A.] Leeds Inst Mol Med, Leeds, W Yorkshire, England. [Gillanders, Elizabeth M.] NHGRI, NIH, Baltimore, MD USA. [Goldstein, Alisa M.] NCI, NIH, Baltimore, MD USA. [Kanetsky, Peter A.] Univ Penn, Philadelphia, PA 19104 USA. [Bakker, Egbert; Gruis, Nelleke A.] Leiden Univ, Med Ctr, Leiden, Netherlands. RI Bakker, Egbert/D-3525-2009; Demenais, Florence/G-3298-2013 OI Bakker, Egbert/0000-0002-2843-7357; Demenais, Florence/0000-0001-8361-0936 NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 19 BP 757 EP 758 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600030 ER PT J AU Heckerman, D Kadie, C Zhang, X Schymick, J Ravits, J Traynor, B Listgarten, J AF Heckerman, David Kadie, Carl Zhang, Xiang Schymick, Jennifer Ravits, John Traynor, Bryan Listgarten, Jennifer TI A Natural Aggregation Function for Pathway/Network-Based Approaches to GWAS and Gene Expression Analysis SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Schymick, Jennifer; Traynor, Bryan] NIH, Bethesda, MD 20892 USA. [Ravits, John] Benaroya Res Inst, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 17 BP 757 EP 757 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600028 ER PT J AU Wheeler, E Soranzo, N Sanna, S Gieger, C Radke, D Dupuis, J Stolerman, E Bouatia-Naji, N Langenberg, C Prokopenko, I Sandhu, MS Kao, L Wareham, NJ Florez, JC Uda, M Barroso, I Meigs, JB AF Wheeler, Eleanor Soranzo, Nicole Sanna, Serena Gieger, Christian Radke, Doerte Dupuis, Josee Stolerman, Elliot Bouatia-Naji, Nabila Langenberg, Claudia Prokopenko, Inga Sandhu, Manjinder S. Kao, Linda Wareham, N. J. Florez, Jose C. Uda, Manuela Barroso, Ines Meigs, James B. CA MAGIC Investigators TI A Large Genome-wide Association Study of Glycated Hemoglobin Identifies Ten Common Variants not Mediated Through BMI SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Wheeler, Eleanor; Soranzo, Nicole; Barroso, Ines] Wellcome Trust Sanger Inst, Cambridge, England. [Sanna, Serena; Uda, Manuela] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Gieger, Christian] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Radke, Doerte] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Dupuis, Josee] NHLBI, Framingham, MA USA. [Stolerman, Elliot] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Stolerman, Elliot] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Bouatia-Naji, Nabila] Inst Pasteur, CNRS, UMR 8090, F-59019 Lille, France. [Bouatia-Naji, Nabila] Univ Lille 2, Lille, France. [Langenberg, Claudia; Wareham, N. J.] MRC, Epidemiol Unit, Cambridge, England. [Prokopenko, Inga] WTCHG, Oxford, England. [Prokopenko, Inga] OCDEM, Oxford, England. [Sandhu, Manjinder S.] Univ Cambridge, Cambridge, England. [Kao, Linda] Johns Hopkins Univ, Dept Epidemiol & Med, Baltimore, MD USA. [Florez, Jose C.] Harvard Univ, Sch Med, Boston, MA USA. [Florez, Jose C.] Broad Inst, Cambridge, MA USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RI BOUATIA-NAJI, NABILA/D-5863-2013 NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 21 BP 758 EP 759 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600032 ER PT J AU Prokunina-Olsson, L Porter-Gill, P Tarway, M Burrell, A Tang, W Thomas, G Yeager, M Albanes, D AF Prokunina-Olsson, Ludmila Porter-Gill, Patricia Tarway, McAnthony Burrell, Allison Tang, Wei Thomas, Gilles Yeager, Meredith Albanes, Demetrius TI Fine-mapping of JAZF1 Region Associated With Prostate Cancer Susceptibility SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Prokunina-Olsson, Ludmila; Porter-Gill, Patricia; Tarway, McAnthony; Burrell, Allison; Tang, Wei] NCI, Lab Translat Genom, NIH, Bethesda, MD 20892 USA. [Thomas, Gilles; Yeager, Meredith] NCI, CGF, DCEG, NIH, Bethesda, MD 20892 USA. [Albanes, Demetrius] NCI, NEB, DCEG, NIH, Bethesda, MD 20892 USA. RI Tang, Wei/H-7103-2013; Albanes, Demetrius/B-9749-2015 OI Tang, Wei/0000-0002-7089-4391; NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 42 BP 764 EP 764 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600052 ER PT J AU Simpson, CL Cropp, CD Wahlfors, T George, A Nati, H Tammela, TT Schleutker, J Bailey-Wilson, JE AF Simpson, Claire L. Cropp, Cheryl D. Wahlfors, Tiina George, Asha Nati, Ha Tammela, Teuvo Tammela Schleutker, Johanna Bailey-Wilson, Joan E. TI Fine-Mapping in a Genomewide Linkage Scan of Prostate Cancer Susceptibility in Finland SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [George, Asha] NHGRI, NIH, Fox Chase Canc Ctr, Bethesda, MD 20892 USA. [Wahlfors, Tiina; Nati, Ha; Tammela, Teuvo Tammela; Schleutker, Johanna] Univ Tampere, Inst Med Technol, FIN-33101 Tampere, Finland. [Wahlfors, Tiina; Nati, Ha; Tammela, Teuvo Tammela; Schleutker, Johanna] Tampere Univ Hosp, Tampere, Finland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 46 BP 765 EP 766 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600056 ER PT J AU Umbach, DM Shi, M Weinberg, CR AF Umbach, David M. Shi, Min Weinberg, Clarice R. TI Studying Case-parent Triads to Identify Haplotype-by-Exposure Interactions SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Umbach, David M.; Shi, Min; Weinberg, Clarice R.] NIEHS, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 77 BP 774 EP 774 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600087 ER PT J AU Chen, GJ Zhou, J Doumatey, A Shriner, D Chen, YX Gerry, N Herbert, A Christman, M Rotimi, C Adeyemo, A AF Chen, Guan Jie Zhou, Jie Doumatey, Ayo Shriner, Daniel Chen, Yuanxiu Gerry, Noman Herbert, Alan Christman, Michael Rotimi, Charles Adeyemo, Adebowale TI Developing Admixture Mapping Panels for African Americans from Commercial High Density SNP Chips SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Chen, Guan Jie; Zhou, Jie; Doumatey, Ayo; Shriner, Daniel; Rotimi, Charles; Adeyemo, Adebowale] NHGRI, CRGGH, NIH, Bethesda, MD 20892 USA. [Chen, Yuanxiu] Howard Univ, Natl Human Genome Ctr, Washington, DC USA. [Herbert, Alan] Boston Univ, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 100 BP 780 EP 781 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600110 ER PT J AU Timofeev, N Hartley, SH Baldwin, CT Dworkis, DA Farrer, LA Gladwin, M Klings, ES Milton, JN Perls, TT Steinberg, MH Sebastiani, P AF Timofeev, Nadia Hartley, Steven H. Baldwin, Clinton T. Dworkis, Daniel A. Farrer, Lindsay A. Gladwin, Mark Klings, Elizabeth S. Milton, Jacqueline N. Perls, Thomas T. Steinberg, Martin H. Sebastiani, Paola TI Clustering Based on Genetic Ancestry SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Timofeev, Nadia; Hartley, Steven H.; Milton, Jacqueline N.; Sebastiani, Paola] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Baldwin, Clinton T.] Boston Univ, Sch Med, Ctr Human Genet, Boston, MA 02215 USA. [Dworkis, Daniel A.; Farrer, Lindsay A.; Klings, Elizabeth S.; Perls, Thomas T.; Steinberg, Martin H.] Boston Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Gladwin, Mark] NHLBI, Vasc Med Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 101 BP 781 EP 781 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600111 ER PT J AU Murray, T Terri, BH Jacqueline, HB Alan, SF Kung-Yee, L Ingo, R Tao, W Richard, RA Mary, ML Jeffery, MC Ronald, MG Allen, W Rolv, LT Yah-Huei, WC Hong, W Huang, SZ Vincent, Y Samuel, CS Ha, JS Kaare, C AF Murray, Tanda Terri, Beaty H. Jacqueline, Hetmanski B. Alan, Scott F. Kung-Yee, Liang Ingo, Ruczinski Tao, Wu Richard, Redetta A. Mary, Marazita L. Jeffery, Murray C. Ronald, Munger G. Allen, Wilcox Rolv, Lie T. Yah-Huei, Wu-Chou Hong, Wang Huang Shangzhi Vincent, Yeow Samuel, Chong S. Ha, Jee Sun Kaare, Christensen CA GENEVA Consortium TI Genetic Distance and Population Structure Analysis of Parents Drawn from a Family Based Genome Wide Association Study of Oral Clefts SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Murray, Tanda; Terri, Beaty H.; Jacqueline, Hetmanski B.; Kung-Yee, Liang; Ingo, Ruczinski; Tao, Wu] Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD 21218 USA. [Alan, Scott F.; Richard, Redetta A.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Mary, Marazita L.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Jeffery, Murray C.] Univ Iowa, Childrens Hosp, Iowa City, IA 52242 USA. [Ronald, Munger G.] Utah State Univ, Logan, UT 84322 USA. [Allen, Wilcox] NIEHS, NIH, Epidemiol Branch, Bethesda, MD USA. [Rolv, Lie T.] Univ Bergen, N-5020 Bergen, Norway. [Yah-Huei, Wu-Chou] Chang Gung Mem Hosp, Kaohsiung, Taiwan. [Hong, Wang] Peking Univ, Hlth Sci Ctr, Beijing, Peoples R China. [Vincent, Yeow] Wuhan Univ, Sch Stornatol, Wuhan, Peoples R China. [Samuel, Chong S.] Natl Univ Singapore, Singapore, Singapore. [Ha, Jee Sun] Yonsei Univ, Seoul 120749, South Korea. [GENEVA Consortium] NIDCR, NHGRI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 105 BP 782 EP 782 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600115 ER PT J AU Konig, IR Thompson, JR Preuss, M Assimes, TL Blankenberg, S Boerwinkle, E Cupples, A Epstein, S Hall, A Hengstenberg, C Kathiresan, S Laaksonen, R Marz, W McPherson, R O'Donnell, CJ Quertermous, T Rader, D Reilly, M Roberts, R Stewart, A Thorsteinsdottir, U Ziegler, A Erdmann, J Samani, NJ Schunkert, H AF Koenig, Inke R. Thompson, John R. Preuss, Michael Assimes, Themistocles L. Blankenberg, Stefan Boerwinkle, Eric Cupples, Adrienne Epstein, Stephen Hall, Alistair Hengstenberg, Christian Kathiresan, Sekar Laaksonen, Reijo Maerz, Winfried McPherson, Ruth O'Donnell, Christopher J. Quertermous, Thomas Rader, Daniel Reilly, Mureclach Roberts, Robert Stewart, Alex Thorsteinsdottir, Unnur Ziegler, Andreas Erdmann, Jeanette Samani, Nilesh J. Schunkert, Heribert CA CARDIoGRAM TI Coronary ARtery DIsease Genome-wide Replication And Meta-Analysis (CARDIoGRAM) - Design of a prospective meta-analysis of 14 genome-wide association studies SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Koenig, Inke R.; Preuss, Michael; Ziegler, Andreas] Med Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany. [Thompson, John R.] Univ Leicester, Dept Hlth Sci & Genet, Leicester LE1 7RH, Leics, England. [Preuss, Michael; Erdmann, Jeanette; Schunkert, Heribert] Med Univ Lubeck, Med Klin 2, Lubeck, Germany. [Assimes, Themistocles L.; Quertermous, Thomas] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Blankenberg, Stefan] Johannes Gutenberg Univ Mainz, Dept Med 2, D-6500 Mainz, Germany. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Cupples, Adrienne] Boston Univ, Dept Biostat & Epidemiol, Boston, MA 02215 USA. [Epstein, Stephen] Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, Washington, DC USA. [Hall, Alistair] Univ Leeds, LIGHT, Leeds LS2 9JT, W Yorkshire, England. [Hengstenberg, Christian] Univ Regensburg, Klin & Poliklin Innere Med 2, D-8400 Regensburg, Germany. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Laaksonen, Reijo] Tampere Univ Hosp, Ctr Sci, Tampere, Finland. [Maerz, Winfried] Versorgungszentrum Lab Diagnost Heidelberg, Synlab Med, Heidelberg, Germany. [McPherson, Ruth; Roberts, Robert; Stewart, Alex] Univ Ottawa, Div Cardiol, Inst Heart, Ottawa, ON K1N 6N5, Canada. [O'Donnell, Christopher J.] NHLBI, Bethesda, MD USA. [O'Donnell, Christopher J.] NIH, Framingham Heart Dis Study, Bethesda, MD USA. [Rader, Daniel; Reilly, Mureclach] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Rader, Daniel; Reilly, Mureclach] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Samani, Nilesh J.] Univ Leicester, Glenfield Gen Hosp, Dept Cardiovasc Sci, Leicester LE1 7RH, Leics, England. RI Laaksonen, Reijo/D-6323-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 113 BP 784 EP 785 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600123 ER PT J AU Dupuis, J Langenberg, C Prokopenko, I Saxena, R Soranzo, N Jackson, AU Wheeler, E Glazer, NL Bouatia-Naji, N McCullogh, L Gloyn, A Sladek, R Froguel, P Watanabe, RM Meigs, JB Groop, L Boehnke, M McCarthy, MI Florez, JC Barroso, I AF Dupuis, Josee Langenberg, Claudia Prokopenko, Inga Saxena, Richa Soranzo, Nicole Jackson, Anne U. Wheeler, Eleanor Glazer, Nicole L. Bouatia-Naji, Nabila McCullogh, Laura Gloyn, Anna Sladek, Robert Froguel, Philippe Watanabe, Richard M. Meigs, James B. Groop, Leif Boehnke, Michael McCarthy, Mark I. Florez, Jose C. Barroso, Ines CA MAGIC Investigators TI Novel Genetic Loci Implicated in Fasting Glucose Homeostasis and Their Impact on Related Metabolic Traits SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Dupuis, Josee] NHLBI, Framingham, MA USA. [Langenberg, Claudia] MRC, Epidemiol Unit, Cambridge, England. [Prokopenko, Inga; McCarthy, Mark I.] WTCHG, Oxford, England. [Prokopenko, Inga; McCullogh, Laura; Gloyn, Anna; McCarthy, Mark I.] OCDEM, Oxford, England. [Saxena, Richa; Meigs, James B.; Florez, Jose C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Saxena, Richa; Meigs, James B.; Florez, Jose C.] Harvard Univ, Sch Med, Boston, MA USA. [Saxena, Richa; Meigs, James B.; Florez, Jose C.] Broad Inst, Cambridge, MA USA. [Soranzo, Nicole; Wheeler, Eleanor; Barroso, Ines] Wellcome Trust Sanger Inst, Cambridge, England. [Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Glazer, Nicole L.] Univ Washington, Seattle, WA 98195 USA. [Bouatia-Naji, Nabila; Froguel, Philippe] Inst Pasteur, Ctr Immunol & Biol Parasitaire, CNRS, UMR8090, F-59019 Lille, France. [Sladek, Robert] McGill Univ, Montreal, PQ, Canada. [Sladek, Robert] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Watanabe, Richard M.] Univ So Calif, Los Angeles, CA USA. [Groop, Leif] Lund Univ, Malmo Univ Hosp, Malmo, Sweden. RI BOUATIA-NAJI, NABILA/D-5863-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 124 BP 788 EP 788 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600133 ER PT J AU Shriner, D Adeyemo, A Chen, GJ Rotimi, CN AF Shriner, Daniel Adeyemo, Adebowale Chen, Guanjie Rotimi, Charles N. TI Practical Considerations for Imputation of Untyped Markers in Admixed Populations SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Shriner, Daniel; Adeyemo, Adebowale; Chen, Guanjie; Rotimi, Charles N.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 129 BP 789 EP 790 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600138 ER PT J AU Wilson, AF Kim, Y Sung, H Cai, JL McMahon, FJ Sorant, AJM AF Wilson, Alexander F. Kim, Yoonhee Sung, Heejong Cai, Juanliang McMahon, Francis J. Sorant, Alexa J. M. TI Tiled regression: the use of regression methods in hotspot defined genomic segments to identify independent genetic variants responsible for variation in quantitative traits SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Wilson, Alexander F.; Kim, Yoonhee; Sung, Heejong; Cai, Juanliang; Sorant, Alexa J. M.] NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Bethesda, MD 20892 USA. [McMahon, Francis J.] NIMH, Genet Basis Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 142 BP 793 EP 793 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600151 ER PT J AU Cropp, CD Simpson, CL Wahlfors, T George, A Nati, H Tammela, T Schleutker, J Bailey-Wilson, JE AF Cropp, Cheryl D. Simpson, Claire L. Wahlfors, Tiina George, Asha Nati, Ha Tammela, Teuvo Schleutker, Johanna Bailey-Wilson, Joan E. TI Genome-Wide Linkage Scan for Prostate Cancer Susceptibility in Combined Finnish Populations Identifies Evidence of Linkage on 17q21-22 SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Cropp, Cheryl D.; Simpson, Claire L.; George, Asha; Bailey-Wilson, Joan E.] NHGRI, NIH, Philadelphia, PA USA. [Wahlfors, Tiina; Nati, Ha; Schleutker, Johanna] Univ Tampere, Inst Med Technol, FIN-33101 Tampere, Finland. [Wahlfors, Tiina; Nati, Ha; Schleutker, Johanna] Tampere Univ Hosp, Tampere, Finland. [George, Asha] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Tammela, Teuvo] Univ Tampere, Tampere Univ Hosp, Dept Urol, FIN-33101 Tampere, Finland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 166 BP 800 EP 801 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600174 ER PT J AU Duggal, P Wojciechowski, R Klein, AP Cheng, CY Lee, K Klein, R Klein, BEK Bailey-Wilson, JE AF Duggal, Priya Wojciechowski, Robert Klein, Alison P. Cheng, Ching-Yu Lee, Kristine Klein, Ronald Klein, Barbara E. K. Bailey-Wilson, Joan E. TI Linkage and Association Analysis for Ocular Cup/Disc Ratio SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Duggal, Priya] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Wojciechowski, Robert; Cheng, Ching-Yu; Bailey-Wilson, Joan E.] NHGRI, NIH, Bethesda, MD 20892 USA. [Klein, Alison P.] Johns Hopkins Med Inst, Baltimore, MD USA. [Lee, Kristine; Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Madison, WI 53706 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 167 BP 801 EP 801 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600175 ER PT J AU Beckmann, L Huesing, A Setiawan, WV Ziegler, R Hankinson, S Kaaks, R AF Beckmann, Lars Huesing, Anika Setiawan, Wendy V. Ziegler, Regina Hankinson, Susan Kaaks, Rudolf TI Adjustment for Multiple, Correlated Tests in Pathway Analysis of Sex Steroid Hormone Levels in Pre- and Postmenopausal Women from the Breast and Prostate Cancer Cohort Consortium (BPC3) SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Beckmann, Lars; Huesing, Anika; Kaaks, Rudolf] German Canc Res Ctr, Div Canc Epidemiol, D-6900 Heidelberg, Germany. [Setiawan, Wendy V.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Ziegler, Regina] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hankinson, Susan] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Hankinson, Susan] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Hankinson, Susan] Harvard Sch, Dept Epidemiol, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 177 BP 804 EP 804 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600185 ER PT J AU Addington, AM Gauthier, J Spiegelman, D Lee, Y Long, R Rouleau, G Rapoport, JL AF Addington, Anjene M. Gauthier, Julie Spiegelman, Dan Lee, Yohan Long, Robert Rouleau, Guy Rapoport, Judith L. TI Rare and Common Variants in NRXN1 (2p16.3) Associated with Childhood onset Schizophrenia (COS) SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Addington, Anjene M.; Lee, Yohan; Long, Robert; Rapoport, Judith L.] NIH, Bethesda, MD 20892 USA. [Gauthier, Julie; Spiegelman, Dan; Rouleau, Guy] Univ Montreal, Montreal, PQ H3C 3J7, Canada. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 206 BP 812 EP 812 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600213 ER PT J AU Kim, Y Tierney, E Porter, FD Roberson, EDO Bailey-Wilson, JE AF Kim, Yoonhee Tierney, Elaine Porter, Forbe D. Roberson, Eli D. O. Bailey-Wilson, Joan E. TI Hypocholesterolemic Autism: Follow-up Association Studies on the Linkage Regions of Chromosomes 5 and 10 SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Kim, Yoonhee; Bailey-Wilson, Joan E.] NHGRI, NIH, Baltimore, MD USA. [Tierney, Elaine] Kennedy Krieger Inst, Baltimore, MD USA. [Porter, Forbe D.] NICHHD, NIH, Bethesda, MD 20892 USA. [Roberson, Eli D. O.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 223 BP 817 EP 817 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600230 ER PT J AU Sung, H Kim, Y Cai, JL Sorant, AJM McMahon, FJ Wilson, AF AF Sung, Heejong Kim, Yoonhee Cai, Juanliang Sorant, Alexa J. M. McMahon, Francis J. Wilson, Alexander F. TI Tiled Logistic Regression for Response to Antidepressant Treatment SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Sung, Heejong; Kim, Yoonhee; Cai, Juanliang; Sorant, Alexa J. M.; Wilson, Alexander F.] NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [McMahon, Francis J.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 249 BP 825 EP 825 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600256 ER PT J AU Hamilton, CM Kraft, P Strader, L Pratt, J Hammond, J Hendershot, T Huggins, W Jackman, D Kwok, R Maiese, D Nettles, D Pan, H Wagener, D Zmuda, M Junkins, H Li, RL Ramos, E Harlan, W Haines, J AF Hamilton, Carol M. Kraft, Peter Strader, Lisa Pratt, Joseph Hammond, Jane Hendershot, Tabitha Huggins, Wayne Jackman, Dean Kwok, Richard Maiese, Deborah Nettles, Destiney Pan, Helen Wagener, Diane Zmuda, Mike Junkins, Heather Li, Rongling Ramos, Erin Harlan, William Haines, Jonathan TI The PhenX Toolkit-Get the Most from Your Measures SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 18th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-20, 2009 CL Honolulu, HI SP Int Genet Epidemiol Soc C1 [Kraft, Peter] Harvard Univ, Cambridge, MA 02138 USA. [Junkins, Heather; Li, Rongling; Ramos, Erin] NHGRI, Bethesda, MD USA. [Harlan, William] NIH, Bethesda, MD 20892 USA. [Haines, Jonathan] Vanderbilt Univ, Nashville, TN 37235 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2009 VL 33 IS 8 MA 254 BP 827 EP 827 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 529TK UT WOS:000272540600261 ER PT J AU Speechley, M Barton, JC Passmore, L Harrison, H Reboussin, DM Harris, EL Rivers, CA Fadojutimi-Akinsiku, M Wenzel, L Diaz, S AF Speechley, Mark Barton, James C. Passmore, Leah Harrison, Helen Reboussin, David M. Harris, Emily L. Rivers, Charles A. Fadojutimi-Akinsiku, Margaret Wenzel, Lari Diaz, Sharmin TI Potential Nonresponse Bias in a Clinical Examination After Initial Screening Using Iron Phenotyping and HFE Genotyping in the Hemochromatosis and Iron Overload Screening Study SO GENETIC TESTING AND MOLECULAR BIOMARKERS LA English DT Article ID TRANSFERRIN SATURATION VALUES; SERUM FERRITIN CONCENTRATIONS; HEREDITARY HEMOCHROMATOSIS; HEIRS; WHITES AB Background: Little is known about the factors affecting participation in clinical assessments after HEmochromatosis and IRon Overload Screening. Methods: Initial screening of 101,168 primary care patients in the HEmochromatosis and IRon Overload Screening study was performed using serum iron measures and hemochromatosis gene (HFE) genotyping. Using iron phenotypes and HFE genotypes, we identified 2256 cases and 1232 controls eligible to participate in a clinical examination. To assess the potential for nonresponse bias, we compared the sociodemographic, health status, and attitudinal characteristics of participants and nonparticipants using adjusted odds ratios (ORs) and 95% confidence interval (CI). Results: Overall participation was 74% in cases and 52% in controls; in both groups, participation was highest at a health maintenance organization and lowest among those under 45 years of age (cases: OR = 0.68; 95% CI 0.53, 0.87; controls: OR = 0.59; 95% CI 0.44, 0.78). In controls only, participation was also lower among those over 65 years of age than the reference group aged 46-64 (OR = 0.64; 95% CI 0.47, 0.88). Among cases, participation was higher in HFE C282Y homozygotes (OR = 3.98; 95% CI 2.60, 6.09), H63D homozygotes (OR = 2.79; 95% CI 1.23, 6.32), and C282Y/H63D compound heterozygotes (OR = 1.82; 95% CI 1.03, 3.22) than in other genotypes, and lower among non-Caucasians and those who preferred a non-English language than in Caucasians and those who preferred English (p < 0.0001). Conclusions: Subjects with greatest risk to have iron overload (C282Y homozygotes; cases >= 45 years; Caucasians) were more likely to participate in a postscreening clinical examination than other subjects. We detected no evidence of strong selection bias. C1 [Speechley, Mark] Univ Western Ontario, Dept Epidemiol & Biostat, London, ON N6A 5C1, Canada. [Barton, James C.] So Iron Disorders Ctr, Birmingham, AL USA. [Passmore, Leah; Reboussin, David M.] Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. [Harrison, Helen] London Hlth Sci Ctr, London, ON, Canada. [Harris, Emily L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Rivers, Charles A.] Univ Alabama, Microbiol Immunogenet Program, Birmingham, AL USA. [Fadojutimi-Akinsiku, Margaret; Diaz, Sharmin] Howard Univ, Washington, DC 20059 USA. [Wenzel, Lari] Univ Calif Irvine, Dept Med, Ctr Hlth Policy Res, Irvine, CA 92717 USA. RP Speechley, M (reprint author), Univ Western Ontario, Dept Epidemiol & Biostat, Room K201,Kresge Bldg, London, ON N6A 5C1, Canada. EM speechly@uwo.ca FU NHLBI [UH1-HL03679-05]; University of Minnesota [N01-HC-05185]; Howard University [N01-HC-05186, M01-RR10284]; University of Alabama at Birmingham [N01-HC-05188]; Center for Health Research, Kaiser Permanente [N01-HC-05189]; University of California, Irvine [N01-HC-05190]; London Health Sciences Centre [N01-HC-05191]; Wake Forest University [N01-HC-05192]; University of Alabama at Birmingham General Clinical Research Center (GCRC) [M01-RR00032]; Southern Iron Disorders Center; National Center for Research Resources National Institutes of Health [M01 RR000827] FX Additional support was provided by the University of Alabama at Birmingham General Clinical Research Center (GCRC) grant M01-RR00032, Southern Iron Disorders Center (J.C.B.), Howard University GCRC grant M01-RR10284, Howard University Research Scientist Award UH1-HL03679-05 from the National Heart, Lung, and Blood Institute and the Office of Research on Minority Health (Dr. Victor R. Gordeuk), and grant UC Irvine M01 RR000827 from the General Clinical Research Centers Program of the National Center for Research Resources National Institutes of Health (Dr. Christine E. McLaren). NR 19 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1945-0265 J9 GENET TEST MOL BIOMA JI Genet. Test. Mol. Biomark. PD DEC PY 2009 VL 13 IS 6 BP 721 EP 728 DI 10.1089/gtmb.2009.0003 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 531AC UT WOS:000272633800004 PM 19860558 ER PT J AU Pavelec, DM Lachowiec, J Duchaine, TF Smith, HE Kennedy, S AF Pavelec, Derek M. Lachowiec, Jennifer Duchaine, Thomas F. Smith, Harold E. Kennedy, Scott TI Requirement for the ERI/DICER Complex in Endogenous RNA Interference and Sperm Development in Caenorhabditis elegans SO GENETICS LA English DT Article ID DOUBLE-STRANDED-RNA; C-ELEGANS; FISSION YEAST; GENOME REARRANGEMENT; GENE-EXPRESSION; SOMATIC-CELLS; MOUSE OOCYTES; MUTANTS; NEMATODE; HETEROCHROMATIN AB Small regulatory RNAs are key regulators of gene expression. One class of small regulatory RNAs, termed the endogenous small interfering RNAs (endo siRNAs), is thought. to negatively regulate cellular transcripts via an RNA interference (RNAi)-like mechanism termed endogenous RNAi (endo RNAi). A complex of proteins composed of ERI-1/3/5, RRF-3, and DICER (the ERI/DICER complex) mediates endo RNAi processes in Caenorhabditis elegans. We conducted a genetic screen to identify additional components of the endo RNAi machinery. Our screen recovered alleles of eri-9, which encodes a novel DICER-interacting protein, and a missense mutation within the helicase domain of DICER [DCR-1(G492R)]. ERI-9(-) and DCR-1 (G492) animals exhibit defects in endo siRNA expression and a concomitant to regulate mRNAs that exhibit sequence homology to these endo siRNAs, indicating that ERI-9 and the DCR-1 helicase domain function in the C. elegans endo RNAi pathway. We define a subset of Eri mutant animals (including eri-1, rrf-3, eri-3, and dcr-1, but not eri-9 or ergo-1) that exhibit temperature-sensitive, sperm-specific sterility and defects in X chromosome segregation. Among these mutants we find multiple aberrations in sperm development beginning with cytokinesis and extending through terminal differentiation. These results identify novel components of the endo RNAi machinery, demonstrate differential requirements for the Eri factors in the sperm-producing germline, and begin to delineate the functional requirement for the ERI/DICER complex in sperm development. C1 [Pavelec, Derek M.; Lachowiec, Jennifer; Kennedy, Scott] Univ Wisconsin, Dept Med Genet, Madison, WI 53706 USA. [Pavelec, Derek M.; Lachowiec, Jennifer; Kennedy, Scott] Univ Wisconsin, Dept Pharmacol, Madison, WI 53706 USA. [Pavelec, Derek M.] Univ Wisconsin, Program Mol & Cellular Pharmacol, Madison, WI 53706 USA. [Duchaine, Thomas F.] McGill Univ, McGill Canc Ctr, Montreal, PQ H3G 1Y6, Canada. [Duchaine, Thomas F.] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada. [Smith, Harold E.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Kennedy, S (reprint author), 2434 Genet Biotechnol Ctr Bldg,425 Henry Mall, Madison, WI 53706 USA. EM sgkennedy@wisc.edu NR 58 TC 59 Z9 70 U1 1 U2 19 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD DEC PY 2009 VL 183 IS 4 BP 1283 EP 1295 DI 10.1534/genetics.109.108134 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 528HV UT WOS:000272435000009 PM 19797044 ER PT J AU Yang, IV Wade, CM Kang, HM Alper, S Rutledge, H Lackford, B Eskin, E Daly, MJ Schwartz, DA AF Yang, Ivana V. Wade, Claire M. Kang, Hyun Min Alper, Scott Rutledge, Holly Lackford, Brad Eskin, Eleazar Daly, Mark J. Schwartz, David A. TI Identification of Novel Genes That Mediate Innate Immunity Using Inbred Mice SO GENETICS LA English DT Article ID WHOLE-GENOME ASSOCIATION; TOLL-LIKE RECEPTORS; SALMONELLA-ENTERITIDIS; INFLAMMATORY RESPONSE; POPULATION-STRUCTURE; CONGENIC STRAINS; HUMAN-DISEASE; LOCI; LIPOPOLYSACCHARIDE; PERSISTENCE AB Innate immunity is the first line of defense against microbial infections. Although polymorphisms in toll-like receptors (TLRs) and downstream signaling molecules (CD14, TLR2, TLR4, TLR5, and IRAK4) affect the innate immune response, these variants account for only a portion of the ability of the host to respond to bacteria, fungi, and viruses. To identify other genes involved in the innate immune response, we challenged 16 inbred murine strains with lipopolysaccharide (LPS) systemically and measured serum concentrations of pro-inflammatory cytokines IL-1 beta, IL-6, and TNF alpha, and the chemokine KC 6 hr post-treatment. Loci that segregate with strain phenotypes were identified by whole genome association (WGA) mapping of cytokine concentrations. Published gene expression profiles and quantitative trait loci (QTL) were then utilized to prioritize loci and genes that potentially regulate the host response to LPS. Sixteen loci were selected for further investigation by combining WGA analysis with previously published QTL for murine response to LPS or gram negative bacteria. Thirty-eight genes within these loci were then selected for further investigation on the basis of the significance of the identified locus, transcriptional response to LPS, and biological plausibility. RNA interference-mediated inhibition of 4 of 38 candidate genes was shown to block the production of IL-6 in J774A.1 macrophages. In summary, our analysis identified 4 genes that have not previously been implicated in innate immunity, namely, 1110058L19Rik, 4933415F23Rik, Fbxo9, and Ipo7. These genes could represent potential sepsis biomarkers or therapeutic targets that should be further investigated in human populations. C1 [Yang, Ivana V.; Schwartz, David A.] Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. [Yang, Ivana V.; Alper, Scott; Schwartz, David A.] Natl Jewish Hlth, Ctr Genes Environm & Hlth, Denver, CO 80206 USA. [Alper, Scott] Natl Jewish Hlth, Dept Immunol, Denver, CO 80206 USA. [Wade, Claire M.; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Wade, Claire M.; Daly, Mark J.] MIT, Cambridge, MA 02142 USA. [Wade, Claire M.; Daly, Mark J.] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. [Kang, Hyun Min] Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA. [Rutledge, Holly; Lackford, Brad] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Eskin, Eleazar] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90095 USA. [Eskin, Eleazar] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. RP Yang, IV (reprint author), Natl Jewish Hlth, Dept Med, 1400 Jackson St,A630, Denver, CO 80206 USA. EM yangi@njhealth.org RI Eskin, Eleazar/J-9187-2012; OI Eskin, Eleazar/0000-0003-1149-4758; Wade, Claire/0000-0003-3413-4771 FU Department of Veterans Affairs; National Institute of Environmental Health Sciences [ES11375, ES011961]; National Institutes of Health, National Institute of the Environmental Health Sciences, and National Heart, Lung, and Blood Institute FX This study was funded by the Department of Veterans Affairs (merit review), the National Institute of Environmental Health Sciences (ES11375 and ES011961), and the Intramural Research Program of the National Institutes of Health, National Institute of the Environmental Health Sciences, and National Heart, Lung, and Blood Institute. NR 29 TC 37 Z9 37 U1 0 U2 6 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD DEC PY 2009 VL 183 IS 4 BP 1535 EP 1544 DI 10.1534/genetics.109.107540 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 528HV UT WOS:000272435000026 PM 19805818 ER PT J AU Desprat, R Thierry-Mieg, D Lailler, N Lajugie, J Schildkraut, C Thierry-Mieg, J Bouhassira, EE AF Desprat, Romain Thierry-Mieg, Danielle Lailler, Nathalie Lajugie, Julien Schildkraut, Carl Thierry-Mieg, Jean Bouhassira, Eric E. TI Predictable dynamic program of timing of DNA replication in human cells SO GENOME RESEARCH LA English DT Article ID EMBRYONIC STEM-CELLS; CPG ISLANDS; S-PHASE; TRANSCRIPTION; ORIGINS; DOMAINS; GENOME; ORGANIZATION; CHROMOSOMES; ACTIVATION AB The organization of mammalian DNA replication is poorly understood. We have produced high-resolution dynamic maps of the timing of replication in human erythroid, mesenchymal, and embryonic stem (ES) cells using TimEX, a method that relies on gaussian convolution of massive, highly redundant determinations of DNA copy-number variations during S phase to produce replication timing profiles. We first obtained timing maps of 3% of the genome using high-density oligonucleotide tiling arrays and then extended the TimEX method genome-wide using massively parallel sequencing. We show that in untransformed human cells, timing of replication is highly regulated and highly synchronous, and that many genomic segments are replicated in temporal transition regions devoid of initiation, where replication forks progress unidirectionally from origins that can be hundreds of kilobases away. Absence of initiation in one transition region is shown at the molecular level by single molecule analysis of replicated DNA (SMARD). Comparison of ES and erythroid cells replication patterns revealed that these cells replicate about 20% of their genome in different quarters of S phase. Importantly, we detected a strong inverse relationship between timing of replication and distance to the closest expressed gene. This relationship can be used to predict tissue-specific timing of replication profiles from expression data and genomic annotations. We also provide evidence that early origins of replication are preferentially located near highly expressed genes, that mid-firing origins are located near moderately expressed genes, and that late-firing origins are located far from genes. C1 [Desprat, Romain; Lailler, Nathalie; Lajugie, Julien; Schildkraut, Carl; Bouhassira, Eric E.] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Desprat, Romain; Lailler, Nathalie; Lajugie, Julien; Bouhassira, Eric E.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. [Thierry-Mieg, Danielle; Thierry-Mieg, Jean; Bouhassira, Eric E.] NIH, NCBI, Bethesda, MD 20894 USA. RP Schildkraut, C (reprint author), Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. EM carl.schildkraut@einstein.yu.edu; eric.bouhassira@einstein.yu.edu RI THIERRY-MIEG, Jean/F-1975-2017 OI THIERRY-MIEG, Jean/0000-0002-0396-6789 FU Intramural Research Program of the NIH; National Library of Medicine; [GM075037]; [HL088467]; [N08S-001]; [N08T-006] FX R. D., E. E. B., and N. L. are supported in part by grants GM075037 and HL088467. E. E. B., N. L., and J. L. are supported in parts by grants NYSTEM N08S-001 and N08T-006. None of the investigators declared any conflict of interest. D. T. M. and J. T. M. are supported by the Intramural Research Program of the NIH, National Library of Medicine. We thank Dr. David Lipman for discussions. NR 32 TC 68 Z9 69 U1 0 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD DEC PY 2009 VL 19 IS 12 BP 2288 EP 2299 DI 10.1101/gr.094060.109 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 526FP UT WOS:000272273400013 PM 19767418 ER PT J AU Peterson, J Garges, S Giovanni, M McInnes, P Wang, L Schloss, JA Bonazzi, V McEwen, JE Wetterstrand, KA Deal, C Baker, CC Di Francesco, V Howcroft, TK Karp, RW Lunsford, RD Wellington, CR Belachew, T Wright, M Giblin, C David, H Mills, M Salomon, R Mullins, C Akolkar, B Begg, L Davis, C Grandison, L Humble, M Khalsa, J Little, AR Peavy, H Pontzer, C Portnoy, M Sayre, MH Starke-Reed, P Zakhari, S Read, J Watson, B Guyer, M AF Peterson, Jane Garges, Susan Giovanni, Maria McInnes, Pamela Wang, Lu Schloss, Jeffery A. Bonazzi, Vivien McEwen, Jean E. Wetterstrand, Kris A. Deal, Carolyn Baker, Carl C. Di Francesco, Valentina Howcroft, T. Kevin Karp, Robert W. Lunsford, R. Dwayne Wellington, Christopher R. Belachew, Tsegahiwot Wright, Michael Giblin, Christina David, Hagit Mills, Melody Salomon, Rachelle Mullins, Christopher Akolkar, Beena Begg, Lisa Davis, Cindy Grandison, Lindsey Humble, Michael Khalsa, Jag Little, A. Roger Peavy, Hannah Pontzer, Carol Portnoy, Matthew Sayre, Michael H. Starke-Reed, Pamela Zakhari, Samir Read, Jennifer Watson, Bracie Guyer, Mark CA NIH HMP Working Grp TI The NIH Human Microbiome Project SO GENOME RESEARCH LA English DT Article ID MOLECULAR ANALYSIS; BACTERIAL BIOTA; HUMAN GENOME; METAGENOMICS; DIVERSITY; COMMUNITY; SEQUENCE; CLONING; FLORA AB The Human Microbiome Project (HMP), funded as an initiative of the NIH Roadmap for Biomedical Research (http://nihroadmap.nih.gov), is a multi-component community resource. The goals of the HMP are: ( 1) to take advantage of new, high-throughput technologies to characterize the human microbiome more fully by studying samples from multiple body sites from each of at least 250 "normal'' volunteers; ( 2) to determine whether there are associations between changes in the microbiome and health/disease by studying several different medical conditions; and ( 3) to provide both a standardized data resource and new technological approaches to enable such studies to be undertaken broadly in the scientific community. The ethical, legal, and social implications of such research are being systematically studied as well. The ultimate objective of the HMP is to demonstrate that there are opportunities to improve human health through monitoring or manipulation of the human microbiome. The history and implementation of this new program are described here. C1 [Peterson, Jane; McInnes, Pamela; Wang, Lu; Schloss, Jeffery A.; Bonazzi, Vivien; McEwen, Jean E.; Wellington, Christopher R.; Belachew, Tsegahiwot; Guyer, Mark; NIH HMP Working Grp] NHGRI, NIH, Bethesda, MD 20892 USA. [Garges, Susan; Deal, Carolyn; Di Francesco, Valentina; Wright, Michael; Giblin, Christina; David, Hagit; Mills, Melody; Salomon, Rachelle] NIAID, NIH, Bethesda, MD 20892 USA. [McInnes, Pamela; Lunsford, R. Dwayne; Read, Jennifer] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Baker, Carl C.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Howcroft, T. Kevin; Davis, Cindy] NCI, NIH, Bethesda, MD 20892 USA. [Karp, Robert W.; Mullins, Christopher; Akolkar, Beena] NIDDKD, NIH, Bethesda, MD 20892 USA. [Begg, Lisa] NIH, Off Director, Bethesda, MD 20892 USA. [Grandison, Lindsey; Zakhari, Samir] NIAAA, NIH, Bethesda, MD 20892 USA. [Humble, Michael] NIEHS, NIH, Bethesda, MD 20892 USA. [Khalsa, Jag] NIDA, NIH, Bethesda, MD 20892 USA. [Little, A. Roger] NIMH, NIH, Bethesda, MD 20892 USA. [Peavy, Hannah] NHLBI, NIH, Bethesda, MD 20892 USA. [Pontzer, Carol] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Portnoy, Matthew] NIGMS, NIH, Bethesda, MD 20892 USA. [Sayre, Michael H.] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. [Read, Jennifer] NICHHD, NIH, Bethesda, MD 20892 USA. [Watson, Bracie] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Peterson, J (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM jane_peterson@nih.gov RI Ducey, Thomas/A-6493-2011; Little, A/O-6191-2014 OI Little, A/0000-0001-6831-0177 FU NIH Roadmap for Medical Research; National Human Genome Research Institute FX This work was supported by funding from the NIH Roadmap for Medical Research and the National Human Genome Research Institute. The authors thank the PIs and staff at the HMP largescale sequencing centers at Baylor College of Medicine ( especially Richard Gibbs, Joe Petrosino, Sarah Highlander, and Jim Versalovic), The Broad Institute ( especially Bruce Birren and Doyle Ward), The J. Craig Venter Institute ( especially Robert Strausberg, Karen Nelson, and Barb Methe), theWashington University School of Medicine ( especially George Weinstock and Erica Sodergren), and the Data Analysis Coordination Center at the University of Maryland ( especially Owen White and JenniferWortman) for their permission to cite the data, results, and plans discussed in this marker paper as well as for their help with the manuscript. We thank the HMP Working Group Co-chairs, Lawrence Tabak, Griffith Rodgers, and Anthony Fauci, and the NIH Roadmap staff, Mary Perry and Elizabeth Wilder, for their guidance through the inception and launch of this project. NR 30 TC 514 Z9 536 U1 11 U2 111 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD DEC PY 2009 VL 19 IS 12 BP 2317 EP 2323 DI 10.1101/gr.096651.109 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 526FP UT WOS:000272273400016 ER PT J AU Temple, G Gerhard, DS Rasooly, R Feingold, EA Good, PJ Robinson, C Mandich, A Derge, JG Lewis, J Shoaf, D Collins, FS Jang, W Wagner, L Shenmen, CM Misquitta, L Schaefer, CF Buetow, KH Bonner, TI Yankie, L Ward, M Phan, L Astashyn, A Brown, G Farrell, C Hart, J Landrum, M Maidak, BL Murphy, M Murphy, T Rajput, B Riddick, L Webb, D Weber, J Wu, W Pruitt, KD Maglott, D Siepel, A Brejova, B Diekhans, M Harte, R Baertsch, R Kent, J Haussler, D Brent, M Langton, L Comstock, CLG Stevens, M Wei, CC van Baren, MJ Salehi-Ashtiani, K Murray, RR Ghamsari, L Mello, E Lin, CW Pennacchio, C Schreiber, K Shapiro, N Marsh, A Pardes, E Moore, T Lebeau, A Muratet, M Simmons, B Kloske, D Sieja, S Hudson, J Sethupathy, P Brownstein, M Bhat, N Lazar, J Jacob, H Gruber, CE Smith, MR McPherson, J Garcia, AM Gunaratne, PH Wu, JQ Muzny, D Gibbs, RA Young, AC Bouffard, GG Blakesley, RW Mullikin, J Green, ED Dickson, MC Rodriguez, AC Grimwood, J Schmutz, J Myers, RM Hirst, M Zeng, T Tse, K Moksa, M Deng, M Ma, K Mah, D Pang, J Taylor, G Chuah, E Deng, A Fichter, K Go, A Lee, S Wang, J Griffith, M Morin, R Moore, RA Mayo, M Munro, S Wagner, S Jones, SJM Holt, RA Marra, MA Lu, S Yang, SW Hartigan, J Graf, M Wagner, R Letovksy, S Pulido, JC Robison, K Esposito, D Hartley, J Wall, VE Hopkins, RF Ohara, O Wiemann, S AF Temple, Gary Gerhard, Daniela S. Rasooly, Rebekah Feingold, Elise A. Good, Peter J. Robinson, Cristen Mandich, Allison Derge, Jeffrey G. Lewis, Jeanne Shoaf, Debonny Collins, Francis S. Jang, Wonhee Wagner, Lukas Shenmen, Carolyn M. Misquitta, Leonie Schaefer, Carl F. Buetow, Kenneth H. Bonner, Tom I. Yankie, Linda Ward, Ming Phan, Lon Astashyn, Alex Brown, Garth Farrell, Catherine Hart, Jennifer Landrum, Melissa Maidak, Bonnie L. Murphy, Michael Murphy, Terence Rajput, Bhanu Riddick, Lillian Webb, David Weber, Janet Wu, Wendy Pruitt, Kim D. Maglott, Donna Siepel, Adam Brejova, Brona Diekhans, Mark Harte, Rachel Baertsch, Robert Kent, Jim Haussler, David Brent, Michael Langton, Laura Comstock, Charles L. G. Stevens, Michael Wei, Chaochun van Baren, Marijke J. Salehi-Ashtiani, Kourosh Murray, Ryan R. Ghamsari, Lila Mello, Elizabeth Lin, Chenwei Pennacchio, Christa Schreiber, Kirsten Shapiro, Nicole Marsh, Amber Pardes, Elizabeth Moore, Troy Lebeau, Anita Muratet, Mike Simmons, Blake Kloske, David Sieja, Stephanie Hudson, James Sethupathy, Praveen Brownstein, Michael Bhat, Narayan Lazar, Joseph Jacob, Howard Gruber, Chris E. Smith, Mark R. McPherson, John Garcia, Angela M. Gunaratne, Preethi H. Wu, Jiaqian Muzny, Donna Gibbs, Richard A. Young, Alice C. Bouffard, Gerard G. Blakesley, Robert W. Mullikin, Jim Green, Eric D. Dickson, Mark C. Rodriguez, Alex C. Grimwood, Jane Schmutz, Jeremy Myers, Richard M. Hirst, Martin Zeng, Thomas Tse, Kane Moksa, Michelle Deng, Merinda Ma, Kevin Mah, Diana Pang, Johnson Taylor, Greg Chuah, Eric Deng, Athena Fichter, Keith Go, Anne Lee, Stephanie Wang, Jing Griffith, Malachi Morin, Ryan Moore, Richard A. Mayo, Michael Munro, Sarah Wagner, Susan Jones, Steven J. M. Holt, Robert A. Marra, Marco A. Lu, Sun Yang, Shuwei Hartigan, James Graf, Marcus Wagner, Ralf Letovksy, Stanley Pulido, Jacqueline C. Robison, Keith Esposito, Dominic Hartley, James Wall, Vanessa E. Hopkins, Ralph F. Ohara, Osamu Wiemann, Stefan CA MGC Project Team TI The completion of the Mammalian Gene Collection (MGC) SO GENOME RESEARCH LA English DT Article ID GENOME BROWSER DATABASE; HUMAN TRANSCRIPTOME; EDITING SITES; CDNA-CLONES; PROJECT; RNA; IDENTIFICATION; PREDICTION; SEQUENCES; RECOVERY AB Since its start, the Mammalian Gene Collection (MGC) has sought to provide at least one full-protein-coding sequence cDNA clone for every human and mouse gene with a RefSeq transcript, and at least 6200 rat genes. The MGC cloning effort initially relied on random expressed sequence tag screening of cDNA libraries. Here, we summarize our recent progress using directed RT-PCR cloning and DNA synthesis. The MGC now contains clones with the entire protein-coding sequence for 92% of human and 89% of mouse genes with curated RefSeq (NM-accession) transcripts, and for 97% of human and 96% of mouse genes with curated RefSeq transcripts that have one or more PubMed publications, in addition to clones for more than 6300 rat genes. These high-quality MGC clones and their sequences are accessible without restriction to researchers worldwide. C1 [Temple, Gary; Bouffard, Gerard G.; Blakesley, Robert W.; Mullikin, Jim; Green, Eric D.] NHGRI, NIH, Genome Technol Branch, Bethesda, MD 20892 USA. [Gerhard, Daniela S.] NCI, NIH, Bethesda, MD 20892 USA. [Rasooly, Rebekah] NIDDK, NIH, Bethesda, MD 20892 USA. [Derge, Jeffrey G.; Lewis, Jeanne; Shoaf, Debonny] NCI, SAIC Frederic Inc, Frederick, MD 21702 USA. [Jang, Wonhee; Wagner, Lukas; Shenmen, Carolyn M.; Yankie, Linda; Ward, Ming; Phan, Lon; Astashyn, Alex; Brown, Garth; Farrell, Catherine; Hart, Jennifer; Landrum, Melissa; Maidak, Bonnie L.; Murphy, Michael; Murphy, Terence; Rajput, Bhanu; Riddick, Lillian; Webb, David; Weber, Janet; Wu, Wendy; Pruitt, Kim D.; Maglott, Donna; Bhat, Narayan] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Misquitta, Leonie; Schaefer, Carl F.; Buetow, Kenneth H.] NCI, Ctr Bioinformat, Rockville, MD 20852 USA. [Bonner, Tom I.; Brownstein, Michael] NIMH, NIH, Bethesda, MD 20892 USA. [Siepel, Adam; Brejova, Brona] Cornell Univ, Ithaca, NY 14853 USA. [Diekhans, Mark; Harte, Rachel; Baertsch, Robert; Kent, Jim; Haussler, David] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Brent, Michael; Langton, Laura; Comstock, Charles L. G.; Wei, Chaochun; van Baren, Marijke J.] Washington Univ, Ctr Genome Sci, St Louis, MO 63130 USA. [Brent, Michael; Stevens, Michael] Washington Univ, Dept Comp Sci, St Louis, MO 63130 USA. [Salehi-Ashtiani, Kourosh; Murray, Ryan R.; Ghamsari, Lila; Mello, Elizabeth; Lin, Chenwei] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Salehi-Ashtiani, Kourosh; Murray, Ryan R.; Ghamsari, Lila; Mello, Elizabeth; Lin, Chenwei] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Pennacchio, Christa; Schreiber, Kirsten; Shapiro, Nicole; Marsh, Amber; Pardes, Elizabeth] Lawrence Livermore Natl Lab, IMAGE Consortium, Biol & Biotechnol Res Program, Livermore, CA 94550 USA. [Moore, Troy; Simmons, Blake; Kloske, David; Sieja, Stephanie] Open Biosyst, Huntsville, AL 35806 USA. [Lebeau, Anita; Muratet, Mike; Hudson, James] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Lazar, Joseph; Jacob, Howard] Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA. [Gruber, Chris E.; Smith, Mark R.] Express Genom Inc, Frederick, MD 21701 USA. [McPherson, John; Garcia, Angela M.; Gunaratne, Preethi H.; Wu, Jiaqian; Muzny, Donna; Gibbs, Richard A.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Gunaratne, Preethi H.] Univ Houston, Houston, TX 77004 USA. [Young, Alice C.; Bouffard, Gerard G.; Blakesley, Robert W.; Mullikin, Jim; Green, Eric D.] Natl Human Genome Inst, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Dickson, Mark C.; Rodriguez, Alex C.; Grimwood, Jane; Schmutz, Jeremy; Myers, Richard M.] Stanford Univ, Dept Genet, Stanford Human Genome Ctr, Sch Med, Stanford, CA 94305 USA. [Hirst, Martin; Zeng, Thomas; Tse, Kane; Moksa, Michelle; Deng, Merinda; Ma, Kevin; Mah, Diana; Pang, Johnson; Taylor, Greg; Chuah, Eric; Deng, Athena; Fichter, Keith; Go, Anne; Lee, Stephanie; Wang, Jing; Griffith, Malachi; Morin, Ryan; Moore, Richard A.; Mayo, Michael; Munro, Sarah; Wagner, Susan; Jones, Steven J. M.; Holt, Robert A.; Marra, Marco A.] BC Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Lu, Sun; Yang, Shuwei] GeneCopoeia Inc, Rockville, MD 20850 USA. [Hartigan, James] Beckman Coulter Genom, Beverly, MA 01915 USA. [Graf, Marcus; Wagner, Ralf] Geneart AG, D-93053 Regensburg, Germany. [Letovksy, Stanley; Pulido, Jacqueline C.; Robison, Keith] Codon Devices Inc, Cambridge, MA 02139 USA. [Esposito, Dominic; Hartley, James; Wall, Vanessa E.; Hopkins, Ralph F.] NCI SAIC Frederick, Prot Express Lab, Frederick, MD 21702 USA. [Ohara, Osamu] Kazusa DNA Res Inst, Chiba 2920818, Japan. [Wiemann, Stefan] German Canc Res Ctr, D-69120 Heidelberg, Germany. RP Temple, G (reprint author), NHGRI, NIH, Genome Technol Branch, Bethesda, MD 20892 USA. EM gtemple@mail.nih.gov RI Marra, Marco/B-5987-2008; Ohara, Osamu/G-5448-2015; Hirst, Martin/B-7684-2016; Brejova, Brona/I-3718-2014; Ohara, Osamu/A-9119-2012; Schmutz, Jeremy/N-3173-2013; Jones, Steven/C-3621-2009; McPherson, John/D-2633-2017; Tang, Macy/B-9798-2014; Holt, Robert/C-3303-2009; Griffith, Malachi/P-1285-2014; Wiemann, Stefan/E-4424-2013; OI Ohara, Osamu/0000-0002-3328-9571; Brejova, Brona/0000-0002-9483-1766; Schmutz, Jeremy/0000-0001-8062-9172; McPherson, John/0000-0001-8049-9347; Wei, Chaochun/0000-0002-1031-034X; Griffith, Malachi/0000-0002-6388-446X; Wiemann, Stefan/0000-0003-4683-3174; Siepel, Adam/0000-0002-3557-7219; Salehi-Ashtiani, Kourosh/0000-0002-6521-5243; Simmons, Blake/0000-0002-1332-1810 FU National Cancer Institute; National Institutes of Health [N01-C0-12400]; Center for Cancer Systems Biology; Dana-Farber Cancer Institute; Ellison Foundation FX We thank Robert L. Strausberg and Richard D. Klausner, who initiated theMGCproject and helped to manage it during its first four years. The MGC Program received excellent guidance from members of the External Scientific Committee: Barbara Wold, Philip Sharp, Geoffrey Duyk, Connie Cepko, Stewart Scherer, Lincoln Stein, Ronald Davis, Howard Jacob, and Edward Harlow. The Mammalian Gene Collection Program was an NIH interinstitute effort that received financial and scientific support from 19 institutes within the NIH. A complete list of these institutes is provided on the MGC website. Greg Schuler and Karl Sirotkin provided valuable bioinformatics advice to MGC. We thank the Vineet Bafna laboratory for screening our predicted SEGs against its MS/MS spectra database. We also appreciate the valuable support and advice of the NIH MGC Inter-Institute Coordinating Committee: Andrea Beckel-Mitchener, Anthony Carter, Hemin Chin, Jennifer Couch, Pete Dudley, Nancy Freeman, Maria Giovanni, Q. Max Guo, John Harding, Steven Klein, Cheryl Kraft, Gabrielle Leblanc, Anna McCormick, Susan Old, Raymond O'Neill, Jane Peterson, Jonathan Pollock, Zhaoxia Ren, John Satterlee, William Sharrock, Rochelle Small, Phillip Smith, Susan Sparks, Danilo Tagle, and Jose Velazquez. Assya Abdallah provided excellent assistance with the final manuscript preparation. TheXGCProgram received excellent guidance from Aaron Zorn, Ken Cho, Bruce Blumberg, Richard Harland, Robert Grainger, and Jane Rogers. The ZGC Program received excellent guidance from the members of its advisory committee: Bruce Birren, Will Talbot, MonteWesterfield, and Len Zon. Four rat cDNA libraries were contributed by the Cancer Genome Anatomy Project, NCI. This project was funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract no. N01-C0-12400. The portion of this work carried out at the Center for Cancer Systems Biology, at the Dana-Farber Cancer Institute, was funded in part by a grant from the Ellison Foundation. NR 37 TC 56 Z9 56 U1 0 U2 11 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD DEC PY 2009 VL 19 IS 12 BP 2324 EP 2333 DI 10.1101/gr.095976.109 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 526FP UT WOS:000272273400017 ER PT J AU Wentzensen, N Zuna, RE Sherman, ME Gold, MA Schiffman, M Dunn, ST Jeronimo, J Zhang, R Walker, J Wang, SS AF Wentzensen, Nicolas Zuna, Rosemary E. Sherman, Mark E. Gold, Michael A. Schiffman, Mark Dunn, S. Terence Jeronimo, Jose Zhang, Roy Walker, Joan Wang, Sophia S. TI Accuracy of cervical specimens obtained for biomarker studies in women with CIN3 SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Cervical cancer; HPV; SUCCEED; Epidemiology; Molecular; Colposcopy; Biopsy ID COLPOSCOPICALLY DIRECTED BIOPSY; ASCUS-LSIL TRIAGE; INTEROBSERVER AGREEMENT; HUMAN-PAPILLOMAVIRUS; CANCER; EXCISION AB Objective. We developed a protocol to collect representative cervical specimens based oil colposcopic evaluation from women treated with loop electrosurgical excision procedure (LEEP). Methods. We analyzed the histology of biopsies targeting the worst and a normal area oil the cervical surface in 74 women referred for LFEP because of cervical intraepithelial neoplasia grade 3 (CIN3) detected in a previous biopsy. Lesions and normal tissue were identified in colposcopy. marked, and removed after LEEP. Cervical cytology specimens collected at the same time were analyzed using Pap cytology and human papillomavirus (HPV) genotyping. Results. All but two women had an abnormal colposcopic impression with 59 of 68 (87%) showing an impression of CIN2 or greater. In 19 of 58 (33%) women, the histology result of the frozen specimen targeting the worst lesion was <= CIN1. In 18 of 46 (40%) women, the histology of the frozen specimen targeting normal tissue was CIN2+. A concordant histology result in specimens targeting the worst lesion was associated with a greater extension of the CIN3 in the LEEP (p trend = 0.002) and a HSIL cytology result (p trend = 0.02). Conclusion. It is challenging to sample representative cervical tissue. Even in women with confirmed CIN3, colposcopy performance to identify the worst lesion oil the cervix was limited. Correctly identified CIN3s were more likely to be larger lesions that may have a higher risk of progression to cancer. Published by Elsevier Inc. C1 [Wentzensen, Nicolas; Sherman, Mark E.; Gold, Michael A.; Schiffman, Mark; Wang, Sophia S.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20854 USA. [Zuna, Rosemary E.; Dunn, S. Terence; Zhang, Roy; Walker, Joan] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OR USA. [Zuna, Rosemary E.; Dunn, S. Terence; Zhang, Roy; Walker, Joan] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Oklahoma City, OR USA. [Gold, Michael A.] Vanderbilt Univ, Nashville, TN USA. [Jeronimo, Jose] PATH, Seattle, WA USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 5014, Rockville, MD 20854 USA. EM wentzenn@gmail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 16 TC 13 Z9 14 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD DEC PY 2009 VL 115 IS 3 BP 493 EP 496 DI 10.1016/j.ygyno.2009.09.001 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 522BK UT WOS:000271972500032 PM 19773045 ER PT J AU Quillen, K Wong, E Scheinberg, P Young, NS Walsh, TJ Wu, CO Leitman, SF AF Quillen, Karen Wong, Edward Scheinberg, Phillip Young, Neal S. Walsh, Thomas J. Wu, Colin O. Leitman, Susan F. TI Granulocyte transfusions in severe aplastic anemia: an eleven-year experience SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE granulocyte; transfusions; severe aplastic anemia ID COLONY-STIMULATING FACTOR; NEUTROPENIA-RELATED INFECTIONS; LIFE-THREATENING INFECTIONS; STEM-CELL TRANSPLANTATION; ANTI-THYMOCYTE GLOBULIN; PEDIATRIC-PATIENTS; FUNGAL-INFECTIONS; G-CSF; DONORS; EFFICACY AB Background Infections, particularly those caused by invasive fungi, are a major cause of death in patients with severe aplastic anemia. The purpose of this study was to analyze our experience with granulocyte transfusions in such patients. Design and Methods A retrospective analysis was performed on all patients with severe aplastic anemia who had received granulocyte transfusions between 1997 and 2007 in our institute. Survival to hospital discharge was the primary outcome. Secondary outcomes included microbiological, radiographic and clinical responses of the infection at 7 and 30 days after initiating granulocyte therapy, and post-transfusion absolute neutrophil count, stratified by HLA alloimmunization status. Results Thirty-two patients with severe aplastic anemia underwent granulocyte transfusions; the majority had received horse antithymocyte globulin and cyclosporine A. One quarter of patients had demonstrable HLA alloimmunization prior to the initiation of granulocyte therapy. Infections were evenly divided between invasive bacterial and fungal infections unresponsive to maximal antibiotic and/or antifungal therapy. The median number of granulocyte components transfused was nine (range, 2-43). The overall survival to hospital discharge was 58%. Survival was strongly correlated with hematopoietic recovery. Among the 18 patients who had invasive fungal infections, 44% survived to hospital discharge. Response at 7 and 30 days correlated with survival. The mean post-transfusion absolute neutrophil count did not differ significantly between response groups (i.e. patients grouped according to whether they had complete or partial resolution of infection, stable disease or progressive infection). There was also no difference in mean post-transfusion absolute neutrophil count between the patients divided according to HLA alloimmunization status. Conclusions Granulocyte transfusions may have an adjunctive role in severe infections in patients with severe aplastic anemia. HLA alloimmunization is not an absolute contraindication to granulocyte therapy. C1 [Quillen, Karen; Wong, Edward; Leitman, Susan F.] NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Scheinberg, Phillip; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD USA. [Wu, Colin O.] NHLBI, Off Biostat Res, NIH, Bethesda, MD USA. RP Quillen, K (reprint author), Boston Univ, Med Ctr, Dept Lab Med, 88 E Newton St, Boston, MA 02118 USA. EM kq@bu.edu OI Quillen, Karen/0000-0002-4243-0864; Scheinberg, Phillip/0000-0002-9047-4538 NR 30 TC 31 Z9 35 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD DEC PY 2009 VL 94 IS 12 BP 1661 EP 1668 DI 10.3324/haematol.2009.010231 PG 8 WC Hematology SC Hematology GA 553ZR UT WOS:000274405800007 PM 19996117 ER PT J AU Kristinsson, SY Bjorkholm, M Andersson, TML Eloranta, S Dickman, PW Goldin, LR Blimark, C Mellqvist, UH Wahlin, A Turesson, I Landgren, O AF Kristinsson, Sigurdur Y. Bjorkholm, Magnus Andersson, Therese M-L Eloranta, Sandra Dickman, Paul W. Goldin, Lynn R. Blimark, Cecilie Mellqvist, Ulf-Henrik Wahlin, Anders Turesson, Ingemar Landgren, Ola TI Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance: a population-based study SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE monoclonal gammopathy of undetermined significance; multiple myeloma; prognosis; survival; sex; older age; cause of death; population-based ID LONG-TERM; MALIGNANT-TRANSFORMATION; RELATIVE SURVIVAL; MULTIPLE-MYELOMA; NATURAL-HISTORY; DISORDERS; SWEDEN; RISK AB Background There are limited data on survival patterns among patients with monoclonal gammopathy of undetermined significance. Design and Methods We compared the survival of 4,259 patients with monoclonal gammopathy of undetermined significance, collected from hematology outpatient units in Sweden, with the survival of the general population by computing relative survival ratios. We also compared causes of death in these patients with those in 16,151 matched controls. Results One-, 5-, 10-, and 15-year relative survival ratios were 0.98 (95% Cl 0.97-0.99), 0.93 (0.91-0.95), 0.82 (0.79-0.84), and 0.70 (0.64-0.76), respectively. Younger age at diagnosis of the gammopathy was associated with a significantly lower excess mortality compared to that in older patients (p<0.001). The excess mortality among patients with gammopathy increased with longer follow-up (p<0.0001). IgM (versus IgG/A) gammopathy was associated with a superior survival (p=0.038). Patients with monoclonal gammopathy of undetermined significance had an increased risk of dying from multiple myeloma (hazards ratio (HR)=553; 95% Cl 77-3946), Waldenstrom's macroglobulinemia (HR=infinity), other lymphoproliferative malignancies (6.5; 2.8-15.1), other hematologic malignancies (22.9; 8.9-58.7), amyloidosis (HR=infinity), bacterial infections (3.4; 1.7-6.7), ischemic heart disease (1.3; 1.1-1.4), other heart disorders (1.5; 1.2-1.8), other hematologic conditions (6.9; 2.7-18), liver (2.1; 1.1-4.2), and renal diseases (3.2; 2.0-4.9). Conclusions Our finding of decreased life expectancy in patients with monoclonal gammopathy of undetermined significance, which was most pronounced in the elderly and explained by both malignant transformation and non-malignant causes, is of importance in the understanding and clinical management of this disease. The underlying mechanisms may be causally related to the gammopathy, but may also be explained by underlying disease that led to the detection of the hematologic disease. Our results are of importance since they give a true estimation of survival in patients with monoclonal gammopathy of undetermined significance diagnosed in clinical practice. C1 [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Landgren, Ola] Karolinska Univ, Hosp Solna, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. [Andersson, Therese M-L; Eloranta, Sandra; Dickman, Paul W.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Goldin, Lynn R.; Landgren, Ola] NCI, NIH, Bethesda, MD 20892 USA. [Blimark, Cecilie; Mellqvist, Ulf-Henrik] Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Dept Med, Gothenburg, Sweden. [Wahlin, Anders] Umea Univ Hosp, Ctr Canc, Sect Hematol, S-90185 Umea, Sweden. [Turesson, Ingemar] Malmo Univ Hosp, Sect Hematol, Dept Med, Malmo, Sweden. RP Kristinsson, SY (reprint author), Karolinska Univ, Hosp Solna, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. EM sigurdur.kristinsson@karolins-ka.se RI Dickman, Paul/B-4572-2013; Wahlin, Anders/F-6043-2013; Kristinsson, Sigurdur /M-2910-2015; Andersson, Therese/E-7107-2016 OI Dickman, Paul/0000-0002-5788-3380; Wahlin, Anders/0000-0001-6402-0463; Kristinsson, Sigurdur /0000-0002-4964-7476; Andersson, Therese/0000-0001-8644-9041 FU NIH; National Cancer Institute; Swedish Cancer Society; Stockholm County Council; Karolinska Institutet Foundations FX Funding: this research was supported by the Intramural Research Program of the NIH and the National Cancer Institute, and by grants from the Swedish Cancer Society, Stockholm County Council, and the Karolinska Institutet Foundations. NR 19 TC 36 Z9 37 U1 0 U2 2 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD DEC PY 2009 VL 94 IS 12 BP 1714 EP 1720 DI 10.3324/haematol.2009.010066 PG 7 WC Hematology SC Hematology GA 553ZR UT WOS:000274405800014 PM 19608666 ER PT J AU Brudno, J Calado, RT Boyer, TD Young, NS AF Brudno, Jennifer Calado, Rodrigo T. Boyer, Thomas D. Young, Neal S. TI CONSTITUTIONAL TELOMERASE MUTATIONS CAUSING TELOMERE EROSION ARE GENETIC RISK FACTORS FOR DEVELOPMENT OF CIRRHOSIS SO HEPATOLOGY LA English DT Meeting Abstract CT Annual Conference of the Asia-Pacific-Association-for-the-Study-of-the-Liver CY MAR 25-28, 2010 CL Beijing, PEOPLES R CHINA SP Asia Pacific Assoc Study Liver, China Natl Convent Ctr C1 [Brudno, Jennifer; Calado, Rodrigo T.; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Boyer, Thomas D.] Univ Arizona, Dept Med, Tucson, AZ USA. [Brudno, Jennifer] NIH Pfizer, Clin Res Training Program, Bethesda, MD USA. RI Calado, Rodrigo/G-2619-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2009 VL 50 IS 6 MA LB11 BP 7A EP 8A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 527BI UT WOS:000272340600066 ER PT J AU Farci, P Diaz, G Chen, ZC Govindarajan, S Tice, AB Agulto, L Pittaluga, S Boon, D Yu, C Engle, RE Haas, M Purcell, RH Zamboni, F AF Farci, Patrizia Diaz, Giacomo Chen, Zhaochun Govindarajan, Sugantha Tice, Ashley B. Agulto, Liane Pittaluga, Stefania Boon, Denali Yu, Claro Engle, Ronald E. Haas, Mark Purcell, Robert H. Zamboni, Fausto TI MASSIVE INTRAHEPATIC PRODUCTION OF IGM AND IGG ANTIBODIES TO HBCAG, WITH COMPLEMENT DEPOSITION, PROVIDES EVIDENCE FOR A MAJOR ROLE OF HUMORAL IMMUNITY IN THE PATHOGENESIS OF HBV-ASSOCIATED ACUTE LIVER FAILURE SO HEPATOLOGY LA English DT Meeting Abstract CT Annual Conference of the Asia-Pacific-Association-for-the-Study-of-the-Liver CY MAR 25-28, 2010 CL Beijing, PEOPLES R CHINA SP Asia Pacific Assoc Study Liver, China Natl Convent Ctr C1 [Farci, Patrizia; Chen, Zhaochun; Tice, Ashley B.; Agulto, Liane; Boon, Denali; Yu, Claro; Engle, Ronald E.; Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Diaz, Giacomo] Univ Cagliari, Dipartimento Sci & Tecnol Biomed, Cagliari, Italy. [Govindarajan, Sugantha] Univ So Calif, Rancho Los Amigos Med Ctr, Pathol Lab, Downey, CA 90242 USA. [Pittaluga, Stefania] NCI, Pathol Lab, Hematopathol Sect, NIH, Bethesda, MD 20892 USA. [Haas, Mark] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Zamboni, Fausto] Azienda Osped G Brotzu, Chirurg Gen & Ctr Trapianti, Cagliari, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2009 VL 50 IS 6 MA LB22 BP 13A EP 13A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 527BI UT WOS:000272340600076 ER PT J AU Goodman, ZD Stoddard, AM Bonkovsky, HL Fontana, RJ Ghany, MG Morgan, TR Wright, EC Brunt, EM Kleiner, DE Shiffmann, ML Everson, GT Lindsay, KL Dienstag, JL Morishima, C AF Goodman, Zachary D. Stoddard, Anne M. Bonkovsky, Herbert L. Fontana, Robert J. Ghany, Marc G. Morgan, Timothy R. Wright, Elizabeth C. Brunt, Elizabeth M. Kleiner, David E. Shiffmann, Mitchell L. Everson, Gregory T. Lindsay, Karen L. Dienstag, Jules L. Morishima, Chihiro CA HALT-C Trial Grp TI Fibrosis Progression in Chronic Hepatitis C: Morphometric Image Analysis in the HALT-C Trial SO HEPATOLOGY LA English DT Article ID LIVER-BIOPSY; INTERFERON; THERAPY; PEGINTERFERON; CIRRHOSIS AB Computer-assisted morphometry can provide precise measurement of hepatic fibrosis on a continuous scale. Previous morphometric studies of large cohorts of patients with treatment refractory chronic hepatitis C have shown a mean increase in fibrosis of 30% to 58% in 1 year. The aim of the present study was to quantify fibrosis progression in biopsy specimens obtained over 1.5 to 44 5 years from three groups of patients with baseline bridging fibrosis or cirrhosis (Ishak stages 3-6) enrolled in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial. The main group of 346 lead-in nonresponders (viremic after 24 weeks of peginterferon-ribavirin therapy) had a mean fibrosis increase of 61% over pretreatment baseline after 2 years and 80% after 4 years. In contrast, the 78 breakthrough/relapse patients (undetectable serum hepatitis C virus RNA after 24 weeks of peginterferon-ribavirin and receiving antiviral therapy for 48 weeks) showed a mean increase in fibrosis of 48% when biopsied 36 months from pretreatment baseline but no further increase at 60 months. Finally, the 111 express patients with baseline biopsies following unsuccessful peginterferon-ribavirin outside the trial had significantly more baseline fibrosis than the others but an increase of only 21% after 21 months and a slight decrease at 45 months. Maintenance therapy with low-dose peginterferon had no effect on fibrosis changes in any of the groups. Conclusion: Morphometry demonstrated complex, nonlinear changes in fibrosis over time in this heterogeneous cohort of patients with interferon-refractory chronic hepatitis C. (HEPATOLOGY 2009;50:1738-1749.) C1 [Goodman, Zachary D.] Armed Forces Inst Pathol, Div Hepat Pathol, Washington, DC 20306 USA. [Goodman, Zachary D.] Vet Adm Special Reference Lab Pathol, Washington, DC USA. [Stoddard, Anne M.] New England Res Inst, Watertown, MA 02172 USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Mol & Struct Biol, Farmington, CT USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Liver Biliary Pancreat Ctr, Farmington, CT USA. [Fontana, Robert J.] Univ Michigan, Med Ctr, Dept Internal Med, Ann Arbor, MI 48109 USA. [Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Wright, Elizabeth C.] NIDDK, Off Director, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Morgan, Timothy R.] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. [Morgan, Timothy R.] VA Long Beach Healthcare Syst, Gastroenterol Serv, Long Beach, CA USA. [Brunt, Elizabeth M.] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Shiffmann, Mitchell L.] Virginia Commonwealth Univ, Med Ctr, Hepatol Sect, Richmond, VA USA. [Everson, Gregory T.] Univ Colorado Denver, Dept Internal Med, Div Gastroenterol & Hepatol, Sect Hepatol, Aurora, CO USA. [Lindsay, Karen L.] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Dienstag, Jules L.] Massachusetts Gen Hosp, Med Serv, Gastrointestinal Unit, Boston, MA USA. [Dienstag, Jules L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Morishima, Chihiro] Univ Washington, Dept Lab Med, Div Virol, Seattle, WA 98195 USA. RP Goodman, ZD (reprint author), Amer Int Pathol Labs, 8403 Colesville Rd, Silver Spring, MD 20910 USA. EM zgoodman@aiplabloratories.com OI Kleiner, David/0000-0003-3442-4453 FU National Center for Research Resources, National Institutes of Health; Hoffmann-La Roche, Inc. FX Supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infections Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the General Clinical Research Center, and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health. Additional support eras provided by Hoffmann-La Roche, Inc., through a Cooperative Research and Development Agreement with the National Institutes of Health. (See Appendix for contract and grant details.) NR 15 TC 39 Z9 39 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2009 VL 50 IS 6 BP 1738 EP 1749 DI 10.1002/hep.23211 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 527BI UT WOS:000272340600010 PM 19824074 ER PT J AU Hikita, H Takehara, T Kodama, T Shimizu, S Hosui, A Miyagi, T Tatsumi, T Ishida, H Ohkawa, K Li, W Kanto, T Hiramatsu, N Hennighausen, L Yin, XM Hayashi, N AF Hikita, Hayato Takehara, Tetsuo Kodama, Takahiro Shimizu, Satoshi Hosui, Atsushi Miyagi, Takuya Tatsumi, Tomohide Ishida, Hisashi Ohkawa, Kazuyoshi Li, Wei Kanto, Tatsuya Hiramatsu, Naoki Hennighausen, Lothar Yin, Xiao-Ming Hayashi, Norio TI BH3-Only Protein Bid Participates in the Bcl-2 Network in Healthy Liver Cells SO HEPATOLOGY LA English DT Article ID HUMAN HEPATOCELLULAR CARCINOMAS; CYTOCHROME-C RELEASE; HEPATOCYTE APOPTOSIS; BCL-2-REGULATED APOPTOSIS; DEFICIENT MICE; BH3 MIMETICS; DEATH; PATHWAY; LIFE; FAS AB Bcl-2 homology domain 3 (BH3)-only protein Bid is posttranslationally cleaved by caspase-8 into its truncated form (tBid) and couples with stress signals to the mitochondrial cell death pathway. However, the physiological relevance of Bid is not clearly understood. Hepatocyte-specific knockout (KO) of Bcl-xL leads to naturally-occurring apoptosis despite co-expression of Mcl-1, which shares a similar anti-apoptotic function. We generated Bcl-xL KO, Bcl-xL/Bid double KO, Bcl-xL/Bak double KO, Bcl-xL/Bax double KO, and Bcl-xL/Bak/Bax triple KO mice and found that hepatocyte apoptosis caused by Bcl-xL deficiency was completely dependent on Bak and Bax, and surprisingly on Bid. This indicated that, in the absence of Bid, Bcl-xL is not required for the integrity of differentiated hepatocytes, suggesting a complicated interaction between core Bcl-2 family proteins and BH3-only proteins even in a physiological setting. Indeed, a small but significant level of tBid was present in wild-type liver under physiological conditions. tBid was capable of binding to Bcl-xL and displacing Bak and Bax from Bcl-xL, leading to release of cytochrome c from wildtype mitochondria. Bcl-xL-deficient mitochondria were more susceptible to tBid-induced cytochrome c release. Finally, administration of ABT-737, a pharmacological inhibitor of Bcl-2/Bcl-xL, caused Bak/Bax-dependent liver injury, but this was clearly ameliorated with a Bid KO background. Conclusion: Bid, originally considered to be a sensor for apoptotic stimuli, is constitutively active in healthy liver cells and is involved in the Bak/Bax-dependent mitochondrial cell death pathway. Healthy liver cells are addicted to a single Bcl-2-like molecule because of BH3 stresses, and therefore special caution may be required for the use of the Bcl-2 inhibitor for cancer therapy. (HEPATOLOGY 2009;50:1972-1980.) C1 [Hikita, Hayato; Takehara, Tetsuo; Kodama, Takahiro; Shimizu, Satoshi; Hosui, Atsushi; Miyagi, Takuya; Tatsumi, Tomohide; Ishida, Hisashi; Ohkawa, Kazuyoshi; Li, Wei; Kanto, Tatsuya; Hiramatsu, Naoki; Hayashi, Norio] Osaka Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, Suita, Osaka 5650871, Japan. [Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD USA. [Yin, Xiao-Ming] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. RP Hayashi, N (reprint author), Osaka Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. EM hayashin@gb.med.osaka-u.ac.jp OI Kodama, Takahiro/0000-0002-6250-1324 FU Ministry of Education, Culture, Sports, Science, and Technology, Japan FX Supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (to T Takehara). NR 34 TC 14 Z9 14 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2009 VL 50 IS 6 BP 1972 EP 1980 DI 10.1002/hep.23207 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 527BI UT WOS:000272340600033 PM 19839062 ER PT J AU Ji, JF Wang, XW AF Ji, Junfang Wang, Xin Wei TI What Is the Relationship Among MicroRNA-181, Epithelial Cell-Adhesion Molecule (EpCAM) and beta-Catenin in Hepatic Cancer Stem Cells Reply SO HEPATOLOGY LA English DT Letter ID HEPATOCELLULAR-CARCINOMA CELLS C1 [Ji, Junfang; Wang, Xin Wei] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Ji, JF (reprint author), NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RI Wang, Xin/B-6162-2009 NR 4 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2009 VL 50 IS 6 BP 2048 EP 2048 DI 10.1002/hep.23363 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 527BI UT WOS:000272340600044 ER PT J AU Zhang, XZ Frank, AC Gille, CM Daucher, M Kabat, J Becker, S Lempicki, RA Cortez, KJ Polis, MA Subramanian, GM Kottili, S AF Zhang, Xiaozhen Frank, Astrid C. Gille, Christine M. Daucher, Marybeth Kabat, Juraj Becker, Steven Lempicki, Richard A. Cortez, Karoll J. Polis, Michael A. Subramanian, G. Mani Kottili, Shyam TI Altered regulation of extrinsic apoptosis pathway in HCV-infected HCC cells enhances susceptibility to mapatumumab-induced apoptosis SO HEPATOLOGY RESEARCH LA English DT Article DE hepatitis C virus cell culture system; hepatocellular carcinoma; tumor necrosis factor-related apoptosis inducing ligand agonistic antibodies ID HEPATITIS-C VIRUS; HUMAN HEPATOCELLULAR-CARCINOMA; HUMAN-IMMUNODEFICIENCY-VIRUS; MONOCLONAL-ANTIBODY; CANCER-THERAPY; IN-VITRO; TRAIL; DEATH; LIGAND; LIVER AB Background: Hepatitis C virus (HCV)-infected patients, including those co-infected with human immunodeficiency virus (HIV), are at increased risk of developing hepatocellular carcinoma (HCC). We evaluated the ability of agonistic human monoclonal antibodies to tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, mapatumumab and lexatumumab, respectively, to induce TRAIL-receptor mediated apoptosis (TRMA) in HCC (HCV-infected and -uninfected) cells and in peripheral blood cells (HIV-infected and -uninfected). Methods: Susceptibility to antibody-mediated TRMA was measured by caspase 3/7 activity and by confocal microscopy. Surface expression of receptors on HCV-uninfected and -infected Huh7.5 cells was measured by flow cytometry and confocal microscopy. Inhibitor of Apoptosis Protein (IAP) RNA levels were quantified by RT-PCR. DNA Microarray was performed using RNA isolated from Huh7.5 cells (HCV-infected and uninfected) using Affymetrix U133A chips. Results: Mapatumumab preferentially induces TRMA of HCV-infected Huh7.5 cells by binding to TRAIL-R1. Higher basal expression of TRAIL-R2 compared to that of TRAIL-R1 on HCV-uninfected Huh7.5 cells were observed. Lexatumumab induces TRMA of both HCV-infected and -uninfected cells by binding to TRAIL-R2. IFN-alpha has minimal effect on mapatumumab- and lexatumumab-induced TRMA. HCV infection of Huh7.5 cells up-regulates TRAIL-R1 expression and X-linked Inhibitor of apoptosis protein and survivin gene expression. Neither antibody had a pro-apoptotic effect on PBMCs from patients with HIV infection ex vivo. Conclusion: Both mapatumumab and lexatumumab are excellent candidates for therapy of HCC. HCV infection of Huh7.5 cells selectively up-regulates TRAIL-R1 receptor, associated with increased susceptibility to mapatumumab-mediated TRMA. HCV infection up-regulated IAP genes, offering promise for future combination therapy using TRAIL agonists and IAP inhibitors. C1 [Zhang, Xiaozhen; Frank, Astrid C.; Gille, Christine M.; Daucher, Marybeth; Polis, Michael A.; Kottili, Shyam] NIAID, Immunopathogenesis Sect, NIH, LIR,DHHS, Bethesda, MD 20892 USA. [Kabat, Juraj; Becker, Steven] NIAID, Biol Imaging Facil, RTB, NIH,DHHS, Bethesda, MD 20892 USA. [Lempicki, Richard A.] SAIC Frederick Inc, Frederick, MD USA. [Cortez, Karoll J.] NCI, NIH, DHHS, Bethesda, MD 20892 USA. [Subramanian, G. Mani] Human Genome Sci Inc, Rockville, MD USA. RP Kottili, S (reprint author), NIAID, Immunopathogenesis Sect, NIH, LIR,DHHS, Bldg 10 Rm 11N204,9000 Rockville Pike, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Polis, Michael/0000-0002-9151-2268 FU National Institute of Allergy and Infectious Diseases FX THIS RESEARCH WAS supported in whole by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. We would also like to thank Apath LLC (St. Louis, MO) and Toray Industries, Japan for providing us with the Huh7.5cells and J6/JFH-1 HCV strains. NR 37 TC 8 Z9 8 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1386-6346 J9 HEPATOL RES JI Hepatol. Res. PD DEC PY 2009 VL 39 IS 12 BP 1178 EP 1189 DI 10.1111/j.1872-034X.2009.00568.x PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 526QB UT WOS:000272306100004 PM 19788693 ER PT J AU Yeager, M Deng, ZM Boland, J Matthews, C Bacior, J Lonsberry, V Hutchinson, A Burdett, LA Qi, LQ Jacobs, KB Gonzalez-Bosquet, J Berndt, SI Hayes, RB Hoover, RN Thomas, G Hunter, DJ Dean, M Chanock, SJ AF Yeager, Meredith Deng, Zuoming Boland, Joseph Matthews, Casey Bacior, Jennifer Lonsberry, Victor Hutchinson, Amy Burdett, Laura A. Qi, Liqun Jacobs, Kevin B. Gonzalez-Bosquet, Jesus Berndt, Sonja I. Hayes, Richard B. Hoover, Robert N. Thomas, Gilles Hunter, David J. Dean, Michael Chanock, Stephen J. TI Comprehensive resequence analysis of a 97 kb region of chromosome 10q11.2 containing the MSMB gene associated with prostate cancer SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; 94 AMINO-ACIDS; RADICAL PROSTATECTOMY; FUNCTIONAL-ANALYSIS; ANDROGEN RECEPTOR; SECRETORY PROTEIN; COMMON VARIANT; RISK LOCUS; EXPRESSION; 8Q24 AB Genome-wide association studies of prostate cancer have identified single nucleotide polymorphism (SNP) markers in a region of chromosome 10q11.2, harboring the microseminoprotein-beta (MSMB) gene. Both the gene product of MSMB, the prostate secretory protein 94 (PSP94) and its binding protein (PSPBP), have been previously investigated as serum biomarkers for prostate cancer progression. Recent functional work has shown that different alleles of the significantly associated SNP in the promoter of MSMB found to be associated with prostate cancer risk, rs10993994, can influence its expression in tumors and in vitro studies. Since it is plausible that additional variants in this region contribute to the risk of prostate cancer, we have used next-generation sequencing technology to resequence a similar to 97-kb region that includes the area surrounding MSMB (chr10: 51,168,025-51,265,101) in 36 prostate cancer cases, 26 controls of European origin, and 8 unrelated CEPH individuals in order to identify additional variants to investigate in functional studies. We identified 241 novel polymorphisms within this region, including 142 in the 51-kb block of linkage disequilibrium (LD) that contains rs10993994 and the proximal promoter of MSMB. No sites were observed to be polymorphic within the exons of MSMB. C1 [Yeager, Meredith] NCI, Adv Technol Ctr, Gaithersburg, MD 20877 USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Dept Epidemiol, Boston, MA 02115 USA. [Dean, Michael] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Yeager, Meredith; Deng, Zuoming; Boland, Joseph; Matthews, Casey; Bacior, Jennifer; Lonsberry, Victor; Hutchinson, Amy; Burdett, Laura A.; Qi, Liqun] NCI, Core Genotyping Facil, Adv Technol Program, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. [Jacobs, Kevin B.] Bioinformed Consulting Serv, Gaithersburg, MD 20877 USA. [Hayes, Richard B.] New York Univ Langone, Med Ctr, Div Epidemiol, New York, NY 10016 USA. [Yeager, Meredith; Deng, Zuoming; Boland, Joseph; Matthews, Casey; Bacior, Jennifer; Lonsberry, Victor; Hutchinson, Amy; Burdett, Laura A.; Qi, Liqun; Jacobs, Kevin B.; Gonzalez-Bosquet, Jesus; Berndt, Sonja I.; Hayes, Richard B.; Hoover, Robert N.; Thomas, Gilles; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Yeager, M (reprint author), NCI, Adv Technol Ctr, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. EM yeagerm@mail.nih.gov RI Dean, Michael/G-8172-2012; OI Dean, Michael/0000-0003-2234-0631; Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 36 TC 10 Z9 11 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD DEC PY 2009 VL 126 IS 6 BP 743 EP 750 DI 10.1007/s00439-009-0723-9 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 521MG UT WOS:000271924900002 PM 19644707 ER PT J AU Hazra, A Kraft, P Lazarus, R Chen, C Chanock, SJ Jacques, P Selhub, J Hunter, DJ AF Hazra, Aditi Kraft, Peter Lazarus, Ross Chen, Constance Chanock, Stephen J. Jacques, Paul Selhub, Jacob Hunter, David J. TI Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway SO HUMAN MOLECULAR GENETICS LA English DT Article ID METHYLMALONYL-COA MUTASE; HELICOBACTER-PYLORI INFECTION; HUMAN METHYLENETETRAHYDROFOLATE REDUCTASE; PLASMA HOMOCYSTEINE CONCENTRATIONS; PROSTATE-CANCER RISK; COLORECTAL-CANCER; BREAST-CANCER; ALKALINE-PHOSPHATASE; VITAMIN-B-12 DEFICIENCY; CARDIOVASCULAR-DISEASE AB Low plasma B-vitamin levels and elevated homocysteine have been associated with cancer, cardiovascular disease and neurodegenerative disorders. Common variants in FUT2 on chromosome 19q13 were associated with plasma vitamin B(12) levels among women in a genome-wide association study in the Nurses' Health Study (NHS) NCI-Cancer Genetic Markers of Susceptibility (CGEMS) project. To identify additional loci associated with plasma vitamin B(12), homocysteine, folate and vitamin B(6) (active form pyridoxal 5'-phosphate, PLP), we conducted a meta-analysis of three GWA scans (total n = 4763, consisting of 1658 women in NHS-CGEMS, 1647 women in Framingham-SNP-Health Association Resource (SHARe) and 1458 men in SHARe). On chromosome 19q13, we confirm the association of plasma vitamin B(12) with rs602662 and rs492602 (P-value = 1.83 x 10(-15) and 1.30 x 10(-14), respectively) in strong linkage disequilibrium (LD) with rs601338 (P = 6.92 x 10(-15)), the FUT2 W143X nonsense mutation. We identified additional genome-wide significant loci for plasma vitamin B(12) on chromosomes 6p21 (P = 4.05 x 10(-08)), 10p12 (P-value=2.87 x 10(-9)) and 11q11 (P-value=2.25 x 10(-10)) in genes with biological relevance. We confirm the association of the well-studied functional candidate SNP 5,10-methylene tetrahydrofolate reductase (MTHFR) Ala222Val (dbSNP ID: rs1801133; P-value=1.27 x 10(-8)), on chromosome 1p36 with plasma homocysteine and identify an additional genome-wide significant locus on chromosome 9q22 (P-value=2.06 x 10(-8)) associated with plasma homocysteine. We also identified genome-wide associations with variants on chromosome 1p36 with plasma PLP (P-value=1.40 x 10(-15)). Genome-wide significant loci were not identified for plasma folate. These data reveal new biological candidates and confirm prior candidate genes for plasma homocysteine, plasma vitamin B(12) and plasma PLP. C1 [Hazra, Aditi; Kraft, Peter; Chen, Constance; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Hazra, Aditi; Lazarus, Ross; Hunter, David J.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Lazarus, Ross] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA 02115 USA. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, DHHS, US NIH, Bethesda, MD 20892 USA. [Jacques, Paul; Selhub, Jacob] Tufts Univ, Vitamin Metab & Aging Lab, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Jacques, Paul; Selhub, Jacob] Tufts Univ, Nutr Epidemiol Program, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. RP Hazra, A (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM ahazra@hsph.harvard.edu OI lazarus, ross/0000-0003-3939-1961 FU National Institutes of Health [U54 CA100971, P01 CA87969, P01 CA55075, U01 CA098233, R01 CA 065725, R01 CA070817, R03 CA133937]; National Heart, Lung and Blood Institute (NHLBI) FX The Framingham Heart Study is conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with Boston University. NR 98 TC 68 Z9 70 U1 0 U2 10 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 DEC 1 PY 2009 VL 18 IS 23 BP 4677 EP 4687 DI 10.1093/hmg/ddp428 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 516WL UT WOS:000271573900020 PM 19744961 ER PT J AU Vilboux, T Kayser, M Introne, W Suwannarat, P Bernardini, I Fischer, R O'Brien, K Kleta, R Huizing, M Gahl, WA AF Vilboux, Thierry Kayser, Michael Introne, Wendy Suwannarat, Pim Bernardini, Isa Fischer, Roxanne O'Brien, Kevin Kleta, Robert Huizing, Marjan Gahl, William A. TI Mutation Spectrum of Homogentisic Acid Oxidase (HGD) in Alkaptonuria SO HUMAN MUTATION LA English DT Article DE alkaptonuria; AKU; homogentisic acid; homogentisate dioxygenase; HGD; mutation analysis; missense variation; pathogenicity prediction ID PROTEIN FUNCTION; 1,2-DIOXYGENASE GENE; EGYPTIAN MUMMY; POLYMORPHISMS; OCHRONOSIS; AKU; DIOXYGENASE; SLOVAKIA; FAMILIES; PIGMENT AB Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder, characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint an spine arthritis, and destruction of cardiac valves. AKU is due to mutations in the homogentisate dioxygenase gene (HGD) that converts homogentisic acid to maleylacetoacetic acid in the tyrosine catabolic pathway. Here we report a comprehensive mutation analysis of 93 patients enrolled in our study, as well as an extensive update of all previously published HGD mutations associated with AKU. Within our patient cohort, we identified 52 HGD variants, of which 22 were novel. This yields a total of 91 identified HGD variations associated with AKU to date, including 62 missense, 13 splice site, 10 frameshift, 5 nonsense, and 1 no-stop mutation. Most HGD variants reside in exons 3, 6, 8, and 13. We assessed the potential effect of all missense variations on protein function, using five bioinformatic tools specifically designed for interpretation of missense variants (SIFT, POLYPHEN, PANTHER, PMUT, and SNAP). We also analyzed the potential effect of splice-site variants using two different tools (BDGP and NetGene2). This study provides valuable resources for molecular analysis of alkaptonuria and expands our knowledge of the molecular basis of this disease. Hum Mutat 30:1611-1619, 2009. Published 2009 Wiley Liss, Inc. C1 [Vilboux, Thierry; Kayser, Michael; Suwannarat, Pim; Bernardini, Isa; Fischer, Roxanne; Kleta, Robert; Huizing, Marjan; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Introne, Wendy; O'Brien, Kevin; Gahl, William A.] NIH, Off Rare Dis, Intramural Program, Bethesda, MD 20892 USA. RP Vilboux, T (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM vilbouxt@mail.nih.gov FU National Human Genome Research Institute; National Institutes of Health, Bethesda, MD FX We thank Chanika Phomphutkul and David Adams for expert advice on this study and for assistance with mutation prediction tools, and Maya Tuchman and Carla Ciccone for skillful laboratory assistance. This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD. NR 63 TC 24 Z9 26 U1 0 U2 9 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD DEC PY 2009 VL 30 IS 12 BP 1611 EP 1619 DI 10.1002/humu.21120 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 533BH UT WOS:000272796400002 PM 19862842 ER PT J AU Parle-McDermott, A Pangilinan, F O'Brien, KK Mills, JL Magee, AM Troendle, J Sutton, M Scott, JM Kirke, PN Molloy, AM Brody, LC AF Parle-McDermott, Anne Pangilinan, Faith O'Brien, Kirsty K. Mills, James L. Magee, Alan M. Troendle, James Sutton, Marie Scott, John M. Kirke, Peadar N. Molloy, Anne M. Brody, Lawrence C. TI A Common Variant in MTHFD1L is Associated With Neural Tube Defects and mRNA Splicing Efficiency SO HUMAN MUTATION LA English DT Article DE MTHFD1L; NTD; splicing; polymorphism; association; folate; mitochondria ID MITOCHONDRIAL C-1-TETRAHYDROFOLATE SYNTHASE; TRACT BINDING-PROTEIN; ONE-CARBON METABOLISM; HAPLOTYPE RECONSTRUCTION; POPULATION; DISEASE; POLYMORPHISM; SYNTHETASE; DISRUPTION; PREVENTION AB Polymorphisms in folate-related genes have emerged as important risk factors in a range of diseases including neural tube defects (NTDs), cancer, and coronary artery disease (CAD). Having previously identified a polymorphism within the cytoplasmic folate enzyme, MTHFD1, as a maternal risk factor for NTDs, we considered the more recently identified mitochondrial paralogue, MTHFD1L, as a candidate gene for NTD association. We identified a common deletion/insertion polymorphism, rs3832406, c.781-6823ATT(7-9), which influences splicing efficiency and is strongly associated with NTD risk. Three alleles of rs3832406 were detected in the Irish population with varying numbers of ATT repeats: Allele 1 consists of ATT(7), whereas Alleles 2 and 3 consist of ATT(8) and ATT(9), respectively. Allele 2 of this triallelic polymorphism showed a decreased case risk as demonstrated by case-control logistic regression (P = 0.002) and by transmission disequilibrium test (TDT) (P=0.001), whereas Allele 1 showed an increased case risk. Allele 3 showed no influence on NTD risk and represents the lowest frequency allele (0.15). Additional single nucleotide polymorphism (SNP) genotyping in the same genomic region provides additional supportive evidence of an association. We demonstrate that two of the three alleles of rs3832406 are functionally different and influence the splicing efficiency of the alternate MTHFD1L mRNA transcripts. Hum Mutat 30:1650-1656, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Parle-McDermott, Anne; O'Brien, Kirsty K.; Magee, Alan M.] Dublin City Univ, Sch Biotechnol, Nutr Genom Grp, Dublin 9, Ireland. [Pangilinan, Faith; Brody, Lawrence C.] NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Bethesda, MD 20892 USA. [Mills, James L.; Troendle, James] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Sutton, Marie; Kirke, Peadar N.] Hlth Res Board, Child Hlth Epidemiol Unit, Dublin, Ireland. [Scott, John M.] Trinity Coll Dublin, Sch Biochem & Immunol, Dublin 2, Ireland. [Molloy, Anne M.] Trinity Coll Dublin, Sch Med, Dublin 2, Ireland. RP Parle-McDermott, A (reprint author), Dublin City Univ, Sch Biotechnol, Nutr Genom Grp, Dublin 9, Ireland. EM anne.parle-mcdermott@dcu.ie OI Molloy, Anne/0000-0002-1688-9049; O'Brien, Kirsty/0000-0002-0240-1292 FU National Human Genome Research Institute; National Institute of Child Health and Human Development; Health Research Board (HRB), Ireland [RP/2005/58] FX These Studies would not be possible without the participation of the affected families, and their recruitment by the Irish Association of Spina Bifida and Hydrocephalus and the Irish Public Health Nurses. The authors also thank Peter Chines and Kristine Krebs for their computational assistance. Grant sponsors: Intramural research programs of the National Human Genome Research Institute, the National Institute of Child Health and Human Development and the Health Research Board (HRB), Ireland, including all HRB Research Project Grant (to A.P.-M.) (Grant number RP/2005/58). NR 27 TC 29 Z9 29 U1 1 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD DEC PY 2009 VL 30 IS 12 BP 1650 EP 1656 DI 10.1002/humu.21109 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 533BH UT WOS:000272796400006 PM 19777576 ER PT J AU Tian, J Shidyak, A Periyasamy, SM Haller, S Taleb, M El-Okdi, N Elkareh, J Gupta, S Gohara, S Fedorova, OV Cooper, CJ Xie, ZJ Malhotra, D Bagrov, AY Shapiro, JI AF Tian, Jiang Shidyak, Amjad Periyasamy, Sankaridrug M. Haller, Steven Taleb, Mohamed El-Okdi, Nasser Elkareh, Jihad Gupta, Shalini Gohara, Sabry Fedorova, Olga V. Cooper, Christopher J. Xie, Zijian Malhotra, Deepak Bagrov, Alexei Y. Shapiro, Joseph I. TI Spironolactone Attenuates Experimental Uremic Cardiomyopathy by Antagonizing Marinobufagenin SO HYPERTENSION LA English DT Article DE cardiomyopathy; renal failure; cardiotonic steroids; collagen; fibrosis ID MINERALOCORTICOID RECEPTOR BLOCKADE; LEFT-VENTRICULAR MASS; CHRONIC-RENAL-FAILURE; CARDIAC FIBROSIS; HEART-FAILURE; ANGIOTENSIN-II; CARDIOVASCULAR-DISEASE; COLLAGEN-METABOLISM; HYPERTENSIVE-RATS; NA/K-ATPASE AB Spironolactone has been noted to attenuate cardiac fibrosis. We have observed that the cardiotonic steroid marinobufagenin plays an important role in the diastolic dysfunction and cardiac fibrosis seen with experimental renal failure. We performed the following studies to determine whether and how spironolactone might ameliorate these changes. First, we studied rats subjected to partial nephrectomy or administration of exogenous marinobufagenin. We found that spironolactone (20 mg/kg per day) attenuated the diastolic dysfunction as assessed by ventricular pressure-volume loops and essentially eliminated cardiac fibrosis as assessed by trichrome staining and Western blot. Next, we examined the effects of spironolactone and its major metabolite, canrenone (both 100 nM), on marinobufagenin stimulation of rat cardiac fibroblasts. Both spironolactone and canrenone prevented the stimulation of collagen production by 1 nM marinobufagenin but not 100 nM marinobufagenin, as assessed by proline incorporation and procollagen 1 expression, as well as signaling through the sodium-potassium-ATPase, as evidenced by protein kinase C isoform delta translocation and extracellular signal regulated kinase 1/2 activation. Both spironolactone and canrenone also altered ouabain binding to cultured porcine cells in a manner consistent with competitive inhibition. Our data suggest that some of the antifibrotic effects of spironolactone may be attributed to antagonism of marinobufagenin signaling through the sodium-potassium-ATPase. (Hypertension. 2009; 54: 1313-1320.) C1 [Tian, Jiang; Shidyak, Amjad; Periyasamy, Sankaridrug M.; Haller, Steven; Taleb, Mohamed; El-Okdi, Nasser; Elkareh, Jihad; Gupta, Shalini; Gohara, Sabry; Cooper, Christopher J.; Xie, Zijian; Malhotra, Deepak; Shapiro, Joseph I.] Univ Toledo, Coll Med, Dept Med, Toledo, OH 43614 USA. [Tian, Jiang; Shidyak, Amjad; Periyasamy, Sankaridrug M.; Haller, Steven; Taleb, Mohamed; El-Okdi, Nasser; Elkareh, Jihad; Gupta, Shalini; Gohara, Sabry; Cooper, Christopher J.; Xie, Zijian; Malhotra, Deepak; Shapiro, Joseph I.] Univ Toledo, Coll Med, Dept Physiol & Pharmacol, Toledo, OH 43614 USA. [Fedorova, Olga V.; Bagrov, Alexei Y.] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Shapiro, JI (reprint author), Univ Toledo, Coll Med, Dept Med, Mail Stop 1186 HSC,3000 Arlington Ave, Toledo, OH 43614 USA. EM joseph.shapiro@utoledo.edu FU National Institutes of Health [HL-67963, HL-36573, HL-071556, GM-78565] FX Portions of this work were supported by grants from the National Institutes of Health (HL-67963, HL-36573, HL-071556, and GM-78565), as well as intramural support from the National Institute on Aging Laboratory of Cardiovascular Science. NR 56 TC 37 Z9 37 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD DEC PY 2009 VL 54 IS 6 BP 1313 EP U76 DI 10.1161/HYPERTENSIONAHA.109.140038 PG 15 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 521TB UT WOS:000271945900025 PM 19884563 ER PT J AU Badal, A Kyprianou, I Banh, DP Badano, A Sempau, J AF Badal, Andreu Kyprianou, Iacovos Banh, Diem Phuc Badano, Aldo Sempau, Josep TI penMesh-Monte Carlo Radiation Transport Simulation in a Triangle Mesh Geometry SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Computer-aided design; Monte Carlo; NCAT; PENELOPE; penMesh; triangle mesh ID PENELOPE; TOOLKIT; PACKAGE; SPECT; CODE AB We have developed a general-purpose Monte Carlo simulation code, called penMesh, that combines the accuracy of the radiation transport physics subroutines from PENELOPE and the flexibility of a geometry based on triangle meshes. While the geometric models implemented in most general-purpose codes-such as PENELOPE's quadric geometry-impose some limitations in the shape of the objects that can be simulated, triangle meshes can be used to describe any free-form (arbitrary) object. Triangle meshes are extensively used in computer-aided design and computer graphics. We took advantage of the sophisticated tools already developed in these fields, such as an octree structure and an efficient ray-triangle intersection algorithm, to significantly accelerate the triangle mesh ray-tracing. A detailed description of the new simulation code and its ray-tracing algorithm is provided in this paper. Furthermore, we show how it can be readily used in medical imaging applications thanks to the detailed anatomical phantoms already available. In particular, we present a whole body radiography simulation using a triangulated version of the anthropomorphic NCAT phantom. An example simulation of scatter fraction measurements using a standardized abdomen and lumbar spine phantom, and a benchmark of the triangle mesh and quadric geometries in the ray-tracing of a mathematical breast model, are also presented to show some of the capabilities of penMesh. C1 [Badal, Andreu; Sempau, Josep] Univ Politecn Cataluna, Inst Tech Energet, E-08028 Barcelona, Spain. [Badal, Andreu; Kyprianou, Iacovos; Banh, Diem Phuc; Badano, Aldo] US FDA, NIBIB CDRH Lab Assessment Med Imaging Syst, Silver Spring, MD 20993 USA. [Sempau, Josep] Networking Res Ctr Bioengn Biomat & Nanomed CIBER, Barcelona 08028, Spain. RP Badal, A (reprint author), Univ Politecn Cataluna, Inst Tech Energet, E-08028 Barcelona, Spain. EM andreu.badal-soler@fda.hhs.gov; iacovos.kyprianou@fda.hhs.gov RI Sempau, Josep/J-7834-2013; OI Sempau, Josep/0000-0002-2754-7685; badano, aldo/0000-0003-3712-6670 FU U.S. Food and Drug Administration (FDA) Office of Womens' Health; NIH-NIBIB; U.S. Department of Energy; FDA; Spanish Ministerio de Educacion V Ciencia [FIS2006-07016] FX This work was supported in part by the U.S. Food and Drug Administration (FDA) Office of Womens' Health, in part by the NIH-NIBIB, and in part by an appointment to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA. The work of J. Sempau was supported by the Spanish Ministerio de Educacion V Ciencia under Project FIS2006-07016. NR 33 TC 22 Z9 22 U1 1 U2 10 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD DEC PY 2009 VL 28 IS 12 BP 1894 EP 1901 DI 10.1109/TMI.2009.2021615 PG 8 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 525UO UT WOS:000272242100004 PM 19435677 ER PT J AU Sun, P Zhou, QF Zhu, BP Wu, DW Hu, CL Cannata, JM Tian, J Han, PD Wang, GF Shung, KK AF Sun, Ping Zhou, Qifa Zhu, Benpeng Wu, Dawei Hu, Changliong Cannata, Jonathan M. Tian, Jin Han, Pengdi Wang, Gaofeng Shung, K. Kirk TI Design and Fabrication of PIN-PMN-PT Single-Crystal High-Frequency Ultrasound Transducers SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Article ID GROWTH AB High-frequency PIN-PMN-PT single crystal ultrasound transducers at center frequencies of 35 MHz and 60 MHz were successfully fabricated using lead indium niobate-lead magnesium niobate-lead titanate (0.23PIN-0.5PMN-0.27PT) single crystal. The new PIN-PMN-PT single crystal has higher coercivity (6.0 kV/cm) and higher Curie temperature (160 degrees C) than PMN-PT crystal. Experimental results showed that the PIN-PMN-PT transducers have similar performance but better thermal stability compared with the PMN-PT transducers. C1 [Sun, Ping; Wang, Gaofeng] Wuhan Univ, Sch Phys Sci & Technol, Wuhan 430072, Peoples R China. [Sun, Ping; Zhou, Qifa; Zhu, Benpeng; Wu, Dawei; Hu, Changliong; Cannata, Jonathan M.; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, NIH, Resource Ctr Med Ultrason Transducer Technol, Los Angeles, CA 90089 USA. [Tian, Jin; Han, Pengdi] HC Mat Corp, Bolingbrook, IL USA. RP Sun, P (reprint author), Wuhan Univ, Sch Phys Sci & Technol, Wuhan 430072, Peoples R China. EM pingsun@usc.edu RI wu, dawei/D-3158-2014 FU NIH [P41-EB2182]; China Scholar Council (CSC) FX This work was partially supported by NIH Grant. No. P41-EB2182 and China Scholar Council (CSC). NR 12 TC 32 Z9 33 U1 1 U2 17 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0885-3010 J9 IEEE T ULTRASON FERR JI IEEE Trans. Ultrason. Ferroelectr. Freq. Control PD DEC PY 2009 VL 56 IS 12 BP 2760 EP 2763 DI 10.1109/TUFFC.2009.1367 PG 4 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA 530LJ UT WOS:000272593100017 PM 20040413 ER PT J AU Thammavongsa, V Schaefer, M Filzen, T Collins, KL Carrington, M Bangia, N Raghavan, M AF Thammavongsa, Vilasack Schaefer, Malinda Filzen, Tracey Collins, Kathleen L. Carrington, Mary Bangia, Naveen Raghavan, Malini TI Assembly and intracellular trafficking of HLA-B*3501 and HLA-B*3503 SO IMMUNOGENETICS LA English DT Article DE MHC class I; Tapasin; Antigen presentation/processing; TAP transporter; HLA-B*3501; HLA-B*3503; HLA-B*4402; HLA-B*4405; HLA-B*5701 ID MHC CLASS-I; CYTOTOXIC T-LYMPHOCYTES; COMPLEX CLASS-I; CELL-SURFACE; HLA-B; HISTOCOMPATIBILITY ANTIGEN; MONOCLONAL-ANTIBODIES; ENDOPLASMIC-RETICULUM; PEPTIDE BINDING; HEAVY-CHAINS AB Residue 116 of major histocompatibility complex (MHC) class I heavy chains is an important determinant of assembly, that can influence rates of ER-Golgi trafficking, binding to the transporter associated with antigen processing (TAP), tapasin dependence of assembly, and the efficiency and specificity of peptide binding. Here, we investigated assembly and peptide-binding differences between HLA-B*3501(S116) and HLA-B*3503(F116), two alleles differing only at position 116 of the MHC class I heavy chain, that are associated respectively with normal or rapid AIDS progression. A reduced intracellular maturation rate was observed for HLA-B*3503 in HIV-infected and uninfected cells, which correlated with enhanced binding of HLA-B*3503 to TAP. No significant differences in the intrinsic efficiency of in vitro peptide binding by HLA-B*3501 and HLA-B*3503 were measurable with several common peptides or peptide libraries, and both allotypes were relatively tapasin-independent for their assembly. However, thermostability differences between the two allotypes were measurable in a CD4(+) T cell line. These findings suggest that compared to HLA-B*3501, a reduced intracellular peptide repertoire for HLA-B*3503 could contribute to its slower intracellular trafficking and stronger association with rapid AIDS progression. C1 [Filzen, Tracey; Collins, Kathleen L.; Raghavan, Malini] Univ Michigan, Dept Microbiol & Immunol, Sch Med, Ann Arbor, MI 48109 USA. [Thammavongsa, Vilasack; Schaefer, Malinda] Univ Michigan, Grad Program Immunol, Sch Med, Ann Arbor, MI 48109 USA. [Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick, Frederick, MD 21702 USA. [Bangia, Naveen] Roswell Pk Canc Inst, Dept Immunol, CCC, Buffalo, NY 14263 USA. RP Raghavan, M (reprint author), Univ Michigan, Dept Microbiol & Immunol, Sch Med, 5641 Med Sci Bldg 2, Ann Arbor, MI 48109 USA. EM malinir@umich.edu FU NIH [AI44155] FX This work was supported by an NIH grant (AI44155) to MR and an American Heart Association pre-doctoral fellowship to VT. The authors wish to thank Dr. Matt Androlewicz for anti- TAP1 anti- sera. We also thank the University of Michigan Biomedical Research core facilities for peptide synthesis and purification. We thank Dr. Syed Monem Rizvi for assistance with Fig. 6g- j. NR 44 TC 9 Z9 9 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD DEC PY 2009 VL 61 IS 11-12 BP 703 EP 716 DI 10.1007/s00251-009-0399-2 PG 14 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 540SP UT WOS:000273359700001 PM 19838694 ER PT J AU Fitzgerald, W Chen, S Walz, C Zimmerberg, J Margolis, L Grivel, JC AF Fitzgerald, Wendy Chen, Silvia Walz, Carl Zimmerberg, Joshua Margolis, Leonid Grivel, Jean-Charles TI Immune suppression of human lymphoid tissues and cells in rotating suspension culture and onboard the International Space Station SO IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL LA English DT Article DE Immune response; Space flight; Microgravity ID PROTEIN-KINASE-C; SIMULATED MICROGRAVITY; EX-VIVO; IMMUNODEFICIENCY; PATHOGENESIS; ACTIVATION; INFECTION; FLIGHT AB The immune responses of human lymphoid tissue explants or cells isolated from this tissue were studied quantitatively under normal gravity and microgravity. Microgravity was either modeled by solid body suspension in a rotating, oxygenated culture vessel or was actually achieved on the International Space Station (ISS). Our experiments demonstrate that tissues or cells challenged by recall antigen or by polyclonal activator in modeled microgravity lose all their ability to produce antibodies and cytokines and to increase their metabolic activity. In contrast, if the cells were challenged before being exposed to modeled microgravity suspension culture, they maintained their responses. Similarly, in microgravity in the ISS, lymphoid cells did not respond to antigenic or polyclonal challenge, whereas cells challenged prior to the space flight maintained their antibody and cytokine responses in space. Thus, immune activation of cells of lymphoid tissue is severely blunted both in modeled and true microgravity. This suggests that suspension culture via solid body rotation is sufficient to induce the changes in cellular physiology seen in true microgravity. This phenomenon may reflect immune dysfunction observed in astronauts during space flights. If so, the ex vivo system described above can be used to understand cellular and molecular mechanisms of this dysfunction. C1 [Fitzgerald, Wendy; Chen, Silvia; Zimmerberg, Joshua; Margolis, Leonid; Grivel, Jean-Charles] NICHHD, NASA, NIH Ctr Dimens Tissue Culture 3, Lab Cellular & Mol Biophys,Program Phys Biol,NIH, Bethesda, MD 20892 USA. [Walz, Carl] NASA, Lyndon B Johnson Space Ctr, Astronaut Off, Houston, TX 77058 USA. RP Grivel, JC (reprint author), NICHHD, NASA, NIH Ctr Dimens Tissue Culture 3, Lab Cellular & Mol Biophys,Program Phys Biol,NIH, Bethesda, MD 20892 USA. EM grivelj@mail.nih.gov FU Intramural NIH HHS [ZIA HD001409-25] NR 23 TC 8 Z9 8 U1 4 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-2690 J9 IN VITRO CELL DEV-AN JI In Vitro Cell. Dev. Biol.-Anim. PD DEC PY 2009 VL 45 IS 10 BP 622 EP 632 DI 10.1007/s11626-009-9225-2 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 519FC UT WOS:000271749400007 PM 19609626 ER PT J AU Warawa, JM Long, D Rosenke, R Gardner, D Gherardini, FC AF Warawa, Jonathan M. Long, Dan Rosenke, Rebecca Gardner, Don Gherardini, Frank C. TI Role for the Burkholderia pseudomallei Capsular Polysaccharide Encoded by the wcb Operon in Acute Disseminated Melioidosis SO INFECTION AND IMMUNITY LA English DT Article ID SIGNATURE-TAGGED MUTAGENESIS; SECRETION SYSTEM; IN-VIVO; INTERFERON-GAMMA; VIRULENCE GENES; C57BL/6 MICE; IFN-GAMMA; INFECTION; LIPOPOLYSACCHARIDE; SURVIVAL AB The capsular polysaccharide of Burkholderia pseudomallei is an essential virulence determinant that is required for protection from host serum cidal activity and opsonophagocytosis. In this study, the immune response directed against a B. pseudomallei capsule mutant (JW270) was investigated in an acute respiratory murine model. JW270 was significantly attenuated in this model (similar to 2 logs) to levels resembling those of avirulent Burkholderia thailandensis. At lethal doses, JW270 colonized the lung, liver, and spleen at levels similar to the wild-type strain levels and was found to trigger reduced pathology in the liver and spleen. Several cytokine responses were altered in these tissues, and importantly, the levels of gamma interferon were reduced in the livers and spleens of JW270-infected mice but not in the lungs. These results suggest that the capsular polysaccharide of B. pseudomallei is a critical virulence determinant in respiratory tract infections and that it is an important antigen for generating the Th1 immune response commonly observed in systemic melioidosis. Furthermore, the data suggest that host recognition of B. pseudomallei capsular polysaccharide in the lungs may not be as important to the disease outcome as the innate immune response in the peripheral organs. C1 [Warawa, Jonathan M.; Gherardini, Frank C.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Long, Dan; Rosenke, Rebecca; Gardner, Don] NIAID, Rocky Mt Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Gherardini, FC (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM fgherardini@niaid.nih.gov FU NIH NIAID FX This work was supported by the Intramural Research Program of the NIH NIAID. NR 46 TC 19 Z9 19 U1 0 U2 4 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 DEC PY 2009 VL 77 IS 12 BP 5252 EP 5261 DI 10.1128/IAI.00824-09 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 519LC UT WOS:000271767100006 PM 19752033 ER PT J AU Arakawa, T Tachibana, M Miyata, T Harakuni, T Kohama, H Matsumoto, Y Tsuji, N Hisaeda, H Stowers, A Torii, M Tsuboi, T AF Arakawa, Takeshi Tachibana, Mayumi Miyata, Takeshi Harakuni, Tetsuya Kohama, Hideyasu Matsumoto, Yasunobu Tsuji, Naotoshi Hisaeda, Hajime Stowers, Anthony Torii, Motomi Tsuboi, Takafumi TI Malaria Ookinete Surface Protein-Based Vaccination via the Intranasal Route Completely Blocks Parasite Transmission in both Passive and Active Vaccination Regimens in a Rodent Model of Malaria Infection SO INFECTION AND IMMUNITY LA English DT Article ID PLASMODIUM-FALCIPARUM; CHOLERA-TOXIN; MINIMAL VARIATION; VACCINES; ANTIBODIES; IMMUNITY; VIVAX; PVS25; PFS25; CANDIDATES AB Malaria vaccines based on ookinete surface proteins (OSPs) of the malaria parasites block oocyst development in feeding mosquitoes and hence disrupt the parasite life cycle and prevent the disease from being transmitted to other individuals. To investigate whether a noninvasive mucosal vaccination regimen effectively blocks parasite transmission in vivo, Plasmodium yoelii Pys25, a homolog of the Pfs25 and Pvs25 OSPs of Plasmodium falciparum and Plasmodium vivax, respectively, was intranasally (i.n.) administered using a complement-deficient DBA/2 mouse malaria infection model, in which a highly elevated level of oocysts develops in feeding mosquitoes. Vaccinated mice developed a robust antibody response when the vaccine antigen was given together with cholera toxin adjuvant. The induced immune serum was passively transferred to DBA/2 mice 3 days after infection with P. yoelii 17XL, and Anopheles stephensi mosquitoes were allowed to feed on the infected mice before or after serum transfusion. This passive immunization completely blocked oocyst development; however, immune serum induced by the antigen or adjuvant alone did not have such a profound antiparasite effect. Further, when i.n. vaccinated mice were infected with the parasite and then mosquitoes were allowed to directly feed on the infected mice, complete blockage of transmission was again observed. To our knowledge, this is the first time that mucosal vaccination has been demonstrated to be efficacious for directly preventing parasite transmission from vaccinated animals to mosquitoes, and the results may provide important insight into rational design of nonparenteral vaccines for use against human malaria. C1 [Tsuboi, Takafumi] Ehime Univ, Cell Free Sci & Technol Res Ctr, Matsuyama, Ehime 7908577, Japan. [Arakawa, Takeshi; Miyata, Takeshi; Harakuni, Tetsuya; Kohama, Hideyasu] Univ Ryukyus, Trop Biosphere Res Ctr, COMB, Mol Microbiol Grp, Okinawa 9030213, Japan. [Arakawa, Takeshi] Univ Ryukyus, Grad Sch Med, Div Host Def & Vaccinol, Okinawa 9030215, Japan. [Tachibana, Mayumi; Torii, Motomi] Ehime Univ, Sch Med, Dept Mol Parasitol, Shigenobu, Ehime 7910295, Japan. [Matsumoto, Yasunobu] Univ Tokyo, Grad Sch Agr & Life Sci, Dept Global Agr Sci, Lab Global Anim Resource Sci,Bunkyo Ku, Tokyo 1138657, Japan. [Tsuji, Naotoshi] Natl Agr Res Org, Natl Inst Anim Hlth, Tsukuba, Ibaraki 3050856, Japan. [Hisaeda, Hajime; Stowers, Anthony] NIAID, Malaria Vaccine Dev Unit, NIH, Rockville, MD USA. RP Tsuboi, T (reprint author), Ehime Univ, Cell Free Sci & Technol Res Ctr, 3 Bunkyo Cho, Matsuyama, Ehime 7908577, Japan. EM tsuboi@ccr.ehime-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [18390129] FX This work was supported by the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. It was also supported in part by Grant-in-Aid for Scientific Research 18390129 from MEXT, Japan. NR 28 TC 9 Z9 10 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 DEC PY 2009 VL 77 IS 12 BP 5496 EP 5500 DI 10.1128/IAI.00640-09 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 519LC UT WOS:000271767100030 PM 19752035 ER PT J AU Palmore, TN Vandersluis, JP Morris, J Michelin, A Ruprecht, LM Schmitt, JM Henderson, DK AF Palmore, Tara N. Vandersluis, J. Patrick Morris, Joan Michelin, Angela Ruprecht, Lisa M. Schmitt, James M. Henderson, David K. TI A Successful Mandatory Influenza Vaccination Campaign Using an Innovative Electronic Tracking System SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID HEALTH-CARE WORKERS; RANDOMIZED CONTROLLED-TRIAL; LONG-TERM-CARE; ELDERLY-PEOPLE; NURSING-HOMES; MORTALITY; RATES; HOSPITALS; PROGRAM; INFECTIONS AB BACKGROUND. Although influenza vaccination of healthcare workers reduces influenza-like illness and overall mortality among patients, national rates of vaccination for healthcare providers are unacceptably low. We report the implementation of a new mandatory vaccination policy by means of a streamlined electronic enrollment and vaccination tracking system at the National Institutes of Health (NIH) Clinical Center. OBJECTIVE. To evaluate the outcome of a new mandatory staff influenza vaccination program. METHODS. A new hospital policy endorsed by all the component NIH institutes and the Clinical Center departments mandated that employees who have patient contact either be vaccinated annually against influenza or sign a declination specifying the reason(s) for refusal. Those who fail to comply would be required to appear before the Medical Executive Committee to explain their rationale. We collected in a database the names of all physician and nonphysician staff who had patient contact. When a staff member either was vaccinated or declined vaccination, a simple system of badge scanning and bar-coded data entry captured essential data. The database was continuously updated, and it provided a list of noncompliant employees with whom to follow up. RESULTS. By February 12, 2009, all 2,754 identified patient-care employees either were vaccinated or formally declined vaccination. Among those, 2,424 (88%) were vaccinated either at the NIH or elsewhere, 36 (1.3%) reported medical contraindications, and 294 (10.7%) declined vaccination for other reasons. Among the 294 employees without medical contraindications who declined, the most frequent reason given for declination was concern about side effects. CONCLUSIONS. Implementation of a novel vaccination tracking process and a hospital policy requiring influenza vaccination or declination yielded dramatic improvement in healthcare worker vaccination rates and likely will result in increased patient safety in our hospital. C1 [Palmore, Tara N.; Michelin, Angela; Ruprecht, Lisa M.; Henderson, David K.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Morris, Joan; Schmitt, James M.] NIH, Occupat Med Serv, Div Occupat Hlth & Safety, Bethesda, MD 20892 USA. [Vandersluis, J. Patrick] HealthRx, Fairfax, VA USA. RP Henderson, DK (reprint author), NIH, Ctr Clin, 10 Ctr Dr,MSC 1504, Bethesda, MD 20892 USA. EM dkh@nih.gov FU National Institutes of Health Clinical Center and National Institutes of Health Office of Research Services' Division of Occupational Health and Safety FX Financial support. National Institutes of Health Clinical Center and National Institutes of Health Office of Research Services' Division of Occupational Health and Safety. NR 29 TC 35 Z9 36 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD DEC PY 2009 VL 30 IS 12 BP 1137 EP 1142 DI 10.1086/648084 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 515CL UT WOS:000271444100002 PM 19860562 ER PT J AU Glocker, E Kotlarz, D Boztug, K Gertz, E Schaffer, A Koletzko, S Shah, N Segal, A Snapper, S Grimbacher, B Klein, C AF Glocker, E. Kotlarz, D. Boztug, K. Gertz, E. Schaffer, A. Koletzko, S. Shah, N. Segal, A. Snapper, S. Grimbacher, B. Klein, C. TI Early-onset inflammatory bowel disease caused by loss-of-function mutations in the IL10-receptor genes SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract CT Conference on Advances in Inflammatory Bowel Diseases Crohns and Research Conference CY DEC 03-06, 2009 CL Hollywood, FL SP Crohns & Coitis Fdn Natl Clin & Res C1 [Glocker, E.; Grimbacher, B.] Royal Free Hosp, Dept Immunol, London NW3 2QG, England. [Kotlarz, D.; Boztug, K.] Hannover Med Sch, Dept Pediat Hematol Oncol, D-3000 Hannover, Germany. [Gertz, E.; Schaffer, A.] NIH, Natl Ctr Biotechnol Informat, DHHS, Bethesda, MD USA. [Koletzko, S.] Univ Munich, Dr von Haunersches Kinderspital, D-80337 Munich, Germany. [Shah, N.] UCL, Dept Paediat Gastroenterol, Great Ormond St Hosp, London, England. [Segal, A.] UCL, Dept Med, London, England. [Snapper, S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD DEC PY 2009 VL 15 IS 12 SU S BP S56 EP S56 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 530DK UT WOS:000272569000178 ER PT J AU Sohn, J Yfantis, H Hussain, S Khan, M Goto, A Bowman, E Hofseth, L Wogan, G Harris, C AF Sohn, J. Yfantis, H. Hussain, S. Khan, M. Goto, A. Bowman, E. Hofseth, L. Wogan, G. Harris, C. TI Accelerated DNA Damage Response in Inflammatory Bowel Disease: A molecular basis for Cellular Senescence and Cancer Susceptibility SO INFLAMMATORY BOWEL DISEASES LA English DT Meeting Abstract CT Conference on Advances in Inflammatory Bowel Diseases Crohns and Research Conference CY DEC 03-06, 2009 CL Hollywood, FL SP Crohns & Coitis Fdn Natl Clin & Res C1 [Sohn, J.; Hussain, S.; Khan, M.; Goto, A.; Bowman, E.; Harris, C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Yfantis, H.] Univ Maryland, Sch Med, Pathol & Lab Med, Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Yfantis, H.] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Hofseth, L.] S Carolina Coll Pharm, Dept Pharmaceut & Biomed Sci, Columbia, SC USA. [Wogan, G.] MIT, Dept Biol Engn, Ctr Environm Hlth Sci, Cambridge, MA 02139 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD DEC PY 2009 VL 15 IS 12 SU S BP S29 EP S29 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 530DK UT WOS:000272569000083 ER PT J AU Hansen, D Johnson, M Norton, E McDonough, A AF Hansen, Derek Johnson, Margeaux Norton, Elizabeth McDonough, Anne TI Virtual provider pessimism: analysing instant messaging reference encounters with the pair perception comparison method SO INFORMATION RESEARCH-AN INTERNATIONAL ELECTRONIC JOURNAL LA English DT Article AB Introduction. We examine the differences between user and provider perceptions of the same instant messaging reference encounter. We summarize previoius studies of face-to-face reference encounters, identifying a common phenomenon we call provider pessimism - when users of a service are more satisfied than providers think they will be. We then look for this phenomenon in an instant messaging reference setting. Method. The pair perception comparison method is introduced to systematically compare user and provider perceptions of the same encounter. We implement the method by administering separate satisfaction surveys to undergraduate users and Master's of Library Science student providers immediately after a shared instant messaging reference encounter. Analysis. A total of twenty-six matched surveys were compared using paired sample statistics to identify significant discrepancies. Results. We find evidence of provider pessimism for overall satisfaction, the tempo of the interaction, ease of use of the system, friendliness of the provider, accuracy of the references, provider follow-up and spelling and grammar used by the provider. Conclusion. Our findings suggest that new virtual reference providers should have increased confidence in their abilities and not be overly concerned with potentially stressful features of instant messaging such as typing quickly or misspelling words. Future use of the pair perception comparison method can more systematically identify discrepancies in user and provider perceptions. C1 [Hansen, Derek] Univ Maryland, Coll Informat Studies, Ctr Adv Study Communities & Informat, iSch, College Pk, MD 20742 USA. [Johnson, Margeaux] Univ Florida, Marston Sci Lib, Gainesville, FL 32611 USA. [Norton, Elizabeth] Natl Lib Med, Div Specialized Informat Serv, Bethesda, MD 20894 USA. [McDonough, Anne] Univ Maryland, Univ Publicat, College Pk, MD 20742 USA. RP Hansen, D (reprint author), Univ Maryland, Coll Informat Studies, Ctr Adv Study Communities & Informat, iSch, College Pk, MD 20742 USA. EM shakmatt@gmail.com; margeaux@ufl.edu; nortonef@gmail.com; anne.mcdonough@gmail.com NR 18 TC 1 Z9 1 U1 1 U2 1 PU UNIV SHEFFIELD DEPT INFORMATION STUDIES PI SHEFFIELD PA UNIV SHEFFIELD, WESTERN BANK, SHEFFIELD S10 2TN, S YORKS, ENGLAND SN 1368-1613 J9 INFORM RES JI Inf. Res. PD DEC PY 2009 VL 14 IS 4 AR 416 PG 20 WC Information Science & Library Science SC Information Science & Library Science GA 551FZ UT WOS:000274193700004 ER PT J AU Hu, ZJ Bai, L Tizabi, Y Southerland, W AF Hu, Zeng-Jian Bai, Li Tizabi, Yousef Southerland, William TI Computational Modeling Study of Human Nicotinic Acetylcholine Receptor for Developing New Drugs in the Treatment of Alcoholism SO INTERDISCIPLINARY SCIENCES-COMPUTATIONAL LIFE SCIENCES LA English DT Article DE homology modeling; nicotinic acetylcholine receptor; molecular modeling; docking; ligand-binding interface; alcoholism AB Alcohol abuse and alcoholism are serious and costly problem in USA. Thus, the development of anti-alcoholism agents could be very significant. The understanding of the neurochemical basis underlying the addictive properties of drugs of abuse is imperative for the development of new pharmacological means to reverse the addictive state, prevent relapse or to reduce the intake of addictive compounds. The nicotinic acetylcholine receptors (nAChRs) are important therapeutic targets for various diseases. Recent studies have revealed that the alpha 3 beta 2, alpha 3 beta 3, and alpha 6 subunits of nAChR protein family might be pharmacological targets for developing new drugs in the treatment of alcoholism. We have performed computational homology modeling of the alpha 3 beta 2, alpha 3 beta 3, and alpha 6 subunits of human nACHRs based upon the recently determined crystal structure of the extracellular domain (ECD) of the mouse nAChR alpha 1 subunit complexed with alpha-bungarotoxin at 1.94 angstrom resolution. For comparison, we also built the ECD models of alpha 4 beta 2, and alpha 7 subunits of human nACHRs which are neurochemical targets for cessation of smoking. The three-dimensional (3D) models of the ECD of the monomer, and pentamer of these human nAChR were constructed. The docking of the agonist in the ligand-binding pocket of the human nAChR dimers was also performed. Since the nAChR ligand-binding site is a useful target for mutagenesis studies and the rational design of drugs against various diseases, these models provide useful information for future investigation. C1 [Hu, Zeng-Jian; Southerland, William] Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC 20059 USA. [Bai, Li] NINDS, Bethesda, MD 20892 USA. [Tizabi, Yousef] Howard Univ, Coll Med, Dept Pharmacol, Washington, DC 20059 USA. RP Hu, ZJ (reprint author), Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC 20059 USA. EM huzengjian@yahoo.com FU RCMI-NIH [2G12RR03048] FX This work is supported by grant RCMI-NIH 2G12RR03048. NR 52 TC 10 Z9 10 U1 1 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1913-2751 J9 INTERDISCIP SCI JI Interdiscip. Sci. PD DEC PY 2009 VL 1 IS 4 BP 254 EP 262 DI 10.1007/s12539-009-0052-7 PG 9 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA V28VS UT WOS:000208708900002 PM 20640803 ER PT J AU Cook, MB Sigurdson, AJ Jones, IM Thomas, CB Graubard, BI Korde, L Greene, MH McGlynn, KA AF Cook, M. B. Sigurdson, A. J. Jones, I. M. Thomas, C. B. Graubard, B. I. Korde, L. Greene, M. H. McGlynn, K. A. TI Endogenous DNA damage and testicular germ cell tumors SO INTERNATIONAL JOURNAL OF ANDROLOGY LA English DT Article DE comet assay; DNA damage; non-seminoma; seminoma; testicular neoplasms ID RISK-FACTORS; COMET ASSAY; CANCER-PATIENTS; BREAST-CANCER; UNITED-STATES; PERIPHERAL LYMPHOCYTES; GENETIC INSTABILITY; EUROPEAN COUNTRIES; TESTIS CANCER; 2ND CANCERS AB P>Testicular germ cell tumors are comprised of two histologic groups, seminomas and non-seminomas. We postulated that the possible divergent pathogeneses of these histologies may be partially explained by variable levels of net endogenous DNA damage. To test our hypothesis, we conducted a case-case analysis of 51 seminoma and 61 non-seminoma patients using data and specimens from the Familial Testicular Cancer study and the U.S. Radiologic Technologists cohort. A lymphoblastoid cell line was cultured for each patient and the alkaline comet assay was used to determine four parameters: tail DNA, tail length, comet distributed moment (CDM) and Olive tail moment (OTM). Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. Values for tail length, tail DNA, CDM and OTM were modelled as categorical variables using the 50th and 75th percentiles of the seminoma group. Tail DNA was significantly associated with non-seminoma compared with seminoma (OR(50th percentile) = 3.31, 95% CI: 1.00, 10.98; OR(75th percentile) = 3.71, 95% CI: 1.04, 13.20; p for trend = 0.039). OTM exhibited similar, albeit statistically non-significant, risk estimates (OR(50th percentile) = 2.27, 95% CI: 0.75, 6.87; OR(75th percentile) = 2.40, 95% CI: 0.75, 7.71; p for trend = 0.12) whereas tail length and CDM showed no association. In conclusion, the results for tail DNA and OTM indicate that net endogenous levels are higher in patients who develop non-seminoma compared with seminoma. This may partly explain the more aggressive biology and younger age-of-onset of this histologic subgroup compared with the relatively less aggressive, later-onset seminoma. C1 [Cook, M. B.; McGlynn, K. A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Sigurdson, A. J.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Jones, I. M.; Thomas, C. B.] Lawrence Livermore Natl Lab, Livermore, CA USA. [Graubard, B. I.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Korde, L.; Greene, M. H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Cook, MB (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, EPS 5003,6120 Execut Blvd, Bethesda, MD 20892 USA. EM cookmich@mail.nih.gov RI Cook, Michael/A-5641-2009 OI Cook, Michael/0000-0002-0533-7302 FU U.S. Department of Energy, National Nuclear Security Administration [DE-AC52-07NA27344] FX The authors wish to thank Diane Kampa from the University of Minnesota for subject recruitment and Laura Bowen of IMS for data management. The work was in part conducted under the auspices of the Lawrence Livermore National Laboratory, operated by Lawrence Livermore National Security, LLC, for the U.S. Department of Energy, National Nuclear Security Administration under Contract DE-AC52-07NA27344. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. NR 59 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-6263 J9 INT J ANDROL JI Int. J. Androl. PD DEC PY 2009 VL 32 IS 6 BP 599 EP 606 DI 10.1111/j.1365-2605.2008.00905.x PG 8 WC Andrology SC Endocrinology & Metabolism GA 516DI UT WOS:000271521500002 PM 18657195 ER PT J AU Arbyn, M Ronco, G Cuzick, J Wentzensen, N Castle, PE AF Arbyn, Marc Ronco, Guglielmo Cuzick, Jack Wentzensen, Nicolas Castle, Philip E. TI How to evaluate emerging technologies in cervical cancer screening? SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE cervical cancer screening; human papillomavirus; HPV; biomarker; diagnostic test accuracy; guidelines; health technology assessment ID RANDOMIZED CONTROLLED-TRIAL; ATYPICAL SQUAMOUS-CELLS; HUMAN-PAPILLOMAVIRUS; INTRAEPITHELIAL NEOPLASIA; NATURAL-HISTORY; INTEROBSERVER AGREEMENT; CONVENTIONAL CYTOLOGY; DIAGNOSTIC-ACCURACY; MESSENGER-RNA; LESION TRIAGE AB Excellent recommendations exist for studying therapeutic and diagnostic questions. We observe that good guidelines on assessment of evidence for screening questions are currently lacking. Guidelines for diagnostic research (STARD), involving systematic application of the reference test (gold standard) to all subjects of large study populations, are not pertinent in situations of screening for disease that is currently not yet present. A five-step framework is proposed for assessing the potential use of a biomarker as a screening tool for cervical cancer: i) correlation studies establishing a trend between the rate of biomarker expression and severity of neoplasia; ii) diagnostic studies in a clinical setting where all women are submitted to verification by the reference standard; iii) biobank-based studies with assessment in archived cytology samples of the biomarker in cervical cancer cases and controls; iv) prospective cohort studies with baseline assessment of the biomarker and monitoring of disease; v) randomised intervention trials aiming to observe reduced incidence of cancer (or its surrogate, severe dysplasia) in the experimental arm at subsequent screening rounds. The 5-phases framework should guide researchers and test developers in planning assessment of new biomarkers and protect clinicians and stakeholders against premature claims for insufficiently evaluated products. (c) 2009 UICC C1 [Arbyn, Marc] Sci Inst Publ Hlth, Canc Epidemiol Unit, Belgian Canc Ctr, B-1050 Brussels, Belgium. [Arbyn, Marc] IARC, European Cooperat Dev & Implementat Canc Screenin, Lyon, France. [Ronco, Guglielmo] Ctr Prevenz Oncol, Canc Epidemiol Unit, Utrecht, Netherlands. [Cuzick, Jack] Univ London, Wolfson Inst Prevent Med & Canc Res, Dept Math & Stat, Canc Res UK Ctr Epidemiol, London, England. [Wentzensen, Nicolas; Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. RP Arbyn, M (reprint author), Sci Inst Publ Hlth, Canc Epidemiol Unit, Belgian Canc Ctr, J Wytsmanst 14, B-1050 Brussels, Belgium. EM marc.arbyn@iph.fgov.be FU The Belgian Foundation Against Cancer, Brussels, Belgium; The Gynaecological Cancer Cochrane Review Collaboration (Bath, United Kingdom); European Commission; Directorate of SANCO (Luxembourg, Grand-Duchy of Luxembourg); 7th Framework programme of DG Research (Brussels, Belgium); IWT; University of Antwerp [060081] FX Grant sponsors: The Belgian Foundation Against Cancer, Brussels, Belgium; The Gynaecological Cancer Cochrane Review Collaboration (Bath, United Kingdom); The European Commission through the ECCG (European Cooperation on development and implementation of Cancer screening and prevention Guidelines, via IARC, Lyon. France), funded by Directorate of SANCO (Luxembourg, Grand-Duchy of Luxembourg) and through the EUROCOURSE Network (Europe against Cancer: Optimisation of the Use of Registries for Scientific Excellence in research, via the Comprehensive Cancer Centre South (Eindhoven, The Netherlands) funded by the 7th Framework programme of DG Research (Brussels, Belgium): IWT (Institute for the Promotion of Innovation by Science and Technology in Flanders (through the Unit of Health Economics and Modelling Infectious Diseases, Vaccine & Infectious Disease Institute, University of Antwerp; project number 060081). NR 80 TC 58 Z9 60 U1 1 U2 11 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 1 PY 2009 VL 125 IS 11 BP 2489 EP 2496 DI 10.1002/ijc.24774 PG 8 WC Oncology SC Oncology GA 516BK UT WOS:000271516500001 PM 19626591 ER PT J AU Zuna, RE Moore, WE Shanesmith, RP Dunn, ST Wang, SS Schiffman, M Blakey, GL Teel, T AF Zuna, Rosemary E. Moore, William E. Shanesmith, Rebecca P. Dunn, S. Terence Wang, Sophia S. Schiffman, Mark Blakey, Gregory L. Teel, Travis TI Association of HPV16 E6 variants with diagnostic severity in cervical cytology samples of 354 women in a US population SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE human papillomavirus; cervical carcinogenesis; cervical intraepithelial lesions; HPV variants; cervical neoplasia ID HUMAN-PAPILLOMAVIRUS TYPE-16; MOLECULAR VARIANTS; INTRAEPITHELIAL NEOPLASIA; WORLDWIDE PERSPECTIVE; DISEASE PROGRESSION; NUCLEOTIDE-SEQUENCE; GENE VARIATIONS; CANCER; RISK; CARCINOMA AB It has been suggested that DNA sequence variants of HPV16 contribute to differences in the behavior of individual cervical lesions. To address this question, we have analyzed the association of HPV16 variants with diagnostic severity in 354 HPV16-positive Oklahoman women. HPV16 variant status was determined by PCR amplification and DNA sequencing of the E6 open reading frame. European sequences were identified in 86% of samples and 14% were non-European. Of the 51 non-European cases, 61% were Asian-American, 23% African and 16% were Native American variants. European prototype and related variants were present in comparable numbers (43% each) but the relative proportion of each differed with diagnostic category. In general, the proportion of European variants and non-European variants increased with diagnostic severity while the European prototype decreased. When adjusted for age and race (white, black or Hispanic), the increased risk for carcinoma/severe dysplasia for non-European variants was statistically significant with an odds ratio of 3.8 (1.3-10.7). However, the analogous comparison for the European variants, although also showing increased association with carcinoma/severe dysplasia, did not reach statistical significance (OR = 1.6 (95% CI 0.7-3.6). Overall, HPV16 European sequences (both prototype and related variants), were predominant in Oklahoman women including those with cancers. This suggests that while there appear to be differences among the HPV16-variant categories in risk for progression to invasive cancer, all variant categories are associated with the development of invasive cancer. (c) 2009 UICC C1 [Zuna, Rosemary E.; Shanesmith, Rebecca P.; Dunn, S. Terence; Blakey, Gregory L.; Teel, Travis] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73104 USA. [Moore, William E.] Univ Oklahoma, Hlth Sci Ctr, OU Prevent Res Ctr, Oklahoma City, OK 73104 USA. [Wang, Sophia S.; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Zuna, RE (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, BMSB 451,940 SL Young Blvd, Oklahoma City, OK 73104 USA. EM rosemary-zuna@oushc.edu FU Oklahoma Center for the Advancement of Science and Technology [OCAST HR05-136]; National Cancer Institute [R03-CA 117523, N02-CP-31102]; Intramural Research Program of the National Institutes of Health FX Grant sponsor: Oklahoma Center for the Advancement of Science and Technology; Grant number: OCAST HR05-136; Grant sponsor: National Cancer Institute; Grant number: R03-CA 117523; Grant sponsor: National Cancer Institute; Grant number: N02-CP-31102; Grant sponsor: Intramural Research Program of the National Institutes of Health. NR 41 TC 43 Z9 44 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 1 PY 2009 VL 125 IS 11 BP 2609 EP 2613 DI 10.1002/ijc.24706 PG 5 WC Oncology SC Oncology GA 516BK UT WOS:000271516500015 PM 19569178 ER PT J AU Hoyo, C Schildkraut, JM Murphy, SK Chow, WH Vaughan, TL Risch, H Marks, JR Jirtle, RL Calingeart, B Mayne, S Fraumeni, J Gammon, MD AF Hoyo, Cathrine Schildkraut, Joellen M. Murphy, Susan K. Chow, Wong-Ho Vaughan, Thomas L. Risch, Harvey Marks, Jeffrey R. Jirtle, Randy L. Calingeart, Brian Mayne, Susan Fraumeni, Joseph, Jr. Gammon, Marilie D. TI IGF2R polymorphisms and risk of esophageal and gastric adenocarcinomas SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE genetic association; neoplasm; esophagus; gastric-cardia; gastric; insulin-like growth factors ID RECEPTOR M6P/IGF2R; UNITED-STATES; BIRTH-WEIGHT; GROWTH; CARDIA; INSULIN-LIKE-GROWTH-FACTOR-2; ACTIVATION; CARCINOMA; VARIANTS; BINDING AB The mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes a protein that plays a critical role in tumor suppression, in part by modulating bioavailability of a potent mitogen, insulin-like growth factor-2 (IGF2). We tested the hypothesis that the common nonsynonymous genetic variants in M6P/IGF2R c.901C > G (Leu > Val) in exon 6 and c.5002G > A (Gly > Arg) in exon 34 are associated with risk of esophageal and gastric cancers. Study participants in this population-based study comprise 197 controls and 182 cases, including 105 with esophageal-gastric cardia adenocarcinoma (EGA), 57 with noncardia gastric adenocarcinoma and 20 with esophageal squamous (ES) cell carcinoma. Among white males, odds ratios (ORs) were elevated in relation to carrying at least 1 c.901C > G allele for EGA [OR = 1.9; 95% confidence intervals (CIs) = 1.0-3.6] and noncardia gastric cancer (OR = 2.5; 95% CI = 1.2-5.5), but not ES. Exploratory subgroup analyses suggested that associations between EGA and this variant were stronger among irregular or nonusers of nonsteroidal anti-inflammatory drugs (NSAIDs) (OR = 2.3; 95% CI = 1.2-4.2) and cigarette smokers (OR = 2.1; 95% CI = 1.0-4.2). An association between carrying the c.5002G > A genotype and EGA was not evident. These findings suggest that nonsynonymous polymorphisms in M6P/IGF2R may contribute to the risks of EGA and noncardia adenocarcinomas. Larger studies are required to confirm these findings. (c) 2009 UICC C1 [Hoyo, Cathrine] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Hoyo, Cathrine; Schildkraut, Joellen M.; Calingeart, Brian] Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Canc Prevent Detect & Control Program, Durham, NC 27710 USA. [Murphy, Susan K.] Duke Univ, Div Gynecol Oncol, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Chow, Wong-Ho; Fraumeni, Joseph, Jr.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Vaughan, Thomas L.] Univ Washington, Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98195 USA. [Vaughan, Thomas L.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [Risch, Harvey; Mayne, Susan] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Risch, Harvey; Mayne, Susan] Yale Canc Ctr, New Haven, CT USA. [Marks, Jeffrey R.] Duke Univ, Dept Expt Surg, Durham, NC 27710 USA. [Jirtle, Randy L.] Duke Univ, Dept Radiat Oncol, Durham, NC 27710 USA. [Gammon, Marilie D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. RP Hoyo, C (reprint author), Duke Univ, Med Ctr, Dept Community & Family Med, Hanes House Room 347,Trent Dr,Box 2914, Durham, NC 27710 USA. EM hoyo0001@mc.duke.edu OI Murphy, Susan/0000-0001-8298-7272 FU National Cancer Institute, NIH [K01 CA1 04517]; O'Keefe Foundation FX Grant sponsor: National Cancer Institute, NIH; Grant number: K01 CA1 04517; Grant sponsor: O'Keefe Foundation. NR 23 TC 13 Z9 13 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 1 PY 2009 VL 125 IS 11 BP 2673 EP 2678 DI 10.1002/ijc.24623 PG 6 WC Oncology SC Oncology GA 516BK UT WOS:000271516500023 PM 19626700 ER PT J AU Udler, MS Azzato, EM Healey, CS Ahmed, S Pooley, KA Greenberg, D Shah, M Teschendorff, AE Caldas, C Dunning, AM Ostrander, EA Caporaso, NE Easton, D Pharoah, PD AF Udler, Miriam S. Azzato, Elizabeth M. Healey, Catherine S. Ahmed, Shahana Pooley, Karen A. Greenberg, David Shah, Mitul Teschendorff, Andrew E. Caldas, Carlos Dunning, Alison M. Ostrander, Elaine A. Caporaso, Neil E. Easton, Douglas Pharoah, Paul D. TI Common germline polymorphisms in COMT, CYP19A1, ESR1, PGR, SULT1E1 and STS and survival after a diagnosis of breast cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast cancer; survival; polymorphism; genetic epidemiology ID CATECHOL-O-METHYLTRANSFERASE; GENETIC POLYMORPHISMS; EXPRESSION SIGNATURE; POSTMENOPAUSAL WOMEN; RISK; ASSOCIATION; CARCINOGENESIS; PROGESTERONE; ENDOMETRIAL; METABOLISM AB Although preliminary evidence suggests that germline variation in genes involved in steroid hormone metabolism may alter breast cancer prognosis, this has not been systematically evaluated. We examined associations between germline polymorphisms in 6 genes involved in the steroid hormone metabolism and signaling pathway (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival among women with breast cancer participating in SEARCH, a population-based case-control study. Blood samples from up to 4,470 women were genotyped for 4 possible functional SNPs in CYP19A1 and 106 SNPs tagging the common variation in the remainder of the genes. The genotypes of each polymorphism were tested for association with survival after breast cancer diagnosis using Cox regression analysis. Significant evidence of an association was observed for a COMT polymorphism (rs4818 p = 0.016) under the codominant model. This SNP appeared to fit a dominant model better (HR = 0.80 95% CI: 0.69-0.95, p = 0.009); however, the result was only marginally significant after permutation analysis adjustment for multiple hypothesis tests (p = 0.047). To further evaluate this finding, somatic expression microarray data from 8 publicly available datasets were used to test the association between survival and tumor COMT gene expression; no statistically significant associations were observed. A correlated SNP in COMT, rs4860, has recently been associated with breast cancer prognosis in Chinese women in a dominant model. These results suggest that COMT rs4818, or a variant it tags, is associated with breast cancer prognosis. Further study of COMT and its putative association with breast cancer prognosis is warranted. (c) 2009 UICC C1 [Udler, Miriam S.; Azzato, Elizabeth M.; Healey, Catherine S.; Ahmed, Shahana; Pooley, Karen A.; Shah, Mitul; Dunning, Alison M.; Easton, Douglas; Pharoah, Paul D.] Univ Cambridge, Dept Publ Hlth & Primary Care & Oncol, Strangeways Res Lab, Cambridge CB1 8RN, England. [Udler, Miriam S.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Azzato, Elizabeth M.; Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Greenberg, David] Eastern Canc Registrat & Informat Ctr, Unit C Magog Court, Cambridge CB22 3AD, England. [Teschendorff, Andrew E.; Caldas, Carlos] Univ Cambridge, Li Ka Shing Ctr, Canc Res UK, Cambridge Res Inst, Cambridge CB2 0RE, England. [Teschendorff, Andrew E.; Caldas, Carlos] Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge CB2 0RE, England. [Teschendorff, Andrew E.] UCL, Inst Canc, Med Genom Grp, London WC1E 6BT, England. RP Pharoah, PD (reprint author), Strangeways Res Labs, Worts Causeway, Cambridge CB1 8RN, England. EM paul.pharoah@srl.cam.ac.uk RI Caldas, Carlos/A-7543-2008; OI Dunning, Alison Margaret/0000-0001-6651-7166; Ostrander, Elaine/0000-0001-6075-9738 FU Cancer Research UK; Intramural Research Program of the NIH; NCI; DCEG NIH-Cambridge Graduate Partnership Program; NHGRI FX Grant sponsors: Cancer Research UK; Intramural Research Program of the NIH, NCI, DCEG NIH-Cambridge Graduate Partnership Program; Intramural Research Program of the NHGRI. NR 38 TC 26 Z9 27 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 1 PY 2009 VL 125 IS 11 BP 2687 EP 2696 DI 10.1002/ijc.24678 PG 10 WC Oncology SC Oncology GA 516BK UT WOS:000271516500025 PM 19551860 ER PT J AU Lai, H Redheuil, A Tong, WJ Bluemke, DA Lima, JAC Ren, SQ Lai, SH AF Lai, Hong Redheuil, Alban Tong, Wenjing Bluemke, David A. Lima, Joao A. C. Ren, Shiquan Lai, Shenghan TI HIV infection and abnormal regional ventricular function SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE HIV infection; Regional left ventricular dysfunction; Tagging MRI; Myocardium strain; Random-effects model ID CARDIOVASCULAR-DISEASE; MYOCARDIAL-FUNCTION; ANTIRETROVIRAL THERAPY; HARP MRI; HEART; ATHEROSCLEROSIS; ASSOCIATION; POPULATION; IMAGES; MOTION AB To examine the effect of HIV infection on regional left ventricular dysfunction in cardiovascularly asymptomatic individuals. Nineteen HIV-negative and 27 HIV-positive cardiovascularly asymptomatic study participants in Baltimore, Maryland were selected and underwent tagged cardiac magnetic resonance imaging. Regional left ventricular myocardial mid-wall peak systolic circumferential strain (Ecc) and early diastolic strain rate (SRE) of the left ventricle were assessed with the use of the harmonic phase analysis. The average Ecc and SRE measurements were compared between HIV-negative and HIV-positive individuals. Compared with the HIV-negatives, the HIV-positives had lower average Ecc and SRE measurements in 90% of the 16 standard left ventricular segments. Of the 14 segments with decreased Ecc strain, 3 were statistically significant and of 14 with decreased strain rate (SRE), 6 were statistically significant. HIV infection may be associated with subclinical regional left ventricular systolic and diastolic dysfunction in individuals free of overt cardiovascular disease. C1 [Tong, Wenjing; Ren, Shiquan; Lai, Shenghan] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Lai, Hong; Bluemke, David A.; Lima, Joao A. C.; Lai, Shenghan] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21287 USA. [Redheuil, Alban; Lima, Joao A. C.; Lai, Shenghan] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & BioEngn, Bethesda, MD 20892 USA. RP Lai, SH (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, 600 N Wolfe St,Pathol 301, Baltimore, MD 21287 USA. EM slai@jhmi.edu RI Ren, Shiquan/B-4640-2009; OI Bluemke, David/0000-0002-8323-8086 FU National Institute on Drug Abuse, National Institutes of Health [NIH R01-DA 12777, DA15020] FX We thank the study participants for their contributions. The study was supported by grants from the National Institute on Drug Abuse, National Institutes of Health (NIH R01-DA 12777 and DA15020). NR 27 TC 9 Z9 11 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD DEC PY 2009 VL 25 IS 8 BP 809 EP 817 DI 10.1007/s10554-009-9493-7 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 524XW UT WOS:000272178700010 PM 19763877 ER PT J AU Liu, ST Bluemke, DA AF Liu, Songtao Bluemke, David A. TI Can a simple fingertip temperature measurement predict a cardiac event? SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Editorial Material ID ENDOTHELIAL FUNCTION; REACTIVE HYPEREMIA; EUROPEAN-SOCIETY; WORKING GROUP; DYSFUNCTION; HYPERTENSION; STATEMENT; RISK C1 [Liu, Songtao; Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. RP Bluemke, DA (reprint author), NIH, Ctr Clin, 9000 Rockville Pike,Bldg 10 Rm 1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU Intramural NIH HHS [ZIA EB000065-01] NR 9 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD DEC PY 2009 VL 25 IS 8 BP 867 EP 868 DI 10.1007/s10554-009-9524-4 PG 2 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 524XW UT WOS:000272178700017 PM 19911305 ER PT J AU Cook, MB Akre, O Forman, D Madigan, MP Richiardi, L McGlynn, KA AF Cook, Michael B. Akre, Olof Forman, David Madigan, M. Patricia Richiardi, Lorenzo McGlynn, Katherine A. TI A systematic review and meta-analysis of perinatal variables in relation to the risk of testicular cancer-experiences of the mother SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Review DE Epidemiology; meta-analysis; pregnancy; review; systematic; testicular neoplasms ID GERM-CELL TUMORS; MATERNAL AGE; BIRTH-ORDER; CARCINOMA-INSITU; TESTIS CANCER; UNITED-STATES; SIBSHIP SIZE; MALES BORN; PREGNANCY; POPULATION AB Methods EMBASE, PubMed, Scopus and Web of Science databases were searched using sensitive search strategies. Meta-analysis was undertaken using STATA 10. Results A total of 5865 references were retrieved, of which 67 met the inclusion criteria and contributed data to at least one perinatal analysis. Random effects meta-analysis found maternal bleeding during pregnancy [odds ratio (OR) 1.33, 95% confidence interval (CI) 1.02-1.73], birth order (primiparous vs not, 1.08, 95% CI 1.01-1.16; second vs first, OR 0.94, 95% CI 0.88-0.99; third vs first, OR 0.91, 95% CI 0.83-1.01; fourth vs first, OR 0.80, 95% CI 0.69-0.94) and sibship size (2 vs 1, OR 0.93, 95% CI 0.75-1.15; 3 vs 1, OR 0.89, 95% CI 0.74-1.07; 4 vs 1, OR 0.75, 95% CI 0.62-0.90) to be associated with testicular cancer risk. Meta-analyses that produced summary estimates which indicated no association included maternal age, maternal nausea, maternal hypertension, pre-eclampsia, breech delivery and caesarean section. Meta-regression provided evidence that continent of study is important in the relationship between caesarean section and testicular cancer (P = 0.035), and a meta-analysis restricted to the three studies from the USA was suggestive of association (OR 1.67, 95% CI 1.07-2.56). Conclusions This systematic review and meta-analysis has found evidence for associations of maternal bleeding, birth order, sibship size and possibly caesarean section with risk of testicular cancer. C1 [Cook, Michael B.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. [Akre, Olof] Karolinska Sjukhuset, Karolinska Inst, Stockholm, Sweden. [Forman, David] Univ Leeds, Canc Epidemiol Grp, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England. [Richiardi, Lorenzo] Univ Turin, Dept Biomed Sci & Human Oncol, Canc Epidemiol Unit, I-10124 Turin, Italy. RP Cook, MB (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS Suite 550,Room 5012, Rockville, MD 20852 USA. EM michael.cook@nih.gov RI Cook, Michael/A-5641-2009; OI Cook, Michael/0000-0002-0533-7302; richiardi, lorenzo/0000-0003-0316-9402 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 66 TC 33 Z9 34 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD DEC PY 2009 VL 38 IS 6 BP 1532 EP 1542 DI 10.1093/ije/dyp287 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 528RP UT WOS:000272464700015 PM 19776243 ER PT J AU Cole, SR Chu, HT Nie, L Schisterman, EF AF Cole, Stephen R. Chu, Haitao Nie, Lei Schisterman, Enrique F. TI Estimating the odds ratio when exposure has a limit of detection SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Biomarkers; epidemiologic methods; limit of detection; statistical method ID ANTIRETROVIRAL THERAPY; VIRAL LOAD; REGRESSION; MODELS; INFERENCE; MARKERS; ZERO; MASS AB Methods We calculate the odds of anti-HIV therapy naivete in 45 HIV-infected men as a function of measured log(10) plasma HIV RNA viral load using five approaches including ad hoc methods as well as a maximum likelihood estimate (MLE). We also generated simulations of a binary outcome with 10% incidence and a 1.5-fold increased odds per log increase in a log-normally distributed exposure with 25, 50 and 75% of exposure data below LOD. Simulated data were analysed using the same five methods, as well as the full data. Results In the example, the estimated odds ratio (OR) varied by 1.22-fold across methods, from 1.45 to 1.77 per log(10) copies of viral load and the standard error for the log OR varied by 1.52-fold across methods, from 0.31 to 0.47. In the simulations, use of full data or the MLE was unbiased with appropriate confidence interval (CI) coverage. However, as the proportion of exposure below LOD increased, substituting LOD, LOD/root 2 or LOD/2 was increasingly biased with increasingly inappropriate CI coverage. Finally, exclusion of values below LOD was unbiased but imprecise. Conclusions In this example and the settings explored by simulation, and among methods readily available to investigators (i.e. sans full data), the MLE provided an unbiased and appropriately precise estimate of the exposure-outcome OR. C1 [Cole, Stephen R.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Cole, Stephen R.] Univ N Carolina, Ctr AIDS Res, Chapel Hill, NC USA. [Chu, Haitao] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Chu, Haitao] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Nie, Lei] Fed Drug Adm, DB4 OB OTS CDER, Silver Spring, MD USA. [Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Bethesda, MD USA. RP Cole, SR (reprint author), McGavran Greenberg Hall,Campus Box 7435, Chapel Hill, NC 27599 USA. EM cole@unc.edu RI Chu, Haitao /J-7576-2012; OI Chu, Haitao/0000-0003-0932-598X; Schisterman, Enrique/0000-0003-3757-641X FU American Chemical Council; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH [R03-AI-071763, R01-AA-017594, P30-AI-50410]; National Cancer Institute [CA16086]; American Chemistry Council FX American Chemical Council and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH grants R03-AI-071763, R01-AA-017594 and P30-AI-50410 (to S. R. C.); Lineberger Cancer Center Core Grant CA16086 from the National Cancer Institute and P30-AI-50410 from the National Institutes of Health (to H. C.); Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health and the American Chemistry Council (to E. F. S.). NR 23 TC 35 Z9 36 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD DEC PY 2009 VL 38 IS 6 BP 1674 EP 1680 DI 10.1093/ije/dyp269 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 528RP UT WOS:000272464700031 PM 19667054 ER PT J AU Kim, G Minig, L Kohn, EC AF Kim, Geoffrey Minig, Lucas Kohn, Elise C. TI Proteomic Profiling in Ovarian Cancer SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article; Proceedings Paper CT International Symposium on Advanced Ovarian Cancer - Optimal Therapy CY FEB 27, 2009 CL Valencia, SPAIN SP European Soc Med Oncol, Spanish Ovarian Canc Grp DE Ovarian cancer; Proteomics; Tissue microarray; Mass spectrometry ID PHASE PROTEIN MICROARRAYS; MASS-SPECTROMETRY; GENE-EXPRESSION; CLEAR-CELL; CARCINOMAS; BIOMARKER; MARKERS; FUTURE AB Objective: To describe the role of proteomic profiling in the diagnosis and treatment of ovarian cancer. Methods: We report a thorough review of the literature, ongoing trials, and our group's experience with proteomic profiling for early detection, recurrence, and treatment of ovarian cancer. Results/Conclusions: Ovarian cancer remains the deadliest gynecologic malignancy in the western world and is most often diagnosed at a rarely curable late stage. Novel applications of proteomic techniques, such as mass spectrometry, show promise in the quest for reliable multimodality screening programs for the early detection of ovarian cancer. Proteomic analysis Of tissue samples has underscored the heterogeneity of this disease process. Development of validated assays that survey the genetic and/or proteomic makeup of an individual tumor will add greatly to the histological classification of the tumor and may lead to different treatment approaches tailored to the unique expression pattern of each individual patient. As novel agents that disrupt signal propagation develop, proteomic profiling by reverse-phase protein at-rays can characterize the in-tumor efficacy of the agent by quantification of the changes in expression levels of activated proteins. Together, better understanding of the potential diagnostic and therapeutic targets followed with proof-of-target effect will lead to rational combinations of novel therapy and improve individual ovarian cancer patient outcome. C1 [Kim, Geoffrey; Kohn, Elise C.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Minig, Lucas] NCI, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kim, G (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM kimgeof@mail.nih.gov NR 26 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD DEC PY 2009 VL 19 BP S2 EP S6 DI 10.1111/IGC.0b013e3181c03929 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 537YY UT WOS:000273151800002 PM 19955909 ER PT J AU Aboud, S Msamanga, G Read, JS Wang, L Mfalila, C Sharma, U Martinson, F Taha, TE Goldenberg, RL Fawzi, WW AF Aboud, Said Msamanga, Gernard Read, Jennifer S. Wang, Lei Mfalila, Chelu Sharma, Usha Martinson, Francis Taha, Taha E. Goldenberg, Robert L. Fawzi, Wafaie W. TI Effect of prenatal and perinatal antibiotics on maternal health in Malawi, Tanzania, and Zambia SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE Antibiotics; HIV; Maternal morbidity; Maternal mortality; Pregnancy ID RANDOMIZED CLINICAL-TRIAL; PREMATURE RUPTURE; MEMBRANES; CHORIOAMNIONITIS; TRANSMISSION; DELIVERY; HIV-1; WOMEN AB Objective: We assessed the effect Of prenatal and peripartum antibiotics on maternal morbidity and mortality among HIV-infected and uninfected women. Methods: A Multicenter trial was conducted at clinical sites in 4 Sub-Saharan African cities: Blantyre and Lilongwe, Malawi; Dar es Salaam, Tanzania: and Lusaka, Zambia. A total of 1558 HIV-infected and 271 uninfected pregnant women who were eligible to receive both the prenatal and peripartum antibiotic/placebo regimens were enrolled. Pregnant women were interviewed at 20-24 weeks of gestation and a physical examination was performed. Women were randomized to receive either antibiotics or placebo. At the 26-30 week visit, participants were given antibiotics or placebo to be taken every 4 hours beginning at the onset of labor and continuing after delivery 3 times a day until a 1-week course was completed. Logistic regression and Cox proportional hazards models were used. Results: There were no significant differences between the antibiotic and placebo groups for medical conditions, obstetric complications, physical examination findings, puerperal sepsis, and death in either the HIV-infected or the uninfected cohort. Conclusion: Administration of study antibiotics during pregnancy had no effect on maternal morbidity and mortality among HIV-infected and uninfected pregnant women. (C) 2009 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Aboud, Said] Muhimbili Univ Hlth & Allied Sci, Dept Microbiol & Immunol, Dar Es Salaam, Tanzania. [Msamanga, Gernard] Muhimbili Univ Hlth & Allied Sci, Dept Community Hlth, Dar Es Salaam, Tanzania. [Read, Jennifer S.] NICHD, Pediat Adolescent & Maternal AIDS Branch, NIH, DHHS, Bethesda, MD USA. [Wang, Lei; Mfalila, Chelu] Fred Hutchinson Canc Res Ctr, SCHARP, Seattle, WA 98104 USA. [Sharma, Usha] NIAID, Prevent Sci Program, NIH, Bethesda, MD 20892 USA. [Martinson, Francis] UNC Project, Lilongwe, Malawi. [Fawzi, Wafaie W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Taha, Taha E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Goldenberg, Robert L.] Drexel Univ, Coll Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. RP Aboud, S (reprint author), Muhimbili Univ Hlth & Allied Sci, Dept Microbiol & Immunol, POB 65001, Dar Es Salaam, Tanzania. EM aboudsaid@yahoo.com FU HIV Prevention Trials Network (HPTN); U.S. National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health; Department of Health and Human Services [N01-AI-035173, N01-AI-045200, N01-AI-035173-117/412]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Mental Health; Office of AIDS Research, of the National Institutes of Health; U.S. Department of Health and Human Services, through Harvard University [U01-AI-048006]; Johns Hopkins University [U01-AI-048005]; University of Alabama at Birmingham [U01-AI-047972]; AIDS International Training and Research Program [D43 TW01035-07] FX The HPTN 024 trial was supported by the HIV Prevention Trials Network (HPTN) and sponsored by the U.S. National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services, through contracts N01-AI-035173, N01-AI-045200, and N01-AI-035173-117/412. In addition, the trial was supported by the HIV Prevention Trials Network (HPTN) and sponsored by NIAID; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; the National Institute of Mental Health; and the Office of AIDS Research, of the National Institutes of Health, U.S. Department of Health and Human Services, through Harvard University (U01-AI-048006); Johns Hopkins University (U01-AI-048005); and the University of Alabama at Birmingham (U01-AI-047972). Support for this work was also provided by the AIDS International Training and Research Program (D43 TW01035-07). NR 14 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD DEC PY 2009 VL 107 IS 3 BP 202 EP 207 DI 10.1016/j.ijgo.2009.07.037 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 526MO UT WOS:000272294100006 PM 19716560 ER PT J AU Demner-Fushman, D Antani, S Simpson, M Thoma, GR AF Demner-Fushman, Dina Antani, Sameer Simpson, Matthew Thoma, George R. TI Annotation and retrieval of clinically relevant images SO INTERNATIONAL JOURNAL OF MEDICAL INFORMATICS LA English DT Article DE Medical informatics computing; Information storage and retrieval; Image interpretation; Computer-assisted; Natural language processing ID ISSUES AB Purpose: Medical images are a significant information source for clinical decision-making. Currently available information retrieval and decision support systems rely primarily on the text of scientific publications to find evidence in support of clinical information needs. The images and illustrations are available only within the full text of a scientific publication and do not directly contribute evidence to such systems. Our first goal is to explore whether image features facilitate finding relevant images that appear in publications. Our second goal is to find promising approaches for providing clinical evidence at the point of service, leveraging information contained in the text and images. Methods: We studied two approaches to finding illustrative evidence: a supervised machine-learning approach, in which images are classified as being relevant to an information need or not, and a pipeline information retrieval approach, in which images were retrieved using associated text and then re-ranked using content-based image retrieval (CBIR) techniques. Results: Our information retrieval approach did not benefit from combining textual and image information. However, given sufficient training data for the machine-learning approach, we achieved 56% average precision at 94% recall using textual features, and 27% average precision at 86% recall using image features. Combining these classifiers resulted in improvement up to 81% precision at 96% recall (74% recall at 85% precision, on average) for the requests with over 180 positive training examples. Conclusions: Our supervised machine-learning methods that combine information from image and text are capable of achieving image annotation and retrieval accuracy acceptable for providing clinical evidence, given sufficient training data. Published by Elsevier Ireland Ltd C1 [Demner-Fushman, Dina] NIH, Commun Engn Branch, Lister Hill Natl Ctr Biomed Commun, US Natl Lib Med, Bethesda, MD 20894 USA. RP Demner-Fushman, D (reprint author), NIH, Commun Engn Branch, Lister Hill Natl Ctr Biomed Commun, US Natl Lib Med, Bldg 38A,Room 10S-1020,8600 Rockville Pike MSC 38, Bethesda, MD 20894 USA. EM ddemner@mail.nih.gov OI Antani, Sameer/0000-0002-0040-1387 FU National Institutes of Health FX This work was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. We thank Emilia Apostolova for implementing the caption segmentation algorithm. NR 26 TC 14 Z9 14 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1386-5056 J9 INT J MED INFORM JI Int. J. Med. Inform. PD DEC PY 2009 VL 78 IS 12 BP E59 EP E67 DI 10.1016/j.ijmedinf.2009.05.003 PG 9 WC Computer Science, Information Systems; Health Care Sciences & Services; Medical Informatics SC Computer Science; Health Care Sciences & Services; Medical Informatics GA 522YM UT WOS:000272036200017 PM 19546026 ER PT J AU Dunton, GF Berrigan, D Ballard-Barbash, R Graubard, B Atienza, AA AF Dunton, G. F. Berrigan, D. Ballard-Barbash, R. Graubard, B. Atienza, A. A. TI Joint associations of physical activity and sedentary behaviors with body mass index: results from a time use survey of US adults SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE physical activity; transportation; sedentary behaviors; television watching; body mass index; adults ID STATE-SPECIFIC PREVALENCE; AUSTRALIAN ADULTS; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME; UNITED-STATES; ENERGY-EXPENDITURE; ABDOMINAL OBESITY; SITTING TIME; YOUNG-ADULTS; LIFE-STYLE AB Objective: Obesity risk is negatively associated with physical activity and positively associated with time spent in sedentary behaviors. Yet, it is not known how different combinations of sedentary and active behavior are associated with body mass index (BMI). This study examined the interaction between time spent in physical activity and sedentary behavior on BMI in US adults. Design: Cross-sectional, data from the 2006 American Time Use Survey. Subjects: 10 984 non-underweight adults (aged 21 + years). Measurement: A phone interview assessed all activities performed in the past 24 h, height, weight, health status, and other sociodemographic characteristics. Time spent in (1) moderate-to-vigorous leisure-time physical activity (MVPA), ( 2) active transportation ( walking, biking), ( 3) sedentary leisure activities (TV/movie watching, computer use, playing games, reading), and ( 4) sedentary transportation ( motorized vehicles) was determined from activity coding. BMI was calculated. Results: After adjusting for age, gender, education level, race/ethnicity, and health status, sample-weighted linear regressions found significant interactions for leisure MVPA x TV/movies, leisure MVPA x playing games, active transportation x sedentary transportation, and active transportation x reading (Ps<0.0001). For example, the group of adults watching <60 min per day of TV/movies and engaging in >= 60 min per day of leisure MVPA had lower average BMI compared to the group watching <60 min per day of TV/movies and reporting <60 min per day of leisure MVPA (P<0.0001). In contrast, for adults watching >= 189 min per day of TV/movies, there was not a significant difference in BMI by time spent in leisure MVPA. Conclusion: Data from a US time use survey indicate that the strength of the association between certain types of sedentary behavior and BMI varies according to time spent in certain types of physical activity and vice versa. International Journal of Obesity ( 2009) 33, 1427-1436; doi: 10.1038/ijo.2009.174; published online 6 October 2009 C1 [Dunton, G. F.; Atienza, A. A.] NCI, Hlth Promot Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Berrigan, D.; Ballard-Barbash, R.] NCI, Off Associate Director, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Graubard, B.] NCI, Biostat Branch, Epidemiol & Biostat Program, Div Canc Epidemiol & Biostat, Bethesda, MD 20892 USA. RP Dunton, GF (reprint author), Univ So Calif, Dept Prevent Med IPR, 1000 S,Fremont Ave,Unit 8,Bldg 5,Room 5229, Alhambra, CA 91803 USA. EM dunton@usc.edu FU Cancer Prevention Fellowship Program; Office of the Director; National Cancer Institute; National Institutes of Health FX We thank Karen Hamrick, PhD of the Economic Research Service at the US Department of Agriculture and the ATUS staff at the US Bureau of Labor and Statistics for their assistance with this project. The first author was supported by the Cancer Prevention Fellowship Program, Office of the Director, National Cancer Institute, National Institutes of Health during the preparation of this paper. She is now in the Department of Preventive Medicine at the University of Southern California. The views and opinions expressed in this paper are those of the authors and not necessarily those of the Department of Health and Human Services, the National Institutes of Health, or the National Cancer Institute. NR 53 TC 35 Z9 35 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD DEC PY 2009 VL 33 IS 12 BP 1427 EP 1436 DI 10.1038/ijo.2009.174 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 532FT UT WOS:000272732100013 PM 19806160 ER PT J AU You, MY Li, GZ Yang, JY Yang, MQ AF You, Mingyu Li, Guo-Zheng Yang, Jack Y. Yang, Mary Qu TI AN ENHANCED LIPSCHITZ EMBEDDING CLASSIFIER FOR MULTI-EMOTION SPEECH ANALYSIS SO INTERNATIONAL JOURNAL OF PATTERN RECOGNITION AND ARTIFICIAL INTELLIGENCE LA English DT Article DE Enhanced Lipschitz embedding; emotion recognition; dimensionality reduction ID NONLINEAR DIMENSIONALITY REDUCTION; RECOGNITION; EXPRESSION AB This paper proposes an Enhanced Lipschitz Embedding based Classifier (ELEC) for the classification of multi-emotions from speech signals. ELEC adopts geodesic distance to preserve the intrinsic geometry at all scales of speech corpus, instead of Euclidean distance. Based on the minimal geodesic distance to vectors of different emotions, ELEC maps the high dimensional feature vectors into a lower space. Through analyzing the class labels of the neighbor training vectors in the compressed low space, ELEC classifies the test data into six archetypal emotional states, i.e. neutral, anger, fear, happiness, sadness and surprise. Experimental results on clear and noisy data set demonstrate that compared with the traditional methods of dimensionality reduction and classification, ELEC achieves 15% improvement on average for speaker-independent emotion recognition and 11% for speaker-dependent. C1 [You, Mingyu; Li, Guo-Zheng] Tongji Univ, Dept Control Sci & Engn, Shanghai 201804, Peoples R China. [You, Mingyu] Nanjing Univ, State Key Lab Novel Software Technol, Nanjing 210093, Peoples R China. [Yang, Jack Y.] Harvard Univ, Harvard Med Sch, Cambridge, MA 02140 USA. [Yang, Mary Qu] NHGRI, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20852 USA. RP Li, GZ (reprint author), Tongji Univ, Dept Control Sci & Engn, Shanghai 201804, Peoples R China. EM myyou@tongji.edu.cn; gzli@tongji.edu.cn; jyang@hadron.mgh.Harvard.edu; yangma@mail.NIH.GOV RI Li, Guo-Zheng /D-5744-2011 OI Li, Guo-Zheng /0000-0001-5568-0347 FU Natural Science Foundation of China [20503015, 60873129]; STCSM [07DZ19726]; Shanghai Rising-Star Program [08QA1403200] FX This work was supported by the Natural Science Foundation of China under grant nos. 20503015 and 60873129, the STCSM "Innovation Action Plan" Project of China under grant no. 07DZ19726, and the Shanghai Rising-Star Program under grant no. 08QA1403200. NR 26 TC 1 Z9 2 U1 1 U2 4 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA 5 TOH TUCK LINK, SINGAPORE 596224, SINGAPORE SN 0218-0014 J9 INT J PATTERN RECOGN JI Int. J. Pattern Recognit. Artif. Intell. PD DEC PY 2009 VL 23 IS 8 BP 1685 EP 1700 DI 10.1142/S0218001409007764 PG 16 WC Computer Science, Artificial Intelligence SC Computer Science GA 541OK UT WOS:000273425500007 ER PT J AU Nunez-Troconis, J Delgado, M Gonzalez, J Velasquez, J Mindiola, R Whitby, D Conde, B Munroe, DJ AF Nunez-Troconis, Jose Delgado, Mariela Gonzalez, Julia Velasquez, Jesvy Mindiola, Raimy Whitby, Denise Conde, Betty Munroe, David J. TI Human papillomavirus false positive cytological diagnosis in low grade squamous intraepithelial lesion. SO INVESTIGACION CLINICA LA English DT Article DE Human Papillomavirus; false positive; low-grade squamous intraepithelial lesion; pap smear; hybrid capture 2 ID CERVICAL-CANCER; PAP-SMEAR; VISUAL INSPECTION; WOMEN; RISK; HPV; ABNORMALITIES; PREVALENCE; INFECTION AB The purpose of this study was to investigate the number of Human Papilloma-virus false positive cytological diagnosis in low grade squamous intraepithelial lesions (LSIL). Three hundred and two women who assisted to an Out-Patient Gynecologic Clinic in Maracaibo, Venezuela, were recruited for this study. Each patient had the Pap smear and a cervical swab for Hybrid Capture 2 (HC2). Three cytotechnologists reviewed the Pap smears and two pathologists rescreened all of them. The cytotechnologists reported 161 (53.3%) Pap smears negatives for intraepithelial lesion (IL) or malignancy, and 141 cases (46.7%) with epithelial abnormalities. They reported 46% of 302 patients with HPV infection in Pap smear slides. The pathologists found that 241 (79.8%) Pap smears were negatives for IL or malignancy and 61 (20.2%), with abnormal Pap smears. They found 14.6% HPV infection in all Pap smears (p<0.0001; 46% vs 14.6%). The HC2 study showed that 47 samples (15.6%) were positive for HPV. The study found that 114 Pap smears (False Positive: 85%) of 134 reported by the cytotechnologists and 24 (False Positive: 43%) of 56 cytologies reported by the pathologists as LSIL, were negative for HPV infection determined by HC2 (p<0.00003). The present study suggests that the cytotechnologists overdiagnosed cellular changes associated with HPV infection in the Pap smear, increasing the FP cytological diagnosis of LSIL. C1 [Nunez-Troconis, Jose] Univ Zulia, Hosp Manuel Noriega Trigo, Dept Obstet & Ginecol, Fac Med, Maracaibo 4011, Venezuela. [Delgado, Mariela; Gonzalez, Julia] Policlin Maracaibo, Lab Patol, Maracaibo, Venezuela. [Velasquez, Jesvy; Mindiola, Raimy] Univ Zulia, Fac Med, Lab Reg Referencia Virol, Maracaibo 4011, Venezuela. [Whitby, Denise; Conde, Betty] NCI, Viral Oncol Sect, Core Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. [Munroe, David J.] NCI, Lab Mol Technol, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Nunez-Troconis, J (reprint author), Apartado 525, Maracaibo 4001A, Venezuela. EM jtnunezt@gmail.com FU National Cancer Institute, National Institutes of Health [N01-C0-12400]; Fogarty Foundation/NCI/PAHO FX We thank all the members of the Social Service and nurses who work at the Gynecological Out-Patient Clinic of Manuel Noriega Trigo Hospital for their assistance and help. NR 31 TC 1 Z9 1 U1 2 U2 3 PU INST INVESTIGACION CLINICA PI MARACAIBO PA APARTADO 23, MARACAIBO 4001-A, VENEZUELA SN 0535-5133 J9 INVEST CLIN JI Invest. Clin. PD DEC PY 2009 VL 50 IS 4 BP 447 EP 454 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 524RH UT WOS:000272160000004 PM 20306718 ER PT J AU Schneider, BJ Worden, FP Gadgeel, SM Parchment, RE Hodges, CM Zwiebel, J Dunn, RL Wozniak, AJ Kraut, MJ Kalemkerian, GP AF Schneider, Bryan J. Worden, Francis P. Gadgeel, Shirish M. Parchment, Ralph E. Hodges, Collette M. Zwiebel, James Dunn, Rodney L. Wozniak, Antoinette J. Kraut, Michael J. Kalemkerian, Gregory P. TI Phase II trial of fenretinide (NSC 374551) in patients with recurrent small cell lung cancer SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Fenretinide; 4-HPR; Small cell lung cancer; Relapsed ID SYNTHETIC RETINOID FENRETINIDE; BREAST-CANCER; CARCINOMA CELLS; APOPTOSIS; LINES; ACID; INDUCTION; N-(4-HYDROXYPHENYL)RETINAMIDE; 4-HYDROXYPHENYLRETINAMIDE; PHARMACOKINETICS AB Background Alterations in retinoid signaling appear to be involved in the pathogenesis of small cell lung cancer (SCLC). Fenretinide [N-(4-hydroxyphenyl)retinamide], a synthetic retinoid, inhibits the growth of SCLC cells in vitro via the induction of apoptosis. Since these data suggested that SCLC is the adult solid tumor that is most susceptible to fenretinide, a trial to evaluate the clinical activity of fenretinide in patients with SCLC was considered the definitive test of its clinical potential in adult oncology. Methods Patients with progressive SCLC after one or two prior chemotherapy regimens and a performance status of 0-2 were eligible for the study. Patients with stable, treated brain metastases were eligible. Fenretinide 900 mg/m(2) twice daily was administered orally on days 1-7 of each 21-day cycle. Blood and saliva were collected pre-treatment and on day 7 of cycle 1 to measure fenretinide and retinol levels by high-pressure liquid chromatography (HPLC). Results Nineteen patients were enrolled. Fifteen patients had one prior chemotherapy regimen and four patients had two prior regimens. The median time from diagnosis to enrollment was 10 months. A median of two cycles of fenretinide was administered. There were no objective responses, but four of 17 evaluable patients (24%) had stable disease after 2-17 cycles. The median time to treatment failure was 5.7 weeks overall, while the four patients with stable disease demonstrated treatment failure at 11, 13, 19, and 52 weeks. Median survival was 25 weeks, with one patient alive 22 months after the start of treatment. The 1-year survival rate was 29%. Toxicity included mild, reversible visual changes (haziness, altered night vision), grade 1-3 nausea/vomiting, and grade 1-2 diarrhea. The mean day 7 plasma fenretinide level was 2.90 +/- 1.66 mu g/ml (7.40 +/- 4.25 mu M; n = 14). The mean pre-treatment and day 7 plasma retinol levels were 0.47 +/- 0.16 mu g/ml and 0.05 +/- 0.07 mu g/ml (n = 8), respectively. The mean day 7 salivary fenretinide level was 0.08 +/- 0.18 mu g/ml, with no correlation between salivary and plasma drug levels. Conclusions Fenretinide is well tolerated in patients with SCLC and stabilization of disease was noted in 24% of patients with this aggressive disease. However, after the first stage of enrollment, the response rate did not meet criteria to proceed with full trial accrual. Plasma concentrations of fenretinide that induce cytotoxicity in vitro in SCLC cell lines are clinically achievable, but there were no objective responses. Non-invasive drug monitoring using saliva underestimates systemic exposure. C1 [Schneider, Bryan J.] Weill Cornell Med Coll, Dept Internal Med, Div Hematol Oncol, New York, NY 10021 USA. [Worden, Francis P.; Hodges, Collette M.; Kalemkerian, Gregory P.] Univ Michigan, Div Hematol Oncol, Dept Internal Med, Ann Arbor, MI 48109 USA. [Gadgeel, Shirish M.; Wozniak, Antoinette J.] Karmanos Canc Inst, Div Hematol & Oncol, Detroit, MI 48201 USA. [Parchment, Ralph E.; Zwiebel, James] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. [Dunn, Rodney L.] Univ Michigan, Dept Urol, Biostat Core Facil, Ctr Canc, Ann Arbor, MI 48109 USA. [Kraut, Michael J.] Providence Canc Inst, Southfield, MI 48075 USA. [Parchment, Ralph E.] NCI Frederick, Lab Human Toxicol Pharmacol, Frederick, MD 21702 USA. [Zwiebel, James] NCI, Bethesda, MD 20892 USA. RP Schneider, BJ (reprint author), Weill Cornell Med Coll, Dept Internal Med, Div Hematol Oncol, 525 E 68th St,J-321, New York, NY 10021 USA. EM bjs2004@med.cornell.edu; fworden@med.umich.edu; gadgeels@karmanos.org; parchmentr@verizon.net; zwiebelj@ctep.nci.nih.gov; rldunn@med.umich.edu; wozniakt@karmanos.org; mkraut@providence-hospital.org; kalemker@umich.edu NR 36 TC 9 Z9 9 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD DEC PY 2009 VL 27 IS 6 BP 571 EP 578 DI 10.1007/s10637-009-9228-6 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 521UR UT WOS:000271950500009 PM 19225720 ER PT J AU Cho, YE Wang, JJ Chew, EY Ferris, FL Mitchell, P Chan, CC Tuo, JS AF Cho, Youngeun Wang, Jie Jin Chew, Emily Y. Ferris, Frederick L., III Mitchell, Paul Chan, Chi-Chao Tuo, Jingsheng TI Toll-like Receptor Polymorphisms and Age-Related Macular Degeneration: Replication in Three Case-Control Samples SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID BLUE MOUNTAINS EYE; VISUAL-LOSS; RISK-FACTORS; FACTOR-H; DISEASE; AREDS; PREVALENCE; AUSTRALIA; SMOKING; VARIANT AB PURPOSE. Innate immunity appears to play a key role in age-related macular degeneration (AMD). Although two previous studies reported that gene variations in Toll-like receptor (TLR)-3 and -4 are associated with AMD, other studies have not confirmed these associations. In this study, three independent samples (two U. S. clinic-based case-control study samples and one Australian population-based study sample) were used to further assess the association of the polymorphisms rs3775291 in TLR3 and rs4986790 in TLR4 with AMD. METHODS. AMD cases and unrelated controls were collected from the National Eye Institute Clinical Center (NEI, n = 320), the Age-Related Eye Disease Study (AREDS, n = 483), and the Blue Mountains Eye Study (BMES, n = 852). DNA extracted from subjects was genotyped for rs3775291 and rs4986790, and the associations with AMD were investigated. RESULTS. Neither of the two polymorphisms rs3775291 and rs4986790 had a statistically significant association with AMD in any of the three sample sets or in combinations of the sets. Analysis of the combined geographic atrophy or neovascular AMD cases in the NEI, AREDS, and BMES sample sets also failed to demonstrate statistically significant associations of those two single nucleotide polymorphisms with advanced AMD. CONCLUSIONS. Even with previously verified samples sets and adequate study powers, the results did not confirm the reported associations of TLR3 rs3775291 and TLR4 rs4986790 with AMD in the three independent samples, individually or combined. (Invest Ophthalmol Vis Sci. 2009; 50: 5614-5618) DOI: 10.1167/iovs.09-3688 C1 [Cho, Youngeun; Chan, Chi-Chao; Tuo, Jingsheng] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Chew, Emily Y.; Ferris, Frederick L., III] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Ctr Vis Res, Dept Ophthalmol, Westmead, NSW 2145, Australia. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Westmead Millennium Inst, Westmead, NSW 2145, Australia. RP Tuo, JS (reprint author), NEI, Immunol Lab, NIH, 10-10N103,10 Ctr Dr, Bethesda, MD 20892 USA. EM tuoj@nei.nih.gov RI Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; OI Wang, Jie Jin/0000-0001-9491-4898; Tuo, Jingsheng/0000-0002-1372-7810 FU Intramural Research Program of National Eye Institute, National Institutes of Health (NIH); Australian National Health and Medical Research Council FX Supported by the Intramural Research Program of National Eye Institute, National Institutes of Health (NIH), the Contracts from NIH for AREDS, and the Australian National Health and Medical Research Council. NR 28 TC 29 Z9 31 U1 0 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2009 VL 50 IS 12 BP 5614 EP 5618 DI 10.1167/iovs.09-3688 PG 5 WC Ophthalmology SC Ophthalmology GA 527GS UT WOS:000272355900015 PM 19628747 ER PT J AU Huber, G Beck, SC Grimm, C Sahaboglu-Tekgoz, A Paquet-Durand, F Wenzel, A Humphries, P Redmond, TM Seeliger, MW Fischer, MD AF Huber, Gesine Beck, Susanne C. Grimm, Christian Sahaboglu-Tekgoz, Ayse Paquet-Durand, Francois Wenzel, Andreas Humphries, Peter Redmond, T. Michael Seeliger, Mathias W. Fischer, M. Dominik TI Spectral Domain Optical Coherence Tomography in Mouse Models of Retinal Degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID LEBERS CONGENITAL AMAUROSIS; PHOTORECEPTOR DEGENERATION; BETA-SUBUNIT; ROD PHOSPHODIESTERASE; RETINITIS-PIGMENTOSA; HIGH-SPEED; GENE; RPE65; MICE; MUTATIONS AB PURPOSE. Spectral domain optical coherence tomography (SD-OCT) allows cross-sectional visualization of retinal structures in vivo. Here, the authors report the efficacy of a commercially available SD-OCT device to study mouse models of retinal degeneration. METHODS. C57BL/6 and BALB/c wild-type mice and three different mouse models of hereditary retinal degeneration (Rho(-/-), rd1, RPE65(-/-)) were investigated using confocal scanning laser ophthalmoscopy (cSLO) for en face visualization and SD-OCT for cross-sectional imaging of retinal structures. Histology was performed to correlate structural findings in SD-OCT with light microscopic data. RESULTS. In C57BL/6 and BALB/c mice, cSLO and SD-OCT imaging provided structural details of frequently used control animals (central retinal thickness, CRT(C57BL/6) = 237 +/- 2 mu m and CRT(BALB/c) = 211 +/- 10 mu m). RPE65(-/-) mice at 11 months of age showed a significant reduction of retinal thickness (CRT(RPE65) = 193 +/- 2 mu m) with thinning of the outer nuclear layer. Rho(-/-) mice at P28 demonstrated degenerative changes mainly in the outer retinal layers (CRT(Rho) = 193 +/- 2 mu m). Examining rd1 animals before and after the onset of retinal degeneration allowed monitoring of disease progression (CRT(rd1 P11) = 246 +/- 4 mu m, CRT(rd1 P28) = 143 +/- 4 mu m). Correlation of CRT assessed by histology and SD-OCT was high (r(2) = 0.897). CONCLUSIONS. The authors demonstrated cross-sectional visualization of retinal structures in wild-type mice and mouse models for retinal degeneration in vivo using a commercially available SD-OCT device. This method will help to reduce numbers of animals needed per study by allowing longitudinal study designs and will facilitate characterization of disease dynamics and evaluation of putative therapeutic effects after experimental interventions. (Invest Ophthalmol Vis Sci. 2009;50:5888-5895) DOI:10.1167/iovs.09-3724 C1 [Huber, Gesine; Beck, Susanne C.; Seeliger, Mathias W.; Fischer, M. Dominik] Univ Tubingen, Inst Ophthalm Res, Ctr Ophthalmol, Div Ocular Neurodegenerat, D-72076 Tubingen, Germany. [Sahaboglu-Tekgoz, Ayse; Paquet-Durand, Francois] Ctr Ophthalmol, Inst Ophthalm Res, Div Expt Ophthalmol, Tubingen, Germany. [Huber, Gesine] Univ Munich, Fac Vet Med, Inst Anim Welf Ethol & Anim Hyg, Munich, Germany. [Grimm, Christian; Wenzel, Andreas] Univ Zurich, Dept Ophthalmol, Lab Retinal Cell Biol, Zurich, Switzerland. [Humphries, Peter] Trinity Coll Dublin, Ocular Genet Unit, Dublin, Ireland. [Redmond, T. Michael] NEI, NIH, Bethesda, MD 20892 USA. RP Fischer, MD (reprint author), Univ Tubingen, Inst Ophthalm Res, Ctr Ophthalmol, Div Ocular Neurodegenerat, D-72076 Tubingen, Germany. EM dominik.fischer@med.uni-tuebingen.de RI Paquet-Durand, Francois/C-6094-2008; Paquet-Durand, Francois/G-6709-2015 OI Paquet-Durand, Francois/0000-0001-7355-5742 FU Deutsche Forschungsgemeinschaft [Se837/5-2, Se837/7-1 (KFO 134), Se837/6-1, PA1751/1-1]; German Ministry of Education and Research [0314106]; European Union [LSHG-CT-512036, EU HEALTH-F2-2008-200234]; Kerstan Foundation, EU [MEST-CT-2005-020235] FX Supported by Deutsche Forschungsgemeinschaft Grants Se837/5-2 & Se837/7-1 (KFO 134), Se837/6-1, and PA1751/1-1; German Ministry of Education and Research Grant 0314106; European Union Grants LSHG-CT-512036 and EU HEALTH-F2-2008-200234, Kerstan Foundation, EU (MEST-CT-2005-020235). NR 40 TC 110 Z9 111 U1 2 U2 9 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2009 VL 50 IS 12 BP 5888 EP 5895 DI 10.1167/iovs.09-3724 PG 8 WC Ophthalmology SC Ophthalmology GA 527GS UT WOS:000272355900052 PM 19661229 ER PT J AU Li, R Maminishkis, A Zahn, G Vossmeyer, D Miller, SS AF Li, Rong Maminishkis, Arvydas Zahn, Grit Vossmeyer, Doerte Miller, Sheldon S. TI Integrin alpha 5 beta 1 Mediates Attachment, Migration, and Proliferation in Human Retinal Pigment Epithelium: Relevance for Proliferative Retinal Disease SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ALPHA(5)BETA(1) INTEGRIN; MACULAR DEGENERATION; EPIRETINAL MEMBRANES; VASCULAR DEVELOPMENT; BLOOD-VESSELS; MOUSE EMBRYOS; CELLS; FIBRONECTIN; VITREORETINOPATHY; PHAGOCYTOSIS AB PURPOSE. The aim of this study was to determine the expression and localization of integrin alpha 5 beta 1 in human retinal pigment epithelium (RPE) and its ability to modulate RPE cell attachment, proliferation, migration, and F-actin cytoskeleton distribution. METHODS. Expression and localization of alpha 5 beta 1 were analyzed on human RPE by immunoblot/immunofluorescence. Polarized secretion of fibronectin was measured. RPE attachments to different substrates were determined using cell attachment screening kits. BrdU incorporation and wound-healing assays were used to test hfRPE proliferation and migration. F-actin cytoskeleton was visualized with phalloidin. RESULTS. Integrin alpha 5 beta 1 was detected in native adult and fetal human RPE. The alpha 5-subunit is predominantly localized at the apical membrane of hfRPE, whereas the beta 1-subunit is uniformly detected at the apical/basolateral membranes. The authors also found that hfRPE cultures secrete significant amounts of fibronectin to the apical bath. JSM6427, a specific integrin alpha 5 beta 1 antagonist, significantly inhibited hfRPE cell attachment to fibronectin, but not laminin, or collagen I or IV. JSM6427 also showed a strong inhibitory effect on bFGF, PDGF-BB, and serum-induced cell migration and proliferation. Furthermore, JSM6427 induced significant disruption of the F-actin cytoskeleton of dividing RPE cells but had no effect on quiescent cells. CONCLUSIONS. The apical localization of alpha 5 beta 1 and the secretion of fibronectin to the apical bath suggest the presence of an autocrine loop that can guide the migration of RPE. The strong inhibitory effects of JSM6427 on human RPE cell attachment, proliferation, and migration is probably mediated by F-actin cytoskeletal disruption in proliferating cells and suggests a potential clinical use of this compound in proliferative retinopathies. (Invest Ophthalmol Vis Sci. 2009;50:5988-5996) DOI:10.1167/iovs.09-3591 C1 [Li, Rong; Maminishkis, Arvydas; Miller, Sheldon S.] NEI, NIH, Bethesda, MD 20892 USA. [Zahn, Grit; Vossmeyer, Doerte] Jerini AG, Berlin, Germany. RP Miller, SS (reprint author), NEI, NIH, 31 Ctr Dr,MSC 2510, Bethesda, MD 20892 USA. EM millers@nei.nih.gov FU National Institutes of Health, National Eye Institute FX Supported by the Intramural Research Program of the National Institutes of Health, National Eye Institute. NR 56 TC 16 Z9 17 U1 0 U2 7 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2009 VL 50 IS 12 BP 5988 EP 5996 DI 10.1167/iovs.09-3591 PG 9 WC Ophthalmology SC Ophthalmology GA 527GS UT WOS:000272355900064 PM 19608542 ER PT J AU Vagenas, P Williams, VG Piatak, M Bess, JW Lifson, JD Blanchard, JL Gettie, A Robbiani, M AF Vagenas, Panagiotis Williams, Vennansha G. Piatak, Michael, Jr. Bess, Julian W., Jr. Lifson, Jeffrey D. Blanchard, James L. Gettie, Agegnehu Robbiani, Melissa TI Tonsillar Application of AT-2 SIV Affords Partial Protection Against Rectal Challenge With SIVmac239 SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT Conference on Modern Mucosal Vaccines, Adjuvants and Microbicides CY OCT, 2008 CL Oporto, PORTUGAL DE CpG ISS-ODN; mucosal; SIV; vaccine ID SIMIAN IMMUNODEFICIENCY VIRUS; PLASMACYTOID DENDRITIC CELLS; RHESUS MACAQUES; ANTIBODY-RESPONSES; IMMUNE-RESPONSES; CPG OLIGODEOXYNUCLEOTIDES; AIDS VACCINE; DNA VACCINE; T-CELLS; INTRANASAL IMMUNIZATION AB Background: Although mucosal responses are important for preventing infections with HIV, the optimal strategies for inducing them remain unclear. To evaluate vaccine strategies targeting the oral mucosal lymphoid tissue inductive sites as an approach to provide immunity at distal sites, we vaccinated healthy macaques via the palatine/lingual tonsils with aldrithiol 2 (AT-2) inactivated Simian immunodeficiency virus (SIV)mac239, combined with CpG-C immunostimulatory oligonucleotide (CpG-C ISS-ODN, C274) as the adjuvant. Methods: Macaques received 5 doses of C274 or control ODN C661 and AT-2 SIV on the tonsillar tissues every 6 weeks before being challenged rectally with SIVmac239, 8 weeks after the last immunization. Results: Although no T-cell or B-cell responses were detected in the blood before challenge, antibody (Ab) responses were detected in the rectum. Immunization with AT-2 SIV significantly reduced the frequency of infection compared with nonimmunized controls, irrespective of adjuvant. In the vaccinated animals that became infected, peak viremias were somewhat reduced. SIV-specific responses were detected in the blood once animals became infected with no detectable differences between the differently immunized groups and the controls. Conclusion: This work provides evidence that vaccine immunogens applied to the oral mucosal associated lymphoid tissues can provide benefit against rectal challenge, a finding with important implications for mucosal vaccination strategies. C1 [Vagenas, Panagiotis; Williams, Vennansha G.; Robbiani, Melissa] Populat Council, HIV AIDS Program, Ctr Biomed Res, New York, NY 10065 USA. [Piatak, Michael, Jr.; Bess, Julian W., Jr.; Lifson, Jeffrey D.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Blanchard, James L.] Tulane Univ, Hlth Sci Ctr, Tulane Natl Primate Res Ctr, Covington, LA USA. [Gettie, Agegnehu] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. RP Robbiani, M (reprint author), Populat Council, HIV AIDS Program, Ctr Biomed Res, 1230 York Ave, New York, NY 10065 USA. EM mrobbiani@popcouncil.org RI Vagenas, Panagiotis/H-7850-2013 OI Vagenas, Panagiotis/0000-0003-2107-0377 FU NCI NIH HHS [N01 CO012400, N01 CO 124000]; NCRR NIH HHS [P51 RR000164-370001, P51 RR000164, RR00164]; NIAID NIH HHS [R37 AI040877]; NIDCR NIH HHS [R01 DE016256-01, R01 DE016256] NR 70 TC 17 Z9 17 U1 0 U2 1 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 DEC 1 PY 2009 VL 52 IS 4 BP 433 EP 442 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 518UY UT WOS:000271721600001 PM 19779309 ER PT J AU Avidan, NU Goldstein, D Rozenberg, L McLaughlin, M Ferenci, P Masur, H Buti, M Fauci, AS Polis, MA Kottilil, S AF Avidan, Neumann U. Goldstein, Deborah Rozenberg, Lynn McLaughlin, Maiy Ferenci, Peter Masur, Henry Buti, Maria Fauci, Anthony S. Polis, Michael A. Kottilil, Shyam TI Hepatitis C Viral Kinetics During Treatment With Peg IFN-alpha-2b in HIV/HCV Coinfected Patients as a Function of Baseline CD4(+) T-Cell Counts SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HCV; HIV; viral kinetics; sustained viral response ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; ALPHA-2A PLUS RIBAVIRIN; INTERFERON-ALPHA; DYNAMICS; EFFICACY; THERAPY; TRIAL; IFN; HCV AB Background: HIV/hepatitis C virus (HCV) coinfected patients are known to have lower sustained viral response (SVR) rates than HCV monoinfected patients. However, the role of CD4(+) T-cell counts on viral kinetics and outcome is not fully understood. Methods: HCV RNA kinetics (bDNA v3, lower limit of detection [LD] = 615 IU/mL) was analyzed in 32 HIV/HCV coinfected persons treated with Pegylated-interferon-alpha 2b (1.5 mu g/kg weekly) and ribavirin (1-1.2 g daily) for 48 weeks and compared with results obtained from 12 HCV monoinfected patients treated with the same regimen. Results: Baseline CD4(+) T-cell counts >= 450 cells/mm(3) were significantly (P < 0.002) associated with SVR in coinfected genotype I patients. First phase decline was significantly lower among patients with low as compared with high CD4 counts (P < 0.03) and among coinfected compared with monoinfected patients (P < 0.002). Second phase decline slope showed a similar trend for coinfected patients. Conclusions: Low baseline CD4(+) T-cell count is associated with slower HCV viral kinetics and worse response to treatment among HIV coinfected patients, suggesting HCV treatment response depends on immune status. HCV genotype I coinfected patients have slower first phase viral kinetics than HCV monoinfected patients. First phase viral decline (>1.0 log) and second phase viral decline slope (>0.3 log/wk) are excellent predictors of SVR for coinfected patients. C1 [Avidan, Neumann U.; Rozenberg, Lynn] Bar Ilan Univ, Ramat Gan, Israel. [Kottilil, Shyam] NIAID, Immunopathogenesis Sect, NIH, LIR,DHHS, Bethesda, MD 20892 USA. [Avidan, Neumann U.] NIDDK, LBM, NIH, DHHS, Bethesda, MD USA. [Goldstein, Deborah] Sci Applicat Int Corp Frederick, Frederick, MD USA. [Ferenci, Peter] Univ Hosp Vienna, Vienna, Austria. [Masur, Henry] NIH, CCMD, CC, DHHS, Bethesda, MD 20892 USA. [Buti, Maria] Univ Valle Hebron, Gen Hosp, Barcelona, Spain. [Buti, Maria] Ciber Ehd Intituto Carlos III, Barcelona, Spain. RP Kottilil, S (reprint author), NIAID, Immunopathogenesis Sect, NIH, LIR,DHHS, Bldg 10,Rm 11N204,9000 Rockville Pike, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov OI Polis, Michael/0000-0002-9151-2268 FU National Institute of Health (National Institute of Allergy and Infectious Diseases and National Institute Of Digestive Diseases and Kidney) FX Supported in whole by the Intramural Research Program of the National Institute of Health (National Institute of Allergy and Infectious Diseases and National Institute Of Digestive Diseases and Kidney). NR 24 TC 13 Z9 15 U1 0 U2 1 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 DEC 1 PY 2009 VL 52 IS 4 BP 452 EP 458 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 518UY UT WOS:000271721600003 PM 19797971 ER PT J AU Koch, R Jaffe, ES Mensing, C Zeis, M Schmitz, N Sander, CA AF Koch, Richard Jaffe, Elaine S. Mensing, Christian Zeis, Matthias Schmitz, Norbert Sander, Christian A. TI Cutaneous gamma/delta T-cell lymphoma SO JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT LA English DT Article DE gamma/delta-T-cell-receptor; cutaneous lymphoma; hematopoietic stem cell transplantation AB Only 40 cases of primary cutaneous gamma/delta T-cell lymphoma (GD-TCL) have been described. GD-TCL was included as a provisional entity in the WHO-EORTC classification of cutaneous lymphomas in 2005. GD-TCL often failed to respond to polychemotherapy and radiation therapy and have a poor prognosis with a mean survival of only 15 months. We present a patient treated with surgery, immunomodulatory therapy, and polychemotherapy. He then received hematopoietic stem cell transplantation and has been in complete remission since. Allogeneic stem cell transplantation appears to be a promising therapeutic option for aggressive and generally fatal lymphomas like GD-TCL. C1 [Koch, Richard; Mensing, Christian; Sander, Christian A.] Asklepios Klin St Georg, Eduard Arning Klin Dermatol & Allergol, D-20099 Hamburg, Germany. [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. [Zeis, Matthias; Schmitz, Norbert] Asklepios Klin St Georg, Dept Hematol, D-20099 Hamburg, Germany. RP Koch, R (reprint author), Asklepios Klin St Georg, Eduard Arning Klin Dermatol & Allergol, Lohmuhlenstr 5, D-20099 Hamburg, Germany. EM ri.koch@asklepios.com FU Intramural NIH HHS [ZIA BC011070-04] NR 7 TC 18 Z9 20 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1610-0379 J9 J DTSCH DERMATOL GES JI J. Dtsch. Dermatol. Ges. PD DEC PY 2009 VL 7 IS 12 BP 1065 EP 1067 DI 10.1111/j.1610-0387.2009.07209.x PG 3 WC Dermatology SC Dermatology GA 521VR UT WOS:000271954000006 PM 19694889 ER PT J AU Lee, CT Lehrmann, E Hayashi, T Amable, R Tsai, SY Chen, J Sanchez, JF Shen, J Becker, KG Freed, WJ AF Lee, Chun-Ting Lehrmann, Elin Hayashi, Teruo Amable, Rose Tsai, Shang-Yi Chen, Jia Sanchez, Joseph F. Shen, James Becker, Kevin G. Freed, William J. TI Gene Expression Profiling Reveals Distinct Cocaine-Responsive Genes in Human Fetal CNS Cell Types SO JOURNAL OF ADDICTION MEDICINE LA English DT Article DE cocaine; microarray; gene expression profiling; human fetal CNS cells; brain development ID CEREBRAL-CORTEX; MOUSE-BRAIN; IN-UTERO; EXPOSURE; PROTEIN; APOPTOSIS; EZRIN; INHIBITION; NEOCORTEX; MICROGLIA AB Objectives: Prenatal exposure to cocaine causes cytoarchitectural alterations in the developing neocortex. Previously, we reported that cocaine inhibits neural progenitor cell proliferation through oxidative endoplasmic reticulum stress and consequent down-regulation of cyclin A, whereas cyclin A expression was increased in astrocytes. In the present study, cell type-specific responses to cocaine were further explored. Methods: Gene expression profiles were examined in 5 types of cells obtained from the human fetal cerebral cortex at 20 weeks gestation. Cells were treated with 100 mu M cocaine in vitro for 24 hours, followed by gene expression analysis using a human neural/stem cell/drug abuse-focused cDNA array, with verification by quantitative real-time reverse-transcriptase polymerase chain reaction. Results: Cocaine influenced transcription of distinct categories of genes in a cell type-specific manner. Cocaine down-regulated cytoskeleton-related genes including ezrin, gamma 2 actin, alpha 3d tubulin, and alpha 8 tubulin in neural and/or A2B5+ progenitor cells. In contrast, cocaine modulated immune and cell death-related genes in microglia and astrocytes. In microglia, cocaine up-regulated the immunoregulatory and proapoptotic genes interleukin-1 beta and BCL2-associated X protein. In astrocytes, cocaine down-regulated the immune response gene glucocorticoid receptor and up-regulated the antiapoptotic genes 14-3-3 epsilon and HVEM. Therefore, cell types comprising the developing neocortex show differential responses to cocaine. Conclusions: These data suggest that cocaine causes cytoskeletal abnormalities leading to disturbances in neural differentiation and migration in progenitor cells, while altering immune and apoptotic responses in glia. Understanding the mechanisms of cocaine's effects on human central nervous system cells may help in the development of therapeutic strategies to prevent or ameliorate cocaine-induced impairments in fetal brain development. C1 [Lee, Chun-Ting; Lehrmann, Elin; Hayashi, Teruo; Amable, Rose; Tsai, Shang-Yi; Chen, Jia; Sanchez, Joseph F.; Freed, William J.] NIDA, Cellular Neurobiol Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Shen, James] ScienCell Res Labs, San Diego, CA USA. [Becker, Kevin G.] NIA, Gene Express & Genom Unit, IRP, NIH,DHHS, Baltimore, MD 21224 USA. RP Lee, CT (reprint author), NIDA, Cellular Neurobiol Res Branch, Intramural Res Program, NIH,DHHS, 333 Cassell Dr,Triad Bldg,Room 3505, Baltimore, MD 21224 USA. EM clee@mail.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU NIDA; NIA; NIH; DHHS; U.S. Provisional Application [60/893,218] FX Supported by the IR-Ps of NIDA and NIA, NIH, DHHS. U.S. Provisional Application No. 60/893,218 filed 06 Mar 2007: "Cytochrome P450 Inhibitors for Treatment of Cocaine-Induced Fetal Brain Injury" (to CTL, WJF). NR 40 TC 17 Z9 18 U1 0 U2 2 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 DEC PY 2009 VL 3 IS 4 BP 218 EP 226 PG 9 WC Substance Abuse SC Substance Abuse GA 528VG UT WOS:000272474500006 PM 20948987 ER PT J AU Goldbach-Mansky, R Kastner, DL AF Goldbach-Mansky, Raphaela Kastner, Daniel L. TI Autoinflammation: The prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Autoinflammatory diseases; neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic; cutaneous, and arthritis (CINCA); cryopin-associated periodic syndromes (CAPS); deficiency of the IL-1 receptor antagonist; NLRP3; IL1RN; IL-1 receptor antagonist; anakinra; neonatal disorder; genetic disease; IL-1 ID INTERLEUKIN-1 RECEPTOR ANTAGONIST; FAMILIAL MEDITERRANEAN FEVER; JUVENILE IDIOPATHIC ARTHRITIS; MUCKLE-WELLS-SYNDROME; ENCODING MEVALONATE KINASE; ONSET STILLS-DISEASE; HYPERIMMUNOGLOBULINEMIA-D; RHEUMATOID-ARTHRITIS; ARTICULAR SYNDROME; PERIODIC SYNDROMES AB The discovery of the genetic causes of a rare group of immune-mediated inflammatory conditions that mimic infections and allergic conditions in their clinical presentation and the molecular understanding of the function of the mutated molecules in these diseases has led to a revolution in our understanding of the pathogenesis of systemic and local inflammation. The proteins mutated in a number of these so-called autoinflammatory diseases are part of, or regulate the activity of, intracellular molecular complexes, the inflammasomes, that sense "danger" to the body and coordinate an initial immune response. Our understanding of specific triggers of the inflammasomes, coupled with the recognition that inflammasomes are critical for activation of the proinflammatory cytokine IL-1, has provided a rational and very effective target in the treatment of a number of these rare autoinflammatory diseases. In addition, the ongoing discovery of the role of inflammasomes and IL-1 activation and secretion in a number of genetically complex disorders have fundamentally changed our view of disease pathogenesis in a growing number of disorders that were heretofore not even thought of as "immunologic" diseases. (J Allergy Clin Immunol 2009; 124:1141-9.) C1 [Goldbach-Mansky, Raphaela; Kastner, Daniel L.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Goldbach-Mansky, R (reprint author), NIAMS, NIH, Bldg 10,Rm 6D-47B,10 Ctr Dr, Bethesda, MD 20892 USA. EM goldbacr@mail.nih.gov FU Intramural NIH HHS [Z01 AR041138-06, Z01 AR041138-05, ZIA AR041139-07, Z01 AR041139-06, ZIA AR041138-07, Z01 AR041139-05] NR 72 TC 84 Z9 94 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2009 VL 124 IS 6 BP 1141 EP 1149 DI 10.1016/j.jaci.2009.11.016 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 536VH UT WOS:000273071500002 PM 20004775 ER PT J AU Griffith, LM Cowan, MJ Notarangelo, LD Puck, JM Buckley, RH Candotti, F Conley, ME Fleisher, TA Gaspar, HB Kohn, DB Ochs, HD O'Reilly, RJ Rizzo, JD Roifman, CM Small, TN Shearer, WT AF Griffith, Linda M. Cowan, Morton J. Notarangelo, Luigi D. Puck, Jennifer M. Buckley, Rebecca H. Candotti, Fabio Conley, Mary Ellen Fleisher, Thomas A. Gaspar, H. Bobby Kohn, Donald B. Ochs, Hans D. O'Reilly, Richard J. Rizzo, J. Douglas Roifman, Chaim M. Small, Trudy N. Shearer, William T. CA Workshop TI Improving cellular therapy for primary immune deficiency diseases: Recognition, diagnosis, and management SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Allogeneic hematopoietic stem cell transplantation; gene therapy; primary immunodeficiency; clinical trial ID SEVERE COMBINED IMMUNODEFICIENCY; VERSUS-HOST-DISEASE; AUTOIMMUNE HEMOLYTIC-ANEMIA; GENE-THERAPY; MARROW-TRANSPLANTATION; MOLECULAR DEFECTS; EUROPEAN-SOCIETY; THYMIC OUTPUT; BLOOD; CELLS AB More than 20 North American academic centers account for the majority of hematopoietic stem cell transplantation (HCT) procedures for primary immunodeficiency diseases (PIDs), with smaller numbers performed at additional sites. Given the importance of a timely diagnosis of these rare diseases and the diversity of practice sites, there is a need for guidance as to best practices in management of patients with PIDs before, during, and in follow-up for definitive treatment. In this conference report of immune deficiency experts and HCT physicians who care for patients with PIDs, we present expert guidance for (1) PID diagnoses that are indications for HCT, including severe combined immunodeficiency disease (SCID), combined immunodeficiency disease, and other non-SCID diseases; (2) the critical importance of a high degree of suspicion of the primary care physician and timeliness of diagnosis for PIDs; (3) the need for rapid referral to an immune deficiency expert, center with experience in HCT, or both for patients with PIDs; (4) medical management of a child with suspicion of SCID/combined immunodeficiency disease while confirming the diagnosis, including infectious disease management and workup; (5) the posttransplantation follow-up visit schedule; (6) antimicrobial prophylaxis after transplantation, including gamma globulin administration; and (7) important indications for return to the transplantation center after discharge. Finally, we discuss the role of high-quality databases in treatment of PIDs and HCT as an element of the infrastructure that will be needed for productive multicenter clinical trials in these rare diseases. (J Allergy Clin Immunol 2009;124:1152-60.) C1 [Shearer, William T.] Texas Childrens Hosp, Baylor Coll Med, Dept Allergy & Immunol, Houston, TX 77030 USA. [Griffith, Linda M.] NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Cowan, Morton J.] UCSF Childrens Hosp, Pediat Blood & Marrow Transplant Div, San Francisco, CA USA. [Notarangelo, Luigi D.] Harvard Univ, Childrens Hosp, Sch Med, Div Immunol, Boston, MA 02115 USA. [Notarangelo, Luigi D.] Harvard Univ, Childrens Hosp, Sch Med, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Puck, Jennifer M.] Univ Calif San Francisco, Dept Pediat, Inst Human Genet, San Francisco, CA 94143 USA. [Buckley, Rebecca H.] Duke Univ, Sch Med, Durham, NC 27706 USA. [Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Conley, Mary Ellen] Univ Tennessee, Coll Med, Dept Pediat, Memphis, TN USA. [Conley, Mary Ellen] St Jude Childrens Hosp, Dept Immunol, Memphis, TN 38105 USA. [Fleisher, Thomas A.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Gaspar, H. Bobby] UCL, Great Ormond St Hosp, Inst Child Hlth, London WC1E 6BT, England. [Kohn, Donald B.] Univ Calif Los Angeles, Dept Microbiol, Los Angeles, CA 90024 USA. [Kohn, Donald B.] Univ Calif Los Angeles, Dept Immunol, Los Angeles, CA USA. [Kohn, Donald B.] Univ Calif Los Angeles, Dept Mol Genet, Los Angeles, CA USA. [Ochs, Hans D.] Seattle Childrens Hosp, Res Inst, Ctr Immunol & Immunotherapy, Seattle, WA USA. [O'Reilly, Richard J.; Small, Trudy N.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. [O'Reilly, Richard J.; Small, Trudy N.] Mem Sloan Kettering Canc Ctr, Dept Immunol, New York, NY 10021 USA. [Rizzo, J. Douglas] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Roifman, Chaim M.] Univ Toronto, Hosp Sick Children, Div Immunol & Allergy, Toronto, ON M5G 1X8, Canada. RP Shearer, WT (reprint author), Texas Childrens Hosp, Baylor Coll Med, Dept Allergy & Immunol, MC FC330-01,6621 Fannin St,Ste A-380, Houston, TX 77030 USA. EM wshearer@bcm.edu RI Notarangelo, Luigi/F-9718-2016; Kohn, Donald/N-5085-2016; OI Notarangelo, Luigi/0000-0002-8335-0262; Kohn, Donald/0000-0003-1840-6087; Malech, Harry/0000-0001-5874-5775 FU Division of Allergy, Immunology and Transplantation; National Institute of Allergy and Infectious Diseases; Office of Rare Diseases Research, National Institutes of Health, Bethesda, Md FX This workshop was supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases. and the Office of Rare Diseases Research. National Institutes of Health, Bethesda, Md.; Disclosure of potential conflict of interest: M. J. Cowan has received research support from the National Institutes of Health; has provided expert witness testimony on the topic of transplant-related mortality and is Chair of PSIG at the American Society for Blood and Marrow Transplantation. L. D. Notarangelo has received research support from the Manton Foundation, and is on the Steering Committee for the United States Immunodeficiency Network. J. Puck has received research support from the National Institutes of Health, Jeffrey Modell Foundation, United States Immunodeficiency Network. and Baxter. Inc. R. H. Buckley has received research support from the National Institutes of Health, and is Chair of the Medical Advisory Committee for the Immune Deficiency Foundation. M. E. Conley is a consultant for Pharmacyclics; has received royalties from Santa Cruz Biotechnology: and has received research support from the National Institutes of Health. H. R. Gaspar has received research support from the Medical Research Council (UK) and the European Union. H.D. Ochs is on advisory boards for Baxter and CSL Behring, and has received research support from the Jeffrey Modell Foundation, Genetic Defects of Immunity (NIH/NIAID), and Flebogamma 5%. T.N. Small is speaker for Pfizer; is on an advisory board for Wyeth: is on the Data and Safety Monitoring Committee for the American Medical Directors Association: and is married to an employee of Pfizer. The other authors declare that they have no relevant conflicts of interest to disclose. NR 40 TC 47 Z9 51 U1 2 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2009 VL 124 IS 6 BP 1152 EP 1160 DI 10.1016/j.jaci.2009.10.022 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 536VH UT WOS:000273071500003 PM 20004776 ER PT J AU Notarangelo, LD Fischer, A Geha, RS Casanova, JL Chapel, H Conley, ME Cunningham-Rundles, C Etzioni, A Hammartrom, L Nonoyama, S Ochs, HD Puck, J Roifman, C Seger, R Wedgwood, J AF Notarangelo, Luigi D. Fischer, Alain Geha, Raif S. Casanova, Jean-Laurent Chapel, Helen Conley, Mary Ellen Cunningham-Rundles, Charlotte Etzioni, Amos Hammartrom, Lennart Nonoyama, Shigeaki Ochs, Hans D. Puck, Jennifer Roifman, Chaim Seger, Reinhard Wedgwood, Josiah TI Primary immunodeficiencies: 2009 update SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Primary immunodeficiencies; T cells; B cells; severe combined immunodeficiency; predominantly antibody deficiencies; DNA repair defects; phagocytes; complement; immune dysregulation syndromes; innate immunity; autoinflammatory disorders AB More than 50 years after Ogdeon Bruton's discovery of congenital agammaglobulinemia, human primary immunodeficiencies (PIDs) continue to unravel novel molecular and cellular mechanisms that govern development and function of the human immune system. This report provides the updated classification of PIDs that has been compiled by the International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies after its biannual meeting in Dublin, Ireland, in June 2009. Since the appearance of the last classification in 2007, novel forms of PID have been discovered, and additional pathophysiology mechanisms that account for PID in human beings have been unraveled. Careful analysis and prompt recognition of these disorders is essential to prompt effective forms of treatment and thus to improve survival and quality of life in patients affected with PIDs. (J Allergy Clin Immunol 2009;124:1161-78.) C1 [Notarangelo, Luigi D.; Geha, Raif S.] Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Notarangelo, Luigi D.; Geha, Raif S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Fischer, Alain] Hop Necker Enfants Malad, Paris, France. [Casanova, Jean-Laurent] Rockefeller Univ, New York, NY 10021 USA. [Chapel, Helen] Oxford Radcliffe Hosp, Dept Clin Immunol, Oxford, England. [Conley, Mary Ellen] Univ Tennessee, Memphis, TN USA. [Conley, Mary Ellen] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Cunningham-Rundles, Charlotte] Mt Sinai Sch Med, New York, NY USA. [Etzioni, Amos] Technion Israel Inst Technol, Bruce Rappaport Fac Med, Meyers Children Hosp, IL-31096 Haifa, Israel. [Hammartrom, Lennart] Karolinska Univ, Huddinge Hosp, Div Clin Immunol, Stockholm, Sweden. [Nonoyama, Shigeaki] Natl Def Med Coll, Dept Pediat, Tokorozawa, Saitama 359, Japan. [Ochs, Hans D.] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Puck, Jennifer] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Roifman, Chaim] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Seger, Reinhard] Univ Zurich, Kinderklin, Zurich, Switzerland. [Wedgwood, Josiah] NIAID, Bethesda, MD 20892 USA. RP Notarangelo, LD (reprint author), Childrens Hosp, Div Immunol, 1 Blackfan Circle, Boston, MA 02115 USA. EM luigi.notarangelo@childrens.harvard.edu; raif.geha@childrens.harvard.edu RI Notarangelo, Luigi/F-9718-2016 OI Notarangelo, Luigi/0000-0002-8335-0262 FU Jeffrey Modell Foundation; National Institute of Allergy and Infectious Diseases [R13-AI-066891]; National Institutes of Health [Al-35714]; Baxter Healthcare; Talecris; Biotest; Baxter Corp.; March of Dimes; European Community; Swedish Research Council FX Disclosure of potential conflict of interest: J.-L Casanova has consulted for Centocor. H. Chapel has received research support from Baxter Healthcare, Talecris, and Biotest. M. E. Conley has received research support from the National Institutes of Health. C. Cunningham-Rundles has received research support front Baxter Corp. A. Fischer has contracted for INSERM, the European Community, and the French National Research Agency. R.S. Geha has received research support from the National Institutes of Health and the March of Dimes. L. Hammartrom has received research support from the National Institutes of Health, the European Community, and the Swedish Research Council. H. D. Ochs is on advisory boards for Baxter and CSL Behring and has received research support from the Jeffrey Modell Foundation, the National Institutes of Health/National Institute of Allergy and Infectious Diseases, and Flebogamma. J. Puck has received research support from the National Institutes of Health, the Jeffrey Modell Foundation, and Baxter; is on committees for USID Net and the Immune Deficiency Foundation and is a board member of the Immune Tolerance Institute. The rest of the authors have declared that they have no conflict of interest. NR 0 TC 254 Z9 268 U1 1 U2 15 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2009 VL 124 IS 6 BP 1161 EP 1178 DI 10.1016/j.jaci.2009.10.013 PG 18 WC Allergy; Immunology SC Allergy; Immunology GA 536VH UT WOS:000273071500004 ER PT J AU Alexis, NE Zhou, HB Lay, JC Harris, B Hernandez, ML Lu, TS Bromberg, PA Diaz-Sanchez, D Devlin, RB Kleeberger, SR Peden, DB AF Alexis, Neil E. Zhou, Haibo Lay, John C. Harris, Bradford Hernandez, Michelle L. Lu, Tsui-Shan Bromberg, Philip A. Diaz-Sanchez, David Devlin, Robert B. Kleeberger, Steven R. Peden, David B. TI The glutathione-S-transferase Mu 1 null genotype modulates ozone-induced airway inflammation in human subjects SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Glutathione-S-transferase Mu 1; ozone; pollution; inflammation; polymorphonuclear neutrophil; macrophage; dendritic cell ID ANTIOXIDANT SUPPLEMENTATION; HEALTHY-INDIVIDUALS; ASTHMATIC-CHILDREN; ALLERGIC RESPONSES; CHILDHOOD ASTHMA; EPITHELIAL-CELLS; PASSIVE SMOKING; IN-VIVO; EXPOSURE; GSTM1 AB Background: The glutathione-S-transferase Mu 1 (GSTM1) null genotype has been reported to be a risk factor for acute respiratory disease associated with increases in ambient air ozone levels. Ozone is known to cause an immediate decrease in lung function and increased airway inflammation. However, it is not known whether GSTM1 modulates these ozone responses in vivo in human subjects. Objective: The purpose of this study was to determine whether the GSTM1 null genotype modulates ozone responses in human subjects. Methods: Thirty-five healthy volunteers were genotyped for the GSTM1 null mutation and underwent a standard ozone exposure protocol to determine whether lung function and inflammatory responses to ozone were different between the 19 GSTM1 wild type and 16 GSTM1 null volunteers. Results: GSTM1 did not modulate lung function responses to acute ozone. Granulocyte influx 4 hours after challenge was similar between GSTM1 normal and null volunteers. However, GSTM1 null volunteers had significantly increased airway neutrophils 24 hours after challenge, as well as increased expression of HLA-DR on airway macrophages and dendritic cells. Conclusion: The GSTM1 null genotype is associated with increased airways inflammation 24 hours after ozone exposure, which is consistent with the lag time observed between increased ambient air ozone exposure and exacerbations of lung disease. (J Allergy Clin Immunol 2009;124:1222-8.) C1 [Alexis, Neil E.; Zhou, Haibo; Lay, John C.; Harris, Bradford; Hernandez, Michelle L.; Lu, Tsui-Shan; Bromberg, Philip A.; Peden, David B.] Univ N Carolina, Ctr Environm Med Asthma & Lung Biol, Sch Med, Chapel Hill, NC 27599 USA. [Bromberg, Philip A.; Peden, David B.] Univ N Carolina, Dept Med, Sch Med, Chapel Hill, NC 27599 USA. [Alexis, Neil E.; Lay, John C.; Harris, Bradford; Hernandez, Michelle L.; Peden, David B.] Univ N Carolina, Dept Pediat, Sch Med, Chapel Hill, NC 27599 USA. [Zhou, Haibo; Lu, Tsui-Shan] Gillings Sch Global Publ Hlth, Dept Biostat, Chapel Hill, NC USA. [Diaz-Sanchez, David; Devlin, Robert B.] US EPA, Environm Publ Hlth Div, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Kleeberger, Steven R.] Natl Inst Environm Hlth Sci, Lab Resp Biol, Res Triangle Pk, NC USA. RP Peden, DB (reprint author), Univ N Carolina, Ctr Environm Med Asthma & Lung Biol, Sch Med, 104 Mason Farm Rd,CB 7310, Chapel Hill, NC 27599 USA. EM peden@med.unc.edu RI Lay, John/A-6380-2012 FU National Institutes of Health [R01ES012706, P30ES010126, P01AT002620]; US Environmental Protection Agency [CR-83346301]; National Institute of Environmental Health Sciences Division of Intramural Research FX Supported by National Institutes of Health grants R01ES012706, P30ES010126, and P01AT002620. US Environmental Protection Agency Cooperative Agreement CR-83346301, and the National Institute of Environmental Health Sciences Division of Intramural Research. Although the research described in this article has been funded wholly or in part by the United States Environmental Protection Agency through Cooperative agreement CR-83346301 with the Center for Environmental Medicine and Lung Biology at the University of North Carolina at Chapel Hill, it has not been subjected to the Agency's required peer and policy review and therefore does not necessarily reflect the views of the Agency, and no official endorsement should be inferred. NR 32 TC 37 Z9 38 U1 0 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2009 VL 124 IS 6 BP 1222 EP 1228 DI 10.1016/j.jaci.2009.07.036 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 536VH UT WOS:000273071500013 PM 19796798 ER PT J AU Engelhardt, KR McGhee, S Winkler, S Sassi, A Woellner, C Lopez-Herrera, G Chen, A Kim, HS Lloret, MG Schulze, I Ehl, S Thiel, J Pfeifer, D Veelken, H Niehues, T Siepermann, K Weinspach, S Reisli, I Keles, S Genel, F Kutuculer, N Camcioglu, Y Somer, A Karakoc-Aydiner, E Barlan, I Gennery, A Metin, A Degerliyurt, A Pietrogrande, MC Yeganeh, M Baz, Z Al-Tamemi, S Klein, C Puck, JM Holland, SM McCabe, ERB Grimbacher, B Chatila, TA AF Engelhardt, Karin R. McGhee, Sean Winkler, Sabine Sassi, Atfa Woellner, Cristina Lopez-Herrera, Gabriela Chen, Andrew Kim, Hong Sook Lloret, Maria Garcia Schulze, Ilka Ehl, Stephan Thiel, Jens Pfeifer, Dietmar Veelken, Hendrik Niehues, Tim Siepermann, Kathrin Weinspach, Sebastian Reisli, Ismail Keles, Sevgi Genel, Ferah Kutuculer, Necil Camcioglu, Yildiz Somer, Ayper Karakoc-Aydiner, Elif Barlan, Isil Gennery, Andrew Metin, Ayse Degerliyurt, Aydan Pietrogrande, Maria C. Yeganeh, Mehdi Baz, Zeina Al-Tamemi, Salem Klein, Christoph Puck, Jennifer M. Holland, Steven M. McCabe, Edward R. B. Grimbacher, Bodo Chatila, Talal A. TI Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Autosomal recessive hyper-IgE syndrome; human gene mutation; DOCK8; primary immunodeficiency; molluscum contagiosum; recurrent infection; T cells; T(H)17 cells; eosinophils; IgE regulation; copy number variations; genomic deletions ID IDENTIFICATION; REARRANGEMENTS; GENOME AB Background: The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60% to 70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining patients with hyper-IgE syndrome, the genetic etiology has not yet been identified. Objectives: We aimed to identify a gene that is mutated or deleted in autosomal recessive hyper-IgE syndrome. Methods: We performed genome-wide single nucleotide polymorphism analysis for 9 patients with autosomal-recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with 12 patients from 7 additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal-recessive hyper-IgE syndrome. Results: Subtelomeric biallelic microdeletions were identified in 5 patients at the terminus of chromosome 9p. In all 5 patients, the deleted interval involved dedicator of cytokinesis 8 (DOCK8), encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of patients without large deletions revealed 16 patients from 9 unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, and single exon deletions and microdeletions. DOCK8 deficiency was associated with impaired activation of CD4(+) and CD8(+)T cells. Conclusion: Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of wautosomal-recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T-cell activation and T(H)17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE. (J Allergy Clin Immunol 2009;124:1289-302.) C1 [Engelhardt, Karin R.; Winkler, Sabine; Woellner, Cristina; Lopez-Herrera, Gabriela; Grimbacher, Bodo] Royal Free Hosp, Dept Immunol & Mol Pathol, London NW3 2QG, England. [Engelhardt, Karin R.; Winkler, Sabine; Woellner, Cristina; Lopez-Herrera, Gabriela; Grimbacher, Bodo] UCL, London NW3 2QG, England. [McGhee, Sean; Chen, Andrew; Kim, Hong Sook; Lloret, Maria Garcia; Chatila, Talal A.] Univ Calif Los Angeles, David Geffen Sch Med, Div Immunol Allergy & Rheumatol, Dept Pediat, Los Angeles, CA 90095 USA. [Sassi, Atfa] Inst Pasteur Tunis, Lab Immunol Vaccinol & Genet Mol, Tunis, Tunisia. [Schulze, Ilka; Ehl, Stephan; Thiel, Jens] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany. [Pfeifer, Dietmar; Veelken, Hendrik] Univ Med Ctr Freiburg, Dept Hematol Oncol, Freiburg, Germany. [Niehues, Tim; Siepermann, Kathrin] HELIOS Klinikum Krefeld, Zentrum Kinder & Jugendmed, Krefeld, Germany. [Weinspach, Sebastian] Univ Dusseldorf, Dept Pediat Oncol Hematol & Clin Immunol, Ctr Child & Adolescent Med, Dusseldorf, Germany. [Reisli, Ismail; Keles, Sevgi] Selcuk Univ, Div Pediat Allergy & Immunol, Konya, Turkey. [Genel, Ferah] Behcet Uz State Hosp, Div Pediat Immunol, Izmir, Turkey. [Kutuculer, Necil] Ege Univ, Fac Med, Dept Pediat, Izmir, Turkey. [Camcioglu, Yildiz] Istanbul Univ, Cerrahpasa Med Fac, Div Pediat Allergy Immunol & Infect Dis, Istanbul, Turkey. [Somer, Ayper] Istanbul Univ, Istanbul Fac Med, Div Infect Dis & Immunol, Istanbul, Turkey. [Karakoc-Aydiner, Elif; Barlan, Isil] Marmara Univ, Div Pediat Allergy & Immunol, Istanbul, Turkey. [Gennery, Andrew] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Metin, Ayse; Degerliyurt, Aydan] SB Ankara Diskapi Childrens Hosp, Pediat Immunol Unit, Ankara, Turkey. [Pietrogrande, Maria C.] Univ Milan, Fdn IRCCS Policlin Milano, Dept Maternal & Pediat Sci, Milan, Italy. [Yeganeh, Mehdi] Univ Tehran Med Sci, Childrens Med Ctr, Immunol Asthma & Allergy Res Inst, Tehran, Iran. [Baz, Zeina] Univ Med Ctr, St George Hosp, Dept Pediat, Beirut, Lebanon. [Al-Tamemi, Salem] Sultan Qaboos Univ, Dept Pediat, Muscat, Oman. [Klein, Christoph] Hannover Biomed Res Sch, Dept Pediat Hematol Oncol, Hannover, Germany. [Puck, Jennifer M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Holland, Steven M.] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Holland, Steven M.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. [Holland, Steven M.] Univ Calif Los Angeles, Dept Bioengn, Los Angeles, CA USA. [Holland, Steven M.] Univ Calif Los Angeles, Ctr Soc & Genet, Los Angeles, CA USA. RP Grimbacher, B (reprint author), Royal Free Hosp, Dept Immunol & Mol Pathol, Pond St, London NW3 2QG, England. EM b.grimbacher@ucl.ac.uk; tchatila@mednet.ucla.edu OI Veelken, Hendrik/0000-0002-9108-3125 FU National Institutes of Health [5R01AI065617, IR21AI087627]; EU [MEXT-CT-2006-042316, FP7/2007-2013, HEALTH-F2-2008-201549] FX Supported by National Institutes of Health grants 5R01AI065617 and IR21AI087627 to T.C. and by the EU Marie-Curie grant MEXT-CT-2006-042316 and the European Community's 7th Framework Programme FP7/2007-2013 grant EURO-PADnet HEALTH-F2-2008-201549 to B.G. NR 22 TC 201 Z9 204 U1 1 U2 17 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2009 VL 124 IS 6 BP 1289 EP 1302 DI 10.1016/j.jaci.2009.10.038 PG 14 WC Allergy; Immunology SC Allergy; Immunology GA 536VH UT WOS:000273071500022 PM 20004785 ER PT J AU Ogbogu, PU Bochner, BS Butterfield, JH Gleich, GJ Huss-Marp, J Kahn, JE Leiferman, KM Nutman, TB Pfab, F Ring, J Rothenberg, ME Roufosse, F Sajous, MH Sheikh, J Simon, D Simon, HU Stein, ML Wardlaw, A Weller, PF Klion, AD AF Ogbogu, Princess U. Bochner, Bruce S. Butterfield, Joseph H. Gleich, Gerald J. Huss-Marp, Johannes Kahn, Jean Emmanuel Leiferman, Kristin M. Nutman, Thomas B. Pfab, Florian Ring, Johannes Rothenberg, Marc E. Roufosse, Florence Sajous, Marie-Helene Sheikh, Javed Simon, Dagmar Simon, Hans-Uwe Stein, Miguel L. Wardlaw, Andrew Weller, Peter F. Klion, Amy D. TI Hypereosinophilic syndrome: A multicenter, retrospective analysis of clinical characteristics and response to therapy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Eosinophil; hypereosinophilic syndrome; FIP1L1-PDGFRA ID IDIOPATHIC EOSINOPHILIA; LYMPHOCYTIC VARIANT; IMATINIB; MEPOLIZUMAB; PREVALENCE; FUSION AB Background: Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by persistent blood eosinophilia >= 1.5 X 10(9)/L, absence of a secondary cause, and evidence of eosinophil-associated pathology. With the exception of a recent multicenter trial of mepolizumab (anti-IL-5 mAb), published therapeutic experience has been restricted to case reports and small case series. Objective: The purpose of the study was to collect and summarize baseline demographic, clinical, and laboratory characteristics in a large, diverse cohort of patients with HES and to review responses to treatment with conventional and novel therapies. Methods: Clinical and laboratory data from 188 patients with HES, seen between January 2001 and December 2006 at 11 institutions in the United States and Europe, were collected retrospectively by chart review. Results: Eighteen of 16.1. patients (11%) tested were Fip1-like I-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) mutation-positive, and 29 of 168 patients tested (17%) had a demonstrable aberrant or clonal T-cell population. Corticosteroid monotherapy induced complete or partial responses at I month in 85% (120/141) of patients with most remaining on maintenance doses (median, 10 mg prednisone equivalent daily for 2 months to 20 years). Hydroxyurea and IFN-alpha (used in 64 and 46 patients, respectively) were also effective, but their use was limited by toxicity. Imatinib (used in 68 patients) was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001). Conclusion: This study, the largest clinical analysis of patient's with HES to date, not only provides useful information for clinicians but also should stimulate prospective trials to optimize treatment of HES. (J Allergy Clin Immunol 2009;124:1319-25.) C1 [Ogbogu, Princess U.; Nutman, Thomas B.; Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Bochner, Bruce S.; Sajous, Marie-Helene] Johns Hopkins Univ, Sch Med, Dept Med, Div Clin Immunol & Allergy, Baltimore, MD 21205 USA. [Butterfield, Joseph H.] Mayo Clin, Div Allerg Dis, Rochester, MN USA. [Leiferman, Kristin M.] Univ Utah, Dept Dermatol, Salt Lake City, UT 84112 USA. [Gleich, Gerald J.] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. [Huss-Marp, Johannes; Pfab, Florian] Tech Univ Munich, Helmholtz Ctr Munich, ZAUM Ctr Allergy & Environm, Div Environm Dermatol & Allergy, Munich, Germany. [Huss-Marp, Johannes; Pfab, Florian; Ring, Johannes] Tech Univ Munich, Dept Dermatol & Allergy Biederstein, Munich, Germany. [Kahn, Jean Emmanuel] Hop Foch, Dept Internal Med, Suresnes, France. [Kahn, Jean Emmanuel] CHRU Lille, Dept Immunol, French Eosinophil Network, Lille, France. [Rothenberg, Marc E.; Stein, Miguel L.] Cincinnati Childrens Hosp, Med Ctr, Div Allergy & Immunol, Cincinnati, OH USA. [Roufosse, Florence] Univ Libre Bruxelles, Hop Erasme, Dept Med Interne, Brussels, Belgium. [Roufosse, Florence] Univ Libre Bruxelles, Inst Med Immunol, Gosselies, Belgium. [Sheikh, Javed; Weller, Peter F.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Simon, Dagmar] Univ Bern, Inselspital, Dept Dermatol, CH-3012 Bern, Switzerland. [Simon, Hans-Uwe] Univ Bern, Inst Pharmacol, CH-3012 Bern, Switzerland. [Wardlaw, Andrew] Univ Leicester, Inst Lung Hlth, Leicester LE1 7RH, Leics, England. RP Klion, AD (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 50,Rm 6351, Bethesda, MD 20892 USA. EM aklion@nih.gov OI Simon, Hans-Uwe/0000-0002-9404-7736; Klion, Amy/0000-0002-4986-5326; Wardlaw, Andrew/0000-0001-6583-0791 FU Division of Intramural Research of the NIAID/NIH; NIH [AI41472, AI72265, AI061097]; Dana Foundation; Swiss National Science Foundation; Belgian National Fund for Scientific Research; Campaign Urging Research for Eosinophilic Disorders FX Supported by the Division of Intramural Research of the NIAID/NIH (A.D.K., P.U.O., T.B.N.), grants AI41472 and AI72265 from the NIH (B.S.B.), grant AI061097 from the NIH (G.J.G.), the Human Immunology grant program of the Dana Foundation (B.S.B,). the Swiss National Science Foundation (H.-U.S.), the Belgian National Fund for Scientific Research (F.R.), and the Campaign Urging Research for Eosinophilic Disorders (M.E.R.). B.S.B. is a Cosner Scholar in Translational Research from Johns Hopkins University. The funding organizations had no role in the design and conduct of the study; collection. management, analysis, and interpretation of the data; and preparation or review of the manuscript. The manuscript was approved by the Division of Intramural Research. NIAID/NIH. NR 17 TC 145 Z9 160 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2009 VL 124 IS 6 BP 1319 EP 1325 DI 10.1016/j.jaci.2009.09.022 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 536VH UT WOS:000273071500026 PM 19910029 ER PT J AU Prussin, C Lee, J Foster, B AF Prussin, Calman Lee, Joohee Foster, Barbara TI Eosinophilic gastrointestinal disease and peanut allergy are alternatively associated with IL-5(+) and IL-5(-) T(H)2 responses SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Food allergy; peanut; T cell; T(H)2; eosinophil-associated gastrointestinal disease; IL-4; IL-5; flow cytometry ID T-CELL RESPONSES; PERIPHERAL-BLOOD; CD154 EXPRESSION; ADULT PATIENTS; TH2 CELLS; ESOPHAGITIS; CYTOKINE; INDIVIDUALS; DISORDERS; CHILDREN AB Background: Both anaphylactic food allergy and eosinophil-associated gastrointestinal disorders are associated with T(H)2 responses and food-specific IgE, yet they have very different clinical presentations. Objective: To determine whether the clinical differences between anaphylactic food allergy and eosinophil-associated gastrointestinal disorders are reflected in different T(H)2 responses to foods. Methods: Subjects with peanut allergy (PA), subjects with allergic eosinophilic gastroenteritis (AEG), and nonatopic subjects were enrolled. Antigen-specific IL-4, IL-5, IFN-gamma, and TNF T-cell responses to peanut, soy, and shrimp were measured by using intracellular cytokine staining and polychromatic flow cytometry. Results: Two distinct subpopulations of T(H)2 cells were found: IL-5(+) T,2 (IL-4(+), IL-5(+)) and IL-5(-) T(H)2 (IL-4(+), IL-5(-)) cells. Peanut-specific IL-5(+) T(H)2 cells were present at a 20-fold greater frequency in AEG versus PA (81 vs 4 per 10(6) CD4 cells; P = .05), whereas there were similar frequencies of IL-5(-) T(H)2 cells (67 vs 41 per 106). For all foods, IL-5(+) T(H)2 cells accounted for a significantly greater fraction of the antigen-specific cells in AEG relative to PA (29% vs 4%; P < .0001). In PA but not AEG, IL-5(-) T(H)2 responses to peanut were highly correlated with peanut-specific IgE (r = 0.87 vs 0.55, respectively). All subject groups elicited similar very low-magnitude T(H)1 responses to food antigens. Conclusion: T(H)2 responses are composed of 2 subpopulations: IL-5(+) T(H)2 and IL-5(-) T(H)2 cells. IL-5(+) T(H)2 food allergen-specific T cells are singularly associated with AEG, whereas PA is associated with a dominant IL-5(-) T(H)2 response. These results suggest heterogeneity within the T(H)2 cytokine response, with different T(H)2 responses alternatively favoring IgE-mediated or eosinophil-dominant immunopathology. (J Allergy Clin Immunol 2009;124:1326-32.) C1 [Prussin, Calman; Lee, Joohee; Foster, Barbara] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Prussin, C (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C207, Bethesda, MD 20892 USA. EM cprussin@niaid.nih.gov OI Prussin, Calman/0000-0002-3917-3326 FU National Institute of Allergy and Infectious Diseases, NIH FX Supported by the National Institute of Allergy and Infectious Diseases, NIH, Intramural Research Program. NR 27 TC 47 Z9 48 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2009 VL 124 IS 6 BP 1326 EP 1332 DI 10.1016/j.jaci.2009.09.048 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 536VH UT WOS:000273071500027 PM 20004787 ER PT J AU Willson, S Stussman, B Maitland, A Nahin, RL AF Willson, Stephanie Stussman, Barbara Maitland, Aaron Nahin, Richard L. TI Role of Self-Concept in Answering Survey Questions on Complementary and Alternative Medicine: Challenges to and Strategies for Improving Data Quality SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Article AB Objectives: The aim of this study was to assess the construct validity of survey questions about the use of herbal and other nonvitamin/nonmineral dietary supplements. Design: We conducted one-on-one, in-depth cognitive interviews with 32 respondents to test questions from the complementary and alternative medicine (CAM) supplement for the 2007 National Health Interview Survey. Respondents were sampled purposively according to their use of CAM. Interviewers probed respondents for their understanding of the questions, and analysis was guided by grounded theory, an approach that generates explanations of response error that are closely tied to the empirical data. Results: We found two sources of misinterpretation of CAM questions. First, some respondents did not have any pre-established definition of what constitutes an herbal supplement while others had interpretations that did not match the intended definitions. These problems are common to many survey questions. However, a second finding is that misinterpretation also arose when respondents incorporated notions of self-concept into the act of taking "natural herbs,'' and answered based on their understanding of this image rather than on actual behavior. Conclusions: There are several sources of misinterpretation of CAM questions. One of the most important sources is whether or not the respondent has created a concept of self-image that includes the use of herbal supplements. Common questionnaire design techniques such as providing definitions to respondents will not help to eliminate misinterpretation due to self-image. We found that careful question wording that does not evoke definitions of self, combined with visual aids that narrow the focus of the questions, can lead to more accurate answers. C1 [Willson, Stephanie; Stussman, Barbara; Maitland, Aaron] Natl Ctr Hlth Stat, Off Res & Methodol, Hyattsville, MD 20782 USA. [Nahin, Richard L.] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. RP Willson, S (reprint author), Natl Ctr Hlth Stat, Off Res & Methodol, 3311 Toledo Rd,Room 3223, Hyattsville, MD 20782 USA. EM swillson@cdc.gov OI Nahin, Richard/0000-0002-3682-4816 NR 8 TC 4 Z9 4 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1075-5535 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD DEC PY 2009 VL 15 IS 12 BP 1319 EP 1325 DI 10.1089/acm.2008.0580 PG 7 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 532MZ UT WOS:000272754300014 PM 19954343 ER PT J AU Lakatta, EG AF Lakatta, Edward G. TI SPONTANEOUS FORMS OF CALCIUM RELEASE THAT STAY LOCAL SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Letter C1 NIA, Cardiovasc Sci Lab, Bethesda, MD 20892 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD DEC PY 2009 VL 107 IS 6 BP 1987 EP 1987 PG 1 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 526PO UT WOS:000272304400044 ER PT J AU Hattori, T Saito, K Takemura, M Ito, H Ohta, H Wada, H Sei, Y Kawamura, M Seishima, M AF Hattori, Takayuki Saito, Kuniaki Takemura, Masao Ito, Hiroyasu Ohta, Hirotoshi Wada, Hisayasu Sei, Yoshitatsu Kawamura, Mitsunobu Seishima, Mitsuru TI Statin-Induced Ca2+ Release was Increased in B Lymphocytes in Patients who Showed Elevated Serum Creatine Kinase During Statin Treatment SO JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS LA English DT Article DE Statin drugs; Calcium release; Ryanodine receptor; B lymphocyte ID COA REDUCTASE INHIBITORS; MALIGNANT HYPERTHERMIA SUSCEPTIBILITY; SKELETAL-MUSCLE FIBERS; RYANODINE RECEPTOR; IN-VITRO; CONTRACTURE TEST; CELLS; ATORVASTATIN; CHOLESTEROL; APOPTOSIS AB Aim: Statins are effective in lowering cholesterol levels, but cause fatal rhabdomyolysis in susceptible individuals. Because it has been hypothesized that muscle damage could result from alterations in Ca2+ homeostasis in muscle cells, we tested whether measuring statin-induced changes in intracellular calcium ([Ca2+](i)) is useful for predicting susceptibility to statin-muscle damage, using human CD19+ primary B lymphocytes. Methods: Statin-induced alterations in [Ca2+](i) were studied using the human THP-1 cell line and CD19+ primary B lymphocytes. Changes in [Ca2+](i) were measured directly in fluo-3- loaded cells using either single or dual-color flow cytometry. Results: The Ca2+ release study suggested that statin-induced changes in [Ca2+](i) were due to Ca2+ release from ryanodine-sensitive Ca2+ stores and mitochondrial compartments. Further, statin users who experienced elevated creatine kinase (n=8) exhibited significantly greater statin-induced Ca2+ release in B cells than healthy volunteers (n=45) and statin users without elevated creatine kinase (n=16), while no difference was seen between the latter two groups. Conclusion: Statin-induced Ca2+ release from ryanodine-sensitive stores and mitochondria may contribute to myotoxicity. The laboratory test for Ca2+ release using CD19+ primary B lymphocytes may be useful to predict susceptibility to statin-induced muscle toxicity prior to statin use. C1 [Hattori, Takayuki; Saito, Kuniaki; Takemura, Masao; Ito, Hiroyasu; Ohta, Hirotoshi; Wada, Hisayasu; Seishima, Mitsuru] Gifu Univ, Grad Sch Med, Dept Informat Clin Med, Gifu 5011194, Japan. [Saito, Kuniaki] Kyoto Univ, Grad Sch Med, Kyoto, Japan. [Saito, Kuniaki] Kyoto Univ, Fac Med, Kyoto, Japan. [Sei, Yoshitatsu] NIMH, Bethesda, MD 20892 USA. [Kawamura, Mitsunobu] Tokyo Teishin Hosp, Div Endocrinol & Metab, Tokyo, Japan. RP Seishima, M (reprint author), Gifu Univ, Grad Sch Med, Dept Informat Clin Med, Gifu 5011194, Japan. EM seishima@gifu-u.ac.jp OI Kawamura, Mitsunobu/0000-0002-8212-7990 FU Ministry for Education, Culture, Sports, Science and Technology of Japan [18590525] FX This Study was supported by a Grant-in-Aid for Scientific Research (18590525) from the Ministry for Education, Culture, Sports, Science and Technology of Japan. The authors thank Daiichi-Sankyo Co. Ltd (Tokyo, Japan) for the generous gift of statins, including simvastatin, fluvastatin, rosuvastatin, and pravastatin. The authors also thank Mr. John Cole for proofreading the English of this manuscript. NR 41 TC 3 Z9 3 U1 0 U2 0 PU JAPAN ATHEROSCLEROSIS SOC PI TOKYO PA NICHINAI-KAIKAN B1, 3-28-8 HONGO BUNKYO-KU, TOKYO, 113-0033, JAPAN SN 1340-3478 EI 1880-3873 J9 J ATHEROSCLER THROMB JI J. Atheroscler. Thromb. PD DEC PY 2009 VL 16 IS 6 BP 870 EP 877 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 541WU UT WOS:000273452800021 PM 20032581 ER PT J AU Wallace, GL Silvers, JA Martin, A Kenworthy, LE AF Wallace, Gregory L. Silvers, Jennifer A. Martin, Alex Kenworthy, Lauren E. TI Brief Report: Further Evidence for Inner Speech Deficits in Autism Spectrum Disorders SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism; Asperger's syndrome; Inner speech; Executive function; Problem solving; Language ID DIAGNOSTIC INTERVIEW; WORKING-MEMORY; PRIVATE SPEECH; CHILDREN; TASK; LONDON; TOWER; PERFORMANCE AB Recent research indicates that individuals with autism do not effectively use inner speech during the completion of cognitive tasks. We used Articulatory Suppression (AS) to interfere with inner speech during completion of alternate items from the Tower of London (TOL). AS detrimentally affected TOL performance among typically developing (TD) adolescents (n = 25), but did not significantly diminish performance among adolescents with high functioning (IQ > 80) autism spectrum disorders (n = 28). Moreover, the TD group's TOL performance under AS was indistinguishable from the autism group's impaired baseline TOL performance. These findings suggest that diminished inner speech usage among individuals with high functioning autism spectrum disorders (relative to TD controls) may contribute to executive dysfunction associated with these disorders. C1 [Wallace, Gregory L.; Silvers, Jennifer A.; Martin, Alex; Kenworthy, Lauren E.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Kenworthy, Lauren E.] George Washington Univ, Sch Med & Hlth Sci, Childrens Natl Med Ctr, Washington, DC 20052 USA. [Kenworthy, Lauren E.] George Washington Univ, Sch Med & Hlth Sci, Dept Psychiat & Behav Sci, Ctr Autism Spectrum Disorders, Washington, DC 20052 USA. RP Wallace, GL (reprint author), NIMH, Lab Brain & Cognit, 10 Ctr Dr,MSC 1366,Bldg 10,Room 4C104, Bethesda, MD 20892 USA. EM gregwallace@mail.nih.gov RI martin, alex/B-6176-2009; OI Wallace, Gregory/0000-0003-0329-5054 FU Intramural NIH HHS [Z99 MH999999] NR 25 TC 27 Z9 27 U1 3 U2 10 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD DEC PY 2009 VL 39 IS 12 BP 1735 EP 1739 DI 10.1007/s10803-009-0802-8 PG 5 WC Psychology, Developmental SC Psychology GA 519LF UT WOS:000271767400011 PM 19565331 ER PT J AU Parham, F Austin, C Southall, N Huang, R Tice, R Portier, C AF Parham, Fred Austin, Chris Southall, Noel Huang, Ruili Tice, Raymond Portier, Christopher TI Dose-Response Modeling of High-Throughput Screening Data SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE high-throughput screening; dose response; statistical modeling; viability assay AB The National Toxicology Program is developing a high-throughput screening (HTS) program to set testing priorities for compounds of interest, to identify mechanisms of action, and potentially to develop predictive models for human toxicity. This program will generate extensive data on the activity of large numbers of chemicals in a wide variety of biochemical-and cell-based assays. The first step in relating patterns of response among batteries of HTS assays to in vivo toxicity is to distinguish between positive and negative compounds in individual assays. Here, the authors report on a statistical approach developed to identify compounds positive or negative in an HTS cytotoxicity assay based on data collected from screening 1353 compounds for concentration-response effects in 9 human and 4 rodent cell types. In this approach, the authors develop methods to normalize the data (removing bias due to the location of the compound on the 1536-well plates used in the assay) and to analyze for concentration-response relationships. Various statistical tests for identifying significant concentration-response relationships and for addressing reproducibility are developed and presented. (Journal of Biomolecular Screening 2009:1216-1227) C1 [Parham, Fred; Portier, Christopher] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Austin, Chris; Southall, Noel; Huang, Ruili] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Tice, Raymond] NIEHS, NIH, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Parham, F (reprint author), NIEHS, NIH, MD A3-06,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM parham@niehs.nih.gov RI Southall, Noel/H-8991-2012; Portier, Christopher/A-3160-2010 OI Southall, Noel/0000-0003-4500-880X; Portier, Christopher/0000-0002-0954-0279 FU NIH; National Institute of Environmental Health Sciences; National Human Genome Research Institute FX We thank Menghang Xia for providing the data sets on which the analysis was based. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, and the National Human Genome Research Institute. NR 11 TC 11 Z9 11 U1 0 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD DEC PY 2009 VL 14 IS 10 BP 1216 EP 1227 DI 10.1177/1087057109349355 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 530ZX UT WOS:000272632600007 PM 19828774 ER PT J AU Wang, YG Dasso, M AF Wang, Yonggang Dasso, Mary TI SUMOylation and deSUMOylation at a glance SO JOURNAL OF CELL SCIENCE LA English DT Article ID UBIQUITIN-LIKE PROTEINS; E3 LIGASE ACTIVITY; IN-VIVO; STRUCTURAL BASIS; CONJUGATING ENZYME; SUMO MODIFICATIONS; COMPLEX; YEAST; INSIGHTS; RANGAP1 C1 [Wang, Yonggang; Dasso, Mary] NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Dasso, M (reprint author), NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. EM mdasso@helix.nih.gov OI Dasso, Mary/0000-0002-5410-1371 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural [Z01 HD001902] FX This work was supported through Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural funds (Z01 HD001902). Deposited in PMC for release after 12 months. NR 59 TC 71 Z9 73 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 DEC 1 PY 2009 VL 122 IS 23 BP 4249 EP 4252 DI 10.1242/jcs.050542 PG 4 WC Cell Biology SC Cell Biology GA 521SP UT WOS:000271944600001 PM 19923268 ER PT J AU Ma, H Blake, T Chitnis, A Liu, P Balla, T AF Ma, Hui Blake, Trevor Chitnis, Ajay Liu, Paul Balla, Tamas TI Crucial role of phosphatidylinositol 4-kinase III alpha in development of zebrafish pectoral fin is linked to phosphoinositide 3-kinase and FGF signaling SO JOURNAL OF CELL SCIENCE LA English DT Article DE PI4K; PI3K; FGF signaling; Zebrafish; Limb development ID GROWTH-FACTOR; EMBRYONIC-DEVELOPMENT; VERTEBRATE LIMB; MAP-KINASE; PHOSPHOLIPASE-C-GAMMA-1; HEMATOPOIESIS; EXPRESSION; RECEPTORS; OUTGROWTH; MKP3 AB Phosphatidylinositol 4-kinases (PI4Ks) catalyze the first committed step in the synthesis of phosphoinositides, important lipid regulators of signaling and trafficking pathways. Here we cloned Pik4a, one of the zebrafish PI4K enzymes, and studied its role(s) in vertebrate development using morpholino oligonucleotide-based gene silencing in zebrafish. Downregulation of Pik4a led to multiple developmental abnormalities, affecting the brain, heart, trunk and most prominently causing loss of pectoral fins. Strikingly similar defects were caused by treatment of the developing embryos with the phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. To investigate the cause of the pectoral fin developmental defect, we focused on fibroblast growth factor (FGF) signaling pathways because vertebrate limb development requires the concerted action of a series of FGF ligands. Using in situ hybridization, the pectoral fin defect was traced to disruption of the early FGF signaling loops that are crucial for the establishment of the sharp signaling center formed by the apical ectodermal ridge and the underlying mesenchyme. This, in turn caused a prominent loss of the induction of one of the mitogen-activated protein kinase (MAPK) phosphatases, Mkp3, an essential intermediate in vertebrate limb development. These changes were associated with impaired proliferation in the developing fin bud due to a loss of balance between the MAPK and PI3K branch of FGF-initiated signals. Our results identify Pik4a as an upstream partner of PI3Ks in the signaling cascade orchestrated by FGF receptors with a prominent role in forelimb development. C1 [Ma, Hui; Balla, Tamas] NICHHD, Sect Mol Signal Transduct, NIH, Bethesda, MD 20892 USA. [Blake, Trevor; Liu, Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Chitnis, Ajay] NICHHD, Sect Neural Dev Dynam, NIH, Bethesda, MD 20892 USA. RP Balla, T (reprint author), NICHHD, Sect Mol Signal Transduct, NIH, Bethesda, MD 20892 USA. EM ballat@mail.nih.gov RI Liu, Paul/A-7976-2012; OI Liu, Paul/0000-0002-6779-025X; Balla, Tamas/0000-0002-9077-3335 FU National Institute of Child Health and Human Development; National Human Genome Research Institute of the National Institutes of Health FX We would like to thank Gregory Palardy for his help with the injections and Milton English for his technical suggestions. This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development and the National Human Genome Research Institute of the National Institutes of Health. Deposited in PMC for release after 12 months. NR 34 TC 13 Z9 14 U1 0 U2 3 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 DEC 1 PY 2009 VL 122 IS 23 BP 4303 EP 4310 DI 10.1242/jcs.057646 PG 8 WC Cell Biology SC Cell Biology GA 521SP UT WOS:000271944600007 PM 19887586 ER PT J AU Liao, CZ Nicklaus, MC AF Liao, Chenzhong Nicklaus, Marc C. TI Comparison of Nine Programs Predicting pK(a) Values of Pharmaceutical Substances SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID DENSITY-FUNCTIONAL THEORY; PH-TITRATION DATA; COMPUTATIONAL DETERMINATION; DISSOCIATION-CONSTANTS; IONIZATION-CONSTANTS; NONLINEAR-REGRESSION; SUBSTITUTED PHENOLS; ACCURATE PREDICTION; ACIDITY CONSTANTS; AQUEOUS-SOLUTION AB Knowledge of the possible ionization states of a pharmaceutical substance, embodied in the pK(a) values (logarithm of the acid dissociation constant), is vital for understanding many properties essential to drug development. We compare nine commercially available or free programs for predicting ionization constants. Eight of these programs are based oil empirical methods: ACD/pK(a) DB 12.0, ADME Boxes 4.9, ADMET Predictor 3.0, Epik 1.6, Marvin 5.1.4, Pallas pKalc Net 2.0, Pipeline Pilot 5.0, and SPARC 4.2; one program is based on a quantum chemical method: Jaguar 7.5. We compared their performances by applying them to 197 pharmaceutical substances with 261 carefully determined and highly reliable experimental pK(a) values from a literature source. The programs ADME Boxes 4.9, ACD/pK(a) DB 12.0, and SPARC 4.2 ranked as the top three with mean absolute deviations of 0.389, 0.478, and 0.651 and r(2) values of 0.944, 0.908, and 0.894, respectively. ACD/pK(a) DB 12.0 predicted all sites, whereas ADME Boxes 4.9 and SPARC 4.2 failed to predict 5 and 18 sites, respectively. The performance of the quantum chemical-based program Jaguar 7.5 was not as expected, with a mean absolute deviation of 1.283 and an r(2) value of 0.579, indicating the potential for further development of this type of approach to pK(a) prediction. C1 [Liao, Chenzhong; Nicklaus, Marc C.] NCI, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. RP Nicklaus, MC (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, 376 Boyles St, Frederick, MD 21702 USA. EM mn1@helix.nih.gov RI Nicklaus, Marc/N-4183-2014; OI Nicklaus, Marc/0000-0002-4775-7030 NR 42 TC 63 Z9 66 U1 3 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD DEC PY 2009 VL 49 IS 12 BP 2801 EP 2812 DI 10.1021/ci900289x PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA 535AB UT WOS:000272937800017 PM 19961204 ER PT J AU Das, D Koh, Y Tojo, Y Ghosh, AK Mitsuya, H AF Das, Debananda Koh, Yasuhiro Tojo, Yasushi Ghosh, Arun K. Mitsuya, Hiroaki TI Prediction of Potency of Protease Inhibitors Using Free Energy Simulations with Polarizable Quantum Mechanics-Based Ligand Charges and a Hybrid Water Model SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID ORALLY BIOAVAILABLE INHIBITOR; RESOLUTION CRYSTAL-STRUCTURES; STRUCTURE-BASED DESIGN; VIRUS TYPE-1 PROTEASE; HIV-1 PROTEASE; DRUG-RESISTANCE; MOLECULAR DOCKING; IN-VITRO; ACTIVE-SITE; BINDING AB Reliable and robust prediction of the binding affinity for drug molecules continues to be a daunting challenge. We simulated the binding interactions and free energy of binding of nine protease inhibitors (PIS) with wild-type and various mutant proteases by performing GBSA simulations in which each PI's partial charge was determined by quantum mechanics (QM) and the partial charge accounts for the polarization induced by the protease environment. We employed a hybrid solvation model that retains selected explicit water molecules in the protein with surface-generalized Born (SGB) implicit solvent. We examined the correlation of the free energy with the antiviral potency of PIS with regard to amino acid Substitutions in protease. The GBSA free energy thus simulated showed strong correlations (r > 0.75) with antiviral IC(50) Values Of PIS when amino acid substitutions were present in the protease active site. We also simulated the binding free energy of PIS with P2-bis-tetrahydrofuranylurethane (bis-THF) or related cores. utilizing a bis-THF-containing protease crystal structure as a template. The free energy showed a strong correlation (r = 0.93) with experimentally determined anti-HIV-1 potency. The present data suggest that the presence of selected explicit water in protein and protein polarization-induced quantum charges for the inhibitor, compared to lack of explicit water and a static force-field-based charge model, can serve as ail improved lead optimization tool and warrants further exploration. C1 [Das, Debananda; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Koh, Yasuhiro; Tojo, Yasushi; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, Dept Hematol, Kumamoto 8608556, Japan. [Koh, Yasuhiro; Tojo, Yasushi; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, Dept Infect Dis, Kumamoto 8608556, Japan. [Ghosh, Arun K.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Ghosh, Arun K.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. RP Mitsuya, H (reprint author), 10 Ctr Dr,Room 5A11-MSC 1868, Bethesda, MD 20892 USA. EM hmitsuya@helix.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Institutes of Health [GM 53386]; Kumamoto University; Ministry of Education, Culture, Sports, Science, and Technology; Ministry of Health, Labor and Welfare of Japan FX This work was Supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (D.D. and H.M.), a grant from the National Institutes of Health (GM 53386 to A.K.G.), a grant from the Kumamoto University Global Center of Excellence Program, Global Education and Research Center Aiming at the control of AIDS (H.M.) supported by the Ministry of Education, Culture, Sports, Science, and Technology (Monbu-Kagakusho), a Grant-in-Aid for Scientific Research (Priority Areas to H.M.) from the Ministry of Education, Culture, Sports, Science, and Technology (Monbu-Kagakusho) of Japan (H.M.), and a Grant for Promotion of AIDS Research from the Ministry of Health, Labor and Welfare (Kosei-Rodosho) of Japan (H.M.). The work utilized the computational resources of the Biowulf cluster at the NIH. NR 52 TC 33 Z9 33 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD DEC PY 2009 VL 49 IS 12 BP 2851 EP 2862 DI 10.1021/ci900320p PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA 535AB UT WOS:000272937800021 PM 19928916 ER PT J AU Valluri, SC Zito, JM Safer, DJ Zuckerman, IH Mullins, CD Korelitz, JJ Mattison, DR Taylor-Zapata, P AF Valluri, Satish C. Zito, Julie M. Safer, Daniel J. Zuckerman, Ilene H. Mullins, C. D. Korelitz, James J. Mattison, Donald R. Taylor-Zapata, Perdita TI Impact of the 2004 FDA Pediatric Suicidality Warnings on Antidepressant and Psychotherapy Treatment for New-Onset Depression SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 49th Annual National-Institute-of-Mental-Health/New-Clinical-Drug-Evaluation-Unit Meeting CY JUN 29-JUL 02, 2009 CL Hollywood, FL SP Natl Inst Ment Hlth, New Clin Drug Evaluat Unit C1 [Valluri, Satish C.; Zito, Julie M.; Zuckerman, Ilene H.; Mullins, C. D.] Univ Maryland, Baltimore, MD 21201 USA. [Safer, Daniel J.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Korelitz, James J.] WESTAT Corp, Rockville, MD 20850 USA. [Mattison, Donald R.; Taylor-Zapata, Perdita] NICHHD, Bethesda, MD 20892 USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 2 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD DEC PY 2009 VL 19 IS 6 BP 784 EP 784 PG 1 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 536OL UT WOS:000273053600030 ER PT J AU Hardin, MG Mandell, D Mueller, SC Dahl, RE Pine, DS Ernst, M AF Hardin, Michael G. Mandell, Darcy Mueller, Sven C. Dahl, Ronald E. Pine, Daniel S. Ernst, Monique TI Inhibitory control in anxious and healthy adolescents is modulated by incentive and incidental affective stimuli SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Emotion; motivation; cognitive control; affective context; anxiety disorders; facial expressions ID ANTISACCADE TASK; EYE-MOVEMENT; DEPRESSED ADOLESCENTS; ANXIETY DISORDERS; PREFRONTAL CORTEX; NEURAL MECHANISMS; COGNITIVE CONTROL; REWARD; ATTENTION; CHILDREN AB Background: Anxiety disorders are characterized by elevated, sustained responses to threat, that manifest as threat attention biases. Recent evidence also suggests exaggerated responses to incentives. How these characteristics influence cognitive control is under debate and is the focus of the present study. Methods: Twenty-five healthy adolescents and 25 adolescents meeting DSM-IV diagnostic criteria for an anxiety disorder were compared on a task of response inhibition. Inhibitory control was assayed with an antisaccade task that included both incentive (monetary reward) and incidental emotion (facial expression) cues presented prior to the execution of inhibitory behavior. Results: Inhibitory control was enhanced following exposure to threat cues (fear faces) only in adolescent patients, and following exposure to positive cues (happy faces) only in healthy adolescents. Results also revealed a robust performance improvement associated with monetary incentives. This incentive effect did not differ by group. No interaction between incentives and emotional cues was detected. Conclusions: These findings suggest that biased processing of threat in anxious adolescents affects inhibitory control, perhaps by raising arousal prior to behavioral performance. The absence of normalization of performance in anxious adolescents following exposure to positive emotional cues is a novel finding and will require additional exploration. Future studies will need to more specifically examine how perturbations in positive emotion processes contribute to the symptomatology and the pathogenesis of anxiety disorders. C1 [Hardin, Michael G.; Mandell, Darcy; Mueller, Sven C.; Pine, Daniel S.; Ernst, Monique] NIMH, Emot Dev & Affect Neurosci Branch, Mood & Anxiety Disorders Program, NIH,DHHS, Bethesda, MD 20892 USA. [Dahl, Ronald E.] Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA 15260 USA. [Dahl, Ronald E.] Univ Pittsburgh, Med Ctr, Dept Pediat, Pittsburgh, PA 15260 USA. RP Hardin, MG (reprint author), NIMH, Emot Dev & Affect Neurosci Branch, Mood & Anxiety Disorders Program, NIH,DHHS, 15K N Dr, Bethesda, MD 20892 USA. EM hardinm@mail.nih.gov FU Intramural Research Program of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health. We would like to thank Harvey Iwamoto for his programming assistance. NR 40 TC 34 Z9 34 U1 4 U2 15 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD DEC PY 2009 VL 50 IS 12 BP 1550 EP 1558 DI 10.1111/j.1469-7610.2009.02121.x PG 9 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 516DN UT WOS:000271522000014 PM 19573033 ER PT J AU Timmers, HJLM Chen, CC Carrasquillo, JA Whatley, M Ling, A Havekes, B Eisenhofer, G Martiniova, L Adams, KT Pacak, K AF Timmers, Henri J. L. M. Chen, Clara C. Carrasquillo, Jorge A. Whatley, Millie Ling, Alexander Havekes, Bastiaan Eisenhofer, Graeme Martiniova, Lucia Adams, Karen T. Pacak, Karel TI Comparison of F-18-Fluoro-L-DOPA, F-18-Fluoro-Deoxyglucose, and F-18-Fluorodopamine PET and I-123-MIBG Scintigraphy in the Localization of Pheochromocytoma and Paraganglioma SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; ENDOCRINE NEOPLASIA TYPE-2; HIPPEL-LINDAU-SYNDROME; F-18 DOPA PET; NEUROENDOCRINE TUMORS; METASTATIC PHEOCHROMOCYTOMA; MIBG SCINTIGRAPHY; METAIODOBENZYLGUANIDINE; I-123-METAIODOBENZYLGUANIDINE; TRANSPORTERS AB Context: Besides I-123-metaiodobenzylguanidine (MIBG), positron emission tomography (PET) agents are available for the localization of paraganglioma (PGL), including F-18-3,4-dihydroxyphenylalanine (DOPA), F-18-fluoro-2-deoxy-D-glucose (F-18-FDG), and F-18-fluorodopamine (F-18-FDA). Objective: The objective of the study was to establish the optimal approach to the functional imaging of PGL and examine the link between genotype-specific tumor biology and imaging. Design: This was a prospective observational study. Intervention: There were no interventions. Patients: Fifty-two patients (28 males, 24 females, aged 46.8 +/- 14.2 yr): 20 with nonmetastatic PGL (11 adrenal), 28 with metastatic PGL (13 adrenal), and four in whom PGL was ruled out; 22 PGLs were of the succinate dehydrogenase subunit B (SDHB) genotype. Main Outcome Measures: Sensitivity of F-18-DOPA, F-18-FDG, and F-18-FDA PET, I-123-MIBG scintigraphy, computed tomography (CT), and magnetic resonance imaging (MRI) for the localization of PGL were measured. Results: Sensitivities for localizing nonmetastatic PGL were 100% for CT and/or MRI, 81% for F-18-DOPA PET, 88% for F-18-FDG PET/CT, 78% for F-18-FDA PET/CT, and 78% for I-123-MIBG scintigraphy. For metastatic PGL, sensitivity in reference to CT/MRI was 45% for F-18-DOPA PET, 74% for F-18-FDG PET/CT, 76% for F-18-FDA PET/CT, and 57% for I-123-MIBG scintigraphy. In patients with SDHB metastatic PGL, F-18-FDA and F-18-FDG have a higher sensitivity (82 and 83%) than I-123-MIBG (57%) and F-18-DOPA (20%). Conclusions: F-18-FDA PET/CT is the preferred technique for the localization of the primary PGL and to rule out metastases. Second best, equal alternatives are F-18-DOPA PET and I-123-MIBG scintigraphy. For patients with known metastatic PGL, we recommend F-18-FDA PET in patients with an unknown genotype, F-18-FDG or F-18-FDA PET in SDHB mutation carriers, and F-18-DOPA or F-18-FDA PET in non-SDHB patients. (J Clin Endocrinol Metab 94: 4757-4767, 2009) C1 [Timmers, Henri J. L. M.] Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol, NL-6500 HB Nijmegen, Netherlands. [Timmers, Henri J. L. M.; Havekes, Bastiaan; Martiniova, Lucia; Adams, Karen T.; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod & Adult Endocrinol Program, NIH, Bethesda, MD 20892 USA. [Chen, Clara C.; Carrasquillo, Jorge A.; Whatley, Millie] NIH, Dept Nucl Med, Bethesda, MD 20892 USA. [Ling, Alexander] NIH, Dept Diagnost Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Carrasquillo, Jorge A.] Mem Sloan Kettering Canc Ctr, Nucl Med Sect, Dept Radiol, New York, NY 10021 USA. [Havekes, Bastiaan] Univ Hosp Maastricht, Dept Internal Med, Div Endocrinol, NL-6202 AZ Maastricht, Netherlands. Univ Dresden, Inst Clin Chem & Lab Med, D-01307 Dresden, Germany. [Eisenhofer, Graeme] Univ Dresden, Dept Med, D-01307 Dresden, Germany. RP Timmers, HJLM (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM h.timmers@endo.umcn.nl RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 FU National Institute of Child Health and Human Development/National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development/National Institutes of Health. NR 42 TC 166 Z9 169 U1 0 U2 10 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 2009 VL 94 IS 12 BP 4757 EP 4767 DI 10.1210/jc.2009-1248 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 527PQ UT WOS:000272379400023 PM 19864450 ER PT J AU Gustafson, JK Yanoff, LB Easter, BD Brady, SM Keil, MF Roberts, MD Sebring, NG Han, JC Yanovski, SZ Hubbard, VS Yanovski, JA AF Gustafson, Jennifer K. Yanoff, Lisa B. Easter, Benjamin D. Brady, Sheila M. Keil, Margaret F. Roberts, Mary D. Sebring, Nancy G. Han, Joan C. Yanovski, Susan Z. Hubbard, Van S. Yanovski, Jack A. TI The Stability of Metabolic Syndrome in Children and Adolescents SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NUTRITION EXAMINATION SURVEY; INSULIN-RESISTANCE SYNDROME; 3RD NATIONAL-HEALTH; OVERWEIGHT AFRICAN-AMERICAN; CORONARY HEART-DISEASE; TREATMENT PANEL-III; RISK-FACTORS; CARDIOVASCULAR RISK; PREVALENCE; CHILDHOOD AB Context: Some studies suggest the presence of metabolic syndrome before adulthood may identify those at high risk for later cardiovascular morbidity, but there are few data examining the reliability of pediatric metabolic syndrome. Objective: To examine the short-and long-term stability of pediatric metabolic syndrome. Design: Metabolic syndrome was defined as having at least three of the following: waist circumference, blood pressure, and fasting serum triglycerides in the 90th or higher percentile for age/sex; high-density lipoprotein-cholesterol 10th or lower percentile for age/sex; and fasting serum glucose of at least 100 mg/dl. Short-term metabolic syndrome stability (repeated measurements within 60 d) was assessed in obese youth ages 6-17 yr. Long-term metabolic syndrome stability(repeated measurements more than 1.5 yr apart) was studied in 146 obese and nonobese children age 6-12 yr at baseline. Patients and Setting: Convenience samples of obese and nonobese youth ages 6-17 yr participating in research studies were collected at a clinical research hospital. Results: Short-term metabolic syndrome stability (repeat measurements performed 19.7 +/- 13.1 d apart) was assessed in 220 children. The diagnosis of metabolic syndrome was unstable in 31.6% of cases. At their short-term follow-up visit, incidence of metabolic syndrome among participants who did not have metabolic syndrome at baseline was 24%. In the long term (repeat measurements performed 5.6 +/- 1.9 yr apart), the diagnosis of metabolic syndrome was unstable in 45.5% of cases. Conclusions: Cutoff-point-based definitions for pediatric metabolic syndrome have substantial instability in the short and long term. The value of making a cutoff-point-based diagnosis of metabolic syndrome during childhood or adolescence remains in question. (J Clin Endocrinol Metab 94: 4828-4834, 2009) C1 [Gustafson, Jennifer K.; Yanoff, Lisa B.; Easter, Benjamin D.; Brady, Sheila M.; Keil, Margaret F.; Roberts, Mary D.; Han, Joan C.; Yanovski, Susan Z.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Growth & Obes, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Sebring, Nancy G.] Natl Inst Diabet & Digest Kidney Dis, Dept Nutr, Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Yanovski, Susan Z.] Natl Inst Diabet & Digest Kidney Dis, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. [Hubbard, Van S.] NIH, Div Nutr Res Coordinat, US Dept HHS, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), NICHHD, Unit Growth & Obes, NICHD, NIH,Hatfield Clin Res Ctr, 9000 Rockville Pike,Room 1E-3330,MSC 1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural Research Program; NIH [Z01-HD-00641]; NICHD; National Center for Minority Health and Health Disparities FX This work was supported by the Intramural Research Program, NIH, Grant Z01-HD-00641 (to J.A.Y.) from NICHD with supplemental funding from the National Center for Minority Health and Health Disparities. J.A.Y., J.C.H., V.S.H., and N.G.S. are Commissioned Officers in the U. S. Public Health Service, Department of Health and Human Services. NR 44 TC 36 Z9 39 U1 1 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 2009 VL 94 IS 12 BP 4828 EP 4834 DI 10.1210/jc.2008-2665 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 527PQ UT WOS:000272379400031 PM 19837941 ER PT J AU Memmott, RM Dennis, PA AF Memmott, Regan M. Dennis, Phillip A. TI LKB1 and Mammalian Target of Rapamycin As Predictive Factors for the Anticancer Efficacy of Metformin SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID PEUTZ-JEGHERS-SYNDROME; BREAST-CANCER; GENE; KINASE; CELLS C1 [Memmott, Regan M.; Dennis, Phillip A.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Memmott, RM (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NR 9 TC 31 Z9 31 U1 0 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 DEC 1 PY 2009 VL 27 IS 34 BP E226 EP E226 DI 10.1200/JCO.2009.25.3963 PG 1 WC Oncology SC Oncology GA 524XK UT WOS:000272177500040 PM 19858366 ER PT J AU Machado-Vieira, R Yuan, PX Brutsche, N DiazGranados, N Luckenbaugh, D Manji, HK Zarate, CA AF Machado-Vieira, Rodrigo Yuan, Peixiong Brutsche, Nancy DiazGranados, Nancy Luckenbaugh, David Manji, Husseini K. Zarate, Carlos A., Jr. TI Brain-Derived Neurotrophic Factor and Initial Antidepressant Response to an N-Methyl-D-Aspartate Antagonist SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID DEPRESSED-PATIENTS; MOOD DISORDERS; RATING-SCALE; BDNF LEVELS; ELECTROCONVULSIVE SEIZURES; MAJOR DEPRESSION; BLOOD-BRAIN; SERUM; KETAMINE; EXPRESSION AB Objective: A model has been proposed to explain the pathophysiology of mood disorders based on decreased neurotrophin levels during mood episodes; treatment with antidepressants and mood stabilizers is associated with clinical improvement. This study investigated whether changes in brain-derived neurotrophic factor (BDNF) levels are associated with the initial antidepressant effects of ketamine, a high-affinity N-methyl-D-aspartate (NMDA) antagonist. Method: Twenty-three subjects aged 18 to 65 years with DSM-IV major depressive disorder (treatment resistant) participated in this study, which was conducted between October 2006 and May 2008. The subjects were given an open-label intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and rated using various depression scales at baseline and at 40, 80, 120, and 230 minutes postinfusion. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale score. BDNF levels were obtained at the same time points as depression rating scale scores. Results: Despite a significant (P < .001) improvement in MADRS scores after subjects received ketamine treatment, no changes in BDNF levels were observed in subjects after they received ketamine compared to baseline. Also, no association was found between antidepressant response and BDNF levels. Conclusions: This study demonstrates that ketamine's rapid initial antidepressant effects are not mediated by BDNF. Further studies are necessary to shed light on the neurobiological basis of these effects. C1 [Machado-Vieira, Rodrigo; Yuan, Peixiong; Brutsche, Nancy; DiazGranados, Nancy; Luckenbaugh, David; Manji, Husseini K.; Zarate, Carlos A., Jr.] NIMH, Mood & Anxiety Disorders Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Machado-Vieira, Rodrigo; Yuan, Peixiong; DiazGranados, Nancy; Manji, Husseini K.; Zarate, Carlos A., Jr.] NIMH, Lab Mol Psychiat & Expt Therapeut, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), CRC, Unit SE 7, 10 Ctr Dr,Room 7-3445, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov RI MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Intramural Research Program; National Alliance for Research on Schizophrenia and Depression FX This study was supported by the Intramural Research Program at the NIMH and the National Alliance for Research on Schizophrenia and Depression (Dr. Zarate). NR 35 TC 70 Z9 73 U1 2 U2 12 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD DEC PY 2009 VL 70 IS 12 BP 1662 EP 1666 DI 10.4088/JCP.08m04659 PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 540YQ UT WOS:000273377700006 PM 19744406 ER PT J AU Gagne, JJ Patrick, AR Wang, PS Schneeweiss, S AF Gagne, Joshua J. Patrick, Amanda R. Wang, Philip S. Schneeweiss, Sebastian TI Health Advisories and Patterns of Patient Monitoring Among New Users of Antidepressant Medications SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE antidepressants; monitoring; health advisories ID PEDIATRIC-PATIENTS; SUICIDALITY; FREQUENCY; WARNINGS; OUTCOMES; SSRIS; RATES AB Introduction: In 2003, more intense monitoring of patients initiating antidepressants was advised because of emerging concerns of suicidality. We sought to identify patterns of patient monitoring after antidepressant initiation in British Columbia before and after issuance of health advisories. Materials and Methods: We conducted a cohort study of antidepressant initiators between 1999 and 2005 using healthcare utilization data of all British Columbia residents. For the periods before (1999-2001) and after (2004-2005), health advisories concerning suicidality associated with antidepressants, we assessed monitoring intensity by calculating weekly physician and psychotherapy visit rates since antidepressant initiation. We also estimated monitoring patterns as the proportion of individuals who received weekly in-person contact during the first 4 weeks of treatment, then biweekly visits for 4 weeks, and then a visit at 12 weeks, as a proxy for intensive monitoring. Results: Patterns of monitoring intensity were similar before and after the health advisories, but the level of intensity was lower after the advisory period. Overall, monitoring intensity peaked in the 4 weeks after antidepressant initiation. Weekly numbers of visits per subject during these 4 weeks were between 0.44 and 0.49 before the advisory and from 0.39 to 0.44 after the advisory. Among all initiators stratified by year of initiation, between 21% and 25% received intensive monitoring, and this proportion generally decreased on a yearly basis. Discussion: Monitoring intensity for patients with depression initiating antidepressants decreased after the period of emergence and greater awareness of the association between antidepressants and suicidality. C1 [Gagne, Joshua J.; Patrick, Amanda R.; Schneeweiss, Sebastian] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA. [Gagne, Joshua J.; Schneeweiss, Sebastian] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wang, Philip S.] NIMH, Bethesda, MD 20892 USA. [Schneeweiss, Sebastian] Harvard Univ, Sch Med, Boston, MA USA. RP Gagne, JJ (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Suite 3030,1620 Tremont St, Boston, MA 02120 USA. EM jgagne1@partners.org RI Schneeweiss, Sebastian/C-2125-2013 FU U.S. National Institute of Mental Health [MH078708]; Pfizer; Ortho-McNeil Janssen Scientific Affairs FX Dr Schneeweiss has received an investigator-initiated research grant from Pfizer to study the safety of coxibs. Dr Gagne previous); participated in a postdoctoral fellowship administered through Jefferson Medical College and supported by Ortho-McNeil Janssen Scientific Affairs and that ended in 2007. Dr Patrick declares no conflict of interest. Dr Wang is an employee of the National Institute of Mental Health NR 15 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD DEC PY 2009 VL 29 IS 6 BP 590 EP 594 DI 10.1097/JCP.0b013e3181bf4eb9 PG 5 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 522NG UT WOS:000272004300013 PM 19910726 ER PT J AU Lugassy, C Torres-Munoz, JE Kleinman, HK Ghanem, G Vernon, S Barnhill, RL AF Lugassy, Claire Torres-Munoz, Jorge E. Kleinman, Hynda K. Ghanem, Ghanem Vernon, Stephen Barnhill, Raymond L. TI Overexpression of malignancy-associated laminins and laminin receptors by angiotropic human melanoma cells in a chick chorioallantoic membrane model SO JOURNAL OF CUTANEOUS PATHOLOGY LA English DT Article ID EXTRAVASCULAR MIGRATORY METASTASIS; TUMOR INVASION; GAMMA-2 CHAIN; LUNG ADENOCARCINOMAS; ANGIOGENESIS; EXPRESSION; CARCINOMA; MATRIX; IDENTIFICATION; ALPHA-4-CHAIN AB Background As distinct from intravascular/lymphatic dissemination, extravascular migratory metastasis (EVMM) has been described as a potential additional mechanism of melanoma spread in which tumor cells migrate along the external surfaces of vessels. Angiotropic melanoma cells are linked to the endothelium by a matrix containing laminin. In addition, it has been shown that C16 laminin-derived peptide increases extravascular migration of human green fluorescent protein (GFP) melanoma cells along vessels in a chicken chorioallantoic membrane model (CAM). In this study, we have tested the hypothesis that expression levels of some genes related to lamimin and metastasis are differentially expressed in vascularized angiotropic melanoma areas vs. avascular melanoma areas from the same tumor. Design C8161 human melanoma cells in a shell-less chick CAM assay were used to study EVMM associated with the presence of vascularized angiotropic melanoma areas. For both high-quality histomorphology and RNA preservation in paraffin-embedded tissue, we used a methanol-based fixative coupled with microwave-assisted rapid tissue processing as previously described. Using laser capture microdissection, angiotropic melanoma areas as well as avascular areas were microdissected. Using quantitative real time polymerase chain reaction (QRT-PCR), six genes have been studied: LAMC2 (laminin gamma 2 chain), LAMA4 (laminin alpha 4 chain), ITGB1 (integrin beta 1), ITGB3 (integrin beta 3), RSPA (ribosomal protein), and MMP2 (matrix metallopeptidase 2). QRT-PCR data were normalized to human GAPDH housekeeping gene and values were compared against Human Total RNA. Final results were expressed as percentage of expression. Results All tumors demonstrated a similar pattern, i.e. EVMM of angiotropic melanoma cells. The microdissected histopathological sections presented both angiotropic areas and avascular areas. All genes were overexpressed in angiotropic melanoma areas vs. avascular melanoma areas, especially LAMC2, LAMA4 and ITGB3 (respectively, 165.18, 208.86, and 483.69%). Conclusion This study shows that several genes related to laminin are overexpressed in angiotropic melanoma areas vs. avascular melanoma areas. Since extravascular migration of melanoma cells along vessels has been demonstrated in the CAM model, taken together these results suggests that some laminins and laminin receptors may play a role in extravascular migratory metastasis. This model may represent a promising strategy to analyze differential gene expression in EVMM. Lugassy C, Torres-Munoz JE, Kleinman HK, Ghanem G, Vernon S, Barnhill RL. Overexpression of malignancy-associated laminins and laminin receptors by angiotropic human melanoma cells in a chick chorioallantoic membrane model. C1 [Barnhill, Raymond L.] Univ Paris Diderot, Hop St Louis, APHP, Dept Pathol, Paris, France. [Lugassy, Claire; Torres-Munoz, Jorge E.; Vernon, Stephen; Barnhill, Raymond L.] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA. [Barnhill, Raymond L.] Univ Miami, Miller Sch Med, Dept Dermatol, Miami, FL 33136 USA. [Barnhill, Raymond L.] Univ Paris Diderot, Hosp St Louis, Dept Dermatol, Paris, France. [Ghanem, Ghanem] Free Univ Brussels, Dept Cell Physiol, Brussels, Belgium. [Kleinman, Hynda K.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Barnhill, RL (reprint author), Univ Paris Diderot, Hop St Louis, APHP, Dept Pathol, Paris, France. EM Raymond.barnhill@sls.aphp.fr FU GFP [C8161] FX We sincerely thank Drs. C. Petito and A. Morales for their continued support of this research, Dr. M. Nadji for help with immunohistochemistry, and Dr. D. Welch for providing the GFP C8161 human melanoma cells. NR 32 TC 10 Z9 10 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0303-6987 J9 J CUTAN PATHOL JI J. Cutan. Pathol. PD DEC PY 2009 VL 36 IS 12 BP 1237 EP 1243 DI 10.1111/j.1600-0560.2009.01273.x PG 7 WC Dermatology; Pathology SC Dermatology; Pathology GA 511SD UT WOS:000271186300001 PM 19469865 ER PT J AU Clark, KW Gierada, DS Marquez, G Moore, SM Maffitt, DR Moulton, JD Wolfsberger, MA Koppel, P Phillips, SR Prior, FW AF Clark, Kenneth W. Gierada, David S. Marquez, Guillermo Moore, Stephen M. Maffitt, David R. Moulton, Joan D. Wolfsberger, Mary A. Koppel, Paul Phillips, Stanley R. Prior, Fred W. TI Collecting 48,000 CT Exams for the Lung Screening Study of the National Lung Screening Trial SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE Cancer detection; chest CT; clinical trial; computed tomography; de-identification; lung diseases; digital image management; image database; image libraries; national lung screening trial; lung screening study; CT image library ID CANCER-INSTITUTE; IMPLEMENTATION; PROSTATE AB From 2002-2004, the Lung Screening Study (LSS) of the National Lung Screening Trial (NLST) enrolled 34,614 participants, aged 55-74 years, at increased risk for lung cancer due to heavy cigarette smoking. Participants, randomized to standard chest X-ray (CXR) or computed tomography (CT) arms at ten screening centers, received up to three imaging screens for lung cancer at annual intervals. Participant medical histories and radiologist-interpreted screening results were transmitted to the LSS coordinating center, while all images were retained at local screening centers. From 2005-2007, all CT exams were uniformly de-identified and delivered to a central repository, the CT Image Library (CTIL), on external hard drives (94%) or CD/DVD (5.9%), or over a secure Internet connection (0.1%). Of 48,723 CT screens performed, only 176 (0.3%) were unavailable (lost, corrupted, compressed) while 48,547 (99.7%) were delivered to the CTIL. Described here is the experience organizing, implementing, and adapting the clinical-trial workflow surrounding the image retrieval, de-identification, delivery, and archiving of available LSS-NLST CT exams for the CTIL, together with the quality assurance procedures associated with those collection tasks. This collection of CT exams, obtained in a specific, well-defined participant population under a common protocol at evenly spaced intervals, and its attending demographic and clinical information, are now available to lung-disease investigators and developers of computer-aided-diagnosis algorithms. The approach to large scale, multi-center trial CT image collection detailed here may serve as a useful model, while the experience reported should be valuable in the planning and execution of future equivalent endeavors. C1 [Clark, Kenneth W.; Gierada, David S.; Moore, Stephen M.; Maffitt, David R.; Moulton, Joan D.; Wolfsberger, Mary A.; Koppel, Paul; Phillips, Stanley R.; Prior, Fred W.] Washington Univ, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Marquez, Guillermo] Natl Canc Inst, Early Detect Res Grp, Bethesda, MD USA. RP Clark, KW (reprint author), Washington Univ, Mallinckrodt Inst Radiol, 510 S Kingshighway, St Louis, MO 63110 USA. EM clarkk@mir.wustl.edu FU NCI NIH HHS [N01 CN25476] NR 11 TC 12 Z9 13 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0897-1889 J9 J DIGIT IMAGING JI J. Digit. Imaging PD DEC PY 2009 VL 22 IS 6 BP 667 EP 680 DI 10.1007/s10278-008-9145-9 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 524QX UT WOS:000272159000013 PM 18777192 ER PT J AU DuPont, RL AF DuPont, Robert L. TI REFLECTIONS ON THE EARLY HISTORY OF NATIONAL INSTITUTE ON DRUG ABUSE (NIDA): IMPLICATIONS FOR TODAY SO JOURNAL OF DRUG ISSUES LA English DT Article ID HEROIN-ADDICTION EPIDEMIC; CRIME AB The National Institute on Drug Abuse (NIDA) was formed in September, 1973 from a Division of the National Institute on Mental Health (NIMH), from the three-decade old Addiction Research Center (ARC) in Lexington Kentucky, and from the two year old Special Action Office for Drug Abuse Prevention (SAODAP), the original White House drug office. The legislation authorizing NIDA was passed by both Houses of Congress and signed by the president with bipartisan unanimity in response to the drug abuse epidemic, which had begun in the late 1960s. NIDA was the embodiment of the new Federal drug abuse strategy that, for the first time, balanced the traditional focus on law enforcement (supply reduction) with a new focus on treatment, prevention, and research (what became known as demand reduction). The current article offers a review of the early history of NIDA and its implications for future research. C1 [DuPont, Robert L.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP DuPont, RL (reprint author), Natl Inst Drug Abuse, Bethesda, MD 20892 USA. NR 12 TC 3 Z9 3 U1 0 U2 0 PU J DRUG ISSUES INC PI TALLAHASSEE PA FLORIDA STATE UNIV, SCHOOL CRIMINOLOGY CRIMINAL JUSTICE, PO BOX 66696, TALLAHASSEE, FL 32313-6696 USA SN 0022-0426 J9 J DRUG ISSUES JI J. Drug Issues PD WIN PY 2009 VL 39 IS 1 BP 5 EP 14 PG 10 WC Substance Abuse SC Substance Abuse GA 451ZH UT WOS:000266508900002 ER PT J AU Guydish, JR AF Guydish, Joseph R. TI DRUG ABUSE RESEARCH: TODAY AND TOMORROW SO JOURNAL OF DRUG ISSUES LA English DT Article AB Many of the papers in this theme issue originated as presentations at a conference entitled 'Reflections on 40 Years of Drug Abuse Research.' At the conference, leaders in the drug abuse field presented their work, as well as their visions and concerns for the future of drug abuse research, and many of those presentations are included as papers in this issue of the Journal of Drug Issues. At the end of the conference, and after hearing presentations from senior researchers in the field, several mid-career investigators were invited to reflect on the conference and on the field of drug abuse research at this time in its history. This brief article offers reactions to the conference, in terms of its meaning for the future of drug abuse research. C1 [Guydish, Joseph R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Guydish, Joseph R.] Univ Calif San Francisco, Dept Psychiat, NIDA, Treatment Res Center, San Francisco, CA 94143 USA. RP Guydish, JR (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. OI Guydish, Joseph/0000-0003-2115-3340 NR 6 TC 0 Z9 0 U1 0 U2 0 PU J DRUG ISSUES INC PI TALLAHASSEE PA FLORIDA STATE UNIV, SCHOOL CRIMINOLOGY CRIMINAL JUSTICE, PO BOX 66696, TALLAHASSEE, FL 32313-6696 USA SN 0022-0426 J9 J DRUG ISSUES JI J. Drug Issues PD WIN PY 2009 VL 39 IS 1 BP 227 EP 230 PG 4 WC Substance Abuse SC Substance Abuse GA 451ZH UT WOS:000266508900019 ER PT J AU Tom, SE Kuh, D Guralnik, JM Mishra, GD AF Tom, S. E. Kuh, D. Guralnik, J. M. Mishra, G. D. TI Patterns in trouble sleeping among women at mid-life: results from a British prospective cohort study SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID MENOPAUSAL TRANSITION; LIFE-COURSE; UK POPULATION; BIRTH COHORT; INSOMNIA; SYMPTOMS; DISTURBANCE; PREVALENCE; PREDICTORS; COMMUNITY AB Background: Although trouble sleeping is a common problem among women at mid-life, patterns in trouble sleeping relating to social and health-related risk factors are unclear. This analysis describes the dynamics of trouble sleeping among women at mid-life. Methods: The National Survey of Health and Development is a nationally representative study of births in 1946 in England, Scotland, and Wales followed up through mid-life. Multistate life table analysis utilised 893 women interviewed annually between ages 48 to 54 years. Results: Women spent an average of 2.6 years with trouble sleeping, and the average length of a continuous episode of trouble sleeping was 2.4 years. Among women who reported at least one episode, the average number of episodes was 1.5. Health-related risk factors at age 43 of number of physical conditions, anxiety and depression symptoms, use of prescription medication, and current or past trouble sleeping were related to increased total and per episode duration of trouble sleeping over the 7-year study interval and increased duration per episode. Differences associated with these risk factors ranged from 1.2 to 1.8 years for duration over the study interval and 0.5 to 0.8 years per episode. There was no association between average number of episodes per woman reporting at least one episode and these health-related risk factors at age 43. Conclusions: This study provides support for association between increased duration of trouble sleeping, in total and per episode, and health risk factors at age 43, suggesting a long-term relationship between risk factors and sleep. C1 [Tom, S. E.; Guralnik, J. M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Tom, S. E.; Kuh, D.; Mishra, G. D.] Royal Free & Univ Coll Med Sch, Natl Survey Hlth & Dev, MRC, London WC1E 6BT, England. RP Tom, SE (reprint author), NIA, Lab Epidemiol Demog & Biometry, Gateway Bldg,3C309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. EM tomse@mail.nih.gov RI Mishra, Gita/F-8052-2011 OI Mishra, Gita/0000-0001-9610-5904 FU Medical Research Council; Intramural Research Program; National Institute on Aging; NIH FX The Medical Research Council provided funding for the National Survey of Health and Development and financial support for GM and DK. Supported in part by the Intramural Research Program, National Institute on Aging, NIH. NR 31 TC 5 Z9 5 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD DEC PY 2009 VL 63 IS 12 BP 974 EP 979 DI 10.1136/jech.2008.079616 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 521SQ UT WOS:000271944700005 PM 19608560 ER PT J AU Pennington, JAT Fisher, RA AF Pennington, Jean A. T. Fisher, Rachel A. TI Classification of fruits and vegetables SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Article; Proceedings Paper CT 32nd National Nutrient Database Conference CY MAY 14-14, 2008 CL Ottawa, CANADA DE Antioxidants; Classification; Dietary assessment; Dietary guidance; Food composition; Fruits; Phytonutrients; TAC; Total antioxidant capacity; Vegetables ID FOOD GUIDANCE-SYSTEM; ANTIOXIDANT CAPACITY; FATTY-ACID; SEEDS AB Classifications for fruits and vegetables are most helpful for dietary assessment and guidance if they are based on the composition of these foods. This work determined whether levels of food components in fruits and vegetables correlated with classification criteria based on botanic family, color, part of plant, and total antioxidant capacity (TAC). A database of 104 commonly consumed fruits and vegetables was created that contained food components known to be provided primarily by these foods. A mathematical clustering algorithm was used to group the foods into homogeneous clusters based on food component levels and the classification criteria. Most useful in categorizing were the botanic families rose, rue (citrus), amaryllis, goosefoot, and legume: color groupings blue/black, dark green/green, orange/peach, and red/purple: and plant parts fruit-berry, seeds or pods, and leaves. Groupings based on TAC levels did not match well with the identified clusters. Clusters were often best defined by a combination of classification variables such as color and part of plant. Results suggest that the groupings dark green leafy vegetables: cabbage family vegetables; lettuces: allium family bulbs; legumes; deep orange/yellow fruits, roots, and tubers: citrus family fruits; tomatoes and other red vegetables and fruits: and red/purple/blue berries are predictive for food components provided by fruits and vegetables. Published by Elsevier Inc. C1 [Pennington, Jean A. T.; Fisher, Rachel A.] NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. RP Fisher, RA (reprint author), NIH, Div Nutr Res Coordinat, Bldg 10, Bethesda, MD 20892 USA. EM fisherrachel@mail.nih.gov NR 26 TC 37 Z9 38 U1 1 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1575 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD DEC PY 2009 VL 22 BP S23 EP S31 DI 10.1016/j.jfca.2008.11.012 PG 9 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA 540ZB UT WOS:000273379000005 ER PT J AU Zimmerman, TP Hull, SG McNutt, S Mittl, B Islam, N Guenther, PM Thompson, FE Potischman, NA Subar, AF AF Zimmerman, Thea Palmer Hull, Stephen G. McNutt, Suzanne Mittl, Beth Islam, Noemi Guenther, Patricia M. Thompson, Frances E. Potischman, Nancy A. Subar, Amy F. TI Challenges in converting an interviewer-administered food probe database to self-administration in the National Cancer Institute automated self-administered 24-hour recall (ASA24) SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Article; Proceedings Paper CT 32nd National Nutrient Database Conference CY MAY 14-14, 2008 CL Ottawa, CANADA DE National Health and Nutrition Examination Survey; NHANES; 24-Hour recall; Self-administered 24-hour dietary recall; ASA24; Food portion photograph; AMPM interview; Food data management; Food composition ID SYSTEM AB The National Cancer Institute (NCI) is developing an automated, self-administered 24-hour dietary recall (ASA24) application to collect and code dietary intake data. The goal of the ASA24 development is to create a web-based dietary interview based on the US Department of Agriculture (USDA) Automated Multiple Pass Method (AMPM) instrument currently used in the National Health and Nutrition Examination Survey (NHANES). The ASA24 food list, detail probes, and portion probes were drawn from the AMPM instrument; portion-size pictures from Baylor College of Medicine's Food Intake Recording Software System (FIRSSt) were added; and the food code/portion code assignments were linked to the USDA Food and Nutrient Database for Dietary Studies (FNDDS). The requirements that the interview be self-administered and fully auto-coded presented several challenges as the AMPM probes and responses were linked with the FNDDS food codes and portion pictures. This linking was accomplished through a "food pathway," or the sequence of steps that leads from a respondent's initial food selection, through the AMPM probes and portion pictures, to the point at which a food code and gram weight portion size are assigned. The ASA24 interview database that accomplishes this contains more than 1100 food probes and more than 2 million food pathways and will include about 10,000 pictures of individual foods depicting up to 8 portion sizes per food. The ASA24 will make the administration of multiple days of recalls in large-scale studies economical and feasible. (C) 2009 Elsevier Inc. All rights reserved. C1 [Zimmerman, Thea Palmer; Hull, Stephen G.; McNutt, Suzanne; Mittl, Beth] Westat Corp, Rockville, MD USA. [Islam, Noemi] Baylor Coll Med, Houston, TX 77030 USA. [Guenther, Patricia M.] USDA, Ctr Nutr Policy & Promot, Washington, DC USA. [Thompson, Frances E.; Potischman, Nancy A.; Subar, Amy F.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. RP Zimmerman, TP (reprint author), Westat Corp, 2311 Saybrook Rd, University Hts, OH 44118 USA. EM theazimmerman@westat.com FU NCI NIH HHS [N02 PC064406] NR 13 TC 32 Z9 32 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1575 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD DEC PY 2009 VL 22 BP S48 EP S51 DI 10.1016/j.jfca.2009.02.003 PG 4 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA 540ZB UT WOS:000273379000009 PM 20161418 ER PT J AU Iwata-Okada, M Okuyama, T Kobayashi, S Kawai, T Horiuchi, Y Kiyokawa, N Li, XK Fujimoto, J Otsu, M Kume, A Ariga, T Mizukami, T Nunoi, H Onodera, M Kang, EM Malech, HL Kuratsuji, T AF Iwata-Okada, Mayumi Okuyama, Torayuki Kobayashi, Shin-ichi Kawai, Toshinao Horiuchi, Yasuomi Kiyokawa, Nobutaka Li, Xiao-Kang Fujimoto, Junichiro Otsu, Makoto Kume, Akihiro Ariga, Tadashi Mizukami, Tomoyuki Nunoi, Hiroyuki Onodera, Masafumi Kang, Elizabeth M. Malech, Harry L. Kuratsuji, Tadatoshi TI PROGRESS TOWARD CLINICAL TRIAL OF GENE THERAPY FOR CHRONIC GRANULOMATOUS DISEASE IN JAPAN SO JOURNAL OF GENE MEDICINE LA English DT Meeting Abstract CT 14th Annual Meeting of the Japan-Society-of-Gene-Therapy CY JUN 12-14, 2008 CL Sapporo Med Univ Sch Med, Sapporo, JAPAN HO Sapporo Med Univ Sch Med C1 [Otsu, Makoto] Univ Tokyo, Inst Med Sci, Tokyo 1138654, Japan. [Kume, Akihiro] Jichi Med Univ, Shimotsuke, Tochigi, Japan. [Ariga, Tadashi] Hokkaido Univ, Sapporo, Hokkaido 060, Japan. [Mizukami, Tomoyuki; Nunoi, Hiroyuki] Miyazaki Univ, Miyazaki, Japan. [Kang, Elizabeth M.; Malech, Harry L.] NIH, Bethesda, MD 20892 USA. RI Ariga, Tadashi/A-4252-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD DEC PY 2009 VL 11 IS 12 BP 1151 EP 1151 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 532EL UT WOS:000272728100042 ER PT J AU Kawai, T Choi, U Lantz, LM Ohashi, T Eto, Y Malech, HL AF Kawai, Toshinao Choi, Uimook Lantz, Larry M. Ohashi, Toya Eto, Yoshikatsu Malech, Harry L. TI ENHANCED ENGRAFTMENT OF HUMAN HEMATOPOIETIC STEM CELLS INFECTED WITH INTEGRATION DEFECTIVE LENTIVIRUS VECTOR ENCODING WHIM-TYPE MUTANT CXCR4 IN NOD/SCID MOUSE XENOGRAFT MODEL SO JOURNAL OF GENE MEDICINE LA English DT Meeting Abstract CT 14th Annual Meeting of the Japan-Society-of-Gene-Therapy CY JUN 12-14, 2008 CL Sapporo Med Univ Sch Med, Sapporo, JAPAN HO Sapporo Med Univ Sch Med C1 [Kawai, Toshinao; Choi, Uimook; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Lantz, Larry M.] NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Kawai, Toshinao; Ohashi, Toya; Eto, Yoshikatsu] Jikei Univ, Dept Gene Therapy, Inst DNA Med, Sch Med, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD DEC PY 2009 VL 11 IS 12 BP 1167 EP 1167 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 532EL UT WOS:000272728100077 ER PT J AU Murga-Zamalloa, CA Swaroop, A Khanna, H AF Murga-Zamalloa, Carlos A. Swaroop, Anand Khanna, Hemant TI RPGR-containing protein complexes in syndromic and non-syndromic retinal degeneration due to ciliary dysfunction SO JOURNAL OF GENETICS LA English DT Review DE primary cilia; centrosome; transition zone; ciliopathies; photoreceptor; retinal degeneration; retina; RPGR; RP2; CEP290; RPGRIP1L; NPHP ID LINKED RETINITIS-PIGMENTOSA; GUANINE-NUCLEOTIDE-EXCHANGE; LEBER CONGENITAL AMAUROSIS; REGULATOR (RPGR)-INTERACTING PROTEIN; INTRAFLAGELLAR TRANSPORT PROTEIN; VERTEBRATE PRIMARY CILIUM; NORTH-AMERICAN COHORT; SENIOR-LOKEN-SYNDROME; GTPASE REGULATOR; JOUBERT-SYNDROME AB Dysfunction of primary cilia due to mutations in cilia-centrosomal proteins is associated with pleiotropic disorders. The primary (or sensory) cilium of photoreceptors mediates polarized trafficking of proteins for efficient phototransduction. Retinitis pigmentosa GTPase regulator (RPGR) is a cilia-centrosomal protein mutated in >70% of X-linked RP cases and 10%-20% of simplex RP males. Accumulating evidence indicates that RPGR may facilitate the orchestration of multiple ciliary protein complexes. Disruption of these complexes due to mutations in component proteins is an underlying cause of associated photoreceptor degeneration. Here, we highlight the recent developments in understanding the mechanism of cilia-dependent photoreceptor degeneration due to mutations in RPGR and RPGR-interacting proteins in severe genetic diseases, including retinitis pigmentosa, Leber congenital amaurosis (LCA), Joubert syndrome, and Senior-Loken syndrome, and explore the physiological relevance of photoreceptor ciliary protein complexes. C1 [Murga-Zamalloa, Carlos A.; Khanna, Hemant] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. [Swaroop, Anand] NEI, N NRL, NIH, Bethesda, MD 20892 USA. RP Khanna, H (reprint author), Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. EM hkhanna@med.umich.edu OI Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute; National Institutes of Health [EY007961]; Foundation Fighting Blindness (FFB); Midwest Eye Banks and Transplantation Center FX This work is supported by National Eye Institute intramural funds and grants from the National Institutes of Health (EY007961), Foundation Fighting Blindness (FFB), and Midwest Eye Banks and Transplantation Center. NR 111 TC 14 Z9 14 U1 0 U2 2 PU INDIAN ACAD SCIENCES PI BANGALORE PA C V RAMAN AVENUE, SADASHIVANAGAR, P B #8005, BANGALORE 560 080, INDIA SN 0022-1333 J9 J GENET JI J. Genet. PD DEC PY 2009 VL 88 IS 4 SI SI BP 399 EP 407 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 553AH UT WOS:000274336300003 PM 20090203 ER PT J AU Burgard, SA Ailshire, JA AF Burgard, Sarah A. Ailshire, Jennifer A. TI Putting Work to Bed: Stressful Experiences on the Job and Sleep Quality SO JOURNAL OF HEALTH AND SOCIAL BEHAVIOR LA English DT Article ID SOCIOECONOMIC-STATUS; WHITEHALL-II; HEALTH; INSOMNIA; INSECURITY; COHORT; ASSOCIATIONS; INEQUALITIES; PREVALENCE; DISORDERS AB Most adults spend one-third of every day sleeping and another third of most days at work. However, there is little analysis of the possible connections between common workplace experiences and sleep quality. This study uses the longitudinal and nationally-representative Americans' Changing Lives study to examine whether and how common conditions and experiences at work may "follow workers home" and impinge on their quality of sleep. We also explore how competing stressful experiences at home may influence sleep quality, and whether these are more salient than work experiences. Results show that frequently being bothered or upset at work is associated with poorer sleep quality, and the association is not explained by stressful experiences at home. These findings are discussed in relation to the sociological literatures on work, stress, and emotion. C1 [Burgard, Sarah A.] Univ Michigan, Dept Sociol, Ctr Populat Studies, Ann Arbor, MI 48109 USA. [Ailshire, Jennifer A.] Univ Michigan, Natl Inst Aging Trainee, Ctr Populat Studies, Ann Arbor, MI 48109 USA. RP Burgard, SA (reprint author), Univ Michigan, Dept Sociol, Ctr Populat Studies, 500 S State St, Ann Arbor, MI 48109 USA. EM burgards@umich.edu FU NIA NIH HHS [P30 AG012846, P30 AG012846-14, R01 AG018418, T32 AG000221, T32 AG000221-19]; NICHD NIH HHS [R24 HD041028, R24 HD041028-10] NR 51 TC 34 Z9 34 U1 2 U2 27 PU AMER SOCIOLOGICAL ASSOC PI WASHINGTON PA 1307 NEW YORK AVE NW #700, WASHINGTON, DC 20005-4712 USA SN 0022-1465 J9 J HEALTH SOC BEHAV JI J. Health Soc. Behav. PD DEC PY 2009 VL 50 IS 4 BP 476 EP 492 PG 17 WC Public, Environmental & Occupational Health; Psychology, Social SC Public, Environmental & Occupational Health; Psychology GA 534EU UT WOS:000272879900007 PM 20099452 ER PT J AU Rahman, KM Duggal, P Harris, JB Saha, SK Streatfield, PK Ryan, ET Calderwood, SB Qadri, F Yunus, M LaRocque, RC AF Rahman, Kazi Mizanur Duggal, Priya Harris, Jason B. Saha, Sajal Kumar Streatfield, Peter Kim Ryan, Edward T. Calderwood, Stephen B. Qadri, Firdausi Yunus, Mohammad LaRocque, Regina C. TI Familial Aggregation of Vibrio cholerae-associated Infection in Matlab, Bangladesh SO JOURNAL OF HEALTH POPULATION AND NUTRITION LA English DT Article DE Case-control studies; Cholera; Familial aggregation; Risk factors; Vibrio cholerae; Bangladesh ID GENETIC SUSCEPTIBILITY; BLOOD-GROUP; IMPACT; DYNAMICS; OUTBREAK; DISEASE; RISK AB Vibrio cholerae is a major cause of diarrhoeal illness in endemic regions, such as Bangladesh. Understanding the factors that determine an individual's susceptibility to infection due to V cholerae may lead to improved prevention and control strategies. Increasing evidence suggests that human genetic factors affect the severity of V. cholerae-associated infection. This study, therefore, sought to characterize the heritable component of susceptibility to infection due to V cholerae using the Matlab Health and Demographic Surveillance System database of the International Centre for Diarrhoeal Disease Research, Bangladesh. In total, 144 pedigrees that included a cholera patient and 341 pedigrees without a cholera patient were evaluated during 1 January-31 December 1992. The odds of the sibling of a patient being admitted with cholera were 7.67 times the odds of the sibling of an unaffected individual being admitted with cholera [95% confidence interval (CI) 2.40-24.5, p<0.001], after adjustment for gender, age, socioeconomic status, and hygiene practices. Although exposure to environmental reservoirs is essential in the epidemiology of cholera, household-specific factors, such as familial relatedness to an index case, may also be important determinants of risk of cholera. Further analysis of human genetic factors that contribute to susceptibility to cholera may be productive. C1 [Rahman, Kazi Mizanur] ICDDR B, Child Hlth Unit, Div Publ Hlth Sci, Dhaka 1000, Bangladesh. [Duggal, Priya] NHGRI, NIH, Baltimore, MD USA. [Harris, Jason B.; Ryan, Edward T.; Calderwood, Stephen B.; LaRocque, Regina C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Rahman, KM (reprint author), ICDDR B, Child Hlth Unit, Div Publ Hlth Sci, GPO Box 128, Dhaka 1000, Bangladesh. EM mizan@icddrb.org FU National Institutes of Health (NIH) [D43-TW05572, K01-TW07409, K01-TW07144]; National Institute of Allergy and Infectious Diseases [U01-AI58935, R03-AI063079]; Massachusetts General Hospital FX This research was funded by the Fogarty International Center of the National Institutes of Health (NIH) (Grant No. D43-TW05572 for K.M.R.), the Intramural Program of the National Human Genome Research Institute of the NIH (P.D.), the Fogarty International Center of the NIH (Grant No. K01-TW07409 for J.B.H.), the National Institute of Allergy and Infectious Diseases (Grant No. U01-AI58935 for S.B.C.), the National Institute of Allergy and Infectious Diseases (Grant No. R03-AI063079 for F.Q.), a Claflin Distinguished Scholar Award from the Massachusetts General Hospital (R.C.L.), and the Fogarty International Center of the NIH (Grant No. K01-TW07144 for R.C.L.). ICDDR,B acknowledges with gratitude the commitment of the above-mentioned institutes to the Centre's research efforts. NR 23 TC 7 Z9 7 U1 0 U2 1 PU I C D D R B-CENTRE HEALTH POPULATION RESEARCH PI DHAKA PA MOHAKHALI, 1212 DHAKA, BANGLADESH SN 1606-0997 J9 J HEALTH POPUL NUTR JI J. Heatlh Popul. Nutr. PD DEC PY 2009 VL 27 IS 6 BP 733 EP 738 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 548GN UT WOS:000273948200004 PM 20099756 ER PT J AU Larrayoz, IM Pang, T Benicky, J Pavel, J Sanchez-Lemus, E Saavedra, JM AF Larrayoz, Ignacio M. Pang, Tao Benicky, Julius Pavel, Jaroslav Sanchez-Lemus, Enrique Saavedra, Juan M. TI Candesartan reduces the innate immune response to lipopolysaccharide in human monocytes SO JOURNAL OF HYPERTENSION LA English DT Article DE angiotensin receptor blockers; cytokines; inflammation; inhibitor of kappa B alpha; interleukin 6; interleukin-1 beta; renin-angiotensin system; transcription factors; tumor necrosis factor alpha ID NF-KAPPA-B; SPONTANEOUSLY HYPERTENSIVE-RATS; LIPOPROTEIN RECEPTOR LOX-1; RENIN-ANGIOTENSIN SYSTEM; GENE-EXPRESSION PROFILE; NITRIC-OXIDE SYNTHASE; TOLL-LIKE RECEPTORS; AT(1) RECEPTOR; ENDOTHELIAL-CELLS; MONONUCLEAR-CELLS AB Objective Inhibition of angiotensin II receptor type 1 (AT(1)) reduces chronic inflammation associated with hypertension. We asked whether AT(1) receptor inhibition would reduce the innate inflammatory response induced by bacterial lipopolysaccharide (LPS). Methods We used unstimulated human circulating monocytes obtained from healthy donors by counterflow centrifugal elutriation. Monocytes were studied in vitro after incubation with LPS (50 ng/ml) with and without 1 mu mol/l candesartan, an AT(1) receptor blocker. Angiotensin II receptor mRNA expression was determined by reverse transcriptase-PCR and receptor binding by autoradiography; inflammatory factor mRNA expression was studied by reverse transcriptase-PCR and cytokine release by ELISA. Results Human monocytes did not express detectable AT(1) receptors, and angiotensin II did not induce inflammatory factor mRNA expression or cytokine release. However, candesartan substantially reduced the LPS-induced expression of the mRNAs for the LPS recognition protein cluster of differentiation 14, the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1 beta and interleukin-6 and the lectin-like oxidized low-density lipoprotein receptor. In addition, candesartan reduced the activation of the nuclear factor kappa B pathway, the tumor necrosis factor alpha and interleukin-6 secretion, and the ROS formation induced by LPS, without affecting the secretion of interleukin-10. Conclusion We hypothesize that the anti-inflammatory effects of candesartan in these cells are likely mediated by mechanisms unrelated to AT(1) receptor blockade. Our results demonstrate that candesartan significantly reduces the innate immune response to LPS in human circulating monocytes. The anti-inflammatory effects of candesartan may be of importance not only in hypertension but also in other inflammatory disorders. J Hypertens 27:2365-2376 (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Larrayoz, Ignacio M.; Pang, Tao; Benicky, Julius; Pavel, Jaroslav; Sanchez-Lemus, Enrique; Saavedra, Juan M.] NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH,DHHS, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH,DHHS, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Saavedrj@mail.nih.gov RI Larrayoz, Ignacio/I-5613-2012 OI Larrayoz, Ignacio/0000-0003-1629-152X FU Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA FX This study was supported by the Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA. Candesartan was a gift from Astra Zeneca, R&D, Molndal, Sweden. J.P. is currently affiliated with the Institute of Neurobiology, Slovak Academy of Sciences. NR 61 TC 20 Z9 20 U1 0 U2 1 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 DEC PY 2009 VL 27 IS 12 BP 2365 EP 2376 DI 10.1097/HJH.0b013e3283314bc7 PG 12 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 528DH UT WOS:000272420800011 PM 19730394 ER PT J AU Kawasaki, R Cheung, N Wang, JJ Klein, R Klein, BEK Cotch, MF Sharrett, AR Shea, S Islam, FMA Wong, TY AF Kawasaki, Ryo Cheung, Ning Wang, Jie Jin Klein, Ronald Klein, Barbara E. K. Cotch, Mary Frances Sharrett, A. Richey Shea, Steven Islam, F. M. Amirul Wong, Tien Y. TI Retinal vessel diameters and risk of hypertension: the Multiethnic Study of Atherosclerosis SO JOURNAL OF HYPERTENSION LA English DT Article DE hypertension; microcirculation; retinal vessel diameter; retinopathy; the Multi-Ethnic Study of Atherosclerosis ID INCIDENT SEVERE HYPERTENSION; MICROVASCULAR SIGNS; METABOLIC SYNDROME; VASCULAR CALIBER; BLOOD-PRESSURE; EYE; MICROCIRCULATION; RETINOPATHY; MESA; COMMUNITIES AB Objective To describe the prospective relationship of retinal vessel diameters with risk of hypertension in a multiethnic population-based cohort. Methods The Multi-Ethnic Study of Atherosclerosis is a population-based study of subclinical cardiovascular disease among white, African-American, Hispanic, and Chinese American adults aged 45-84 years. Retinal vessel diameters were measured using a standardized imaging software at the second examination (considered baseline in this analysis) and summarized as the central retinal artery/vein equivalent. Presence of retinopathy and retinal focal arteriolar narrowing and arteriovenous nicking was assessed by trained graders. Incidence of hypertension was defined among participants at risk as systolic blood pressure at least 140 mmHg, diastolic blood pressure at least 90 mmHg, or use of an antihypertensive medication. Results Of the initial 6237 participants at baseline, 2583 were at risk of hypertension. After 3.2 +/- 0.5 years of follow-up, 448 (17.3%) participants developed hypertension. After adjusting for age, sex, race/ethnicity, the average of mean arterial blood pressure in the first and second examination, and other vascular risk factors, persons with narrower retinal arteriolar diameter and wider venular diameter at baseline were more likely to develop hypertension [odds ratio per SD decrease in central retinal artery equivalent 1.20, 95% confidence intervals 1.02, 1.42; and odds ratio per SD increase in central retinal vein equivalent 1.18, 95% confidence interval 1.02, 1.37]. Persons with focal arteriolar narrowing were also more likely to develop hypertension (odds ratio 1.80, 95% confidence interval 1.09, 2.97). Conclusion Findings from this multiethnic population confirm that narrower retinal arteriolar diameter and wider venular diameter are associated with the development of hypertension independent of traditional risk factors. J Hypertens 27:2386-2393 (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 168751, Singapore. [Kawasaki, Ryo; Cheung, Ning; Wang, Jie Jin; Islam, F. M. Amirul; Wong, Tien Y.] Univ Melbourne, Dept Ophthalmol, Ctr Eye Res Australia, Royal Victorian Eye & Ear Hosp, Melbourne, Vic, Australia. [Kawasaki, Ryo] Yamagata Univ, Dept Ophthalmol & Visual Sci, Fac Med, Yamagata 990, Japan. [Wang, Jie Jin] Univ Sydney, Ctr Vis Res, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Shea, Steven] Columbia Univ, Dept Med, New York, NY USA. [Shea, Steven] Columbia Univ, Dept Epidemiol, New York, NY USA. [Sharrett, A. Richey] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Wong, TY (reprint author), Natl Univ Singapore, Singapore Eye Res Inst, 11 3rd Hosp Ave, Singapore 168751, Singapore. EM ophwty@nus.edu.sg RI Cheung, Ning Danny/F-2043-2013; Wang, Jie Jin/P-1499-2014; OI Wang, Jie Jin/0000-0001-9491-4898; Cotch, Mary Frances/0000-0002-2046-4350; Klein, Ronald/0000-0002-4428-6237 FU National Heart, Lung and Blood Institute [N01-HC-95159, N01-HC-95165, N01-HC-95169, R01HL69979]; National Eye Institute, USA [Z01EY00403] FX The present study is supported by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 and Grant R01HL69979 (RK TYW) from the National Heart, Lung and Blood Institute and a NIH Intramural Research Award Z01EY00403 (MFC) from the National Eye Institute, USA. NR 39 TC 44 Z9 44 U1 0 U2 1 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 DEC PY 2009 VL 27 IS 12 BP 2386 EP 2393 DI 10.1097/HJH.0b013e3283310f7e PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 528DH UT WOS:000272420800013 PM 19680136 ER PT J AU Belyakov, IM Ahlers, JD AF Belyakov, Igor M. Ahlers, Jeffrey D. TI What Role Does the Route of Immunization Play in the Generation of Protective Immunity against Mucosal Pathogens? SO JOURNAL OF IMMUNOLOGY LA English DT Review ID SIMIAN IMMUNODEFICIENCY VIRUS; T-CELL RESPONSES; CD103(+) DENDRITIC CELLS; PRIME-BOOST IMMUNIZATION; ORAL CHOLERA VACCINE; INFLUENZA-VIRUS; SYSTEMIC IMMUNIZATION; MYCOBACTERIUM-TUBERCULOSIS; INTRARECTAL IMMUNIZATION; VIRAL DISSEMINATION AB The route of vaccination is important in influencing immune responses at the initial site of pathogen invasion where protection is most effective. Immune responses required for mucosal protection can differ vastly depending on the individual pathogen. For some mucosal pathogens, including acute self-limiting infections, high-titer neutralizing Abs that enter tissue parenchyma or transude into the mucosal lumen are sufficient for clearing cell-free virus. However, for pathogens causing chronic infections such as HM hepatitis C virus, herpes viruses, mycobacteria, and fungal and parasitic infections, a single arm of the immune response generated by systemic vaccination may be insufficient for protection. Induction of the mucosal innate and adaptive immune systems, including CD4(+) T help, Th17, high avidity CD8(+) CTL, and secretory IgA and IgG1 neutralizing Abs, at the site of pathogen entry may be required for effective protection against highly invasive pathogens that lead to chronic infection and may be generated predominantly by mucosal vaccination. The Journal of Immunology, 2009, 183: 6883-6892. C1 [Belyakov, Igor M.] Midw Res Inst, Frederick, MD 21702 USA. [Ahlers, Jeffrey D.] NIAID, NIH, Bethesda, MD 20817 USA. RP Belyakov, IM (reprint author), Midw Res Inst, 110 Thomas Johnson Dr, Frederick, MD 21702 USA. EM IGORBELYAKOV@yahoo.com NR 93 TC 108 Z9 110 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 DEC 1 PY 2009 VL 183 IS 11 BP 6883 EP 6892 DI 10.4049/jimmunol.0901466 PG 10 WC Immunology SC Immunology GA 528WX UT WOS:000272478800005 PM 19923474 ER PT J AU Shi, GP Ramaswamy, M Vistica, BP Cox, CA Tan, CY Wawrousek, EF Siegel, RM Gery, I AF Shi, Guangpu Ramaswamy, Madhu Vistica, Barbara P. Cox, Catherine A. Tan, Cuiyan Wawrousek, Eric F. Siegel, Richard M. Gery, Igal TI Unlike Th1, Th17 Cells Mediate Sustained Autoimmune Inflammation and Are Highly Resistant to Restimulation-Induced Cell Death SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IL-17-PRODUCING T-CELLS; CENTRAL-NERVOUS-SYSTEM; FAS LIGAND; IFN-GAMMA; NONSPECIFIC CELLS; DENDRITIC CELLS; IL-17; DISEASE; ENCEPHALOMYELITIS; ANTIGEN AB Both Th1 and Th17 T cell subsets can mediate inflammation, but the kinetics of the pathogenic processes mediated by these two subsets have not been investigated. Using an experimental system in which TCR-transgenic Th1 or Th17 cells specific for hen egg lysozyme induce ocular inflammation in recipient mice expressing eye-restricted hen egg lysozyme, we found important differences in the in vivo behavior of these two subsets. Th1 cells initially proliferated considerably faster and invaded the eye more quickly than their Th17 counterparts, but then disappeared rapidly. By contrast, Th17 cells accumulated and remained the majority of the infiltrating CD4(+) cells in the eye for as long as 25 days after transfer, mediating more long-lasting pathological changes. Unlike Th1, Th17 cells were highly resistant to restimulation-induced apoptosis, a major pathway by which autoimmune and chronically restimulated Th1 cells are eliminated. Th17 cells had reduced Fas ligand production and resistance to Fas-induced apoptosis, relative to Th1 cells, despite similar surface expression of Fas. Th17-induced ocular inflammation also differed from Th1-induced inflammation by consisting of more neutrophils, whereas Th1-induced disease had higher proportions of CD8 cells. Taken together, our data show that pathogenic processes triggered by Th17 lag behind those induced by Th1, but then persist remarkably longer, apparently due to the relative resistance of Th17 cells to restimulation-induced cell death. The long-lasting inflammation induced by Th17 cells is in accord with these cells being involved in chronic conditions in humans. The Journal of Immunology, 2009, 183: 7547-7556. C1 [Shi, Guangpu; Vistica, Barbara P.; Cox, Catherine A.; Tan, Cuiyan; Gery, Igal] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wawrousek, Eric F.] NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Ramaswamy, Madhu; Siegel, Richard M.] NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Gery, I (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N208, Bethesda, MD 20892 USA. EM geryi@nei.nih.gov OI Siegel, Richard/0000-0001-5953-9893 FU National Eye Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Eye Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. NR 65 TC 35 Z9 35 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 1 PY 2009 VL 183 IS 11 BP 7547 EP 7556 DI 10.4049/jimmunol.0900519 PG 10 WC Immunology SC Immunology GA 528WX UT WOS:000272478800077 PM 19890052 ER PT J AU Hall, BF Fauci, AS AF Hall, B. Fenton Fauci, Anthony S. TI Malaria Control, Elimination, and Eradication: The Role of the Evolving Biomedical Research Agenda SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID GENOME SEQUENCE C1 [Hall, B. Fenton] NIAID, Parasitol Int Programs Branch, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Hall, BF (reprint author), NIAID, Parasitol Int Programs Branch, Div Microbiol & Infect Dis, NIH, 6610 Rockledge Dr,Rm 3107,MSC 6604, Bethesda, MD 20892 USA. EM lhall@niaid.nih.gov NR 18 TC 16 Z9 17 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 1 PY 2009 VL 200 IS 11 BP 1639 EP 1643 DI 10.1086/646611 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 518AP UT WOS:000271662100003 PM 19877843 ER PT J AU Miller, LH Pierce, SK AF Miller, Louis H. Pierce, Susan K. TI Perspective on Malaria Eradication: Is Eradication Possible without Modifying the Mosquito? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material C1 [Miller, Louis H.] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. [Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Miller, LH (reprint author), NIAID, Malaria Vaccine Dev Branch, NIH, Twinbrook 1,5640 Fishers Ln,Rm 1111,MSC 8152, Rockville, MD 20852 USA. EM lomiller@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 7 TC 2 Z9 2 U1 2 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 1 PY 2009 VL 200 IS 11 BP 1644 EP 1645 DI 10.1086/646612 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 518AP UT WOS:000271662100004 PM 19877845 ER PT J AU Xi, LF Hughes, JP Edelstein, ZR Kiviat, NB Koutsky, LA Mao, C Ho, J Schiffman, M AF Xi, Long Fu Hughes, James P. Edelstein, Zoe R. Kiviat, Nancy B. Koutsky, Laura A. Mao, Constance Ho, Jesse Schiffman, Mark TI Human Papillomavirus (HPV) Type 16 and Type 18 DNA Loads at Baseline and Persistence of Type-Specific Infection during a 2-Year Follow-Up SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CERVICAL INTRAEPITHELIAL NEOPLASIA; HUMAN-IMMUNODEFICIENCY-VIRUS; RISK HUMAN-PAPILLOMAVIRUS; CARCINOMA IN-SITU; FORMER SOVIET-UNION; VIRAL LOAD; INDEPENDENT STATES; NATURAL-HISTORY; WOMEN; CLEARANCE AB Background. Studies of viral load-associated persistence of human papillomavirus (HPV) infection are rare, with inconsistent results reported. Methods. The study subjects were 741 and 289 women who were positive for HPV type 16 (HPV-16) and HPV type 18 (HPV-18), respectively, at the time of enrollment into in the ASCUS-LSIL ( Atypical Squamous Cells of Undetermined Significance-Low-Grade Squamous Intraepithelial Lesion) Triage Study and who returned 1 or more times for HPV testing during a biannual 2-year follow-up. The numbers of HPV-16 and HPV-18 copies per nanogram of cellular DNA at baseline were measured by use of real-time polymerase chain reaction. Results. Women with, compared with women without, persistent infection at month 6 of follow-up had a higher viral load at enrollment (P < .001, for HPV-16; P = .01, for HPV-18). The association of each 1-log(10) increase in viral load with persistence of HPV-16 or HPV-18 during the first 6 months of the study was statistically significant among women with multiple HPV types at enrollment ( for HPV-16: odds ratio [ OR], 1.53 [ 95% confidence interval {CI}, 1.29-1.82]; for HPV-18: OR, 1.35 [ 95% CI, 1.09-1.68]) but not among women with monotype infections ( in tests assessing the interaction between viral load and coinfection, P = .002 for HPV-16 and P = .34 for HPV-18). Among women who continued to have positive results at month 6, 12, or 18, persistence of infection for another 6 months was unassociated with the viral load at baseline. Conclusion. Prevalent infection with a higher viral load of HPV-16 or HPV-18 was associated with short-but not long-term persistence. C1 [Xi, Long Fu; Kiviat, Nancy B.; Ho, Jesse] Univ Washington, Dept Pathol, Sch Med, Seattle, WA 98195 USA. [Mao, Constance] Univ Washington, Dept Obstet & Gynecol, Sch Med, Seattle, WA 98195 USA. [Xi, Long Fu; Edelstein, Zoe R.; Koutsky, Laura A.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Hughes, James P.] Univ Washington, Dept Biostat, Sch Publ Hlth, Seattle, WA 98195 USA. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Xi, LF (reprint author), Northgate Execut Ctr 1,Bldg B,155 NE 100th St,Ste, Seattle, WA 98125 USA. EM longfu@u.washington.edu FU Public Health Service [CA 84396] FX Financial support: Public Health Service ( grant CA 84396 to L. F. X.). NR 44 TC 23 Z9 23 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 1 PY 2009 VL 200 IS 11 BP 1789 EP 1797 DI 10.1086/647993 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 518AP UT WOS:000271662100024 PM 19848609 ER PT J AU Carrillo-Carrasco, N Sloan, J Valle, D Hamosh, A Venditti, CP AF Carrillo-Carrasco, N. Sloan, J. Valle, D. Hamosh, A. Venditti, C. P. TI Hydroxocobalamin dose escalation improves metabolic control in cblC SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article ID COMBINED METHYLMALONIC ACIDURIA; CLINICAL HETEROGENEITY; HOMOCYSTINURIA CBLC; FOLATE-DEFICIENCY; COBALAMIN; ACIDEMIA; MUTATIONS; SPECTRUM; DISORDER; MMACHC AB Cobalamin C (cblC), a combined form of methylmalonic acidaemia and hyperhomocysteinaemia, is recognized as the most frequent inborn error of intracellular cobalamin metabolism. This condition can be detected by expanded newborn screening and can have an acute neonatal presentation that is life-threatening if not suspected and promptly treated. Intramuscular (IM) hydroxocobalamin (OHCbl) is the main treatment for patients with cblC, but formal dosing guidelines do not exist. A clinical improvement and a decrease of plasma methylmalonic acid (MMA) and total homocysteine (tHcy) levels, and an increase in methionine are typically observed after its initiation. It is well recognized that despite treatment, long-term complications such as developmental delay and progressive visual loss, may still develop. We describe the biochemical response of a 13-year-old boy with worsening metabolic parameters despite strict adherence to a conventional treatment regimen. We progressively increased the OHCbl dose from 1 to 20 mg IM per day and observed a dose-dependent response with an 80% reduction of plasma MMA (25 to 5.14 mu mol/L; normal range < 0.27 mu mol/L), a 55% reduction of tHcy (112 to 50 mu mol/L; normal range: 0-13 mu mol/L) and a greater than twofold increase in methionine (17 to 36 mu mol/L; normal range: 7-47 mu mol/L). This suggests that higher OHCbl doses might be required to achieve an optimal biochemical response in cblC patients, but it is unknown whether it may slow or eliminate other complications. Future clinical trials to determine the benefits of higher-dose OHCbl therapy in patients with cblC and other disorders of intracellular cobalamin metabolism should be planned. C1 [Carrillo-Carrasco, N.; Sloan, J.; Venditti, C. P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Valle, D.; Hamosh, A.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. RP Venditti, CP (reprint author), NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bldg 49,Room 4A18, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov RI Carrillo-Carrasco, Nuria/B-9034-2009 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808 FU National Human Genome Research Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 21 TC 22 Z9 22 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD DEC PY 2009 VL 32 IS 6 BP 728 EP 731 DI 10.1007/s10545-009-1257-y PG 4 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 543JO UT WOS:000273572600007 PM 19821145 ER PT J AU Senthilselvan, A Chenard, L Kirychuk, S Predicala, B Schwartz, DA Burch, LH Rennie, DC Willson, PJ Dosman, JA AF Senthilselvan, Ambikaipakan Chenard, Liliane Kirychuk, Shelley Predicala, Bernardo Schwartz, David A. Burch, Lauranell H. Rennie, Donna C. Willson, Philip J. Dosman, James A. TI Gender-Related Tumor Necrosis Factor-alpha Responses in Naive Volunteers With Toll-Like Receptor 4 Polymorphisms Exposed in a Swine Confinement Facility SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID INFLAMMATORY RESPONSE; AIRWAY RESPONSIVENESS; ENDOTOXIN EXPOSURE; IMMUNE-RESPONSES; LUNG-FUNCTION; DUST; LIPOPOLYSACCHARIDE; INHALATION; BUILDINGS; MUTATIONS AB The aim of this work is to better understand the responses of people that are exposed to agricultural organic dust and other factors in modern swine production. We investigated the effects of toll-like receptor 4 (TLR4) genotype and gender on respiratory responses of naive volunteers (18-28 years) to swine barn exposure. Non-smoking healthy subjects (16 men and 13 women) with TLR4 299 (Asp299Gly) and/ or 399 (Thr399Ile) polymorphisms (TLR4 299/399) and age-sex matched subjects with TLR4 wild-type alleles spent 5 h in a nonexposed environment (baseline day) and 5 h in a swine facility (exposure day). The results showed significant decreases between baseline and exposure days in across-shift forced vital capacity (FVC), forced expiratory volume in 1 second (FEV(1)), forced midexpiratory flow rate (FEF(25-75)), and FEV(1)/FVC ratio and in methacholine concentration that reduced FEV1 by 20% (PC(20)) in all groups; however, there were no differences by sex or genotype. Similarly, nasal cytokines, serum cytokines, and blood neutrophil count increased after exposure; in contrast, however, these were influenced by gender. The increase in serum tumor necrosis factor-alpha (TNF-alpha) between baseline and exposure was gender-dependent with male sex associated with a significant increase in the wild-type group and female sex associated with a significant increase in the polymorphic group. These results suggest that for persons exposed to a swine facility, one's immunological response varies with gender as well as TLR4 genotype. C1 [Senthilselvan, Ambikaipakan] Univ Alberta, Sch Publ Hlth, Dept Publ Hlth Sci, Edmonton, AB T6G 2G3, Canada. [Chenard, Liliane; Kirychuk, Shelley; Rennie, Donna C.; Willson, Philip J.; Dosman, James A.] Univ Saskatchewan, Canadian Ctr Hlth & Safety Agr, Saskatoon, SK, Canada. [Predicala, Bernardo] Prairie Swine Ctr Inc, Saskatoon, SK, Canada. [Schwartz, David A.] Natl Jewish Med & Res Ctr, Denver, CO USA. [Burch, Lauranell H.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Senthilselvan, A (reprint author), Univ Alberta, Sch Publ Hlth, Dept Publ Hlth Sci, 13-106B Clin Sci Bldg, Edmonton, AB T6G 2G3, Canada. EM sentil@ualberta.ca FU Canadian Institutes of Health Research [MOP-57907] FX This study was supported by a grant from the Canadian Institutes of Health Research (Grant no: MOP-57907). The authors want to acknowledge the technical support provided by Evelyne Assayag, Randine Sorowski, and Natasha Thiessen. NR 47 TC 1 Z9 1 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD DEC PY 2009 VL 29 IS 12 BP 781 EP 790 DI 10.1089/jir.2009.0002 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 533TN UT WOS:000272848300002 PM 19929430 ER PT J AU Kim, BS Miyagawa, F Cho, YH Bennett, CL Clausen, BE Katz, SI AF Kim, Brian S. Miyagawa, Fumi Cho, Young-Hun Bennett, Clare L. Clausen, Bjorn E. Katz, Stephen I. TI Keratinocytes Function as Accessory Cells for Presentation of Endogenous Antigen Expressed in the Epidermis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID STEADY-STATE CONDITIONS; DERMAL DENDRITIC CELLS; VERSUS-HOST-DISEASE; LANGERHANS CELLS; T-CELLS; CONTACT HYPERSENSITIVITY; SKIN-DISEASE; LYMPH-NODES; IN-VIVO; TRANSGENIC MICE AB The precise contribution(s) of skin dendritic cells (DCs) to immune responses in the skin has not been well delineated. We developed an intradermal (i.d.) injection model in which CD8(+) T (OT-I) cells that express ovalbumin (OVA) peptide-specific TCRs (V alpha 2/V beta 5) are delivered directly to the dermis of transgenic (Tg) mice expressing OVA in the epidermis. After i.d. injection, these mice reliably develop skin graft-versus-host disease (GVHD) by day 7. To determine the relative contribution of Langerhans cells (LCs) to the ensuing GVHD-like reaction, we generated K14-OVA x Langerin-diphtheria-toxin-receptor (Langerin-DTR) Tg mice to allow conditional ablation of LCs in the epidermis. To delineate the role of dermal DCs (dDCs) in the reaction, we also generated K14-OVA Tg chimeras using beta(2)-microglobulin-deficient (beta(2)m) congenic donor bone marrow cells. Dermal DCs in these mice cannot present OVA to autoreactive T cells (OT-I cells), whereas the LCs are antigen presentation-competent. Unexpectedly, OT-I cell injection into diphtheria toxin (DT)-treated beta(2)m -> K14-OVA x Langerin-DTR Tg mice resulted in skin GVHD. Thus, in vivo, both LC and dDC appear to be dispensable for the induction of keratinocyte-directed, CD8-mediated effector immune responses. Furthermore and surprisingly, OVA-expressing epidermal cells depleted of LCs that could not initiate allogeneic epidermal lymphocyte reactions activated naive OT-I cells in vitro. These results indicate that keratinocytes may function as accessory cells competent to prime naive skin-reactive T cells. C1 [Kim, Brian S.; Miyagawa, Fumi; Cho, Young-Hun; Katz, Stephen I.] Natl Canc Inst, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Kim, Brian S.] Howard Hughes Med Inst, NIH, Res Scholars Program, Bethesda, MD 20817 USA. [Bennett, Clare L.; Clausen, Bjorn E.] Univ Amsterdam, Dept Cell Biol & Histol, Acad Med Ctr, Amsterdam, Netherlands. [Bennett, Clare L.; Clausen, Bjorn E.] Erasmus Univ, Med Ctr, Dept Immunol, Ge Rotterdam, Netherlands. RP Katz, SI (reprint author), Natl Canc Inst, Dermatol Branch, NIH, Bethesda, MD 20892 USA. EM katzs@od.niams.nih.gov RI CLAUSEN, Bjorn/A-8229-2010; bennett, clare/J-5249-2013 OI CLAUSEN, Bjorn/0000-0002-2484-7842; bennett, clare/0000-0001-9146-2347 FU Center for Cancer Research Intramural Research Program; NCI; NIH; Landsteiner Foundation for Blood Transfusion Research (LSBR) FX We thank Jay Linton for his excellent technical expertise, Dr Xu Feng and Dr Takashi Kakinuma for helpful suggestions, and Dr Mark Udey for critical discussions and review of the paper. This study was supported in part by the Center for Cancer Research Intramural Research Program, NCI, NIH, and by the Landsteiner Foundation for Blood Transfusion Research (LSBR) (BEC) and a VIDI fellow of The Netherlands Organization for Scientific Research (NWO) (BEC). NR 40 TC 27 Z9 28 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD DEC PY 2009 VL 129 IS 12 BP 2805 EP 2817 DI 10.1038/jid.2009.176 PG 13 WC Dermatology SC Dermatology GA 519YS UT WOS:000271807200012 PM 19554018 ER PT J AU Kosaka, N Ogawa, M Sato, N Choyke, PL Kobayashi, H AF Kosaka, Nobuyuki Ogawa, Mikako Sato, Noriko Choyke, Peter L. Kobayashi, Hisataka TI In Vivo Real-Time, Multicolor, Quantum Dot Lymphatic Imaging SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID HORIZONS AB The lymphatic network is complex and difficult to visualize in real-time in vivo. Moreover, the direction of flow within lymphatic networks is often unpredictable especially in areas with well-developed "watershed'' or overlapping lymphatics. Herein, we report a method of in vivo real-time multicolor lymphatic imaging using cadmium-selenium quantum dots (Qdots) with a fluorescence imaging system that enables the simultaneous visualization of up to five distinct lymphatic basins in real-time. Five visually well-distinguishable carboxyl-Qdots (Qdot 545, 565, 585, 605, and 655) were selected and injected subdermally into mice at five different sites, and serially imaged in vivo or in situ under surgery with real-time multicolor lymphatic imaging. In all seven mice, in vivo lymphatic images successfully distinguished all five lymphatic basins with different colors in real-time. These visualizations of lymph node lasted up to at least 7 days. This method could have a considerable potential in lymphatic research for studying the anatomy and flow within the lymphatic system as well as in some limited clinical settings where real-time visible fluorescence could facilitate procedures under surgery or endoscopy. C1 [Kosaka, Nobuyuki; Ogawa, Mikako; Sato, Noriko; Choyke, Peter L.; Kobayashi, Hisataka] Natl Canc Inst, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), Natl Canc Inst, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room 1B40,MSC1088, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 17 TC 49 Z9 51 U1 2 U2 16 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 DEC PY 2009 VL 129 IS 12 BP 2818 EP 2822 DI 10.1038/jid.2009.161 PG 5 WC Dermatology SC Dermatology GA 519YS UT WOS:000271807200013 PM 19536144 ER PT J AU Lyons, JG Patel, V Roue, N Halliday, GM Gutkind, JS AF Lyons, J. G. Patel, V. Roue, N. Halliday, G. M. Gutkind, J. S. TI Snail transcription factors up-regulate the expression of pro-inflammatory genes in keratinocytes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 5th Annual Scientific Meeting of the Australasian-Society-for-Dermatology-Research CY MAY 21-22, 2008 CL Sydney, AUSTRALIA SP Australasian Soc Dermatol Res C1 [Lyons, J. G.; Roue, N.; Halliday, G. M.] Univ Sydney, Marshall Dermatol Res Labs, Sydney, NSW 2006, Australia. [Lyons, J. G.; Roue, N.] RPA Hosp, Sydney Head & Neck Canc Inst, Camperdown, NSW, Australia. [Lyons, J. G.; Patel, V.; Gutkind, J. S.] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RI Gutkind, J. Silvio/A-1053-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD DEC PY 2009 VL 129 IS 12 BP 2909 EP 2909 PG 1 WC Dermatology SC Dermatology GA 519YS UT WOS:000271807200026 ER PT J AU Brenzovich, J Macey, M Fernando, J Chong, HJ Barnstein, B Mirmonsef, P Morales, JK Kimura, A Cruz, TD Ryan, JJ AF Brenzovich, Jennifer Macey, Matthew Fernando, Josephine Chong, Hey Jin Barnstein, Brian Mirmonsef, Paria Morales, Johanna K. Kimura, Akiko Cruz, Tracey Dawson Ryan, John J. TI IgE signaling suppresses Fc epsilon RI beta expression SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE mast cells; allergy; Fc epsilon RI; beta-chain; IgE ID BASOPHILIC LEUKEMIA-CELLS; HIGH-AFFINITY RECEPTOR; MAST-CELL; IMMUNOGLOBULIN-E; ALLERGIC RESPONSES; STAT5 EXPRESSION; ACTIVATION; SUBUNIT; AMPLIFIER; ENDOCYTOSIS AB Activation of the high-affinity receptor for IgE, Fc epsilon RI, is known to elicit its rapid down-regulation through internalization and degradation. In keeping with this, expression of all three Fc epsilon RI subunits is decreased at the protein level after cross-linkage of IgE with antigen. However, we find that the Fc epsilon RI beta-subunit is also selectively suppressed at the mRNA level, through a pathway primarily involving Fyn, Syk, PI3K, and NF-kappa B. IgG or calcium ionophore, stimuli known to mimic portions of the IgE signaling cascade, similarly suppressed beta-subunit expression. LPS, a NF-kappa B-activating TLR ligand, did not alter beta-subunit expression. As IgE increases Fc epsilon RI expression, we examined the coordinated regulation of Fc epsilon RI subunits during culture with IgE, followed by cross-linkage with antigen. IgE increased the expression of all three Fc epsilon RI subunits and strikingly induced expression of the antagonistic beta(T). The ratio of beta:beta(T) protein expression decreased significantly during culture with IgE and was reset to starting levels by antigen cross-linkage. These changes in protein levels were matched by similar fluctuations in beta and beta(T) mRNAs. Fc epsilon RI beta is a key regulator of IgER expression and function, a gene in which polymorphisms correlate with allergic disease prevalence. The ability of IgE and Fc epsilon RI signaling to coordinate expression of the beta and beta(T) subunits may comprise a homeostatic feedback loop-one that could promote chronic inflammation and allergic disease if dysregulated. J. Leukoc. Biol. 86: 1351-1358; 2009. C1 [Brenzovich, Jennifer; Macey, Matthew; Fernando, Josephine; Chong, Hey Jin; Barnstein, Brian; Mirmonsef, Paria; Morales, Johanna K.; Cruz, Tracey Dawson; Ryan, John J.] Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. [Cruz, Tracey Dawson] Virginia Commonwealth Univ, Dept Forens Sci, Richmond, VA 23284 USA. [Kimura, Akiko] Natl Inst Diabet Digest & Kidney Disorders, NIH, Bethesda, MD USA. RP Ryan, JJ (reprint author), Virginia Commonwealth Univ, Dept Biol, Box 842012, Richmond, VA 23284 USA. EM jjryan@vcu.edu FU NIH [1R01 AI59638]; Jeffress Trust Foundation [J-833] FX This work was supported by grants from the NIH (1R01 AI59638) and The Jeffress Trust Foundation (J-833; to J. J. R.). NR 28 TC 4 Z9 4 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD DEC PY 2009 VL 86 IS 6 BP 1351 EP 1358 DI 10.1189/jlb.0409231 PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 525DF UT WOS:000272193000011 PM 19741159 ER PT J AU Gao, F Kiesewetter, D Chang, L Ma, KZ Rapoport, SI Igarashi, M AF Gao, Fei Kiesewetter, Dale Chang, Lisa Ma, Kaizong Rapoport, Stanley I. Igarashi, Miki TI Whole-body synthesis secretion of docosahexaenoic acid from circulating eicosapentaenoic acid in unanesthetized rats SO JOURNAL OF LIPID RESEARCH LA English DT Article DE stable isotopes; liver; n-3 polyunsaturated fatty acid; brain; diet ID ALPHA-LINOLENIC ACID; POLYUNSATURATED FATTY-ACIDS; LOW-DENSITY-LIPOPROTEIN; BRAIN PHOSPHOLIPIDS; BIPOLAR DEPRESSION; LIVER CONVERSION; PUFA DEPRIVATION; LIPID-METABOLISM; DOUBLE-BLIND; AWAKE RATS AB Dietary docosahexaenoic acid (DHA; 22:6n-3) and eicosapentaenoic acid (EPA; 20:5n-3) are considered important for maintaining normal heart and brain function, but little EPA is found in brain, and EPA cannot be elongated to DHA in rat heart due to the absence of elongase-2. Ingested EPA may have to be converted in the liver to DHA for it to be fully effective in brain and heart, but the rate of conversion is not agreed on. This rate was determined in male adult rats fed a standard n-3 PUFA, containing diet by infusing unesterified albumin-bound [U-C-13]EPA intravenously for 2 h and measuring esterified [C-13] labeled PUFAs in arterial plasma lipoproteins, as well as the specific activity of unesterified plasma EPA. Whole-body (presumably hepatic) synthesis secretion rates from circulating unesterified EPA, calculated from peak first derivatives of plasma esterified concentration x volume curves, equaled 2.61 mu mol/day for docosapentaenoic acid (22:5n-3) and 5.46 mu mol/day for DHA. The DHA synthesis rate was 24-fold greater than the reported brain DHA consumption rate in rats. Thus, dietary EPA could help to maintain brain and heart DHA homeostasis because it is converted at a relatively high rate in the liver to circulating DHA.-Gao, F., D. Kiesewetter, L. Chang, K. Ma, S. I. Rapoport, and M. Igarashi. Whole-body synthesis secretion of docosahexaenoic acid from circulating eicosapentaenoic acid in unanesthetized rats. J. Lipid Res. 2009. 50: 2463-2470. C1 [Gao, Fei; Chang, Lisa; Ma, Kaizong; Rapoport, Stanley I.; Igarashi, Miki] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Kiesewetter, Dale] Natl Inst Biomed Imaging & Bioengn, Positron Emiss Tomog Radiochem Grp, NIH, Bethesda, MD 20892 USA. RP Gao, F (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM gaof@mail.nih.gov FU National Institute on Aging, National Institutes of Health, Bethesda, MD FX This research was supported entirely by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Bethesda, MD. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 69 TC 16 Z9 17 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD DEC PY 2009 VL 50 IS 12 BP 2463 EP 2470 DI 10.1194/jlr.M900223-JLR200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 519LV UT WOS:000271769000014 PM 19571329 ER PT J AU Huizing, M Pederson, B Hess, RA Griffin, A Helip-Wooley, A Westbroek, W Dorward, H O'Brien, KJ Golas, G Tsilou, E White, JG Gahl, WA AF Huizing, M. Pederson, B. Hess, R. A. Griffin, A. Helip-Wooley, A. Westbroek, W. Dorward, H. O'Brien, K. J. Golas, G. Tsilou, E. White, J. G. Gahl, W. A. TI Clinical and cellular characterisation of Hermansky-Pudlak syndrome type 6 SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID LYSOSOME-RELATED ORGANELLES; PROTEIN TRAFFICKING; COMPLEX; BIOGENESIS; BLOC-1; DISEASE; ENDOSOMES; DEFECTS; GENES; HPS1 AB Background: In the last decade, Hermansky-Pudlak syndrome (HPS) has arisen as an instructive disorder for cell biologists to study the biogenesis of lysosome related organelles (LROs). Of the eight human HPS subtypes, only subtypes 1 through 5 are well described. Aim: To characterise extensively the HPS-6 subtype, caused by defects in HPS6, a subunit of the biogenesis of lysosome related organelles complex-2 (BLOC-2). Methods: Mutation analysis for the HPS6 gene was performed on DNA from our group of unclassified HPS patients. The clinical phenotype of patients with HPS6 mutations was then carefully ascertained, and their cultured dermal melanocytes were employed for cellular immunofluorescence studies. Results: Molecular studies showed a variety of mutations in the single exon HPS6 gene, including frame shift, missense, and nonsense mutations as well as a,20 kb deletion spanning the entire HPS6 genomic region. Cellular studies revealed that the melanogenic proteins tyrosinase and tyrosinase related protein 1 failed to be efficiently delivered to the melanosomes of HPS-6 patients, explaining their hypopigmentation. Clinical studies indicated that HPS-6 patients exhibit oculocutaneous albinism and a bleeding diathesis. Importantly, granulomatous colitis and pulmonary fibrosis, debilitating features present in HPS subtypes 1 and 4, were not detected in our HPS-6 patients. Conclusion: The HPS-6 subtype resembles other BLOC-2 defective subtypes (that is, HPS-3 and HPS-5) in its molecular, cellular and clinical findings. These findings are not only important for providing a prognosis to newly diagnosed HPS-6 patients, but also for further elucidation of HPS function in the biogenesis of LROs. C1 [Huizing, M.; Pederson, B.; Hess, R. A.; Griffin, A.; Helip-Wooley, A.; Westbroek, W.; Dorward, H.; O'Brien, K. J.; Golas, G.; Gahl, W. A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [O'Brien, K. J.; Golas, G.; Gahl, W. A.] NIH, Off Rare Dis, Intramural Program, Off Director, Bethesda, MD 20892 USA. [Tsilou, E.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [White, J. G.] Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 USA. RP Huizing, M (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1851,Bldg 10,Room 10C-103, Bethesda, MD 20892 USA. EM mhuizing@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA FX This work was supported by the Intramural Research programs of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. NR 30 TC 20 Z9 20 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD DEC PY 2009 VL 46 IS 12 BP 803 EP 810 DI 10.1136/jmg.2008.065961 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 526KT UT WOS:000272288200002 PM 19843503 ER PT J AU Choi, BY Madeo, AC King, KA Zalewski, CK Pryor, SP Muskett, JA Nance, WE Butman, JA Brewer, CC Griffith, AJ AF Choi, B. Y. Madeo, A. C. King, K. A. Zalewski, C. K. Pryor, S. P. Muskett, J. A. Nance, W. E. Butman, J. A. Brewer, C. C. Griffith, A. J. TI Segregation of enlarged vestibular aqueducts in families with non-diagnostic SLC26A4 genotypes SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID WIEDEMANN-BECKWITH SYNDROME; PENDRED-SYNDROME; HEARING-LOSS; MONOZYGOTIC TWINS; PHENOTYPE CORRELATIONS; PDS MUTATIONS; GENE; DEAFNESS; DFNB4; FREQUENCIES AB Background: Hearing loss with enlarged vestibular aqueduct (EVA) can be inherited as an autosomal recessive trait caused by bi-allelic mutations of SLC26A4. However, many EVA patients have non-diagnostic SLC26A4 genotypes with only one or no detectable mutant alleles. Methods and results: In this study, the authors were unable to detect occult SLC26A4 mutations in EVA patients with non-diagnostic genotypes by custom comparative genomic hybridisation (CGH) microarray analysis or by sequence analysis of conserved non-coding regions. The authors sought to compare the segregation of EVA among 71 families with two (M2), one (M1) or no (M0) detectable mutant alleles of SLC26A4. The segregation ratios of EVA in the M1 and M2 groups were similar, but the segregation ratio for M1 was significantly higher than in the M0 group. Haplotype analyses of SLC26A4-linked STR markers in M0 and M1 families revealed discordant segregation of EVA with these markers in eight of 24 M0 families. Conclusion: The results support the hypothesis of a second, undetected SLC26A4 mutation that accounts for EVA in the M1 patients, in contrast to non-genetic factors, complex inheritance, or aetiologic heterogeneity in the M0 group of patients. These results will be helpful for counselling EVA families with non-diagnostic SLC26A4 genotypes. C1 [Madeo, A. C.; King, K. A.; Zalewski, C. K.; Pryor, S. P.; Muskett, J. A.; Brewer, C. C.; Griffith, A. J.] NIDCD, Otolaryngol Branch, NIH, Rockville, MD 20850 USA. [Choi, B. Y.] NIDCD, Mol Genet Lab, NIH, Rockville, MD 20850 USA. [Nance, W. E.] Virginia Commonwealth Univ, Med Coll Virginia, Dept Human Genet, Richmond, VA 23298 USA. [Butman, J. A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Griffith, AJ (reprint author), NIDCD, Otolaryngol Branch, NIH, 5 Res Court,Room 1A-13D, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov RI Butman, John/A-2694-2008; Madeo, Anne/K-2880-2012; Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU NIH [Z01-DC-000039, Z01-DC-000060, Z01-DC-000064]; National Human Genome Research Institute FX This work was supported by NIH intramural research funds Z01-DC-000039, Z01-DC-000060 and Z01-DC-000064 and the Intramural Research Program of the National Human Genome Research Institute. NR 27 TC 18 Z9 20 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD DEC PY 2009 VL 46 IS 12 BP 856 EP 861 DI 10.1136/jmg.2009.067892 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 526KT UT WOS:000272288200009 PM 19578036 ER PT J AU Davis, FD Crowe, SJ AF Davis, F. Daniel Crowe, Samuel J. TI Organ Markets and the Ends of Medicine SO JOURNAL OF MEDICINE AND PHILOSOPHY LA English DT Article DE bodily integrity; dignity; ends of medicine; organ markets; organ transplantation ID KIDNEY-DISEASE; TRANSPLANTATION; DONATION AB As the gap between the need for and supply of human organs continues to widen, the aim of securing additional sources of these "gifts of the body" has become a seemingly overriding moral imperative, one that could-and some argue, should-override the widespread ban on organ markets. As a medical practice, organ transplantation entails the inherent risk that one human being, a donor, will become little more than a means to the end of healing for another human being and that he or she will come to have a purely instrumental value. With the establishment of organ markets, not only will the harms of instrumentalization be a reality-the ends of medicine will be further compromised and confused. C1 [Davis, F. Daniel] Georgetown Univ, Ctr Clin Bioeth, Washington, DC USA. [Crowe, Samuel J.] NIH, Off Sci Policy, Off Director, Washington, DC USA. RP Davis, FD (reprint author), 5513 Nebraska Ave NW, Washington, DC USA. EM fdanieldavis@gmail.com NR 45 TC 7 Z9 7 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0360-5310 EI 1744-5019 J9 J MED PHILOS JI J. Med. Philos. PD DEC PY 2009 VL 34 IS 6 BP 586 EP 605 DI 10.1093/jmp/jhp047 PG 20 WC Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Biomedical Social Sciences GA 523PK UT WOS:000272086300004 PM 19880547 ER PT J AU Modi, HR Katyare, SS AF Modi, Hiren R. Katyare, Surendra S. TI Effect of Treatment with Cadmium on Structure-Function Relationships in Rat Liver Mitochondria: Studies on Oxidative Energy Metabolism and Lipid/Phospholipids Profiles SO JOURNAL OF MEMBRANE BIOLOGY LA English DT Article DE Cadmium (Cd); Oxidative energy metabolism; Cytochromes; Dehydrogenases; Mitochondrial lipid/phospholipid profile; Total phospholipid; Cholesterol; Liver mitochondria ID SPRAGUE-DAWLEY RATS; PROTEIN-SYNTHESIS; INDUCED HEPATOTOXICITY; MEMBRANE; TOXICITY; FLUIDITY; PRETREATMENT; INHIBITION; MICROSOMES; TOLERANCE AB Effects of treatment with a single intraperitoneal injection of cadmium (Cd) on oxidative energy metabolism and lipid/phospholipid profiles of rat liver mitochondria were examined at the end of 1 week and 1 month. Following Cd treatment the body weight increased only in the 1 month group, whereas the liver weight increased in both groups. State 3 and 4 respiration rates in general decreased significantly, with the maximum effect being seen with succinate. The 1 week Cd group showed decreased respiratory activity with glutamate, pyruvate + malate, and succinate as the substrates. In the 1 month Cd-treated group respiration rates recovered with glutamate and pyruvate + malate but not with succinate. All cytochrome contents decreased in the 1 week Cd-treated group but recovered in the 1 month group. ATPase activity registered an increase in both Cd-treated groups. Dehydrogenase activities increased in the 1 week group but decreased in the 1 month Cd-treated group. The mitochondrial cholesterol content increased in the 1 week Cd-treated group. In the 1 week Cd-treated group the lysophospholipid (Lyso), sphingomyelin (SPM), and diphosphatidylglycerol (DPG) components increased. By contrast, the phosphatidylethanolamine (PE) component decreased. In the 1 month Cd-treated group the phosphatidylinositol, phosphatidylserine, and DPG components increased, whereas the Lyso, SPM, and phosphatidylcholine components decreased. The results demonstrate that single-dose Cd treatment can have adverse effects on liver mitochondrial oxidative energy metabolism and lipid/phosphopholipid profiles, which in turn can affect membrane structure-function relationships. C1 [Modi, Hiren R.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Modi, Hiren R.; Katyare, Surendra S.] Maharaja Sayajirao Univ Baroda, Dept Biochem, Fac Sci, Vadodara 390002, Gujarat, India. RP Modi, HR (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike Bldg 9,Room 1S126, Bethesda, MD 20892 USA. EM modi_hiren@yahoo.co.in NR 52 TC 5 Z9 5 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-2631 J9 J MEMBRANE BIOL JI J. Membr. Biol. PD DEC PY 2009 VL 232 IS 1-3 BP 47 EP 57 DI 10.1007/s00232-009-9217-x PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Physiology SC Biochemistry & Molecular Biology; Cell Biology; Physiology GA 524CF UT WOS:000272120700005 PM 19921325 ER PT J AU Rana, ZA Gundersen, K Buonanno, A AF Rana, Zaheer A. Gundersen, Kristian Buonanno, Andres TI The ups and downs of gene regulation by electrical activity in skeletal muscles SO JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY LA English DT Review DE Skeletal-muscle; Fibre-types; Activity NFATc1; Gene-regulation ID FIBER-TYPE; CONTRACTILE PROPERTIES; SLOW MUSCLE; RAT MUSCLES; DIFFERENTIAL REGULATION; SELECTIVE INNERVATION; TRANSGENIC MICE; FIRING PATTERNS; EXPRESSION; TRANSCRIPTION AB Adult skeletal muscles retain an adaptive capacity to switch between slow-and fast-twitch properties that are largely dependent on motoneuron activity. Our studies on the transcriptional regulation of the Troponin I slow (TnIs) and fast (TnIf) genes uncovered a dual mechanism of transcriptional enhancement and repression by a single activity pattern, that promotes the phenotypic differences among myofibers while preserving their adaptive capacity. Using the Tnf Fast Intronic Regulatory Element (FIRE), we initially demonstrated that fast-patterned activity (infrequent, high frequency depolarization) is necessary to up-regulate FIRE-dependent transcription and that its effect differs dramatically from muscle denervation. Hence, the "fast muscle program" is not a default state mimicked simply by denervation or muscle inactivity. Next, we found that slow-patterned activity (tonic, slow frequency stimulation) selectively represses FIRE-dependent transcription while enhancing transcription from the TnIs Slow Upstream Regulatory Element. Unexpectedly, repression of the TnIf FIRE by slow-patterned activity is mediated by an NFAT element that directly binds NFATc1, a transcription factor that translocates to the nucleus selectively by slow-pattern depolarization and has been implicated in the up-regulation of the slow muscle program. Transfection of siRNAs targeting NFATc1 or mutation of the TnIFIRE NFAT site result in the upregulation of FIRE-dependent transcription in slow muscle, but have no effect in fast muscle. These findings demonstrate a novel function of NFAT as a repressor of transcription of fast contractile genes in slow muscles and, more importantly, they illustrate how specific activity patterns can enhance the phenotypic differences among fibretypes by differentially regulating transcription in a use-dependent manner while retaining the adaptive properties of adult muscles. C1 [Rana, Zaheer A.; Gundersen, Kristian] Univ Oslo, Dept Mol Biosci, Oslo, Norway. [Buonanno, Andres] NICHHD, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Rana, ZA (reprint author), Univ Oslo, Dept Mol Biosci, Oslo, Norway. EM z.a.rana@imbv.uio.no FU Intramural NIH HHS [Z01 HD000711-19, ZIA HD000711-20] NR 40 TC 9 Z9 9 U1 1 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0142-4319 J9 J MUSCLE RES CELL M JI J. Muscle Res. Cell Motil. PD DEC PY 2009 VL 30 IS 7-8 SI SI BP 255 EP 260 DI 10.1007/s10974-010-9200-2 PG 6 WC Cell Biology SC Cell Biology GA 629ZN UT WOS:000280240400002 PM 20135341 ER PT J AU Monosov, IE Thompson, KG AF Monosov, Ilya E. Thompson, Kirk G. TI Frontal Eye Field Activity Enhances Object Identification During Covert Visual Search SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID LATERAL INTRAPARIETAL AREA; TRANSCRANIAL MAGNETIC STIMULATION; SACCADE TARGET SELECTION; SPATIAL ATTENTION; PARIETAL CORTEX; SUPERIOR COLLICULUS; TASK-DIFFICULTY; BOTTOM-UP; TOP-DOWN; VISUOSPATIAL ATTENTION AB Monosov IE, Thompson KG. Frontal eye field activity enhances object identification during covert visual search. J Neurophysiol 102: 3656-3672, 2009. First published October 14, 2009; doi:10.1152/jn.00750.2009. We investigated the link between neuronal activity in the frontal eye field (FEF) and the enhancement of visual processing associated with covert spatial attention in the absence of eye movements. We correlated activity recorded in the FEF of monkeys manually reporting the identity of a visual search target to performance accuracy and reaction time. Monkeys were cued to the most probable target location with a cue array containing a popout color singleton. Neurons exhibited spatially selective responses for the popout cue stimulus and for the target of the search array. The magnitude of activity related to the location of the cue prior to the presentation of the search array was correlated with trends in behavioral performance across valid, invalid, and neutral cue trial conditions. However, the speed and accuracy of the behavioral report on individual trials were predicted by the magnitude of spatial selectivity related to the target to be identified, not for the spatial cue. A minimum level of selectivity was necessary for target detection and a higher level for target identification. Muscimol inactivation of FEF produced spatially selective perceptual deficits in the covert search task that were correlated with the effectiveness of the inactivation and were strongest on invalid cue trials that require an endogenous attention shift. These results demonstrate a strong functional link between FEF activity and covert spatial attention and suggest that spatial signals from FEF directly influence visual processing during the time that a stimulus to be identified is being processed by the visual system. C1 [Monosov, Ilya E.; Thompson, Kirk G.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Monosov, Ilya E.] Brown Univ, Brown Dept Neurosci, NIH, Grad Partnership Program, Providence, RI 02912 USA. RP Thompson, KG (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Rm 2A50, Bethesda, MD 20892 USA. EM kgt@nei.nih.gov FU National Eye Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health. NR 83 TC 32 Z9 32 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD DEC PY 2009 VL 102 IS 6 BP 3656 EP 3672 DI 10.1152/jn.00750.2009 PG 17 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 528RB UT WOS:000272463200048 PM 19828723 ER PT J AU Weingarten, DM Asthagiri, AR Butman, JA Sato, S Wiggs, EA Damaska, B Heiss, JD AF Weingarten, David M. Asthagiri, Ashok R. Butman, John A. Sato, Susumu Wiggs, Edythe A. Damaska, Bonita Heiss, John D. TI Cortical mapping and frameless stereotactic navigation in the high-field intraoperative magnetic resonance imaging suite Technical note SO JOURNAL OF NEUROSURGERY LA English DT Article DE brain mapping; intraoperative magnetic resonance imaging; brain tumor surgery; stereotactic techniques ID LOW-GRADE GLIOMAS; ELECTRICAL-STIMULATION; MOTOR CORTEX; CEREBRAL-CORTEX; FUNCTIONAL MRI; LOCALIZATION; RESECTION; NEUROSURGERY; GUIDANCE; SURGERY AB Frameless stereotactic neuronavigation provides tracking of surgical instruments on radiographic images and orients the surgeon to tumor margins at surgery. Bipolar electrical stimulation mapping (ESM) delineates safe limits for resection of brain tumors adjacent to eloquent cortex. These standard techniques could complement the capability of intraoperative MR (iMR) imaging to evaluate for occult residual disease during surgery and promote more complete tumor removal. The use of frameless neuronavigation in the high-field iMR imaging suite requires that a few pieces of standard equipment be replaced by nonferromagnetic instruments. Specific use of ESM in a high-field iMR imaging suite has not been reported in the literature. To study whether frameless neuronavigation and electrical stimulation mapping could be successfully integrated in the high-field iMR imaging suite, the authors employed these modalities in 10 consecutive cases involving patients undergoing conscious craniotomy for primary brain tumors located in or adjacent to eloquent cortices. Equipment included a custom high-field MR imaging -compatible head holder and dynamic reference frame attachment, a standard MR imaging -compatible dynamic reference frame, a standard MR imaging machine with a table top that could be translated to a pedestal outside the 5-gauss line for the operative intervention, and standard neuronavigational and cortical stimulation equipment. Both ESM and frameless stereotactic guidance were performed outside the 5-gauss line. The presence of residual neoplasm was evaluated using iMR imaging; resection was continued until eloquent areas were encountered or iMR imaging confirmed complete removal of any residual tumor. Mapping identified essential language (5 patients), sensory (6), and motor (7) areas. The combined use of frameless stereotactic navigation, ESM, and iMR imaging resulted in complete radiographic resection in 7 cases and resection to an eloquent margin in 3 cases. Postoperative MR imaging confirmed final iMR imaging findings. No patient experienced a permanent new neurological deficit. Familiar techniques such as frameless navigation and ESM can be rapidly, inexpensively, safely, and effectively integrated into the high-field iMR imaging suite. (DOI: 10.3171/2009.5.JNS09164) C1 [Heiss, John D.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Sato, Susumu] Natl Inst Neurol Disorders & Stroke, Clin Epilepsy Sect, Bethesda, MD 20892 USA. [Wiggs, Edythe A.] Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, Bethesda, MD 20892 USA. [Butman, John A.; Damaska, Bonita] NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Heiss, JD (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bldg 10,Room 5D37, Bethesda, MD 20892 USA. EM heissj@ninds.nih.gov RI Butman, John/A-2694-2008; Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Neurologic Disorders and Stroke at the National Institutes of Health. NR 37 TC 14 Z9 16 U1 0 U2 2 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2009 VL 111 IS 6 BP 1185 EP 1190 DI 10.3171/2009.5.JNS09164 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 529CM UT WOS:000272493300012 PM 19499978 ER PT J AU Benzinger, TLS Brody, D Cardin, S Curley, KC Mintun, MA Mun, SK Wong, KH Wrathall, JR AF Benzinger, Tammie L. S. Brody, David Cardin, Sylvain Curley, Kenneth C. Mintun, Mark A. Mun, Seong K. Wong, Kenneth H. Wrathall, Jean R. CA Workshop Sci Organizing Team Prese TI Blast-Related Brain Injury: Imaging for Clinical and Research Applications: Report of the 2008 St. Louis Workshop SO JOURNAL OF NEUROTRAUMA LA English DT Article DE animal models of blast-related injury; blast physics; blast-related traumatic brain injury; brain imaging; post-traumatic stress disorder ID MAGNETIC-RESONANCE-SPECTROSCOPY; OPERATION-IRAQI-FREEDOM; WHITE-MATTER; HEAD-INJURY; TEMPORAL WINDOW; COMBAT VETERANS; VULNERABILITY; ASSOCIATION; TRAUMA; HUMANS AB Blast-related traumatic brain injury (bTBI) and post-traumatic stress disorder (PTSD) have been of particular relevance to the military and civilian health care sectors since the onset of the Global War on Terror, and TBI has been called the "signature injury'' of this war. Currently there are many questions about the fundamental nature, diagnosis, and long-term consequences of bTBI and its relationship to PTSD. This workshop was organized to consider these questions and focus on how brain imaging techniques may be used to enhance current diagnosis, research, and treatment of bTBI. The general conclusion was that although the study of blast physics in non-biological systems is mature, few data are presently available on key topics such as blast exposure in combat scenarios, the pathological characteristics of human bTBI, and imaging signatures of bTBI. Addressing these gaps is critical to the success of bTBI research. Foremost among our recommendations is that human autopsy and pathoanatomical data from bTBI patients need to be obtained and disseminated to the military and civilian research communities, and advanced neuroimaging used in studies of acute, subacute, and chronic cases, to determine whether there is a distinct pathoanatomical signature that correlates with long-term functional impairment, including PTSD. These data are also critical for the development of animal models to illuminate fundamental mechanisms of bTBI and provide leads for new treatment approaches. Brain imaging will need to play an increasingly important role as gaps in the scientific knowledge of bTBI and PTSD are addressed through increased coordination, cooperation, and data sharing among the academic and military biomedical research communities. C1 [Wong, Kenneth H.; Wrathall, Jean R.] Georgetown Univ, Med Ctr, Washington, DC 20057 USA. [Benzinger, Tammie L. S.; Brody, David; Mintun, Mark A.] Washington Univ, Mallinckrodt Inst Radiol, St Louis, MO USA. [Cardin, Sylvain; Curley, Kenneth C.] USA, Med Res & Mat Command, Telemed & Adv Technol Res Ctr, Ft Detrick, MD USA. [Mun, Seong K.] Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. [Curley, Kenneth C.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Walter Reed Army Inst Res, Silver Spring, MD USA. Naval Med Res Ctr, Silver Spring, MD USA. Univ Texas Galveston, Med Branch, Galveston, TX 77550 USA. Univ Maryland, College Pk, MD 20742 USA. James S McDonnell Fdn, St Louis, MO USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Weill Cornell Med Coll, New York, NY USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Pittsburgh, Pittsburgh, PA USA. St Louis Vet Adm, Med Ctr, St Louis, MO USA. Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. Univ Illinois, Coll Med, Chicago, IL USA. Def & Vet Brain Injury Ctr, Washington, DC USA. Univ Calif San Francisco, San Francisco, CA USA. Virginia Commonwealth Univ, Richmond, VA USA. Vet Adm Puget Sound Hlth Care Syst, Seattle, WA USA. Univ Washington, Med Ctr, Seattle, WA 98195 USA. Virginia Hosp Ctr, Arlington, VA USA. Dyn FX Consulting Ltd, Toronto, ON, Canada. Univ Penn, Philadelphia, PA 19104 USA. Banyan Biomarkers Inc, Alachua, FL USA. Wayne State Univ, Detroit, MI USA. [Cardin, Sylvain; Curley, Kenneth C.] USA, Inst Surg Res, Ft Sam Houston, TX 78234 USA. RP Wrathall, JR (reprint author), Georgetown Univ, Med Ctr, 3970 Reservoir Rd,NW, Washington, DC 20057 USA. EM Wrathali_@georgetown.edu OI Kochanek, Patrick/0000-0002-2627-913X; Bayly, Philip/0000-0003-4303-0704; Pancrazio, Joseph/0000-0001-8276-3690; Mukherjee, Pratik/0000-0001-7473-7409 NR 77 TC 42 Z9 43 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD DEC PY 2009 VL 26 IS 12 BP 2127 EP 2144 DI 10.1089/neu.2009.0885 PG 18 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 536AI UT WOS:000273013200001 PM 19508154 ER PT J AU Zafonte, R Friedewald, WT Lee, SM Levin, B Diaz-Arrastia, R Ansel, B Eisenberg, H Timmons, SD Temkin, N Novack, T Ricker, J Merchant, R Jallo, J AF Zafonte, Ross Friedewald, William T. Lee, Shing M. Levin, Bruce Diaz-Arrastia, Ramon Ansel, Beth Eisenberg, Howard Timmons, Shelly D. Temkin, Nancy Novack, Thomas Ricker, Joseph Merchant, Randall Jallo, Jack TI The Citicoline Brain Injury Treatment (COBRIT) Trial: Design and Methods SO JOURNAL OF NEUROTRAUMA LA English DT Article DE citicoline; clinical trial; COBRIT; therapy; traumatic brain injury ID ACUTE ISCHEMIC-STROKE; MULTIPLE END-POINTS; RANDOMIZED EFFICACY TRIAL; CDP-CHOLINE; CLINICAL-TRIALS; CEREBRAL-ISCHEMIA; HEAD-INJURY; IN-VIVO; SCALE; HIPPOCAMPAL AB Traumatic brain injury (TBI) is a major cause of death and disability. In the United States alone approximately 1.4 million sustain a TBI each year, of which 50,000 people die, and over 200,000 are hospitalized. Despite numerous prior clinical trials no standard pharmacotherapy for the treatment of TBI has been established. Citicoline, a naturally occurring endogenous compound, offers the potential of neuroprotection, neurorecovery, and neurofacilitation to enhance recovery after TBI. Citicoline has a favorable side-effect profile in humans and several meta-analyses suggest a benefit of citicoline treatment in stroke and dementia. COBRIT is a randomized, double-blind, placebo-controlled, multi-center trial of the effects of 90 days of citicoline on functional outcome in patients with complicated mild, moderate, and severe TBI. In all, 1292 patients will be recruited over an estimated 32 months from eight clinical sites with random assignment to citicoline (1000mg twice a day) or placebo (twice a day), administered enterally or orally. Functional outcomes are assessed at 30, 90, and 180 days after the day of randomization. The primary outcome consists of a set of measures that will be analyzed as a composite measure using a global test procedure at 90 days. The measures comprise the following core battery: the California Verbal Learning Test II; the Controlled Oral Word Association Test; Digit Span; Extended Glasgow Outcome Scale; the Processing Speed Index; Stroop Test part 1 and Stroop Test part 2; and Trail Making Test parts A and B. Secondary outcomes include survival, toxicity, and rate of recovery. C1 [Lee, Shing M.; Levin, Bruce] Columbia Univ, Dept Biostat, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Zafonte, Ross] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Phys Med & Rehabil,Spaulding Rehabil Hosp, Boston, MA USA. [Friedewald, William T.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Diaz-Arrastia, Ramon] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Ansel, Beth] NICHHD, TBI & Stroke Rehabil Res Program, Natl Ctr Med Rehabil Res, Bethesda, MD 20892 USA. [Eisenberg, Howard] Univ Maryland Hosp S, Dept Neurosurg, Baltimore, MD USA. [Timmons, Shelly D.] Univ Tennessee, Ctr Hlth Sci, Dept Neurosurg, Memphis, TN 38163 USA. [Timmons, Shelly D.] Univ Tennessee, Ctr Hlth Sci, Neurotrauma Div, Semmes Murphey Clin, Memphis, TN 38163 USA. [Temkin, Nancy] Univ Washington, Dept Neurol Surg & Biostat, Seattle, WA 98195 USA. [Novack, Thomas] Univ Alabama, Dept Phys Med & Rehabil, Birmingham, AL USA. [Ricker, Joseph] Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Merchant, Randall] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Richmond, VA USA. [Jallo, Jack] Thomas Jefferson Univ, Dept Neurosurg, Philadelphia, PA 19107 USA. RP Friedewald, WT (reprint author), Columbia Univ, Dept Biostat, Mailman Sch Publ Hlth, Room 647,722 W 168th St, New York, NY 10032 USA. EM wtf1@columbia.edu RI Friedewald, William/C-8034-2011 FU National Institute Award [U01HD042823, U01HD042738, U01HD042687, U01HD042736, U01HD042678, U01HD042686, U01HD042653, U01HD042689, U01HD042652] FX The study is supported in part by National Institute Award numbers NICHD U01HD042823, U01HD042738, U01HD 042687, U01HD042736, U01HD042678, U01HD042686, U01H D042653, U01HD042689, and U01HD042652, to eight clinical sites and a data coordinating center. NR 57 TC 29 Z9 30 U1 2 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD DEC PY 2009 VL 26 IS 12 BP 2207 EP 2216 DI 10.1089/neu.2009.1015 PG 10 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 536AI UT WOS:000273013200008 PM 19803786 ER PT J AU Karacay, H Sharkey, RM Gold, DV Ragland, DR McBride, WJ Rossi, EA Chang, CH Goldenberg, DM AF Karacay, Habibe Sharkey, Robert M. Gold, David V. Ragland, Dan R. McBride, William J. Rossi, Edmund A. Chang, Chien-Hsing Goldenberg, David M. TI Pretargeted Radioimmunotherapy of Pancreatic Cancer Xenografts: TF10-Y-90-IMP-288 Alone and Combined with Gemcitabine SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE bispecific antibody; gemcitabine; pancreatic cancer; pretargeting; Y-90 ID MONOCLONAL-ANTIBODY PAM4; BISPECIFIC ANTIBODY; THERAPEUTIC ADVANTAGE; DOSE-FRACTIONATION; COLON-CANCER; RECOMBINANT; TRIVALENT; CARCINOMA; RADIATION; MUC1 AB Pancreatic cancer is a silent disease that most commonly presents in an already metastatic form. Current treatment options provide little survival benefit. Radiolabeled PAM4 IgG, a monoclonal antibody that recognizes a unique epitope associated with a mucin found almost exclusively in pancreatic cancer, has shown encouraging therapeutic effects in animal models and in early clinical testing (Y-90-humanized PAM4 IgG, Y-90-clivatuzumab tetraxetan). The studies reported herein examine a new pretargeting procedure for delivering therapeutic radionuclides. Methods: We prepared a humanized, recombinant tri-Fab bispecific monoclonal antibody (bsmAb) (TF10) using specificity for targeting pancreatic cancer of PAM4 and another Fab binding to a hapten (histamine-succinyl-glycine [HSG]) and tested this in a pretargeting setting with a Y-90-1,4,7,10-tetraazacyclododecane-N,N',N '',N'''-tetraacetic acid-di-HSG-peptide (pretargeted radioimmunotherapy [PT-RAIT]). Nude mice bearing established Capan-1 human pancreatic cancer xenografts were given TF10 and then received the Y-90 peptide as a single bolus dose 19 h later, or the therapy cycle was fractionated weekly. Other studies examined different combinations with gemcitabine. Results: PT-RAIT of 18.5 MBq (similar to 50% of its maximum tolerated dose [MTD]) was as effective as the MTD of Y-90-PAM4 IgG (5.55 MBq). Three monthly doses of 9.25 MBq of PT-RAIT combined with a monthly cycle of gemcitabine (3 weekly, 6-mg doses) significantly enhanced survival, compared with PT-RAIT alone. Adding gemcitabine as a radiosensitizer to 9.25 MBq of PT-RAIT enhanced objective responses. Weekly fractionation of the PT-RAIT, as compared with a single treatment, improved responses. Conclusion: PAM4-based PT-RAIT with Y-90 hapten peptide is an effective treatment for pancreatic cancer, with less toxicity than Y-90-PAM4 IgG, in this model. Combinations with gemcitabine and dose fractionation of the PT-RAIT enhanced therapeutic responses. C1 [Sharkey, Robert M.] Garden State Canc Center, Ctr Mol Med & Immunol, Belleville, NJ 07109 USA. [Ragland, Dan R.] NIAID, Ft Detrick, MD USA. [McBride, William J.; Chang, Chien-Hsing] Immunomedics Inc, Morris Plains, NJ USA. [Rossi, Edmund A.; Chang, Chien-Hsing] IBC Pharmaceut Inc, Morris Plains, NJ USA. RP Sharkey, RM (reprint author), Garden State Canc Center, Ctr Mol Med & Immunol, 520 Belleville Ave, Belleville, NJ 07109 USA. EM rmsharkey@gscancer.org FU NIH [CA115755] FX We thank Ali Mostafa, Jayson Jebsen, Tom Jackson, Christine Johnson, and Dion Yeldell for technical assistance. This work was supported in part by NIH grant CA115755. NR 32 TC 28 Z9 28 U1 0 U2 7 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD DEC PY 2009 VL 50 IS 12 BP 2008 EP 2016 DI 10.2967/jnumed.109.067686 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 529YM UT WOS:000272555300019 PM 19949026 ER PT J AU Eilat-Adar, S Mete, M Nobmann, ED Xu, JQ Fabsitz, RR Ebbesson, SOE Howard, BV AF Eilat-Adar, Sigal Mete, Mihriye Nobmann, Elizabeth D. Xu, Jiaqiong Fabsitz, Richard R. Ebbesson, Sven O. E. Howard, Barbara V. TI Dietary Patterns are Linked to Cardiovascular Risk Factors but Not to Inflammatory Markers in Alaska Eskimos SO JOURNAL OF NUTRITION LA English DT Article ID CORONARY-HEART-DISEASE; FATTY-ACIDS; NUTRITION TRANSITION; GREENLAND ESKIMOS; ATHEROSCLEROSIS; WOMEN; ASSOCIATION; GOCADAN; NATIVES; COHORT AB Despite the tradition of a diet high in fish oils and abundant physical activity, coronary artery disease is increasing among Alaska Eskimos. Explanations for this observation include lifestyle changes. In this cross-sectional analysis, we evaluated dietary patterns of Alaska Eskimos and investigated the relations between these dietary patterns and known cardiovascular risk factors, including inflammatory markers. We used a principal component analysis with data from FFQ collected in 2000-2004 to determine dietary patterns of Alaska Eskimos. Four dietary patterns were identified: a traditional pattern, plus 3 patterns based on purchased food, one of which reflected healthy food choices. The traditional dietary pattern was associated with lower triglycerides (P < 0.001) and blood pressure (P = 0.04) and slightly higher LDL cholesterol (LDL-C) (P = 0.05). Whereas the healthy purchased diet was associated with a trend toward lower LDL-C (P = 0.09), the beverages and sweets diet was positively associated with LDL-C (P = 0.02). Diet pattern was not associated with inflammatory markers or pathogen burden. Our data show that the traditional diet is related to a better profile of cardiovascular disease risk factors and should be encouraged. Programs are needed to encourage the availability of healthy food choices for those not able to obtain traditional foods. J. Nutr. 139: 2322-2328, 2009. C1 [Eilat-Adar, Sigal; Mete, Mihriye; Howard, Barbara V.] MedStar Res Inst, Hyattsville, MD 20783 USA. [Eilat-Adar, Sigal] Wingate Inst Phys Educ & Sports, Zinman Coll Phys Educ & Sports, IL-42902 Netanya, Israel. [Eilat-Adar, Sigal] Tel Aviv Univ, Sackler Fac Med, Dept Epidemiol & Prevent Med, IL-69978 Tel Aviv, Israel. [Nobmann, Elizabeth D.] IDM Consulting, Anchorage, AK 99504 USA. [Xu, Jiaqiong] Methodist Hosp, Res Inst, Houston, TX 77030 USA. [Fabsitz, Richard R.] NHLBI, Bethesda, MD 20892 USA. [Ebbesson, Sven O. E.] Norton Sound Hlth Corp, Nome, AK 99762 USA. RP Eilat-Adar, S (reprint author), MedStar Res Inst, Hyattsville, MD 20783 USA. EM eilatsi@017.net.il FU National Heart, Lung, and Blood Institute, Bethesda, MD [5U1HL064244-09] FX Supported by the National Heart, Lung, and Blood Institute, Bethesda, MD (grant 5U1HL064244-09). NR 37 TC 24 Z9 24 U1 0 U2 4 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD DEC PY 2009 VL 139 IS 12 BP 2322 EP 2328 DI 10.3945/jn.109.110387 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 528WY UT WOS:000272478900015 PM 19828690 ER PT J AU Jackson, WM Aragon, AB Bulken-Hoover, JD Nesti, LJ Tuan, RS AF Jackson, Wesley M. Aragon, Amber B. Bulken-Hoover, Jamie D. Nesti, Leon J. Tuan, Rocky S. TI Putative Heterotopic Ossification Progenitor Cells Derived from Traumatized Muscle SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE mesenchymal progenitor cells; mesenchymal stem cells; osteoprogenitor cells; heterotopic ossification; osteogenesis ID MESENCHYMAL STEM-CELLS; HUMAN BONE-MARROW; OSTEOGENIC DIFFERENTIATION; SKELETAL-MUSCLE; TISSUE AB Heterotopic ossification (HO) is a frequent complication following combat-related trauma, but the pathogenesis of traumatic HO is poorly understood. Building on our recent identification of mesenchymal progenitor cells (MPCs) in traumatically injured muscle, the goal of this study was to evaluate the osteogenic potential of the MPCs in order to assess the role of these cells in HO formation. Compared to bone marrow-derived mesenchymal stem cells (MSCs), a well-characterized population of osteoprogenitor cells, the MPCs exhibited several significant differences during osteogenic differentiation and in the expression of genes related to osteogenesis. Upon osteogenic induction, MPCs showed increased alkaline phosphatase activity, production of a mineralized matrix, and up-regulated expression of the osteoblast-associated genes CBFA1 and alkaline phosphatase. However, MPCs did not appear to reach terminal differentiation as the expression of osteocalcin was not substantially up-regulated. With the exception of a few genes, the osteogenic gene expression profile of traumatized muscle-derived MPCs was comparable to that of the MSCs after osteogenic induction. These findings indicate that traumatized muscle-derived MPCs have the potential to function as osteoprogenitor cells when exposed to the appropriate biochemical environment and are the putative osteoprogenitor cells that initiate ectopic bone formation in HO. (C) 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:1645-1.651, 2009 C1 [Jackson, Wesley M.; Aragon, Amber B.; Bulken-Hoover, Jamie D.; Nesti, Leon J.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Aragon, Amber B.; Bulken-Hoover, Jamie D.; Nesti, Leon J.] Walter Reed Army Med Ctr, Dept Orthopaed & Rehabil, Washington, DC 20307 USA. [Nesti, Leon J.] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD 20814 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU Military Amputee Research Program at WRAMC [PO5-A011]; NIH NIAMS Intramural Research Program [Z01 AR41131] FX This study was supported by a grant from the Military Amputee Research Program at WRAMC (PO5-A011) and by the NIH NIAMS Intramural Research Program (Z01 AR41131). Dr. Nesti and Dr. Tuan were co-senior authors of this article. NR 22 TC 41 Z9 41 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD DEC PY 2009 VL 27 IS 12 BP 1645 EP 1651 DI 10.1002/jor.20924 PG 7 WC Orthopedics SC Orthopedics GA 523UV UT WOS:000272101000016 PM 19517576 ER PT J AU Gorton, GE Abel, MF Oeffinger, DJ Bagley, A Rogers, SP Damiano, D Romness, M Tylkowski, C AF Gorton, George Edwin, III Abel, Mark F. Oeffinger, Donna J. Bagley, Anita Rogers, Sarah P. Damiano, Diane Romness, Mark Tylkowski, Chester TI A Prospective Cohort Study of the Effects of Lower Extremity Orthopaedic Surgery on Outcome Measures in Ambulatory Children With Cerebral Palsy SO JOURNAL OF PEDIATRIC ORTHOPAEDICS LA English DT Article DE cerebral palsy; outcomes; children; orthopaedic surgery ID RECTUS-FEMORIS TRANSFER; SPASTIC DIPLEGIA; MULTILEVEL SURGERY; GAIT ANALYSIS; GASTROCNEMIUS RECESSION; FUNCTIONAL ASSESSMENT; KINETIC EVALUATION; ANKLE; LONG; QUESTIONNAIRE AB Background: Lower-extremity musculotendinous surgery is standard treatment for ambulatory children with deformities such as joint contractures and bony torsions resulting from cerebral palsy (CP). However, evidence of efficacy is limited to retrospective, uncontrolled studies with small sample sizes focusing on gait variables and clinical examination measures. The aim of this study was to prospectively examine whether lower-extremity musculotendinous surgery in ambulatory children with CP improves impairments and function measured by gait and clinical outcome tools beyond changes found in a concurrent matched control group. Methods: Seventy-five children with spastic CP (Gross Motor Function Classification System levels I to III, age 4 to 18 y) that underwent surgery to improve gait were individually matched on the basis of sex, Gross Motor Function Classification System level, and CP subtype to a nonsurgical cohort, minimizing differences in age and Gross Motor Function Measure Dimension E. At baseline and at least 12 months after baseline or surgery, participants completed gait analysis and Gross Motor Function Measure, and parents completed outcome questionnaires. Mean changes at follow-up were compared using analysis of covariance adjusted for baseline differences. Results: Surgery ranged from single-level soft tissue release to multilevel bony and/or soft tissue procedures. At follow-up, after correcting for baseline differences, Gillette Gait Index, Pediatric Outcomes Data Collection Instrument Expectations, and Pediatric Quality of Life Inventory (PedsQL) Physical Functioning improved significantly for the surgical group compared with the nonsurgical group, which showed minimal change. Conclusions: On the basis of a matched concurrent data set, there was significant improvement in function after 1 year for a surgical group compared with a nonsurgical group as measured by the Gillette Gait Index, with few significant changes noted in outcome measures. Changes over 1 year are minimal in the nonsurgical group, supporting the possibility of ethically performing a randomized controlled trial using nonsurgical controls. C1 [Gorton, George Edwin, III] Shriners Hosp Children, Springfield, MA 01104 USA. [Abel, Mark F.; Romness, Mark] Univ Virginia, Charlottesville, VA USA. [Oeffinger, Donna J.; Rogers, Sarah P.; Tylkowski, Chester] Shriners Hosp Children, Lexington, KY USA. [Bagley, Anita] Shriners Hosp Children, Sacramento, CA USA. [Damiano, Diane] NIH, Funct & Appl Biomech Sect, Bethesda, MD 20892 USA. RP Gorton, GE (reprint author), Shriners Hosp Children, 516 Carew St, Springfield, MA 01104 USA. EM ggorton@shrinenet.org RI Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU Shriners Hospitals for Children; Clinical Outcomes Study Advisory Board [9140] FX This work was funded by Shriners Hospitals for Children, Clinical Outcomes Study Advisory Board Grant No. 9140 "A cross-sectional and longitudinal assessment of outcome instruments in patients with ambulatory cerebral palsy." NR 49 TC 29 Z9 31 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-6798 J9 J PEDIATR ORTHOPED JI J. Pediatr. Orthop. PD DEC PY 2009 VL 29 IS 8 BP 903 EP 909 DI 10.1097/BPO.0b013e3181c11c0c PG 7 WC Orthopedics; Pediatrics SC Orthopedics; Pediatrics GA 526SN UT WOS:000272313900014 PM 19934707 ER PT J AU Coyle, K Rother, KI Weise, M Ahmed, A Miller, FW Rider, LG AF Coyle, Kathleen Rother, Kristina I. Weise, Martina Ahmed, Alaa Miller, Frederick W. Rider, Lisa G. TI Metabolic Abnormalities and Cardiovascular Risk Factors in Children with Myositis SO JOURNAL OF PEDIATRICS LA English DT Article AB Objective To characterize the metabolic abnormalities and risk factors for future cardiovascular disease in children with myositis. Study design Seventeen patients with severe juvenile myositis, primarily referred because of refractory disease, were examined with standardized disease activity and damage measures. Body mass index, fasting insulin and lipid levels, 2-hour oral glucose tolerance test results, and cytokine levels were obtained. Results Most patients ( 71%) had blood pressures > 75th percentile; 23.5% of patients had hypertension; and body mass index was > 85th percentile in 47%. Metabolic abnormalities were also frequent: 41.2% had an elevated fasting insulin level, 47.1% had hypertriglyceridemia, and 25% met criteria for the metabolic syndrome. Although insulin resistance was common (on the basis of homeostasis model assessment and glucose-to-insulin ratio), insulin secretion appeared to be unaffected. Thigh muscle damage assessed with magnetic resonance imaging significantly correlated with fasting insulin level, glucose level, and glucose-to-insulin ratio. Glucose indices also correlated with the proinflammatory cytokines interleukin (IL)-2 and IL-12 and inversely with anti-inflammatory cytokines IL-1RA and IL-10. Conclusions In this referral cohort of children with severe juvenile myositis, metabolic abnormalities and predictors of cardiovascular disease were common, suggesting an increased risk of future cardiovascular disease. Indicators of insulin resistance correlated with muscle damage on magnetic resonance imaging and proinflammatory cytokines and inversely with anti-inflammatory cytokines. C1 [Coyle, Kathleen] NIAMSD, NIH, Bethesda, MD 20892 USA. [Rother, Kristina I.] NIDDK, NIH, Bethesda, MD 20892 USA. [Weise, Martina] NICHHD, NIH, Bethesda, MD 20892 USA. [Ahmed, Alaa] Specialty Labs, Santa Monica, CA USA. [Miller, Frederick W.; Rider, Lisa G.] NIEHS, Environm Autoimmun Grp, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Rider, LG (reprint author), NIEHS, Environm Autoimmun Grp, NIH, CRC, Bldg 10,Room 4-2352,MSC 1301, Bethesda, MD 20892 USA. EM riderl@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU intramural research programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Diabestes and Digestive and Kidney Diseases; National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services FX Supported by the intramural research programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Diabestes and Digestive and Kidney Diseases, and National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services. The authors declare no conflicts of interest. NR 39 TC 6 Z9 6 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD DEC PY 2009 VL 155 IS 6 BP 882 EP 887 DI 10.1016/j.jpeds.2009.06.009 PG 6 WC Pediatrics SC Pediatrics GA V38CQ UT WOS:000209321900024 PM 19643439 ER PT J AU Jobson, AG Lountos, GT Lorenzi, PL Llamas, J Connelly, J Cerna, D Tropea, JE Onda, A Zoppoli, G Kondapaka, S Zhang, GT Caplen, NJ Cardellina, JH Yoo, SS Monks, A Self, C Waugh, DS Shoemaker, RH Pommier, Y AF Jobson, Andrew G. Lountos, George T. Lorenzi, Philip L. Llamas, Jenny Connelly, John Cerna, David Tropea, Joseph E. Onda, Akikazu Zoppoli, Gabriele Kondapaka, Sudhir Zhang, Guangtao Caplen, Natasha J. Cardellina, John H., II Yoo, Stephen S. Monks, Anne Self, Christopher Waugh, David S. Shoemaker, Robert H. Pommier, Yves TI Cellular Inhibition of Checkpoint Kinase 2 (Chk2) and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor PV1019 [7-Nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide] SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MOLECULAR INTERACTION MAP; DNA-DAMAGE CHECKPOINT; PROTEIN-KINASE; THREONINE-68 PHOSPHORYLATION; SELECTIVE INHIBITOR; UP-REGULATION; ACTIVATION; ATM; IDENTIFICATION; ABROGATION AB Chk2 is a checkpoint kinase involved in the ataxia telangiectasia mutated pathway, which is activated by genomic instability and DNA damage, leading to either cell death (apoptosis) or cell cycle arrest. Chk2 provides an unexplored therapeutic target against cancer cells. We recently reported 4,4'-diacetyldiphenylurea- bis(guanylhydrazone) (NSC 109555) as a novel chemotype Chk2 inhibitor. We have now synthesized a derivative of NSC 109555, PV1019 (NSC 744039) [7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide], which is a selective submicromolar inhibitor of Chk2 in vitro. The cocrystal structure of PV1019 bound in the ATP binding pocket of Chk2 confirmed enzymatic/biochemical observations that PV1019 acts as a competitive inhibitor of Chk2 with respect to ATP. PV1019 was found to inhibit Chk2 in cells. It inhibits Chk2 autophosphorylation (which represents the cellular kinase activation of Chk2), Cdc25C phosphorylation, and HDMX degradation in response to DNA damage. PV1019 also protects normal mouse thymocytes against ionizing radiation-induced apoptosis, and it shows synergistic antiproliferative activity with topotecan, camptothecin, and radiation in human tumor cell lines. We also show that PV1019 and Chk2 small interfering RNAs can exert antiproliferative activity themselves in the cancer cells with high Chk2 expression in the NCI-60 screen. These data indicate that PV1019 is a potent and selective inhibitor of Chk2 with chemotherapeutic and radiosensitization potential. C1 [Jobson, Andrew G.; Lorenzi, Philip L.; Llamas, Jenny; Onda, Akikazu; Zoppoli, Gabriele; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Caplen, Natasha J.] NCI, Gene Silencing Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Lountos, George T.; Tropea, Joseph E.; Waugh, David S.] NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21701 USA. [Kondapaka, Sudhir; Cardellina, John H., II; Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21701 USA. [Connelly, John; Monks, Anne] NCI, Lab Funct Genom, SAIC Frederick, Frederick, MD 21701 USA. [Cerna, David] NCI, Mol Radiat Therapeut Branch, SAIC Frederick, Frederick, MD 21701 USA. [Zhang, Guangtao; Self, Christopher] Provid Pharmaceut, N Brunswick, NJ USA. [Yoo, Stephen S.] NCI, Mol Radiat Therapeut Branch, Radiat Res Program, Div Canc Treatment & Diag,NIH, Rockville, MD USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Zoppoli, Gabriele/A-9540-2010; Lountos, George/B-3983-2015; Zoppoli, Gabriele/B-6935-2016; Caplen, Natasha/H-2768-2016 OI Zoppoli, Gabriele/0000-0003-3890-5588; Caplen, Natasha/0000-0002-0001-9460 FU Health National Cancer Institute; U.S. Department of Energy, Office of Science; Office of Basic Energy Sciences [W-31-109-Eng-38] FX This work was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute. X-ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamlines 22-ID and 22-BM at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at http://www.sercat.org/members. html. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [Contract W-31-109-Eng-38]. NR 40 TC 49 Z9 50 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD DEC PY 2009 VL 331 IS 3 BP 816 EP 826 DI 10.1124/jpet.109.154997 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 523RY UT WOS:000272093400006 PM 19741151 ER PT J AU Pedraza, O Dotson, VM Willis, FB Graff-Radford, NR Lucas, JA AF Pedraza, Otto Dotson, Vonetta M. Willis, Floyd B. Graff-Radford, Neill R. Lucas, John A. TI Internal Consistency and Test-Retest Stability of the Geriatric Depression Scale-Short Form in African American Older Adults SO JOURNAL OF PSYCHOPATHOLOGY AND BEHAVIORAL ASSESSMENT LA English DT Article DE Geriatric depression scale; GDS; Depression; African American; Reliability ID PRIMARY-CARE PATIENTS; SYMPTOMS; RELIABILITY; PREVALENCE; VALIDITY; DISEASE AB The Geriatric Depression Scale (GDS) is one of the most widely used self-rated mood questionnaires for older adults. It is highly correlated with clinical diagnoses of depression and has demonstrated validity across different patient populations. However, the reliability of the GDS among African American older adults remains to be firmly established. In a baseline sample of 401 African American adults age 51 and over, the GDS-15 item short form demonstrates good internal consistency (KR20 = .71). Stability over a 15-month interval in a retest sample of 51 adults is deemed adequate (r = .68). These findings support the use of the GDS-15 item short form as a reliable mood questionnaire among African American older adults. C1 [Pedraza, Otto; Lucas, John A.] Mayo Clin, Dept Psychiat & Psychol, Jacksonville, FL 32224 USA. [Dotson, Vonetta M.] NIA, Lab Personal & Cognit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Willis, Floyd B.] Mayo Clin, Dept Family Med, Jacksonville, FL 32224 USA. [Graff-Radford, Neill R.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. RP Pedraza, O (reprint author), Mayo Clin, Dept Psychiat & Psychol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM otto.pedraza@mayo.edu RI Dotson, Vonetta/K-6090-2015; OI Dotson, Vonetta/0000-0002-3043-3320 FU Intramural NIH HHS [Z01 AG000194-01]; NIA NIH HHS [P50 AG016574, R03 AG024539, R03 AG024539-01] NR 34 TC 9 Z9 9 U1 1 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0882-2689 J9 J PSYCHOPATHOL BEHAV JI J. Psychopathol. Behav. Assess. PD DEC PY 2009 VL 31 IS 4 BP 412 EP 416 DI 10.1007/s10862-008-9123-z PG 5 WC Psychology, Clinical SC Psychology GA 507ZD UT WOS:000270894600014 PM 20161488 ER PT J AU Stelzer, R Hutz, RJ AF Stelzer, Rosemary Hutz, Reinhold J. TI Gold Nanoparticles Enter Rat Ovarian Granulosa Cells and Subcellular Organelles, and Alter In-Vitro Estrogen Accumulation SO JOURNAL OF REPRODUCTION AND DEVELOPMENT LA English DT Article DE Estrogen; Granulosa cells; Nanoparticles; Steroidogenesis; Transmission electron microscopy ID ULTRAFINE PARTICLES; CARBON NANOTUBES; COLLOIDAL GOLD; TOXICITY; DELIVERY; SIZE AB Nanoparticle technology refers to research and technology developed at the atomic or molecular level for materials of approximately 1-100 nm in length. Through accidental or involuntary exposure, nanoparticles are potentially toxic to the body, including reproductive organs. Ovarian granulosa cells play a major role in maintaining ovarian function, health, and female fertility. Since these cells are involved in steroidogenesis, we wished to evaluate whether nanoparticles affected them after traversing their membranes. Cells were co-incubated with 10 nm gold particles for up to 24 h. Transmission electron micrographs were taken of GC treated with 10 nm gold particles in order to compare and contrast ultrastructural locations of nanoparticles with treatment. From micrograph comparisons of treated vs. untreated GC at various culture times, it appeared that some intracellular organelles involved in steroidogenesis were infiltrated and/or altered due to the presence of the nanogold particles. Medium samples were taken in order to determine estradiol-17beta (E2) accumulation /secretion by untreated vs. treated cells. GC incubated with 10 nm nanogold particles for 1, 3, or 5 h were found to accumulate significantly increased amounts of estrogen compared with untreated cells. Conversely, at 24 h there was a significant attenuation with respect to controls. The data presented here provide insight into the toxicologic effects gold nanoparticles elicit on ovarian granulosa cells. C1 [Stelzer, Rosemary; Hutz, Reinhold J.] Univ Wisconsin, Dept Biol Sci, Milwaukee, WI 53211 USA. [Hutz, Reinhold J.] Univ Wisconsin, NIEHS Childrens Environm Hlth Sci Core Ctr, Milwaukee, WI 53211 USA. RP Hutz, RJ (reprint author), Univ Wisconsin, Dept Biol Sci, Milwaukee, WI 53211 USA. EM rjhutz@uwm.edu FU College of Letters and Science, UWM FX We gratefully acknowledge Dr H Owen for her technical assistance regarding TEM micrographs, and Dr R Klaper for assistance with nanoparticle methodologies. Research was supported in part by the College of Letters and Science, UWM. NR 39 TC 24 Z9 25 U1 3 U2 10 PU SOCIETY REPRODUCTION & DEVELOPMENT-SRD PI TSUKUBA PA C/O KAZUHIRO KIKUCHI, PHD DVM, NATL INST AGROBIOLOGICAL SCIENCES KANNONDAI 2-1-2, TSUKUBA, IBARAKI 305-8602, JAPAN SN 0916-8818 J9 J REPROD DEVELOP JI J. Reprod. Dev. PD DEC PY 2009 VL 55 IS 6 BP 685 EP 690 PG 6 WC Agriculture, Dairy & Animal Science; Reproductive Biology SC Agriculture; Reproductive Biology GA 538XP UT WOS:000273218000016 PM 19789424 ER PT J AU Berenson, KR Gyurak, A Ayduk, O Downey, G Garner, MJ Mogg, K Bradley, BP Pine, DS AF Berenson, Kathy R. Gyurak, Anett Ayduk, Oezlem Downey, Geraldine Garner, Matthew J. Mogg, Karin Bradley, Brendan P. Pine, Daniel S. TI Rejection sensitivity and disruption of attention by social threat cues SO JOURNAL OF RESEARCH IN PERSONALITY LA English DT Article DE Rejection sensitivity; Attention; Emotional Stroop; Visual Probe; Borderline personality disorder ID EMOTIONAL STROOP; ADULT ATTACHMENT; SELF-ESTEEM; ANXIETY; BIAS; INFORMATION; TASK; INTERFERENCE; CHILDREN; PSYCHOPATHOLOGY AB Two studies tested the hypothesis that Rejection Sensitivity (RS) increases vulnerability to disruption of attention by social threat cues, as would be consistent with prior evidence that it motivates individuals to prioritize detecting and managing potential rejection at a cost to other personal and interpersonal goals. In Study 1, RS predicted disruption of ongoing goal-directed attention by social threat but not negative words in an Emotional Stroop task. In Study 2, RS predicted attentional avoidance of threatening but not pleasant faces in a Visual Probe task. Threat-avoidant attention was also associated with features of borderline personality disorder. This research extends understanding of processes by which RS contributes to a self-perpetuating cycle of interpersonal problems and distress. (C) 2009 Elsevier Inc. All rights reserved. C1 [Berenson, Kathy R.; Downey, Geraldine] Columbia Univ, Dept Psychol, New York, NY 10027 USA. [Gyurak, Anett; Ayduk, Oezlem] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Garner, Matthew J.; Mogg, Karin; Bradley, Brendan P.] Univ Southampton, Southampton, Hants, England. [Pine, Daniel S.] NIMH, Bethesda, MD 20892 USA. RP Berenson, KR (reprint author), Columbia Univ, Dept Psychol, 405 Schermerhorn Hall, New York, NY 10027 USA. EM berenson@psych.columbia.edu RI Mogg, Karin/C-1181-2008; Bradley, Brendan/B-9724-2008; Garner, Matthew/E-4205-2010; OI Mogg, Karin/0000-0002-2738-7378; Garner, Matthew/0000-0001-9481-2226; Bradley, Brendan/0000-0003-2801-4271 FU NIMH NIH HHS [R01 MH081948, R01 MH081948-03, T32 MH020006, R01 MH069703-05, R01 MH069703] NR 56 TC 60 Z9 64 U1 11 U2 26 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0092-6566 J9 J RES PERS JI J. Res. Pers. PD DEC PY 2009 VL 43 IS 6 BP 1064 EP 1072 DI 10.1016/j.jrp.2009.07.007 PG 9 WC Psychology, Social SC Psychology GA 523ZO UT WOS:000272113800013 PM 20160869 ER PT J AU Wise, BL Demissie, S Cupples, LA Felson, DT Yang, M Shearman, AM Aliabadi, P Hunter, DJ AF Wise, Barton L. Demissie, Serkalem Cupples, L. Adrienne Felson, David T. Yang, Mei Shearman, Amanda M. Aliabadi, Piran Hunter, David J. TI The Relationship of Estrogen Receptor-alpha and -beta Genes with Osteoarthritis of the Hand SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE OSTEOARTHRITIS; ESTROGEN RECEPTOR GENES; FRAMINGHAM OSTEOARTHRITIS STUDY; HAND ID KNEE OSTEOARTHRITIS; REPLACEMENT THERAPY; RADIOGRAPHIC OSTEOARTHRITIS; CANDIDATE GENES; WOMEN; ASSOCIATION; PREVALENCE; DISEASE; MEN; ARTHRITIS AB Objective. We examined reported associations between radiographic hand osteoarthritis (OA) and single-nucleotide polymorphisms (SNP) in 2 candidate genes associated with OA in other joints: estrogen receptor alpha (ESR1) and beta (ESR2). Methods. In 539 Framingham Offspring Study participants (49% men; mean age 61 +/- 9 yrs) joint-specific radiographic hand OA was defined as Kellgren/Lawrence (K/L) scores >= 2 in the first carpometacarpal joint (CMC), distal interphalangeal joints (DIP), first-digit interphalangeal joint (IP), or proximal interphalangeal joints (PIP). Four SNP were genotyped for ESR1 (PvuII-rs2234693, XbaI-rs9340799, rs2077647, and rs1801132) and 4 for ESR2 (rs1256031, rs1256034, rs1256059, rs944460). Logistic regression analyses were performed to evaluate the relationships between genotypes and hand OA, adjusting for age, sex, height, and weight. Results. Radiographic hand OA was identified in at least one investigated joint of DIP (39%), PIP (33%), and first CMC (40%). There was no evidence of association between OA and genotype at any polymorphism. We found no significant association between our OA phenotypes or generalized or severe generalized OA as defined by Ushiyama and heterozygosity for rs2234693 and rs9340799, although in metaanalysis with the former study this heterozygosity remained significantly associated with generalized or severe generalized OA. Conclusion. We found no significant association between hand OA and the investigated polymorphisms of ESR1 or ESR2 despite published reports of association and a priori hypotheses implicating their potential roles. However, we could not absolutely exclude associations with rs2234693, rs9340799, or rs944460. (First Release Nov 1 2009; J Rheumatol 2009;36:2772-9; doi: 10.3899/jrheum.081208) C1 NHLBI, NIH, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Wise, BL (reprint author), Univ Calif Davis, Med Ctr, Ctr Healthy Aging, 4800 2nd Ave,Suite 2600, Sacramento, CA 95817 USA. RI Hunter, David/A-4622-2010; OI Hunter, David/0000-0003-3197-752X; Cupples, L. Adrienne/0000-0003-0273-7965; Felson, David/0000-0002-2668-2447; Wise, Barton/0000-0002-6540-6031 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; National Institutes of Health (NIH) [AR47785, 5K12HD051958] FX Supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), by the National Institutes of Health (NIH) Grant AR47785, and NIH-sponsored University of California, Davis School of Medicine Building Interdisciplinarly Research Careers in Women Health Program, NIH 5K12HD051958. NR 20 TC 10 Z9 11 U1 0 U2 4 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD DEC PY 2009 VL 36 IS 12 BP 2772 EP 2779 DI 10.3899/jrheum.081208 PG 8 WC Rheumatology SC Rheumatology GA 533WN UT WOS:000272856200022 PM 19884274 ER PT J AU Steeve, RW Moore, CA AF Steeve, Roger W. Moore, Christopher A. TI Mandibular Motor Control During the Early Development of Speech and Nonspeech Behaviors SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article DE speech; development; motor control; mandible; human ID PSYCHOBIOLOGY; COORDINATION; MOVEMENTS; MUSCLES AB Purpose: The mandible is often portrayed as a primary structure of early babble production, but empiricists still need to specify (a) how mandibular motor control and kinematics vary among different types of multisyllabic babble, (b) whether chewing or jaw oscillation relies on a coordinative infrastructure that can be exploited for early types of multisyllables, and (c) whether the organization of motor control and associated kinematics varies across the nonspeech behaviors that are candidate motor stereotypies for speech. Method: Electromyographic signals were obtained from mandibular muscle groups, and associated kinematics were measured longitudinally from a typically developing infant from 9 to 22 months during jaw oscillation, chewing, and several types of early multisyllabic babble. Results: Measures of early motor control and mandibular kinematics for multisyllabic productions indicated task-dependent changes across syllable types and significant differences across babble and nonspeech behaviors. Differences in motor control were also observed across nonspeech behaviors. Conclusions: Motor control for babble appears to be influenced by the balanced interaction between developing motor and linguistic systems, such that variation in linguistic complexity systematically evinces changes in motor organization apparently to meet these demands. This same effect was noted among chewing and jaw oscillation; task-dependent changes in mandibular control were noted across behaviors. C1 [Steeve, Roger W.] Univ Wyoming, Div Commun Disorders, Dept 3311, Laramie, WY 82071 USA. [Moore, Christopher A.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. RP Steeve, RW (reprint author), Univ Wyoming, Div Commun Disorders, Dept 3311, 1000 E Univ Ave, Laramie, WY 82071 USA. EM rsteeve@uwyo.edu FU NCRR NIH HHS [P20 RR016474, P20 RR16474]; NIDCD NIH HHS [R01 DC00822, T32 DC000033, T32 DC00033, R01 DC000822, F31 DC000295, F31 DC00295] NR 41 TC 13 Z9 14 U1 0 U2 6 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1092-4388 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD DEC 1 PY 2009 VL 52 IS 6 BP 1530 EP 1554 DI 10.1044/1092-4388(2009/08-0020) PG 25 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 528YK UT WOS:000272482700009 PM 19717649 ER PT J AU Wu, MX Yu, KF Liu, AY AF Wu, Mi-Xia Yu, Kai-Fun Liu, Ai-Yi TI Estimation of variance components in the mixed effects models: A comparison between analysis of variance and spectral decomposition SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE Analysis of variance; Best linear unbiased estimate; Least squares estimate; mixed effects model; Spectral decomposition ID CONFIDENCE-INTERVALS; RATIO AB The mixed effects models with two variance components are often used to analyze longitudinal data. For these models, we compare two approaches to estimating the variance components, the analysis of variance approach and the spectral decomposition approach. We establish a necessary and sufficient condition for the two approaches to yield identical estimates, and some sufficient conditions for the superiority of one approach over the other, under the mean squared error criterion. Applications of the methods to circular models and longitudinal data are discussed. Furthermore, simulation results indicate that better estimates of variance components do not necessarily imply higher power of the tests or shorter confidence intervals. (C) 2009 Elsevier B.V. All rights reserved. C1 [Wu, Mi-Xia] Beijing Univ Technol, Coll Appl Sci, Beijing 100022, Peoples R China. [Yu, Kai-Fun; Liu, Ai-Yi] NICHHD, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Rockville, MD 20852 USA. RP Wu, MX (reprint author), Beijing Univ Technol, Coll Appl Sci, Beijing 100124, Peoples R China. EM wumixia@bjut.edu.cn OI Liu, Aiyi/0000-0002-6618-5082 FU National Institute of Child Health and Human Development, National Institutes of Health; Higher Learning Under the Jurisdiction of Beijing Municipality PHR (IHLB); National Natural Science Foundation of China (NSFC) [10801005, 10771010] FX This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health. Wu's research was also partially supported by Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality PHR (IHLB) and National Natural Science Foundation of China (NSFC 10801005) and (NSFC 10771010). The opinions expressed in this article are not necessarily of the National Institutes of Health. The authors wish to thank two referees for their valuable suggestions which considerably improved this paper. NR 17 TC 2 Z9 4 U1 1 U2 7 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 DEC 1 PY 2009 VL 139 IS 12 BP 3962 EP 3973 DI 10.1016/j.jspi.2009.03.014 PG 12 WC Statistics & Probability SC Mathematics GA 500PQ UT WOS:000270316000002 PM 20160928 ER PT J AU Sheer, AJ Gorelick, DA Collins, CC Schroeder, JR Heishman, SJ Leff, MK Moolchan, ET AF Sheer, Amy J. Gorelick, David A. Collins, Charles C. Schroeder, Jennifer R. Heishman, Stephen J. Leff, Michelle K. Moolchan, Eric T. TI Interest in marijuana treatment programs among teenage smokers and nonsmokers SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Adolescent; Marijuana; Tobacco; Cessation; Treatment ID CANNABIS; HEALTH AB Little is known about adolescents' interest in marijuana treatment programs. This question was evaluated by telephone interview in a convenience sample of 575 adolescents responding to advertisements for tobacco research studies. Eighty-one percent of respondents endorsed the need for marijuana treatment programs for adolescents. These adolescents were younger and less likely to smoke tobacco, smoke marijuana, or use alcohol than those not endorsing such a need. Among the 192 marijuana smokers, the 58.8% who endorsed the need for marijuana treatment programs took their first puff of marijuana at a younger age than those who did not endorse the need. Those who were willing to participate in a marijuana treatment program were more likely African American and took their first marijuana puff at a younger age than those not interested in treatment. These findings suggest that most adolescent marijuana smokers endorse the need for and are willing to attend marijuana treatment programs. Published by Elsevier Inc. C1 [Gorelick, David A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Schroeder, Jennifer R.] Schroeder Stat Consulting, Ellicott City, MD 21042 USA. [Moolchan, Eric T.] Off Med Director, Alkermes Inc, Cambridge, MA 02139 USA. RP Gorelick, DA (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM dgorelic@mail.nih.gov FU Intramural NIH HHS [Z01 DA000241-15, Z01 DA000240-16, Z01 DA000240-15, Z01 DA000241-16] NR 9 TC 2 Z9 2 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD DEC PY 2009 VL 37 IS 4 BP 421 EP 425 DI 10.1016/j.jsat.2009.04.007 PG 5 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 518BY UT WOS:000271666300013 PM 19556094 ER PT J AU Aman, MG McDougle, CJ Scahill, L Handen, B Arnold, LE Johnson, C Stigler, KA Bearss, K Butter, E Swiezy, NB Sukhodolsky, DD Ramadan, Y Pozdol, SL Nikolov, R Lecavalier, L Kohn, AE Koenig, K Hollway, JA Korzekwa, P Gavaletz, A Mulick, JA Hall, KL Dziura, J Ritz, L Trollinger, S Yu, SY Vitiello, B Wagner, A AF Aman, Michael G. McDougle, Christopher J. Scahill, Lawrence Handen, Benjamin Arnold, L. Eugene Johnson, Cynthia Stigler, Kimberly A. Bearss, Karen Butter, Eric Swiezy, Naomi B. Sukhodolsky, Denis D. Ramadan, Yaser Pozdol, Stacie L. Nikolov, Roumen Lecavalier, Luc Kohn, Arlene E. Koenig, Kathleen Hollway, Jill A. Korzekwa, Patricia Gavaletz, Allison Mulick, James A. Hall, Kristy L. Dziura, James Ritz, Louise Trollinger, Stacte Yu, Sunkyung Vitiello, Benedetto Wagner, Ann CA Res Units Pediat Psychopharmacolog TI Medication and Parent Training in Children With Pervasive Developmental Disorders and Serious Behavior Problems: Results From a Randomized Clinical Trial SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE parent management training; pervasive developmental disorders; autistic disorder; risperidone; aripiprazole ID INTENSIVE EARLY INTERVENTION; AUTISM-SPECTRUM DISORDERS; YOUNG-CHILDREN; RISPERIDONE; PROGRAM; SYMPTOMS; CHALLENGES; CHECKLIST; PATTERNS; SCALE AB Objective: many children with pervasive developmental disorders (PDDs) have serious, functionally impairing behavioral problems. We tested whether combined treatment (COMB) with risperidone and parent training (PT) in behavior management is superior to medication alone (MED) in improving severe behavioral problems in children with PDDs. Method: This 24-week, three-site, randomized, parallel-groups clinical trial enrolled 124 children, aged 4 through 13 years, with PDDs, accompanied by frequent tantrums, self-injury, and aggression. The children were randomized 3:2 to COMB (n = 75) or MED (n = 49). The participants received risperidone monotherapy from 0.5 to 3.5 mg/day (with switch to aripiprazole if risperidone was ineffective). Parents in the COMB group (n = 75; 60.5%) received a mean of 10.9 PT sessions. The primary measure of compliance was the Home Situations Questionnaire (HSQ) score. Results: Primary: intent-to-treat random effects regression showed that COMB was superior to MED on HSQ (p = .006) [effect size at week 24 (d) = 0.34]. The HSQ score declined from 4.31 (+/-1.67) to 1.23 (+/-1.36) for COMB compared with 4.16 (+/-1.47) to 1.68 (+/-1.36) for MED. Secondary: groups did not differ on Clinical Global Impressions-Improvement scores at endpoint; compared with MED, COMB showed significant reductions on Aberrant Behavior Checklist Irritability (d = 0.48; p =.01), Stereotypic Behavior (d = 0.23; p = .04), and Hyperactivity/Noncompliance subscales (d = 0.55; p = .04). Final risperidone mean dose for MED was 2.26 mg/day (0.071 mg/kg), compared with 1.98 mg/day for COMB (0.066 mg/kg) (p = .04). Conclusions: Medication plus PT resulted in greater reduction of serious maladaptive behavior than MED in children with PDDs, with a lower risperidone dose. J. Am. Acad. Child Addlesc. Psychiatry, 2009;48(12):1143-1154. C1 [Aman, Michael G.] Ohio State Univ, Nisonger Ctr UCEDD, Columbus, OH 43210 USA. [McDougle, Christopher J.; Stigler, Kimberly A.; Swiezy, Naomi B.; Pozdol, Stacie L.; Kohn, Arlene E.; Korzekwa, Patricia] Indiana Univ, Bloomington, IN 47405 USA. [Scahill, Lawrence; Bearss, Karen; Sukhodolsky, Denis D.; Nikolov, Roumen; Koenig, Kathleen; Gavaletz, Allison; Dziura, James; Yu, Sunkyung] Yale Univ, New Haven, CT 06520 USA. [Handen, Benjamin; Johnson, Cynthia] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Ritz, Louise; Vitiello, Benedetto; Wagner, Ann] NIMH, Bethesda, MD 20892 USA. RP Aman, MG (reprint author), Ohio State Univ, Nisonger Ctr UCEDD, 1581 Dodd Dr, Columbus, OH 43210 USA. EM aman.1@osu.edu OI Sukhodolsky, Denis/0000-0002-5401-792X; Scahill, Lawrence/0000-0001-5073-1707 FU National Institute of Mental Health [U10MH66768, U10MH66766, U10MH66764] FX This work was funded by the National Institute of Mental Health by the following RUPP grants: Ohio State University, U10MH66768; Indiana University, U10MH66766; and Yale University, U10MH66764. Johnson & Johnson Pharmaceutical Research & Development provided active risperidone for the study. NR 53 TC 101 Z9 103 U1 4 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD DEC PY 2009 VL 48 IS 12 BP 1143 EP 1154 DI 10.1097/CHI.0b013e3181bfd669 PG 12 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 523DG UT WOS:000272051500003 PM 19858761 ER PT J AU Goldstein, BI Shamseddeen, W Spirito, A Emslie, G Clarke, G Wagner, KD Asarnow, JR Vitiello, B Ryan, N Birmaher, B Mayes, T Onorato, M Zelazny, J Brent, DA AF Goldstein, Benjamin I. Shamseddeen, Wael Spirito, Anthony Emslie, Graham Clarke, Greg Wagner, Karen Dineen Asarnow, Joan Rosenbaum Vitiello, Benedetto Ryan, Neal Birmaher, Boris Mayes, Taryn Onorato, Matthew Zelazny, Jamie Brent, David A. TI Substance Use and the Treatment of Resistant Depression in Adolescents SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE substance use; depression; treatment ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; ALCOHOL-USE; SUICIDAL IDEATION; MAJOR DEPRESSION; USE DISORDERS; ANXIETY DISORDERS; CANNABIS USE; DRUG-USE; ABUSE AB Objective: Despite the known association between substance use disorders and major depressive disorder (MDD) among adolescents, little is known regarding substance use among adolescents with MDD. Method: Youths with MDD who had not improved after an adequate selective serotonin reuptake inhibitor trial (N = 334) were enrolled in the Treatment of SSRI-Resistant Depression in Adolescents trial. Analyses examined substance use (via the Drug Use Severity Index) and changes therein in relation to treatment and depressive symptoms. Adolescents meeting substance use disorder criteria via the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version at baseline were excluded. Results: Substance use was common: 28.1% reported repeated experimentation at baseline. Substance-related impairment was associated with baseline depression severity, older age, physical/sexual abuse, family conflict, hopelessness, and comorbid oppositional defiant disorder/conduct disorder. There was significant improvement in substance-related impairment among adolescents who responded to MDD treatment. Baseline suicidal ideation was higher among the subjects who progressed to high substance-related impairment (>= 75th percentile) versus those whose substance-related impairment remained low (<75th percentile), and parental depressive symptoms predicted persistence of high substance-related impairment during the study. The MDD response was best among the adolescents with low 12-week substance-related impairment scores regardless of whether they had high or low baseline substance-related impairment. There were no significant differential effects of specific treatments, pharmacological or cognitive-behavioral therapy, on substance use. Conclusions: Substance use is common among adolescents with treatment-resistant MDD. The subjects who had persistently low substance-related impairment or who demonstrated reduced substance-related impairment had better MDD treatment response, although the direction of this association is uncertain. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(12):1182-1192. C1 [Brent, David A.] Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. [Goldstein, Benjamin I.; Shamseddeen, Wael; Ryan, Neal; Birmaher, Boris; Zelazny, Jamie] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Spirito, Anthony] Brown Univ, Providence, RI 02912 USA. [Emslie, Graham; Mayes, Taryn] Univ Texas SW Med Ctr, Dallas, TX USA. [Wagner, Karen Dineen; Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. [Clarke, Greg] Kaiser Permanente, Oakland, CA USA. [Asarnow, Joan Rosenbaum] Univ Calif Los Angeles, Los Angeles, CA USA. [Onorato, Matthew] Nationwide Childrens Hosp, Columbus, OH 43205 USA. RP Brent, DA (reprint author), Western Psychiat Inst & Clin, 3811 OHara St,Room 315 Bellefield Towers, Pittsburgh, PA 15213 USA. EM brentda@upmc.edu FU NIMH [MH61835, MH61856, MH61864, MH61869, MH61958, MH62014, MH66371] FX This work was supported by NIMH grants MH61835, MH61856, MH61864, MH61869, MH61958, MH62014, and the Advanced Center for Early-Onset Mood and Anxiety Disorders (MH66371; primary investigator, D.A.B.). NR 43 TC 18 Z9 18 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD DEC PY 2009 VL 48 IS 12 BP 1182 EP 1192 DI 10.1097/CHI.0b013e3181bef6e8 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 523DG UT WOS:000272051500007 PM 19858762 ER PT J AU Le, DSNT Chen, KW Pannacciulli, N Gluck, M Reiman, EM Krakoff, J AF Le, Due Son Nguyen Trung Chen, Kewei Pannacciulli, Nicola Gluck, Marci Reiman, Eric M. Krakoff, Jonathan TI Reanalysis of the Obesity-Related Attenuation in the Left Dorsolateral Prefrontal Cortex Response to a Satiating Meal Using Gyral Regions-of-Interest SO JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; WORKING-MEMORY; DECISION-MAKING; LESS ACTIVATION; BRAIN RESPONSES; FRONTAL-CORTEX; LEAN WOMEN; HUMANS; STIMULATION; FOOD AB Objective: The left dorsolateral prefrontal cortex (LDLPFC). which includes the inferior (IFG), middle (MFG), and superior (SFG) frontal gyri, has been implicated in satiation. Using a voxel-based approach, we previously identified an LDLPFC region (as reported as peak voxel) in which a reduced neuronal response to a meal was associated with obesity. In this study, we sought to determine which gyri in the LDLPFC best distinguished the neuronal responses to a meal using a different statistical approach. Methods: We reanalyzed brain responses to a meal using the hypothesis-driven region-of-interest based (ROI) approach. Regional cerebral blood flow (rCBF), a marker of neuronal activity in the LDLPFC and its 3 gyri, was acquired in 2 conditions (hunger and after the satiating meal) using O-15-water positron emission tomography scans. rCBF was extracted and estimated using masks of the 3 gyri that were created in mRIcro and Statistical Parametric Mapping 5 software. Results: Using the ROI approach, a satiation-related reduction in LDLPFC rCBF was observed in the obese (p = 0.04) and tended to be significantly greater than that in lean subjects (p = 0.07). The rCBF reduction was greater in the obese subjects than in the lean subjects in the left IFG (p = 0.03) and MFG (p = 0.004) after adjustment was made for age, sex, and number of voxels in these gyri, but not in the SFG (p = 0.5). Conclusions: Our results are consistent with those obtained by the voxel-based approach in showing the association between obesity and a satiation-related reduction in LDLPFC activity. This LDLPFC response preferentially involves the IFG and MFG. We suggest that these brain regions could be targeted by new therapeutic interventions. C1 [Le, Due Son Nguyen Trung; Pannacciulli, Nicola; Gluck, Marci; Krakoff, Jonathan] Univ Arizona, Obes & Diabet Clin Res Sect, NIDDK, NIH,DHHS, Phoenix, AZ USA. [Chen, Kewei; Reiman, Eric M.] Univ Arizona, Positron Emiss Tomog Ctr, Banner Good Samaritan Med Ctr, Phoenix, AZ USA. [Reiman, Eric M.] Univ Arizona, Banner Alzheimers Inst, Dept Psychiat, Phoenix, AZ USA. Translat Genom Res Inst, Phoenix, AZ USA. RP Le, DSNT (reprint author), ODCRS PECRB NIDDK NIH DHHS, 4212 N 16th St, Phoenix, AZ 85016 USA. EM duesonmd@gmail.com RI Chen, kewei/P-6304-2015 OI Chen, kewei/0000-0001-8497-3069 FU NIH, NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. We are especially grateful to Dr Clifton Bogardus (Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Phoenix, AZ, United States) for helpful comments and suggestions. NR 37 TC 12 Z9 12 U1 1 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0731-5724 EI 1541-1087 J9 J AM COLL NUTR JI J. Am. Coll. Nutr. PD DEC PY 2009 VL 28 IS 6 BP 667 EP 673 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 608JB UT WOS:000278578700006 PM 20516266 ER PT J AU Herman, SD Liu, K Tian, L Guralnik, JM Ferrucci, L Criqui, MH Liao, YH McDermott, MM AF Herman, Seth D. Liu, Kiang Tian, Lu Guralnik, Jack M. Ferrucci, Luigi Criqui, Michael H. Liao, Yihua McDermott, Mary M. TI Baseline Lower Extremity Strength and Subsequent Decline in Functional Performance at 6-Year Follow-Up in Persons with Lower Extremity Peripheral Arterial Disease SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE intermittent claudication; physical functioning; SPPB; peripheral arterial disease ID ANKLE BRACHIAL INDEX; INTERMITTENT CLAUDICATION; PHYSICAL-ACTIVITY; LEG SYMPTOMS; ASSOCIATIONS; CLASSIFICATION; OSTEOARTHRITIS; MORTALITY; CRITERIA AB OBJECTIVES: To evaluate associations between baseline lower extremity strength and decline in functional performance over 6 years of follow-up in men and women with lower extremity peripheral arterial disease (PAD). DESIGN: Prospective observational study. SET'TING: Three Chicago-area hospitals. PARTICIPANTS: Three hundred seventy-four men and women with PAD. MEASUREMENTS: Baseline isometric hip extension, hip flexion, knee flexion, and knee extension strength were measured using a musculoskeletal fitness evaluation chair. Usual and fastest-paced 4-m walking speed, 6-minute walk, and Short Physical Performance Battery (SPPB) were assessed at baseline and annually thereafter. Analyses were adjusted for age, sex, race, ankle-brachial index (ABI), comorbidities, and other confounders. RESULTS: In women with PAD, weaker baseline hip and knee flexion strength were associated with faster average annual decline in usual-pace 4-m walking speed (P trend <.001 and .02, respectively) and SPPB (P trend = .02 and .01, respectively). In women, weaker hip extension strength was associated with faster decline in usual-pace 4-m walking speed and SPPB (P trend = .01 and <.01, respectively). There were no significant associations between baseline strength and decline in 6-minute walk in women. There were no significant associations between any baseline strength measure and functional decline in men. CONCLUSION: Weaker baseline leg strength is associated with faster functional decline in nonendurance measures of functional performance in women with PAD but not in men with PAD. J Am Geriatr Soc 57:2246-2252, 2009. C1 [McDermott, Mary M.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Herman, Seth D.] Inst Rehabil, Dept Phys Med & Rehabil, Chicago, IL USA. [Herman, Seth D.; Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Liu, Kiang; Liao, Yihua] Northwestern Univ, Dept Phys Med & Rehabil, Feinberg Sch Med, Chicago, IL 60611 USA. [Tian, Lu] Stanford Univ, Div Biostat, Dept Hlth Policy & Res, Palo Alto, CA 94304 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. RP McDermott, MM (reprint author), 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU National Heart Lung and Blood Institute [R01-HL58099, R01-HI-64739, R01.-HL071223, R01-HL076298]; National Center for Research Resources [RR-00048]; National Institutes of Health (NIH); Intramural Research Program; National Institute on Aging FX Supported by Grants R01-HL58099, R01-HI-64739, R01.-HL071223, and R01-HL076298 from the National Heart Lung and Blood Institute and Grant RR-00048 from the National Center for Research Resources, National Institutes of Health (NIH). Supported in part by the Intramural Research Program, National Institute on Aging, NIH. NR 17 TC 17 Z9 21 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2009 VL 57 IS 12 BP 2246 EP 2252 DI 10.1111/j.1532-5415.2009.02562.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 535NN UT WOS:000272976400009 PM 19874404 ER PT J AU Humphrey, SM Neveol, A Browne, A Gobeil, J Ruch, P Darmoni, SJ AF Humphrey, Susanne M. Neveol, Aurelie Browne, Allen Gobeil, Julien Ruch, Patrick Darmoni, Stefan J. TI Comparing a Rule-Based Versus Statistical System for Automatic Categorization of MEDLINE Documents According to Biomedical Specialty SO JOURNAL OF THE AMERICAN SOCIETY FOR INFORMATION SCIENCE AND TECHNOLOGY LA English DT Article ID DISEASE; CISMEF AB Automatic document categorization is an important research problem in Information Science and Natural Language Processing. Many applications, including Word Sense Disambiguation and Information Retrieval in large collections, can benefit from such categorization. This paper focuses on automatic categorization of documents from the biomedical literature into broad discipline-based categories. Two different systems are described and contrasted: CISMeF, which uses rules based on human indexing of the documents by the Medical Subject Headings (MeSH) controlled vocabulary in order to assign metaterms (MTs), and Journal Descriptor Indexing (JDI), based on human categorization of about 4,000 journals and statistical associations between journal descriptors (JDs) and textwords in the documents. We evaluate and compare the performance of these systems against a gold standard of humanly assigned categories for 100 MEDLINE documents, using six measures selected from trec_eval. The results show that for five of the measures performance is comparable, and for one measure JDI is superior. We conclude that these results favor JDI, given the significantly greater intellectual overhead involved in human indexing and maintaining a rule base for mapping MeSH terms to MTs. We also note a JDI method that associates JDs with MeSH indexing rather than textwords, and it may be worthwhile to investigate whether this JDI method (statistical) and CISMeF (rule-based) might be combined and then evaluated showing they are complementary to one another. C1 [Humphrey, Susanne M.; Neveol, Aurelie; Browne, Allen] NIH, US Natl Lib Med, Bethesda, MD 20894 USA. [Gobeil, Julien] Univ Geneva, Med Informat Serv, CH-1211 Geneva 14, Switzerland. [Gobeil, Julien] Univ Hosp Geneva, CH-1211 Geneva 14, Switzerland. [Ruch, Patrick] Univ Appl Sci, Dept Informat Sci, BiTeM Grp, CH-1227 Geneva, Carouge, Switzerland. [Darmoni, Stefan J.] Univ Rouen, Inst Biomed Res, LITIS EA 4108, GCSIS, F-76031 Rouen, France. [Darmoni, Stefan J.] Rouen Univ Hosp, CISMeF Grp, Rouen, France. RP Humphrey, SM (reprint author), 2123 Arcola Ave, Wheaton, MD 20902 USA. EM susan-nehumphrey@yahoo.com; neveola@nlm.nih.gov; browne@nlm.nih.gov; julien.gobeill@sim.hcuge.ch; Patrick.Ruch@unige.ch; Stefan.Darmoni@chu-rouen.fr RI Stefan, Darmoni/H-4554-2016 FU NIH; National Library of Medicine; Oak Ridge Institute for Science and Education FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine an appointment of A. Neveol to the Lister Hill Center Fellows Program; appointments of P. Ruch and S.J. Darmoni to the to the Lister Hill Center Visitors Program, sponsored by the National Library of Medicine and administered by the Oak Ridge Institute for Science and Education. NR 38 TC 4 Z9 4 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1532-2882 J9 J AM SOC INF SCI TEC JI J. Am. Soc. Inf. Sci. Technol. PD DEC PY 2009 VL 60 IS 12 BP 2530 EP 2539 DI 10.1002/asi.21170 PG 10 WC Computer Science, Information Systems; Information Science & Library Science SC Computer Science; Information Science & Library Science GA 525ZT UT WOS:000272257800012 PM 19956557 ER PT J AU Qin, J Zhang, B Leung, DHY AF Qin, Jing Zhang, Biao Leung, Denis H. Y. TI Empirical Likelihood in Missing Data Problems SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Empirical likelihood; Estimating functions; Missing data; Surrogate end point ID GENERAL ESTIMATING EQUATIONS; IN-COVARIABLES MODELS; MAXIMUM-LIKELIHOOD; LINEAR-MODELS; NUISANCE PARAMETERS; LOGISTIC-REGRESSION; SAMPLE PROPERTIES; VALIDATION DATA; INCOMPLETE DATA; INFERENCE AB Missing data is a ubiquitous problem in medical and social sciences. It is well known that inferences based only on the complete data may not only lose efficiency, but may also lead to biased results if the data is not missing completely at random (MCAR). The inverse-probability weighting method proposed by Horvitz and Thompson (1952) is a popular alternative when the data is not MCAR. The Horvitz-Thompson method, however, is sensitive to the inverse weights and may suffer from loss of efficiency. In this paper, we propose a unified empirical likelihood approach to missing data problems and explore the use of empirical likelihood to effectively combine unbiased estimating equations when the number of estimating equations is greater than the number of unknown parameters. One important feature of this approach is the separation of the complete data unbiased estimating equations from the incomplete data unbiased estimating equations. The proposed method can achieve semiparametric efficiency if the probability of missingness is correctly specified. Simulation results show that the proposed method has better finite sample performance than its competitors. Supplemental materials for this paper, including proofs of the main theoretical results and the R code used for the NHANES example, are available online on the journal website. C1 [Qin, Jing] NIAID, NIH, Bethesda, MD 20892 USA. [Zhang, Biao] Univ Toledo, Dept Math, Toledo, OH 43606 USA. [Leung, Denis H. Y.] Singapore Management Univ, Sch Econ, Singapore 178903, Singapore. RP Qin, J (reprint author), NIAID, NIH, 6700B Rockledge Dr MSC 7609, Bethesda, MD 20892 USA. EM bzhang@utnet.utoledo.edu RI LEUNG, Denis Heng Yan/D-1439-2009 FU National Science Foundation [DMS-0603873] FX Jing Qin is Mathematical Statistician, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 6700B Rockledge Drive MSC 7609, Bethesda, MD 20892. Biao Zhang is Professor, Department of Mathematics, University of Toledo, 2801 W. Bancroft St., Toledo, OH 43606 (Email: bzhang@utnet.utoledo.edu). Denis H. Y. Leung is Professor, School of Economics, Singapore Management University, 90 Stamford Road, Singapore 178903. We thank the two referees, an Associate Editor, and the Editor for their insightful comments that have led to a substantially improved article. We also would like to thank Dr. Barry Grubard from National Cancer Institute for help on the National Health and Nutrition Examination Survey data. B. Zhang wishes to thank the National Science Foundation for partial support through grant DMS-0603873. NR 42 TC 34 Z9 36 U1 0 U2 8 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD DEC PY 2009 VL 104 IS 488 BP 1492 EP 1503 DI 10.1198/jasa.2009.tm08163 PG 12 WC Statistics & Probability SC Mathematics GA 548VB UT WOS:000273995500018 ER PT J AU Ammary-Risch, N Kwon, HT Scarbrough, W Higginbotham, E Heath-Watson, S AF Ammary-Risch, Neyal Kwon, Harry T. Scarbrough, William Higginbotham, Eve Heath-Watson, Shelly TI Minority Primary Care Physicians' Knowledge, Attitudes, and Practices on Eye Health and Preferred Sources of Information SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE ophthalmic; primary care; minority health; health disparities ID OPEN-ANGLE GLAUCOMA; ANGELES LATINO EYE; UNITED-STATES; DIABETIC-RETINOPATHY; LANGUAGE CONCORDANCE; OCULAR HYPERTENSION; VISUAL IMPAIRMENT; PREVALENCE; ADULTS; SERVICES AB Background: Racial and ethnic disparities exist in the prevalence of certain eye diseases. Minority primary care physicians are in a unique position to help prevent vision loss and blindness, especially among minority populations. Methods: To measure physicians' knowledge and attitudes regarding eye heath and to better understand the facts regarding patient information and counseling concerning eye health and disease, the National Eye Institute included key eye health knowledge, attitude, and practice questions in the 2007 DocStyles Survey, a Web-based survey of primary care physicians about physician perceptions and attitudes concerning communication with patients. Results: A-total of 428 minority primary care physicians responded to the survey. Results indicate that minority primary care physicians have favorable attitudes regarding eye health and the role they should play in talking with patients about eye health. Approximately 60% indicated that they could identify patients at higher risk for eye disease; however, only 52% of physicians indicated that they have adequate knowledge to advise their patients on vision health. Regarding information sources, most minority physicians prefer to obtain information about vision and eye health from professional journals, medical Web sites, and continuing medical education. Conclusions: Findings from this research reveal both a need and an opportunity with regard to increasing physician confidence in identifying patients at higher risk for eye disease and advising their patients on eye health. C1 [Kwon, Harry T.; Scarbrough, William; Heath-Watson, Shelly] ICF Macro, Rockville, MD 20852 USA. [Ammary-Risch, Neyal] NEI, Natl Eye Hlth Educ Program, NIH, Bethesda, MD 20892 USA. [Higginbotham, Eve] Morehouse Sch Med, Atlanta, GA 30310 USA. RP Scarbrough, W (reprint author), ICF Macro, 11420 Rockville Pike, Rockville, MD 20852 USA. EM william.h.scarbrough.iii@macrointernational.com FU National Eye Institute [263-01-D-0174 NICS 39] FX This paper was written with the support of the National Eye Institute under contract 263-01-D-0174 NICS 39. NR 18 TC 4 Z9 4 U1 0 U2 4 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD DEC PY 2009 VL 101 IS 12 BP 1247 EP 1253 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 536ZK UT WOS:000273082300007 PM 20070013 ER PT J AU Kelly, RJ Hnatiuk, O Giaccone, G AF Kelly, Ronan J. Hnatiuk, Oleh Giaccone, Giuseppe TI Antiangiogenesis Induced Tumor Cavitation in Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Editorial Material C1 [Giaccone, Giuseppe] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Hnatiuk, Oleh] NHLBI, NIH, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, NIH, Room 12N221,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD DEC PY 2009 VL 4 IS 12 BP 1573 EP 1575 PG 3 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 523ST UT WOS:000272095500022 PM 20009913 ER PT J AU Loeb, S Carter, HB Schaeffer, EM Ferrucci, L Kettermann, A Metter, EJ AF Loeb, Stacy Carter, H. Ballentine Schaeffer, Edward M. Ferrucci, Luigi Kettermann, Anna Metter, E. Jeffrey TI Should Prostate Specific Antigen be Adjusted for Body Mass Index? Data From the Baltimore Longitudinal Study of Aging SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; prostate-specific antigen; obesity; hemodilution ID RADICAL PROSTATECTOMY; PSA CONCENTRATION; OBESITY; CANCER; MEN; TESTOSTERONE; ADULTS; RISK; AGE AB Purpose: Obesity may be associated with lower prostate specific antigen through hemodilution. We examined the relationship between body mass index and prostate specific antigen by age in men without prostate cancer in a longitudinal aging study to determine whether prostate specific antigen must be adjusted for body mass index. Materials and Methods: The study population included 994 men (4,937 observations) without prostate cancer in the Baltimore Longitudinal Study of Aging. Mixed effects models were used to examine the relationship between prostate specific antigen and body mass index in kg/m(2) by age. Separate models were explored in men with prostate cancer censored at diagnosis, for percent body fat measurements, for weight changes with time and adjusting for initial prostate size in 483 men (2,523 observations) with pelvic magnetic resonance imaging measurements. Results: In men without prostate cancer body mass index was not significantly associated with prostate specific antigen after adjusting for age (p = 0.06). A 10-point body mass index increase was associated with a prostate specific antigen difference of -0.03 ng/ml (95% CI -0.40-0.49). Results were similar when men with prostate cancer were included, when percent body fat was substituted for body mass index, and after adjusting for prostate volume. Longitudinal weight changes also had no significant association with prostate specific antigen. Conclusions: Consistent with prior studies, we found an inverse relationship between obesity and serum prostate specific antigen. However, the magnitude of the difference was small. Thus, adjusting prostate specific antigen for body mass index does not appear warranted. C1 Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Ferrucci, Luigi; Metter, E. Jeffrey] NIA, NIH, Clin Res Branch, Baltimore, MD 21224 USA. RP Loeb, S (reprint author), 600 N Wolfe St,Marburg 100, Baltimore, MD 21287 USA. EM stacyloeb@gmail.com OI Loeb, Stacy/0000-0003-3933-9207 FU National Institutes of Health, National Institute on Aging FX Supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 20 TC 16 Z9 16 U1 0 U2 1 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 DEC PY 2009 VL 182 IS 6 BP 2646 EP 2651 DI 10.1016/j.juro.2009.08.041 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 518CU UT WOS:000271668600040 PM 19836806 ER PT J AU Cao, YJ Mager, DE Simonsick, EM Hilmer, SN Ling, SM Windham, BG Crentsil, V Yasar, S Fried, LP Abernethy, DR AF Cao, Y. J. Mager, D. E. Simonsick, E. M. Hilmer, S. N. Ling, S. M. Windham, B. G. Crentsil, V. Yasar, S. Fried, L. P. Abernethy, D. R. TI Physical and Cognitive Performance and Burden of Anticholinergics, Sedatives, and ACE Inhibitors in Older Women Editorial Comment SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Cao, Y. J.; Mager, D. E.; Simonsick, E. M.; Hilmer, S. N.; Ling, S. M.; Windham, B. G.; Crentsil, V.; Yasar, S.; Fried, L. P.; Abernethy, D. R.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Cao, YJ (reprint author), NIA, Intramural Res Program, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD DEC PY 2009 VL 182 IS 6 BP 2836 EP 2836 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 518CU UT WOS:000271668600105 ER PT J AU Yang, ZL Moss, B AF Yang, Zhilong Moss, Bernard TI Interaction of the Vaccinia Virus RNA Polymerase-Associated 94-Kilodalton Protein with the Early Transcription Factor SO JOURNAL OF VIROLOGY LA English DT Article ID TRIPHOSPHATE PHOSPHOHYDROLASE-I; H4L SUBUNIT; POLY(A) POLYMERASE; STIMULATORY FACTOR; TERMINATION FACTOR; ELONGATION-FACTOR; PROMOTER DNA; STAGE GENES; PURIFICATION; VIRIONS AB A multisubunit RNA polymerase (RPO) encoded by vaccinia virus (VACV), in conjunction with specific factors, transcribes early, intermediate, and late viral genes. However, an additional virus-encoded polypeptide referred to as the RPO-associated protein of 94 kDa (RAP94) is tightly bound to the RPO for the transcription of early genes. Unlike the eight RPO core subunits, RAP94 is synthesized exclusively at late times after infection. Furthermore, RAP94 is necessary for the packaging of RPO and other components needed for early transcription in assembling virus particles. The direct association of RAP94 with NPH I, a DNA-dependent ATPase required for transcription termination, and the multifunctional poly(A) polymerase small subunit/2'-O-methyltransferase/ elongation factor was previously demonstrated. That RAP94 provides a structural and functional link between the core RPO and the VACV early transcription factor (VETF) has been suspected but not previously demonstrated. Using VACV recombinants that constitutively or inducibly express VETF subunits and RAP94 with affinity tags, we showed that (i) VETF associates only with RPO containing RAP94 in vivo and in vitro, (ii) the association of RAP94 with VETF requires both subunits of the latter, (iii) neither viral DNA nor other virus-encoded late proteins are required for the interaction of RAP94 with VETF and core RPO subunits, (iv) different domains of RAP94 bind VETF and core subunits of RPO, and (v) NPH I and VETF bind independently and possibly simultaneously to the N-terminal region of RAP94. Thus, RAP94 provides the bridge between the RPO and proteins needed for transcription initiation, elongation, and termination. C1 [Yang, Zhilong; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 33 N Dr,MSC 3210, Bethesda, MD 20892 USA. EM bmoss@nih.gov RI Yang, Zhilong/E-8967-2010 FU Division of Intramural Research, NIAID; NIH FX The research was supported by the Division of Intramural Research, NIAID, NIH. NR 38 TC 14 Z9 20 U1 0 U2 1 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 DEC PY 2009 VL 83 IS 23 BP 12018 EP 12026 DI 10.1128/JVI.01653-09 PG 9 WC Virology SC Virology GA 515JI UT WOS:000271465600003 PM 19759131 ER PT J AU Kerr, PJ Kitchen, A Holmes, EC AF Kerr, Peter J. Kitchen, Andrew Holmes, Edward C. TI Origin and Phylodynamics of Rabbit Hemorrhagic Disease Virus SO JOURNAL OF VIROLOGY LA English DT Article ID AUSTRALIAN WILD RABBITS; RHDV-LIKE VIRUS; PHYLOGENETIC ANALYSIS; ORYCTOLAGUS-CUNICULUS; NEW-ZEALAND; SEROLOGICAL EVIDENCE; MOLECULAR SEQUENCES; ANTIGENIC VARIANTS; BIOLOGICAL-CONTROL; EPIDEMIOLOGY AB To determine the origin, phylogenetic relationships, and evolutionary dynamics of rabbit hemorrhagic disease virus (RHDV), we examined 210 partial and complete capsid gene nucleotide sequences. Using a Bayesian Markov chain Monte Carlo approach, we estimated that these sequences evolved at a rate of 3.9 x 10(-4) to 11.9 x 10(-4) nucleotide substitutions per site per year. This rate was consistent across subsets of data, was robust in response to recombination, and casts doubt on the provenance of viral strains isolated from the 1950s to the 1970s, which share strong sequence similarity to modern isolates. Using the same analysis, we inferred that the time to the most recent common ancestor for a joint group of RHDV and rabbit calicivirus sequences was < 550 years ago and was < 150 years ago for the RHDV isolates that have spread around the world since 1984. Importantly, multiple lineages of RHDV were clearly circulating before the major Chinese outbreak of 1984, a finding indicative of an early evolution of RHDV virulence. Four phylogenetic groups within RHDV were defined and analyzed separately. Each group shared a common ancestor in the mid-1960s or earlier, and each showed an expansion of populations starting before 1984. Notably, the group characterized by the antigenic variant RHDVa harbors the greatest genetic diversity, compatible with an elevated fitness. Overall, we contend that the high virulence of RHDV likely evolved once in the early part of the 20th century, well before the documented emergence of rabbit hemorrhagic disease in 1984. C1 [Kitchen, Andrew; Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Kerr, Peter J.] CSIRO Entomol, Canberra, ACT 2601, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ech15@psu.edu RI Kerr, Peter/C-2463-2009; OI Holmes, Edward/0000-0001-9596-3552 NR 38 TC 47 Z9 48 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 DEC PY 2009 VL 83 IS 23 BP 12129 EP 12138 DI 10.1128/JVI.01523-09 PG 10 WC Virology SC Virology GA 515JI UT WOS:000271465600014 PM 19759153 ER PT J AU Dunn, LL McWilliams, MJ Das, K Arnold, E Hughes, SH AF Dunn, Linda L. McWilliams, Mary Jane Das, Kalyan Arnold, Eddy Hughes, Stephen H. TI Mutations in the Thumb Allow Human Immunodeficiency Virus Type 1 Reverse Transcriptase To Be Cleaved by Protease in Virions SO JOURNAL OF VIROLOGY LA English DT Article ID PALM SUBDOMAINS; STRAND TRANSFER; RNASE-H; RESISTANCE; MUTANTS; COMPLEX; DNA; PROCESSIVITY; REPLICATION; INSTABILITY AB Although human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) has been extensively studied, there are still significant questions about the effects of mutations on the maturation and stability of RT. We show here that a significant fraction (>80%) of the single point mutations we generated in the thumb subdomain of HIV-1 (RT) affect the stability of RT in virions. Fragments of the unstable mutant RTs can be detected in Western blots of virion proteins; however, the degree of degradation varies. The titers of the mutants whose virions contain degraded RTs are reduced. Some, but not all, of the unstable RT thumb subdomain mutants we analyzed have a temperature-sensitive phenotype. A preliminary survey of mutations in other subdomains of RT shows that some of these mutations also destabilize RT. The stability of the RT mutants is enhanced by the addition of a protease inhibitor, suggesting that the viral protease plays an important role in the degradation of the mutant RTs. These results confirm and extend earlier reports of mutations that affect the stability of RT in virions. The data suggest that the stability of a mutant RT in virions could be a major factor in determining the virus titer and, by extension, viral fitness, which could affect whether a mutation in RT is acceptable to the virus. C1 [Dunn, Linda L.; McWilliams, Mary Jane; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Das, Kalyan; Arnold, Eddy] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, POB B,Bldg 539,Rm 130A, Frederick, MD 21702 USA. EM hughes@ncifcrf.gov FU National Institutes of Health [AI 27690]; National Cancer Institute; Center for Cancer Research FX We are grateful to Eric Freed for helpful discussions. We thank Michael Abram for assistance with the ritonavir experiments, George Kassey for fluorescence- activated cell sorting analysis, Jiro Wada and Tammy Schroyer for assistance on figures, and Teresa Burdette for help with the manuscript. NR 30 TC 14 Z9 14 U1 1 U2 8 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 DEC PY 2009 VL 83 IS 23 BP 12336 EP 12344 DI 10.1128/JVI.00676-09 PG 9 WC Virology SC Virology GA 515JI UT WOS:000271465600032 PM 19759158 ER PT J AU Gibbs, JD Ornoff, DM Igo, HA Zeng, JY Imani, F AF Gibbs, John D. Ornoff, Douglas M. Igo, Heather A. Zeng, Jennifer Y. Imani, Farhad TI Cell Cycle Arrest by Transforming Growth Factor beta 1 Enhances Replication of Respiratory Syncytial Virus in Lung Epithelial Cells SO JOURNAL OF VIROLOGY LA English DT Article ID TGF-BETA; AIRWAY HYPERRESPONSIVENESS; MEASLES-VIRUS; ASTHMA; INFECTION; EXPRESSION; DISEASE; SUPPRESSION; PROTEIN; FIBROSIS AB Respiratory syncytial virus (RSV) is a common respiratory viral infection in children which is associated with immune dysregulation and subsequent induction and exacerbations of asthma. We recently reported that treatment of primary human epithelial cells (PHBE cells) with transforming growth factor beta (TGF-beta) enhanced RSV replication. Here, we report that the enhancement of RSV replication is mediated by induction of cell cycle arrest. These data were confirmed by using pharmacologic inhibitors of cell cycle progression, which significantly enhanced RSV replication. Our data also showed that RSV infection alone resulted in cell cycle arrest in A549 and PHBE cells. Interestingly, our data showed that RSV infection induced the expression of TGF-beta in epithelial cells. Blocking of TGF-beta with anti-TGF-beta antibody or use of a specific TGF-beta receptor signaling inhibitor resulted in rescue of the RSV-induced cell cycle arrest, suggesting an autocrine mechanism. Collectively, our data demonstrate that RSV regulates the cell cycle through TGF-beta in order to enhance its replication. These findings identify a novel pathway for upregulation of virus replication and suggest a plausible mechanism for association of RSV with immune dysregulation and asthma. C1 [Gibbs, John D.; Ornoff, Douglas M.; Igo, Heather A.; Zeng, Jennifer Y.; Imani, Farhad] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Imani, F (reprint author), NIEHS, Lab Resp Biol, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM imani@niehs.nih.gov FU National Institute of Environmental Health Sciences; NIH FX This research was supported entirely by the Intramural Research Program at the National Institute of Environmental Health Sciences, NIH. NR 49 TC 33 Z9 35 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 DEC PY 2009 VL 83 IS 23 BP 12424 EP 12431 DI 10.1128/JVI.00806-09 PG 8 WC Virology SC Virology GA 515JI UT WOS:000271465600041 PM 19759128 ER PT J AU Nelson, S Poddar, S Lin, TY Pierson, TC AF Nelson, Steevenson Poddar, Subhajit Lin, Tsai-Yu Pierson, Theodore C. TI Protonation of Individual Histidine Residues Is Not Required for the pH-Dependent Entry of West Nile Virus: Evaluation of the "Histidine Switch" Hypothesis SO JOURNAL OF VIROLOGY LA English DT Article ID ANTIBODY-MEDIATED NEUTRALIZATION; FLAVIVIRUS INFECTION ENHANCEMENT; VIRAL MEMBRANE-FUSION; ENVELOPE GLYCOPROTEIN; DENGUE-VIRUS; CONSERVED HISTIDINE; CRYSTAL-STRUCTURE; CELLULAR ENTRY; MACROPHAGES; PARTICLES AB Histidine residues have been hypothesized to function as sensors of environmental pH that can trigger the activity of viral fusion proteins. We investigated a requirement for histidine residues in the envelope (E) protein of West Nile virus during pH-dependent entry into cells. Each histidine was individually replaced with a nonionizable amino acid and tested functionally. In each instance, mutants capable of orchestrating pH-dependent infection were identified. These results do not support a requirement for any single histidine as a pH-sensing "switch," and they suggest that additional features of the E protein are involved in triggering pH-dependent steps in the flavivirus life cycle. C1 [Nelson, Steevenson; Poddar, Subhajit; Lin, Tsai-Yu; Pierson, Theodore C.] NIH, Viral Pathogenesis Sect, Viral Dis Lab, Bethesda, MD 20892 USA. RP Pierson, TC (reprint author), NIH, Viral Pathogenesis Sect, Viral Dis Lab, 33 North Dr,Bldg 33,Room 1E19A-2, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov RI Lin, Tsai-Yu/B-8873-2016 OI Lin, Tsai-Yu/0000-0002-8076-1584 FU NIH; National Institutes of Allergy and Infectious Diseases (NIAID). FX We thank members of our laboratory for useful discussions and their comments on the manuscript. NR 35 TC 27 Z9 28 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC PY 2009 VL 83 IS 23 BP 12631 EP 12635 DI 10.1128/JVI.01072-09 PG 5 WC Virology SC Virology GA 515JI UT WOS:000271465600062 PM 19776132 ER PT J AU Fejzo, MS Poursharif, B Korst, LM Munch, S MacGibbon, KW Romero, R Goodwin, TM AF Fejzo, Marlena S. Poursharif, Borzouyeh Korst, Lisa M. Munch, Shari MacGibbon, Kimber W. Romero, Roberto Goodwin, T. Murphy TI Symptoms and Pregnancy Outcomes Associated with Extreme Weight Loss among Women with Hyperemesis Gravidarum SO JOURNAL OF WOMENS HEALTH LA English DT Article ID PRENATAL EXPOSURE; PERSONALITY-DISORDER; SEVERE NAUSEA; LARGE COHORT; FAMINE; BURDEN AB Objective: To report the weight loss and associated symptoms experienced by a large cohort of women with hyperemesis gravidarum (HG). Methods: Data were obtained from an HG website registry, where women with HG were recruited on-line. Respondents were included if they experienced at least 1 live birth >27 weeks' gestation. Extreme weight loss was defined as a loss of >15% of prepregnancy weight. Results: Of the 819 women surveyed, 214 (26.1%) met criteria for extreme weight loss. These women were twice as likely to be Hispanic or nonwhite. Extreme weight loss (p<0.001) was associated with indicators of the severity of HG, such as hospitalization and use of parenteral nutrition, and with multiple symptoms during pregnancy, such as gallbladder and liver dysfunction, renal failure, and retinal hemorrhage. Among all women surveyed, 22.0% reported that symptoms lasted throughout pregnancy; this finding was nearly twice as likely among women with extreme weight Loss: 63 of 214 (29.4%) vs. 117 of 605 (19.3%) (OR 1.73, 95% CI 1.2-2.5, p-0.003). For some women, symptoms continued postpartum and included food aversions, muscle pain, nausea, and posttraumatic stress. Approximately 16% of babies were born prematurely, and 8% reportedly weighed <2500 g. Among women with extreme weight loss, 9.3% reported having a child with a behavioral disorder. Conclusions: Extreme weight loss is common among women with HG, suggesting that HG is a form of prolonged starvation in pregnancy and that the long-term effects of this condition on women and their offspring warrant further investigation. C1 [Fejzo, Marlena S.; Poursharif, Borzouyeh; Korst, Lisa M.; Goodwin, T. Murphy] Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Munch, Shari] Rutgers State Univ, Sch Social Work, New Brunswick, NJ 08903 USA. [MacGibbon, Kimber W.] Hyperemesis Educ & Res Fdn, Leesburg, VA USA. [Romero, Roberto] NICHHD, NIH, Dept Hlth & Human Serv, Perinatol Res Branch, Detroit, MI USA. RP Korst, LM (reprint author), Univ So Calif, Dept Obstet & Gynecol, 2020 Zonal Ave,201, Los Angeles, CA 90033 USA. EM Korst@usc.edu OI MacGibbon, Kimber/0000-0002-6534-3114 FU Intramural Research Program of the National Institute of Child Health and Human Development; National Institutes of Health, Department of Health and Human Services [N01-HD-2-3342] FX This research was supported in part by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, contract number N01-HD-2-3342. NR 36 TC 38 Z9 38 U1 2 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD DEC PY 2009 VL 18 IS 12 BP 1981 EP 1987 DI 10.1089/jwh.2009.1431 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 538TI UT WOS:000273206500010 PM 20044860 ER PT J AU Espeland, MA Tindle, HA Bushnell, CA Jaramillo, SA Kuller, LH Margolis, KL Mysiw, WJ Maldjian, JA Melhem, ER Resnick, SM AF Espeland, Mark A. Tindle, Hilary A. Bushnell, Cheryl A. Jaramillo, Sarah A. Kuller, Lewis H. Margolis, Karen L. Mysiw, W. Jerry Maldjian, Joseph A. Melhem, Elias R. Resnick, Susan M. CA Womens Hlth Initiative Memory Stud TI Brain Volumes, Cognitive Impairment, and Conjugated Equine Estrogens SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Hormone therapy; Magnetic resonance imaging; Women's health ID HEALTH INITIATIVE MEMORY; POSTMENOPAUSAL HORMONE-THERAPY; RANDOMIZED CONTROLLED-TRIAL; WHITE-MATTER LESIONS; WHIMS-MRI; HIPPOCAMPAL ATROPHY; CELL-PROLIFERATION; PLUS PROGESTIN; DENTATE GYRUS; WOMEN AB Background. Postmenopausal conjugated equine estrogens (CEE) therapies increase the risk of cognitive impairment in women aged 65 years or older and are associated with smaller regional brain volumes; however, the link between these two phenomena has not been established. Methods. Standardized magnetic resonance imaging was performed on 1,403 women, 1-4 years after they had participated in randomized placebo-controlled clinical trials of CEE-based therapies. Women included in this report were aged 65-80 years and free of dementia and mild cognitive impairment (MCI) when originally enrolled in the trials, which lasted an average of 4-6 years and were conducted at 14 academic U. S. medical centers. The associations that regional brain volumes and ischemic lesion volumes had with the development of cognitive impairment (i.e., dementia or MCI) were contrasted between treatment groups using analyses of covariance. Results. Fifty-three women developed MCI or probable dementia during follow-up. Among women who had been prescribed CEE-based therapies, cognitive impairment was associated with relatively smaller hippocampal (p =.0002) and total brain volumes (p =.03). Qualitatively, these associations appeared to be independent of their level of pretreatment cognitive function. Among women who had been prescribed placebo, these relationships were not evident; instead, cognitive impairment was associated with greater ischemic lesion volume in the frontal lobe (p =.007) and overall (p =.02). Conclusion. A mechanism by which CEE-based postmenopausal hormone therapy induces cognitive impairment appears to be through increased brain atrophy. C1 [Espeland, Mark A.; Jaramillo, Sarah A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Tindle, Hilary A.] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA 15260 USA. [Bushnell, Cheryl A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Neurol, Winston Salem, NC 27103 USA. [Kuller, Lewis H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Margolis, Karen L.] HealthPartners Res Fdn, Minneapolis, MN USA. [Mysiw, W. Jerry] Ohio State Univ, Sch Med, Dept Phys Med & Rehabil, Columbus, OH 43210 USA. [Maldjian, Joseph A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol, Winston Salem, NC USA. [Melhem, Elias R.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Resnick, Susan M.] NIA, Lab Personal & Cognit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Espeland, MA (reprint author), Wake Forest Univ Hlth Sci, Dept Biostat Sci, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM mespelan@wfubmc.edu RI Melhem, Elias/E-5205-2013; Mysiw, Walter/E-3724-2011 FU National Heart, Lung, and Blood Institute of the National Institutes of Health, U.S. Department of Health and Human Services; Wyeth Pharmaceuticals, Inc.; National Institute on Aging, National Institutes of Health FX The Women's Health Initiative is funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health, U.S. Department of Health and Human Services. The Women's Health Initiative Memory Study was funded in part by Wyeth Pharmaceuticals, Inc., St. Davids, PA. S. M. R. is supported by the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 34 TC 26 Z9 28 U1 0 U2 3 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD DEC PY 2009 VL 64 IS 12 BP 1243 EP 1250 DI 10.1093/gerona/glp128 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 516WI UT WOS:000271573600005 PM 19729392 ER PT J AU Newman, AB Sachs, MC Arnold, AM Fried, LP Kronmal, R Cushman, M Psaty, BM Harris, TB Robbins, JA Burke, GL Kuller, LH Lumley, T AF Newman, Anne B. Sachs, Michael C. Arnold, Alice M. Fried, Linda P. Kronmal, Richard Cushman, Mary Psaty, Bruce M. Harris, Tamara B. Robbins, John A. Burke, Gregory L. Kuller, Lewis H. Lumley, Thomas TI Total and Cause-Specific Mortality in the Cardiovascular Health Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Mortality risk; Cause of death; Elderly participants ID C-REACTIVE PROTEIN; OLDER-ADULTS; LUNG-FUNCTION; RISK-FACTORS; ASSOCIATION; CANCER; SMOKING; DISEASE; WOMEN; ATHEROSCLEROSIS AB Background. Few cohort studies have adequate numbers of carefully reviewed deaths to allow an analysis of unique and shared risk factors for cause-specific mortality. Shared risk factors could be targeted for prevention of premature death and the study of longevity. Methods. A total of 5,888 community-dwelling persons aged 65 years or older living in four communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up was 16 years. Total and cause-specific mortality, including cardiovascular disease, stroke, cancer, dementia, pulmonary disease, infection, and other cause, were examined as outcomes. Variables previously associated with total mortality were examined for each cause of death using Cox proportional hazard models. Results. Multiple risk factors were related to total mortality. When examining specific causes, many factors were related to cardiovascular death, whereas fewer were related to other causes. For most causes, risk factors were specific for that cause. For example, apolipoprotein E e 4 was strongly associated for dementia death and forced vital capacity with pulmonary death. Age, male sex, markers of inflammation, and cognitive function were related to multiple causes of death. Conclusions. In these older adults, associations of risk factors with a given cause of death were related to specific deficits in that same organ system. Inflammation may represent a common pathway to all causes of death. C1 [Newman, Anne B.; Kuller, Lewis H.] Univ Pittsburgh, Dept Epidemiol & Med, Pittsburgh, PA 15213 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. [Sachs, Michael C.; Arnold, Alice M.; Kronmal, Richard; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT 05405 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Biol & Demog, Bethesda, MD 20892 USA. [Robbins, John A.] Univ Calif Davis, Dept Internal Med, Sacramento, CA 95817 USA. [Burke, Gregory L.] Wake Forest Univ, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. RP Newman, AB (reprint author), Univ Pittsburgh, Dept Epidemiol & Med, 130 N Bellefield Ave,Room 532, Pittsburgh, PA 15213 USA. EM newmana@edc.pitt.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institute on Aging [R01-AG-023629]; National Heart, Lung, and Blood Institute [N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079, N01-HC-85086, N01 HC-15103, N01 HC-55222, U01 HL080295, HL-075366]; National Institute of Neurological Disorders and Stroke; University of Pittsburgh [P30-AG-024827] FX The study was supported through R01-AG-023629 from the National Institute on Aging. The Cardiovascular Health Study was supported from contracts N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079 through N01-HC-85086, N01 HC-15103, N01 HC-55222, and U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through HL-075366 from the National Heart, Lung and Blood Institute, and the University of Pittsburgh Claude. D. Pepper Older Americans Independence Center P30-AG-024827. NR 44 TC 33 Z9 34 U1 0 U2 2 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD DEC PY 2009 VL 64 IS 12 BP 1251 EP 1261 DI 10.1093/gerona/glp127 PG 11 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 516WI UT WOS:000271573600006 PM 19723772 ER PT J AU Cecchi, F Molino-Lova, R Di Iorio, A Conti, AA Mannoni, A Lauretani, F Benvenuti, E Bandinelli, S Macchi, C Ferrucci, L AF Cecchi, Francesca Molino-Lova, Raffaello Di Iorio, Angelo Conti, Andrea Alberto Mannoni, Alessandro Lauretani, Fulvio Benvenuti, Enrico Bandinelli, Stefania Macchi, Claudio Ferrucci, Luigi TI Measures of Physical Performance Capture the Excess Disability Associated With Hip Pain or Knee Pain in Older Persons SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Hip pain; Knee pain; Older persons; Performance; Disability ID LOWER-EXTREMITY FUNCTION; HEALTH-STATUS; BACK-PAIN; SUBSEQUENT DISABILITY; MUSCULOSKELETAL PAIN; MOBILITY LIMITATION; OSTEOARTHRITIS; ADULTS; COMMUNITY; AGE AB Background. Hip pain (HP) and knee pain (KP) may specifically affect function and performance; few studies investigate the functional impact of HP or KP in the same population. Methods. Population-based sample of older individuals living in the Chianti area (Tuscany, Italy) (1998-2000); 1006 persons (564 women and 442 men) were included in this analysis; 11.9% reported HP and 22.4% reported KP in the past 4 weeks. Self-reported disability and lower extremity performance, measured by 400-m walk test and by the short physical performance battery (SPPB, including standing balance, chair raising, and 4-m walk test), were compared in participants reporting HP or KP versus those free of these conditions; the relationship of HP or KP with performance and self-reported disability was studied, adjusting for age, sex, hip or knee flexibility, muscle strength, multiple joint pain, major medical conditions, and depression. Results. Participants reporting HP were more likely to report disability in shopping, cutting toenails, carrying a shopping bag, and using public transportation; those with KP reported more disability in cutting toenails and carrying a shopping bag. Participants reporting HP or KP had significantly lower SPPB scores. Adjusting by SPPB, pain no longer predicted self-reported disability, except for "HP-carrying a shopping bag." Conclusions. In our cohort of older persons, those with HP reported disability in a wider range of activities than those with KP. Physical performance measured by SPPB was impaired in both conditions. Reduced lower extremity performance captures the excess disability associated with either HP or KP. C1 [Cecchi, Francesca; Molino-Lova, Raffaello; Conti, Andrea Alberto; Macchi, Claudio] Fdn Don Carlo Gnocchi, Inst Recovery & Care Sci Character, Florence, Italy. [Di Iorio, Angelo] Univ G dAnnunzio, Dept Med & Sci Aging, Lab Clin Epidemiol, Geriatr Unit, Chieti, Italy. [Mannoni, Alessandro] Florence Hlth Agcy, Rheumatol Unit, Florence, Italy. [Mannoni, Alessandro] Qual Improvement Network, Florence, Italy. [Lauretani, Fulvio] Tuscany Hlth Reg Agcy, Florence, Italy. [Benvenuti, Enrico; Bandinelli, Stefania] Florence Hlth Agcy, Geriatr Unit, Florence, Italy. [Macchi, Claudio] Univ Florence, Dept Crit Care Med & Surg, I-50121 Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, ASTRA, Baltimore, MD 21224 USA. RP Cecchi, F (reprint author), Fdn Don C Gnocchi, V Caccini 18, I-50141 Florence, Italy. EM francescacecchi2002@libero.it RI Lauretani, Fulvio/K-5115-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; Cecchi, Franco/0000-0002-2035-5621 FU Italian Ministry of Health [ICS 110.1\RS97.71]; National Institute on Aging [N01-AG-916413, N01-AG-821336, 263 MD 9164 13, 263 MD 821336]; National Institutes of Health in the United States; National Institute on Aging, National Institutes of Health, United States FX The InCHIANTI study was supported as a "targeted project" (ICS 110.1\RS97.71) by the Italian Ministry of Health, by the National Institute on Aging (Contracts N01-AG-916413 and N01-AG-821336 and Contracts 263 MD 9164 13 and 263 MD 821336) of the National Institutes of Health in the United States, and in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health, United States. NR 43 TC 18 Z9 19 U1 3 U2 5 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD DEC PY 2009 VL 64 IS 12 BP 1316 EP 1324 DI 10.1093/gerona/glp125 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 516WI UT WOS:000271573600015 PM 19797345 ER PT J AU Fuller-Thomson, E Yu, B Nuru-Jeter, A Guralnik, JM Minkler, M AF Fuller-Thomson, E. Yu, B. Nuru-Jeter, A. Guralnik, J. M. Minkler, M. TI Basic ADL Disability and Functional Limitation Rates Among Older Americans From 2000-2005: The End of the Decline? SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Disability; Activities of daily living; Functional limitations; American Community Survey; National Nursing Home Survey ID RECENT TRENDS; AGE DISABILITY; UNITED-STATES; POPULATION; PREVALENCE AB Background. This study sought to determine whether the rates of basic activities of daily living (ADL) disabilities and functional limitations declined, remained the same, or increased between 2000 and 2005 when (a) only community-dwelling Americans aged 65 and older were examined and (b) when institutionalized older adults were included. Method. Using data from the American Community Survey and the National Nursing Home Survey, we calculated annual prevalence rates of basic ADL disabilities and functional limitations and fitted regression lines to examine trends over time. Results. The rates of basic ADL disabilities among community-dwelling adults aged 65 and older increased 9% between 2000 and 2005. When institutionalized elders were included, basic ADL disability rates were stable among men but increased among women. Functional limitation rates did not significantly change between 2000 and 2005. Conclusion. These findings suggest an end of the decline in disability rates among older Americans, which, if confirmed, could have important implications for health care. C1 [Fuller-Thomson, E.] Univ Toronto, Factor Inwentash Fac Social Work, Sandra Rotman Chair Social Work, Toronto, ON M5S 1A1, Canada. [Fuller-Thomson, E.] Univ Toronto, Dept Family & Community Med, Toronto, ON M5S 1A1, Canada. [Yu, B.; Guralnik, J. M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Nuru-Jeter, A.; Minkler, M.] Univ Calif Berkeley, Div Community Hlth & Human Dev, Berkeley, CA 94720 USA. RP Fuller-Thomson, E (reprint author), Univ Toronto, Factor Inwentash Fac Social Work, Sandra Rotman Chair Social Work, 246 Bloor St W, Toronto, ON M5S 1A1, Canada. EM esme.fuller.thomson@utoronto.ca FU Retirement Research Foundation [2006-073]; National Institute on Aging, National Institutes of Health FX This work was supported by a grant from the Retirement Research Foundation (grant number 2006-073) and by the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 16 TC 57 Z9 57 U1 1 U2 8 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD DEC PY 2009 VL 64 IS 12 BP 1333 EP 1336 DI 10.1093/gerona/glp130 PG 4 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 516WI UT WOS:000271573600017 PM 19723771 ER PT J AU Miller, FG Truog, RD AF Miller, Franklin G. Truog, Robert D. TI The Incoherence of Determining Death by Neurological Criteria: Reply to John Lizza SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article AB Human life and death should be defined biologically. It is important not to conflate the definition of death with the criteria for when it has occurred. What is distinctively "human" from a scientific or normative perspective has nothing to do with what makes humans alive or dead. We are biological organisms, despite the fact that what is meaningful about human life is not defined in biological terms. Consequently, as in the rest of the realm of living beings, human beings die when they no longer function biologically as organisms. In contrast, a determination of exactly when death has occurred, required to serve various social purposes, combines social and normative considerations with biological facts. C1 [Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Miller, Franklin G.] NIMH, Bethesda, MD 20892 USA. [Miller, Franklin G.] Georgetown Univ, Kennedy Inst Eth, Washington, DC 20057 USA. [Truog, Robert D.] Childrens Hosp, Boston, MA 02115 USA. [Truog, Robert D.] Harvard Univ, Sch Med, Boston, MA USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 2 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD DEC PY 2009 VL 19 IS 4 BP 397 EP 399 PG 3 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA 550AI UT WOS:000274097300005 ER PT J AU Hill, VL Simpson, VZ Higgins, JM Hu, ZH Stevens, RA Metcalf, JA Baseler, M AF Hill, Valerie L. Simpson, Virginia Z. Higgins, Jeanette M. Hu, Zonghui Stevens, Randy A. Metcalf, Julia A. Baseler, Michael TI Evaluation of the Performance of the Sysmex XT-2000i Hematology Analyzer With Whole Blood Specimens Stored at Room Temperature SO LABMEDICINE LA English DT Article ID FLOW-CYTOMETRY; STORAGE C1 [Hill, Valerie L.; Simpson, Virginia Z.; Higgins, Jeanette M.; Stevens, Randy A.; Baseler, Michael] NCI, AIDS Monitoring Lab, Clin Serv Program, SAIC Frederick, Frederick, MD 21701 USA. [Hu, Zonghui; Metcalf, Julia A.] NIH, NIAID, Bethesda, MD 20892 USA. RP Hill, VL (reprint author), NCI, AIDS Monitoring Lab, Clin Serv Program, SAIC Frederick, Frederick, MD 21701 USA. FU National Cancer Institute and National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This project has been funded in whole or in part with federal funds from the National Cancer Institute and National Institutes of Health under contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the National Institute of Allergy and Infectious Diseases. NR 12 TC 13 Z9 13 U1 0 U2 1 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0007-5027 J9 LABMEDICINE JI Labmedicine PD DEC PY 2009 VL 40 IS 12 BP 709 EP 718 DI 10.1309/T0FJYP2RBXEHX4 PG 10 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 522HW UT WOS:000271989500002 PM 20431699 ER PT J AU Fonseca, R Bergsagel, PL Drach, J Shaughnessy, J Gutierrez, N Stewart, AK Morgan, G Van Ness, B Chesi, M Minvielle, S Neri, A Barlogie, B Kuehl, WM Liebisch, P Davies, F Chen-Kiang, S Durie, BGM Carrasco, R Sezer, O Reiman, T Pilarski, L Avet-Loiseau, H AF Fonseca, R. Bergsagel, P. L. Drach, J. Shaughnessy, J. Gutierrez, N. Stewart, A. K. Morgan, G. Van Ness, B. Chesi, M. Minvielle, S. Neri, A. Barlogie, B. Kuehl, W. M. Liebisch, P. Davies, F. Chen-Kiang, S. Durie, B. G. M. Carrasco, R. Sezer, Orhan Reiman, Tony Pilarski, Linda Avet-Loiseau, H. TI International Myeloma Working Group molecular classification of multiple myeloma: spotlight review SO LEUKEMIA LA English DT Review DE multiple myeloma; genetics; cytogenetics; molecular; prognosis; gene expression profiling ID IN-SITU HYBRIDIZATION; STEM-CELL TRANSPLANTATION; ADVERSE PROGNOSTIC-FACTOR; COOPERATIVE-ONCOLOGY-GROUP; BORTEZOMIB PLUS MELPHALAN; GROWTH-FACTOR RECEPTOR-3; P53 GENE DELETION; HIGH-DOSE THERAPY; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY AB Myeloma is a malignant proliferation of monoclonal plasma cells. Although morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. These genetic subtypes are associated with unique clinicopathological features and dissimilar outcome. At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. The latter is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. The three main IgH translocations in myeloma are the t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Trisomies and a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified including deletions of chromosomes 13 and 17 and abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell survival and proliferation have also been identified such as nuclear factor-B-activating mutations and other deregulation factors for the cyclin-dependent pathways regulators. Further understanding of the biological subtypes of the disease has come from the application of novel techniques such as gene expression profiling and array-based comparative genomic hybridization. The combination of data arising from these studies and that previously elucidated through other mechanisms allows for most myeloma cases to be classified under one of several genetic subtypes. This paper proposes a framework for the classification of myeloma subtypes and provides recommendations for genetic testing. This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials. Leukemia (2009) 23, 2210-2221; doi:10.1038/leu.2009.174; published online 1 October 2009 C1 [Fonseca, R.; Bergsagel, P. L.; Stewart, A. K.; Chesi, M.] Mayo Clin, Dept Hematol Oncol, Scottsdale, AZ USA. [Drach, J.] Univ Hosp Vienna, Dept Med, Div Clin Oncol, Vienna, Austria. [Shaughnessy, J.; Barlogie, B.] Univ Arkansas Med Sci, MIRT, Dept MIRT, Little Rock, AR 72205 USA. [Gutierrez, N.] Hosp Univ Salamanca, CIC, Dept Hematol, Salamanca, Spain. [Morgan, G.; Davies, F.] Royal Marsden Hosp, Inst Canc Res, Sutton, Surrey, England. [Van Ness, B.] Univ Minnesota, Inst Human Genet, Dept Genet, Minneapolis, MN 55455 USA. [Minvielle, S.; Avet-Loiseau, H.] Univ Nantes, Nantes, France. [Minvielle, S.; Avet-Loiseau, H.] Inst Biol, Hematol Lab, Nantes, France. [Neri, A.] Univ Milan, Ist Sci Med, Osped Maggiore, Serv Ematol,IRCCS, I-20122 Milan, Italy. [Kuehl, W. M.] NCI, Genet Branch, Bethesda, MD 20892 USA. [Liebisch, P.] Univ Ulm, Dept Internal Med 3, D-7900 Ulm, Germany. [Chen-Kiang, S.] Columbia Univ, Dept Pathol, Weill Cornell Med Coll, New York, NY USA. [Durie, B. G. M.] Samuel Oschin Comprehens Canc Inst, Cedars Sinai Outpatient Canc Ctr, Los Angeles, CA USA. [Carrasco, R.] Harvard Univ, Dana Farber Canc Inst, Dept Med Oncol Hematol Neoplasia, Boston, MA 02115 USA. [Sezer, Orhan] Univ Klinikum Charite, Dept Hem Onc, Berlin, Germany. [Reiman, Tony] Dalhousie Univ, Dept Oncol, John Reg Hosp, Halifax, NS, Canada. [Pilarski, Linda] Univ Alberta, Cross Canc Inst, Edmonton, AB, Canada. RP Fonseca, R (reprint author), Mayo Clin Arizona, Dept Haematol Oncol, Collaborative Res Bldg 3-006,13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM fonseca.rafael@mayo.edu RI 2009, Secribsal/A-1266-2012; Bergsagel, Peter/A-7842-2011; Minvielle, Stephane/K-8251-2015; OI Bergsagel, Peter/0000-0003-1523-7388; neri, antonino/0000-0001-9047-5912; Fonseca, Rafael/0000-0002-5938-3769; Gutierrez, Norma/0000-0001-5834-9510 FU Cylene and Proteolix; Merck. B Van Ness serves on the IMF Scientific Advisory Board; NCI, Millennium, Celgene; Novartis FX R Fonseca is a consultant for Genzyme, Celgene, BMS, Otsuka, Halozyme and Medtronic. His research was funded by Cylene and Proteolix. PL Bergsagel is on the advisory board of Amgen, Genentech, Celgene. Hid research was funded by Merck. B Van Ness serves on the IMF Scientific Advisory Board. The rest of the authors declare no conflict of interest. Shaughnessy's work was patented by Myelogix, Genzyme and Novartis. He is a scientific advisor to Myelogix, Genzyme, Novartis and Celgene. He receives royalties from Myelogix, Genzyme, Novartis and Celgene, and is the owner of Myelogix. Bart Barlogie's research was funded by NCI, Millennium, Celgene and Novartis. He has received honoraria from Millennium, Celgene and IMF. He is on the speakers Bureau of Millennium, Celgene and SWOG, and is a consultant for Celegene and Genzyme. He also has membership on an entity's Board of Directors or advisory committees of IMF, MMRF and SWOG. NR 88 TC 365 Z9 381 U1 6 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD DEC PY 2009 VL 23 IS 12 BP 2210 EP 2221 DI 10.1038/leu.2009.174 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA 533HO UT WOS:000272814600003 PM 19798094 ER PT J AU Hosgood, HD Baris, D Zhang, YW Berndt, SI Menashe, I Morton, LM Lee, KM Yeager, M Zahm, SH Chanock, S Zheng, TZ Lan, Q AF Hosgood, H. Dean, III Baris, Dalsu Zhang, Yawei Berndt, Sonja I. Menashe, Idan Morton, Lindsay M. Lee, Kyoung-Mu Yeager, Meredith Zahm, Shelia H. Chanock, Stephen Zheng, Tongzhang Lan, Qing TI Genetic variation in cell cycle and apoptosis related genes and multiple myeloma risk SO LEUKEMIA RESEARCH LA English DT Article DE Multiple myeloma; Caspase; BAX; RIPK1; Cell cycle ID CHRONIC LYMPHOCYTIC-LEUKEMIA; PROMOTER REGION; BAX GENE; POLYMORPHISMS; CANCER; SUSCEPTIBILITY; ASSOCIATION; SURVIVAL; DNA; PATHOGENESIS AB Genetic variation may be an important risk factor for multiple myeloma. A hallmark of tumor formation and growth is cell cycle dysregulation and apoptosis avoidance. We previously reported the association of genetic variation in caspase genes, the apoptotic-regulating family, and multiple myeloma risk. To further examine if genetic variation in key cell cycle and apoptosis genes alters multiple myeloma risk, we genotyped 276 tag SNPs in 27 gene regions in a population-based case-control study of non-Hispanic Caucasian women 1,108 cases; 482 controls) in Connecticut. Logistic regression assessed the effect of each SNP on multiple myeloma risk and the minP test assessed the association at the gene region level. Three gene regions were significantly associated with risk of multiple myeloma (BAX minP = 0.018, CASP9 minP = 0.025, and RIPK1 minP = 0.037). Further explorations identified the most significant variant of BAX, RIPK1, and CASP9 to be rs1042265, rs9391981, and rs751643, respectively. The A variant at rs1042265 (OR(GA+AA) = 0.40, 95% CI = 0.21-0.78) and the C variant at rs9391981 (OR(GC+CC) = 0.32, 95% CI = 0.12-0.81) were associated with a decreased risk of multiple myeloma. The G variant at rs7516435 was associated with an increased risk of multiple myeloma (OR(AG) = 1.48, 95% CI = 0.94-2.32; OR(GG) = 2.59, 95% CI = 1.30-5.15; P(trend) = 0.005). Haplotype analyses supported the SNP findings. These findings suggest that genetic variation in cell cycle and apoptosis genes may play a key role in multiple myeloma and warrant further investigation through replication studies. Published by Elsevier Ltd. C1 [Hosgood, H. Dean, III] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Zhang, Yawei; Zheng, Tongzhang] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. RP Hosgood, HD (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 8118,MCS 7240, Bethesda, MD 20892 USA. EM hosgoodd@mail.nih.gov RI Zahm, Shelia/B-5025-2015; Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 FU National Cancer Institute; National Institutes of Health [N01-CO-12400] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, undercontract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 37 TC 14 Z9 17 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD DEC PY 2009 VL 33 IS 12 BP 1609 EP 1614 DI 10.1016/j.leukres.2009.03.013 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 506LO UT WOS:000270776500006 PM 19362737 ER PT J AU Vatsveen, TK Tian, E Kresse, SH Meza-Zepeda, LA Gabrea, A Glebov, O Dai, HY Sundan, A Kuehl, WM Borset, M AF Vatsveen, Thea Kristin Tian, Erming Kresse, Stine H. Meza-Zepeda, Leonardo A. Gabrea, Ana Glebov, Oleg Dai, Hong Yan Sundan, Anders Kuehl, W. Michael Borset, Magne TI OH-2, a hyperdiploid myeloma cell line without an IGH translocation, has a complex translocation juxtaposing MYC near MAFB and the IGK locus SO LEUKEMIA RESEARCH LA English DT Article DE Hyperdiploid; Array CGH; FISH; MYC; MAFB; IGK ID MULTIPLE-MYELOMA; LEUKEMIA; TUMORS; CLASSIFICATION; IMMUNOGLOBULIN; PATHOGENESIS; ABERRATIONS; GROWTH AB Multiple myeloma can be classified into hyperdiploid (HRD) (with 48-74 chromosomes) and non-hyperdiploid tumors (usually with immunoglobulin heavy chain trans locations). The CH-2 human myeloma cell line (HMCL) retains the same HRD genotype as the primary tumor, with extra copies of chromosomes 3, 7, 15, 19, and 21. Both OH-2 and primary cells have a complex secondary translocation in which the IGK 3' enhancer is inserted between MYC and MAFB, resulting in dysregulation of both oncogenes. OH-2 provides a unique example of an HMCL and the corresponding primary tumor that are shown to share the same HRD genotype. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Vatsveen, Thea Kristin; Tian, Erming; Sundan, Anders; Borset, Magne] Norwegian Univ Sci & Technol, Fac Med, Dept Canc Res & Mol Med, N-7489 Trondheim, Norway. [Vatsveen, Thea Kristin; Glebov, Oleg] St Olavs Univ Hosp, Dept Pathol & Med Genet, Trondheim, Norway. [Kresse, Stine H.; Meza-Zepeda, Leonardo A.] Univ Oslo, Rikshosp, Radiumhosp, Dept Tumor Biol, N-0027 Oslo, Norway. [Meza-Zepeda, Leonardo A.] Univ Oslo, Norwegian Microarray Consortium, Dept Mol Biosci, Oslo, Norway. [Gabrea, Ana; Glebov, Oleg; Kuehl, W. Michael] NCI, Genet Branch, Bethesda, MD 20892 USA. [Borset, Magne] St Olavs Univ Hosp, Dept Immunol & Transfus Med, Trondheim, Norway. RP Vatsveen, TK (reprint author), Norwegian Univ Sci & Technol, Fac Med, Dept Canc Res & Mol Med, Olav Kyrres Gt 9, N-7489 Trondheim, Norway. EM thea.k.vatsveen@ntnu.no OI Borset, Magne/0000-0001-5179-2835 FU Norwegian Research Council [170637/V40]; Familien Blix'Fond; Intramural Research Program of the NIH; National Cancer Institute, Center for Cancer Research FX This work was supported by the Norwegian Research Council (Grant 170637/V40), Familien Blix'Fond, Rakel og Otto Bruuns legat and the University of Oslo (EMBIO), and also by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (W.M.K.). The genomic microarrays were provided by the Norwegian Microarray Consortium (NMC) at the national technology platform, and supported by the functional genomics programme (FUGE) in the Research Council of Norway. NR 23 TC 8 Z9 8 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD DEC PY 2009 VL 33 IS 12 BP 1670 EP 1677 DI 10.1016/j.leukres.2009.03.001 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 506LO UT WOS:000270776500016 PM 19395026 ER PT J AU Choi, AMK Reynolds, HY Colombini-Hatch, S Rothgeb, A Blaisdell, CJ Gail, DB AF Choi, Augustine M. K. Reynolds, Herbert Y. Colombini-Hatch, Sandra Rothgeb, Ann Blaisdell, Carol J. Gail, Dorothy B. TI NHLBI Workshop: Respiratory Medicine-Related Research Training for Adult and Pediatric Fellows SO LUNG LA English DT Review DE Physicians scientists; Respiratory research academic medicine; Pulmonary trainees ID SCIENTISTS; PULMONARY; CAREER AB The pulmonary physician-scientist has a special niche to generate basic research findings and apply them to a clinical disease and perhaps impact its medical care. The availability of new high throughput-based scientific technologies in the "omics era" has made this an opportune time for physician scientists to prepare and embark on an academic career in respiratory disease research. However, maintaining an adequate flow through the research pipeline of physician-scientist investigators studying respiratory system diseases is currently a challenge. There may not be a sufficient workforce emerging to capitalize on current research opportunities. The National Heart, Lung, and Blood Institute (NHLBI) organized a workshop to assess ways to attract and properly train advanced fellows to pursue research careers in adult and pediatric lung diseases. Participants included representatives from the various pulmonary training programs, respiratory-related professional societies, and NHLBI staff. Deliberation centered on present barriers that might affect interest in pursuing research training, devising better incentives to attract more trainees, and how current research support offered by the NHLBI and the Professional Societies (in partnership with Industry and Patient Support groups) might be better coordinated and optimized to ensure a continued pipeline of pulmonary investigators. Major recommendations offered are: (1) Attract trainees to pulmonary/critical care medicine-based research careers by increasing research exposure and opportunities for high school, college, and medical students. (2) Increase awareness of the outstanding physician-scientist role models in the lung community for trainees. (3) Facilitate mechanisms by which the lung community (NHLBI, professional societies, and partners) can better support and bridge senior fellows as they transition from Institutional Training Grants (T32) to Career Series (K) awards in their early faculty career development. C1 [Reynolds, Herbert Y.; Colombini-Hatch, Sandra; Blaisdell, Carol J.; Gail, Dorothy B.] NHLBI, Lung Biol & Dis Branch, Div Lung Dis, Bethesda, MD 20892 USA. [Choi, Augustine M. K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Rothgeb, Ann] NHLBI, Airway Biol & Dis Branch, Div Lung Dis, Bethesda, MD 20892 USA. RP Reynolds, HY (reprint author), NHLBI, Lung Biol & Dis Branch, Div Lung Dis, 6701 Rockledge Dr,Suite 10042,2 Rockledge Ctr,MSC, Bethesda, MD 20892 USA. EM Reynoldh@nhlbi.nih.gov NR 11 TC 6 Z9 6 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0341-2040 J9 LUNG JI Lung PD DEC PY 2009 VL 187 IS 6 BP 347 EP 366 DI 10.1007/s00408-009-9172-4 PG 20 WC Respiratory System SC Respiratory System GA 516LU UT WOS:000271544500001 PM 19763688 ER PT J AU Ferkol, T Zeitlin, P Abman, S Blaisdell, CJ O'Brodovich, H AF Ferkol, Thomas Zeitlin, Pamela Abman, Steven Blaisdell, Carol J. O'Brodovich, Hugh TI NHLBI Training Workshop Report: The Vanishing Pediatric Pulmonary Investigator and Recommendations for Recovery SO LUNG LA English DT Article DE Clinician scientist; Training pipeline ID PULMONOLOGY; FUTURE AB The adequacy of the pipeline of advanced pulmonary fellows to supply appropriately trained and committed researchers to enter academic careers was the major topic of a recently held National Heart Lung and Blood Institute NHLBI Workshop: Respiratory Medicine-Related Research Training for Adult and Pediatric Fellows. The special challenges and opportunities for the academic pediatric pulmonary trainee were discussed as part of this workshop and are presented as a companion article to the report by the full workshop. Surveys were conducted of pediatric chairs of academic departments and pediatric pulmonary training directors in the United States to examine the current status and opportunities for the pediatric pulmonary trainee. Strategies for recruitment and retention of talented young trainees and junior faculty are proposed. C1 [Blaisdell, Carol J.] NHLBI, NIH, Bethesda, MD 20892 USA. [Abman, Steven] Univ Colorado, Sch Med, Aurora, CO 80045 USA. [Zeitlin, Pamela] Johns Hopkins Sch Med, Eudowood Div Pediat Resp Sci, Baltimore, MD 21287 USA. [Ferkol, Thomas] Washington Univ, Sch Med, St Louis, MO 63110 USA. [O'Brodovich, Hugh] Stanford Sch Med, Stanford, CA 94305 USA. RP Ferkol, T (reprint author), NHLBI, NIH, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM ferkol_t@kids.wustl.edu; pzeitlin@jhmi.edu; Steven.Abman@UCHSC.edu; blaisdellcj@nhlbi.nih.gov; Hugh.OBrodovich@stanford.edu NR 8 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0341-2040 J9 LUNG JI Lung PD DEC PY 2009 VL 187 IS 6 BP 367 EP 374 DI 10.1007/s00408-009-9184-0 PG 8 WC Respiratory System SC Respiratory System GA 516LU UT WOS:000271544500002 PM 19806399 ER PT J AU Shmueli, K de Zwart, JA van Gelderen, P Li, TQ Dodd, SJ Duyn, JH AF Shmueli, Karin de Zwart, Jacco A. van Gelderen, Peter Li, Tie-Qiang Dodd, Stephen J. Duyn, Jeff H. TI Magnetic Susceptibility Mapping of Brain Tissue In Vivo Using MRI Phase Data SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE magnetic susceptibility mapping; phase imaging; brain anatomy; iron; orientation dependence; R(2)(star) ID HIGH-FIELD MRI; RESONANCE; IRON; CONTRAST; IMAGES; INHOMOGENEITY; DESIGN; GRAY; HEAD AB Phase images in susceptibility-weighted MRI of brain provide excellent contrast. However, the phase is affected by tissue geometry and orientation relative to the main magnetic field (B(0)), and phase changes extend beyond areas of altered susceptibility. Magnetic susceptibility, on the other hand, is an intrinsic tissue property, closely reflecting tissue composition. Therefore, recently developed inverse Fourier-based methods were applied to calculate susceptibility maps from high-resolution phase images acquired at a single orientation at 7 T in the human brain (in vivo and fixed) and at 11.7 T in fixed marmoset brain. In susceptibility images, the contrast of cortical layers was more consistent than in phase images and was independent of the structures' orientation relative to B(0). The contrast of iron-rich deep-brain structures (red nucleus and substantia nigra) in susceptibility images agreed more closely with iron-dominated R(2)(star) images than the phase image contrast, which extended outside the structures. The mean susceptibility in these regions was significantly correlated with their estimated iron content. Susceptibility maps calculated using this method overcome the orientation-dependence and non-locality of phase image contrast and seem to reflect underlying tissue composition. Susceptibility images should be easier to interpret than phase images and could improve our understanding of the sources of susceptibility contrast. Magn Reson Med 62: 1510-1522, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Shmueli, Karin; de Zwart, Jacco A.; van Gelderen, Peter; Li, Tie-Qiang; Duyn, Jeff H.] Natl Inst Neurol Disorders & Stroke, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Dodd, Stephen J.] Natl Inst Neurol Disorders & Stroke, Funct & Mol Metab Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Shmueli, K (reprint author), Natl Inst Neurol Disorders & Stroke, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,Bldg 10,Rm B1D-728, Bethesda, MD 20892 USA. EM shmuelik@mail.nih.gov RI Duyn, Jozef/F-2483-2010; Shmueli, Karin/B-9432-2017; OI Li, Tieqiang/0000-0002-6636-8938; Li, Tie-Qiang/0000-0002-4866-5904 FU National Institute of Neurological Disorders and Stroke; National Institutes of Health FX We thank Susan Guttman for her assistance with human subject experiments. This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. We thank the National Institutes of Health Fellows Editorial Board for their suggestions. NR 29 TC 183 Z9 187 U1 0 U2 16 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD DEC PY 2009 VL 62 IS 6 BP 1510 EP 1522 DI 10.1002/mrm.22135 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 523IX UT WOS:000272067600018 PM 19859937 ER PT J AU Kellman, P Chefd'hotel, C Lorenz, CH Mancini, C Arai, AE McVeigh, ER AF Kellman, Peter Chefd'hotel, Christophe Lorenz, Christine H. Mancini, Christine Arai, Andrew E. McVeigh, Elliot R. TI High Spatial and Temporal Resolution Cardiac Cine MRI from Retrospective Reconstruction of Data Acquired in Real Time Using Motion Correction and Resorting SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; heart; real-time; parallel MRI; SENSE; navigator; motion correction; nonrigid; myocardial function ID LEFT-VENTRICULAR VOLUME; BREATH-HOLD; IMAGE-RECONSTRUCTION; RESPIRATORY MOTION; RAPID EVALUATION; HEART; ANGIOGRAPHY; MASS; ENHANCEMENT; GRAPPA AB Cine MRI is used for assessing cardiac function and flow and is typically based on a breath-held, segmented data acquisition. Breath holding is particularly difficult for patients with congestive heart failure or in pediatric cases. Real-time imaging may be used without breath holding or ECG triggering. However, despite the use of rapid imaging sequences and accelerated parallel imaging, real-time imaging typically has compromised spatial and temporal resolution compared with gated, segmented breath-held studies. A new method is proposed that produces a cardiac cine across the full cycle, with both high spatial and temporal resolution from a retrospective reconstruction of data acquired over multiple heartbeats during free breathing. The proposed method was compared with conventional cine images in 10 subjects. The resultant image quality for the proposed method (4.2 +/- 0.4) without breath holding or gating was comparable to the conventional cine (4.4 +/- 0.5) on a five-point scale (P = n.s.). Motion-corrected averaging of real-time acquired cardiac images provides a means of attaining high-quality cine images with many of the benefits of real-time imaging, such as free-breathing acquisition and tolerance to arrhythmias. Magn Reson Med 62:1557-1564, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Kellman, Peter; Mancini, Christine; Arai, Andrew E.] NHLBI, Cardiac Energet Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Chefd'hotel, Christophe] Siemens Corp Res, Princeton, NJ USA. [Lorenz, Christine H.] Siemens Corp Res, Baltimore, MD USA. [McVeigh, Elliot R.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. RP Kellman, P (reprint author), NHLBI, Cardiac Energet Lab, NIH, DHHS, 10 Ctr Dr,MSC-1061,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM kellman@nih.gov FU NIH, National Heart, Lung, and Blood Institute; National Heart, Lung, and Blood Institute; Siemens Medical Solutions FX This research was supported by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute, and a Cooperative Research and Development Agreement between the National Heart, Lung, and Blood Institute and Siemens Medical Solutions. NR 29 TC 36 Z9 36 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD DEC PY 2009 VL 62 IS 6 BP 1557 EP 1564 DI 10.1002/mrm.22153 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 523IX UT WOS:000272067600022 PM 19780155 ER PT J AU Li, TQ Yao, B van Gelderen, P Merkle, H Dodd, S Talagala, L Koretsky, AP Duyn, J AF Li, Tie-Qiang Yao, Bing van Gelderen, Peter Merkle, Hellmut Dodd, Stephen Talagala, Lalith Koretsky, Alan P. Duyn, Jeff TI Characterization of T(2)(star) Heterogeneity in Human Brain White Matter SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE T(2)(star); heterogeneity; susceptibility; MRI contrast; iron; myelin; histology ID HIGH-FIELD MRI; MAGNETIZATION-TRANSFER; IRON CONTENT; DISEASE; TISSUE; OLIGODENDROCYTES; FERRITIN; RAT AB Recent in vivo MRI studies at 7.0 T have demonstrated extensive heterogeneity of T(2)(star) relaxation in white matter of the human man brain. In order to study the origin of this heterogeneity, we performed T(2)(star) measurements at 1.5, 3.0, and 7.0 T in normal volunteers. Formalin-fixed brain tissue specimens were also studied using T(2)(star)-weighted MRI, histologic staining, chemical analysis, and electron microscopy. We found that T(2)(star) relaxation rate (R(2)(star) = 1/T(2)(star)) in white matter in living human brain is linearly dependent on the main magnetic field strength, and the T(2)(star) heterogeneity in white matter observed at 7.0 T can also be detected, albeit more weakly, at 1.5 and 3.0 T. The T(2)(star) heterogeneity exists also in white matter of the formalin-fixed brain tissue specimens, with prominent differences between the major fiber bundles such as the cingulum (CG) and the superior corona radiata. The white matter specimen with substantia difference in T(2)(star) has no significant difference in the total iron content, as determined by chemical analysis. On the other hand, evidence from histologic staining and electron microscopy demonstrates these tissue specimens have apparent difference in myelin content and microstructure. Magn Reson Med 62:1652-1657, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Li, Tie-Qiang; Yao, Bing; van Gelderen, Peter; Merkle, Hellmut; Dodd, Stephen; Talagala, Lalith; Koretsky, Alan P.; Duyn, Jeff] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Li, TQ (reprint author), Karolinska Huddinge, Dept Med Phys, C2-63, S-14186 Stockholm, Sweden. EM tieqiang.li@karolinska.se RI Duyn, Jozef/F-2483-2010; 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 NIH, NINDS FX The authors acknowledge experimental assistance from Drs. K. Matsuda and S. Chen. This work was supported by the intramural research program of the NIH, NINDS. A Matlab program for calculating the surface order parameter is available by contacting the corresponding author. NR 29 TC 43 Z9 44 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD DEC PY 2009 VL 62 IS 6 BP 1652 EP 1657 DI 10.1002/mrm.22156 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 523IX UT WOS:000272067600032 PM 19859939 ER PT J AU Siegel, SJ Percopo, CM Dyer, KD Zhao, W Roth, VL Mercer, JM Rosenberg, HF AF Siegel, Steven J. Percopo, Caroline M. Dyer, Kimberly D. Zhao, Wei Roth, V. Louise Mercer, John M. Rosenberg, Helene F. TI RNase 1 genes from the family Sciuridae define a novel rodent ribonuclease cluster SO MAMMALIAN GENOME LA English DT Article ID PANCREATIC RIBONUCLEASE; A SUPERFAMILY; STRUCTURAL BASIS; HOST-DEFENSE; EVOLUTION; MAMMALS; PHYLOGENY; EXPANSION; PROTEIN AB The RNase A ribonucleases are a complex group of functionally diverse secretory proteins with conserved enzymatic activity. We have identified novel RNase 1 genes from four species of squirrel (order Rodentia, family Sciuridae). Squirrel RNase 1 genes encode typical RNase A ribonucleases, each with eight cysteines, a conserved CKXXNTF signature motif, and a canonical His(12)-Lys(41)-His(119) catalytic triad. Two alleles encode Callosciurus prevostii RNase 1, which include a Ser(18)a dagger"Pro, analogous to the sequence polymorphisms found among the RNase 1 duplications in the genome of Rattus exulans. Interestingly, although the squirrel RNase 1 genes are closely related to one another (77-95% amino acid sequence identity), the cluster as a whole is distinct and divergent from the clusters including RNase 1 genes from other rodent species. We examined the specific sites at which Sciuridae RNase 1s diverge from Muridae/Cricetidae RNase 1s and determined that the divergent sites are located on the external surface, with complete sparing of the catalytic crevice. The full significance of these findings awaits a more complete understanding of biological role of mammalian RNase 1s. C1 [Siegel, Steven J.; Percopo, Caroline M.; Dyer, Kimberly D.; Zhao, Wei; Rosenberg, Helene F.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Roth, V. Louise; Mercer, John M.] Duke Univ, Dept Biol, Durham, NC 27708 USA. RP Rosenberg, HF (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C215,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU NIAID DIR; National Science Foundation [DEB 9726855] FX This work was supported by NIAID DIR funding to HFR and National Science Foundation # DEB 9726855 to JMM and VLR. NR 30 TC 2 Z9 3 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD DEC PY 2009 VL 20 IS 11-12 BP 749 EP 757 DI 10.1007/s00335-009-9215-4 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 534NU UT WOS:000272905200005 PM 19771477 ER PT J AU Oguge, NO Durden, LA Keirans, JE Balami, HD Schwan, TG AF Oguge, N. O. Durden, L. A. Keirans, J. E. Balami, H. D. Schwan, T. G. TI Ectoparasites (sucking lice, fleas and ticks) of small mammals in southeastern Kenya SO MEDICAL AND VETERINARY ENTOMOLOGY LA English DT Article DE Ectoparasites; fleas; small mammals; sucking lice; ticks; Kenya ID SIPHONAPTERA; PLAGUE; WORLD AB During 1998-2000, at least 14 species (n = 309) of small mammals were live-trapped and examined for ectoparasites in moist forests of the Taita and Shimba Hills and drier savannah habitats of Nguruman, southeastern Kenya. Ectoparasites were recorded from 11 species of mammals. Five species of sucking lice [Hoplopleura inexpectans Johnson, H. intermedia Kellogg & Ferris, Polyplax reclinata (Nitzsch), P. waterstoni Bedford and Schizophthirus graphiuri Ferris], six species of fleas (Ctenophthalmus leptodactylous Hubbard, Dinopsyllus grypurus Jordan & Rothschild, D. lypusus Jordan & Rothschild, Hypsophthalmus campestris Jordan & Rothschild, Listropsylla basilewskyi Smit and Xiphiopsylla lippa Jordan) and at least six species of ticks (Amblyomma sp., Haemaphysalis sp., Ixodes sp., I. alluaudi Neumann, I. cumulatimpunctatus Schulze, I. muniensis Arthur & Burrow and Rhipicephalus sp.) were recorded from these hosts. Four of the five species of sucking lice were host specific whereas P. reclinata was recorded from two different species of white-toothed shrews, Crocidura spp. Although fleas and ticks were less host specific, C. leptodactylous, D. grypurus and I. cumulatimpunctatus were only recorded from the murid rodent Praomys delectorum (Thomas), Amblyomma sp. was only recorded from the nesomyid rodent Beamys hindei Thomas, Rhipicephalus sp. was only recorded from the murid Lemniscomys striatus (L.) and I. muniensis was only recorded from the dormouse Graphiurus microtis (Noack). More species of ectoparasites and significantly greater infestation prevalences were recorded from small mammals in moist habitats compared with those from the savannah habitat. At least one of the fleas recorded, D. lypusus, is a known vector of Yersinia pestis Lehmann & Neumann, the causative agent of plague, which is present in the region. C1 [Durden, L. A.; Balami, H. D.] Georgia So Univ, Dept Biol, Statesboro, GA 30460 USA. [Oguge, N. O.] Earthwatch Inst Kenya, Nairobi, Kenya. [Durden, L. A.; Keirans, J. E.] Georgia So Univ, Inst Arthropodol & Parasitol, Statesboro, GA 30460 USA. [Schwan, T. G.] NIAID, Rocky Mt Labs, Lab Zoonot Pathogens, Hamilton, MT 59840 USA. RP Durden, LA (reprint author), Georgia So Univ, Dept Biol, 69 Georgia Ave, Statesboro, GA 30460 USA. EM ldurden@georgiasouthern.edu FU NIH [AI 40729]; Division of Intramural Research; NIAID; NIH FX This work was supported in part by NIH grant AI 40729 and by the Division of Intramural Research, NIAID, NIH. We are grateful to Robert E. Lewis (Ames, Iowa, U.S.A.) for confirming the identity of the male specimen of Xiphiopsylla lippa. Bernard Agwanda (National Museums of Kenya) assisted with field collections of ectoparasites. NR 21 TC 15 Z9 15 U1 3 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-283X EI 1365-2915 J9 MED VET ENTOMOL JI Med. Vet. Entomol. PD DEC PY 2009 VL 23 IS 4 BP 387 EP 392 PG 6 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 522CG UT WOS:000271974700010 PM 19941604 ER PT J AU Paul, SM Chamberlin, AP Hatt, C Nayak, AV Danoff, JV AF Paul, Scott M. Chamberlin, Andrew P. Hatt, Charles Nayak, Amritha V. Danoff, Jerome V. TI Reliability, validity, and precision of an active stereophotogrammetry system for three-dimensional evaluation of the human torso SO MEDICAL ENGINEERING & PHYSICS LA English DT Article DE Stereophotogrammetry; Scoliosis; Anthropometry ID FETAL ALCOHOL SYNDROME; BREAST; RECONSTRUCTION; IMAGES AB To determine the reliability, stability, validity and precision of a stereophotogrammetry (SP) system for use in quantifying the complex three-dimensional structure of the human torso, we performed assessments of the system using images of geometric solids and a human-form mannequin. Analysis of geometric solids revealed excellent intra- and interrater reliability of the system for linear, surface area and volume measurements (r > 0.99, P < 0.001). Overall, no significant difference was found between SP and manual measurements (F = 4.23, P > 0.06). The system exhibited excellent stability in images of the mannequin over time (r > 0.99). The limit of precision (error > 5%) of the system to detect objects on the surface of the mannequin was estimated at an object size of 23.5 cm(2) for surface area and 32 mL for volume. These results demonstrate the capability of SP of the torso to be used as a reliable, stable and valid measure of torso morphology to be applied as a clinical outcome tool in studies of bony and soft tissue pathologies such as scoliosis, rib deformities, obesity or edema. Published by Elsevier Ltd on behalf of IPEM. C1 [Paul, Scott M.; Chamberlin, Andrew P.; Danoff, Jerome V.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Hatt, Charles] Michigan Tech Res Inst, Ann Arbor, MI USA. [Danoff, Jerome V.] George Washington Univ, Med Ctr, Dept Exercise Sci, Washington, DC 20037 USA. [Nayak, Amritha V.] Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA. RP Paul, SM (reprint author), NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. EM spaul@cc.nih.gov OI Paul, Scott/0000-0003-1274-6670 FU Intramural NIH HHS [Z99 CL999999] NR 16 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1350-4533 J9 MED ENG PHYS JI Med. Eng. Phys. PD DEC PY 2009 VL 31 IS 10 BP 1337 EP 1342 DI 10.1016/j.medengphy.2009.08.011 PG 6 WC Engineering, Biomedical SC Engineering GA 534UG UT WOS:000272922200018 PM 19819750 ER PT J AU Wang, SJ Yao, JH Liu, JM Petrick, N Van Uitert, RL Periaswamy, S Summers, RM AF Wang, Shijun Yao, Jianhua Liu, Jiamin Petrick, Nicholas Van Uitert, Robert L. Periaswamy, Senthil Summers, Ronald M. TI Registration of prone and supine CT colonography scans using correlation optimized warping and canonical correlation analysis SO MEDICAL PHYSICS LA English DT Article DE colon registration; correlation optimized warping; dynamic time warping; canonical correlation analysis; virtual colonoscopy ID FALSE POSITIVES; COLONIC POLYPS; VIRTUAL COLONOSCOPY; REDUCTION; CAD AB Purpose: In computed tomographic colonography (CTC), a patient will be scanned twice-Once supine and once prone-to improve the sensitivity for polyp detection. To assist radiologists in CTC reading, in this paper we propose an automated method for colon registration from supine and prone CTC scans. Methods: We propose a new colon centerline registration method for prone and supine CTC scans using correlation optimized warping (COW) and canonical correlation analysis (CCA) based on the anatomical structure of the colon. Four anatomical salient points on the colon are first automatically distinguished. Then correlation optimized warping is applied to the segments defined by the anatomical landmarks to improve the global registration based on local correlation of segments. The COW method was modified by embedding canonical correlation analysis to allow multiple features along the colon centerline to be used in our implementation. Results: We tested the COW algorithm on a CTC data set of 39 patients with 39 polyps (19 training and 20 test cases) to verify the effectiveness of the proposed COW registration method. Experimental results on the test set show that the COW method significantly reduces the average estimation error in a polyp location between supine and prone scans by 67.6%, from 46.27 +/- 52.97 to 14.98 mm +/- 11.41 mm, compared to the normalized distance along the colon centerline algorithm (p < 0.01). Conclusions: The proposed COW algorithm is more accurate for the colon centerline registration compared to the normalized distance along the colon centerline method and the dynamic time warping method. Comparison results showed that the feature combination of z-coordinate and curvature achieved lowest registration error compared to the other feature combinations used by COW. The proposed method is tolerant to centerline errors because anatomical landmarks help prevent the propagation of errors across the entire colon centerline. [DOI: 10.1118/1.3259727] C1 [Wang, Shijun; Yao, Jianhua; Liu, Jiamin; Summers, Ronald M.] NIH, Ctr Clin, Imaging Biomarkers & Comp Aided Diag Lab, Bethesda, MD 20892 USA. [Petrick, Nicholas] US FDA, NIBIB, CDRH, Lab Assessment Med Imaging Syst, Silver Spring, MD 20993 USA. [Van Uitert, Robert L.; Periaswamy, Senthil] iCAD Inc, Nashua, NH 03062 USA. RP Summers, RM (reprint author), NIH, Ctr Clin, Imaging Biomarkers & Comp Aided Diag Lab, Bldg 10,Room 1C368X,MSC 1182, Bethesda, MD 20892 USA. EM wangshi@cc.nih.gov; rms@nih.gov RI Wang, Shijun/E-5005-2010 FU NIH U.S. Food and Drug Administration FX This research was supported by the Intramural Research Programs of the NIH Clinical Center and the U.S. Food and Drug Administration (NP). We thank Dr. Perry Pickhardt, Dr. J. Richard Choi, and Dr. William Schindler for providing CT colonography data. NR 21 TC 20 Z9 21 U1 0 U2 2 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 EI 2473-4209 J9 MED PHYS JI Med. Phys. PD DEC PY 2009 VL 36 IS 12 BP 5595 EP 5603 DI 10.1118/1.3259727 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 524QJ UT WOS:000272157500024 PM 20095272 ER PT J AU Rouault, TA Zhang, DL Jeong, SY AF Rouault, Tracey A. Zhang, De-Liang Jeong, Suh Young TI Brain iron homeostasis, the choroid plexus, and localization of iron transport proteins SO METABOLIC BRAIN DISEASE LA English DT Article DE Choroid plexus; Iron transport; Blood brain barrier; Blood-CSF barrier; Ferroportin; Ceruloplasmin ID BARRIER; METABOLISM; RAT; CERULOPLASMIN; INVOLVEMENT; DEFICIENCY; ABSORPTION; DISEASE; CELLS; MICE AB Maintenance of appropriate iron homeostasis in the brain is important, but the mechanisms involved in brain iron uptake are incompletely understood. Here, we have analyzed where messenger RNAs that encode iron transport proteins are expressed in the brain, using the Allen Brain atlas, and we conclude that several important iron transporters are highly expressed in the choroid plexus. Based on recent estimates of the surface area of the choroid plexus and on MRI imaging studies of manganese uptake in the brain, we propose that the choroid plexus may have a much greater role than has been previously appreciated in brain iron transport. C1 [Rouault, Tracey A.; Zhang, De-Liang; Jeong, Suh Young] NICHHD, Program Mol Med, NIH, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Program Mol Med, NIH, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov OI Jeong, Suh Young/0000-0002-6376-7001; Zhang, Deliang/0000-0001-9478-5344 FU National Institute of Child Health and Human Development, Bethesda, MD FX This work was supported by the intramural program of the National Institute of Child Health and Human Development, Bethesda, MD. We thank David Darling for permission to use the choroid plexus schematic in Fig. 1. We are grateful to Dr. Samuel David for the permission to use ceruloplasmin null mice data. We also thank the Allan Brain Institute for use of their online materials. In situ hybridization figures were obtained from the Allen Mouse Brain Atlas [Internet]. Seattle (WA) Allen Institute for Brain Science. NR 36 TC 45 Z9 45 U1 0 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-7490 J9 METAB BRAIN DIS JI Metab. Brain Dis. PD DEC PY 2009 VL 24 IS 4 BP 673 EP 684 DI 10.1007/s11011-009-9169-y PG 12 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 527IQ UT WOS:000272361100011 PM 19851851 ER PT J AU Sassi, A Brichacek, B Hieny, S Yarovinsky, F Golding, H Grivel, JC Sher, A Margolis, L AF Sassi, Atfa Brichacek, Beda Hieny, Sara Yarovinsky, Felix Golding, Hana Grivel, Jean-Charles Sher, Alan Margolis, Leonid TI Toxoplasma gondii inhibits R5 HIV-1 replication in human lymphoid tissues ex vivo SO MICROBES AND INFECTION LA English DT Article DE HIV; Toxoplasma gondii; Cyclophilin; Ex vivo; Human lymphoid tissue ID GB-VIRUS-C; CXCR4-TROPIC HIV-1; INFECTION; SUPPRESSION; AIDS; COINFECTION; MACROPHAGES; MIP-1-ALPHA; CYTOKINES; MEASLES AB Critical events of HIV-1 pathogenesis occur in lymphoid tissues where HIV-1 is typically accompanied by infections with other pathogens (HIV co-pathogens). Co-pathogens greatly affect the clinical course of the disease and the transmission of HIV. The apicomplexan parasite Toxoplasma gondii is a common HIV co-pathogen associated with AIDS development. Here, we examined the interaction of T. gondii and HIV in coinfected human lymphoid tissue ex vivo. Both pathogens readily replicate in ex vivo infected blocks of human tonsillar tissue. Surprisingly, we found that live T. gondii preferentially inhibits R5 HIV-1 replication in coinfected tissues. This effect is reproduced by treatment of the tissue blocks with recombinant C-18, a T. gondii-encoded cyclophilin that binds to CCR5. These ex vivo findings raise the possibility that, in addition to being a co-factor in HIV disease, T. gondii may influence the outcome of viral infection by preferentially suppressing R5 variants. Published by Elsevier Masson SAS. C1 [Grivel, Jean-Charles] NICHHD, NIH, Sect Intercellular Interact, Program Phys Biol, Bethesda, MD 20892 USA. [Hieny, Sara; Sher, Alan] NIAID, Immunol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. [Yarovinsky, Felix] Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA. [Golding, Hana] Fed Food & Drug Adm, Lab Retrovirus Res, Bethesda, MD 20892 USA. RP Grivel, JC (reprint author), NICHHD, NIH, Sect Intercellular Interact, Program Phys Biol, 10 Ctr Dr,Room 9D58,Bldg 10, Bethesda, MD 20892 USA. EM grivelj@mail.nih.gov FU NIH, National Institute of Child Health; National Institute of Allergy and Infectious Diseases and Human Development FX We thank Dr. M. Santi and the entire staff of the Department of Pathology of Children's National Medical Center for their generous assistance in obtaining human tonsillar tissues. We also thank Dr. D. Kabat of the Department of Biochemistry and Molecular Biology and Proteomics Shared Resource, Oregon Health and Science University, Portland, OR, for providing JR-CSF. This research was supported, in part, by the Intramural Research Program of the NIH, National Institute of Child Health, the National Institute of Allergy and Infectious Diseases and Human Development and by the Intramural AIDS Targeted Anti-viral Program (IATAP) of the NIH. NR 30 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD DEC PY 2009 VL 11 IS 14-15 BP 1106 EP 1113 DI 10.1016/j.micinf.2009.08.004 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 539FL UT WOS:000273238900003 PM 19671446 ER PT J AU Cattin, AL Le Beyec, J Barreau, F Saint-Just, S Houllier, A Gonzalez, FJ Robine, S Pincon-Raymond, M Cardot, P Lacasa, M Ribeiro, A AF Cattin, Anne-Laure Le Beyec, Johanne Barreau, Frederick Saint-Just, Susan Houllier, Anne Gonzalez, Frank J. Robine, Sylvie Pincon-Raymond, Martine Cardot, Philippe Lacasa, Michel Ribeiro, Agnes TI Hepatocyte Nuclear Factor 4 alpha, a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID A-IV GENE; COLORECTAL-CANCER CELLS; BETA-CATENIN; POLY(ADP-RIBOSE) POLYMERASE-1; TIGHT JUNCTIONS; E-CADHERIN; EXPRESSION; RECEPTOR; DIFFERENTIATION; MICE AB Hepatocyte nuclear factor 4 alpha (HNF-4 alpha) is a transcription factor which is highly expressed in the intestinal epithelium from duodenum to colon and from crypt to villus. The homeostasis of this constantly renewing epithelium relies on an integrated control of proliferation, differentiation, and apoptosis, as well as on the functional architecture of the epithelial cells. In order to determine the consequences of HNF-4 alpha loss in the adult intestinal epithelium, we used a tamoxifen-inducible Cre-loxP system to inactivate the Hnf-4a gene. In the intestines of adult mice, loss of HNF-4 alpha led to an increased proliferation in crypts and to an increased expression of several genes controlled by the Wnt/beta-catenin system. This control of the Wnt/beta-catenin signaling pathway by HNF-4 alpha was confirmed in vitro. Cell lineage was affected, as indicated by an increased number of goblet cells and an impairment of enterocyte and enteroendocrine cell maturation. In the absence of HNF-4 alpha, cell-cell junctions were destabilized and paracellular intestinal permeability increased. Our results showed that HNF-4 alpha modulates Wnt/beta-catenin signaling and controls intestinal epithelium homeostasis, cell function, and cell architecture. This study indicates that HNF-4 alpha regulates the intestinal balance between proliferation and differentiation, and we hypothesize that it might act as a tumor suppressor. C1 [Cattin, Anne-Laure; Le Beyec, Johanne; Saint-Just, Susan; Houllier, Anne; Pincon-Raymond, Martine; Cardot, Philippe; Lacasa, Michel; Ribeiro, Agnes] Univ Paris 06, Ctr Rech Cordeliers, UMRS 872, F-75006 Paris, France. [Cattin, Anne-Laure; Le Beyec, Johanne; Saint-Just, Susan; Houllier, Anne; Pincon-Raymond, Martine; Cardot, Philippe; Lacasa, Michel; Ribeiro, Agnes] INSERM, U872, F-75006 Paris, France. [Cattin, Anne-Laure; Le Beyec, Johanne; Saint-Just, Susan; Houllier, Anne; Pincon-Raymond, Martine; Cardot, Philippe; Lacasa, Michel; Ribeiro, Agnes] Univ Paris 05, UMRS 872, F-75006 Paris, France. [Barreau, Frederick] EPHE, Pharmacol Cellulaire & Mol Lab, F-75006 Paris, France. [Saint-Just, Susan] Inst Curie, CNRS, UMR Morphogenesis & Intracellular Signaling 144, F-75231 Paris, France. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Robine, Sylvie] Univ Paris Diderot, Hop Robert Debre, AP HP, INSERM,Serv Gastroenterol,UMR S843, Paris, France. RP Ribeiro, A (reprint author), Univ Paris 06, Ctr Rech Cordeliers, UMRS 872, F-75006 Paris, France. EM agnes.ribeiro-pillet@crc.jussieu.fr FU INSERM, France; Pierre & Marie Curie University, Paris, France; Ministere de l'Enseignement Superieur et de la Recherche FX This work was supported by INSERM, France, and Pierre & Marie Curie University, Paris, France. A.-L. Cattin is the recipient of a doctoral fellowship from the Ministere de l'Enseignement Superieur et de la Recherche. NR 54 TC 58 Z9 61 U1 0 U2 14 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC 1 PY 2009 VL 29 IS 23 BP 6294 EP 6308 DI 10.1128/MCB.00939-09 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 516AF UT WOS:000271513300012 PM 19805521 ER PT J AU Moayeri, M Leppla, SH AF Moayeri, Mahtab Leppla, Stephen H. TI Cellular and systemic effects of anthrax lethal toxin and edema toxin SO MOLECULAR ASPECTS OF MEDICINE LA English DT Review DE Anthrax; Lethal toxin; Edema toxin; Pathogenesis; Animal models ID T-LYMPHOCYTE ACTIVATION; BACILLUS-ANTHRACIS; MURINE MACROPHAGES; SIGNALING PATHWAYS; IN-VIVO; INDUCED CYTOTOXICITY; DENDRITIC CELLS; CASPASE-1 ACTIVATION; TREATED MACROPHAGES; INHALATION ANTHRAX AB Anthrax lethal toxin (LT) and edema toxin (ET) are the major virulence factors of anthrax and can replicate the lethality and symptoms associated with the disease. This review provides an overview of our current understanding of anthrax toxin effects in animal models and the cytotoxicity (necrosis and apoptosis) induced by LT in different cells. A brief reexamination of early historic findings on toxin in vivo effects in the context of our current knowledge is also presented. Published by Elsevier Ltd. C1 [Moayeri, Mahtab; Leppla, Stephen H.] NIAID, Bacterial Toxins & Therapeut Sect, NIH, Bethesda, MD 20892 USA. RP Moayeri, M (reprint author), NIAID, Bacterial Toxins & Therapeut Sect, NIH, Bldg 33,Room 1W20B, Bethesda, MD 20892 USA. EM mmoayeri@niaid.nih.gov; sleppla@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000929-05] NR 146 TC 143 Z9 145 U1 3 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0098-2997 EI 1872-9452 J9 MOL ASPECTS MED JI Mol. Asp. Med. PD DEC PY 2009 VL 30 IS 6 SI SI BP 439 EP 455 DI 10.1016/j.mam.2009.07.003 PG 17 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 532NE UT WOS:000272755000012 PM 19638283 ER PT J AU Andres, AM Hubisz, MJ Indap, A Torgerson, DG Degenhardt, JD Boyko, AR Gutenkunst, RN White, TJ Green, ED Bustamante, CD Clark, AG Nielsen, R AF Andres, Aida M. Hubisz, Melissa J. Indap, Amit Torgerson, Dara G. Degenhardt, Jeremiah D. Boyko, Adam R. Gutenkunst, Ryan N. White, Thomas J. Green, Eric D. Bustamante, Carlos D. Clark, Andrew G. Nielsen, Rasmus TI Targets of Balancing Selection in the Human Genome SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE overdominance; frequency-dependent selection; heterosis; human evolution; population genetics; human diversity ID HISTOCOMPATIBILITY COMPLEX LOCI; NATURAL-SELECTION; GENETIC-VARIATION; NUCLEOTIDE SUBSTITUTION; OVERDOMINANT SELECTION; CYSTIC-FIBROSIS; HONEY-BEES; POLYMORPHISM; POPULATION; EVOLUTION AB Balancing selection is potentially an important biological force for maintaining advantageous genetic diversity in populations, including variation that is responsible for long-term adaptation to the environment. By serving as a means to maintain genetic variation, it may be particularly relevant to maintaining phenotypic variation in natural populations. Nevertheless, its prevalence and specific targets in the human genome remain largely unknown. We have analyzed the patterns of diversity and divergence of 13,400 genes in two human populations using an unbiased single-nucleotide polymorphism data set, a genome-wide approach, and a method that incorporates demography in neutrality tests. We identified an unbiased catalog of genes with signatures of long-term balancing selection, which includes immunity genes as well as genes encoding keratins and membrane channels; the catalog also shows enrichment in functional categories involved in cellular structure. Patterns are mostly concordant in the two populations, with a small fraction of genes showing population-specific signatures of selection. Power considerations indicate that our findings represent a subset of all targets in the genome, suggesting that although balancing selection may not have an obvious impact on a large proportion of human genes, it is a key force affecting the evolution of a number of genes in humans. C1 [Andres, Aida M.; Green, Eric D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Andres, Aida M.; Torgerson, Dara G.; Green, Eric D.; Clark, Andrew G.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. [Hubisz, Melissa J.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Indap, Amit; Degenhardt, Jeremiah D.; Boyko, Adam R.; Gutenkunst, Ryan N.; Bustamante, Carlos D.] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY 14853 USA. [White, Thomas J.] Celera Diagnost, Alameda, CA USA. [Nielsen, Rasmus] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Nielsen, Rasmus] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. RP Andres, AM (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM andresa@mail.nih.gov RI Nielsen, Rasmus/D-4405-2009; Andres, Aida/B-4088-2014 OI Nielsen, Rasmus/0000-0003-0513-6591; Andres, Aida/0000-0002-8590-9672 FU National Institutes of Health [HL072904, GM065509] FX This work was supported by the National Institutes of Health (grants HL072904 and GM065509 to A. M. A. and A. G. C.) This work was supported in part by the Intramural Program of the National Human Genome Research Institute, National Institutes of Health. NR 68 TC 112 Z9 112 U1 0 U2 38 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD DEC PY 2009 VL 26 IS 12 BP 2755 EP 2764 DI 10.1093/molbev/msp190 PG 10 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 520CV UT WOS:000271818500010 PM 19713326 ER PT J AU Liu, L Rao, JN Zou, TT Xiao, L Wang, PY Turner, DJ Gorospe, M Wang, JY AF Liu, Lan Rao, Jaladanki N. Zou, Tongtong Xiao, Lan Wang, Peng-Yuan Turner, Douglas J. Gorospe, Myriam Wang, Jian-Ying TI Polyamines Regulate c-Myc Translation through Chk2-dependent HuR Phosphorylation SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID RNA-BINDING PROTEIN; INTESTINAL EPITHELIAL-CELLS; AU-RICH ELEMENTS; MESSENGER-RNA; IEC-6 CELLS; GENE-EXPRESSION; MUCOSAL GROWTH; DEPLETION; INHIBITION; P53 AB All mammalian cells depend on polyamines for normal growth and proliferation, but the exact roles of polyamines at the molecular level remain largely unknown. The RNA-binding protein HuR modulates the stability and translation of many target mRNAs. Here, we show that in rat intestinal epithelial cells (IECs), polyamines enhanced HuR association with the 3'-untranslated region of the c-Myc mRNA by increasing HuR phosphorylation by Chk2, in turn promoting c-Myc translation. Depletion of cellular polyamines inhibited Chk2 and reduced the affinity of HuR for c-Myc mRNA; these effects were completely reversed by addition of the polyamine putrescine or by Chk2 overexpression. In cells with high content of cellular polyamines, HuR silencing or Chk2 silencing reduced c-Myc translation and c-Myc expression levels. Our findings demonstrate that polyamines regulate c-Myc translation in IECs through HuR phosphorylation by Chk2 and provide new insight into the molecular functions of cellular polyamines. C1 [Liu, Lan; Rao, Jaladanki N.; Zou, Tongtong; Xiao, Lan; Wang, Peng-Yuan; Turner, Douglas J.; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. [Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Liu, Lan; Rao, Jaladanki N.; Zou, Tongtong; Xiao, Lan; Wang, Peng-Yuan; Turner, Douglas J.; Wang, Jian-Ying] Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Wang, JY (reprint author), Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. EM jwang@smail.umaryland.edu FU Department of Veterans Affairs; National Institutes of Health [DK-57819, DK-61972, DK-68491] FX This work was supported by a Merit Review grant (to J.-Y.W.) from the Department of Veterans Affairs and by National Institutes of Health grants DK-57819, DK-61972, and DK-68491 (to J.-Y.W.). J.-Y.W. is a Research Career Scientist, Medical Research Service, U.S. Department of Veterans Affairs. M.G. is supported by the National Institute on Aging-Intramural Research Program, National Institutes of Health. NR 72 TC 47 Z9 50 U1 1 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD DEC 1 PY 2009 VL 20 IS 23 BP 4885 EP 4898 DI 10.1091/mbc.E09-07-0550 PG 14 WC Cell Biology SC Cell Biology GA 528TR UT WOS:000272470400002 PM 19812253 ER PT J AU Dey, A Nishiyama, A Karpova, T McNally, J Ozato, K AF Dey, Anup Nishiyama, Akira Karpova, Tatiana McNally, James Ozato, Keiko TI Brd4 Marks Select Genes on Mitotic Chromatin and Directs Postmitotic Transcription SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID BROMODOMAIN PROTEIN BRD4; RNA-POLYMERASE-II; P-TEFB; HISTONE MODIFICATIONS; ACETYLATED CHROMATIN; CELL-CYCLE; IN-VIVO; CHROMOSOMES; MITOSIS; EXPRESSION AB On entry into mitosis, many transcription factors dissociate from chromatin, resulting in global transcriptional shutdown. During mitosis, some genes are marked to ensure the inheritance of their expression in the next generation of cells. The nature of mitotic gene marking, however, has been obscure. Brd4 is a double bromodomain protein that localizes to chromosomes during mitosis and is implicated in holding mitotic memory. In interphase, Brd4 interacts with P-TEFb and functions as a global transcriptional coactivator. We found that throughout mitosis, Brd4 remained bound to the transcription start sites of many M/G1 genes that are programmed to be expressed at the end of, or immediately after mitosis. In contrast, Brd4 did not bind to genes that are expressed at later phases of cell cycle. Brd4 binding to M/G1 genes increased at telophase, the end phase of mitosis, coinciding with increased acetylation of histone H3 and H4 in these genes. Increased Brd4 binding was accompanied by the recruitment of P-TEFb and de novo M/G1 gene transcription, the events impaired in Brd4 knockdown cells. In sum, Brd4 marks M/G1 genes for transcriptional memory during mitosis, and upon exiting mitosis, this mark acts as a signal for initiating their prompt transcription in daughter cells. C1 [Dey, Anup; Nishiyama, Akira; Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, Program Genom Differentiat, Bethesda, MD 20892 USA. [Karpova, Tatiana; McNally, James] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, Program Genom Differentiat, Bethesda, MD 20892 USA. EM ozatok@nih.gov NR 45 TC 108 Z9 109 U1 3 U2 8 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD DEC 1 PY 2009 VL 20 IS 23 BP 4899 EP 4909 DI 10.1091/mbc.E09-05-0380 PG 11 WC Cell Biology SC Cell Biology GA 528TR UT WOS:000272470400003 PM 19812244 ER PT J AU Amiott, EA Cohen, MM Saint-Georges, Y Weissman, AM Shaw, JM AF Amiott, Elizabeth A. Cohen, Mickael M. Saint-Georges, Yann Weissman, Allan M. Shaw, Janet M. TI A Mutation Associated with CMT2A Neuropathy Causes Defects in Fzo1 GTP Hydrolysis, Ubiquitylation, and Protein Turnover SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MARIE-TOOTH-DISEASE; REGULATES MITOCHONDRIAL MORPHOLOGY; CLASS-V-MYOSIN; SACCHAROMYCES-CEREVISIAE; IN-VITRO; MITOFUSIN-2 MUTATIONS; MAMMALIAN HOMOLOGS; BUDDING YEAST; FUSION; MFN2 AB Charcot-Marie-Tooth disease type 2A (CMT2A) is caused by mutations in the gene MFN2 and is one of the most common inherited peripheral neuropathies. Mfn2 is one of two mammalian mitofusin GTPases that promote mitochondrial fusion and maintain organelle integrity. It is not known how mitofusin mutations cause axonal degeneration and CMT2A disease. We used the conserved yeast mitofusin FZO1 to study the molecular consequences of CMT2A mutations on Fzo1 function in vivo and in vitro. One mutation (analogous to the CMT2A I213T substitution in the GTPase domain of Mfn2) not only abolishes GTP hydrolysis and mitochondrial membrane fusion but also reduces Mdm30-mediated ubiquitylation and degradation of the mutant protein. Importantly, complexes of wild type and the mutant Fzo1 protein are GTPase active and restore ubiquitylation and degradation of the latter. These studies identify diverse and unexpected effects of CMT2A mutations, including a possible role for mitofusin ubiquitylation and degradation in CMT2A pathogenesis, and provide evidence for a novel link between Fzo1 GTP hydrolysis, ubiquitylation, and mitochondrial fusion. C1 [Amiott, Elizabeth A.; Shaw, Janet M.] Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA. [Cohen, Mickael M.; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. [Saint-Georges, Yann] Univ Paris 11, Inst Genet & Microbiol, F-91405 Orsay, France. RP Shaw, JM (reprint author), Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA. EM shaw@biochem.utah.edu RI Cohen, Mickael/F-4122-2011; OI Saint-Georges-Chaumet, Yann/0000-0002-1123-254X FU United Mitochondrial Disease Foundation [UMDF 08-064]; National Institutes of Health [5 T32 HD07576-22, GM-53466]; Charcot-Marie-Tooth Association; National Center for Research Resources [M01-RR00064] FX We thank Huyen Bui for preliminary work with the L819V mutant, Jane Macfarlane for expertise in mutagenesis and plasmid construction, Adam Day for technical assistance, and J. Michael McCaffery at the Integrated Imaging Center of Johns Hopkins University for TEM analysis. E. A. A. is currently supported by a research grant from the United Mitochondrial Disease Foundation (UMDF 08-064 Mitochondrial Fusion Defects in Neurological Disease) and previously received support from the National Institutes of Health T32 institutional training grant 5 T32 HD07576-22. Additional research support was provided by the Charcot-Marie-Tooth Association (Y.S.-G.), the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (to A. M. W.), and National Institutes of Health grant GM-53466 (to J.M.S.). Support for sequencing, antibody, and oligonucleotide services at the University of Utah is provided by a National Center for Research Resources grant (M01-RR00064; to L. Betz, P. I.). NR 72 TC 28 Z9 29 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD DEC 1 PY 2009 VL 20 IS 23 BP 5026 EP 5035 DI 10.1091/mbc.E09-07-0622 PG 10 WC Cell Biology SC Cell Biology GA 528TR UT WOS:000272470400014 PM 19812251 ER PT J AU Sun, F Chan, EL Wu, ZL Yang, XJ Marquez, VE Yu, Q AF Sun, Feng Chan, Eli Wu, Zhenlong Yang, Xiaojing Marquez, Victor E. Yu, Qiang TI Combinatorial pharmacologic approaches target EZH2-mediated gene repression in breast cancer cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID HISTONE DEACETYLASE INHIBITION; EMBRYONIC STEM-CELLS; GROUP PROTEIN EZH2; DNA METHYLATION; PROSTATE-CANCER; DEVELOPMENTAL GENES; COLORECTAL-CANCER; 5-AZA-2'-DEOXYCYTIDINE; DEMETHYLATION; PATHWAY AB Polycomb protein EZH2-mediated gene silencing is implicated in breast tumorigenesis through methylation of histone H3 on Lysine 27 (H3K27). We have previously shown that S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A can modulate histone methylation and disrupt EZH2 complex. Here, we used 3-deazaneplanocin A, together with other chromatin remodeling agents, as well as RNA interference-mediated EZH2 depletion, to probe the role of EZH2 in coordination with other epigenetic components in gene regulation in breast cancer cells. Through genome-wide gene expression analysis, coupled with extensive chromatin immunoprecipitation analysis of histone modifications, we have identified a variety of gene sets that are regulated either by EZH2 alone or through the coordinated action of EZH2 with HDAC and/or DNA methylation. We further found that tumor antigen GAGEs were regulated by distinct epigenetic mechanisms in a cell context-dependent manner, possibly reflecting mechanistic heterogeneity in breast cancer. Intriguingly, we found that EZH2 regulates a remarkable cohort of genes whose functions are highly enriched in immunoresponse and autocrine inflammation network, and that their transcriptional activation upon EZH2 perturbation is cancer specific, revealing a potential novel role of EZH2 in regulating cancer immunity. These findings show the complexity and diversity of epigenetic regulation in human cancer and underscore the importance for developing combinatorial pharmacologic approaches for effective epigenetic gene reactivation. [Mol Cancer Ther 2009;8(12):3191-202] C1 [Sun, Feng; Wu, Zhenlong; Yang, Xiaojing; Yu, Qiang] ASTAR, Genome Inst Singapore, Singapore 138672, Singapore. [Sun, Feng; Chan, Eli] Natl Univ Singapore, Dept Pharm, Singapore 117548, Singapore. [Yu, Qiang] Natl Univ Singapore, Dept Physiol, Singapore 117548, Singapore. [Marquez, Victor E.] NCI, Med Chem Lab, Frederic, MD USA. RP Yu, Q (reprint author), ASTAR, Genome Inst Singapore, 60 Biopolis St,02-01 Genome, Singapore 138672, Singapore. EM yuq@gis.a-star.edu.sg RI Yang, Xiaojing/G-9201-2012 FU A*Star [GIS/06-711101]; Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX Grant support: A*Star grant GIS/06-711101 (Q. Yu). V. Marquez is supported by the intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 42 TC 38 Z9 39 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD DEC PY 2009 VL 8 IS 12 BP 3191 EP 3202 DI 10.1158/1535-7163.MCT-09-0479 PG 12 WC Oncology SC Oncology GA 531EW UT WOS:000272647500003 PM 19934278 ER PT J AU Olivo-Marston, SE Hursting, SD Lavigne, J Perkins, SN Maarouf, RS Yakar, S Harris, CC AF Olivo-Marston, Susan E. Hursting, Stephen D. Lavigne, Jackie Perkins, Susan N. Maarouf, Rami S. Yakar, Shoshana Harris, Curtis C. TI Genetic Reduction of Circulating Insulin-Like Growth Factor-1 Inhibits Azoxymethane-Induced Colon Tumorigenesis in Mice SO MOLECULAR CARCINOGENESIS LA English DT Article DE IGF-1; colon; azoxymethane ID IGF-BINDING PROTEIN-3; ABERRANT CRYPT FOCI; POSTNATAL-DEVELOPMENT; TUMOR-DEVELOPMENT; CANCER; CARCINOGENESIS; RISK; CHEMOPREVENTION; SUSCEPTIBILITY; ACTIVATION AB High levels of insulin-like growth factor-1 (IGF-1) have been associated with a significant increase in colon cancer risk. Additionally, IGF-1 inhibits apoptosis and stimulates proliferation of colonic epithelial cells in vitro. Unfortunately, IGF-1 knockout mice have severe developmental abnormalities and most do not survive, making it difficult to study how genetic ablation of IGF-1 affects colon tumorigenesis. To test the hypothesis that inhibition of IGF-1 prevents colon tumorigenesis, we utilized a preexisting mouse model containing a deletion of the igf1 gene in the liver through a Cre//oxP system. These liver-specific IGF-1 deficient (LID) mice display a 50-75% reduction in circulating IGF-1 levels. We conducted a pilot study to assess the impact of liver-specific IGF-1 deficiency on azoxymethane (AOM)-induced colon tumors. LID mice had a significant inhibition of colon tumor multiplicity in the proximal area of the colon compared to their wild-type littermates. We examined markers of proliferation and apoptosis in the colons of the LID and wild-type mice to see if these were consistent with tumorigenesis. We observed a decrease in proliferation in the colons of the LID mice and an increase in apoptosis. Finally, we examined cytokine levels to determine whether IGF-1 interacts with inflammatory pathways to affect colon tumorigenesis. We observed a significant reduction in the levels of 7 out of 10 cytokines that were measured in the LID mice as compared to wild-type littermates. Results from this pilot study support the hypothesis that reductions in circulating IGF-1 levels may prevent colon tumorigenesis and affect both proliferation and apoptosis. Future experiments will investigate downstream genes of the IGF-1 receptor. (C) 2009 Wiley-Liss, Inc. C1 [Olivo-Marston, Susan E.; Maarouf, Rami S.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hursting, Stephen D.; Perkins, Susan N.] Univ Texas Austin, Austin, TX 78712 USA. [Hursting, Stephen D.] Univ Texas MD Anderson Canc Ctr, Smithville, TX USA. [Lavigne, Jackie] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Yakar, Shoshana] Mt Sinai Sch Med, New York, NY USA. RP Olivo-Marston, SE (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37,Room 3054,37 Convent Dr,MSC 4258, Bethesda, MD 20892 USA. FU Lisa Riffle and the Animal Care Facility in Frederick, Maryland FX We thank Lisa Riffle and the Animal Care Facility in Frederick, Maryland, for their Support and work on this study. NR 31 TC 26 Z9 27 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD DEC PY 2009 VL 48 IS 12 BP 1071 EP 1076 DI 10.1002/mc.20577 PG 6 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 529PB UT WOS:000272528600001 PM 19760669 ER PT J AU Hewitt, SC O'Brien, JE Jameson, JL Kissling, GE Korach, KS AF Hewitt, Sylvia C. O'Brien, Jeanne E. Jameson, J. Larry Kissling, Grace E. Korach, Kenneth S. TI Selective Disruption of ER alpha DNA-Binding Activity Alters Uterine Responsiveness to Estradiol SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; DIFFERENTIAL EXPRESSION PATTERNS; BREAST-CANCER; TARGET GENES; IN-VIVO; WNT; UTERUS; GROWTH; PATHWAY AB In vitro models have been used to demonstrate that estrogen receptors (ERs) can regulate estrogen-responsive genes either by directly interacting with estrogen-responsive element (ERE) DNA motifs or by interacting with other transcription factors such as AP1. In this study, we evaluated estrogen (E(2))-dependent uterine gene profiles by microarray in the KIKO mouse, an in vivo knock-in mouse model that lacks the DNA-binding function of ER alpha and is consequently restricted to non-ERE-mediated responses. The 2- or 24-h E(2)-mediated uterine gene responses were distinct in wild-type (WT), KIKO, and alpha ERKO genotypes, indicating that unique sets of genes are regulated by ERE and non-ERE pathways. After 2 h E(2) treatment, 38% of the WT transcripts were also regulated in the KIKO, demonstrating that the tethered mechanism does operate in this in vivo model. Surprisingly, 1438 E(2)-regulated transcripts were unique in the KIKO mouse and were not seen in either WT or alpha ERKO. Pathway analyses revealed that some canonical pathways, such as the Jak/Stat pathway, were affected in a similar manner by E(2) in WT and KIKO. In other cases, however, the WT and KIKO differed. One example is the Wnt/beta-catenin pathway; this pathway was impacted, but different members of the pathway were regulated by E(2) or were regulated in a different manner, consistent with differences in biological responses. In summary, this study provides a comprehensive analysis of uterine genes regulated by E(2) via ERE and non-ERE pathways. (Molecular Endocrinology 23: 2111-2116, 2009) C1 [Hewitt, Sylvia C.; Korach, Kenneth S.] NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [O'Brien, Jeanne E.; Jameson, J. Larry] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Hewitt, SC (reprint author), NIEHS, Reprod & Dev Toxicol Lab, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM curtiss@niehs.nih.gov OI Jameson, James/0000-0001-9538-4059; Korach, Kenneth/0000-0002-7765-418X FU National Institutes of Health (NIH), National Institute of Environmental Health Sciences [PO1 HD21921] FX This work was supported by in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences, and also by NIH Grant PO1 HD21921. NR 26 TC 25 Z9 26 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD DEC PY 2009 VL 23 IS 12 BP 2111 EP 2116 DI 10.1210/me.2009-0356 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 524IR UT WOS:000272137500017 PM 19812388 ER PT J AU Acchione, M Lipschultz, CA DeSantis, ME Shanmuganathan, A Li, M Wlodawer, A Tarasov, S Smith-Gill, SJ AF Acchione, Mauro Lipschultz, Claudia A. DeSantis, Morgan E. Shanmuganathan, Aranganathan Li, Mi Wlodawer, Alexander Tarasov, Sergey Smith-Gill, Sandra J. TI Light chain somatic mutations change thermodynamics of binding and water coordination in the HyHEL-10 family of antibodies SO MOLECULAR IMMUNOLOGY LA English DT Article DE Enthalpy; Van't Hoff; Affinity maturation; CDR; Flexibility; Glycine; Water; X-ray crystallography ID STRUCTURAL CONSEQUENCES; MONOCLONAL-ANTIBODIES; IMMUNE-RESPONSE; PROTEIN ANTIGEN; AFFINITY; LYSOZYME; COMPLEX; FLEXIBILITY; MOLECULES; SPECIFICITY AB Thermodynamic and structural studies addressed the increased affinity due to L-chain somatic mutations in the HyHEL-10 family of affinity matured IgG antibodies, using ITC, SPR with van't Hoff analysis, and X-ray crystallography. When compared to the parental antibody H26L26, the H26L10 and H26L8 chimeras binding to lysozyme showed an increase in favorable Delta G degrees of -1.2 +/- 0.1 kcal mol(-1) and -1.3 +/- 0.1 kcal mol(-1), respectively. Increase in affinity of the H26L10 chimera was due to a net increase in favorable enthalpy change with little difference in change in entropy compared to H26L26. The H26L8 chimera exhibited the greatest increase in favorable enthalpy but also showed an increase in unfavorable entropy change, with the result being that the affinities of both chimeras were essentially equivalent. Site-directed L-chain mutants identified the shared somatic mutation S30G as the dominant contributor to increasing affinity to lysozyme. This mutation was not influenced by H-chain somatic mutations. Residue 30L is at the periphery of the binding interface and S30G effects an increase in hydrophobicity and decrease in H-bonding ability and size, but does not make any new energetically important antigen contacts. A new 1.2-angstrom structure of the H10L10-HEL complex showed changes in the pattern of both inter- and intra-molecular water bridging with no other significant structural alterations near the binding interface compared to the H26L26-HEL complex. These results highlight the necessity for investigating both the structure and the thermodynamics associated with introduced mutations, in order to better assess and understand their impact on binding. Furthermore, it provides an important example of how backbone flexibility and water-bridging may favorably influence the thermodynamics of an antibody-antigen interaction. (C) 2009 Published by Elsevier Ltd. C1 [Acchione, Mauro; Lipschultz, Claudia A.; DeSantis, Morgan E.; Shanmuganathan, Aranganathan; Smith-Gill, Sandra J.] NCI, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Li, Mi; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Li, Mi] SAIC Frederick, Basic Res Program, Frederick, MD USA. [Tarasov, Sergey] Biophys Resource Struct Biophys Lab, Frederick, MD USA. RP Smith-Gill, SJ (reprint author), NCI, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21701 USA. EM SmithGiS@mail.nih.gov FU U.S. Department of Energy [W-31-109-Eng-38]; National Cancer Institute, NIH [HHSN261200800001E] FX Diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamline 22-BM, located at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. We thank Dr. Rob Walter for his assistance in the data collection. This project was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and in part with Federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 51 TC 17 Z9 17 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD DEC PY 2009 VL 47 IS 2-3 BP 457 EP 464 DI 10.1016/j.molimm.2009.08.018 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 537HK UT WOS:000273103700036 PM 19781789 ER PT J AU Kino, T Chrousos, GP AF Kino, Tomoshige Chrousos, George P. TI Tumor-associated, Estrogen Receptor-related Antigen EBAG9: Linking Intracellular Vesicle Trafficking, Immune Homeostasis, and Malignancy SO MOLECULAR INTERVENTIONS LA English DT Editorial Material ID CELL-DEATH; SISO CELLS; T-CELLS; CANCER; GROWTH; RCAS1; MECHANISMS; EXPRESSION; ESTRADIOL; TAMOXIFEN C1 [Kino, Tomoshige] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, GR-11527 Athens, Greece. RP Kino, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. EM chrousge@med.uoa.gr FU Intramural NIH HHS [ZIA HD000615-29] NR 28 TC 3 Z9 3 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD DEC PY 2009 VL 9 IS 6 BP 294 EP 298 DI 10.1124/mi.9.6.4 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539NS UT WOS:000273262200002 PM 20048134 ER PT J AU Pelletier, M Siegel, RM AF Pelletier, Martin Siegel, Richard M. TI Wishing Away Inflammation? New Links between Serotonin and TNF Signaling SO MOLECULAR INTERVENTIONS LA English DT Editorial Material ID ADJUVANT-INDUCED ARTHRITIS; RHEUMATOID-ARTHRITIS; HUMAN MONOCYTES; RECEPTORS; RAT C1 [Pelletier, Martin; Siegel, Richard M.] NIAMS, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20814 USA. RP Pelletier, M (reprint author), NIAMS, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20814 USA. EM martin.pelletier@nih.gov; siegelr@mail.nih.gov OI Siegel, Richard/0000-0001-5953-9893 FU Intramural NIH HHS NR 15 TC 5 Z9 5 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD DEC PY 2009 VL 9 IS 6 BP 299 EP 301 DI 10.1124/mi.9.6.5 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539NS UT WOS:000273262200003 PM 20048135 ER PT J AU Makiela-Dzbenska, K Jaszczur, M Banach-Orlowska, M Jonczyk, P Schaaper, RM Fijalkowska, IJ AF Makiela-Dzbenska, Karolina Jaszczur, Malgorzata Banach-Orlowska, Magdalena Jonczyk, Piotr Schaaper, Roel M. Fijalkowska, Iwona J. TI Role of Escherichia coli DNA polymerase I in chromosomal DNA replication fidelity SO MOLECULAR MICROBIOLOGY LA English DT Article ID SOS MUTATOR ACTIVITY; BETA-SLIDING-CLAMP; III HOLOENZYME; POL-II; TRANSLESION SYNTHESIS; INDUCED MUTAGENESIS; ADAPTIVE MUTATION; LAGGING-STRAND; GENETIC REQUIREMENTS; MUTANTS AB P>We have investigated the possible role of Escherichia coli DNA polymerase (Pol) I in chromosomal replication fidelity. This was done by substituting the chromosomal polA gene by the polAexo variant containing an inactivated 3'-> 5' exonuclease, which serves as a proofreader for this enzyme's misinsertion errors. Using this strain, activities of Pol I during DNA replication might be detectable as increases in the bacterial mutation rate. Using a series of defined lacZ reversion alleles in two orientations on the chromosome as markers for mutagenesis, 1.5- to 4-fold increases in mutant frequencies were observed. In general, these increases were largest for lac orientations favouring events during lagging strand DNA replication. Further analysis of these effects in strains affected in other E. coli DNA replication functions indicated that this polAexo mutator effect is best explained by an effect that is additive compared with other error-producing events at the replication fork. No evidence was found that Pol I participates in the polymerase switching between Pol II, III and IV at the fork. Instead, our data suggest that the additional errors produced by polAexo are created during the maturation of Okazaki fragments in the lagging strand. C1 [Makiela-Dzbenska, Karolina; Jaszczur, Malgorzata; Banach-Orlowska, Magdalena; Jonczyk, Piotr; Fijalkowska, Iwona J.] Polish Acad Sci, Inst Biochem & Biophys, Warsaw, Poland. [Schaaper, Roel M.] Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Fijalkowska, IJ (reprint author), Polish Acad Sci, Inst Biochem & Biophys, Pawinskiego 5A, Warsaw, Poland. EM iwonaf@ibb.waw.pl RI Makiela-Dzbenska, Karolina/E-6751-2016; Fijalkowska, Iwona/I-7796-2016 FU Polish Ministry of Science and Higher Education [2 P04A 061 30, N301 030034]; NIH [Z01 ES065086]; National Institute of Environmental Health Sciences FX We thank Drs Aneta Kaniak, Adrianna Skoneczna and Jaroslaw Ciesla for support with the PCR experiments, and Drs Thomas Kunkel and Mark Itsko of the NIEHS for their careful reading of the manuscript for this paper. This work was supported by Grant 2 P04A 061 30 (to K.M.-D., M.J., I.J.F. and P.J.) and Grant N301 030034 (to I.J.F. and K.M.-D.) from the Polish Ministry of Science and Higher Education, and by funds allocated to project number Z01 ES065086 of the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 77 TC 17 Z9 17 U1 1 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD DEC PY 2009 VL 74 IS 5 BP 1114 EP 1127 DI 10.1111/j.1365-2958.2009.06921.x PG 14 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 524GG UT WOS:000272131200007 PM 19843230 ER PT J AU Moon, K Gottesman, S AF Moon, Kyung Gottesman, Susan TI A PhoQ/P-regulated small RNA regulates sensitivity of Escherichia coli to antimicrobial peptides SO MOLECULAR MICROBIOLOGY LA English DT Article ID SMALL NONCODING RNAS; SYSTEM PHOP-PHOQ; SALMONELLA-TYPHIMURIUM; OUTER-MEMBRANE; MOLECULAR CHARACTERIZATION; COMPARATIVE GENOMICS; 2-COMPONENT SYSTEM; STRESS-RESPONSE; CHAPERONE HFQ; POLYMYXIN-B AB P>Non-coding small RNAs (sRNAs) play a major role in post-transcriptional regulation of gene expression. Of the 80 sRNAs that have been identified in E. coli, one-third bind to the RNA chaperone Hfq. Hfq both stabilizes these sRNAs in vivo and stimulates pairing to targets in vitro. A novel Hfq-dependent RNA, called here MgrR, was identified by its ability to bind Hfq. Expression of MgrR requires the PhoQ/PhoP two-component system; the PhoP response regulator is active under low Mg2+ concentrations and is an important virulence regulator in Salmonella; mgrR is also found in Salmonella species. Negatively regulated targets of MgrR identified using microarrays include eptB, involved in lipopolysaccharide (LPS) modification, and ygdQ, encoding a hypothetical protein. Cell sensitivity to the antimicrobial polymyxin B is affected by LPS modifications, and cells carrying an mgrR deletion were approximately 10 times more resistant than wild-type cells to polymyxin B. Thus, lower Mg2+ concentrations, sensed by PhoQ/PhoP, lead to expression of MgrR, changing LPS. sRNAs have previously been shown to regulate many outer membrane proteins. This work demonstrates that LPS, a major contributor of bacterial interactions with mammalian cells, is also subject to regulation by sRNAs. C1 [Moon, Kyung; Gottesman, Susan] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. EM susang@helix.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We thank members of the Gottesman lab for advice and materials. We thank A. Battesti, P. Milanesio, P. Mandin, N. De Lay, N. Majdalani and G. Storz for comments on the manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 70 TC 64 Z9 70 U1 4 U2 12 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD DEC PY 2009 VL 74 IS 6 BP 1314 EP 1330 DI 10.1111/j.1365-2958.2009.06944.x PG 17 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 531IZ UT WOS:000272659700005 PM 19889087 ER PT J AU Barker, JR Chong, A Wehrly, TD Yu, JJ Rodriguez, SA Liu, JR Celli, J Arulanandam, BP Klose, KE AF Barker, Jeffrey R. Chong, Audrey Wehrly, Tara D. Yu, Jieh-Juen Rodriguez, Stephen A. Liu, Jirong Celli, Jean Arulanandam, Bernard P. Klose, Karl E. TI The Francisella tularensis pathogenicity island encodes a secretion system that is required for phagosome escape and virulence SO MOLECULAR MICROBIOLOGY LA English DT Article ID VI-SECRETION; PROTEIN SECRETION; PSEUDOMONAS-AERUGINOSA; EDWARDSIELLA-TARDA; SUBSP NOVICIDA; CELLS; IDENTIFICATION; GROWTH; MGLA; TRANSLOCATION AB P>Francisella tularensis causes the human disease tularemia. F. tularensis is able to survive and replicate within macrophages, a trait that has been correlated with its high virulence, but it is unclear the exact mechanism(s) this organism uses to escape killing within this hostile environment. F. tularensis virulence is dependent upon the Francisella pathogenicity island (FPI), a cluster of genes that we show here shares homology with type VI secretion gene clusters in Vibrio cholerae and Pseudomonas aeruginosa. We demonstrate that two FPI proteins, VgrG and IglI, are secreted into the cytosol of infected macrophages. VgrG and IglI are required for F. tularensis phagosomal escape, intramacrophage growth, inflammasome activation and virulence in mice. Interestingly, VgrG secretion does not require the other FPI genes. However, VgrG and other FPI genes, including PdpB (an IcmF homologue), are required for the secretion of IglI into the macrophage cytosol, suggesting that VgrG and other FPI factors are components of a secretion system. This is the first report of F. tularensis FPI virulence proteins required for intramacrophage growth that are translocated into the macrophage. C1 [Barker, Jeffrey R.; Yu, Jieh-Juen; Rodriguez, Stephen A.; Liu, Jirong; Arulanandam, Bernard P.; Klose, Karl E.] Univ Texas San Antonio, S Texas Ctr Emerging Infect Dis, San Antonio, TX USA. [Barker, Jeffrey R.; Yu, Jieh-Juen; Rodriguez, Stephen A.; Liu, Jirong; Arulanandam, Bernard P.; Klose, Karl E.] Univ Texas San Antonio, Dept Biol, San Antonio, TX USA. [Chong, Audrey; Wehrly, Tara D.; Celli, Jean] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, Hamilton, MT USA. RP Klose, KE (reprint author), Univ Texas San Antonio, S Texas Ctr Emerging Infect Dis, San Antonio, TX USA. EM karl.klose@utsa.edu RI Arulanandam, Bernard/O-9501-2014 FU NIAID NIH HHS [P01 AI057986-04] NR 39 TC 106 Z9 106 U1 0 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD DEC PY 2009 VL 74 IS 6 BP 1459 EP 1470 DI 10.1111/j.1365-2958.2009.06947.x PG 12 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 531IZ UT WOS:000272659700015 PM 20054881 ER PT J AU Scimemi, A Beato, M AF Scimemi, Annalisa Beato, Marco TI Determining the Neurotransmitter Concentration Profile at Active Synapses SO MOLECULAR NEUROBIOLOGY LA English DT Review DE Time course; Diffusion; Competitive low-affinity antagonist; Neurotransmitter; Synapse ID BRAIN EXTRACELLULAR-SPACE; FLUORESCENCE CORRELATION SPECTROSCOPY; MONTE-CARLO-SIMULATION; PHOTOACTIVATED LOCALIZATION MICROSCOPY; SYNAPTICALLY RELEASED GLUTAMATE; CULTURED HIPPOCAMPAL-NEURONS; MINIATURE GABAERGIC CURRENTS; FROG NEUROMUSCULAR-JUNCTIONS; ADRENAL CHROMAFFIN CELLS; KISS-AND-RUN AB Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission. C1 [Scimemi, Annalisa] NINDS, Synapt Physiol Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Beato, Marco] UCL, Dept Neurosci Physiol & Pharmacol, London WC1E 6BT, England. RP Scimemi, A (reprint author), NINDS, Synapt Physiol Sect, Porter Neurosci Res Ctr, NIH, 35 Convent Dr,Bldg 35,Room 3C-1006, Bethesda, MD 20892 USA. EM scimemia@ninds.nih.gov; m.beato@ucl.ac.uk RI Scimemi, Annalisa/O-5396-2014 OI Scimemi, Annalisa/0000-0003-4975-093X FU NINDS Intramural Research Program; Human Frontier Science Program [RGP50/2006]; Wellcome Trust [07662/Z/0/A] FX A. S. is supported by the NINDS Intramural Research Program and Human Frontier Science Program (RGP50/2006). M. B. is a Royal Society University Research Fellow and recipient of a Wellcome Trust Grant (Project Grant 07662/Z/0/A). The Authors would like to thank D. M. Kullmann, K. A. Pelkey and L. G. Wu for valuable comments on the manuscript. Open Access This article is distributed under NR 144 TC 23 Z9 23 U1 0 U2 10 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD DEC PY 2009 VL 40 IS 3 BP 289 EP 306 DI 10.1007/s12035-009-8087-7 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 520NI UT WOS:000271851300007 PM 19844813 ER PT J AU Carter, RL Fricks, IP Barrett, MO Burianek, LE Zhou, YX Ko, HJ Das, A Jacobson, KA Lazarowski, ER Harden, TK AF Carter, Rhonda L. Fricks, Ingrid P. Barrett, Matthew O. Burianek, Lauren E. Zhou, Yixing Ko, Hyojin Das, Arijit Jacobson, Kenneth A. Lazarowski, Eduardo R. Harden, T. Kendall TI Quantification of G(i)-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y(14) Receptor SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; FUNCTIONAL SELECTIVITY; ADENOSINE RECEPTOR; EPITHELIAL-CELLS; GPR105 KIAA0001; P2Y RECEPTORS; PHARMACOLOGY; EXPRESSION; RELEASE; CALCIUM AB The P2Y(14) receptor was initially identified as a G protein-coupled receptor activated by UDP-glucose and other nucleotide sugars. We have developed several cell lines that stably express the human P2Y(14) receptor, allowing facile examination of its coupling to native G(i) family G proteins and their associated downstream signaling pathways (J Pharmacol Exp Ther 330: 162-168, 2009). In the current study, we examined P2Y(14) receptor-dependent inhibition of cyclic AMP accumulation in human embryonic kidney (HEK) 293, C6 glioma, and Chinese hamster ovary (CHO) cells stably expressing this receptor. Not only was the human P2Y(14) receptor activated by UDP-glucose, but it also was activated by UDP. The apparent efficacies of UDP and UDP-glucose were similar, and the EC50 values (74, 33, and 29 nM) for UDP-dependent activation of the P2Y(14) receptor in HEK293, CHO, and C6 glioma cells, respectively, were similar to the EC50 values (323, 132, and 72 nM) observed for UDP-glucose. UDP and UDP-glucose also stimulated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in P2Y(14) receptor-expressing HEK293 cells but not in wild-type HEK293 cells. A series of analogs of UDP were potent P2Y(14) receptor agonists, but the naturally occurring nucleoside diphosphates, CDP, GDP, and ADP exhibited agonist potencies over 100-fold less than that observed with UDP. Two UDP analogs were identified that selectively activate the P2Y(14) receptor over the UDP-activated P2Y(6) receptor, and these molecules stimulated phosphorylation of ERK1/2 in differentiated human HL-60 promyeloleukemia cells, which natively express the P2Y(14) receptor but had no effect in wild-type HL-60 cells, which do not express the receptor. We conclude that UDP is an important cognate agonist of the human P2Y(14) receptor. C1 [Carter, Rhonda L.; Fricks, Ingrid P.; Barrett, Matthew O.; Burianek, Lauren E.; Zhou, Yixing; Harden, T. Kendall] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Lazarowski, Eduardo R.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA. [Lazarowski, Eduardo R.] Univ N Carolina, Sch Med, Cyst Fibrosis Ctr, Chapel Hill, NC 27599 USA. [Ko, Hyojin; Das, Arijit; Jacobson, Kenneth A.] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Harden, TK (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. EM tkh@med.unc.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Institutes of Health National Institute of General Medicine [GM38213]; National Institutes of Health National Heart, Lung, and Blood Institute [HL34322]; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the National Institutes of Health National Institute of General Medicine [Grant GM38213]; the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL34322]; and by the Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. NR 30 TC 43 Z9 43 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD DEC PY 2009 VL 76 IS 6 BP 1341 EP 1348 DI 10.1124/mol.109.058578 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 522WU UT WOS:000272031600021 PM 19759354 ER PT J AU Wildman, DE Jameson, NM Opazo, JC Yi, SV AF Wildman, Derek E. Jameson, Natalie M. Opazo, Juan C. Yi, Soojin V. TI A fully resolved genus level phylogeny of neotropical primates (Platyrrhini) SO MOLECULAR PHYLOGENETICS AND EVOLUTION LA English DT Article DE Pitheciidae; Cebidae; Atelidae; Callitrichoidea; New World monkeys; Neotropics; Non-genic markers ID NEW-WORLD MONKEYS; EPSILON-GLOBIN GENE; G6PD DNA-SEQUENCES; BRAIN SIZE; MOLECULAR PHYLOGENY; CAVIOMORPH RODENTS; CALLIMICO-GOELDII; EVOLUTION; GENOME; DIVERSIFICATION AB There are more than 125 species of extant New World monkeys (Primates: Platyrrhini) found in approximately 15 genera. The phylogenetic relationships of these neotropical primates have been extensively studied from a molecular perspective. While these studies have been successful at inferring many of the relationships within the platyrrhines, key questions remain. The current study provides a framework for using non-genic, non-coding markers in comparative primate phylogenomic studies in species whose genomes are not yet scheduled for complete sequencing. A random genomic shotgun library was generated from the nocturnal Owl monkey Aotus lemurinus. Eleven unlinked, non-coding, non-genic, non-repetitive, nuclear DNA markers derived from this library were sequenced in at least one representative species of every platyrrhine genus. The combined sequence from these markers yielded a 7.7 kb multiple sequence alignment of 22 taxa. We analyzed these markers independently and combined with a 10 kb dataset consisting of "traditional," previously published markers located within or directly adjacent to genes. Parsimony, maximum likelihood, and Bayesian analysis converged on a single topology for the platyrrhine generic relationships. Notably, we confidently inferred that Pitheciidae is the sister taxon to the other two platyrrhine families (Cebidae, Atelidae). This relationship is supported by high values of branch support as well as topology tests. Additionally, Aotus formed a sister taxon to a clade comprising Cebus and Saimiri. With a fully resolved platyrrhine phylogeny in place it is now possible to design and test hypotheses regarding the evolution and diversification of platyrrhine phenotypes and life histories. (C) 2009 Elsevier Inc. All rights reserved. C1 [Wildman, Derek E.] Wayne State Univ, Ctr Mol Med & Genet, Dept Obstet & Gynecol, Perinatol Res Branch,NICHD,NIH,DHHS,Sch Med, Detroit, MI 48201 USA. [Yi, Soojin V.] Georgia Inst Technol, Inst Biosyst, Inst Biosci & Bioengn, Sch Biol, Atlanta, GA 30332 USA. RP Wildman, DE (reprint author), Wayne State Univ, Ctr Mol Med & Genet, Dept Obstet & Gynecol, Perinatol Res Branch,NICHD,NIH,DHHS,Sch Med, 540 E Canfield Ave,3218 Scott Hall, Detroit, MI 48201 USA. EM dwildman@med.wayne.edu RI Opazo, Juan/A-9363-2009; OI Opazo, Juan/0000-0001-7938-4083 FU National Science Foundation [BCS-0751508, BCS-0751481] FX This research was funded by National Science Foundation Grants (BCS-0751508) to D.W. and (BCS-0751481) to S.Y. The authors acknowledge the kind gift of samples from the laboratories of Dr. Morris Goodman (Wayne State University, Detroit, MI) and Dr. Caro-Beth Stewart (SUNY, Albany). NR 71 TC 68 Z9 68 U1 3 U2 35 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1055-7903 J9 MOL PHYLOGENET EVOL JI Mol. Phylogenet. Evol. PD DEC PY 2009 VL 53 IS 3 BP 694 EP 702 DI 10.1016/j.ympev.2009.07.019 PG 9 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 531ED UT WOS:000272644800008 PM 19632342 ER PT J AU Jessmon, P Leach, RE Armant, DR AF Jessmon, Philip Leach, Richard E. Armant, D. Randall TI Diverse Functions of HBEGF During Pregnancy SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Review ID EPIDERMAL-GROWTH-FACTOR; ENDOMETRIAL STROMAL CELLS; NECROSIS-FACTOR-ALPHA; SERUM-FREE MEDIUM; FACTOR HB-EGF; HUMAN TROPHOBLAST; HUMAN PLACENTA; OXIDATIVE STRESS; GENE-EXPRESSION; BLASTOCYST IMPLANTATION AB The establishment of pregnancy requires an intimate physical interaction and a molecular dialogue between the conceptus and the maternal reproductive tract that commences at implantation and continues until the placenta is formed and fully functional. Failure of the regulatory processes that ensure the fidelity of this relationship can precipitate a catastrophic pregnancy loss. One of the earliest identified molecular mediators of blastocyst implantation is heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF), which signals between the endometrium and implanting trophoblast cells to synchronize their corresponding developmental programs. HBEGF expression by trophoblast cells of the developing placenta appears to regulate extravillous differentiation and provide cytoprotection in a sometimes-hostile environment. This versatile member of the EGF signaling system will be examined in light of its associations with key events during early pregnancy. C1 [Jessmon, Philip; Armant, D. Randall] Wayne State Univ, Sch Med, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Jessmon, Philip; Armant, D. Randall] Wayne State Univ, Sch Med, CS Mott Ctr Human Growth & Dev, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Jessmon, Philip; Armant, D. Randall] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Leach, Richard E.] Michigan State Univ, Coll Human Med, Dept Obstet Gynecol & Reprod Sci, Grand Rapids, MI USA. RP Armant, DR (reprint author), Wayne State Univ, Sch Med, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, 275 E Hancock Ave, Detroit, MI 48201 USA. EM d.armant@wayne.edu OI Armant, D. Randall/0000-0001-5904-9325 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS and NIH [U54HD040093] FX This study was supported, in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS and NIH Grant U54HD040093. NR 109 TC 29 Z9 33 U1 1 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1040-452X J9 MOL REPROD DEV JI Mol. Reprod. Dev. PD DEC PY 2009 VL 76 IS 12 BP 1116 EP 1127 DI 10.1002/mrd.21066 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA 513YZ UT WOS:000271361500003 PM 19565643 ER PT J AU Lee, S Ryu, JH Park, K Lee, A Lee, SY Youn, IC Ahn, CH Yoon, SM Myung, SJ Moon, DH Chen, X Choi, K Kwon, IC Kim, K AF Lee, Seulki Ryu, Ju Hee Park, Kyeongsoon Lee, Aeju Lee, Seung-Young Youn, In-Chan Ahn, Cheol-Hee Yoon, Soon Man Myung, Seung-Jae Moon, Dae Hyuk Chen, Xiaoyuan Choi, Kuiwon Kwon, Ick Chan Kim, Kwangmeyung TI Polymeric Nanoparticle-Based Activatable Near-Infrared Nanosensor for Protease Determination In Vivo SO NANO LETTERS LA English DT Article ID MATRIX METALLOPROTEINASES; CANCER; PROBES; MECHANISM AB We report here a new protease activatable strategy based on a polymer nanoparticle platform. This nanosensor delivers chemically labeled matrix metalloproteinase (MMP)-activatable fluorogenic peptides to the specific MMPs of interest in vivo. Intravenous administration of the nanosensor in an MMP-positive SCC-7 xenograft tumor and a colon cancer mouse model verified the enzyme specificity of the nanosensor in vivo. The design platform of the nanosensor is flexible and can be fine-tuned for a wide array of applications such as the detection of biomarkers, early diagnosis of disease, and monitoring therapeutic efficacy. C1 [Lee, Seulki; Ryu, Ju Hee; Park, Kyeongsoon; Lee, Aeju; Lee, Seung-Young; Youn, In-Chan; Choi, Kuiwon; Kwon, Ick Chan; Kim, Kwangmeyung] Korea Inst Sci & Technol, Biomed Res Ctr, Seoul 136791, South Korea. [Lee, Seulki; Choi, Kuiwon] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Ahn, Cheol-Hee] Seoul Natl Univ, Sch Mat Sci & Engn, Seoul 151742, South Korea. [Yoon, Soon Man; Myung, Seung-Jae; Moon, Dae Hyuk] Univ Ulsan, Coll Med, Asan Med Ctr, Seoul 138736, South Korea. RP Kim, K (reprint author), Korea Inst Sci & Technol, Biomed Res Ctr, 39-1 Hawolgok Dong, Seoul 136791, South Korea. EM kim@kist.re.kr OI Myung, Seung-Jae/0000-0003-0585-4016; Lee, Seung-Young/0000-0003-1349-3759 FU Real-Time Molecular Imaging Project; Pioneer Research Program; Global Research Laboratory; Korea Health 21 RD Project [A062254] FX This work was financially supported by the Real-Time Molecular Imaging Project, Pioneer Research Program, and Global Research Laboratory Project of MEST and by a grant to the Intramural Research Program of the KIST, and by a grant (A062254) of the Korea Health 21 R&D Project. NR 18 TC 77 Z9 79 U1 4 U2 39 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 J9 NANO LETT JI Nano Lett. PD DEC PY 2009 VL 9 IS 12 BP 4412 EP 4416 DI 10.1021/nl902709m PG 5 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 527VC UT WOS:000272395400078 PM 19842672 ER PT J AU Liepold, LO Abedin, MJ Buckhouse, ED Frank, JA Young, MJ Douglas, T AF Liepold, Lars O. Abedin, Md Joynal Buckhouse, Emily D. Frank, Joseph A. Young, Mark J. Douglas, Trevor TI Supramolecular Protein Cage Composite MR Contrast Agents with Extremely Efficient Relaxivity Properties SO NANO LETTERS LA English DT Article ID COWPEA MOSAIC-VIRUS; HEAT-SHOCK-PROTEIN; VIRAL NANOPARTICLES; IN-VIVO; COMPLEXES; GADOLINIUM; PARTICLES; INTERIOR; ARCHITECTURE; ATTACHMENT AB A DTPA-Gd containing polymer was grown in the interior of a heat shock protein cage resulting in T(1) particle relaxivities of 4200 mM(-1) sec(-1) for the 12 nm particle. Relaxivity parameters were determined, and this analysis suggests that the rotational correlation time has been optimized while the water exchange lifetime is longer than optimal. This synthetic approach holds much promise for the development of next generation contrast agents and this report will aid in their design. C1 [Liepold, Lars O.; Abedin, Md Joynal; Buckhouse, Emily D.; Young, Mark J.; Douglas, Trevor] Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. [Liepold, Lars O.; Abedin, Md Joynal; Buckhouse, Emily D.; Douglas, Trevor] Montana State Univ, Ctr Bioinspired Nanomat, Bozeman, MT 59717 USA. [Young, Mark J.] Montana State Univ, Dept Plant Sci, Bozeman, MT 59717 USA. [Frank, Joseph A.] NIH, Frank Lab Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, Intramural Res Program, NIH, Bethesda, MD USA. RP Douglas, T (reprint author), Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. RI Douglas, Trevor/F-2748-2011 FU National Institutes of Health [R21E13005364]; National Science Foundation [CBET-0709358]; Office of Naval Research [N00014-03-1-0692] FX This research was supported in part by grants from the National Institutes of Health (R21E13005364) and the National Science Foundation (CBET-0709358), and the Office of Naval Research (N00014-03-1-0692). NR 43 TC 39 Z9 39 U1 0 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 J9 NANO LETT JI Nano Lett. PD DEC PY 2009 VL 9 IS 12 BP 4520 EP 4526 DI 10.1021/nl902884p PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 527VC UT WOS:000272395400098 PM 19888720 ER PT J AU Wimmer, E Mueller, S Tumpey, TM Taubenberger, JK AF Wimmer, Eckard Mueller, Steffen Tumpey, Terrence M. Taubenberger, Jeffery K. TI Synthetic viruses: a new opportunity to understand and prevent viral disease SO NATURE BIOTECHNOLOGY LA English DT Review ID 1918 PANDEMIC VIRUS; SPANISH INFLUENZA-VIRUS; COMPLETE NUCLEOTIDE-SEQUENCE; REVERSE GENETICS; A-VIRUSES; MAMMALIAN-CELLS; MESSENGER-RNA; CHEMICAL-SYNTHESIS; ESCHERICHIA-COLI; INFECTIOUS VIRUS AB Rapid progress in DNA synthesis and sequencing is spearheading the deliberate, large-scale genetic alteration of organisms. These new advances in DNA manipulation have been extended to the level of whole-genome synthesis, as evident from the synthesis of poliovirus, from the resurrection of the extinct 1918 strain of influenza virus and of human endogenous retroviruses and from the restructuring of the phage T7 genome. The largest DNA synthesized so far is the 582,970 base pair genome of Mycoplasma genitalium, although, as yet, this synthetic DNA has not been 'booted' to life. As genome synthesis is independent of a natural template, it allows modification of the structure and function of a virus's genetic information to an extent that was hitherto impossible. The common goal of this new strategy is to further our understanding of an organism's properties, particularly its pathogenic armory if it causes disease in humans, and to make use of this new information to protect from, or treat, human viral disease. Although only a few applications of virus synthesis have been described as yet, key recent findings have been the resurrection of the 1918 influenza virus and the generation of codon-and codon pair-deoptimized polioviruses. C1 [Wimmer, Eckard; Mueller, Steffen] SUNY Stony Brook, Dept Mol Genet & Microbiol, New York, NY USA. [Tumpey, Terrence M.] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Influenza Div, Atlanta, GA USA. [Taubenberger, Jeffery K.] NIAID, Infect Dis Lab, NIH, Bethesda, MD USA. RP Wimmer, E (reprint author), SUNY Stony Brook, Dept Mol Genet & Microbiol, New York, NY USA. EM ewimmer@ms.cc.sunysb.edu FU US National Institutes of Health ( NIH) [AI075219, AI15122]; US Defense Advanced Research Project Agency [N65236]; National Institute of Allergies and Infectious Diseases ( NIAID) FX We are indebted to our colleagues who have participated in the work described here and who have in part edited the manuscript, particularly A. Paul and B. Futcher, and we thank J. Shendure, L. Steward and A. B. Burgin for information provided. The work described here was supported partially by US National Institutes of Health ( NIH) grants AI075219 and AI15122 and contract N65236 from the US Defense Advanced Research Project Agency to E. W.; and partially by the intramural research program of the NIH and the National Institute of Allergies and Infectious Diseases ( NIAID). The findings and conclusions in this report are those of the author( s) and do not necessarily represent the views of the funding agency. NR 109 TC 55 Z9 57 U1 2 U2 34 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD DEC PY 2009 VL 27 IS 12 BP 1163 EP 1172 DI 10.1038/nbt.1593 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 531YC UT WOS:000272708300033 PM 20010599 ER PT J AU Smyth, JT Petranka, JG Boyles, RR DeHaven, WI Fukushima, M Johnson, KL Williams, JG Putney, JW AF Smyth, Jeremy T. Petranka, John G. Boyles, Rebecca R. DeHaven, Wayne I. Fukushima, Miwako Johnson, Katina L. Williams, Jason G. Putney, James W., Jr. TI Phosphorylation of STIM1 underlies suppression of store-operated calcium entry during mitosis SO NATURE CELL BIOLOGY LA English DT Article ID ACTIVATES CRAC CHANNELS; PLASMA-MEMBRANE; CA2+ INFLUX; MAST-CELLS; DEPLETION; KINASE; ORAI1; IDENTIFICATION; MICRODOMAINS; HOMEOSTASIS AB Store-operated Ca(2+) entry (SOCE) and Ca(2+) release-activated Ca(2+) currents (I(crac)) are strongly suppressed during mitosis, the only known physiological situation in which Ca(2+) store depletion is uncoupled from the activation of Ca(2+) influx. We found that the endoplasmic reticulum (ER) Ca(2+) sensor STIM1 failed to rearrange into near-plasma membrane puncta in mitotic cells, a critical step in the SOCE-activation pathway. We also found that STIM1 from mitotic cells is recognized by the phospho-specific MPM-2 antibody, suggesting that STIM1 is phosphorylated during mitosis. Removal of ten MPM-2 recognition sites by truncation at amino acid 482 abolished MPM-2 recognition of mitotic STIM1, and significantly rescued STIM1 rearrangement and SOCE response in mitosis. We identified Ser 486 and Ser 668 as mitosis-specific phosphorylation sites, and STIM1 containing mutations of these sites to alanine also significantly rescued mitotic SOCE. Therefore, phosphorylation of STIM1 at Ser 486 and Ser 668, and possibly other sites, underlies suppression of SOCE during mitosis. C1 [Smyth, Jeremy T.; Petranka, John G.; Boyles, Rebecca R.; DeHaven, Wayne I.; Fukushima, Miwako; Putney, James W., Jr.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Johnson, Katina L.; Williams, Jason G.] NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov OI Boyles, Rebecca/0000-0003-0073-6854 FU Intramural Program; National Institute of Environmental Health Sciences; National Institutes of Health FX We thank J. Tucker and H. Rutledge for assistance with confocal microscopy and C. Bortner and M. Sifre for help with flow cytometry. C. Williams and D. Miller reviewed the manuscript and offered helpful suggestions. This work was supported by the Intramural Program, National Institute of Environmental Health Sciences, National Institutes of Health. NR 39 TC 91 Z9 92 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD DEC PY 2009 VL 11 IS 12 BP 1465 EP U190 DI 10.1038/ncb1995 PG 18 WC Cell Biology SC Cell Biology GA 525XO UT WOS:000272251300014 PM 19881501 ER PT J AU Lundberg, JO Gladwin, MT Ahluwalia, A Benjamin, N Bryan, NS Butler, A Cabrales, P Fago, A Feelisch, M Ford, PC Freeman, BA Frenneaux, M Friedman, J Kelm, M Kevil, CG Kim-Shapiro, DB Kozlov, AV Lancaster, JR Lefer, DJ McColl, K McCurry, K Patel, RP Petersson, J Rassaf, T Reutov, VP Richter-Addo, GB Schechter, A Shiva, S Tsuchiya, K van Faassen, EE Webb, AJ Zuckerbraun, BS Zweier, JL Weitzberg, E AF Lundberg, Jon O. Gladwin, Mark T. Ahluwalia, Amrita Benjamin, Nigel Bryan, Nathan S. Butler, Anthony Cabrales, Pedro Fago, Angela Feelisch, Martin Ford, Peter C. Freeman, Bruce A. Frenneaux, Michael Friedman, Joel Kelm, Malte Kevil, Christopher G. Kim-Shapiro, Daniel B. Kozlov, Andrey V. Lancaster, Jack R., Jr. Lefer, David J. McColl, Kenneth McCurry, Kenneth Patel, Rakesh P. Petersson, Joel Rassaf, Tienush Reutov, Valentin P. Richter-Addo, George B. Schechter, Alan Shiva, Sruti Tsuchiya, Koichiro van Faassen, Ernst E. Webb, Andrew J. Zuckerbraun, Brian S. Zweier, Jay L. Weitzberg, Eddie TI Nitrate and nitrite in biology, nutrition and therapeutics SO NATURE CHEMICAL BIOLOGY LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; DIETARY NITRATE; REDUCTASE-ACTIVITY; BLOOD-PRESSURE; OXIDE PRODUCTION; HUMANS; DEOXYHEMOGLOBIN; HEMOGLOBIN; PHYSIOLOGY; TOLERANCE AB Inorganic nitrate and nitrite from endogenous or dietary sources are metabolized in vivo to nitric oxide (NO) and other bioactive nitrogen oxides. The nitrate-nitrite-NO pathway is emerging as an important mediator of blood flow regulation, cell signaling, energetics and tissue responses to hypoxia. The latest advances in our understanding of the biochemistry, physiology and therapeutics of nitrate, nitrite and NO were discussed during a recent 2-day meeting at the Nobel Forum, Karolinska Institutet in Stockholm. C1 [Lundberg, Jon O.; Weitzberg, Eddie] Karolinska Inst, Dept Physiol & Pharmacol, Sect Anesthesiol & Intens Care Med, Stockholm, Sweden. [Gladwin, Mark T.; Shiva, Sruti] Univ Pittsburgh, Pulm Allergy & Crit Care Med & Vasc Med Inst, Pittsburgh, PA USA. [Ahluwalia, Amrita; Webb, Andrew J.] Queen Mary Univ London, Ctr Clin Pharmacol, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Benjamin, Nigel] Univ Exeter & Plymouth, Exeter, Devon, England. [Bryan, Nathan S.] Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Inst Mol Med, Houston, TX USA. [Butler, Anthony] Univ St Andrews, St Andrews KY16 9AJ, Fife, Scotland. [Cabrales, Pedro] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Fago, Angela] Aarhus Univ, Dept Biol Sci, Aarhus, Denmark. [Feelisch, Martin] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Ford, Peter C.] Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA. [Freeman, Bruce A.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Frenneaux, Michael] Univ Birmingham, Birmingham, W Midlands, England. [Friedman, Joel] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Kelm, Malte; Rassaf, Tienush] Univ Dusseldorf, Dusseldorf, Germany. [Kevil, Christopher G.] Louisiana State Univ, Dept Pathol, Hlth Sci Ctr, Shreveport, LA 71105 USA. [Kim-Shapiro, Daniel B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [Kozlov, Andrey V.] Ludwig Boltzmann Inst Expt & Clin Traumatol, Vienna, Austria. [Lancaster, Jack R., Jr.; Patel, Rakesh P.] Univ Alabama, Birmingham, AL USA. [Lefer, David J.] Emory Univ, Sch Med, Atlanta, GA USA. [McColl, Kenneth] Univ Glasgow, Glasgow, Lanark, Scotland. [McCurry, Kenneth] Cleveland Clin, Cleveland, OH 44106 USA. [Petersson, Joel] Uppsala Univ, Dept Med Cell Biol, Uppsala, Sweden. [Richter-Addo, George B.] Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. [Reutov, Valentin P.] Russian Acad Sci, Inst Higher Nervous Act & Neurophysiol, Moscow, Russia. [Schechter, Alan] NIDDKD, NIH, Bethesda, MD 20892 USA. [Tsuchiya, Koichiro] Univ Tokushima, Inst Hlth Biosci, Tokushima 770, Japan. [van Faassen, Ernst E.] Univ Utrecht, Utrecht, Netherlands. [Zweier, Jay L.] Ohio State Univ, Dept Med, Columbus, OH 43210 USA. [Zweier, Jay L.] Ohio State Univ, Dept Physiol, Columbus, OH 43210 USA. [Zweier, Jay L.] Ohio State Univ, Dept Biochem, Columbus, OH 43210 USA. RP Lundberg, JO (reprint author), Karolinska Inst, Dept Physiol & Pharmacol, Sect Anesthesiol & Intens Care Med, Stockholm, Sweden. EM jon.lundberg@ki.se; eddie.weitzberg@ki.se RI Ford, Peter/D-1826-2011; Kevil, Christopher/G-9318-2011; Lefer, David/A-6372-2012; Freeman, Bruce/H-9342-2012; Feelisch, Martin/C-3042-2008; Fago, Angela/J-5946-2013; Cabrales, Pedro/A-1930-2014; Institute (DINS), Debye/G-7730-2014 OI Ford, Peter/0000-0002-5509-9912; Feelisch, Martin/0000-0003-2320-1158; Fago, Angela/0000-0001-7315-2628; Schechter, Alan N/0000-0002-5235-9408; Patel, Rakesh/0000-0002-1526-4303; Cabrales, Pedro/0000-0002-8794-2839; FU British Heart Foundation [SP/08/006/25110]; NHLBI NIH HHS [R01 HL064937, R01 HL058115, R01 HL080482, R01 HL080482-04, R37 HL058091] NR 44 TC 240 Z9 263 U1 7 U2 55 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD DEC PY 2009 VL 5 IS 12 BP 865 EP 869 DI 10.1038/nchembio.260 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 519HV UT WOS:000271756900002 PM 19915529 ER PT J AU Thomas, R Apps, R Qi, Y Gao, XJ Male, V O'hUigin, C O'Connor, G Ge, DL Fellay, J Martin, JN Margolick, J Goedert, JJ Buchbinder, S Kirk, GD Martin, MP Telenti, A Deeks, SG Walker, BD Goldstein, D McVicar, DW Moffett, A Carrington, M AF Thomas, Rasmi Apps, Richard Qi, Ying Gao, Xiaojiang Male, Victoria O'hUigin, Colm O'Connor, Geraldine Ge, Dongliang Fellay, Jacques Martin, Jeffrey N. Margolick, Joseph Goedert, James J. Buchbinder, Susan Kirk, Gregory D. Martin, Maureen P. Telenti, Amalio Deeks, Steven G. Walker, Bruce D. Goldstein, David McVicar, Daniel W. Moffett, Ashley Carrington, Mary TI HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C SO NATURE GENETICS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NATURAL-KILLER-CELLS; CLASS-I MOLECULES; MHC CLASS-I; SINGLE AMINO-ACID; HIV-1 INFECTION; MONOCLONAL-ANTIBODIES; INHIBITORY RECEPTORS; TROPHOBLAST CELLS; AIDS AB A variant 35 kb upstream of the HLA-C gene (-35C/T) was previously shown to associate with HLA-C mRNA expression level and steady-state plasma HIV RNA levels. We genotyped this variant in 1,698 patients of European ancestry with HIV. Individuals with known seroconversion dates were used for disease progression analysis and those with longitudinal viral load data were used for viral load analysis. We further tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. We show that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high-expressing HLA-C alleles progress more slowly to AIDS and control viremia significantly better than individuals with low HLA-C expressing alleles. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells. C1 [Thomas, Rasmi; Qi, Ying; Gao, Xiaojiang; O'hUigin, Colm; Martin, Maureen P.; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. [Apps, Richard; Male, Victoria; Moffett, Ashley] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Ge, Dongliang; Fellay, Jacques; Goldstein, David] Duke Univ, Ctr Populat Genom & Pharmacogenet, Durham, NC USA. [Martin, Jeffrey N.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Margolick, Joseph] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Goedert, James J.] Natl Canc Inst, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Rockville, MD USA. [Buchbinder, Susan] San Francisco Dept Publ Hlth, HIV Res Sect, San Francisco, CA USA. [Kirk, Gregory D.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Telenti, Amalio] Univ Lausanne, Inst Microbiol, Lausanne, Switzerland. [Deeks, Steven G.] San Francisco Gen Hosp, San Francisco, CA 94110 USA. [Walker, Bruce D.] MIT & Harvard, Ragon Inst MGH, Boston, MA USA. RP Carrington, M (reprint author), NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. EM carringm@mail.nih.gov RI Ge, Dongliang/A-2073-2010; Moffett, Ashley/J-9754-2013; SHCS, all/G-4072-2011; SHCS, int. coll. A/G-4083-2011; Fellay, Jacques/A-6681-2009; McVicar, Daniel/G-1970-2015 OI Fellay, Jacques/0000-0002-8240-939X; FU National Cancer Institute, National Institutes of Health [HHSN261200800001E, N02-CP-55504, R01-DA04334, R01-DA12568]; Intramural Research Program of the NIH; National Cancer Institute, Center for Cancer Research; Bill & Melinda Gates Foundation; Swiss National Science Foundation; SCOPE; Clinical and Translational Sciences Award [UL1 RR024131]; Center for AIDS Research [P30 AI27763]; Cambridge Center for Trophoblast Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contracts HHSN261200800001E, N02-CP-55504, R01-DA04334 and R01-DA12568. 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. This research was partially funded by a grant from the Bill & Melinda Gates Foundation as part of the Collaboration for AIDS Vaccine Discovery. We would also like to acknowledge the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation, and the SCOPE study was funded by the UL1 RR024131 (Clinical and Translational Sciences Award) and P30 AI27763 (Center for AIDS Research) grants. R. A. is funded by the Cambridge Center for Trophoblast Research. We also thank R. Fernando and the Anthony Nolan Research Institute for the Luminex analysis. NR 41 TC 155 Z9 159 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD DEC PY 2009 VL 41 IS 12 BP 1290 EP U46 DI 10.1038/ng.486 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 524LN UT WOS:000272144900009 PM 19935663 ER PT J AU Simon-Sanchez, J Schulte, C Bras, JM Sharma, M Gibbs, JR Berg, D Paisan-Ruiz, C Lichtner, P Scholz, SW Hernandez, DG Kruger, R Federoff, M Klein, C Goate, A Perlmutter, J Bonin, M Nalls, MA Illig, T Gieger, C Houlden, H Steffens, M Okun, MS Racette, BA Cookson, MR Foote, KD Fernandez, HH Traynor, BJ Schreiber, S Arepalli, S Zonozi, R Gwinn, K van der Brug, M Lopez, G Chanock, SJ Schatzkin, A Park, Y Hollenbeck, A Gao, JJ Huang, XM Wood, NW Lorenz, D Deuschl, G Chen, HL Riess, O Hardy, JA Singleton, AB Gasser, T AF Simon-Sanchez, Javier Schulte, Claudia Bras, Jose M. Sharma, Manu Gibbs, J. Raphael Berg, Daniela Paisan-Ruiz, Coro Lichtner, Peter Scholz, Sonja W. Hernandez, Dena G. Krueger, Rejko Federoff, Monica Klein, Christine Goate, Alison Perlmutter, Joel Bonin, Michael Nalls, Michael A. Illig, Thomas Gieger, Christian Houlden, Henry Steffens, Michael Okun, Michael S. Racette, Brad A. Cookson, Mark R. Foote, Kelly D. Fernandez, Hubert H. Traynor, Bryan J. Schreiber, Stefan Arepalli, Sampath Zonozi, Ryan Gwinn, Katrina van der Brug, Marcel Lopez, Grisel Chanock, Stephen J. Schatzkin, Arthur Park, Yikyung Hollenbeck, Albert Gao, Jianjun Huang, Xuemei Wood, Nick W. Lorenz, Delia Deuschl, Guenther Chen, Honglei Riess, Olaf Hardy, John A. Singleton, Andrew B. Gasser, Thomas TI Genome-wide association study reveals genetic risk underlying Parkinson's disease SO NATURE GENETICS LA English DT Article ID PROGRESSIVE SUPRANUCLEAR PALSY; LINKAGE DISEQUILIBRIUM; TAU GENE; HAPLOTYPE; MUTATIONS; SYSTEM; SNCA AB We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding a-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS1, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease. C1 [Schulte, Claudia; Sharma, Manu; Berg, Daniela; Gasser, Thomas] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Simon-Sanchez, Javier; Bras, Jose M.; Gibbs, J. Raphael; Scholz, Sonja W.; Hernandez, Dena G.; Federoff, Monica; Nalls, Michael A.; Cookson, Mark R.; Traynor, Bryan J.; Arepalli, Sampath; Zonozi, Ryan; van der Brug, Marcel; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Simon-Sanchez, Javier] Vrije Univ Amsterdam Med Ctr, Sect Med Genom, Dept Clin Genet, Amsterdam, Netherlands. [Schulte, Claudia; Sharma, Manu; Berg, Daniela; Gasser, Thomas] German Ctr Neurodegenerat Dis, Tubingen, Germany. [Bras, Jose M.] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal. [Gibbs, J. Raphael; Paisan-Ruiz, Coro; Scholz, Sonja W.; Hernandez, Dena G.; Houlden, Henry; Wood, Nick W.; Hardy, John A.] UCL, Dept Mol Neurosci, Inst Neurol, London, England. [Gibbs, J. Raphael; Paisan-Ruiz, Coro; Scholz, Sonja W.; Hernandez, Dena G.; Houlden, Henry; Wood, Nick W.; Hardy, John A.] UCL, Reta Lila Weston Labs, Inst Neurol, London, England. [Lichtner, Peter] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Klein, Christine] Univ Lubeck, Dept Neurol, Sect Clin & Mol Neurogenet, Lubeck, Germany. [Goate, Alison; Perlmutter, Joel; Racette, Brad A.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Goate, Alison; Perlmutter, Joel; Racette, Brad A.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Bonin, Michael; Riess, Olaf] Univ Tubingen, Inst Human Genet, Dept Med Genet, Tubingen, Germany. [Illig, Thomas; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Steffens, Michael] Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-5300 Bonn, Germany. [Okun, Michael S.; Foote, Kelly D.; Fernandez, Hubert H.] Univ Florida, Movement Disorders Ctr, Gainesville, FL USA. [Schreiber, Stefan] Univ Kiel, Inst Klin Mol Biol, D-24098 Kiel, Germany. [Gwinn, Katrina] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [van der Brug, Marcel] Scripps Res Inst, Dept Neurosci, Scripps, FL USA. [Lopez, Grisel] NINDS, Parkinsons Dis Clin, NIH, Bethesda, MD 20892 USA. [Chanock, Stephen J.; Schatzkin, Arthur; Park, Yikyung] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. [Gao, Jianjun; Chen, Honglei] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Radiol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Kinesiol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Bioengn, Hershey, PA 17033 USA. [Lorenz, Delia; Deuschl, Guenther] Univ Kiel, Neurol Klin, Univ Klinikum Schleswig Holstein, D-2300 Kiel, Germany. RP Gasser, T (reprint author), Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. EM singleta@mail.nih.gov; thomas.gasser@uni-tuebingen.de RI Paisan-Ruiz, Coro/C-2912-2009; Schreiber, Stefan/B-6748-2008; Gibbs, J. Raphael/A-3984-2010; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Traynor, Bryan/G-5690-2010; Bras, Jose/A-1428-2011; Houlden, Henry/C-1532-2008; Deuschl, Gunther/A-7986-2010; Wood, Nicholas/C-2505-2009; OI Chen, Honglei/0000-0003-3446-7779; Gwinn, Katrina/0000-0002-8277-651X; Scholz, Sonja/0000-0002-6623-0429; Steffens, Michael/0000-0002-6445-8593; Park, Yikyung/0000-0002-6281-489X; Gieger, Christian/0000-0001-6986-9554; Schreiber, Stefan/0000-0003-2254-7771; Houlden, Henry/0000-0002-2866-7777; Wood, Nicholas/0000-0002-9500-3348; Bras, Jose/0000-0001-8186-0333; Okun, Michael/0000-0002-6247-9358; Schulte, Claudia/0000-0003-4006-1265 FU Intramural Research Programs of the National Institute on Aging; National Institute of Neurological Disorders and Stroke; National Institute of Environmental Health Sciences; National Cancer Institute; National Institutes of Health; Department of Health and Human Services [Z01 AG000949-02, Z01-ES101986]; Forschungszentrum fur Umwelt und Gesundheit (GSF); German Federal Ministry of Education, Science, Research and Technology; State of Bavaria; German National Genome Network [01GS08134]; German Ministry for Education and Research; German Federal Ministry of Education and Research (BMBF) NGFN [01GR0468]; National Institutes of Health NINDS [P30NS05710]; Clinical Sciences Translational Award [RR024992]; Medical Research Council, UK FX The study was additionally funded by the German National Genome Network (NGFNplus #01GS08134; German Ministry for Education and Research) and in addition by the German Federal Ministry of Education and Research (BMBF) NGFN (01GR0468). This work also was supported by the National Institutes of Health NINDS P30NS05710 (Neuroscience Blueprint Grant) and Clinical Sciences Translational Award RR024992 to Washington University in St. Louis and the Greater St. Louis Chapter of the American Parkinson Disease Association. Authors received support from the Medical Research Council, UK. NR 22 TC 820 Z9 829 U1 6 U2 112 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD DEC PY 2009 VL 41 IS 12 BP 1308 EP U68 DI 10.1038/ng.487 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 524LN UT WOS:000272144900012 PM 19915575 ER PT J AU Raychaudhuri, S Thomson, BP Remmers, EF Eyre, S Hinks, A Guiducci, C Catanese, JJ Xie, G Stahl, EA Chen, R Alfredsson, L Amos, CI Ardlie, KG Barton, A Bowes, J Burtt, NP Chang, M Coblyn, J Costenbader, KH Criswell, LA Crusius, JBA Cui, J De Jager, PL Ding, B Emery, P Flynn, E Harrison, P Hocking, LJ Huizinga, TWJ Kastner, DL Ke, XY Kurreeman, FAS Lee, AT Liu, XD Li, YH Martin, P Morgan, AW Padyukov, L Reid, DM Seielstad, M Seldin, MF Shadick, NA Steer, S Tak, PP Thomson, W van der Helm-van Mil, AHM van der Horst-Bruinsma, IE Weinblatt, ME Wilson, AG Wolbink, GJ Wordsworth, P Altshuler, D Karlson, EW Toes, REM de Vries, N Begovich, AB Siminovitch, KA Worthington, J Klareskog, L Gregersen, PK Daly, MJ Plenge, RM AF Raychaudhuri, Soumya Thomson, Brian P. Remmers, Elaine F. Eyre, Stephen Hinks, Anne Guiducci, Candace Catanese, Joseph J. Xie, Gang Stahl, Eli A. Chen, Robert Alfredsson, Lars Amos, Christopher I. Ardlie, Kristin G. Barton, Anne Bowes, John Burtt, Noel P. Chang, Monica Coblyn, Jonathan Costenbader, Karen H. Criswell, Lindsey A. Crusius, J. Bart A. Cui, Jing De Jager, Phillip L. Ding, Bo Emery, Paul Flynn, Edward Harrison, Pille Hocking, Lynne J. Huizinga, Tom W. J. Kastner, Daniel L. Ke, Xiayi Kurreeman, Fina A. S. Lee, Annette T. Liu, Xiangdong Li, Yonghong Martin, Paul Morgan, Ann W. Padyukov, Leonid Reid, David M. Seielstad, Mark Seldin, Michael F. Shadick, Nancy A. Steer, Sophia Tak, Paul P. Thomson, Wendy van der Helm-van Mil, Annette H. M. van der Horst-Bruinsma, Irene E. Weinblatt, Michael E. Wilson, Anthony G. Wolbink, Gert Jan Wordsworth, Paul Altshuler, David Karlson, Elizabeth W. Toes, Rene E. M. de Vries, Niek Begovich, Ann B. Siminovitch, Katherine A. Worthington, Jane Klareskog, Lars Gregersen, Peter K. Daly, Mark J. Plenge, Robert M. CA BIRAC Consortium Consortium, Y TI Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISM; MULTIPLE-SCLEROSIS; SUSCEPTIBILITY LOCI; CELIAC-DISEASE; PTPN22; REPLICATION; PTPRC; CD45; MUTATION AB To discover new rheumatoid arthritis (RA) risk loci, we systematically examined 370 SNPs from 179 independent loci with P < 0.001 in a published meta-analysis of RA genome-wide association studies (GWAS) of 3,393 cases and 12,462 controls(1). We used Gene Relationships Across Implicated Loci (GRAIL)(2), a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci(1,3-11). We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three were convincingly validated: CD2-CD58 (rs11586238, P = 1 x 10(-6) replication, P = 1 x 10(-9) overall), CD28 (rs1980422, P = 5 x 10(-6) replication, P = 1 x 10(-9) overall) and PRDM1 (rs548234, P = 1 x 10(-5) replication, P = 2 x 10(-8) overall). An additional four were replicated (P < 0.0023): TAGAP (rs394581, P = 0.0002 replication, P = 4 x 10(-7) overall), PTPRC (rs10919563, P = 0.0003 replication, P = 7 x 10(-7) overall), TRAF6-RAG1 (rs540386, P = 0.0008 replication, P = 4 x 10(-6) overall) and FCGR2A (rs12746613, P = 0.0022 replication, P = 2 x 10(-5) overall). Many of these loci are also associated to other immunologic diseases. C1 [Raychaudhuri, Soumya; Stahl, Eli A.; Chen, Robert; Coblyn, Jonathan; Costenbader, Karen H.; Cui, Jing; Kurreeman, Fina A. S.; Shadick, Nancy A.; Weinblatt, Michael E.; Karlson, Elizabeth W.; Plenge, Robert M.] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Raychaudhuri, Soumya; Thomson, Brian P.; Guiducci, Candace; Ardlie, Kristin G.; Burtt, Noel P.; De Jager, Phillip L.; Altshuler, David; Daly, Mark J.; Plenge, Robert M.] Broad Inst, Cambridge, MA USA. [Raychaudhuri, Soumya; Altshuler, David; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Remmers, Elaine F.; Kastner, Daniel L.] NIAMSD, Genet & Genom Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Eyre, Stephen; Hinks, Anne; Barton, Anne; Bowes, John; Flynn, Edward; Ke, Xiayi; Martin, Paul; Thomson, Wendy; Worthington, Jane] Univ Manchester, Arthrit Res Campaign Epidemiol Unit, Manchester, Lancs, England. [Catanese, Joseph J.; Chang, Monica; Li, Yonghong; Begovich, Ann B.] Celera, Alameda, CA USA. [Xie, Gang; Liu, Xiangdong; Siminovitch, Katherine A.] Univ Toronto, Mt Sinai Hosp, Dept Med, Toronto, ON M5G 1X5, Canada. [Xie, Gang; Liu, Xiangdong; Siminovitch, Katherine A.] Univ Hlth Network, Toronto, ON, Canada. [Alfredsson, Lars; Ding, Bo] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Amos, Christopher I.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Criswell, Lindsey A.] Univ Calif San Francisco, Dept Med, Rosalind Russell Med Res Ctr Arthrit, San Francisco, CA USA. [Crusius, J. Bart A.] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Immunogenet Lab, Amsterdam, Netherlands. [De Jager, Phillip L.] Brigham & Womens Hosp, Dept Neurol, Ctr Neurol Dis, Boston, MA 02115 USA. [Emery, Paul; Morgan, Ann W.] Univ Leeds, Leeds Inst Mol Med, Natl Inst Hlth Res, Leeds Musculoskeletal Biomed Res Unit, Leeds LS2 9JT, W Yorkshire, England. [Harrison, Pille; Wordsworth, Paul] Univ Oxford, Inst Musculoskeletal Sci, Botnar Res Ctr, Oxford, England. [Hocking, Lynne J.; Reid, David M.] Univ Aberdeen, Div Appl Med, Musculoskeletal & Genet Sect, Aberdeen AB9 1FX, Scotland. [Huizinga, Tom W. J.; Kurreeman, Fina A. S.; van der Helm-van Mil, Annette H. M.; Toes, Rene E. M.] Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands. [Lee, Annette T.; Gregersen, Peter K.] N Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. [Padyukov, Leonid; Klareskog, Lars] Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden. [Seielstad, Mark] Genome Inst Singapore, Singapore, Singapore. [Seldin, Michael F.] Univ Calif Davis, Rowe Program Genet, Davis, CA 95616 USA. [Steer, Sophia] Kings Coll Hosp London, Natl Hlth Serv Fdn Trust, London, England. [Tak, Paul P.; de Vries, Niek] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [van der Horst-Bruinsma, Irene E.] Vrije Univ Amsterdam, Med Ctr, Dept Rheumatol, Amsterdam, Netherlands. [Wilson, Anthony G.] Univ Sheffield, Sch Med & Biomed Sci, Sheffield, S Yorkshire, England. [Wolbink, Gert Jan] Jan van Breemen Inst, Amsterdam, Netherlands. [Wolbink, Gert Jan] Univ Amsterdam, Acad Med Ctr, Sanquin Res Landsteiner Lab, NL-1105 AZ Amsterdam, Netherlands. [Begovich, Ann B.] Roche Diagnost, Pleasanton, CA USA. RP Raychaudhuri, S (reprint author), Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, 75 Francis St, Boston, MA 02115 USA. EM soumya@broad.mit.edu; rplenge@partners.org RI Altshuler, David/A-4476-2009; de Vries, Niek/J-9348-2013; Siminovitch, Katherine/K-1475-2013; Worthington, Jane/M-9770-2014; Barton, Anne/N-2053-2014; Bowes, John/B-3472-2015; Hinks, Anne/E-1853-2015; OI Altshuler, David/0000-0002-7250-4107; de Vries, Niek/0000-0002-6257-8604; Worthington, Jane/0000-0003-0544-042X; Barton, Anne/0000-0003-3316-2527; Bowes, John/0000-0003-4659-031X; Hinks, Anne/0000-0001-8843-3967; McInnes, Iain/0000-0002-6462-4280; Hocking, Lynne J/0000-0002-2414-2826; Alfredsson, Lars/0000-0003-1688-6697; Seielstad, Mark/0000-0001-5783-1401; Martin, Paul/0000-0002-1016-6851; Klareskog, Lars/0000-0001-9601-6186; Thomson, Wendy/0000-0002-9022-5179; Eyre, Stephen/0000-0002-1251-6974; Padyukov, Leonid/0000-0003-2950-5670; Young-Min, Steven/0000-0001-8270-6207 FU US National Institutes of Health (NIH) Career Development Award [1K08AR055688-01A1]; American College of Rheumatology Bridge Grant; NIH [AI55314-3, U01 HG004171, DK62432, R01 DK083756-1, DK64869, NO1-AR-2-2263, RO1 AR44422]; Fox Trot Fund; William Randolph Hearst Fund of Harvard University; Burroughs Wellcome Fund; National Center for Research Resources [U54 RR020278]; Millennium Pharmaceuticals; Intramural Research Program of the National Institute of Arthritis; Musculoskeletal and Skin Diseases of the NIH; Canadian Institutes for Health Research [MOP79321, IIN-84042]; Ontario Research Fund [RE01061]; Canada Research Chair; Biogen-Idec; National Heart, Lung, and Blood Institute's (STAMPEED); [R01HL087676] FX S. R. is supported by a US National Institutes of Health (NIH) Career Development Award (1K08AR055688-01A1) and an American College of Rheumatology Bridge Grant. R. M. P. is supported by a K08 grant from the NIH (AI55314-3), a private donation from the Fox Trot Fund, the William Randolph Hearst Fund of Harvard University, the American College of Rheumatology 'Within Our Reach' campaign and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. M. J. D. is supported by NIH grants through the U01 (HG004171, DK62432) and R01 (DK083756-1, DK64869) mechanisms. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) Registry is supported by a grant from Millennium Pharmaceuticals and Biogen-Idec. The North American Rheumatoid Arthritis Consortium (NARAC) is supported by the NIH (NO1-AR-2-2263 and RO1 AR44422). This research was also supported in part by the Intramural Research Program of the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the NIH. This research was also supported in part by grants to KAS from the Canadian Institutes for Health Research (MOP79321 and IIN-84042) and the Ontario Research Fund (RE01061) and by a Canada Research Chair. We acknowledge the help of C. E. van der Schoot for healthy control samples for the Genetics Network Rheumatology Amsterdam (GENRA) and the help of B. A. C. Dijkmans, D. van Schaardenburg, A. S. Pe a, P. L. Klarenbeek, Z. Zhang, M. T. Nurmohammed, W. F. Lems, R. R. J. van de Stadt, W. H. Bos, J. Ursum, M. G. M. Bartelds, D. M. Gerlag, M. G. H. van der Sande, C. A. Wijbrandts and M. M. J. Herenius in gathering GENRA patient samples and data. We thank the Myocardial Infarction Genetics Consortium (MIGen) study for the use of genotype data from their healthy controls in our study. The MIGen study was funded by the US NIH and National Heart, Lung, and Blood Institute's SNP Typing for Association with Multiple Phenotypes from Existing Epidemiologic Data (STAMPEED) genomics research program R01HL087676 and a grant from the National Center for Research Resources. We thank the Johanna Seddon Progression of AMD Study, AMD Registry Study, Family Study of AMD, The US Twin Study of AMD and the Age-Related Eye Disease Study (AREDS) for use of genotype data from their healthy controls in our study. We thank D. Hafler and the Multiple Sclerosis collaborative for use of genotype data from their healthy controls recruited at Brigham and Women's Hospital. NR 43 TC 181 Z9 184 U1 4 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD DEC PY 2009 VL 41 IS 12 BP 1313 EP U76 DI 10.1038/ng.479 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 524LN UT WOS:000272144900013 PM 19898481 ER PT J AU Yang, XO Angkasekwinai, P Zhu, JF Peng, J Liu, ZD Nurieva, R Liu, XK Chung, Y Chang, SH Sun, B Dong, C AF Yang, Xuexian O. Angkasekwinai, Pornpimon Zhu, Jinfang Peng, Juan Liu, Zhiduo Nurieva, Roza Liu, Xikui Chung, Yeonseok Chang, Seon Hee Sun, Bing Dong, Chen TI Requirement for the basic helix-loop-helix transcription factor Dec2 in initial T(H)2 lineage commitment SO NATURE IMMUNOLOGY LA English DT Article ID T-CELLS; SCHISTOSOMA-MANSONI; TH2 DIFFERENTIATION; EXPRESSION; RESPONSES; GENE; JUNB; IL-2; IDENTIFICATION; GENERATION AB How naive CD4(+) T cells commit to the T helper type 2 (T(H)2) lineage is poorly understood. Here we show that the basic helix-loop-helix transcription factor Dec2 was selectively expressed in T(H)2 cells. CD4(+) T cells from Dec2- deficient mice showed defective T(H)2 differentiation in vitro and in vivo in an asthma model and in response to challenge with a parasite antigen. Dec2 promoted expression of interleukin 4 (IL-4), IL-5 and IL-13 during early T(H)2 differentiation and directly bound to and activated transcription of genes encoding the transcription factors JunB and GATA-3. As GATA-3 induces Dec2 expression, our findings also indicate a feed-forward regulatory circuit during T(H)2 differentiation. C1 [Yang, Xuexian O.; Angkasekwinai, Pornpimon; Peng, Juan; Nurieva, Roza; Liu, Xikui; Chung, Yeonseok; Chang, Seon Hee; Dong, Chen] Univ Texas Houston, MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. [Angkasekwinai, Pornpimon] Thammasat Univ, Fac Allied Hlth Sci, Pathum Than, Thailand. [Zhu, Jinfang] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Peng, Juan] Wuhan Univ, Zhongnan Hosp, Dept Resp Dis, Wuhan, Hubei, Peoples R China. [Liu, Zhiduo; Sun, Bing] Chinese Acad Sci, Inst Biochem & Cell Biol, Shanghai, Peoples R China. RP Dong, C (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Dept Immunol, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM xoyang@mdanderson.org; bsun@sibs.ac.cn; cdong@mdanderson.org RI dong, chen /B-3181-2009; Zhu, Jinfang/B-7574-2012; OI dong, chen /0000-0002-0084-9130; Chung, Yeonseok/0000-0001-5780-4841 FU National Institutes of Health; MD Anderson Center for Targeted Therapy; American Heart Association; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Ministry of Education of China; Leukemia and Lymphoma Society FX We thank S. Rivera and J. Parker-Thornburg of the MD Anderson Genetic Engineered Mouse Facility for help in generating knockout and transgenic animals; K. Murphy (Washington University) for the GFP-RV and GFP-RV-GATA-3 vectors; Y. Belkaid (National Institute of Allergy and Infectious Diseases, National Institutes of Health) for S. mansoni eggs and suggestions; and members of the Dong laboratory for help and discussion. Supported by the National Institutes of Health (C.D. and R.N.), the MD Anderson Center for Targeted Therapy (C.D. and R.N.), the American Heart Association (X.O.Y. and R.N.), the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (J.Z.), the Ministry of Education of China (J.P.) and the Leukemia and Lymphoma Society (C.D.). NR 40 TC 45 Z9 46 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD DEC PY 2009 VL 10 IS 12 BP 1260 EP U5 DI 10.1038/ni.1821 PG 8 WC Immunology SC Immunology GA 520TX UT WOS:000271872800009 PM 19881507 ER PT J AU Randall, KL Lambe, T Johnson, A Treanor, B Kucharska, E Domaschenz, H Whittle, B Tze, LE Enders, A Crockford, TL Bouriez-Jones, T Alston, D Cyster, JG Lenardo, MJ Mackay, F Deenick, EK Tangye, SG Chan, TD Camidge, T Brink, R Vinuesa, CG Batista, FD Cornall, RJ Goodnow, CC AF Randall, Katrina L. Lambe, Teresa Johnson, Andy Treanor, Bebhinn Kucharska, Edyta Domaschenz, Heather Whittle, Belinda Tze, Lina E. Enders, Anselm Crockford, Tanya L. Bouriez-Jones, Tiphaine Alston, Duncan Cyster, Jason G. Lenardo, Michael J. Mackay, Fabienne Deenick, Elissa K. Tangye, Stuart G. Chan, Tyani D. Camidge, Tahra Brink, Robert Vinuesa, Carola G. Batista, Facundo D. Cornall, Richard J. Goodnow, Christopher C. TI Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production SO NATURE IMMUNOLOGY LA English DT Article ID COMMON VARIABLE IMMUNODEFICIENCY; HUMORAL IMMUNE-RESPONSES; MARGINAL ZONE; POSITIVE SELECTION; PHOSPHATIDYLINOSITOL 3-KINASE; SIGNAL-TRANSDUCTION; NEGATIVE SELECTION; PLASMA-CELL; ANTIGEN; CD19 AB To identify genes and mechanisms involved in humoral immunity, we did a mouse genetic screen for mutations that do not affect the first wave of antibody to immunization but disrupt response maturation and persistence. The first two mutants identified had loss-of-function mutations in the gene encoding a previously obscure member of a family of Rho-Rac GTP-exchange factors, DOCK8. DOCK8-mutant B cells were unable to form marginal zone B cells or to persist in germinal centers and undergo affinity maturation. Dock8 mutations disrupted accumulation of the integrin ligand ICAM-1 in the B cell immunological synapse but did not alter other aspects of B cell antigen receptor signaling. Humoral immunodeficiency due to Dock8 mutation provides evidence that organization of the immunological synapse is critical for signaling the survival of B cell subsets required for long-lasting immunity. C1 [Randall, Katrina L.; Kucharska, Edyta; Domaschenz, Heather; Whittle, Belinda; Tze, Lina E.; Enders, Anselm; Vinuesa, Carola G.; Goodnow, Christopher C.] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 0200, Australia. [Randall, Katrina L.] Canberra Hosp, Dept Immunol, Garran, ACT, Australia. [Lambe, Teresa; Johnson, Andy; Crockford, Tanya L.; Bouriez-Jones, Tiphaine; Alston, Duncan; Cornall, Richard J.] Univ Oxford, Nuffield Dept Clin Med, Oxford, England. [Johnson, Andy] NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD USA. [Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD USA. [Treanor, Bebhinn; Batista, Facundo D.] Lincolns Inn Fields, London Res Inst, Canc Res UK, London, England. [Cyster, Jason G.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Cyster, Jason G.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Mackay, Fabienne] Monash Univ, Fac Med Nursing & Hlth Sci, Dept Immunol, Melbourne, Vic 3004, Australia. [Deenick, Elissa K.; Tangye, Stuart G.; Chan, Tyani D.; Camidge, Tahra; Brink, Robert] St Vincents Hosp, Garvan Inst Med Res, Darlinghurst, NSW 2010, Australia. RP Goodnow, CC (reprint author), Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 0200, Australia. EM richard.cornall@ndm.ox.ac.uk; chris.goodnow@anu.edu.au RI Brink, Robert/B-7910-2010; Enders, Anselm/B-1165-2011; Vinuesa, Carola/B-1108-2010; Mackay, Fabienne/B-7440-2008; Randall, Katrina/F-1883-2013; Tangye, Stuart/H-4023-2014; Lambe, Teresa/E-5733-2016; OI Brink, Robert/0000-0002-9586-3655; Enders, Anselm/0000-0001-5933-6463; Vinuesa, Carola/0000-0001-9799-0298; Mackay, Fabienne/0000-0002-6074-2693; Lambe, Teresa/0000-0001-7711-897X; Deenick, Elissa/0000-0002-9271-0004 FU Wellcome Trust; Australian Research Council; National Health and Medical Research Council; Medical Research Council; Ramaciotti Foundation; Deutsche Forschungsgemeinschaft; Cancer Research UK; Andrew McMichael Trust Fund; National Institute for Health Research Biomedical Research Centre Programme FX We thank M. Townsend, D. Howard, H. Ferry and C. Gillespie for technical assistance; the staff of the Australian National University Bioscience Division and Oxford Biomedical Services Unit for animal husbandry; the Australian Phenomics Facility genotyping and mapping team for genetic analysis, R. Rigby, B. Balakishnan and L. Beaton (Australian National University) for advice and reagents; J. Cannons and P. Schwartzberg (National Institutes of Health) for B cell-T cell conjugation methods and SAP-deficient mice; C. Jenne, S. Watson and T. Pham (University of California, San Francisco) for collaboration; R. Schwartz (National Institutes of Health) for support with advice and reagents; and H. Su (National Institutes of Health) for sharing findings about human DOCK8 deficiency before publication. Supported by the Wellcome Trust (R.J.C. and C.C.G.), the Australian Research Council (C.C.G.), the National Health and Medical Research Council (C.C.G., R.B., S.G.T., C.G.V., F.M., K.L.R., L.E.T. and E.K.D.), the Medical Research Council (T.L. and R.J.C.), The Ramaciotti Foundation (A.E. and C.C.G.), Deutsche Forschungsgemeinschaft (A.E.), Cancer Research UK (F.D.B.), the Andrew McMichael Trust Fund (R.J.C.) and the National Institute for Health Research Biomedical Research Centre Programme (R.J.C.). NR 57 TC 128 Z9 130 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD DEC PY 2009 VL 10 IS 12 BP 1283 EP U8 DI 10.1038/ni.1820 PG 10 WC Immunology SC Immunology GA 520TX UT WOS:000271872800012 PM 19898472 ER PT J AU Gadina, M O'Shea, JJ AF Gadina, Massimo O'Shea, John J. TI BENCH TO BEDSIDE Turncoat regulatory T cells SO NATURE MEDICINE LA English DT Editorial Material ID IN-VIVO; LINEAGE; GENERATION; PLASTICITY; LEADS C1 [Gadina, Massimo] NIAMSD, Translat Immunol Sect, Bethesda, MD 20892 USA. [O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. RP Gadina, M (reprint author), NIAMSD, Translat Immunol Sect, Bethesda, MD 20892 USA. EM gadinama@mail.nih.gov FU Intramural NIH HHS [ZIA AR041161-02, ZIC AR041181-01, Z01 AR041159-01, Z01 AR041160-01, Z01 AR041106-14, Z01 AR041132-07, ZIA AR041159-02, ZIA AR041167-02, ZIA AR041106-15, Z01 AR041106-13, Z01 AR041167-01] NR 9 TC 3 Z9 5 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD DEC PY 2009 VL 15 IS 12 BP 1365 EP 1365 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 527YS UT WOS:000272407800015 PM 19966774 ER PT J AU Cerchietti, LC Lopes, EC Yang, SN Hatzi, K Bunting, KL Tsikitas, LA Mallik, A Robles, AI Walling, J Varticovski, L Shaknovich, R Bhalla, KN Chiosis, G Melnick, A AF Cerchietti, Leandro C. Lopes, Eloisi C. Yang, Shao Ning Hatzi, Katerina Bunting, Karen L. Tsikitas, Lucas A. Mallik, Alka Robles, Ana I. Walling, Jennifer Varticovski, Lyuba Shaknovich, Rita Bhalla, Kapil N. Chiosis, Gabriela Melnick, Ari TI A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas SO NATURE MEDICINE LA English DT Article ID MESSENGER-RNA DECAY; TYROSINE KINASE; CANCER-CELLS; HEAT-SHOCK-PROTEIN-90; EXPRESSION; CHAPERONE; DEGRADATION; APOPTOSIS; BINDING; PHOSPHORYLATION AB We report that heat shock protein 90 (Hsp90) inhibitors selectively kill diffuse large B cell lymphomas (DLBCLs) that depend on the BCL-6 transcriptional repressor. We found that endogenous Hsp90 interacts with BCL-6 in DLBCL cells and can stabilize BCL-6 mRNA and protein. Hsp90 formed a complex with BCL-6 at its target promoters, and Hsp90 inhibitors derepressed BCL-6 target genes. A stable mutant of BCL-6 rescued DLBCL cells from Hsp90 inhibitor-induced apoptosis. BCL-6 and Hsp90 were almost invariantly coexpressed in the nuclei of primary DLBCL cells, suggesting that their interaction is relevant in this disease. We examined the pharmacokinetics, toxicity and efficacy of PU-H71, a recently developed purine-derived Hsp90 inhibitor. PU-H71 preferentially accumulated in lymphomas compared to normal tissues and selectively suppressed BCL-6-dependent DLBCLs in vivo, inducing reactivation of key BCL-6 target genes and apoptosis. PU-H71 also induced cell death in primary human DLBCL specimens. C1 [Lopes, Eloisi C.; Chiosis, Gabriela] Sloan Kettering Inst, Dept Mol Pharmacol & Chem, New York, NY USA. [Cerchietti, Leandro C.; Yang, Shao Ning; Hatzi, Katerina; Bunting, Karen L.; Tsikitas, Lucas A.; Mallik, Alka; Melnick, Ari] Cornell Univ, Weill Cornell Med Coll, Div Hematol & Oncol, New York, NY 10021 USA. [Cerchietti, Leandro C.; Hatzi, Katerina; Bunting, Karen L.; Melnick, Ari] Cornell Univ, Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10021 USA. [Robles, Ana I.; Varticovski, Lyuba] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Walling, Jennifer] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. [Shaknovich, Rita] Cornell Univ, Weill Cornell Med Coll, Dept Pathol, New York, NY 10021 USA. [Bhalla, Kapil N.] Georgia Canc Ctr, Coll Med, Augusta, GA USA. RP Chiosis, G (reprint author), Sloan Kettering Inst, Dept Mol Pharmacol & Chem, New York, NY USA. EM chiosisg@mskcc.org; amm2014@med.cornell.edu OI Cerchietti, Leandro/0000-0003-0608-1350 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [R56 CA104348, R01 CA104348, R01 CA104348-05, R01-CA10434, R56 CA104348-06] NR 37 TC 88 Z9 90 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD DEC PY 2009 VL 15 IS 12 BP 1369 EP U3 DI 10.1038/nm.2059 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 527YS UT WOS:000272407800016 PM 19966776 ER PT J AU Barry, CE Boshoff, HI Dartois, V Dick, T Ehrt, S Flynn, J Schnappinger, D Wilkinson, RJ Young, D AF Barry, Clifton E., III Boshoff, Helena I. Dartois, Veronique Dick, Thomas Ehrt, Sabine Flynn, JoAnne Schnappinger, Dirk Wilkinson, Robert J. Young, Douglas TI The spectrum of latent tuberculosis: rethinking the biology and intervention strategies SO NATURE REVIEWS MICROBIOLOGY LA English DT Review ID NONREPLICATING MYCOBACTERIUM-TUBERCULOSIS; STATIONARY-PHASE CULTURES; T-CELL RESPONSES; PULMONARY TUBERCULOSIS; GENE-EXPRESSION; ISONIAZID PROPHYLAXIS; RABBIT MODEL; CYNOMOLGUS MACAQUES; BACTERICIDAL ACTION; LOGARITHMIC-PHASE AB Immunological tests provide evidence of latent tuberculosis in one third of the global population, which corresponds to more than two billion individuals. Latent tuberculosis is defined by the absence of clinical symptoms but carries a risk of subsequent progression to clinical disease, particularly in the context of co-infection with HIV. In this Review we discuss the biology of latent tuberculosis as part of a broad range of responses that occur following infection with Mycobacterium tuberculosis, which result in the formation of physiologically distinct granulomatous lesions that provide microenvironments with differential ability to support or suppress the persistence of viable bacteria. We then show how this model can be used to develop a rational programme to discover effective drugs for the eradication of M. tuberculosis infection. C1 [Wilkinson, Robert J.; Young, Douglas] Natl Inst Med Res, MRC, Div Mycobacterial Res, London NW7 1AA, England. [Barry, Clifton E., III; Boshoff, Helena I.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Dartois, Veronique; Dick, Thomas] Novartis Inst Trop Dis, Singapore 138670, Singapore. [Ehrt, Sabine; Schnappinger, Dirk] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA. [Flynn, JoAnne] Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. [Wilkinson, Robert J.] Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Wilkinson, Robert J.; Young, Douglas] Univ London Imperial Coll Sci Technol & Med, Ctr Mol Microbiol & Infect, London SW7 2AZ, England. [Wilkinson, Robert J.; Young, Douglas] Univ London Imperial Coll Sci Technol & Med, Div Med, London SW7 2AZ, England. RP Young, D (reprint author), Natl Inst Med Res, MRC, Div Mycobacterial Res, London NW7 1AA, England. EM d.young@imperial.ac.uk RI Barry, III, Clifton/H-3839-2012; OI Wilkinson, Robert/0000-0002-2753-1800 FU Bill and Melinda Gates Foundation; Wellcome Trust; National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) [RO1 HL075845] FX We are grateful to colleagues in the Grand Challenges in Global Health project "Drugs for Treatment of Latent Tuberculosis" for stimulating discussion and to the Bill and Melinda Gates Foundation and the Wellcome Trust for financial support. This work was also funded (in part) by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) and by NIH RO1 HL075845 (J.L.F.). We also thank our Novartis colleagues in Singapore, Basel, Cambridge and La Jolla for discussions and collaboration. NR 92 TC 543 Z9 550 U1 18 U2 100 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD DEC PY 2009 VL 7 IS 12 BP 845 EP 855 DI 10.1038/nrmicro2236 PG 11 WC Microbiology SC Microbiology GA 519HW UT WOS:000271757000009 PM 19855401 ER PT J AU Hurst, FP Neff, RT Jindal, RM Roberts, JR Lentine, KL Agodoa, LY Abbott, KC AF Hurst, Frank P. Neff, Robert T. Jindal, Rahul M. Roberts, Jefferson R. Lentine, Krista L. Agodoa, Lawrence Y. Abbott, Kevin C. TI Incidence, predictors and associated outcomes of rhabdomyolysis after kidney transplantation SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors; calcineurin inhibitors; renal transplantation; rhabdomyolysis; USRDS ID SICKLE-CELL TRAIT; CERIVASTATIN-INDUCED RHABDOMYOLYSIS; RENAL-TRANSPLANT; PATIENT; CYCLOSPORINE; SIMVASTATIN; TACROLIMUS; RECIPIENTS; ATORVASTATIN; THERAPY AB Background. There are several case reports of rhabdomyolysis (RM) in renal transplant recipients, but the actual incidence of this complication is not known. Most of the reported cases have been attributed to drug-drug interactions with calcineurin inhibitors, with the majority of interactions reported between cyclosporine and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins). Pharmacokinetic studies have demonstrated that cyclosporine increases statin drug levels, presumably via competitive inhibition of cytochrome P450 3A4. Methods. In a retrospective cohort of 20 366 adult Medicare primary renal transplant recipients in the USRDS database transplanted from 1 January 2003 to 31 July 2005 and followed through 31 December 2005, we assessed Medicare claims for RM and dyslipidaemia (HPL), which was used as a surrogate for statin use. Results. The incidence rate of RM post-transplant for the study period was 1.4 (95% CI 1.1-1.8) per 1000 person-years. By Cox regression analysis, cyclosporine (versus tacrolimus) use [AHR 2.36 (95% CI 1.23-4.35); P=0.006] and black race [AHR 2.33 (95% CI 1.30-4.17); P = 0.005] were associated with RM. By Cox non-proportional hazards regression, RM was associated with graft loss (including death) [AHR 2.84 (95% CI 1.70-4.72); P < 0.001]. Conclusions. RM is a rare complication after renal transplantation and is significantly associated with allograft loss (including death). RM is significantly more likely to occur with cyclosporine (versus tacrolimus)-based immunosuppression and possibly in persons of black race. Increased surveillance for RM is warranted in these at-risk patients. C1 [Hurst, Frank P.; Neff, Robert T.; Abbott, Kevin C.] Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. [Hurst, Frank P.; Neff, Robert T.; Roberts, Jefferson R.; Abbott, Kevin C.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [Jindal, Rahul M.] Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC 20307 USA. [Roberts, Jefferson R.] Walter Reed Army Med Ctr, Rheumatol Serv, Washington, DC 20307 USA. [Lentine, Krista L.] St Louis Univ, Sch Med, Div Nephrol, Ctr Outcomes Res, St Louis, MO USA. [Agodoa, Lawrence Y.] NIDDK, NIH, Bethesda, MD USA. RP Hurst, FP (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. EM frank.hurst@us.army.mil OI Abbott, Kevin/0000-0003-2111-7112 NR 33 TC 13 Z9 13 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD DEC PY 2009 VL 24 IS 12 BP 3861 EP 3866 DI 10.1093/ndt/gfp416 PG 6 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 524ZR UT WOS:000272183400051 PM 19729463 ER PT J AU Wen, PY Yung, WKA Lamborn, KR Norden, AD Cloughesy, TF Abrey, LE Fine, HA Chang, SM Robins, HI Fink, K DeAngelis, LM Mehta, M Di Tomaso, E Drappatz, J Kesari, S Ligon, KL Aldape, K Jain, RK Stiles, CD Egorin, MJ Prados, MD AF Wen, Patrick Y. Yung, W. K. Alfred Lamborn, Kathleen R. Norden, Andrew D. Cloughesy, Timothy F. Abrey, Lauren E. Fine, Howard A. Chang, Susan M. Robins, H. Ian Fink, Karen DeAngelis, Lisa M. Mehta, Minesh Di Tomaso, Emmanuelle Drappatz, Jan Kesari, Santosh Ligon, Keith L. Aldape, Ken Jain, Rakesh K. Stiles, Charles D. Egorin, Merrill J. Prados, Michael D. TI Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08) SO NEURO-ONCOLOGY LA English DT Article DE imatinib; meningioma; pharmacokinetics; toxicities ID CHRONIC MYELOID-LEUKEMIA; GROWTH-FACTOR RECEPTORS; MALIGNANT GLIOMAS; TYROSINE KINASE; FACTOR PDGF; EXPRESSION; HYDROXYUREA; PHARMACOKINETICS; AUTOCRINE; CELLS AB Platelet-derived growth factor (PDGF) and its receptors (PDGFR) are frequently coexpressed in meningiomas, potentially contributing to their pathogenesis. The North American Brain Tumor Consortium conducted a phase II study to evaluate the therapeutic potential of imatinib mesylate (Gleevec), a PDGFR inhibitor, in patients with recurrent meningiomas. Patients were stratified into benign (WHO grade I) meningiomas or atypical (WHO grade II) and malignant (WHO grade III) meningiomas. The primary end point was 6-month progression-free survival (6M-PFS). Patients requiring enzyme-inducing antiepileptic drugs were ineligible. Patients received imatinib at a dose of 600 mg/day for the first 4-week cycle and then gradually increased to 800 mg/day for subsequent cycles, if there were no unacceptable toxicities. Plasma concentrations of imatinib and its active metabolite, CGP74588, were assessed. Twenty-three heavily pre-treated patients were enrolled into the study (13 benign, 5 atypical, and 5 malignant meningiomas), of whom 22 were eligible. The study was closed prematurely due to slow accrual. Tissue was available only from a minority of patients, but in these specimens there was uniform distribution of PDGFR, the drug target. Imatinib was generally well tolerated. Of 19 patients evaluable for response, 10 progressed at the first scan, and 9 were stable. There were no complete or partial responses. Overall median PFS was 2 months (range, 0.7-34 months); 6M-PFS was 29.4%. For benign meningiomas, median PFS was 3 months (range, 1.1-34 months); 6M-PFS was 45%. For atypical and malignant meningiomas, median PFS was 2 months (range, 0.7-3.7 months); 6M-PFS was 0%. Cycle I trough concentrations of imatinib and CGP74588 were 2,129 +/- 1,600 ng/ml and 517 +/- 326 ng/ml, respectively. Single-agent imatinib was well tolerated but had no significant activity in recurrent meningiomas. Trough Plasma concentrations of imatinib exceeded those associated with imatinib activity in chronic myelogenous leukemia. Neuro-Oncology 11, 853-860, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00173, March 17, 2009. URL http://neuro-oncology.dukejournals.org; DOI: 10.1215/15228517-2009-010) C1 [Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. [Yung, W. K. Alfred; Aldape, Ken] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lamborn, Kathleen R.; Chang, Susan M.; Prados, Michael D.] Univ Calif San Francisco, San Francisco Med Ctr, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Abrey, Lauren E.; DeAngelis, Lisa M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Fine, Howard A.] NIH, Neurooncol Branch, Bethesda, MD 20892 USA. [Robins, H. Ian; Mehta, Minesh] Univ Wisconsin, Madison, WI USA. [Fink, Karen] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Di Tomaso, Emmanuelle; Jain, Rakesh K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Egorin, Merrill J.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. RP Wen, PY (reprint author), Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, SW430D,44 Binney St, Boston, MA 02115 USA. EM pwen@partners.org RI Kesari, Santosh/E-8461-2013; OI mehta, minesh/0000-0002-4812-5713 FU National Institutes of Health to the North American Brain Tumor Consortium (NABTC) [CA 62399] FX Support for this article, which is designated the NABTC Study 01-08, was received through prime award CA 62399 from the National Institutes of Health to the North American Brain Tumor Consortium (NABTC) investigators who coauthored this article and through the individual NABTC and General Clinical Research Center (GCRC) grants listed below. NR 49 TC 59 Z9 60 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD DEC PY 2009 VL 11 IS 6 BP 853 EP 860 DI 10.1215/15228517-2009-010 PG 8 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 535MU UT WOS:000272974100015 PM 19293394 ER PT J AU Nam, DH Lee, J Joo, KM Jin, J Kang, BG Kong, DS Lee, JI Hong, SC Kim, JH AF Nam, Do-Hyun Lee, Jeongwu Joo, Kyeung Min Jin, Juyoun Kang, Bong Gu Kong, Doo-Sik Lee, Jung-Il Hong, Seung-Chyul Kim, Jong Hyun TI AN ESSENTIAL ROLE OF C-MET/HGF SIGNALING IN GLIOBLASTOMA-INITIATING CELLS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 3rd Quadrennial Meeting of the World-Federation-of-Neuro-Oncoloyg/6th Meeting of the Asian-Society-for-Neuro-Oncology CY MAY 11-14, 2009 CL Yokohama, JAPAN SP World Federat Neuro Oncol, Asian Soc Neuro Oncol C1 [Nam, Do-Hyun; Joo, Kyeung Min; Jin, Juyoun; Kang, Bong Gu; Kong, Doo-Sik; Lee, Jung-Il; Hong, Seung-Chyul; Kim, Jong Hyun] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurosurg, Seoul, South Korea. [Nam, Do-Hyun; Joo, Kyeung Min; Jin, Juyoun; Kang, Bong Gu; Kong, Doo-Sik; Lee, Jung-Il; Hong, Seung-Chyul; Kim, Jong Hyun] Sungkyunkwan Univ, Sch Med, Samsung Biomed Res Inst, Seoul, South Korea. [Lee, Jeongwu] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD DEC PY 2009 VL 11 IS 6 BP 878 EP 878 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 535MU UT WOS:000272974100039 ER PT J AU Lai, JS Gershon, R Blitz, D Magasi, S Nowinski, C Reuben, D Rymer, W Weintraub, S Wagster, M AF Lai, Jin-Shei Gershon, Richard Blitz, David Magasi, Susan Nowinski, Cindy Reuben, David Rymer, William Weintraub, Sandra Wagster, Molly TI A NEW ASSESSMENT TOOL FOR MEASURING NEUROLOGICAL AND BEHAVIORAL FUNCTION ACROSS LIFESPAN: THE NIH TOOLBOX SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 3rd Quadrennial Meeting of the World-Federation-of-Neuro-Oncoloyg/6th Meeting of the Asian-Society-for-Neuro-Oncology CY MAY 11-14, 2009 CL Yokohama, JAPAN SP World Federat Neuro Oncol, Asian Soc Neuro Oncol C1 [Lai, Jin-Shei; Gershon, Richard; Blitz, David; Magasi, Susan; Nowinski, Cindy] NorthShore Univ HealthSyst, Ctr Outcomes Res & Educ, Evanston, IL USA. [Lai, Jin-Shei; Gershon, Richard; Magasi, Susan; Nowinski, Cindy; Weintraub, Sandra] Northwestern Univ, Chicago, IL 60611 USA. [Rymer, William] Rehabil Inst Chicago, Chicago, IL 60611 USA. [Reuben, David] Univ Calif Los Angeles, Los Angeles, CA USA. [Wagster, Molly] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD DEC PY 2009 VL 11 IS 6 BP 911 EP 911 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 535MU UT WOS:000272974100171 ER PT J AU Joo, KM Lee, J Jin, J Kang, BG Kong, DS Lee, JI Hong, SC Kim, JH Nam, DH AF Joo, Kyeung Min Lee, Jeongwu Jin, Juyoun Kang, Bong Gu Kong, Doo-Sik Lee, Jung-Ii Hong, Seung-Chyul Kim, Jong Hyun Nam, Do-Hyun TI HUMAN NEURAL STEM CELLS CAN TARGET AND DELIVER THERAPEUTIC GENES TO BREAST CANCER BRAIN METASTASES SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 3rd Quadrennial Meeting of the World-Federation-of-Neuro-Oncoloyg/6th Meeting of the Asian-Society-for-Neuro-Oncology CY MAY 11-14, 2009 CL Yokohama, JAPAN SP World Federat Neuro Oncol, Asian Soc Neuro Oncol C1 [Joo, Kyeung Min; Jin, Juyoun; Kang, Bong Gu; Kong, Doo-Sik; Lee, Jung-Ii; Hong, Seung-Chyul; Kim, Jong Hyun; Nam, Do-Hyun] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurosurg, Seoul, South Korea. [Joo, Kyeung Min; Jin, Juyoun; Kang, Bong Gu; Kong, Doo-Sik; Lee, Jung-Ii; Hong, Seung-Chyul; Kim, Jong Hyun; Nam, Do-Hyun] Sungkyunkwan Univ, Sch Med, Samsung Biomed Res Inst, Seoul, South Korea. [Lee, Jeongwu] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD DEC PY 2009 VL 11 IS 6 BP 927 EP 927 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 535MU UT WOS:000272974100240 ER PT J AU Chi, AS Gerstner, ER Eichler, AF Chea, HK Shearer, N Drappatz, J Wen, PY Ivy, SP Loeffler, JS Sorensen, AG Jain, RK Batchelor, TT AF Chi, Andrew S. Gerstner, Elisabeth R. Eichler, April F. Chea, Houng K. Shearer, Nancy Drappatz, Jan Wen, Patrick Y. Ivy, S. Percy Loeffler, Jay S. Sorensen, A. Gregory Jain, Rakesh K. Batchelor, Tracy T. TI A PHASE IB TRIAL OF CEDIRANIB IN ADDITION TO STANDARD TEMOZOLOMIDE AND RADIATION THERAPY IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 3rd Quadrennial Meeting of the World-Federation-of-Neuro-Oncoloyg/6th Meeting of the Asian-Society-for-Neuro-Oncology CY MAY 11-14, 2009 CL Yokohama, JAPAN SP World Federat Neuro Oncol, Asian Soc Neuro Oncol C1 [Chi, Andrew S.; Gerstner, Elisabeth R.; Eichler, April F.; Chea, Houng K.; Shearer, Nancy; Batchelor, Tracy T.] Massachusetts Gen Hosp, Dept Neurol, Div Neurooncol, Boston, MA 02114 USA. [Drappatz, Jan; Wen, Patrick Y.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Ivy, S. Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Loeffler, Jay S.; Jain, Rakesh K.] Harvard Univ, Sch Med, Dept Radiat Oncol, Massachusetts Gen Hosp, Boston, MA USA. [Sorensen, A. Gregory] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD DEC PY 2009 VL 11 IS 6 BP 946 EP 947 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 535MU UT WOS:000272974100333 ER PT J AU Clarimon, J Djaldetti, R Lleo, A Guerreiro, RJ Molinuevo, JL Paisan-Ruiz, C Gomez-Isla, T Blesa, R Singleton, A Hardy, J AF Clarimon, J. Djaldetti, R. Lleo, A. Guerreiro, R. J. Molinuevo, J. L. Paisan-Ruiz, C. Gomez-Isla, T. Blesa, R. Singleton, A. Hardy, J. TI Whole genome analysis in a consanguineous family with early onset Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Dementia; Alzheimer's disease, Genetics; Early-onset; Recessive; Autozygosity ID APOLIPOPROTEIN-E; ASSOCIATION; POPULATION; ALLELE AB Early-onset. Alzheimer's disease (EOAD) is a clinically and genetically heterogeneous condition in which the typical features appear significantly earlier in life (before 65 years). Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in autosomal dominant forms of EOAD. However, in about 50% of Mendelian cases and in most of the sporadic EOAD patients, no mutations have been found. We present clinical characteristics of an Israeli family comprising two affected siblings with EOAD born to neurologically healthy parents who were first cousins (both parents died after 90 years old). Sequence analysis of PSEN1, PSEN2, APP, TAU, PGRN, and PRNP failed to reveal any mutations in the affected siblings. Because the disease in this family is consistent with an autosomal recessive mode of inheritance we identified all homozygous regions identical by descent (IBD) in both siblings, by high-density SKIP genotyping. We provide here the first catalog of autozygosity in EOAD and suggest that the regions identified are excellent candidate loci for a recessive genetic lesion causing this disease. (C) 2008 Elsevier Inc. All rights reserved. C1 [Clarimon, J.; Lleo, A.; Gomez-Isla, T.; Blesa, R.] Hosp Santa Creu & Sant Pau, Dept Neurol, Alzheimers Lab, Memory Unit, Barcelona 08025, Spain. [Clarimon, J.; Lleo, A.; Gomez-Isla, T.; Blesa, R.] Hosp Santa Creu & Sant Pau, CIBERNED, Barcelona 08025, Spain. [Djaldetti, R.] Rabin Med Ctr, Dept Neurol, Petah Tiqwa, Israel. [Djaldetti, R.] Felsenstein Res Ctr, Petah Tiqwa, Israel. [Djaldetti, R.] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Guerreiro, R. J.; Paisan-Ruiz, C.; Singleton, A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Guerreiro, R. J.] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal. [Molinuevo, J. L.] Hosp Clin & Univ Barcelona, Inst Neurosci, Dept Neurol, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain. [Paisan-Ruiz, C.; Hardy, J.] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Paisan-Ruiz, C.; Hardy, J.] Inst Neurol, Reta Lila Weston Labs, London WC1N 3BG, England. RP Clarimon, J (reprint author), Hosp Santa Creu & Sant Pau, Dept Neurol, Alzheimers Lab, Memory Unit, St Antoni Ma Claret 167, Barcelona 08025, Spain. RI Paisan-Ruiz, Coro/C-2912-2009; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Guerreiro, Rita/A-1327-2011; OI Clarimon, Jordi/0000-0002-6824-6942; Molinuevo, Jose Luis/0000-0003-0485-6001 FU "CIBERNED", Ministerio de Sanidad y Consurno, Spain FX We are indebted to the patients for their generous participation in this work. The present work was partially supported by a research Grant from "CIBERNED", Ministerio de Sanidad y Consurno, Spain. NR 14 TC 10 Z9 10 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD DEC PY 2009 VL 30 IS 12 BP 1986 EP 1991 DI 10.1016/j.neurobiolaging.2008.02.008 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 512LZ UT WOS:000271252200010 PM 18387709 ER PT J AU Sim, VL Caughey, B AF Sim, Valerie L. Caughey, Byron TI Ultrastructures and strain comparison of under-glycosylated scrapie prion fibrils SO NEUROBIOLOGY OF AGING LA English DT Article DE Prion; Glycosylphosphatidylinositol anchor; PrP; Amyloid; Protofilament; Scrapie; Neurodegeneration; Strain comparison; Fibril; Electron microscopy; Atomic force microscopy; Ultrastructure ID CREUTZFELDT-JAKOB-DISEASE; ATOMIC-FORCE MICROSCOPY; PROTEIN AMYLOID FIBRILS; IN-VITRO; SPONGIFORM ENCEPHALOPATHY; INFECTED BRAIN; CONFORMATION; POLYMORPHISM; AGGREGATION; CONVERSION AB Prions, composed primarily of misfolded, often fibrillar, polymers of prion protein, have poorly understood structures. Heavy surface glycosylation may obscure visualization of their fibrillar cores, so we purified severely under-glycosylated prion protein fibrils from scrapie-infected transgenic mice expressing anchorless prion protein Using electron and atomic force microscopy, we obtained dimensions and morphological information about prion protein core protofilaments which variably intertwined to form scrapie fibrils. Occasional isolated protofilaments were observed, suggesting that the lateral association of protofilaments is neither essential nor invariant in prion protein polymerization. Strain comparisons suggested basic structural differences, ME7 and 22L fibrils contained thinner protofilaments, 22L fibrils preferred left-handed twists, and 22L fibril periodicities averaged 106 nm per half-turn, compared with 64 and 66 nm for RML and ME7 fibrils, respectively The strains displayed overlapping fibril morphologies, providing evidence that prion fibril morphology is influenced, but not dictated, by strain-dependent differences in protofilament. structure. These measurements of the amyloid core of scrapie fibrils should aid development of models of prion structure and strain determination. Published by Elsevier Inc. C1 [Sim, Valerie L.; Caughey, Byron] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Sim, VL (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 South 4th St, Hamilton, MT 59840 USA. RI Sim, Valerie/C-4137-2013 OI Sim, Valerie/0000-0002-0088-8666 FU U.S. National Institute of Allergy and Infectious Diseases; Alberta Heritage Foundation for Medical Research FX This research was funded by the Intramural Research Program of the U.S. National Institute of Allergy and Infectious Diseases. V Sim is also supported by a clinical research fellowship from The Alberta Heritage Foundation for Medical Research We thank G. Baron for suggestions on purifying anchorless PrP-res, and G. Raymond, R. Race. K Meade-White, and B. Chesebro for providing the infected and uninfected anchorless and wildtype mouse brains. We acknowledge G. Raymond and A. Hughson for preparation of the standard PrP-res samples, and thank F. Hayes and D. Dorward for instruction in use of the transmission and scanning electron microscopes. We also thank B. Chesebro, R. Moore, and S. Best for the critical reading of this manuscript. NR 38 TC 44 Z9 44 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD DEC PY 2009 VL 30 IS 12 BP 2031 EP 2042 DI 10.1016/j.neurobiolaging.2008.02.016 PG 12 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 512LZ UT WOS:000271252200015 PM 18394757 ER PT J AU Weissman, L de Souza-Pinto, NC Mattson, MP Bohr, VA AF Weissman, Lior de Souza-Pinto, Nadja C. Mattson, Mark P. Bohr, Vilhelm A. TI DNA base excision repair activities in mouse models of Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; DNA repair; Oxidative stress; Oxidative DNA damage AB Alzheimer's disease (AD) has been correlated with elevated levels of oxidative DNA damage. Base excision repair (BER) is the main repair pathway for the removal of oxidative DNA base modifications. We have recently found significant functional deficiencies in BER in brains of sporadic AD and amnestic mild cognitive impairment patients. In this study we tested whether altered BER activities are associated with appearance of symptoms in different brain regions of pre-symptomatic and symptomatic mice harboring mutant APP alone or in combination with Tau and PSI. Our results suggest that unlike in humans, the development of AD-like pathology in the studied mouse models is not associated with deficiencies in BER. (C) 2008 Elsevier Inc. All rights resen.-ed. C1 [Weissman, Lior; de Souza-Pinto, Nadja C.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Mattson, Mark P.] NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012; Souza-Pinto, Nadja/C-3462-2013; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X; FU Intramural NIH HHS [Z01 AG000733-12, Z01 AG000726-15, Z01 AG000727-15, Z01 AG000735-11] NR 0 TC 17 Z9 17 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD DEC PY 2009 VL 30 IS 12 BP 2080 EP 2081 DI 10.1016/j.neurobiolaging.2008.02.014 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 512LZ UT WOS:000271252200019 PM 18378358 ER PT J AU Wagster, MV AF Wagster, Molly V. TI Cognitive Aging Research: An Exciting Time for a Maturing Field SO NEUROPSYCHOLOGY REVIEW LA English DT Editorial Material C1 NIA, Div Neurosci, Bethesda, MD 20892 USA. RP Wagster, MV (reprint author), NIA, Div Neurosci, 7201 Wisconsin Ave,Gateway Bldg Suite 350, Bethesda, MD 20892 USA. EM wagsterm@nia.nih.gov NR 0 TC 3 Z9 3 U1 1 U2 2 PU CONSULTANTS BUREAU/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1040-7308 J9 NEUROPSYCHOL REV JI Neuropsychol. Rev. PD DEC PY 2009 VL 19 IS 4 BP 523 EP 525 DI 10.1007/s11065-009-9121-2 PG 3 WC Psychology, Clinical; Neurosciences SC Psychology; Neurosciences & Neurology GA 524XR UT WOS:000272178200008 PM 19943133 ER PT J AU Hasler, G Mondillo, K Drevets, WC Blair, JR AF Hasler, Gregor Mondillo, Krystal Drevets, Wayne C. Blair, James R. TI Impairments of Probabilistic Response Reversal and Passive Avoidance Following Catecholamine Depletion SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE dopamine; norepinephrine; reinforcement learning; remitted major depressive disorder; attention; stroop ID PREFRONTAL SEROTONIN DEPLETION; CONGRUENT MEMORY BIAS; ORBITOFRONTAL CORTEX; COGNITIVE INFLEXIBILITY; TRYPTOPHAN DEPLETION; PARKINSONS-DISEASE; NUCLEUS-ACCUMBENS; DECISION-MAKING; DOPAMINE; REWARD AB Catecholamines, particularly dopamine, have been implicated in various aspects of the reward function including the ability to learn through reinforcement and to modify flexibly responses to changing reinforcement contingencies. We examined the impact of catecholamine depletion (CD) achieved by oral administration of alpha-methyl-paratyrosine (AMPT) on probabilistic reversal learning and passive avoidance (PA) in 15 female subjects with major depressive disorder in full remission (RMDD) and 12 healthy female controls. The CD did not affect significantly the acquisition phase of the reversal learning task. However, CD selectively impaired reversal of the 80-20 contingency pair. In the PA learning task, CD was associated with reduced responding toward rewarding stimuli, although the RMDD and control subjects did not differ regarding these CD-induced changes in reward processing. Interestingly, the performance decrement produced by AMPT on both of these tasks was associated with the level of decreased metabolism in the perigenual anterior cingulate cortex. In an additional examination using the affective Stroop task we found evidence for impaired executive attention as a trait abnormality in MDD. In conclusion, this study showed specific effects of CD on the processing of reward-related stimuli in humans and confirms earlier investigations that show impairments of executive attention as a neuropsychological trait in affective illness. Neuropsychopharmacology (2009) 34, 2691-2698; doi:10.1038/npp.2009.95; published online 12 August 2009 C1 [Hasler, Gregor] Univ Zurich Hosp, Dept Psychiat, CH-8091 Zurich, Switzerland. [Mondillo, Krystal] Ohio Univ, Dept Psychol, Easton, PA USA. [Drevets, Wayne C.; Blair, James R.] NIMH, Mood & Anxiety Disorders Program, Sect Brain Imaging, NIH, Bethesda, MD 20892 USA. RP Hasler, G (reprint author), Univ Zurich Hosp, Dept Psychiat, Culmannstr 8, CH-8091 Zurich, Switzerland. EM g.hasler@bluewin.ch RI Hasler, Gregor/E-4845-2012 OI Hasler, Gregor/0000-0002-8311-0138 FU National Institutes of Mental Health FX This research was supported by the Intramural Research Program of the National Institutes of Mental Health. Compensation for professional services Dr Hasler: Eli Lilly, Switzerland; Servier, Switzerland. Krystal Mondillo: none. Dr Drevets: American Psychiatric Association. Dr Blair: none. NR 52 TC 13 Z9 13 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2009 VL 34 IS 13 BP 2691 EP 2698 DI 10.1038/npp.2009.95 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 517TC UT WOS:000271639700010 PM 19675538 ER PT J AU Chauvet, C Lardeux, V Goldberg, SR Jaber, M Solinas, M AF Chauvet, Claudia Lardeux, Virginie Goldberg, Steven R. Jaber, Mohamed Solinas, Marcello TI Environmental Enrichment Reduces Cocaine Seeking and Reinstatement Induced by Cues and Stress but Not by Cocaine SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE environment; addiction; stress; relapse; protracted abstinence; behavioral therapy ID ANXIOGENIC DRUG YOHIMBINE; NORADRENERGIC MECHANISMS; IMPULSIVE CHOICE; NERVOUS-SYSTEM; RATS; RELAPSE; EXPERIENCE; BEHAVIOR; REWARD; MODEL AB Whereas earlier studies have focused on the preventive effects of enriched environments (EE) in drug addiction, in a recent study we suggested that EE can also have 'curative' effects. In fact, we found that cocaine addiction-related behaviors can be eliminated by housing cocaine-treated mice in EE during periods of forced abstinence. However, those results were obtained with two simple models of addiction, conditioned place preference (CPP), and behavioral sensitization. In this study, we used intravenous drug self-administration procedures in rats to further investigate the beneficial effects of EE on cocaine addiction in a reinstatement model of relapse. Singly housed rats learned to self-administer cocaine during 10 consecutive daily sessions (0.6 mg/injection, 6 h/day). They were then housed three per cage in either standard environments (SE) or EE and were kept abstinent in the animal facility until testing for extinction and reinstatement. We found that 30 days of EE significantly and consistently reduced cocaine seeking during a 6-h extinction session. In addition, EE significantly reduced cue- and stress-induced reinstatement. Surprisingly, given our earlier results in mice with CPP, EE did not reduce cocaine-induced reinstatement regardless of the level of exposure to cocaine and the duration of the period of abstinence and exposure to EE. Altogether, these results support the hypothesis that EE can reduce cocaine-induced craving and highlight the importance of positive life conditions in facilitating abstinence and preventing relapse to cocaine addiction. Neuropsychopharmacology (2009) 34, 2767-2778; doi:10.1038/npp.2009.127; published online 9 September 2009 C1 [Chauvet, Claudia; Lardeux, Virginie; Jaber, Mohamed; Solinas, Marcello] Univ Poitiers, CNRS, Inst Physiol & Biol Cellulaires, F-86022 Poitiers, France. [Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD USA. RP Solinas, M (reprint author), Univ Poitiers, CNRS, Inst Physiol & Biol Cellulaires, 6187 Pole Biol Sante,40 Ave Recteur Pineau, F-86022 Poitiers, France. EM marcello.solinas@univ-poitiers.fr RI Solinas, Marcello/M-3500-2016 OI Solinas, Marcello/0000-0002-0664-5964 FU University of Poitiers, Mission Interministerielle de la Lutte contre les Drogues et la Toxicomanie (MILDT-INSERM); MILDT-INSERM-INCA; Region Poitou Charentes; National Institute on Drug Abuse, National Institutes of Health; Department of Health and Human Services, Baltimore, Maryland; French Ministry of Research FX We thank N Thiriet and D Belin for their helpful discussion and NIDA/NIH for donation of the Coulbourn cages. This work was supported by Centre National pour la Recherche Scientifique, University of Poitiers, Mission Interministerielle de la Lutte contre les Drogues et la Toxicomanie (MILDT-INSERM, 2006-2007 and MILDT-INSERM-INCA 2007-2009), Region Poitou Charentes, and the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland. C Chauvet is a recipient of a PhD fellowship from the French Ministry of Research. NR 58 TC 78 Z9 78 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2009 VL 34 IS 13 BP 2767 EP 2778 DI 10.1038/npp.2009.127 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 517TC UT WOS:000271639700017 PM 19741591 ER PT J AU Parascandola, M Augustson, E Rose, A AF Parascandola, Mark Augustson, Erik Rose, Allison TI Characteristics of current and recent former smokers associated with the use of new potential reduced-exposure tobacco products SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID HARM REDUCTION; CONSUMER AWARENESS; LIGHT CIGARETTES; ATTITUDES; INDUSTRY; PREPS; PERCEPTIONS; BELIEFS; SMOKING; THINK AB To identify sociodemographic characteristics associated with having tried a potentialy reduced-exposure tobacco product (PREP) and to compare the smoking and quitting behaviors and attitudes of smokers who have tried a PREP product with non-PREP users. Analysis is based on a sample of 43,419 current and recent former smokers from the 2003 Tobacco Use Supplement to the Current Population Survey. Overall, PREP use is low (2.5%). Current daily and someday only smokers have higher rates of use (2.9% and 2.4%, respectively) compared with former smokers (1.5%). PREP use is higher in southern states and among younger smokers, non-Hispanic Whites, and those with some college education. Smokers who have tried a PREP product are more likely to smoke light or ultra-light cigarettes, report more symptoms of nicotine dependence, smoke more cigarettes per day, report a higher number of quit attempts, and seek quitting assistance from pharmacotherapy and behavioral therapies compared with non-PREP users. These findings support the concern that current smokers who are highly dependent yet motivated to quit smoking may seek PREPs as an alternative strategy to smoking cessation. C1 [Parascandola, Mark; Augustson, Erik] NCI, Tobacco Control Res Branch, Bethesda, MD 20892 USA. [Rose, Allison] NCI, Clin Monitoring Res Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Parascandola, M (reprint author), NCI, Tobacco Control Res Branch, 6130 Execut Blvd MSC 7337,Execut Plaza N,Room 403, Bethesda, MD 20892 USA. EM paramark@mail.nih.gov FU National Cancer Institute; National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 33 TC 5 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD DEC PY 2009 VL 11 IS 12 BP 1431 EP 1438 DI 10.1093/ntr/ntp157 PG 8 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 524ZY UT WOS:000272184100006 PM 19915081 ER PT J AU Onyshchenko, MI Gaynutdinov, TI Englund, EA Appella, DH Neumann, RD Panyutin, IG AF Onyshchenko, Mykola I. Gaynutdinov, Timur I. Englund, Ethan A. Appella, Daniel H. Neumann, Ronald D. Panyutin, Igor G. TI Stabilization of G-quadruplex in the BCL2 promoter region in double-stranded DNA by invading short PNAs SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PEPTIDE NUCLEIC-ACID; HUMAN TELOMERIC DNA; DUPLEX DNA; INTRAMOLECULAR QUADRUPLEX; STRUCTURAL POLYMORPHISM; REGULATORY ELEMENT; PROXIMAL PROMOTER; UP-REGULATION; PROTEIN; EXPRESSION AB Numerous regulatory genes have G-rich regions that can potentially form quadruplex structures, possibly playing a role in transcription regulation. We studied a G-rich sequence in the BCL2 gene 176-bp upstream of the P1 promoter for G-quadruplex formation. Using circular dichroism (CD), thermal denaturation and dimethyl sulfate (DMS) footprinting, we found that a single-stranded oligonucleotide with the sequence of the BCL2 G-rich region forms a potassium-stabilized G-quadruplex. To study G-quadruplex formation in double-stranded DNA, the G-rich sequence of the BCL2 gene was inserted into plasmid DNA. We found that a G-quadruplex did not form in the insert at physiological conditions. To induce G-quadruplex formation, we used short peptide nucleic acids (PNAs) that bind to the complementary C-rich strand. We examined both short duplex-forming PNAs, complementary to the central part of the BCL2 gene, and triplex-forming bis-PNAs, complementary to sequences adjacent to the G-rich BCL2 region. Using a DMS protection assay, we demonstrated G-quadruplex formation within the G-rich sequence from the promoter region of the human BCL2 gene in plasmid DNA. Our results show that molecules binding the complementary C-strand facilitate G-quadruplex formation and introduce a new mode of PNA-mediated sequence-specific targeting. C1 [Onyshchenko, Mykola I.; Gaynutdinov, Timur I.; Neumann, Ronald D.; Panyutin, Igor G.] NIDDK, Dept Radiol & Imaging Sci, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Englund, Ethan A.; Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Panyutin, IG (reprint author), NIDDK, Dept Radiol & Imaging Sci, Ctr Clin, NIH, Bethesda, MD 20892 USA. EM igorp@helix.nih.gov OI Onyshchenko, Mykola/0000-0003-4663-0991 FU NIH, Clinical Center; NIDDK FX This research was supported by the Intramural Research Program of the NIH, Clinical Center and NIDDK. Funding for open access charge: National Institutes of Health, Intramural Research Program, Clinical Center. NR 60 TC 30 Z9 31 U1 1 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD DEC PY 2009 VL 37 IS 22 BP 7570 EP 7580 DI 10.1093/nar/gkp840 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 534ZB UT WOS:000272935000028 PM 19820116 ER PT J AU Zhang, X Zou, TT Rao, JN Liu, L Xiao, L Wang, PY Cui, YH Gorospe, M Wang, JY AF Zhang, Xian Zou, Tongtong Rao, Jaladanki N. Liu, Lan Xiao, Lan Wang, Peng-Yuan Cui, Yu-Hong Gorospe, Myriam Wang, Jian-Ying TI Stabilization of XIAP mRNA through the RNA binding protein HuR regulated by cellular polyamines SO NUCLEIC ACIDS RESEARCH LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; KAPPA-B ACTIVATION; X-LINKED INHIBITOR; AU-RICH ELEMENTS; INDUCED APOPTOSIS; GENE-EXPRESSION; UP-REGULATION; DOWN-REGULATION; CODING REGION; TRANSLATION AB The X chromosome-linked inhibitor of apoptosis protein (XIAP) is the most potent intrinsic caspase inhibitor and plays an important role in the maintenance of intestinal epithelial integrity. The RNA binding protein, HuR, regulates the stability and translation of many target transcripts. Here, we report that HuR associated with both the 3'-untranslated region and coding sequence of the mRNA encoding XIAP, stabilized the XIAP transcript and elevated its expression in intestinal epithelial cells. Ectopic HuR overexpression or elevated cytoplasmic levels of endogenous HuR by decreasing cellular polyamines increased [HuR/XIAP mRNA] complexes, in turn promoting XIAP mRNA stability and increasing XIAP protein abundance. Conversely, HuR silencing in normal and polyamine-deficient cells rendered the XIAP mRNA unstable, thus reducing the steady state levels of XIAP. Inhibition of XIAP expression by XIAP silencing or by HuR silencing reversed the resistance of polyamine-deficient cells to apoptosis. Our findings demonstrate that HuR regulates XIAP expression by stabilizing its mRNA and implicates HuR-mediated XIAP in the control of intestinal epithelial apoptosis. C1 [Zhang, Xian; Zou, Tongtong; Rao, Jaladanki N.; Liu, Lan; Xiao, Lan; Wang, Peng-Yuan; Cui, Yu-Hong; Wang, Jian-Ying] Univ Maryland, Sch Med, Cell Biol Grp, Dept Surg, Baltimore, MD 21224 USA. [Zhang, Xian; Zou, Tongtong; Rao, Jaladanki N.; Liu, Lan; Cui, Yu-Hong; Wang, Jian-Ying] Baltimore Vet Affairs Med Ctr, Baltimore, MD 21224 USA. [Xiao, Lan; Wang, Peng-Yuan; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21224 USA. [Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, IRP, NIH, Baltimore, MD 21224 USA. RP Wang, JY (reprint author), Univ Maryland, Sch Med, Cell Biol Grp, Dept Surg, Baltimore, MD 21224 USA. EM jwang@smail.umaryland.edu FU US Department of Veterans Affairs; National Institutes of Health [DK57819, DK61972, DK68491] FX Merit Review Grant from US Department of Veterans Affairs and National Institutes of Health (DK57819, DK61972, DK68491 to J.-Y.W.). Funding for open access charge: National Institutes of Health and Department of Veterans Affairs. NR 75 TC 41 Z9 43 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD DEC PY 2009 VL 37 IS 22 BP 7623 EP 7637 DI 10.1093/nar/gkp755 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 534ZB UT WOS:000272935000033 PM 19825980 ER PT J AU Grady, C Edgerly, M AF Grady, Christine Edgerly, Maureen TI Science, Technology, and Innovation: Nursing Responsibilities in Clinical Research SO NURSING CLINICS OF NORTH AMERICA LA English DT Article DE Clinical research; Ethics; Science; Nursing responsibilities; Human subjects ID NURSES AB Clinical research is a systematic investigation of human biology, health, or illness involving human beings. It builds on laboratory and animal studies and often involves clinical trials, which are specifically designed to test the safety and efficacy of interventions in humans. Nurses are critical to the conduct of ethical clinical research and face clinical, ethical, and regulatory challenges in research in many diverse roles. Understanding and addressing the ethical challenges that complicate clinical research is integral to upholding the moral commitment that nurses make to patients, including protecting their rights and ensuring their safety as patients and as research participants. C1 [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Edgerly, Maureen] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Grady, C (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10-1C118, Bethesda, MD 20892 USA. EM cgrady@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 25 TC 7 Z9 8 U1 1 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0029-6465 J9 NURS CLIN N AM JI Nurs. Clin. North Am. PD DEC PY 2009 VL 44 IS 4 BP 471 EP + DI 10.1016/j.cnur.2009.07.011 PG 12 WC Nursing SC Nursing GA 529MT UT WOS:000272522200009 PM 19850183 ER PT J AU Chung, HR Perez-Escamilla, R AF Chung, Hae-Rang Perez-Escamilla, Rafael TI Risk factors of type 2 diabetes among Korean adults: The 2001 Korean national health and nutrition examination survey SO NUTRITION RESEARCH AND PRACTICE LA English DT Article DE Type 2 diabetes; risk factor; Korean adult; Korea health and nutrition examination survey 2001 ID POSTMENOPAUSAL WOMEN; WAIST CIRCUMFERENCE; CIGARETTE-SMOKING; UNITED-STATES; SOUTH-KOREA; OBESITY; PREVALENCE; MELLITUS; MORTALITY; TRENDS AB This study aimed to identify risk factors for type 2 diabetes (T2D) in Korea, a rapidly changing country. Data of 5,132 adults aged 20-85 were used from the 2001 Korean Health and Nutrition Examination Survey. Multiple logistic regression was carried out to identify risk factors for T2D. Three models were specified: (i) socioeconomic and demographic factors (model 1: age, gender, education, poverty income ratio, employment), (ii) behavioral risk factors and covariates (model 2: obesity, physical activity, smoking, alcohol drinking, dietary quality, family history of T2D, co-morbidity) and (iii) socioeconomic, demographic, and behavioral factors (model 3). The prevalence of T2D was 7.4%. Less education (OR 1.41, 95% CI 1.08-1.84), age (OR 2.19, 95% CI 1.56-3.08 in 40-59 yrs, OR 4.05, 95% CI 2.76-5.95 in 60 yrs + comparing to 20-39 yrs) and abdominal obesity (OR 2.24, 95% CI 1.79-2.82) were risk factors for T2D even after controlling for other factors simultaneously. There was a significant association of T2D with ever smoking (OR 1.34, 95% CI 1.06-1.67). The relationship of age with T2D was modified by gender in model 1 and the relationship of smoking with T2D was modified by obesity in model 2. Less educated, older, obese or ever smokers were more likely to have T2D. Gender mediated the relationship of age, and obesity mediated the relationship of smoking, with T2D. Intervention programs for T2D in Korea should take the interactions among risk factors into account. C1 [Chung, Hae-Rang] Univ Connecticut, Dept Nutr Sci, Connecticut NIH EXPORT Ctr Eliminating Hlth Dispa, Storrs, CT 06269 USA. RP Chung, HR (reprint author), Univ Connecticut, Dept Nutr Sci, Connecticut NIH EXPORT Ctr Eliminating Hlth Dispa, Storrs, CT 06269 USA. EM hrchung@nutrikorea.com NR 43 TC 4 Z9 6 U1 0 U2 5 PU KOREAN NUTRITION SOC PI SEOUL PA 804 KST CTR, 635-4 YEOGSAM-SONG KANGNAM-KU, SEOUL, 135-703, SOUTH KOREA SN 1976-1457 J9 NUTR RES PRACT JI Nutr. Res. Pract. PD WIN PY 2009 VL 3 IS 4 BP 286 EP 294 DI 10.4162/nrp.2009.3.4.286 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 585AF UT WOS:000276796000005 PM 20098581 ER PT J AU Bawazeer, NM Al-Daghri, NM Valsamakis, G Al-Rubeaan, KA Sabico, SLB Huang, TTK Mastorakos, GP Kumar, S AF Bawazeer, Nahla M. Al-Daghri, Nasser M. Valsamakis, George Al-Rubeaan, Khalid A. Sabico, Shaun Louie B. Huang, Terry T. -K. Mastorakos, George P. Kumar, Sudhesh TI Sleep Duration and Quality Associated With Obesity Among Arab Children SO OBESITY LA English DT Article ID METABOLIC SYNDROME; CHILDHOOD; RISK; OVERWEIGHT; LINK AB The link between sleep duration and obesity has been well established in adults, but several epidemiological studies revealed inconsistent findings in adolescents and younger children. This study aimed to investigate the relationship between sleep length and obesity in Saudi students. A total of 5,877 Saudi students, boys (55.2%) and girls (44.8%), aged between 10 and 19 years were randomly selected from elementary, intermediate, and secondary schools in different regions of Riyadh. A questionnaire on sleep behaviors was given. Anthropometry included BMI and waist and hip circumferences. Sleeping <= 7 h significantly increased the risk of obesity in both boys and girls (all age categories) (odds ratio = 1.25-1.38, 95% confidence intervals = 1.02-1.89). Overall prevalence of overweight and obese were higher among those sleeping intermittently (18.68%) than those sleeping continuously (14.5%) (P = 0.024). Short sleep duration and poor sleep quality are significantly associated with obesity among Arab youth. Further studies need to employ more objective measures of sleep, such as actigraphy, and examine the mechanism of these associations. C1 [Al-Daghri, Nasser M.; Sabico, Shaun Louie B.] King Saud Univ, Coll Sci, Dept Biochem, Riyadh 11451, Saudi Arabia. [Kumar, Sudhesh] Univ Warwick, Warwick Med Sch, Clin Sci Res Inst, Coventry CV4 7AL, W Midlands, England. [Al-Rubeaan, Khalid A.] King Saud Univ, Univ Diabet Ctr, Riyadh, Saudi Arabia. [Huang, Terry T. -K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Mastorakos, George P.] Univ Athens, Sch Med, Endocrine Unit, Aretaie Univ Hosp, GR-11527 Athens, Greece. RP Al-Daghri, NM (reprint author), King Saud Univ, Coll Sci, Dept Biochem, Riyadh 11451, Saudi Arabia. EM aldaghri2000@hotmail.com RI Al-Daghri, Nasser/G-7736-2011; Sabico, Shaun Louie/C-9086-2011; kumar, sudhesh/D-6945-2013 OI kumar, sudhesh/0000-0003-4326-5941 FU College of Science Research Center, King Saud University [BI0 2006/29] FX We thank the staff of University Diabetes Center for the recruitment of subjects and collection of data. We thank the College of Science Research Center, King Saud University (BI0 2006/29) for their support. NR 13 TC 23 Z9 24 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD DEC PY 2009 VL 17 IS 12 BP 2251 EP 2253 DI 10.1038/oby.2009.169 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 523RD UT WOS:000272091200020 PM 19498352 ER PT J AU Reddy, UM Ko, CW Raju, TNK Willinger, M AF Reddy, Uma M. Ko, Chia-Wen Raju, Tonse N. K. Willinger, Marian TI Delivery Indications at Late-Preterm Gestations and Infant Mortality Rates in the United States EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Reddy, Uma M.; Ko, Chia-Wen; Raju, Tonse N. K.; Willinger, Marian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Reddy, UM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD DEC PY 2009 VL 64 IS 12 BP 780 EP 781 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 529SM UT WOS:000272537500005 ER PT J AU Hosgood, HD Zhang, L Shen, M Berndt, SI Vermeulen, R Li, G Yin, S Yeager, M Yuenger, J Rothman, N Chanock, S Smith, M Lan, Q AF Hosgood, H. D., III Zhang, L. Shen, M. Berndt, S. I. Vermeulen, R. Li, G. Yin, S. Yeager, M. Yuenger, J. Rothman, N. Chanock, S. Smith, M. Lan, Q. TI Association between genetic variants in VEGF, ERCC3 and occupational benzene haematotoxicity SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MESENCHYMAL STEM-CELLS; ACUTE MYELOID-LEUKEMIA; MOLECULAR EPIDEMIOLOGY; DNA-REPAIR; HEMATOTOXICITY; POLYMORPHISMS; MECHANISM; SUSCEPTIBILITY; METABOLITES AB Introduction: Benzene is an established human haematotoxin, with substantial interindividual variation in benzene-induced toxicity. Methods: To further examine if genetic variation contributes to benzene haematotoxicity, we analysed 1023 tagSNPs in 121 gene regions important for benzene metabolism, haematopoiesis, leukaemia and lymphoma among 250 workers exposed to benzene and 140 unexposed controls in a cross-sectional study carried out in China. Linear regression was used to analyse the relationship between genetic polymorphisms and total white blood cell (WBC) count and its subtypes, adjusting for potential confounders and occupational exposure to benzene and toluene among exposed workers. The minp test assessed the association on the gene region level. The false discovery rate method was used to control for multiple comparisons. Results: VEGF (minp=0.0030) and ERCC3 (minp=0.0042) were the most significantly associated gene regions with altered WBC counts among benzene-exposed workers, after accounting for multiple comparisons. Highly significant changes were also found for WBC subtype counts, including granulocytes, CD4+ T cells and lymphocytes for VEGF and granulocytes and NK cells for ERCC3. Further, in workers exposed to <1 ppm, a SNP in VEGF was associated with changes in WBC and granulocyte counts, and SNPs in ERCC3 were associated with changes in WBC, NK cell and granulocyte counts. Discussion: Our findings suggest that genetic variation in VEGF, which plays an important role in blood vessel growth, and ERCC3, which is a member of the DNA repair pathway and is responsible for repairing bulky DNA adducts formed by chemicals, may contribute to individual susceptibility to benzene-induced haematotoxicity at relatively low levels of benzene exposure. C1 [Hosgood, H. D., III] NCI, Div Canc Epidemiol & Genet, NIH,Occupat & Environm Epidemiol Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Zhang, L.; Yeager, M.; Yuenger, J.; Chanock, S.] NCI, Ctr Canc Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Vermeulen, R.] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Li, G.; Yin, S.] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. [Smith, M.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. RP Hosgood, HD (reprint author), NCI, Div Canc Epidemiol & Genet, NIH,Occupat & Environm Epidemiol Branch, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 8118,MCS 7240, Bethesda, MD 20892 USA. EM hosgoodd@mail.nih.gov RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU NIH intramural research program; NIH [RO1ES06721, P42ES04705, P30ES01896] FX This project was supported in part by the NIH intramural research program, and by NIH grants RO1ES06721, P42ES04705 and P30ES01896 (to MTS). NR 45 TC 11 Z9 11 U1 0 U2 3 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD DEC PY 2009 VL 66 IS 12 BP 848 EP 853 DI 10.1136/oem.2008.044024 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 524JW UT WOS:000272140600011 PM 19773279 ER PT J AU Chan, CC Fisson, S Bodaghi, B AF Chan, Chi-Chao Fisson, Sylvain Bodaghi, Bahram TI The Future of Primary Intraocular Lymphoma (Retinal Lymphoma) SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Article DE primary intraocular lymphoma; retinal lymphoma; genetics; imaging; therapy; mouse model; pathology ID CENTRAL-NERVOUS-SYSTEM; PRIMARY CNS LYMPHOMA; INTERLEUKIN-10 GENE POLYMORPHISMS; RECURRENT PRIMARY CNS; FACTOR-H POLYMORPHISM; NON-HODGKINS-LYMPHOMA; STEM-CELL RESCUE; MACULAR DEGENERATION; INTRAVITREAL METHOTREXATE; MALIGNANT LYMPHOCYTES AB Basic science and clinical investigations in cancer research have contributed to our understanding of the genetic causes of various neoplasms and discovery of novel therapeutic interventions to fight malignancies such as lymphoma. During this exciting time, we have witnessed the advent of new technologies to further characterize primary intraocular lymphoma (PIOL), or retinal lymphoma, which is selected as the first "Disease of the Year" by Ocular Immunology and Inflammation. Different comprehensive aspects of PIOL, including epidemiology, clinical manifestations, diagnosis, pathophysiology, therapy, and animal models are discussed. The future of PIOL holds an opportunity to really understand the unique cytologic, histopathologic, physiological and immunologic features, as well as the genotypic traits (gene expression, interaction, polymorphism, epigenetics, etc.) and epidemiology. This information will empower us to truly make a difference in patients' managements with this devastating disease. While most of this technology already exists, much work still needs to be done to make translational therapy a reality for PIOL patients in the future. C1 [Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20895 USA. [Fisson, Sylvain] Univ Paris 06, INSERM, UMR S 872, Cordeliers Res Ctr, F-75005 Paris, France. [Bodaghi, Bahram] Univ Paris 06, Dept Ophthalmol, Hosp Pitie Salpetriere, F-75005 Paris, France. RP Chan, CC (reprint author), NEI, NIH, 10 Ctr Dr,10-10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov FU NEI Intramural Research Program - NIH; French National Cancer Institute (INCa) FX Funding Supports: the NEI Intramural Research Program - NIH, the French National Cancer Institute (INCa). NR 66 TC 7 Z9 8 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0927-3948 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PD DEC PY 2009 VL 17 IS 6 BP 375 EP 379 DI 10.3109/09273940903434804 PG 5 WC Ophthalmology SC Ophthalmology GA 527XH UT WOS:000272404000001 PM 20001255 ER PT J AU Janik, JE Morris, JC AF Janik, John E. Morris, John C. TI Survivin(g) Adult T-cell Leukemia/Lymphoma The Tobinai Article Reviewed SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 [Janik, John E.; Morris, John C.] NCI, Clin Trials Team, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Janik, JE (reprint author), NCI, Clin Trials Team, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 11 TC 0 Z9 1 U1 1 U2 1 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD DEC PY 2009 VL 23 IS 14 BP 1256 EP 1266 PG 3 WC Oncology SC Oncology GA V18PX UT WOS:000208017800005 PM 20120838 ER PT J AU Christen, WG Glynn, RJ Chew, EY Buring, JE AF Christen, William G. Glynn, Robert J. Chew, Emily Y. Buring, Julie E. TI Low-Dose Aspirin and Medical Record-Confirmed Age-related Macular Degeneration in a Randomized Trial of Women SO OPHTHALMOLOGY LA English DT Article ID PROTECTS ENDOTHELIAL-CELLS; CHOROIDAL NEOVASCULARIZATION; LASER PHOTOCOAGULATION; CARDIOVASCULAR-DISEASE; PRIMARY PREVENTION; BETA-CAROTENE; PHYSICIANS-HEALTH; OXIDATIVE STRESS; CLINICAL-TRIALS; VITAMIN-E AB Objective: To test whether alternate-day low-dose aspirin affects incidence of age-related macular degeneration (AMD) in a large-scale randomized trial of women. Design: Randomized, double-masked, placebo-controlled trial. Participants: Thirty-nine thousand eight hundred seventy-six healthy female health professionals aged 45 years or older. Intervention: Participants were assigned randomly to receive either 100 mg aspirin on alternate days or placebo and were followed up for the presence of AMD for an average of 10 years. Main Outcome Measures: Incident AMD responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-report confirmed by medical record review. Results: After 10 years of treatment and follow-up, there were 111 cases of AMD in the aspirin group and 134 cases in the placebo group (hazard ratio, 0.82; 95% confidence interval, 0.64-1.06). Conclusions: In a large-scale randomized trial of female health professionals with 10 years of treatment and follow-up, low-dose aspirin had no large beneficial or harmful effect on risk of AMD. C1 [Christen, William G.; Glynn, Robert J.; Buring, Julie E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Glynn, Robert J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Chew, Emily Y.] NEI, Bethesda, MD 20892 USA. [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. RP Christen, WG (reprint author), 900 Commonwealth Ave E, Boston, MA 02215 USA. EM wchristen@rics.bwh.harvard.edu FU National Institutes of Health, Bethesda, Maryland [CA47988, HL43851, EY06633] FX Supported by the National Institutes of Health, Bethesda, Maryland (grant nos.: CA47988, HL43851,and EY06633). Pills and packaging were provided by Bayer Healthcare and the Natural Source Vitamin E Association. NR 53 TC 26 Z9 29 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD DEC PY 2009 VL 116 IS 12 BP 2386 EP 2392 DI 10.1016/j.ophtha.2009.05.031 PG 7 WC Ophthalmology SC Ophthalmology GA 530HE UT WOS:000272579200019 PM 19815293 ER PT J AU Gillies, MC Zhu, MD Chew, E Barthelmes, D Hughes, E Ali, H Holz, FG Scholl, HPN Issa, PC AF Gillies, Mark C. Zhu, Meidong Chew, Emily Barthelmes, Daniel Hughes, Edward Ali, Haipha Holz, Frank G. Scholl, Hendrik P. N. Issa, Peter Charbel TI Familial Asymptomatic Macular Telangiectasia Type 2 SO OPHTHALMOLOGY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; JUXTAFOVEOLAR RETINAL TELANGIECTASIS; IDIOPATHIC PARAFOVEAL TELANGIECTASIS; MONOZYGOTIC TWINS; PERIFOVEAL TELANGIECTASIA; FULL-THICKNESS AB Objective: To report findings in asymptomatic family members of patients with macular telangiectasia type 2. Design: Prospective, observational, cross-sectional case series. Participants: Four patients with symptomatic macular telangiectasia type 2 (index patients) and 5 relatives, including 2 sets of monozygotic twins. Methods: Screening of family members of participants in a non-interventional natural history study of macular telangiectasia type 2. Ophthalmologic examination included best-corrected visual acuity testing, fundus biomicroscopy, fluorescein angiography (FA), optical coherence tomography (OCT), and fundus autofluorescence (FAF) imaging. Main Outcome Measures: Evidence for macular telangiectasia type 2 in any of the imaging methods used and visual function of the family members studied. Results: In the first family, 2 of 3 daughters of a severely affected 68-year-old woman had features of macular telangiectasia type 2. Although one of the daughters was diagnosed by biomicroscopic examination, the second daughter was diagnosed only by subtle changes on OCT and FAF imaging. Both affected daughters were asymptomatic and were unaware that they had the condition. In the second family, clinical examination showed that the 60-year-old brother of the 75-year-old index patient obviously was affected, despite a lack of any subjective visual dysfunction. The 65-year-old monozygotic twin of the third index patient showed a slight retinal thinning within a small area temporal to the foveola in both eyes as well as minor staining on FA and a subtle monocular loss of macular pigment. The 56-year-old asymptomatic monozygotic twin of the last proband had opacification of the retina with leakage on FA in the right eye. The fellow eye was unremarkable except for an abnormal FAF signal that was present in both eyes. Conclusions: Macular telangiectasia type 2 may be more common than previously assumed, but patients may not seek ophthalmic care if their visual function is normal. The study of these early, asymptomatic cases may yield valuable insights into the pathogenesis of the condition. Further research is warranted to determine whether there is an underlying, dominantly inherited genetic abnormality in macular telangiectasia type 2 of variable penetrance and expressivity. C1 [Gillies, Mark C.; Zhu, Meidong; Hughes, Edward; Ali, Haipha] Univ Sydney, Save Sight Inst, Dept Clin Ophthalmol & Eye Hlth, Sydney, NSW 2001, Australia. [Chew, Emily] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Barthelmes, Daniel] Univ Zurich Hosp, Dept Ophthalmol, CH-8091 Zurich, Switzerland. [Holz, Frank G.; Scholl, Hendrik P. N.; Issa, Peter Charbel] Univ Bonn, Dept Ophthalmol, D-5300 Bonn, Germany. RP Gillies, MC (reprint author), Univ Sydney, Save Sight & Eye Hlth Inst, Dept Clin Ophthalmol, GPO Box 4337, Sydney, NSW 2001, Australia. EM mark@eye.usyd.edu.au RI Charbel Issa, Peter/F-9603-2011; gillies, mark/B-3242-2012; OI Charbel Issa, Peter/0000-0002-0351-6673 FU Lowy Medical Research Institute, Sydney, Australia; Faculty of Medicine, University of Bonn, Bonn, Germany [0-137.0011]; EU [FP6]; EVI-GENORET [LSHG-CT-2005-512036]; European Commission, Brussels, Belgium FX Supported by the Lowy Medical Research Institute, Sydney, Australia (The MacTel Project); BONFOR Program, Faculty of Medicine, University of Bonn, Bonn, Germany (grant no.: 0-137.0011); and EU FP6, Integrated Project "EVI-GENORET" (LSHG-CT-2005-512036), European Commission, Brussels, Belgium. The funding organizations had no role in the design or conduct of this research. NR 33 TC 30 Z9 32 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD DEC PY 2009 VL 116 IS 12 BP 2422 EP 2429 DI 10.1016/j.ophtha.2009.05.010 PG 8 WC Ophthalmology SC Ophthalmology GA 530HE UT WOS:000272579200024 PM 19815294 ER PT J AU Hatziagorou, E Walsh, TJ Tsanakas, JN Roilides, E AF Hatziagorou, Elpis Walsh, Thomas J. Tsanakas, John N. Roilides, Emmanuel TI Aspergillus and the paediatric lung SO PAEDIATRIC RESPIRATORY REVIEWS LA English DT Article DE children; neonates; allergic bronchopulmonary aspergillosis; aspergilloma; invasive pulmonary aspergillosis ID ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS; INVASIVE PULMONARY ASPERGILLOSIS; CHRONIC GRANULOMATOUS-DISEASE; B LIPID COMPLEX; CYSTIC-FIBROSIS; FUNGAL-INFECTIONS; AMPHOTERICIN-B; IMMUNOCOMPROMISED CHILDREN; PRIMARY IMMUNODEFICIENCIES; TRANSPLANT RECIPIENTS AB Aspergillus spp produce a wide range of saprophytic and invasive syndromes in the lungs, including allergic bronchopulmonary aspergillosis (ABPA), aspergilloma and invasive pulmonary aspergillosis (IPA). ABPA results from hypersensitivity to the fungus, and mainly affects patients with asthma or cystic fibrosis (CF). The treatment of choice consists of systemic corticosteroids and itraconazole. Aspergilloma is managed by observation or surgery. IPA is predominantly seen in patients with haematological malignancies, chronic granulomatous disease or immunosuppressive treatment. With the use of aggressive therapies for end-stage CF, such as heart-lung transplantation, the potential for a patient to convert from colonization or ABPA to IPA has increased. Suggestive clinical and radiological findings, supplemented with mycological data using serology and molecular biology, have enhanced the capacity to diagnose IPA in paediatric patients. While voriconazole is considered the first-line therapy in IPA, several other antifungal agents may be appropriate alternatives. (C) 2009 Elsevier Ltd, All rights reserved. C1 [Hatziagorou, Elpis; Tsanakas, John N.; Roilides, Emmanuel] Aristotle Univ Thessaloniki, Dept Paediat 3, Hippokrat Hosp, GR-54642 Thessaloniki, Greece. [Walsh, Thomas J.; Roilides, Emmanuel] NCI, Immunocompromised Host Sect, Paediat Oncol Branch, Bethesda, MD 20892 USA. RP Roilides, E (reprint author), Aristotle Univ Thessaloniki, Dept Paediat 3, Hippokrat Hosp, Konstantinoupoleos 49, GR-54642 Thessaloniki, Greece. EM roilides@med.auth.gr RI Hatziagorou, Elpis/D-3247-2012 NR 59 TC 5 Z9 6 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1526-0542 J9 PAEDIATR RESPIR REV JI Paediatr. Respir. Rev. PD DEC PY 2009 VL 10 IS 4 BP 178 EP 185 DI 10.1016/j.prrv.2009.06.006 PG 8 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA 527LT UT WOS:000272369300005 PM 19879507 ER PT J AU Pyrgos, V Shoham, S Roilides, E Walsh, TJ AF Pyrgos, Vasilios Shoham, Shmuel Roilides, Emmanuel Walsh, Thomas J. TI Pneumocystis pneumonia in children SO PAEDIATRIC RESPIRATORY REVIEWS LA English DT Review DE pneumocystis pneumonia (pcp); immunocompromised children; t-lymphocytes; corticosteroids; trimethoprim-sulphamethoxazole ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; RENAL-TRANSPLANT RECIPIENTS; JIROVECI CARINII PNEUMONIA; VIRUS-INFECTED PATIENTS; INFANT-DEATH-SYNDROME; HYPER-IGM SYNDROME; TRIMETHOPRIM-SULFAMETHOXAZOLE; BRONCHOALVEOLAR LAVAGE; ALVEOLAR MACROPHAGES; CYTOMEGALOVIRUS-INFECTION AB Pneumocystis pneumonia (PCP) is a life-threatening infection in immunocompromised children with quantitative and qualitative defects in T lymphocytes. At risk are children with lymphoid malignancies, HIV infection. corticosteroid therapy, transplantation and primary immunodeficiency states. Diagnosis is established through direct examination or polymerase chain reaction (PCR) from respiratory secretions. Trimethoprim-sulphamethoxazole is used for initial therapy in most patients, while pentamidine, atovaquone, clindamycin plus primaquine, and dapsone plus trimethoprim are alternatives. Prophylaxis of high-risk patients reduces but does not eliminate the risk of PCP. Improved understanding of the pathogenesis of PCP is important for future advances against this life-threatening infection. Published by Elsevier B.V. C1 [Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Pyrgos, Vasilios; Shoham, Shmuel] Washington Hosp Ctr, Infect Dis Sect, Washington, DC 20010 USA. [Roilides, Emmanuel] Aristotle Univ Thessaloniki, Hippokrat Hosp, Dept Pediat 3, GR-54642 Thessaloniki, Greece. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, CRC 1-5750,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov NR 108 TC 15 Z9 19 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1526-0542 J9 PAEDIATR RESPIR REV JI Paediatr. Respir. Rev. PD DEC PY 2009 VL 10 IS 4 BP 192 EP 198 DI 10.1016/j.prrv.2009.06.010 PG 7 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA 527LT UT WOS:000272369300007 PM 19879509 ER PT J AU Arora, NK Street, RL Epstein, RM Butow, PN AF Arora, Neeraj K. Street, Richard L., Jr. Epstein, Ronald M. Butow, Phyllis N. TI Facilitating patient-centered cancer communication: A road map SO PATIENT EDUCATION AND COUNSELING LA English DT Editorial Material C1 [Arora, Neeraj K.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Street, Richard L., Jr.] Texas A&M Univ, College Stn, TX USA. [Street, Richard L., Jr.] Baylor Coll Med, Houston, TX 77030 USA. [Street, Richard L., Jr.] Houston Ctr Qual Care & Utilizat Studies, Houston, TX USA. [Epstein, Ronald M.] Univ Rochester, Med Ctr, Rochester Ctr Improve Commun Hlth Care, Dept Family Med, Rochester, NY 14642 USA. [Epstein, Ronald M.] Univ Rochester, Med Ctr, Rochester Ctr Improve Commun Hlth Care, Dept Psychiat & Oncol, Rochester, NY 14642 USA. [Butow, Phyllis N.] Univ Sydney, Sch Psychol, Ctr Med Psychol & Evidence Based Decis Making CeM, Sydney, NSW 2006, Australia. RP Arora, NK (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7344,EPN 4092, Bethesda, MD 20892 USA. EM aroran@mail.nih.gov NR 23 TC 23 Z9 23 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD DEC PY 2009 VL 77 IS 3 BP 319 EP 321 DI 10.1016/j.pec.2009.11.003 PG 3 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 538BI UT WOS:000273158600001 PM 19948297 ER PT J AU Farrell, MH Chan, ECY Ladouceur, LK Stein, JM AF Farrell, Michael H. Chan, Evelyn C. Y. Ladouceur, Lynnea K. Stein, Jeffrey M. TI A structured implicit abstraction method to evaluate whether content of counseling before prostate cancer screening is consistent with recommendations by experts SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Communication; Doctor-patient relationship; Prostate-specific antigen; Risk counseling; Informed consent ID SHARED DECISION-MAKING; STANDARDIZED PATIENTS; PEDIATRIC RESIDENTS; ANTIGEN TEST; MEDICARE BENEFICIARIES; PATIENT COMMUNICATION; QUALITY; HEALTH; SKILLS; MEN AB Objective: To assess the content of counseling about prostate-specific antigen (PSA) screening. Guidelines recommend informed consent before screening because of concerns about benefits versus risks. As part of the professional practice standard for informed consent, clinicians should include content customarily provided by experts. Methods: 40 transcripts of conversations between medicine residents and standardized patients were abstracted using an instrument derived from an expert Delphi panel that ranked 10 "facts that experts believe men ought to know." Results: Transcripts contained definite criteria for an average of 1.7 facts, and either definite or partial criteria for 5.1 facts. Second- and third-year residents presented more facts than interns (p = 0.01). The most common facts were "false positive PSA tests can occur" and "use of the PSA test as a screening test is controversial." There was an r = 0.88 correlation between inclusion by residents and the experts' ranking. Conclusion: Counseling varied but most transcripts included some expert-recommended, facts. The absence of other facts could be a quality deficit or an effort to prioritize messages and lessen cognitive demands on the patient. Practice implications: Clinicians should adapt Counseling for each patient, but our abstraction approach may help to assess the quality of informed consent over larger populations. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Farrell, Michael H.] Med Coll Wisconsin, Ctr Patient Care & Outcomes Res, Milwaukee, WI 53226 USA. [Chan, Evelyn C. Y.] Uni Texas Hlth Sci Ctr Houston, Houston, TX USA. [Ladouceur, Lynnea K.] NIAID, NIH, Div AIDS, Bethesda, MD 20892 USA. [Stein, Jeffrey M.] Yale Univ, Sch Med, New Haven, CT USA. RP Farrell, MH (reprint author), Med Coll Wisconsin, Ctr Patient Care & Outcomes Res, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM mfarrell@mcw.edu OI Farrell, Michael/0000-0002-2842-0205 FU National Heart, Lung, and Blood Institute [K01 HL072530, R01 HL086691] FX The authors are grateful to Dr. Stephen Huot and to the faculty and residents of the Yale University Primary Care Internal Medicine Residency Program. Dr. Farrell is supported in part by grants K01 HL072530 and R01 HL086691 from the National Heart, Lung, and Blood Institute. There are no personal or other relationships with other people or organizations that could inappropriately influence, or be perceived to influence, this research. NR 54 TC 3 Z9 3 U1 3 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD DEC PY 2009 VL 77 IS 3 BP 322 EP 327 DI 10.1016/j.pec.2009.09.023 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 538BI UT WOS:000273158600002 PM 19837527 ER PT J AU Arora, NK Weaver, KE Clayman, ML Oakley-Girvan, I Potosky, AL AF Arora, Neeraj K. Weaver, Kathryn E. Clayman, Marla L. Oakley-Girvan, Ingrid Potosky, Arnold L. TI Physicians' decision-making style and psychosocial outcomes among cancer survivors SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Patient-physician communication; Participatory decision-making style; Cancer survivorship; Health-related quality of life; Patient outcomes; Mediation analysis ID QUALITY-OF-LIFE; BREAST-CANCER; PATIENTS PERCEPTIONS; PATIENT PREFERENCES; ALTERNATIVE MEDICINE; PRIMARY-CARE; COMMUNICATION; INVOLVEMENT; TRUST; SATISFACTION AB Objective: We evaluated pathways linking physicians' decision-making style with cancer survivors' health-related quality of life (HRQOL). Methods: We analyzed survey data from 623 survivors diagnosed with leukemia, colorectal, or bladder cancer in Northern California, 2-5 years prior to the Study. Of these, 395 reported making a medical decision in the past 12 months and were asked about their physician's decision-making style. We evaluated the association of physician style with proximal communication outcomes (trust and participation self-efficacy), intermediate cognitive outcomes (perceived control and uncertainty), and distal health outcomes (physical and mental HRQOL). Results: Overall, 54% of survivors reported a sub-optimal decision-making style for their physician. With the exception of physical health, physician style was associated with all proximal, intermediate, and distal outcomes (p <= 0.01). We identified two significant pathways by which a participatory physician style may be associated with survivors' mental health: (I) by increasing survivors' participation self-efficacy and thereby enhancing their perceptions of personal control (p < 0.01); (2) by enhancing survivors' level of trust and thereby reducing their perceptions of uncertainty (p < 0.05). Conclusion: A participatory physician style may improve survivors' mental health by a complex two-step mechanism of improving survivors' proximal communication and intermediate cognitive Outcomes. Practice implications: Physicians who adopt a participatory decision-making style are likely to facilitate patient empowerment and enhance patients' HRQOL. Published by Elsevier Ireland Ltd. C1 [Arora, Neeraj K.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Weaver, Kathryn E.] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, Bethesda, MD 20892 USA. [Clayman, Marla L.] Northwestern Univ, Div Gen Internal Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Oakley-Girvan, Ingrid] No Calif Canc Ctr, Fremont, CA USA. [Potosky, Arnold L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Arora, NK (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7344,EPN 4092, Bethesda, MD 20892 USA. EM aroran@mail.nih.gov OI Clayman, Marla/0000-0001-8491-3672 FU National Cancer Institute [N01-PC-35136] FX Funding for data collection was provided by the National Cancer Institute as a contract to the Northern California Cancer Center, contract #N01-PC-35136 NR 50 TC 43 Z9 43 U1 1 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD DEC PY 2009 VL 77 IS 3 BP 404 EP 412 DI 10.1016/j.pec.2009.10.004 PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 538BI UT WOS:000273158600013 PM 19892508 ER PT J AU Talaat, KR Rothman, JA Cohen, JI Santi, M Choi, JK Guzman, M Zimmerman, R Nallasamy, S Brucker, A Quezado, M Pittaluga, S Patronas, NJ Klion, AD Nichols, KE AF Talaat, Kawsar R. Rothman, Jennifer A. Cohen, Jeffrey I. Santi, Mariarita Choi, John K. Guzman, Miguel Zimmerman, Robert Nallasamy, Sudha Brucker, Alexander Quezado, Martha Pittaluga, Stefania Patronas, Nicholas J. Klion, Amy D. Nichols, Kim E. TI Lymphocytic Vasculitis Involving the Central Nervous System Occurs in Patients With X-Linked Lymphoproliferative Disease in the Absence of Epstein-Barr Virus Infection SO PEDIATRIC BLOOD & CANCER LA English DT Article DE central nervous system; vasculitis; X-linked lymphoproliferative disease ID STEM-CELL TRANSPLANTATION; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; RETINAL NECROSIS; VACCINATION AB X-linked lymphoproliferative disease (XLP) is an immunodeficiency caused by defects in the adaptor molecule SAP. The manifestations of XLP generally Occur following Epstein-Barr virus (EBV) infection and include fulminant mononucleosis, hypogamma-globulinemia and lymphoma. in this report, we describe two unrelated patients with fatal T-cell-mediated central nervous system vasculitis for whom repeated serologic and molecular testing for EBV was negative. In both patients, clonal T-cell populations were observed, but neither demonstrated evidence of lymphoma. Thus, loss of SAP function can lead to dysregulated immune responses characterized by the uncontrolled expansion and activation of T cells independent of EBV infection. Pediatr Blood Cancer 2009;53:1120-1123. (C) 2009 Wiley-Liss, Inc. C1 [Nichols, Kim E.] Childrens Hosp Philadelphia, Dept Oncol, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Talaat, Kawsar R.; Klion, Amy D.] NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. [Cohen, Jeffrey I.] NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Santi, Mariarita; Choi, John K.; Guzman, Miguel] Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA 19104 USA. [Zimmerman, Robert] Childrens Hosp Philadelphia, Dept Radiol, Philadelphia, PA 19104 USA. [Nallasamy, Sudha; Brucker, Alexander] Scheie Eye Inst, Penn Presbyterian Med Ctr, Philadelphia, PA USA. [Quezado, Martha; Pittaluga, Stefania] NIH, Pathol Lab, Bethesda, MD 20892 USA. [Patronas, Nicholas J.] NIH, Warren G Magnuson Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. RP Nichols, KE (reprint author), Childrens Hosp Philadelphia, Dept Oncol, Div Hematol Oncol, Wood Bldg 4th Floor Mailbox,3516 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM nicholsk@email.chop.edu OI Klion, Amy/0000-0002-4986-5326 FU National Institutes of Health FX We thank John Butman, MD, for assistance in formatting the radiology figures of Patient no. 2. We also thank all of the people who helped to take excellent care of these patients. This work was supported in part by the intramural program of the National Institutes of Health. NR 20 TC 12 Z9 15 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC 1 PY 2009 VL 53 IS 6 BP 1120 EP 1123 DI 10.1002/pbc.22185 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 502FL UT WOS:000270440900038 PM 19621458 ER PT J AU Bishu, S Madhavan, D Perez, P Civitello, L Liu, SY Fessler, M Holland, SM Jain, A Pao, M AF Bishu, Shrinivas Madhavan, Deepak Perez, Phillip Civitello, Lucy Liu, Shuying Fessler, Margaret Holland, Steven M. Jain, Ashish Pao, Maryland TI CD40 Ligand Deficiency: Neurologic Sequelae With Radiographic Correlation SO PEDIATRIC NEUROLOGY LA English DT Article ID HYPER-IGM SYNDROME; CYTOTOXIC T-LYMPHOCYTES; CHRONIC ENTEROVIRAL MENINGOENCEPHALITIS; PRIMARY-IMMUNODEFICIENCY; MULTIFOCAL LEUKOENCEPHALOPATHY; IMMUNOLOGICAL FEATURES; CELL HELP; ENCEPHALITIS; HYPOGAMMAGLOBULINEMIA; AGAMMAGLOBULINEMIA AB Patients with CD40 ligand deficiency are susceptible to central nervous system infections, but to date the neurologic progression or long-term outcome of central nervous system complications have not been reported in detail. Characterizing the central nervous system complications of immune deficiencies can lead to the identification of new pathogens. For this study, clinical data were reviewed on patients with both CD40 ligand deficiency and neurodegeneration, identified from a larger cohort of 31 patients. Five patients had progressive neurologic and cognitive decline in the absence of clinical signs of acute fulminant encephalitis, with anatomic brain abnormalities and high mortality (60%). Despite multiple evaluations, no pathogens were identified in four patients, all of whom were on standard intravenous immunoglobulin therapy at illness presentation. This clinical phenotype of progressive decline without acute fulminant encephalitis is similar to chronic enteroviral encephalitis in X-linked agammaglobulinemia, another condition with severe humoral immune defects. Whether infection secondary to subtherapeutic levels of central nervous system immunoglobulin G (IgG), inadequately protective levels of serum IgG, or impaired CD40 ligand-dependent IgG-independent antiviral responses contributed remains undetermined. Emerging gene-chip techniques applied in patients with primary immune deficiencies may identify heretofore unknown viruses. Prospective neurocognitive and evaluation of patients with CD40 ligand deficiency may identify affected patients before overt clinical signs appear. Published by Elsevier Inc. C1 [Bishu, Shrinivas] NIMH, Sect Neuroadaptat & Prot Metab, NIH, Bethesda, MD 20892 USA. [Madhavan, Deepak] Univ Nebraska Med Ctr, Dept Neurol Sci, Omaha, NE USA. [Perez, Phillip] Georgetown Univ, Dept Psychiat, Washington, DC USA. [Civitello, Lucy] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Liu, Shuying; Fessler, Margaret; Jain, Ashish] NIAID, Host Def Lab, Bethesda, MD 20892 USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Pao, Maryland] NIMH, Psychiat Consultat Liaison Serv, Off Clin Director, Bethesda, MD 20892 USA. RP Bishu, S (reprint author), NIMH, Sect Neuroadaptat & Prot Metab, NIH, 9000 Rockville Pike,Bldg 10,Room 2D54, Bethesda, MD 20892 USA. EM shrinivas@uky.edu FU National Institute of Mental Health; National Institute of Allergy and Infectious Disease, National Institutes of Health FX Ashish Jain, MD provided the patients with CD40L deficiency and the editorial oversight and expertise oil primary immune deficiencies. Maryland Pao, MD was the originator of the concept and provided the filial editorial oversight and filial data analysis. NR 42 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD DEC PY 2009 VL 41 IS 6 BP 419 EP 427 DI 10.1016/j.pediatrneurol.2009.07.003 PG 9 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 525PA UT WOS:000272227200005 PM 19931163 ER PT J AU Laptook, AR Shankaran, S Ambalavanan, N Carlo, WA McDonald, SA Higgins, RD Das, A AF Laptook, Abbot R. Shankaran, Seetha Ambalavanan, Namasivayam Carlo, Waldemar A. McDonald, Scott A. Higgins, Rosemary D. Das, Abhik CA Hypothermia Subcomm NICHD Neonatal TI Outcome of Term Infants Using Apgar Scores at 10 Minutes Following Hypoxic-Ischemic Encephalopathy SO PEDIATRICS LA English DT Article DE Apgar scores; hypoxic-ischemic encephalopathy; cardiopulmonary resuscitation ID CEREBRAL-PALSY; BABIES BORN; RESUSCITATION; POPULATION; ASPHYXIA; ASSOCIATION; CHILDREN AB OBJECTIVE: The objective of this study was to determine whether Apgar scores at 10 minutes are associated with death or disability in early childhood after perinatal hypoxic-ischemic encephalopathy. METHODS: This was a secondary analysis of infants who were enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network hypothermia trial. Infants who were born at >= 36 weeks' gestation and had clinical and/or biochemical abnormalities at birth and encephalopathy at <6 hours were studied. Logistic regression and classification and regression-tree analysis were used to determine associations between Apgar scores at 10 minutes and neurodevelopmental outcome, adjusting for covariates. Death or disability (moderate or severe) at 18 to 22 months of age was the measured outcome. RESULTS: Twenty of 208 infants were excluded (missing data). More than 90% of the infants had Apgar scores of 0 to 2 at 1 minute, and Apgar scores at 5 and 10 minutes shifted to progressively higher values; at 10 minutes, 27% of infants had Apgar scores of 0 to 2. After adjustment, each point decrease in Apgar score at 10 minutes was associated with a45% increase in the odds of death or disability. Death or disability occurred in 76%, 82%, and 80% of infants with 10-minute Apgar scores of 0, 1, and 2, respectively. Classification and regression-tree analysis indicated that Apgar scores at 10 minutes were discriminators of outcome. CONCLUSIONS: Apgar scores at 10 minutes provide useful prognostic data before other evaluations are available for infants with hypoxicischemic encephalopathy. Death or moderate/severe disability is common but not uniform with Apgar scores of <3; caution is needed before adopting a specific time interval to guide duration of resuscitation. Pediatrics 2009;124:1619-1626 C1 [Laptook, Abbot R.] Women & Infants Hosp Rhode Isl, Dept Pediat, Providence, RI 02906 USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Ambalavanan, Namasivayam; Carlo, Waldemar A.] Univ Alabama, Div Neonatol, Birmingham, AL USA. [McDonald, Scott A.] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hu, NIH, Bethesda, MD USA. [Das, Abhik] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. RP Laptook, AR (reprint author), Women & Infants Hosp Rhode Isl, Dept Pediat, 101 Dudley St, Providence, RI 02906 USA. EM alaptook@wihri.org RI Myers , Gary /I-4901-2013; OI Myers , Gary /0000-0003-4317-015X; Ambalavanan, Namasivayam/0000-0003-0731-9092 FU Case Western Reserve University [U10 HD21364]; University of Texas Houston [U10 HD21373]; Wayne State University [U10 HD21385]; University of Miami [U10 HD21397]; Emory University [U10 HD27851]; University of Cincinnati [U10 HD27853]; Indiana University [U10 HD27856]; Yale University [U10 HD27871]; Stanford University [U10 HD27880]; Brown University [U10 HD27904]; University of Alabama at Birmingham [U10 HD34216, RTI U10 HD36790]; University of California-San Diego [U10 HD40461]; Duke University [U10 HD40492]; Wake Forest University [U10 HD40498]; University of Rochester [U10 HD40521]; University of Texas Southwestern Medical Center at Dallas [U10 HD40689]; General Clinical Research Centers [GCRC M01 RR30, GCRC M01 RR39, GCRC M01 RR44, GCRC M01 RR70, GCRC M01 RR80, GCRC M01 RR633, GCRC M01 RR750, GCRC M01 RR6022, GCRC M01 RR7122, GCRC M01 RR8084, GCRC M01 RR16587] FX This study was supported in part by grants Case Western Reserve University U10 HD21364, University of Texas Houston U10 HD21373, Wayne State University U10 HD21385, University of Miami U10 HD21397, Emory University U10 HD27851, University of Cincinnati U10 HD27853, Indiana University U10 HD27856, Yale University U10 HD27871, Stanford University U10 HD27880, Brown University U10 HD27904, University of Alabama at Birmingham U10 HD34216, RTI U10 HD36790, University of California-San Diego U10 HD40461, Duke University U10 HD40492, Wake Forest University U10 HD40498, University of Rochester U10 HD40521, University of Texas Southwestern Medical Center at Dallas U10 HD40689, General Clinical Research Centers grants GCRC M01 RR30, GCRC M01 RR39, GCRC M01 RR44, GCRC M01 RR70, GCRC M01 RR80, GCRC M01 RR633, GCRC M01 RR750, GCRC M01 RR6022, GCRC M01 RR7122, GCRC M01 RR8084, and GCRC M01 RR16587. NR 30 TC 57 Z9 61 U1 1 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD DEC PY 2009 VL 124 IS 6 BP 1619 EP 1626 DI 10.1542/peds.2009-0934 PG 8 WC Pediatrics SC Pediatrics GA 524SE UT WOS:000272162400015 PM 19948631 ER PT J AU Bocchini, JA Bernstein, HH Bradley, JS Brady, MT Byington, CL Fisher, MC Glode, MP Jackson, MA Keyserling, HL Kimberlin, DW Orenstein, WA Schutze, GE Willoughby, RE Dennehy, PH Frenck, RW Bell, B Bortolussi, R Clover, RD Fischer, MA Gellin, B Gorman, RL Pratt, RD Lee, L Read, JS Starke, JR Swanson, J Baker, CJ Long, SS Pickering, LK Ledbetter, EO Meissner, HC Rubin, LG Hall, C Frantz, J AF Bocchini, Joseph A., Jr. Bernstein, Henry H. Bradley, John S. Brady, Michael T. Byington, Carrie L. Fisher, Margaret C. Glode, Mary P. Jackson, Mary Anne Keyserling, Harry L. Kimberlin, David W. Orenstein, Walter A. Schutze, Gordon E. Willoughby, Rodney E. Dennehy, Penelope H. Frenck, Robert W., Jr. Bell, Beth Bortolussi, Robert Clover, Richard D. Fischer, Marc A. Gellin, Bruce Gorman, Richard L. Pratt, R. Douglas Lee, Lucia Read, Jennifer S. Starke, Jeffrey R. Swanson, Jack Baker, Carol J. Long, Sarah S. Pickering, Larry K. Ledbetter, Edgar O. Meissner, H. Cody Rubin, Lorry G. Hall, Caroline Frantz, Jennifer TI Policy Statement-Modified Recommendations for Use of Palivizumab for Prevention of Respiratory Syncytial Virus Infections SO PEDIATRICS LA English DT Article DE RSV bronchiolitis; palivizumab; immunoprophylaxis ID PREMATURE-INFANTS BORN; INVESTIGATORS COLLABORATIVE NETWORK; CONGENITAL HEART-DISEASE; 35 COMPLETED WEEKS; HIGH-RISK INFANTS; REQUIRING HOSPITALIZATION; REDUCES HOSPITALIZATION; MONOCLONAL-ANTIBODY; COST-EFFECTIVENESS; GESTATIONAL-AGE AB Palivizumab was licensed in June 1998 by the US Food and Drug Administration for prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients who are at increased risk of severe disease. Safety and efficacy have been established for infants born at or before 35 weeks' gestation with or without chronic lung disease of prematurity and for infants and children with hemodynamically significant heart disease. The American Academy of Pediatrics (AAP) published a policy statement on the use of palivizumab in November 1998 (American Academy of Pediatrics, Committee on Infectious Diseases and Committee on Fetus and Newborn. Pediatrics. 1998; 102[5]: 1211-1216) and revised it in December 2003 (American Academy of Pediatrics, Committee on Infectious Diseases and Committee on Fetus and Newborn. Pediatrics. 2003; 112[6 pt 1]: 1442-1446), and an AAP technical report on palivizumab was published in 2003 (Meissner HC, Long SS; American Academy of Pediatrics, Committee on Infectious Diseases and Committee on Fetus and Newborn. Pediatrics. 2003; 112[6 pt 1]: 1447-1452). On the basis of the availability of additional data regarding seasonality of RSV disease as well as the limitations in available data on risk factors for identifying children who are at increased risk of serious RSV lower respiratory tract disease, AAP recommendations for immunoprophylaxis have been updated in an effort to ensure optimal balance of benefit and cost from this expensive intervention. This statement updates and replaces the 2003 AAP statement and the 2006 Red Book and is consistent with the 2009 Red Book recommendations. Pediatrics 2009; 124: 1694-1701 C1 [Bell, Beth; Fischer, Marc A.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Bortolussi, Robert] Canadian Paediat Soc, Ottawa, ON, Canada. [Clover, Richard D.] Amer Acad Family Phys, Leakwood, KS 66211 USA. [Gorman, Richard L.; Read, Jennifer S.] Natl Inst Hlth, Bethesda, MD 20892 USA. [Pratt, R. Douglas; Lee, Lucia] US FDA, Rockville, MD 20857 USA. OI Dennehy, Penelope/0000-0002-2259-5370; Byington, Carrie/0000-0002-7350-9495 NR 32 TC 143 Z9 149 U1 1 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD DEC PY 2009 VL 124 IS 6 BP 1694 EP 1701 DI 10.1542/peds.2009-2345 PG 8 WC Pediatrics SC Pediatrics GA 524SE UT WOS:000272162400026 ER PT J AU Aldrovandi, GM Chu, C Shearer, WT Li, D Walter, J Thompson, B McIntosh, K Foca, M Meyer, WA Ha, BF Rich, KC Moye, J AF Aldrovandi, Grace M. Chu, Clara Shearer, William T. Li, Daner Walter, Jan Thompson, Bruce McIntosh, Kenneth Foca, Marc Meyer, William A., III Ha, Belinda F. Rich, Kenneth C. Moye, Jack, Jr. TI Antiretroviral Exposure and Lymphocyte mtDNA Content Among Uninfected Infants of HIV-1-Infected Women SO PEDIATRICS LA English DT Article DE HIV; mitochondria; antiretroviral agents ID HIV-INFECTED PATIENTS; BLOOD MONONUCLEAR-CELLS; MITOCHONDRIAL-DNA DEPLETION; REVERSE-TRANSCRIPTASE INHIBITORS; IN-UTERO; PERINATAL EXPOSURE; CORD BLOOD; CHILDREN; THERAPY; TOXICITY AB OBJECTIVE: Concern for potential adverse effects of antiretroviral (ARV) chemotherapy used to prevent mother-to-child HIV transmission has led the US Public Health Service to recommend long-term follow-up of ARV-exposed children. Nucleoside reverse transcriptase inhibitor ARV agents can inhibit DNA polymerase gamma, impairing mitochondrial DNA (mtDNA) synthesis and resulting in depletion or dysfunction. METHODS: We measured the mtDNA content of stored peripheral blood mononuclear cells (PBMCs) of 411 healthy children who were born to HIV-uninfected women and 213 uninfected infants who were born to HIV-infected women with or without in utero and neonatal ARV exposure. Cryopreserved PBMC mtDNA was quantified by using the Primagen Retina Mitox assay. RESULTS: Geometric mean PBMC mtDNA levels were lower at birth in infants who were born to HIV-infected women. Among HIV-exposed children, mtDNA levels were lowest in those who were not exposed to ARVs, higher in those with exposure to zidovudine alone, and higher still in those with combination nucleoside reverse transcriptase inhibitor exposure. A similar pattern was observed in the corresponding women. Levels of mtDNA increased during the first 5 years of life in all HIV-exposed children but achieved normal levels only in those with ARV exposure. CONCLUSIONS: Levels of mtDNA are lower than normal in HIV-exposed children. Contrary to expectation, PBMC mtDNA levels are significantly higher in ARV-exposed, HIV-uninfected infants and their infected mothers compared with ARV-unexposed infants and women. By 5 years, levels of PBMC mtDNA rise to normal concentrations in ARV-exposed children but remain depressed in ARV-unexposed children. Pediatrics 2009; 124: e1189-e1197 C1 [Aldrovandi, Grace M.; Walter, Jan] Univ So Calif, Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA. [Chu, Clara; Li, Daner; Thompson, Bruce] Clin Trials & Surveys Corp, Baltimore, MD USA. [Shearer, William T.] Baylor Coll Med, Dept Pediat, Div Allergy & Immunol, Houston, TX 77030 USA. [McIntosh, Kenneth] Childrens Hosp, Dept Pediat, Div Infect Dis, Boston, MA 02115 USA. [Foca, Marc] Columbia Univ, Dept Pediat, Div Infect Dis, New York, NY 10027 USA. [Meyer, William A., III] Quest Diagnost Inc, Baltimore, MD USA. [Ha, Belinda F.] GlaxoSmithKline Inc, Res Triangle Pk, NC USA. [Rich, Kenneth C.] Univ Illinois, Dept Pediat, Div Immunol, Chicago, IL USA. [Moye, Jack, Jr.] Ctr Res Mothers & Children, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. [Moye, Jack, Jr.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Aldrovandi, GM (reprint author), Univ So Calif, Childrens Hosp Los Angeles, Saban Res Inst, 4650 Sunset Blvd,MS 51, Los Angeles, CA 90027 USA. EM galdrovandi@chla.usc.edu OI moye, john/0000-0001-9976-8586 FU National Institutes of Health (NIH) [U01 AI 34858, 9U01 DA 15054, U01 DA 15053, HD-3-6117, U01 AI 34841, U01 HD 41983, N01 AI 85339, U01 AI 50274-01, GCRC RR00188, GCRC RR00645, U01 AI27551, R01 AI94029, P30 AI36211, U01 AI41110, U01 AI 27550, U01 AI 27541, U01 AI32921, U01 AI41089, U01 AI32907, U01 AI27559]; American Academy of Allergy Asthma & Immunology Basic and Clinical Immunology Interest Section Research Award; GlaxoSmithKline FX The WITS was funded by National Institutes of Health (NIH) grants U01 AI 34858, 9U01 DA 15054, U01 DA 15053, HD-3-6117, U01 AI 34841, U01 HD 41983, N01 AI 85339, and U01 AI 50274-01, with additional support from the local clinical research centers as follows: Baylor College of Medicine (Houston, TX), NIH GCRC RR00188; Columbia University (New York, NY), NIH GCRC RR00645. The P1009 study was funded by NIH grants U01 AI27551, R01 AI94029, P30 AI36211, U01 AI41110, U01 AI 27550, U01 AI 27541, U01 AI32921, U01 AI41089, U01 AI32907, U01 AI27559, U01 AI41089, M01 RR-00188, M01 RR-00865, M01 RR01271, M01 RR-00240, and N01 HD33162 and by the American Academy of Allergy Asthma & Immunology Basic and Clinical Immunology Interest Section Research Award (to Dr Shearer). Independent funding for mtDNA testing was provided by an unrestricted grant from GlaxoSmithKline (Research Triangle Park, NC) to Childrens Hospital Los Angeles. NR 48 TC 25 Z9 27 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD DEC PY 2009 VL 124 IS 6 BP E1189 EP E1197 DI 10.1542/peds.2008-2771 PG 9 WC Pediatrics SC Pediatrics GA 524SE UT WOS:000272162400047 PM 19933732 ER PT J AU Tiede, DM Mardis, KL Zuo, XB AF Tiede, David M. Mardis, Kristy L. Zuo, Xiaobing TI X-ray scattering combined with coordinate-based analyses for applications in natural and artificial photosynthesis SO PHOTOSYNTHESIS RESEARCH LA English DT Review DE X-ray scattering; Photosynthesis; Artificial photosynthesis; Solution structure; Supramolecular chemistry; Molecular dynamics; Structure-function ID PHOTOACTIVE YELLOW PROTEIN; SMALL-ANGLE SCATTERING; MOLECULAR-DYNAMICS SIMULATION; MANGANESE-STABILIZING SUBUNIT; STRUCTURAL-CHARACTERIZATION; SYNCHROTRON-RADIATION; BIOLOGICAL MACROMOLECULES; FUNCTIONAL DYNAMICS; NEUTRON-SCATTERING; PHOTOSYSTEM-II AB Advances in X-ray light sources and detectors have created opportunities for advancing our understanding of structure and structural dynamics for supramolecular assemblies in solution by combining X-ray scattering measurement with coordinate-based modeling methods. In this review the foundations for X-ray scattering are discussed and illustrated with selected examples demonstrating the ability to correlate solution X-ray scattering measurements to molecular structure, conformation, and dynamics. These approaches are anticipated to have a broad range of applications in natural and artificial photosynthesis by offering possibilities for structure resolution for dynamic supramolecular assemblies in solution that can not be fully addressed with crystallographic techniques, and for resolving fundamental mechanisms for solar energy conversion by mapping out structure in light-excited reaction states. C1 [Tiede, David M.] Argonne Natl Lab, Chem Sci & Engn Div, Argonne, IL 60439 USA. [Mardis, Kristy L.] Chicago State Univ, Dept Chem & Phys, Chicago, IL 60628 USA. [Zuo, Xiaobing] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. RP Tiede, DM (reprint author), Argonne Natl Lab, Chem Sci & Engn Div, Argonne, IL 60439 USA. EM tiede@anl.gov; kmardis@csu.edu; zuox@mail.nih.gov RI Zuo, Xiaobing/F-1469-2010; OI Mardis, Kristy/0000-0003-2633-9304; Zuo, Xiaobing/0000-0002-0134-4804 FU Office of Science, Basic Energy Sciences, U.S. Department of Energy [DE-AC02-06CH11357]; National Science Foundation [HRD0413000]; National Institutes of Health [1SC2GM083717] FX This study was supported by the Office of Science, Basic Energy Sciences, U.S. Department of Energy under contract numbers DE-AC02-06CH11357 (D.M.T. and work at APS Sector 12), National Science Foundation IL-LSAMP grant HRD0413000, and National Institutes of Health Grant 1SC2GM083717 (K.L.M.). The software program, solX, used for coordinated based X- ray scattering calculations is available by request to D. M. T. or X. Z. NR 78 TC 11 Z9 11 U1 0 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0166-8595 J9 PHOTOSYNTH RES JI Photosynth. Res. PD DEC PY 2009 VL 102 IS 2-3 BP 267 EP 279 DI 10.1007/s11120-009-9475-6 PG 13 WC Plant Sciences SC Plant Sciences GA 519UV UT WOS:000271795400015 PM 19636808 ER PT J AU Paliy, M Melnik, R Shapiro, BA AF Paliy, Maxim Melnik, Roderick Shapiro, Bruce A. TI Molecular dynamics study of the RNA ring nanostructure: a phenomenon of self-stabilization SO PHYSICAL BIOLOGY LA English DT Article ID DNA; PROTEINS; CATIONS; IONS AB We study mechanical and thermodynamic properties of RNA nanostructures focusing on a hexagonal nanoring discussed in Yingling and Shapiro (2007 Nano Lett. 7 2328). We are concerned with the following main issues: (i) the stability of the nanoring versus temperature; (ii) the effect of the environment (solvent, counterions) on its stability; (iii) conformations and dynamics under external force. The process of evaporation of the ions from the ring upon temperature drop has been found, demonstrating a surprising feature-the uptake of ions by the nanoring increases with the temperature. The connection of this behavior to the dielectric constant of water, hydration and structural changes in the nanoring is discussed. Several properties of the nanoring, such as elastic and transport coefficients, have been determined. A measure of the tensile elasticity of the ring against its uniform 2D in-plane compression has been given, as K(eff) <= 0.01 GPa, which is a much lower value compared to typical values found for soft matter other than RNA. C1 [Paliy, Maxim; Melnik, Roderick] Wilfrid Laurier Univ, Lab M2NeT, Waterloo, ON N2L 3C5, Canada. [Shapiro, Bruce A.] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. RP Paliy, M (reprint author), Wilfrid Laurier Univ, Lab M2NeT, 75 Univ Ave W, Waterloo, ON N2L 3C5, Canada. FU NSERC; CRC Program; NIH; National Cancer Institute; Center for Cancer Research; Shared Hierarchical Academic Research Computing Network FX MP and RM are grateful to the NSERC and the CRC Program for the support. BAS was supported in part by the intramural research program of the NIH, National Cancer Institute, Center for Cancer Research. This work was made possible by the facilities of the Shared Hierarchical Academic Research Computing Network (SHARCNET: www.sharcnet.ca). The authors are grateful to Sarah Woodson for helpful comments and suggestions. NR 27 TC 15 Z9 15 U1 0 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 1478-3967 J9 PHYS BIOL JI Phys. Biol. PD DEC PY 2009 VL 6 IS 4 AR 046003 DI 10.1088/1478-3975/6/4/046003 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 525CJ UT WOS:000272190400003 PM 19741282 ER PT J AU O'Connell, MP Weeraratna, AT AF O'Connell, Michael P. Weeraratna, Ashani T. TI Hear the Wnt Ror: how melanoma cells adjust to changes in Wnt SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Review DE Ror2; Wnt5A; melanoma; metastasis; endosome; clathrin ID TYROSINE KINASE ROR2; HEPARAN-SULFATE PROTEOGLYCANS; WNT/BETA-CATENIN PATHWAY; NEGATIVE BREAST-CANCER; EMBRYONIC STEM-CELLS; N-TERMINAL KINASE; BETA-CATENIN; MALIGNANT-MELANOMA; SIGNALING PATHWAY; GENE-EXPRESSION AB P>The interplay between canonical and non-canonical Wnt pathways in development and tumorigenesis is tightly regulated. In this review we will describe the yin and the yang of canonical and non-canonical Wnt signaling pathways during melanocyte development, and melanoma genesis. Canonical Wnt signaling, represented by Wnts such as Wnt1 and Wnt3A, signals via beta-catenin to promote melanocyte differentiation and tumor development. Non-canonical Wnt signaling, specifically Wnt5A, regulates canonical pathways, and signals to induce melanoma metastasis. This review will focus on the role of Wnt5A during melanoma progression, and its relationship to canonical Wnt signaling. C1 [O'Connell, Michael P.; Weeraratna, Ashani T.] NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Weeraratna, AT (reprint author), NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. EM weerarat@mail.nih.gov FU Intramural Research Program of the National Institute on Aging FX MPO and ATW are supported by the Intramural Research Program of the National Institute on Aging. We sincerely apologize to all the authors whose wonderful work was not cited here due to space constraints, and the more editorial rather than encyclopedic nature of this review. We also apologize for the liberal use of sailing-related puns. NR 160 TC 45 Z9 50 U1 0 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD DEC PY 2009 VL 22 IS 6 BP 724 EP 739 DI 10.1111/j.1755-148X.2009.00627.x PG 16 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 507DF UT WOS:000270830600009 PM 19708915 ER PT J AU Chen, KG Valencia, JC Gillet, JP Hearing, VJ Gottesman, MM AF Chen, Kevin G. Valencia, Julio C. Gillet, Jean-Pierre Hearing, Vincent J. Gottesman, Michael M. TI Involvement of ABC transporters in melanogenesis and the development of multidrug resistance of melanoma SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Review DE melanoma; multidrug resistance; melanosome; ATP-binding cassette; transporters; ABCB5; ABCC2 ID BINDING CASSETTE TRANSPORTER; TYROSINASE-RELATED PROTEIN-2; OVARIAN-CARCINOMA CELLS; P-GLYCOPROTEIN; MALIGNANT-MELANOMA; DRUG-RESISTANCE; INDUCED APOPTOSIS; CYTOTOXIC DRUGS; CANCER-CELLS; EXPRESSION AB P>Because melanomas are intrinsically resistant to conventional radiotherapy and chemotherapy, many alternative treatment approaches have been developed such as biochemotherapy and immunotherapy. The most common cause of multidrug resistance (MDR) in human cancers is the expression and function of one or more ATP-binding cassette (ABC) transporters that efflux anticancer drugs from cells. Melanoma cells express a group of ABC transporters (such as ABCA9, ABCB1, ABCB5, ABCB8, ABCC1, ABCC2, and ABCD1) that may be associated with the resistance of melanoma cells to a broad range of anticancer drugs and/or of melanocytes to toxic melanin intermediates and metabolites. In this review, we propose a model (termed the ABC-M model) in which the intrinsic MDR of melanoma cells is at least in part because of the transporter systems that may also play a critical role in reducing the cytotoxicity of the melanogenic pathway in melanocytes. The ABC-M model suggests molecular strategies to reverse MDR function in the context of the melanogenic pathway, which could open therapeutic avenues towards the ultimate goal of circumventing clinical MDR in patients with melanoma. C1 [Chen, Kevin G.; Valencia, Julio C.; Gillet, Jean-Pierre; Hearing, Vincent J.; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Chen, Kevin G.] Natl Inst Neurol Disorders & Stroke, NIH, Stem Cell Unit, Bethesda, MD USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM mgottesman@nih.gov RI Chen, Kevin/D-6769-2011; gillet, jean-pierre/A-3714-2012 OI Chen, Kevin/0000-0003-2983-6330; FU Intramural Research Program of the 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. We thank colleagues Richard Leapman, Barry Lai, and Guofeng Zhang for their contributions that made this review possible. We thank George Leiman for his assistance in preparing the manuscript and for editorial advice. NR 63 TC 68 Z9 68 U1 2 U2 14 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD DEC PY 2009 VL 22 IS 6 BP 740 EP 749 DI 10.1111/j.1755-148X.2009.00630.x PG 10 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 507DF UT WOS:000270830600010 PM 19725928 ER PT J AU Chen, DH Lin, QS Box, N Roop, D Ishii, S Matsuzaki, K Fan, T Hornyak, TJ Reed, JA Stavnezer, E Timchenko, NA Medrano, EE AF Chen, Dahu Lin, Qiushi Box, Neil Roop, Dennis Ishii, Shunsuke Matsuzaki, Koichi Fan, Tao Hornyak, Thomas J. Reed, Jon A. Stavnezer, Ed Timchenko, Nikolai A. Medrano, Estela E. TI SKI knockdown inhibits human melanoma tumor growth in vivo SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE melanoma; SKI; TGF-beta; Smad3 linker phosphorylation; c-MYC; PAI-1 ID HUMAN COLORECTAL CARCINOGENESIS; ONCOGENIC PROTEIN SKI; FACTOR-BETA; TGF-BETA; C-SKI; MALIGNANT-MELANOMA; SMAD PROTEINS; MEDIATED TRANSCRIPTION; CUTANEOUS MELANOMA; CELL-PROLIFERATION AB P>The SKI protein represses the TGF-beta tumor suppressor pathway by associating with the Smad transcription factors. SKI is upregulated in human malignant melanoma tumors in a disease-progression manner and its overexpression promotes proliferation and migration of melanoma cells in vitro. The mechanisms by which SKI antagonizes TGF-beta signaling in vivo have not been fully elucidated. Here we show that human melanoma cells in which endogenous SKI expression was knocked down by RNAi produced minimal orthotopic tumor xenograft nodules that displayed low mitotic rate and prominent apoptosis. These minute tumors exhibited critical signatures of active TGF-beta signaling including high levels of nuclear Smad3 and p21Waf-1, which are not found in the parental melanomas. To understand how SKI promotes tumor growth we used gain- and loss-of-function approaches and found that simultaneously to blocking the TGF-beta-growth inhibitory pathway, SKI promotes the switch of Smad3 from tumor suppression to oncogenesis by favoring phosphorylations of the Smad3 linker region in melanoma cells but not in normal human melanocytes. In this context, SKI is required for preventing TGF-beta-mediated downregulation of the oncogenic protein c-MYC, and for inducing the plasminogen activator inhibitor-1, a mediator of tumor growth and angiogenesis. Together, the results indicate that SKI exploits multiple regulatory levels of the TGF-beta pathway and its deficiency restores TGF-beta tumor suppressor and apoptotic activities in spite of the likely presence of oncogenic mutations in melanoma tumors. C1 [Chen, Dahu; Lin, Qiushi; Timchenko, Nikolai A.; Medrano, Estela E.] Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA. [Box, Neil; Roop, Dennis; Medrano, Estela E.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Box, Neil; Roop, Dennis; Reed, Jon A.; Medrano, Estela E.] Baylor Coll Med, Dept Dermatol, Houston, TX 77030 USA. [Ishii, Shunsuke] RIKEN, Tsukuba Inst, Tsukuba, Ibaraki, Japan. [Matsuzaki, Koichi] Kansai Med Univ, Dept Gastroenterol & Hepatol, Osaka, Japan. [Fan, Tao; Hornyak, Thomas J.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stavnezer, Ed] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Timchenko, Nikolai A.] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. RP Medrano, EE (reprint author), Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA. EM medrano@bcm.tmc.edu RI Box, Neil/F-3591-2010; Ishii, Shunsuke/A-5271-2016 OI Box, Neil/0000-0002-3486-0346; FU National Institutes of Health [2RO1CA084282, RO1CA10070]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was funded by the National Institutes of Health grants 2RO1CA084282 (E. E. M.) and RO1CA10070 (N. A. T.), and in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (T. F. and T. J. H.). NR 70 TC 19 Z9 20 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD DEC PY 2009 VL 22 IS 6 BP 761 EP 772 DI 10.1111/j.1755-148X.2009.00603.x PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 507DF UT WOS:000270830600012 PM 19845874 ER PT J AU Buac, K Xu, M Cronin, J Weeraratna, AT Hewitt, SM Pavan, WJ AF Buac, Kristina Xu, Mai Cronin, Julie Weeraratna, Ashani T. Hewitt, Stephen M. Pavan, William J. TI NRG1/ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE Erbb3; neuregulin; melanocytes; melanoma; neural crest ID TYROSINE KINASE-ACTIVITY; NUCLEAR-LOCALIZATION; PROGNOSTIC VALUE; PROSTATE-CANCER; ERBB3 RECEPTOR; GROWTH-FACTOR; TUMOR-GROWTH; IN-VIVO; C-KIT; EXPRESSION AB P>Neuregulin (NRG) signaling through the receptor tyrosine kinase, ERBB3, is required for embryonic development, and dysregulated signaling has been associated with cancer progression. Here, we show that NRG1/ERBB3 signaling inhibits melanocyte (MC) maturation and promotes undifferentiated, migratory and proliferative cellular characteristics. Embryonic analyses demonstrated that initial MC specification and distribution were not dependent on ERBB3 signaling. However NRG1/ERBB3 signaling was both necessary and sufficient to inhibit differentiation of later stages of MC development in culture. Analysis of tissue arrays of human melanoma samples suggests that ERBB3 signaling may also contribute to metastatic progression of melanoma as ERBB3 was phosphorylated in primary tumors compared with nevi or metastatic lesions. Neuregulin 1-treated MCs demonstrated increased proliferation and invasion and altered morphology concomitant with decreased levels of differentiation genes, increased levels of proliferation genes and altered levels of melanoma progression and metastases genes. ERBB3 activation in primary melanomas suggests that NRG1/ERBB3 signaling may contribute to the progression of melanoma from benign nevi to malignancies. We propose that targeting ERBB3 activation and downstream genes identified in this study may provide novel therapeutic interventions for malignant melanoma. C1 [Buac, Kristina; Cronin, Julie; Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Buac, Kristina] George Washington Univ, Washington, DC USA. [Xu, Mai; Weeraratna, Ashani T.] NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. [Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Pavan, WJ (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM bpavan@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU National Human Genome Research Institute's Intramural Research Program; Intramural Research Program of the National Institute on Aging FX We thank Dieter Riethmacher for providing Erbb3KO1/+ and Erbb3KO2/+ mice; Dorothy Bennett for Melan-Ink4a cells; Heinz Arnheiter for MITF antibody; Vincent Hearing for TYR, TYRP1, DCT and SL antibodies. Thanks to Stacy Anderson for cell cycle analysis and Julia Fekecs for graphic design. This work was supported by the National Human Genome Research Institute's Intramural Research Program and the Intramural Research Program of the National Institute on Aging. NR 55 TC 40 Z9 41 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD DEC PY 2009 VL 22 IS 6 BP 773 EP 784 DI 10.1111/j.1755-148X.2009.00616.x PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 507DF UT WOS:000270830600013 PM 19659570 ER PT J AU Maxhimer, JB Shih, HB Isenberg, JS Miller, TW Roberts, DD AF Maxhimer, Justin B. Shih, Hubert B. Isenberg, Jeffrey S. Miller, Thomas W. Roberts, David D. TI Thrombospondin-1/CD47 Blockade following Ischemia-Reperfusion Injury Is Tissue Protective SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article; Proceedings Paper CT 54th Annual Meeting of the Plastic-Surgery-Research-Council CY MAY 27-30, 2009 CL Pittsburgh, PA SP Plast Surg Res Council ID INDEPENDENT CELL-DEATH; NITRIC-OXIDE; T-CELL; IMMUNE-RESPONSE; FLAP SURVIVAL; ISLAND FLAPS; CD47; RAT; ANTIBODY; EXPRESSION AB Background: Nitric oxide has prosurvival effects that can limit ischemia-reperfusion injuries. However, the matrix glycoprotein thrombospondin-1 is induced following ischemia-reperfusion injury and limits nitric oxide signaling by engaging its cell surface receptor CD47. In this article, the authors examine whether postinjury blocking of this inhibitory signal can protect from ischemia-reperfusion injury in a rat flap model. Methods: A total of 40 tissue flaps were created in rats based solely on the deep inferior epigastric vessels. Microvascular clamps were used to create 45 minutes of ischemia time to the flaps. The flaps were then treated using a monoclonal antibody to CD47 or an isotype-matched control immunoglobulin G(1) 5 or 30 minutes after clamp removal. Twenty-four or 72 hours postoperatively, the necrotic area of the flap was determined, and serum, deep inferior epigastric vessels, and flaps were harvested for analysis from five rats in each respective group. Results: Treatment with a CD47 antibody 5 minutes after reperfusion significantly reduces flap necrosis compared with immunoglobulin G(1) control (9 percent versus 43 percent; p < 0.01). The protective effect is even more dramatic when treatment is delayed until 30 minutes after reperfusion (10 percent versus 88 percent for control; p < 0.01). Markers of neutrophil and endothelial cell activation along with total leukocytes are reduced in CD47 antibody-treated flaps, as are tissue malondialdehyde levels. Levels of cyclic guanosine monophosphate are elevated 72 hours postoperatively in the CD47 antibody-treated deep inferior epigastric vessels versus the control flaps. Conclusions: Therapies targeting the thrombospondin-1 receptor CD47 offer potential for increasing tissue survival in ischemia-reperfusion injuries. The ability to protect when given after ischemia-reperfusion injury enables a broader clinical applicability. (Plast. Reconstr. Surg. 124: 1880, 2009.) C1 [Roberts, David D.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Surg, Baltimore, MD USA. NIH, Howard Hughes Med Inst, Res Scholar Program, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Sch Med, Vasc Med Inst, Pittsburgh, PA 15260 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2A33,10 Ctr Dr,MSC1500, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008; Miller, Thomas/G-1215-2011 OI Roberts, David/0000-0002-2481-2981; Miller, Thomas/0000-0001-8645-2785 FU Howard Hughes Medical Institute; Intramural NIH HHS [ZIA SC009172-21] NR 62 TC 29 Z9 29 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD DEC PY 2009 VL 124 IS 6 BP 1880 EP 1889 DI 10.1097/PRS.0b013e3181bceec3 PG 10 WC Surgery SC Surgery GA 530TQ UT WOS:000272615600018 PM 19952644 ER PT J AU Jin, TQ Ito, Y Luan, XH Dangaria, S Walker, C Allen, M Kulkarni, A Gibson, C Braatz, R Liao, XB Diekwisch, TGH AF Jin, Tianquan Ito, Yoshihiro Luan, Xianghong Dangaria, Smit Walker, Cameron Allen, Michael Kulkarni, Ashok Gibson, Carolyn Braatz, Richard Liao, Xiubei Diekwisch, Thomas G. H. TI Elongated Polyproline Motifs Facilitate Enamel Evolution through Matrix Subunit Compaction SO PLOS BIOLOGY LA English DT Article ID SECONDARY STRUCTURE; AMELOGENIN PROTEIN; NEURAL CREST; RANA-PIPIENS; II HELICES; HYDROXYAPATITE; SEQUENCE; ORIGINS; GENE; BIOMINERALIZATION AB Vertebrate body designs rely on hydroxyapatite as the principal mineral component of relatively light-weight, articulated endoskeletons and sophisticated tooth-bearing jaws, facilitating rapid movement and efficient predation. Biological mineralization and skeletal growth are frequently accomplished through proteins containing polyproline repeat elements. Through their well-defined yet mobile and flexible structure polyproline-rich proteins control mineral shape and contribute many other biological functions including Alzheimer's amyloid aggregation and prolamine plant storage. In the present study we have hypothesized that polyproline repeat proteins exert their control over biological events such as mineral growth, plaque aggregation, or viscous adhesion by altering the length of their central repeat domain, resulting in dramatic changes in supramolecular assembly dimensions. In order to test our hypothesis, we have used the vertebrate mineralization protein amelogenin as an exemplar and determined the biological effect of the four-fold increased polyproline tandem repeat length in the amphibian/mammalian transition. To study the effect of polyproline repeat length on matrix assembly, protein structure, and apatite crystal growth, we have measured supramolecular assembly dimensions in various vertebrates using atomic force microscopy, tested the effect of protein assemblies on crystal growth by electron microscopy, generated a transgenic mouse model to examine the effect of an abbreviated polyproline sequence on crystal growth, and determined the structure of polyproline repeat elements using 3D NMR. Our study shows that an increase in PXX/PXQ tandem repeat motif length results (i) in a compaction of protein matrix subunit dimensions, (ii) reduced conformational variability, (iii) an increase in polyproline II helices, and (iv) promotion of apatite crystal length. Together, these findings establish a direct relationship between polyproline tandem repeat fragment assemblies and the evolution and the design of vertebrate mineralized tissue microstructures. Our findings reveal that in the greater context of chordate evolution, the biological control of apatite growth by polyproline-based matrix assemblies provides a molecular basis for the evolution of the vertebrate body plan. C1 [Jin, Tianquan; Ito, Yoshihiro; Luan, Xianghong; Dangaria, Smit; Walker, Cameron; Diekwisch, Thomas G. H.] Univ Illinois, Chicago Coll Dent, Brodie Lab Craniofacial Genet, Chicago, IL 60607 USA. [Liao, Xiubei] Univ Illinois, Dept Biochem & Mol Biol, Chicago, IL USA. [Braatz, Richard] Univ Illinois, Dept Chem & Biomol Engn, Urbana, IL 61801 USA. [Gibson, Carolyn] Univ Penn, Philadelphia, PA 19104 USA. [Kulkarni, Ashok] NIH, Funct Genom Unit, Bethesda, MD 20892 USA. RP Jin, TQ (reprint author), Univ Illinois, Chicago Coll Dent, Brodie Lab Craniofacial Genet, Chicago, IL 60607 USA. EM tomdkw@uic.edu FU National Institutes of Health [DE13378, DE18900] FX Funding for this study has been provided by the National Institutes of Health grants DE13378 and DE18900 (http://www.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 20 Z9 20 U1 4 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD DEC PY 2009 VL 7 IS 12 AR e1000262 DI 10.1371/journal.pbio.1000262 PG 10 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 536RC UT WOS:000273060500009 PM 20027208 ER PT J AU Wall, ME Markowitz, DA Rosner, JL Martin, RG AF Wall, Michael E. Markowitz, David A. Rosner, Judah L. Martin, Robert G. TI Model of Transcriptional Activation by MarA in Escherichia coli SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID LAMBDA-PRM PROMOTER; RNA-POLYMERASE; TERMINAL DOMAIN; BINDING-SITES; HSP70 GENE; REPRESSOR; PROTEIN; DNA; MELANOGASTER; ORIENTATION AB The AraC family transcription factor MarA activates similar to 40 genes (the marA/soxS/rob regulon) of the Escherichia coli chromosome resulting in different levels of resistance to a wide array of antibiotics and to superoxides. Activation of marA/soxS/rob regulon promoters occurs in a well-defined order with respect to the level of MarA; however, the order of activation does not parallel the strength of MarA binding to promoter sequences. To understand this lack of correspondence, we developed a computational model of transcriptional activation in which a transcription factor either increases or decreases RNA polymerase binding, and either accelerates or retards post-binding events associated with transcription initiation. We used the model to analyze data characterizing MarA regulation of promoter activity. The model clearly explains the lack of correspondence between the order of activation and the MarA-DNA affinity and indicates that the order of activation can only be predicted using information about the strength of the full MarA-polymerase-DNA interaction. The analysis further suggests that MarA can activate without increasing polymerase binding and that activation can even involve a decrease in polymerase binding, which is opposite to the textbook model of activation by recruitment. These findings are consistent with published chromatin immunoprecipitation assays of interactions between polymerase and the E. coli chromosome. We find that activation involving decreased polymerase binding yields lower latency in gene regulation and therefore might confer a competitive advantage to cells. Our model yields insights into requirements for predicting the order of activation of a regulon and enables us to suggest that activation might involve a decrease in polymerase binding which we expect to be an important theme of gene regulation in E. coli and beyond. C1 [Wall, Michael E.; Markowitz, David A.] Los Alamos Natl Lab, Comp Computat & Stat Sci Div, Los Alamos, NM 87545 USA. [Wall, Michael E.] Los Alamos Natl Lab, Biosci Div, Los Alamos, NM USA. [Wall, Michael E.] Los Alamos Natl Lab, Ctr Nonlinear Studies, Los Alamos, NM 87545 USA. [Rosner, Judah L.; Martin, Robert G.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wall, ME (reprint author), Los Alamos Natl Lab, Comp Computat & Stat Sci Div, Los Alamos, NM 87545 USA. EM mewall@lanl.gov OI Alexandrov, Ludmil/0000-0003-3596-4515 FU Department of Energy [DE-FG02-97ER25308]; National Institutes of Health FX This work was supported by funding from the Department of Energy (LANL Laboratory-Directed Research & Development, MEW) and the National Institutes of Health (Intramural Research Program, RGM and JLR). Early modeling and analysis of promoter activity data were made possible by Department of Energy Computational Science Graduate Fellowship Grant DE-FG02-97ER25308 to DAM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 15 Z9 16 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD DEC PY 2009 VL 5 IS 12 AR e1000614 DI 10.1371/journal.pcbi.1000614 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 551SE UT WOS:000274229000032 PM 20019803 ER PT J AU Fellay, J Ge, DL Shianna, KV Colombo, S Ledergerber, B Cirulli, ET Urban, TJ Zhang, KL Gumbs, CE Smith, JP Castagna, A Cozzi-Lepri, A De Luca, A Easterbrook, P Gunthard, HF Mallal, S Mussini, C Dalmau, J Martinez-Picado, J Miro, JM Obel, N Wolinsky, SM Martinson, JJ Detels, R Margolick, JB Jacobson, LP Descombes, P Antonarakis, SE Beckmann, JS O'Brien, SJ Letvin, NL McMichael, AJ Haynes, BF Carrington, M Feng, S Telenti, A Goldstein, DB AF Fellay, Jacques Ge, Dongliang Shianna, Kevin V. Colombo, Sara Ledergerber, Bruno Cirulli, Elizabeth T. Urban, Thomas J. Zhang, Kunlin Gumbs, Curtis E. Smith, Jason P. Castagna, Antonella Cozzi-Lepri, Alessandro De Luca, Andrea Easterbrook, Philippa Guenthard, Huldrych F. Mallal, Simon Mussini, Cristina Dalmau, Judith Martinez-Picado, Javier Miro, Jose M. Obel, Niels Wolinsky, Steven M. Martinson, Jeremy J. Detels, Roger Margolick, Joseph B. Jacobson, Lisa P. Descombes, Patrick Antonarakis, Stylianos E. Beckmann, Jacques S. O'Brien, Stephen J. Letvin, Norman L. McMichael, Andrew J. Haynes, Barton F. Carrington, Mary Feng, Sheng Telenti, Amalio Goldstein, David B. CA NIAID Ctr HIV AIDS Vaccine Immunol TI Common Genetic Variation and the Control of HIV-1 in Humans SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; HLA-C; HOST GENETICS; INFECTION; AIDS; PROGRESSION; DISEASE; POLYMORPHISM; RESISTANCE; HCP5 AB To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians. C1 [Fellay, Jacques; Ge, Dongliang; Shianna, Kevin V.; Cirulli, Elizabeth T.; Urban, Thomas J.; Gumbs, Curtis E.; Feng, Sheng; Goldstein, David B.] Duke Univ, Ctr Human Genome Variat, Duke Inst Genome Sci & Policy, Durham, NC 27706 USA. [Shianna, Kevin V.; Smith, Jason P.] Duke Univ, Genom Anal Facil, Duke Inst Genome Sci & Policy, Durham, NC USA. [Colombo, Sara; Zhang, Kunlin; Telenti, Amalio] Univ Lausanne, Inst Microbiol, Lausanne, Switzerland. [Ledergerber, Bruno; Guenthard, Huldrych F.] Univ Zurich, Univ Hosp, Div Infect Dis & Hosp Epidemiol, Zurich, Switzerland. [Zhang, Kunlin] Chinese Acad Sci, Inst Psychol, Behav Genet Ctr, Beijing 100101, Peoples R China. [Castagna, Antonella] Vita Salute San Raffaele Univ & Diagnost & Ric Sa, Clin Infect Dis, Milan, Italy. [Cozzi-Lepri, Alessandro] UCL, Res Dept Infect & Populat Hlth, London, England. [De Luca, Andrea] Univ Cattolica Sacro Cuore, Inst Clin Infect Dis, I-00168 Rome, Italy. [Easterbrook, Philippa] Kings Coll London, Acad Dept HIV GUM, Weston Educ Ctr, Guys Hosp, London WC2R 2LS, England. [Easterbrook, Philippa] Kings Coll London, Acad Dept HIV GUM, Weston Educ Ctr, Kings Hosp, London WC2R 2LS, England. [Easterbrook, Philippa] Kings Coll London, Acad Dept HIV GUM, St Thomas Hosp, Weston Educ Ctr, London, England. [Mallal, Simon] Royal Perth Hosp, Ctr Clin Immunol & Biomed Stat, Inst Immunol & Infect Dis, Perth, WA, Australia. [Mallal, Simon] Murdoch Univ, Perth, WA, Australia. [Mussini, Cristina] Azienda Osped Univ, Infect Dis Clin, Modena, Italy. [Dalmau, Judith; Martinez-Picado, Javier] IrsiCaixa Fdn, Badalona, Spain. [Dalmau, Judith; Martinez-Picado, Javier] Hosp Badalona Germans Trias & Pujol, Badalona, Spain. [Martinez-Picado, Javier] ICREA, Barcelona, Spain. [Miro, Jose M.] Univ Barcelona, Hosp Clin, IDIBAPS, Barcelona, Spain. [Obel, Niels] Univ Copenhagen Hosp, Rigshosp, Dept Infect Dis, DK-2100 Copenhagen, Denmark. [Wolinsky, Steven M.] Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. [Martinson, Jeremy J.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Detels, Roger] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Margolick, Joseph B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Jacobson, Lisa P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Descombes, Patrick] Univ Geneva, Natl Ctr Competence Res Frontiers Genet, Geneva, Switzerland. [Antonarakis, Stylianos E.] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland. [Beckmann, Jacques S.] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Beckmann, Jacques S.] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland. [O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21701 USA. [Letvin, Norman L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Viral Pathogenesis, Boston, MA 02215 USA. [McMichael, Andrew J.] John Radcliffe Hosp, MRC, Human Immunol Unit, Weatherall Inst Mol Med, Oxford OX3 9DU, England. [Haynes, Barton F.] Duke Univ, Duke Human Vaccine Inst, Durham, NC USA. [Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. [Carrington, Mary] Massachusetts Gen Hosp, Ragon Inst, MIT& Harvard, Boston, MA 02114 USA. RP Fellay, J (reprint author), Duke Univ, Ctr Human Genome Variat, Duke Inst Genome Sci & Policy, Durham, NC 27706 USA. EM amalio.telenti@chuv.ch; d.goldstein@duke.edu RI Ledergerber, Bruno/B-5656-2009; Beckmann, Jacques S /A-9772-2008; De Luca, Andrea/G-8810-2011; Wolinsky, Steven/B-2893-2012; gunthard, huldrych/F-1724-2011; Martinez-Picado, Javier/G-5507-2012; Infektiologie, USZ/A-6921-2011; SHCS, all/G-4072-2011; SHCS, int. coll. A/G-4083-2011; Fellay, Jacques/A-6681-2009; Antonarakis, Stylianos/N-8866-2014; OI Ledergerber, Bruno/0000-0002-6881-4401; Martinson, Jeremy/0000-0003-4673-7238; Wolinsky, Steven/0000-0002-9625-6697; Beckmann, Jacques S /0000-0002-9741-1900; gunthard, huldrych/0000-0002-1142-6723; Martinez-Picado, Javier/0000-0002-4916-2129; Fellay, Jacques/0000-0002-8240-939X; Antonarakis, Stylianos/0000-0001-8907-5823; Cirulli Rogers, Liz/0000-0001-7808-2809 FU NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI) [AI067854]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Swiss National Science Foundation; Infectigen Foundation FX Funding: Funding was provided by the NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI) grant AI067854. This project has also been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E, and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. AT and SEA are supported by the Swiss National Science Foundation and by the Infectigen Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 206 Z9 210 U1 3 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD DEC PY 2009 VL 5 IS 12 AR e1000791 DI 10.1371/journal.pgen.1000791 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 542CT UT WOS:000273469700041 PM 20041166 ER PT J AU Goula, AV Berquist, BR Wilson, DM Wheeler, VC Trottier, Y Merienne, K AF Goula, Agathi-Vassiliki Berquist, Brian R. Wilson, David M., III Wheeler, Vanessa C. Trottier, Yvon Merienne, Karine TI Stoichiometry of Base Excision Repair Proteins Correlates with Increased Somatic CAG Instability in Striatum over Cerebellum in Huntington's Disease Transgenic Mice SO PLOS GENETICS LA English DT Article ID DNA-POLYMERASE-BETA; TRINUCLEOTIDE REPEAT INSTABILITY; ABASIC ENDONUCLEASE ACTIVITY; KNOCK-IN MOUSE; MYOTONIC-DYSTROPHY; DEPENDENT MANNER; LIGASE-I; BRAIN; EXPANSION; GENE AB Huntington's disease (HD) is a progressive neurodegenerative disorder caused by expansion of an unstable CAG repeat in the coding sequence of the Huntingtin (HTT) gene. Instability affects both germline and somatic cells. Somatic instability increases with age and is tissue-specific. In particular, the CAG repeat sequence in the striatum, the brain region that preferentially degenerates in HD, is highly unstable, whereas it is rather stable in the disease-spared cerebellum. The mechanisms underlying the age-dependence and tissue-specificity of somatic CAG instability remain obscure. Recent studies have suggested that DNA oxidation and OGG1, a glycosylase involved in the repair of 8-oxoguanine lesions, contribute to this process. We show that in HD mice oxidative DNA damage abnormally accumulates at CAG repeats in a length-dependent, but age-and tissue-independent manner, indicating that oxidative DNA damage alone is not sufficient to trigger somatic instability. Protein levels and activities of major base excision repair (BER) enzymes were compared between striatum and cerebellum of HD mice. Strikingly, 59-flap endonuclease activity was much lower in the striatum than in the cerebellum of HD mice. Accordingly, Flap Endonuclease-1 (FEN1), the main enzyme responsible for 59-flap endonuclease activity, and the BER cofactor HMGB1, both of which participate in long-patch BER (LP-BER), were also significantly lower in the striatum compared to the cerebellum. Finally, chromatin immunoprecipitation experiments revealed that POL beta was specifically enriched at CAG expansions in the striatum, but not in the cerebellum of HD mice. These in vivo data fit a model in which POL beta strand displacement activity during LP-BER promotes the formation of stable 59-flap structures at CAG repeats representing pre-expanded intermediate structures, which are not efficiently removed when FEN1 activity is constitutively low. We propose that the stoichiometry of BER enzymes is one critical factor underlying the tissue selectivity of somatic CAG expansion. C1 [Goula, Agathi-Vassiliki; Trottier, Yvon; Merienne, Karine] UdS, INSERM, CNRS,UMR 7104, Dept Neurobiol & Genet,Inst Genet & Mol & Cellula, Illkirch Graffenstaden, France. [Berquist, Brian R.; Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Wilson, David M., III] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Goula, AV (reprint author), UdS, INSERM, CNRS,UMR 7104, Dept Neurobiol & Genet,Inst Genet & Mol & Cellula, Illkirch Graffenstaden, France. EM yvon@igbmc.fr; merienne@igbmc.fr RI Trottier, Yvon/H-8852-2016 FU CNRS; INSERM; Hereditary Disease Foundation (USA); NIH (National Institute of Neurological Disease and Stroke) [NS049206]; Intramural Research Program of the NIH, National Institute on Aging FX Funding: This work was supported by funds from CNRS and INSERM, by the Hereditary Disease Foundation (USA), by the NIH (National Institute of Neurological Disease and Stroke) grant NS049206, and by the Intramural Research Program of the NIH, National Institute on Aging. The funders have not been implicated in the design, realization, and analysis of the study. They were not involved in manuscript preparation or the decision to submit. NR 55 TC 69 Z9 69 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD DEC PY 2009 VL 5 IS 12 AR e1000749 DI 10.1371/journal.pgen.1000749 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 542CT UT WOS:000273469700001 PM 19997493 ER PT J AU Richards, JB Waterworth, D O'Rahilly, S Hivert, MF Loos, RJF Perry, JRB Tanaka, T Timpson, NJ Semple, RK Soranzo, N Song, K Rocha, N Grundberg, E Dupuis, J Florez, JC Langenberg, C Prokopenko, I Saxena, R Sladek, R Aulchenko, Y Evans, D Waeber, G Erdmann, J Burnett, MS Sattar, N Devaney, J Willenborg, C Hingorani, A Witteman, JCM Vollenweider, P Glaser, B Hengstenberg, C Ferrucci, L Melzer, D Stark, K Deanfield, J Winogradow, J Grassl, M Hall, AS Egan, JM Thompson, JR Ricketts, SL Konig, IR Reinhard, W Grundy, S Wichmann, HE Barter, P Mahley, R Kesaniemi, YA Rader, DJ Reilly, MP Epstein, SE Stewart, AFR Van Duijn, CM Schunkert, H Burling, K Deloukas, P Pastinen, T Samani, NJ McPherson, R Smith, GD Frayling, TM Wareham, NJ Meigs, JB Mooser, V Spector, TD AF Richards, J. Brent Waterworth, Dawn O'Rahilly, Stephen Hivert, Marie-France Loos, Ruth J. F. Perry, John R. B. Tanaka, Toshiko Timpson, Nicholas John Semple, Robert K. Soranzo, Nicole Song, Kijoung Rocha, Nuno Grundberg, Elin Dupuis, Josee Florez, Jose C. Langenberg, Claudia Prokopenko, Inga Saxena, Richa Sladek, Robert Aulchenko, Yurii Evans, David Waeber, Gerard Erdmann, Jeanette Burnett, Mary-Susan Sattar, Naveed Devaney, Joseph Willenborg, Christina Hingorani, Aroon Witteman, Jaquelin C. M. Vollenweider, Peter Glaser, Beate Hengstenberg, Christian Ferrucci, Luigi Melzer, David Stark, Klaus Deanfield, John Winogradow, Janina Grassl, Martina Hall, Alistair S. Egan, Josephine M. Thompson, John R. Ricketts, Sally L. Koenig, Inke R. Reinhard, Wibke Grundy, Scott Wichmann, H-Erich Barter, Phil Mahley, Robert Kesaniemi, Y. Antero Rader, Daniel J. Reilly, Muredach P. Epstein, Stephen E. Stewart, Alexandre F. R. Van Duijn, Cornelia M. Schunkert, Heribert Burling, Keith Deloukas, Panos Pastinen, Tomi Samani, Nilesh J. McPherson, Ruth Smith, George Davey Frayling, Timothy M. Wareham, Nicholas J. Meigs, James B. Mooser, Vincent Spector, Tim D. CA GIANT Consortium TI A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels SO PLOS GENETICS LA English DT Article ID MOLECULAR-WEIGHT ADIPONECTIN; BONE-MINERAL DENSITY; SMALL G-PROTEINS; INSULIN-RESISTANCE; PLASMA ADIPONECTIN; METABOLIC SYNDROME; CIRCULATING ADIPONECTIN; MYOCARDIAL-INFARCTION; SERUM CONCENTRATION; APM1 GENE AB The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms ( SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P <= 5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P <= 0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5610 26, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk. C1 [Richards, J. Brent; Grundberg, Elin; Sladek, Robert] McGill Univ, Jewish Gen Hosp, Dept Med, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent; Grundberg, Elin; Sladek, Robert] McGill Univ, Jewish Gen Hosp, Dept Human Genet, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent; Grundberg, Elin; Sladek, Robert] McGill Univ, Jewish Gen Hosp, Dept Epidemiol & Biostat, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent; Soranzo, Nicole; Spector, Tim D.] Kings Coll London, London WC2R 2LS, England. [Waterworth, Dawn; Song, Kijoung; Mooser, Vincent] GlaxoSmithKline Inc, Div Genet, King Of Prussia, PA USA. [O'Rahilly, Stephen; Semple, Robert K.; Rocha, Nuno; Burling, Keith] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs, Cambridge CB2 2QQ, England. [Hivert, Marie-France; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Hivert, Marie-France; Florez, Jose C.; Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Loos, Ruth J. F.; Wareham, Nicholas J.] Addenbrookes Hosp, Inst Metab Sci, Epidemiol Unit, MRC, Cambridge, England. [Perry, John R. B.; Melzer, David; Frayling, Timothy M.] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Tanaka, Toshiko] Medstar Res Inst, Baltimore, MD USA. [Timpson, Nicholas John; Evans, David; Glaser, Beate; Smith, George Davey] Ctr Causal Anal Translat Epidemiol, MRC, Dept Social Med, Bristol, Avon, England. [Soranzo, Nicole; Deloukas, Panos] Wellcome Trust Sanger Inst, Hinxton, England. [Grundberg, Elin; Pastinen, Tomi] McGill Univ, Montreal, PQ, Canada. [Grundberg, Elin; Pastinen, Tomi] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Florez, Jose C.; Saxena, Richa] Massachusetts Gen Hosp, Dept Med, Ctr Human, Genet Res & Diabet Ctr,Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.; Saxena, Richa] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.; Saxena, Richa] MIT, Cambridge, MA 02139 USA. [Prokopenko, Inga] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Prokopenko, Inga] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Aulchenko, Yurii; Witteman, Jaquelin C. M.; Van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Waeber, Gerard; Vollenweider, Peter] Univ Lausanne Hosp, CHU Vaudois, Dept Internal Med, Lausanne, Switzerland. [Erdmann, Jeanette; Willenborg, Christina; Schunkert, Heribert] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Burnett, Mary-Susan; Devaney, Joseph; Epstein, Stephen E.] Washington Hosp Ctr, Cardiovasc Res Inst, Washington, DC 20010 USA. [Sattar, Naveed] Univ Glasgow, British Heart Fdn, Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Willenborg, Christina; Koenig, Inke R.] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany. [Hingorani, Aroon] UCL, Ctr Clin Pharmacol, London, England. [Hengstenberg, Christian; Stark, Klaus; Winogradow, Janina; Grassl, Martina; Reinhard, Wibke] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany. [Deanfield, John] Great Ormond St Hosp Sick Children, Cardiothorac Unit, Natl Hlth Serv Trust, London WC1N 3JH, England. [Hall, Alistair S.] Univ Leeds, Fac Med & Hlth, Leeds Inst Mol Med, Leeds, W Yorkshire, England. [Hall, Alistair S.] Univ Leeds, Fac Med & Hlth, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England. [Egan, Josephine M.] NIA, Clin Invest Lab, Baltimore, MD 21224 USA. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Ricketts, Sally L.] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge, England. [Grundy, Scott] Univ Texas SW Med Ctr Dallas, Dept Clin Nutr, Ctr Human Nutr, Dallas, TX 75390 USA. [Wichmann, H-Erich] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Sci Biometry & Epidemiol, Munich, Germany. [Barter, Phil] Heart Res Inst, Sydney, NSW, Australia. [Mahley, Robert] Gladstone Inst Neurol Dis, San Francisco, CA USA. [Mahley, Robert] Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, Cardiovasc Res Inst, San Francisco, CA 94141 USA. [Kesaniemi, Y. Antero] Univ Oulu, Dept Internal Med, SF-90220 Oulu, Finland. [Kesaniemi, Y. Antero] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Stewart, Alexandre F. R.; McPherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON, Canada. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. RP Richards, JB (reprint author), McGill Univ, Jewish Gen Hosp, Dept Med, Montreal, PQ H3T 1E2, Canada. EM brent.richards@mcgill.ca RI Erdmann, Jeanette/P-7513-2014; Stark, Klaus/D-3813-2009; Stewart, Alexandre/A-5677-2011; Willenborg, Christina/D-2668-2012; Deloukas, Panos/B-2922-2013; Colaus, PsyColaus/K-6607-2013; Aulchenko, Yurii/M-8270-2013; Prokopenko, Inga/H-3241-2014; Fox, Laura /C-6249-2016; Konig, Inke/A-4544-2009; Erdmann, Jeanette/A-4417-2009; Davey Smith, George/A-7407-2013; OI Timpson, Nicholas/0000-0002-7141-9189; Stewart, Alexandre/0000-0003-2673-9164; Erdmann, Jeanette/0000-0002-4486-6231; Dupuis, Josee/0000-0003-2871-3603; Soranzo, Nicole/0000-0003-1095-3852; Semple, Robert/0000-0001-6539-3069; St Pourcain, Beate/0000-0002-4680-3517; Melzer, David/0000-0002-0170-3838; Sladek, Robert/0000-0002-2730-1204; Evans, David/0000-0003-0663-4621; Stark, Klaus/0000-0002-7832-1942; Willenborg, Christina/0000-0001-5217-6882; Deloukas, Panos/0000-0001-9251-070X; Aulchenko, Yurii/0000-0002-7899-1575; Prokopenko, Inga/0000-0003-1624-7457; Davey Smith, George/0000-0002-1407-8314; Monsalve, Beatriz Elena/0000-0002-5994-866X FU Wellcome Trust [080952/Z/06/Z, 078986/Z/06/Z]; United Kingdom Medical Research Council Centre for Obesity and Related Metabolic Diseases; Canadian Institutes of Health Research (CIHR); the Cardiovascular Institute of the University of Pennsylvania; GlaxoSmithKline; Deutsche Forschungsgemeinschaft; German Federal Ministry of Education and Research ( BMBF) in the context of the German National Genome Research Network [NGFN-2, NGFN-plus]; EU [LSHM-CT-2006-037593]; German Federal Ministry of Education and Research; State of Bavaria; Cancer Research United Kingdom; Medical Research Council; BHF; UK Medical Research Council; University of Bristol; British Heart Foundation [MRC PG/07/002]; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, N02-HL-6-4278]; Framingham Heart Study SNP Health Association Resource (SHARe) project; National Institutes of Health; National Center for Research Resources, General Clinical Research Centers Program [M01-RR-01066]; American Diabetes Association Career Development Award; sanofi-aventis; NIH NCRR Shared Instrumentation [1S10RR163736-01A1]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; National Institute for Diabetes and Digestive and Kidney Diseases ( NIDDK) [R01 DK078616, K24 DK080140, K23 DK65978]; Massachusetts General Hospital Physician Scientist Development Award; Doris Duke Charitable Foundation Clinical Scientist Development Award; Centre de Recherche Medicale de l'Universite de Sherbrooke (CRMUS); CIHR; European Community [FP7/2007-2013, HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413]; FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]; Department of Health via the National Institute for Health Research ( NIHR); St Thomas' NHS Foundation Trust in partnership with King's College London; Biotechnology and Biological Sciences Research Council (BBSRC) [Biotechnology and Biological Sciences Research Council ( BBSRC) project grant (G20234]; National Eye Institute via an NIH/CIDR genotyping project FX N01-HC-25195), National Institute for Diabetes and Digestive and Kidney Diseases ( NIDDK) R01 DK078616 to JBM, JD, and JCF, NIDDK K24 DK080140 to JBM, NIDDK Research Career Award K23 DK65978, a Massachusetts General Hospital Physician Scientist Devlopment Award and a Doris Duke Charitable Foundation Clinical Scientist Development Award to JCF, and the Boston University Linux Cluster for Genetic Analysis ( LinGA) funded by the NIH NCRR Shared Instrumentation grant (1S10RR163736-01A1). MFH was supported by the Centre de Recherche Medicale de l'Universite de Sherbrooke (CRMUS) and the CIHR. TwinsUK: The study was funded by the Wellcome Trust, European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F2-2008-201865-GEFOS and (FP7/2007-2013), ENGAGE project grant agreement HEALTH-F4-2007-201413, and the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from the Department of Health via the National Institute for Health Research ( NIHR) comprehensive Biomedical Research Centre award to Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. TDS is an NIHR senior Investigator. The project also received support from a Biotechnology and Biological Sciences Research Council ( BBSRC) project grant (G20234). The authors acknowledge the funding and support of the National Eye Institute via an NIH/CIDR genotyping project ( PI: Terri Young). We thank the staff from the Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, quality control, and genotyping led by Leena Peltonen and Panos Deloukas; Le Centre National de Genotypage, France, led by Mark Lathrop, for genotyping; Duke University, North Carolina, USA, led by David Goldstein, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by Aarno Palotie. Genotyping was also performed by CIDR as part of an NEI/NIH project grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 78 Z9 80 U1 0 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD DEC PY 2009 VL 5 IS 12 AR e1000768 DI 10.1371/journal.pgen.1000768 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 542CT UT WOS:000273469700019 PM 20011104 ER PT J AU Bayer, AM Hunter, GC Gilman, RH del Carpio, JGC Naquira, C Bern, C Levy, MZ AF Bayer, Angela M. Hunter, Gabrielle C. Gilman, Robert H. Cornejo del Carpio, Juan G. Naquira, Cesar Bern, Caryn Levy, Michael Z. TI Chagas Disease, Migration and Community Settlement Patterns in Arequipa, Peru SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID TRIATOMA-INFESTANS; LATIN-AMERICA; TRYPANOSOMA-CRUZI; ARGENTINA; MODEL AB Background: Chagas disease is one of the most important neglected tropical diseases in the Americas. Vectorborne transmission of Chagas disease has been historically rare in urban settings. However, in marginal communities near the city of Arequipa, Peru, urban transmission cycles have become established. We examined the history of migration and settlement patterns in these communities, and their connections to Chagas disease transmission. Methodology/Principal Findings: This was a qualitative study that employed focus group discussions and in-depth interviews. Five focus groups and 50 in-depth interviews were carried out with 94 community members from three shantytowns and two traditional towns near Arequipa, Peru. Focus groups utilized participatory methodologies to explore the community's mobility patterns and the historical and current presence of triatomine vectors. In-depth interviews based on event history calendars explored participants' migration patterns and experience with Chagas disease and vectors. Focus group data were analyzed using participatory analysis methodologies, and interview data were coded and analyzed using a grounded theory approach. Entomologic data were provided by an ongoing vector control campaign. We found that migrants to shantytowns in Arequipa were unlikely to have brought triatomines to the city upon arrival. Frequent seasonal moves, however, took shantytown residents to valleys surrounding Arequipa where vectors are prevalent. In addition, the pattern of settlement of shantytowns and the practice of raising domestic animals by residents creates a favorable environment for vector proliferation and dispersal. Finally, we uncovered a phenomenon of population loss and replacement by low-income migrants in one traditional town, which created the human settlement pattern of a new shantytown within this traditional community. Conclusions/Significance: The pattern of human migration is therefore an important underlying determinant of Chagas disease risk in and around Arequipa. Frequent seasonal migration by residents of peri-urban shantytowns provides a path of entry of vectors into these communities. Changing demographic dynamics of traditional towns are also leading to favorable conditions for Chagas disease transmission. Control programs must include surveillance for infestation in communities assumed to be free of vectors. C1 [Bayer, Angela M.] Univ Calif Los Angeles, David Geffen Sch Med, Div Infect Dis, Los Angeles, CA 90095 USA. [Bayer, Angela M.; Hunter, Gabrielle C.; Gilman, Robert H.] AB PRISMA, Lima, Peru. [Gilman, Robert H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Cornejo del Carpio, Juan G.] Minist Salud, Direcc Reg, Arequipa, Peru. [Naquira, Cesar] Univ Peruana Cayetano Heredia, Lima, Peru. [Bern, Caryn] Ctr Dis Control & Prevent, Div Parasit Dis, Atlanta, GA USA. [Levy, Michael Z.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Levy, Michael Z.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Bayer, AM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Infect Dis, Los Angeles, CA 90095 USA. EM ABayer@mednet.ucla.edu FU NIH NIAID [5P50AI074285-02, K01AI079162-02]; NIH NIMH [T32MH080634-03] FX This work was funded by NIH NIAID 5P50AI074285-02 and K01AI079162-02. Angela Bayer is currently a Postdoctoral Fellow under NIH NIMH T32MH080634-03. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 23 Z9 25 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2009 VL 3 IS 12 AR e567 DI 10.1371/journal.pntd.0000567 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 536RB UT WOS:000273060400011 PM 20016830 ER PT J AU Moreira, LA Saig, E Turley, AP Ribeiro, JMC O'Neill, SL McGraw, EA AF Moreira, Luciano A. Saig, Emad Turley, Andrew P. Ribeiro, Jose M. C. O'Neill, Scott L. McGraw, Elizabeth A. TI Human Probing Behavior of Aedes aegypti when Infected with a Life-Shortening Strain of Wolbachia SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID FEEDING-BEHAVIOR; SALIVARY-GLANDS; MOSQUITO; TRANSMISSION; DROSOPHILA; CULICIDAE; SELECTION; VIRULENT; DIPTERA; SUCCESS AB Background: Mosquitoes are vectors of many serious pathogens in tropical and sub-tropical countries. Current control strategies almost entirely rely upon insecticides, which increasingly face the problems of high cost, increasing mosquito resistance and negative effects on non-target organisms. Alternative strategies include the proposed use of inherited life-shortening agents, such as the Wolbachia bacterium. By shortening mosquito vector lifespan, Wolbachia could potentially reduce the vectorial capacity of mosquito populations. We have recently been able to stably transinfect Aedes aegypti mosquitoes with the life-shortening Wolbachia strain wMelPop, and are assessing various aspects of its interaction with the mosquito host to determine its likely impact on pathogen transmission as well as its potential ability to invade A. aegypti populations. Methodology/Principal Findings: Here we have examined the probing behavior of Wolbachia-infected mosquitoes in an attempt to understand both the broader impact of Wolbachia infection on mosquito biology and, in particular, vectorial capacity. The probing behavior of wMelPop-infected mosquitoes at four adult ages was examined and compared to uninfected controls during video-recorded feeding trials on a human hand. Wolbachia-positive insects, from 15 days of age, showed a drastic increase in the time spent pre-probing and probing relative to uninfected controls. Two other important features for blood feeding, saliva volume and apyrase content of saliva, were also studied. Conclusions/Significance: As A. aegypti infected with wMelPop age, they show increasing difficulty in completing the process of blood feeding effectively and efficiently. Wolbachia-infected mosquitoes on average produced smaller volumes of saliva that still contained the same amount of apyrase activity as uninfected mosquitoes. These effects on blood feeding behavior may reduce vectorial capacity and point to underlying physiological changes in Wolbachia-infected mosquitoes. C1 [Moreira, Luciano A.; Saig, Emad; Turley, Andrew P.; O'Neill, Scott L.; McGraw, Elizabeth A.] Univ Queensland, Sch Biol Sci, St Lucia, Qld, Australia. [Moreira, Luciano A.] CPqRR FIOCRUZ, Rene Rachou Res Ctr, Lab Malaria, Belo Horizonte, MG, Brazil. [Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Moreira, LA (reprint author), Univ Queensland, Sch Biol Sci, St Lucia, Qld, Australia. EM e.mcgraw@uq.edu.au RI Entomologiamolecular, Inct/J-8214-2013; O'Neill, Scott/B-3568-2009; McGraw, Elizabeth/A-6658-2012 OI O'Neill, Scott/0000-0002-4131-3615; Ribeiro, Jose/0000-0002-9107-0818; McGraw, Elizabeth/0000-0001-7973-088X 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 of Australia FX This research was supported by grants from the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative of the Bill and Melinda Gates Foundation (SLO) and The National Health and Medical Research Council of Australia (EAM and SLO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 55 Z9 59 U1 3 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2009 VL 3 IS 12 AR e568 DI 10.1371/journal.pntd.0000568 PG 6 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 536RB UT WOS:000273060400012 PM 20016848 ER PT J AU Oliveira, F Doumbia, S Anderson, JM Faye, O Diarra, SS Traore, P Cisse, M Camara, G Tall, K Coulibaly, CA Samake, S Sissoko, I Traore, B Diallo, D Keita, S Fairhurst, RM Valenzuela, JG Kamhawi, S AF Oliveira, Fabiano Doumbia, Seydou Anderson, Jennifer M. Faye, Ousmane Diarra, Souleymane S. Traore, Pierre Cisse, Moumine Camara, Guimba Tall, Koureissi Coulibaly, Cheick A. Samake, Sibiry Sissoko, Ibrahim Traore, Bourama Diallo, Daouda Keita, Somita Fairhurst, Rick M. Valenzuela, Jesus G. Kamhawi, Shaden TI Discrepant Prevalence and Incidence of Leishmania Infection between Two Neighboring Villages in Central Mali Based on Leishmanin Skin Test Surveys SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID PHLEBOTOMUS-DUBOSCQI; CUTANEOUS LEISHMANIASIS; MAJOR INFECTION; SENSITIVITY; RESPONSES; DIPTERA; KENYA AB Apart from a single report, the last publication of cutaneous leishmaniasis (CL) in Mali dates back more than 20 years. The absence of information on the current status of CL in Mali led us to conduct a cohort study in Kemena and Sougoula, two villages in Central Mali from which cases of CL have been recently diagnosed by Mali's reference dermatology center in Bamako. In May 2006, we determined the baseline prevalence of Leishmania infection in the two villages using the leishmanin skin test (LST). LST-negative individuals were then re-tested over two consecutive years to estimate the annual incidence of Leishmania infection. The prevalence of Leishmania infection was significantly higher in Kemena than in Sougoula (45.4% vs. 19.9%; OR: 3.36, CI: 2.66-4.18). The annual incidence of Leishmania infection was also significantly higher in Kemena (18.5% and 17% for 2007 and 2008, respectively) than in Sougoula (5.7% for both years). These data demonstrate that the risk of Leishmania infection was stable in both villages and confirm the initial observation of a significantly higher risk of infection in Kemena (OR: 3.78; CI: 2.45-6.18 in 2007; and OR: 3.36; CI: 1.95-5.8 in 2008; P<0.005). The absence of spatial clustering of LST-positive individuals in both villages indicated that transmission may be occurring anywhere within the villages. Although Kemena and Sougoula are only 5 km apart and share epidemiologic characteristics such as stable transmission and random distribution of LST-positive individuals, they differ markedly in the prevalence and annual incidence of Leishmania infection. Here we establish ongoing transmission of Leishmania in Kemena and Sougoula, Central Mali, and are currently investigating the underlying factors that may be responsible for the discrepant infection rates we observed between them. C1 [Oliveira, Fabiano; Anderson, Jennifer M.; Fairhurst, Rick M.; Valenzuela, Jesus G.; Kamhawi, Shaden] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Doumbia, Seydou; Diarra, Souleymane S.; Coulibaly, Cheick A.; Samake, Sibiry; Sissoko, Ibrahim; Traore, Bourama; Diallo, Daouda] Univ Bamako, Fac Med Pharm & Odontostomatol, Bamako, Mali. [Faye, Ousmane; Traore, Pierre; Cisse, Moumine; Camara, Guimba; Tall, Koureissi; Keita, Somita] Ctr Natl Appui Lutte Malad, Bamako, Mali. RP Oliveira, F (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM skamhawi@niaid.nih.gov RI Oliveira, Fabiano/B-4251-2009 OI Oliveira, Fabiano/0000-0002-7924-8038 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 10 Z9 10 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2009 VL 3 IS 12 AR e565 DI 10.1371/journal.pntd.0000565 PG 6 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 536RB UT WOS:000273060400010 PM 20016847 ER PT J AU McCormick, PJ Segarra, M Gasperini, P Gulino, AV Tosato, G AF McCormick, Peter J. Segarra, Marta Gasperini, Paola Gulino, A. Virginia Tosato, Giovanna TI Impaired Recruitment of Grk6 and beta-Arrestin2 Causes Delayed Internalization and Desensitization of a WHIM Syndrome-Associated CXCR4 Mutant Receptor SO PLOS ONE LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; BONE-MARROW; BETA-ARRESTIN; FACTOR-I; G-CSF; NEUTROPHIL HOMEOSTASIS; EXTRACELLULAR SIGNAL; MYELOID CELLS; STEM-CELLS; CXCL12 AB WHIM (warts, hypogammaglobulinemia, infections, and myelokatexis) syndrome is a rare immunodeficiency syndrome linked to heterozygous mutations of the chemokine receptor CXCR4 resulting in truncations of its cytoplasmic tail. Leukocytes from patients with WHIM syndrome display impaired CXCR4 internalization and enhanced chemotaxis in response to its unique ligand SDF-1/CXCL12, which likely contribute to the clinical manifestations. Here, we investigated the biochemical mechanisms underlying CXCR4 deficiency in WHIM syndrome. We report that after ligand activation, WHIM-associated mutant CXCR4 receptors lacking the carboxy-terminal 19 residues internalize and activate Erk 1/2 slower than wild-type (WT) receptors, while utilizing the same trafficking endocytic pathway. Recruitment of beta-Arrestin 2, but not beta-Arrestin 1, to the active WHIM-mutant receptor is delayed compared to the WT CXCR4 receptor. In addition, while both kinases Grk3 and Grk6 bind to WT CXCR4 and are critical to its trafficking to the lysosomes, Grk6 fails to associate with the WHIM-mutant receptor whereas Grk3 associates normally. Since beta-Arrestins and Grks play critical roles in phosphorylation and internalization of agonist-activated G protein-coupled receptors, these results provide a molecular basis for CXCR4 dysfunction in WHIM syndrome. C1 [McCormick, Peter J.; Segarra, Marta; Gasperini, Paola; Gulino, A. Virginia; Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP McCormick, PJ (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM mccormpe@mail.nih.gov RI McCormick, Peter/E-7387-2012 OI McCormick, Peter/0000-0002-2225-5181 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 39 Z9 40 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 1 PY 2009 VL 4 IS 12 AR e8102 DI 10.1371/journal.pone.0008102 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MT UT WOS:000272828700014 PM 19956569 ER PT J AU Bennuru, S Nutman, TB AF Bennuru, Sasisekhar Nutman, Thomas B. TI Lymphangiogenesis and Lymphatic Remodeling Induced by Filarial Parasites: Implications for Pathogenesis SO PLOS PATHOGENS LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MATRIX-METALLOPROTEINASE ACTIVITY; CELLS IN-VITRO; BRUGIA-MALAYI; BANCROFTIAN FILARIASIS; WUCHERERIA-BANCROFTI; IMMUNE-RECONSTITUTION; NUDE-MICE; FACTOR-A; PAHANGI AB Even in the absence of an adaptive immune system in murine models, lymphatic dilatation and dysfunction occur in filarial infections, although severe irreversible lymphedema and elephantiasis appears to require an intact adaptive immune response in human infections. To address how filarial parasites and their antigens influence the lymphatics directly, human lymphatic endothelial cells were exposed to filarial antigens, live parasites, or infected patient serum. Live filarial parasites or filarial antigens induced both significant LEC proliferation and differentiation into tube-like structures in vitro. Moreover, serum from patently infected (microfilaria positive) patients and those with longstanding chronic lymphatic obstruction induced significantly increased LEC proliferation compared to sera from uninfected individuals. Differentiation of LEC into tube-like networks was found to be associated with significantly increased levels of matrix metalloproteases and inhibition of their TIMP inhibitors (Tissue inhibitors of matrix metalloproteases). Comparison of global gene expression induced by live parasites in LEC to parasite-unexposed LEC demonstrated that filarial parasites altered the expression of those genes involved in cellular organization and development as well as those associated with junction adherence pathways that in turn decreased trans-endothelial transport as assessed by FITC-Dextran. The data suggest that filarial parasites directly induce lymphangiogenesis and lymphatic differentiation and provide insight into the mechanisms underlying the pathology seen in lymphatic filariasis. C1 [Bennuru, Sasisekhar; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bennuru, S (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM bennurus@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This project was funded primarily by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 28 Z9 30 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2009 VL 5 IS 12 AR e1000688 DI 10.1371/journal.ppat.1000688 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 551RP UT WOS:000274227000012 PM 20011114 ER PT J AU Enose-Akahata, Y Matsuura, E Oh, U Jacobson, S AF Enose-Akahata, Yoshimi Matsuura, Eiji Oh, Unsong Jacobson, Steven TI High Expression of CD244 and SAP Regulated CD8(+) T Cell Responses of Patients with HTLV-I Associated Neurologic Disease SO PLOS PATHOGENS LA English DT Article ID VIRUS TYPE-I; LINKED LYMPHOPROLIFERATIVE-DISEASE; NATURAL-KILLER-CELLS; TROPICAL SPASTIC PARAPARESIS; KAPPA-B SITE; PERIPHERAL-BLOOD; PROVIRAL LOAD; CUTTING EDGE; GENE-PRODUCT; LEUKEMIA-VIRUS AB HTLV-I-specific CD8(+) T cells have been characterized with high frequencies in peripheral blood and cerebrospinal fluid and production of proinflammatory cytokines, which contribute to central nervous system inflammation in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, little is known about the differences in CD8+ T cell activation status between asymptomatic carrier (ACs) and patients with HAM/TSP. The expression of CD244, a signaling lymphocyte activation molecule (SLAM) family receptor, was significantly higher on CD8(+) T cells in HTLV-I-infected patients, both ACs and patients with HAM/TSP, than those on healthy normal donors (NDs). Blockade of CD244 inhibited degranulation and IFN-gamma production in CD8(+) T cells of patients with HAM/TSP, suggesting that CD244 is associated with effector functions of CD8(+) T cells in patients with HAM/TSP. Moreover, SLAM-associated protein (SAP) was overexpressed in patients with HAM/TSP compared to ACs and NDs. SAP expression in Tax-specific CTLs was correlated in the HTLV-I proviral DNA loads and the frequency of the cells in HTLV-I-infected patients. SAP knockdown by siRNA also inhibited IFN-gamma production in CD8(+) T cells of patients with HAM/TSP. Thus, the CD244/SAP pathway was involved in the active regulation of CD8(+) T cells of patients with HAM/TSP, and may play roles in promoting inflammatory neurological disease. C1 [Enose-Akahata, Yoshimi; Matsuura, Eiji; Oh, Unsong; Jacobson, Steven] Natl Inst Neurol Disorders & Stroke, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD USA. RP Enose-Akahata, Y (reprint author), Natl Inst Neurol Disorders & Stroke, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD USA. EM jacobsons@ninds.nih.gov RI MATSUURA, EIJI/E-1231-2013 OI MATSUURA, EIJI/0000-0001-8215-8853 FU NINDS, NIH FX This research was supported by the Intramural Research Program of the NINDS, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 12 Z9 12 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2009 VL 5 IS 12 AR e1000682 DI 10.1371/journal.ppat.1000682 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 551RP UT WOS:000274227000006 PM 19997502 ER PT J AU Gao, XF Wan, FY Mateo, K Callegari, E Wang, D Deng, WY Puente, J Li, F Chaussee, MS Finlay, BB Lenardo, MJ Hardwidge, PR AF Gao, Xiaofei Wan, Fengyi Mateo, Kristina Callegari, Eduardo Wang, Dan Deng, Wanyin Puente, Jose Li, Feng Chaussee, Michael S. Finlay, B. Brett Lenardo, Michael J. Hardwidge, Philip R. TI Bacterial Effector Binding to Ribosomal Protein S3 Subverts NF-kappa B Function SO PLOS PATHOGENS LA English DT Article ID ENTEROPATHOGENIC ESCHERICHIA-COLI; INTESTINAL EPITHELIAL-CELLS; HEMOLYTIC-UREMIC SYNDROME; INNATE IMMUNE-RESPONSES; III SECRETION; FLUORESCENCE COMPLEMENTATION; CITROBACTER-RODENTIUM; VIRULENCE FACTOR; DNA-REPAIR; NON-LOCUS AB Enteric bacterial pathogens cause food borne disease, which constitutes an enormous economic and health burden. Enterohemorrhagic Escherichia coli (EHEC) causes a severe bloody diarrhea following transmission to humans through various means, including contaminated beef and vegetable products, water, or through contact with animals. EHEC also causes a potentially fatal kidney disease (hemolytic uremic syndrome) for which there is no effective treatment or prophylaxis. EHEC and other enteric pathogens (e. g., enteropathogenic E. coli (EPEC), Salmonella, Shigella, Yersinia) utilize a type III secretion system (T3SS) to inject virulence proteins (effectors) into host cells. While it is known that T3SS effectors subvert host cell function to promote diarrheal disease and bacterial transmission, in many cases, the mechanisms by which these effectors bind to host proteins and disrupt the normal function of intestinal epithelial cells have not been completely characterized. In this study, we present evidence that the E. coli O157:H7 nleH1 and nleH2 genes encode T3SS effectors that bind to the human ribosomal protein S3 (RPS3), a subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) transcriptional complexes. NleH1 and NleH2 co-localized with RPS3 in the cytoplasm, but not in cell nuclei. The N-terminal region of both NleH1 and NleH2 was required for binding to the N-terminus of RPS3. NleH1 and NleH2 are autophosphorylated Ser/Thr protein kinases, but their binding to RPS3 is independent of kinase activity. NleH1, but not NleH2, reduced the nuclear abundance of RPS3 without altering the p50 or p65 NF-kappa B subunits or affecting the phosphorylation state or abundance of the inhibitory NF-kappa B chaperone I kappa B alpha NleH1 repressed the transcription of a RPS3/NF-kappa B-dependent reporter plasmid, but did not inhibit the transcription of RPS3-independent reporters. In contrast, NleH2 stimulated RPS3-dependent transcription, as well as an AP-1-dependent reporter. We identified a region of NleH1 (N40-K45) that is at least partially responsible for the inhibitory activity of NleH1 toward RPS3. Deleting nleH1 from E. coli O157: H7 produced a hypervirulent phenotype in a gnotobiotic piglet model of Shiga toxin-producing E. coli infection. We suggest that NleH may disrupt host innate immune responses by binding to a cofactor of host transcriptional complexes. C1 [Gao, Xiaofei; Hardwidge, Philip R.] Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66103 USA. [Wan, Fengyi; Lenardo, Michael J.] NIAID, Immunol Lab, Bethesda, MD 20892 USA. [Mateo, Kristina; Wang, Dan; Li, Feng] S Dakota State Univ, Dept Vet Sci, Brookings, SD 57007 USA. [Callegari, Eduardo; Chaussee, Michael S.] Univ S Dakota, Div Basic Biomed Sci, Sanford Sch Med, Vermillion, SD 57069 USA. [Deng, Wanyin; Finlay, B. Brett] Univ British Columbia, Michael Smith Labs, Vancouver, BC V5Z 1M9, Canada. [Puente, Jose] Univ Nacl Autonoma Mexico, Dept Mol Microbiol, Cuernavaca 62191, Morelos, Mexico. RP Gao, XF (reprint author), Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66103 USA. EM phardwidge@kumc.edu FU NCRR [P20 RR016443]; NIH [AI070339]; NIH, NIAID FX This publication was made possible by NIH Grant Number P20 RR016443 from the NCRR and was supported in part by NIH grant AI070339 (PRH) and the Intramural Research Program of the NIH, NIAID (FW and MJL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 84 Z9 86 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2009 VL 5 IS 12 AR e1000708 DI 10.1371/journal.ppat.1000708 PG 18 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 551RP UT WOS:000274227000031 PM 20041225 ER PT J AU Lin, L Ibrahim, AS Xu, X Farber, JM Avanesian, V Baquir, B Fu, Y French, SW Edwards, JE Spellberg, B AF Lin, Lin Ibrahim, Ashraf S. Xu, Xin Farber, Joshua M. Avanesian, Valentina Baquir, Beverlie Fu, Yue French, Samuel W. Edwards, John E., Jr. Spellberg, Brad TI Th1-Th17 Cells Mediate Protective Adaptive Immunity against Staphylococcus aureus and Candida albicans Infection in Mice SO PLOS PATHOGENS LA English DT Article ID TUMOR-NECROSIS-FACTOR; RECOMBINANT N-TERMINUS; CINC MESSENGER-RNA; HOST-DEFENSE; CHEMOKINETIC PROPERTIES; PSEUDOMONAS-AERUGINOSA; IMPROVES SURVIVAL; INTERFERON-GAMMA; RISK-FACTORS; SEPTIC RATS AB We sought to define protective mechanisms of immunity to Staphylococcus aureus and Candida albicans bloodstream infections in mice immunized with the recombinant N-terminus of Als3p (rAls3p-N) vaccine plus aluminum hydroxide (Al(OH(3)) adjuvant, or adjuvant controls. Deficiency of IFN-gamma but not IL-17A enhanced susceptibility of control mice to both infections. However, vaccine-induced protective immunity against both infections required CD4+ T-cell-derived IFN-gamma and IL-17A, and functional phagocytic effectors. Vaccination primed Th1, Th17, and Th1/17 lymphocytes, which produced proinflammatory cytokines that enhanced phagocytic killing of both organisms. Vaccinated, infected mice had increased IFN-gamma, IL-17, and KC, increased neutrophil influx, and decreased organism burden in tissues. In summary, rAls3p-N vaccination induced a Th1/Th17 response, resulting in recruitment and activation of phagocytes at sites of infection, and more effective clearance of S. aureus and C. albicans from tissues. Thus, vaccine-mediated adaptive immunity can protect against both infections by targeting microbes for destruction by innate effectors. C1 [Lin, Lin; Ibrahim, Ashraf S.; Avanesian, Valentina; Baquir, Beverlie; Fu, Yue; Edwards, John E., Jr.; Spellberg, Brad] Harbor UCLA Med Ctr, Div Infect Dis, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Ibrahim, Ashraf S.; Fu, Yue; French, Samuel W.; Edwards, John E., Jr.; Spellberg, Brad] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Xu, Xin; Farber, Joshua M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [French, Samuel W.] Harbor UCLA Med Ctr, Dept Pathol, Torrance, CA 90509 USA. [Spellberg, Brad] Harbor UCLA Med Ctr, Div Gen Internal Med, Torrance, CA 90509 USA. RP Lin, L (reprint author), Harbor UCLA Med Ctr, Div Infect Dis, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. EM bspellberg@labiomed.org RI a, a/M-9467-2013 FU Public Health Service [R01 AI072052, R01 AI077681]; NIH, National Institute of Allergy and Infectious Diseases FX This work was supported by Public Health Service grants R01 AI072052 and R01 AI077681 to BS. This work was also supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 199 Z9 200 U1 3 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2009 VL 5 IS 12 AR e1000703 DI 10.1371/journal.ppat.1000703 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 551RP UT WOS:000274227000026 PM 20041174 ER PT J AU Schmitz, JE Zahn, RC Brown, CR Rett, MD Li, M Tang, HL Pryputniewicz, S Byrum, RA Kaur, A Montefiori, DC Allan, JS Goldstein, S Hirsch, VM AF Schmitz, Joern E. Zahn, Roland C. Brown, Charles R. Rett, Melisa D. Li, Ming Tang, Haili Pryputniewicz, Sarah Byrum, Russell A. Kaur, Amitinder Montefiori, David C. Allan, Jonathan S. Goldstein, Simoy Hirsch, Vanessa M. TI Inhibition of Adaptive Immune Responses Leads to a Fatal Clinical Outcome in SIV-Infected Pigtailed Macaques but Not Vervet African Green Monkeys SO PLOS PATHOGENS LA English DT Article ID SIMIAN-IMMUNODEFICIENCY-VIRUS; T-CELL DEPLETION; NEUTRALIZING ANTIBODY-RESPONSES; SOOTY MANGABEYS; AIDS PATHOGENESIS; VIRAL REPLICATION; RHESUS-MONKEYS; NATURAL HOSTS; MONOCLONAL-ANTIBODY; VIREMIA AB African green monkeys (AGM) and other natural hosts for simian immunodeficiency virus (SIV) do not develop an AIDS-like disease following SIV infection. To evaluate differences in the role of SIV-specific adaptive immune responses between natural and nonnatural hosts, we used SIV(agmVer90) to infect vervet AGM and pigtailed macaques (PTM). This infection results in robust viral replication in both vervet AGM and pigtailed macaques (PTM) but only induces AIDS in the latter species. We delayed the development of adaptive immune responses through combined administration of anti-CD8 and anti-CD20 lymphocyte-depleting antibodies during primary infection of PTM (n = 4) and AGM (n = 4), and compared these animals to historical controls infected with the same virus. Lymphocyte depletion resulted in a 1-log increase in primary viremia and a 4-log increase in post-acute viremia in PTM. Three of the four PTM had to be euthanized within 6 weeks of inoculation due to massive CMV reactivation and disease. In contrast, all four lymphocyte-depleted AGM remained healthy. The lymphocyte depleted AGM showed only a trend toward a prolongation in peak viremia but the groups were indistinguishable during chronic infection. These data show that adaptive immune responses are critical for controlling disease progression in pathogenic SIV infection in PTM. However, the maintenance of a disease-free course of SIV infection in AGM likely depends on a number of mechanisms including non-adaptive immune mechanisms. C1 [Schmitz, Joern E.; Zahn, Roland C.; Rett, Melisa D.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Viral Pathogenesis, Boston, MA 02215 USA. [Brown, Charles R.; Goldstein, Simoy; Hirsch, Vanessa M.] NIAID, Mol Microbiol Lab, NIH, Baltimore, MD USA. [Li, Ming; Tang, Haili; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Lab AIDS Vaccine Res & Dev, Durham, NC 27710 USA. [Pryputniewicz, Sarah; Kaur, Amitinder] New England Reg Primate Res Ctr, Div Immunol, Southborough, MA 01772 USA. [Byrum, Russell A.] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Allan, Jonathan S.] SW Fdn Biomed Res, Dept Virol & Immunol, San Antonio, TX USA. RP Schmitz, JE (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Viral Pathogenesis, Boston, MA 02215 USA. EM jschmitz@bidmc.harvard.edu; vhirsch@niaid.nih.gov FU NIAID; NIH [RR00168, AI43890, AI30034, AI065335, AI040101, RR016001]; Harvard Medical School [AI060354] FX This work was supported by the intramural program of NIAID, and NIH awards RR00168 (New England Primate Research Center), AI43890 (AK), AI30034 (DCM), AI065335 (JES), and the Harvard Medical School Center for AIDS Research grant AI060354. Reagents used in this work were provided by the NIH Nonhuman Primate Reagent Resource (grants AI040101 and RR016001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 24 Z9 24 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2009 VL 5 IS 12 AR e1000691 DI 10.1371/journal.ppat.1000691 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 551RP UT WOS:000274227000015 PM 20011508 ER PT J AU Wang, J Simons-Morton, BG Farhart, T Luk, JW AF Wang, Jing Simons-Morton, Bruce G. Farhart, Tilda Luk, Jeremy W. TI Socio-Demographic Variability in Adolescent Substance Use: Mediation by Parents and Peers SO PREVENTION SCIENCE LA English DT Article DE Adolescent substance use; Parental knowledge; Peer substance use; Socio-demographic differences; Family structure ID FAMILY-STRUCTURE; SELF-REPORTS; DRUG-USE; ALCOHOL-USE; SMOKING; DRINKING; VALIDITY; REINTERPRETATION; INVOLVEMENT; ADJUSTMENT AB The current study examined socio-demographic variability in adolescent substance use and the mediating roles of maternal knowledge, paternal knowledge and peer substance use. The data were obtained from the United States records (N = 8,795) of the Health Behavior in School-Aged Children 2005/2006 Survey, in grades 6 through 10. The analyses employed multiple indicator multiple cause and structural equation models. Adolescent substance use was measured by frequencies of alcohol use, being drunk, and cigarette and marijuana use in the past month. Peer influence had a direct influence on adolescent substance use. Maternal knowledge had both direct and indirect influences on adolescent substance use through its negative association with substance-using peers, whereas paternal knowledge only had an indirect influence. Parental knowledge and peer substance use totally mediated differences in adolescent substance use by grade; differences between Caucasian and African-American or Hispanic adolescents; and differences between adolescents from two-parent families and those from single-mother, single-father or mother-stepfather families. Parental knowledge and peer substance were important mediators which largely accounted for variability in the prevalence of adolescent substance use by grade, race/ethnicity, and family structure. C1 [Wang, Jing; Simons-Morton, Bruce G.; Farhart, Tilda; Luk, Jeremy W.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Prevent Res Branch, Bethesda, MD 20892 USA. RP Wang, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Prevent Res Branch, 6100 Bldg,Room 7B13,MSC 7510, Bethesda, MD 20892 USA. EM wangji2@mail.nih.gov RI Price, Katie/H-1931-2012; OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [Z99 HD999999] NR 41 TC 27 Z9 27 U1 2 U2 11 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 J9 PREV SCI JI Prev. Sci. PD DEC PY 2009 VL 10 IS 4 BP 387 EP 396 DI 10.1007/s11121-009-0141-1 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 519AH UT WOS:000271736900010 PM 19582581 ER PT J AU Singer, M AF Singer, Maxine TI JOSEPH S. FRUTON BIOGRAPHICAL MEMOIRS SO PROCEEDINGS OF THE AMERICAN PHILOSOPHICAL SOCIETY LA English DT Biographical-Item C1 [Singer, Maxine] Carnegie Inst Sci, Washington, DC 20015 USA. [Singer, Maxine] NCI, Bethesda, MD 20892 USA. RP Singer, M (reprint author), Carnegie Inst Sci, Washington, DC 20015 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER PHILOSOPHICAL SOC PI PHILADELPHIA PA 104 SOUTH FIFTH ST, PHILADELPHIA, PA 19106-3387 USA SN 0003-049X J9 P AM PHILOS SOC JI Proc. Amer. Philos. Soc. PD DEC PY 2009 VL 153 IS 4 BP 447 EP 454 PG 8 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA 582AW UT WOS:000276568500005 ER PT J AU Wang, YM Opperman, L Wickens, M Hall, TMT AF Wang, Yeming Opperman, Laura Wickens, Marvin Hall, Traci M. Tanaka TI Structural basis for specific recognition of multiple mRNA targets by a PUF regulatory protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE crystal structure; RNA; translational regulation; fem-3 binding factor; base flipping ID CAENORHABDITIS-ELEGANS GERMLINE; PUMILIO-HOMOLOGY DOMAIN; C-ELEGANS; BINDING-SPECIFICITY; MITOSIS/MEIOSIS DECISION; STEM-CELLS; NANOS; YEAST; FBF; IDENTIFICATION AB Caenorhabditis elegans fem-3 binding factor (FBF) is a founding member of the PUMILIO/FBF (PUF) family of mRNA regulatory proteins. It regulates multiple mRNAs critical for stem cell maintenance and germline development. Here, we report crystal structures of FBF in complex with 6 different 9-nt RNA sequences, including elements from 4 natural mRNAs. These structures reveal that FBF binds to conserved bases at positions 1-3 and 7-8. The key specificity determinant of FBF vs. other PUF proteins lies in positions 4-6. In FBF/RNA complexes, these bases stack directly with one another and turn away from the RNA-binding surface. A short region of FBF is sufficient to impart its unique specificity and lies directly opposite the flipped bases. We suggest that this region imposes a flattened curvature on the protein; hence, the requirement for the additional nucleotide. The principles of FBF/RNA recognition suggest a general mechanism by which PUF proteins recognize distinct families of RNAs yet exploit very nearly identical atomic contacts in doing so. C1 [Opperman, Laura; Wickens, Marvin] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. [Wang, Yeming; Hall, Traci M. Tanaka] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wickens, M (reprint author), Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. EM wickens@biochem.wisc.edu; hall4@niehs.nih.gov RI Wang, Yeming/C-9082-2013 FU National Institutes of Health, National Institute of Environmental Health Sciences; National Institutes of Health; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX We are grateful to J. Williams and the National Institute of Environmental Health Sciences Protein Microcharacterization Facility for mass spectrometry analyses; J. Gonczy, L. Pedersen, and J. Krahn for crystallographic and data collection support; G. Kissling and Y. Lu for statistical support; and L. Vanderploeg and A. Steinberg for graphics. We are grateful to C. Stumpf for discussions and help with figures. We appreciate our colleagues' comments on the manuscript. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (to T. H.) and by extramural grants from the National Institutes of Health (to M. W.). The Advanced Photon Source used for this study was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract W-31-109-Eng-38. NR 44 TC 60 Z9 62 U1 2 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 1 PY 2009 VL 106 IS 48 BP 20186 EP 20191 DI 10.1073/pnas.0812076106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 525YQ UT WOS:000272254400013 PM 19901328 ER PT J AU Zhu, DY Stumpf, CR Krahn, JM Wickens, M Hall, TMT AF Zhu, Deyu Stumpf, Craig R. Krahn, Joseph M. Wickens, Marvin Hall, Traci M. Tanaka TI A 5 ' cytosine binding pocket in Puf3p specifies regulation of mitochondrial mRNAs SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE crystal structure; RNA; translational regulation ID PUMILIO-HOMOLOGY DOMAIN; CAENORHABDITIS-ELEGANS; TRANSLATIONAL CONTROL; PROTEIN; YEAST; FAMILY; GENE; BIOGENESIS; STABILITY; SOFTWARE AB A single regulatory protein can control the fate of many mRNAs with related functions. The Puf3 protein of Saccharomyces cerevisiae is exemplary, as it binds and regulates more than 100 mRNAs that encode proteins with mitochondrial function. Here we elucidate the structural basis of that specificity. To do so, we explore the crystal structures of Puf3p complexes with 2 cognate RNAs. The key determinant of Puf3p specificity is an unusual interaction between a distinctive pocket of the protein with an RNA base outside the "core" PUF-binding site. That interaction dramatically affects binding affinity in vitro and is required for regulation in vivo. The Puf3p structures, combined with those of Puf4p in the same organism, illuminate the structural basis of natural PUF-RNA networks. Yeast Puf3p binds its own RNAs because they possess a -2C and is excluded from those of Puf4p which contain an additional nucleotide in the core-binding site. C1 [Stumpf, Craig R.; Wickens, Marvin] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. [Zhu, Deyu; Krahn, Joseph M.; Hall, Traci M. Tanaka] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Wickens, M (reprint author), Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. EM wickens@biochem.wisc.edu; hall4@niehs.nih.gov RI Stumpf, Craig/B-8703-2014 OI Stumpf, Craig/0000-0002-9946-8986 FU National Institutes of Health, National Institute of Environmental Health Sciences; National Institutes of Health; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX We are grateful to our colleagues for critical comments on the manuscript. We thank A. Sigova of the University of Massachusetts Medical School for the yeast genomic DNA, A. Clark for advice on purifying yeast genomic DNA, L. Pedersen for crystallography support, G. Kissling for statistical support, and A. Steinberg and L. Vanderploeg for graphics design. Special thanks to J. Higgin, who performed the initial expression studies for Puf3p. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (T. H.) and by extramural grants from the National Institutes of Health (to M. W.). The Advanced Photon Source used for this study was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. NR 43 TC 47 Z9 47 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 1 PY 2009 VL 106 IS 48 BP 20192 EP 20197 DI 10.1073/pnas.0812079106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 525YQ UT WOS:000272254400014 PM 19918084 ER PT J AU Ehrlich, ES Wang, T Luo, K Xiao, ZX Niewiadomska, AM Martinez, T Xu, WP Neckers, L Yu, XF AF Ehrlich, Elana S. Wang, Tao Luo, Kun Xiao, Zuoxiang Niewiadomska, Anna Maria Martinez, Tara Xu, Wanping Neckers, Len Yu, Xiao-Fang TI Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chaperone; erbb2 ID SOCS-BOX; ADENOVIRUS E4ORF6; BINDING DOMAIN; COMPLEX; DEGRADATION; CHAPERONE; VIF; ONCOPROTEINS; APOBEC3G; PATHWAY AB We report a link between Cullin5 (Cul5) E3 ubiquitin ligase and the heat shock protein 90 (Hsp90) chaperone complex. Hsp90 participates in the folding of its client proteins into their functional conformation. Many Hsp90 clients have been reported to be aberrantly expressed in a number of cancers. We demonstrate Cul5 interaction with members of the Hsp90 chaperone complex as well as the Hsp90 client, ErbB2. We observed recruitment of Cul5 to the site of ErbB2 at the plasma membrane and subsequent induction of polyubiquitination and proteasomal degradation. We also demonstrate Cul5 involvement in regulation of another Hsp90 client, Hif-1 alpha. We observed Cul5 degradation of ErbB2 to occur independently of ElonginB-ElonginC function. The involvement of Cul5 in Hsp90 client regulation has implications in the effectiveness of Hsp90 targeted chemotherapy, which is currently undergoing clinical trials. The link between Cul5 and Hsp90 client regulation may represent an avenue for cancer drug development. C1 [Ehrlich, Elana S.; Wang, Tao; Luo, Kun; Xiao, Zuoxiang; Niewiadomska, Anna Maria; Martinez, Tara; Yu, Xiao-Fang] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Xu, Wanping; Neckers, Len] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Yu, XF (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. EM xfyu@jhsph.edu RI Wang, Tao/B-1331-2016 FU NIAID NIH HHS [R01 AI062644, R56 AI062644, AI062644] NR 35 TC 45 Z9 45 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 1 PY 2009 VL 106 IS 48 BP 20330 EP 20335 DI 10.1073/pnas.0810571106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 525YQ UT WOS:000272254400037 PM 19933325 ER PT J AU Kines, RC Thompson, CD Lowy, DR Schiller, JT Day, PM AF Kines, Rhonda C. Thompson, Cynthia D. Lowy, Douglas R. Schiller, John T. Day, Patricia M. TI The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE furin; HSPG; mouse model; proprotein convertase ID MINOR CAPSID PROTEIN; HEPARAN-SULFATE; TRANSGENIC MICE; L2; ANTIBODIES; FURIN; NEUTRALIZATION; TYPE-16; KERATINOCYTES; INHIBITION AB Using a murine challenge model, we previously determined that human papillomavirus (HPV) pseudovirions initially bind preferentially to the cervicovaginal basement membrane (BM) at sites of trauma. We now report that the capsids undergo a conformational change while bound to the BM that results in L2 cleavage by a proprotein convertase (PC), furin, and/or PC5/6, followed by the exposure of an N-terminal cross-neutralization L2 epitope and transfer of the capsids to the epithelial cell surface. Prevention of this exposure by PC inhibition results in detachment of the pseudovirions from the BM and their eventual loss from the tissue, thereby preventing infection. Pseudovirions whose L2 had been precleaved by furin can bypass the PC inhibition of binding and infectivity. Cleavage of heparan sulfate proteoglycans (HSPG) with heparinase III prevented infection and BM binding by the precleaved pseudovirions, but did not prevent them from binding robustly to cell surfaces. These results indicate that the infectious process has evolved so that the initial steps take place on the BM, in contrast to the typical viral infection that is initiated by binding to the cell surface. The data are consistent with a dynamic model of in vivo HPV infection in which a conformational change and PC cleavage on the BM allows transfer of virions from HSPG attachment factors to an L1-specific receptor on basal keratinocytes migrating into the site of trauma. C1 [Kines, Rhonda C.; Thompson, Cynthia D.; Lowy, Douglas R.; Schiller, John T.; Day, Patricia M.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Day, PM (reprint author), NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. EM pmd@nih.gov FU National Institutes of Health; National Cancer Institute; Center for Cancer Research FX We gratefully acknowledge the gift of the 17/36 antiserum from Richard Roden, Johns Hopkins University and the rat anti-HPV16 L1 antiserum from Yawei Ni, DelSite Biotechnologies. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 27 TC 106 Z9 109 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 1 PY 2009 VL 106 IS 48 BP 20458 EP 20463 DI 10.1073/pnas.0908502106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 525YQ UT WOS:000272254400059 PM 19920181 ER PT J AU Karlen, A Karlsson, TE Mattsson, A Lundstromer, K Codeluppi, S Pham, TM Backman, CM Ogren, SO Aberg, E Hoffman, AF Sherling, MA Lupica, CR Hoffer, BJ Spenger, C Josephson, A Brene, S Olson, L AF Karlen, Alexandra Karlsson, Tobias E. Mattsson, Anna Lundstromer, Karin Codeluppi, Simone Pham, Therese M. Backman, Cristina M. Ogren, Sven Ove Aberg, Elin Hoffman, Alexander F. Sherling, Michael A. Lupica, Carl R. Hoffer, Barry J. Spenger, Christian Josephson, Anna Brene, Stefan Olson, Lars TI Nogo receptor 1 regulates formation of lasting memories SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE behavior; hippocampus; long-term potentiation; myelin inhibitors; synaptic plasticity ID MYELIN-ASSOCIATED GLYCOPROTEIN; LONG-TERM POTENTIATION; AXONAL REGENERATION; NEURITE OUTGROWTH; SYNAPTIC PLASTICITY; VISUAL-CORTEX; MESSENGER-RNA; FAMILY-MEMBER; INHIBITOR; GROWTH AB Formation of lasting memories is believed to rely on structural alterations at the synaptic level. We had found that increased neuronal activity down-regulates Nogo receptor-1 (NgR1) in brain regions linked to memory formation and storage, and postulated this to be required for formation of lasting memories. We now show that mice with inducible overexpression of NgR1 in forebrain neurons have normal long-term potentiation and normal 24-h memory, but severely impaired month-long memory in both passive avoidance and swim maze tests. Blocking transgene expression normalizes these memory impairments. Nogo, Lingo-1, Troy, endogenous NgR1, and BDNF mRNA expression levels were not altered by transgene expression, suggesting that the impaired ability to form lasting memories is directly coupled to inability to down-regulate NgR1. Regulation of NgR1 may therefore serve as a key regulator of memory consolidation. Understanding the molecular underpinnings of synaptic re-arrangements that carry lasting memories may facilitate development of treatments for memory dysfunction. C1 [Karlen, Alexandra; Karlsson, Tobias E.; Mattsson, Anna; Lundstromer, Karin; Codeluppi, Simone; Ogren, Sven Ove; Aberg, Elin; Josephson, Anna; Olson, Lars] Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. [Pham, Therese M.; Brene, Stefan] Karolinska Inst, Dept Neurobiol, Caring Sci & Soc, S-14186 Huddinge, Sweden. [Spenger, Christian] Karolinska Inst, Dept Clin Sci Intervent & Technol, S-14186 Huddinge, Sweden. [Hoffman, Alexander F.; Sherling, Michael A.; Lupica, Carl R.; Hoffer, Barry J.] Natl Inst Drug Abuse, NIH, Baltimore, MD 21224 USA. RP Olson, L (reprint author), Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden. EM lars.olson@ki.se RI codeluppi, simone/I-4143-2012; backman, cristina/C-1276-2013; Hoffman, Alexander/H-3035-2012; OI codeluppi, simone/0000-0002-7053-0520; Hoffman, Alexander/0000-0002-2676-0628; Karlsson, Tobias/0000-0002-9919-3353; Ogren, Sven Ove/0000-0003-2573-5276 FU Swedish Medical Research Council, Torsten; Ragnar Soderberg's Foundation; Swedish Brain Foundation; Hallsten Foundation; Swedish Brain Power; AFA (Arbetsmarknadens forsakringsaktiebolag) Sweden; U. S. Public Health Service; National Institute on Drug Abuse; National Institutes of Health; Karolinska Institute FX We thank Eva Lindqvist and Karin Pernold for excellent technical assistance, and Mattias Karlen for the artwork. This work was supported by The Swedish Medical Research Council, Torsten and Ragnar Soderberg's Foundation, The Swedish Brain Foundation, the Hallsten Foundation, Swedish Brain Power, AFA (Arbetsmarknadens forsakringsaktiebolag) Sweden, U. S. Public Health Service grants, National Institute on Drug Abuse, National Institutes of Health, and the Karolinska Institute. NR 44 TC 52 Z9 52 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 1 PY 2009 VL 106 IS 48 BP 20476 EP 20481 DI 10.1073/pnas.0905390106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 525YQ UT WOS:000272254400062 PM 19915139 ER PT J AU Wang, YZ Duan, XL Li, YF Liang, XJ AF Wang Ying-Ze Duan Xiang-Lin Li Yong-Fu Liang Xing-Jie TI Multidrug Resistance Mediated by Half ABC Transporter ABCG2 SO PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS LA Chinese DT Article DE ABCG2; ABC transporter; multidrug resistance (MDR); cancer chemotherapy ID TYROSINE KINASE INHIBITOR; BINDING CASSETTE ABC; BREAST-CANCER CELLS; SIDE-POPULATION; DRUG TRANSPORTER; HUMAN PLACENTA; STEM-CELLS; EXPRESSION; GENE; PROTEIN AB Cancers are often intrinsically resistant or become resistant to treatment with conventional chemotherapy. This broad-spectrum resistance results in large part, but not solely, from overexpression of a variety of members of the ATP-binding cassette (ABC) superfamily of transport proteins. ABCG2 (ABCP/MXR/BCRP), as a half ABC transporter, is a novel member of the ABC membrane transporters, which can actively transport a wide spectrum of drugs with varying chemical structures or cellular targets. ABCG2 is overexpressed in the intestine, liver, placenta, and the blood-brain barrier, where it plays a role in protecting the organs from potentially harmful ingested toxins. Moreover, ABCG2 is also highly expressed in hematopoietic stem cells, it seems that ABCG2 has a key function in stem cell regulation or protection from a variety of xenobiotics. Multiple of SNP (single nucleotide polymorphisms) in ABCG2 may affect absorption and distribution, altering the effectiveness and toxicity of drugs in patients. Like other members of the ABC transporter superfamily, such as MDR1 and MRP1, ABCG2 is expressed in a variety of malignancies. Overexpression of ABCG2 in tumor cells confers cancer multidrug resistance to a variety of newly developed anticancer drugs including mitoxantrone, topotecan, epirubicin, anthracyclines and camptothecins. Furthermore, ABCG2 are advocated for use as potentially selectable markers in stem cell based gene therapy. Given the profound impact of ABCG2 on multidrug resistance in tumor cells and on in vivo pharmacology and toxicology, a complete understanding of the mechanism and biological function of ABCG2 will be important for understanding its normal physiology as well as potentially for the development of novel chemotherapeutic treatment strategies. The discovery, the biochemistry, the normal physiology and the current insight of human ABCG2 were introduced. C1 [Wang Ying-Ze; Duan Xiang-Lin] Hebei Normal Univ, Lab Iron Metab & Mol Biol, Coll Life Sci, Shijiazhuang 050016, Peoples R China. [Wang Ying-Ze; Liang Xing-Jie] Chinese Acad Sci, Key Lab Biomed Effects Nanomat & Nanosafety, Natl Ctr Nanosci & Technol, Beijing 100190, Peoples R China. [Wang Ying-Ze] Hebei Univ Sci & Technol, Coll Biosci & Bioengn, Shijiazhuang 050018, Peoples R China. [Li Yong-Fu] NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Duan, XL (reprint author), Hebei Normal Univ, Lab Iron Metab & Mol Biol, Coll Life Sci, Shijiazhuang 050016, Peoples R China. EM xlduan0311@163.com; liangxj@nanoctr.cn FU Chinese Academy of Sciences (CAS) [07165111 ZX]; China-Finland Nanotechnology [2008DFA01510]; National Basic Research [2009CB930200] FX This work was supported by grants from The Chinese Academy of Sciences (CAS) "Hundred Talents Program" (07165111 ZX), China-Finland Nanotechnology (2008DFA01510) and National Basic Research Program of China (2009CB930200). NR 24 TC 0 Z9 1 U1 1 U2 13 PU CHINESE ACAD SCIENCES, INST BIOPHYSICS PI BEIJING PA 15 DATUN RD, CHAOYAND DISTRICT, BEIJING, 100101, PEOPLES R CHINA SN 1000-3282 J9 PROG BIOCHEM BIOPHYS JI Prog. Biochem. Biophys. PD DEC PY 2009 VL 36 IS 12 BP 1523 EP 1529 DI 10.3724/SP.J.1206.2009.00245 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 537EN UT WOS:000273095900003 ER PT J AU Louis, JM Ishima, R Aniana, A Sayer, JM AF Louis, John M. Ishima, Rieko Aniana, Annie Sayer, Jane M. TI Revealing the dimer dissociation and existence of a folded monomer of the mature HIV-2 protease SO PROTEIN SCIENCE LA English DT Article DE HIV/AIDS; retroviral protease; dimer dissociation; light scattering; NMR; enzyme kinetics ID IMMUNODEFICIENCY-VIRUS TYPE-1; INHIBITORS; PROTEINASE; STABILITY; SUBSTRATE; SEQUENCES; AUTOPROTEOLYSIS; REPLICATION; MECHANISMS; RESISTANCE AB Purification and in vitro protein-folding schemes were developed to produce monodisperse samples of the mature wild-type HIV-2 protease (PR2), enabling a comprehensive set of biochemical and biophysical studies to assess the dissociation of the dimeric protease. An E37K substitution in PR2 significantly retards autoproteolytic cleavage during expression. Furthermore, it permits convenient measurement of the dimer dissociation of PR2(E37K) (elevated K(d) similar to 20 nM) by enzyme kinetics. Differential scanning calorimetry reveals a T(m) of 60.5 for PR2 as compared with 65.7 degrees C for HIV-1 protease (PR1). Consistent with weaker binding of the clinical inhibitor darunavir (DRV) to PR2, the T(m) of PR2 increases by 14.8 degrees C in the presence of DRV as compared with 22.4 degrees C for PR1. Dimer interface mutations, such as a T26A substitution in the active site (PR2(T26A)) or a deletion of the C-terminal residues 96-99 (PR2(1-95)), drastically increase the K(d) (>10(5)-fold). PR2(T26A) and PR2(1-95) consist predominantly of folded monomers, as determined by nuclear magnetic resonance (NMR) and size-exclusion chromatography coupled with multiangle light scattering and refractive index measurements (SMR), whereas wild-type PR2 and its active-site mutant PR2(D25N) are folded dimers. Addition of twofold excess active-site inhibitor promotes dimerization of PR2(T26A) but not of PR2(1-95), indicating that subunit interactions involving the C-terminal residues are crucial for dimer formation. Use of SMR and NMR with PR2 facilitates probing for potential inhibitors that restrict protein folding and/or dimerization and, thus, may provide insights for the future design of inhibitors to circumvent drug resistance. C1 [Louis, John M.; Aniana, Annie; Sayer, Jane M.] NIDDKD, Chem Phys Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Ishima, Rieko] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA. RP Louis, JM (reprint author), NIDDK, LCP, NIH, Bldg 5,Room B2-29, Bethesda, MD 20892 USA. FU NIDDK, National Institutes of Health (NIH); National Science Foundation [MCB 0814905] FX Grant sponsor Intramural Research Program of the NIDDK, National Institutes of Health (NIH); Grant sponsor National Science Foundation. Grant number. MCB 0814905 NR 41 TC 14 Z9 14 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD DEC PY 2009 VL 18 IS 12 BP 2442 EP 2453 DI 10.1002/pro.261 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 532NV UT WOS:000272757200003 PM 19798742 ER PT J AU He, HJ Zong, YP Bernier, M Wang, LL AF He, Hua-Jun Zong, Yaping Bernier, Michel Wang, Lili TI Sensing the insulin signaling pathway with an antibody array SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Antibody array; Insulin resistance; Insulin signaling pathway; Multiplexed bead array; Phorbol 12-myristate 13-acetate ID PHASE PROTEIN MICROARRAYS; RECEPTOR SUBSTRATE-1; SUSPENSION ARRAYS; MASS-SPECTROMETRY; GENE-EXPRESSION; IKK-BETA; RESISTANCE; PHOSPHORYLATION; OBESITY; PHOSPHOPROTEOMICS AB The development of insulin resistance and type 2 diabetes is determined by various factors, including defects within the insulin signaling pathway. Mediators of insulin resistance operate through activation of various protein kinase C isoforms, I kappa B kinase beta (IKK beta), and/or c-Jun N-terminal kinase, and subsequent inhibition of the proximal insulin signaling pathway via the insulin receptor substrate 1 and Akt. These mechanisms are still largely unresolved because of the complexity of the molecular events. In this study, an expression and activation state profiling of multiple known key signaling biomolecules involved in insulin metabolic and mitogenic signaling pathways was evaluated using a phosphospecific antibody array platform. The results of the arrayed antibodies were verified by the multiplexed bead array assay and conventional Western blot analysis, and confirmed the well-known inhibitory effects of phorbol esters on insulin signaling pathway activation. Of interest, the increase in protein kinase C signaling responses with phorbol esters was associated with activation of the lipid phosphatase PTEN and a 27 kDa HSP. Thus, this insulin signaling antibody array provides a powerful and effective way to investigate the mechanism of insulin resistance and likely assist the development of innovative therapeutic drugs for type 2 diabetes. C1 [He, Hua-Jun; Wang, Lili] Natl Inst Stand & Technol, Div Biochem Sci, Gaithersburg, MD 20899 USA. [Zong, Yaping] Full Moon BioSyst Inc, Sunnyvale, CA USA. [Bernier, Michel] NIA, Diabet Sect, Lab Clin Investigat, NIH, Baltimore, MD 21224 USA. RP Wang, LL (reprint author), Natl Inst Stand & Technol, Div Biochem Sci, Gaithersburg, MD 20899 USA. EM lili.wang@nist.gov OI Bernier, Michel/0000-0002-5948-368X FU NIH, National Institute on Aging FX The authors thank Sutapa Kole for her expert assistance with cell culture and Western blot analyses. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through an R&D contract with MedStar Research Institute. NR 39 TC 5 Z9 5 U1 1 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD DEC PY 2009 VL 3 IS 12 BP 1440 EP 1450 DI 10.1002/prca.200900020 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 538KZ UT WOS:000273184700009 PM 21136963 ER PT J AU Villafuerte, SM Vallabhaneni, K Sliwerska, E McMahon, FJ Young, EA Burmeister, M AF Villafuerte, Sandra M. Vallabhaneni, Kamala Sliwerska, Elzbieta McMahon, Francis J. Young, Elizabeth A. Burmeister, Margit TI SSRI response in depression may be influenced by SNPs in HTR1B and HTR1A SO PSYCHIATRIC GENETICS LA English DT Article DE association; depression; haplotype; HTR1A; HTR1B; selective serotonin reuptake inhibitor ID SEROTONIN TRANSPORTER GENE; TRANSCRANIAL MAGNETIC STIMULATION; OBSESSIVE-COMPULSIVE DISORDER; PLACEBO-CONTROLLED TRIAL; 5-HT REUPTAKE INHIBITOR; RECEPTOR GENE; ANTIDEPRESSANT RESPONSE; MAJOR DEPRESSION; RAT-BRAIN; AUTORECEPTOR ANTAGONIST AB Objectives Desensitization of serotonin 1A (HTR1A) and 1B (HTR1B) autoreceptors has been proposed to be involved in the delayed onset of response to selective serotonin reuptake inhibitors (SSRIs). Variations in gene expression in these genes may thus affect SSRI response. Methods Here, we test this hypothesis in two samples from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D), and show evidence for involvement of several genetic variants alone and in interaction. Initially, three functional single nucleotide polymorphisms (SNPs) in the HTR1B gene and in the HTR1A gene were analyzed in 153 depressed patients treated with citalopram. The 16-item Quick Inventory of Depressive Symptomatology Clinician scores were evaluated over time with respect to genetic variation. Results Individuals homozygous for the -1019 G allele (rs6295) in HTR1A showed the higher baseline 16-item Quick Inventory of Depressive Symptomatology Clinician scores (P=0.033), and by 12 weeks had a significantly lower response rate (P=0.005). HTR1B haplotypes were estimated according to the previously reported in-vitro expression levels. Individuals who were homozygous for the high-expression haplotype showed significantly slower response to citalopram (P=0.034). We then analyzed more SNPs in the extended overall STAR*D sample. Although we could not directly test the same functional SNPs, we found that homozygotes for the G allele at rs1364043 in HTR1A (P=0.045) and the C allele of rs6298 in HTR1B showed better response to citalopram over time (P=0.022). Test for interaction between rs6298 in HTR1B and rs1364043 in HTR1A was significant (overall P=0.032). Conclusion Our data suggest that an enhanced capacity of HTR1B or HTR1A transcriptional activity may impair desensitization of the autoreceptors during SSRI treatment. Psychiatr Genet 19:281-291 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Villafuerte, Sandra M.; Vallabhaneni, Kamala; Sliwerska, Elzbieta; Young, Elizabeth A.; Burmeister, Margit] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Villafuerte, Sandra M.; Young, Elizabeth A.; Burmeister, Margit] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [McMahon, Francis J.] NIMH, NIH, Bethesda, MD 20892 USA. RP Villafuerte, SM (reprint author), Univ Michigan, Mol & Behav Neurosci Inst, 109 Zina Pitcher Pl,BSRB 5063, Ann Arbor, MI 48109 USA. EM svillafu@umich.edu RI Burmeister, Margit/A-3157-2013; OI Burmeister, Margit/0000-0002-1914-2434; McMahon, Francis/0000-0002-9469-305X FU Nancy Pritzker Depression Network; NIMH Intramural Research Program FX This study was supported by the Nancy Pritzker Depression Network and in part by the NIMH Intramural Research Program. The authors thank the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study for collaboration in recruitment for this study. They also express their appreciation to Dr Srijan Sen for his helpful discussions, and Brady West from the Center for Statistical Consultation and Research at the University of Michigan for his excellent statistical assistance. NR 60 TC 37 Z9 39 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD DEC PY 2009 VL 19 IS 6 BP 281 EP 291 DI 10.1097/YPG.0b013e32832a506e PG 11 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 517GR UT WOS:000271601800001 PM 19829169 ER PT J AU Andrews, G Goldberg, DP Krueger, RF Carpenter, WT Hyman, SE Sachdev, P Pine, DS AF Andrews, G. Goldberg, D. P. Krueger, R. F. Carpenter, W. T., Jr. Hyman, S. E. Sachdev, P. Pine, D. S. TI Exploring the feasibility of a meta-structure for DSM-V and ICD-11: could it improve utility and validity? SO PSYCHOLOGICAL MEDICINE LA English DT Review DE Classification; DSM-V; ICD-11; mental disorders; meta structure ID COMMON MENTAL-DISORDERS; COMORBIDITY; STABILITY; HEALTH AB Background. The organization of mental disorders into 16 DSM-IV and 10 ICD-10 chapters is complex and based on clinical presentation. We explored the feasibility of a more parsimonious meta-structure based on both risk factors and clinical factors. Method. Most DSM-IV disorders were allocated to one of five clusters as a starting premise. Teams of experts then reviewed the literature to determine within-cluster similarities on 11 predetermined validating criteria. Disorders were included and excluded as determined by the available data. These data are intended to inform the grouping of disorders in the DSM-V and ICD-11 processes. Results. The final clusters were neurocognitive (identified principally by neural substrate abnormalities), neuro-developmental (identified principally by early and continuing cognitive deficits), psychosis (identified principally by clinical features and biomarkers for information processing deficits), emotional (identified principally by the temperamental antecedent of negative emotionality), and externalizing (identified principally by the temperamental antecedent of disinhibition). Conclusions. Large groups of disorders were found to share risk factors and also clinical picture. There could be advantages for clinical practice, public administration and research from the adoption of such an organizing principle. C1 [Andrews, G.; Sachdev, P.] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Goldberg, D. P.] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Krueger, R. F.] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Krueger, R. F.] Washington Univ, Dept Psychiat, St Louis, MO 63130 USA. [Carpenter, W. T., Jr.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Carpenter, W. T., Jr.] VISN 5 Mental Illness Res Educ & Clin Ctr, Baltimore, MD USA. [Hyman, S. E.] Harvard Univ, Cambridge, MA 02138 USA. [Pine, D. S.] NIMH, Bethesda, MD 20892 USA. RP Andrews, G (reprint author), 299 Forbes St, Darlinghurst, NSW 2010, Australia. EM gavina@unsw.edu.au RI Andrews, Gavin/J-6537-2012; OI Andrews, Gavin/0000-0002-4315-2173; Sachdev, Perminder/0000-0002-9595-3220 NR 24 TC 126 Z9 129 U1 4 U2 15 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD DEC PY 2009 VL 39 IS 12 BP 1993 EP 2000 DI 10.1017/S0033291709990250 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 527LU UT WOS:000272369400007 PM 19796425 ER PT J AU Andrews, G Pine, DS Hobbs, MJ Anderson, TM Sunderland, M AF Andrews, G. Pine, D. S. Hobbs, M. J. Anderson, T. M. Sunderland, M. TI Neurodevelopmental disorders: Cluster 2 of the proposed meta-structure for DSM-V and ICD-11 SO PSYCHOLOGICAL MEDICINE LA English DT Review DE Childhood; DSM-V; disorder; meta-structure; neurodevelopment ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEVELOPMENTAL COORDINATION DISORDER; DEFICIT HYPERACTIVITY DISORDER; RECEPTIVE LANGUAGE DISORDER; AUTISM SPECTRUM DISORDER; SUBSTANCE USE DISORDERS; EARLY ADULT LIFE; FOLLOW-UP; ASPERGER-SYNDROME; FAMILY-HISTORY AB Background. DSM-IV and ICD-10 are atheoretical and largely descriptive. Although this achieves good reliability, the validity of diagnoses can be increased by an understanding of risk factors and other clinical features. In an effort to group mental disorders on this basis, five clusters have been proposed. We now consider the second cluster, namely neurodevelopmental disorders. Method. We reviewed the literature in relation to 11 validating criteria proposed by a DSM-V Task Force Study Group. Results. This cluster reflects disorders of neurodevelopment rather than a 'childhood' disorders cluster. It comprises disorders subcategorized in DSM-IV and ICD-10 as Mental Retardation; Learning, Motor, and Communication Disorders; and Pervasive Developmental Disorders. Although these disorders seem to be heterogeneous, they share similarities on some risk and clinical factors. There is evidence of a neurodevelopmental genetic phenotype, the disorders have an early emerging and continuing course, and all have salient cognitive symptoms. Within-cluster co-morbidity also supports grouping these disorders together. Other childhood disorders currently listed in DSM-IV share similarities with the Externalizing and Emotional clusters. These include Conduct Disorder, Attention Deficit Hyperactivity Disorder and Separation Anxiety Disorder. The Tic, Eating/Feeding and Elimination disorders, and Selective Mutisms were allocated to the 'Not Yet Assigned' group. Conclusion. Neurodevelopmental disorders meet some of the salient criteria proposed by the American Psychiatric Association (APA) to suggest a classification cluster. C1 [Andrews, G.; Hobbs, M. J.; Anderson, T. M.; Sunderland, M.] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Pine, D. S.] NIMH, Bethesda, MD 20892 USA. RP Andrews, G (reprint author), 299 Forbes St, Darlinghurst, NSW 2010, Australia. EM gavina@unsw.edu.au RI Andrews, Gavin/J-6537-2012; Hobbs, Megan/F-7353-2013; OI Andrews, Gavin/0000-0002-4315-2173; Hobbs, Megan/0000-0003-0131-0089; Sunderland, Matthew/0000-0001-8452-364X FU Intramural NIH HHS [ZIA MH002782-09, ZIA MH002780-09, ZIA MH002781-09] NR 112 TC 27 Z9 30 U1 7 U2 18 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD DEC PY 2009 VL 39 IS 12 BP 2013 EP 2023 DI 10.1017/S0033291709990274 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 527LU UT WOS:000272369400009 PM 19796427 ER PT J AU Strobl, C Malley, J Tutz, G AF Strobl, Carolin Malley, James Tutz, Gerhard TI An Introduction to Recursive Partitioning: Rationale, Application, and Characteristics of Classification and Regression Trees, Bagging, and Random Forests SO PSYCHOLOGICAL METHODS LA English DT Review DE regression; classification; prediction; variable importance ID GENE-EXPRESSION; LOGISTIC-REGRESSION; VARIABLE IMPORTANCE; MODEL-SELECTION; PREDICTION; ALGORITHMS; FRAMEWORK; BIAS; REGULARIZATION; CLASSIFIERS AB Recursive partitioning methods have become popular and widely used tools for nonparametric regression and classification in many scientific fields. Especially random forests, which can deal with large numbers of predictor variables even in the presence of complex interactions, have been applied successfully in genetics, clinical medicine, and bioinformatics within the past few years. High-dimensional problems are common not only in genetics, but also in some areas of psychological research, where only a few subjects can be measured because of time or cost constraints, yet a large amount of data is generated for each subject. Random forests have been shown to achieve a high prediction accuracy in such applications and to provide descriptive variable importance measures reflecting the impact of each variable in both main effects and interactions. The aim of this work is to introduce the principles of the standard recursive partitioning methods as well as recent methodological improvements, to illustrate their usage for low and high-dimensional data exploration, but also to point out limitations of the methods and potential pitfalls in their practical application. Application of the methods is illustrated with freely available implementations in the R system for statistical computing. C1 [Strobl, Carolin; Tutz, Gerhard] Univ Munich, Dept Stat, D-80539 Munich, Germany. [Malley, James] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Strobl, C (reprint author), Univ Munich, Dept Stat, Ludwigstr 33, D-80539 Munich, Germany. EM carolin.strobl@stat.uni-muenchen.de FU Intramural NIH HHS [ZIA CT000271-07] NR 107 TC 409 Z9 410 U1 17 U2 120 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1082-989X EI 1939-1463 J9 PSYCHOL METHODS JI Psychol. Methods PD DEC PY 2009 VL 14 IS 4 BP 323 EP 348 DI 10.1037/a0016973 PG 26 WC Psychology, Multidisciplinary SC Psychology GA 530EA UT WOS:000272570600002 PM 19968396 ER PT J AU Klein, WMP Harris, PR AF Klein, William M. P. Harris, Peter R. TI Self-Affirmation Enhances Attentional Bias Toward Threatening Components of a Persuasive Message SO PSYCHOLOGICAL SCIENCE LA English DT Article ID HEALTH-RISK INFORMATION; DEFENSIVENESS AB We explored whether self-affirmation enhances attentional bias toward threatening elements of a persuasive message. Female alcohol consumers read an article linking alcohol to breast cancer and were then exposed supraliminally to threat and nonthreat words from the article (as well as threat and nonthreat words that did not appear in the article). Among moderately heavy drinkers who were not self-affirmed, there emerged an attentional bias away from the threatening words in the article-a result suggesting an avoidant response. However, among moderately heavy drinkers who were self-affirmed, there was a bias toward the threatening words. No attentional biases appeared for threat words not in the message, which suggested that the effect was threat specific. Moreover, no attentional biases were found among the heaviest drinkers. Self-affirmation may facilitate targeted implicit processing of threatening messages, although the effects could attenuate among individuals engaging in high levels of the behavior featured in the message. C1 [Klein, William M. P.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Harris, Peter R.] Univ Sheffield, Sheffield S10 2TN, S Yorkshire, England. RP Klein, WMP (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7326, Bethesda, MD 20892 USA. EM kleinwm@mail.nih.gov NR 27 TC 36 Z9 36 U1 6 U2 26 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0956-7976 J9 PSYCHOL SCI JI Psychol. Sci. PD DEC PY 2009 VL 20 IS 12 BP 1463 EP 1467 PG 5 WC Psychology, Multidisciplinary SC Psychology GA 524SQ UT WOS:000272163600006 PM 19883488 ER PT J AU Lockenhoff, CE De Fruyt, F Terracciano, A McCrae, RR De Bolle, M Costa, PT Aguilar-Vafaie, ME Ahn, CK Ahn, HN Alcalay, L Allik, J Avdeyeva, TV Barbaranelli, C Benet-Martinez, V Blatny, M Bratko, D Cain, TR Crawford, JT Lima, MP Fickova, E Gheorghiu, M Halberstadt, J Hrebickova, M Jussim, L Klinkosz, W Knezevic, G de Figueroa, NL Martin, TA Marusic, I Mastor, KA Miramontez, DR Nakazato, K Nansubuga, F Pramila, VS Realo, A Rolland, JP Rossier, J Schmidt, V Sekowski, A Shakespeare-Finch, J Shimonaka, Y Simonetti, F Siuta, J Smith, PB Szmigielska, B Wang, L Yamaguchi, M Yik, M AF Loeckenhoff, Corinna E. De Fruyt, Filip Terracciano, Antonio McCrae, Robert R. De Bolle, Marleen Costa, Paul T., Jr. Aguilar-Vafaie, Maria E. Ahn, Chang-kyu Ahn, Hyun-nie Alcalay, Lidia Allik, Juri Avdeyeva, Tatyana V. Barbaranelli, Claudio Benet-Martinez, Veronica Blatny, Marek Bratko, Denis Cain, Thomas R. Crawford, Jarret T. Lima, Margarida P. Fickova, Emilia Gheorghiu, Mirona Halberstadt, Jamin Hrebickova, Martina Jussim, Lee Klinkosz, Waldemar Knezevic, Goran Leibovich de Figueroa, Nora Martin, Thomas A. Marusic, Iris Mastor, Khairul Anwar Miramontez, Daniel R. Nakazato, Katsuharu Nansubuga, Florence Pramila, V. S. Realo, Anu Rolland, Jean-Pierre Rossier, Jerome Schmidt, Vanina Sekowski, Andrzej Shakespeare-Finch, Jane Shimonaka, Yoshiko Simonetti, Franco Siuta, Jerzy Smith, Peter B. Szmigielska, Barbara Wang, Lei Yamaguchi, Mami Yik, Michelle TI Perceptions of Aging Across 26 Cultures and Their Culture-Level Associates SO PSYCHOLOGY AND AGING LA English DT Article DE aging; stereotypes; cross-cultural; values; national character stereotypes ID NATIONAL CHARACTER STEREOTYPES; OLDER-ADULTS; UNITED-STATES; YOUNG-ADULTS; AGE-GROUPS; LIFE-SPAN; ATTITUDES; MODERNIZATION; ABILITIES; AMERICAN AB College students (N = 3,435) in 26 cultures reported their perceptions of age-related changes in physical, cognitive, and socioemotional areas of functioning and rated societal views of aging within their culture. There was widespread cross-cultural consensus regarding the expected direction of aging trajectories with (a) perceived declines in societal views of aging, physical attractiveness, the ability to perform everyday tasks, and new learning; (b) perceived increases in wisdom, knowledge, and received respect; and (c) perceived stability in family authority and life satisfaction. Cross-cultural variations in aging perceptions were associated with culture-level indicators of population aging, education levels, values, and national character stereotypes. These associations were stronger for societal views on aging and perceptions of socioemotional changes than for perceptions of physical and cognitive changes. A consideration of culture-level variables also suggested that previously reported differences in aging perceptions between Asian and Western countries may be related to differences in population structure. C1 [Loeckenhoff, Corinna E.; Terracciano, Antonio; McCrae, Robert R.; Costa, Paul T., Jr.] NIA, Baltimore, MD 21224 USA. [De Fruyt, Filip; De Bolle, Marleen] Univ Ghent, Dept Dev Personal & Social Psychol, B-9000 Ghent, Belgium. [Aguilar-Vafaie, Maria E.] Tarbiat Modares Univ, Dept Psychol, Tehran, Iran. [Ahn, Chang-kyu] Pusan Natl Univ, Dept Educ, Pusan, South Korea. [Ahn, Hyun-nie] Ewha Womans Univ, Dept Psychol, Seoul, South Korea. [Alcalay, Lidia; Simonetti, Franco] Pontificia Univ Catolica Chile, Escuela Psicol, Santiago, Chile. [Allik, Juri; Realo, Anu] Univ Tartu, Dept Psychol, EE-50090 Tartu, Estonia. [Avdeyeva, Tatyana V.] Univ St Thomas, Grad Sch Profess Psychol, St Paul, MN USA. [Barbaranelli, Claudio] Univ Roma La Sapienza, Dept Psychol, Rome, Italy. [Benet-Martinez, Veronica; Miramontez, Daniel R.] Univ Calif Riverside, Dept Psychol, Riverside, CA 92521 USA. [Blatny, Marek; Hrebickova, Martina] Acad Sci Czech Republic, Inst Psychol, Prague, Czech Republic. [Bratko, Denis] Univ Zagreb, Fac Philosophy, Dept Psychol, Zagreb 41000, Croatia. [Cain, Thomas R.; Crawford, Jarret T.; Jussim, Lee] Rutgers State Univ, Dept Psychol, Piscataway, NJ 08855 USA. [Lima, Margarida P.] Univ Coimbra, Fac Psychol & Educ Sci, Coimbra, Portugal. [Fickova, Emilia] Slovak Acad Sci, Inst Expt Psychol, Bratislava, Slovakia. [Gheorghiu, Mirona] Queens Univ Belfast, Sch Psychol, Belfast BT7 1NN, Antrim, North Ireland. [Halberstadt, Jamin] Univ Otago, Dept Psychol, Dunedin, New Zealand. [Klinkosz, Waldemar] John Paul II Catholic Univ Lublin, Dept Psychol, Lublin, Poland. [Knezevic, Goran] Univ Belgrade, Fac Philosophy, Dept Psychol, Belgrade, Serbia. [Leibovich de Figueroa, Nora; Schmidt, Vanina] Univ Buenos Aires, Dept Psychol, Res Inst, Buenos Aires, DF, Argentina. [Martin, Thomas A.] Susquehanna Univ, Selinsgrove, PA USA. [Marusic, Iris] Inst Social Res, Zagreb, Croatia. [Mastor, Khairul Anwar] Univ Kebangsaan Malaysia, Sch Gen Studies, Bangi 43600, Malaysia. [Nakazato, Katsuharu] Iwate Prefectural Univ, Fac Social Welf, Takizawa, Iwate, Japan. [Nansubuga, Florence] Makerere Univ, Inst Psychol, Kampala, Uganda. [Pramila, V. S.] Andhra Univ, Dept Psychol, Visakhapatnam, Andhra Pradesh, India. [Rolland, Jean-Pierre] Univ Paris 10, Nanterre, France. [Rossier, Jerome] Univ Lausanne, Inst Psychol, Lausanne, Switzerland. [Shakespeare-Finch, Jane] Queensland Univ Technol, Sch Psychol & Counselling, Brisbane, Qld 4001, Australia. [Shimonaka, Yoshiko] Bunkyo Gakuin Univ, Dept Human Studies, Bunkyo, Japan. [Siuta, Jerzy; Szmigielska, Barbara] Jagiellonian Univ, Inst Psychol, Krakow, Poland. [Smith, Peter B.] Univ Sussex, Dept Psychol, Falmer, England. [Wang, Lei] Peking Univ, Dept Psychol, Beijing 100871, Peoples R China. [Yik, Michelle] Hong Kong Univ Sci & Technol, Hong Kong, Hong Kong, Peoples R China. RP Lockenhoff, CE (reprint author), Cornell Univ, Dept Human Dev, G35 Martha van Rensselaer Hall, Ithaca, NY 14853 USA. EM CEL72@cornell.edu RI Allik, Juri/D-5609-2009; De Fruyt, Filip/A-3083-2009; Rossier, Jerome/A-3494-2009; terracciano, antonio/B-1884-2008; Benet-Martinez, Veronica/B-5398-2011; Hrebickova, Martina/H-4410-2014; Blatny, Marek/H-4293-2014; Wang, Lei/D-2501-2016; Realo, Anu/M-9524-2016; Sekowski, Andrzej/O-7807-2016; OI Shakespeare-Finch, Jane/0000-0003-4237-1320; Allik, Juri/0000-0002-8358-4747; Rossier, Jerome/0000-0002-9924-3672; Benet-Martinez, Veronica/0000-0002-3352-9731; Hrebickova, Martina/0000-0003-4356-567X; Blatny, Marek/0000-0001-9831-0637; Wang, Lei/0000-0002-6156-9028; Costa, Paul/0000-0003-4375-1712; Nansubuga, Florence/0000-0001-6569-8700; Loeckenhoff, Corinna/0000-0003-1605-1323 FU Intramural NIH HHS [ZIA AG000183-22, Z99 AG999999, ZIA AG000180-25, ZIA AG000180-26, ZIA AG000183-23] NR 66 TC 53 Z9 55 U1 5 U2 54 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD DEC PY 2009 VL 24 IS 4 BP 941 EP 954 DI 10.1037/a0016901 PG 14 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 534NR UT WOS:000272904900015 PM 20025408 ER PT J AU Anderson, DE McNeely, JD Windham, BG AF Anderson, D. E. McNeely, J. D. Windham, B. G. TI Device-guided slow-breathing effects on end-tidal CO2 and heart-rate variability SO PSYCHOLOGY HEALTH & MEDICINE LA English DT Article DE breathing; blood pressure; end-tidal CO2; respiration; tidal volume ID BLOOD-PRESSURE; ESSENTIAL-HYPERTENSION; ARTERIAL-PRESSURE; OSCILLATIONS; SENSITIVITY; HYPERCAPNIA; MEDITATION; VARIABLES; SYSTEM; YOGA AB Previous Studies have reported that regular practice of a device-guided slow-breathing (DGB) exercise decreases resting blood pressure (BP) in hypertensive patients. The performance of DGB is associated With acute decreases in sympathetic vascular tone, and it has been Suggested that the decreases in resting BP produced by regular practice of DGB over periods of weeks are due to Chronic decreases in sympathetic nervous system activity. However, the kidneys respond to sympathetically mediated changes in BP by readjustment blood volume levels within a few days. Thus, the mechanism by which DGB could produce long-term BP changes remains to be clarified. Previous research with laboratory animals and human Subjects has shown that slow, shallow breathing that increases pCO(2) potentiates BP sensitivity to high sodium intake. These findings raise the possibility that deeper breathing during DGB that decreases BP might involve opposite changes in pCO(2). The present Study tested the hypothesis that performance of DGB acutely decreases a marker Of pCO(2), end-tidal CO2 (PetCO(2)). Breathing rate, tidal volume, and PetCO(2) Were monitored before, during, and after a 15-min session of DGB by patients with elevated BP. BP, heart rate, and heart-rate variability (HRV) were also Measured Under these conditions. A control group Was also Studied before, during, and after a 15-min session of spontaneous breathing (SB). The DGB group, but not the SB group, showed progressive and substantial increases in tidal volume and low-frequency HRV and decreases in PetCO(2) and systolic BP. The PetCO(2) effects persisted into the posttask, rest period. The findings are consistent with the hypothesis that habitual changes in breathing patterns of the kind observed during DGB could potentiate an antihypertensive adaptation via effects on pCO(2) and its role in cardiovascular homeostasis. C1 [Anderson, D. E.; McNeely, J. D.; Windham, B. G.] NIA, Clin Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Anderson, DE (reprint author), NIA, Clin Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM Andersod@grc.nia.nih.gov FU National Institute on Aging Intramural Research Program (NIH) FX The authors thank Deborah Grady for calling our attention to the value of the RESPeRATE in cardiovascular research, to Margaret Chesney for a careful reading of the manuscript, and to Benjamin Gavish for his advice and encouragement in all phases of the study. This study was supported by the National Institute on Aging Intramural Research Program (NIH). NR 30 TC 1 Z9 2 U1 2 U2 6 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1354-8506 J9 PSYCHOL HEALTH MED JI Psychol. Health Med. PD DEC PY 2009 VL 14 IS 6 BP 667 EP 679 DI 10.1080/13548500903322791 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 550QS UT WOS:000274143700004 PM 20183539 ER PT J AU Preston, KL Vahabzadeh, M Schmittner, J Lin, JL Gorelick, DA Epstein, DH AF Preston, Kenzie L. Vahabzadeh, Massoud Schmittner, John Lin, Jia-Ling Gorelick, David A. Epstein, David H. TI Cocaine craving and use during daily life SO PSYCHOPHARMACOLOGY LA English DT Article DE Craving; Ecological momentary assessment; Cocaine; Mood; Addiction; Psychological theory ID ECOLOGICAL MOMENTARY ASSESSMENT; REAL-TIME; CONTINGENCY MANAGEMENT; SMOKING LAPSE; BOGUS PIPELINE; DRUG-USE; ALCOHOL; RELAPSE; CUE; DEPENDENCE AB Craving is often assumed to cause ongoing drug use and relapse and is a major focus of addiction research. However, its relationship to drug use has not been adequately documented. The aim of this study was to investigate the relationship between craving and drug use in real time and in the daily living environments of drug users. In a prospective, longitudinal, cohort design (ecological momentary assessment), 112 cocaine-abusing individuals in methadone maintenance treatment rated their craving and mood at random times (two to five times daily, prompted by electronic diaries) as they went about their everyday activities. They also initiated an electronic diary entry each time they used cocaine. Drug use was monitored by thrice-weekly urine testing. During periods of urine-verified cocaine use, ratings of cocaine craving increased across the day and were higher than during periods of urine-verified abstinence. During the 5 h prior to cocaine use, ratings of craving significantly increased. These patterns were not seen in ratings of heroin craving or mood (e.g., feeling happy or bored). Cocaine craving is tightly coupled to cocaine use in users' normal environments. Our findings provide previously unavailable support for a relationship that has been seriously questioned in some theoretical accounts. We discuss what steps will be needed to determine whether craving causes use. C1 [Preston, Kenzie L.] NIDA, Intramural Res Program, Treatment Sect, Clin Pharmacol & Therapeut Branch, Baltimore, MD 21224 USA. [Preston, Kenzie L.; Schmittner, John; Epstein, David H.] Natl Inst Drug Abuse, Treatment Sect, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Vahabzadeh, Massoud; Lin, Jia-Ling] Natl Inst Drug Abuse, Biomed Informat Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Preston, KL (reprint author), NIDA, Intramural Res Program, Treatment Sect, Clin Pharmacol & Therapeut Branch, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM kpreston@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU Intramural Research Program (IRP); National Institute on Drug Abuse (NIDA); National Institutes of Health FX This research was supported by the Intramural Research Program (IRP) of the National Institute on Drug Abuse (NIDA), National Institutes of Health. We thank the NIDA IRP Archway Clinic staff for data collection. NR 61 TC 58 Z9 59 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD DEC PY 2009 VL 207 IS 2 BP 291 EP 301 DI 10.1007/s00213-009-1655-8 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 513FP UT WOS:000271308200011 PM 19777216 ER PT J AU Parry, G Horowitz, L Goldmann, D AF Parry, G. Horowitz, L. Goldmann, D. TI Patient safety attitudes of paediatric trainee physicians SO QUALITY & SAFETY IN HEALTH CARE LA English DT Article ID HEALTH-CARE; UNITED-KINGDOM; CULTURE; QUESTIONNAIRE; MANAGEMENT; RESIDENTS; FRAMEWORK; EDUCATION; TEAMWORK; VALIDITY AB Objectives: To measure the patient safety attitudes of trainee physicians at an academic paediatric hospital. Design: Cross-sectional survey. Setting: An academic paediatric hospital. Participants: 209 trainee physicians based at the academic paediatric hospital in January 2004. Main outcome measures: Patient safety attitudes of trainee physicians measured using the Safety Attitudes Questionnaire (Inpatient Version) and a specific trainee survey. Results: In the Safety Attitudes Questionnaire, responses were most positive in areas associated with independent care: job satisfaction (mean factor score = 77.5) safety climate (76.1), working conditions (75.6), perception of management (70.4) and less positively in areas associated with interdependent care: teamwork climate (64.6) and stress recognition (59.1). In the trainee survey, following a principal component analysis to identify summary factors, responses were most positive in the independent areas of clinical supervision and support (75.0), communication with their immediate senior physician (65.5) and orientation of new personnel (63.9), and less positive in the interdependent areas of handoffs and multiple services, (58.1), role identification during codes (51.0) and support following an adverse event (42.8). The combined independent factor scores were higher than the interdependent (difference = 17.9, 95% CI 16.1 to 19.7, p<0.001). Fellows reported higher independent factor scores than residents (5.5, 95% CI 2.2 to 8.9, p = 0.001), but not for the interdependent scores (20.5, 95% CI 23.6 to 2.7, p = 0.767). Conclusions: Trainees appear comfortable with caring independently for patients but less so caring interdependently. With experience, trainee physicians may experience improvement in their ability to act independently but not interdependently. Recently developed patient safety culture instruments may enable additional understanding of what could be implemented to make improvements. C1 [Parry, G.; Goldmann, D.] Childrens Hosp Boston, Dept Med, Boston, MA USA. [Horowitz, L.] NIMH, NIH, Bethesda, MD 20892 USA. [Goldmann, D.] Inst Healthcare Improvement, Cambridge, MA USA. RP Parry, G (reprint author), Childrens Hosp Boston, Dept Med, Boston, MA USA. EM gparry@ihi.org FU Commonwealth Fund FX GP was supported in writing this paper by the Commonwealth Fund, a national, private foundation based in New York City that supports independent research on health and social issues. The views presented here are those of the authors and not necessarily those of Commonwealth Fund, its director, officers or staff. NR 29 TC 4 Z9 4 U1 2 U2 12 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1475-3898 J9 QUAL SAF HEALTH CARE JI Qual. Saf. Health Care PD DEC PY 2009 VL 18 IS 6 BP 462 EP 466 DI 10.1136/qshc.2006.020230 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 526VV UT WOS:000272324100012 PM 19955458 ER PT J AU Miller, DL Kwon, D Bonavia, GH AF Miller, Donald L. Kwon, Deukwoo Bonavia, Grant H. TI Reference Levels for Patient Radiation Doses in Interventional Radiology: Proposed Initial Values for US Practice SO RADIOLOGY LA English DT Article ID DIAGNOSTIC REFERENCE LEVELS; RAD-IR; CARDIOLOGY; FLUOROSCOPY; EXPERIENCE; QUALITY; SKIN; UK AB Purpose: To propose initial values for patient reference levels for fluoroscopically guided procedures in the United States. Materials and Methods: This secondary analysis of data from the Radiation Doses in Interventional Radiology Procedures (RAD-IR) study was conducted under a protocol approved by the institutional review board and was HIPAA compliant. Dose distributions (percentiles) were calculated for each type of procedure in the RAD-IR study where there were data from at least 30 cases. Confidence intervals for the dose distributions were determined by using bootstrap resampling. Weight banding and size correction methods for normalizing dose to patient body habitus were tested. Results: The different methods for normalizing patient radiation dose according to patient weight gave results that were not significantly different (P > .05). The 75th percentile patient radiation doses normalized with weight banding were not significantly different from those that were uncorrected for body habitus. Proposed initial reference levels for various interventional procedures are provided for reference air kerma, kerma-area product, fluoroscopy time, and number of images. Conclusion: Sufficient data exist to permit an initial proposal of values for reference levels for interventional radiologic procedures in the United States. For ease of use, reference levels without correction for body habitus are recommended. A national registry of radiation-dose data for interventional radiologic procedures is a necessary next step to refine these reference levels. (C) RSNA, 2009 C1 [Miller, Donald L.; Bonavia, Grant H.] Natl Naval Med Ctr, Dept Radiol, Bethesda, MD 20889 USA. [Miller, Donald L.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Radiol & Radiol Sci, Bethesda, MD 20814 USA. [Kwon, Deukwoo] NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Miller, DL (reprint author), Natl Naval Med Ctr, Dept Radiol, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM donald.miller@med.navy.mil FU National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 50 TC 51 Z9 53 U1 0 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD DEC PY 2009 VL 253 IS 3 BP 753 EP 764 DI 10.1148/radiol.2533090354 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 525WF UT WOS:000272247300022 PM 19789226 ER PT J AU Bandeen-Roche, K Walston, JD Huang, Y Semba, RD Ferrucci, L AF Bandeen-Roche, Karen Walston, Jeremy D. Huang, Yi Semba, Richard D. Ferrucci, Luigi TI Measuring Systemic Inflammatory Regulation in Older Adults: Evidence and Utility SO REJUVENATION RESEARCH LA English DT Article ID NECROSIS-FACTOR-ALPHA; C-REACTIVE PROTEIN; FUNCTIONAL DECLINE; VARIABLE CLUSTERS; PHYSICAL FUNCTION; MUSCLE STRENGTH; GENE-EXPRESSION; HEALTH ABC; INTERLEUKIN-6; DISEASE AB Aging is frequently accompanied by a proinflammatory state with adverse health consequences. This state is commonly assessed by markers in serum, either in isolation or ad hoc combination. We sought, alternatively, to develop scores summarizing multiple markers in accordance with biology on inflammatory regulation and evaluate their value added for discriminating functional outcomes in older adults. Data came from InCHIANTI (Invecchiare in Chianti; Aging in the Chianti Area) study participants age 65 years and older. Serum concentrations of seven inflammatory biomediators were subjected to latent variable analysis implementing a biological model of counterbalancing up- and down-regulation processes. Resulting process constructs were approximated by principal component scores; these, and individual markers, were evaluated as predictors of mobility impairment and frailty status in regression analyses, adjusting for key confounders. The biomediators' interrelationships were well predicted by the hypothesized biology. The up- regulation score was independently associated with worsened mobility functioning and frailty risk. For mobility, the association was stronger than, persisted independently of, and accounted for association with each biomediator. The down regulation score was associated with frailty outcomes. We conclude that systemic inflammation is relevant to the process that leads to functional loss in older persons and can be validly measured through biologically informed summary of inflammatory markers. C1 [Bandeen-Roche, Karen] Johns Hopkins Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Walston, Jeremy D.] Johns Hopkins Med Inst, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. [Huang, Yi] Univ Maryland, Dept Math & Stat, Baltimore, MD 21201 USA. [Semba, Richard D.] Johns Hopkins Med Inst, Dept Ophthalmol, Baltimore, MD 21205 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Bandeen-Roche, K (reprint author), Johns Hopkins Sch Publ Hlth, Dept Biostat, 615 N Wolfe St, Baltimore, MD 21205 USA. EM kbandeen@jhsph.edu FU InCHIANTI [ICS 110.1/RS97.71]; National Institute on Aging (NIA) [263 MD 9164 13, 263 MD 821336, R01 AG027012, P50 AG021334-01] FX Yi Huang was a Ph.D. student in the Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health while the bulk of this research was conducted. The InCHIANTI study was supported as a targeted project (ICS 110.1/RS97.71) by the Italian Ministry of Health as well as by National Institute on Aging (NIA) contracts 263 MD 9164 13 and 263 MD 821336. Funding for this study was also provided by NIA grants R01 AG027012 and P50 AG021334-01. NR 48 TC 34 Z9 34 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-1684 J9 REJUV RES JI Rejuv. Res. PD DEC PY 2009 VL 12 IS 6 BP 403 EP 410 DI 10.1089/rej.2009.0883 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 538JO UT WOS:000273180600004 PM 20041734 ER PT J AU Norian, JM Malik, M Parker, CY Joseph, D Leppert, PC Segars, JH Catherino, WH AF Norian, John M. Malik, Minnie Parker, Candace Y. Joseph, Doina Leppert, Phyllis C. Segars, James H. Catherino, William H. TI Transforming Growth Factor beta 3 Regulates the Versican Variants in the Extracellular Matrix-Rich Uterine Leiomyomas SO REPRODUCTIVE SCIENCES LA English DT Article DE Versican variants; TGF-beta 3; leiomyomas; immortalized cells; extracellular matrix ID SMOOTH-MUSCLE-CELLS; HORMONE ANALOG THERAPY; TGF-BETA; CHONDROITIN SULFATE; NORMAL MYOMETRIUM; GENE-EXPRESSION; MESSENGER-RNA; IN-VITRO; SIGNAL-TRANSDUCTION; CELLULAR BIOLOGY AB Uterine leiomyoma are common, benign tumors that are enriched in extracellular matrix. The tumors are characterized by a disoriented and loosely packed collagen fibril structure similar to other diseases with disrupted Transforming growth factor beta (TGF-beta) signaling. Here we characterized TGF-beta 3 signaling and the expression patterns of the critical extracellular matrix component versican in leiomyoma and myometrial tissue and cell culture. We also demonstrate the regulation of the versican variants by TGF-beta 3. Using leiomyoma and matched myometrium from 15 patients, messenger RNA (mRNA) from leiomyoma and myometrium was analyzed by semiquantitative real time reverse transcription-polymerase chain reaction (RT-PCR), while protein analysis was done by western blot. Transforming growth factor beta 3 transcripts were increased 4-fold in leiomyoma versus matched myometrium. Phosphorylated-TGF-beta RII and phosphorylated-Smad 2/3 complex were greater in leiomyoma as documented by Western blot. The inhibitor Smad7 transcripts were decreased 0.44-fold. The glycosaminoglycan (GAG)-rich versican variants were elevated in leiomyoma versus myometrial tissue: specifically V0 (4.27 +/- 1.12) and V1 (2.01 +/- 0.27). Treatment of leiomyoma and myometrial cells with TGF-beta 3 increased GAG-rich versican variant expression 7 to 12 fold. Neutralizing TGF-beta 3 antibody decreased the expression of the GAG-rich versican variants 2 to 8 fold in leiomyoma cells. Taken together, the aberrant production of excessive and disorganized extracellular matrix that defines the leiomyoma phenotype involves the activation of the TGF-beta signaling pathway and excessive production of GAG-rich versican variants. C1 [Norian, John M.; Malik, Minnie; Parker, Candace Y.; Joseph, Doina; Segars, James H.; Catherino, William H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Norian, John M.; Parker, Candace Y.; Segars, James H.; Catherino, William H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod Biol & Med Branch, NIH, Bethesda, MD USA. [Leppert, Phyllis C.] Duke Univ, Sch Med, Dept Obstet & Gynecol, Durham, NC USA. RP Catherino, WH (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, 4301 Jones Bridge Rd,A-3078, Bethesda, MD 20814 USA. EM wcatherino@usuhs.mil FU Berlex Foundation; Eunice Kennedy Shriver National Institute for Child Health and Human Development, NIH FX This study was supported by the Berlex Foundation and by the intramural research program of the Reproductive Biology and Medicine Branch, the Eunice Kennedy Shriver National Institute for Child Health and Human Development, NIH. NR 74 TC 55 Z9 59 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD DEC PY 2009 VL 16 IS 12 BP 1153 EP 1164 DI 10.1177/1933719109343310 PG 12 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 521FS UT WOS:000271906400005 PM 19700613 ER PT J AU Orians, CE Abed, J Drew, CH Rose, SW Cohen, JH Phelps, J AF Orians, Carlyn E. Abed, Joanne Drew, Christina H. Rose, Shyanika Wijesinha Cohen, Jennifer H. Phelps, Jerry TI Scientific and public health impacts of the NIEHS Extramural Asthma Research Program: insights from primary data SO RESEARCH EVALUATION LA English DT Article ID PROMOTION; MODEL; FIT AB A conceptual model was developed to guide evaluation of the long-term impacts of research grant programs at the National Institutes of Health, National Institute of Environmental Health Sciences. The model was then applied to the extramural asthma research portfolio in two stages: (1) using extant data sources, (2) involving primary data collection with asthma researchers and individuals in positions to use asthma research in development of programs, policies and practices. Reporting on the second stage, this article describes how we sought to broaden the perspectives included in the assessment and obtain a more nuanced picture of research impacts by engaging those involved in conducting or using the research. C1 [Orians, Carlyn E.; Cohen, Jennifer H.] Battelle Ctr Publ Hlth Res, Seattle, WA 98109 USA. [Orians, Carlyn E.; Cohen, Jennifer H.] Battelle Ctr Publ Hlth Evaluat Battelle, Seattle, WA 98109 USA. [Abed, Joanne] Battelle Mem Inst, Arlington, VA 22201 USA. [Drew, Christina H.; Phelps, Jerry] NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. [Rose, Shyanika Wijesinha] Battelle Mem Inst, Durham, NC 27713 USA. RP Orians, CE (reprint author), Battelle Ctr Publ Hlth Res, 1100 Dexter Ave N,Suite 400, Seattle, WA 98109 USA. EM orians@battelle.org FU Intramural NIH HHS [Z99 ES999999] NR 18 TC 5 Z9 5 U1 2 U2 6 PU BEECH TREE PUBLISHING PI GUILDFORD PA 10 WATFORD CLOSE,, GUILDFORD GU1 2EP, SURREY, ENGLAND SN 0958-2029 J9 RES EVALUAT JI Res. Evaluat. PD DEC PY 2009 VL 18 IS 5 BP 375 EP 385 DI 10.3152/095820209X480698 PG 11 WC Information Science & Library Science SC Information Science & Library Science GA 561ND UT WOS:000274983400005 PM 21921976 ER PT J AU Hosgood, HD Menashe, I He, XZ Chanock, S Lan, Q AF Hosgood, H. Dean, III Menashe, Idan He, Xingzhou Chanock, Stephen Lan, Qing TI PTEN identified as important risk factor of chronic obstructive pulmonary disease SO RESPIRATORY MEDICINE LA English DT Article DE COPD; Cell cycle; Apoptosis; AKT; PTEN ID TUMOR-SUPPRESSOR PTEN; LUNG-CANCER; XUAN-WEI; GROWTH-FACTOR; CHINA; EPIDEMIOLOGY; INFLAMMATION; PHOSPHATASE; IMPROVEMENT; EXPRESSION AB Common genetic variation may play an important role in altering chronic obstructive pulmonary disease (COPD) risk. In Xuanwei, China, the COPD rate is more than twice the Chinese national average, and COPD is strongly associated with in-home coat use. To identify genetic variation that may be associated with COPD in a population with substantial in-home coat smoke exposures, we evaluated 1261 single nucleotide polymorphisms (SNPs) in 380 candidate genes potentially relevant for cancer and other human diseases in a population-based case-control study in Xuanwei (53 cases; 107 controls). PTEN was the most significantly associated gene with COPD in a min P analysis using 20,000 permutations (P 0.00005). SNP-based analyses found that homozygote variant carriers of PTEN rs701848 (OR(TT) = 0.12, 95% Cl = 0.03-0.47) had a significant decreased risk of COPD. PTEN, or phosphatase and tensin homolog, is an important regulator of cell cycle progression and cellular survival via the AKT signaling pathway. Our exploratory analysis suggests that genetic variation in PTEN may be an important risk factor of COPD in Xuanwei. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuanwei and other populations with coat smoke exposures. Published by Elsevier Ltd. C1 [Hosgood, H. Dean, III] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [He, Xingzhou] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. RP Hosgood, HD (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 8118,MCS 7240, Bethesda, MD 20892 USA. EM hosgoodd@mail.nih.gov FU National Cancer Institute FX This project has been funded in whole or in part with federal funds from the National Cancer Institute. NR 25 TC 12 Z9 12 U1 2 U2 5 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 J9 RESP MED JI Respir. Med. PD DEC PY 2009 VL 103 IS 12 BP 1866 EP 1870 DI 10.1016/j.rmed.2009.06.016 PG 5 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 526FK UT WOS:000272272900013 PM 19625176 ER PT J AU Barozzi, P Potenza, L Riva, G Vallerini, D Quadrelli, C Bosco, R Morselli, M Forghieri, F Volzone, F Rossi, G Ferri, C Bonini, C Ciceri, F Bordignon, C Whitby, D Schulz, TF Torelli, G Luppi, M AF Barozzi, Patrizia Potenza, Leonardo Riva, Giovanni Vallerini, Daniela Quadrelli, Chiara Bosco, Raffaella Morselli, Monica Forghieri, Fabio Volzone, Francesco Rossi, Giulio Ferri, Clodoveo Bonini, Chiara Ciceri, Fabio Bordignon, Claudio Whitby, Denise Schulz, Thomas F. Torelli, Giuseppe Luppi, Mario TI Changes in T-Cell Responses Against Human Herpesvirus-8 Correlate with the Disease Course of Iatrogenic Kaposi's Sarcoma in a Patient with Undifferentiated Arthritis SO SEMINARS IN ARTHRITIS AND RHEUMATISM LA English DT Review DE Kaposi sarcoma; HHV-8; undifferentiated arthritis; immunosuppression ID ACTIVE ANTIRETROVIRAL THERAPY; RHEUMATOID-ARTHRITIS; LYMPHOCYTE EPITOPES; IDENTIFICATION; INFECTION; FAILURE AB Objectives: To describe the first in-depth analysis of both the T-cell responses against human herpesvirus-8 (HHV-8) and the HHV-8 viral load in 1 patient who developed iatrogenic HHV-8-associated-Kaposi's sarcoma (KS) following immunosuppressive treatment for undifferentiated arthritis and to review the literature on iatrogenic KS (IKS). Methods: T-cell responses against HHV-8 lytic and latent antigens were analyzed by ex vivo enzyme-linked immunospot (Elispot) and HHV-8 viral load was assessed by quantitative polymerase chain reaction, in sequential peripheral blood samples from a 55-year-old woman who developed skin/mucosal and visceral KS, while receiving treatment with cyclosporine, methotrexate, and methylprednisolone for undifferentiated arthritis. Results: KS may result from HHV-8 infection in patients undergoing immunosuppressive treatment for rheumatic diseases and this is the first case of IKS occurring in undifferentiated arthritis. A role for immune surveillance in the pathogenesis of IKS is supported by the observation of disease regression following discontinuation of immunosuppressive therapy. In a 4-year follow-up, we showed that variations of the virus-specific immune responses but not of the viral load correlated well with the disease course, characterized by 2 remission and subsequent relapse phases, following changes of immunosuppressive therapy. Conclusions: We have provided evidence of a clear-cut correlation between changes in immunologic markers of HHV-8 infection and the disease course of this viral associated tumor, concomitant with variations of immunosuppressive treatment. Thus, ex vivo enzyme-linked immunospot for HHV-8-specific T-cell responses represents a new tool for the clinical management of rheumatic patients with IKS. (C) 2009 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 39:170-175 C1 [Barozzi, Patrizia; Potenza, Leonardo; Riva, Giovanni; Vallerini, Daniela; Quadrelli, Chiara; Bosco, Raffaella; Morselli, Monica; Forghieri, Fabio; Volzone, Francesco; Torelli, Giuseppe; Luppi, Mario] Univ Modena & Reggio Emilia, Dept Hematol & Oncol, Azienda Osped Policlin, I-41100 Modena, Italy. [Rossi, Giulio] Univ Modena & Reggio Emilia, Dept Diagnost & Lab Serv & Legal Med, Azienda Osped Policlin, Sect Pathol Anat, I-41100 Modena, Italy. [Ferri, Clodoveo] Univ Modena & Reggio Emilia, Dept Rheumatol, Azienda Osped Policlin, I-41100 Modena, Italy. [Bonini, Chiara; Ciceri, Fabio; Bordignon, Claudio] Ist Sci San Raffaele, Expt Hematol Lab, Canc Immunotherapy & Gene Therapy Program, Hematol & Bone Marrow Transplantat Unit, I-20132 Milan, Italy. [Whitby, Denise] NCI, Viral Epidemiol Sect, AIDS Vaccine Program, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. [Schulz, Thomas F.] Hannover Med Sch, Inst Virol, D-30623 Hannover, Germany. RP Luppi, M (reprint author), Univ Modena & Reggio Emilia, Dept Hematol & Oncol, Azienda Osped Policlin, Via Pozzo 71, I-41100 Modena, Italy. EM mario.luppi@unimore.it RI Rossi, Giulio/C-5576-2011; bonini, chiara/I-9202-2012; Luppi, Mario/J-3668-2016; Rossi, Giulio/K-6217-2016; Potenza, Leonardo/P-9579-2016; Barozzi, Patrizia/Q-2638-2016; OI Luppi, Mario/0000-0002-0373-1154; Rossi, Giulio/0000-0001-8855-1218; Potenza, Leonardo/0000-0002-2738-6105; Barozzi, Patrizia/0000-0002-8936-1114; BONINI, Maria Chiara/0000-0002-0772-1674; Rossi, Antonio/0000-0003-3295-0345 FU Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy; European Commission [LSHC-CT-2005-018704]; Associazione Italiana Lotta alle Leucemie, Linfoma e Mieloma; Programma di ricerca Regione-Universita FX This study was supported by the the Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy (M.L.); the European Commission's FP6 Life-Science-Health Programme (INCA project; LSHC-CT-2005-018704) (M.L.); the Associazione Italiana Lotta alle Leucemie, Linfoma e Mieloma (AIL)-Modena-ONLUS (L.P.); and the Programma di ricerca Regione-Universita 2007 to 2009 (G.T.). NR 25 TC 3 Z9 3 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0049-0172 J9 SEMIN ARTHRITIS RHEU JI Semin. Arthritis Rheum. PD DEC PY 2009 VL 39 IS 3 BP 170 EP 175 DI 10.1016/j.semarthrit.2008.05.005 PG 6 WC Rheumatology SC Rheumatology GA 598ZD UT WOS:000277878300004 PM 18639317 ER PT J AU Pearl, PL Shamim, S Theodore, WH Gibson, KM Forester, K Combs, SE Lewin, D Dustin, I Reeves-Tyer, P Jakobs, C Sato, S AF Pearl, Phillip L. Shamim, Sadat Theodore, William H. Gibson, K. Michael Forester, Katherine Combs, Susan E. Lewin, Daniel Dustin, Irene Reeves-Tyer, Patricia Jakobs, Cornelis Sato, Susumu TI Polysomnographic Abnormalities in Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency SO SLEEP LA English DT Article DE SSADH; GABA; REM ID GAMMA-HYDROXYBUTYRIC ACID; BRAIN; SPECTROSCOPY AB Objectives: Patients with SSADH deficiency, a disorder of chronically elevated endogenous GABA and GHB, were studied for Sleep symptoms and polysomnography. We hypothesized that patients would have excessive daytime somnolence and decreased REM sleep. Design: Polysomnography and MSLT were performed on patients enrolled for comprehensive clinical studies of SSADH deficiency. Setting: Sleep studies were obtained in the sleep laboratories at CNMC and NIH. Patients: Sleep recordings were obtained in 10 patients with confirmed SSADH deficiency. Interventions: Thirteen overnight polysomnograms were obtained in 10 patients (7 male, 3 female, ages 11-27 y). Eleven MSLT studies were completed in 8 patients. Measurements and Results: Polysomnograms showed prolongation of REM stage latency (mean 272 +/- 89 min) and decreased percent stage REM (mean 8.9%, range 0.3% to 13.8%). Decreased mean sleep latency was present in 6 of 11 MSLTs. Conclusions: SSADH deficiency is associated with prolonged latency to stage REM and decreased percent stage REM. This disorder represents a model of chronic GABA and GHB accumulation associated with suppression of REM sleep. C1 [Pearl, Phillip L.; Forester, Katherine; Combs, Susan E.; Lewin, Daniel] George Washington Univ, Childrens Natl Med Ctr, Sch Med, Dept Neurol,Neurosci Ctr, Washington, DC 20010 USA. [Pearl, Phillip L.; Shamim, Sadat; Theodore, William H.; Dustin, Irene; Reeves-Tyer, Patricia; Sato, Susumu] NINDS, Sleep Lab, NIH, Bethesda, MD 20892 USA. [Gibson, K. Michael] Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Pittsburgh, PA USA. [Jakobs, Cornelis] Vrije Univ Amsterdam, Med Ctr, Dept Clin Chem, Amsterdam, Netherlands. RP Pearl, PL (reprint author), George Washington Univ, Childrens Natl Med Ctr, Sch Med, Dept Neurol,Neurosci Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. EM ppearl@cnmc.org FU Delman Fund for Pediatric Neurology Research [NS 40270/HD58553]; NINDS/NIH Intramural Program FX Institutions where work was performed: Children's National Medical Center, Washington, DC and NINDS, NIH, Bethesda, MD NR 18 TC 9 Z9 10 U1 0 U2 0 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD DEC 1 PY 2009 VL 32 IS 12 BP 1645 EP 1648 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 527OL UT WOS:000272376300017 PM 20041601 ER PT J AU Earley, CJ Allen, RP Connor, JR Ferrucci, L Troncoso, J AF Earley, Christopher J. Allen, Richard P. Connor, James R. Ferrucci, Luigi Troncoso, Juan TI The dopaminergic neurons of the A11 system in RLS autopsy brains appear normal SO SLEEP MEDICINE LA English DT Article DE Restless Legs Syndrome; A11 dopaminergic system; Hypothalamus; Tyrosine hydroxylase; Gliosis; Hypothalamus; Human autopsy; Brain ID RESTLESS LEGS SYNDROME; SPINAL-CORD; MICE AB Although the positive clinical benefits of levodopa have fostered the concept of an abnormality in the dopaminergic system in Restless Legs Syndrome (RLS), research into the nigro-striatal (PET/SPECT studies) or tubero-infundibular (i.e., prolactin secretion) dopaminergic pathways has shown limited positive results. Some research groups have focused on the A11 dopaminergic system in the hypothalamus as this is the primary source of descending dopaminergic input into the spinal cord, an area of the nervous system believed by some investigators to be involved in RLS symptom development. Some investigators have now proposed lesioning or toxin-inhibiting the A11 system as a model of RLS, even though there has been no clear clinical or autopsy data to suggest that RLS is a neurodegenerative disorder. In this study, the A11 cell bodies were identified in 6 RLS and 6 aged-matched control autopsy cases. Cells were stained for tyrosine hydroxylase (TH), and stereological measure of the individual TH (+) cell volume was made. Regional assessment of gliosis as assessed by immunostaining for glial fibrillary acidic protein (GFAP) was made in the surrounding tissue. General histological staining was also performed on the tissue. This study found no significant difference between RLS or control cases on any measure used: TH (+) cell volume, fractional GFAP staining, OF general histological examination. Nor was there histological indication of any significant inflammation or concurrent ongoing pathology in these RLS cases. The findings do not support the concept of dramatic cell loss or of a neurodegenerative process in the A11 hypothalamic region of patients with RLS. However, that does not exclude the possibility that the A11 system is involved in RLS symptoms. Changes at the cellular level in dopaminergic metabolism or at the distal synapse with changes in receptors or transporters were not evaluated in this study. (C) 2009 Elsevier B.V. All rights reserved. C1 [Earley, Christopher J.; Allen, Richard P.] Johns Hopkins Univ, Johns Hopkins Bayview Med Ctr, Dept Neurol, Baltimore, MD 21224 USA. [Connor, James R.] Penn State Coll Med, Dept Neurosurg, Hershey, PA USA. [Ferrucci, Luigi] NIA, Baltimore Longitudinal Study Aging, NIH, Baltimore, MD 21224 USA. [Troncoso, Juan] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21224 USA. RP Earley, CJ (reprint author), Johns Hopkins Univ, Johns Hopkins Bayview Med Ctr, Dept Neurol, 5501 Hopkins Bayview Circle,AAC 1B-82, Baltimore, MD 21224 USA. EM cearley@jhmi.edu FU NIH [PO1-AG21190]; RLS Foundation; Harvard Brain Tissue Resource Center [R24 MH/NS068855] FX We thank Ms. Gay Rudow for excellent technical assistance. Financial support for this study came from NIH Grant, PO1-AG21190. We thank the RLS Foundation, the Harvard Brain Tissue Resource Center (R24 MH/NS068855) and the NIH/NIA Baltimore Longitudinal Study on Ageing (BLSA) for contributing the brains. NR 11 TC 37 Z9 37 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 J9 SLEEP MED JI Sleep Med. PD DEC PY 2009 VL 10 IS 10 BP 1155 EP 1157 DI 10.1016/j.sleep.2009.01.006 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 532QF UT WOS:000272763800016 PM 19307154 ER PT J AU Alaraisanen, A Miettunen, J Rasanen, P Fenton, W Koivumaa-Honkanen, HTJ Isohanni, M AF Alaraisanen, Antti Miettunen, Jouko Rasanen, Pirkko Fenton, Wayne Koivumaa-Honkanen, Heli-Tuulie Jeannette Isohanni, Matti TI Suicide rate in schizophrenia in the Northern Finland 1966 Birth Cohort SO SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY LA English DT Article DE Schizophrenia; Suicide; Mortality; Cohort studies ID RISK-FACTORS; DEINSTITUTIONALIZATION; MORTALITY; REGISTER AB Suicide rate among schizophrenia patients may vary for several reasons, one of the most important being the time point of the suicide during the illness process. However, prospective studies on suicide risk in population-based cohort of individuals with new-onset schizophrenia have been lacking. The data were collected for 10,934 individuals alive in Finland at the age of 16 from the genetically homogenous, population-based Northern Finland 1966 Birth Cohort ascertained already during mid-pregnancy. The Finnish Hospital Discharge Register was used until the end of 1997 (age 31) to identify cases with mental disorder. Case records were scrutinized and diagnoses were re-checked for DSM-III-R criteria. One hundred subjects met the DSM-III-R criteria for schizophrenia. Deaths by the end of year 2005 (age 39) were ascertained from death certificates. Suicides (n = 7) accounted for 50% of all the deaths at age from 16 to 39. Seven (7.0%) subjects with schizophrenia had committed suicide; suicide rate being 2.9% (1/35) for women and 9.2% (6/65) for men. Furthermore, 71% of suicides in schizophrenia occurred during the first 3 years after onset of illness. The suicide rate for patients with new-onset schizophrenia followed until the age of 39 was high and accounted for half of the deaths. Great majority of the suicides took place during the first years of the illness. C1 [Alaraisanen, Antti; Miettunen, Jouko; Rasanen, Pirkko; Koivumaa-Honkanen, Heli-Tuulie Jeannette; Isohanni, Matti] Univ Oulu, Dept Psychiat, Inst Clin Med, Oulu 90014, Finland. [Fenton, Wayne] NIMH, Bethesda, MD 20892 USA. [Koivumaa-Honkanen, Heli-Tuulie Jeannette] Lapland Hosp Dist, Dept Psychiat, Muurola, Finland. [Koivumaa-Honkanen, Heli-Tuulie Jeannette] Kuopio Univ Hosp, Dept Psychiat, SF-70210 Kuopio, Finland. RP Alaraisanen, A (reprint author), Univ Oulu, Dept Psychiat, Inst Clin Med, POB 5000, Oulu 90014, Finland. EM antti.alaraisanen@oulu.fi; jouko.miettunen@oulu.fi; pirkko.rasanen@oulu.fi; heli.koivumaa@lshp.fi; matti.isohanni@oulu.fi RI Koivumaa-Honkanen, Heli /L-1274-2015; OI Miettunen, Jouko/0000-0003-0575-2669 FU Academy of Finland; Sigrid Juselius Foundation; Stanley Medical Research Institute; Duodecim Association; Jalmari and Rauha Ahokas Foundation; Lundbeck Foundation; Finnish Cultural Foundation; Orion Research Foundation FX This work was supported by unrestricted grants from the Academy of Finland, the Sigrid Juselius Foundation, the Stanley Medical Research Institute, the Duodecim Association, Jalmari and Rauha Ahokas Foundation, Lundbeck Foundation, Finnish Cultural Foundation and Orion Research Foundation. NR 19 TC 19 Z9 21 U1 4 U2 6 PU DR DIETRICH STEINKOPFF VERLAG PI HEIDELBERG PA TIERGARTENSTRASSE 17, 69121 HEIDELBERG, GERMANY SN 0933-7954 J9 SOC PSYCH PSYCH EPID JI Soc. Psychiatry Psychiatr. Epidemiol. PD DEC PY 2009 VL 44 IS 12 BP 1107 EP 1110 DI 10.1007/s00127-009-0033-5 PG 4 WC Psychiatry SC Psychiatry GA 515WS UT WOS:000271504200011 PM 19319456 ER PT J AU Furukawa, T Ito, K Nuka, S Hashimoto, J Takei, H Takahara, M Ogino, T Young, MF Shinomura, T AF Furukawa, Takashi Ito, Kazuo Nuka, Satoshi Hashimoto, Junichi Takei, Hiroshi Takahara, Masatoshi Ogino, Toshihiko Young, Marian F. Shinomura, Tamayuki TI Absence of Biglycan Accelerates the Degenerative Process in Mouse Intervertebral Disc SO SPINE LA English DT Article DE intervertebral disc; biglycan; knock-out-mouse; degeneration; SLRP (small leucine rich repeat proteoglycan) ID BONE-MINERAL DENSITY; GROWTH-FACTOR-BETA; POSTMENOPAUSAL WOMEN; ARTICULAR-CARTILAGE; DEFICIENT MICE; LUMBAR SPINE; DECORIN; OSTEOPOROSIS; COLLAGEN; OSTEOARTHRITIS AB Study Design. A study of the histologic changes of the intervertebral discs (IVDs) in biglycan (Bgn)-deficient mice. Objective. In this study, we investigate whether the absence of Bgn accelerates the degenerative process in mouse intervertebral disc (IVD). Summary of Background Data. Proteoglycans and collagen fibrils are major components in the extracellular matrix (ECM) composition of IVD. The ECM of IVD contains several members of the small leucine repeat proteoglycans (SLRPs) family. Bgn is one member of SLRPs family, and showed a unique expression with age and degeneration in the human IVD. To date, there have been no in vivo studies to see whether SLRPs have a role in maintaining the structural integrity of IVD. To explore the functions of Bgn in the IVD, we examined discs in Bgn-deficient mice. Methods. A total of 30 spine specimens were harvested from wild-type (WT) and Bgn-deficient mice. Five specimens for each genotype at 4-, 6-, and 9-month old were examined in the experiments. Histologic analysis of the IVD was performed. Histologic gradings were performed separately on nucleus pulposus, anulus fibrosus, and endplate according to the classification system proposed by Boos et al. Results. We found that Bgn-deficient mice developed an early onset of disc degeneration compared with WT mice. The degenerative scores of Bgn-deficient mice were significantly higher than those of WT mice at 4-and 9-month-old. High scores for nucleus pulposus and anulus fibrosus in Bgn-deficient mice significantly affected the difference in total degenerative scores at 9 months of age. Conclusion. Bgn deficiency significantly accelerated disc degeneration. C1 [Furukawa, Takashi; Ito, Kazuo; Hashimoto, Junichi; Takei, Hiroshi; Takahara, Masatoshi; Ogino, Toshihiko] Yamagata Univ, Sch Med, Dept Orthopaed Surg, Yamagata 9909585, Japan. [Nuka, Satoshi] Sapporo Med Univ, Dept Orthopaed Surg, Sapporo, Hokkaido, Japan. [Young, Marian F.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Shinomura, Tamayuki] Tokyo Med & Dent Univ, Dept Hard Tissue Engn, Tokyo, Japan. RP Ito, K (reprint author), Yamagata Univ, Sch Med, Dept Orthopaed Surg, 2-2-2 Iida Nishi, Yamagata 9909585, Japan. EM kz-ito@med.id.yamagata-u.ac.jp FU Yamagata Health Support FX Supported by a grant from the Yamagata Health Support. NR 27 TC 15 Z9 18 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD DEC 1 PY 2009 VL 34 IS 25 BP E911 EP E917 DI 10.1097/BRS.0b013e3181b7c7ec PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 527EI UT WOS:000272349200024 PM 19940720 ER PT J AU Clegg, LX Hankey, BF Tiwari, R Feuer, EJ Edwards, BK AF Clegg, Limin X. Hankey, Benjamin F. Tiwari, Ram Feuer, Eric J. Edwards, Brenda K. TI Estimating average annual per cent change in trend analysis SO STATISTICS IN MEDICINE LA English DT Article DE confidence interval for trends; geometric means; trend comparisons ID CANCER; NATION; RATES AB Trends in incidence or mortality rates over a specified time interval are usually described by the conventional annual per cent change (cAPC), under the assumption of a constant rate of change. When this assumption does not hold over the entire time interval, the trend may be characterized using the annual per cent changes from segmented analysis (sAPCs). This approach assumes that the change in rates is constant over each time partition defined by the transition points, but varies among different time partitions. Different groups (e.g. racial subgroups), however, may have different transition points and thus different time partitions over which they have constant rates of change, making comparison of sAPCs; problematic across groups over a common time interval of interest (e.g. the past 10 years). We propose a new measure, the average annual per cent change (AAPC), which uses sAPCs to summarize and compare trends for a specific time period. The advantage of the proposed AAPC is that it takes into account the trend transitions, whereas cAPC does not and can lead to erroneous conclusions. In addition, when the trend is constant over the entire time interval of interest, the AAPC has the advantage of reducing to both cAPC and sAPC. Moreover, because the estimated AAPC is based on the segmented analysis over the entire data series, any selected subinterval within a single time partition will yield the same AAPC estimate-that is it will be equal to the estimated sAPC for that time partition. The cAPC, however, is re-estimated using data only from that selected subinterval; thus, its estimate may be sensitive to the subinterval selected. The AAPC estimation has been incorporated into the segmented regression (free) software Joinpoint, which is used by many registries throughout the world for characterizing trends in cancer rates. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Clegg, Limin X.] US Dept Vet Affairs, Off Inspector Gen, Washington, DC USA. [Hankey, Benjamin F.] Informat Management Serv Inc, Silver Spring, MD USA. [Tiwari, Ram] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Feuer, Eric J.; Edwards, Brenda K.] NCI, Surveillance Res Program, Bethesda, MD 20892 USA. RP Clegg, LX (reprint author), US Dept Vet Affairs, Off Inspector Gen, 801 1 St NW,Room 1018, Washington, DC USA. EM lin_clegg@nih.gov NR 16 TC 118 Z9 123 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD DEC PY 2009 VL 28 IS 29 BP 3670 EP 3682 DI 10.1002/sim.3733 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 533EU UT WOS:000272807300007 PM 19856324 ER PT J AU Andrews, PW Arias-Diaz, J Auerbach, J Alvarez, M Ahrlund-Richter, L Baker, D Benvenisty, N Ben-Josef, D Blin, G Borghese, L Borstlap, J Bruce, K Brustle, O Buckle, R Camby, C Choo, A Chen, W Collins, D Colman, A Crombie, C Crook, J Cypess, R De Sousa, P Dhawan, J Douay, L Dvorak, P Dyke, T Eriksson, L Firpo, M Fitzgerald, C Glover, C Gokhale, P Greene, M Ha, HY Hampl, A Healy, L Hei, D Holm, F Hovatta, O Hunt, C Hwang, SM Inamdar, M Isasi, R Itskovitz-Eldor, J Jessie, N Kim, DW Kirzner, R Kiatpongsan, S Knowles, B Kuo, HC Laughlin, M Lavon, N Ludwig, T Lakov, M Lee, DR Macauley, J Mckay, R Menasche, P Menendez, P Michalska, A Mileikovskaia, M Minger, S Mishra, G Moody, J Montgomery, K Morris, C Mummery, C Nagy, A Nakamura, Y Nakatsuji, N Nishikawa, SI Oh, S Oh, SK Olson, P Otonkoski, T Patole, M Park, HS Pei, XT Pera, M Puceat, M Rajala, K Reubinoff, B Robins, A Rooke, H Rumayor, V Scotman, H Sherlock, J Simon, C Sipp, D Skinner, R Smith, D Stacey, G Stefanovic, S Strehl, R Taft, R Takahashi, T Talib, S Terstegge, S Turner, R Tuuri, T Yu, J Zandstra, P Zapata, A Zeng, FY Zhou, Q Tannenbaum, S AF Andrews, Peter W. Arias-Diaz, Javard Auerbach, Jonathan Alvarez, Manuel Ahrlund-Richter, Lars Baker, Duncan Benvenisty, Nissim Ben-Josef, Dalit Blin, Guillaume Borghese, Lodovica Borstlap, Joeri Bruce, Kevin Bruestle, Oliver Buckle, Robin Camby, Carine Choo, Andre Chen, Wannhsin Collins, Daniel Colman, Alan Crombie, Catriona Crook, Jeremy Cypess, Ray De Sousa, Paul Dhawan, Jyotsna Douay, Luc Dvorak, Petr Dyke, Timothy Eriksson, Lena Firpo, Meri Fitzgerald, Claire Glover, Clive Gokhale, Paul Greene, Michele Ha, Hye-Yeong Hampl, Ales Healy, Lyn Hei, Derek Holm, Frida Hovatta, Outi Hunt, Charles Hwang, Shiaw-Min Inamdar, Maneesha Isasi, Rosario Itskovitz-Eldor, Joseph Jessie, Nancy Kim, Dong-Wook Kirzner, Rosemarie Kiatpongsan, Sorapop Knowles, Barbara Kuo, Hung-Chih Laughlin, Mary Lavon, Neta Ludwig, Tenneille Lakov, Majlinda Lee, Dong-Ryul Macauley, John McKay, Ronald Menasche, Phillipe Menendez, Pablo Michalska, Anna Mileikovskaia, Maria Minger, Stephen Mishra, Gyan Moody, Jennifer Montgomery, Karen Morris, Clive Mummery, Christine Nagy, Andras Nakamura, Yukio Nakatsuji, Norio Nishikawa, Shin-Ichi Oh, Steve Oh, Sun Kyung Olson, Patricia Otonkoski, Timo Patole, Milind Park, Hyun-Sook Pei, Xuetao Pera, Martin Puceat, Michel Rajala, Kristiina Reubinoff, Benjamin Robins, Allan Rooke, Heather Rumayor, Victor Scotman, Heli Sherlock, Jon Simon, Carlos Sipp, Douglas Skinner, Rebecca Smith, David Stacey, Glyn Stefanovic, Sonia Strehl, Raimund Taft, Robert Takahashi, Tsuneo Talib, Sohel Terstegge, Stefanie Turner, Rodney Tuuri, Timo Yu, John Zandstra, Peter Zapata, Augustin Zeng, Fanyi Zhou, Qi Tannenbaum, Shelly CA Int Stem Cell Banking Initiative TI Consensus Guidance for Banking and Supply of Human Embryonic Stem Cell Lines for Research Purposes SO STEM CELL REVIEWS AND REPORTS LA English DT Article DE Human embryonic stem cells; Cell banking; Standardisation; Microbiological testing; Pluripotency; Quality control ID CULTURES; PCR; EXCLUSION; MOSAICISM; TABLES C1 [Healy, Lyn; Hunt, Charles; Stacey, Glyn] Natl Inst Biol Stand & Controls, S Mimms, Herts, England. [Arias-Diaz, Javard; Gokhale, Paul; Rumayor, Victor; Zapata, Augustin] Inst Salud Carlos III, Madrid, Spain. [Auerbach, Jonathan] GlobalStem Inc, Rockville, MD USA. [Andrews, Peter W.] Univ Sheffield, Ctr Stem Cell Biol, Sheffield S10 2TN, S Yorkshire, England. [Alvarez, Manuel; Zandstra, Peter] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Ahrlund-Richter, Lars; Holm, Frida; Hovatta, Outi] Karolinska Inst, Stockholm, Sweden. [Baker, Duncan] Univ Sheffield, Natl Hlth Serv, Sheffield S10 2TN, S Yorkshire, England. [Benvenisty, Nissim] Hebrew Univ Jerusalem, Inst Life Sci, IL-91904 Jerusalem, Israel. [Ben-Josef, Dalit] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. [Blin, Guillaume; Puceat, Michel; Stefanovic, Sonia] INSERM, Evry, France. [Borghese, Lodovica] Univ Bonn, D-5300 Bonn, Germany. [Borstlap, Joeri] Charite, D-13353 Berlin, Germany. [Bruce, Kevin; Collins, Daniel; De Sousa, Paul] Roslin Cells, Edinburgh, Midlothian, Scotland. [Bruestle, Oliver; Terstegge, Stefanie] Univ Bonn, Inst Reconstruct Neurobiol, D-5300 Bonn, Germany. [Buckle, Robin; Crombie, Catriona] MRC, London, England. [Camby, Carine] Agence Biomed, Paris, France. [Choo, Andre; Oh, Steve] Bioproc Technol Inst, Singapore, Singapore. [Chen, Wannhsin] Ind Technol Res Inst, Hsinchu, Taiwan. [Colman, Alan] ASTAR, Biopolis, Singapore, Singapore. [Crook, Jeremy] OBrien Inst, Melbourne, Vic, Australia. [Cypess, Ray; Kirzner, Rosemarie] Amer Type Culture Collect, Mannassas, VA USA. [Dhawan, Jyotsna] Ctr Cellular & Mol Biol, Hyderabad 500007, Andhra Pradesh, India. [Douay, Luc] Univ Paris 06, Paris, France. [Dvorak, Petr; Hampl, Ales] Masaryk Univ, Brno, Czech Republic. [Dyke, Timothy; Morris, Clive] Natl Hlth & Med Res Council, Canberra, ACT, Australia. [Eriksson, Lena] Univ York, York YO10 5DD, N Yorkshire, England. [Firpo, Meri] Univ Minnesota, Stem Cell Inst, Minneapolis, MN USA. [Firpo, Meri] Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN USA. [Fitzgerald, Claire] Harvard Univ, Howard Hughes Med Inst, Boston, MA 02115 USA. [Greene, Michele] Millipore Corp, Bedford, MA USA. [Ha, Hye-Yeong] Korean Stem Cell Res Ctr, Seoul, South Korea. [Hampl, Ales] Inst Expt Med, Brno, Czech Republic. Univ Wisconsin, Waisman Ctr, Madison, WI 53706 USA. [Hwang, Shiaw-Min] Bioresource Collect & Res Ctr, Taipei, Taiwan. [Inamdar, Maneesha] Indian Inst Sci, Jawaharlal Nehru Ctr Adv Sci Res, Bangalore 560012, Karnataka, India. [Isasi, Rosario] Univ Montreal, Montreal, PQ, Canada. [Itskovitz-Eldor, Joseph] Rambam Med Ctr, Haifa, Israel. [Itskovitz-Eldor, Joseph] Technion Israel Inst Technol, Haifa, Israel. [Kim, Dong-Wook] Yonsei Univ, Coll Med, Stem Cell Res Ctr, Seoul, South Korea. [Kiatpongsan, Sorapop] Chulalongkorn Univ, Bangkok, Thailand. [Knowles, Barbara] ASTAR, Med Biol Inst, Singapore, Singapore. [Kuo, Hung-Chih] Acad Sinica, Genom Res Ctr, Inst Cellular & Organism Biol, Taipei 115, Taiwan. [Laughlin, Mary] Univ Hosp Cleveland, Cleveland Int Soc Cell Therapy Representat, Case Med Ctr ISCT, Cleveland, OH 44106 USA. [Lavon, Neta] Hebrew Univ Jerusalem, Inst Life Sci, IL-91905 Jerusalem, Israel. [Lavon, Neta] Cedars Sinai Med Ctr, Int Stem Cell Inst, Los Angeles, CA 90048 USA. [Lakov, Majlinda] Newcastle Ctr Life, Newcastle Upon Tyne, Tyne & Wear, England. [Lee, Dong-Ryul] Cha Hosp, Seoul, South Korea. [Macauley, John; Taft, Robert] Jackson Lab, Bar Harbor, ME 04609 USA. [McKay, Ronald] Natl Inst Hlth, Washington, DC USA. [Menasche, Phillipe] Hosp European, Paris, France. [Menendez, Pablo] Andalusian Stem Cell Bank, Granada, Spain. [Michalska, Anna; Skinner, Rebecca] Australian Stem Cell Ctr, Melbourne, Vic, Australia. [Nagy, Andras] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Minger, Stephen] Kings Coll London, London, England. [Mishra, Gyan; Patole, Milind] Natl Ctr Cell Sci, Pune, Maharashtra, India. [Mummery, Christine] Leiden Univ, Med Ctr, Leiden, Netherlands. [Nakamura, Yukio] RIKEN, BioResource Ctr, Ibaraki, Japan. Kyoto Univ, Kyoto, Japan. [Nishikawa, Shin-Ichi; Sipp, Douglas] RIKEN, Ctr Dev Biol, Kobe, Hyogo, Japan. [Oh, Sun Kyung] Seoul Natl Univ, Coll Med, MRC, IRMP, Seoul, South Korea. [Olson, Patricia; Talib, Sohel] Calif Inst Regenerat Med, San Francisco, CA USA. [Otonkoski, Timo; Tuuri, Timo] Univ Helsinki, Helsinki, Finland. [Park, Hyun-Sook] MCTT Inc, Seoul, South Korea. [Pei, Xuetao] Beijing Inst Transfus, Beijing, Peoples R China. [Pera, Martin] Univ So Calif, Los Angeles, CA USA. [Rajala, Kristiina; Scotman, Heli] Univ Tampere, Tampere Univ Hosp, Regea Inst Regenerat Med, FIN-33101 Tampere, Finland. [Reubinoff, Benjamin] Hadassah Univ Med Org, Jerusalem, Israel. [Rooke, Heather] Int Soc Stem Cell Res, Deerfield, IL USA. [Sherlock, Jon; Turner, Rodney] Appl Biosyst Part Life Technol, Foster City, CA USA. [Simon, Carlos] Univ Valencia, Valencia, Spain. [Smith, David] CABI Europe UK, Egham, Surrey, England. [Strehl, Raimund] Cellartis AB, Gothenburg, Sweden. [Takahashi, Tsuneo] Univ Tokyo, Tokyo, Japan. [Zeng, Fanyi] Shanghai Jiao Tong Univ, Shanghai Inst Med Genet, Shanghai 200030, Peoples R China. [Zhou, Qi] Chinese Acad Sci, Beijing, Peoples R China. [Tannenbaum, Shelly] Hebrew Univ Jerusalem, Med Ctr, Jerusalem, Israel. [Yu, John] Acad Sinica, Inst Cellular & Organism Biol, Genom Res Ctr, Taipei 115, Taiwan. RP Stacey, G (reprint author), Natl Inst Biol Stand & Controls, S Mimms, Herts, England. EM Glyn.Stacey@nibsc.hpa.org.uk RI Stefanovic, Sonia/O-5240-2016; Dvorak, Petr/N-8936-2016; Otonkoski, Timo/F-1189-2011; Simon, Carlos/G-2186-2014; PERA, MARTIN/A-9812-2012; Ahrlund-Richter, Lars/C-6226-2012; Vopenkova, Katerina/C-7133-2012; YU, JOHN/G-8954-2012; De Sousa, Paul/H-7416-2013; Dvorak, Petr/G-2509-2013; Arias-Diaz, Javier/A-3860-2016; Nakamura, Yukio/A-5263-2016; Hampl, Ales/N-1632-2016; Sipp, Douglas/C-9218-2017 OI Stefanovic, Sonia/0000-0003-4202-2534; Dvorak, Petr/0000-0002-3229-140X; Simon, Carlos/0000-0003-0902-9531; PERA, MARTIN/0000-0001-6239-0428; De Sousa, Paul/0000-0003-0745-2504; Dvorak, Petr/0000-0002-3229-140X; Arias-Diaz, Javier/0000-0002-3002-3305; Sipp, Douglas/0000-0002-5979-0938 FU International Stem Cell Forum FX We would like to thank the International Stem Cell Forum for funding this initiative. Details of the 'Forum' can be found at www.stemcellforum.org. Thanks also to the Jackson Laboratory (Bar Harbor, Maine, USA) who hosted meetings of the International Stem Cell Banking Initiative to establish this guidance and to Mrs Gill Cathro who assisted in the preparation of these meetings. NR 24 TC 23 Z9 24 U1 2 U2 17 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1550-8943 EI 1558-6804 J9 STEM CELL REV REP JI Stem Cell Rev. Rep. PD DEC PY 2009 VL 5 IS 4 BP 301 EP 314 DI 10.1007/s12015-009-9085-x PG 14 WC Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 542DA UT WOS:000273470400001 ER PT J AU Harvey, AJ Armant, DR Bavister, BD Nichols, SM Brenner, CA AF Harvey, A. J. Armant, D. R. Bavister, B. D. Nichols, S. M. Brenner, C. A. TI Inner Cell Mass Localization of NANOG Precedes OCT3/4 in Rhesus Monkey Blastocysts SO STEM CELLS AND DEVELOPMENT LA English DT Article ID EMBRYONIC STEM-CELLS; MOUSE EMBRYO; PREIMPLANTATION EMBRYOS; TRANSCRIPTION FACTOR; OCT-4 EXPRESSION; TROPHECTODERM DIFFERENTIATION; IN-VITRO; ES CELLS; CDX2; FERTILIZATION AB The mechanism by which the inner cell mass (ICM) and trophectoderm (TE) become specified is poorly understood. Considerable species variation is evident in the expression of lineage-specific and embryonic stem cell (ESC) regulatory markers. We sought to investigate localization patterns of these markers in rhesus macaque compact morulae and blastocysts. NANOG protein was restricted to the ICM of blastocysts. In contrast to a previous report, the expression of CDX2 was detected in the primate blastocyst, localized specifically to the TE. Unlike the mouse embryo, OCT4 protein was detected using two different antibodies in both the ICM and TE. The ubiquitous pattern of OCT4 expression is consistent with observations in human, cow, and pig embryos. Significantly, lack of restricted OCT4 protein, and ICM localization of NANOG in primate blastocysts, suggests that NANOG may determine inner cell mass fate more specifically during primate development or may be less susceptible to culture artifacts. These results contrast markedly with current mechanistic hypotheses, although other factors may lie upstream of NANOG to constitute a complex interactive network. This difference may also underlie observations that regulatory mechanisms in ESC differ between mice and primates. C1 [Harvey, A. J.] Wayne State Univ, Dept Physiol, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Armant, D. R.] Wayne State Univ, Dept Anat & Cell Biol, Detroit, MI 48202 USA. [Armant, D. R.] NICHD, NIH, Reprod Biol & Med Branch, Bethesda, MD USA. [Nichols, S. M.] Univ Puerto Rico, Reprod Biol Program, Unit Comparat Med, Caribbean Primate Res Ctr, Sabana Seca, PR USA. RP Harvey, AJ (reprint author), Wayne State Univ, Dept Physiol, Dept Obstet & Gynecol, Detroit, MI 48202 USA. EM aharvey@med.wayne.edu OI Armant, D. Randall/0000-0001-5904-9325; HARVEY, ALEXANDRA/0000-0001-6696-0950 FU NCRR NIH HHS [R21 RR021881-01, R21 RR021881-02, R21 RR021881-03, R21 RR021881-04, R24 RR015395-05, RR015395, RR021881]; NICHD NIH HHS [HD045966, HD046553, R01 HD045966, R01 HD045966-05, R01 HD045966-05S1, R03 HD046553-01A1, R03 HD046553-02, R03 HD046553-02S1, R03 HD046553-03] NR 53 TC 22 Z9 23 U1 1 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD DEC PY 2009 VL 18 IS 10 BP 1451 EP 1458 DI 10.1089/scd.2009.0122 PG 8 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 530KZ UT WOS:000272591600009 PM 19537945 ER PT J AU Smith, WS Lev, MH English, JD Camargo, EC Chou, M Johnston, SC Gonzalez, G Schaefer, PW Dillon, WP Koroshetz, WJ Furie, KL AF Smith, Wade S. Lev, Michael H. English, Joey D. Camargo, Erica C. Chou, Maggie Johnston, S. Claiborne Gonzalez, Gilberto Schaefer, Pamela W. Dillon, William P. Koroshetz, Walter J. Furie, Karen L. TI Significance of Large Vessel Intracranial Occlusion Causing Acute Ischemic Stroke and TIA SO STROKE LA English DT Article DE CT angiography; prognosis ID PROGNOSTIC MODELS; MINOR STROKE; VALIDATION; ATTACK; SCORE; RISK AB Background and Purpose-Acute ischemic stroke due to large vessel occlusion (LVO)-vertebral, basilar, carotid terminus, middle and anterior cerebral arteries-likely portends a worse prognosis than stroke unassociated with LVO. Because little prospective angiographic data have been reported on a cohort of unselected patients with stroke and with transient ischemic attack, the clinical impact of LVO has been difficult to quantify. Methods-The Screening Technology and Outcome Project in Stroke Study is a prospective imaging-based study of stroke outcomes performed at 2 academic medical centers. Patients with suspected acute stroke who presented within 24 hours of symptom onset and who underwent multimodality CT/CT angiography were approached for consent for collection of clinical data and 6-month assessment of outcome. Demographic and clinical variables and 6-month modified Rankin Scale scores were collected and combined with blinded interpretation of the CT angiography data. The OR of each variable, including occlusion of intracranial vascular segment in predicting good outcome and 6-month mortality, was calculated using univariate and multivariate logistic regression. Results-Over a 33-month period, 735 patients with suspected stroke were enrolled. Of these, 578 were adjudicated as stroke and 97 as transient ischemic attack. Among patients with stroke, 267 (46%) had LVO accounting for the stroke and 13 (13%) of patients with transient ischemic attack had LVO accounting for transient ischemic attack symptoms. LVO predicted 6-month mortality (OR, 4.5; 95% CI, 2.7 to 7.3; P<0.001). Six-month good outcome (modified Rankin Scale score <= 2) was negatively predicted by LVO (0.33; 0.24 to 0.45; P<0.001). Based on multivariate analysis, the presence of basilar and internal carotid terminus occlusions, in addition to National Institutes of Health Stroke Scale and age, independently predicted outcome. Conclusion-Large vessel intracranial occlusion accounted for nearly half of acute ischemic strokes in unselected patients presenting to academic medical centers. In addition to age and baseline stroke severity, occlusion of either the basilar or internal carotid terminus segment is an independent predictor of outcome at 6 months. (Stroke. 2009;40:3834-3840.) C1 [Smith, Wade S.; English, Joey D.; Johnston, S. Claiborne] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Dillon, William P.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Lev, Michael H.; Gonzalez, Gilberto; Schaefer, Pamela W.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Camargo, Erica C.; Furie, Karen L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Chou, Maggie] Columbia Univ, Dept Neurol, New York, NY USA. [Koroshetz, Walter J.] NINDS, Bethesda, MD 20892 USA. RP Smith, WS (reprint author), Univ Calif San Francisco, Dept Neurol, 505 Parnassus Ave, San Francisco, CA 94143 USA. EM smithw@neurology.ucsf.edu FU Department of Health and Human Services, Agency for Healthcare Research and Quality [RO1-HS011392-01A1]; Deane Institute FX W. S. S. has significant ownership interests and has served as a consultant to Concentric Medical, Inc (significant). K. L. F. is employed with Massachusetts General Hospital, has received financial support from Deane Institute (both significant), and has served as a consultant to Novartis, Biosante, and GE Healthcare (Modest). W.J.K. has an ownership interest in Neurologica (Modest). There are no other conflicts to report. NR 16 TC 97 Z9 101 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD DEC PY 2009 VL 40 IS 12 BP 3834 EP 3840 DI 10.1161/STROKEAHA.109.561787 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 531KD UT WOS:000272663900028 PM 19834014 ER PT J AU Leblanc, GG Golanov, E Awad, IA Young, WL AF Leblanc, Gabrielle G. Golanov, Eugene Awad, Issam A. Young, William L. CA Biol Vasc Malformations Brain NIN TI Biology of Vascular Malformations of the Brain SO STROKE LA English DT Article DE angiogenesis; arteriovenous malformation; cerebral hemorrhage; genetics; physiologic; vascular malformations ID HEREDITARY HEMORRHAGIC TELANGIECTASIA; CEREBRAL CAVERNOUS MALFORMATIONS; ENDOTHELIAL GROWTH-FACTOR; RECEPTOR-LIKE KINASE-1; MICE LACKING ENDOGLIN; SMOOTH-MUSCLE-CELLS; ARTERIOVENOUS-MALFORMATIONS; TGF-BETA; MOUSE MODEL; NATURAL-HISTORY AB Background and Purpose-This review discusses recent research on the genetic, molecular, cellular, and developmental mechanisms underlying the etiology of vascular malformations of the brain (VMBs), including cerebral cavernous malformation, sporadic brain arteriovenous malformation, and the arteriovenous malformations of hereditary hemorrhagic telangiectasia. Summary of Review-The identification of gene mutations and genetic risk factors associated with cerebral cavernous malformation, hereditary hemorrhagic telangiectasia, and sporadic arteriovenous malformation has enabled the development of animal models for these diseases and provided new insights into their etiology. All of the genes associated with VMBs to date have known or plausible roles in angiogenesis and vascular remodeling. Recent work suggests that the angiogenic process most severely disrupted by VMB gene mutation is that of vascular stabilization, the process whereby vascular endothelial cells form capillary tubes, strengthen their intercellular junctions, and recruit smooth muscle cells to the vessel wall. In addition, there is now good evidence that in some cases, cerebral cavernous malformation lesion formation involves a genetic 2-hit mechanism in which a germline mutation in one copy of a cerebral cavernous malformation gene is followed by a somatic mutation in the other copy. There is also increasing evidence that environmental second hits can produce lesions when there is a mutation to a single allele of a VMB gene. Conclusions-Recent findings begin to explain how mutations in VMB genes render vessels vulnerable to rupture when challenged with other inauspicious genetic or environmental factors and have suggested candidate therapeutics. Understanding of the cellular mechanisms of VMB formation and progression in humans has lagged behind that in animal models. New knowledge of lesion biology will spur new translational work. Several well-established clinical and genetic database efforts are already in place, and further progress will be facilitated by collaborative expansion and standardization of these. (Stroke. 2009;40:e694-e702.) C1 [Leblanc, Gabrielle G.; Golanov, Eugene] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Awad, Issam A.] Univ Chicago, Pritzker Sch Med, Evanston, IL USA. [Awad, Issam A.] N Shore Univ Hlth Syst, Evanston, IL USA. [Young, William L.] Univ Calif San Francisco, Cerebrovasc Res Ctr, San Francisco, CA 94143 USA. RP Leblanc, GG (reprint author), Biomed Consulting, 3020 Tilden St NW 503, Washington, DC 20008 USA. EM QHRTS21@gmail.com RI faurobert, eva/M-2735-2013; Golanov, Eugene/B-6462-2011; OI Golanov, Eugene/0000-0003-0220-822X; Derry, Brent/0000-0002-1977-8475; Stapf, Christian/0000-0002-3193-1006; Al-Shahi Salman, Rustam/0000-0002-2108-9222 FU Angioma Alliance; HHT Foundation International; Sturge-Weber Foundation; The Aneurysm and AVM Foundation (TAAF) FX This review is based in part on discussions at a workshop entitled "Biology of Vascular Malformations of the Brain" that was held by the National Institutes of Neurological Disorders and Stroke in Washington, DC, March 13 to 14, 2008. An agenda, participant list, and report of recommendations can be found at the workshop web site (www.ninds.nih.gov/news_and_events/proceedings/index.htm). The workshop was supported in part by funds from the Angioma Alliance, the HHT Foundation International, Sturge-Weber Foundation, and The Aneurysm and AVM Foundation (TAAF). NR 100 TC 72 Z9 75 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD DEC PY 2009 VL 40 IS 12 BP E694 EP E702 DI 10.1161/STROKEAHA.109.563692 PG 9 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 531KD UT WOS:000272663900045 PM 19834013 ER PT J AU Maas, R Boger, R Seshadri, S AF Maas, Renke Boeger, Rainer Seshadri, Sudha TI Asymmetric Dimethylarginine and Hypertension in Carotid Artery Disease Response SO STROKE LA English DT Letter ID ASSOCIATION; INHIBITOR; ADMA; RISK; MEN C1 [Maas, Renke] Univ Erlangen Nurnberg, Inst Expt & Clin Pharmacol & Toxicol, Nurnberg, Germany. [Boeger, Rainer] Univ Med Ctr Hamburg Eppendorf, Inst Expt & Clin Pharmacol, Clin Pharmacol Unit, Hamburg, Germany. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Seshadri, Sudha] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. RP Maas, R (reprint author), Univ Erlangen Nurnberg, Inst Expt & Clin Pharmacol & Toxicol, Nurnberg, Germany. NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD DEC PY 2009 VL 40 IS 12 BP E704 EP E704 DI 10.1161/STROKEAHA.109.565333 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 531KD UT WOS:000272663900047 ER PT J AU Menon, RS Kidwell, CS AF Menon, Ravi S. Kidwell, Chelsea S. TI Neuroimaging Demonstration of Evolving Small Vessel Ischemic Injury in Cerebral Amyloid Angiopathy SO STROKE LA English DT Article DE amyloid angiopathy; cerebrovascular disease ID LOBAR HEMORRHAGE; ROTTERDAM SCAN; RISK-FACTORS; MICROBLEEDS; DIAGNOSIS; DISEASE; MRI AB Background and Purpose-Cerebral amyloid angiopathy is a small to medium vasculopathy most commonly associated with symptomatic intracerebral hemorrhage and microbleeds. Summary of Case-We present a patient with cerebral microbleeds and likely amyloid angiopathy with evolving ischemic lesions visualized on diffusion-weighted imaging. Conclusions-This case captures with serial MRI the evolving and dynamic nature of cerebral amyloid angiopathy and particularly illustrates the subclinical, yet progressive, ischemic aspects of this vasculopathic process. (Stroke. 2009;40:e675-e677.) C1 [Menon, Ravi S.; Kidwell, Chelsea S.] Georgetown Univ, Dept Neurol, Washington, DC 20007 USA. [Menon, Ravi S.; Kidwell, Chelsea S.] Georgetown Univ, Stroke Ctr, Washington, DC 20007 USA. [Menon, Ravi S.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Menon, Ravi S.] Washington Hosp Ctr, Stroke Ctr, Washington, DC 20010 USA. RP Menon, RS (reprint author), Georgetown Univ, Dept Neurol, 4000 Reservoir Rd,NW,Suite 150, Washington, DC 20007 USA. EM ravi.menon@gunet.georgetown.edu NR 11 TC 16 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD DEC PY 2009 VL 40 IS 12 BP E675 EP E677 DI 10.1161/STROKEAHA.109.552935 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 531KD UT WOS:000272663900042 PM 19850897 ER PT J AU Powell, AC Alexander, HR Chang, R Marx, SJ Skarulis, M Pingpank, JF Bartlett, DL Hughes, M Weinstein, LS Simonds, WF Collins, MF Shawker, T Chen, CC Reynolds, J Cochran, C Steinberg, SM Libutti, SK AF Powell, Anathea C. Alexander, H. Richard Chang, Richard Marx, Stephen J. Skarulis, Monica Pingpank, James F. Bartlett, David L. Hughes, Marybeth Weinstein, Lee S. Simonds, William F. Collins, Michael F. Shawker, Thomas Chen, Clara C. Reynolds, James Cochran, Craig Steinberg, Seth M. Libutti, Steven K. TI Reoperation for parathyroid adenoma: A contemporary experience SO SURGERY LA English DT Article ID PRIMARY HYPERPARATHYROIDISM; RECURRENT HYPERPARATHYROIDISM; PREOPERATIVE LOCALIZATION; PERSISTENT; SURGERY; STRATEGY AB Background. We reviewed reoperations for persistent or recurrent sporadic parathyroid adenoma to evaluate and compare our current results and outcomes to our previous experience. Methods. From 1996 to 2008, 237 patients with persistent or recurrent hyperparathyroidism after failed operation underwent reoperation. Patients were re-explored with the assistance of non-invasive and sometimes invasive imaging. Results. A missed adenoma was suspected pre-operatively in 163 patients. Reoperation resulted in long-term resolution of hypercalcemia in 92%. Adenomas were in entopic locations in 32 %; the most frequent ectopic location was the thymus (20 %). Sestamibi scanning and ultrasonography were the most successful non-invasive imaging studies (96% positive predictive value (PPV) and 84% PPV respectively). Forty-four percent of patients had a reoperation based solely on non-invasive imaging. Of the invasive procedures performed, arteriography resulted in the best localization (92 % PPV). Permanent recurrent laryngeal nee injury occurred in 1.8%. Conclusion. Compared to our prior experience (1982-1995), outcomes remained similar (92 % resolution of hypercalcemia and 1.8% recurrent nerve injury currently versus 96 % and 1.3% previously). Fewer patients received invasive studies for pre-operative localization (56 % vs 73%, respectively). The decreased use of invasive imaging is due to technical improvements and greater confidence in the combination of ultrasonography and sestamibi scanning. (Surgery 2009; 146: 1144-55.) C1 [Powell, Anathea C.; Alexander, H. Richard; Pingpank, James F.; Bartlett, David L.; Hughes, Marybeth; Libutti, Steven K.] NCI, Tumor Angiogenesis Sect, Surg Branch, Bethesda, MD 20892 USA. [Chang, Richard; Shawker, Thomas; Chen, Clara C.; Reynolds, James] Warren F Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD USA. [Marx, Stephen J.; Skarulis, Monica; Weinstein, Lee S.; Simonds, William F.; Cochran, Craig] NIDDK, Metab Dis Branch, Bethesda, MD USA. [Collins, Michael F.] NIDCR, Skeletal Clin Studies Unit, Bethesda, MD USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Libutti, SK (reprint author), Albert Einstein Coll Med, Montefiore Med Ctr, 3400 Bainbridge Ave,4th Floor, Bronx, NY 10467 USA. EM slibutti@montefiore.org OI Weinstein, Lee/0000-0002-1899-5152 FU NCI; NIDDK FX Supported by the intramural NIH programs of NCI and NIDDK. NR 24 TC 23 Z9 25 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD DEC PY 2009 VL 146 IS 6 BP 1144 EP 1155 DI 10.1016/j.surg.2009.09.015 PG 12 WC Surgery SC Surgery GA 536YB UT WOS:000273078700024 PM 19958942 ER PT J AU Kumar, V Yap, J Muroyama, A Malhotra, SV AF Kumar, Vineet Yap, Jeremy Muroyama, Andrew Malhotra, Sanjay V. TI Highly Efficient Method for C-5 Halogenation of Pyrimidine-Based Nucleosides in Ionic Liquids SO SYNTHESIS-STUTTGART LA English DT Article DE ionic liquids; nucleosides; halogenation ID HERPES-SIMPLEX-VIRUS; 5-SUBSTITUTED 2'-DEOXYURIDINES; SELECTIVE BENZOYLATION; URACIL NUCLEOSIDES; ANTIVIRAL ACTIVITY; ANALOGS; DERIVATIVES; IODINATION; CELLS; ACID AB A novel, highly efficient, convenient, and benign methodology for C-5 halogenation of pyrimidine-based nucleosides has been developed using N-halosuccinimides as halogenating reagents without using any catalyst in ionic liquid medium. The ionic liquids were successfully recovered and reused for all the reactions. C1 [Kumar, Vineet; Yap, Jeremy; Muroyama, Andrew; Malhotra, Sanjay V.] NCI Frederick, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Malhotra, SV (reprint author), NCI Frederick, Lab Synthet Chem, SAIC Frederick Inc, 1050 Boyles St, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov FU National Cancer Institute; National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 37 TC 19 Z9 19 U1 1 U2 7 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0039-7881 J9 SYNTHESIS-STUTTGART JI Synthesis PD DEC 1 PY 2009 IS 23 BP 3957 EP 3962 DI 10.1055/s-0029-1217042 PG 6 WC Chemistry, Organic SC Chemistry GA 535MX UT WOS:000272974400004 ER PT J AU Duffy, A Kummar, S AF Duffy, Austin Kummar, Shivaani TI Targeting mitogen-activated protein kinase kinase (MEK) in solid tumors SO TARGETED ONCOLOGY LA English DT Review DE MEK inhibition; Predictive markers; Targeted therapy ID SIGNAL-REGULATED KINASE; INHIBITOR AZD6244 ARRY-142886; HER2-POSITIVE BREAST-CANCER; CELL LUNG-CANCER; PANCREATIC-CANCER; COLORECTAL-CANCER; HEPATOCELLULAR-CARCINOMA; ADJUVANT CHEMOTHERAPY; PHASE-II; RAF AB The Raf-mitogen activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) protein kinase signaling cascade is an important intracellular pathway whose activation influences many fundamental cellular processes and whose aberrancy is associated with cancer cell growth. In addition to activation from within by, for example, Raf mutations, this pathway is frequently activated from above by mutated Ras or epidermal growth factor receptor (EGFR). Given the near ubiquity of derangements affecting at least part of this network in cancer, there is a strong and clear rationale for interrupting it. In recent times, in colorectal and lung cancer, Ras and EGFR mutant status have been shown to be critically important and mutually exclusive predictors of response to anti-EGFR therapies. These developments underline the importance of targeting downstream effectors, and MEK inhibition has been the subject of intense scientific and clinical research for some time now. This article reviews the current status of MEK inhibitors with regard to their clinical development. C1 [Duffy, Austin; Kummar, Shivaani] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Duffy, A (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, 9000 Rockville Pike,10-13N240G, Bethesda, MD 20892 USA. EM duffya@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute, Center for Cancer Research FX 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 56 TC 17 Z9 17 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1776-2596 EI 1776-260X J9 TARGET ONCOL JI Target. Oncol. PD DEC PY 2009 VL 4 IS 4 BP 267 EP 273 DI 10.1007/s11523-009-0125-x PG 7 WC Oncology SC Oncology GA 524WQ UT WOS:000272175500003 PM 19899001 ER PT J AU Kelly, RJ Rixe, O AF Kelly, Ronan J. Rixe, Olivier TI Axitinib-a selective inhibitor of the vascular endothelial growth factor (VEGF) receptor SO TARGETED ONCOLOGY LA English DT Review DE Axitinib; VEGF receptor inhibitor; Renal cell carcinoma; Pancreatic carcinoma; Tyrosine kinese inhibitor ID RENAL-CELL CARCINOMA; ADVANCED PANCREATIC-CANCER; THYROID-CARCINOMA; RANDOMIZED-TRIAL; PHASE-II; TYROSINE KINASES; HIGH EXPRESSION; POOR-PROGNOSIS; GEMCITABINE; AG-013736 AB An improved understanding of the molecular biology involved in many solid tumors has led to the development of novel targeted agents. Axitinib is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases 1, 2, and 3. This review presents preclinical and clinical data available for axitinib, including findings from key phase II clinical trials in a wide variety of tumors including melanomas and renal, pancreatic, thyroid, breast, lung, and colorectal carcinomas. The differences between axitinib and other VEGFR inhibitors are explored and details of the possible use of blood pressure elevation and erythropoietin blood levels as predictive markers of VEGF/VEGFR pathway inhibition are outlined. Ongoing Phase III studies in pancreatic and metastatic renal cell carcinoma should help to determine the optimum utilization of these agents at the appropriate stage of disease. C1 [Rixe, Olivier] Univ Cincinnati, Coll Med, Div Hematol Oncol, Cincinnati, OH 45267 USA. [Kelly, Ronan J.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Rixe, O (reprint author), Univ Cincinnati, Coll Med, Div Hematol Oncol, 231 Albert Sabin Way ML 0562, Cincinnati, OH 45267 USA. EM olivier.rixe@uc.edu NR 49 TC 38 Z9 39 U1 2 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1776-2596 EI 1776-260X J9 TARGET ONCOL JI Target. Oncol. PD DEC PY 2009 VL 4 IS 4 BP 297 EP 305 DI 10.1007/s11523-009-0126-9 PG 9 WC Oncology SC Oncology GA 524WQ UT WOS:000272175500006 PM 19876699 ER PT J AU Gray, TR LaGasse, LL Smith, LM Derauf, C Grant, P Shah, R Arria, AM Della Grotta, SA Strauss, A Haning, WF Lester, BM Huestis, MA AF Gray, Teresa R. LaGasse, Linda L. Smith, Lynne M. Derauf, Chris Grant, Penny Shah, Rizwan Arria, Amelia M. Della Grotta, Sheri A. Strauss, Arthur Haning, William F. Lester, Barry M. Huestis, Marilyn A. TI Identification of Prenatal Amphetamines Exposure by Maternal Interview and Meconium Toxicology in the Infant Development, Environment and Lifestyle (IDEAL) Study SO THERAPEUTIC DRUG MONITORING LA English DT Article DE prenatal drug exposure; amphetamines; cannabis; tobacco; meconium ID MEDITERRANEAN CITY; AMNIOTIC-FLUID; DRUG-USE; METHAMPHETAMINE; PREGNANCY; COCAINE; IMMUNOASSAY; ABUSE AB The Infant Development Environment and Lifestyle study is investigating the effects of prenatal methamphetamine (MAMP) exposure on infant and child development; potential concurrent exposure to cannabis and tobacco also are evaluated. Maternal self-reported drug use and/or meconium toxicology results defined drug exposure status. It is unclear how the frequency, duration, and magnitude of maternal MAMP exposure affect qualitative and quantitative meconium results. Interviews regarding maternal drug use were collected shortly after birth; meconium specimens were screened for amphetamines, cannabis, and cotinine by immunoassay and confirmed by gas chromatography mass spectrometry The majority of MAMP- and cannabis-exposed infants were identified by maternal interview alone. Meconium tests were more likely to be positive if the mother reported MAMP and cannabis use, particularly in the third trimester. Less than half of immunoassay-positive amphetamines (31.0%) and cannabis (17.9%) meconium results were confirmed by gas chromatography mass spectrometry. Tobacco exposure was equally detected by immunoassay cotinine screening and maternal report. Meconium concentrations did not correlate with maternal self-report status or trimester of use or frequency or route of MAMP use. Maternal self-report was more sensitive than meconium testing for identifying MAMP and cannabis-exposed neonates; however, the timing of drug exposure may influence meconium toxicology results. Most women stopped MAMP and cannabis use before the third trimester. In the first trimester, meconium has not yet formed, and based on our recent results for opiates and cocaine, drug use in the second trimester appears to be poorly reflected in meconium. Low confirmation rates in meconium reinforce the need for confirmatory testing following positive screening results and additional research to identify alternative biomarkers. C1 [Gray, Teresa R.; Huestis, Marilyn A.] NIDA, NIH, Baltimore, MD USA. [LaGasse, Linda L.; Della Grotta, Sheri A.; Lester, Barry M.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Smith, Lynne M.] Harbor UCLA Med Ctr, Los Angeles Biomed Inst, Torrance, CA 90509 USA. [Derauf, Chris; Haning, William F.] Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. [Grant, Penny] Univ Oklahoma, Tulsa, OK USA. [Shah, Rizwan] Blank Childrens Hosp Iowa Hlth, Des Moines, IA USA. [Arria, Amelia M.] Univ Maryland, College Pk, MD 20742 USA. [Strauss, Arthur] Long Beach Mem Med Ctr, Long Beach, CA USA. RP Huestis, MA (reprint author), 251 Bayview Blvd,Suite 200,05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov OI Arria, Amelia/0000-0002-6360-9265 FU Intramural Research Program; National Institute on Drug Abuse; National Institutes of Health; IDEAL [NIDA R01DA014948] FX This research was funded by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health (TR.G., M.A.H.), and IDEAL grant NIDA R01DA014948. NR 19 TC 22 Z9 22 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD DEC PY 2009 VL 31 IS 6 BP 769 EP 775 PG 7 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 527BW UT WOS:000272342200017 PM 19935364 ER PT J AU Glauser, BF Rezendel, RM Melo, FR Pereira, MS Francischetti, IMB Monteiro, RQ Rezaie, AR Mourao, PAS AF Glauser, Bianca F. Rezendel, Ricardo M. Melo, Fabio R. Pereira, Mariana S. Francischetti, Ivo M. B. Monteiro, Robson Q. Rezaie, Alireza R. Mourao, Paulo A. S. TI Anticoagulant activity of a sulfated galactan: Serpin-independent effect and specific interaction with factor Xa SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Antithrombotic drug; heparin; heparin-binding exosite; prothrombinase complex; sulfated galactan; tenase complex ID HEPARIN-BINDING EXOSITE; MOLECULAR-WEIGHT HEPARIN; ALGAE BOTRYOCLADIA-OCCIDENTALIS; CONTAMINATED HEPARIN; ANTITHROMBIN-III; ALPHA-THROMBIN; COFACTOR-II; ACTIVATION; INHIBITION; FUCANS AB An algal sulfated galactan has high anticoagulant and antithrombotic activities. Its serpin-dependent anticoagulant action is due to promoting thrombin and factor (F)Xa inhibition by antithrombin and heparin cofactor II. Here, we evaluated the anticoagulant effect of the algal sulfated galactan using serpin-free plasma. In contrast to heparin, the sulfated galactan is still able to prolong coagulation time and delay thrombin and FXa generation in serpin-free plasma. We further investigated this effect using purified blood coagulation proteins, discovering that sulfated galactan inhibits the intrinsic tenase and prothrombinase complexes, which are critical for FXa and thrombin generation, respectively. We also investigated the mechanism by which sulfated galactan promotes FXa inhibition by antithrombin using specific recombinant mutants of the protease. We show that sulfated galactan interacts with the heparin-binding exosite of FXa and Arg-236 and Lys-240 of this site are critical residues for this interaction, as observed for heparin. Thus, sulfated galactan and heparin have similar high-affinity and specificity for interaction with FXa, though they have differences in their chemical structures. Similar to heparin, the ability of sulfated galactan to potentiate FXa inhibition by antithrombin is calcium-dependent. However, in contrast to heparin, this effect is not entirely dependent on the conformation of the gamma-carboxyglutamic acid-rich domain of the protease. In conclusion, sulfated galactan and heparin have some similar effects on blood coagulation, but also differ significantly at the molecular level. This sulfated galactan opens new perspective for the development of antithrombotic drugs. C1 [Glauser, Bianca F.; Rezendel, Ricardo M.; Melo, Fabio R.; Pereira, Mariana S.; Mourao, Paulo A. S.] Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Lab Tecido Conjunt, Rio De Janeiro, Brazil. [Glauser, Bianca F.; Monteiro, Robson Q.; Mourao, Paulo A. S.] Univ Fed Rio de Janeiro, Inst Bioquim Med, Rio De Janeiro, Brazil. [Pereira, Mariana S.] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Rio De Janeiro, Brazil. [Francischetti, Ivo M. B.] NIAID, Sect Med Entomol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Rezaie, Alireza R.] St Louis Univ, Sch Med, Edward A Doisy Dept Biochem & Mol Biol, St Louis, MO 63104 USA. RP Mourao, PAS (reprint author), Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Lab Tecido Conjunt, Cidade Univ, Rio De Janeiro, Brazil. EM pmourao@hucff.ufrj.br RI Inbeb, Inct/K-2317-2013; Monteiro, Robson/B-8007-2014; Sa Pereira, Mariana/C-2211-2015 FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) [HL-62565] FX This work was supported by grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) and HL-62565 (ARR). We would like to thank Adriana A. Piquet for technical assistance. NR 33 TC 11 Z9 12 U1 0 U2 3 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD DEC PY 2009 VL 102 IS 6 BP 1183 EP 1193 DI 10.1160/TH09-04-0273 PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 535MR UT WOS:000272973700024 PM 19967150 ER PT J AU Cheng, SY Ringel, MD AF Cheng, Sheue-Yann Ringel, Matthew D. TI Frontiers in Thyroid Cancer: December 2009 SO THYROID LA English DT Editorial Material C1 [Cheng, Sheue-Yann] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ringel, Matthew D.] Ohio State Univ, Coll Med, Arthur G James Comprehens Canc Ctr, Div Endocrinol, Columbus, OH 43210 USA. [Ringel, Matthew D.] Ohio State Univ, Coll Med, Arthur G James Comprehens Canc Ctr, Div Oncol, Columbus, OH 43210 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37,Rm 5128 37 Convent Dr,MSC 4264, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov NR 9 TC 5 Z9 5 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD DEC PY 2009 VL 19 IS 12 BP 1297 EP 1298 DI 10.1089/thy.2009.1612 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 531TX UT WOS:000272692900001 PM 20001712 ER PT J AU Kim, CS Zhu, XG AF Kim, Caroline S. Zhu, Xuguang TI Lessons from Mouse Models of Thyroid Cancer SO THYROID LA English DT Review ID HORMONE-BETA-RECEPTOR; POORLY DIFFERENTIATED CARCINOMAS; TISSUE-SPECIFIC EXPRESSION; ATHYMIC NUDE-MICE; PHASE-II TRIAL; TRANSGENIC MICE; PAPILLARY CARCINOMAS; GENETIC ALTERATIONS; TUMOR PROGRESSION; RET/PTC1 ONCOGENE AB Background: Thyroid cancer is the most common endocrine tumor and is increasing in incidence. The aim of this study was to review mouse models of differentiated thyroid cancer and how they elucidate human thyroid cancer biology. Summary: Differentiated thyroid cancer, primarily papillary and follicular, comprises the majority of thyroid cancers. There has been tremendous growth in the cross-talk between basic science and clinical practice for thyroid cancer management. Insight into the framework of genes responsible for differentiated thyroid cancer has been gained through the use of mouse models. Common genetic alterations found in human papillary thyroid cancer such as RET/PTC rearrangements or the BRAF(V600E) mutation have genetically modified mouse counterparts. These and other preclinical mouse models have validated the importance of the cyclic adenosine monophosphate (cAMP)/protein kinase A and mitogen-activated protein kinase (MAPK) signaling pathways in papillary thyroid cancer (PTC). RAS mutations have a role in both papillary and follicular thyroid cancer development. Mice with overactivation of the phosphatidylinol-3-kinase (PI3K)-AKT and/or thyrotropin-regulated signaling pathways have been found to develop follicular thyroid cancer. Additional mouse models of thyroid cancer that utilize inducible expression systems are in development or are being characterized and will better reflect the majority of human thyroid cancers which are non-hereditary. Advances in in vivo imaging of mice allow for earlier detection of metastasis and the ability to follow tumor growth or regression which may be used in evaluation of pharmaceutical agents. Conclusions: Mouse models have expanded our understanding of the altered signaling pathways that contribute to thyroid cancer tumorigenesis and provide a powerful tool to develop novel diagnostic approaches and therapies. C1 [Zhu, Xuguang] NCI, Mol Biol Lab, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Kim, Caroline S.] Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA USA. [Kim, Caroline S.] Tufts Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA USA. RP Zhu, XG (reprint author), NCI, Mol Biol Lab, NIH, Ctr Canc Res, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM xzhu@mail.nih.gov FU Thyroid, Head and Neck Cancer Foundation/American Thyroid Association; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported in part by a grant from the Thyroid, Head and Neck Cancer Foundation/American Thyroid Association (to C. S. K.) and the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (to X.Z.). The authors regret any reference omissions due to length restrictions. NR 105 TC 21 Z9 21 U1 0 U2 11 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD DEC PY 2009 VL 19 IS 12 BP 1317 EP 1331 DI 10.1089/thy.2009.1609 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 531TX UT WOS:000272692900004 PM 20001715 ER PT J AU Vriens, MR Suh, I Moses, W Kebebew, E AF Vriens, Menno R. Suh, Insoo Moses, Willieford Kebebew, Electron TI Clinical Features and Genetic Predisposition to Hereditary Nonmedullary Thyroid Cancer SO THYROID LA English DT Article ID FAMILIAL ADENOMATOUS POLYPOSIS; FINE-NEEDLE-ASPIRATION; C-CELL HYPERPLASIA; SUSCEPTIBILITY LOCUS; GERMLINE MUTATIONS; RET PROTOONCOGENE; GARDNERS-SYNDROME; LINKAGE ANALYSIS; CARCINOMA; TUMORS AB Background: Approximately 5% of the nonmedullary thyroid cancers are hereditary. Hereditary nonmedullary thyroid cancer may occur as a minor component of familial cancer syndromes (familial adenomatous polyposis, Gardner's syndrome, Cowden's disease, Carney's complex type 1, Werner's syndrome, and papillary renal neoplasia) or as a primary feature (familial nonmedullary thyroid cancer [FNMTC]). The goal of this article was to review our current knowledge on the hereditary nonmedullary thyroid cancer. Summary: Epidemiologic and clinical kindred studies have demonstrated that FNMTC is a unique clinical entity. Most studies suggest that FNMTC is associated with more aggressive disease than sporadic cases, with higher rates of multicentric tumors, lymph node metastasis, extrathyroidal invasion, and shorter disease-free survival. A hereditary predisposition to nonmedullary thyroid cancer is well established, but the susceptibility genes for isolated FNMTC have not been identified. However, additional susceptibility loci for FNMTC have been recently identified in classic isolated cases of FNMTC (1q21, 6q22, 8p23.1-p22, and 8q24). Conclusions: More studies are needed to validate chromosomal susceptibility loci and identify the susceptibility genes for FNMTC. The discovery of the predisposing genes may allow for screening and early diagnosis, which could lead to improved outcomes for patients and their families. C1 [Kebebew, Electron] NCI, Endocrine Surg Sect, Surg Branch, CRC, Bethesda, MD 20892 USA. [Vriens, Menno R.; Suh, Insoo; Moses, Willieford] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. RP Kebebew, E (reprint author), NCI, Endocrine Surg Sect, Surg Branch, CRC, Room 4-5952 10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov NR 59 TC 42 Z9 50 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD DEC PY 2009 VL 19 IS 12 BP 1343 EP 1349 DI 10.1089/thy.2009.1607 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 531TX UT WOS:000272692900006 PM 20001717 ER PT J AU Williams, R Chen, YF Endres, R Middleton, D Trucco, M Williams, JD Knowler, W AF Williams, R. Chen, Y. -F. Endres, R. Middleton, D. Trucco, M. Williams, J. Dunn Knowler, W. TI Molecular variation at the HLA-A, B, C, DRB1, DQA1, and DQB1 loci in full heritage American Indians in Arizona: private haplotypes and their evolution SO TISSUE ANTIGENS LA English DT Article DE Pima; private alleles; restricted variation; Tohono O'odham; transplantation ID ASHI MINORITY WORKSHOPS; CLASS-I POLYMORPHISM; PIMA-INDIANS; DIABETES-MELLITUS; GENETIC ADMIXTURE; NATIVE-AMERICANS; ALPHA-2 HELIX; ALLELES; POPULATION; FREQUENCY AB A sample of 492 full heritage, unrelated residents of the Gila River Indian Community (GRIC) of Arizona were characterized for their high-resolution DNA alleles at the HLA-A, B, C, DRB1, DQA1, and DQB1 loci. Only five allelic categories are found at HLA-A, 10 at HLA-B, 8 at HLA-C and HLA-DR, and 4 at DQA1 and DQB1. There is little evidence for population structure at the 6 loci. Two 'private' alleles, B*5102 and B*4005, which are found nearly exclusively in American Indian populations in the desert southwest and northern Mexico, are likely new mutations after the first inhabitation of the area, the evolution of which are reflected in the contemporary distribution of their respective haplotypes. DRB1*1402 has the highest reported frequency of any specificity at the DRB1 locus, 0.7461, and serves as a sensitive probe for locating related east Asian populations. The haplotypes in this population also exhibit a highly restricted distribution and strong genetic disequilibria, which has important implications for matching solid organ and bone marrow allografts. It is shown that, when one considers HLA-A-B-DRB1 homozygotes as allograft donors for all full heritage members of the GRIC, 50% of the community would find a non-mismatched organ within the homozygotes for the six most common haplotypes. This raises questions about transplantation policy and whether, in the presence of high-frequency private alleles and a restricted number of haplotypes, the full heritage American Indian community of the desert southwest should act as its own pool of donors for its affected members. C1 [Williams, R.; Knowler, W.] Inst Diabet & Digest & Kidney Dis, NIH, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Chen, Y. -F.] Tzu Chi Univ, Hualien, Taiwan. [Endres, R.; Williams, J. Dunn] Blood Syst Labs, HLA Lab, Tempe, AZ USA. [Middleton, D.] Royal Liverpool & Broadgreen Univ Hosp, Liverpool, Merseyside, England. [Trucco, M.] Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15261 USA. RP Williams, R (reprint author), NIDDK, NIH, Diabet Epidemiol & Clin Res Sect, 1550 E Indian Sch Rd, Phoenix, AZ USA. EM williamsr@mail.nih.gov FU Blood Systems Foundation [BSF45-3, BSF45-4]; Blood Systems, Inc., Scottsdale, Arizona; NIDDK FX We thank the members of the Gila River Indian Community for their cooperation and participation in this study, and we thank the staff of the Diabetes Epidemiology and Clinical Research Section, NIDDK, for conducting the examinations. This research was partially supported by grants BSF45-3 and BSF45-4 from Blood Systems Foundation, Blood Systems, Inc., Scottsdale, Arizona and by the Intramural Research Program of the NIDDK. NR 53 TC 3 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD DEC PY 2009 VL 74 IS 6 BP 520 EP 533 DI 10.1111/j.1399-0039.2009.01381.x PG 14 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 517VL UT WOS:000271646900008 PM 19845915 ER PT J AU Ramaswamy, S Greco, JB Uluer, MC Zhang, ZJ Zhang, ZL Fishbein, KW Spencer, RG AF Ramaswamy, Sharan Greco, Jane B. Uluer, Mehmet C. Zhang, Zijun Zhang, Zhuoli Fishbein, Kenneth W. Spencer, Richard G. TI Magnetic Resonance Imaging of Chondrocytes Labeled with Superparamagnetic Iron Oxide Nanoparticles in Tissue-Engineered Cartilage SO TISSUE ENGINEERING PART A LA English DT Article ID MESENCHYMAL STEM-CELLS; IN-VIVO TRACKING; HOLLOW-FIBER BIOREACTOR; PROGENITOR CELLS; T-CELLS; DIFFERENTIATION; TRANSPLANTATION; CONSTRUCTS; MICROSCOPY; AGENTS AB The distribution of cells within tissue-engineered constructs is difficult to study through nondestructive means, such as would be required after implantation. However, cell labeling with iron-containing particles may prove to be a useful approach to this problem, because regions containing such labeled cells have been shown to be readily detectable using magnetic resonance imaging (MRI). In this study, we used the Food and Drug Administration-approved superparamagnetic iron oxide (SPIO) contrast agent Feridex in combination with transfection agents to label chondrocytes and visualize them with MRI in two different tissue-engineered cartilage constructs. Correspondence between labeled cell spatial location as determined using MRI and histology was established. The SPIO-labeling process was found not to affect the phenotype or viability of the chondrocytes or the production of major cartilage matrix constituents. We believe that this method of visualizing and tracking chondrocytes may be useful in the further development of tissue engineered cartilage therapeutics. C1 [Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, Gerontol Res Ctr, NIH,Lab Clin Invest, Baltimore, MD 21224 USA. [Uluer, Mehmet C.; Zhang, Zijun] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. RP Spencer, RG (reprint author), NIA, Magnet Resonance Imaging & Spect Sect, Gerontol Res Ctr, NIH,Lab Clin Invest, Room 4D-06,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM spencer@helix.nih.gov OI Fishbein, Kenneth/0000-0002-6353-4603 FU National Institutes of Health, National Institute on Aging FX We acknowledge Robert Wersto for performing flow cytometry analyses and Stephanie Leen for performing biochemical assays. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 49 TC 31 Z9 34 U1 1 U2 19 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC PY 2009 VL 15 IS 12 BP 3899 EP 3910 DI 10.1089/ten.tea.2008.0677 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 529OZ UT WOS:000272528400021 PM 19788362 ER PT J AU Tindle, HA Shiffman, S Hartman, AM Bost, JE AF Tindle, H. A. Shiffman, S. Hartman, A. M. Bost, J. E. TI Switching to "lighter" cigarettes and quitting smoking SO TOBACCO CONTROL LA English DT Article ID LUNG CARCINOGENS; TAR CIGARETTES; SMOKERS; NICOTINE; BRAND; ABSTINENCE; CESSATION; INDUSTRY; BELIEFS; YIELD AB Objective: Smokers who switch to "lighter" cigarettes may be diverted from quitting smoking. We assessed factors associated with switching and the association between switching and (1) making a quit attempt, and (2) recent quitting, yielding a measure of net quitting (attempts x recent quitting). Design: In 2003, a total of 30 800 ever-smokers who smoked in the past year provided history of switching and 3 reasons for switching: harm reduction, quitting smoking and flavour. Among those who made a past-year quit attempt, recent quitting was defined as >= 90-day abstinence when surveyed. Multivariable logistic regression identified determinants of outcomes. Results: In all, 12 009 (38%) of ever-smokers switched. Among switchers, the most commonly cited reasons were flavour only (26%) and all 3 reasons (18%). Switchers (vs non-switchers) were more likely to make a quit attempt between 2002 and 2003 (51% vs 41%, p<0.001, adjusted odds ratio (AOR) 1.58, (95% confidence interval (CI) 1.48 to 1.69)), but less likely to have recently quit (9% vs 17%, p<0.001; AOR 0.40 (95% CI 0.35 to 0.45)), yielding lower overall net quitting (4.3% vs 7.0%, p<0.001; AOR 0.54, (95% CI 0.47 to 0.61)). The effects of switching on outcomes were most pronounced for reasons including quitting smoking, whereas switching for harm reduction alone had no association with outcomes. Conclusion: Compared with no switching, a history of switching was associated with 46% lower odds of net quitting. C1 [Tindle, H. A.] Univ Pittsburgh, Ctr Res Hlth Care, Pittsburgh, PA USA. [Hartman, A. M.] NCI, Bethesda, MD 20892 USA. RP Tindle, HA (reprint author), 230 McKee Pl,Suite 600, Pittsburgh, PA 15213 USA. EM tindleha@upmc.edu RI Shiffman, Saul/K-7337-2012 FU National Center for Research Resources (NCRR); National Institutes of Health (NIH); NIH Roadmap for Medical Research [KL2 RR024154-03] FX This publication was made possible by a grant from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research (KL2 RR024154-03 to HAT). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on the NCRR is available at http://www.ncrr.nih.gov/.Information on re-engineering the clinical research enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp. NR 35 TC 9 Z9 9 U1 1 U2 3 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PD DEC PY 2009 VL 18 IS 6 BP 485 EP 490 DI 10.1136/tc.2008.029314 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 526IC UT WOS:000272280400019 PM 19892697 ER PT J AU Hoenerhoff, MJ Hong, HH Ton, TV Lahousse, SA Sills, RC AF Hoenerhoff, Mark J. Hong, Hue Hua Ton, Tai-vu Lahousse, Stephanie A. Sills, Robert C. TI A Review of the Molecular Mechanisms of Chemically Induced Neoplasia in Rat and Mouse Models in National Toxicology Program Bioassays and Their Relevance to Human Cancer SO TOXICOLOGIC PATHOLOGY LA English DT Review DE animal models; cancer; carcinogenesis; genotoxins/non-genotoxins; toxicologic pathology; rodent pathology; risk identification ID BETA-CATENIN MUTATIONS; HUMAN HEPATOCELLULAR CARCINOMAS; HUMAN-MALIGNANT MESOTHELIOMA; SQUAMOUS-CELL CARCINOMAS; MICE FOLLOWING EXPOSURE; SPORADIC BREAST-CANCER; GROWTH-FACTOR RECEPTOR; HUMAN LUNG-CANCER; PLUS UVA PUVA; ETHYLENE-OXIDE AB Tumor response in the B6C3F1 mouse, F344 rat, and other animal models following exposure to various compounds provides evidence that people exposed to these or similar compounds may be at risk for developing cancer. Although tumors in rodents and humans are often morphologically similar, underlying mechanisms of tumorigenesis are often unknown and may be different between the species. Therefore, the relevance of an animal tumor response to human health would be better determined if the molecular pathogenesis were understood. The underlying molecular mechanisms leading to carcinogenesis are complex and involve multiple genetic and epigenetic events and other factors. To address the molecular pathogenesis of environmental carcinogens, the authors examine rodent tumors (e.g., lung, colon, mammary gland, skin, brain, mesothelioma) for alterations in cancer genes and epigenetic events that are associated with human cancer. National Toxicology Program (NTP) studies have identified several genetic alterations in chemically induced rodent neoplasms that are important in human cancer. Identification of such alterations in rodent models of chemical carcinogenesis caused by exposure to environmental contaminants, occupational chemicals, and other compounds lends further support that they are of potential human health risk. These studies also emphasize the importance of molecular evaluation of chemically induced rodent tumors for providing greater public health significance for NTP evaluated compounds. C1 [Hoenerhoff, Mark J.; Hong, Hue Hua; Ton, Tai-vu; Lahousse, Stephanie A.; Sills, Robert C.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Hoenerhoff, MJ (reprint author), NIEHS, Cellular & Mol Pathol Branch, 111 TW Alexander Dr, Durham, NC 27519 USA. EM hoenerhm@mail.nih.gov FU NIH, National Institute of Environmental Health Sciences FX We thank the many toxicologists, pathologists, and NTP/NIEHS staff who contributed to this research. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 155 TC 18 Z9 18 U1 1 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD DEC PY 2009 VL 37 IS 7 BP 835 EP 848 DI 10.1177/0192623309351726 PG 14 WC Pathology; Toxicology SC Pathology; Toxicology GA 529YQ UT WOS:000272555800002 PM 19846892 ER PT J AU Nyska, A Cunningham, M Snell, M Malarkey, D Sutton, D Dunnick, J AF Nyska, Abraham Cunningham, Michael Snell, Michael Malarkey, David Sutton, D. Dunnick, June TI The Pivotal Role of Electron Microscopic Evaluation in Investigation of the Cardiotoxicity of bis(2-chloroethoxy)methane in Rats and Mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE cardiotoxicity; evaluation techniques; bis(2-chloroethoxy)methane (CEM) ID MITOCHONDRIAL; DAMAGE AB Electron microscopy and light microscopy have been used to evaluate the cardiotoxicity of bis(2-chloroethoxy)methane (CEM) in F344/N rats and B6C3F1 mice. Rats received vehicle control or CEM at 50 mg/kg/day, and mice, vehicle control or CEM at doses up to 100 mg/kg/day, by oral gavage for up to sixteen days. Cardiotoxicity in rats at 50 mg/kg consisted of myocardial degeneration, including myocardial inflammation, myofiber vacuolation, and/or myofiber necrosis. There was no light microscopic evidence for cardiotoxicity in mice even at doses twice that of rats, but cardiotoxic damage was seen after electron microscopic evaluations including mitochondrial disintegration and vacuolation. Mice with mitochondrial damage may be more susceptible to subsequent cardiotoxic events and have a reduced capacity to respond when energy demands increase. Oral treatment of rats with CEM caused cardiotoxic lesions similar to those reported after dermal administration (Dunnick, Johnson, et al. 2004). The F344/N rat is more sensitive than the B6C3F1 Mouse to the cardiotoxic effects of CEM. C1 [Dunnick, June] NIEHS, Lab Expt Pathol, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Dunnick, J (reprint author), NIEHS, Lab Expt Pathol, Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM nyska@niehs.nih.gov; dunnickj@niehs.nih.gov FU National Institute of Environmental Health Sciences Intramural Program, Research Triangle Park, NC FX We thank Dr. Mark Cesta, NIEHS, and Dr. Deepa Rao, NIEHS, for their excellent review of the manuscript. This work was supported by the National Institute of Environmental Health Sciences Intramural Program, Research Triangle Park, NC. NR 18 TC 3 Z9 4 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD DEC PY 2009 VL 37 IS 7 BP 873 EP 877 DI 10.1177/0192623309347908 PG 5 WC Pathology; Toxicology SC Pathology; Toxicology GA 529YQ UT WOS:000272555800005 PM 19770349 ER PT J AU Yoshizawa, K Brix, AE Sells, DM Jokinen, MP Wyde, M Orzech, DP Kissling, GE Walker, NJ Nyska, A AF Yoshizawa, Katsuhiko Brix, Amy E. Sells, Donald M. Jokinen, Micheal P. Wyde, Michael Orzech, Denis P. Kissling, Grace E. Walker, Nigel J. Nyska, Abraham TI Reproductive Lesions in Female Harlan Sprague-Dawley Rats Following Two-Year Oral Treatment with Dioxin and Dioxin-like Compounds SO TOXICOLOGIC PATHOLOGY LA English DT Article DE carcinogenesis; carcinoma; dioxin; rat; squamous cell carcinoma; squamous metaplasia; uterus ID ARYL-HYDROCARBON RECEPTOR; TOXIC EQUIVALENCY FACTORS; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN TCDD; POLYCHLORINATED-BIPHENYLS; ESTROGEN-RECEPTOR; RETINOIC ACID; UTERINE ADENOCARCINOMA; NEONATAL EXPOSURE; PRENATAL EXPOSURE; DONRYU RATS AB Results from previously published animal studies suggest that prenatal and postnatal exposure to dioxin and dioxin-like compounds (DLCs) may profoundly affect the reproductive system of both sexes via endocrine disruption. In the present work, we evaluate the toxicity and carcinogenicity of various DLCs, with an emphasis on their effect on the reproductive organs, induced by chronic exposure of female adult Harlan Sprague-Dawley rats. This investigation represents part of an initiative of the National Toxicology Program to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins, furans, and biphenyls. For fourteen, thirty-one, or fifty-three weeks or for two years, animals were administered by gavage 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2',4,4',5,5'-Hexachlorobiphenyl (PCB153); 2,3',4,4',5-pentachlorobiphenyl (PCB118); a tertiary mixture of TCDD, PCB126, and PeCDF; a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and PCB118. The ranges of treatment-related changes in the reproductive system included chronic active inflammation in the ovary that occurred in the 1,000 and 3,000 mu g/kg core groups (two-year exposure) of PCB153 and in the 300 ng/3,000 mu g/kg core group of binary mixture of PCB126 and PCB153. Increases in the incidence of acute and/or chronic active inflammation of the uterus were observed in all dosed groups, including the stop-exposure group (withdrawal after thirty-week exposure) of PeCDF and the 1,000 mu g/kg and/or higher group dosed with PCB153. The incidence of cystic endometrial hyperplasia was marginally increased in the 92 PeCDF ng/kg group at two years. The incidence of squamous metaplasia was significantly increased in the 44 ng/kg and higher dose group, including the stop-exposure group. The incidence of uterine squamous cell carcinoma was significantly or marginally increased in the 6 ng/kg core and 100 ng/kg stop-exposure groups of TCDD and in the 300 ng/300 mu g/kg core group that received the binary Mixture of PCB126 and 153. The incidence of uterine carcinoma was marginally increased in the 92 ng/kg PeCDF group at two years and clearly increased in the 1,000 and 4,600 mu g/kg PCB118 core group and the 4,600 mu g/kg stop group. In the studies of PCB126, the tertiary mixture, and the binary mixture of PCB126 and PCB118, no increased incidence of any change occurred in the reproductive systems. The range of changes seen with the different Compounds suggests that more than one mechanism may have been involved in promoting the female reproductive pathology. C1 [Yoshizawa, Katsuhiko] Kansai Med Univ, Osaka, Japan. [Brix, Amy E.] Expt Pathol Labs EPL Inc, Res Triangle Pk, NC USA. [Sells, Donald M.] Battelle Mem Inst, Columbus Labs, Columbus, OH 43201 USA. [Jokinen, Micheal P.] Pathol Associates Inc, Durham, NC USA. [Wyde, Michael; Orzech, Denis P.; Walker, Nigel J.; Nyska, Abraham] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Nyska, A (reprint author), Haharuv 18,POB 184, IL-23840 Timrat, Israel. EM anyska@bezeqint.net RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 FU NIH, National Institute of Environmental Health Sciences FX The authors thank all involved in the design and conduct of these NTP studies, with special appreciation expressed to Drs. John Bucher, Angelique Braen, and Milton Hejtrnancik. We gratefully acknowledge Dr. Retha Newbold, Dr. Bhanu Singh, and Ms. JoAnne Johnson for critical review of the manuscript. The authors declare that they have no competing financial interests. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 92 TC 9 Z9 9 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD DEC PY 2009 VL 37 IS 7 BP 921 EP 937 DI 10.1177/0192623309351721 PG 17 WC Pathology; Toxicology SC Pathology; Toxicology GA 529YQ UT WOS:000272555800011 PM 19843953 ER PT J AU Arias-Loza, PA Muehlfelder, M Elmore, SA Maronpot, R Hu, K Blode, H Hegele-Hartung, C Fritzemeier, KH Ertl, G Pelzer, T AF Arias-Loza, Paula-Anahi Muehlfelder, Melanie Elmore, Susan A. Maronpot, Robert Hu, Kai Blode, Hartmut Hegele-Hartung, Christa Fritzemeier, Karl Heinrich Ertl, Georg Pelzer, Theo TI Differential Effects of 17 beta-Estradiol and of Synthetic Progestins on Aldosterone-Salt-Induced Kidney Disease SO TOXICOLOGIC PATHOLOGY LA English DT Article DE sex; aldosterone; renal injury; progesterone; sex hormones ID ESTROGEN RECEPTOR-BETA; II TYPE-2 RECEPTOR; HYPERTENSIVE-RATS; GENDER-DIFFERENCES; OXIDATIVE STRESS; TREATED RATS; MEDROXYPROGESTERONE ACETATE; PATHOPHYSIOLOGICAL ROLE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION AB Elevated mineralocorticoid levels and female sex hormones have been shown to confer opposing effects on renal injury, but their combined effects are still unknown. Objective: Identify the function of estrogens and of different synthetic progestins on aldosterone salt-mediated renal disease. Methods: The role of 17 beta-estradiol, medroxyprogesterone acetate (MPA), and drospirenone during renal injury was studied in Wistar rats subjected to uni-nephrectomy plus aldosterone salt treatment. Results: Aldo-salt treatment of intact, ovariectomized, and estradiol-treated female rats resulted in remnant kidney hypertrophy without structural damage. Co-treatment with MPA, but not with drospirenone, increased kidney hypertrophy, fluid turnover, sodium retention, and potassium excretion. Medroxyprogesterone acetate also caused glomerular, vascular, tubular, and interstitial lesions that were accompanied by increased blood pressure and enhanced NADPH oxidase (p67phox) and sodium channel (alpha-ENaC) expression, Drospirenone, a progestin with anti-mineralocorticoid function, and spironolactone prevented kidney hypertrophy, hypertension, and sodium retention. Drospirenone and spironolactone also increased renal angiotensin II type 2 receptor expression and relieved aldosterone-induced suppression of serum angiotensin II levels. Conclusion: The choice of specific synthetic progestins has profound implications on the development of kidney injury and renal gene expression under conditions of elevated aldosterone serum levels and salt intake. C1 [Arias-Loza, Paula-Anahi; Muehlfelder, Melanie; Hu, Kai; Ertl, Georg; Pelzer, Theo] Univ Wurzburg, Dept Med, D-97080 Wurzburg, Germany. [Elmore, Susan A.] NIEHS, Cellular & Mol Pathol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Maronpot, Robert] Maronpot Consulting LLC, Raleigh, NC USA. [Blode, Hartmut; Hegele-Hartung, Christa; Fritzemeier, Karl Heinrich] Schering AG, D-1000 Berlin, Germany. RP Pelzer, T (reprint author), Univ Wurzburg, Internal Med Dept ZIM, Oberdurrbacher Str 6, D-97080 Wurzburg, Germany. EM Pelzer_T@klinik.uni-wuerzburg.de FU Interdisciplinary Center for Clinical Research [Z4-70, E83-N]; NIH, National Institute of Environmental Health Sciences; Schering AG Berlin FX T. Pelzer received support from the Interdisciplinary Center for Clinical Research "IZKF" Wurzburg (Z4-70, E83-N). This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. T. Pelzer has received financial support toward the evaluation of novel steroid hormone receptor ligands from Schering AG Berlin. NR 49 TC 11 Z9 11 U1 2 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD DEC PY 2009 VL 37 IS 7 BP 969 EP 982 DI 10.1177/0192623309350475 PG 14 WC Pathology; Toxicology SC Pathology; Toxicology GA 529YQ UT WOS:000272555800015 PM 19841131 ER PT J AU Huang, RL Southall, N Xia, MG Cho, MH Jadhav, A Nguyen, DT Inglese, J Tice, RR Austin, CP AF Huang, Ruili Southall, Noel Xia, Menghang Cho, Ming-Hsuang Jadhav, Ajit Nguyen, Dac-Trung Inglese, James Tice, Raymond R. Austin, Christopher P. TI Weighted Feature Significance: A Simple, Interpretable Model of Compound Toxicity Based on the Statistical Enrichment of Structural Features SO TOXICOLOGICAL SCIENCES LA English DT Article DE modeling; toxicity prediction; structural features; cell viability; caspase-3; 7 activation; in vivo toxicity ID AUTOMATED STRUCTURE EVALUATION; BIOLOGICAL-ACTIVITY; CHEMICAL-STRUCTURE; CYTOTOXICITY ASSAYS; COVALENT BINDING; CARCINOGENICITY; PREDICTION; BIOACTIVATION; MUTAGENICITY; TOXICOLOGY AB In support of the U.S. Tox21 program, we have developed a simple and chemically intuitive model we call weighted feature significance (WFS) to predict the toxicological activity of compounds, based on the statistical enrichment of structural features in toxic compounds. We trained and tested the model on the following: (1) data from quantitative high-throughput screening cytotoxicity and caspase activation assays conducted at the National Institutes of Health Chemical Genomics Center, (2) data from Salmonella typhimurium reverse mutagenicity assays conducted by the U.S. National Toxicology Program, and (3) hepatotoxicity data published in the Registry of Toxic Effects of Chemical Substances. Enrichments of structural features in toxic compounds are evaluated for their statistical significance and compiled into a simple additive model of toxicity and then used to score new compounds for potential toxicity. The predictive power of the model for cytotoxicity was validated using an independent set of compounds from the U.S. Environmental Protection Agency tested also at the National Institutes of Health Chemical Genomics Center. We compared the performance of our WFS approach with classical classification methods such as Naive Bayesian clustering and support vector machines. In most test cases, WFS showed similar or slightly better predictive power, especially in the prediction of hepatotoxic compounds, where WFS appeared to have the best performance among the three methods. The new algorithm has the important advantages of simplicity, power, interpretability, and ease of implementation. C1 [Huang, Ruili; Southall, Noel; Xia, Menghang; Cho, Ming-Hsuang; Jadhav, Ajit; Nguyen, Dac-Trung; Inglese, James; Austin, Christopher P.] NIH, Dept Hlth & Human Serv, Chem Genom Ctr, Bethesda, MD 20892 USA. [Tice, Raymond R.] NIEHS, Dept Hlth & Human Serv, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27713 USA. RP Huang, RL (reprint author), NIH, Dept Hlth & Human Serv, Chem Genom Ctr, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM huangru@mail.nih.gov RI Southall, Noel/H-8991-2012; OI Southall, Noel/0000-0003-4500-880X; Nguyen, Dac-Trung/0000-0003-2591-9948 FU NIH [Y2-ES-7020-01, U54MH084681]; National Institute of Environmental Health Sciences; National Human Genome Research Institute FX Intramural Research Programs (NIH Interagency agreement #Y2-ES-7020-01) of the National Toxicology Program; National Institute of Environmental Health Sciences and the National Human Genome Research Institute; National Institutes of Health (NIH); and the NIH Roadmap for Medical Research Molecular Libraries Program (U54MH084681). NR 39 TC 14 Z9 14 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD DEC PY 2009 VL 112 IS 2 BP 385 EP 393 DI 10.1093/toxsci/kfp231 PG 9 WC Toxicology SC Toxicology GA 520FH UT WOS:000271825400012 PM 19805409 ER PT J AU Zhao, BZ Yin, JJ Bilski, PJ Chignell, CF Roberts, JE He, YY AF Zhao, Baozhong Yin, Jun-Jie Bilski, Piotr J. Chignell, Colin F. Roberts, Joan E. He, Yu-Ying TI Enhanced photodynamic efficacy towards melanoma cells by encapsulation of Pc4 in silica nanoparticles SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Photodynamic therapy; Nanoparticles; Melanoma; Phthalocyanine; Singlet oxygen; Apoptosis ID PHTHALOCYANINE PHOTOSENSITIZER PC-4; THERAPY-MEDIATED APOPTOSIS; SINGLET OXYGEN; CANCER-THERAPY; RADIOPROTECTIVE AGENT; PLASMA-MEMBRANE; CYTOCHROME-C; IN-VITRO; DELIVERY; DAMAGE AB Nanoparticles have been explored recently as an efficient means of delivering photosensitizers for cancer diagnosis and photodynamic therapy (PDT). Silicon phthalocyanine 4 (Pc4) is Currently being clinically tested as a photosensitizer for PDT. Unfortunately, Pc4 aggregates in aqueous solutions, which dramatically reduces its PDT efficacy and therefore limits its clinical application. We have encapsulated Pc4 using silica nanoparticles (Pc4SNP), which not only improved the aqueous solubility, stability, and delivery of the photodynamic drug but also increased its photodynamic efficacy compared to free Pc4 molecules. Pc4SNP generated photo-induced singlet oxygen more efficiently than free Pc4 as measured by chemical probe and EPR trapping techniques. Transmission electron microscopy and dynamic light scattering measurements showed that the size of the particles is in the range of 25-30 nm. Cell viability measurements demonstrated that Pc4SNP was more phototoxic to A375 or B16-F10 melanoma cells than free Pc4. Pc4SNP photodamaged melanoma cells primarily through apoptosis. Irradiation of A375 cells in the presence of Pc4SNP resulted in a significant increase in intracellular protein-derived peroxides, suggesting a Type II (singlet oxygen) mechanism for phototoxicity. More Pc4SNP than free Pc4 was localized in the mitochondria and lysosomes. Our results show that these stable, monodispersed silica nanoparticles may be an effective new formulation for Pc4 in its preclinical and clinical studies. We expect that modifying the surface of silicon nanoparticles encapsulating the photosensitizers with antibodies specific to melanoma cells will lead to even better early diagnosis and targeted treatment of melanoma in the future. (C) 2009 Elsevier Inc. All rights reserved. C1 [He, Yu-Ying] Univ Chicago, Dept Med, Dermatol Sect, Chicago, IL 60637 USA. [Zhao, Baozhong; Bilski, Piotr J.; Chignell, Colin F.] NIEHS, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. [Yin, Jun-Jie] Food & Drug Adm, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Roberts, Joan E.] Fordham Univ, Dept Nat Sci, Bronx, NY 10458 USA. RP He, YY (reprint author), Univ Chicago, Dept Med, Dermatol Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM yyhe@medicine.bsd.uchicago.edu RI Zhao, Baozhong/B-5865-2011; Yin, Jun Jie /E-5619-2014 FU NIH, National institute of Environmental Health Sciences; Department of Medicine and the Section of Dermatology at the University of Chicago; University of Chicago Cancer Research Center; CTSA FX This research was supported by the Intramural Research Program of the NIH, National institute of Environmental Health Sciences, the Department of Medicine and the Section of Dermatology at the University of Chicago, the University of Chicago Cancer Research Center, and the CTSA. The authors are indebted to Dr. Ann Motten, NIEHS, for critical reading of the manuscript and Dr. Carl Bortner and Maria Sifre for their assistance with flow cytometry. NR 54 TC 98 Z9 99 U1 4 U2 43 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD DEC 1 PY 2009 VL 241 IS 2 BP 163 EP 172 DI 10.1016/j.taap.2009.08.010 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 518SD UT WOS:000271712600005 PM 19695274 ER PT J AU Masilamani, M Peruzzi, G Borrego, F Coligan, JE AF Masilamani, Madhan Peruzzi, Giovanna Borrego, Francisco Coligan, John E. TI Endocytosis and Intracellular Trafficking of Human Natural Killer Cell Receptors SO TRAFFIC LA English DT Review DE NK cell receptors; endocytosis; intra-cellular trafficking ID HUMAN NK CELLS; CLATHRIN-INDEPENDENT ENDOCYTOSIS; PROTEIN-KINASE-C; CD8(+) T-CELLS; CD94/NKG2A INHIBITORY RECEPTOR; IFN-GAMMA PRODUCTION; TGF-BETA RECEPTOR; IG-LIKE RECEPTORS; FC-EPSILON-RI; DENDRITIC CELLS AB Natural killer (NK) cells play a vital role in the defense against viral infections and tumor development. NK cell function is primarily regulated by the sum of signals from a broad array of activation and inhibitory receptors. Key to generating the input level of either activating or inhibitory signals is the maintenance of receptor expression levels on the cell surface. Although the mechanisms of endocytosis and trafficking for some cell surface receptors, such as transferrin receptor and certain immune receptors, are very well known, that is not the situation for receptors expressed by NK cells. Recent studies have uncovered that endocytosis and trafficking routes characteristic for specific activation and inhibitory receptors can regulate the functional responses of NK cells. In this review, we summarize the current knowledge of receptor endocytosis and trafficking, and integrate this with our current understanding of NK cell receptor trafficking. C1 [Peruzzi, Giovanna; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Masilamani, Madhan] Mt Sinai Sch Med, Dept Pediat, Jaffe Food Allergy Inst, New York, NY 10029 USA. [Borrego, Francisco] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. RP Coligan, JE (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Twinbrook 2,Room 205,12441 Parklawn Dr, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov OI Peruzzi, Giovanna/0000-0002-6517-9107; Masilamani, Madhan/0000-0001-8181-8848 FU Division of Intramural Research, NIAID/NIH; Jaffe Food Allergy Institute, Mount Sinai School of Medicine FX This work is supported by funds from the Division of Intramural Research, NIAID/NIH to J. E. C., Intramural program, FDA to F. B. and by the Jaffe Food Allergy Institute, Mount Sinai School of Medicine to M. M. We would like to thank Dr Konrad Krzewski for his critical reading of the review. NR 173 TC 6 Z9 6 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD DEC PY 2009 VL 10 IS 12 BP 1735 EP 1744 DI 10.1111/j.1600-0854.2009.00973.x PG 10 WC Cell Biology SC Cell Biology GA 518ST UT WOS:000271714300002 PM 19719476 ER PT J AU Donaldson, JG Williams, DB AF Donaldson, Julie G. Williams, David B. TI Intracellular Assembly and Trafficking of MHC Class I Molecules SO TRAFFIC LA English DT Article DE antigen presentation; endocytosis; endoplasmic reticulum; membrane traffic; molecular chaperones; peptide loading complex; ubiquitylation ID COMPLEX CLASS-I; CLATHRIN-INDEPENDENT ENDOCYTOSIS; PEPTIDE-LOADING COMPLEX; NEGATIVE CELL-LINE; ENDOPLASMIC-RETICULUM; HISTOCOMPATIBILITY MOLECULES; RECYCLING PATHWAY; DOWN-REGULATION; QUALITY-CONTROL; ANTIGEN PRESENTATION AB The presentation of antigenic peptides by class I molecules of the major histocompatibility complex begins in the endoplasmic reticulum (ER) where the co-ordinated action of molecular chaperones, folding enzymes and class I-specific factors ensures that class I molecules are loaded with high-affinity peptide ligands that will survive prolonged display at the cell surface. Once assembled, class I molecules are released from the quality-control machinery of the ER for export to the plasma membrane where they undergo dynamic endocytic cycling and turnover. We review recent progress in our understanding of class I assembly, anterograde transport and endocytosis and highlight some of the events targeted by viruses as a means to evade detection by cytotoxic T cells and natural killer cells. C1 [Donaldson, Julie G.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Williams, David B.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. [Williams, David B.] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM jdonalds@helix.nih.gov; david.williams@utoronto.ca FU Canadian Cancer Society; Canadian Institutes of Health Research; Intramural Research Program of the National Heart, Lung and Blood Institute, NIH FX We thank Sebastian Springer for sharing unpublished work and apologize to colleagues whose work we were unable to cite because of length restrictions. DBW acknowledges support from the Canadian Cancer Society and the Canadian Institutes of Health Research. JGD is supported by the Intramural Research Program of the National Heart, Lung and Blood Institute, NIH. NR 71 TC 45 Z9 47 U1 1 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD DEC PY 2009 VL 10 IS 12 BP 1745 EP 1752 DI 10.1111/j.1600-0854.2009.00979.x PG 8 WC Cell Biology SC Cell Biology GA 518ST UT WOS:000271714300003 PM 19761542 ER PT J AU Popoff, V Mardones, GA Bai, SK Chambon, V Tenza, D Burgos, PV Shi, AB Benaroch, P Urbe, S Lamaze, C Grant, BD Raposo, G Johannes, L AF Popoff, Vincent Mardones, Gonzalo A. Bai, Siau-Kun Chambon, Valerie Tenza, Daniele Burgos, Patricia V. Shi, Anbing Benaroch, Philippe Urbe, Sylvie Lamaze, Christophe Grant, Barth D. Raposo, Graca Johannes, Ludger TI Analysis of Articulation Between Clathrin and Retromer in Retrograde Sorting on Early Endosomes SO TRAFFIC LA English DT Article DE Hrs; retrograde transport; retromer; RME-8; Shiga toxin ID TRANS-GOLGI NETWORK; MANNOSE 6-PHOSPHATE RECEPTORS; TYROSINE KINASE SUBSTRATE; TO-TGN TRANSPORT; J-DOMAIN PROTEIN; SHIGA TOXIN; MAMMALIAN RETROMER; EARLY/RECYCLING ENDOSOMES; B-FRAGMENT; TRAFFICKING AB Clathrin and retromer have key functions for retrograde trafficking between early endosomes and the trans-Golgi network (TGN). Previous studies on Shiga toxin suggested that these two coat complexes operate in a sequential manner. Here, we show that the curvature recognition subunit component sorting nexin 1 (SNX1) of retromer interacts with receptor-mediated endocytosis-8 (RME-8) protein, and that RME-8 and SNX1 colocalize on early endosomes together with a model cargo of the retrograde route, the receptor-binding B-subunit of Shiga toxin (STxB). RME-8 has previously been found to bind to the clathrin uncoating adenosine triphosphatase (ATPase) Hsc70, and we now report that depletion of RME-8 or Hsc70 affects retrograde trafficking at the early endosomes-TGN interface of STxB and the cation-independent mannose 6-phosphate receptor, an endogenous retrograde cargo protein. We also provide evidence that retromer interacts with the clathrin-binding protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) not only via SNX1, as previously published (Chin Raynor MC, Wei X, Chen HQ, Li L. Hrs interacts with sorting nexin 1 and regulates degradation of epidermal growth factor receptor. J Biol Chem 2001;276:7069-7078), but also via the core complex component Vps35. Hrs codistributes at the ultrastructural level with STxB on early endosomes, and interfering with Hrs function using antibodies or mild overexpression inhibits retrograde transport. Our combined data suggest a model according to which the functions in retrograde sorting on early endosomes of SNX1/retromer and clathrin are articulated by RME-8, and possibly also by Hrs. C1 [Popoff, Vincent; Bai, Siau-Kun; Chambon, Valerie; Lamaze, Christophe; Johannes, Ludger] Inst Curie, Ctr Rech, Traff Signaling & Delivery Lab, F-75248 Paris 05, France. [Popoff, Vincent; Bai, Siau-Kun; Chambon, Valerie; Tenza, Daniele; Lamaze, Christophe; Raposo, Graca; Johannes, Ludger] CNRS, UMR144, F-75700 Paris, France. [Mardones, Gonzalo A.; Burgos, Patricia V.] NICHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Tenza, Daniele; Raposo, Graca] Inst Curie, Ctr Rech, Struct & Membrane Compartments Lab, F-75248 Paris 05, France. [Shi, Anbing; Grant, Barth D.] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. [Benaroch, Philippe] INSERM, Curie UMR653, Lab Transport Intracellulaire & Immunite, F-75248 Paris 05, France. [Urbe, Sylvie] Univ Liverpool, Physiol Lab, Liverpool L69 3BX, Merseyside, England. RP Johannes, L (reprint author), Inst Curie, Ctr Rech, Traff Signaling & Delivery Lab, 26 Rue Ulm, F-75248 Paris 05, France. EM johannes@curie.fr OI Grant, Barth/0000-0002-5943-8336 FU Association pour la Recherche contre le Cancer [ARC 3143]; NICHD (NIH); BDI FX We thank Harald Stenmark, Michel Bornens, Peter McPherson, Kiyotoshi Sekiguchi, Pete Cullen, and Jean Salamero for reagents. This work was supported by a grant from Association pour la Recherche contre le Cancer (ARC 3143), the intramural program of NICHD (NIH), and a BDI fellowship to VP. NR 55 TC 53 Z9 53 U1 2 U2 9 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD DEC PY 2009 VL 10 IS 12 BP 1868 EP 1880 DI 10.1111/j.1600-0854.2009.00993.x PG 13 WC Cell Biology SC Cell Biology GA 518ST UT WOS:000271714300013 PM 19874558 ER PT J AU Baird, K Wayne, AS AF Baird, Kristin Wayne, Alan S. TI Extracorporeal photo-apheresis for the treatment of steroid-resistant graft versus host disease SO TRANSFUSION AND APHERESIS SCIENCE LA English DT Article ID TOLEROGENIC DENDRITIC CELLS; REGULATORY T-CELLS; TRANSPLANT RECIPIENTS; ALLOGRAFT-REJECTION; RECURRENT REJECTION; PROGNOSTIC-FACTORS; PEDIATRIC-PATIENTS; APOPTOTIC CELLS; CHRONIC GVHD; IN-VITRO AB Acute and chronic graft versus host disease are frequent and potentially severe complications of allogeneic hematopoietic stem cell transplantation and are among the leading causes of non-relapse transplant-related mortality. For patients with steroid refractory disease, prognosis is particularly poor and although a variety of treatment options are available, responses are commonly transient and the side effects often intolerable. Since it was first introduced for the treatment of cutaneous T-cell lymphoma, extracorporeal photo-apheresis has been utilized as an immunomodulatory, therapy for certain autoimmune diseases and solid organ transplant rejection. Recently, extracorporeal photo-apheresis has become a promising alternative for patients with graft versus host disease with disabling or potentially lethal complications. Here we review the experience of extracorporeal photo-apheresis for the treatment of steroid refractory acute and chronic graft versus host disease based on the current literature. Published by Elsevier Ltd. C1 [Baird, Kristin; Wayne, Alan S.] NCI, Pediat Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. RP Baird, K (reprint author), NCI, Pediat Oncol Branch, CCR, NIH, Bldg 10,Room 1W-3750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kbaird@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 65 TC 5 Z9 5 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1473-0502 J9 TRANSFUS APHER SCI JI Transfus. Apher. Sci. PD DEC PY 2009 VL 41 IS 3 BP 209 EP 216 DI 10.1016/j.transci.2009.09.007 PG 8 WC Hematology SC Hematology GA 528EC UT WOS:000272423200011 PM 19819186 ER PT J AU Clarke, LP Croft, BS Nordstrom, R Zhang, HM Kelloff, G Tatum, J AF Clarke, Laurence P. Croft, Barbara S. Nordstrom, Robert Zhang, Huiming Kelloff, Gary Tatum, J. TI Quantitative Imaging for Evaluation of Response to Cancer Therapy SO TRANSLATIONAL ONCOLOGY LA English DT Editorial Material ID ONCOLOGIC DRUG DEVELOPMENT; LUNG-CANCER; BIOMARKER; WORKSHOP; PROGRESS; PROMISE; PROJECT C1 [Clarke, Laurence P.; Croft, Barbara S.; Nordstrom, Robert; Zhang, Huiming; Kelloff, Gary; Tatum, J.] NCI, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. RP Clarke, LP (reprint author), Suite 6066,EPN 6130 Execut Blvd, Bethesda, MD 20892 USA. EM lclarke@mail.nih.gov RI Croft, Barbara/D-1248-2013 OI Croft, Barbara/0000-0003-2544-150X NR 19 TC 24 Z9 25 U1 0 U2 0 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD DEC PY 2009 VL 2 IS 4 BP 195 EP 197 DI 10.1593/tlo.09217 PG 3 WC Oncology SC Oncology GA 529XD UT WOS:000272551800001 PM 19956378 ER PT J AU Chakkera, HA Hanson, RL Raza, SM DiStefano, JK Millis, MP Heilman, RL Mulligan, DC Reddy, KS Mazur, MJ Hamawi, K Moss, AA Mekeel, KL Cerhan, JR AF Chakkera, H. A. Hanson, R. L. Raza, S. M. DiStefano, J. K. Millis, M. P. Heilman, R. L. Mulligan, D. C. Reddy, K. S. Mazur, M. J. Hamawi, K. Moss, A. A. Mekeel, K. L. Cerhan, J. R. TI Pilot Study: Association of Traditional and Genetic Risk Factors and New-Onset Diabetes Mellitus Following Kidney Transplantation SO TRANSPLANTATION PROCEEDINGS LA English DT Article ID GENOME-WIDE ASSOCIATION; TRANSCRIPTION-FACTOR-7-LIKE-2 TCF7L2 GENE; IMPAIRED GLUCOSE-TOLERANCE; RENAL-ALLOGRAFT RECIPIENTS; PANCREATIC BETA-CELL; INSULIN-RESISTANCE; COMMON VARIANTS; LIFE-STYLE; CYCLOSPORINE; TACROLIMUS AB Introduction. New-onset diabetes mellitus, which occurs after kidney transplant and type 2 diabetes mellitus (T2DM), shares common risk factors and antecedents in impaired insulin secretion and action. Several genetic polymorphisms have been shown to be associated with T2DM. We hypothesized that transplant recipients who carry risk alleles for T2DM are "tipped over" to develop diabetes mellitus in the posttransplant milieu. Methods. We investigated the association of genetic and traditional risk factors present before transplantation and the development of new-onset diabetes mellitus after kidney transplantation (NODAT). Markers in 8 known T2DM-linked genes were genotyped using either the iPLEX assay or allelic discrimination (AD)-PCR in the study cohort testing for association with NODAT. We used univariate and multivariate logistic regression models for the association of pretransplant nongenetic and genetic variables with the development of NODAT. Results. The study cohort included 91 kidney transplant recipients with at least 1 year posttransplant follow-up, including 22 who developed NODAT. We observed that increased age, family history of T2DM, pretransplant obesity, and triglyceridemia were associated with NODAT development. In addition, we observed positive trends, although statistically not significant, for association between T2DM-associated genes and NODAT. Conclusions. These findings demonstrated an increased NODAT risk among patient with a positive family history for T2DM, which, in conjunction with the observed positive predictive trends of known T2DM-associated genetic polymorphisms with NODAT, was Suggestive of a genetic predisposition to NODAT. C1 [Chakkera, H. A.; Hanson, R. L.; Mulligan, D. C.; Reddy, K. S.; Mazur, M. J.; Hamawi, K.; Moss, A. A.; Mekeel, K. L.] Mayo Clin, Div Transplantat Med, Phoenix, AZ 85259 USA. [DiStefano, J. K.; Millis, M. P.] Translat Genom Res Inst, Phoenix, AZ USA. [Heilman, R. L.] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Cerhan, J. R.] Mayo Clin, Div Epidemiol, Rochester, MN USA. RP Chakkera, HA (reprint author), Mayo Clin, Div Transplant Med, 5777 E Mayo Blvd, Phoenix, AZ 85259 USA. EM chakkera.harini@mayo.edu OI Cerhan, James/0000-0002-7482-178X FU Intramural NIH HHS [Z01 DK069096-01] NR 43 TC 15 Z9 15 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0041-1345 EI 1873-2623 J9 TRANSPL P JI Transplant. Proc. PD DEC PY 2009 VL 41 IS 10 BP 4172 EP 4177 DI 10.1016/j.transproceed.2009.08.063 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 535LD UT WOS:000272968800028 PM 20005362 ER PT J AU Tsai, CJ Ma, BY Nussinov, R AF Tsai, Chung-Jung Ma, Buyong Nussinov, Ruth TI Protein-protein interaction networks: how can a hub protein bind so many different partners? SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID ALTERNATIVE TRANSLATION INITIATION; SYSTEMS BIOLOGY APPROACH; SACCHAROMYCES-CEREVISIAE; FUNCTIONAL DIVERSITY; INTRINSIC DISORDER; HUMAN GENOME; CELL-CYCLE; RECOGNITION; SPECIFICITY; INSIGHTS AB How can a single hub protein bind so many different partners? Numerous studies have sought differences between hubs and non-hubs to explain what makes a protein a hub and how a shared hub-binding site can be promiscuous, yet at the same time be specific. Here, we suggest that the problem is largely non-existent and resides in the popular representation of protein interaction networks: protein products derived from a single gene, even if different, are clustered in maps into a single node. This leads to the impression that a single protein binds to a very large number of partners. In reality, it does not; rather, protein networks reflect the combination of multiple proteins, each with a distinct conformation. C1 [Tsai, Chung-Jung; Ma, Buyong; Nussinov, Ruth] NCI, Ctr Canc Res Nanobiol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Ctr Canc Res Nanobiol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU National Cancer Institute; National Institutes of Health [HHSN261200800001E]; NIH; Center for Cancer Research FX This project has been funded, in whole or in part, with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. This research was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 57 TC 67 Z9 69 U1 1 U2 18 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD DEC PY 2009 VL 34 IS 12 BP 594 EP 600 DI 10.1016/j.tibs.2009.07.007 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 533EY UT WOS:000272807700002 PM 19837592 ER PT J AU Palmer, DC Restifo, NP AF Palmer, Douglas C. Restifo, Nicholas P. TI Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function SO TRENDS IN IMMUNOLOGY LA English DT Review ID INDUCIBLE SH2 PROTEIN; GROWTH-HORMONE; IN-VIVO; DENDRITIC CELLS; PROTEASOMAL DEGRADATION; NEGATIVE REGULATION; ANTITUMOR IMMUNITY; HELPER-CELLS; HOMEOSTATIC PROLIFERATION; ADOPTIVE IMMUNOTHERAPY AB Cytokines are key modulators of T cell biology, but their influence can be attenuated by suppressors of cytokine signaling (SOCS), a family of proteins consisting of eight members, SOCS1-7 and CIS. SOCS proteins regulate cytokine signals that control the polarization of CD4(+) T cells into Th1, Th2, Th17, and T regulatory cell lineages, the maturation of CD8(+) T cells from naive to "stem-cell memory" (Tscm), central memory (Tcm), and effector memory (Tem) states, and the activation of these lymphocytes. Understanding how SOCS family members regulate T cell maturation, differentiation, and function might prove critical in improving adoptive immunotherapy for cancer and therapies aimed at treating autoimmune and infectious diseases. C1 [Palmer, Douglas C.; Restifo, Nicholas P.] NCI, NIH, Bethesda, MD 20892 USA. RP Palmer, DC (reprint author), NCI, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM palmerd@mail.nih.gov; restifon@mail.nih.gov RI Restifo, Nicholas/A-5713-2008; Palmer, Douglas/B-9454-2008; OI Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580 FU National Cancer Institute of the National Institutes of Health FX Research was supported by the intramural program of the National Cancer Institute of the National Institutes of Health. This article was written in partial fulfillment of a Phl) degree for the George Washington University, Washington, DC. The authors would like to thank Megan Bachinski, Lindsay Garvin, Robert Reger, and Dorina Frasheri for help with this manusciipt. We would also like to thank Alan Hoofting for his help with generation of the figures. NR 152 TC 116 Z9 124 U1 2 U2 20 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD DEC PY 2009 VL 30 IS 12 BP 592 EP 602 DI 10.1016/j.it.2009.09.009 PG 11 WC Immunology SC Immunology GA 531DS UT WOS:000272643500006 PM 19879803 ER PT J AU Barbey, AK Krueger, F Grafman, J AF Barbey, Aron K. Krueger, Frank Grafman, Jordan TI An evolutionarily adaptive neural architecture for social reasoning SO TRENDS IN NEUROSCIENCES LA English DT Review ID WASON SELECTION TASK; ROSTROLATERAL PREFRONTAL CORTEX; COGNITIVE NEUROSCIENCE; ORBITOFRONTAL CORTEX; DECISION-MAKING; MORAL JUDGMENT; HUMAN ALTRUISM; COOPERATION; SYSTEMS; DAMAGE AB Recent progress in cognitive neuroscience highlights the involvement of the prefrontal cortex (PFC) in social cognition. Accumulating evidence demonstrates that representations within the lateral PFC enable people to coordinate their thoughts and actions with their intentions to support goal-directed social behavior. Despite the importance of this region in guiding social interactions, remarkably little is known about the functional organization and forms of social inference processed by the lateral PFC. Here, we introduce a cognitive neuroscience framework for understanding the inferential architecture of the lateral PFC, drawing upon recent theoretical developments in evolutionary psychology and emerging neuroscience evidence about how this region can orchestrate behavior on the basis of evolutionarily adaptive social norms for obligatory, prohibited and permissible courses of action. C1 [Barbey, Aron K.; Krueger, Frank; Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Barbey, Aron K.] Georgetown Univ, Dept Psychol, Washington, DC 20057 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM GrafmanJ@ninds.nih.gov RI Barbey, Aron/L-7312-2015; OI Barbey, Aron/0000-0002-6092-0912; Grafman, Jordan H./0000-0001-8645-4457 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke FX The authors are supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. We are grateful to Lawrence W. Barsalou, Denise Cummins, Amita Srivastava and three anonymous reviewers for helpful comments on earlier drafts. NR 95 TC 32 Z9 32 U1 4 U2 12 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD DEC PY 2009 VL 32 IS 12 BP 603 EP 610 DI 10.1016/j.tins.2009.09.001 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 531DW UT WOS:000272643900001 PM 19782410 ER PT J AU Smith, JL Bu, W Burdick, RC Pathak, VK AF Smith, Jessica L. Bu, Wei Burdick, Ryan C. Pathak, Vinay K. TI Multiple ways of targeting APOBEC3-virion infectivity factor interactions for anti-HIV-1 drug development SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 REVERSE TRANSCRIPTION; E3 UBIQUITIN LIGASE; CD4(+) T-CELLS; CYTIDINE DEAMINASE APOBEC3G; AMINO-ACID-RESIDUES; VIF PROTEIN; ANTIVIRAL ACTIVITY; RETROVIRAL INFECTION; VIRAL INFECTIVITY AB HIV-1 infections and the resulting AIDS pandemic remain a global challenge in the absence of a protective vaccine and because of rapid selection of drug-resistant viral variants in response to all currently available antiviral therapies. The development of new and highly active antiviral agents would greatly facilitate effective clinical management of HIV-1 infections and delay the onset of AIDS. Recent advances in our understanding of intracellular immunity conferred by host cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F) and the mechanism by which the virally encoded virion infectivity factor (Vif) protein induces their proteasomal degradation provide fresh opportunities for the development of novel antiviral treatments. Interestingly, the Vif-A3G and Vif-A3F interactions that overcome this host defense mechanism are structurally distinct and provide two potential targets for antiviral drug development. This review provides an overview of current knowledge of APOBEC3-Vif interactions and recent efforts to target these interactions for antiviral drug development. C1 [Smith, Jessica L.; Bu, Wei; Burdick, Ryan C.; Pathak, Vinay K.] NCI, Viral Mutat Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Bu, Wei] SAIC Frederick, Frederick, MD 21702 USA. RP Pathak, VK (reprint author), NCI, Viral Mutat Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM vinay.pathak@nih.gov FU NIH National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E.] FX We especially thank Wei-Shau Hu, Eric Freed and Narasimhan J. Venkatachari for valuable critical comments during manuscript preparation. This research was supported in part by the Intramural Research Program of the NIH National Cancer Institute, Center for Cancer Research. This project was also funded in part by federal funds from the National Cancer Institute, National Institutes of Health under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 125 TC 34 Z9 36 U1 0 U2 7 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD DEC PY 2009 VL 30 IS 12 BP 638 EP 646 DI 10.1016/j.tips.2009.09.006 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 538YU UT WOS:000273221200006 PM 19837465 ER PT J AU Engmann, C Jehan, I Ditekemena, J Garces, A Phiri, M Mazariegos, M Chomba, E Pasha, O Tshefu, A Hemed, Y McClure, EM Thorsten, V Bann, C Goldenberg, RL Bose, C Setel, P Carlo, WA Wright, LL AF Engmann, C. Jehan, I. Ditekemena, J. Garces, A. Phiri, M. Mazariegos, M. Chomba, E. Pasha, O. Tshefu, A. Hemed, Y. McClure, E. M. Thorsten, V. Bann, C. Goldenberg, R. L. Bose, C. Setel, P. Carlo, W. A. Wright, L. L. TI Using verbal autopsy to ascertain perinatal cause of death: are trained non-physicians adequate? SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Article DE perinatal mortality; education; non-physicians; verbal autopsy ID 4-MILLION NEONATAL DEATHS; THE-TRAINER; TANZANIA; BURDEN; STILLBIRTH; COMMUNITY; COUNTRIES; MORTALITY; DISEASE; RATES AB OBJECTIVES To develop a standardized verbal autopsy (VA) training program and evaluate whether its implementation resulted in comparable knowledge required to classify perinatal cause of death (COD) by physicians and non-physicians. METHODS Training materials, case studies, and written and mock scenarios for this VA program were developed using conventional VA and ICD-10 guidelines. This program was used to instruct physicians and non-physicians in VA methodology using a train-the-trainer model. Written tests of cognitive and applied knowledge required to classify perinatal COD were administered before and after training to evaluate the effect of the VA training program. RESULTS Fifty-three physicians and non-physicians (nurse-midwives/nurses and Community Health Workers [CHW]) from Pakistan, Zambia, the Democratic Republic of Congo, and Guatemala were trained. Cognitive and applied knowledge mean scores among all trainees improved significantly (12.8 and 28.8% respectively, P < 0.001). Cognitive and applied knowledge post-training test scores of nurse-midwives/nurses were comparable to those of physicians. CHW (high-school graduates with 15 months or less formal health/nursing training) had the largest improvements in post-training applied knowledge with scores comparable to those of physicians and nurse-midwives/nurses. However, CHW cognitive knowledge post-training scores were significantly lower than those of physicians and nurses. CONCLUSIONS With appropriate training in VA, cognitive and applied knowledge required to determine perinatal COD is similar for physicians and nurses-midwives/nurses. This suggests that midwives and nurses may play a useful role in determining COD at the community level, which may be a practical way to improve the accuracy of COD data in rural, remote, geographic areas. C1 [Engmann, C.] Univ N Carolina, UNC Hosp, Sch Med, Dept Pediat,Div Neonatal Perinatal Med, Chapel Hill, NC 27599 USA. [Jehan, I.; Pasha, O.] Aga Khan Univ, Karachi, Pakistan. [Ditekemena, J.; Tshefu, A.] Kinshasa Sch Publ Hlth, Kinshasa, Congo. [Garces, A.; Mazariegos, M.] San Carlos Univ, IMSALUD, Guatemala City, Guatemala. [Phiri, M.; Chomba, E.] Univ Teaching Hosp, Lusaka, Zambia. [Hemed, Y.] MEASURE EVALUATION, Dar Es Salaam, Tanzania. [McClure, E. M.; Thorsten, V.; Bann, C.] Res Triangle Inst, Durham, NC USA. [Goldenberg, R. L.] Drexel Univ, Philadelphia, PA 19104 USA. [Setel, P.] Bill & Melinda Gates Fdn, Seattle, WA USA. [Carlo, W. A.] Univ Alabama Birmingham, Birmingham, AL USA. [Wright, L. L.] Eunice K Shriver Natl Inst Child Hlth & Human Dev, Bethesda, MD USA. RP Engmann, C (reprint author), Univ N Carolina, UNC Hosp, Sch Med, Dept Pediat,Div Neonatal Perinatal Med, CB 7596,4th Floor, Chapel Hill, NC 27599 USA. EM cengmann@med.unc.edu FU NICHD NIH HHS [U01 HD 40636, U01 HD040607, U01 HD040636] NR 32 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1360-2276 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD DEC PY 2009 VL 14 IS 12 BP 1496 EP 1504 DI 10.1111/j.1365-3156.2009.02395.x PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 516FH UT WOS:000271526900011 PM 19799757 ER PT J AU Lee, W Krisko, A Shetty, A Yeo, L Hassan, SS Gotsch, F Mody, S Goncalves, LF Romero, R AF Lee, W. Krisko, A. Shetty, A. Yeo, L. Hassan, S. S. Gotsch, F. Mody, S. Goncalves, L. F. Romero, R. TI Non-invasive fetal lung assessment using diffusion-weighted imaging SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE diffusion-weighted imaging; fetus; lung; magnetic resonance imaging ID PRELIMINARY EXPERIENCE; IN-VIVO; COEFFICIENT; MRI; BRAIN; DIAGNOSIS; KIDNEYS AB Objectives The main goal was to develop a reproducible method for estimating the diffusion of water in human fetal lung tissue using diffusion-weighted imaging (DWI). A secondary objective was to determine the relationship of the apparent diffusion coefficients (ADCs) in the fetal lung to menstrual age and total lung volume. Methods Normal pregnant volunteers were scanned on a 1.5-Tesla (T) magnetic resonance imaging (MRI) system. The MRI system was equipped with 40-mT/m gradients (slew rate 200 T/m/s, rise time 0.2 ms). A six-channel body array coil was used for signal reception. Single-shot DWI utilized TE/TR 125/3400 ms, slice thickness 4 mm, field of view 280 mm x 280 mm, interstice gap 0.8 mm and a matrix of 128 x 128. The voxel size was 2.5 mm x 2.5 mm x 4.0 mm. Two b-values (0 and 1000) were chosen along three orthogonal directions. ADC maps were created using assigned b-values. Simple linear regression was performed with Pearson correlation coefficient. Interexaminer and intraexaminer bias, and 95% limits of agreement (LOA) were determined using Bland-Altman plots. Results Forty-seven scans were performed at a mean +/- SD of 29.2 +/- 4.5 weeks. The median coefficient of variation for A DC was 5.6% (interquartile range, 4.0-8.1%). No differences in A DC values were found between right and left lungs. Normally distributed ADC measurements were not significantly correlated with either total lung volume (r(2) = 0.0001, P = 0.94) or menstrual age (r(2) = 0.003, P = 0.70). The mean ADC value was 1.75 (95% CI, 1.63-1.86). Mean +/- SD intraexaminer bias was -0.15 +/- 2.3 (95% LOA, -4.7 to +4.4) and interexaminer bias was 2.2 +/- 3.5 (95% LOA, -4.7 to +9.1). Conclusions Our findings suggest that ADC measurements of the fetal lung are reproducible between blinded examiners and are independent of menstrual age, as well as lung volume. Copyright (C) 2009 ISUOG. Published by John Wiley & Sons, Ltd. C1 [Lee, W.; Krisko, A.] William Beaumont Hosp, Div Fetal Imaging, Dept Obstet & Gynecol, Royal Oak, MI 48073 USA. [Shetty, A.] William Beaumont Hosp, Res Inst, Dept Diagnost Radiol, Royal Oak, MI 48073 USA. [Lee, W.; Yeo, L.; Hassan, S. S.; Gotsch, F.; Goncalves, L. F.; Romero, R.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Lee, W.; Yeo, L.; Hassan, S. S.; Goncalves, L. F.; Romero, R.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Mody, S.] Wayne State Univ, Dept Pediat Imaging, Detroit, MI 48202 USA. [Romero, R.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48202 USA. RP Lee, W (reprint author), William Beaumont Hosp, Div Fetal Imaging, Dept Obstet & Gynecol, 3601 W 13 Mile Rd, Royal Oak, MI 48073 USA. EM wlee@beaumont.edu FU Intramural NIH HHS [Z99 HD999999] NR 21 TC 3 Z9 4 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD DEC PY 2009 VL 34 IS 6 BP 673 EP 677 DI 10.1002/uog.7446 PG 5 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 536XR UT WOS:000273077700011 PM 19859908 ER PT J AU Schwan, TG Raffel, SJ Schrumpf, ME Gill, JS Piesman, J AF Schwan, Tom G. Raffel, Sandra J. Schrumpf, Merry E. Gill, James S. Piesman, Joseph TI Characterization of a Novel Relapsing Fever Spirochete in the Midgut, Coxal Fluid, and Salivary Glands of the Bat Tick Carios kelleyi SO VECTOR-BORNE AND ZOONOTIC DISEASES LA English DT Article DE Borrelia; Relapsing fever; Vector-borne ID BORRELIA-TURICATAE; ACARI; ARGASIDAE; RICKETTSIA; PROTEINS; FLORIDA; TEXAS; DOGS AB Bat ticks, Carios kelleyi, from Iowa were examined for the presence of relapsing fever group borreliae. A novel spirochete was characterized by DNA sequence analysis of polymerase chain reaction amplicons for the 16S rRNA, flaB, and glpQ genes in either triturated tick pools or single ticks. All loci and the concatenated DNA sequence of 3,289 bases identified the Carios bacterium as a relapsing fever spirochete most closely related to, but distinct from, Borrelia turicatae. Spirochetes reactive with a Borrelia-specific monoclonal antibody were observed microscopically in the coxal fluid and salivary glands from one tick. These data confirm the presence of a novel species of relapsing fever spirochete in bat ticks and the potential for new enzootic foci for endemic relapsing fever that warrants further investigation. The name Borrelia johnsonii is proposed for this novel spirochete in honor of Dr. Russell C. Johnson. C1 [Schwan, Tom G.; Raffel, Sandra J.; Schrumpf, Merry E.] NIAID, Rocky Mt Labs, NIH, Lab Zoonot Pathogens, Hamilton, MT 59840 USA. [Gill, James S.] Iowa State Univ, Dept Vet Microbiol & Prevent Med, Ames, IA USA. [Piesman, Joseph] Ctr Dis Control & Prevent, Ft Collins, CO USA. RP Schwan, TG (reprint author), NIAID, Rocky Mt Labs, NIH, Lab Zoonot Pathogens, 903 S 4th St, Hamilton, MT 59840 USA. EM tschwan@niaid.nih.gov FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX We thank A. Snyder for collecting the ticks used in our study and Gary Hettrick for help with the figures. This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 34 TC 8 Z9 8 U1 1 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-3667 J9 VECTOR-BORNE ZOONOT JI Vector-Borne Zoonotic Dis. PD DEC PY 2009 VL 9 IS 6 BP 643 EP 647 DI 10.1089/vbz.2008.0177 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 530GE UT WOS:000272576300011 PM 19281412 ER PT J AU Keefe, LM Moro, MH Vinasco, J Hill, C Wu, CC Raizman, EA AF Keefe, Lisa M. Moro, Manuel H. Vinasco, Javier Hill, Catherine Wu, Ching C. Raizman, Eran A. TI The Use of Harvested White-Tailed Deer (Odocoileus virginianus) and Geographic Information System (GIS) Methods to Characterize Distribution and Locate Spatial Clusters of Borrelia burgdorferi and Its Vector Ixodes scapularis in Indiana SO VECTOR-BORNE AND ZOONOTIC DISEASES LA English DT Article DE Borrelia burgdorferi; Ixodes scapularis; GIS; White-tailed deer; SaTScan ID LYME-DISEASE SPIROCHETE; UNITED-STATES; IXODIDAE; ACARI; EPIDEMIOLOGY; COLLECTIONS; ABUNDANCE; DAMMINI; CLIMATE AB Ixodes scapularis (Say) is the vector for Borrelia burgdorferi (Bb) the causative agent of Lyme disease (LD). The increased number and presence of ticks in the environment pose a significant health risk to people and many domestic animals including dogs, cats, and horses. This study characterized the distribution and expansion of I. scapularis and Bb and identified areas of increased risk of LD transmission in Indiana using geographical information systems (GIS) and spatial analysis. A cross-sectional sampling was performed for 3 consecutive years (2005-2007). A total of 3,412 harvested white-tailed deer (Odocoileus virginianus) were searched for ticks at Department of Natural Resources manned deer check-in stations. Hunters were asked for verbal permission to search the deer and to indicate on a road atlas where the deer was killed. All deer points were digitized into a GIS database. Identification of clustering in space and time for these organisms was performed using geostatistical software. Multiple spatial clusters of I. scapularis-infested deer were identified in western Indiana. B. burgdorferi was isolated from tick pools in 11 counties. In addition to the I. scapularis clusters, one spatial cluster of Bb-infected ticks was identified. Our current survey results and cluster analysis indicate that the western geographic regions of Indiana should be considered by the healthcare community to be at increased risk of LD compared with the rest of Indiana. C1 [Keefe, Lisa M.; Wu, Ching C.; Raizman, Eran A.] Purdue Univ, Sch Vet Med, Dept Comparat Pathobiol, W Lafayette, IN 47907 USA. [Moro, Manuel H.] NIH, Div Comparat Med, Natl Ctr Res Resources, Bethesda, MD 20892 USA. [Vinasco, Javier] Kansas State Univ, Coll Vet Med, Dept Diagnost Med Pathobiol, Manhatan, KS USA. [Hill, Catherine] Purdue Univ, Sch Agr, Dept Entomol, W Lafayette, IN 47907 USA. RP Raizman, EA (reprint author), Purdue Univ, Sch Vet Med, Dept Comparat Pathobiol, 725 Harrison St, W Lafayette, IN 47907 USA. EM eraizman@purdue.edu NR 37 TC 4 Z9 4 U1 2 U2 18 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-3667 J9 VECTOR-BORNE ZOONOT JI Vector-Borne Zoonotic Dis. PD DEC PY 2009 VL 9 IS 6 BP 671 EP 680 DI 10.1089/vbz.2008.0162 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 530GE UT WOS:000272576300015 PM 19272000 ER PT J AU He, J Kraft, AJ Fan, JA Van Dyke, M Wang, LH Bose, ME Khanna, M Metallo, JA Henrickson, KJ AF He, Jie Kraft, Andrea J. Fan, Jiang Van Dyke, Meredith Wang, Lihua Bose, Michael E. Khanna, Marilyn Metallo, Jacob A. Henrickson, Kelly J. TI Simultaneous Detection of CDC Category "A" DNA and RNA Bioterrorism Agents by Use of Multiplex PCR & RT-PCR Enzyme Hybridization Assays SO VIRUSES-BASEL LA English DT Review DE Multiplex PCR; simultaneous detection; Variola major; Bacillus anthracis; Yersinia pestis; Francisella tularensis; Ebola virus; Lassa fever virus; Rift Valley Fever virus; Hantavirus; dengue virus ID REVERSE TRANSCRIPTION-PCR; POLYMERASE CHAIN-REACTION; NUCLEIC-ACID EXTRACTION; BACILLUS-ANTHRACIS; DENGUE VIRUS; RAPID DETECTION; FRANCISELLA-TULARENSIS; SYBR GREEN; DIAGNOSIS; PLASMID AB Assays to simultaneously detect multiple potential agents of bioterrorism are limited. Two multiplex PCR and RT-PCR enzyme hybridization assays (mPCR-EHA, mRT-PCR-EHA) were developed to simultaneously detect many of the CDC category "A" bioterrorism agents. The "Bio T" DNA assay was developed to detect: Variola major (VM), Bacillus anthracis (BA), Yersinia pestis (YP), Francisella tularensis (FT) and Varicella zoster virus (VZV). The "Bio T" RNA assay (mRT-PCR-EHA) was developed to detect: Ebola virus (Ebola), Lassa fever virus (Lassa), Rift Valley fever (RVF), Hantavirus Sin Nombre species (HSN) and dengue virus (serotypes 1-4). Sensitivity and specificity of the 2 assays were tested by using genomic DNA, recombinant plasmid positive controls, RNA transcripts controls, surrogate (spiked) clinical samples and common respiratory pathogens. The analytical sensitivity (limit of detection (LOD)) of the DNA asssay for genomic DNA was 1x10(0)similar to 1x10(2) copies/mL for BA, FT and YP. The LOD for VZV whole organism was 1x10(-2) TCID(50)/mL. The LOD for recombinant controls ranged from 1x10(2)similar to 1x10(3)copies/mL for BA, FT, YP and VM. The RNA assay demonstrated LOD for RNA transcript controls of 1x10(4)similar to 1x10(6) copies/mL without extraction and 1x10(5)similar to 1x10(6) copies/mL with extraction for Ebola, RVF, Lassa and HSN. The LOD for dengue whole organisms was similar to 1x10(-4) dilution for dengue 1 and 2, 1x10(4) LD(50)/mL and 1x10(2) LD(50)/mL for dengue 3 and 4. The LOD without extraction for recombinant plasmid DNA controls was similar to 1x10(3) copies/mL (1.5 input copies/reaction) for Ebola, RVF, Lassa and HSN. No cross-reactivity of primers and probes used in both assays was detected with common respiratory pathogens or between targeted analytes. Clinical sensitivity was estimated using 264 surrogate clinical samples tested with the BioT DNA assay and 549 samples tested with the BioT RNA assay. The clinical specificity is 99.6% and 99.8% for BioT DNA assay and BioT RNA assay, respectively. The surrogate sensitivities of these two assays were 100% (95% CI 83-100) for FT, BA (pX02), YP, VM, VZV, dengue 2,3,4 and 95% (95% CI 75-100) for BA (pX01) and dengue 1 using spiked clinical specimens. The specificity of both BioT multiplex assays on spiked specimens was 100% (95% CI 99-100). Compared to other available assays (culture, serology, PCR, etc.) both the BioT DNA mPCR-EHA and BioT RNA mRT-PCR-EHA are rapid, sensitive and specific assays for detecting many category "A" Bioterrorism agents using a standard thermocycler. C1 [He, Jie; Kraft, Andrea J.; Fan, Jiang; Van Dyke, Meredith; Wang, Lihua; Bose, Michael E.; Metallo, Jacob A.; Henrickson, Kelly J.] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Khanna, Marilyn] NIH, Bethesda, MD 20892 USA. [Henrickson, Kelly J.] Childrens Hosp Wisconsin, Childrens Res Inst, Milwaukee, WI 53201 USA. RP Henrickson, KJ (reprint author), Med Coll Wisconsin, Dept Pediat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM jhe@mcw.edu; akraft@mcw.edu; jfan@mcw.edu; mvandyke@mcw.edu; lwang@mcw.edu; mbose@mcw.edu; khannama@niaid.nih.gov; jmetallo@mcw.edu; khenrick@mcw.edu FU NIAID [U01-AI654374, U01-AI066584] FX This work was supported by NIAID grant U01-AI654374 and U01-AI066584. NR 38 TC 18 Z9 19 U1 2 U2 18 PU MDPI AG PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD DEC PY 2009 VL 1 IS 3 BP 441 EP 459 DI 10.3390/v1030441 PG 19 WC Virology SC Virology GA 632HL UT WOS:000280413200005 PM 20224751 ER PT J AU Fabris, D Marino, JP Le Grice, SFJ AF Fabris, Daniele Marino, John P. Le Grice, Stuart F. J. TI Revisiting Plus-Strand DNA Synthesis in Retroviruses and Long Terminal Repeat Retrotransposons: Dynamics of Enzyme: Substrate Interactions SO VIRUSES-BASEL LA English DT Review DE retroviruses; LTR-retrotransposons; polypurine tract; plus strand DNA synthesis; NMR spectroscopy; single molecule spectroscopy; antiviral strategies ID HIV-1 REVERSE-TRANSCRIPTASE; HUMAN-IMMUNODEFICIENCY-VIRUS; H PRIMER GRIP; POLYPURINE TRACT SELECTION; RNASE-H; ANGSTROM RESOLUTION; MASS-SPECTROMETRY; CRYSTAL-STRUCTURE; RNA/DNA HYBRIDS; PACKAGING SIGNAL AB Although polypurine tract (PPT)-primed initiation of plus-strand DNA synthesis in retroviruses and LTR-containing retrotransposons can be accurately duplicated, the molecular details underlying this concerted series of events remain largely unknown. Importantly, the PPT 3' terminus must be accommodated by ribonuclease H (RNase H) and DNA polymerase catalytic centers situated at either terminus of the cognate reverse transcriptase (RT), and in the case of the HIV-1 enzyme, similar to 70 angstrom apart. Communication between RT and the RNA/DNA hybrid therefore appears necessary to promote these events. The crystal structure of the HIV-1 RT/PPT complex, while informative, positions the RNase H active site several bases pairs from the PPT/U3 junction, and thus provides limited information on cleavage specificity. To fill the gap between biochemical and crystallographic approaches, we review a multidisciplinary approach combining chemical probing, mass spectrometry, NMR spectroscopy and single molecule spectroscopy. Our studies also indicate that nonnucleoside RT inhibitors affect enzyme orientation, suggesting initiation of plus-strand DNA synthesis as a potential therapeutic target. C1 [Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. [Fabris, Daniele] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Catonsville, MD 21228 USA. [Marino, John P.] Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. [Marino, John P.] NIST, Rockville, MD 20850 USA. RP Le Grice, SFJ (reprint author), NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. EM legrices@mail.nih.gov FU National Institutes of Health [GM643208, GM59107]; National Science Foundation [CHE-0439067]; National Cancer Institute, National Institutes of Health FX D.F. is supported by grants from the National Institutes of Health (GM643208) and the National Science Foundation (CHE-0439067) and J.P.M. by National Institutes of Health grant GM59107. S.F.J.L.G. is supported by the intramural research program of the National Cancer Institute, National Institutes of Health. Certain commercial equipment, instruments, and materials are identified in this paper in order to specify the experimental procedure. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the material or equipment identified is necessarily the best available for the purpose. NR 48 TC 3 Z9 3 U1 0 U2 1 PU MDPI AG PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD DEC PY 2009 VL 1 IS 3 BP 657 EP 677 DI 10.3390/v1030657 PG 21 WC Virology SC Virology GA 632HL UT WOS:000280413200015 PM 21994564 ER PT J AU Xiao, XD Chen, WZ Feng, Y Dimitrov, DS AF Xiao, Xiaodong Chen, Weizao Feng, Yang Dimitrov, Dimiter S. TI Maturation Pathways of Cross-Reactive HIV-1 Neutralizing Antibodies SO VIRUSES-BASEL LA English DT Article DE germline; antibody; immune responses; HIV; escape; vaccine ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; BINDING-SITE; GLYCOPROTEIN; GP120; EPITOPE; LIBRARY; GP41; 2G12; IDENTIFICATION AB Several human monoclonal antibodies (hmAbs) and antibody fragments, including the best characterized in terms of structure-function b12 and Fab X5, exhibit relatively potent and broad HIV-1 neutralizing activity. However, the elicitation of b12 or b12-like antibodies in vivo by vaccine immunogens based on the HIV-1 envelope glycoprotein (Env) has not been successful. B12 is highly divergent from the closest corresponding germline antibody while X5 is less divergent. We have hypothesized that the relatively high degree of specific somatic hypermutations may preclude binding of the HIV-1 envelope glycoprotein (Env) to closest germline antibodies, and that identifying antibodies that are intermediates in the pathways to maturation could help design novel vaccine immunogens to guide the immune system for their enhanced elicitation. In support of this hypothesis we have previously found that a germline-like b12 (monovalent and bivalent scFv as an Fc fusion protein or IgG) lacks measurable binding to an Env as measured by ELISA with a sensitivity in the mu M range [1]; here we present evidence confirming and expanding these findings for a panel of Envs. In contrast, a germline-like scFv X5 bound Env with high (nM) affinity. To begin to explore the maturation pathways of these antibodies we identified several possible b12 intermediate antibodies and tested their neutralizing activity. These intermediate antibodies neutralized only some HIV-1 isolates and with relatively weak potency. In contrast, germline-like scFv X5 neutralized a subset of the tested HIV-1 isolates with comparable efficiencies to that of the mature X5. These results could help explain the relatively high immunogenicity of the coreceptor binding site on gp120 and the abundance of CD4-induced (CD4i) antibodies in HIV-1-infected patients (X5 is a CD4i antibody) as well as the maturation pathway of X5. They also can help identify antigens that can bind specifically to b12 germline and intermediate antibodies that together with Envs could be used as a conceptually novel type of candidate vaccines. Such candidate vaccines based on two or more immunogens could help guiding the immune system through complex maturation pathways for elicitation of antibodies that are similar or identical to antibodies with known properties. C1 [Xiao, Xiaodong; Chen, Weizao; Feng, Yang; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. RP Xiao, XD (reprint author), NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. EM xiaox@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; Gates Foundation FX We thank Christopher Broder, Gerald Quinnan, Barton Haynes, Dennis Burton and Tim Fouts for providing reagents, Igor Sidorov and the members of our group Zhongyu Zhu and John Owens for help. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by the Gates Foundation to DSD. NR 31 TC 35 Z9 36 U1 0 U2 2 PU MDPI AG PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD DEC PY 2009 VL 1 IS 3 BP 802 EP 817 DI 10.3390/v1030802 PG 16 WC Virology SC Virology GA 632HL UT WOS:000280413200022 PM 21994570 ER PT J AU Arnold, MM Patton, JT AF Arnold, Michelle M. Patton, John T. TI Rotavirus Antagonism of the Innate Immune Response SO VIRUSES-BASEL LA English DT Review DE rotavirus; NSP1; interferon regulatory factor; IRF ID INTERFERON REGULATORY FACTOR-3; INTESTINAL EPITHELIAL-CELLS; HOST-RANGE RESTRICTION; GROUP-A ROTAVIRUS; PLASMACYTOID DENDRITIC CELLS; VIRAL DIARRHEA VIRUS; SWINE-FEVER VIRUS; BOVINE ROTAVIRUS; PROTEASOMAL DEGRADATION; EXTRAINTESTINAL SPREAD AB Rotavirus is a primary cause of severe dehydrating gastroenteritis in infants and young children. The virus is sensitive to the antiviral effects triggered by the interferon (IFN)-signaling pathway, an important component of the host cell innate immune response. To counteract these effects, rotavirus encodes a nonstructural protein (NSP1) that induces the degradation of proteins involved in regulating IFN expression, such as members of the IFN regulatory factor (IRF) family. In some instances, NSP1 also subverts IFN expression by causing the degradation of a component of the E3 ubiquitin ligase complex responsible for activating NF-kappa B. By antagonizing multiple components of the IFN-induction pathway, NSP1 aids viral spread and contributes to rotavirus pathogenesis. C1 [Arnold, Michelle M.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 50 S Dr MSC 8026,Room 6314, Bethesda, MD 20892 USA. EM arnoldm@niaid.nih.gov; jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 FU National Institute of Allergy and Infectious Diseases at the National Institutes of Health FX We thank Kristen Guglielmi and Sarah McDonald for critical review of this manuscript. M.M.A. and J.T.P. are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. NR 113 TC 9 Z9 9 U1 1 U2 6 PU MDPI AG PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD DEC PY 2009 VL 1 IS 3 BP 1035 EP 1056 DI 10.3390/v1031035 PG 22 WC Virology SC Virology GA 632HL UT WOS:000280413200034 PM 21994581 ER PT J AU Gertz, EM Sengupta, K Difilippantonio, MJ Ried, T Schaffer, AA AF Gertz, E. Michael Sengupta, Kundan Difilippantonio, Michael J. Ried, Thomas Schaeffer, Alejandro A. TI Evaluating annotations of an Agilent expression chip suggests that many features cannot be interpreted SO BMC GENOMICS LA English DT Article ID GENE; INFORMATION; SEQUENCES; PROFILES; DATABASE; IDENTIFICATION; CELLS; NCBI AB Background: While attempting to reanalyze published data from Agilent 4 x 44 human expression chips, we found that some of the 60-mer olignucleotide features could not be interpreted as representing single human genes. For example, some of the oligonucleotides align with the transcripts of more than one gene. We decided to check the annotations for all autosomes and the X chromosome systematically using bioinformatics methods. Results: Out of 42683 reporters, we found that 25505 (60%) passed all our tests and are considered "fully valid". 9964 (23%) reporters did not have a meaningful identifier, mapped to the wrong chromosome, or did not pass basic alignment tests preventing us from correlating the expression values of these reporters with a unique annotated human gene. The remaining 7214 (17%) reporters could be associated with either a unique gene or a unique intergenic location, but could not be mapped to a transcript in RefSeq. The 7214 reporters are further partitioned into three different levels of validity. Conclusion: Expression array studies should evaluate the annotations of reporters and remove those reporters that have suspect annotations. This evaluation can be done systematically and semiautomatically, but one must recognize that data sources are frequently updated leading to slightly changing validation results over time. C1 [Gertz, E. Michael; Schaeffer, Alejandro A.] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med,DHHS, Bethesda, MD 20892 USA. [Sengupta, Kundan; Difilippantonio, Michael J.; Ried, Thomas] NCI, Sect Canc Genom, Genet Branch, Ctr Canc Res,NIH,DHHS, Bethesda, MD 20892 USA. RP Gertz, EM (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med,DHHS, Bethesda, MD 20892 USA. EM gertz@ncbi.nlm.nih.gov; senguptak@mail.nih.gov; difilipm@mail.nih.gov; riedt@mail.nih.gov; schaffer@ncbi.nlm.nih.gov RI Schaffer, Alejandro/F-2902-2012; OI Gertz, E. Michael/0000-0001-8390-4387 FU NIH, NLM; NIH, NCI FX This research was supported by the Intramural Research Program of the NIH, NLM (EMG, AAS) and by the Intramural Research Program of the NIH, NCI (KS, MJD, TR). NR 22 TC 9 Z9 9 U1 0 U2 0 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 NOV 30 PY 2009 VL 10 AR 566 DI 10.1186/1471-2164-10-566 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 533AC UT WOS:000272792300001 PM 19948035 ER PT J AU Guan, ZQ Hughes, CM Kosiyatrakul, S Norio, P Sen, R Fiering, S Allis, CD Bouhassira, EE Schildkraut, CL AF Guan, Zeqiang Hughes, Christina M. Kosiyatrakul, Settapong Norio, Paolo Sen, Ranjan Fiering, Steven Allis, C. David Bouhassira, Eric E. Schildkraut, Carl L. TI Decreased replication origin activity in temporal transition regions SO JOURNAL OF CELL BIOLOGY LA English DT Article ID HEAVY-CHAIN LOCUS; DNA-REPLICATION; GENOME-WIDE; CELLS; ACTIVATION; DOMAINS; VISUALIZATION; TRANSCRIPTION; ORGANIZATION; EXPRESSION AB In the mammalian genome, early-and late-replicating domains are often separated by temporal transition regions (TTRs) with novel properties and unknown functions. We identified a TTR in the mouse immunoglobulin heavy chain (Igh) locus, which contains replication origins that are silent in embryonic stem cells but activated during B cell development. To investigate which factors contribute to origin activation during B cell development, we systematically modified the genetic and epigenetic status of the endogenous Igh TTR and used a single-molecule approach to analyze DNA replication. Introduction of a transcription unit into the Igh TTR, activation of gene transcription, and enhancement of local histone modifications characteristic of active chromatin did not lead to origin activation. Moreover, very few replication initiation events were observed when two ectopic replication origin sequences were inserted into the TTR. These findings indicate that the Igh TTR represents a repressive compartment that inhibits replication initiation, thus maintaining the boundaries between early and late replication domains. C1 [Guan, Zeqiang; Kosiyatrakul, Settapong; Norio, Paolo; Bouhassira, Eric E.; Schildkraut, Carl L.] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Hughes, Christina M.; Allis, C. David] Rockefeller Univ, Lab Chromatin Biol, New York, NY 10021 USA. [Sen, Ranjan] NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. [Fiering, Steven] Dartmouth Med Sch, Dept Microbiol & Immunol, Lebanon, NH 03756 USA. [Fiering, Steven] Dartmouth Med Sch, Dept Genet, Lebanon, NH 03756 USA. [Fiering, Steven] Dartmouth Med Sch, Norris Cotton Canc Ctr, Lebanon, NH 03756 USA. RP Guan, ZQ (reprint author), Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. EM zguan@aecom.yu.edu; schildkr@aecom.yu.edu FU National Institutes of Health [GM045751, GM053512, GM038925, DK56845] FX This work was supported by National Institutes of Health grants (GM045751 to C. L. Schildkraut, GM053512 to C. D. Allis, GM038925 to R. Sen, and DK56845 to E. E. Bouhassira). NR 37 TC 28 Z9 28 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD NOV 30 PY 2009 VL 187 IS 5 BP 623 EP 635 DI 10.1083/jcb.200905144 PG 13 WC Cell Biology SC Cell Biology GA 524ZM UT WOS:000272182900007 PM 19951913 ER PT J AU Watson, A Kent, P Alam, M Paller, AS Umbach, DM Yoon, JW Iannaccone, PM Walterhouse, DO AF Watson, Andrea Kent, Paul Alam, Murad Paller, Amy S. Umbach, David M. Yoon, Joon Won Iannaccone, Philip M. Walterhouse, David O. TI GLI1 genotypes do not predict basal cell carcinoma risk: a case control study SO MOLECULAR CANCER LA English DT Article ID ULTRAVIOLET-RADIATION; SKIN-CANCER; SUSCEPTIBILITY; VARIANTS; SITE; TRANSCRIPTION; ASSOCIATIONS; POLYMORPHISM; ACTIVATION; HISTOLOGY AB Background: Susceptibility to basal cell carcinoma results from complex interactions between ultraviolet radiation exposure and genetic factors. The GLI1 oncogene is believed to play a role in the genesis of these tumors. We determined whether GLI1 polymorphisms were risk factors for developing basal cell carcinoma, either alone or in combination with patterns of past sun exposure, and whether there were functional differences among different GLI1 haplotypes. Results: GLI1 genotypes at c. 2798 and c. 3298 from 201 basal cell carcinoma patients were compared to 201 age and sex-matched controls. Neither genotype nor haplotype frequencies differed between cases and controls. However, the odds of developing basal cell carcinoma on the trunk compared to the head/neck appeared somewhat lower with carriers of the c. 3298GC than the CC genotype. There was no evidence for interactions between skin type, childhood sunburning, average adult sun exposure, adult sunbathing, or intermittency of sun exposure and GLI1 haplotype. Additionally, we found no significant differences in transcription activation or cell transforming ability among the four GLI1 haplotypes. Conclusion: These results suggest that different GLI1 genotypes alone or in combination with past sun exposure patterns as assessed in this study do not affect basal cell carcinoma risk. C1 [Yoon, Joon Won; Iannaccone, Philip M.; Walterhouse, David O.] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA. [Yoon, Joon Won; Iannaccone, Philip M.; Walterhouse, David O.] Childrens Mem Res Ctr, Dev Biol Program, Chicago, IL USA. [Watson, Andrea] Univ Minnesota, Dept Pediat, Duluth, MN 55812 USA. [Alam, Murad; Paller, Amy S.] Rush Univ, Med Ctr, Dept Pediat, Chicago, IL 60612 USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Walterhouse, DO (reprint author), Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA. EM Awatson1@smdc.org; P_Kent@rush.edu; m-alam@northwestern.edu; Apaller@nmff.org; umbach@niehs.nih.gov; j-yoon2@northwestern.edu; pmi@northwestern.edu; d-walterhouse@northwestern.edu FU Washington Square Foundation; Illinois Department of Public Aid; Illinois Regenerative Medicine Institute Initiative; George M. Eisenberg Foundation for Charities; NIH; National Institute of Environmental Health Sciences FX This work was supported in part by the Washington Square Foundation, the Illinois Department of Public Aid ("Excellence in Academic Medicine" Award), the Illinois Regenerative Medicine Institute Initiative, the George M. Eisenberg Foundation for Charities, and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 19 TC 1 Z9 1 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD NOV 30 PY 2009 VL 8 AR 113 DI 10.1186/1476-4598-8-113 PG 7 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 530JR UT WOS:000272586500001 PM 19948058 ER PT J AU Crostarosa, F Aravantinou, M Akpogheneta, OJ Jasny, E Shaw, A Kenney, J Piatak, M Lifson, JD Teitelbaum, A Hu, LY Chudolij, A Zydowsky, TM Blanchard, J Gettie, A Robbiani, M AF Crostarosa, Federica Aravantinou, Meropi Akpogheneta, Onome J. Jasny, Edith Shaw, Andrew Kenney, Jessica Piatak, Michael, Jr. Lifson, Jeffrey D. Teitelbaum, Aaron Hu, Lieyu Chudolij, Anne Zydowsky, Thomas M. Blanchard, James Gettie, Agegnehu Robbiani, Melissa TI A Macaque Model to Study Vaginal HSV-2/Immunodeficiency Virus Co-Infection and the Impact of HSV-2 on Microbicide Efficacy SO PLOS ONE LA English DT Article ID HERPES-SIMPLEX-VIRUS; PLASMACYTOID DENDRITIC CELLS; LENTIVIRUS-INDUCED PROTECTION; RHESUS MACAQUES; T-CELLS; CD8(+) LYMPHOCYTES; TYPE-2 HSV-2; DEPO-PROVERA; DOUBLE-BLIND; HIV-1 LEVELS AB Background: Herpes simplex virus type-2 (HSV-2) infection enhances the transmission and acquisition of human immunodeficiency virus (HIV). This occurs in symptomatic and asymptomatic stages of HSV-2 infection, suggesting that obvious herpetic lesions are not required to increase HIV spread. An animal model to investigate the underlying causes of the synergistic action of the two viruses and where preventative strategies can be tested under such complex physiological conditions is currently unavailable. Methodology/Principal Findings: We set out to establish a rhesus macaque model in which HSV-2 infection increases the susceptibility to vaginal infection with a model immunodeficiency virus (simian-human immunodeficiency virus, SHIV-RT), and to more stringently test promising microbicides. HSV-2 exposure significantly increased the frequency of vaginal SHIV-RT infection (n = 6). Although cervical lesions were detected in only similar to 10% of the animals, long term HSV-2 DNA shedding was detected (in 50% of animals followed for 2 years). Vaginal HSV-2 exposure elicited local cytokine/chemokine (n = 12) and systemic low-level HSV-2-specific adaptive responses in all animals (n = 8), involving CD4(+) and CD8(+) HSV-specific T cells (n = 5). Local cytokine/chemokine responses were lower in co-infected animals, while simian immunodeficiency virus (SIV)-specific adaptive responses were comparable in naive and HSV-2-infected animals (n = 6). Despite the increased frequency of SHIV-RT infection, a new generation microbicide gel, comprised of Carraguard (R) and a non-nucleoside reverse transcriptase inhibitor MIV-150 (PC-817), blocked vaginal SHIV-RT infection in HSV-2-exposed animals (n = 8), just as in naive animals. Conclusions/Significance: We established a unique HSV-2 macaque model that will likely facilitate research to define how HSV-2 increases HIV transmission, and enable more rigorous evaluation of candidate anti-viral approaches in vivo. C1 [Crostarosa, Federica; Aravantinou, Meropi; Akpogheneta, Onome J.; Jasny, Edith; Shaw, Andrew; Kenney, Jessica; Teitelbaum, Aaron; Hu, Lieyu; Chudolij, Anne; Zydowsky, Thomas M.; Robbiani, Melissa] Populat Council, Ctr Biomed Res, New York, NY 10021 USA. [Piatak, Michael, Jr.; Lifson, Jeffrey D.] NCI, SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick, MD 21701 USA. [Blanchard, James] Tulane Univ, Hlth Sci Ctr, Tulane Natl Primate Res Ctr, Covington, LA USA. [Gettie, Agegnehu] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. RP Crostarosa, F (reprint author), Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10021 USA. EM mrobbiani@popcouncil.org FU USAID Cooperative Agreement [GPO-A-00-04-00019-00]; Swedish Ministry of Foreign Affairs; NIH [R37 AI040877, U19 AI065412, RR00164]; National Cancer Institute (NCI) [N01 CO 124000]; F.M. Kirby Foundation FX This work was supported by the USAID Cooperative Agreement GPO-A-00-04-00019-00, the Swedish Ministry of Foreign Affairs, NIH grants R37 AI040877, U19 AI065412, the NIH base grant RR00164, and in part with Federal funds from the National Cancer Institute (NCI), NIH, under contract N01 CO 124000 (JDL and MP are employed at SAIC, but are funded by NCI. SAIC provided no funds for this research. JDL and MP provided reagents and analytical support.). MR is a 2002 Elizabeth Glaser Scientist. FC and OJA were supported by the F. M. Kirby Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 40 Z9 42 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 30 PY 2009 VL 4 IS 11 AR e8060 DI 10.1371/journal.pone.0008060 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MQ UT WOS:000272828400014 PM 20011586 ER PT J AU Wang, J Lin, M Crenshaw, A Hutchinson, A Hicks, B Yeager, M Berndt, S Huang, WY Hayes, RB Chanock, SJ Jones, RC Ramakrishnan, R AF Wang, Jun Lin, Min Crenshaw, Andrew Hutchinson, Amy Hicks, Belynda Yeager, Meredith Berndt, Sonja Huang, Wen-Yi Hayes, Richard B. Chanock, Stephen J. Jones, Robert C. Ramakrishnan, Ramesh TI High-throughput single nucleotide polymorphism genotyping using nanofluidic Dynamic Arrays SO BMC GENOMICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BREAST-CANCER; HAPLOTYPE MAP; SEQUENCE; GENE; SNPS; PROSTATE; ALLELES; RISK; LOCI AB Background: Single nucleotide polymorphisms (SNPs) have emerged as the genetic marker of choice for mapping disease loci and candidate gene association studies, because of their high density and relatively even distribution in the human genomes. There is a need for systems allowing medium multiplexing (ten to hundreds of SNPs) with high throughput, which can efficiently and cost-effectively generate genotypes for a very large sample set (thousands of individuals). Methods that are flexible, fast, accurate and cost-effective are urgently needed. This is also important for those who work on high throughput genotyping in non-model systems where off-the-shelf assays are not available and a flexible platform is needed. Results: We demonstrate the use of a nanofluidic Integrated Fluidic Circuit (IFC) - based genotyping system for medium-throughput multiplexing known as the Dynamic Array, by genotyping 994 individual human DNA samples on 47 different SNP assays, using nanoliter volumes of reagents. Call rates of greater than 99.5% and call accuracies of greater than 99.8% were achieved from our study, which demonstrates that this is a formidable genotyping platform. The experimental set up is very simple, with a time-to-result for each sample of about 3 hours. Conclusion: Our results demonstrate that the Dynamic Array is an excellent genotyping system for medium-throughput multiplexing (30-300 SNPs), which is simple to use and combines rapid throughput with excellent call rates, high concordance and low cost. The exceptional call rates and call accuracy obtained may be of particular interest to those working on validation and replication of genome-wide-association (GWA) studies. C1 [Wang, Jun; Lin, Min; Jones, Robert C.; Ramakrishnan, Ramesh] Fluidigm Corp, San Francisco, CA USA. [Crenshaw, Andrew; Hutchinson, Amy; Hicks, Belynda; Yeager, Meredith] NCI, Core Genotyping Facil, SAIC Frederick Inc, Adv Technol Program,FCRDC, Frederick, MD 21701 USA. [Crenshaw, Andrew; Hutchinson, Amy; Hicks, Belynda; Yeager, Meredith; Berndt, Sonja; Huang, Wen-Yi; Hayes, Richard B.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Ramakrishnan, R (reprint author), Fluidigm Corp, San Francisco, CA USA. EM jun.wang@fluidigm.com; min.lin@fluidigm.com; crenshaw@broad.mit.edu; hutchiam@mail.nih.gov; hicksbel@mail.nih.gov; yeagerm@mail.nih.gov; berndts@mail.nih.gov; huangw@mail.nih.gov; richard.hayes2@nyumc.org; chanocks@mail.nih.gov; bob.jones@fluidigm.com; ramesh.ramakrishnan@fluidigm.com RI Baird, Cheryl/F-6569-2011; OI Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and by the Intramural Research Program of the National Cancer Institute, NIH. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 27 TC 61 Z9 63 U1 0 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 NOV 28 PY 2009 VL 10 AR 561 DI 10.1186/1471-2164-10-561 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 532ZZ UT WOS:000272792000001 PM 19943955 ER PT J AU Burastero, SE Figini, M Frigerio, B Lusso, P Mollica, L Lopalco, L AF Burastero, Samuele E. Figini, Mariangela Frigerio, Barbara Lusso, Paolo Mollica, Luca Lopalco, Lucia TI Protective versus pathogenic anti-CD4 immunity: insights from the study of natural resistance to HIV infection SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROVIDE INTERMOLECULAR HELP; MONOCLONAL-ANTIBODY THERAPY; T-CELLS; RHEUMATOID-ARTHRITIS; HUMORAL RESPONSES; PERIPHERAL-BLOOD; SOOTY MANGABEYS; CD4 MOLECULE; FOLLOW-UP AB HIV-1 exposure causes several dramatic unbalances in the immune system homeostasis. Here, we will focus on the paradox whereby CD4 specific autoimmune responses, which are expected to contribute to the catastrophic loss of most part of the T helper lymphocyte subset in infected patients, may display the characteristics of an unconventional protective immunity in individuals naturally resistant to HIV-1 infection. Reference to differences in fine epitope mapping of these two oppositely polarized outcomes will be presented, with particular reference to partially or totally CD4-gp120 complex-specific antibodies. The fine tuning of the anti-self immune response to the HIV-1 receptor may determine whether viral exposure will result in infection or, alternatively, protective immunity. Along this line, an efficacious anti-HIV strategy can rely on the active (i.e., through immunization) or passive targeting of cryptic epitopes of the CD4-gp120 complex, including those harboured within the CD4 molecule. Such epitopes are expected to be safe from genetic drift and thus allow for broad spectrum of efficacy. Moreover, since these epitopes are not routinely exposed in uninfected individuals, they are expected to become targets of neutralizing antibodies or other specifically designed molecules only after viral exposure, with a predictable low impact in terms of potentially harmful anti-CD4 self-reactivity. The experimentum naturae of naturally resistant individuals indicates a strategy to design innovative strategies to neutralize HIV-1 by acting on the sharp edge between harmful and protective self-reactivity. C1 [Burastero, Samuele E.] Ist Sci San Raffaele, Div Immunol Infect Dis & Transplants, Unit Clin & Mol Allergy, I-20132 Milan, Italy. [Figini, Mariangela] Fdn IRCCS Natl Inst Tumor, Dept Expt Oncol & Labs, Unit Mol Therapies, I-20132 Milan, Italy. [Lusso, Paolo] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Mollica, Luca] Ist Sci San Raffaele, Dulbecco Telethon Inst, Biomol NMR Lab, I-20132 Milan, Italy. [Lopalco, Lucia] Ist Sci San Raffaele, Div Immunol Infect Dis & Transplants, Unit Immunobiol HIV, I-20132 Milan, Italy. RP Burastero, SE (reprint author), Ist Sci San Raffaele, Div Immunol Infect Dis & Transplants, Unit Clin & Mol Allergy, 58 Via Olgettina, I-20132 Milan, Italy. EM s.burastero@hsr.it; mariangela.figini@istitutotumori.mi.it; Barbara.Frigerio@istitutotumori.mi.it; plusso@niaid.nih.gov; l.mollica@hsr.it; l.lopalco@hsr.it RI Frigerio, Barbara/K-8669-2016; Figini, Mariangela/K-8753-2016; OI Frigerio, Barbara/0000-0001-6700-5744; Figini, Mariangela/0000-0001-9001-8754; Lopalco, Lucia/0000-0003-3812-1759 FU Istituto Superiore di Sanita, Rome, AIDS Program FX SB, LL and PL were funded by Istituto Superiore di Sanita, Rome, AIDS Program. NR 75 TC 4 Z9 4 U1 1 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 NOV 28 PY 2009 VL 7 AR 101 DI 10.1186/1479-5876-7-101 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 530IQ UT WOS:000272583300001 PM 19943950 ER PT J AU Rozenberg, L Haagmans, BL Neumann, AU Chen, G McLaughlin, M Levy-Drummer, RS Masur, H Dewar, RL Ferenci, P Silva, M Viola, MS Polis, MA Kottilil, S AF Rozenberg, Lynn Haagmans, Bart L. Neumann, Avidan U. Chen, Grace McLaughlin, Mary Levy-Drummer, Rachel S. Masur, H. Dewar, Robin L. Ferenci, Peter Silva, Marcelo Viola, Maria S. Polis, Michael A. Kottilil, Shyam TI Therapeutic response to peg-IFN-alpha-2b and ribavirin in HIV/HCV co-infected African-American and Caucasian patients as a function of HCV viral kinetics and interferon pharmacodynamics SO AIDS LA English DT Article DE HCV viral kinetics; HIV co-infection; interferon pharmacodynamics ID CHRONIC HEPATITIS-C; HUMAN-IMMUNODEFICIENCY-VIRUS; ALPHA-2A PLUS RIBAVIRIN; HIV-COINFECTED PATIENTS; PEGINTERFERON ALPHA-2A; PEGYLATED INTERFERON-ALPHA-2B; ANTIRETROVIRAL THERAPY; PROTEASE INHIBITORS; RANDOMIZED-TRIAL; DYNAMICS AB Method : In this study we sought to characterize the relationship between several pharmacokinetic and pharmacodynamic parameters and virologic responses among HIV/hepatitis C virus genotype-1 co-infected patients receiving pegylated interferon-alpha-2b (peg-IFN2b) and ribavirin. We also tried to establish the underlying mechanisms that lead to poor sustained virologic responder rates observed with African-Americans against Caucasians and compared their results with those observed in a cohort of hepatitis C virus mono-infected patients. Results : Among our studied population, a viral decline of more than 1.0 log a, day I combined with viral load of less than 5.0 log IU/ml at clay 28 predicted sustained virologic responders with negative predictive value 100% and positive predictive value 100%. African-Americans had significantly (P<0.01) slower hepatitis C virus viral kinetics as compared to Caucasians. However, peg-IFN2b concentrations and pharmacokinetic parameters, peg-IFN2b(max) and peg-IFN2b half-life, were similar in both groups and did not predict sustained virologic responders. Nevertheless, the pharmacodynamic parameter EC(50), estimated from nonlinear fitting of the viral kinetics together with peg-IFN2b concentration data, showed that HIV/ hepatitis C virus co-infected African-Americans have lower sensitivity to interferon-alpha thus giving rise to slower viral decline. The combined pharmacokinetic/pharmacodynamic parameter IFN(max)/EC(90) was an excellent predictor of sustained virologic responders, thus showing the importance of maintaining peg-IFN2b levels above EC(90) to achieve successful treatment. Conclusion : Further Studies are needed to evaluate whether these pharmacodynamic predictions are a result of differential host response to peg-IFN2b or other viral factors conferring relative resistance to peg-IFN2b. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Kottilil, Shyam] NIAID, Immunopathogenesis Sect, NIH, LIR,DHHS, Bethesda, MD 20892 USA. [Rozenberg, Lynn; Neumann, Avidan U.; Levy-Drummer, Rachel S.] Bar Ilan Univ, Goodman Fac Life Sci, Ramat Gan, Israel. [Haagmans, Bart L.] Erasmus MC, Rotterdam, Netherlands. [Chen, Grace] NIAID, LID, NIH, DHHS, Bethesda, MD 20892 USA. [Masur, H.] NIH, CCMD, CC, DHHS, Bethesda, MD 20892 USA. [Dewar, Robin L.] Sci Applicat Int Corp Frederick, Frederick, MD USA. [Ferenci, Peter] Univ Klin Innere Med IV, Vienna, Austria. [Silva, Marcelo; Viola, Maria S.] Hosp Univ Austral, Liver Unit, Buenos Aires, DF, Argentina. RP Kottilil, S (reprint author), NIAID, Immunopathogenesis Sect, NIH, LIR,DHHS, Bldg 10,Rm 11N204,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Skottilil@niaid.nih.gov OI Polis, Michael/0000-0002-9151-2268 FU NIH FX The research was supported by the Intramural Research Program of the NIH (National Institute of Allergy and Infectious Diseases and National Institute of Digestive Diseases and Kidney). L.R., A.U.N., and R.L.D. did mathematical modeling and viral kinetic analysis, M.M. was the nurse specialist for the study, R.D. performed HCV viral load assays, B.L. performed pharmacokinetic assays, G.C. organized data and helped with manuscript, M.A.P, H.M. helped with study design and PE, M.S., and S.K. were Principal investigators for the studies. NR 36 TC 16 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD NOV 27 PY 2009 VL 23 IS 18 BP 2439 EP 2450 DI 10.1097/QAD.0b013e32832ff1c0 PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 524IA UT WOS:000272135800008 PM 19898214 ER PT J AU Kiwanuka, N Laeyendecker, O Quinn, TC Wawer, MJ Shepherd, J Robb, M Kigozi, G Kagaayi, J Serwadda, D Makumbi, FE Reynolds, SJ Gray, RH AF Kiwanuka, Noah Laeyendecker, Oliver Quinn, Thomas C. Wawer, Maria J. Shepherd, James Robb, Merlin Kigozi, Godfrey Kagaayi, Joseph Serwadda, David Makumbi, Fred E. Reynolds, Steven J. Gray, Ronald H. TI HIV-1 subtypes and differences in heterosexual HIV transmission among HIV-discordant couples in Rakai, Uganda SO AIDS LA English DT Article; Proceedings Paper CT 17th International AIDS Conference CY AUG 03-08, 2008 CL Mexico City, MEXICO DE discordant couples; HIV transmission; HIV-1 subtype; Uganda ID IMMUNODEFICIENCY-VIRUS TYPE-1; DISEASE PROGRESSION; AIDS-PREVENTION; COMMUNITY TRIAL; COITAL ACT; INFECTION; COHORT; TANZANIA; THAILAND; SEQUENCE AB Objective: To determine whether heterosexual transmission of HIV differs according to HIV-1 subtype. Design: A retrospective observational cohort. Methods: HIV-1 subtype effects on heterosexual HIV-1 transmission were determined among 268 HIV-discordant couples retrospectively identified from a population cohort in Rakai, Uganda. HIV-1 subtype (gag and gp41 sequencing and multiregion hybridization assay) and viral loads (reverse transcriptase PCR) were determined. Adjusted incidence rate ratios (adj IRR) of HIV transmission by subtype were estimated by multivariable Poisson regression adjusting for characteristics of index HIV-positive and HIV-negative partners. Results: Adjusting for index HIV-positive partners' age, viral load, stage of disease, genital ulcer disease, and HIV-negative partners' genital ulcer disease and nonuse of condoms, subtype A viruses were associated with a higher rate of transmission than subtype D [adj.IRR 1.98, 95% confidence interval (CI) 1.17-3.34], but no differences in transmission were observed between recombinant viruses and subtype D (aIRR 1.53, P=0.25). Index-positive partners' age less than 30 years (adj.IRR 3.44, 95%. Cl 1.75-6.78) and viral load (adj.IRR 2.37, 95% Cl 1.75-3.21), and index-negative partners' genital ulcer disease (adj.IRR 1.71, 95% Cl 1.08-2.70) and nonuse of condoms (adj.IRR 1.94, 95% Cl 1.15-3.28) were significant determinants of HIV transmission. Conclusion: In Rakai, Uganda, subtype A viruses have a significantly higher rate of heterosexual transmission than subtype D viruses. Differential subtype transmission efficiency may be important for HIV vaccine evaluation and could contribute to subtype-specific HIV epidemics in sub-Saharan Africa. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Kiwanuka, Noah; Serwadda, David; Makumbi, Fred E.] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Kiwanuka, Noah; Kigozi, Godfrey; Kagaayi, Joseph; Makumbi, Fred E.] Uganda Virus Res Inst, Rakai Hlth Sci Program, Entebbe, Uganda. [Laeyendecker, Oliver; Quinn, Thomas C.; Reynolds, Steven J.] NIAID, NIH, Bethesda, MD 20892 USA. [Laeyendecker, Oliver; Quinn, Thomas C.; Shepherd, James] Johns Hopkins Sch Med, Baltimore, MD USA. [Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Robb, Merlin] Henry M Jackson Fdn, Rockville, MD USA. RP Kiwanuka, N (reprint author), Makerere Univ, Sch Publ Hlth, POB 7072, Kampala, Uganda. EM nkiwanuka@rhsp.org RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU FIC NIH HHS [#2D43 TW000010-19, D43 TW000010, D43 TW000011, D43 TW000011-20]; Intramural NIH HHS [Z99 AI999999]; NIAID NIH HHS [R01 AI034826-05S1, R01 AI034826-05]; PHS HHS [#RO1 A134826] NR 31 TC 50 Z9 51 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD NOV 27 PY 2009 VL 23 IS 18 BP 2479 EP 2484 DI 10.1097/QAD.0b013e328330cc08 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 524IA UT WOS:000272135800012 PM 19841572 ER PT J AU Nanda, JS Cheung, YN Takacs, JE Martin-Marcos, P Saini, AK Hinnebusch, AG Lorsch, JR AF Nanda, Jagpreet S. Cheung, Yuen-Nei Takacs, Julie E. Martin-Marcos, Pilar Saini, Adesh K. Hinnebusch, Alan G. Lorsch, Jon R. TI eIF1 Controls Multiple Steps in Start Codon Recognition during Eukaryotic Translation Initiation SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE initiation codon; eIF5; protein synthesis; ribosome; kinetics ID SACCHAROMYCES-CEREVISIAE; IN-VIVO; PREINITIATION COMPLEX; MULTIFACTOR COMPLEX; RIBOSOMAL-SUBUNIT; SITE SELECTION; GTP HYDROLYSIS; 40S RIBOSOME; YEAST; PROTEIN AB Eukaryotic translation initiation factor (eIF) 1 is a central mediator of start codon recognition. Dissociation of eIF1 from the preinitiation complex (PIC) allows release of phosphate from the G-protein factor eIF2, triggering downstream events in initiation. Mutations that weaken binding of eIF1 to the PIC decrease the fidelity of start codon recognition (Sui(-) phenotype) by allowing increased eIF1 release at non-AUG codons. Consistent with this, overexpression of these mutant proteins suppresses their Sui(-) phenotypes. Here, we have examined mutations at the penultimate residue of eIF1, G107, that produce Sui(-) phenotypes without increasing the rate of eIF1 release. We provide evidence that, in addition to its role in gating phosphate release, dissociation of eIF1. triggers conversion from an open, scanning-competent state of the PIC to a stable, closed one. We also show that eIF5 antagonizes binding of eIF1 to the complex and that key interactions of eIF1 with its partners are modulated by the charge at and around G107. Our data indicate that eIF1 plays multiple roles in start codon recognition and suggest that prior to AUG recognition it prevents eIF5 from binding to a key site in the PIC required for triggering downstream events. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Cheung, Yuen-Nei; Martin-Marcos, Pilar; Saini, Adesh K.; Hinnebusch, Alan G.] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Nanda, Jagpreet S.; Takacs, Julie E.; Lorsch, Jon R.] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov; jlorsch@jhmi.edu RI Nanda, Jagpreet/F-9833-2011; OI Lorsch, Jon/0000-0002-4521-4999 FU NIH [GM62128]; NIH NICHD FX We thank members of our laboratories and Tom Dever for comments on the manuscript. This work was funded by a grant from the NIH to J.R.L. (GM62128) and by the Intramural Research Program of the NIH NICHD to A.G.H. NR 42 TC 52 Z9 53 U1 0 U2 2 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 NOV 27 PY 2009 VL 394 IS 2 BP 268 EP 285 DI 10.1016/j.jmb.2009.09.017 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 522GK UT WOS:000271985700009 PM 19751744 ER PT J AU Pavel, J Terron, JA Benicky, J Falcon-Neri, A Rachakonda, A Inagami, T Saavedra, JM AF Pavel, Jaroslav Terron, Jose A. Benicky, Julius Falcon-Neri, Alicia Rachakonda, Amita Inagami, Tadashi Saavedra, Juan M. TI Increased Angiotensin II AT(1) receptor mRNA and binding in spleen and lung of AT(2) receptor gene disrupted mice SO REGULATORY PEPTIDES LA English DT Article DE Renin-angiotensin system; Angiotensin receptor types; Gene-disruption; Autoradiography; In situ hybridization ID SPONTANEOUSLY HYPERTENSIVE-RATS; TYPE-2 RECEPTOR; DEFICIENT MICE; AT1 RECEPTOR; QUANTITATIVE AUTORADIOGRAPHY; DIFFERENTIAL REGULATION; CARDIAC-HYPERTROPHY; KNOCKOUT MICE; UP-REGULATION; NITRIC-OXIDE AB To clarify the relationship between Angiotensin II AT(1) and AT(2) receptors, we studied AT(1) receptor mRNA and binding expression in tissues from AT(2) receptor gene disrupted (AT(2)(-/-)) female mice, where AT(2) receptors are not expressed in vivo, using in situ hybridization and quantitative autoradiography. Wild type mice expressed AT(1A) receptor mRNA and AT, receptor binding in lung parenchyma, the spleen, predominantly in the red pulp, and in liver parenchyma. In wild type mice, lung AT(2) receptors were expressed in lung bronchial epithelium and smooth muscle, and were not present in the lung parenchyma, the spleen or the liver. This indicates that AT(1) and AT(2) receptors were not expressed in the same cells. In AT(2)(-/-) mice, we found higher AT(1A) receptor mRNA and AT(1) receptor binding in lung parenchyma and in the red pulp of the spleen, but not in the liver, when compared to littermate wild type controls. Our results suggest that impaired AT(2) receptor function upregulates AT(1) receptor transcription and expression in a tissue-specific manner and in cells not expressing AT(2) receptors. AT(1) upregulation explains the increased sensitivity to Angiotensin II characteristic of the AT(2)(-/-) phenotype, consistent with enhanced AT(1) receptor activation in a number of tissues. Published by Elsevier B.V. C1 [Pavel, Jaroslav; Terron, Jose A.; Benicky, Julius; Falcon-Neri, Alicia; Saavedra, Juan M.] NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Rachakonda, Amita; Inagami, Tadashi] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA. [Rachakonda, Amita; Inagami, Tadashi] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH,US Dept HHS, Bldg 10,Room 2D57,10 Ctr Dr MSC 1514, Bethesda, MD 20892 USA. EM Saavedrj@mail.nih.gov FU National Institute of Mental Health, USA; NIH [HL58205] FX This study was supported by the Division of Intramural Research Programs, National Institute of Mental Health, Department of Health and Human Services, USA (J.P., J.A.T, J.B., A.F-N, J.M.S.) and NIH grant HL58205 (A.R. and T.I.) NR 75 TC 5 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD NOV 27 PY 2009 VL 158 IS 1-3 BP 156 EP 166 DI 10.1016/j.regpep.2009.09.004 PG 11 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 516QA UT WOS:000271556100024 PM 19766151 ER PT J AU Stocker, G Fischer, M Rieder, D Bindea, G Kainz, S Oberstolz, M McNally, JG Trajanoski, Z AF Stocker, Gernot Fischer, Maria Rieder, Dietmar Bindea, Gabriela Kainz, Simon Oberstolz, Michael McNally, James G. Trajanoski, Zlatko TI iLAP: a workflow-driven software for experimental protocol development, data acquisition and analysis SO BMC BIOINFORMATICS LA English DT Article ID MINIMUM INFORMATION; FUNCTIONAL GENOMICS; PROTEOMICS; NOTEBOOKS; SYSTEM; MANAGEMENT; STANDARDS; STORAGE; MODEL; FUGE AB Background: In recent years, the genome biology community has expended considerable effort to confront the challenges of managing heterogeneous data in a structured and organized way and developed laboratory information management systems (LIMS) for both raw and processed data. On the other hand, electronic notebooks were developed to record and manage scientific data, and facilitate data-sharing. Software which enables both, management of large datasets and digital recording of laboratory procedures would serve a real need in laboratories using medium and high-throughput techniques. Results: We have developed iLAP (Laboratory data management, Analysis, and Protocol development), a workflow-driven information management system specifically designed to create and manage experimental protocols, and to analyze and share laboratory data. The system combines experimental protocol development, wizard-based data acquisition, and high-throughput data analysis into a single, integrated system. We demonstrate the power and the flexibility of the platform using a microscopy case study based on a combinatorial multiple fluorescence in situ hybridization (m-FISH) protocol and 3D-image reconstruction. iLAP is freely available under the open source license AGPL from http://genome.tugraz.at/iLAP/. Conclusion: iLAP is a flexible and versatile information management system, which has the potential to close the gap between electronic notebooks and LIMS and can therefore be of great value for a broad scientific community. C1 [Stocker, Gernot; Fischer, Maria; Rieder, Dietmar; Bindea, Gabriela; Kainz, Simon; Oberstolz, Michael; Trajanoski, Zlatko] Graz Univ Technol, Inst Genom & Bioinformat, A-8010 Graz, Austria. [McNally, James G.] NCI, Ctr Canc Res, Core Imaging Facil, Lab Receptor Biol & Gene Express,NIH, Bethesda, MD 20892 USA. RP Trajanoski, Z (reprint author), Graz Univ Technol, Inst Genom & Bioinformat, Petersgasse 14, A-8010 Graz, Austria. EM gernot.stocker@tugraz.at; maria.fischer@tugraz.at; dietmar.rieder@tugraz.at; gabriela.bindea@tugraz.at; simon.kainz@tugraz.at; michael.oberstolz@student.tugraz.at; mcnallyj@dce41.nci.nih.gov; zlatko.trajanoski@tugraz.at FU Austrian Ministry for Science and Research; GEN-AU Project Bioinformatics Integration Network (BIN) FX The authors thank the staff of the Institute for Genomics and Bioinformatics for valuable comments and contributions. Special thanks go to Hillary Mueller and Tatiana Karpova from the Laboratory of Receptor Biology and Gene Expression, National Cancer Institute. Special thanks also go to Will Moore for the ongoing successful collaboration regarding the common protocol exchange format. During the large scale analysis on the high-performance computing cluster we were supported by Scientific Volume Imaging http://www.svi.nl with a cluster license of Huygens Deconvolution Software. This work was supported by the Austrian Ministry for Science and Research, GEN-AU Project Bioinformatics Integration Network (BIN). NR 32 TC 9 Z9 9 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 NOV 26 PY 2009 VL 10 AR 390 DI 10.1186/1471-2105-10-390 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 532SR UT WOS:000272770500002 PM 19941647 ER PT J AU Dexheimer, TS Gediya, LK Stephen, AG Weidlich, I Antony, S Marchand, C Interthal, H Nicklaus, M Fisher, RJ Njar, VC Pommier, Y AF Dexheimer, Thomas S. Gediya, Lalji K. Stephen, Andrew G. Weidlich, Iwona Antony, Smitha Marchand, Christophe Interthal, Heidrun Nicklaus, Marc Fisher, Robert J. Njar, Vincent C. Pommier, Yves TI 4-Pregnen-21-ol-3,20-dione-21-(4-bromobenzenesulfonate) (NSC 88915) and Related Novel Steroid Derivatives as Tyrosyl-DNA Phosphodiesterase (Tdp1) Inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID TOPOISOMERASE-I INHIBITORS; STRAND BREAK REPAIR; SPINOCEREBELLAR ATAXIA; POLY(ADP-RIBOSE) POLYMERASE; COVALENT COMPLEXES; ANTITUMOR-ACTIVITY; AXONAL NEUROPATHY; CANCER-THERAPY; HUMAN-CELLS; DAMAGE AB Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an enzyme that catalyzes the hydrolysis of 3'-phosphotyrosyl bonds. Such linkages form in vivo when topoisomerase 1 (Top1) processes DNA. For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes. Tdp1 inhibitors have been regarded as potential therapeutics in combination with Top1 inhibitors, such as the camptothecin derivatives, topotecan, and irinotecan, which are used to treat human cancers. Using a novel high-throughput screening assay, we have identified the C21-substituted progesterone derivative, NSC 88915 (1), as a potential Tdp1 inhibitor. Secondary screening and cross-reactivity studies with related DNA processing enzymes confirmed that compound 1 possesses specific Tdp1 inhibitory activity. Deconstruction of compound 1 into discrete functional groups reveals that both components are required for inhibition of Tdp1 activity. Moreover, the synthesis of analogues of compound I has provided insight into the structural requirements for the inhibition of Tdp1. Surface plasmon resonance shows that compound 1 binds to Tdp1, whereas an inactive analogue fails to interact with the enzyme. On the basis of molecular docking and mechanistic studies, we propose that these compounds are competitive inhibitors, which mimics the oligonucleotide-peptide Tdp1 substrate. These steroid derivatives represent a novel chemotype and provide a new scaffold for developing small molecule inhibitors of Tdp1. C1 [Dexheimer, Thomas S.; Antony, Smitha; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gediya, Lalji K.; Njar, Vincent C.] Univ Maryland, Dept Pharmacol & Expt Therapeut, Sch Med, Baltimore, MD 21201 USA. [Gediya, Lalji K.; Njar, Vincent C.] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Gediya, Lalji K.; Njar, Vincent C.] Thomas Jefferson Univ, Dept Pharmaceut Sci, Jefferson Sch Pharm, Philadelphia, PA 19107 USA. [Stephen, Andrew G.; Fisher, Robert J.] SAIC Frederick Inc, Prot Chem Lab, Adv Technol Program, NCI Frederick, Frederick, MD 21702 USA. [Weidlich, Iwona; Nicklaus, Marc] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Interthal, Heidrun] Univ Edinburgh, Inst Cell Biol, Edinburgh, Midlothian, Scotland. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov OI Nicklaus, Marc/0000-0002-4775-7030 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The wild-type Tdp1 and SCANT mutant Tdp1 constructs were generous gifts from Drs. J. J. Champoux (University of Washington) and Dr. H. Nash (Laboratory of Molecular Biology, National Institute of Mental Health, NIH), respectively. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 53 TC 20 Z9 21 U1 1 U2 10 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 NOV 26 PY 2009 VL 52 IS 22 BP 7122 EP 7131 DI 10.1021/jm901061s PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 520FJ UT WOS:000271825600017 PM 19883083 ER PT J AU Ziolkowska, NE Michejda, CJ Bujacz, GD AF Ziolkowska, Natasza E. Michejda, Christopher J. Bujacz, Grzegorz D. TI Structural investigation of HIV-1 nonnucleoside reverse transcriptase inhibitors: 2-Aryl-substituted benzimidazoles SO JOURNAL OF MOLECULAR STRUCTURE LA English DT Article DE AIDS; HIV-1; Reverse transcriptase inhibitor; Drug design; Crystal structure ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL ACTIVITY; BIOLOGICAL-ACTIVITY; POTENT; REPLICATION; DELAVIRDINE; INFECTION; TYPE-1 AB Acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) is one of the most destructive epidemics in history. Inhibitors of HIV enzymes are the main targets to develop drugs against that disease. Nonnucleoside reverse transcriptase inhibitors of HIV-1 (NNRTIs) are potentially effective and nontoxic. Structural studies provide information necessary to design more active compounds. The crystal structures of four NNRTI derivatives of 2-aryl-substituted N-benzyl-benzimidazole are presented here. Analysis of the geometrical parameters shows that the structures of the investigated inhibitors are rigid. The important geometrical parameter is the dihedral angle between the planes of the n-electron systems of the benzymidazole and benzyl moieties. The values of these dihedral angles are in a narrow range for all investigated inhibitors. There is no significant difference between the structure of the free inhibitor and the inhibitor in the complex with RT HIV-1. Xray structures of the investigated inhibitors are a good basis for modeling enzyme-inhibitor interactions in rational drug design. (C) 2009 Elsevier B.V. All rights reserved. C1 [Ziolkowska, Natasza E.; Bujacz, Grzegorz D.] Tech Univ Lodz, Inst Tech Biochem, PL-90924 Lodz, Poland. [Michejda, Christopher J.] NCI, Mol Aspects Drug Design Sect, Frederick, MD 21702 USA. RP Bujacz, GD (reprint author), Tech Univ Lodz, Inst Tech Biochem, Ul Stefanowskiego 4-10, PL-90924 Lodz, Poland. EM gdbujacz@p.lodz.pl FU Polish Committee for Scientific Research, KBN [4P05F 03114] FX This work was supported by the Polish Committee for Scientific Research, KBN, Grant No. 4P05F 03114. Authors are grateful to Wieslaw Majzner for his assistance in collecting data on CAD4 diffractometer and Jerry N. Alexandratos for editorial suggestions. NR 30 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-2860 J9 J MOL STRUCT JI J. Mol. Struct. PD NOV 26 PY 2009 VL 937 IS 1-3 BP 34 EP 38 DI 10.1016/j.molstruc.2009.08.005 PG 5 WC Chemistry, Physical SC Chemistry GA 520IS UT WOS:000271838100005 ER PT J AU Kelly-Hope, LA Hemingway, J McKenzie, FE AF Kelly-Hope, Louise A. Hemingway, Janet McKenzie, F. Ellis TI Environmental factors associated with the malaria vectors Anopheles gambiae and Anopheles funestus in Kenya SO MALARIA JOURNAL LA English DT Article ID PLASMODIUM-FALCIPARUM TRANSMISSION; SUB-SAHARAN AFRICA; INSECTICIDE RESISTANCE; WEST-AFRICA; SPATIAL-DISTRIBUTION; EQUATORIAL-GUINEA; CHROMOSOMAL FORMS; FEEDING-BEHAVIOR; ADULT ANOPHELES; RICE IRRIGATION AB Background: The Anopheles gambiae and Anopheles funestus mosquito species complexes are the primary vectors of Plasmodium falciparum malaria in sub-Saharan Africa. To better understand the environmental factors influencing these species, the abundance, distribution and transmission data from a south-eastern Kenyan study were retrospectively analysed, and the climate, vegetation and elevation data in key locations compared. Methods: Thirty villages in Malindi, Kilifi and Kwale Districts with data on An. gambiae sensu strict, Anopheles arabiensis and An. funestus entomological inoculation rates (EIRs), were used as focal points for spatial and environmental analyses. Transmission patterns were examined for spatial autocorrelation using the Moran's I statistic, and for the clustering of high or low EIR values using the Getis-Ord Gi* statistic. Environmental data were derived from remote-sensed satellite sources of precipitation, temperature, specific humidity, Normalized Difference Vegetation Index (NDVI), and elevation. The relationship between transmission and environmental measures was examined using bivariate correlations, and by comparing environmental means between locations of high and low clustering using the Mann-Whitney U test. Results: Spatial analyses indicated positive autocorrelation of An. arabiensis and An. funestus transmission, but not of An. gambiae s.s., which was found to be widespread across the study region. The spatial clustering of high EIR values for An. arabiensis was confined to the lowland areas of Malindi, and for An. funestus to the southern districts of Kilifi and Kwale. Overall, An. gambiae s.s. and An. arabiensis had similar spatial and environmental trends, with higher transmission associated with higher precipitation, but lower temperature, humidity and NDVI measures than those locations with lower transmission by these species and/or in locations where transmission by An. funestus was high. Statistical comparisons indicated that precipitation and temperatures were significantly different between the An. arabiensis and An. funestus high and low transmission locations. Conclusion: These finding suggest that the abundance, distribution and malaria transmission of different malaria vectors are driven by different environmental factors. A better understanding of the specific ecological parameters of each malaria mosquito species will help define their current distributions, and how they may currently and prospectively be affected by climate change, interventions and other factors. C1 [Kelly-Hope, Louise A.; Hemingway, Janet] Univ Liverpool, Liverpool Sch Trop Med, Vector Grp, Liverpool L3 5QA, Merseyside, England. [Kelly-Hope, Louise A.; McKenzie, F. Ellis] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Kelly-Hope, LA (reprint author), Univ Liverpool, Liverpool Sch Trop Med, Vector Grp, Liverpool L3 5QA, Merseyside, England. EM L.Kelly-Hope@liverpool.ac.uk; hemingway@liverpool.ac.uk; mckenzel@mail.nih.gov OI Hemingway, Janet/0000-0002-3200-7173 NR 55 TC 37 Z9 40 U1 4 U2 27 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD NOV 26 PY 2009 VL 8 AR 268 DI 10.1186/1475-2875-8-268 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 534IQ UT WOS:000272890200001 PM 19941637 ER PT J AU Krepkiy, D Mihailescu, M Freites, JA Schow, EV Worcester, DL Gawrisch, K Tobias, DJ White, SH Swartz, KJ AF Krepkiy, Dmitriy Mihailescu, Mihaela Freites, J. Alfredo Schow, Eric V. Worcester, David L. Gawrisch, Klaus Tobias, Douglas J. White, Stephen H. Swartz, Kenton J. TI Structure and hydration of membranes embedded with voltage-sensing domains SO NATURE LA English DT Article ID DEPENDENT K+ CHANNEL; MOLECULAR-DYNAMICS SIMULATIONS; NEUTRON-DIFFRACTION DATA; FOCUSED ELECTRIC-FIELD; PARTICLE MESH EWALD; POTASSIUM CHANNEL; GATING-CHARGE; X-RAY; LIPID-MEMBRANE; FUNCTIONAL RECONSTITUTION AB Despite the growing number of atomic-resolution membrane protein structures, direct structural information about proteins in their native membrane environment is scarce. This problem is particularly relevant in the case of the highly charged S1-S4 voltage-sensing domains responsible for nerve impulses, where interactions with the lipid bilayer are critical for the function of voltage-activated ion channels. Here we use neutron diffraction, solid-state nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulations to investigate the structure and hydration of bilayer membranes containing S1-S4 voltage-sensing domains. Our results show that voltage sensors adopt transmembrane orientations and cause a modest reshaping of the surrounding lipid bilayer, and that water molecules intimately interact with the protein within the membrane. These structural findings indicate that voltage sensors have evolved to interact with the lipid membrane while keeping energetic and structural perturbations to a minimum, and that water penetrates the membrane, to hydrate charged residues and shape the transmembrane electric field. C1 [Mihailescu, Mihaela; Freites, J. Alfredo; Worcester, David L.; White, Stephen H.] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92697 USA. [Mihailescu, Mihaela; Freites, J. Alfredo; Worcester, David L.; White, Stephen H.] Univ Calif Irvine, Ctr Biomembrane Syst, Irvine, CA 92697 USA. [Freites, J. Alfredo; Tobias, Douglas J.] Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA. [Freites, J. Alfredo; Tobias, Douglas J.] Univ Calif Irvine, Inst Surface & Interface Sci, Irvine, CA 92697 USA. [Schow, Eric V.] Univ Calif Irvine, Dept Phys & Astron, Irvine, CA 92697 USA. [Schow, Eric V.] Univ Calif Irvine, Inst Genom & Bioinformat, Irvine, CA 92697 USA. [Mihailescu, Mihaela; Worcester, David L.; White, Stephen H.] NIST, NIST Ctr Neutron Res, Gaithersburg, MD 20899 USA. [Worcester, David L.] Univ Missouri, Div Biol, Columbia, MO 65211 USA. [Gawrisch, Klaus] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Krepkiy, Dmitriy; Swartz, Kenton J.] NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP White, SH (reprint author), Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92697 USA. EM stephen.white@uci.edu; swartzk@ninds.nih.gov RI White, Stephen/B-1053-2009; Tobias, Douglas/B-6799-2015 OI White, Stephen/0000-0001-8540-7907; FU Intramural Research Programs of the NINDS, NIH [GM86685]; National Institute on Alcohol Abuse and Alcoholism, NIH [GM74737]; National Institute of General Medical Science; US National Science Foundation (NSF) [CHE-0750175] FX We thank the US National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) DNA sequencing facility for DNA sequencing, H. Jaffe in the NINDS protein sequencing facility for mass spectrometry and peptide sequencing and T. Kitaguchi for cloning KvAP. We also thank T. Kimura, M. Mayer, M. Milescu, J. Mindell and S. Silberberg for discussions. This work was supported by the Intramural Research Programs of the NINDS, NIH ( K. J. S.), and the National Institute on Alcohol Abuse and Alcoholism, NIH ( K. G.); NIH grants GM74737 ( S. H. W.) and Program Project GM86685 from the NINDS and the National Institute of General Medical Science ( S. H. W., D. J. T.); and US National Science Foundation (NSF) grant CHE-0750175 ( D. J. T.). We are grateful for allocation of computer time on the NSF-supported Teragrid resources provided by the Texas Advanced Computing Center, and the support of the National Institute of Standards and Technology, US Department of Commerce, in providing the neutron research facilities used for neutron diffraction experiments. The identification of any commercial product or trade name does not imply endorsement or recommendation by the US National Institute of Standards and Technology. NR 81 TC 119 Z9 119 U1 6 U2 69 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD NOV 26 PY 2009 VL 462 IS 7272 BP 473 EP U168 DI 10.1038/nature08542 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524LG UT WOS:000272144200036 PM 19940918 ER PT J AU Netzer, N Goodenbour, JM David, A Dittmar, KA Jones, RB Schneider, JR Boone, D Eves, EM Rosner, MR Gibbs, JS Embry, A Dolan, B Das, S Hickman, HD Berglund, P Bennink, JR Yewdell, JW Pan, T AF Netzer, Nir Goodenbour, Jeffrey M. David, Alexandre Dittmar, Kimberly A. Jones, Richard B. Schneider, Jeffrey R. Boone, David Eves, Eva M. Rosner, Marsha R. Gibbs, James S. Embry, Alan Dolan, Brian Das, Suman Hickman, Heather D. Berglund, Peter Bennink, Jack R. Yewdell, Jonathan W. Pan, Tao TI Innate immune and chemically triggered oxidative stress modifies translational fidelity SO NATURE LA English DT Article ID GENETIC-CODE; QUALITY-CONTROL; CELLS; EVOLUTION; ANTIOXIDANTS; MITOCHONDRIA; PROTEINS; CANDIDA AB Translational fidelity, essential for protein and cell function, requires accurate transfer RNA (tRNA) aminoacylation. Purified aminoacyl-tRNA synthetases exhibit a fidelity of one error per 10,000 to 100,000 couplings(1,2). The accuracy of tRNA aminoacylation in vivo is uncertain, however, and might be considerably lower(3-6). Here we show that in mammalian cells, approximately 1% of methionine (Met) residues used in protein synthesis are aminoacylated to non-methionyl-tRNAs. Remarkably, Met-misacylation increases up to tenfold upon exposing cells to live or non-infectious viruses, toll-like receptor ligands or chemically induced oxidative stress. Met is misacylated to specific non-methionyl-tRNA families, and these Met-misacylated tRNAs are used in translation. Met-misacylation is blocked by an inhibitor of cellular oxidases, implicating reactive oxygen species (ROS) as the misacylation trigger. Among six amino acids tested, tRNA misacylation occurs exclusively with Met. As Met residues are known to protect proteins against ROS-mediated damage(7), we propose that Met-misacylation functions adaptively to increase Met incorporation into proteins to protect cells against oxidative stress. In demonstrating an unexpected conditional aspect of decoding mRNA, our findings illustrate the importance of considering alternative iterations of the genetic code. C1 [Netzer, Nir; David, Alexandre; Gibbs, James S.; Embry, Alan; Dolan, Brian; Das, Suman; Hickman, Heather D.; Berglund, Peter; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Goodenbour, Jeffrey M.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Dittmar, Kimberly A.; Pan, Tao] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA. [Jones, Richard B.; Eves, Eva M.; Rosner, Marsha R.] Univ Chicago, Ben May Inst, Chicago, IL 60637 USA. [Schneider, Jeffrey R.; Boone, David] Univ Chicago, Dept Med, Chicago, IL 60637 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@nih.gov; taopan@uchicago.edu RI yewdell, jyewdell@nih.gov/A-1702-2012; Das, Suman/C-8760-2009; David, Alexandre/B-2447-2013 OI David, Alexandre/0000-0003-3365-1339 FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX The authors are grateful to D. Klinman for his gift of CpG oligonucleotides and advice, A. Schilling for supervision and advice on mass spectrometry experiments, and C. Nicchitta, T. Pierson, P. Cluzel, R. Levine, A. Iwasaki and S. Amigorena for insight and advice. This work was supported by the Division of Intramural Research, the National Institute of Allergy and Infectious Diseases, and by National Institutes of Health extramural pilot projects. NR 24 TC 129 Z9 133 U1 1 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD NOV 26 PY 2009 VL 462 IS 7272 BP 522 EP 526 DI 10.1038/nature08576 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524LG UT WOS:000272144200048 PM 19940929 ER PT J AU Wu, YJ Wang, CX Sun, H LeRoith, D Yakar, S AF Wu, Yingjie Wang, Chunxin Sun, Hui LeRoith, Derek Yakar, Shoshana TI High-Efficient FLPo Deleter Mice in C57BL/6J Background SO PLOS ONE LA English DT Article ID TRANSGENIC MICE; CRE RECOMBINASE; MAMMALIAN-CELLS; EXPRESSION; GENE; WIDESPREAD; MOUSE AB Conditional gene manipulation in mice becomes a routine for genetic studies of mammalian gene functions. Additional site-specific recombinases such as FLP or phi 31 provide one more level of gene manipulation flexibility. The recombination activity of the currently available FLP deleter mice remains low. We generated a new FLP deleter mouse line with the mouse codon-optimized FLPo gene in C57BJ/6 background, which showed superior recombination efficacy in comparison to FLPe deleter mice. 100% complete removal of FRT-flanked Neo cassette was observed in all F1 progeny mice carrying both FLPo and Neo cassette, which can be transmitted to F2 generation independent of FLPo activity. Our new FLPo transgenic mice (on pure C57BJ/6 background) will largely facilitate the gene targeting process and is valuable for conditional gene manipulation. C1 [Wu, Yingjie; Sun, Hui; LeRoith, Derek; Yakar, Shoshana] Mt Sinai Sch Med, Endocrinol Diabet & Bone Dis Div, New York, NY USA. [Wang, Chunxin] NINDS, Biochem Sect, SNB, NIH, Bethesda, MD 20892 USA. RP Wu, YJ (reprint author), Mt Sinai Sch Med, Endocrinol Diabet & Bone Dis Div, New York, NY USA. EM shoshana.yakar@mssm.edu RI Wang, Chunxin/B-9312-2016 OI Wang, Chunxin/0000-0001-6015-6806 FU NIH [AR054919, AR055141] FX This work is funded by the NIH grants AR054919, AR055141 to S.Y. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 22 Z9 23 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 NOV 26 PY 2009 VL 4 IS 11 AR e8054 DI 10.1371/journal.pone.0008054 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MN UT WOS:000272828100010 PM 19956655 ER PT J AU Schaefer, GO Emanuel, EJ Wertheimer, A AF Schaefer, G. Owen Emanuel, Ezekiel J. Wertheimer, Alan TI Participating in Biomedical Research Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Schaefer, G. Owen; Emanuel, Ezekiel J.; Wertheimer, Alan] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Schaefer, GO (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM wertheimera@cc.nih.gov NR 1 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD NOV 25 PY 2009 VL 302 IS 20 BP 2202 EP 2202 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 523NI UT WOS:000272080500016 ER PT J AU Leveille, SG Jones, RN Kiely, DK Hausdorff, JM Shmerling, RH Guralnik, JM Kiel, DP Lipsitz, LA Bean, JF AF Leveille, Suzanne G. Jones, Richard N. Kiely, Dan K. Hausdorff, Jeffrey M. Shmerling, Robert H. Guralnik, Jack M. Kiel, Douglas P. Lipsitz, Lewis A. Bean, Jonathan F. TI Chronic Musculoskeletal Pain and the Occurrence of Falls in an Older Population SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LOWER-EXTREMITY FUNCTION; DISABLED WOMEN; EXECUTIVE FUNCTION; PREVENTING FALLS; MOBILIZE BOSTON; ELDERLY PERSONS; KNEE PAIN; COMMUNITY; RISK; OSTEOARTHRITIS AB Context Chronic pain is a major contributor to disability in older adults; however, the potential role of chronic pain as a risk factor for falls is poorly understood. Objective To determine whether chronic musculoskeletal pain is associated with an increased occurrence of falls in a cohort of community-living older adults. Design, Setting, and Participants The Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) Boston Study is a population-based longitudinal study of falls involving 749 adults aged 70 years and older. Participants were enrolled from September 2005 through January 2008. Main Outcome Measure Participants recorded falls on monthly calendar postcards mailed to the study center during an 18-month period. Results There were 1029 falls reported during the follow-up. A report of 2 or more locations of musculoskeletal pain at baseline was associated with greater occurrence of falls. The age-adjusted rates of falls per person-year were 1.18 (95% confidence interval [CI], 1.13-1.23) for the 300 participants with 2 or more sites of joint pain, 0.90 (95% CI, 0.87-0.92) for the 181 participants with single-site pain, and 0.78 (95% CI, 0.74-0.81) for the 267 participants with no joint pain. Similarly, more severe or disabling pain at baseline was associated with higher fall rates (P < .05). The association persisted after adjusting for multiple confounders and fall risk factors. The greatest risk for falls was observed in persons who had 2 or more pain sites (adjusted rate ratio [RR], 1.53; 95% CI, 1.17-1.99), and those in the highest tertiles of pain severity (adjusted RR, 1.53; 95% CI, 1.12-2.08) and pain interference with activities (adjusted RR, 1.53; 95% CI, 1.15-2.05), compared with their peers with no pain or those in the lowest tertiles of pain scores. Conclusions Chronic pain measured according to number of locations, severity, or pain interference with daily activities was associated with greater risk of falls in older adults. JAMA. 2009;302(20):2214-2221 C1 [Leveille, Suzanne G.] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. [Leveille, Suzanne G.; Jones, Richard N.; Shmerling, Robert H.; Kiel, Douglas P.; Lipsitz, Lewis A.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Leveille, Suzanne G.; Jones, Richard N.; Hausdorff, Jeffrey M.; Shmerling, Robert H.; Kiel, Douglas P.; Lipsitz, Lewis A.; Bean, Jonathan F.] Harvard Univ, Sch Med, Boston, MA USA. [Jones, Richard N.; Kiely, Dan K.; Kiel, Douglas P.; Lipsitz, Lewis A.] Hebrew SeniorLife, Inst Aging Res, Boston, MA USA. [Bean, Jonathan F.] Spaulding Rehabil Hosp, Boston, MA USA. [Hausdorff, Jeffrey M.] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Neurol, IL-69978 Tel Aviv, Israel. [Hausdorff, Jeffrey M.] Tel Aviv Univ, Dept Phys Therapy, IL-69978 Tel Aviv, Israel. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Leveille, SG (reprint author), Univ Massachusetts, Coll Nursing & Hlth Sci, 100 Morrissey Blvd, Boston, MA 02125 USA. EM suzanne.leveille@umb.edu RI Bean, Jonathan/F-5798-2017; OI Bean, Jonathan/0000-0001-8385-8210; Kiel, Douglas/0000-0001-8474-0310; Jones, Richard/0000-0002-1049-218X FU National Institute on Aging Research Nursing Home Program Project [P01AG004390]; Intramural Research Program, National Institute on Aging, NIH; Pfizer Inc FX This research was supported by grant P01AG004390 from the National Institute on Aging Research Nursing Home Program Project. Dr Guralnik's time was funded by the Intramural Research Program, National Institute on Aging, NIH. The coding of the medication data for the MOBILIZE Boston Study was supported by an unrestricted grant from Pfizer Inc, none of which was to support salary, stipends, or other funding except for salaries for research staff who were not involved in this article. NR 48 TC 139 Z9 148 U1 3 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD NOV 25 PY 2009 VL 302 IS 20 BP 2214 EP 2221 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 523NI UT WOS:000272080500025 PM 19934422 ER PT J AU Rudrabhatla, P Albers, W Pant, HC AF Rudrabhatla, Parvathi Albers, Wayne Pant, Harish C. TI Peptidyl-Prolyl Isomerase 1 Regulates Protein Phosphatase 2A-Mediated Topographic Phosphorylation of Neurofilament Proteins SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; RNA-POLYMERASE-II; AXONAL-TRANSPORT; NEURODEGENERATIVE DISEASES; ALZHEIMER-DISEASE; EPITHELIAL-CELLS; SPINAL-CORD; PIN1; NEURONS; IDENTIFICATION AB In normal neurons, neurofilament (NF) proteins are phosphorylated in the axonal compartment. However, in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), NF proteins are aberrantly hyperphosphorylated within the cell bodies. The aberrant hyperphosphorylation of NF accumulations found in neurodegeneration could be attributable to either deregulation of proline-directed Ser/Thr kinase(s) activity or downregulation of protein phosphatase(s) activity. In this study, we found that protein phosphatase 2A (PP2A) expression is high in neuronal cell bodies and that inhibition of PP2A activity by okadaic acid (OA), microcystin LR (mLR), or fostriecin (Fos) leads to perikaryal hyperphosphorylation of NF. Peptidyl-prolyl isomerase Pin1 inhibits the dephosphorylation of NF by PP2A in vitro. In cortical neurons, Pin1 modulates the topographic phosphorylation of the proline-directed Ser/Thr residues within the tail domain of NF proteins by inhibiting the dephosphorylation by PP2A. Inhibition of Pin1 inhibits OA-induced aberrant perikaryal phosphorylation of NF. Treatment of cortical neurons with OA or Fos prevents the general anterograde transport of transfected green fluorescent protein-high-molecular-mass (NF-H) into axons caused by hyperphosphorylation of NF-H, and inhibition of Pin1 rescues this effect. Furthermore, inhibition of Pin1 inhibits the OA- or Fos-induced neuronal apoptosis. We show that OA-induced hyperphosphorylation of NF is a consequence of dephosphorylation of NF and is independent of c-Jun N-terminal protein kinase, extracellular signal-regulated kinase, and cyclin-dependent kinase-5 pathways. This study highlights a novel signaling role of PP2A by Pin1 and implicates Pin1 as a therapeutic target to reduce aberrant phosphorylation of NF proteins in neurodegenerative disorders such as AD, PD, and ALS. C1 [Pant, Harish C.] Natl Inst Neurol Disorders & Stroke, Cytoskeletal Regulatory Prot Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), Natl Inst Neurol Disorders & Stroke, Cytoskeletal Regulatory Prot Sect, Neurochem Lab, NIH, Bldg 49,Room 2A28, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke FX This work was supported by the National Institutes of Health intramural research programs of National Institute of Neurological Disorders and Stroke. We thank Christine Winters for providing rat cortices. We thank Dr. Veeranna for helpful discussions. NR 59 TC 21 Z9 21 U1 0 U2 8 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 NOV 25 PY 2009 VL 29 IS 47 BP 14869 EP 14880 DI 10.1523/JNEUROSCI.4469-09.2009 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 525AI UT WOS:000272185100020 PM 19940183 ER PT J AU Simonyan, K Ostuni, J Ludlow, CL Horwitz, B AF Simonyan, Kristina Ostuni, John Ludlow, Christy L. Horwitz, Barry TI Functional But Not Structural Networks of the Human Laryngeal Motor Cortex Show Left Hemispheric Lateralization during Syllable But Not Breathing Production SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CEREBRAL BLOOD-FLOW; RHESUS-MONKEY; AUDITORY-CORTEX; HUMAN BRAIN; AREA; SPEECH; ACTIVATION; LANGUAGE; FMRI; SUPPLEMENTARY AB The laryngeal motor cortex (LMC) is indispensible for the vocal motor control of speech and song production. Patients with bilateral lesions in this region are unable to speak and sing, although their nonverbal vocalizations, such as laughter and cry, are preserved. Despite the importance of the LMC in the control of voluntary voice production in humans, the literature describing its connections remains sparse. We used diffusion tensor probabilistic tractography and functional magnetic resonance imaging-based functional connectivity analysis to identify LMC networks controlling two tasks necessary for speech production: voluntary voice as repetition of two different syllables and voluntary breathing as controlled inspiration and expiration. Peaks of activation during all tasks were found in the bilateral ventral primary motor cortex in close proximity to each other. Functional networks of the LMC during voice production but not during controlled breathing showed significant left-hemispheric lateralization (p < 0.0005). However, structural networks of the LMC associated with both voluntary voice production and controlled breathing had bilateral hemispheric organization. Our findings indicate the presence of a common bilateral structural network of the LMC, upon which different functional networks are built to control various voluntary laryngeal tasks. Bilateral organization of functional LMC networks during controlled breathing supports its indispensible role in all types of laryngeal behaviors. Significant left-hemispheric lateralization of functional networks during simple but highly learned voice production suggests the readiness of the LMC network for production of a complex voluntary behavior, such as human speech. C1 [Simonyan, Kristina; Ludlow, Christy L.] NINDS, Laryngeal & Speech Sect, Med Neurol Branch, Bethesda, MD 20892 USA. [Ostuni, John] NINDS, Clin Neurosci Program, Bethesda, MD 20892 USA. [Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, Bethesda, MD 20892 USA. RP Simonyan, K (reprint author), Mt Sinai Sch Med, Dept Neurol, 1 Gustave L Levy Pl,Box 1137, New York, NY 10029 USA. EM kristina.simonyan@mssm.edu OI Simonyan, Kristina/0000-0001-7444-0437; Ludlow, Christy/0000-0002-2015-6171 FU National Institutes of Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders FX This research was supported by the Intramural Research Programs of the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the National Institute on Deafness and Other Communication Disorders. We thank Rick Reynolds and Drs. Ziad Saad and Gang Chen for their support with PPI analysis, Sandra B. Martin for her help with subjects' recruitment, and Dr. Pamela R. Kearney for medical evaluation of participants. NR 64 TC 48 Z9 48 U1 1 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 NOV 25 PY 2009 VL 29 IS 47 BP 14912 EP 14923 DI 10.1523/JNEUROSCI.4897-09.2009 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 525AI UT WOS:000272185100024 PM 19940187 ER PT J AU Wright, MC Potluri, S Wang, XY Dentcheva, E Gautam, D Tessler, A Wess, J Rich, MM Son, YJ AF Wright, Megan C. Potluri, Srilatha Wang, Xueyong Dentcheva, Eva Gautam, Dinesh Tessler, Alan Wess, Juergen Rich, Mark M. Son, Young-Jin TI Distinct Muscarinic Acetylcholine Receptor Subtypes Contribute to Stability and Growth, But Not Compensatory Plasticity, of Neuromuscular Synapses SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PERISYNAPTIC SCHWANN-CELLS; AMYOTROPHIC-LATERAL-SCLEROSIS; CILIARY NEUROTROPHIC FACTOR; RAT SKELETAL-MUSCLE; JUNCTION IN-VIVO; PROTEIN-KINASE-C; KNOCKOUT MICE; MOTOR-NERVE; TRANSMITTER RELEASE; GLIA INTERACTIONS AB Muscarinic acetylcholine receptors (mAChRs) modulate synaptic function, but whether they influence synaptic structure remains unknown. At neuromuscular junctions (NMJs), mAChRs have been implicated in compensatory sprouting of axon terminals in paralyzed or denervated muscles. Here we used pharmacological and genetic inhibition and localization studies of mAChR subtypes at mouse NMJs to demonstrate their roles in synaptic stability and growth but not in compensatory sprouting. M(2) mAChRs were present solely in motor neurons, whereas M(1), M(3), and M(5) mAChRs were associated with Schwann cells and/or muscle fibers. Blockade of all five mAChR subtypes with atropine evoked pronounced effects, including terminal sprouting, terminal withdrawal, and muscle fiber atrophy. In contrast, methoctramine, an M(2/4)-preferring antagonist, induced terminal sprouting and terminal withdrawal, but no muscle fiber atrophy. Consistent with this observation, M(2)(-/-) but no other mAChR mutant mice exhibited spontaneous sprouting accompanied by extensive loss of parental terminal arbors. Terminal sprouting, however, seemed not to be the causative defect because partial loss of terminal branches was common even in the M(2)(-/-) NMJs without sprouting. Moreover, compensatory sprouting after paralysis or partial denervation was normal in mice deficient in M(2) or other mAChR subtypes. We also found that many NMJs of M(5)(-/-) mice were exceptionally small and reduced in proportion to the size of parental muscle fibers. These findings show that axon terminals are unstable without M(2) and that muscle fiber growth is defective without M(5). Subtype-specific muscarinic signaling provides a novel means for coordinating activity-dependent development and maintenance of the tripartite synapse. C1 [Wright, Megan C.; Potluri, Srilatha; Dentcheva, Eva; Tessler, Alan; Son, Young-Jin] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19129 USA. [Wang, Xueyong; Rich, Mark M.] Wright State Univ, Dept Neurosci Cell Biol & Physiol, Dayton, OH 45435 USA. [Gautam, Dinesh; Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. [Tessler, Alan] Dept Vet Affairs Hosp, Dept Neurol, Philadelphia, PA 19104 USA. RP Son, YJ (reprint author), Drexel Univ, Coll Med, Dept Neurobiol & Anat, 2900 Queen Lane, Philadelphia, PA 19129 USA. EM yson@drexelmed.edu FU National Institutes of Health [NS045091, NS062320, NS057228]; Veterans Administration; National Institutes of Health intramural funds FX This work was supported by National Institutes of Health Grants NS045091, NS062320 (Y.-J.S.), and NS057228 (M. M. R.), the Veterans Administration (A. T.), and National Institutes of Health intramural funds (J. W.). We thank John Houle and Benjamin Keeler for help with laser microdissection and PCR analysis. We also thank Srishti Bhagat for technical assistance and Tim Himes and the members of the Son laboratory for their comments on this manuscript. NR 91 TC 19 Z9 21 U1 0 U2 2 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 NOV 25 PY 2009 VL 29 IS 47 BP 14942 EP 14955 DI 10.1523/JNEUROSCI.2276-09.2009 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 525AI UT WOS:000272185100027 PM 19940190 ER PT J AU Koenigs, M Barbey, AK Postle, BR Grafman, J AF Koenigs, Michael Barbey, Aron K. Postle, Bradley R. Grafman, Jordan TI Superior Parietal Cortex Is Critical for the Manipulation of Information in Working Memory SO JOURNAL OF NEUROSCIENCE LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; SHORT-TERM-MEMORY; POSTERIOR PARIETAL; ATTENTION SHIFTS; EPISODIC MEMORY; NEURAL ACTIVITY; BRAIN; NEGLECT; LESIONS; LOBE AB In recent years, theoretical perspectives on posterior parietal function have evolved beyond the traditional visuospatial processing models to include more diverse cognitive operations, such as long-term and working memory. However, definitive neuropsychological evidence supporting the superior parietal lobule's purported role in working memory has been lacking. Here, we studied human brain lesion patients to determine whether the superior parietal lobule is indeed necessary for working memory. We assessed a wide range of memory functions in three participant groups: superior parietal lesions (n = 19), lesions not involving superior parietal cortex (n = 146), and no brain lesions (n = 55). Superior parietal damage was reliably associated with deficits on tests involving the manipulation and rearrangement of information in working memory, but not on working memory tests requiring only rehearsal and retrieval processes, nor on tests of long-term memory. These results indicate that superior parietal cortex is critically important for the manipulation of information in working memory. C1 [Koenigs, Michael; Postle, Bradley R.] Univ Wisconsin, Dept Psychiat, Madison, WI 53719 USA. [Barbey, Aron K.; Grafman, Jordan] Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Barbey, Aron K.] Georgetown Univ, Dept Psychol, Washington, DC 20057 USA. [Postle, Bradley R.] Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. RP Koenigs, M (reprint author), Univ Wisconsin, Dept Psychiat, 6001 Res Pk Blvd, Madison, WI 53719 USA. EM mrkoenigs@wisc.edu; grafmanj@ninds.nih.gov RI Barbey, Aron/L-7312-2015; OI Barbey, Aron/0000-0002-6092-0912; Grafman, Jordan H./0000-0001-8645-4457; Koenigs, Michael/0000-0002-5799-4881 FU U.S. National Institute of Neurological Disorders and Stroke intramural research program; United States Army Medical Research and Material Command [DAMD17-01-1-0675] FX This work was supported by funding from the U.S. National Institute of Neurological Disorders and Stroke intramural research program and a project grant from the United States Army Medical Research and Material Command administered by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: a 30-year post-injury follow-up study, grant number DAMD17-01-1-0675). We thank V. Raymont for assistance with patient testing and lesion tracing, and S. Bonifant for data management. NR 42 TC 115 Z9 116 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 NOV 25 PY 2009 VL 29 IS 47 BP 14980 EP 14986 DI 10.1523/JNEUROSCI.3706-09.2009 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 525AI UT WOS:000272185100030 PM 19940193 ER PT J AU Xu, JH Chen, JJ Toptygin, D Tcherkasskaya, O Callis, P King, J Brand, L Knutson, JR AF Xu, Jianhua Chen, Jiejin Toptygin, Dmitri Tcherkasskaya, Olga Callis, Patrik King, Jonathan Brand, Ludwig Knutson, Jay R. TI Femtosecond Fluorescence Spectra of Tryptophan in Human gamma-Crystallin Mutants: Site-Dependent Ultrafast Quenching SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID TIME-RESOLVED FLUORESCENCE; CONFORMATIONAL HETEROGENEITY; CYCLIC HEXAPEPTIDES; CATARACT FORMATION; ELECTRON-TRANSFER; AQUEOUS-SOLUTION; S-CRYSTALLIN; HUMAN LENS; PROTEINS; DECAY AB The eye lens Crystallin proteins are subject to UV irradiation throughout life, and the photochemistry of damage proceeds through the excited state; thus, their tryptophan (Trp) fluorescence lifetimes are physiologically important properties. The time-resolved fluorescence spectra of single Trps in human gamma D- and gamma S-Crystallins have been measured with both an upconversion spectrophoto-fluorometer on the 300 fs to 100 ps time scale, and a time correlated single photon counting apparatus on the 100 ps to 10 ns time scale, respectively. Three Trps in each wild type protein were replaced by phenylalanine, leading to single-Trp mutants: W68-only and W156-only of H gamma D- and W72-only and W162-only of HyS-Crystallin. These proteins exhibit similar ultrafast signatures: positive definite decay associated spectra (DAS) for 50-65 ps decay constants that indicate dominance of fast, heterogeneous quenching. The quenched population (judged by amplitude) of this DAS differs among mutants. Trps 68, 156 in human gamma D- and Trp72 in human gamma S-Crystallin are buried, but water can reach amide oxygen and ring HE1 atoms through narrow channels. QM-MM simulations of quenching by electron transfer predict heterogeneous decay times from 50-500 ps that agree with our experimental results. Further analysis of apparent radiative lifetimes allow us to deduce that substantial subpopulations of Trp are fully quenched in even faster (sub-300 fs) processes for several of the mutants. The quenching of Trp fluorescence of human gamma D- and gamma S-Crystallin may protect them from ambient light induced photo damage. C1 [Xu, Jianhua; Tcherkasskaya, Olga; Knutson, Jay R.] NHLBI, Opt Spect Sect, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Chen, Jiejin; King, Jonathan] MIT, Dept Biol, Cambridge, MA 02139 USA. [Toptygin, Dmitri; Brand, Ludwig] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Callis, Patrik] Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. RP Knutson, JR (reprint author), NHLBI, Opt Spect Sect, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. EM jaysan@helix.nih.gov FU NIH [GM 38759, GM 17980]; NHLBI; NSF [MCB 0416965, MCB 0719248, MCB-0133064, MCB-0446542]; NEI [EY 015834] FX This research was supported [in part] by the Intramural Research Program of the NIH, NHLBI. This work was also supported by NIH grant GM 38759, GM 17980 and by NSF grants MCB 0416965, MCB 0719248, MCB-0133064, MCB-0446542 and NEI Grant EY 015834. NR 54 TC 16 Z9 16 U1 3 U2 30 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 NOV 25 PY 2009 VL 131 IS 46 BP 16751 EP 16757 DI 10.1021/ja904857t PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 525AL UT WOS:000272185400044 PM 19919143 ER PT J AU Noh, SJ Miller, SH Lee, YT Goh, SH Marincola, FM Stroncek, DF Reed, C Wang, E Miller, JL AF Noh, Seung-Jae Miller, Samuel H. Lee, Y. Terry Goh, Sung-Ho Marincola, Francesco M. Stroncek, David F. Reed, Christopher Wang, Ena Miller, Jeffery L. TI Let-7 microRNAs are developmentally regulated in circulating human erythroid cells SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID EXPRESSION PATTERNS; BREAST-CANCER; STEM-CELLS; DIFFERENTIATION; ERYTHROPOIESIS; TARGETS; LOCUS; DEATH AB Background: MicroRNAs are similar to 22nt-long small non-coding RNAs that negatively regulate protein expression through mRNA degradation or translational repression in eukaryotic cells. Based upon their importance in regulating development and terminal differentiation in model systems, erythrocyte microRNA profiles were examined at birth and in adults to determine if changes in their abundance coincide with the developmental phenomenon of hemoglobin switching. Methods: Expression profiling of microRNA was performed using total RNA from four adult peripheral blood samples compared to four cord blood samples after depletion of plasma, platelets, and nucleated cells. Labeled RNAs were hybridized to custom spotted arrays containing 474 human microRNA species (miRBase release 9.1). Total RNA from Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines provided a hybridization reference for all samples to generate microRNA abundance profile for each sample. Results: Among 206 detected miRNAs, 79% of the microRNAs were present at equivalent levels in both cord and adult cells. By comparison, 37 microRNAs were up-regulated and 4 microRNAs were down-regulated in adult erythroid cells (fold change > 2; p < 0.01). Among the up-regulated subset, the let-7 miRNA family consistently demonstrated increased abundance in the adult samples by array-based analyses that were confirmed by quantitative PCR (4.5 to 18.4 fold increases in 6 of 8 let-7 miRNA). Profiling studies of messenger RNA (mRNA) in these cells additionally demonstrated down-regulation of ten let-7 target genes in the adult cells. Conclusion: These data suggest that a consistent pattern of up-regulation among let-7 miRNA in circulating erythroid cells occurs in association with hemoglobin switching during the fetal-to-adult developmental transition in humans. C1 [Noh, Seung-Jae; Lee, Y. Terry; Goh, Sung-Ho; Miller, Jeffery L.] Natl Inst Diabet Digest & Kidney Dis, Mol Med Branch, NIH, Bethesda, MD USA. [Miller, Samuel H.; Marincola, Francesco M.; Stroncek, David F.; Wang, Ena] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Reed, Christopher] Natl Naval Med Ctr, Dept Obstet & Gynecol, Bethesda, MD USA. [Goh, Sung-Ho] Natl Canc Ctr, Goyang Si, Gyeonggi Do, South Korea. RP Miller, JL (reprint author), Natl Inst Diabet Digest & Kidney Dis, Mol Med Branch, NIH, Bethesda, MD USA. EM nohseung@niddk.nih.gov; shm5061@psu.edu; tl100s@nih.gov; andrea@ncc.re.kr; FMarincola@cc.nih.gov; DStroncek@cc.nih.gov; Christopher.reed@med.navy.mil; EWang@cc.nih.gov; jm7f@nih.gov FU The Intramural Research Programs of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Clinical Center (Bethesda, MD) FX The Intramural Research Programs of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Clinical Center (Bethesda, MD) supported this research. We are additionally thankful for technical assistance from the NIDDK's microarray core facility. NR 26 TC 24 Z9 26 U1 0 U2 6 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 NOV 25 PY 2009 VL 7 AR 98 DI 10.1186/1479-5876-7-98 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 536NA UT WOS:000273049900001 PM 19939273 ER PT J AU Robbiani, DF Bunting, S Feldhahn, N Bothmer, A Camps, J Deroubaix, S McBride, KM Klein, IA Stone, G Eisenreich, TR Ried, T Nussenzweig, A Nussenzweig, MC AF Robbiani, Davide F. Bunting, Samuel Feldhahn, Niklas Bothmer, Anne Camps, Jordi Deroubaix, Stephanie McBride, Kevin M. Klein, Isaac A. Stone, Gary Eisenreich, Thomas R. Ried, Thomas Nussenzweig, Andre Nussenzweig, Michel C. TI AID Produces DNA Double-Strand Breaks in Non-Ig Genes and Mature B Cell Lymphomas with Reciprocal Chromosome Translocations SO MOLECULAR CELL LA English DT Article ID CLASS-SWITCH RECOMBINATION; INDUCED CYTIDINE DEAMINASE; ACTIVATION-INDUCED DEAMINASE; SOMATIC HYPERMUTATION; V(D)J RECOMBINATION; C-MYC; ONCOGENIC TRANSLOCATIONS; GENOMIC INSTABILITY; ANTIBODY DIVERSITY; TUMOR AB Cancer-initiating translocations such as those associated with lymphomas require the formation of paired DNA double-strand breaks (DSBs). Activation-induced cytidine deaminase (AID) produces widespread somatic mutation in mature B cells; however, the extent of "off-target" DSB formation and its role in translocation-associated malignancy is unknown. Here, we show that deregulated expression of AID causes widespread genome instability, which alone is insufficient to induce B cell lymphoma; transformation requires concomitant loss of the tumor suppressor p53. Mature B cell lymphomas arising as a result of deregulated AID expression are phenotypically diverse and harbor clonal reciprocal translocations involving a group of Immunoglobulin (Ig) and non-Ig genes that are direct targets of AID. This group includes miR-142, a previously unknown micro-RNA target that is translocated in human B cell malignancy. We conclude that AID produces DSBs throughout the genome, which can lead to lymphoma-associated chromosome translocations in mature B cells. C1 [Robbiani, Davide F.; Feldhahn, Niklas; Bothmer, Anne; Deroubaix, Stephanie; McBride, Kevin M.; Klein, Isaac A.; Eisenreich, Thomas R.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Eisenreich, Thomas R.; Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Bunting, Samuel; Nussenzweig, Andre] Natl Canc Inst, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Camps, Jordi; Stone, Gary; Ried, Thomas] Natl Canc Inst, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussen@mail.rockefeller.edu RI mcbride, kevin/E-8230-2011 FU Fondazione Ettore e Valeria Rossi; NIH [AI037526, GM07739]; National Cancer Institute; Center for Cancer Research; Leukemia and Lymphoma Society; HHMI Investigator FX We thank all members of the Nussenzweig labs for discussions, Klara Velinzon for FACSorting, and David Bosque for help in managing the mouse colonies. The work was supported, in part, by a Fondazione Ettore e Valeria Rossi grant to D.F.R. and by an NIH grant to M.C.N. (AI037526). A.N. and S.B. were supported by the Intramural Research Program of the NIH, National Cancer Institute, and the Center for Cancer Research. I.A.K. was supported by NIH MSTP grant GM07739. D.F.R. was and N.F. is a Fellow of the Leukemia and Lymphoma Society. A.B. is a predoctoral Fellow of the Cancer Research Institute, and M.C.N. is an HHMI Investigator. NR 73 TC 142 Z9 143 U1 1 U2 11 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 NOV 25 PY 2009 VL 36 IS 4 BP 631 EP 641 DI 10.1016/j.molcel.2009.11.007 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 529RL UT WOS:000272534800011 PM 19941823 ER PT J AU Sing, GC Joiner, WM Nanayakkara, T Brayanov, JB Smith, MA AF Sing, Gary C. Joiner, Wilsaan M. Nanayakkara, Thrishantha Brayanov, Jordan B. Smith, Maurice A. TI Primitives for Motor Adaptation Reflect Correlated Neural Tuning to Position and Velocity SO NEURON LA English DT Article ID DEPENDENT FORCE-FIELDS; MUSCLE SYNERGIES; INTERNAL-MODELS; ADAPTIVE-CONTROL; WORKING-MEMORY; MOVEMENT; CEREBELLUM; DYNAMICS; ARM; REPRESENTATION AB The motor commands required to control voluntary movements under various environmental conditions may be formed by adaptively combining a fixed set of motor primitives. Since this motor output must contend with state-dependent physical dynamics during movement, these primitives are thought to depend on the position and velocity of motion. Using a recently developed "error-clamp" technique, we measured the fine temporal structure of changes in motor output during adaptation. Interestingly, these measurements reveal that motor primitives echo a key feature of the neural coding of limb motion-correlated tuning to position and velocity. We show that this correlated tuning explains why initial stages of motor learning are often rapid and stereotyped, whereas later stages are slower and stimulus specific. With our new understanding of these primitives, we design dynamic environments that are intrinsically the easiest or most difficult to learn, suggesting a theoretical basis for the rational design of improved procedures for motor training and rehabilitation. C1 [Sing, Gary C.; Nanayakkara, Thrishantha; Brayanov, Jordan B.; Smith, Maurice A.] Harvard Univ, Neuromotor Control Lab, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Joiner, Wilsaan M.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Smith, Maurice A.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. RP Smith, MA (reprint author), Harvard Univ, Neuromotor Control Lab, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. EM mas@seas.harvard.edu RI Nanayakkara, Thrishantha/B-1504-2008 FU McKnight Endowment for Neuroscience; Alfred P. Sloan Foundation; Wallace H. Coulter Foundation FX We wish to thank Mark Wagner and Emery Brown for helpful discussions. This work was supported by grants from the McKnight Endowment for Neuroscience, the Alfred P. Sloan Foundation, and the Wallace H. Coulter Foundation to M.A.S. The authors have declared that no competing interests exist. NR 65 TC 47 Z9 47 U1 2 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD NOV 25 PY 2009 VL 64 IS 4 BP 575 EP 589 DI 10.1016/j.neuron.2009.10.001 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 527PL UT WOS:000272378900014 PM 19945398 ER PT J AU Deakin, IH Law, AJ Oliver, PL Schwab, MH Nave, KA Harrison, PJ Bannerman, DM AF Deakin, Inga H. Law, Amanda J. Oliver, Peter L. Schwab, Markus H. Nave, Klaus Armin Harrison, Paul J. Bannerman, David M. TI Behavioural characterization of neuregulin 1 type I overexpressing transgenic mice SO NEUROREPORT LA English DT Article DE behavioural phenotype; neuregulin; schizophrenia; transgenic ID SCHIZOPHRENIA; GENE; SUSCEPTIBILITY; NEUROBIOLOGY; EXPRESSION; KNOCKOUT; VARIANT; MODELS; RISK AB Neuregulin 1 (NRG1) is a pleiotropic growth factor involved in diverse aspects of brain development and function. In schizophrenia, expression of the NRG1 type I isoform is selectively increased. However, virtually nothing is known about the roles of this isoform in brain. We have studied transgenic mice overexpressing type I NRG1 (NRG1(type 1-tg)) using a series of behavioural tests. NRG1(type 1-tg) mice have a tremor, are impaired on the accelerating rotarod, and have reduced prepulse inhibition in the context of an increased baseline startle response. There is no overall anxiety or activity phenotype, although female NRG1(type 1-tg) mice show mild increases in anxiety on some measures. The pattern of results shows both similarities and differences to those reported in hypomorphic NRG1 mice, and may be relevant for interpreting the increased NRG1 type I expression observed in schizophrenia. NeuroReport 20:1523-1528 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Deakin, Inga H.; Law, Amanda J.; Harrison, Paul J.] Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England. [Oliver, Peter L.] Univ Oxford, MRC, Funct Genom Unit, Dept Physiol Anat & Genet, Oxford OX3 7JX, England. [Bannerman, David M.] Univ Oxford, Dept Expt Psychol, Oxford OX3 7JX, England. [Law, Amanda J.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Schwab, Markus H.; Nave, Klaus Armin] Max Planck Inst Expt Med, Dept Neurogenet, D-37075 Gottingen, Germany. RP Harrison, PJ (reprint author), Univ Oxford, Warneford Hosp, Dept Psychiat, Neurosci Bldg, Oxford OX3 7JX, England. EM paul.harrison@psych.ox.ac.uk RI Oliver, Peter/F-1453-2010; Nave, Klaus-Armin/C-8883-2011; Law, Amanda/G-6372-2012; OI Law, Amanda/0000-0002-2574-1564 FU Wellcome Trust; UK Medical Research Council; National Multiple Sclerosis Society; Deutsche Forschungsgemeinschaft FX The authors thank Phil Burnet, Rob Deacon, Sharon Eastwood, Amy Taylor and Mary Walker for their contributions. I.H.D. and D.M.B. are supported by the Wellcome Trust. AJ.L. is supported by the UK Medical Research Council. M.H.S. and K.A.N. acknowledge grant support from the National Multiple Sclerosis Society and the Deutsche Forschungsgemeinschaft (CMPB). NR 25 TC 39 Z9 41 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD NOV 25 PY 2009 VL 20 IS 17 BP 1523 EP 1528 DI 10.1097/WNR.0b013e328330f6e7 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 520NQ UT WOS:000271852500004 PM 19829162 ER PT J AU Hall, KD Guo, J Dore, M Chow, CC AF Hall, Kevin D. Guo, Juen Dore, Michael Chow, Carson C. TI The Progressive Increase of Food Waste in America and Its Environmental Impact SO PLOS ONE LA English DT Article ID BODY-WEIGHT; ENERGY-EXPENDITURE; FAT; MASS AB Food waste contributes to excess consumption of freshwater and fossil fuels which, along with methane and CO2 emissions from decomposing food, impacts global climate change. Here, we calculate the energy content of nationwide food waste from the difference between the US food supply and the food consumed by the population. The latter was estimated using a validated mathematical model of metabolism relating body weight to the amount of food eaten. We found that US per capita food waste has progressively increased by similar to 50% since 1974 reaching more than 1400 kcal per person per day or 150 trillion kcal per year. Food waste now accounts for more than one quarter of the total freshwater consumption and similar to 300 million barrels of oil per year. C1 [Hall, Kevin D.; Guo, Juen; Dore, Michael; Chow, Carson C.] NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. RP Hall, KD (reprint author), NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov; carsonc@niddk.nih.gov RI Hall, Kevin/F-2383-2010; Chow, Carson/A-7970-2009 FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 133 Z9 136 U1 19 U2 92 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 NOV 25 PY 2009 VL 4 IS 11 AR e7940 DI 10.1371/journal.pone.0007940 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MK UT WOS:000272827800008 PM 19946359 ER PT J AU Koushik, SV Blank, PS Vogel, SS AF Koushik, Srinagesh V. Blank, Paul S. Vogel, Steven S. TI Anomalous Surplus Energy Transfer Observed with Multiple FRET Acceptors SO PLOS ONE LA English DT Article ID INTRINSICALLY FLUORESCENT PROTEINS; LIVING CELLS; SPECTROSCOPIC RULER; CRYSTAL-STRUCTURE; LIVE CELLS; ACTIVATION; MATURATION; MICROSCOPY; EFFICIENCY; DYNAMICS AB Background: Forster resonance energy transfer (FRET) is a mechanism where energy is transferred from an excited donor fluorophore to adjacent chromophores via non-radiative dipole-dipole interactions. FRET theory primarily considers the interactions of a single donor-acceptor pair. Unfortunately, it is rarely known if only a single acceptor is present in a molecular complex. Thus, the use of FRET as a tool for measuring protein-protein interactions inside living cells requires an understanding of how FRET changes with multiple acceptors. When multiple FRET acceptors are present it is assumed that a quantum of energy is either released from the donor, or transferred in toto to only one of the acceptors present. The rate of energy transfer between the donor and a specific acceptor (k(D -> A)) can be measured in the absence of other acceptors, and these individual FRET transfer rates can be used to predict the ensemble FRET efficiency using a simple kinetic model where the sum of all FRET transfer rates is divided by the sum of all radiative and non-radiative transfer rates. Methodology/Principal Findings: The generality of this approach was tested by measuring the ensemble FRET efficiency in two constructs, each containing a single fluorescent-protein donor (Cerulean) and either two or three FRET acceptors (Venus). FRET transfer rates between individual donor-acceptor pairs within these constructs were calculated from FRET efficiencies measured after systematically introducing point mutations to eliminate all other acceptors. We find that the amount of energy transfer observed in constructs having multiple acceptors is significantly greater than the FRET efficiency predicted from the sum of the individual donor to acceptor transfer rates. Conclusions/Significance: We conclude that either an additional energy transfer pathway exists when multiple acceptors are present, or that a theoretical assumption on which the kinetic model prediction is based is incorrect. C1 [Koushik, Srinagesh V.; Vogel, Steven S.] NIAAA, NIH, Rockville, MD 20852 USA. [Blank, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Vogel, SS (reprint author), NIAAA, NIH, Rockville, MD 20852 USA. EM stevevog@mail.nih.gov RI Vogel, Steven/A-3585-2012; OI Vogel, Steven/0000-0002-3005-2667 FU NIH; NIAAA FX This research was supported by the intramural research program of the NIH, NIAAA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 36 Z9 36 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 25 PY 2009 VL 4 IS 11 AR e8031 DI 10.1371/journal.pone.0008031 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MK UT WOS:000272827800019 PM 19946626 ER PT J AU Rodrigo, WWSI Block, OKT Lane, C Sukupolvi-Petty, S Goncalvez, AP Johnson, S Diamond, MS Lai, CJ Rose, RC Jin, X Schlesinger, JJ AF Rodrigo, W. W. Shanaka I. Block, Olivia K. T. Lane, Christopher Sukupolvi-Petty, Soila Goncalvez, Ana P. Johnson, Syd Diamond, Michael S. Lai, Ching-Juh Rose, Robert C. Jin, Xia Schlesinger, Jacob J. TI Dengue virus neutralization is modulated by IgG antibody subclass and Fc gamma receptor subtype SO VIROLOGY LA English DT Article DE Dengue virus; Virus neutralization; Humanized monoclonal antibody; Fc receptor ID HUMAN MONOCLONAL-ANTIBODY; WEST-NILE-VIRUS; DEPENDENT ENHANCEMENT; DIFFERENTIAL BINDING; CONSTANT-REGION; TYPE-2 VIRUSES; CELL-LINE; INFECTION; AFFINITY; DETERMINANTS AB Severe dengue virus (DENV) infection is epidemiologically linked to pre-existing anti-DENY antibodies acquired by maternal transfer or primary infection. A possible explanation is that DENY immune complexes evade neutralization by engaging Fc gamma receptors (Fc gamma R) on monocytes, natural targets for DENV in humans. Using epitope-matched humanized monoclonal antibodies (mAbs) and stable Fc gamma R-transfected CV-1 cells, we found that DENY neutralization by IgG1, IgG3, and IgG4 mAbs was enhanced in high-affinity Fc gamma RIA transfectants and diminished in low-affinity Fc gamma RIIA transfectants, whereas neutralization by IgG2 mAbs (low-affinity ligands for both Fc gamma Rs) was diminished equally. In Fc gamma R-negative Vero cells, IgG3 mAbs exhibited the strongest neutralizing activity and IgG2, the weakest. Our results demonstrate that DENY neutralization is modulated by the Fc region in an IgG subclass manner, likely through effects on virion and Fc gamma R binding. Thus, the IgG antibody subclass profile generated by DENY infection or vaccination may independently influence the magnitude of the neutralizing response. (C) 2009 Elsevier Inc. All rights reserved. C1 [Schlesinger, Jacob J.] Univ Rochester, Sch Med & Dent, Dept Med, Div Infect Dis, Rochester, NY 14642 USA. [Rodrigo, W. W. Shanaka I.] Univ Rochester, Dept Pathol & Lab Med, Rochester, NY 14642 USA. [Block, Olivia K. T.; Rose, Robert C.; Jin, Xia] Univ Rochester, Dept Microbiol & Immunol, Rochester, NY 14642 USA. [Sukupolvi-Petty, Soila; Diamond, Michael S.] Washington Univ, Dept Med, St Louis, MO 63110 USA. [Sukupolvi-Petty, Soila; Diamond, Michael S.] Washington Univ, Dept Mol Microbiol, St Louis, MO 63110 USA. [Sukupolvi-Petty, Soila; Diamond, Michael S.] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Goncalvez, Ana P.; Lai, Ching-Juh] NIH, Infect Dis Lab, Bethesda, MD 20892 USA. [Johnson, Syd] MacroGenics Inc, Rockville, MD 20850 USA. RP Schlesinger, JJ (reprint author), Univ Rochester, Sch Med & Dent, Dept Med, Div Infect Dis, Box 689,601 Elmwood Ave, Rochester, NY 14642 USA. EM jacob_schlesinger@urmc.rochester.edu FU Pediatric Dengue Vaccine Initiative of the International Vaccine Institute [TR 03/04, TR16]; NIH [R01 AI073755, U01AI77955] FX We thank Lihua Rong and Danielle Alcena for expert technical assistance. The work was funded by grants from the Pediatric Dengue Vaccine Initiative of the International Vaccine Institute (TR 03/04 to J.J.S.; TR16 to X.J.) and the NIH (R01 AI073755 and U01AI77955) to M.S.D. NR 30 TC 29 Z9 30 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 0042-6822 J9 VIROLOGY JI Virology PD NOV 25 PY 2009 VL 394 IS 2 BP 175 EP 182 DI 10.1016/j.virol.2009.09.024 PG 8 WC Virology SC Virology GA 521MC UT WOS:000271924500001 PM 19833371 ER PT J AU Haywood, LJ Ford, CE Crow, RS Davis, BR Massie, BM Einhorn, PT Williard, A AF Haywood, L. Julian Ford, Charles E. Crow, Richard S. Davis, Barry R. Massie, Barry M. Einhorn, Paula T. Williard, Angela CA ALLHAT Collaborative Res Grp TI Atrial Fibrillation at Baseline and During Follow-Up in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE hypertension; atrial fibrillation; clinical trial; chlorthalidone; amlodipine; lisinopril; doxazosin; pravastatin ID RANDOMIZED CONTROLLED-TRIALS; II RECEPTOR BLOCKADE; RISK-FACTORS; MAJOR OUTCOMES; BLOOD-PRESSURE; FAILURE; PREVALENCE; THERAPY; STROKE; CHLORTHALIDONE AB Objectives The ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) determined that treatment with amlodipine, lisinopril, or doxazosin was not superior to thiazide-like diuretic (chlorthalidone) in preventing coronary heart disease (CHD) or other cardiovascular events. This subanalysis examines baseline prevalence and in-trial incidence of new-onset atrial fibrillation (AF) or atrial flutter (AFL) and their influence on clinical outcomes. Background Limited information is available on whether atrial fibrillation incidence is affected differentially by different classes of antihypertensive medications or treatment with statins. Methods AF/AFL was identified from baseline and follow-up electrocardiograms performed biannually. Analyses were performed to identify characteristics associated with baseline AF/AFL and its subsequent incidence. Results AF/AFL was present at baseline in 423 participants (1.1%), more frequent in men (odds ratio: 1.72; 95% confidence interval [CI]: 1.37 to 2.17) and nonblacks (odds ratio: 2.09; 95% CI: 1.58 to 2.75). Its prevalence increased with age (p < 0.001) and was associated with CHD, cardiovascular disease, obesity, and high-density lipoprotein cholesterol <35 mg/dl. New-onset AF/AFL was associated with the same baseline risk factors plus electrocardiogram left ventricular hypertrophy. It occurred in 641 participants (2.0%) and, excluding doxazosin, did not differ by antihypertensive treatment group or, in a subset of participants, by pravastatin versus usual care. Baseline AF/AFL was associated with increased mortality (hazard ratio [HR]: 2.82; 95% CI: 2.36 to 3.37; p < 0.001), stroke (HR: 3.63; 95% CI: 2.72 to 4.86; p < 0.001), heart failure (HR: 3.17; 95% CI: 2.38 to 4.25; p < 0.001), and fatal CHD or nonfatal myocardial infarction (HR: 1.64; 95% CI: 1.22 to 2.21; p < 0.01). There was a nearly 2.5-fold increase in mortality risk when AF/AFL was present at baseline or developed during the trial (HR: 2.42; 95% CI: 2.11 to 2.77; p < 0.001). Conclusions In this high-risk hypertensive population, pre-existing and new-onset AF/AFL were associated with increased mortality. Excluding doxazosin, treatment assignment to either antihypertensive drugs or pravastatin versus usual care did not affect AF/AFL incidence. (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]; NCT00000542) (J Am Coll Cardiol 2009; 54:2023-31) (C) 2009 by the American College of Cardiology Foundation C1 [Haywood, L. Julian] Los Angeles Cty Univ So Calif Med Ctr, Los Angeles, CA USA. [Ford, Charles E.; Davis, Barry R.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX USA. [Crow, Richard S.] Univ Minnesota, Minneapolis, MN USA. [Massie, Barry M.] San Francisco VA Med Ctr, San Francisco, CA USA. [Einhorn, Paula T.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Williard, Angela] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. RP Ford, CE (reprint author), Univ Texas Sch Publ Hlth, 1200 Herman Pressler Dr,E-827, Houston, TX 77030 USA. EM charles.e.ford@uth.tmc.edu FU Pfizer, Inc FX From the Los Angeles County/University of Southern California Medical Center, Los Angeles, California; dagger University of Texas Health Science Center at Houston, School of Public Health, Houston, Texas; University of Minnesota, Minneapolis, Minnesota; San Francisco Veterans Affairs Medical Center, San Francisco, California; parallel to Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland; and the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana. This research was supported by Health and Human Services contract number N01-HC-35130 from the National Heart, Lung, and Blood Institute, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland. Additional financial support was provided by Pfizer, Inc. Study medications were supplied by Pfizer, Inc. (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin). Dr. Davis is on the Data Safety Monitoring Board of Takeda Pharmaceuticals. NR 35 TC 83 Z9 90 U1 3 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD NOV 24 PY 2009 VL 54 IS 22 BP 2023 EP 2031 DI 10.1016/j.jacc.2009.08.020 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 521EH UT WOS:000271902500006 PM 19926008 ER PT J AU Siebner, HR Callicott, JH Sommer, T Mattay, VS AF Siebner, H. R. Callicott, J. H. Sommer, T. Mattay, V. S. TI FROM THE GENOME TO THE PHENOME AND BACK: LINKING GENES WITH HUMAN BRAIN FUNCTION AND STRUCTURE USING GENETICALLY INFORMED NEUROIMAGING SO NEUROSCIENCE LA English DT Article DE brain mapping; genome; imaging genetics; neuroimaging; phenomics ID NEUROBIOLOGY; TRAITS AB In recent years, an array of brain mapping techniques has been successfully employed to link individual differences in circuit function or structure in the living human brain with individual variations in the human genome. Several proof-of-principle studies provided converging evidence that brain imaging can establish important links between genes and behaviour. The overarching goal is to use genetically informed brain imaging to pinpoint neurobiological mechanisms that contribute to behavioural intermediate phenotypes or disease states. This special issue on "Linking Genes to Brain Function in Health and Disease" provides an overview over how the "imaging genetics" approach is currently applied in the various fields of systems neuroscience to reveal the genetic underpinnings of complex behaviours and brain diseases. While the rapidly emerging field of imaging genetics holds great promise, the integration of genetic and neuroimaging data also poses major methodological and conceptual challenges. Therefore, this special issue also focuses on how these challenges can be met to fully exploit the synergism of genetically informed brain imaging. (C) 2009 Published by Elsevier Ltd on behalf of IBRO. C1 [Siebner, H. R.] Univ Copenhagen, Hvidovre Hosp, Danish Res Ctr Magnet Resonance, DK-1168 Copenhagen, Denmark. [Callicott, J. H.] NIMH, Unit Dynam Imaging Genet, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Sommer, T.] Univ Med Ctr Hamburg Eppendorf, Dept Syst Neurosci, Hamburg, Germany. [Mattay, V. S.] NIMH, Neuroimaging Core Facil, Genes Cognit & Psychosis Program, Intramural Res Program, Bethesda, MD 20892 USA. RP Siebner, HR (reprint author), Univ Copenhagen, Hvidovre Hosp, Danish Res Ctr Magnet Resonance, DK-1168 Copenhagen, Denmark. EM hartwig.siebner@drcmr.dk RI Siebner, Hartwig/G-4052-2016; OI Callicott, Joseph/0000-0003-1298-3334 FU Intramural NIH HHS [Z01 MH002905-01] NR 32 TC 6 Z9 6 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD NOV 24 PY 2009 VL 164 IS 1 BP 1 EP 6 DI 10.1016/j.neuroscience.2009.09.009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 517JI UT WOS:000271609000001 PM 19751805 ER PT J AU Dickinson, D Elvevag, B AF Dickinson, D. Elvevag, B. TI GENES, COGNITION AND BRAIN THROUGH A COMT LENS SO NEUROSCIENCE LA English DT Review DE prefrontal cortex; executive function; working memory ID CATECHOL-O-METHYLTRANSFERASE; TO-NOISE RATIO; CEREBRAL-BLOOD-FLOW; DEFICIT-HYPERACTIVITY-DISORDER; DORSOLATERAL PREFRONTAL CORTEX; VAL(108/158) MET GENOTYPE; VERBAL WORKING-MEMORY; DOPAMINE D1 RECEPTORS; VAL(158)MET GENOTYPE; PARKINSONS-DISEASE AB Various genes are known to modulate the delicate balance of dopamine in prefrontal cortex and influence cortical information processing. Catechol-O-methyltransferase (COMT) on chromosome 22q11 is the most widely studied of these genes. Val158Met, a common, functional variant in the coding sequence that increases or decreases the enzymatic activity of the gene has been shown to impact the efficiency of prefrontally-mediated cognition, specifically executive functioning, working memory, fluid intelligence and attentional control. We review the rapidly evolving literature exploring the association between COMT genotype and cognitive performance, and illustrate how this polymorphism has served a pivotal role in characterizing various interacting dimensions of complexity in the relationship between genes and cognition. We review how Val158Met has been used to help develop and validate behavioral and neurophysiological phenotypes, as a critical tool in dissecting overlapping neural functional systems and exploring interactions within and between genes, and in exploring how gene effects on cognition are modulated by environmental, demographic and developmental factors. Despite the impressive range of findings, the COMT story is also a bracing reminder of how much work remains to translate this knowledge into practical clinical applications. Published by Elsevier Ltd on behalf of IBRO. C1 [Dickinson, D.; Elvevag, B.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Dickinson, D.] Univ Maryland, Sch Med, Dept Psychiat, VISN MIRECC, Baltimore, MD 21201 USA. RP Dickinson, D (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,3C104,MSC 1379, Bethesda, MD 20892 USA. EM Dwight.Dickinson@nih.gov; brita@elvevaag.net FU National Institute of Mental Health, National Institutes of Health FX We thank Daniel Weinberger for his inspiration and insight concerning the genetics of cognition. This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. NR 129 TC 93 Z9 97 U1 0 U2 10 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 NOV 24 PY 2009 VL 164 IS 1 SI SI BP 72 EP 87 DI 10.1016/j.neuroscience.2009.05.014 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 517JI UT WOS:000271609000007 PM 19446012 ER PT J AU Savitz, JB Drevets, WC AF Savitz, J. B. Drevets, W. C. TI IMAGING PHENOTYPES OF MAJOR DEPRESSIVE DISORDER: GENETIC CORRELATES SO NEUROSCIENCE LA English DT Review DE endophenotype; 5-HT1A receptor; serotonin transporter; major depressive disorder; genome-wide association; epigenetics ID SEROTONIN TRANSPORTER BINDING; POSITRON-EMISSION-TOMOGRAPHY; WHITE-MATTER HYPERINTENSITIES; LATE-LIFE DEPRESSION; FACTOR VAL66MET POLYMORPHISM; REDUCED HIPPOCAMPAL VOLUMES; SUBGENUAL PREFRONTAL CORTEX; MESSENGER-RNA EXPRESSION; GENOME-WIDE ASSOCIATION; FUNCTIONAL MAGNETIC-RESONANCE AB Imaging techniques are a potentially powerful method of identifying phenotypes that are associated with, or are indicative of, a vulnerability to developing major depressive disorder (MDD). Here we identify seven promising MDD-associated traits identified by magnetic resonance imaging (MRI) or positron emission tomography (PET). We evaluate whether these traits are state-independent, heritable endophenotypes, or state-dependent phenotypes that may be useful markers of treatment efficacy. In MDD, increased activity of the amygdala in response to negative stimuli appears to be a mood-congruent phenomenon, and is likely moderated by the 5-HT transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR). Hippocampal volume loss is characteristic of elderly or chronically-ill samples and may be impacted by the val66met brain-derived neurotrophic factor (BDNF) gene variant and the 5-HTTLPR SLC6A4 polymorphism. White matter pathology is salient in elderly MDD cohorts but is associated with cerebrovascular disease, and is unlikely to be a useful marker of a latent MDD diathesis. Increased blood flow or metabolism of the subgenual anterior cingulate cortex (sgACC), together with gray matter volume loss in this region, is a well-replicated finding in MDD. An attenuation of the usual pattern of fronto-limbic connectivity, particularly a decreased temporal correlation in amygdala-anterior cingulate cortex (ACC) activity, is another MDD-associated trait. Concerning neuroreceptor PET imaging, decreased 5-HT(1A) binding potential in the raphe, medial temporal lobe, and medial prefrontal cortex (mPFC) has been strongly associated with MDD, and may be impacted by a functional single nucleotide polymorphism in the promoter region of the 5-HT(1A) gene (HTR1A: -1019 C/G; rs6295). Potentially indicative of inter-study variation in MDD etiology or mood state, both increased and decreased binding potential of the 5-HT transporter has been reported. Challenges facing the field include the problem of phenotypic and etiological heterogeneity, technological limitations, the confounding effects of medication, and non-disease related inter-individual variation in brain morphology and function. Further advances are likely as epigenetic, copy-number variant, gene-gene interaction, and genome-wide association (GWA) approaches are brought to bear on imaging data. Published by Elsevier Ltd on behalf of IBRO. C1 [Savitz, J. B.; Drevets, W. C.] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Savitz, JB (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, B15K,North Dr, Bethesda, MD 20892 USA. EM savitzj@mail.nih.gov RI Savitz, Jonathan/C-3088-2009 OI Savitz, Jonathan/0000-0001-8143-182X FU Intramural NIH HHS [Z99 MH999999] NR 362 TC 124 Z9 134 U1 10 U2 34 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 NOV 24 PY 2009 VL 164 IS 1 BP 300 EP 330 DI 10.1016/j.neuroscience.2009.03.082 PG 31 WC Neurosciences SC Neurosciences & Neurology GA 517JI UT WOS:000271609000025 PM 19358877 ER PT J AU Agarwal, R Mori, Y Cheng, YL Jin, Z Olaru, AV Hamilton, JP David, S Selaru, FM Yang, J Abraham, JM Montgomery, E Morin, PJ Meltzer, SJ AF Agarwal, Rachana Mori, Yuriko Cheng, Yulan Jin, Zhe Olaru, Alexandru V. Hamilton, James P. David, Stefan Selaru, Florin M. Yang, Jian Abraham, John M. Montgomery, Elizabeth Morin, Patrice J. Meltzer, Stephen J. TI Silencing of Claudin-11 Is Associated with Increased Invasiveness of Gastric Cancer Cells SO PLOS ONE LA English DT Article ID TIGHT JUNCTION; MICROSATELLITE INSTABILITY; PROMOTER METHYLATION; DOWN-REGULATION; HMLH1 PROMOTER; GENE PROMOTER; EXPRESSION; CARCINOMA; PROTEIN; HYPERMETHYLATION AB Background: Claudins are membrane proteins that play critical roles in tight junction (TJ) formation and function. Members of the claudin gene family have been demonstrated to be aberrantly regulated, and to participate in the pathogenesis of various human cancers. In the present study, we report that claudin-11 (CLDN11) is silenced in gastric cancer via hypermethylation of its promoter region. Methodology/Principal Findings: Levels of CLDN11 methylation and mRNA expression were measured in primary gastric cancer tissues, noncancerous gastric mucosae, and cell lines of gastric origin using quantitative methylation-specific PCR (qMSP) and quantitative reverse transcriptase-PCR (qRT-PCR), respectively. Analyses of paired gastric cancers and adjacent normal gastric tissues revealed hypermethylation of the CLDN11 promoter region in gastric cancers, and this hypermethylation was significantly correlated with downregulation of CLDN11 expression vs. normal tissues. The CLDN11 promoter region was also hypermethylated in all gastric cancer cell lines tested relative to immortalized normal gastric epithelial cells. Moreover, CLDN11 mRNA expression was inversely correlated with its methylation level. Treatment of CLDN11-nonexpressing gastric cancer cells with 5-aza-29-deoxycytidine restored CLDN11 expression. Moreover, siRNA-mediated knockdown of CLDN11 expression in normal gastric epithelial cells increased their motility and invasiveness. Conclusions/Significance: These data suggest that hypermethylation of CLDN11, leading to downregulated expression, contributes to gastric carcinogenesis by increasing cellular motility and invasiveness. A further understanding of the mechanisms underlying the role of claudin proteins in gastric carcinogenesis will likely help in the identification of novel approaches for diagnosis and therapy of gastric cancer. C1 [Agarwal, Rachana; Mori, Yuriko; Cheng, Yulan; Jin, Zhe; Olaru, Alexandru V.; Hamilton, James P.; David, Stefan; Selaru, Florin M.; Yang, Jian; Abraham, John M.; Meltzer, Stephen J.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Montgomery, Elizabeth] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Morin, Patrice J.] NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. RP Agarwal, R (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. EM ragarwa9@jhmi.edu FU United States National Institutes of Health [CA085069, CA138677, CA146799] FX This work was supported by the United States National Institutes of Health grants CA085069, CA138677 and CA146799 to SJ Meltzer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 41 Z9 44 U1 0 U2 5 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 NOV 24 PY 2009 VL 4 IS 11 AR e8002 DI 10.1371/journal.pone.0008002 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MH UT WOS:000272827500027 PM 19956721 ER PT J AU Choi, J Oh, S Lee, D Oh, HJ Park, JY Lee, SB Lim, DS AF Choi, Juhyun Oh, Sangphil Lee, Dongjun Oh, Hyun Jung Park, Jik Young Lee, Sean Bong Lim, Dae-Sik TI Mst1-FoxO Signaling Protects Naive T Lymphocytes from Cellular Oxidative Stress in Mice SO PLOS ONE LA English DT Article ID STERILE-20 KINASE; HISTONE H2B; IN-VIVO; CELLS; APOPTOSIS; RECEPTOR; MST1; PHOSPHORYLATION; PROLIFERATION; TRANSLOCATION AB Background: The Ste-20 family kinase Hippo restricts cell proliferation and promotes apoptosis for proper organ development in Drosophila. In C. elegans, Hippo homolog also regulates longevity. The mammalian Ste20-like protein kinase, Mst1, plays a role in apoptosis induced by various types of apoptotic stress. Mst1 also regulates peripheral naive T cell trafficking and proliferation in mice. However, its functions in mammals are not fully understood. Methodology/Principal Findings: Here, we report that the Mst1-FoxO signaling pathway plays a crucial role in survival, but not apoptosis, of naive T cells. In Mst1(-/-) mice, peripheral T cells showed impaired FoxO1/3 activation and decreased FoxO protein levels. Consistently, the FoxO targets, Sod2 and catalase, were significantly down-regulated in Mst1(-/-) T cells, thereby resulting in elevated levels of intracellular reactive oxygen species (ROS) and induction of apoptosis. Expression of constitutively active FoxO3a restored Mst1(-/-) T cell survival. Crossing Mst1 transgenic mice (Mst1 Tg) with Mst1(-/-) mice reduced ROS levels and restored normal numbers of peripheral naive T cells in Mst1 Tg; Mst1(-/-) progeny. Interestingly, peripheral T cells from Mst1(-/-) mice were hypersensitive to gamma-irradiation and paraquat-induced oxidative stresses, whereas those from Mst1 Tg mice were resistant. Conclusions/Significance: These data support the hypothesis that tolerance to increased levels of intracellular ROS provided by the Mst1-FoxOs signaling pathway is crucial for the maintenance of naive T cell homeostasis in the periphery. C1 [Choi, Juhyun; Oh, Sangphil; Lee, Dongjun; Oh, Hyun Jung; Lim, Dae-Sik] Korea Adv Inst Sci & Technol, Natl Res Lab Mol Genet, Dept Biol Sci, Biomed Res Ctr, Taejon 305701, South Korea. [Park, Jik Young; Lee, Sean Bong] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Choi, J (reprint author), Korea Adv Inst Sci & Technol, Natl Res Lab Mol Genet, Dept Biol Sci, Biomed Res Ctr, Taejon 305701, South Korea. EM daesiklim@kaist.ac.kr RI Lim, Dae-Sik/C-1599-2011; OI Lim, Dae-Sik/0000-0003-2356-7555; lee, dongjun/0000-0001-6828-401X FU NRL (National Research Laboratory) Program; Nuclear Research Grant; 21st Century Frontier Functional Human Genome Project FX This study was supported by grants from the NRL (National Research Laboratory) Program, a Nuclear Research Grant, and the 21st Century Frontier Functional Human Genome Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 53 Z9 53 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 24 PY 2009 VL 4 IS 11 AR e8011 DI 10.1371/journal.pone.0008011 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MH UT WOS:000272827500034 PM 19956688 ER PT J AU May, K Grube, M Malhotra, I Long, CA Singh, S Mandaliya, K Siegmund, W Fusch, C Schneider, H King, CL AF May, Karen Grube, Markus Malhotra, Indu Long, Carole A. Singh, Sanjay Mandaliya, Kishor Siegmund, Werner Fusch, Christoph Schneider, Henning King, Christopher L. TI Antibody-Dependent Transplacental Transfer of Malaria Blood-Stage Antigen Using a Human Ex Vivo Placental Perfusion Model SO PLOS ONE LA English DT Article ID MEROZOITE SURFACE PROTEIN-1; UMBILICAL-CORD-BLOOD; PLASMODIUM-FALCIPARUM INFECTION; PAPUA-NEW-GUINEA; IMMUNE-COMPLEXES; IN-VITRO; DIAPLACENTAL TRANSPORT; ERYTHROCYTE INVASION; IMMUNOGLOBULIN-G; FC-RECEPTORS AB Prenatal exposure to allergens or antigens released by infections during pregnancy can stimulate an immune response or induce immunoregulatory networks in the fetus affecting susceptibility to infection and disease later in life. How antigen crosses from the maternal to fetal environment is poorly understood. One hypothesis is that transplacental antigen transfer occurs as immune complexes, via receptor-mediated transport across the syncytiotrophoblastic membrane and endothelium of vessels in fetal villi. This hypothesis has never been directly tested. Here we studied Plasmodium falciparum merozoite surface protein 1 (MSP1) that is released upon erythrocyte invasion. We found MSP1 in cord blood from a third of newborns of malaria-infected women and in >90% following treatment with acid dissociation demonstrating MSP1 immune complexes. Using an ex vivo human placental model that dually perfuses a placental cotyledon with independent maternal and fetal circuits, immune-complexed MSP1 transferred from maternal to fetal circulation. MSP1 alone or with non-immune plasma did not transfer; pre-incubation with human plasma containing anti-MSP1 was required. MSP1 bound to IgG was detected in the fetal perfusate. Laser scanning confocal microscopy demonstrated MSP1 in the fetal villous stroma, predominantly in fetal endothelial cells. MSP1 co-localized with IgG in endothelial cells, but not with placental macrophages. Thus we show, for the first time, antibody-dependent transplacental transfer of an antigen in the form of immune complexes. These studies imply frequent exposure of the fetus to certain antigens with implications for management of maternal infections during pregnancy and novel approaches to deliver vaccines or drugs to the fetus. C1 [May, Karen; Grube, Markus; Siegmund, Werner] Ernst Moritz Arndt Univ Greifswald, Dept Pharmacol, Greifswald, Germany. [Fusch, Christoph] Ernst Moritz Arndt Univ Greifswald, Dept Pediat, Greifswald, Germany. [Malhotra, Indu; King, Christopher L.] Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. [Long, Carole A.; Singh, Sanjay] NIH, Malaria Vaccine Dev Unit, Bethesda, MD 20892 USA. [Long, Carole A.; Singh, Sanjay] NIH, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Mandaliya, Kishor] Mombasa Gen Hosp, Kenyan Minist Hlth, Pathol Serv, Mombasa, Kenya. [Schneider, Henning] Univ Bern, Dept Obstet & Gynecol, CH-3000 Bern, Switzerland. [King, Christopher L.] Louis B Stokes Vet Affairs Med Ctr, Cleveland, OH USA. RP May, K (reprint author), Ernst Moritz Arndt Univ Greifswald, Dept Pharmacol, Greifswald, Germany. EM cxk21@case.edu FU Departments of Pharmacology and Pediatrics, Ernst Moritz Arndt University of Greifswald; National Institutes of Health [AI064687]; Veterans Affairs Research Service FX This work was supported by Departments of Pharmacology and Pediatrics, Ernst Moritz Arndt University of Greifswald, National Institutes of Health grant AI064687, and the Veterans Affairs Research Service. HS was Alfried Krupp Wissenschaftskolleg Fellow. The Department of Obstetrics and Gynecology, University of Greifswald provided the fresh placentas for the perfusion studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 25 Z9 25 U1 0 U2 5 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 NOV 24 PY 2009 VL 4 IS 11 AR e7986 DI 10.1371/journal.pone.0007986 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MH UT WOS:000272827500016 PM 19956710 ER PT J AU Stevens, LA Levine, RL Gochuico, BR Moss, J AF Stevens, Linda A. Levine, Rodney L. Gochuico, Bernadette R. Moss, Joel TI ADP-ribosylation of human defensin HNP-1 results in the replacement of the modified arginine with the noncoded amino acid ornithine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE posttranslational modification; NAD; bacterial toxins ID HUMAN NEUTROPHIL PEPTIDE-1; EPITHELIAL-CELLS; ALPHA-DEFENSINS; RIBOSYLTRANSFERASE ACTIVITY; ADVANCED GLYCATION; RIBOSE; PROTEINS; FIBROSIS; COLLAGEN; ANALOGS AB Defensins ( e. g., human neutrophil peptides, or HNPs) contribute to innate immunity through diverse actions, including microbial killing; high concentrations are present in the lung in response to inflammation. Arginines are critical for HNP activity, which is decreased by their replacement with ornithine. ADP-ribosyltransferases (ARTs) catalyze transfer of ADP-ribose from NAD to an acceptor arginine in a protein substrate, whereas ADP-ribosylarginine hydrolases release ADPribose. ART1 on the surface of airway epithelial cells ADP-ribosylated HNP-1 specifically on arginines 14 and 24, with ADP-ribosylation altering biological activity. Di- and mono-ADP-ribosylated HNP-1 were isolated from bronchoalveolar lavage fluid (BALF) of patients with asthma and idiopathic pulmonary fibrosis (IPF), suggesting a role for ADP-ribosylation in disease. In the present study, we observed that ART1-catalyzed ADP-ribosylation of HNP-1 in vitro generated a product with ADP-ribose on arginine 24, and ornithine replacing arginine at position 14. We hypothesized that ADP-ribosylarginine is susceptible to a nonenzymatic hydrolytic reaction yielding ornithine. On incubation of di- or mono-ADP-ribosyl-HNP-1 at 37 degrees C, ADP-ribosylarginine was partially replaced by ornithine, whereas ornithine was not detected by amino acid analysis and mass spectrometry of unmodified HNP-1 incubated under the same conditions. Further, ornithine was produced from the model compound, ADP-ribosylarginine. BALF from an IPF patient contained ADP-ribosyl-HNP-ornithine as well as mono- and di-ADP-ribosylated HNP-1, consistent with in vivo conversion of arginine to ornithine. Targeted ADP-ribosylation of specific arginines by transferases, resulting in their replacement with ornithine, is an alternative pathway for regulation of protein function through posttranslational modification. C1 [Stevens, Linda A.; Moss, Joel] NHLBI, Translat Med Branch, Bethesda, MD 20892 USA. [Levine, Rodney L.] NHLBI, Biochem Lab, Bethesda, MD 20892 USA. [Gochuico, Bernadette R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Translat Med Branch, Bldg 10, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov RI Levine, Rodney/D-9885-2011 FU National Institutes of Health, National Heart, Lung, and Blood Institute FX We thank Dr. Martha Vaughan and Dr. Gustavo Pacheco-Rodriguez (National Heart, Lung, and Blood Institute) for helpful discussions and critical review of the manuscript. These studies were supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute. NR 32 TC 26 Z9 27 U1 1 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 NOV 24 PY 2009 VL 106 IS 47 BP 19796 EP 19800 DI 10.1073/pnas.0910633106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524YS UT WOS:000272180900013 PM 19897717 ER PT J AU Hailfinger, S Lenz, G Ngo, V Posvitz-Fejfar, A Rebeaud, F Guzzardi, M Penas, EMM Dierlamm, J Chan, WC Staudt, LM Thome, M AF Hailfinger, Stephan Lenz, Georg Ngo, Vu Posvitz-Fejfar, Anita Rebeaud, Fabien Guzzardi, Montserrat Penas, Eva-Maria Murga Dierlamm, Judith Chan, Wing C. Staudt, Louis M. Thome, Margot TI Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DLBCL; NF-kB ID NF-KAPPA-B; T-CELL; C-FLIP; EXPRESSION; LYMPHOCYTES; INHIBITORS; CARMA1; DIFFERENTIATION; CHEMOTHERAPY; MALIGNANCIES AB A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is relevant for tumor growth. Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype. Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines. These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy. C1 [Hailfinger, Stephan; Posvitz-Fejfar, Anita; Rebeaud, Fabien; Guzzardi, Montserrat; Thome, Margot] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Lenz, Georg; Ngo, Vu; Staudt, Louis M.] NCI, Ctr Canc Res, Metab Branch, Bethesda, MD 20892 USA. [Penas, Eva-Maria Murga; Dierlamm, Judith] Univ Med Ctr Hamburg Eppendorf, Dept Hematol & Oncol, D-20246 Hamburg, Germany. [Chan, Wing C.] Univ Nebraska, Dept Pathol & Microbiol, Omaha, NE 68198 USA. RP Thome, M (reprint author), Univ Lausanne, Dept Biochem, Chemin Boveresses 155, CH-1066 Epalinges, Switzerland. EM margot.thomeMiazza@unil.ch RI Thome, Margot/F-8167-2011; Lenz, Georg/I-6844-2012; Murga Penas, Eva Maria/K-2897-2016 OI Thome, Margot/0000-0002-5656-2139; Murga Penas, Eva Maria/0000-0003-1000-4286 FU Swiss National Science Foundation; Swiss Cancer League; Pierre Mercier and Leenaards Foundations; National Institutes of Health, National Cancer Institute, Center for Cancer Research; German Merit Foundation; Faculty of Biology and Medicine of the University of Lausanne; German Research Foundation FX We thank Nicolas Fasel (Department of Biochemistry, University of Lausanne, Lausanne, Switzerland) and Nathalie Bonnefoy Berard (University of Lyon, Lyon, France) for reagents, Karen Leroy (Universite Paris 12, Faculte de Medecine, Creteil, France) and Peter Moller (Abteilung fur Pathologie des Universitatklinikums Ulm, Ulm, Germany) for cell lines, and members of the Thome laboratory for critical comments on the manuscript. This work was supported by grants from the Swiss National Science Foundation, the Swiss Cancer League, and the Pierre Mercier and Leenaards Foundations (to M. T.); the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; fellowships from the German Merit Foundation and the Faculty of Biology and Medicine of the University of Lausanne (to S. H.); and a research grant from the German Research Foundation (to G. L.). MLN120B was provided by Millennium Pharmaceuticals. NR 35 TC 101 Z9 102 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 24 PY 2009 VL 106 IS 47 BP 19946 EP 19951 DI 10.1073/pnas.0907511106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524YS UT WOS:000272180900039 PM 19897720 ER PT J AU Cottone, P Sabino, V Roberto, M Bajo, M Pockros, L Frihauf, JB Fekete, EM Steardo, L Rice, KC Grigoriadis, DE Conti, B Koob, GF Zorrilla, EP AF Cottone, Pietro Sabino, Valentina Roberto, Marisa Bajo, Michal Pockros, Lara Frihauf, Jennifer B. Fekete, Eva M. Steardo, Luca Rice, Kenner C. Grigoriadis, Dimitri E. Conti, Bruno Koob, George F. Zorrilla, Eric P. TI CRF system recruitment mediates dark side of compulsive eating SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE eating disorders; obesity; palatability; palatable food dependence; withdrawal ID DEPENDENT RATS; CENTRAL AMYGDALA; PREFERRED FOOD; LIMITED ACCESS; BODY-WEIGHT; FAT DIET; MODEL; INTERMITTENT; ADDICTION; BEHAVIOR AB Dieting to control body weight involves cycles of deprivation from palatable food that can promote compulsive eating. The present study shows that rats withdrawn from intermittent access to palatable food exhibit overeating of palatable food upon renewed access and an affective withdrawal-like state characterized by corticotropin-releasing factor-1 (CRF(1)) receptor antagonist-reversible behaviors, including hypophagia, motivational deficits to obtain less palatable food, and anxiogenic-like behavior. Withdrawal was accompanied by increased CRF expression and CRF(1) electrophysiological responsiveness in the central nucleus of the amygdala. We propose that recruitment of anti-reward extrahy-pothalamic CRF-CRF(1) systems during withdrawal from palatable food, analogous to abstinence from abused drugs, may promote compulsive selection of palatable food, undereating of healthier alternatives, and a negative emotional state when intake of palatable food is prevented. C1 [Cottone, Pietro; Sabino, Valentina; Roberto, Marisa; Pockros, Lara; Frihauf, Jennifer B.; Fekete, Eva M.; Koob, George F.; Zorrilla, Eric P.] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Cottone, Pietro; Sabino, Valentina; Roberto, Marisa; Frihauf, Jennifer B.; Fekete, Eva M.; Koob, George F.; Zorrilla, Eric P.] Scripps Res Inst, Pearson Ctr Alcoholism & Addict Res, La Jolla, CA 92037 USA. [Cottone, Pietro; Sabino, Valentina; Roberto, Marisa; Frihauf, Jennifer B.; Fekete, Eva M.; Conti, Bruno; Zorrilla, Eric P.] Scripps Res Inst, Harold L Dorris Neurol Res Inst, La Jolla, CA 92037 USA. [Bajo, Michal; Conti, Bruno] Scripps Res Inst, Dept Mol & Integrat Neurosci, La Jolla, CA 92037 USA. [Cottone, Pietro; Sabino, Valentina] Boston Univ, Sch Med, Lab Addict Disorders, Dept Pharmacol & Expt Therapeut, Boston, MA 02118 USA. [Frihauf, Jennifer B.] Univ Calif San Diego, Grad Program Neurosci, La Jolla, CA 92093 USA. [Steardo, Luca] Univ Roma La Sapienza, Dept Human Physiol & Pharmacol, I-00185 Rome, Italy. [Rice, Kenner C.] Natl Inst Drug Abuse, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, Kenner C.] Natl Inst Alcohol & Alcoholism, Bethesda, MD 20892 USA. [Grigoriadis, Dimitri E.] Neurocrine Biosci Inc, San Diego, CA 92130 USA. RP Cottone, P (reprint author), Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. EM cottone@bu.edu; ezorrilla@scripps.edu RI Cottone, Pietro/F-5291-2012; Sabino, Valentina/F-5290-2012; koob, george/P-8791-2016; OI Cottone, Pietro/0000-0003-1320-1672; Sabino, Valentina/0000-0002-6680-1279; Steardo, Luca/0000-0003-3570-2195 FU National Institute of Diabetes and Digestive and Kidney Diseases [DK70118, DK26741, P30DK56336]; National Institute on Drug Abuse [DA023680]; National Institute on Alcohol Abuse and Alcoholism [AA016731, AA015566]; National Institute of Neurological Disorders and Stroke [IT32NS061847-01A2]; National Institute on Aging [AG028040]; National Heart, Lung and Blood Institute [HL088083]; Ellison Medical Foundation; Pearson Center for Alcoholism and Addiction Research; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX We thank Mike Arends for editorial assistance, Mary Gichuhi for administrative assistance, and Bob Lintz, Jeanette Helfers, Stephanie Dela Cruz, and Molly Brennan for technical assistance. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK70118, DK26741, and P30DK56336; National Institute on Drug Abuse Grant DA023680; National Institute on Alcohol Abuse and Alcoholism Grants AA016731 and AA015566; National Institute of Neurological Disorders and Stroke Grant IT32NS061847-01A2; National Institute on Aging Grant AG028040; National Heart, Lung and Blood Institute Grant HL088083; the Ellison Medical Foundation; and the Pearson Center for Alcoholism and Addiction Research. A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. This is manuscript number 19807 from The Scripps Research Institute. NR 28 TC 83 Z9 84 U1 0 U2 1 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 NOV 24 PY 2009 VL 106 IS 47 BP 20016 EP 20020 DI 10.1073/pnas.0908789106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524YS UT WOS:000272180900051 PM 19901333 ER PT J AU Dasgupta, U Bamba, T Chiantia, S Karim, P Abou Tayoun, AN Yonamine, I Rawat, SS Rao, RP Nagashima, K Fukusaki, E Puri, V Dolph, PJ Schwille, P Acharya, JK Acharya, U AF Dasgupta, Ujjaini Bamba, Takeshi Chiantia, Salvatore Karim, Pusha Abou Tayoun, Ahmad N. Yonamine, Ikuko Rawat, Satinder S. Rao, Raghavendra Pralhada Nagashima, Kunio Fukusaki, Eiichiro Puri, Vishwajeet Dolph, Patrick J. Schwille, Petra Acharya, Jairaj K. Acharya, Usha TI Ceramide kinase regulates phospholipase C and phosphatidylinositol 4, 5, bisphosphate in phototransduction SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DROSOPHILA-MELANOGASTER; PROTEIN; EXPRESSION; DOMAINS; NORPA; GENE; DEGENERATION; CHOLESTEROL; TURNOVER; BILAYERS AB Phosphoinositide-specific phospholipase C (PLC) is a central effector for many biological responses regulated by G-protein-coupled receptors including Drosophila phototransduction where light sensitive channels are activated downstream of NORPA, a PLC beta homolog. Here we show that the sphingolipid biosynthetic enzyme, ceramide kinase, is a novel regulator of PLC signaling and photoreceptor homeostasis. A mutation in ceramide kinase specifically leads to proteolysis of NORPA, consequent loss of PLC activity, and failure in light signal transduction. The mutant photoreceptors also undergo activity-dependent degeneration. Furthermore, we show that a significant increase in ceramide, resulting from lack of ceramide kinase, perturbs the membrane microenvironment of phosphatidylinositol 4, 5, bisphosphate (PIP(2)), altering its distribution. Fluorescence image correlation spectroscopic studies on model membranes suggest that an increase in ceramide decreases clustering of PIP(2) and its partitioning into ordered membrane domains. Thus ceramide kinase-mediated maintenance of ceramide level is important for the local regulation of PIP(2) and PLC during phototransduction. C1 [Dasgupta, Ujjaini; Karim, Pusha; Yonamine, Ikuko; Rawat, Satinder S.; Acharya, Usha] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. [Dasgupta, Ujjaini; Karim, Pusha; Yonamine, Ikuko; Rawat, Satinder S.; Puri, Vishwajeet; Acharya, Usha] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Bamba, Takeshi; Fukusaki, Eiichiro] Osaka Univ, Dept Biotechnol, Grad Sch Engn, Suita, Osaka 5650871, Japan. [Chiantia, Salvatore; Schwille, Petra] Tech Univ Dresden, Biotechnol Zentrum, D-01187 Dresden, Germany. [Abou Tayoun, Ahmad N.; Dolph, Patrick J.] Dartmouth Coll, Dept Biol, Hanover, NH 03755 USA. [Rao, Raghavendra Pralhada; Acharya, Jairaj K.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. [Nagashima, Kunio] SAIC, EM Facil, Image Anal Lab, Frederick, MD 21702 USA. RP Acharya, U (reprint author), Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. EM usha.acharya@umassmed.edu RI Schwille, Petra/A-4983-2010; Chiantia, Salvatore/A-4546-2010 FU National Institutes of Health [R01EY16469] FX We thank the Bloomington Stock Center, Indiana, Drs. Andy Zelhof, and Eric Baerahcke for fly stocks. We thank Dr. Charles Zuker and Ann Becker and Drs. Craig Montell, Hong-sheng Li, and John Sisson for their gifts of antibodies. We thank Drs. Mike Czech and David Lambright for helpful discussions. We thank Kathya Acharya for her work on the figures. Mr. Jun Yonekubo (Nihon Waters K. K) is gratefully acknowledged for helpful discussions andexperimental support. Thisworkis supported by National Institutes of Health grant R01EY16469 (to U. A.). NR 35 TC 22 Z9 22 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 24 PY 2009 VL 106 IS 47 BP 20063 EP 20068 DI 10.1073/pnas.0911028106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524YS UT WOS:000272180900059 PM 19892737 ER PT J AU Pani, B Ong, HL Brazer, SCW Liu, XB Rauser, K Singh, BB Ambudkar, IS AF Pani, Biswaranjan Ong, Hwei Ling Brazer, So-ching W. Liu, Xibao Rauser, Kristina Singh, Brij B. Ambudkar, Indu S. TI Activation of TRPC1 by STIM1 in ER-PM microdomains involves release of the channel from its scaffold caveolin-1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID OPERATED CA2+ ENTRY; CALCIUM-ENTRY; LIPID RAFTS; STORE; ORAI1; DEPLETION; COMPLEX; CRAC; OLIGOMERIZATION; DOMAINS AB Store-operated Ca(2+) entry (SOCE) is activated by redistribution of STIM1 into puncta in discrete ER-plasma membrane junctional regions where it interacts with and activates store-operated channels (SOCs). The factors involved in precise targeting of the channels and their retention at these specific microdomains are not yet defined. Here we report that caveolin-1 (Cav1) is a critical plasma membrane scaffold that retains TRPC1 within the regions where STIM1 puncta are localized following store depletion. This enables the interaction of TRPC1 with STIM1 that is required for the activation of TRPC1-SOCE. Silencing Cav1 in human submandibular gland (HSG) cells decreased plasma membrane retention of TRPC1, TRPC1-STIM1 clustering, and consequently reduced TRPC1-SOCE, without altering STIM1 puncta. Importantly, activation of TRPC1-SOCE was associated with an increase in TRPC1-STIM1 and a decrease in TRPC1-Cav1 clustering. Consistent with this, overexpression of Cav1 decreased TRPC1-STIM1 clustering and SOCE, both of which were recovered when STIM1 was expressed at higher levels relative to Cav1. Silencing STIM1 or expression of Delta ERM-STIM1 or STIM1((684)EE(685)) mutant prevented dissociation of TRPC1-Cav1 and activation of TRPC1-SOCE. However expression of TRPC1((639)KK(640)) with STIM1((684)EE(685)) restored function and the dissociation of TRPC1 from Cav1 in response to store depletion. Further, conditions that promoted TRPC1-STIM1 clustering and TRPC1-SOCE elicited corresponding changes in SOCE-dependent NFkB activation and cell proliferation. Together these data demonstrate that Cav1 is a critical plasma membrane scaffold for inactive TRPC1. We suggest that activation of TRPC1-SOC by STIM1 mediates release of the channel from Cav1. C1 [Pani, Biswaranjan; Rauser, Kristina; Singh, Brij B.] Univ N Dakota, Dept Biochem & Mol Biol, Sch Med & Hlth Sci, Grand Forks, ND 58201 USA. [Ong, Hwei Ling; Brazer, So-ching W.; Liu, Xibao; Ambudkar, Indu S.] Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Singh, BB (reprint author), Univ N Dakota, Dept Biochem & Mol Biol, Sch Med & Hlth Sci, Grand Forks, ND 58201 USA. EM bsingh@medicine.nodak.edu; indu.ambudkar@nih.gov OI Singh, Brij/0000-0003-0535-5997 FU National Science Foundation [0548733]; National Institutes of Health [DE017102, 5P20RR017699]; National Institute of Dental and Craniofacial Research, Division of Intramural Research; University of North Dakota; North Dakota-Experimental Program FX We thank Dr. Tobias Meyer (Stanford University, CA) for the CFP-STIM1, YFP-STIM1, and D76A-STIM1 plasmids; Drs. Shmuel Muallem (University of Texas Southwestern Medical Center, TX) for the Delta ERM-STIM1, STIM1-KK/EE, and TRPC1-DD/KK; Jonathan Soboloff (Temple University School of Medicine, PA) for the HA-STIM1; and the confocal facility at the University of North Dakota for assistance. We also thank Katherine Johnson for her excellent technical support. This work was supported by National Science Foundation Grant 0548733; National Institutes of Health Grants DE017102 and 5P20RR017699 (to B. B. S.); National Institute of Dental and Craniofacial Research, Division of Intramural Research (I. S. A.), and University of North Dakota and North Dakota-Experimental Program to Stimulate Competitive Research Student fellowships (to B. P.). NR 30 TC 69 Z9 70 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 NOV 24 PY 2009 VL 106 IS 47 BP 20087 EP 20092 DI 10.1073/pnas.0905002106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524YS UT WOS:000272180900063 PM 19897728 ER PT J AU Simonsick, EM Newman, AB Ferrucci, L Satterfield, S Harris, TB Rodondi, N Bauer, DC AF Simonsick, Eleanor M. Newman, Anne B. Ferrucci, Luigi Satterfield, Suzanne Harris, Tamara B. Rodondi, Nicolas Bauer, Douglas C. CA Hlth ABC Study TI Subclinical Hypothyroidism and Functional Mobility in Older Adults SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID DISTANCE CORRIDOR WALK; THYROID-DYSFUNCTION; COGNITIVE FUNCTION; PHYSICAL FUNCTION; HEART-DISEASE; SERUM-LIPIDS; HEALTH ABC; RISK; AGE; MORTALITY AB Background: Health risks associated with subclinical hypothyroidism in older adults are unclear. Our objective was to compare the functional mobility of people aged 70 to 79 years by thyroid function categorized by thyrotropin (TSH) level as euthyroid (>= 0.4 to <4.5 mIU/L), mild subclinical hypothyroid (>= 4.5 to <7.0 mIU/L), or moderate subclinical hypothyroid (>= 7.0 to <= 20.0 mIU/L with a normal free thyroxine level) cross-sectionally and over 2 years. Methods: A total of 2290 community-dwelling residents participating in the year 2 clinic visit (July 1998-June 1999) of the Health, Aging, and Body Composition (Health ABC) Study, who had measured TSH level, had the capacity to walk 20 m unaided, and were not taking thyroid medication or had TSH levels consistent with hyperthyroidism or hypothyroidism. Main outcome measures included self-reported and performance-based measures of mobility (usual and rapid gait speed and endurance walking ability) assessed at study baseline (year 2) and 2 years later. Results: In age- and sex-adjusted analyses, the mild subclinical hypothyroid group (vs; the euthyroid group) demonstrated better mobility (faster mean usual and rapid gait speed [1.20 vs 1.15 m/s and 1.65 vs 1.56 m/s, respectively; P < .001] and had a higher percentage of those with good cardiorespiratory fitness and reported walking ease [39.2% vs 28.0% and 44.7% vs 36.5%, respectively; P < .001]). After 2 years, persons with mild subclinical hypothyroidism experienced a similar decline as the euthyroid group but maintained their mobility advantage. Persons with moderate subclinical hypothyroidism had similar mobility and mobility decline as the euthyroid group. Conclusion: Generally, well-functioning 70- to 79-year-old individuals with subclinical hypothyroidism do not demonstrate increased risk of mobility problems, and those with mild elevations in TSH level show a slight functional advantage. C1 [Simonsick, Eleanor M.; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21225 USA. [Simonsick, Eleanor M.; Ferrucci, Luigi] Johns Hopkins Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Rodondi, Nicolas] Univ Lausanne, Dept Ambulatory Care & Community Med, CH-1015 Lausanne, Switzerland. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Simonsick, EM (reprint author), NIA, Clin Res Branch, Harbor Hosp, 3001 S Hanover St,5th Floor, Baltimore, MD 21225 USA. EM simonsickel@mail.nih.gov RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institutes of Health (NIH), National Institute on Aging [N01-AG-6-2101, N01-AG-2103, N01-AG-6-2106] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging, and NIH contracts This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging, and NIH contracts N01-AG-6-2101, N01-AG-2103, and N01-AG-6-2106.N01-AG-6-2101, N01-AG-2103, and N01-AG-6-2106. NR 27 TC 47 Z9 48 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9926 EI 1538-3679 J9 ARCH INTERN MED JI Arch. Intern. Med. PD NOV 23 PY 2009 VL 169 IS 21 BP 2011 EP 2017 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 522YT UT WOS:000272036900013 PM 19933964 ER PT J AU Serres, MH Kerr, ARW McCormack, TJ Riley, M AF Serres, Margrethe H. Kerr, Alastair R. W. McCormack, Thomas J. Riley, Monica TI Evolution by leaps: gene duplication in bacteria SO BIOLOGY DIRECT LA English DT Article ID ESCHERICHIA-COLI; CROTONASE SUPERFAMILY; MICROBIAL GENOMES; PROTEIN FAMILIES; ACTIVE-SITE; PSI-BLAST; SEQUENCE AB Background: Sequence related families of genes and proteins are common in bacterial genomes. In Escherichia coli they constitute over half of the genome. The presence of families and superfamilies of proteins suggest a history of gene duplication and divergence during evolution. Genome encoded protein families, their size and functional composition, reflect metabolic potentials of the organisms they are found in. Comparing protein families of different organisms give insight into functional differences and similarities. Results: Equivalent enzyme families with metabolic functions were selected from the genomes of four experimentally characterized bacteria belonging to separate genera. Both similarities and differences were detected in the protein family memberships, with more similarities being detected among the more closely related organisms. Protein family memberships reflected known metabolic characteristics of the organisms. Differences in divergence of functionally characterized enzyme family members accounted for characteristics of taxa known to differ in those biochemical properties and capabilities. While some members of the gene families will have been acquired by lateral exchange and other former family members will have been lost over time, duplication and divergence of genes and functions appear to have been a significant contributor to the functional diversity of today's microbes. Conclusions: Protein families seem likely to have arisen during evolution by gene duplication and divergence where the gene copies that have been retained are the variants that have led to distinct bacterial physiologies and taxa. Thus divergence of the duplicate enzymes has been a major process in the generation of different kinds of bacteria. Reviewers: This article was reviewed by Drs. Iyer Aravind, Ardcady Mushegian, and Pierre Pontarotti. C1 [Serres, Margrethe H.; Riley, Monica] Marine Biol Lab, Josephine Bay Paul Ctr, Woods Hole, MA 02543 USA. [Kerr, Alastair R. W.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. [McCormack, Thomas J.] Natl Inst Environm Hlth Sci, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Serres, MH (reprint author), Marine Biol Lab, Josephine Bay Paul Ctr, Woods Hole, MA 02543 USA. EM mserres@mbl.edu; Alastair.Kerr@ed.ac.edu; yandoblu@msn.com; mriley@mbl.edu RI Kerr, Alastair/B-3272-2010; OI Kerr, Alastair/0000-0001-9207-6050 FU U.S. Department of Energy [DE-FG02-08ER64511] FX Thanks to Sulip Goswami, now at Toxikon Corporation, Bedford, Massachusetts, for his careful work carrying out the comparisons of structures at conserved sites in proteins of the three families. This research was supported by the Office of Science (BER), U.S. Department of Energy, Grant No. DE-FG02-08ER64511. NR 41 TC 19 Z9 19 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD NOV 23 PY 2009 VL 4 AR 46 DI 10.1186/1745-6150-4-46 PG 17 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 526YB UT WOS:000272331100001 PM 19930658 ER PT J AU Barluenga, S Fontaine, JG Wang, CH Aouadi, K Chen, RH Beebe, K Neckers, L Winssinger, N AF Barluenga, Sofia Fontaine, Jean-Gonzague Wang, Cuihua Aouadi, Kais Chen, Ruihong Beebe, Kristin Neckers, Len Winssinger, Nicolas TI Inhibition of HSP90 with Pochoximes: SAR and Structure-Based Insights SO CHEMBIOCHEM LA English DT Article DE Hsp90; inhibitors; pochoxime; radicicol; structure-activity relationships ID SHOCK-PROTEIN 90; SMALL-MOLECULE INHIBITORS; N-TERMINAL DOMAIN; BIOLOGICAL EVALUATION; ANTITUMOR-ACTIVITY; IN-VIVO; HEAT-SHOCK-PROTEIN-90 INHIBITOR; ANTICANCER AGENT; CHAPERONE HSP90; TARGETING HSP90 AB The pochoximes, based on the radicicol pharmacophore, are potent inhibitors of heat shock protein 90 (HSP90) that retain their activity in vivo. Herein we report an extended library that broadly explores the structure-activity relationship (SAR) of the pochoximes with four points of diversity. Several modifications were identified that afford improved cellular efficacy, new opportunities for conjugation, and further diversifications. Cocrystal structures of pochoximes A and B with HSP90 show that pochoximes bind to a different conformation of HSP90 than radicicol and provide a rationale for the enhanced affinity of the pochoximes relative to radicicol and the pochonins. C1 [Barluenga, Sofia; Fontaine, Jean-Gonzague; Wang, Cuihua; Aouadi, Kais; Winssinger, Nicolas] Univ Strasbourg, Inst Sci & Ingenierie Supramol, CNRS, UMR7006, F-67000 Strasbourg, France. [Chen, Ruihong] Negenix Pharmaceut, New York, NY 10019 USA. [Beebe, Kristin; Neckers, Len] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Winssinger, N (reprint author), Univ Strasbourg, Inst Sci & Ingenierie Supramol, CNRS, UMR7006, 8 Allee Gaspard Monge, F-67000 Strasbourg, France. EM winssinger@isis.u-strasbg.fr RI Winssinger, Nicolas/B-6710-2017 OI Winssinger, Nicolas/0000-0003-1636-7766 FU Agence National de la Recherche (ANR); Conectus FX This work was funded in part by a grant from the Agence National de la Recherche (ANR) and Conectus. A BDI fellowship (J.-G.F) is also gratefully acknowledged. NR 44 TC 32 Z9 32 U1 0 U2 6 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD NOV 23 PY 2009 VL 10 IS 17 BP 2753 EP 2759 DI 10.1002/cbic.200900494 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 527UC UT WOS:000272391700012 PM 19856365 ER PT J AU Hwang, IY Park, C Harrison, K Kehrl, JH AF Hwang, Il-Young Park, Chung Harrison, Kathleen Kehrl, John H. TI TLR4 signaling augments B lymphocyte migration and overcomes the restriction that limits access to germinal center dark zones SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TOLL-LIKE RECEPTORS; IN-VIVO; ANTIBODY-RESPONSES; DENDRITIC CELLS; INNATE IMMUNITY; UP-REGULATION; PLASMA-CELL; T-CELLS; ACTIVATION; NODE AB B lymphocyte-intrinsic Toll-like receptor (TLR) signals amplify humoral immunity and can exacerbate autoimmune diseases. We identify a new mechanism by which TLR signals may contribute to autoimmunity and chronic inflammation. We show that TLR4 signaling enhances B lymphocyte trafficking into lymph nodes (LNs), induces B lymphocyte clustering and interactions within LN follicles, leads to sustained in vivo B cell proliferation, overcomes the restriction that limits the access of nonantigen-activated B cells to germinal center dark zones, and enhances the generation of memory and plasma cells. Intravital microscopy and in vivo tracking studies of B cells transferred to recipient mice revealed that TLR4-activated, but not nonstimulated, B cells accumulated within the dark zones of preexisting germinal centers even when transferred with antigen-specifi c B cells. The TLR4-activated cells persist much better than nonstimulated cells, expanding both within the memory and plasma cell compartments. TLR-mediated activation of B cells may help to feed and stabilize the spontaneous and ectopic germinal centers that are so commonly found in autoimmune individuals and that accompany chronic inflammation. C1 [Hwang, Il-Young; Park, Chung; Harrison, Kathleen; Kehrl, John H.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Kehrl, JH (reprint author), NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov OI Kehrl, John/0000-0002-6526-159X FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 55 TC 26 Z9 26 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD NOV 23 PY 2009 VL 206 IS 12 BP 2641 EP 2657 DI 10.1084/jem.20091982 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 523MX UT WOS:000272079300007 PM 19917774 ER PT J AU Zamisch, M Tian, LH Grenningloh, R Xiong, YM Wildt, KF Ehlers, M Ho, IC Bosselut, R AF Zamisch, Monica Tian, Linhua Grenningloh, Roland Xiong, Yumei Wildt, Kathryn F. Ehlers, Marc Ho, I-Cheng Bosselut, Remy TI The transcription factor Ets1 is important for CD4 repression and Runx3 up-regulation during CD8 T cell differentiation in the thymus SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CD4-CD8 LINEAGE DIFFERENTIATION; CORE-BINDING-FACTOR; HELPER TYPE-1 CELLS; DNA-BINDING; THYMOCYTE DEVELOPMENT; POSITIVE SELECTION; GENE-EXPRESSION; LYMPHOCYTE DEVELOPMENT; NEGATIVE SELECTION; AUTO-INHIBITION AB The transcription factor Ets1 contributes to the differentiation of CD8 lineage cells in the thymus, but how it does so is not understood. In this study, we demonstrate that Ets1 is required for the proper termination of CD4 expression during the differentiation of major histocompatability class 1 (MHC I)-restricted thymocytes, but not for other events associated with their positive selection, including the initiation of cytotoxic gene expression, corticomedullary migration, or thymus exit. We further show that Ets1 promotes expression of Runx3, a transcription factor important for CD8 T cell differentiation and the cessation of Cd4 gene expression. Enforced Runx3 expression in Ets1-deficient MHC I-restricted thymocytes largely rescued their impaired Cd4 silencing, indicating that Ets1 is not required for Runx3 function. Finally, we document that Ets1 binds at least two evolutionarily conserved regions within the Runx3 gene in vivo, supporting the possibility that Ets1 directly contributes to Runx3 transcription. These findings identify Ets1 as a key player during CD8 lineage differentiation and indicate that it acts, at least in part, by promoting Runx3 expression. C1 [Zamisch, Monica; Tian, Linhua; Xiong, Yumei; Wildt, Kathryn F.; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Grenningloh, Roland; Ho, I-Cheng] Brigham & Womens Hosp, Dept Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Ehlers, Marc] German Rheumatism Res Ctr DRFZ, Lab Tolerance & Autoimmun, D-10117 Berlin, Germany. RP Bosselut, R (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM remy@helix.nih.gov RI Ehlers, Marc/C-9441-2011 FU National Cancer Institute, Center for Cancer Research, National Institutes of Health (NIH) [AI081052]; Max-Planck-Institute for Infection Biology, Germany FX This work was supported in part by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health (NIH), and by NIH grant AI081052. M. Ehlers is a fellow of the Claussen-Simon-Foundation and supported by the Max-Planck-Institute for Infection Biology, Germany. NR 68 TC 39 Z9 39 U1 0 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD NOV 23 PY 2009 VL 206 IS 12 BP 2685 EP 2699 DI 10.1084/jem.20092024 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 523MX UT WOS:000272079300010 PM 19917777 ER PT J AU Hu, HJ Leppla, SH AF Hu, Haijing Leppla, Stephen H. TI Anthrax Toxin Uptake by Primary Immune Cells as Determined with a Lethal Factor-beta-Lactamase Fusion Protein SO PLOS ONE LA English DT Article ID CAPILLARY MORPHOGENESIS PROTEIN-2; BACILLUS-ANTHRACIS; DENDRITIC CELLS; PROTECTIVE ANTIGEN; INHALATION ANTHRAX; MELANOMA-CELLS; MACROPHAGES; RECEPTOR; SPORES; STRAIN AB Background: To initiate infection, Bacillus anthracis needs to overcome the host innate immune system. Anthrax toxin, a major virulence factor of B. anthracis, impairs both the innate and adaptive immune systems and is important in the establishment of anthrax infections. Methodology/Principal Findings: To measure the ability of anthrax toxin to target immune cells, studies were performed using a fusion of the anthrax toxin lethal factor (LF) N-terminal domain (LFn, aa 1-254) with beta-lactamase (LFnBLA). This protein reports on the ability of the anthrax toxin protective antigen (PA) to mediate LF delivery into cells. Primary immune cells prepared from mouse spleens were used in conjunction with flow cytometry to assess cleavage and resulting FRET disruption of a fluorescent b-lactamase substrate, CCF2/AM. In spleen cell suspensions, the macrophages, dendritic cells, and B cells showed about 75% FRET disruption of CCF2/AM due to cleavage by the PA-delivered LFnBLA. LFnBLA delivery into CD4+ and CD8+ T cells was lower, with 40% FRET disruption. When the analyses were done on purified samples of individual cell types, similar results were obtained, with T cells again having lower LFnBLA delivery than macrophages, dendritic cells, and B cells. Relative expression levels of the toxin receptors CMG2 and TEM8 on these cells were determined by real-time PCR. Expression of CMG2 was about 1.5-fold higher in CD8+ cells than in CD4+ and B cells, and 2.5-fold higher than in macrophages. Conclusions/Significance: Anthrax toxin entry and activity differs among immune cells. Macrophages, dendritic cells, and B cells displayed higher LFnBLA activity than CD4+ and CD8+ T cells in both spleen cell suspension and the purified samples of individual cell types. Expression of anthrax toxin receptor CMG2 is higher in CD4+ and CD8+ T cells, which is not correlated to the intracellular LFnBLA activity. C1 [Hu, Haijing; Leppla, Stephen H.] NIAID, Bacterial Toxins & Therapeut Sect, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. RP Hu, HJ (reprint author), NIAID, Bacterial Toxins & Therapeut Sect, Lab Bacterial Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 16 Z9 16 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 23 PY 2009 VL 4 IS 11 AR e7946 DI 10.1371/journal.pone.0007946 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MF UT WOS:000272827300005 PM 19956758 ER PT J AU Niu, XM Nouraie, M Campbell, A Rana, S Minniti, CP Sable, C Darbari, D Dham, N Reading, NS Prchal, JT Kato, GJ Gladwin, MT Castro, OL Gordeuk, VR AF Niu, Xiaomei Nouraie, Mehdi Campbell, Andrew Rana, Sohail Minniti, Caterina P. Sable, Craig Darbari, Deepika Dham, Niti Reading, N. Scott Prchal, Josef T. Kato, Gregory J. Gladwin, Mark T. Castro, Oswaldo L. Gordeuk, Victor R. TI Angiogenic and Inflammatory Markers of Cardiopulmonary Changes in Children and Adolescents with Sickle Cell Disease SO PLOS ONE LA English DT Article ID PULMONARY ARTERIAL-HYPERTENSION; HEMOGLOBIN OXYGEN DESATURATION; REGURGITANT JET VELOCITY; VEGF GENE-EXPRESSION; SMOOTH-MUSCLE-CELLS; PULSE OXIMETRY; RISK-FACTOR; HEMOLYSIS; DEATH; ENDOTHELIUM AB Background: Pulmonary hypertension and left ventricular diastolic dysfunction are complications of sickle cell disease. Pulmonary hypertension is associated with hemolysis and hypoxia, but other unidentified factors are likely involved in pathogenesis as well. Design and Methods: Plasma concentrations of three angiogenic markers (fibroblast growth factor, platelet derived growth factor-BB [PDGF-BB], vascular endothelial growth factor [VEGF]) and seven inflammatory markers implicated in pulmonary hypertension in other settings were determined by Bio-Plex suspension array in 237 children and adolescents with sickle cell disease at steady state and 43 controls. Tricuspid regurgitation velocity (which reflects systolic pulmonary artery pressure), mitral valve E/Edti ratio (which reflects left ventricular diastolic dysfunction), and a hemolytic component derived from four markers of hemolysis and hemoglobin oxygen saturation were also determined. Results: Plasma concentrations of interleukin-8, interleukin-10 and VEGF were elevated in the patients with sickle cell disease compared to controls (P <= 0.003). By logistic regression, greater values for PDGF-BB (P = 0.009), interleukin-6 (P = 0.019) and the hemolytic component (P = 0.026) were independently associated with increased odds of elevated tricuspid regurgitation velocity while higher VEGF concentrations were associated with decreased odds (P = 0.005) among the patients with sickle cell disease. These findings, which are consistent with reports that PDGF-BB stimulates and VEGF inhibits vascular smooth muscle cell proliferation, did not apply to E/Etdi. Conclusions: Circulating concentrations of angiogenic and pro-Inflammatory markers are altered in sickle cell disease children and adolescents with elevated tricuspid regurgitation velocity, a subgroup that may be at risk for developing worsening pulmonary hypertension. Further studies to understand the molecular changes in these children are indicated. C1 [Niu, Xiaomei; Nouraie, Mehdi; Rana, Sohail; Castro, Oswaldo L.; Gordeuk, Victor R.] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Darbari, Deepika] Childrens Natl Med Ctr, Dept Hematol, Washington, DC 20010 USA. [Sable, Craig; Dham, Niti] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. [Campbell, Andrew] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Minniti, Caterina P.; Kato, Gregory J.] Natl Heart Lung & Blood Inst, Pulm & Vasc Med Branch, Ctr Clin, NIH, Bethesda, MD USA. [Reading, N. Scott; Prchal, Josef T.] Univ Utah, ARUP Inst Clin & Expt Pathol, Salt Lake City, UT USA. [Reading, N. Scott; Prchal, Josef T.] Univ Utah, Vet Adm Hosp, Salt Lake City, UT USA. [Gladwin, Mark T.] Univ Pittsburgh, Med Ctr, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Gladwin, Mark T.] Univ Pittsburgh, Hemostasis & Vasc Biol Res Inst, Pittsburgh, PA USA. RP Niu, XM (reprint author), Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. EM vgordeuk@howard.edu RI Kato, Gregory/I-7615-2014; Reading, Noel/J-8911-2016 OI Kato, Gregory/0000-0003-4465-3217; Reading, Noel/0000-0003-0806-5661 FU National Heart, Lung and Blood Institute [2 R25 HL003679-08, 1 R01 HL079912-02]; National Center for Research Resources, National Institutes of Health (NIH), Bethesda, MD [2MOI RR10284-10]; National Institutes of Health FX Supported in part by grants no. 2 R25 HL003679-08 and 1 R01 HL079912-02 from the National Heart, Lung and Blood Institute; by Howard University GCRC grant no. 2MOI RR10284-10 from the National Center for Research Resources, National Institutes of Health (NIH), Bethesda, MD; and by the Intramural Research Program of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 30 Z9 30 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 23 PY 2009 VL 4 IS 11 AR e7956 DI 10.1371/journal.pone.0007956 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MF UT WOS:000272827300013 PM 19956689 ER PT J AU Yucesoy, B Johnson, VJ Fluharty, K Kashon, ML Slaven, JE Wilson, NW Weissman, DN Biagini, RE Germolec, DR Luster, MI AF Yucesoy, Berran Johnson, Victor J. Fluharty, Kara Kashon, Michael L. Slaven, James E. Wilson, Nevin W. Weissman, David N. Biagini, Raymond E. Germolec, Dori R. Luster, Michael I. TI Influence of cytokine gene variations on immunization to childhood vaccines SO VACCINE LA English DT Article DE Genetics; Vaccination; Cytokine ID SINGLE-NUCLEOTIDE POLYMORPHISMS; HEPATITIS-B VACCINATION; IMMUNE-RESPONSES; MEASLES-VACCINE; ANTIBODY-RESPONSE; CELL PROLIFERATION; HUMORAL IMMUNITY; SURFACE-ANTIGEN; VIRUS; INFANTS AB The magnitude of the immune response to vaccinations can be influenced by genetic variability. In the present study, we aimed to investigate whether cytokine or cytokine receptor gene polymorphisms were associated with variations in the immune response to childhood vaccination. The study group consisted of 141 healthy infants who had been immunized with hepatitis B vaccine (HBV), 7-valent pneumococcal conjugate (PCV7), and diphtheria, tetanus, acellular pertussis (DTaP) vaccines according to standard childhood immunization schedules. Genotype analysis was performed on genomic DNA using a 5' nuclease PCR assay. Post vaccination total, isotypic, and antigen-specific serum antibody levels were measured using multiplex immunoassays. Significant associations were observed between SNPs in the TNF alpha, IL-12B, IL-4R alpha, and IL-10 genes and vaccine-specific immune responses (p < 0.05). In addition, SNPs in the IL-1 beta, TNF alpha, IL-2, IL-4, IL-10, IL-4R alpha, and IL-12B genes were associated with variations in serum levels of immunoglobulins (IgG, IgA, IgM) and IgG isotypes (IgG1-IgG3) (p < 0.05). These data suggest that genetic variations in cytokine genes can influence vaccine-induced immune responses in infants, which in turn may influence vaccine efficacy. Published by Elsevier Ltd. C1 [Yucesoy, Berran] NIOSH, Toxicol & Mol Biol Branch, Hlth Effects Lab Div, CDC, Morgantown, WV 26505 USA. [Kashon, Michael L.; Slaven, James E.] NIOSH, Biostat & Epidemiol Branch, CDC, Morgantown, WV 26505 USA. [Wilson, Nevin W.] Univ Nevada, Sch Med, Dept Pediat, Reno, NV 89557 USA. [Weissman, David N.] NIOSH, Div Resp Dis Studies, CDC, Morgantown, WV 26505 USA. [Biagini, Raymond E.] NIOSH, Biomonitoring & Hlth Assessment Branch, CDC, Cincinnati, OH 45226 USA. [Germolec, Dori R.] NIEHS, Toxicol Branch, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Yucesoy, B (reprint author), NIOSH, Toxicol & Mol Biol Branch, Hlth Effects Lab Div, CDC, 1095 Willowdale Rd, Morgantown, WV 26505 USA. EM byucesoy@cdc.gov FU Intramural Research Program of the NIEHS [YI-ES-0001] FX This work was supported in part by an Interagency Agreement with the Intramural Research Program of the NIEHS (YI-ES-0001). NR 51 TC 31 Z9 32 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD NOV 23 PY 2009 VL 27 IS 50 BP 6991 EP 6997 DI 10.1016/j.vaccine.2009.09.076 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 525MT UT WOS:000272220900004 PM 19819209 ER PT J AU Liu, F Park, JE Lee, KS Burke, TR AF Liu, Fa Park, Jung-Eun Lee, Kyung S. Burke, Terrence R., Jr. TI Preparation of orthogonally protected (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) as a phosphatase-stable phosphothreonine mimetic and its use in the synthesis of polo-box domain-binding peptides SO TETRAHEDRON LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; SIGNAL-TRANSDUCTION; CANCER-THERAPY; ASYMMETRIC-SYNTHESIS; PHOSPHONATE-ANALOGS; KINASE INHIBITORS; SMALL MOLECULES; POLO-LIKE-KINASE-1; TYROSINE; TARGETS AB Reported herein is the first stereoselective synthesis of (2S,3R)-4-[bis-(tert-butyloxy)phosphinyl]-2-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-3-methylbutanoic acid [(N-Fmoc, O,O-(bis-(tert-butyl))-Pmab), 4] as a hydrolytically-stable phosphothreonine mimetic bearing orthogonal protection compatible with standard solid-phase protocols. The synthetic approach used employs Evans' oxazolidinone for chiral induction. Also presented is the application of 4 in the solid-phase synthesis of polo-like kinase 1 (Plk1) polo box domain (PBD)-binding peptides. These Pmab-containing pepticles retain PBD binding efficacy similar to a parent pThr containing peptide. Reagent 4 should be a highly useful reagent for the preparation of signal transduction-directed pepticles. Published by Elsevier Ltd. C1 [Liu, Fa; Burke, Terrence R., Jr.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD USA. [Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Liu, F (reprint author), NCI, Med Chem Lab, Ctr Canc Res, NIH, POB B,Bldg 376 Boyles St, Frederick, MD USA. EM liuf@ncifcrf.gov; tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 FU NTH, 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 NTH, 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 U.S. Government. NR 50 TC 17 Z9 17 U1 2 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD NOV 21 PY 2009 VL 65 IS 47 BP 9673 EP 9679 DI 10.1016/j.tet.2009.09.093 PG 7 WC Chemistry, Organic SC Chemistry GA 518SK UT WOS:000271713300002 PM 24954959 ER PT J AU Greggio, E Taymans, JM Zhen, EY Ryder, J Vancraenenbroeck, R Beilina, A Sun, P Deng, JP Jaffe, H Baekelandt, V Merchant, K Cookson, MR AF Greggio, Elisa Taymans, Jean-Marc Zhen, Eugene Yuejun Ryder, John Vancraenenbroeck, Renee Beilina, Alexandra Sun, Peng Deng, Junpeng Jaffe, Howard Baekelandt, Veerle Merchant, Kalpana Cookson, Mark R. TI The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Parkinson's disease; Kinase; GTPase; Autophosphorylation ID LEUCINE-RICH-REPEAT-KINASE-2 LRRK2; NEURONAL TOXICITY; MOUSE-BRAIN; ROC DOMAIN; PROTEIN; MUTATION; MUTANTS; BINDING AB Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common Cause of inherited Parkinson's disease (PD). The protein is large and complex, but pathogenic mutations cluster in a region containing GTPase and kinase domains. LRRK2 can autophosphorylate in vitro within a dimer pair, although the significance of this reaction is unclear. Here, we mapped the sites of autophosphorylation within LRRK2 and found several potential phosphorylation sites within the GTPase domain. Using mass spectrometry, we found that Thr1343 is phosphorylated and, using kinase dead versions of LRRK2, show that this is an autophosphorylation site. However, we also find evidence for additional sites in the GTPase domain and in other regions of the protein suggesting that there may be multiple autophosphorylation sites within LRRK2. These data suggest that the kinase and GTPase activities of LRRK2 may exhibit complex autoregulatory interdependence. Published by Elsevier Inc. C1 [Greggio, Elisa; Beilina, Alexandra; Cookson, Mark R.] NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, Bethesda, MD 20892 USA. [Taymans, Jean-Marc; Baekelandt, Veerle] Katholieke Univ Leuven, Lab Neurobiol & Gene Therapy, Div Mol Med, Dept Mol & Cellular Med, Louvain, Belgium. [Zhen, Eugene Yuejun; Ryder, John; Merchant, Kalpana] Eli Lilly & Co, Integrat Biol, Indianapolis, IN 46285 USA. [Vancraenenbroeck, Renee] Katholieke Univ Leuven, Dept Chem, Lab Biomol Modelling, Louvain, Belgium. [Sun, Peng; Deng, Junpeng] Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA. [Jaffe, Howard] NINDS, Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, 35 Convent Dr, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov RI Greggio, Elisa/H-6119-2013; OI Greggio, Elisa/0000-0002-8172-3598; Taymans, Jean-Marc/0000-0001-5503-5524 FU NIH; National Institute on Aging [AG000948-01]; National Institute of Neurological Diseases and Stroke; Flemish Fund for Scientific Research FWO Vlaanderen [G.0406.06, G.0666.09, NS062287] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (AG000948-01) and the National Institute of Neurological Diseases and Stroke and by the Flemish Fund for Scientific Research FWO Vlaanderen (G.0406.06 and G.0666.09). The National Institute of Neurological Diseases and Stroke also supported this work by Grant NS062287 to J.D. RVC is a research assistant and J.-M.T. is a postdoctoral researcher of the Flemish fund for scientific research (FWO). J.-M.T. is a Fulbright research scholar. The authors thank Evy Lobbestael and Fangye Gao for technical assistance. NR 26 TC 84 Z9 84 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD NOV 20 PY 2009 VL 389 IS 3 BP 449 EP 454 DI 10.1016/j.bbrc.2009.08.163 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 508LT UT WOS:000270933600010 PM 19733152 ER PT J AU Jin, P Ren, JQ Sabatino, M Balakumaran, A Kuznetsov, S Klein, HG Robey, PG Stroncek, D AF Jin, Ping Ren, Jiaqiang Sabatino, Marianna Balakumaran, Arun Kuznetsov, Sergei Klein, Harvey G. Robey, Pamela G. Stroncek, David TI Comparative Global Transcriptome Analysis of Bone Marrow Stromal Cells (BMSC), Human Embryonic Stem (hES) Cells and CD34+Cells SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Jin, Ping; Ren, Jiaqiang; Sabatino, Marianna; Klein, Harvey G.; Stroncek, David] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Balakumaran, Arun; Kuznetsov, Sergei; Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 20 EP 21 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800037 ER PT J AU Hari, PN Barrett, AJ Shrestha, S da Silva, GT Zhang, MJ Dispenzieri, A Milone, GA Lonial, S Ringden, O AF Hari, Parameswaran N. Barrett, A. John Shrestha, Smriti da Silva, Gisela Tunes Zhang, Mei-Jie Dispenzieri, Angela Milone, Gustavo A. Lonial, Sagar Ringden, Olle TI Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplant (HSCT) for Myeloma (MM) - Chronic Graft Versus Host Disease (GVHD) is Associated with Lower Risk of Relapse and Superior Progression Free Survival (PFS) - A CIBMTR Analysis SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Hari, Parameswaran N.; Shrestha, Smriti; Zhang, Mei-Jie] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Barrett, A. John] NHLBI, NIH, Bethesda, MD 20892 USA. [da Silva, Gisela Tunes] Univ Sao Paulo, Sao Paulo, Brazil. [Dispenzieri, Angela] Mayo Clin, Rochester, MN USA. [Milone, Gustavo A.] Angelica Ocampo Fundaleu, Buenos Aires, DF, Argentina. [Lonial, Sagar] Emory Univ, Sch Med, Atlanta, GA USA. [Ringden, Olle] Karolinska Univ Hosp, Stockholm, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 27 EP 28 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800054 ER PT J AU Larochelle, A Gillette, J Cantilena, A Cerf, A Lippincott-Schwartz, J Dunbar, CE AF Larochelle, Andre Gillette, Jennifer Cantilena, Amy Cerf, Alexandra Lippincott-Schwartz, Jennifer Dunbar, Cynthia E. TI A Specialized Polarized Membrane Domain Found On Normal but Not Leukemic Hematopoietic Progenitor Cells Is Required for Homing to the Bone Marrow Microenvironment. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Larochelle, Andre; Cantilena, Amy; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Gillette, Jennifer; Cerf, Alexandra; Lippincott-Schwartz, Jennifer] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 38 EP 39 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800083 ER PT J AU Zhang, JH Mullighan, CG Harvey, RC Buetow, KE Carroll, WL Chen, IM Devidas, M Edmonson, M Gerhard, D Hu, Y Loh, ML Phillips, LA Reaman, GH Relling, MV Smith, M Downing, JR Willman, CL Hunger, SP AF Zhang, Jinghui Mullighan, Charles G. Harvey, Richard C. Buetow, Kenneth E. Carroll, William L. Chen, I-Ming Devidas, Meenakshi Edmonson, Michael Gerhard, Daniela Hu, Ying Loh, Mignon L. Phillips, Letha A. Reaman, Gregory H. Relling, Mary V. Smith, Malcolm Downing, James R. Willman, Cheryl L. Hunger, Stephen P. TI Mutations in the RAS Signaling, B-Cell Development, TP53/RB1, and JAK Signaling Pathways Are Common in High Risk B-Precursor Childhood Acute Lymphoblastic Leukemia (ALL): A Report From the Children's Oncology Group (COG) High-Risk (HR) ALL TARGET Project. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Zhang, Jinghui; Buetow, Kenneth E.] NCI, Ctr Biomed Informat & Informat Technol, NIH, Rockville, MD USA. [Relling, Mary V.] St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Harvey, Richard C.] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. [Carroll, William L.] NYU, Inst Canc, New York, NY USA. [Chen, I-Ming] Univ New Mexico, Dept Pathol, Canc Res & Treatment Ctr, Albuquerque, NM 87131 USA. [Devidas, Meenakshi] Univ Florida, Childrens Oncol Grp, Dept Epidemiol & Hlth Policy Res, Gainesville, FL USA. [Devidas, Meenakshi] Univ Florida, Coll Med, Gainesville, FL USA. [Edmonson, Michael; Hu, Ying] NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. [Loh, Mignon L.] Univ Calif San Francisco, Dept Pediat & Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Reaman, Gregory H.] George Washington Univ, Sch Med & Hlth Sci, Bethesda, MD USA. [Smith, Malcolm] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Willman, Cheryl L.] Univ New Mexico, UNM Canc Res Facil, Canc Res & Treatment Ctr, Albuquerque, NM 87131 USA. [Hunger, Stephen P.] Univ Colorado, Coll Med, Pediat Heme Onc BMT, Aurora, CO USA. NR 0 TC 2 Z9 2 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 40 EP 40 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800086 ER PT J AU Dunleavy, K Pittaluga, S Tay, K Grant, N Chen, CC Shovlin, M Steinberg, S Staudt, LM Jaffe, ES Janik, JE Wilson, WH AF Dunleavy, Kieron Pittaluga, Stefania Tay, Kevin Grant, Nicole Chen, Clara C. Shovlin, Margaret Steinberg, Seth Staudt, Louis M. Jaffe, Elaine S. Janik, John E. Wilson, Wyndham H. TI Comparative Clinical and Biological Features of Primary Mediastinal B-Cell Lymphoma (PMBL) and Mediastinal Grey Zone Lymphoma (MGZL) SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Dunleavy, Kieron; Pittaluga, Stefania; Tay, Kevin; Grant, Nicole; Shovlin, Margaret; Steinberg, Seth; Staudt, Louis M.; Jaffe, Elaine S.; Janik, John E.; Wilson, Wyndham H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Chen, Clara C.] NIH, Dept Nucl Med, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 49 EP 49 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800107 ER PT J AU Sloand, EM Olnes, MJ Weinstein, B Scheinberg, P Young, NS AF Sloand, Elaine M. Olnes, Matthew J. Weinstein, Barbara Scheinberg, Phillip Young, Neal S. TI Alemtuzumab Treatment of Intermediate-1 (INT-1) Myelodysplasia Patients Is Associated with Sustained Improvement in Blood Counts and Cytogenetic Remissions SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Sloand, Elaine M.; Olnes, Matthew J.; Weinstein, Barbara; Scheinberg, Phillip; Young, Neal S.] NHLBI, NIH, Bethesda, MD 20892 USA. RI Scheinberg, Phillip/H-5251-2012 NR 0 TC 1 Z9 1 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 53 EP 53 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800117 ER PT J AU Sloand, EM Olnes, MJ Galili, N Shenoy, A Pfannes, L Wilhelm, F Weinstein, B Scheinberg, P Groopman, JE Raza, A AF Sloand, Elaine M. Olnes, Matthew J. Galili, Naomi Shenoy, Aarthi Pfannes, Loretta Wilhelm, Francois Weinstein, Barbara Scheinberg, Phillip Groopman, Jerome E. Raza, Azra TI ON 01910.Na Suppresses Cyclin D1 Accumulation in trisomy 8 Myelodysplastic Syndromes Patients While Decreasing Bone Marrow CD34+Blast Counts and Aneuploid Clone Size SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Sloand, Elaine M.; Shenoy, Aarthi; Pfannes, Loretta; Weinstein, Barbara; Scheinberg, Phillip] NHLBI, NIH, Bethesda, MD 20892 USA. [Olnes, Matthew J.] NIH, Hematol Branch, Bethesda, MD 20892 USA. [Galili, Naomi; Raza, Azra] St Vincents Comprehens Canc Ctr, New York, NY USA. [Wilhelm, Francois] Onconova Therapeut, Newtown, PA USA. [Groopman, Jerome E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Inst Med, Boston, MA 02215 USA. RI Scheinberg, Phillip/H-5251-2012 NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 54 EP 55 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800121 ER PT J AU De Keersmaecker, K Luna, PJR Della Gatta, G Palomero, T Castillo, M Sulis, ML Tosello, V Gounari, F Kee, B Lenz, J Kelliher, M Aplan, PD Cordon-Cardo, C Ferrando, AA AF De Keersmaecker, Kim Real Luna, Pedro Jose Della Gatta, Giusy Palomero, Teresa Castillo, Mireia Sulis, Maria Luisa Tosello, Valeria Gounari, Fotini Kee, Barbara Lenz, Jack Kelliher, Michelle Aplan, Peter D. Cordon-Cardo, Carlos Ferrando, Adolfo A. TI The HOX11/TLX1 Transcription Factor Oncogene Induces Chromosomal Aneuploidy in T-ALL SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [De Keersmaecker, Kim; Della Gatta, Giusy; Castillo, Mireia; Tosello, Valeria; Ferrando, Adolfo A.] Columbia Univ, Inst Canc Genet, New York, NY USA. [Real Luna, Pedro Jose] Andalusian Stem Cell Bank, Granada, Spain. [Palomero, Teresa] Inst Canc Genet, New York, NY USA. [Gounari, Fotini] Univ Chicago, Sch Med, Dept Med, Chicago, IL 60637 USA. [Kee, Barbara] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Lenz, Jack] Albert Einstein Coll Med, Dept Mol Genet, New York, NY USA. [Kelliher, Michelle] Univ Massachusetts, Sch Med, Worcester, MA USA. [Aplan, Peter D.] NCI, Genet Branch, NIH, CCR, Bethesda, MD 20892 USA. [Cordon-Cardo, Carlos] Columbia Univ, Dept Pathol, New York, NY USA. RI Aplan, Peter/K-9064-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 65 EP 66 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800143 ER PT J AU de Latour, RP Visconte, V Keyvanfar, K Nunez, O Desierto, M Chen, JC Wiestner, A Young, NS AF de Latour, Regis Peffault Visconte, Valeria Keyvanfar, Keyvan Nunez, Olga Desierto, Marie Chen, Jichun Wiestner, Adrian Young, Neal S. TI Endoplasmic Reticulum Stress Is a Target for Therapy in Paroxysmal Nocturnal Hemoglobinuria. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [de Latour, Regis Peffault; Visconte, Valeria; Keyvanfar, Keyvan; Nunez, Olga; Desierto, Marie; Chen, Jichun; Wiestner, Adrian; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 71 EP 72 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800161 ER PT J AU Mullighan, CG Collins-Underwood, JR Phillips, LA Loudin, MG Liu, W Zhang, JH Ma, J Coustan-Smith, E Harvey, RC Willman, CL Cheng, JJ Mikhail, FM Meyer, J Williams, RT Carroll, AJ Heerema, NA Basso, G Pession, A Pui, CH Raimondi, SC Hunger, SP Downing, JR Carroll, WL Rabin, KR AF Mullighan, Charles G. Collins-Underwood, J. Racquel Phillips, Letha A. Loudin, Michael G. Liu, Wei Zhang, Jinghui Ma, Jing Coustan-Smith, Elaine Harvey, Richard C. Willman, Cheryl L. Cheng, Jinjun Mikhail, Fady M. Meyer, Julia Williams, Richard T. Carroll, Andrew J. Heerema, Nyla A. Basso, Giuseppe Pession, Andrea Pui, Ching-Hon Raimondi, Susana C. Hunger, Stephen P. Downing, James R. Carroll, William L. Rabin, Karen R. TI Rearrangement of CRLF2 in B-Progenitor and Down Syndrome Associated Acute Lymphoblastic Leukemia SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Ma, Jing] St Jude Childrens Hosp, Hartwell Ctr, Memphis, TN 38105 USA. [Loudin, Michael G.; Rabin, Karen R.] Baylor Coll Med, Houston, TX 77030 USA. [Zhang, Jinghui] NCI, Ctr Biomed Informat & Informat Technol, NIH, Rockville, MD USA. [Harvey, Richard C.; Willman, Cheryl L.] Univ New Mexico, Canc Res & Treatment Ctr, UNM Canc Res Facil, Albuquerque, NM 87131 USA. [Mikhail, Fady M.; Carroll, Andrew J.] Univ Alabama, Dept Genet, Birmingham, AL USA. [Meyer, Julia; Carroll, William L.] NYU, Inst Canc, New York, NY USA. [Heerema, Nyla A.] Ohio State Univ, Columbus, OH 43210 USA. [Basso, Giuseppe] Univ Padua, Dept Pediat, Padua, Italy. [Pession, Andrea] ANLL Study Grp AIEOP, Bologna, Italy. [Hunger, Stephen P.] Univ Colorado, Coll Med, Pediat Heme Onc BMT, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 80 EP 80 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800183 ER PT J AU Yong, ASM Stephens, N Savani, BN Li, YX Eniafe, R Keyvanfar, K Kurlander, RJ Rezvani, K Barrett, AJ AF Yong, Agnes S. M. Stephens, Nicole Savani, Bipin N. Li, Yixin Eniafe, Rhoda Keyvanfar, Keyvan Kurlander, Roger J. Rezvani, Katayoun Barrett, A. John TI In Chronic Myeloid Leukemia Cytotoxic T Cell Responses to BMI-1 Protein Correlate with Higher Expression of BMI-1 in Leukemia Progenitors, and May Contribute to Improved Outcome After Allogeneic Stem Cell Transplantation SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Yong, Agnes S. M.; Stephens, Nicole; Eniafe, Rhoda; Keyvanfar, Keyvan] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Savani, Bipin N.] Vanderbilt Univ, Nashville, TN USA. [Li, Yixin; Kurlander, Roger J.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Rezvani, Katayoun] Univ London Imperial Coll Sci Technol & Med, Dept Haematol, London, England. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 84 EP 84 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800193 ER PT J AU Astermark, J Schwarz, J Donfield, SM DiMichele, DM Ewenstein, BM Gomperts, ED Nelson, GW Oldenburg, J Shapiro, AD Spotts, G Winkler, CA Berntorp, E AF Astermark, Jan Schwarz, John Donfield, Sharyne M. DiMichele, Donna M. Ewenstein, Bruce M. Gomperts, Edward D. Nelson, George W. Oldenburg, Johannes Shapiro, Amy D. Spotts, Gerald Winkler, Cheryl A. Berntorp, Erik TI Genetic Factors Associated with Inhibitor Development in Hemophilia A: Initial Results From the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Astermark, Jan; Berntorp, Erik] Lund Univ, Malmo Univ Hosp, Malmo Ctr Thrombosis & Haemostasis, Malmo, Sweden. [Schwarz, John; Donfield, Sharyne M.] Rho Inc, Biostat, Chapel Hill, NC USA. [DiMichele, Donna M.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Ewenstein, Bruce M.; Spotts, Gerald] Baxter Healthcare Corp, Westlake Village, CA USA. [Gomperts, Edward D.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Nelson, George W.] NCI, Bioinformat Grp, SAIC, Frederick, MD 21701 USA. [Oldenburg, Johannes] Univ Hosp Bonn, Inst Expt Haematol & Transfus Med, Bonn, Germany. [Shapiro, Amy D.] Indiana Hemophilia & Thrombosis Ctr, Indianapolis, IN USA. [Winkler, Cheryl A.] NCI, Mol Genet Epidemiol Sect, SAIC, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 95 EP 95 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800218 ER PT J AU Lozier, JN Menashe, I Goedert, JJ Rosenberg, PS AF Lozier, Jay N. Menashe, Idan Goedert, James J. Rosenberg, Philip S. TI A Case-Control Study of Candidate Immunoregulatory Genes Reveals Haplotypes That Influence Inhibitor Risk in Severe Hemophilia A SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Lozier, Jay N.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Menashe, Idan; Goedert, James J.; Rosenberg, Philip S.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 95 EP 95 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800219 ER PT J AU Zhao, L Melenhorst, JJ Alemu, L Kirby, M Anderson, SM Hoogstraten-Miller, S Kamikubo, Y Gilliland, DG Liu, PP AF Zhao, Ling Melenhorst, J. Joseph Alemu, Lemlem Kirby, Martha Anderson, Stacie M. Hoogstraten-Miller, Shelley Kamikubo, Yasuhiko Gilliland, D. Gary Liu, Pu Paul TI C-KIT with D816Y/V Mutations Cooperate with CBFB-MYH11 to Accelerate Leukemogenesis in Mice SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Zhao, Ling; Alemu, Lemlem; Liu, Pu Paul] NHGRI, ODS, GMBB, NIH, Bethesda, MD 20892 USA. [Melenhorst, J. Joseph] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Kirby, Martha; Anderson, Stacie M.] NHGRI, Flow Cytometry Core, GMBB, NIH, Bethesda, MD 20892 USA. [Hoogstraten-Miller, Shelley] NHGRI, Anim Program, NIH, Bethesda, MD 20892 USA. [Kamikubo, Yasuhiko] Univ Tokyo, Tokyo, Japan. [Gilliland, D. Gary] Merck Res Labs, Boston, MA USA. RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 116 EP 116 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800275 ER PT J AU Galan, PP Jensen, HM Weniger, MA Chapman, CM Liu, PC Raghavachari, N Shaffer, AL Staudt, LM Wiestner, A AF Galan, Patricia Perez Jensen, Helena Mora Weniger, Marc A. Chapman, Colby M. Liu, Poching Raghavachari, Nalini Shaffer, Arthur L., III Staudt, Louis M. Wiestner, Adrian TI Bortezomib Resistance in Mantle Cell Lymphoma Is Associated with Expression of a Plasmacytoid Differentiation Program SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Galan, Patricia Perez; Jensen, Helena Mora; Weniger, Marc A.; Chapman, Colby M.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Liu, Poching; Raghavachari, Nalini] NHLBI, Genom Core Facil, NIH, Bethesda, MD 20892 USA. [Shaffer, Arthur L., III; Staudt, Louis M.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 121 EP 121 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800288 ER PT J AU Walz, C Lazarides, K Patel, N Hennighausen, L Zaleskas, VM Van Etten, RA AF Walz, Christoph Lazarides, Katherine Patel, Nihal Hennighausen, Lothar Zaleskas, Virginia M. Van Etten, Richard A. TI Essential Role for Stat5a/b in Myeloproliferative Neoplasms Induced by BCR-ABL1 and Jak2 V617F SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Walz, Christoph; Lazarides, Katherine; Patel, Nihal; Zaleskas, Virginia M.; Van Etten, Richard A.] Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA USA. [Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 132 EP 132 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800313 ER PT J AU Herishanu, Y Perez-Gelen, P Liu, D Biancotto, A Vire, B Gibellini, F Njuguna, N Mccoy, P Pittaluga, S Stettler-Stevenson, M Munson, PJ Wilson, WH Wiestner, A AF Herishanu, Yair Perez-Gelen, Patricia Liu, Delong Biancotto, Angelique Vire, Berengere Gibellini, Federica Njuguna, Ndegwa McCoy, Philip Pittaluga, Stefania Stettler-Stevenson, Maryalice Munson, Peter J. Wilson, Wyndham H. Wiestner, Adrian TI Comparative Gene Expression Profiling of Leukemia Cells in Peripheral Blood and Tissue Compartments Reveals a Prominent Role of the Microenvironment for CLL Cell Proliferation SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Herishanu, Yair; Perez-Gelen, Patricia; Vire, Berengere; Gibellini, Federica; Njuguna, Ndegwa; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Herishanu, Yair] Tel Aviv Sourasky Med Ctr, Bethesda, MD USA. [Liu, Delong; Munson, Peter J.] CIT, Math & Stat Comp Lab, DCB, NIH, Bethesda, MD USA. [Biancotto, Angelique; McCoy, Philip] NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. [Pittaluga, Stefania; Stettler-Stevenson, Maryalice] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, CCR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 150 EP 150 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800356 ER PT J AU Ngo, V Lenz, G Xiao, WM Wright, G Staudt, LM AF Ngo, Vu Lenz, Georg Xiao, Wenming Wright, George Staudt, Louis M. TI OCT2 (Octamer Binding Protein 2): An Essential Role in Germinal Center B Cell Differentiation and the "Achilles Heel" of Derived Lymphomas SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Ngo, Vu; Lenz, Georg; Xiao, Wenming; Wright, George; Staudt, Louis M.] NCI, Ctr Clin Canc, NIH, Metab Branch,Bioinformat & Mol Anal Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 153 EP 153 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800363 ER PT J AU Hogart, A Ajay, SS Abaan, HO Anderson, SM Margulies, EH Bodine, DM AF Hogart, Amber Ajay, Subramanian S. Abaan, Hatice Ozel Anderson, Stacie M. Margulies, Elliott H. Bodine, David M. TI Genome-Wide DNA Methylation Patterns Reveal Specific Signatures for HSC, CMP and Erythroblasts SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Hogart, Amber; Anderson, Stacie M.; Bodine, David M.] NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Ajay, Subramanian S.; Abaan, Hatice Ozel; Margulies, Elliott H.] NHGRI, Genome Technol Branch, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 163 EP 163 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800392 ER PT J AU Lin, YW Beharry, ZM Hill, EG Song, JH Wang, WX Xia, ZP Zhang, ZH Aplan, PD Aster, J Smith, CD Kraft, A AF Lin, Yingwei Beharry, Zanna M. Hill, Elizabeth G. Song, Jin H. Wang, Wenxue Xia, Zuping Zhang, Zhenhua Aplan, Peter D. Aster, Jon Smith, Charles D. Kraft, Andrew TI Synergistic Killing of Leukemic Cells by Small Molecule Inhibitors of the Pim Protein Kinases and Inactivators of Additional Signal Transduction Pathways SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Lin, Yingwei; Beharry, Zanna M.; Hill, Elizabeth G.; Song, Jin H.; Wang, Wenxue; Xia, Zuping; Smith, Charles D.; Kraft, Andrew] Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Hollings Canc Ctr, Coll Med,Div Biostat & Epidemiol,Dept Med, Charleston, SC 29425 USA. [Zhang, Zhenhua; Aplan, Peter D.] NCI, Genet Branch, NIH, CCR, Bethesda, MD 20892 USA. [Aster, Jon] Brigham & Womens Hosp, Boston, MA 02115 USA. RI Aplan, Peter/K-9064-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 170 EP 171 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800410 ER PT J AU Galan, PP Chapman, CM Gibellini, F Liu, P Raghavachari, N Roschewski, M Wiestner, A AF Galan, Patricia Perez Chapman, Colby M. Gibellini, Federica Liu, Poching Raghavachari, Nalini Roschewski, Mark Wiestner, Adrian TI The PI3K Inhibitor ON 01910.Na Inhibits Critical Survival Pathways and Induces Apoptosis in CLL Cells through Induction of NOXA and BIM SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Galan, Patricia Perez; Chapman, Colby M.; Gibellini, Federica; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Liu, Poching; Raghavachari, Nalini] NHLBI, Genom Core Facil, NIH, Bethesda, MD 20892 USA. [Roschewski, Mark] Walter Reed Army Med Ctr, Washington, DC 20307 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 171 EP 172 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800413 ER PT J AU Calado, RT Prince, C Peterson, NR Young, NS Maciejewski, JP AF Calado, Rodricio T. Prince, Courtney Peterson, Nathan R. Young, Neal S. Maciejewski, Jaroslaw P. TI Mutations in the Telomerase Reverse Transcriptase Gene Predisposes to Myelodysplastic Syndromes SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Prince, Courtney; Maciejewski, Jaroslaw P.] Cleveland Clin, Taussig Canc Inst, Dept Translat Hematol & Oncol Res, Cleveland, OH 44106 USA. [Calado, Rodricio T.; Peterson, Nathan R.; Young, Neal S.] NHLBI, Hematol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RI Calado, Rodrigo/G-2619-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 172 EP 173 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800416 ER PT J AU Khandanpour, C Sharif-Askari, E Afshar, K Gaudreau, MC Zhu, JF Paul, W Jolicoeur, P Duhrsen, U Moroy, T AF Khandanpour, Cyrus Sharif-Askari, Ehssan Afshar, Khashayar Gaudreau, Marie-Claude Zhu, Jinfang Paul, William Jolicoeur, Paul Duhrsen, Ulrich Moroy, Tarik TI Growth Factor Independence 1 (Gfi1) Is Required for Initiation, Maintenance, Progression, and Transplantability of Lymphoma SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Khandanpour, Cyrus; Sharif-Askari, Ehssan; Afshar, Khashayar; Gaudreau, Marie-Claude; Jolicoeur, Paul; Moroy, Tarik] Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. [Zhu, Jinfang; Paul, William] NIAID, NIH, Bethesda, MD 20892 USA. [Duhrsen, Ulrich] Univ Hosp Essen, Essen, Germany. RI Moroy, Tarik/D-9923-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 186 EP 186 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800448 ER PT J AU Aue, G Lozier, JN Cullinane, AM Gibellini, F Tian, X Samsel, L McCoy, P Wiestner, A AF Aue, Georg Lozier, Jay Nelson Cullinane, Ann Marie Gibellini, Federica Tian, Xin Samsel, Leigh McCoy, Philip Wiestner, Adrian TI Increased Incidence of Thrombosis with Lenalidomide in Chronic Lymphocytic Leukemia: Effect of Lenalidomide On Inflammation, Endothelial Cell Damage and Coagulation. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Aue, Georg; Gibellini, Federica; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Lozier, Jay Nelson; Cullinane, Ann Marie] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Tian, Xin] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Samsel, Leigh; McCoy, Philip] NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 189 EP 189 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800456 ER PT J AU Sripichal, O Kiefer, CM Lee, YT Meier, ER Byrnes, C Dean, A Miller, JL AF Sripichal, Orapan Kiefer, Christine M. Lee, Y. Terry Meier, Emily Riehm Byrnes, Colleen Dean, Ann Miller, Jeffery L. TI During Terminal Differentiation, HbF-Inducing Cytokines Cause Decreased Expression and Reduced Globin Locus Occupancy of BCL11A in Human Erythroblasts SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Sripichal, Orapan; Lee, Y. Terry; Meier, Emily Riehm; Byrnes, Colleen; Miller, Jeffery L.] NIDDK, Mol Med Branch, NIH, Bethesda, MD USA. [Kiefer, Christine M.; Dean, Ann] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 190 EP 190 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800458 ER PT J AU Berg, M Lundqvist, A Betters, D Childs, RW AF Berg, Maria Lundqvist, Andreas Betters, Dawn Childs, Richard W. TI In Vitro Expanded NK Cells Have Increased Natural Cytotoxity Receptors, TRAIL and NKG2D Expression, and Superior Tumor Cytotoxicity Compared to Short-Term IL-2-Activated NK Cells SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Berg, Maria; Lundqvist, Andreas; Betters, Dawn] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 192 EP 192 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800464 ER PT J AU Cherkasova, E Malinzak, E Rao, S Senchenko, VN Kudryavtseva, AV Kiselev, LL Takahashi, Y Harashima, N Linehan, WM Srinivasan, R Lerman, MI Childs, RW AF Cherkasova, Elena Malinzak, Elizabeth Rao, Sheila Senchenko, Vera N. Kudryavtseva, Anna V. Kiselev, Lev L. Takahashi, Yoshiyuki Harashima, Nanae Linehan, W. Marston Srinivasan, Ramaprasad Lerman, Michael I. Childs, Richard W. TI Loss of Function of the VHL Tumor Suppressor Gene Resurrects An Endogenous Retrovirus in Kidney Cancer That Encodes a Tumor Antigen Targeted by Allogeneic T-Cells Following Hematopoietic Cell Transplantation (HCT) SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Cherkasova, Elena; Malinzak, Elizabeth; Senchenko, Vera N.; Kudryavtseva, Anna V.; Kiselev, Lev L.; Lerman, Michael I.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Takahashi, Yoshiyuki; Harashima, Nanae] Nagoya Univ, Grad Sch Med, Dept Pediat, Nagoya, Aichi 4648601, Japan. [Linehan, W. Marston] NCI, NIH, Bethesda, MD 20892 USA. RI Senchenko, Vera/C-8992-2014; Kudryavtseva, Anna/C-9032-2014 OI Senchenko, Vera/0000-0002-3119-515X; Kudryavtseva, Anna/0000-0002-3722-8207 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 193 EP 193 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800468 ER PT J AU Muranski, P Kerkar, SP Borman, ZA Reger, R Sanchez-Perez, L Hinrichs, CS Yu, ZY Palmer, DC Gattioni, L Restifo, NP AF Muranski, Pawel Kerkar, Sid P. Borman, Zachary A. Reger, Robert Sanchez-Perez, Luis Hinrichs, Christian S. Yu, Zhiya Palmer, Douglas C. Gattioni, Luca Restifo, Nicholas P. TI IL-17A-Expressing CD4+T Cells Must Acquire the Expression of T-Bet and IFN-gamma to Destroy Tumor Cells In Vivo SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Muranski, Pawel; Kerkar, Sid P.; Borman, Zachary A.; Reger, Robert; Sanchez-Perez, Luis; Hinrichs, Christian S.; Yu, Zhiya; Palmer, Douglas C.; Gattioni, Luca; Restifo, Nicholas P.] NCI, NIH, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; Muranski, Pawel/E-5572-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 193 EP 194 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800469 ER PT J AU Bunce, E Taylor, J Foley, J Levine, B June, CH Sabatino, M Fellowes, V Stroncek, D Fowler, DH Amarnath, S AF Bunce, Emily Taylor, Justin Foley, Jason Levine, Bruce June, Carl H. Sabatino, Marianna Fellowes, Vicki Stroncek, David Fowler, Daniel H. Amarnath, Shoba TI Ex Vivo Manufacture of Rapamycin-Resistant Human Th1/Tc1 Cells SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Bunce, Emily; Taylor, Justin; Foley, Jason; Fowler, Daniel H.; Amarnath, Shoba] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Levine, Bruce; June, Carl H.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Sabatino, Marianna; Fellowes, Vicki; Stroncek, David] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RI Levine, Bruce/D-1688-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 207 EP 207 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800502 ER PT J AU Mielke, S Shenoy, A Rezvani, K Yong, ASM McIver, ZA Fellowes, VS Savani, BN Kurlander, R Khuu, H Boss, C Barrett, AJ AF Mielke, Stephan Shenoy, Aarthi Rezvani, Katayoun Yong, Agnes S. M. McIver, Zachariah A. Fellowes, Vicki S. Savani, Bipin N. Kurlander, Roger Khuu, Hanh Boss, Carol Barrett, A. John TI Allografts Selectively Photodepleted of GvHD Causing T Cells and Followed by Low-Level Immunosuppression: A Novel Method to Improve Disease Control After HLA-Matched Sibling Transplantations SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Mielke, Stephan] Univ Wurzburg, Dept Med 2, Div Hematol & Oncol, Wurzburg, Germany. [Shenoy, Aarthi; Yong, Agnes S. M.; McIver, Zachariah A.; Barrett, A. John] NHLBI, Hematol Branch, Allotransplantat Sect, NIH, Bethesda, MD 20892 USA. [Rezvani, Katayoun] Univ London Imperial Coll Sci Technol & Med, Dept Haematol, London, England. [Fellowes, Vicki S.; Khuu, Hanh] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Savani, Bipin N.] Vanderbilt Univ, Dept Hematol, Nashville, TN USA. [Kurlander, Roger] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 213 EP 214 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800516 ER PT J AU McIver, ZA Grim, A Naguib, N Barrett, AJ AF McIver, Zachariah A. Grim, Andrew Naguib, Nicolas Barrett, A. John TI Low Absolute CD4 Central Memory Count On Day 30 Is Associated with An Increased Incidence of Chronic Graft-Versus-Host Disease SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [McIver, Zachariah A.; Grim, Andrew; Naguib, Nicolas; Barrett, A. John] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 214 EP 214 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800517 ER PT J AU Pilon, AM Ajay, SS Abaan, HO Margulies, EH Gallagher, PG Bodine, DM AF Pilon, Andre M. Ajay, Subramanian S. Abaan, Hatice Ozel Margulies, Elliott H. Gallagher, Patrick G. Bodine, David M. TI Genome-Wide ChIP-Seq Reveals a Dramatic Shift in the EKLF Binding Profile Between Erythroid Progenitors and Erythroblasts SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Pilon, Andre M.; Bodine, David M.] NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Ajay, Subramanian S.; Abaan, Hatice Ozel; Margulies, Elliott H.] NHGRI, Genome Technol Branch, Rockville, MD USA. [Gallagher, Patrick G.] Yale Univ, Sch Med, New Haven, CT USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 235 EP 235 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800566 ER PT J AU Machado, RF Barst, RJ Yovetich, NA Hassell, KL Goldsmith, JC Woolson, R Gordeuk, VR Gibbs, S Little, JA Kato, GJ Schraufnagel, DE Krishnamurti, L Girgis, RE Morris, CR Berman-Rosenzweig, E Badesch, DB Waclawiw, MA Gladwin, M AF Machado, Roberto F. Barst, Robyn J. Yovetich, Nancy A. Hassell, Kathryn L. Goldsmith, Jonathan C. Woolson, Rob Gordeuk, Victor R. Gibbs, Simon Little, Jane A. Kato, Gregory J. Schraufnagel, Dean E. Krishnamurti, Lakshmanan Girgis, Reda E. Morris, Claudia R. Berman-Rosenzweig, Erika Badesch, David B. Waclawiw, Myron A. Gladwin, Mark TI Safety and Efficacy of Sildenafil Therapy for Doppler-Defined Pulmonary Hypertension in Patients with Sickle Cell Disease: Preliminary Results of the Walk-PHaSST Clinical Trial SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Machado, Roberto F.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Barst, Robyn J.; Berman-Rosenzweig, Erika] Columbia Univ, New York, NY USA. [Yovetich, Nancy A.; Woolson, Rob] Rho Inc, Chapel Hill, NC USA. [Hassell, Kathryn L.] Univ Colorado, HSC, Denver, CO 80202 USA. [Goldsmith, Jonathan C.] NHLBI, Div Blood Dis & Resources, NIH, Bethesda, MD 20892 USA. [Gordeuk, Victor R.] Howard Univ, Washington, DC 20059 USA. [Gibbs, Simon] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England. [Little, Jane A.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Kato, Gregory J.] NHLBI, Vasc Med Branch, Bethesda, MD 20892 USA. [Schraufnagel, Dean E.] Univ Illinois, Chicago, IL USA. [Krishnamurti, Lakshmanan] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Girgis, Reda E.] Johns Hopkins Univ, Dept Cardiol, Baltimore, MD USA. [Morris, Claudia R.] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA. [Waclawiw, Myron A.] Univ Colorado, Pulm Hypertens Ctr, Denver, CO 80202 USA. [Gladwin, Mark] Univ Pittsburgh, Med Ctr, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 0 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 237 EP 238 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800572 ER PT J AU Gordeuk, VR Luchtman-Jones, L Campbell, AD Rana, SR Nouraie, M Sable, C Dham, N Ensing, G Minniti, C Kato, GJ Gladwin, M Castro, OL AF Gordeuk, Victor R. Luchtman-Jones, Lori Campbell, Andrew D. Rana, Schad R. Nouraie, Mehdi Sable, Craig Dham, Niti Ensing, Gregory Minniti, Caterina Kato, Gregory J. Gladwin, Mark Castro, Oswaldo L. TI Hemolysis-Associated Elevation in Tricuspid Regurgitation Velocity Predicts Reduction in Six-Minute Walk Distance After Two Years of Follow up in Children and Adolescents with Sickle Cell Disease SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Nouraie, Mehdi; Castro, Oswaldo L.] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Luchtman-Jones, Lori; Sable, Craig; Dham, Niti] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Campbell, Andrew D.; Ensing, Gregory] Univ Michigan, Med Ctr, Ann Arbor, MI USA. [Rana, Schad R.] Howard Univ Hosp, Dept Pediat & Child Hlth, Washington, DC USA. [Minniti, Caterina; Kato, Gregory J.] NHLBI, Vasc Med Branch, Bethesda, MD 20892 USA. [Gladwin, Mark] Univ Pittsburgh, Med Ctr, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 238 EP 239 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800575 ER PT J AU Taylor, JG Belfer, I Desai, K Youngblood, V Freeman, LA Darbari, DS Kato, GJ Milton, JN Hartley, SW Steinberg, MH Goldman, D Max, MB AF Taylor, James G. Belfer, Inna Desai, Krupa Youngblood, Victoria Freeman, Lita A. Darbari, Deepika S. Kato, Gregory J. Milton, Jacqueline N. Hartley, Stephen W. Steinberg, Martin H. Goldman, David Max, Mitchell B. TI A GCH1 Haplotype Associated with Susceptibility to Vasoocclusive Pain and Impaired Vascular Function in Sickle Cell Anemia SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Taylor, James G.; Desai, Krupa; Youngblood, Victoria; Freeman, Lita A.; Kato, Gregory J.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Belfer, Inna; Max, Mitchell B.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Darbari, Deepika S.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Milton, Jacqueline N.; Hartley, Stephen W.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Goldman, David] Boston Univ, Sch Med, Dept Med, Div Hematol & Oncol, Boston, MA 02118 USA. [Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. RI Kato, Gregory/I-7615-2014; Goldman, David/F-9772-2010 OI Kato, Gregory/0000-0003-4465-3217; Goldman, David/0000-0002-1724-5405 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 239 EP 239 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800576 ER PT J AU Jacobs, CL Lugar, PL Liu, QQ Zhang, J Lipsky, P Dave, S AF Jacobs, Cassandra L. Lugar, Patricia L. Liu, Qingquan Zhang, Jenny Lipsky, Peter Dave, Sandeep TI Molecular Profiling Identifies Plasmablasts as the Cells of Origin of Activated Diffuse Large B Cell Lymphoma SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Lipsky, Peter] NIH, Bethesda, MD 20892 USA. [Liu, Qingquan] Univ Toledo, Dept Biol, Toledo, OH 43606 USA. [Jacobs, Cassandra L.] Duke Univ, Igsp, Durham, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 257 EP 257 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800622 ER PT J AU Rimsza, LM Wright, G Schwartz, M Chan, WC Jaffe, ES Gascoyne, RD Campo, E Rosenwald, A Ott, G Cook, JR Tubbs, RR Braziel, RM Delabie, J Miller, TP Fisher, RI Staudt, LM AF Rimsza, Lisa M. Wright, George Schwartz, Mark Chan, Wing C. Jaffe, Elaine S. Gascoyne, Randy D. Campo, Elias Rosenwald, Andreas Ott, German Cook, James R. Tubbs, Raymond R. Braziel, Rita M. Delabie, Jan Miller, Thomas P. Fisher, Richard I. Staudt, Louis M. TI Accurate Classification of Diffuse Large B Cell Lymphoma Into Germinal Center and Activated B Cell Subtypes Using a Nuclease Protection Assay On Formalin Fixed Paraffin Embedded Tissue: A Study From the Lymphoma and Leukemia Molecular Profiling Project SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Rimsza, Lisa M.] Univ Arizona, Tucson, AZ USA. [Wright, George; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Schwartz, Mark] High Throughput Genom, Res & Dev, Tucson, AZ USA. [Chan, Wing C.] Univ Nebraska, Med Ctr, Omaha, NE USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Campo, Elias] Hosp Clin Barcelona, Barcelona, Spain. [Rosenwald, Andreas] Univ Wurzburg, Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Inst Klin Pathol, Stuttgart, Germany. [Cook, James R.; Tubbs, Raymond R.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Delabie, Jan] Norwegian Radium Hosp, Oslo, Norway. [Miller, Thomas P.] Arizona Canc Ctr, Tucson, AZ USA. [Fisher, Richard I.] James P Wilmot Canc Ctr, Rochester, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 257 EP 257 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800621 ER PT J AU Bullock, GC Delehanty, LL Talbot, AL Gonias, S Tong, WH Rouault, T Chruma, J Goldfarb, A AF Bullock, Grant C. Delehanty, Lorrie L. Talbot, Anne-Laure Gonias, Sara Tong, Wing-Hang Rouault, Tracey Chruma, Jason Goldfarb, Adam TI Iron and Isocitrate Calibrate Erythropoietin Responsiveness of Erythroid Progenitors Via Aconitase Tuning of Protein Kinase C Activity SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Bullock, Grant C.; Delehanty, Lorrie L.; Talbot, Anne-Laure; Gonias, Sara; Goldfarb, Adam] Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. [Tong, Wing-Hang; Rouault, Tracey] NICHD, Bethesda, MD USA. [Chruma, Jason] Univ Virginia, Dept Chem, Charlottesville, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 260 EP 260 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800628 ER PT J AU Noh, SJ Wu, YP Byrnes, C Lee, YT Miller, JL AF Noh, Seung-Jae Wu, Yun-Ping Byrnes, Colleen Lee, Y. Terry Miller, Jeffery L. TI Transferrin Receptor 2 Protein Is Expressed in Mitochondrial-Associated Lysosomes During Human Erythropoiesis SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Noh, Seung-Jae; Byrnes, Colleen; Lee, Y. Terry; Miller, Jeffery L.] NIDDKD, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Wu, Yun-Ping] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 260 EP 260 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800629 ER PT J AU Salit, RB Steinberg, S Fowler, DH Odom, J Bryant, K Bishop, MR AF Salit, Rachel B. Steinberg, Seth Fowler, Daniel H. Odom, Jeanne Bryant, Kelly Bishop, Michael R. TI Targeted Lymphocyte Depletion: A Personalized Approach to Achieve Rapid Complete Donor Chimerism and Enhance Graft-Versus-Tumor Effects Following Reduced Intensity Allogeneic Stem Cell Transplantation for High-Risk Hematologic Malignancies SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Steinberg, Seth] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Odom, Jeanne] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 273 EP 274 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800657 ER PT J AU Leshchenko, V Kuo, PY Shaknovich, R Gellen, T Remache, Y Weniger, M Suh, KS Goy, A Wilson, W Braunschweig, I Verma, A Wiestner, A Melnick, A Parekh, S AF Leshchenko, Violetta Kuo, Pei-Yu Shaknovich, Rita Gellen, Tobias Remache, Yvonne Weniger, Marc Suh, K. Stephen Goy, Andre Wilson, Wyndham Braunschweig, Ira Verma, Amit Wiestner, Adrian Melnick, Ari Parekh, Samir TI Genome-Wide Methylation Analysis of Primary Mantle Cell Lymphomas Identifies Novel Gene Targets for Epigenetic Drug Therapy. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Leshchenko, Violetta; Kuo, Pei-Yu; Gellen, Tobias; Verma, Amit; Parekh, Samir] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10467 USA. [Shaknovich, Rita; Melnick, Ari] Weill Cornell Med Coll, Div Hematol & Oncol, New York, NY USA. [Remache, Yvonne; Suh, K. Stephen; Goy, Andre] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Weniger, Marc; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wilson, Wyndham] NCI, CCR, NIH, Bethesda, MD 20892 USA. [Braunschweig, Ira] Montefiore Med Ctr, Bronx, NY 10467 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 281 EP 282 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800674 ER PT J AU Della Gatta, G Palomero, T Sulis, ML Sole, X Lim, WK De Keersmaecker, K Luna, PJR Tosello, V Gounari, F Kee, B Lenz, J Kelliher, M Aplan, PD Meijerink, JPP Califano, A Ferrando, A AF Della Gatta, Giusy Palomero, Teresa Sulis, Maria Luisa Sole, Xavier Lim, Wei Keat De Keersmaecker, Kim Real Luna, Pedro Jose Tosello, Valeria Gounari, Fotini Kee, Barbara Lenz, Jack Kelliher, Michelle Aplan, Peter D. Meijerink, Jules P. P. Califano, Andrea Ferrando, Adolfo TI Oncogenic Transcriptional Programs Controlled by TLX1/HOX11 and TLX3/HOX11L2 in T-ALL. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Della Gatta, Giusy; Palomero, Teresa; Lim, Wei Keat; De Keersmaecker, Kim; Tosello, Valeria; Califano, Andrea; Ferrando, Adolfo] Columbia Univ, Inst Canc Genet, New York, NY USA. [Real Luna, Pedro Jose] Andalusian Stem Cell Bank, Granada, Spain. [Gounari, Fotini] Univ Chicago, Sch Med, Dept Med, Chicago, IL 60637 USA. [Kee, Barbara] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Lenz, Jack] Albert Einstein Coll Med, Dept Mol Genet, New York, NY USA. [Kelliher, Michelle] UMass Med Sch, Worcester, MA USA. [Aplan, Peter D.] NCI, Genet Branch, NIH, CCR, Bethesda, MD 20892 USA. [Meijerink, Jules P. P.] Sophia Childrens Univ Hosp, ErasmusMC Rotterdam, Dept Pediat Oncol Hematol, Rotterdam, Netherlands. RI Califano, Andrea/F-7239-2012; Aplan, Peter/K-9064-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 282 EP 283 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800677 ER PT J AU Martinez-Garcia, E Popovic, R Min, DJ Will, C Meyer, J Staudt, LM Lamy, L Lauring, J Chen, ZJ Patel, D Licht, JD AF Martinez-Garcia, Eva Popovic, Relja Min, Dong-Joon Will, Christine Meyer, Julia Staudt, Louis M. Lamy, Laurence Lauring, Josh Chen, Zhongjun Patel, Dinshaw Licht, Jonathan D. TI The MMSET Histone Methyl Transferase Alters Chromatin Structure and Gene Expression in t(4;14) Multiple Myeloma Cells. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Martinez-Garcia, Eva; Popovic, Relja; Min, Dong-Joon; Will, Christine; Licht, Jonathan D.] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Div Hematol Oncol, Chicago, IL 60611 USA. [Meyer, Julia] NYU, Med Ctr, New York, NY 10016 USA. [Staudt, Louis M.; Lamy, Laurence] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lauring, Josh] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Chen, Zhongjun; Patel, Dinshaw] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 282 EP 282 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800676 ER PT J AU Uchida, N Hargrove, PW Washington, K Lap, CJ Hsieh, MM Bonifacino, AC Price, SD Krouse, AE Metzger, ME Donahue, RE Persons, D Tisdale, JF AF Uchida, Naoya Hargrove, Phillip W. Washington, Kareem Lap, Coen J. Hsieh, Matthew M. Bonifacino, Aylin C. Price, Sandra D. Krouse, Allen E. Metzger, Mark E. Donahue, Robert E. Persons, Derek Tisdale, John F. TI A Modified HIV1-Based Lentiviral Vector Can Transduce Rhesus Hematopoietic Repopulating Cells as Efficiently as An SIV Vector in An Autologous Transplantation Model SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Uchida, Naoya; Washington, Kareem; Lap, Coen J.; Tisdale, John F.] NHLBI, MCHB, NIH, Bethesda, MD 20892 USA. [Hargrove, Phillip W.; Persons, Derek] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Hsieh, Matthew M.] NIDDK, NIH, Bethesda, MD USA. [Bonifacino, Aylin C.; Price, Sandra D.; Krouse, Allen E.; Metzger, Mark E.; Donahue, Robert E.] NHLBI, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 289 EP 290 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800693 ER PT J AU Mullighan, CG Morin, R Zhang, JH Hirst, M Zhao, YJ Yan, CH Finney, R Edmonson, M Su, XP Buetow, KE Carroll, WL Chen, IM Devidas, M Gerhard, D Harvey, RC Hu, Y Loh, ML Reaman, G Relling, MV Smith, MA Downing, JR Hunger, SP Willman, CL Marra, M AF Mullighan, Charles G. Morin, Ryan Zhang, Jinghui Hirst, Martin Zhao, Yongjun Yan, Chunhua Finney, Richard Edmonson, Michael Su, Xiaoping Buetow, Kenneth E. Carroll, William L. Chen, I-Ming Devidas, Meenakshi Gerhard, Daniela Harvey, Richard C. Hu, Ying Loh, Mignon L. Reaman, Gregory Relling, Mary V. Smith, Malcolm A. Downing, James R. Hunger, Stephen P. Willman, Cheryl L. Marra, Marco TI Next Generation Transcriptomic Resequencing Identifies Novel Genetic Alterations in High-Risk (HR) Childhood Acute Lymphoblastic Leukemia (ALL): A Report From the Children's Oncology Group (COG) HR ALL TARGET Project SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Downing, James R.] St Jude Childrens Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA. [Morin, Ryan] BC Canc Res Ctr, Genome Sci Ctr, Vancouver, BC, Canada. [Zhang, Jinghui; Yan, Chunhua; Buetow, Kenneth E.] NCI, Ctr Biomed Informat & Informat Technol, NIH, Rockville, MD USA. [Hirst, Martin; Zhao, Yongjun] BC Genome Sci Ctr, Vancouver, BC, Canada. [Edmonson, Michael] NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. [Carroll, William L.] NYU, Inst Canc, New York, NY USA. [Chen, I-Ming] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. [Devidas, Meenakshi] Childrens Oncol Grp, Dept Epideiniol & Hlth Policy Res, Gainesville, FL USA. [Devidas, Meenakshi] Univ Florida, Coll Med, Gainesville, FL USA. [Harvey, Richard C.] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. [Loh, Mignon L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Reaman, Gregory] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Hunger, Stephen P.] Univ Colorado, Coll Med, Pediat Heme Onc BMT, Aurora, CO USA. [Willman, Cheryl L.] Univ New Mexico, Canc Res & Treatment Ctr, UNM Canc Res Facil, Albuquerque, NM 87131 USA. [Marra, Marco] British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. RI Hirst, Martin/B-7684-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 293 EP 294 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725800705 ER PT J AU Mullighan, CG Zhang, JH Phillips, LA Pui, CH Downing, JR AF Mullighan, Charles G. Zhang, Jinghui Phillips, Letha A. Pui, Ching-Hon Downing, James R. TI Identification of Novel Recurring Mutations in Relapsed Acute Lymphoblastic Leukemia SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Downing, James R.] St Jude Childrens Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA. [Zhang, Jinghui] NCI, Ctr Biomed Informat & Informat Technol, NIH, Rockville, MD USA. [Pui, Ching-Hon] St Jude Childrens Rsch Hosp, Memphis, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 293 EP 293 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800704 ER PT J AU Dowdell, K Niemela, J Price, S Davis, J Perkins, K Dale, J Puck, JM Oliveira, JB Cohen, J Fleisher, T Rao, VK AF Dowdell, Kennichi Niemela, Julie Price, Susan Davis, Joie Perkins, Katie Dale, Janet Puck, Jennifer M. Oliveira, Joao Bosco Cohen, Jeffrey Fleisher, Thomas Rao, V. Koneti TI Somatic Fas Mutations Account for Nearly One Third of Autoimmune Lymphoproliferative Syndrome (ALPS) Cases with Previously Unknown Genetic Mutations SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Dowdell, Kennichi; Price, Susan; Davis, Joie; Perkins, Katie; Rao, V. Koneti] NIAID, ALPS Unit, LCID, NIH, Bethesda, MD 20892 USA. [Niemela, Julie; Oliveira, Joao Bosco; Fleisher, Thomas] NIH, Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Dale, Janet; Cohen, Jeffrey] NIAID, Med Virol Sect, LCID, NIH, Bethesda, MD 20892 USA. [Puck, Jennifer M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 296 EP 296 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800711 ER PT J AU Boztug, K Kotlarz, D Glocker, E Gertz, ME Schaffer, AA Noyan, F Perro, M Diestelhorst, J Allroth, A Murugan, D Hatscher, N Pfeifer, D Sykora, KW Sauer, M Kreipe, H Lacher, M Nustede, R Woellner, C Baumann, U Salzer, U Koletzko, S Shah, N Segal, A Sauerbrey, A Buderus, S Snapper, S Grimbacher, B Klein, C AF Boztug, Kaan Kotlarz, Daniel Glocker, Erik Gertz, Mike E. Schaeffer, Alejandro A. Noyan, Fatih Perro, Mario Diestelhorst, Jana Allroth, Anna Murugan, Dhaarini Haetscher, Nadine Pfeifer, Dietmar Sykora, Karl-Walter Sauer, Martin Kreipe, Hans Lacher, Martin Nustede, Rainer Woellner, Cristina Baumann, Ulrich Salzer, Ulrich Koletzko, Sibylle Shah, Neil Segal, Anthony Sauerbrey, Axel Buderus, Stefan Snapper, Scott Grimbacher, Bodo Klein, Christoph TI Severe Early-Onset Inflammatory Bowel Disease Caused by IL10 Receptor Deficiency Can Be Cured by Allogeneic Hematopoietic Stem Cell Transplantation SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Boztug, Kaan; Kotlarz, Daniel; Diestelhorst, Jana; Haetscher, Nadine; Sauer, Martin] Hannover Med Sch, Dept Pediat Hematol Oncol, D-3000 Hannover, Germany. [Glocker, Erik; Perro, Mario; Woellner, Cristina; Grimbacher, Bodo] Royal Free Hosp, Dept Immunol, London, England. [Gertz, Mike E.; Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Noyan, Fatih; Allroth, Anna; Murugan, Dhaarini; Klein, Christoph] Hannover Med Sch, Dept Pediat Hematol Oncol, D-3000 Hannover, Germany. [Pfeifer, Dietmar] Univ Freiburg, Med Ctr, Dept Hematol Oncol, D-7800 Freiburg, Germany. [Kreipe, Hans] Hannover Med Sch, Dept Pathol, D-3000 Hannover, Germany. [Lacher, Martin; Koletzko, Sibylle] Univ Munich, Childrens Hosp, D-8000 Munich, Germany. [Nustede, Rainer] Hannover Med Sch, Dept Pediat Surg, D-3000 Hannover, Germany. [Baumann, Ulrich] Hannover Med Sch, Dept Pediat Rheumatol & Clin Immunol, D-3000 Hannover, Germany. [Salzer, Ulrich] Univ Med Ctr Freiburg, Dept Rheumatol & Clin Immunol, Freiburg, Germany. [Shah, Neil] Great Ormond St Hosp Sick Children, Dept Paediat Gastroenterol, London, England. [Segal, Anthony] UCL, Dept Med, London WC1E 6BT, England. [Sauerbrey, Axel] HELIOS Hosp, Dept Pediat, Erfurt, Germany. [Buderus, Stefan] St Marien Hosp Bonn, Dept Pediat, Bonn, Germany. [Snapper, Scott] Massachusetts Gen Hosp, Med MGH, Boston, MA 02114 USA. RI Schaffer, Alejandro/F-2902-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 297 EP 297 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800714 ER PT J AU Weniger, MA Rizzatti, EG Galan, PP Liu, D Munson, PJ Raghavachari, N White, T Disinski, MM Wilson, WH Wiestner, A AF Weniger, Marc A. Rizzatti, Edgar Gil Galan, Patricia Perez Liu, Delong Munson, Peter J. Raghavachari, Nalini White, Therese Disinski, Megan M. Wilson, Wyndham H. Wiestner, Adrian TI NRF2 at the Interface of Oxidative and Endoplasmic Reticulum Stress Pathways Is a Critical Integrator of Bortezomib Response in Mantle Cell Lymphoma in Vitro and In Vivo SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Weniger, Marc A.; Galan, Patricia Perez; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Rizzatti, Edgar Gil] Fleury Med & Saude, Sao Paulo, Brazil. [Liu, Delong; Munson, Peter J.] CIT, Math & Stat Comp Lab, DCB, NIH, Bethesda, MD USA. [Raghavachari, Nalini] NHLBI, Genom Core Facil, NIH, Bethesda, MD 20892 USA. [White, Therese; Disinski, Megan M.; Wilson, Wyndham H.] NCI, CCR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 303 EP 303 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800728 ER PT J AU Lundqvist, A Yokoyama, H Childs, RW AF Lundqvist, Andreas Yokoyama, Hisayuki Childs, Richard W. TI Adoptive Transfer of Natural Killer (NK) Cells to Prevent Gvhd and Enhance GVT Effects After Allogeneic Hematopoietic Cell Transplantation (HCT): The Timing of Donor NK Cell Infusions Critically Impacts Transplant Outcome SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Lundqvist, Andreas; Yokoyama, Hisayuki; Childs, Richard W.] NHLBI, NIH, Hematol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 325 EP 325 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800787 ER PT J AU McIver, ZA Stephens, N Naguib, N Grim, A Barrett, AJ AF McIver, Zachariah A. Stephens, Nicole Naguib, Nicolas Grim, Andrew Barrett, A. John TI Rituximab Administration within 6 Months of Allogeneic SCT Carries Risk of Prolonged and Life Threatening Cytopenias SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [McIver, Zachariah A.; Stephens, Nicole; Naguib, Nicolas; Grim, Andrew; Barrett, A. John] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 328 EP 328 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725800794 ER PT J AU Wayne, AS Bhojwani, D Jeha, S Stetler-Stevenson, M Pui, CH McDevitt, J FitzGerald, DJ Kreitman, RJ Kaucic, K Pastan, I AF Wayne, Alan S. Bhojwani, Deepa Jeha, Sima Stetler-Stevenson, Maryalice Pui, Ching-Hon McDevitt, Jennifer FitzGerald, David J. Kreitman, Robert J. Kaucic, Karen Pastan, Ira TI Phase I Clinical Trial of the Anti-CD22 Immunotoxin CAT-8015 (HA22) for Pediatric Acute Lymphoblastic Leukemia (ALL) SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bhojwani, Deepa; Jeha, Sima; Pui, Ching-Hon] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Stetler-Stevenson, Maryalice] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [McDevitt, Jennifer; Kaucic, Karen] Medimmune LLC, Gaithersburg, MD USA. [FitzGerald, David J.; Kreitman, Robert J.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 345 EP 346 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725801019 ER PT J AU Salit, RB Steinberg, S Fowler, DH Odom, J Bryant, K Bishop, MR AF Salit, Rachel B. Steinberg, Seth Fowler, Daniel H. Odom, Jeanne Bryant, Kelly Bishop, Michael R. TI Targeted Lymphocyte Depletion Prior to Reduced Intensity Allogeneic Stem Cell Transplantation: A Personalized Approach to Facilitate Engraftment SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Steinberg, Seth] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Odom, Jeanne] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 356 EP 357 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725801045 ER PT J AU Kreitman, RJ Tallman, MS Coutre, S Robak, T Wilson, WH Stetler-Stevenson, M Noel, P FitzGerald, DJ Buzoianu, M Lechleider, R Kaucic, K Pastan, I AF Kreitman, Robert J. Tallman, Martin S. Coutre, Steven Robak, Tadeusz Wilson, Wyndham H. Stetler-Stevenson, Maryalice Noel, Pierre FitzGerald, David J. Buzoianu, Manuela Lechleider, Robert Kaucic, Karen Pastan, Ira TI Phase I Dose-Escalation Study of CAT-8015 (HA22), A CD22-Specific Targeted Immunotoxin, in Relapsed or Refractory Hairy Cell Leukemia SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Kreitman, Robert J.; FitzGerald, David J.; Pastan, Ira] NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Tallman, Martin S.] Northwestern Univ, Dept Hematol, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Coutre, Steven] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Robak, Tadeusz] Med Univ Lodz, Dept Haematol, Lodz, Poland. [Wilson, Wyndham H.] NCI, CCR, NIH, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Noel, Pierre] Hematol Serv, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD USA. [Lechleider, Robert] MedImmune LLC, Clin Dev, Gaithersburg, MD USA. [Kaucic, Karen] Medimmune Inc, Gaithersburg, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 366 EP 366 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801068 ER PT J AU Nouraie, M Reading, NS Campbell, A Minniti, C Rana, SR Luchtman-Jones, L Sable, C Dham, N Ensing, G Kato, GJ Gladwin, M Castro, OL Prchal, JT Gordeuk, VR AF Nouraie, Mehdi Reading, Noel S. Campbell, Andrew Minniti, Caterina Rana, Sohail R. Luchtman-Jones, Lori Sable, Craig Dham, Niti Ensing, Gregory Kato, Gregory J. Gladwin, Mark Castro, Oswaldo L. Prchal, Josef T. Gordeuk, Victor R. TI Cytochrome b5 Reductase T116S Mutation and Hemolysis in Sickle Cell Disease SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Nouraie, Mehdi; Castro, Oswaldo L.] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Reading, Noel S.] ARUP Labs, Inst Clin & Expt Pathol, Salt Lake City, UT USA. [Campbell, Andrew] Univ Michigan, Med Ctr, Dept Pediat & Communicable Dis, Ann Arbor, MI USA. [Minniti, Caterina; Kato, Gregory J.] NHLBI, Vasc Med Branch, Bethesda, MD 20892 USA. [Rana, Sohail R.] Howard Univ Hosp, Dept Pediat & Child Hlth, Washington, DC USA. [Luchtman-Jones, Lori; Sable, Craig; Dham, Niti] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Gladwin, Mark] Univ Pittsburgh, Med Ctr, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Prchal, Josef T.] Univ Utah, Salt Lake City, UT USA. RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 372 EP 372 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801083 ER PT J AU Hudecek, M Schmitt, TM Baskar, S Chang, WC Maloney, DG Jensen, MC Rader, CM Riddell, S AF Hudecek, Michael Schmitt, Thomas M. Baskar, Sivasubramanian Chang, Wen-Chung Maloney, David G. Jensen, Michael C. Rader, Christoph M. Riddell, Stanley TI CD8(+) T Cells Engineered to Express a ROR1-Specific Chimeric Antigen Receptor Specifically Recognize ROR1 Positive B Cell Tumors SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting and Exposition of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Hudecek, Michael; Schmitt, Thomas M.; Maloney, David G.; Riddell, Stanley] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Baskar, Sivasubramanian; Rader, Christoph M.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chang, Wen-Chung; Jensen, Michael C.] City Hope Natl Canc Ctr, Div Canc Immunotherapeut & Tumor Immunol, Duarte, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 383 EP 383 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801110 ER PT J AU Bedognetti, D Zoppoli, G Massucco, C Zupo, S Sertoli, MR Ferrarini, M Zanardi, E Provinciali, N Siffredi, G Caltabiano, G Ghio, R Nencioni, A Messina, M Racchi, O Bruzzone, A Sabatino, M Marincola, FM Ascierto, ML Uccellini, L Zoltan, P Ansaldi, F De Maria, A AF Bedognetti, Davide Zoppoli, Gabriele Massucco, Carlotta Zupo, Simonetta Sertoli, Mario Roberto Ferrarini, Manlio Zanardi, Elisa Provinciali, Nicoletta Siffredi, Guido Caltabiano, Graziano Ghio, Riccardo Nencioni, Alessio Messina, Marco Racchi, Omar Bruzzone, Andrea Sabatino, Marianna Marincola, Francesco M. Ascierto, Maria Libera Uccellini, Lorenzo Zoltan, Pos Ansaldi, Filippo De Maria, Andrea TI Patients Treated with Rituximab-Containing Immunochemotherapy Have a Significant and Prolonged Lack of Humoral Response to Influenza Vaccine Associated with a Persistent Depletion of B Memory Cells SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Bedognetti, Davide; Zoppoli, Gabriele; Sabatino, Marianna; Marincola, Francesco M.; Ascierto, Maria Libera; Uccellini, Lorenzo; Zoltan, Pos] NIH, Bethesda, MD 20892 USA. [Bedognetti, Davide; Zoppoli, Gabriele] Univ Genoa, Bethesda, MD USA. [Massucco, Carlotta; Zupo, Simonetta; Sertoli, Mario Roberto; Ferrarini, Manlio; De Maria, Andrea] Natl Inst Canc Res, Genoa, Italy. [Sertoli, Mario Roberto; Ferrarini, Manlio; Zanardi, Elisa; Provinciali, Nicoletta; Siffredi, Guido; Caltabiano, Graziano; Ghio, Riccardo; Nencioni, Alessio; Messina, Marco; Bruzzone, Andrea; Ansaldi, Filippo; De Maria, Andrea] Univ Genoa, Genoa, Italy. [Racchi, Omar] Villa Scassi Hosp, Genoa, Italy. RI Bedognetti, Davide/A-9090-2012; Ascierto, Maria Libera/A-9239-2012; de maria, andrea/F-7116-2016 OI de maria, andrea/0000-0001-5782-333X NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 386 EP 386 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801116 ER PT J AU Petrie, KR Schenk, T Chornet, MB Howell, L Dick, JE Marquez, VE Marton, LJ Woster, PM Casero, RA Zelent, A AF Petrie, Kevin R. Schenk, Tino Chornet, Manuel Boix Howell, Louise Dick, John E. Marquez, Victor E. Marton, Laurence J. Woster, Patrick M. Casero, Robert A., Jr. Zelent, Arthur TI Modulation of Histone H3K4 and H3K27 Methylation Levels Via Pharmacological Inhibition of LSD1 and Degradation of the EZH2-Containing Polycomb Repressive Complex 2 Stimulates ATRA-Mediated Differentiation of AML Cells. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Schenk, Tino; Chornet, Manuel Boix; Howell, Louise; Zelent, Arthur] Inst Canc Res, Sect Haematooncol, Sutton, Surrey, England. [Dick, John E.] Univ Hlth Network, Toronto, ON, Canada. [Marquez, Victor E.] NIH, Med Chem Lab, Frederick, MD USA. [Marton, Laurence J.] Progen Pharmaceut Inc, Redwood City, CA USA. [Woster, Patrick M.] Wayne State Univ, Eugene Applebaum Coll Pharm & Hlth Sci, Detroit, MI USA. [Casero, Robert A., Jr.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. RI Petrie, Kevin/I-7115-2015 OI Petrie, Kevin/0000-0002-9805-9152 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 433 EP 433 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801226 ER PT J AU Calado, RT Regal, JA Kajigaya, S Young, NS AF Calado, Rodrigo T. Regal, Joshua A. Kajigaya, Sachiko Young, Neal S. TI Erosion of Telomeric Single-Stranded Overhang in Patients with Aplastic Anemia Carrying Telomerase Mutations. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Calado, Rodrigo T.; Regal, Joshua A.; Kajigaya, Sachiko; Young, Neal S.] NHLBI, NIH, Bethesda, MD 20892 USA. RI Calado, Rodrigo/G-2619-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 445 EP 445 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801259 ER PT J AU Al-Rahawan, MM Hutson, S Han, PKJ Alter, BP AF Al-Rahawan, Mohamad M. Hutson, Sadie Han, Paul K. J. Alter, Blanche P. TI Immunosuppressive Therapy and Future Response to Androgens or Survival After Hematopoietic Stem Cell Transplantation in Fanconi Anemia. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Al-Rahawan, Mohamad M.] Univ Illinois, Coll Med Peoria, Peoria, IL USA. [Hutson, Sadie] E Tennessee State Univ, Div Grad Studies, Johnson City, TN 37614 USA. [Hutson, Sadie] E Tennessee State Univ, Coll Nursing, Johnson City, TN 37614 USA. [Han, Paul K. J.] NCI, Ctr Outcomes Res & Evaluat, Div Canc Control & Populat Sci, Maine Med Ctr,NIH, Portland, ME USA. [Alter, Blanche P.] NCI, Clin Genet Branch, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 446 EP 446 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801262 ER PT J AU Gadalla, SM Cawthon, R Giri, N Baerlocher, G Lansdorp, PM Alter, BP Savage, SA AF Gadalla, Shahinaz M. Cawthon, Richard Giri, Neelam Baerlocher, Gabriela Lansdorp, Peter M. Alter, Blanche P. Savage, Sharon A. TI Correlation of Telomere Length in Blood, Buccal Cells, and Fibroblasts From Patients with Inherited Bone Marrow Failure Syndromes. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Gadalla, Shahinaz M.; Giri, Neelam; Alter, Blanche P.; Savage, Sharon A.] NCI, Clin Genet Branch, Rockville, MD USA. [Cawthon, Richard] Univ Utah, Dept Human Genet, Salt Lake City, UT USA. [Baerlocher, Gabriela] Univ Hosp Bern, Dept Hematol, CH-3010 Bern, Switzerland. [Lansdorp, Peter M.] BC Canc Res Ctr, Terry Fox Lab, Vancouver, BC, Canada. RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 446 EP 446 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801263 ER PT J AU Johnson, NA Ben-Neriah, S Savage, KJ Lee, T Horsman, DE Connors, JM Chan, WC Lenz, G Wright, G Rimsza, LM Braziel, RM Cook, JR Tubbs, RR Weisenburger, DD Campo, E Rosenwald, A Ott, G Delabie, J Jaffe, ES Staudt, LM Gascoyne, RD AF Johnson, Nathalie A. Ben-Neriah, Susanna Savage, Kerry J. Lee, Tang Horsman, Douglas E. Connors, Joseph M. Chan, Wing C. Lenz, Georg Wright, George Rimsza, Lisa M. Braziel, Rita M. Cook, James R. Tubbs, Raymond R. Weisenburger, Dennis D. Campo, Elias Rosenwald, Andreas Ott, German Delabie, Jan Jaffe, Elaine S. Staudt, Louis M. Gascoyne, Randy D. TI MYC Translocations and Expression Are Clinically Important in R-CHOP Treated Patients with De Novo DLBCL. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Johnson, Nathalie A.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. [Chan, Wing C.; Weisenburger, Dennis D.] Univ Nebraska, Med Ctr, Omaha, NE USA. [Wright, George; Staudt, Louis M.] NCI, Metab Branch, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Rimsza, Lisa M.] Univ Arizona, Tucson, AZ USA. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Cook, James R.; Tubbs, Raymond R.] Cleveland Clin, Cleveland, OH 44106 USA. [Campo, Elias] Hosp Clin Barcelona, Barcelona, Spain. [Rosenwald, Andreas] Univ Wurzburg, Wurzburg, Germany. [Ott, German] LLMPP, Wurzburg, Germany. [Delabie, Jan] Radiumhosp, Oslo, Norway. [Gascoyne, Randy D.] British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. [Gascoyne, Randy D.] British Columbia Canc Agcy, Dept Lab Med, CTAG Lab, Vancouver, BC V5Z 4E6, Canada. [Ben-Neriah, Susanna; Savage, Kerry J.; Horsman, Douglas E.] British Columbia Canc Agcy, Pathol & Lab Med, Vancouver, BC V5Z 4E6, Canada. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 452 EP 452 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801280 ER PT J AU Goldin, LR Lanasa, MC Slager, SL Strom, SS Camp, NJ Cerhan, JR Spector, LG Leis, JF Morrison, VA Rassenti, LZ Rabe, K Fontaine, L Allgood, SD Abbasi, F Kay, NE Call, TG Hanson, CA Weinberg, B Marti, GE Caporaso, NE AF Goldin, Lynn R. Lanasa, Mark C. Slager, Susan L. Strom, Sara S. Camp, Nicola J. Cerhan, James R. Spector, Logan G. Leis, Jose F. Morrison, Vicki A. Rassenti, Laura Z. Rabe, Kari Fontaine, Laura Allgood, Sallie D. Abbasi, Fatima Kay, Neil E. Call, Timothy G. Hanson, Curtis A. Weinberg, Brice Marti, Gerald E. Caporaso, Neil E. TI Monoclonal B-Cell Lymphocytosis is Commonly Observed Among Unaffected Members of High Risk CLL Families SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Goldin, Lynn R.] NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. [Lanasa, Mark C.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Slager, Susan L.; Cerhan, James R.] Mayo Clin, Coll Med, Rochester, MN USA. [Strom, Sara S.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Camp, Nicola J.] Univ Utah, Salt Lake City, UT USA. [Spector, Logan G.] Univ Minnesota, Minneapolis, MN USA. [Leis, Jose F.] Mayo Clin Arizona, Phoenix, AZ USA. [Morrison, Vicki A.] VA Med Ctr, Minneapolis, MN USA. [Rassenti, Laura Z.] Moores UCSD Canc Ctr, CLL Res Consortium, La Jolla, CA USA. [Fontaine, Laura] Westat Corp, Rockville, MD USA. [Abbasi, Fatima] Food & Drug Adm, Cellular & Tissue Therapy Branch, Rockville, MD USA. [Weinberg, Brice] Duke Med Ctr, Durham, NC USA. [Weinberg, Brice] VA Med Ctr, Durham, NC USA. [Marti, Gerald E.] US FDA, CBER, Cellular & Tissue Therapy Branch, Rockville, MD 20857 USA. [Caporaso, Neil E.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 508 EP 508 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801412 ER PT J AU Lanasa, MC Allgood, SD Slager, SL Camp, NJ Kay, NE Spector, LG Rassenti, LZ Hanson, CA Gockerman, JP Goodman, BK Strom, SS Call, TG Cerhan, JR Leis, J Marti, G Goldin, L Weinberg, JB Caporaso, NE AF Lanasa, Mark C. Allgood, Sallie D. Slager, Susan L. Camp, Nicola J. Kay, Neil E. Spector, Logan G. Rassenti, Laura Z. Hanson, Curtis A. Gockerman, Jon P. Goodman, Barbara K. Strom, Sara S. Call, Timothy G. Cerhan, James R. Leis, Jose Marti, Gerald Goldin, Lynn Weinberg, J. Brice Caporaso, Neil E. TI Family-Associated Monoclonal B Lymphocytosis Shows Differences From CLL That Suggest An Indolent Biology SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Lanasa, Mark C.; Allgood, Sallie D.; Gockerman, Jon P.; Goodman, Barbara K.; Weinberg, J. Brice] Duke Univ, Med Ctr, Durham, NC USA. [Slager, Susan L.; Cerhan, James R.] Mayo Clin, Coll Med, Rochester, MN USA. [Camp, Nicola J.] Univ Utah, Salt Lake City, UT USA. [Spector, Logan G.] Univ Minnesota, Minneapolis, MN USA. [Rassenti, Laura Z.] CLL Res Consortium, Moores UCSD Canc Ctr, La Jolla, CA USA. [Leis, Jose] Mayo Clin, Scottsdale, AZ USA. [Strom, Sara S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Marti, Gerald; Goldin, Lynn; Caporaso, Neil E.] NCI, NIH, Bethesda, MD 20892 USA. [Weinberg, J. Brice] Vet Adm Med Ctr, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 511 EP 511 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801421 ER PT J AU Nagel, S Venturini, L Victor, ME Meyer, C Kaufmann, M Scherr, M MacLeod, RAF Drexler, HG AF Nagel, Stefan Venturini, Letizia Victor, Marquez E. Meyer, Corinna Kaufmann, Maren Scherr, Michaela MacLeod, Roderick A. F. Drexler, Hans G. TI Polycomb Repressor Complex 2 Regulates HOXA9 and HOXA10, Activating ID2 in NK/T-Cell Lines SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Nagel, Stefan; Meyer, Corinna; Kaufmann, Maren; MacLeod, Roderick A. F.; Drexler, Hans G.] Deutsch Sammlung Mikroorganism Zellkultur GmbH, Braunschweig, Germany. [Venturini, Letizia; Scherr, Michaela] Hannover Med Sch, Dept Hematol Hemostaseol Oncol & Stem Cell Transp, D-3000 Hannover, Germany. [Victor, Marquez E.] NIH, Med Chem Lab, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 526 EP 526 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801461 ER PT J AU Feng, XM Scheinberg, P Samsel, L Nunez, O Green, S Mccoy, JP Bussel, JB Young, NS AF Feng, Xingmin Scheinberg, Phillip Samsel, Leigh Nunez, Olga Green, Spencer McCoy, J. Philip, Jr. Bussel, James B. Young, Neal S. TI Plasma Cytokines Associated with Low Platelet Counts in Aplastic Anemia and Immune Thrombocytopenia. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Feng, Xingmin; Scheinberg, Phillip; Nunez, Olga; Green, Spencer; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Samsel, Leigh; McCoy, J. Philip, Jr.] NHLBI, Flow Cytometry Core, NIH, Bethesda, MD 20892 USA. [Bussel, James B.] Cornell Univ, Platelet Disorders Ctr, Div Pediat Hematol Oncol, Weill Cornell Med Coll, New York, NY 10021 USA. RI Scheinberg, Phillip/H-5251-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 539 EP 539 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801497 ER PT J AU Sokolic, RA Markello, T Krumwiede, M Fischer, R Garabedian, E Gahl, WA White, JG Candotti, F AF Sokolic, Robert A. Markello, Thomas Krumwiede, Marcy Fischer, Roxanne Garabedian, Elizabeth Gahl, William A. White, James G. Candotti, Fabio TI Reduced Number of Dense Bodies and Reduced Serotonin Content in Platelets of Patients with Wiskott-Aldrich Syndrome SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Sokolic, Robert A.; Markello, Thomas; Fischer, Roxanne; Garabedian, Elizabeth; Gahl, William A.; Candotti, Fabio] NHGRI, NIH, Bethesda, MD 20892 USA. [Krumwiede, Marcy; White, James G.] Univ Minnesota, Dept Pathol, Minneapolis, MN 55455 USA. RI Sokolic, Robert/I-6072-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 540 EP 540 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801501 ER PT J AU Han, KL Changpriroa, CM Malech, HL Kang, EM AF Han, Kyu Lee Changpriroa, Cattlena M. Malech, Harry L. Kang, Elizabeth M. TI Activation of the Adenosine A(2A) Receptor Promotes the Development of Donor-Derived T Regulatory Cells in a Graft-Versus Host Disease Mouse Model. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting and Exposition of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Han, Kyu Lee; Changpriroa, Cattlena M.; Malech, Harry L.; Kang, Elizabeth M.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 547 EP 547 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801519 ER PT J AU Qin, HY Davis, JPE Capitini, CM Fry, TJ AF Qin, Haiying Davis, Jessica P. E. Capitini, Christian M. Fry, Terry J. TI Adoptive Transfer of Primed T Cells Mediates a Graft-Versus-Leukemia Effect against Pediatric ALL. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Qin, Haiying; Davis, Jessica P. E.; Capitini, Christian M.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Fry, Terry J.] Childrens Natl Med Ctr, Div Blood & Marrow Transplantat, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 547 EP 548 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725801520 ER PT J AU Liu, WL Liu, YQ Wang, RH Li, CL Deng, CX Rodgers, GP AF Liu, Wenli Liu, Yueqin Wang, Ruihong Li, Cuiling Deng, Chuxia Rodgers, Griffin P. TI Olfactomedin 4 Is Essential for Superoxide Production and Sensitizes Oxidative Stress-Induced Apoptosis in Neutrophils. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Liu, Wenli; Rodgers, Griffin P.] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wang, Ruihong; Li, Cuiling; Deng, Chuxia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 552 EP 553 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725801536 ER PT J AU Lam, AP Friedman, E Rodgers, GP Hsieh, MM Verma, A AF Lam, Anthony P. Friedman, Ellen Rodgers, Griffin P. Hsieh, Matthew M. Verma, Amit TI The Effect of Neutropenia On Survival Differs by Ethnicity in a Large Inner City Elderly Outpatient Population. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Lam, Anthony P.; Friedman, Ellen; Verma, Amit] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Rodgers, Griffin P.; Hsieh, Matthew M.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 553 EP 553 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801538 ER PT J AU Derolf, AR Andersson, TML Lambert, PC Kristinsson, SY Eloranta, S Landgren, O Dickman, PW Bjorkholm, M AF Derolf, Asa Rangert Andersson, Therese M-L Lambert, Paul C. Kristinsson, Sigurdur Y. Eloranta, Sandra Landgren, Ola Dickman, Paul W. Bjorkholm, Magnus TI Temporal Trends in the Proportion Cured Among Patients Diagnosed with Acute Myeloid Leukemia in Sweden 1973-2001, a Population-Based Study SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Derolf, Asa Rangert; Kristinsson, Sigurdur Y.; Bjorkholm, Magnus] Karolinska Inst, Dept Med, Div Hematol, Stockholm, Sweden. [Andersson, Therese M-L; Eloranta, Sandra; Dickman, Paul W.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Lambert, Paul C.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Derolf, Asa Rangert; Kristinsson, Sigurdur Y.; Bjorkholm, Magnus] Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden. [Landgren, Ola] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RI Kristinsson, Sigurdur /M-2910-2015; Andersson, Therese/E-7107-2016 OI Kristinsson, Sigurdur /0000-0002-4964-7476; Andersson, Therese/0000-0001-8644-9041 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 561 EP 561 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801558 ER PT J AU Shklovskiy-Kordi, NE Zingerman, BV Varticovski, L Kremenetskya, A Vorobjov, A AF Shklovskiy-Kordi, Nikita E. Zingerman, Boris V. Varticovski, Lyuba Kremenetskya, Alexandra Vorobjov, Andrei TI Development of Personal Health Records (PHR) for Patiets with Malignancies Using Interactive Internet Service: Experience at National Center for Hematology in Moscow. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol DE Telemedicine; PHR; EHR C1 [Shklovskiy-Kordi, Nikita E.; Zingerman, Boris V.; Kremenetskya, Alexandra; Vorobjov, Andrei] Natl Ctr Hematol, Moscow, Russia. [Varticovski, Lyuba] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 573 EP 573 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801587 ER PT J AU Li, Y Hu, X Ybarra, R Fu, XQ Qiu, Y Zhao, KJ Huang, SM AF Li, Ying Hu, Xin Ybarra, River Fu, Xueqi Qiu, Yi Zhao, Keji Huang, Suming TI Serine Phosphorylation On TAL1 Regulates Its Interaction with Histone Demethylase LSD1. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Li, Ying; Ybarra, River; Qiu, Yi; Huang, Suming] Univ Florida, Coll Med, Gainesville, FL USA. [Hu, Xin; Fu, Xueqi] Jilin Univ, Edmond H Fischer Signal Transduct Lab, Coll Life Sci, Changchun 130023, Peoples R China. [Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 590 EP 590 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801640 ER PT J AU Winkler, T Cantelina, AR Metais, JY Xu, XL Nguyen, AD Wolfsberg, T Antosiewicz-Bourget, J Thomson, JA Dunbar, CE AF Winkler, Thomas Cantelina, Amy R. Metais, Jean-Yves Xu, Xiuli Nguyen, Anh-Dao Wolfsberg, Tyra Antosiewicz-Bourget, Jessica Thomson, James Alexander Dunbar, Cynthia E. TI Analysis of Viral Integration Sites in Human Induced Pluripotent Stem Cells. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Winkler, Thomas; Cantelina, Amy R.; Metais, Jean-Yves; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Xu, Xiuli] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Nguyen, Anh-Dao; Wolfsberg, Tyra] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Antosiewicz-Bourget, Jessica; Thomson, James Alexander] Univ Wisconsin, Morgridge Inst Res, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 597 EP 598 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725801665 ER PT J AU Nouraie, M Reading, NS Campbell, A Minniti, C Rana, SR Luchtman-Jones, L Gladwin, M Kato, GJ Castro, OL Prchal, JT Gordeuk, VR AF Nouraie, Mehdi Reading, Noel S. Campbell, Andrew Minniti, Caterina Rana, Sohail R. Luchtman-Jones, Lori Gladwin, Mark Kato, Gregory J. Castro, Oswaldo L. Prchal, Josef T. Gordeuk, Victor R. TI Association of G6PD (-202/-376) with Lower Hemoglobin Concentration but Not Increased Hemolysis in Patients with Sickle Cell Anemia. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting and Exposition of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol ID GLUCOSE-6-PHOSPHATE-DEHYDROGENASE DEFICIENCY C1 [Nouraie, Mehdi; Castro, Oswaldo L.] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Reading, Noel S.] ARUP Labs, Salt Lake City, UT USA. [Campbell, Andrew] Univ Michigan, Med Ctr, Dept Pediat & Communicable Dis, Ann Arbor, MI USA. [Minniti, Caterina; Kato, Gregory J.] NHLBI, Vasc Med Branch, Bethesda, MD 20892 USA. [Rana, Sohail R.] Howard Univ Hosp, Dept Pediat & Child Hlth, Washington, DC USA. [Luchtman-Jones, Lori] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Gladwin, Mark] Univ Pittsburgh, Med Ctr, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Prchal, Josef T.] Univ Utah, Salt Lake City, UT USA. RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 3 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 606 EP 606 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801691 ER PT J AU Ballas, SK McCarthy, WF Bauserman, RL Valafar, F Waclawiw, M Barton, BA Kutlar, A AF Ballas, Samir K. McCarthy, William F. Bauserman, Robert L. Valafar, Faramarz Waclawiw, Myron Barton, Bruce A. Kutlar, Abdullah TI Definition of the Responder to Hydroxyurea Therapy: Revisited. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Ballas, Samir K.] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. [McCarthy, William F.; Bauserman, Robert L.; Barton, Bruce A.] Maryland Med Res Inst, Baltimore, MD USA. [Valafar, Faramarz] Univ Georgia, Athens, GA 30602 USA. [Waclawiw, Myron] NIH, Bethesda, MD 20892 USA. [Kutlar, Abdullah] Med Coll Georgia, Augusta, GA 30912 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 607 EP 607 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801693 ER PT J AU Hsu, LL Bead, V Freeman, LA Kato, GJ Taylor, JG Wood, KC Musicki, B Noguchi, CT Berkowitz, D Remaley, AT Amar, M AF Hsu, Lewis L. Bead, Valeriani Freeman, Lita A. Kato, Gregory J. Taylor, James G. Wood, Katherine C. Musicki, Biljana Noguchi, Constance Tom Berkowitz, Dan Remaley, Alan T. Amar, Marcelo TI Apoliprotein A-I Mimetic Peptide and Sickle Vasculopathy: Mouse Model Study of Acute Administration. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Hsu, Lewis L.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Bead, Valeriani] Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Freeman, Lita A.; Kato, Gregory J.; Taylor, James G.; Wood, Katherine C.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Musicki, Biljana] Johns Hopkins Univ, Baltimore, MD USA. [Noguchi, Constance Tom] NIDDK, Mol Med Branch, NIH, Bethesda, MD USA. [Berkowitz, Dan] Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 610 EP 611 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725801701 ER PT J AU Mendelsohn, L Tailor, A Kato, GJ AF Mendelsohn, Laurel Tailor, Anitaben Kato, Gregory J. TI Placental Growth Factor Is Elevated in Patients with Sickle Cell Disease and Associated with Pulmonary Hypertension, Hemolysis, Inflammation, Iron Overload, and Hepatic Dysfunction. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Mendelsohn, Laurel; Kato, Gregory J.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 614 EP 614 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801711 ER PT J AU Machado, RF Hildescheim, M Mendelsohn, L Kato, GJ Gladwin, MT AF Machado, Roberto F. Hildescheim, Mariana Mendelsohn, Laurel Kato, Gregory J. Gladwin, Mark T. TI NT-Pro Brain Natriuretic Peptide Levels and the Risk of Stroke and Death in the Cooperative Study of Sickle Cell Disease. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Machado, Roberto F.] Univ Chicago, Dept Med, Pulm & Crit Care Med Sect, Chicago, IL 60637 USA. [Hildescheim, Mariana] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Mendelsohn, Laurel] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Kato, Gregory J.] NHLBI, Vasc Med Branch, Bethesda, MD 20892 USA. [Gladwin, Mark T.] Univ Pittsburgh, Med Ctr, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 617 EP 617 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801721 ER PT J AU Armstrong, FD Steinberg, MH Ballas, SK Ataga, KI Waclawiw, MA Kutlar, A Swerdlow, PS McCarthy, WF AF Armstrong, F. Daniel Steinberg, Martin H. Ballas, Samir K. Ataga, Kenneth I. Waclawiw, Myron A. Kutlar, Abdullah Swerdlow, Paul S. McCarthy, William F. CA MSH Extension Investigators TI Developmental Outcomes of Offspring of Adults Treated with Hydroxyurea in the Multicenter Study of Hydroxyurea. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Armstrong, F. Daniel] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Steinberg, Martin H.] Boston Univ, Sch Med, Dept Med, Div Hematol & Oncol, Boston, MA 02118 USA. [Ballas, Samir K.] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. [Ataga, Kenneth I.] Univ N Carolina, Chapel Hill, NC USA. [Waclawiw, Myron A.] NIH, Bethesda, MD 20892 USA. [Kutlar, Abdullah] Med Coll Georgia, Augusta, GA 30912 USA. [Swerdlow, Paul S.] Wayne State Univ, Barbara Ann Karmanos Canc Inst, Detroit, MI USA. [McCarthy, William F.] Maryland Med Res Inst, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 618 EP 618 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801723 ER PT J AU Sjoberg, J Halthur, C Kristinsson, SY Landgren, O Dickman, PW Bjorkholm, M AF Sjoberg, Jan Halthur, Cat Kristinsson, Sigurdur Y. Landgren, Ola Dickman, Paul W. Bjorkholm, Magnus TI Improved Patient Survival and Cure for Hodgkin Lymphoma: A Population-Based Study of 6,136 Patients Diagnosed in Sweden 1973-2005. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Sjoberg, Jan; Kristinsson, Sigurdur Y.; Bjorkholm, Magnus] Karolinska Univ Hosp, Dept Med, Div Hematol, Stockholm, Sweden. [Sjoberg, Jan; Halthur, Cat; Kristinsson, Sigurdur Y.; Dickman, Paul W.; Bjorkholm, Magnus] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Landgren, Ola] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 622 EP 622 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801733 ER PT J AU Vire, B Perry, JSA Lee, E Stennett, LS Samsel, L McCoy, P Wilson, WH Bielekova, B Wiestner, A AF Vire, Berengere Perry, Justin S. A. Lee, Elinor Stennett, Lawrence S. Samsel, Leigh McCoy, Philip Wilson, Wyndham H. Bielekova, Bibiana Wiestner, Adrian TI Loss of CD20 Expression and Exhaustion of Effector Cells Limit ADCC in CLL Patients Treated with Rituximab. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Vire, Berengere; Lee, Elinor; Stennett, Lawrence S.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Perry, Justin S. A.; Bielekova, Bibiana] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Samsel, Leigh; McCoy, Philip] NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, CCR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 643 EP 644 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725801790 ER PT J AU Sakhuja, KB Gugliotti, LA Suzuki, Y Kovalchuk, AL Wang, HS Shin, DM Cerritelli, SM Morse, HC Crouch, RJ AF Sakhuja, Kiran B. Gugliotti, Lina A. Suzuki, Yutaka Kovalchuk, Alexander L. Wang, Hongsheng Shin, Dong-Mi Cerritelli, Susana M. Morse, Herbert C., III Crouch, Robert J. TI Constitutive Lymphoid Expression of the Nuclear Form of RNase H1 Is Associated with Development of Immature B Cell Lymphomas. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Sakhuja, Kiran B.; Gugliotti, Lina A.; Suzuki, Yutaka; Cerritelli, Susana M.; Crouch, Robert J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD USA. [Kovalchuk, Alexander L.; Wang, Hongsheng; Shin, Dong-Mi; Morse, Herbert C., III] NIAID, Immunopathol Lab, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 645 EP 645 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725801793 ER PT J AU Biancotto, A Fuchs, JC Dagur, P Wiestner, A McCoy, JP AF Biancotto, Angelique Fuchs, John Chris Dagur, Pradeep Wiestner, Adrian McCoy, J. Philip, Jr. TI Characterization of Treg Subpopulations in Chronic Lymphocytic Leukemia Using 15 Color Flow Cytometry. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Biancotto, Angelique; Fuchs, John Chris] NHLBI, Ctr Human Immunol, CHI, NIH, Bethesda, MD 20892 USA. [Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [McCoy, J. Philip, Jr.] NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 657 EP 657 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725802012 ER PT J AU Caminha, I Fleisher, T Niemela, J Hornung, R Davis, J Perkins, K Dowdell, K Price, S Brown, M Rao, VK Oliveira, JB AF Caminha, Iusta Fleisher, Thomas Niemela, Julie Hornung, Ron Davis, Joie Perkins, Katie Dowdell, Kennichi Price, Susan Brown, Margaret Rao, V. Koneti Oliveira, Joao Bosco TI Identifying Biomarkers in the Autoimmume Lymphoproliferative Syndrome (ALPS): IL-18, TNF-a, Serum Vitamin B12, Soluble FasL, and Plasma IL-10 Levels Are Useful Adjuvant Diagnostic Tools. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Caminha, Iusta; Fleisher, Thomas; Niemela, Julie; Brown, Margaret; Oliveira, Joao Bosco] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Hornung, Ron; Perkins, Katie] NIAID, SAIC Frederick Inc, ALPS Unit, LCID,NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 658 EP 658 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725802015 ER PT J AU Uldrick, T Polizzotto, MN O'Mahony, D Aleman, K Wyvill, K Steinberg, S Pittaluga, S Little, RF Yarchoan, R AF Uldrick, Thomas Polizzotto, Mark N. O'Mahony, Deirdre Aleman, Karen Wyvill, Kathy Steinberg, Seth Pittaluga, Stefania Little, Richard F. Yarchoan, Robert TI Clinical, Biochemical, and Radiographic Responses to Rituximab Combined with Liposomal Doxorubicin (R-Dox) in HIV-Infected Patients with Severe Kaposi Sarcoma-Associated Herpes Virus (KSHV) - Associated Multicentric Castleman's Disease. SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Uldrick, Thomas; Polizzotto, Mark N.; O'Mahony, Deirdre; Aleman, Karen; Wyvill, Kathy; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Steinberg, Seth] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Little, Richard F.] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD NOV 20 PY 2009 VL 114 IS 22 BP 659 EP 659 PG 1 WC Hematology SC Hematology GA 532DS UT WOS:000272725802019 ER PT J AU Piekarz, R Wright, J Frye, R Allen, SL Joske, D Kirschbaum, M Lewis, ID Prince, M Smith, S Jaffe, ES Bates, S AF Piekarz, Richard Wright, John Frye, Robin Allen, Steven L. Joske, David Kirschbaum, Mark Lewis, Ian D. Prince, Miles Smith, Sonali Jaffe, Elaine S. Bates, Susan TI Final Results of a Phase 2 NCI Multicenter Study of Romidepsin in Patients with Relapsed Peripheral T-Cell Lymphoma (PTCL). SO BLOOD LA English DT Meeting Abstract CT 51st Annual Meeting of the American-Society-of-Hematology CY DEC 05-08, 2009 CL New Orleans, LA SP Amer Soc Hematol C1 [Wright, John] NCI, IDB, CTEP, Rockville, MD USA. [Allen, Steven L.] N Shore Univ Hosp, Lake Success, NY USA. [Joske, David] Sir Charles Gairdner Hosp, Haematol Care Ctr, Perth, Wea, Australia. [Kirschbaum, Mark] City Hope Natl Med Ctr, Div Hematol, Duarte, CA 91010 USA. [Lewis, Ian D.] IMVS, Div Haematol, Adelaide, SA, Australia. [Prince, Miles] Peter MacCallum Cencer Ctr, Melbourne, Vic, Australia. [Smith, Sonali] Univ Chicago, Chicago, IL 60637 USA. [Jaffe, Elaine S.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 NOV 20 PY 2009 VL 114 IS 22 BP 661 EP 662 PG 2 WC Hematology SC Hematology GA 532DS UT WOS:000272725802025 ER EF