FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Barabas, O Guynet, C Achard, A Ton-Hoang, B Chandler, M Dyda, F Hickman, AB AF Barabas, Orsolya Guynet, Catherine Achard, Adeline Ton-Hoang, Bao Chandler, Michael Dyda, Fred Hickman, Alison B. TI Structural and Mechanistic Insights into Single-stranded DNA Transposition SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract C1 [Barabas, Orsolya; Dyda, Fred; Hickman, Alison B.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Guynet, Catherine; Achard, Adeline; Ton-Hoang, Bao; Chandler, Michael] CNRS, Lab Microbiol & Genet Mol, F-3102 Toulouse, France. EM ahickman@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD JUN PY 2009 VL 26 IS 6 MA 170 BP 898 EP 898 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 448ZO UT WOS:000266300700181 ER PT J AU Cui, F Wang, DF Zhurkin, VB AF Cui, Feng Wang, Difei Zhurkin, Victor B. TI AT-rich Fragments at the Nucleosome Ends May be Related to Linker Histone Binding: Implications for Nucleosome Positioning SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract ID GENOME C1 [Cui, Feng; Wang, Difei; Zhurkin, Victor B.] NCI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. EM cuif@mail.nih.gov RI Wang, Difei/E-7066-2010 NR 5 TC 0 Z9 0 U1 1 U2 1 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD JUN PY 2009 VL 26 IS 6 MA 197 BP 915 EP 916 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 448ZO UT WOS:000266300700208 ER PT J AU Wang, DF Ulyanov, NB Zhurkin, VB AF Wang, Difei Ulyanov, Nikolai B. Zhurkin, Victor B. TI Sequence Dependence of the 'Kink-and-Slide' Deformations of DNA in Nucleosome. All-atom Simulations of DNA Nonharmonic Behavior SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract C1 [Wang, Difei; Zhurkin, Victor B.] NCI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. [Ulyanov, Nikolai B.] UCSF, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. EM wangdi@mail.nih.gov RI Wang, Difei/E-7066-2010; Ulyanov, Nikolai/G-6998-2014 NR 7 TC 0 Z9 0 U1 1 U2 2 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD JUN PY 2009 VL 26 IS 6 MA 211 BP 924 EP 925 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 448ZO UT WOS:000266300700222 ER PT J AU Clark, DJ AF Clark, David J. TI The Dynamic Chromatin Structure of Transcriptionally Active Yeast Genes SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract ID NUCLEOSOMES; ACTIVATION C1 [Clark, David J.] NICHHD, NIH, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. EM clarkda@mail.nih.gov NR 9 TC 0 Z9 0 U1 0 U2 0 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD JUN PY 2009 VL 26 IS 6 MA 214 BP 926 EP 927 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 448ZO UT WOS:000266300700225 ER PT J AU Harlan, LC Klabunde, CN Ambs, AH Gibson, T Bernstein, L McTiernan, A Meeske, K Baumgartner, KB Ballard-Barbash, R AF Harlan, Linda C. Klabunde, Carrie N. Ambs, Anita H. Gibson, Todd Bernstein, Leslie McTiernan, Anne Meeske, Kathleen Baumgartner, Kathy B. Ballard-Barbash, Rachel TI Comorbidities, therapy, and newly diagnosed conditions for women with early stage breast cancer SO JOURNAL OF CANCER SURVIVORSHIP-RESEARCH AND PRACTICE LA English DT Article DE Therapy; Comorbidity; Healthcare; Disparities; Heart disease; Hypertension; Diabetes AB Purpose To describe comorbidities in breast cancer patients at diagnosis and examine factors associated with self-reported comorbidities 30 months post-diagnosis. Methods Nine hundred forty one of 1,171 women had a medical record abstract and a follow-up survey in the Health, Eating, Activity and Lifestyle Study. Results We compared our breast cancer cohort to a contemporaneous nationally-representative sample of age, race/ethnicity and education matched women without cancer (n=865). Breast cancer patients did not have substantially more comorbidities than women without breast cancer. Women with a hospital record of congestive heart failure significantly less often received chemotherapy or radiation following breast conserving surgery. In multivariate analysis, women who received chemotherapy alone (OR=3.2; 95% CI: 1.5-6.8), chemotherapy plus radiation (OR=1.9; 95% CI: 1.02-3.7) or radiation plus tamoxifen (OR=1.9; 95% CI: 1.1-3.2) were significantly more likely to report at least one new comorbid condition following breast cancer diagnosis than women who received no chemotherapy, tamoxifen or radiation. Overall, women who received adjuvant therapy were more likely to have new comorbidities. Conclusions Comorbidities were not substantially different in breast cancer patients than the non-cancer matched controls. Future research should focus on efforts to minimize comorbidities related to chemotherapy and other combination therapy. C1 [Harlan, Linda C.; Klabunde, Carrie N.; Ambs, Anita H.; Ballard-Barbash, Rachel] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Gibson, Todd] Informat Management Serv Inc, Silver Spring, MD USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Meeske, Kathleen] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Baumgartner, Kathy B.] Univ Louisville, Louisville, KY 40292 USA. RP Harlan, LC (reprint author), NCI, Appl Res Program, 6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM lh50w@nih.gov FU [N01-PC-35139]; [N01-PC-35142]; [N01-PC-35138] FX Funding source N01-PC-35139, N01-PC-35142, N01-PC-35138 NR 17 TC 22 Z9 22 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD JUN PY 2009 VL 3 IS 2 BP 89 EP 98 DI 10.1007/s11764-009-0084-3 PG 10 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA V17XQ UT WOS:000207970300003 PM 19437121 ER PT J AU Soni, KG Mardones, GA Sougrat, R Smirnova, E Jackson, CL Bonifacino, JS AF Soni, Krishnakant G. Mardones, Gonzalo A. Sougrat, Rachid Smirnova, Elena Jackson, Catherine L. Bonifacino, Juan S. TI Coatomer-dependent protein delivery to lipid droplets SO JOURNAL OF CELL SCIENCE LA English DT Article DE ATGL; Lipid droplet; Lipid homeostasis ID DIFFERENTIATION-RELATED PROTEIN; ADIPOSE TRIGLYCERIDE LIPASE; ENDOPLASMIC-RETICULUM; BREFELDIN-A; FAT STORAGE; GOLGI; ER; LIPOLYSIS; CELLS; LIPODYSTROPHY AB Lipid droplets (LDs) are cytoplasmic organelles that store neutral lipids for use as an energy supply in times of nutrient deprivation and for membrane assembly. Misregulation of LD function leads to many human diseases, including lipodystrophy, obesity and neutral lipid storage disorders. A number of proteins have been shown to localize to the surface of lipid droplets, including lipases such as adipose triglyceride lipase (ATGL) and the PAT-domain proteins ADRP (adipophilin) and TIP47, but the mechanism by which they are targeted to LDs is not known. Here we demonstrate that ATGL and ADRP, but not TIP47, are delivered to LDs by a pathway mediated by the COPI and COPII coatomer proteins and their corresponding regulators. C1 [Soni, Krishnakant G.; Mardones, Gonzalo A.; Sougrat, Rachid; Smirnova, Elena; Jackson, Catherine L.; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Jackson, CL (reprint author), CNRS, Lab Enzymol & Biochim Struct, Bat 34, F-91198 Gif Sur Yvette, France. EM jackson@lebs.cnrs-gif.fr; juan@helix.nih.gov RI Jackson, Catherine/A-3421-2013; OI Jackson, Catherine/0000-0002-0843-145X; Sougrat, Rachid/0000-0001-6476-1886; Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural Program of NICHD FX We thank P. Melan on, W. Brown, F. van Kuppeveld, G. Patterson and J. Lippincott-Schwartz for kind gifts of reagents, T. Mrozek for help with 3D rendering of the tomogram, X. Zhu and N. Tsai for expert technical assistance, and R. Mattera and Y. Prabhu for critical review of the manuscript. This work was funded by the Intramural Program of NICHD. Deposited in PMC for release after 12 months. NR 40 TC 107 Z9 108 U1 1 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 JUN 1 PY 2009 VL 122 IS 11 BP 1834 EP 1841 DI 10.1242/jcs.045849 PG 8 WC Cell Biology SC Cell Biology GA 448HS UT WOS:000266254300013 PM 19461073 ER PT J AU Haze, A Taylor, AL Haegewald, S Leiser, Y Shay, B Rosenfeld, E Gruenbaum-Cohen, Y Dafni, L Zimmermann, B Heikinheimo, K Gibson, CW Fisher, LW Young, MF Blumenfeld, A Bernimoulin, JP Deutsch, D AF Haze, Amir Taylor, Angela L. Haegewald, Stefan Leiser, Yoav Shay, Boaz Rosenfeld, Eli Gruenbaum-Cohen, Yael Dafni, Leah Zimmermann, Bernd Heikinheimo, Kristiina Gibson, Carolyn W. Fisher, Larry W. Young, Marian F. Blumenfeld, Anat Bernimoulin, Jean P. Deutsch, Dan TI Regeneration of bone and periodontal ligament induced by recombinant amelogenin after periodontitis SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE amelogenin; periodontal disease; bone regeneration; cementum regeneration; PDL regeneration; CD105; STRO-1 ID MESENCHYMAL STEM-CELLS; ENAMEL MATRIX PROTEINS; GENE SPLICE PRODUCTS; IN-VITRO; MONOCLONAL-ANTIBODY; PROGENITOR CELLS; MORPHOGENETIC PROTEIN-2; TOOTH GERM; RAT MOLARS; EXPRESSION AB Regeneration of mineralized tissues affected by chronic diseases comprises a major scientific and clinical challenge. Periodontitis, one such prevalent disease, involves destruction of the tooth-supporting tissues, alveolar bone, periodontal-ligament and cementum, often leading to tooth loss. In 1997, it became clear that, in addition to their function in enamel formation, the hydrophobic ectodermal enamel matrix proteins (EMPs) play a role in the regeneration of these periodontal tissues. The epithelial EMPs are a heterogeneous mixture of polypeptides encoded by several genes. It was not clear, however, which of these many EMPs induces the regeneration and what mechanisms are involved. Here we show that a single recombinant human amelogenin protein (rHAM(+)), induced in vivo regeneration of all tooth-supporting tissues after creation of experimental periodontitis in a dog model. To further understand the regeneration process, amelogenin expression was detected in normal and regenerating cells of the alveolar bone (osteocytes, osteoblasts and osteoclasts), periodontal ligament, cementum and in bone marrow stromal cells. Amelogenin expression was highest in areas of high bone turnover and activity. Further studies showed that during the first 2 weeks after application, rHAM(+) induced, directly or indirectly, significant recruitment of mesenchymal progenitor cells, which later differentiated to form the regenerated periodontal tissues. The ability of a single protein to bring about regeneration of all periodontal tissues, in the correct spatio-temporal order, through recruitment of mesenchymal progenitor cells, could pave the way for development of new therapeutic devices for treatment of periodontal, bone and ligament diseases based on rHAM(+). C1 [Haze, Amir; Taylor, Angela L.; Leiser, Yoav; Shay, Boaz; Rosenfeld, Eli; Gruenbaum-Cohen, Yael; Dafni, Leah; Blumenfeld, Anat; Deutsch, Dan] Hebrew Univ Jerusalem Hadassah Hosp & Med Sch, Fac Med Dent, Inst Dent Sci, Dent Res Lab, IL-91120 Jerusalem, Israel. [Haegewald, Stefan; Bernimoulin, Jean P.] Charite Univ Med Berlin, Dept Periodontol, D-13353 Berlin, Germany. [Zimmermann, Bernd] Free Univ Berlin, Inst Anat, Charite, D-1000 Berlin, Germany. [Heikinheimo, Kristiina] Univ Turku, Inst Dent, Dept Oral Maxillofacial Surg, Turku, Finland. [Gibson, Carolyn W.] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. [Fisher, Larry W.; Young, Marian F.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Deutsch, D (reprint author), Hebrew Univ Jerusalem Hadassah Hosp & Med Sch, Fac Med Dent, Inst Dent Sci, Dent Res Lab, IL-91120 Jerusalem, Israel. EM dddan@cc.huji.ac.il FU DFG [Be 1142/4-1]; BSF [2003-239]; IRP, NIH, DHHS FX This study was partially supported by DFG grant no. Be 1142/4-1 (J.P.B. and D.D.), by BSF grant no. 2003-239 (D.D. and M.F.Y.) and by the IRP, NIH, DHHS ( M.F.Y. and L.W.F.). NR 69 TC 20 Z9 22 U1 2 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD JUN PY 2009 VL 13 IS 6 BP 1110 EP 1124 DI 10.1111/j.1582-4934.2009.00700.x PG 15 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 466ZG UT WOS:000267703900007 PM 19228267 ER PT J AU Di Bari, MG Ginsburg, E Plant, J Strizzi, L Salomon, DS Vonderhaar, BK AF Di Bari, M. G. Ginsburg, E. Plant, J. Strizzi, L. Salomon, D. S. Vonderhaar, B. K. TI Msx2 Induces Epithelial-Mesenchymal Transition in Mouse Mammary Epithelial Cells Through Upregulation of Cripto-1 SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID GLAND DEVELOPMENT; BREAST-CANCER; BRANCHING MORPHOGENESIS; GENE FAMILY; EXPRESSION; PROGRESSION AB Epithelial-mesenchymal transition (EMT) is a process occurring during both embryogenesis and early stages of invasive cancer. Epithelial cells that undergo EMT become more migratory and invasive with a mesenchymal morphology. Herein we assess EMT induction in a mouse mammary epithelial cell line driven by Msx2, a homeobox-containing transcription factor important during mammary gland development. NMuMG cells, a normal mouse mammary epithelial cell line, stably transfected with a Msx2 cDNA showed downregulation of an epithelial marker E-cadherin and upregulation of the mesenchymal markers vimentin and N-cadherin. Furthermore, overexpression of Cripto-1, a member of the epidermal growth factor-CFC protein family already known to be involved in EMT, was detected in Msx2-transfected cells. The expression of Cripto-1 was accompanied by activation of the tyrosine kinase c-Src pathway and an increase in the invasive ability of the cells. Functional assays also demonstrated inhibition of the invasive behavior of the Msx2-transfected cells by a c-Src specific inhibitor. Moreover, immunohistochemistry of human infiltrating breast carcinomas showed positive staining for Msx2 only in the infiltrating tumor cells while the non-infiltrating tumor cells were negative. These results suggest that Msx2 may play a significant role in promoting EMT in epithelial cells that acquire properties involved in tumor invasion. C1 [Di Bari, M. G.; Ginsburg, E.; Plant, J.; Strizzi, L.; Salomon, D. S.; Vonderhaar, B. K.] NCI, Mol & Cellular Endocrinol Sect, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Vonderhaar, BK (reprint author), NCI, Mol & Cellular Endocrinol Sect, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, Bldg 37 Room 1106AI,37 Convent Dr, Bethesda, MD 20892 USA. EM bv10w@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 30 TC 19 Z9 21 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD JUN PY 2009 VL 219 IS 3 BP 659 EP 666 DI 10.1002/jcp.21712 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 438IA UT WOS:000265547900018 PM 19170109 ER PT J AU Lodish, MB Sinaii, N Patronas, N Batista, DL Keil, M Samuel, J Moran, J Verma, S Popovic, J Stratakis, CA AF Lodish, Maya B. Sinaii, Ninet Patronas, Nicholas Batista, Dalia L. Keil, Meg Samuel, Jonelle Moran, Jason Verma, Somya Popovic, Jadranka Stratakis, Constantine A. TI Blood Pressure in Pediatric Patients with Cushing Syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CARDIOVASCULAR RISK; SURGICAL CURE; DISEASE; HYPERTENSION; CHILDREN; ADOLESCENTS; PATHOPHYSIOLOGY; DIAGNOSIS; MORTALITY; CORONARY AB Context: Hypertension (HTN) has been reported in up to 60% of children with Cushing syndrome (CS), but its course, side effects, and potential differences among various causes of CS have not been adequately studied. Objective: The objective of the study was to measure blood pressure in pediatric patients with CS before and after transphenoidal surgery or adrenalectomy and identify side effects and rates of residual HTN. Design: Data from 86 children with corticotropinomas [Cushing disease (CD)] and 27 children with ACTH-independent CS (AICS) were analyzed. Results: Patients with CD and AICS had significant HTN before surgery; more patients with AICS had systolic HTN (SHTN) than with CD (74 vs. 44%, P = 0.0077), but the rate of diastolic HTN (DHTN) was similar. Both groups experienced significant decreases in SHTN immediately after transphenoidal surgery and adrenalectomy. One year postoperatively, both SHTN and DHTN were lower than the preoperative values in all patients, but as many as 16 and 4% of the patients with CD and 21 and 5% of the patients with AICS still had SHTN and DHTN, respectively. Higher blood pressure preoperatively correlated with cortisol levels. Two patients suffered serious side effects: one with multiple infarcts and another with hypertensive encephalopathy. Conclusions: Children with CS are at risk for residual HTN despite a significant improvement after surgical cure. HTN appears to correlate with the degree of hypercortisolemia. Serious HTN-related side effects, although rare, may occur during the perioperative period. (J Clin Endocrinol Metab 94: 2002-2008, 2009) C1 [Lodish, Maya B.; Batista, Dalia L.; Keil, Meg; Samuel, Jonelle; Moran, Jason; Verma, Somya; Stratakis, Constantine A.] NIH, Sect Endocrinol Genet, Bethesda, MD 20892 USA. [Lodish, Maya B.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol Genet, Pediat Endocrinol Inter Inst Training Program, NIH, Bethesda, MD 20892 USA. [Sinaii, Ninet] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. [Patronas, Nicholas] NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Popovic, Jadranka] Univ Pittsburgh, Div Endocrinol Diabet & Metab, Childrens Hosp Pittsburgh, Med Ctr, Pittsburgh, PA 15213 USA. RP Lodish, MB (reprint author), NICHHD, Sect Endocrinol Genet, Program Dev Endocrinol Genet, NIH,CRC E Labs, Bldg 10,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM lodishma@mail.nih.gov FU National Institute of Child Health and Human Development, National Institutes of Health [Z01-HD-000642-04] FX This work was supported by National Institute of Child Health and Human Development, National Institutes of Health intramural project Z01-HD-000642-04 (to C. A. S.). NR 26 TC 23 Z9 24 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2009 VL 94 IS 6 BP 2002 EP 2008 DI 10.1210/jc.2008-2694 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 453CM UT WOS:000266587800025 PM 19293264 ER PT J AU Bertherat, J Horvath, A Groussin, L Grabar, S Boikos, S Cazabat, L Libe, R Rene-Corail, F Stergiopoulos, S Bourdeau, I Bei, T Clauser, E Calender, A Kirschner, LS Bertagna, X Carney, JA Stratakis, CA AF Bertherat, Jerome Horvath, Anelia Groussin, Lionel Grabar, Sophie Boikos, Sosipatros Cazabat, Laure Libe, Rosella Rene-Corail, Fernande Stergiopoulos, Sotirios Bourdeau, Isabelle Bei, Thalia Clauser, Eric Calender, Alain Kirschner, Lawrence S. Bertagna, Xavier Carney, J. Aidan Stratakis, Constantine A. TI Mutations in Regulatory Subunit Type 1A of Cyclic Adenosine 5 '-Monophosphate-Dependent Protein Kinase (PRKAR1A): Phenotype Analysis in 353 Patients and 80 Different Genotypes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NODULAR ADRENOCORTICAL DISEASE; CARNEY COMPLEX; ENDOCRINE OVERACTIVITY; ADRENAL-HYPERPLASIA; SPOTTY PIGMENTATION; RI-ALPHA; A PKA; GENE; TUMORS; PHOSPHODIESTERASE AB Background: The "complex of myxomas, spotty skin pigmentation, and endocrine overactivity," or "Carney complex" (CNC), is caused by inactivating mutations of the regulatory subunit type 1A of the cAMP-dependent protein kinase (PRKAR1A) gene and as yet unknown defect(s) in other gene(s). Delineation of a genotype-phenotype correlation for CNC patients is essential for understanding PRKAR1A function and providing counseling and preventive care. Methods: A transatlantic consortium studied the molecular genotype and clinical phenotype of 353 patients (221 females and 132 males, age 34 +/- 19 yr) who carried a germline PRKAR1A mutation or were diagnosed with CNC and/or primary pigmented nodular adrenocortical disease. Results: A total of 258 patients (73%) carried 80 different PRKAR1A mutations; 114 (62%) of the index cases had a PRKAR1A mutation. Most PRKAR1A mutations (82%) led to lack of detectable mutant protein (nonexpressed mutations) because of nonsense mRNA mediated decay. Patients with a PRKAR1A mutation were more likely to have pigmented skin lesions, myxomas, and thyroid and gonadal tumors; they also presented earlier with these tumors. Primary pigmented nodular adrenocortical disease occurred earlier, was more frequent in females, and was the only manifestation of CNC with a gender predilection. Mutations located in exons were more often associated with acromegaly, myxomas, lentigines, and schwannomas, whereas the frequent c.491-492delTG mutation was commonly associated with lentigines, cardiac myxomas, and thyroid tumors. Overall, nonexpressed PRKAR1A mutations were associated with less severe disease. Conclusion: CNC is genetically and clinically heterogeneous. Certain tumors are more frequent, with specific mutations providing some genotype-phenotype correlation for PRKAR1A mutations. (J Clin Endocrinol Metab 94: 2085-2091, 2009) C1 [Horvath, Anelia; Boikos, Sosipatros; Stergiopoulos, Sotirios; Bourdeau, Isabelle; Bei, Thalia; Stratakis, Constantine A.] NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Bertherat, Jerome; Groussin, Lionel; Cazabat, Laure; Libe, Rosella; Rene-Corail, Fernande; Clauser, Eric; Bertagna, Xavier] CNRS, INSERM, U 567, UMR 8104,Inst Cochin,Endocrinol Metab & Canc Dept, F-75014 Paris, France. [Bertherat, Jerome; Groussin, Lionel; Grabar, Sophie; Rene-Corail, Fernande; Bertagna, Xavier] Univ Paris 05, F-75005 Paris, France. [Bertherat, Jerome; Groussin, Lionel; Libe, Rosella; Bertagna, Xavier] Hop Cochin, AP HP, Dept Endocrinol, F-75014 Paris, France. [Grabar, Sophie] Hop Cochin, AP HP, Dept Biostat, F-75014 Paris, France. [Clauser, Eric] Hop Cochin, AP HP, Oncogenet Unit, F-75014 Paris, France. CHU Lyon, F-69437 Lyon, France. [Calender, Alain] Univ Lyon 1, CNRS, UMR 5201, Unit Genet & Endocrine Tumors, F-69437 Lyon, France. [Kirschner, Lawrence S.] Ohio State Univ, Dept Internal Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Carney, J. Aidan] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. RP Stratakis, CA (reprint author), NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bldg 10,CRC,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Levesque, Isabelle/A-1899-2012 FU Agence Nationale de la Recherche [ANR-06-MRAR-002]; National Institutes of Health intramural [Z01-HD-000642-04]; Office of Rare Disorders; National Institute of Child Health & Human Development; National Institutes of Health (NIH) FX This work was supported by the Agence Nationale de la Recherche grant for rare diseases (ANR-06-MRAR-002) to develop the Carney Complex Network. It was also supported by National Institutes of Health intramural project Z01-HD-000642-04 (to C. A. S.); and, in part, by a Bench-to-Bedside Award from the Office of Rare Disorders and the National Institute of Child Health & Human Development, National Institutes of Health (NIH) [to C.A.S. and the late Dr. Y. Cho-Chung (National Cancer Institute, NIH)] for the study of patients with PRKAR1A mutations. NR 39 TC 127 Z9 131 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2009 VL 94 IS 6 BP 2085 EP 2091 DI 10.1210/jc.2008-2333 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 453CM UT WOS:000266587800036 PM 19293268 ER PT J AU Nalugoda, F Wagman, J Kiddugavu, M Kiwanuka, N Garrett, E Gray, RH Serwadda, D Wawer, MJ Emanuel, EJ AF Nalugoda, Fred Wagman, Jennifer Kiddugavu, Mohammed Kiwanuka, Noah Garrett, Elizabeth Gray, Ron H. Serwadda, David Wawer, Maria J. Emanuel, Ezekiel J. TI Is There Coercion or Undue Inducement to Participate in Health Research in Developing Countries? An Example from Rakai, Uganda SO JOURNAL OF CLINICAL ETHICS LA English DT Article C1 [Nalugoda, Fred] Rakai Hlth Sci Program, Field Activ, Rakai, Uganda. [Kiwanuka, Noah; Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Garrett, Elizabeth] Med Univ S Carolina, Charleston, SC 29425 USA. [Gray, Ron H.; Wawer, Maria J.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Emanuel, Ezekiel J.] NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Nalugoda, F (reprint author), Rakai Hlth Sci Program, Field Activ, Rakai, Uganda. EM EEmanuel@cc.nih.gov OI Wagman, Jennifer/0000-0002-9957-1932 NR 19 TC 2 Z9 2 U1 0 U2 0 PU UNIV PUBLISHING GROUP PI HAGERSTOWN PA 138 W WASHINGTON ST, STE 403-405, HAGERSTOWN, MD 21740 USA SN 1046-7890 J9 J CLIN ETHIC JI J. Clin. Ethics PD SUM PY 2009 VL 20 IS 2 BP 141 EP 149 PG 9 WC Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Biomedical Social Sciences GA V18MZ UT WOS:000208010200005 PM 19554819 ER PT J AU Blackstone, C AF Blackstone, Craig TI Infantile parkinsonism-dystonia: a dopamine "transportopathy" SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID SYNAPSE IN-VIVO AB The dopamine transporter (DAT) retrieves the neurotransmitter dopamine from the synaptic cleft at dopaminergic synapses. Variations in solute carrier family 6A, member 3 (SLC6A3/DAT1), the human gene encoding DAT, have been implicated in attention deficit hyperactivity and bipolar disorders, and DAT is a prominent site of action for drugs such as amphetamines and cocaine. In this issue of the JCI, Kurian et al. report that an autosomal recessive infantile parkinsonism-dystonia is caused by loss-of-function mutations in DAT that impair dopamine reuptake (see the related article beginning on page 1595). Though this might be predicted to result in dopamine excess in the synaptic cleft, it likely also causes depletion of presynaptic dopamine stores and possibly downregulation of postsynaptic dopamine receptor function, resulting in impairments in dopaminergic neurotransmission consistent with the clinical presentation. This is the first report of a genetic alteration in DAT function underlying a parkinsonian disorder. C1 Natl Inst Neurol Disorders & Stroke, Cellular Neurol Unit, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Blackstone, C (reprint author), Natl Inst Neurol Disorders & Stroke, Cellular Neurol Unit, Neurogenet Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov FU Intramural NIH HHS NR 20 TC 7 Z9 7 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2009 VL 119 IS 6 BP 1455 EP 1458 DI 10.1172/JCI39632 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 453HH UT WOS:000266601000011 PM 19504720 ER PT J AU Washington, AV Gibot, S Acevedo, I Gattis, J Quigley, L Feltz, R De La Mota, A Schubert, RL Gomez-Rodriguez, J Cheng, J Dutra, A Pak, E Chertov, O Rivera, L Morales, J Lubkowski, J Hunter, R Schwartzberg, PL McVicar, DW AF Washington, A. Valance Gibot, Sebastien Acevedo, Ismael Gattis, James Quigley, Laura Feltz, Robert De La Mota, Alina Schubert, Rebecca L. Gomez-Rodriguez, Julio Cheng, Jun Dutra, Amalia Pak, Evgenia Chertov, Oleg Rivera, Linette Morales, Jessica Lubkowski, Jacek Hunter, Robert Schwartzberg, Pamela L. McVicar, Daniel W. TI TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID DISSEMINATED INTRAVASCULAR COAGULATION; MOESIN PHOSPHORYLATION; ACTIN-BINDING; FAMILY-MEMBER; THREONINE 558; CUTTING EDGE; RECEPTOR; SEPSIS; ACTIVATION; INHIBITION AB Triggering receptor expressed on myeloid cells-like (TREM-like) transcript-1 (TLT-1), a type 1 single Ig domain orphan receptor specific to platelet and megakaryocyte a-granules, relocates to the platelet surface upon platelet stimulation. We found here that patients diagnosed with sepsis, in contrast to healthy individuals, had substantial levels of soluble TLT-1 (sTLT-1) in their plasma that correlated with the presence of disseminated intravascular coagulation. sTLT-1 bound to fibrinogen and augmented platelet aggregation in vitro. Furthermore, the cytoplasmic domain of TLT-1 could also bind ezrin/radixin/moesin family proteins, suggesting its ability to link fibrinogen to the platelet cytoskeleton. Accordingly, platelets of Treml1(-/-) mice failed to aggregate efficiently, extending tail-bleeding times. Lipopolysaccharide-treated Treml1(-/-) mice developed higher plasma levels of TNF and D-dimers than wild-type mice and were more likely to succumb during challenge. Finally, Treml1(-/-) mice were predisposed to hemorrhage associated with localized inflammatory lesions. Taken together, our findings suggest that TLT-1 plays a protective role during inflammation by dampening the inflammatory response and facilitating platelet aggregation at sites of vascular injury. Therefore, therapeutic modulation of TLT-1-mediated effects may provide clinical benefit to patients with hypercoagulatory conditions, including those associated with inflammation. C1 [Washington, A. Valance; Quigley, Laura; Feltz, Robert; Schubert, Rebecca L.; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Ft Detrick, MD 21702 USA. [Washington, A. Valance; Acevedo, Ismael; De La Mota, Alina; Rivera, Linette; Morales, Jessica; Hunter, Robert] Univ Cent Caribe, Lab Anat & Cell Biol, Bayamon, PR USA. [Gibot, Sebastien] Hop Cent, Serv Reanimat Med, Nancy, France. [Gibot, Sebastien] Nancy Univ, Fac Med, Contrat Avenir INSERM, Grp Choc, Nancy, France. [Gattis, James; Lubkowski, Jacek] NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21701 USA. [Gomez-Rodriguez, Julio; Cheng, Jun; Dutra, Amalia; Pak, Evgenia; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Chertov, Oleg] SAIC Frederick Inc, NCI, Adv Technol Program, Prot Chem Lab, Frederick, MD USA. RP McVicar, DW (reprint author), NCI, Canc & Inflammat Program, Bldg 560-31-46, Ft Detrick, MD 21702 USA. EM mcvicard@mail.nih.gov RI McVicar, Daniel/G-1970-2015 FU NIH [2G12RR3035]; National Cancer Institute; Center for Cancer Research [N01-Co-12400]; National Center for Research Resources (NCRR); National Institute of General Medical Sciences [SC2GM081237]; Aniara Corp. FX The authors would like to thank the staff of the Protein and Nucleic Acid and Optical Imaging Facilities at Universidad Central del Caribe. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and under contract N01-Co-12400. Additional funding was obtained through grants from the National Center for Research Resources (NCRR), a component of the NIH (2G12RR3035), the National Institute of General Medical Sciences (SC2GM081237), and the Aniara Corp. 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 NIH or the US government. NR 38 TC 38 Z9 38 U1 2 U2 4 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2009 VL 119 IS 6 BP 1489 EP 1501 DI 10.1172/JCI36175 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 453HH UT WOS:000266601000015 PM 19436112 ER PT J AU Sabatino, M Kim-Schulze, S Panelli, MC Stroncek, D Wang, E Taback, B Kim, DW DeRaffele, G Pos, Z Marincola, FM Kaufman, HL AF Sabatino, Marianna Kim-Schulze, Seunghee Panelli, Monica C. Stroncek, David Wang, Ena Taback, Bret Kim, Dae Won DeRaffele, Gail Pos, Zoltan Marincola, Francesco M. Kaufman, Howard L. TI Serum Vascular Endothelial Growth Factor and Fibronectin Predict Clinical Response to High-Dose Interleukin-2 Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RENAL-CELL CARCINOMA; CARBONIC-ANHYDRASE-IX; METASTATIC MELANOMA; IMMUNE RESPONSIVENESS; BIOLOGICAL-ACTIVITY; TUMOR ANGIOGENESIS; CANCER; EXPRESSION AB Purpose High-dose interleukin-2 (IL-2) induces durable therapeutic responses in a small subset of patients with metastatic melanoma and renal cell carcinoma, but simple pretreatment predictors of response have not been identified. Patients and Methods To identify predictive biomarkers of clinical response, sera from patients treated with high-dose IL-2 were collected for analysis using a customized, multiplex antibody-targeted protein array platform that surveyed expression of soluble factors associated with tumor immunobiology. Soluble factors associated with clinical responses were analyzed using a multivariate permutation test, and survival outcomes were determined using Kaplan-Meier and log-rank tests. Results A training set from 10 patients identified 68 potentially relevant soluble factors that were then tested in an independent validation set of 49 patients. Class comparison revealed a cluster of 11 biomarkers that were associated with therapeutic outcome. Vascular endothelial growth factor (VEGF) and fibronectin were identified as independent predictors of response. In particular, high levels of these proteins were correlated with lack of clinical response and decreased overall survival. Conclusion Serum VEGF and fibronectin are easily measured pretreatment biomarkers that could serve to exclude patients unlikely to respond to IL-2 therapy. J Clin Oncol 27:2645-2652. (C) 2009 by American Society of Clinical Oncology C1 NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Kaufman, Howard L.] Columbia Univ, Div Surg Oncol, Tumor Immunol Lab, New York, NY 10032 USA. Univ Pittsburgh, Dept Med, Inst Canc, Pittsburgh, PA USA. RP Kaufman, HL (reprint author), Columbia Univ, Div Surg Oncol, Tumor Immunol Lab, 177 Ft Washington Ave,MHB-7SK, New York, NY 10032 USA. EM hlk2003@columbia.edu RI Pos, Zoltan/C-3623-2014 OI Pos, Zoltan/0000-0002-2574-7616 NR 33 TC 102 Z9 110 U1 1 U2 2 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 JUN 1 PY 2009 VL 27 IS 16 BP 2645 EP 2652 DI 10.1200/JCO.2008.19.1106 PG 8 WC Oncology SC Oncology GA 451EX UT WOS:000266454600014 PM 19364969 ER PT J AU Kummar, S Kinders, R Gutierrez, ME Rubinstein, L Parchment, RE Phillips, LR Ji, JP Monks, A Low, JA Chen, A Murgo, AJ Collins, J Steinberg, SM Eliopoulos, H Giranda, VL Gordon, G Helman, L Wiltrout, R Tomaszewski, JE Doroshow, JH AF Kummar, Shivaani Kinders, Robert Gutierrez, Martin E. Rubinstein, Larry Parchment, Ralph E. Phillips, Lawrence R. Ji, Jiuping Monks, Anne Low, Jennifer A. Chen, Alice Murgo, Anthony J. Collins, Jerry Steinberg, Seth M. Eliopoulos, Helen Giranda, Vincent L. Gordon, Gary Helman, Lee Wiltrout, Robert Tomaszewski, Joseph E. Doroshow, James H. TI Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DNA-DAMAGING AGENTS; POLY(ADP-RIBOSE) POLYMERASE; DRUG DEVELOPMENT; TUMOR-BIOPSIES; CANCER; PARP; ONCOLOGY; MODELS; GENE; MICE AB Purpose We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies. Patients and Methods ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size. Results Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels. Conclusion Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology. J Clin Oncol 27:2705-2711. (C) 2009 by American Society of Clinical Oncology C1 [Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Lab Human Toxicol & Pharmacol, Appl Dev Res Support Directorate, Sci Applicat Int Corp,Frederick Inc, Frederick, MD 21701 USA. Abbott Labs, Abbott Pk, IL 60064 USA. RP Doroshow, JH (reprint author), NCI, Div Canc Treatment & Diag, NIH, Bldg 31,Room 3A44,31 Ctr Dr, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 26 TC 176 Z9 185 U1 1 U2 12 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 JUN 1 PY 2009 VL 27 IS 16 BP 2705 EP 2711 DI 10.1200/JCO.2008.19.7681 PG 7 WC Oncology SC Oncology GA 451EX UT WOS:000266454600022 PM 19364967 ER PT J AU Dahut, WL Aragon-Ching, JB Woo, S Tohnya, TM Gulley, JL Arlen, PM Wright, JJ Ventiz, J Figg, WD AF Dahut, William L. Aragon-Ching, Jeanny B. Woo, Sukyung Tohnya, Tanyifor M. Gulley, James L. Arlen, Philip M. Wright, John J. Ventiz, Jurgen Figg, William D. TI Phase I Study of Oral Lenalidomide in Patients With Refractory Metastatic Cancer SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE Androgen-independent prostate cancer; angiogenesis; CC-5013; lenalidomide; refractory cancer ID INDEPENDENT PROSTATE-CANCER; MULTIPLE-MYELOMA; RENAL IMPAIRMENT; THALIDOMIDE; CC-5013; TRIAL; ANALOGS; ANGIOGENESIS; INHIBITOR; TUMORS AB Objectives of this study were to determine the maximum tolerated dose and to characterize the side effect profile and pharmacokinetics of lenalidomide in patients with advanced refractory solid tumors. Patients were treated on a modified Fibronacci dose escalation scheme with an oral daily dose of lenalidomide. A total of 45 patients with 8 different tumor types were accrued. Doses administered included 5, 10, and 20 mg continuous daily doses, every 28 days ( n = 15), later modified to intermittent doses of 15, 20, 25, 30, 35, and 40 mg, with a 21 days-on and 7 days-off schedule, due to observed side effects. Lenalidomide exhibited a linear pharmacokinetics over a wide range of doses with the mean half-life of 3.9 hours. The renal function affected lenalidomide clearance, resulting in 50% reduction in patients with mild renal impairment compared with patients with normal function (CL/F = 243 mL/min). Stable disease was documented in 12 of 44 evaluable patients, of whom 9 patients had prostate cancer. Most frequent grade 1 and 2 toxicities included fatigue, nausea, pruritus/rash, neutropenia, and neuropathy. Grade 3/4 events were predominantly hematologic. Lenalidomide was well tolerated up to a 35-mg/d intermittent dosing schedule at doses higher than previously indicated for hematologic malignancies. C1 [Dahut, William L.; Aragon-Ching, Jeanny B.; Tohnya, Tanyifor M.; Gulley, James L.; Arlen, Philip M.; Figg, William D.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Woo, Sukyung; Tohnya, Tanyifor M.; Wright, John J.; Figg, William D.] NCI, Clin Pharmacol Program, Bethesda, MD 20892 USA. [Wright, John J.] NCI, Canc Therapy & Evaluat Program, Bethesda, MD 20892 USA. [Ventiz, Jurgen; Figg, William D.] Virginia Commonwealth Univ, Sch Pharm, Dept Pharmaceut, Richmond, VA USA. RP Figg, WD (reprint author), NCI, Med Oncol Branch, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016; OI Gulley, James/0000-0002-6569-2912; Aragon-Ching, Jeanny/0000-0002-6714-141X FU Intramural Research Program of the National Cancer Institute FX Financial disclosure: This work was supported by the Intramural Research Program of the National Cancer Institute. This is a US government work. There are no restrictions on its use. The views expressed within this paper do not necessarily reflect those of the US government. NR 29 TC 34 Z9 34 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JUN PY 2009 VL 49 IS 6 BP 650 EP 660 DI 10.1177/0091270009335001 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 447BC UT WOS:000266165600004 PM 19451403 ER PT J AU Zhang, TT Song, M Hang, TJ Xu, XF Wen, AD Yang, L Jia, L AF Zhang, T. T. Song, M. Hang, T. J. Xu, X. F. Wen, A. D. Yang, L. Jia, L. TI Pharmacokinetic profile of talipexole in healthy volunteers is not altered when it is co-administered with Madopar (co-beneldopa) SO JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS LA English DT Article DE benserazide; co-beneldopa; drug-drug interaction; levodopa; Madopar; pharmacokinetics; talipexole ID TANDEM MASS-SPECTROMETRY; PARKINSONS-DISEASE; HUMAN PLASMA; DOPAMINE AGONIST; DRUG-METABOLISM; CONDUCT AB To investigate the pharmacokinetics of talipexole hydrochloride tablets and the potential influence of Madopar (benserazide and levodopa combination; co-beneldopa) tablets on talipexole's pharmacokinetics when the two tablets are co-administered orally to healthy Chinese volunteers. A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to measure talipexole concentration in human plasma in an open-label, randomized, two-way crossover, single-dose study, with 1-week washout period. Healthy Chinese volunteers were randomized to receive talipexole tablets either alone or together with Madopar tablets by oral administration after an overnight fast. Serial blood samples were collected for a period of 36 h after the administration. Pharmacokinetic parameters C(max), t(max), t(1/2z), mean residence time (MRT), AUC(0-tau), AUC(0-infinity), CL(z)/F and V(z)/F were determined under the non-compartmental model. Pharmacokinetic values of talipexole administered alone to the subjects were compared with those administered simultaneously with Madopar to determine whether or not the differences were statistically significant. The subjects experienced mild gastrointestinal irritation when talipexole was administered alone as well as together with Madopar. For talipexole hydrochloride, there were no significant differences in the pharmacokinetic values between the two administrations. No pharmacokinetic differences based on gender were observed either. A single oral dose of Madopar co-administered with talipexole does not significantly change talipexole's pharmacokinetics in human. C1 [Zhang, T. T.; Song, M.; Hang, T. J.; Xu, X. F.] China Pharmaceut Univ, Dept Pharmaceut Anal, Nanjing 210009, Peoples R China. [Wen, A. D.; Yang, L.] Forth Mil Med Univ, Xijing Hosp, Xian, Peoples R China. [Jia, L.] NCI, Dev Therapeut Program, NIH, Bethesda, MD 20892 USA. RP Hang, TJ (reprint author), China Pharmaceut Univ, Dept Pharmaceut Anal, Nanjing 210009, Peoples R China. EM hangtj@cpu.edu.cn FU Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow [G4 0NR] FX The LC-MS/MS analyses of this study were conducted in the Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education of the People's Republic of China. The authors would like to thank Dr Dave Watson (Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow G4 0NR, UK) for his assistances in editing of this manuscript. NR 17 TC 2 Z9 2 U1 1 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-4727 J9 J CLIN PHARM THER JI J. Clin. Pharm. Ther. PD JUN PY 2009 VL 34 IS 3 BP 345 EP 354 DI 10.1111/j.1365-2710.2008.01008.x PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 443DS UT WOS:000265891000013 PM 19646081 ER PT J AU Bourgeois, JA Coffey, SM Rivera, SM Hessl, D Gane, LW Tassone, F Greco, C Finucane, B Nelson, L Berry-Kravis, E Grigsby, J Hagerman, PJ Hagerman, RJ AF Bourgeois, James A. Coffey, Sarah M. Rivera, Susan M. Hessl, David Gane, Louise W. Tassone, Flora Greco, Claudia Finucane, Brenda Nelson, Lawrence Berry-Kravis, Elizabeth Grigsby, Jim Hagerman, Paul J. Hagerman, Randi J. TI A Review of Fragile X Premutation Disorders: Expanding the Psychiatric Perspective SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Review ID TREMOR/ATAXIA-SYNDROME FXTAS; FMR1 MESSENGER-RNA; INTRANUCLEAR INCLUSIONS; FULL-MUTATION; CGG-REPEAT; MALE CARRIERS; ADULT MALE; COGNITIVE IMPAIRMENT; SUBCORTICAL DEMENTIA; FEMALE CARRIERS AB Context: Fragile X premutation conditions are associated with a significant degree of psychopathology and thus are of interest to the psychiatrist. Remarkable advances at the molecular level have enhanced our understanding of fragile X premutation disorders. Objective: The authors review the genetic, molecular, neuroimaging, and clinical (systemic, neurologic, and psychiatric) manifestations of the premutation carrier state (55-200 CGG repeats) of the fragile X mental retardation 1 (FMRI) gene. Data Sources: The search for the psychiatric clinical manifestations of fragile X-associated conditions was accomplished by PubMed for clinical papers published between 1970 and 2008 with the following search terms: Fragile X syndrome, depression, psychosis, anxiety, and dementia. Study Selection: Articles addressing psychiatric symptoms in premutation carriers based on review of the abstracts were reviewed. As the majority of the literature on this topic is based on case reports and small case series, these were included in the database. Results: Reported clinical manifestations of psychiatric illness in premutation carriers include an apparently significant rate of cognitive, mood, anxiety, and other psychiatric disorders. Fragile X premutation-associated conditions are part of the clinical differential diagnosis of several psychiatric syndromes, particularly in pedigrees with known fragile X syndrome cases. Conclusions: Fragile X-associated psychiatric manifestations serve as a useful model for a molecular genesis of neuropsychiatric illness. Because of the multigenerational expression of fragile X-associated neuropsychiatric illness, there is a prominent role for genetic testing and genetic counseling of patients and their relatives. Genetic testing is confirmatory of the FMRI premutation and is an essential component of the clinical evaluation. Psychopharmacologic and psychotherapeutic treatment of fragile X-associated psychiatric illnesses may improve patient function and assist in adaptation to the burden of a genetic neuropsychiatric illness. (J Clin Psychiatry 2009; 70(6):852-862) (C) Copyright 2008 Physicians Postgraduate Press, Inc. C1 [Bourgeois, James A.] Univ Calif Davis, Davis Med Ctr, Dept Psychiat & Behav Sci, Sacramento, CA 95817 USA. [Coffey, Sarah M.; Rivera, Susan M.; Hessl, David; Gane, Louise W.; Tassone, Flora; Hagerman, Randi J.] Univ Calif Davis, Davis Med Ctr, MIND Inst, Sacramento, CA 95817 USA. [Coffey, Sarah M.; Hagerman, Randi J.] Univ Calif Davis, Davis Med Ctr, Dept Pediat, Sacramento, CA 95817 USA. [Rivera, Susan M.] Univ Calif Davis, Davis Med Ctr, Dept Psychol, Sacramento, CA 95817 USA. [Tassone, Flora; Hagerman, Paul J.] Univ Calif Davis, Davis Med Ctr, Dept Biochem & Mol Med, Sacramento, CA 95817 USA. [Greco, Claudia] Univ Calif Davis, Davis Med Ctr, Dept Pathol, Sacramento, CA 95817 USA. [Finucane, Brenda] Genet Serv Elwyn Inc, Elwyn, PA USA. [Nelson, Lawrence] NICHHD, Integrat Reproduct Med Unit, Intramural Res Program Reproduct & Adult Endocrin, NIH, Bethesda, MD USA. [Berry-Kravis, Elizabeth] Rush Univ, Med Ctr, Dept Pediat, Chicago, IL 60612 USA. [Berry-Kravis, Elizabeth] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Berry-Kravis, Elizabeth] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA. [Grigsby, Jim] Univ Colorado, Dept Med, Denver, CO USA. RP Bourgeois, JA (reprint author), Univ Calif Davis, Davis Med Ctr, Dept Psychiat & Behav Sci, 2230 Stockton Blvd, Sacramento, CA 95817 USA. EM james.bourgeois@ucdmc.ucdavis.edu FU Intramural NIH HHS; NCRR NIH HHS [UL1 RR024922, UL1 RR024922-01, UL1 RR024992]; NIA NIH HHS [RL1 AG032115, RL1 AG032115-01, RL1 AG032119, RL1 AG032119-02]; NICHD NIH HHS [HD036071, HD02274, HD056031, P30 HD002274, P30 HD002274-41S18764, R01 HD036071, R01 HD036071-05, R01 HD056031]; NIDCR NIH HHS [DE019583]; NIMH NIH HHS [K23 MH077554, K23 MH077554-02, MH078041, MH77554, R01 MH078041, R01 MH078041-02]; NINDS NIH HHS [NS044299, R01 NS044299, RL1 NS062412]; PHS HHS [U10/CCU925123] NR 81 TC 105 Z9 106 U1 3 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 JUN PY 2009 VL 70 IS 6 BP 852 EP 862 PG 11 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 464JV UT WOS:000267502100009 PM 19422761 ER PT J AU Spirito, A Abebe, KZ Iyengar, S Brent, D Vitiello, B Clarke, G Wagner, KD Asarnow, J Emslie, G Keller, M AF Spirito, Anthony Abebe, Kaleab Z. Iyengar, Satish Brent, David Vitiello, Benedetto Clarke, Gregory Wagner, Karen Dineen Asarnow, Joan Emslie, Graham Keller, Martin TI Sources of Site Differences in the Efficacy of a Multisite Clinical Trial: The Treatment of SSRI-Resistant Depression in Adolescents SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE multisite clinical trials; site differences; protocol fidelity; sampling factors; The Treatment of SSRI-Resistant Depression in Adolescents study ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; TREATMENT FIDELITY; PREDICTORS; VALIDITY; SCALE AB Site differences in treatment outcomes are not often highlighted when the results of multisite randomized clinical trials (MRCTs) are reported. The primary analyses of a 6-site MRCT, the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study, showed substantial variation by site in the performance of a medication-only condition and a combined medication plus cognitive-behavioral therapy (CBT) condition. Two potential primary causes of site differences in MRCT outcomes were examined in this article: sampling factors, particularly clinical characteristics of participants, and treatment protocol factors, particularly fidelity. The authors found that differences in the clinical characteristics of participants at baseline across site and within site/across conditions were the most salient explanations for site differences and differences within sites across conditions in outcome. Study findings are discussed with respect to the overall study outcomes in TORDIA as well as MRCTs in general. C1 [Spirito, Anthony] Brown Univ, Dept Psychiat & Human Behav, Clin Psychol Training Consortium, Warren Alpert Med Sch, Providence, RI 02912 USA. [Abebe, Kaleab Z.; Iyengar, Satish] Univ Pittsburgh, Dept Stat, Pittsburgh, PA 15260 USA. [Brent, David] Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA 15213 USA. [Vitiello, Benedetto] NIMH, Child Treatment Branch, Bethesda, MD 20892 USA. [Clarke, Gregory] Kaiser Permanente NW, Ctr Hlth Res NW, Portland, OR USA. [Wagner, Karen Dineen] Univ Texas Med Branch, Dept Psychiat & Behav Sci, Galveston, TX USA. [Asarnow, Joan] Univ Calif Los Angeles, Dept Child & Adolescent Psychiat, Los Angeles, CA USA. [Emslie, Graham] Univ Texas SW Med Sch, Dept Child Psychiat, Dallas, TX USA. RP Spirito, A (reprint author), Brown Univ, Dept Psychiat & Human Behav, Clin Psychol Training Consortium, Warren Alpert Med Sch, Box G-S121-4, Providence, RI 02912 USA. EM Anthony_Spirito@brown.edu OI Abebe, Kaleab/0000-0002-3644-8419 FU NIMH NIH HHS [U01 MH061856-07, MH61856, MH61869, P30 MH066371, U01 MH061856, U01 MH061869, U01 MH061869-05, MH066371, MH61835, MH61864, MH61958, MH62014, U01 MH061835, U01 MH061835-07, U01 MH061864, U01 MH061864-07, U01 MH061958, U01 MH061958-07, U01 MH062014, U01 MH062014-07] NR 36 TC 12 Z9 12 U1 1 U2 2 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD JUN PY 2009 VL 77 IS 3 BP 439 EP 450 DI 10.1037/a0014834 PG 12 WC Psychology, Clinical SC Psychology GA 453MN UT WOS:000266614800007 PM 19485586 ER PT J AU Kendall, PC Comer, JS Marker, CD Creed, TA Puliafico, AC Hughes, AA Martin, ED Suveg, C Hudson, J AF Kendall, Philip C. Comer, Jonathan S. Marker, Craig D. Creed, Torrey A. Puliafico, Anthony C. Hughes, Alicia A. Martin, Erin D. Suveg, Cynthia Hudson, Jennifer TI In-Session Exposure Tasks and Therapeutic Alliance Across the Treatment of Childhood Anxiety Disorders SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE alliance; cognitive-behavioral therapy (CBT); anxiety disorders; child; growth curve modeling ID RANDOMIZED CLINICAL-TRIAL; COGNITIVE-BEHAVIORAL TREATMENT; ADOLESCENT PSYCHOTHERAPY; INTERVIEW SCHEDULE; THERAPIST ALLIANCE; WORKING ALLIANCE; PARENT VERSIONS; ANXIOUS YOUTH; DSM-IV; CHILDREN AB The study examined the shape of therapeutic alliance using latent growth curve modeling and data from multiple informants (therapist, child, mother, father). Children (n = 86) with anxiety disorders were randomized to family-based cognitive-behavioral treatment (FCBT; N = 47) with exposure tasks or to family education, support, and attention (FESA: N = 39). Children in FCBT engaged in exposure tasks in Sessions 9-16, whereas FESA participants did not. Alliance growth curves of FCBT and FESA youths were compared to examine the impact of exposure tasks on the shape of the alliance (between-subjects). Within FCBT, the shape of alliance prior to exposure tasks was compared with the shape of alliance following exposure tasks (within-subjects). Therapist, child, mother, and father alliance ratings indicated significant growth in the alliance across treatment sessions. Initial alliance growth was steep and subsequently slowed over time, regardless of the use of exposure tasks. Data did not indicate a rupture in the therapeutic alliance following the introduction of in-session exposures. Results are discussed in relation to the processes, mediators, and ingredients of efficacious interventions as well as in terms of the dissemination of empirically supported treatments. C1 [Kendall, Philip C.] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. [Comer, Jonathan S.] Columbia Univ, New York State Psychiat Inst, Dept Child Psychiat, New York, NY 10027 USA. [Marker, Craig D.] Nova SE Univ, Ctr Psychol Studies, Ft Lauderdale, FL 33314 USA. [Creed, Torrey A.] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Puliafico, Anthony C.] Columbia Univ, Clin Anxiety & Related Disorders, New York, NY 10027 USA. [Hughes, Alicia A.] Penn State Univ, Ctr Child Study, University Pk, PA 16802 USA. [Martin, Erin D.] NIMH, Div Intramural Res Programs, Bethesda, MD 20892 USA. [Suveg, Cynthia] Univ Georgia, Dept Psychol, Athens, GA 30602 USA. [Hudson, Jennifer] Macquarie Univ, Dept Psychol, N Ryde, NSW 2109, Australia. RP Kendall, PC (reprint author), Temple Univ, Dept Psychol, 1701 N 13th St,Weiss Hall, Philadelphia, PA 19122 USA. EM pkendall@temple.edu OI Hudson, Jennie/0000-0001-5778-2670 NR 49 TC 39 Z9 39 U1 4 U2 14 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD JUN PY 2009 VL 77 IS 3 BP 517 EP 525 DI 10.1037/a0013686 PG 9 WC Psychology, Clinical SC Psychology GA 453MN UT WOS:000266614800013 PM 19485592 ER PT J AU Clark, RL Glick, JE Bures, RM AF Clark, Rebecca L. Glick, Jennifer E. Bures, Regina M. TI Immigrant Families Over the Life Course Research Directions and Needs SO JOURNAL OF FAMILY ISSUES LA English DT Article DE immigrant families; living arrangements; children; family formation; secondary data sets ID UNITED-STATES; LIVING ARRANGEMENTS; MEXICAN-AMERICANS; INTERNATIONAL MIGRATION; TRANSNATIONAL MIGRATION; HOUSEHOLD STRUCTURE; UNION DISSOLUTION; CHILDREN; ASSIMILATION; GENDER AB Family researchers and policy makers are giving increasing attention to the consequences of immigration for families. Immigration affects the lives of family members who migrate as well as those who remain behind and has important consequences for family formation, kinship ties, living arrangements, and children's outcomes. We present a selective review of the literature on immigrant families in the United States, focusing on key research themes and needs. A summary of secondary data sets that can be used to study immigrant families is presented as well as suggestions for future research in this increasingly important area of family research and policy. C1 [Bures, Regina M.] Univ Florida, Dept Sociol, Gainesville, FL 32611 USA. [Clark, Rebecca L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Glick, Jennifer E.] Arizona State Univ, Tempe, AZ USA. RP Bures, RM (reprint author), Univ Florida, Dept Sociol, POB 117330, Gainesville, FL 32611 USA. EM rbures@ufl.edu NR 89 TC 27 Z9 28 U1 6 U2 23 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-513X J9 J FAM ISSUES JI J. Fam. Issues PD JUN PY 2009 VL 30 IS 6 BP 852 EP 872 DI 10.1177/0192513X09332162 PG 21 WC Family Studies SC Family Studies GA 443YW UT WOS:000265947700007 ER PT J AU Cote, LR Bornstein, MH AF Cote, Linda R. Bornstein, Marc H. TI Child and Mother Play in Three US Cultural Groups: Comparisons and Associations SO JOURNAL OF FAMILY PSYCHOLOGY LA English DT Article DE play; immigrant; mother; child ID UNITED-STATES; SYMBOLIC PLAY; JAPAN; LANGUAGE; CONTEXT; STABILITY; AMERICAN; FAMILIES; BEHAVIOR AB Child and mother play (n = 113 20-month-olds) among South American Latino immigrants, Japanese immigrants, and European Americans in the United States was investigated. Culturally universal patterns of play dominated the findings. For example, no cultural differences in the prevalence of exploratory or symbolic play were found for either children or their mothers. Regardless of their culture, boys engaged in significantly more exploratory and less symbolic play than did girls when they played by themselves. Few relations were found between child play in the two play sessions. Across cultural groups, children's exploratory play was significantly positively related to both maternal demonstrations and solicitations of exploratory play. The results identify which realms of child growth, parenting, and family function call for special attention and cultural sensitivity, as well as which do not, in the dynamics of immigrant families. C1 [Cote, Linda R.; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res Program Dev Neurosci, NIH, US Dept HHS, Bethesda, MD USA. [Cote, Linda R.] Marymount Univ, Dept Psychol, Arlington, VA 22207 USA. RP Cote, LR (reprint author), Marymount Univ, Dept Psychol, 2807 N Glebe Rd, Arlington, VA 22207 USA. EM linda.cote-reilly@marymount.edu FU Intramural NIH HHS [Z99 HD999999] NR 49 TC 10 Z9 10 U1 2 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0893-3200 J9 J FAM PSYCHOL JI J. Fam. Psychol. PD JUN PY 2009 VL 23 IS 3 BP 355 EP 363 DI 10.1037/a0015399 PG 9 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA 458AM UT WOS:000266982700009 PM 19586198 ER PT J AU Hai, B Yan, X Voutetakis, A Zheng, CY Cotrim, AP Shan, ZC Ding, G Zhang, CM Xu, JJ Goldsmith, CM Afione, S Chiorini, JA Baum, BJ Wang, SL AF Hai, Bo Yan, Xing Voutetakis, Antonis Zheng, Changyu Cotrim, Ana P. Shan, Zhaochen Ding, Gang Zhang, Chunmei Xu, Junji Goldsmith, Corinne M. Afione, Sandra Chiorini, John A. Baum, Bruce J. Wang, Songlin TI Long-term transduction of miniature pig parotid glands using serotype 2 adeno-associated viral vectors SO JOURNAL OF GENE MEDICINE LA English DT Article DE adeno-associated virus; gene therapy; miniature pig; parotid gland; salivary hypofunction ID MEDIATED GENE-TRANSFER; TRANSGENIC SECRETORY PROTEINS; LEBERS CONGENITAL AMAUROSIS; INCREASED FLUID SECRETION; HUMAN AQUAPORIN-1 CDNA; LARGE ANIMAL-MODELS; SALIVARY-GLANDS; ADENOVIRAL VECTOR; IN-VIVO; SUBMANDIBULAR-GLAND AB Background Previously, using an adenoviral vector, we showed that miniature pigs could provide a valuable and affordable large animal model for pre-clinical gene therapy studies to correct parotid gland radiation damage. However, adenoviral vectors lead to short-term transgene expression and, ideally, a more stable correction is required. In the present study, we examined the suitability of using a serotype 2 adeno-associated viral (AAV2) vector to mediate more stable gene transfer in the parotid glands of these animals. Methods Heparan sulfate proteoglycan was detected by immunohistochemistry. beta-galactosidase expression was determined histochemically. An AAV2 vector encoding human erythropoietin (hEpo) was administered via Stensen's duct. Salivary and serum hEpo levels were measured using an enzyme-linked immunosorbent assay. Serum chemistry and hematological analyses were performed and serum antibodies to hEpo were measured throughout the study. Vector distribution was determined by a quantitative polymerase chain reaction. Results Transgene expression was vector dose-dependent, with high levels of hEpo being detected for up to 32 weeks (i.e. the longest time studied). hEpo reached maximal levels during weeks 4-8, but declined to approximately 25% of these values by week 32. Haematocrits were elevated from week 2. Transduced animals exhibited low serum anti-hEpo antibodies (1 : 8-1: 16). Vector biodistribution at animal sacrifice revealed that most copies were in the targeted parotid gland, with few being detected elsewhere. No consistent adverse changes in serum chemistry or hematology parameters were seen. Conclusions AAV2 vectors mediate extended gene transfer to miniature pig parotid glands and should be useful for testing pre-clinical gene therapy strategies aiming to correct salivary gland radiation damage. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Voutetakis, Antonis; Zheng, Changyu; Cotrim, Ana P.; Goldsmith, Corinne M.; Afione, Sandra; Chiorini, John A.; Baum, Bruce J.] NIDCR, MPTB, NIH, DHHS, Bethesda, MD 20892 USA. [Hai, Bo; Yan, Xing; Shan, Zhaochen; Ding, Gang; Zhang, Chunmei; Xu, Junji; Wang, Songlin] Capital Med Univ, Sch Stomatol, Salivary Gland Dis Ctr, Beijing 100050, Peoples R China. [Hai, Bo; Yan, Xing; Shan, Zhaochen; Ding, Gang; Zhang, Chunmei; Xu, Junji; Wang, Songlin] Capital Med Univ, Sch Stomatol, Mol Lab Gene Therapy, Beijing 100050, Peoples R China. [Wang, Songlin] Capital Med Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Beijing 100050, Peoples R China. RP Baum, BJ (reprint author), NIDCR, MPTB, NIH, DHHS, Bldg 10,Room 1N113,MSC-1190, Bethesda, MD 20892 USA. EM bbaum@dir.nidcr.nih.gov; slwang@ccmu.edu.cn FU National Natural Science Foundation of China [30430690]; Beijing Major Scientific Program [D0906007000091]; National Special Foundation for Excellent PhD [200778]; National Institute of Dental and Craniofacial Research FX This study was supported by the National Natural Science Foundation of China (Grant 30430690), Beijing Major Scientific Program Grant (D0906007000091), the National Special Foundation for Excellent PhD (Paper no. 200778), and by the Division of Intramural Research of the National Institute of Dental and Craniofacial Research. NR 49 TC 15 Z9 15 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1099-498X EI 1521-2254 J9 J GENE MED JI J. Gene. Med. PD JUN PY 2009 VL 11 IS 6 BP 506 EP 514 DI 10.1002/jgm.1319 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 459DG UT WOS:000267079700006 PM 19326368 ER PT J AU Adijanto, J Banzon, T Jalickee, S Wang, NS Miller, SS AF Adijanto, Jeffrey Banzon, Tina Jalickee, Stephen Wang, Nam S. Miller, Sheldon S. TI CO2-induced ion and fluid transport in human retinal pigment epithelium SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID SPACE SURROUNDING PHOTORECEPTORS; MICROVILLUS MEMBRANE-VESICLES; LIGHT-DEPENDENT HYDRATION; CHRONIC MACULAR EDEMA; FROG CHOROID-PLEXUS; CEREBROSPINAL-FLUID; BASOLATERAL MEMBRANE; OXYGEN-CONSUMPTION; CAT RETINA; BICARBONATE TRANSPORT AB In the intact eye, the transition from light to dark alters pH, [Ca2+], and [K] in the subretinal space (SRS) separating the photoreceptor outer segments and the apical membrane of the retinal pigment epithelium (RPE). In addition to these changes, oxygen consumption in the retina increases with a concomitant release of CO2 and H2O into the SRS. The RPE maintains SRS pH and volume homeostasis by transporting these metabolic byproducts to the choroidal blood supply. In vitro, we mimicked the transition from light to dark by increasing apical bath CO2 from 5 to 13%; this maneuver decreased cell pH from 7.37 +/- 0.05 to 7.14 +/- 0.06 (n = 13). Our analysis of native and cultured fetal human RPE shows that the apical membrane is significantly more permeable (approximate to 10-fold; n = 7) to CO2 than the basolateral membrane, perhaps due to its larger exposed surface area. The limited CO2 diffusion at the basolateral membrane promotes carbonic anhydrase-mediated HCO3 transport by a basolateral membrane Na/nHCO(3) cotransporter. The activity of this transporter was increased by elevating apical bath CO2 and was reduced by dorzolamide. Increasing apical bath CO2 also increased intracellular Na from 15.7 +/- 3.3 to 24.0 +/- 5.3 mM (n = 6; P < 0.05) by increasing apical membrane Na uptake. The CO2-induced acidification also inhibited the basolateral membrane Cl/HCO3 exchanger and increased net steady-state fluid absorption from 2.8 +/- 1.6 to 6.7 +/- 2.3 mu l x cm(-2) x hr(-1) (n = 5; P < 0.05). The present experiments show how the RPE can accommodate the increased retinal production of CO2 and H2O in the dark, thus preventing acidosis in the SRS. This homeostatic process would preserve the close anatomical relationship between photoreceptor outer segments and RPE in the dark and light, thus protecting the health of the photoreceptors. C1 [Adijanto, Jeffrey; Banzon, Tina; Jalickee, Stephen; Miller, Sheldon S.] NEI, NIH, Bethesda, MD 20892 USA. [Adijanto, Jeffrey; Wang, Nam S.] Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. RP Miller, SS (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM millers@nei.nih.gov RI Wang, Nam Sun/E-4253-2016 FU Intramural NIH HHS NR 76 TC 39 Z9 40 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD JUN PY 2009 VL 133 IS 6 BP 603 EP 622 DI 10.1085/jgp.200810169 PG 20 WC Physiology SC Physiology GA 454OQ UT WOS:000266692400006 PM 19468075 ER PT J AU Duffy, S Holmes, EC AF Duffy, Siobain Holmes, Edward C. TI Validation of high rates of nucleotide substitution in geminiviruses: phylogenetic evidence from East African cassava mosaic viruses SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID LEAF-CURL-VIRUS; RAPID EVOLUTIONARY DYNAMICS; SPONTANEOUS MUTATION; MOLECULAR EVOLUTION; RNA VIRUSES; SEQUENCE COMPARISONS; GENETIC-STRUCTURE; HIGH-FREQUENCY; PLANT-VIRUS; DNA-A AB Whitefly-transmitted geminiviruses are major pathogens of the important crop cassava in Africa. The intensive sampling and sequencing of cassava mosaic disease-causing viruses that occurred in the wake of a severe outbreak in Central Africa (1997-2002) allowed us to estimate the rate of evolution of this virus. East African cassava mosaic virus and related species are obligately bipartite (DNA-A and DNA-B segments), and these two genome segments have different evolutionary histories. Despite these phylogenetic differences, we inferred high rates of nucleotide substitution in both segments: mean rates of 1.60x10(-3) and 1.33x10(-4) substitutions site(-1) year(-1) for DNA-A and DNA-B, respectively. While similarly high substitution rates were found in datasets free of detectable recombination, only that estimated for the coat protein gene (AV1), for which an additional I sequence isolated in 1995 was available, was statistically robust. These high substitution rates also confirm that those previously estimated for the monopartite tomato yellow leaf curl virus (TYLCV) are representative of multiple begomoviruses. We also validated our rate estimates by comparing them with those depicting the emergence of TYLCV in North America. These results further support the notion that geminiviruses evolve as rapidly as many RNA viruses. C1 [Duffy, Siobain; Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Duffy, Siobain] Rutgers State Univ, Sch Biol & Environm Sci, Dept Ecol Evolut & Nat Resources, New Brunswick, NJ 08901 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Duffy, S (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM duffy@aesop.rutgers.edu RI Duffy, Siobain/A-9104-2009 OI Holmes, Edward/0000-0001-9596-3552; Duffy, Siobain/0000-0003-0753-223X FU National Science Foundation [DBI-0630707] FX We would like to thank David Robinson, Scottish Crop Research Institute, Dundee, UK, for providing details of the isolation of EACMV-TZ. This work was supported by a National Science Foundation grant DBI-0630707 to S. D. NR 55 TC 66 Z9 69 U1 0 U2 9 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD JUN PY 2009 VL 90 BP 1539 EP 1547 DI 10.1099/vir.0.009266-0 PG 9 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 453NB UT WOS:000266616200028 PM 19264617 ER PT J AU Bonham, VL Citrin, T Modell, SM Franklin, TH Bleicher, EWB Fleck, LM AF Bonham, Vence L. Citrin, Toby Modell, Stephen M. Franklin, Tene Hamilton Bleicher, Esther W. B. Fleck, Leonard M. TI Community-Based Dialogue: Engaging Communities of Color in the United States' Genetics Policy Conversation SO JOURNAL OF HEALTH POLITICS POLICY AND LAW LA English DT Article ID HEALTH DISPARITIES; AFRICAN-AMERICANS; ETHNIC CATEGORIES; BLACK PATIENTS; HEART-FAILURE; GENOME ERA; RACE; GENES; RISK; ANCESTRY AB Engaging communities of color in the genetics public policy conversation is important for the translation of genetics research into strategies aimed at improving the health of all. Implementing model public participation and consultation processes can be informed by the Communities of Color Genetics Policy Project, which engaged individuals from African American and Latino communities of diverse socioeconomic levels in the process of "rational democratic deliberation" on ethical and policy issues stretching from genome research to privacy and discrimination concerns to public education. The results of the study included the development of a participatory framework based on a combination of the theory of democratic deliberation and the community-based public health model which we describe as "community-based dialogue." C1 [Bonham, Vence L.] NHGRI, NIH, Div Intramural Res, Social & Behav Res Branch, Bethesda, MD USA. [Citrin, Toby; Modell, Stephen M.] Univ Michigan, Sch Publ Hlth, Ctr Publ Hlth & Community Genom, Ann Arbor, MI 48109 USA. [Modell, Stephen M.] Univ Michigan, Sch Publ Hlth, Dept Hlth Policy & Management, Ann Arbor, MI 48109 USA. [Franklin, Tene Hamilton] Meharry Med Coll, Dept Internal Med, Nashville, TN USA. [Franklin, Tene Hamilton] Meharry Med Coll, Dept Obstet & Gynecol, Nashville, TN USA. [Fleck, Leonard M.] Michigan State Univ, Ctr Eth & Humanities Life Sci, E Lansing, MI 48824 USA. RP Bonham, VL (reprint author), NHGRI, NIH, Div Intramural Res, Social & Behav Res Branch, Bethesda, MD USA. FU National Human Genome Research Institute - Ethical, Legal, and Social Implications Program [R01 HG01005] FX The authors acknowledge the contributions of the community partner organizations in the Communities of Color and Genetics Policy Project. Support for this project was provided by the National Human Genome Research Institute - Ethical, Legal, and Social Implications Program, Grant R01 HG01005, and manuscript development (in part) was provided by the Intramural Research Program of the National Human Genome Research Institute. This article represents the views of the authors and not necessarily those of the National Human Genome Research Institute, the National Institutes of Health, or the U. S. Department of Health and Human Services. We wish to thank Peter Jacobson, JD, at the University of Michigan, School of Public Health, for reviewing this article and providing thoughtful comments and Adebola Odunlami, MPH, for her contribution to the preparation of this article. NR 74 TC 13 Z9 13 U1 0 U2 6 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 0361-6878 J9 J HEALTH POLIT POLIC JI J. Health Polit. Policy Law PD JUN PY 2009 VL 34 IS 3 BP 325 EP 359 DI 10.1215/03616878-2009-009 PG 35 WC Health Care Sciences & Services; Health Policy & Services; Medicine, Legal; Social Issues; Social Sciences, Biomedical SC Health Care Sciences & Services; Legal Medicine; Social Issues; Biomedical Social Sciences GA 452PO UT WOS:000266553900003 PM 19451407 ER PT J AU Stevenson, LW Pagani, FD Young, JB Jessup, M Miller, L Kormos, RL Naftel, DC Ulisney, K Desvigne-Nickens, P Kirklin, JK AF Stevenson, Lynne Warner Pagani, Francis D. Young, James B. Jessup, Mariell Miller, Leslie Kormos, Robert L. Naftel, David C. Ulisney, Karen Desvigne-Nickens, Patrice Kirklin, James K. TI INTERMACS Profiles of Advanced Heart Failure: The Current Picture SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article ID TRANSPLANT EVALUATION; SURVIVAL AB Background: The current classification of patients with New York Heart Association Class IV symptoms does not offer adequate description to allow optimal selection of patients for the current options of medical and pacing therapies, cardiac transplantation and mechanical circulatory support. Methods: Seven clinical profiles and an arrhythmia modifier were developed and implemented into the first year of data collection for the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). The INTERMACS Coordinators' Council provided ongoing feedback regarding the characterization of patients receiving implantable devices. Results: The definition of 7 clinical profiles revealed that 80% of current devices are being used in the 2 profiles with the highest levels of clinical compromise. The INTERMACS Coordinators' Council helped to identify gaps in the characterization of hospitalized patients on temporary assist devices and of homebound patients with resting symptoms, which has led to revised definitions of Profile 3 and 4 and the addition of 2 new modifiers, for temporary circulatory Support devices in the hospital, and for frequent rehospitalization of patients at home. Conclusions: Patients considered for mechanical circulatory Support can now be classified using the 7 profiles plus 3 modifiers developed through INTERMACS. Further understanding these profiles and their impact on outcome should help to better select patients and therapies in the advanced stages of disease. J Heart Lung Transplant 2009;28:535-41. Copyright (C) 2009 by the International Society for Heart and Lung Transplantation. C1 [Kirklin, James K.] Univ Alabama, Dept Cardiothorac Surg, Birmingham, AL 35294 USA. [Stevenson, Lynne Warner] Brigham & Womens Hosp, Boston, MA 02115 USA. [Pagani, Francis D.] Univ Michigan, Ann Arbor, MI 48109 USA. [Young, James B.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Jessup, Mariell] Univ Penn, Philadelphia, PA 19104 USA. [Miller, Leslie] Washington Hosp Ctr, Washington, DC 20010 USA. [Kormos, Robert L.] Univ Pittsburgh, Pittsburgh, PA USA. [Ulisney, Karen; Desvigne-Nickens, Patrice] NHLBI, Bethesda, MD 20892 USA. RP Kirklin, JK (reprint author), Univ Alabama, Dept Cardiothorac Surg, 739 Ziegler Res Bldg,703 S 19th St, Birmingham, AL 35294 USA. EM jkirklin@uab.edu FU NIH [HHSN268200548198C] FX Supported by NIH Contract No. HHSN268200548198C. NR 7 TC 194 Z9 198 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD JUN PY 2009 VL 28 IS 6 BP 535 EP 541 DI 10.1016/j.healun.2009.02.015 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 455DG UT WOS:000266736600001 PM 19481012 ER PT J AU Okiyama, W Tanaka, N Nakajima, T Tanaka, E Kiyosawa, K Gonzalez, FJ Aoyama, T AF Okiyama, Wataru Tanaka, Naoki Nakajima, Tamie Tanaka, Eiji Kiyosawa, Kendo Gonzalez, Frank J. Aoyama, Toshifumi TI Polyenephosphatidylcholine prevents alcoholic liver disease in PPAR alpha-null mice through attenuation of increases in oxidative stress SO JOURNAL OF HEPATOLOGY LA English DT Article DE Cytochrome P450 2E1; Acyl-CoA oxidase; NOX-4; MCP-1; TLR-4 ID ACTIVATED-RECEPTOR-ALPHA; KAPPA-B; FATTY LIVER; ETHANOL; EXPRESSION; PROTEASOME; PATHWAY; DEHYDROGENASE; PURIFICATION; DEGRADATION AB Background/Aims: Alcoholic liver disease (ALD) is one of the leading causes of cirrhosis and yet efficient therapeutic strategies are lacking. Polyenephosphatidylcholine (PPC), a major component of essential phospholipids, prevented alcoholic liver fibrosis in baboons, but its precise mechanism remains uncertain. We aimed to explore the effects of PPC on ALD using ethanol-fed peroxisome proliferator-activated receptor alpha (Ppara)-null mice, showing several similarities to human ALD. Methods: Male wild-type and Ppara-null mice were pair-fed a Lieber-DeCarli control or 4% ethanol-containing diet with or without PPC (30 mg/kg/day) for 6 months. Results: PPC significantly ameliorated ethanol-induced hepatocyte damage and hepatitis in Ppara-null mice. These effects were likely a consequence of decreased oxidative stress through down-regulation of reactive oxygen species (ROS)-generating enzymes, including cytochrome P450 2E1, acyl-CoA oxidase, and NADPH oxidases, in addition to restoration of increases in Toll-like receptor 4 and CD14. PPC also decreased Bax and truncated Bid, thus inhibiting apoptosis. Furthermore, PPC suppressed increases in transforming growth factor-beta 1 expression and hepatic stellate cell activation, which retarded hepatic fibrogenesis. Conclusions: PPC exhibited anti-inflammatory, anti-apoptotic, and anti-fibrotic effects on ALD as a result of inhibition of the overexpression of ROS-generating enzymes. Our results demonstrate detailed molecular mechanisms of the antioxidant action of PPC. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Okiyama, Wataru; Tanaka, Naoki; Aoyama, Toshifumi] Shinshu Univ, Grad Sch Med, Inst Aging & Adaptat, Dept Metab Regulat, Matsumoto, Nagano 3908621, Japan. [Okiyama, Wataru; Tanaka, Naoki; Tanaka, Eiji] Shinshu Univ, Sch Med, Dept Gastroenterol, Matsumoto, Nagano 3908621, Japan. [Nakajima, Tamie] Nagoya Univ, Grad Sch Med, Dept Occupat Environm Hlth, Nagoya, Aichi 4648601, Japan. [Kiyosawa, Kendo] Nagano Red Cross Hosp, Dept Internal Med, Nagano, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Tanaka, N (reprint author), Shinshu Univ, Grad Sch Med, Inst Aging & Adaptat, Dept Metab Regulat, Asahi 3-1-1, Matsumoto, Nagano 3908621, Japan. EM naopi@shinshu-u.ac.jp FU Intramural NIH HHS [Z01 BC005708-17] NR 36 TC 38 Z9 40 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD JUN PY 2009 VL 50 IS 6 BP 1236 EP 1246 DI 10.1016/j.jhep.2009.01.025 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 455EF UT WOS:000266739600019 PM 19398233 ER PT J AU Saavedra, JM AF Saavedra, Juan M. TI Opportunities and limitations of genetic analysis of hypertensive rat strains SO JOURNAL OF HYPERTENSION LA English DT Editorial Material ID AT(1) RECEPTOR EXPRESSION; BLOOD-PRESSURE REGULATION; SALT-SENSITIVE RATS; ANGIOTENSIN-II; CONGENIC STRAINS; DISRUPTED MICE; FUNCTIONAL GENOMICS; KNOCKOUT MICE; LYON STRAIN; LOCI C1 NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH,Dept Hlth & Human Serv, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Saavedrj@mail.nih.gov FU Intramural NIH HHS [Z01 MH002762-11] NR 70 TC 11 Z9 11 U1 0 U2 0 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 JUN PY 2009 VL 27 IS 6 BP 1129 EP 1133 DI 10.1097/HJH.0b013e32832bb832 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 454YT UT WOS:000266721300006 PM 19454904 ER PT J AU Joseph, J Pencina, MJ Wang, TJ Hayes, L Tofler, GH Jacques, P Selhub, J Levy, D D'Agostino, RB Benjamin, EJ Vasan, RS AF Joseph, Jacob Pencina, Michael J. Wang, Thomas J. Hayes, Laura Tofler, Geoffrey H. Jacques, Paul Selhub, Jacob Levy, Daniel D'Agostino, Ralph B., Sr. Benjamin, Emelia J. Vasan, Ramachandran S. TI Cross-sectional relations of multiple biomarkers representing distinct biological pathways to plasma markers of collagen metabolism in the community SO JOURNAL OF HYPERTENSION LA English DT Article DE biomarkers; cardiac remodeling; collagen; hyperhomocysteinemia; matrix ID ATRIAL-NATRIURETIC-PEPTIDE; ACUTE MYOCARDIAL-INFARCTION; CARDIOVASCULAR RISK-FACTORS; CORONARY-HEART-DISEASE; SMOOTH-MUSCLE-CELLS; HYPERHOMOCYSTEINEMIA LEADS; HYPERTENSIVE RATS; CARDIAC STRUCTURE; HOMOCYSTEINE; FIBROSIS AB Objective Hyperhomocysteinemia, neurohormonal activation, inflammation and altered fibrinolysis have been linked to atherothrombosis as well as to myocardial fibrosis and heart failure. Hence, we related a panel of biomarkers representing these pathways to plasma markers of collagen metabolism in a large community-based sample. Methods We related nine biomarkers representing select biologic pathways (independent variables: C-reactive protein, B-type natriuretic peptide, N-terminal proatrial natriuretic peptide, aldosterone, renin, fibrinogen, D-dimer, plasminogen activator inhibitor-1 and homocysteine) to three plasma markers of collagen turnover [dependent variables, separate models for each: aminoterminal propeptide of type III collagen, tissue inhibitor of metalloproteinases-1 and matrix metalloproteinase-9 (present versus absent)] in 921 Framingham Heart study participants (mean age 57 years; 58% women). Participants were separated a priori into those with left ventricular end-diastolic dimensions and wall thickness below sex-specific median values (referent group) and either measure at least 90th sex-specific percentile ('remodeled' group). We used stepwise multivariable regression analysis adjusting for cardiovascular risk factors to relate the panel of systemic biomarkers to the three biomarkers of collagen metabolism. Results Plasma homocysteine was positively related to all three markers of collagen metabolism in the remodeled group and to aminoterminal propeptide of type III collagen and tissue inhibitor of metalloproteinases-1 in the referent group. Plasminogen activator inhibitor-1 was positively related to aminoterminal propeptide of type III collagen and tissue inhibitor of metalloproteinases-1 in both groups, whereas the natriuretic peptides were associated positively with these collagen markers in the referent group. Conclusion In our large community-based sample, plasma homocysteine and plasminogen activator inhibitor-1 were positively related to circulating collagen biomarkers, consistent with experimental studies implicating these pathways in cardiovascular collagen turnover. J Hypertens 27:1317-1324 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Joseph, Jacob] VA Boston Healthcare Syst, Boston, MA USA. [Joseph, Jacob; Pencina, Michael J.; Hayes, Laura; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Wang, Thomas J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tofler, Geoffrey H.; Levy, Daniel; D'Agostino, Ralph B., Sr.; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Jacques, Paul; Selhub, Jacob] Tufts Univ, Boston, MA 02111 USA. RP Joseph, J (reprint author), VA Boston Healthcare Syst, Cardiol Sect 111, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM Jacob.joseph@bmc.org OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; NIH [K23-HL-074077, RO1 HL67288, HL080124, K24-HL04334] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract No. N01-HC-25195) and NIH grants K23-HL-074077 (T. J. W.), RO1 HL67288, HL080124 and K24-HL04334 (R. S. V.). NR 34 TC 4 Z9 6 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 JUN PY 2009 VL 27 IS 6 BP 1317 EP 1324 DI 10.1097/HJH.0b013e328329fc20 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 507MP UT WOS:000270858600009 PM 19357531 ER PT J AU Rothfuchs, AG Egen, JG Feng, CG Antonelli, LRV Bafica, A Winter, N Locksley, RM Sher, A AF Rothfuchs, Antonio Gigliotti Egen, Jackson G. Feng, Carl G. Antonelli, Lis R. V. Bafica, Andre Winter, Nathalie Locksley, Richard M. Sher, Alan TI In Situ IL-12/23p40 Production during Mycobacterial Infection Is Sustained by CD11b(high) Dendritic Cells Localized in Tissue Sites Distinct from Those Harboring Bacilli SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; INNATE IMMUNE DEFENSE; IFN-GAMMA; CALMETTE-GUERIN; INTERLEUKIN-12 PRODUCTION; MACROPHAGE RESPONSES; BACTERIAL-INFECTION; TOXOPLASMA-GONDII; ADAPTIVE IMMUNITY; FACTOR-ALPHA AB Although IL-12/23p40 is known to play a major role in host resistance to Mycobacterium spp, the cellular source, tissue localization, and regulation of p40 production during mycobacterial infection in vivo has been unclear. In this study, we used IL-12/23p40eYFP (yet40) reporter mice to track expression of the cytokine following Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection. We found that in spleens of these mice, p40 production is initiated by a transient burst from CD11b(low)CD11c(+) dendritic cells (DC) which are later replaced at the onset of granuloma formation by CD11b(high)CD11c(+) DC as the major source of the cytokine. The latter subset was also found to be the key producer of DC-derived p40 in nonlymphoid tissue and in both spleen and liver optimal production of the cytokine was regulated by endogenous TNF-alpha. Although BCG and p40-expressing DC were both observed in splenic white pulp, p40(+) DC rarely colocalized with bacilli. Indeed, in vitro flow cytometry and confocal microscopy indicated that the presence of intracellular bacteria is not required for p40 production by DC and Transwell experiments confirmed that soluble mycobacterial components are sufficient for inducing cytokine expression by these cells. Moreover, when stimulated with LPS, DC directly infected with BCG showed impaired IL-12p40 production in vitro. Together, our findings establish CD11b(high) DC as a major source of IL-12/23p40 during mycobacterial infection in situ and implicate both soluble mycobacterial products and TNF-a in stimulating sustained production of p40 by these cells. The Journal of Immunology, 2009, 182: 6915-6925. C1 [Rothfuchs, Antonio Gigliotti; Feng, Carl G.; Antonelli, Lis R. V.; Bafica, Andre; Sher, Alan] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Egen, Jackson G.] NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Winter, Nathalie] Inst Pasteur, Mycobacterial Genet Unit, Paris, France. [Locksley, Richard M.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Locksley, Richard M.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Locksley, Richard M.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. RP Rothfuchs, AG (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Room 6148,Bldg 50,50 South Dr, Bethesda, MD 20892 USA. EM rothfuchsa@niaid.nih.gov RI Rothfuchs, Antonio/F-5981-2013; Vacinas, Inct/J-9431-2013; Antonelli, Lis/G-2907-2012; OI Rothfuchs, Antonio/0000-0001-6001-7240; Egen, Jackson/0000-0003-2053-0837 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases [A130663]; National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and Grant A130663 from the National Institute of Allergy and Infectious Diseases (to R.M.L.). NR 49 TC 19 Z9 19 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2009 VL 182 IS 11 BP 6915 EP 6925 DI 10.4049/jimmunol.0900074 PG 11 WC Immunology SC Immunology GA 448JG UT WOS:000266258300035 PM 19454688 ER PT J AU Pasula, R Britigan, BE Turner, J Martin, WJ AF Pasula, Rajamouli Britigan, Bradley E. Turner, Joanne Martin, William J., II TI Airway Delivery of Silica Increases Susceptibility to Mycobacterial Infection in Mice: Potential Role of Repopulating Macrophages SO JOURNAL OF IMMUNOLOGY LA English DT Article ID AFRICAN GOLD MINERS; INTERFERON-GAMMA PRODUCTION; PHAGOSOME-LYSOSOME FUSION; THORACIC LYMPH-NODES; ALVEOLAR MACROPHAGES; PULMONARY TUBERCULOSIS; IFN-GAMMA; DEFICIENT PATIENTS; LUNG FIBROSIS; MURINE MODEL AB Silica exposure results in an increased lifelong risk of developing mycobacterial pulmonary infections. To date, there are no animal models that replicate this finding to permit assessment of the mechanisms underlying susceptibility to mycobacterial infection. To test the hypothesis that prior silica exposure increases risk of mycobacterial infection, we intratracheally (I.T.) administered silica, a control dust (Al(2)O(3)) or saline into mechanically ventilated C57BL/6 mice. Later, the mice received Mycobacterium avium or Mycobacterium tuberculosis I.T. Mice were sacrificed at defined time points and mycobacteria in lung homogenates were quantified. M. avium or M. tuberculosis infection was markedly increased in silica-exposed mice compared with mice exposed to either Al(2)O(3) or saline beginning 3 wk after silica exposure. Similarly, lung sections from silica-exposed mice had many more acid fast bacilli(+) (AFB(+)) organisms than from control mice. Alveolar macrophages (AMs) from bronchoalveolar lavage of silica-exposed mice also revealed a higher number of mycobacteria compared with mice treated with Al(2)O(3) or saline. In addition, passive transfer of AMs from silica-exposed mice to control mice increased M. tuberculosis susceptibility. These results indicate that silica exposure converts mycobacteria-resistant mice into mycobacteria-susceptible mice via a process that likely involves a new population of AMs that are more susceptible to mycobacterial infection. The Journal of Immunology, 2009, 182: 7102-7109. C1 [Pasula, Rajamouli; Britigan, Bradley E.] Univ Cincinnati, Dept Internal Med, Cincinnati, OH 45267 USA. [Britigan, Bradley E.] Vet Affairs Med Ctr, Cincinnati, OH 45267 USA. [Turner, Joanne] Ohio State Univ Hosp, Dept Internal Med, Div Infect Dis, Ctr Microbial Interface Biol, Columbus, OH 43210 USA. [Martin, William J., II] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC 27709 USA. RP Pasula, R (reprint author), Univ Cincinnati, Dept Internal Med, POB 670557, Cincinnati, OH 45267 USA. EM pasular@ucmail.uc.edu RI Turner, Joanne/E-4219-2011; Turner, Joanne/F-4118-2015 FU National Institutes of Health [R01 HL076955]; Veterans Affairs Merit Review Award FX This work was supported by National Institutes of Health Grant R01 HL076955 (to R.P. and B.E.B.) and Veterans Affairs Merit Review Award (to B.E.B.). NR 72 TC 7 Z9 7 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2009 VL 182 IS 11 BP 7102 EP 7109 DI 10.4049/jimmunol.0803642 PG 8 WC Immunology SC Immunology GA 448JG UT WOS:000266258300054 PM 19454707 ER PT J AU Reddy, NM Kleeberger, SR Kensler, TW Yamamoto, M Hassoun, PM Reddy, SP AF Reddy, Narsa M. Kleeberger, Steven R. Kensler, Thomas W. Yamamoto, Masayuki Hassoun, Paul M. Reddy, Sekhar P. TI Disruption of Nrf2 Impairs the Resolution of Hyperoxia-Induced Acute Lung Injury and Inflammation in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; TRANSCRIPTION FACTOR NRF2; DNA-DAMAGE; SECRETORY PRODUCTS; OXIDATIVE STRESS; EPITHELIAL-CELLS; INNATE IMMUNITY; REPAIR; GENE; ACTIVATION AB Aberrant tissue repair and persistent inflammation following oxidant-mediated acute lung injury (ALI) can lead to the development and progression of various pulmonary diseases, but the mechanisms underlying these processes remain unclear. Hyperoxia is widely used in the treatment of pulmonary diseases, but the effects of this oxidant exposure in patients undergoing recovery from ALI are not clearly understood. Nrf2 has emerged as a crucial transcription factor that regulates oxidant stress through the induction of several detoxifying enzymes and other proteins. Using an experimental model of hyperoxia-induced ALI, we have examined the role of oxidant stress in resolving lung injury and inflammation. We found that when exposed to sublethal (72 h) hyperoxia, Nrf2-deficient, but not wild-type mice, succumbed to death during recovery. When both genotypes were exposed to a shorter period of hyperoxia-induced ALI (48 h), the lungs of Nrf2-deficient mice during recovery exhibited persistent cellular injury, impaired alveolar and endothelial cell regeneration, and persistent cellular infiltration by macrophages and lymphocytes. Glutathione (GSH) supplementation in Nrf2-deficient mice immediately after hyperoxia remarkably restored their ability to recover from hyperoxia-induced damage in a manner similar to that of wild-type mice. Thus, the results of the present study indicate that the Nrf2-regulated transcriptional response and, particularly GSH synthesis, is critical for lung tissue repair and the resolution of inflammation in vivo and suggests that a dysfunctional Nrf2-GSH pathway may compromise these processes in vivo. The Journal of Immunology, 2009, 182: 7264-7271. C1 [Reddy, Narsa M.; Kensler, Thomas W.; Reddy, Sekhar P.] Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Hassoun, Paul M.] Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. [Kleeberger, Steven R.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Yamamoto, Masayuki] Tohoku Univ, Dept Med Biochem, Sendai, Miyagi 980, Japan. RP Reddy, SP (reprint author), Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Room E7610-615,N Wolfe St, Baltimore, MD 21205 USA. EM sreddy@jhsph.edu RI Yamamoto, Masayuki/A-4873-2010; Kensler, Thomas/D-8686-2014 OI Kensler, Thomas/0000-0002-6676-261X FU National Institutes of Health [HL66109, ES11863]; Specialized Centers of Clinically Oriented Research [P50 HL073994, HL049441, CA 94076] FX This work was funded by National Institutes of Health Grants HL66109 and ES11863 (to SPR) and Specialized Centers of Clinically Oriented Research Grants P50 HL073994 (to S.P.R. and P.H.), HL049441 (to P.H.), and CA 94076 (to T. W. K). NR 35 TC 79 Z9 81 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 JUN 1 PY 2009 VL 182 IS 11 BP 7264 EP 7271 DI 10.4049/jimmunol.0804248 PG 8 WC Immunology SC Immunology GA 448JG UT WOS:000266258300070 PM 19454723 ER PT J AU Busch, MP Glynn, SA AF Busch, Michael P. Glynn, Simone A. TI Use of Blood-Donor and Transfusion-Recipient Biospecimen Repositories to Address Emerging Blood-Safety Concerns and Advance Infectious Disease Research: The National Heart, Lung, and Blood Institute Biologic Specimen Repository SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID HUMAN-HERPESVIRUS-8 C1 [Busch, Michael P.] Univ Calif San Francisco, Blood Syst Res Inst, San Francisco, CA 94118 USA. [Busch, Michael P.] Univ Calif San Francisco, Res & Sci Programs, San Francisco, CA 94118 USA. [Glynn, Simone A.] NHLBI, Transfus Med & Cellular Therapeut Branch, Div Blood Dis & Resources, Bethesda, MD 20892 USA. RP Busch, MP (reprint author), Univ Calif San Francisco, Blood Syst Res Inst, 270 Masonic Ave, San Francisco, CA 94118 USA. EM mbusch@bloodsystems.org FU NHLBI NIH HHS [N01-HB-57181] NR 9 TC 14 Z9 15 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 JUN 1 PY 2009 VL 199 IS 11 BP 1564 EP 1566 DI 10.1086/598860 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 444SL UT WOS:000266000600002 PM 19385737 ER PT J AU Castle, PE Kreimer, AR Wacholder, S Wheeler, CM Koutsky, LA Rydzak, G Buckman, DW Graubard, B Schiffman, M AF Castle, Philip E. Kreimer, Aimee R. Wacholder, Sholom Wheeler, Cosette M. Koutsky, Laura A. Rydzak, Greg Buckman, Dennis W. Graubard, Barry Schiffman, Mark TI Influence of Loop Electrosurgical Excision Procedure on Subsequent Acquisition of New Human Papillomavirus Infections SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CERVICAL INTRAEPITHELIAL NEOPLASIA; ATYPICAL SQUAMOUS-CELLS; 2006 CONSENSUS GUIDELINES; UNDETERMINED SIGNIFICANCE; RANDOMIZED-TRIAL; CYTOLOGY INTERPRETATIONS; MANAGEMENT STRATEGIES; POOLED ANALYSIS; DNA DETECTION; WOMEN AB Background. The impact of loop electrosurgical excision procedure (LEEP) treatment for cervical precancerous lesions on subsequent acquisition of new human papillomavirus (HPV) infections is not well described. Methods. The acquisition of new HPV infections was compared in HPV-positive women who underwent colposcopy and were treated by LEEP (n = 195) and those who were untreated (n = 1625) at entry into a 2-year study. Cumulative incidence rate ratios (IRRs) for treated versus untreated women at 6- and 24-months of follow-up, with 95% confidence intervals (CIs), were calculated for infection by individual HPV genotypes, any HPV genotypes, any carcinogenic HPV genotypes, any noncarcinogenic HPV genotypes, and phylogenetic groups of HPV genotypes. Results. Treated women were 29% less likely than untreated women to have carcinogenic HPV genotypes detected at 6-month follow-up visits (IRR, 0.71; 95% CI, 0.50-1.00) and were 18% less likely to have these genotypes detected at 24-month follow-up visits (IRR, 0.82; 95% CI, 0.68-1.01). Treated women were 56% less likely to have HPV genotypes of the alpha 9 phylogenetic species (which includes HPV-16) detected at 6-month follow-up visits (IRR, 0.44; 95% CI, 0.23-0.85) and were 40% less likely to have these genotype detected at 24-month follow-up visits (IRR, 0.60; 95% CI, 0.42-0.85). Conclusion. LEEP may reduce the acquisition of certain carcinogenic HPV genotypes related to HPV-16. C1 [Castle, Philip E.; Wacholder, Sholom; Graubard, Barry; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kreimer, Aimee R.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Rydzak, Greg; Buckman, Dennis W.] Informat Management Serv Inc, Silver Spring, MD USA. [Wheeler, Cosette M.] Univ New Mexico, Sch Med, Hlth Sci Ctr, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Wheeler, Cosette M.] Univ New Mexico, Sch Med, Hlth Sci Ctr, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. [Koutsky, Laura A.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Rm 5004,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov RI Kreimer, Aimee/H-1687-2015 FU National Cancer Institute, National Institutes of Health [CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, CN-55105]; Digene; Cytyc; National Testing Laboratories; DenVu; TriPath Imaging; Roche Molecular Systems FX Financial support: The ASCUS-LSIL Triage Study was supported by the National Cancer Institute, National Institutes of Health (contracts CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, and CN-55105). Some equipment and supplies used in these studies were donated or provided at reduced cost by Digene, Cytyc, National Testing Laboratories, DenVu, TriPath Imaging, and Roche Molecular Systems. NR 37 TC 6 Z9 7 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 JUN 1 PY 2009 VL 199 IS 11 BP 1612 EP 1620 DI 10.1086/598981 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 444SL UT WOS:000266000600009 PM 19405865 ER PT J AU Nies-Kraske, E Schacker, TW Condoluci, D Orenstein, J Brenchley, J Fox, C Daucher, M Dewar, R Urban, E Hill, B Guenaga, J Hoover, S Maldarelli, F Hallahan, CW Horn, J Kottilil, S Chun, TW Folino, M Palmer, S Wiegand, A O'Shea, MA Metcalf, JA Douek, DC Coffin, J Haase, A Fauci, AS Dybul, M AF Nies-Kraske, Elizabeth Schacker, Timothy W. Condoluci, David Orenstein, Jan Brenchley, Jason Fox, Cecil Daucher, Marybeth Dewar, Robin Urban, Elizabeth Hill, Brenna Guenaga, Javier Hoover, Shelley Maldarelli, Frank Hallahan, Claire W. Horn, Judith Kottilil, Shyamasundaran Chun, Tae-Wook Folino, Marlene Palmer, Sara Wiegand, Ann O'Shea, M. Angeline Metcalf, Julia A. Douek, Daniel C. Coffin, John Haase, Ashley Fauci, Anthony S. Dybul, Mark TI Evaluation of the Pathogenesis of Decreasing CD4(+) T Cell Counts in Human Immunodeficiency Virus Type 1-Infected Patients Receiving Successfully Suppressive Antiretroviral Therapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 3rd International-AIDS-Society Conference on HIV Pathogenesis and Treatment CY JUL 24-27, 2005 CL Rio de Janeiro, BRAZIL SP Int AIDS Soc ID LYMPH-NODES; HIV-1 INFECTION; VIRAL LOAD; REPLICATION; PLASMA; TISSUE; BLOOD; LAMIVUDINE; RNA; COMBINATION AB Most human immunodeficiency virus (HIV)-infected individuals experience increases in peripheral CD4(+) T cell counts with suppressive antiretroviral therapy (ART) that achieves plasma HIV RNA levels that are less than the limit of detection. However, some individuals experience decreasing CD4(+) T cell counts despite suppression of plasma viremia. We evaluated 4 patients with a history of CD4(+) T cell decline despite successfully suppressive ART, from a median of 719 cells/mm(3) (range, 360-1141 cells/mm(3)) to 227 cells/mm(3) (range, 174-311 cells/mm(3)) over a period of 18-24 months; 3 of the patients were receiving tenofovir and didanosine, which may have contributed to this decrease. There was no evidence of HIV replication, nor of antiretroviral drug resistance in the blood or lymphoid tissue, or increased proliferation or decreased thymic production of naive CD4(+) T cells. All 4 patients had significant fibrosis of the T cell zone of lymphoid tissue, which appeared to be an important factor in the failure to reconstitute T cells. C1 [Nies-Kraske, Elizabeth; Daucher, Marybeth; Urban, Elizabeth; Hallahan, Claire W.; Kottilil, Shyamasundaran; Chun, Tae-Wook; O'Shea, M. Angeline; Metcalf, Julia A.; Fauci, Anthony S.; Dybul, Mark] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. [Brenchley, Jason; Hill, Brenna; Guenaga, Javier; Douek, Daniel C.] Vaccine Res Ctr, Human Immunol Sect, Bethesda, MD USA. [Maldarelli, Frank; Palmer, Sara; Wiegand, Ann; Coffin, John] NCI, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Dewar, Robin] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Fox, Cecil; Hoover, Shelley] Mol Histol Labs, Rockville, MD USA. [Schacker, Timothy W.; Haase, Ashley] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Condoluci, David; Folino, Marlene] Garden State Infect Dis Associates Clin, Voorhees, NJ USA. [Orenstein, Jan; Horn, Judith] George Washington Univ, Washington, DC USA. RP Dybul, M (reprint author), NIAID, Immunoregulat Lab, Bldg 31,Room 7A-03, Bethesda, MD 20892 USA. EM dybulmr@state.gov FU Intramural NIH HHS [Z99 AI999999]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 50 TC 19 Z9 23 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2009 VL 199 IS 11 BP 1648 EP 1656 DI 10.1086/598980 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 444SL UT WOS:000266000600013 PM 19432547 ER PT J AU Lee, PI Ciccone, EJ Read, SW Asher, A Pitts, R Douek, DC Brenchley, JM Sereti, I AF Lee, Philip I. Ciccone, Emily J. Read, Sarah W. Asher, Ava Pitts, Robert Douek, Daniel C. Brenchley, Jason M. Sereti, Irini TI Evidence for Translocation of Microbial Products in Patients with Idiopathic CD4 Lymphocytopenia SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Keystone Meeting on HIV Pathogenesis CY MAR 27-APR 01, 2008 CL Banff, CANADA ID T-CELL DEPLETION; GASTROINTESTINAL-TRACT; HIV-INFECTION; ANTIRETROVIRAL THERAPY; DISEASE; PROGRESSION; ACTIVATION; TISSUE; SITES AB Translocation of microbial products has been described in chronic human immunodeficiency virus (HIV) infection and correlates with activation of the immune system. We investigated the potential translocation of microbial products in idiopathic CD4 lymphocytopenia (ICL), a rare disorder characterized by low CD4 T cell counts in the absence of HIV infection. Plasma lipopolysaccharide (LPS) levels and T cell activation were measured in a cross-sectional cohort study of patients with ICL and HIV infection and healthy control subjects. Increases in CD4 T cell proliferation but not CD8 T cell proliferation were observed in patients with ICL. LPS levels were significantly elevated both in patients with ICL and in patients with HIV infection, and they were strongly correlated with the proportion of proliferating CD4 T cells in the cohort of patients with ICL (r = 0.88; P = .003). The proportions of T helper (Th) 17 and Th1 CD4 cells in peripheral blood were similar between patients with ICL, patients with HIV infection, and control subjects. These findings suggest a potential association of translocation of microbial products with perturbed CD4 T cell homeostasis in individuals with CD4 lymphopenic states other than HIV infection. C1 [Lee, Philip I.; Ciccone, Emily J.; Pitts, Robert; Sereti, Irini] NIAID, Immunoregulat Lab, Clin & Mol Retrovirol Sect, NIH, Bethesda, MD 20892 USA. [Read, Sarah W.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Asher, Ava; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 28 TC 32 Z9 32 U1 0 U2 4 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 JUN 1 PY 2009 VL 199 IS 11 BP 1664 EP 1670 DI 10.1086/598953 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 444SL UT WOS:000266000600015 PM 19432548 ER PT J AU Voyich, JM Vuong, C DeWald, M Nygaard, TK Kocianova, S Griffith, S Jones, J Iverson, C Sturdevant, DE Braughton, KR Whitney, AR Otto, M Deleo, FR AF Voyich, Jovanka M. Vuong, Cuong DeWald, Mark Nygaard, Tyler K. Kocianova, Stanislava Griffith, Shannon Jones, Jennifer Iverson, Courtney Sturdevant, Daniel E. Braughton, Kevin R. Whitney, Adeline R. Otto, Michael DeLeo, Frank R. TI The SaeR/S Gene Regulatory System Is Essential for Innate Immune Evasion by Staphylococcus aureus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT National IDeA Symposium of Biomedical Research Excellence CY AUG 06-08, 2008 CL Washington, DC SP IDeA ID PANTON-VALENTINE LEUKOCIDIN; PATHOGEN SURVIVAL RESPONSE; GROUP-A STREPTOCOCCUS; ANTIMICROBIAL PEPTIDES; COMPLEMENT EVASION; 2-COMPONENT SYSTEM; HUMAN NEUTROPHILS; VIRULENCE; EXPRESSION; DESTRUCTION AB Methicillin-resistant Staphylococcus aureus is problematic both in hospitals and in the community. Currently, we have limited understanding of mechanisms of innate immune evasion used by S. aureus. To that end, we created an isogenic deletion mutant in strain MW2 (USA400) of the saeR/S 2-component gene regulatory system and studied its role in mouse models of pathogenesis and during human neutrophil interaction. In this study, we demonstrate that saeR/S plays a distinct role in S. aureus pathogenesis and is vital for virulence of MW2 in a mouse model of sepsis. Moreover, deletion of saeR/S significantly impaired survival of MW2 in human blood and after neutrophil phagocytosis. Microarray analysis revealed that SaeR/S of MW2 influences expression of a wide variety of genes with diverse biological functions. These data provide new insight into how virulence is regulated in S. aureus and associates a specific staphylococcal gene-regulatory system with invasive staphylococcal disease. C1 [Voyich, Jovanka M.; DeWald, Mark; Nygaard, Tyler K.; Griffith, Shannon; Jones, Jennifer; Iverson, Courtney] Montana State Univ, Dept Vet Mol Biol, Bozeman, MT 59717 USA. [Vuong, Cuong; Kocianova, Stanislava; Braughton, Kevin R.; Whitney, Adeline R.; Otto, Michael; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT USA. [Sturdevant, Daniel E.] NIAID, Genom Unit, Res Technol Sect, Hamilton, MT USA. RP Voyich, JM (reprint author), Montana State Univ, Dept Vet Mol Biol, Bozeman, MT 59717 USA. EM jovanka@montana.edu OI DeLeo, Frank/0000-0003-3150-2516; Otto, Michael/0000-0002-2222-4115 FU Intramural NIH HHS [ZIA AI000900-09]; NCRR NIH HHS [P20RR16455-07, P20 RR020185, P20RR020185, P20 RR016455]; PHS HHS [PAR98-072] NR 41 TC 74 Z9 74 U1 0 U2 7 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 JUN 1 PY 2009 VL 199 IS 11 BP 1698 EP 1706 DI 10.1086/598967 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 444SL UT WOS:000266000600019 PM 19374556 ER PT J AU Pearl, PL Gibson, KM Cortez, MA Wu, Y Snead, OC Knerr, I Forester, K Pettiford, JM Jakobs, C Theodore, WH AF Pearl, P. L. Gibson, K. M. Cortez, M. A. Wu, Y. Snead, O. Carter, III Knerr, I. Forester, K. Pettiford, J. M. Jakobs, C. Theodore, W. H. TI Succinic semialdehyde dehydrogenase deficiency: Lessons from mice and men SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article; Proceedings Paper CT 2nd International Symposium on Pediatric Neurotransmitter Diseases CY JUL 18-19, 2008 CL Washington, DC SP Natl Inst Neurol Disorders & Stroke, Off Rare Dis, John Hopkins Sch Med, PND Assoc ID GAMMA-HYDROXYBUTYRIC ACIDURIA; SSADH DEFICIENCY; GABA-METABOLISM; KETOGENIC DIET; VIGABATRIN; BRAIN; DYSFUNCTION; CHILDREN; SEIZURES; DISTURBANCES AB Succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder of GABA degradation with subsequent elevations in brain GABA and GHB, is a neurometabolic disorder with intellectual disability, epilepsy, hypotonia, ataxia, sleep disorders, and psychiatric disturbances. Neuroimaging reveals increased T2-weighted MRI signal usually affecting the globus pallidus, cerebellar dentate nucleus, and subthalamic nucleus, and often cerebral and cerebellar atrophy. EEG abnormalities are usually generalized spike-wave, consistent with a predilection for generalized epilepsy. The murine phenotype is characterized by failure-to-thrive, progressive ataxia, and a transition from generalized absence to tonic-clonic to ultimately fatal convulsive status epilepticus. Binding and electrophysiological studies demonstrate use-dependent downregulation of GABA(A) and (B) receptors in the mutant mouse. Translational human studies similarly reveal downregulation of GABAergic activity in patients, utilizing flumazenil-PET and transcranial magnetic stimulation for GABA(A) and (B) activity, respectively. Sleep studies reveal decreased stage REM with prolonged REM latencies and diminished percentage of stage REM. An ad libitum ketogenic diet was reported as effective in the mouse model, with unclear applicability to the human condition. Acute application of SGS-742, a GABA(B) antagonist, leads to improvement in epileptiform activity on electrocorticography. Promising mouse data using compounds available for clinical use, including taurine and SGS-742, form the framework for human trials. C1 [Pearl, P. L.; Forester, K.; Pettiford, J. M.] George Washington Univ, Childrens Natl Med Ctr, Sch Med, Dept Neurol, Washington, DC 20010 USA. [Gibson, K. M.] Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Biochem Genet Lab,Dept Pediat,Div Med Genet, Pittsburgh, PA USA. [Cortez, M. A.; Wu, Y.; Snead, O. Carter, III] Hosp Sick Children, Brain & Behav Inst, Div Pediat Neurol, Toronto, ON M5G 1X8, Canada. [Knerr, I.] Univ Erlangen Nurnberg, Childrens & Adolescents Hosp, Erlangen, Germany. [Pearl, P. L.; Jakobs, C.] Vrije Univ Amsterdam Med Ctr, Dept Clin Chem, Metab Unit, Amsterdam, Netherlands. [Theodore, W. H.] NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. [Gibson, K. M.] Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Biochem Genet Lab,Dept Pathol,Div Med Genet, Pittsburgh, PA USA. [Gibson, K. M.] Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Biochem Genet Lab,Dept Human Genet,Div Med Genet, Pittsburgh, PA USA. [Cortez, M. A.; Wu, Y.; Snead, O. Carter, III] Univ Toronto, Toronto, ON, Canada. RP Pearl, PL (reprint author), George Washington Univ, Childrens Natl Med Ctr, Sch Med, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM ppearl@cnmc.org FU NICHD NIH HHS [HD 58553, R01 HD058553, R01 HD058553-01]; NINDS NIH HHS [R01 NS040270, R01 NS040270-07, R01 NS40270, R13 NS 60363, R13 NS060363] NR 45 TC 36 Z9 38 U1 0 U2 6 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 JUN PY 2009 VL 32 IS 3 BP 343 EP 352 DI 10.1007/s10545-009-1034-y PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 451EF UT WOS:000266452800004 PM 19172412 ER PT J AU O'Neil, CC Miller, FG AF O'Neil, Collin C. Miller, Franklin G. TI When Scientists Deceive: Applying the Federal Regulations SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID DECEPTION AB Deception is a useful methodological device for studying attitudes and behavior, but deceptive studies fail to fulfill the informed consent requirements in the U.S. federal regulations. This means that before they can be approved by Institutional Review Boards, they must satisfy the four regulatory conditions for a waiver or alteration of these requirements. To illustrate our interpretation, we apply the conditions to a recent study that used deception to show that subjects judged the same wine as more enjoyable when they believed it had a higher price. C1 [Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. NR 9 TC 7 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1073-1105 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD SUM PY 2009 VL 37 IS 2 BP 344 EP + DI 10.1111/j.1748-720X.2009.00377.x PG 8 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 453KP UT WOS:000266609600015 PM 19493078 ER PT J AU Laird, MHW Rhee, SH Perkins, DJ Medvedev, AE Piao, WJ Fenton, MJ Vogel, SN AF Laird, Michelle H. W. Rhee, Sang Hoon Perkins, Darren J. Medvedev, Andrei E. Piao, Wenji Fenton, Matthew J. Vogel, Stefanie N. TI TLR4/MyD88/PI3K interactions regulate TLR4 signaling SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE Toll-like receptors; co-immunoprecipitation; lipopolysaccharide; Akt ID NF-KAPPA-B; TOLL-LIKE RECEPTORS; NITRIC-OXIDE SYNTHASE; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; GENE-EXPRESSION; TYROSINE PHOSPHORYLATION; MYD88-DEFICIENT MICE; ADAPTER PROTEIN; MONOCYTIC CELLS AB TLRs activate immune responses by sensing microbial structures such as bacterial LPS, viral RNA, and endogenous "danger" molecules released by damaged host cells. MyD88 is an adapter protein that mediates signal transduction for most TLRs and leads to activation of NF-kappa B and MAPKs and production of proinflammatory cytokines. TLR4-mediated signaling also leads to rapid activation of PI3K, one of a family of kinases involved in regulation of cell growth, apoptosis, and motility. LPS stimulates phosphorylation of Akt, a downstream target of PI3K, in wild-type (WT) mouse macrophages. LPS-induced phosphorylation of Akt serine 473 was blunted in MyD88(-/-) macrophages and was completely TLR4-dependent. MyD88 and p85 were shown previously to co-immunoprecipitate, and a YXXM motif within the Toll-IL-1 resistance (TIR) domain of MyD88 was suggested to be important for this interaction. To test this hypothesis, we compared expressed MyD88 variants with mutations within the YXXM motif or lacking the TIR domain or death domain and measured their capacities to bind PI3K p85, MyD88, and TLR4 by co-immunoprecipitation analyses. The YXXM 3 YXXA mutant MyD88 bound more strongly to p85, TLR4, and WT MyD88 than the other variants, yet was significantly less active than WT MyD88, suggesting that sustained interaction of MyD88/PI3K with the TLR4 intracellular "signaling platform" negatively regulates signaling. We propose a hypothetical model in which sustained PI3K activity at the membrane limits the availability of the PI3K substrate, thereby negatively regulating signaling. J. Leukoc. Biol. 85: 966-977; 2009. C1 [Laird, Michelle H. W.; Perkins, Darren J.; Medvedev, Andrei E.; Piao, Wenji; Vogel, Stefanie N.] Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Fenton, Matthew J.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Rhee, Sang Hoon] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gastroenterol, Boston, MA 02215 USA. RP Fenton, MJ (reprint author), NIAID, NIH, 6610 Rockledge Dr,Room 3105, Bethesda, MD 20892 USA. EM svogel@som.umaryland.edu FU NIAID NIH HHS [AI-059524, AI057490, AI18797, R01 AI018797, R01 AI057490, R01 AI059524, R01 AI059524-03, R01 AI059524-04, R01 AI059524-05, R37 AI018797, R56 AI018797, T32 AI007540] NR 66 TC 118 Z9 122 U1 3 U2 12 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUN 1 PY 2009 VL 85 IS 6 BP 966 EP 977 PG 12 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 453TN UT WOS:000266635900008 PM 19289601 ER PT J AU Wojtanik, KM Edgemon, K Viswanadha, S Lindsey, B Haluzik, M Chen, WP Poy, G Reitman, M Londos, C AF Wojtanik, Kari M. Edgemon, Keith Viswanadha, Srikant Lindsey, Brigette Haluzik, Martin Chen, Weiping Poy, George Reitman, Marc Londos, Constantine TI The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan-type familial partial lipodystrophy mutation SO JOURNAL OF LIPID RESEARCH LA English DT Article DE adipocyte differentiation; insulin resistance; lamin A; lamin C; laminopathies; preadipocyte; type 2 diabetes ID DEPENDENT PROTEIN-KINASE; NUCLEAR LAMIN-A; INSULIN-RESISTANCE; ADIPOCYTE DIFFERENTIATION; METABOLIC COMPLICATIONS; GENDER-DIFFERENCES; GENE-EXPRESSION; R482W MUTATION; RAT ADIPOCYTES; TISSUE AB We investigated the role of LMNA in adipose tissue by developing a novel mouse model of lipodystrophy. Transgenic mice were generated that express the LMNA mutation that causes familial partial lipodystrophy of the Dunnigan type (FPLD2). The phenotype observed in FPLD-transgenic mice resembles many of the features of human FPLD2, including lack of fat accumulation, insulin resistance, and enlarged, fatty liver. Similar to the human disease, FPLD-transgenic mice appear to develop normally, but after several weeks they are unable to accumulate fat to the same extent as their wild-type littermates. One poorly understood aspect of lipodystrophies is the mechanism of fat loss. To this end, we have examined the effects of the FPLD2 mutation on fat cell function. Contrary to the current literature, which suggests FPLD2 results in a loss of fat, we found that the key mechanism contributing to the lack of fat accumulation involves not a loss, but an apparent inability of the adipose tissue to renew itself. Specifically, preadipocytes are unable to differentiate into mature and fully functional adipocytes. These findings provide insights not only for the treatment of lipodystrophies, but also for the study of adipogenesis, obesity, and insulin resistance.-Wojtanik, K. M., K. Edgemon, S. Viswanadha, B. Lindsey, M. Haluzik, W. Chen, G. Poy, M. Reitman, and C. Londos. The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan-type familial partial lipodystrophy mutation. J. Lipid Res. 2009. 50: 1068-1079. C1 [Wojtanik, Kari M.; Edgemon, Keith; Viswanadha, Srikant; Lindsey, Brigette; Londos, Constantine] NIDDK, Cellular & Dev Biol Lab, Bethesda, MD 20892 USA. [Poy, George] NIDDK, Genom Core Lab, Bethesda, MD 20892 USA. [Reitman, Marc] NIDDK, Diabet Branch, Bethesda, MD 20892 USA. RP Wojtanik, KM (reprint author), NIDDK, Cellular & Dev Biol Lab, Bethesda, MD 20892 USA. EM wojtanikk@niddk.nih.gov; keith@edgemon.net; srikantv@glenmarkpharma.com; brigette.lindsey@gmail.com; mhalu@lf1.cuni.cz; marc_reitman@merck.com RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 FU National Institute of Diabetes and Digestive and Kidney Diseases intramural program; National Institutes of Health FX This was work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases intramural program, National Institutes of Health. NR 56 TC 24 Z9 27 U1 0 U2 1 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 JUN PY 2009 VL 50 IS 6 BP 1068 EP 1079 DI 10.1194/jlr.M800491-JLR200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 446IE UT WOS:000266114500005 PM 19201734 ER PT J AU Flanders, KC Wakefield, LM AF Flanders, Kathleen C. Wakefield, Lalage M. TI Transforming Growth Factor-beta s and Mammary Gland Involution; Functional Roles and Implications for Cancer Progression SO JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA LA English DT Review DE TGF-beta; Involution; Microenvironment; Wound-healing response; Pregnancy-associated breast cancer ID PROGRAMMED CELL-DEATH; EPITHELIAL-MESENCHYMAL TRANSITION; FACTOR-BETA-3 MESSENGER-RNA; APOPTOSIS-RELATED PROTEINS; GENE-EXPRESSION SIGNATURE; TGF-BETA; BREAST-CANCER; EXTRACELLULAR-MATRIX; TUMOR-SUPPRESSOR; IN-VITRO AB During rodent mammary gland involution there is a dramatic increase in the expression of the transforming growth factor-beta isoform, TGF-beta 3. The TGF-beta s are multifunctional cytokines which play important roles in wound healing and in carcinogenesis. The responses that are activated in the remodeling of the gland during involution have many similarities with the wound healing process and have been postulated to generate a mammary stroma that provides a microenvironment favoring tumor progression. In this review we will discuss the putative role of TGF-beta during involution, as well as its effects on the mammary microenvironment and possible implications for pregnancy-associated tumorigenesis. C1 [Flanders, Kathleen C.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Flanders, KC (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bldg 37 Rm 5046B,37 Convent Dr, Bethesda, MD 20892 USA. EM flanderk@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 135 TC 42 Z9 43 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1083-3021 J9 J MAMMARY GLAND BIOL JI J. Mammary Gland Biol. Neoplasia PD JUN PY 2009 VL 14 IS 2 BP 131 EP 144 DI 10.1007/s10911-009-9122-z PG 14 WC Oncology; Endocrinology & Metabolism; Physiology SC Oncology; Endocrinology & Metabolism; Physiology GA 456EA UT WOS:000266822000006 PM 19396528 ER PT J AU Brooks, J Ding, J Simon-Sanchez, J Paisan-Ruiz, C Singleton, AB Scholz, SW AF Brooks, J. Ding, J. Simon-Sanchez, J. Paisan-Ruiz, C. Singleton, A. B. Scholz, S. W. TI Parkin and PINK1 mutations in early-onset Parkinson's disease: comprehensive screening in publicly available cases and control SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID GENE; HETEROZYGOSITY; ASSOCIATION; ALLELES; ABNORMALITIES; POPULATION; FREQUENCY; VARIANTS; CARRIERS; NUMBER AB Background: Mutations in parkin and PTEN-induced protein kinase (PINK1) represent the two most common causes of autosomal recessive parkinsonism. The possibility that heterozygous mutations in these genes also predispose to disease or lower the age of disease onset has been suggested, but currently there is insufficient data to verify this hypothesis conclusively. Objective: To study the frequency and spectrum of parkin and PINK1 gene mutations and to investigate the role of heterozygous mutations as a risk factor for early-onset Parkinson's disease (PD). Methods: All exons and exon-intron boundaries of PINK1 and parkin were sequenced in 250 patients with early-onset PD and 276 normal controls. Gene dosage measurements were also performed, using high-density single-nucleotide polymorphism arrays. Results: In total 41 variants were found, of which 8 have not been previously described (parkin: p. A38VfsX6, p.C166Y, p.Q171X, p.D243N, p.M458L; PINK1: p.P52L, p.T420T, p.A427E). 1.60% of patients were homozygous or compound heterozygous for pathogenic mutations. Heterozygosity for pathogenic parkin or PINK1 mutations was over-represented in patients compared with healthy controls (4.00% vs. 1.81%) but the difference was not significant (p=0.13). The mean age at disease onset was significantly lower in patients with homozygous or compound heterozygous mutations than in patients with heterozygous mutations (mean difference 11 years, 95% CI 1.4 to 20.6, p=0.03). There was no significant difference in the mean age at disease onset in heterozygous patients compared with patients without a mutation in parkin or PINK1 (mean difference 2 years, 95% CI -3.7 to 7.0, p=0.54). Conclusions: Our data support a trend towards a higher frequency of heterozygosity for pathogenic parkin or PINK1 mutations in patients compared with normal controls, but this effect was small and did not reach significance in our cohort of 250 cases and 276 controls. C1 [Brooks, J.; Ding, J.; Simon-Sanchez, J.; Singleton, A. B.; Scholz, S. W.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Paisan-Ruiz, C.; Scholz, S. W.] UCL, Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Paisan-Ruiz, C.; Scholz, S. W.] UCL, Inst Neurol, Reta Lila Weston Labs, London WC1N 3BG, England. RP Scholz, SW (reprint author), NIA, Neurogenet Lab, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM scholzs@mail.nih.gov RI Paisan-Ruiz, Coro/C-2912-2009; Singleton, Andrew/C-3010-2009; OI Scholz, Sonja/0000-0002-6623-0429 FU NIH, National Institute on Aging, National Institutes of Health, Department of Health and Human Services, USA [Z01 AG000957-05] FX We thank the participants of this study and the submitters for depositing samples at the Coriell Institute for Medical Research (http://www.coriell.org/). This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging, National Institutes of Health, Department of Health and Human Services, USA (Z-number: Z01 AG000957-05). NR 38 TC 35 Z9 38 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD JUN PY 2009 VL 46 IS 6 BP 375 EP 381 DI 10.1136/jmg.2008.063917 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 452JM UT WOS:000266536300003 PM 19351622 ER PT J AU Lacbawan, F Solomon, BD Roessler, E El-Jaick, K Domene, S Velez, JI Zhou, N Hadley, D Balog, JZ Long, R Fryer, A Smith, W Omar, S McLean, SD Clarkson, K Lichty, A Clegg, NJ Delgado, MR Levey, E Stashinko, E Potocki, L VanAllen, MI Clayton-Smith, J Donnai, D Bianchi, DW Juliusson, PB Njolstad, PR Brunner, HG Carey, JC Hehr, U Musebeck, J Wieacker, PF Postra, A Hennekam, RCM van den Boogaard, MJH van Haeringen, A Paulussen, A Herbergs, J Schrander-Stumpel, CTRM Janecke, AR Chitayat, D Hahn, J McDonald-McGinn, DM Zackai, EH Dobyns, WB Muenke, M AF Lacbawan, F. Solomon, B. D. Roessler, E. El-Jaick, K. Domene, S. Velez, J. I. Zhou, N. Hadley, D. Balog, J. Z. Long, R. Fryer, A. Smith, W. Omar, S. McLean, S. D. Clarkson, K. Lichty, A. Clegg, N. J. Delgado, M. R. Levey, E. Stashinko, E. Potocki, L. VanAllen, M. I. Clayton-Smith, J. Donnai, D. Bianchi, D. W. Juliusson, P. B. Njolstad, P. R. Brunner, H. G. Carey, J. C. Hehr, U. Muesebeck, J. Wieacker, P. F. Postra, A. Hennekam, R. C. M. van den Boogaard, M-J H. van Haeringen, A. Paulussen, A. Herbergs, J. Schrander-Stumpel, C. T. R. M. Janecke, A. R. Chitayat, D. Hahn, J. McDonald-McGinn, D. M. Zackai, E. H. Dobyns, W. B. Muenke, M. TI Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID HUMAN SIX3 GENE; CALIFORNIA POPULATION; FOREBRAIN DEVELOPMENT; VENTRAL FOREBRAIN; EYE DEVELOPMENT; NEURAL PLATE; EXPRESSION; DEFECTS; BRAIN; SPECIFICATION AB Background: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. Objective: To characterise genetic and clinical findings in patients with SIX3 mutations. Methods: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. Results: In a cohort of patients (n=800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of nonchromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. Conclusions: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models. C1 [Lacbawan, F.; Solomon, B. D.; Roessler, E.; El-Jaick, K.; Domene, S.; Velez, J. I.; Zhou, N.; Hadley, D.; Balog, J. Z.; Long, R.; Muenke, M.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Lacbawan, F.] SUNY Hlth Sci Ctr, Dept Pathol, Brooklyn, NY 11203 USA. [Fryer, A.] Royal Liverpool Childrens Hosp Alder Hey, Dept Clin Genet, Liverpool, Merseyside, England. [Smith, W.] Maine Med Ctr, Dept Genet, Portland, ME 04102 USA. [Omar, S.] Michigan State Univ, Coll Human Med, Dept Neonatol, E Lansing, MI 48824 USA. [McLean, S. D.] San Antonio Mil Med Ctr, Dept Pediat, San Antonio, TX USA. [McLean, S. D.] San Antonio Mil Med Ctr, Dept Genet, San Antonio, TX USA. [Clarkson, K.; Lichty, A.] Greenwood Genet Ctr, Dept Clin Genet, Columbia, SC USA. [Clegg, N. J.; Delgado, M. R.] Univ Texas SW Med Ctr Dallas, Texas Scottish Rite Hosp Children, Dept Neurol, Dallas, TX 75390 USA. [Levey, E.; Stashinko, E.] Johns Hopkins Univ, Kennedy Krieger Inst, Baltimore, MD USA. [Potocki, L.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Potocki, L.] Texas Childrens Hosp, Houston, TX 77030 USA. [VanAllen, M. I.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Clayton-Smith, J.; Donnai, D.] Univ Manchester, St Marys Hosp, Acad Dept Med Genet, Manchester M13 0JH, Lancs, England. [Clayton-Smith, J.; Donnai, D.] Univ Manchester, St Marys Hosp, Reg Genet Serv, Manchester M13 0JH, Lancs, England. [Bianchi, D. W.] Tufts Univ, Sch Med, Dept Pediat, Div Genet, Boston, MA 02111 USA. [Juliusson, P. B.; Njolstad, P. R.] Haukeland Hosp, Dept Paediat, N-5021 Bergen, Norway. [Njolstad, P. R.] Univ Bergen, Dept Clin Med, Bergen, Norway. [Brunner, H. G.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Carey, J. C.] Univ Utah, Med Ctr, Div Med Genet, Salt Lake City, UT USA. [Hehr, U.] Univ Regensburg, Dept Human Genet, Regensburg, Germany. [Muesebeck, J.] Univ Bremen, Ctr Human Genet, Bremen, Germany. [Wieacker, P. F.] Univ Munster, Inst Human Genet, D-4400 Munster, Germany. [Postra, A.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Hennekam, R. C. M.] Great Ormond St Hosp Sick Children, Inst Child Hlth, London WC1N 3JH, England. [van den Boogaard, M-J H.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [van Haeringen, A.] Leiden Univ, Med Ctr, Dept Human & Clin Genet, Leiden, Netherlands. [Paulussen, A.; Herbergs, J.; Schrander-Stumpel, C. T. R. M.] Univ Limburg, Acad Hosp Maastricht, Dept Clin Genet, Maastricht, Netherlands. [Janecke, A. R.] Innsbruck Med Univ, Div Clin Genet, Innsbruck, Austria. [Chitayat, D.] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Hahn, J.] Stanford Univ, Sch Med, Dept Neurol, Palo Alto, CA 94304 USA. [McDonald-McGinn, D. M.; Zackai, E. H.] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA. [Dobyns, W. B.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Dobyns, W. B.] Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. [Dobyns, W. B.] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov RI Brunner, Han/C-9928-2013; OI Janecke, Andreas/0000-0001-7155-0315; Dobyns, William/0000-0002-7681-2844 FU Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, USA FX This research was supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, USA NR 53 TC 39 Z9 41 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 JUN PY 2009 VL 46 IS 6 BP 389 EP 398 DI 10.1136/jmg.2008.063818 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 452JM UT WOS:000266536300005 PM 19346217 ER PT J AU Madeo, AC Manichaikul, A Pryor, SP Griffith, AJ AF Madeo, A. C. Manichaikul, A. Pryor, S. P. Griffith, A. J. TI Do mutations of the Pendred syndrome gene, SLC26A4, confer resistance to asthma and hypertension? SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID GENOTYPE-PHENOTYPE CORRELATION; HEARING-LOSS; PDS; ENLARGEMENT; DISEASE; KIDNEY AB Background and aims: Mutations of SLC26A4 cause Pendred syndrome, an autosomal recessive disorder comprising goitre and deafness with enlarged vestibular aqueducts (EVA). Recent studies in mouse models implicate Slc26a4 in the pathogenesis of asthma and hypertension. We hypothesise that asthma and hypertension are less prevalent among humans with SLC26A4 mutations. Methods: We reviewed medical histories and SLC26A4 genotypes for 80 individuals with EVA and 130 of their unaffected family members enrolled in a study of EVA. We used Fisher's exact test to compare the prevalence of asthma and hypertension among groups of subjects with zero, one, or two mutant alleles of SLC26A4. Results: Although none of the 21 subjects with two mutant alleles of SLC26A4 had asthma or hypertension, there were no statistically significant differences in the prevalence of asthma or hypertension among subjects with zero, one, or two mutant alleles. Conclusion: There might be a protective effect of SLC26A4 mutations for asthma and hypertension but our study is statistically underpowered to detect this effect. Study sizes of at least 1125 and 504 individuals will be needed for 80% power to detect an effect at alpha=0.05 for asthma and hypertension, respectively. Our hypothesis merits a larger study since it has implications for potential strategies to treat hearing loss by manipulating SLC26A4 expression or function. C1 [Madeo, A. C.; Pryor, S. P.; Griffith, A. J.] Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD 20850 USA. [Madeo, A. C.] NHGRI, NIH, Bethesda, MD 20892 USA. [Manichaikul, A.] Univ Virginia, Dept Biomed Engn, Charlottesville, VA USA. RP Griffith, AJ (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 5 Res Court, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov RI Manichaikul, Ani/B-7726-2009; Madeo, Anne/K-2880-2012 FU NIH [Z01-DC000060, Z01-DC000064]; National Human Genome Research Institute FX We are supported by NIH intramural research funds Z01-DC000060 and Z01-DC000064 and the Intramural Research Program of the National Human Genome Research Institute. NR 19 TC 12 Z9 13 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 JUN PY 2009 VL 46 IS 6 BP 405 EP 406 DI 10.1136/jmg.2008.063610 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 452JM UT WOS:000266536300007 PM 19289392 ER PT J AU Yadav, M Jain, S Bhardwaj, A Nagpal, R Puniya, M Tomar, R Singh, V Parkash, O Prasad, GBKS Marotta, F Yadav, H AF Yadav, Mukesh Jain, Shalini Bhardwaj, Aarti Nagpal, Ravinder Puniya, Monica Tomar, Radha Singh, Vinod Parkash, Om Prasad, G. B. K. S. Marotta, Francesco Yadav, Hariom TI Biological and Medicinal Properties of Grapes and Their Bioactive Constituents: An Update SO JOURNAL OF MEDICINAL FOOD LA English DT Review DE biological functions; grapes; phytochemicals; resveratrol ID MAMMARY EPITHELIAL-CELLS; BREAST-CANCER CELLS; OXIDATIVE STRESS; RED WINE; SIGNALING PATHWAY; PROSTATE-CANCER; NATURAL-PRODUCT; VITIS-VINIFERA; SEED EXTRACT; NITRIC-OXIDE AB The grape is one of the most valued conventional fruits, worldwide. Although most of the parts of the grapevine are useful, primarily, the grape is considered as a source of unique natural products not only for the development of valuable medicines against a number of diseases, but also for manufacturing various industrial products. Over the last few decades, apart from the chemistry of grape compounds, considerable progress has been made towards exploring the biological activities of various grape-derived constituents. Today, it is well established that in addition to serving as food, the grape is a major source of several phytochemicals. The main biologically active and well-characterized constituent from the grape is resveratrol, which is known for various medicinal properties in human diseases. This review discusses the roles of various grape-derived phytochemicals in relation to various diseases. C1 [Yadav, Hariom] NIDDK, Biol Sect, Diabet Branch, NIH,Clin Res Ctr,West Labs, Bethesda, MD 20892 USA. [Yadav, Mukesh; Tomar, Radha] Jiwaji Univ, SOS Chem, Gwalior, India. [Prasad, G. B. K. S.] Jiwaji Univ, SOS Biochem, Gwalior, India. [Singh, Vinod] Barkatullah Univ, Dept Microbiol, Bhopal 462026, Madhya Pradesh, India. [Bhardwaj, Aarti] Meerut Inst Engn & Technol, Meerut, Uttar Pradesh, India. [Parkash, Om] Natl JALMA Inst Leprosy & Other Mycobacterial Dis, Agra, Uttar Pradesh, India. [Nagpal, Ravinder; Puniya, Monica] Natl Dairy Res Inst, Karnal 132001, Haryana, India. [Jain, Shalini] Univ Illinois, Urbana, IL 61801 USA. [Marotta, Francesco] GAIA Fdn, Nutraceut Nutragen Unit, Milan, Italy. RP Yadav, H (reprint author), NIDDK, Biol Sect, Diabet Branch, NIH,Clin Res Ctr,West Labs, Bldg 10,5-5872,South Dr & Old Georgetown Rd, Bethesda, MD 20892 USA. EM yadavhariom@gmail.com OI Yadav, Hariom/0000-0003-4504-1597 NR 81 TC 49 Z9 50 U1 6 U2 20 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-620X J9 J MED FOOD JI J. Med. Food PD JUN PY 2009 VL 12 IS 3 BP 473 EP 484 DI 10.1089/jmf.2008.0096 PG 12 WC Chemistry, Medicinal; Food Science & Technology; Nutrition & Dietetics SC Pharmacology & Pharmacy; Food Science & Technology; Nutrition & Dietetics GA 474BA UT WOS:000268256000002 PM 19627194 ER PT J AU Jain, S Yadav, H Sinha, PR AF Jain, Shalini Yadav, Hariom Sinha, P. R. TI Probiotic Dahi Containing Lactobacillus casei Protects Against Salmonella enteritidis Infection and Modulates Immune Response in Mice SO JOURNAL OF MEDICINAL FOOD LA English DT Article DE dahi; immunodulatory; lymphocyte proliferation; mice; probiotic; Salmonella ID LACTIC-ACID BACTERIA; HIGH-FRUCTOSE DIET; LACTOCOCCUS-LACTIS; FERMENTED MILK; FATTY-ACIDS; RATS; CYTOKINE; PROLIFERATION; INTERFERON; INGESTION AB In the present study, effect of dahi containing probiotic Lactobacillus casei (probiotic dahi) was evaluated to modulate immune response against Salmonella enteritidis infection in mice. Animals were fed with milk products along with standard diet for 2 and 7 days prior to the S. enteritidis challenge and continued on the respective dairy food-supplemented diets during the postchallenge period. Translocation of S. enteritidis in spleen and liver, beta-galactosidase and beta-glucuronidase enzymatic activities and secretory IgA (sIgA) in intestinal fluid, lymphocyte proliferation, and cytokine ( interleukin [IL]-2, IL-4, IL-6, and interferon-gamma [IFN-gamma]) production in cultured splenocytes were assessed on day 2, 5, and 8 of the postchallenge period. Colonization of S. enteritidis in liver and spleen was remarkably low in probiotic dahi-fed mice than mice fed milk and control dahi. The beta-galactosidase and beta-glucuronidase activities in intestinal fluid collected from mice prefed for 7 days with probiotic dahi were significantly lower at day 5 and 8 postchallenge than in mice fed milk and control dahi. Levels of sIgA and lymphocyte proliferation rate were also significantly increased in probiotic dahi-fed mice compared with the other groups. Production of IL-2, IL-6, and IFN-gamma increased, whereas IL-4 decreased in splenic lymphocytes collected from probiotic dahi-fed mice. Data showed that dahi prefed for 7 days before S. enteritidis challenge was more effective than when mice were prefed for 2 days with dahi. Moreover, probiotic dahi was more efficacious in protecting against S. enteritidis infection by enhancing innate and adaptive immunity than fermented milk and normal dahi. Results of the present study suggest that prefeeding of probiotic dahi may strengthen the consumer's immune system and may protect infectious agents like S. enteritidis. C1 [Jain, Shalini; Yadav, Hariom; Sinha, P. R.] Natl Dairy Res Inst, Anim Biochem Div, Karnal 132001, Haryana, India. RP Jain, S (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bldg 8, Bethesda, MD 20892 USA. EM shalinif@mail.nih.gov OI Yadav, Hariom/0000-0003-4504-1597 NR 37 TC 23 Z9 25 U1 0 U2 8 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-620X J9 J MED FOOD JI J. Med. Food PD JUN PY 2009 VL 12 IS 3 BP 576 EP 583 DI 10.1089/jmf.2008.0246 PG 8 WC Chemistry, Medicinal; Food Science & Technology; Nutrition & Dietetics SC Pharmacology & Pharmacy; Food Science & Technology; Nutrition & Dietetics GA 474BA UT WOS:000268256000014 PM 19627206 ER PT J AU Murphy, E Bers, D Rizzuto, R AF Murphy, Elizabeth Bers, Donald Rizzuto, Rosario TI Mitochondria: From basic biology to cardiovascular disease SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Editorial Material ID CYCLOSPORINE-A; CALCIUM; HEART; ISCHEMIA; INJURY; CA2+ C1 [Murphy, Elizabeth] NHLBI, NIH, Bethesda, MD 20892 USA. [Bers, Donald] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA. [Rizzuto, Rosario] Univ Padua, I-35100 Padua, Italy. RP Murphy, E (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM tmurphy92@verizon.net RI Bers, Donald/C-4507-2012; OI Rizzuto, Rosario/0000-0001-7044-5097; Bers, Donald/0000-0002-2237-9483 FU Intramural NIH HHS [Z99 HL999999] NR 27 TC 6 Z9 6 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2009 VL 46 IS 6 BP 765 EP 766 DI 10.1016/j.yjmcc.2009.03.004 PG 2 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 449SU UT WOS:000266351100001 PM 19289126 ER PT J AU Balaban, RS AF Balaban, Robert S. TI Domestication of the cardiac mitochondrion for energy conversion SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Review DE Calcium; Phosphate; Phospho-proteins; Sarcoplasmic reticulum; Dehydrogenases; Potential energy; Homeostasis; F1-F0-ATPase; Homeostasis; Potential energy; Oxygen consumption; Membrane potential ID FATTY-ACID OXIDATION; BOVINE HEART-MITOCHONDRIA; ATPASE INHIBITOR PROTEIN; P-31 NMR-SPECTROSCOPY; KINASE KNOCKOUT MICE; PERFUSED RAT HEARTS; CORONARY BLOOD-FLOW; CREATINE-KINASE; IN-VIVO; INORGANIC-PHOSPHATE AB The control of mitochondria energy conversion by cytosolic processes is reviewed. The nature of the cytosolic and mitochondrial potential energy homeostasis over wide ranges of energy utilization is reviewed and the consequences of this homeostasis in the control network are discussed. An analysis of the major candidate cytosolic signaling molecules ADP, Pi and Ca2+ are reviewed based on the magnitude and source of the cytosolic concentration changes as well as the potential targets of action within the mitochondrial energy conversion system. Based on this analysis, Ca2+ is the best candidate as a cytosolic signaling molecule for this process based on its ability to act as both a feedforward and feedback indicator of ATP hydrolysis and numerous targets within the matrix to provide a balanced activation of ATP production. These targets include numerous dehydrogenases and the F1-F0-ATPase. Pi is also a good candidate since it is an early signal of a mismatch between cytosolic ATP production and ATP synthesis in the presence of creatine kinase and has multiple targets within oxidative phosphorylation including NADH generation, electron flux in the cytochrome chain and a substrate for the F1-F0-ATPase. The mechanism of the coordinated activation of oxidative phosphorylation by these signaling molecules is discussed in light of the recent discoveries of extensive protein phosphorylation sites and other post-translational modifications. From this review it is clear that the control network associated with the maintenance of the cytosolic potential energy homeostasis is extremely complex with multiple pathways orchestrated to balance the sinks and sources in this system. New tools are needed to image and monitor metabolites within sub-cellular compartments to resolve many of these issues as well as the functional characterization of the numerous matrix post-translational events being discovered along with the enzymatic processes generating and removing these protein modifications. Published by Elsevier Inc. C1 NHLBI, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Balaban, RS (reprint author), NHLBI, Cardiac Energet Lab, Bethesda, MD 20892 USA. EM rsb@nih.gov FU Intramural NIH HHS [Z01 HL004601-20] NR 135 TC 43 Z9 44 U1 1 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2009 VL 46 IS 6 BP 832 EP 841 DI 10.1016/j.yjmcc.2009.02.018 PG 10 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 449SU UT WOS:000266351100009 PM 19265699 ER PT J AU Sack, MN AF Sack, Michael N. TI Type 2 diabetes, mitochondrial biology and the heart SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Review DE Mitochondria; Diabetic cardiomyopathy; Type 2 diabetes; Db/db; Ob/ob ID PROLIFERATOR-ACTIVATED-RECEPTOR; FATTY-ACID OXIDATION; MUSCLE INSULIN-RESISTANCE; LEFT-VENTRICULAR FUNCTION; OB/OB MOUSE HEARTS; SKELETAL-MUSCLE; MYOCARDIAL-INFARCTION; CARDIAC DYSFUNCTION; DB/DB MICE; RAT-HEART AB Diabetes is recognized as an independent risk factor for cardiovascular morbidity and mortality. This is due, in large part, to premature atherosclerosis, enhanced thrombogenicity and activation of systemic inflammatory programs with resultant vascular dysfunction. More enigmatic mechanisms underpinning diabetes-associated cardiac pathophysiology include the direct metabolic consequences of this disease on the myocardium. Nevertheless, a role for diabetes-associated disruption in cardiac contractile mechanics and in increasing cardiomyocyte susceptibility to ischemic-stress has been implicated independent of vascular pathology. This review will focus broadly on the direct effects of diabetes on the cardiac myocardium with more specific reference to the role of the modulation of cardiomyocyte mitochondrial function in these disease processes. This focus in part, stems from the growing recognition that in some instances mitochondrial dysfunction is central to the development of insulin resistance and diabetes, and in others, diabetes associated disruption in mitochondrial function exacerbates and accentuates the pathophysiology of diabetes. Published by Elsevier Inc. C1 [Sack, Michael N.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Sack, MN (reprint author), Bld 10 CRC,Room 5-3150,10 Ctr Dr,MSC 1454, Bethesda, MD 20892 USA. EM sackm@nhlbi.nih.gov FU NHLBI Division of Intramural Research FX The author is funded by the NHLBI Division of Intramural Research. This review stems, in part, from a recent National Institute of Health and Society of Heart and Vascular Metabolism funded symposium exploring the role of mitochondrial biology in cardiac physiology and disease. NR 125 TC 28 Z9 29 U1 1 U2 12 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2009 VL 46 IS 6 BP 842 EP 849 DI 10.1016/j.yjmcc.2009.02.001 PG 8 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 449SU UT WOS:000266351100010 PM 19217910 ER PT J AU Bodiga, S Zhang, R Jacobs, DE Larsen, BT Tampo, A Manthati, VL Kwok, WM Zeldin, DC Falck, JR Gutterman, DD Jacobs, ER Medhora, MM AF Bodiga, Sreedhar Zhang, Rong Jacobs, Dexter E. Larsen, Brandon T. Tampo, Akihito Manthati, Vijay L. Kwok, Wai-Meng Zeldin, Darryl C. Falck, John R. Gutterman, David D. Jacobs, Elizabeth R. Medhora, Meetha M. TI Protective actions of epoxyeicosatrienoic acid: Dual targeting of cardiovascular PI3K and K-ATP channels SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Human myocardium; Pulmonary artery; Hypoxia/reoxygenation; Mitochondrial membrane potential; Epoxide hydrolase; Lactate dehydrogenase release ID SOLUBLE EPOXIDE HYDROLASE; SENSITIVE POTASSIUM CHANNELS; ARACHIDONIC-ACID; ISCHEMIA/REPERFUSION INJURY; ENDOTHELIAL-CELLS; VENTRICULAR MYOCYTES; REPERFUSION INJURY; INDUCED APOPTOSIS; OXIDATIVE STRESS; SURVIVAL PATHWAY AB Epoxyeicosatrienoic acid(s) (EETs) have been shown to protect cardiovascular tissue against apoptosis dependent on activation of targets such as ATP-sensitive K+ (K-ATP) channels (sarcolemmal and mitochondrial), calciumactivated K+ channels, extracellular signal-regulated kinase or phosphoinositide 3-kinase (PI3K).Wetested if EETs protect human atrial tissue ex vivo from hypoxia/reoxyge nation (H/R) injury and compared our results with myocardium from two rodent species, rats and mice. EETs reduced myocardial caspase 3 activity in all three species and protected against loss of mitochondrial membrane potential in primary cultures of neonatal rat ventricular myocytes submitted to H/R. In addition, EETs protected mouse pulmonary arteries ex vivo exposed to H/R. Myocardium and pulmonary arteries from genetically engineered mice having elevated plasma levels of EETs (Ephx2(-/-)) exhibited protection from H/R-induced injury over that of wild type controls, suggesting that endogenously produced EETs may have pro-survival effects. Electrophysiological studies in myocytes demonstrated that EETs can stimulate K-ATP currents even when PI3K is inhibited. Similarly, activation of PI3K/Akt occurred in the presence of the K-ATP channel blocker glibenclamide. Based upon loss of protection with EETs in the presence of either wortmannin (a PI3K inhibitor) or glibenclarmide, simultaneous activation of at least 2 pathways, PI3K and K-ATP channels respectively, appears to be required for protection. In conclusion, we demonstrate that exogenous and endogenous EETs have powerful pro-survival effects in cardiovascular tissues including diseased human myocardium, mediated by activation of not only one but at least two pathways, PI3K and K-ATP channels. (C) 2009 Elsevier Inc All rights reserved. C1 [Bodiga, Sreedhar] Med Coll Wisconsin, Ctr Cardiovasc, Milwaukee, WI 53226 USA. [Gutterman, David D.] Vet Affairs Med Ctr, Milwaukee, WI USA. [Manthati, Vijay L.; Falck, John R.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Zhang, Rong] Harbin Med Univ, Dept Pharmacol, Coll Pharm, Harbin 150081, Peoples R China. RP Bodiga, S (reprint author), Med Coll Wisconsin, Ctr Cardiovasc, MEB M4780,8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM sbodiga@mcw.edu OI Falck, John/0000-0002-9219-7845; Bodiga, Sreedhar/0000-0001-5692-7700 FU Intramural NIH HHS [Z01 ES025034-13, Z01 ES025034-14]; NHLBI NIH HHS [HL-68769, HL069996, HL49294, HL68627, P01 HL068769, P01 HL068769-050002, R01 HL049294, R01 HL049294-14, R01 HL068627, R01 HL068627-05, R01 HL069996, R01 HL069996-04]; NIGMS NIH HHS [GM 31278, R01 GM031278, R01 GM031278-24S1] NR 51 TC 28 Z9 28 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2009 VL 46 IS 6 BP 978 EP 988 DI 10.1016/j.yjmcc.2009.01.009 PG 11 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 449SU UT WOS:000266351100026 PM 19336274 ER PT J AU Daly, JW Ware, N Saporito, RA Spande, TF Garraffo, HM AF Daly, John W. Ware, Nathaniel Saporito, Ralph A. Spande, Thomas F. Garraffo, H. Martin TI N-Methyldecahydroquinolines: An Unexpected Class of Alkaloids from Amazonian Poison Frogs (Dendrobatidae) SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID SKIN ALKALOIDS; ARTHROPOD SOURCE; DIETARY SOURCE; DECAHYDROQUINOLINES; PUMILIOTOXINS; ANTS; CLASSIFICATION; INDOLIZIDINES; SOLENOPSIS; AMPHIBIA AB The dominant alkaloids previously identified in skin extracts of Amazonian dendrobatid frogs of the genus Ameerega are histrionicotoxins and 2,5-disubstituted decahydroquinolines. Analysis of alkaloids in skin extracts of Ameerega picta from Bolivia revealed that the alkaloid 257A, previously reported as a 2,5-disubstituted decahydroquinoline, is an N-methyl-2,5-disubstituted decahydroquinoline. We. characterized alkaloids of another 12 of the more than 25 species recently assigned to the genus Ameerega, and five additional N-methyldecahydroquinolines were identified. In some cases, the relative configuration of the N-methyldecahydroquinolines was determined by comparison with the N-methylated products prepared from the corresponding 2,5-disubstituted decahydroquinolines of known relative configuration. A dietary source for N-methyldecahydroquinolines is unknown; however, myrmicine ants are the likely source for the 2,5-disubstituted decahydroquinolines. The alkaloids in skin extracts of three species of another genus of Amazonian poison frog, Adelphobates, were also characterized, but N-methyldecahydroquinolines were not detected. C1 [Daly, John W.; Ware, Nathaniel; Spande, Thomas F.; Garraffo, H. Martin] NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Saporito, Ralph A.] Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA. RP Garraffo, HM (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. EM garraffo@helix.nih.gov FU NIH; National Science Foundation Postdoctoral Fellowship; NIDDK FX The authors wish to thank J. P. Caldwell, V. Ennenbach, J. Frenkel, D. Mebs, C. W. Myers, C. Nishihira, R. SchLultes, G. Skuk, and A. Wisnieski for generously providing skin samples of various dendrobatid frogs, T. Grant for thoughtful discussions that improved the quality of the manuscript, and S. Reichle for generously providing the photo of A. picta in the graphical abstract. N.W. was an NIH student intern, and R.A.S. was supported at NIH by a Courtesy Associate appointment. A National Science Foundation Postdoctoral Fellowship also supported R.A.S. The intramural research program of NIDDK funded all research. NR 26 TC 7 Z9 7 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD JUN PY 2009 VL 72 IS 6 BP 1110 EP 1114 DI 10.1021/np900094v PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 463LB UT WOS:000267432600024 PM 19432407 ER PT J AU Zhang, HR Chen, FL Xu, CP Ping, YF Wang, QL Liang, ZQ Wang, JM Bian, XW AF Zhang, Hua-rong Chen, Fei-lan Xu, Chen-ping Ping, Yi-fang Wang, Qing-liang Liang, Zi-qing Wang, Ji Ming Bian, Xiu-wu TI Incorporation of endothelial progenitor cells into the neovasculature of malignant glioma xenograft SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Endothelial progenitor cells; Glioma; Angiogenesis; Vasculogenesis ID MARROW-DERIVED CELLS; POSTNATAL NEOVASCULARIZATION; CLINICAL-TRIALS; CANCER-PATIENTS; STEM-CELLS; ANGIOGENESIS; THERAPY; BLOOD; VASCULOGENESIS; PITFALLS AB Endothelial progenitor cells (EPCs) are important initiators of vasculogenesis in the process of tumor neovascularization. However, it is unclear how circulating EPCs contribute to the formation of tumor microvessels. In this study, we isolated CD34(+)/CD133(+) cells from human umbilical cord blood (HUCB) and obtained EPCs with the capacities of forming colonies, uptaking acetylated low-density lipoprotein (ac-LDL), binding lectins and expressing vascular endothelial growth factor (VEGF) receptor 2 (VEGFR-2, KDR), CD31 and von Willebrand factor (vWF). These EPCs were actively proliferative and migratory, and could formed capillary-like tubules in response to VEGF. When injected into mice bearing subcutaneously implanted human malignant glioma, EPCs specifically accumulated at the sites of tumors and differentiated into mature endothelial cells (ECs), which accounted for 18% ECs of the tumor microvessels. The incorporation of circulating EPCs into tumor vessel walls significantly affected the morphology and structure of the vasculature. Our results suggest that circulating EPCs constitute important components of tumor microvessel network and contribute to tumor microvascular architecture phenotype heterogeneity. C1 [Zhang, Hua-rong; Chen, Fei-lan; Xu, Chen-ping; Ping, Yi-fang; Wang, Qing-liang; Bian, Xiu-wu] Third Mil Med Univ, Inst Pathol, Southwest Hosp, Chongqing 400038, Peoples R China. [Zhang, Hua-rong; Chen, Fei-lan; Xu, Chen-ping; Ping, Yi-fang; Wang, Qing-liang; Bian, Xiu-wu] Third Mil Med Univ, Southwest Hosp, SW Canc Ctr, Chongqing 400038, Peoples R China. [Liang, Zi-qing] Third Mil Med Univ, Southwest Hosp, Dept Obstet & Gynecol, Chongqing 400038, Peoples R China. [Wang, Ji Ming] Natl Canc Inst, Ctr Canc Res, Canc & Inflammat Program, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Bian, XW (reprint author), Third Mil Med Univ, Inst Pathol, Southwest Hosp, Chongqing 400038, Peoples R China. EM bianxiuwu@263.net RI Bian, Xiuwu/F-1569-2011; Bian, Xiu-wu/D-4736-2017 OI Bian, Xiu-wu/0000-0003-4383-0197 FU National Basic Research Program of China (973 Program) [2006CB708503]; Outstanding Scholar Fellowship [06J012] FX We thank Mrs Wei Sun and Miss Li-Ting Wang (Central Laboratory, Third Military Medical University, Chongqing, China) for their technical assistance in laser confocal scanning microscopy. This study was supported by grants from the National Basic Research Program of China (973 Program, No. 2006CB708503) and the Outstanding Scholar Fellowship of P. L. A. (No. 06J012). NR 34 TC 19 Z9 20 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JUN PY 2009 VL 93 IS 2 BP 165 EP 174 DI 10.1007/s11060-008-9757-4 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 446SP UT WOS:000266141700001 PM 19052696 ER PT J AU Wheeler, D Knapp, E Bandaru, VVR Wang, Y Knorr, D Poirier, C Mattson, MP Geiger, JD Haughey, NJ AF Wheeler, David Knapp, Edward Bandaru, Veera V. R. Wang, Yue Knorr, David Poirier, Christophe Mattson, Mark P. Geiger, Jonathan D. Haughey, Norman J. TI Tumor necrosis factor-alpha-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE ceramide; diacylglycerol; lipid raft; NMDA; receptor trafficking; tumor necrosis factor ID GLIAL TNF-ALPHA; OXIDATIVE STRESS; LIPID RAFTS; HIPPOCAMPAL-NEURONS; ALZHEIMERS-DISEASE; ADULT HIPPOCAMPUS; TRAFFICKING; CERAMIDE; AMPA; SYNAPSES AB The insertion and removal of NMDA receptors from the synapse are critical events that modulate synaptic plasticity. While a great deal of progress has been made on understanding the mechanisms that modulate trafficking of NMDA receptors, we do not currently understand the molecular events required for the fusion of receptor containing vesicles with the plasma membrane. Here, we show that sphingomyelin phosphodiesterase 3 (also known as neutral sphingomyelinase-2) is critical for tumor necrosis factor (TNF) alpha-induced trafficking of NMDA receptors and synaptic plasticity. TNF alpha initiated a rapid increase in ceramide that was associated with increased surface localization of NMDA receptor NR1 subunits and a specific clustering of NR1 phosphorylated on serines 896 and 897 into lipid rafts. Brief applications of TNF alpha increased the rate and amplitude of NMDA-evoked calcium bursts and enhanced excitatory post-synaptic currents. Pharmacological inhibition or genetic mutation of neutral sphingomyelinase-2 prevented TNF alpha-induced generation of ceramide, phosphorylation of NR1 subunits, clustering of NR1, enhancement of NMDA-evoked calcium flux and excitatory post-synaptic currents. C1 [Wheeler, David; Knapp, Edward; Bandaru, Veera V. R.; Haughey, Norman J.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. [Wang, Yue; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Knorr, David; Geiger, Jonathan D.] Univ N Dakota, Dept Physiol Pharmacol & Therapeut, Grand Forks, ND 58201 USA. [Poirier, Christophe] Med Coll Georgia, Vasc Biol Ctr, Augusta, GA 30912 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA. RP Haughey, NJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Meyer 6-109,600 N Wolfe St, Baltimore, MD 21287 USA. EM nhaughe1@jhmi.edu RI Mattson, Mark/F-6038-2012 FU NIH [AG023471, MH077542, AA017408]; National Institute of Aging FX This research was supported by NIH grants AG023471, MH077542 and AA017408 to NJH and the Intramural Research Program of the National Institute of Aging. NR 52 TC 78 Z9 80 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2009 VL 109 IS 5 BP 1237 EP 1249 DI 10.1111/j.1471-4159.2009.06038.x PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 443UB UT WOS:000265935200005 PM 19476542 ER PT J AU Tian, F Hu, XZ Wu, X Jiang, H Pan, HN Marini, AM Lipsky, RH AF Tian, Feng Hu, Xian-Zhang Wu, Xuan Jiang, Hong Pan, Hongna Marini, Ann M. Lipsky, Robert H. TI Dynamic chromatin remodeling events in hippocampal neurons are associated with NMDA receptor-mediated activation of Bdnf gene promoter 1 SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE BDNF; chromatin; gene; histone; NMDA; transcription factor ID CPG-BINDING-PROTEINS; METHYL-D-ASPARTATE; NEUROTROPHIC FACTOR TRANSCRIPTS; HISTONE LYSINE METHYLATION; LONG-TERM POTENTIATION; NF-KAPPA-B; SYNAPTIC PLASTICITY; DNA METHYLATION; EPIGENETIC REGULATION; MEMORY FORMATION AB To determine the epigenetic events associated with NMDA receptor-mediated activation of brain-derived neurotrophic factor gene (Bdnf) promoter 1 by hippocampal neurons in culture, we screened 12 loci across 4.5 kb of genomic DNA 5' of the transcription start site (TSS) of rat Bdnf for specific changes in histone modification and transcription factor binding following NMDA receptor stimulation. Chromatin immunoprecipitation (ChIP) assays showed that NMDA receptor stimulation produced a durable, time-dependent decrease in histone H3 at lysine 9 dimethylation (H3K9me2), within 3 h after NMDA treatment across multiple loci. Concomitant increases in H3K4me2 and H3K9/14 acetylation (H3AcK9/14) were associated with transcriptional activation, but occurred at fewer sites within the promoter. The decrease in H3K9me2 was associated with release of HDAC1, MBD1, MeCP2, and REST from specific locations within promoter 1, although with different kinetics. In addition, occupancy of sites proximal to and distal to the TSS by the transcription factors NF-kappa B, CREB-binding protein (CBP), and cAMP-response element-binding protein were correlated with increased occupancy of RNA polymerase II at two loci proximal to the TSS following NMDA receptor stimulation. These temporal changes in promoter occupancy could occur thousands of base pairs 5' of the TSS, suggesting a mechanism that produces waves of Bdnf transcription. C1 [Tian, Feng; Lipsky, Robert H.] NIAAA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD USA. [Hu, Xian-Zhang; Wu, Xuan; Jiang, Hong; Pan, Hongna; Marini, Ann M.] Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. [Hu, Xian-Zhang; Wu, Xuan; Jiang, Hong; Pan, Hongna; Marini, Ann M.] Uniformed Serv Univ Hlth Sci, Program Neurosci, Bethesda, MD 20814 USA. RP Lipsky, RH (reprint author), 3300 Gallows Rd, Falls Church, VA 22042 USA. EM robert.lipsky@inova.org OI Lipsky, Robert/0000-0001-7753-1473 FU NIH [NIAAA Z01-AA00325]; Defense Brain and Spinal Cord Injury Program (AMM) [F-192EG-C1] FX This study was supported by NIH intramural grant NIAAA Z01-AA00325 (RHL) and extramural grant F-192EG-C1 from the Defense Brain and Spinal Cord Injury Program (AMM). NR 68 TC 36 Z9 38 U1 0 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2009 VL 109 IS 5 BP 1375 EP 1388 DI 10.1111/j.1471-4159.2009.06058.x PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 443UB UT WOS:000265935200016 PM 19476549 ER PT J AU Cabello, N Gandia, J Bertarelli, DCG Watanabe, M Lluis, C Franco, R Ferre, S Lujan, R Ciruela, F AF Cabello, Nuria Gandia, Jorge Bertarelli, Daniela C. G. Watanabe, Masahiko Lluis, Carme Franco, Rafael Ferre, Sergi Lujan, Rafael Ciruela, Francisco TI Metabotropic glutamate type 5, dopamine D-2 and adenosine A(2a) receptors form higher-order oligomers in living cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE adenosine; dopamine; G protein-coupled receptors; glutamate; receptor oligomerization ID PROTEIN-COUPLED RECEPTORS; BIMOLECULAR FLUORESCENCE COMPLEMENTATION; BIOLUMINESCENCE ENERGY-TRANSFER; CENTRAL-NERVOUS-SYSTEM; PLASMA-MEMBRANE; BASAL GANGLIA; RAT STRIATUM; LOCALIZATION; HETEROMERS; NEURONS AB G protein-coupled receptors are known to form homo- and heteromers at the plasma membrane, but the stoichiometry of these receptor oligomers are relatively unknown. Here, by using bimolecular fluorescence complementation, we visualized for the first time the occurrence of heterodimers of metabotropic glutamate mGlu(5) receptors (mGlu(5)R) and dopamine D-2 receptors (D2R) in living cells. Furthermore, the combination of bimolecular fluorescence complementation and bioluminescence resonance energy transfer techniques, as well as the sequential resonance energy transfer technique, allowed us to detect the occurrence receptor oligomers containing more than two protomers, mGlu(5)R, D2R and adenosine A(2A) receptor (A(2A)R). Interestingly, by using high-resolution immunoelectron microscopy we could confirm that the three receptors co-distribute within the extrasynaptic plasma membrane of the same dendritic spines of asymmetrical, putative glutamatergic, striatal synapses. Also, co-immunoprecipitation experiments in native tissue demonstrated the existence of an association of mGlu(5)R, D2R and A(2A)R in rat striatum homogenates. Overall, these results provide new insights into the molecular composition of G protein-coupled receptor oligomers in general and the mGlu(5)R/D2R/A(2A)R oligomer in particular, a receptor oligomer that might constitute an important target for the treatment of some neuropsychiatric disorders. C1 [Cabello, Nuria; Bertarelli, Daniela C. G.; Lluis, Carme; Franco, Rafael] Univ Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. [Cabello, Nuria; Bertarelli, Daniela C. G.; Lluis, Carme; Franco, Rafael] Univ Barcelona, Dept Bioquim & Biol Mol, Fac Biol, Barcelona, Spain. [Gandia, Jorge; Ciruela, Francisco] Univ Barcelona, Fac Med, Unitat Farmacol, Dept Patol & Terapeut Expt, Barcelona 7, Spain. [Watanabe, Masahiko] Hokkaido Univ, Dept Anat, Sapporo, Hokkaido, Japan. [Ferre, Sergi] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. [Lujan, Rafael] Univ Castilla La Mancha, Fac Med, CRIB, Dept Ciencias Med, Albacete, Spain. RP Cabello, N (reprint author), Univ Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. RI WATANABE, Masahiko/A-4055-2012; Ferre, Sergi/K-6115-2014; Ciruela, Francisco/A-5096-2013; Franco, Rafael/C-3694-2015; Gandia, Jorge/P-3373-2016 OI Ferre, Sergi/0000-0002-1747-1779; Ciruela, Francisco/0000-0003-0832-3739; Franco, Rafael/0000-0003-2549-4919; Gandia, Jorge/0000-0003-1711-8075 FU Consolider-Ingenio [CSD2008-00005]; Ministerio de Ciencia e Innovacion; Sociedad Espanola de Farmacologia and Laboratorios Almirall to FC; Junta de Comunidades de Castilla-La Mancha [PAI08-0174-6967] FX This work was supported by grants SAF2008-01462 and Consolider-Ingenio CSD2008-00005 from Ministerio de Ciencia e Innovacion and by Sociedad Espanola de Farmacologia and Laboratorios Almirall to FC. Also, supported by the Junta de Comunidades de Castilla-La Mancha (PAI08-0174-6967) to RL and by the Intramural funds of the National Institute on Drug Abuse, NIH. NR 60 TC 130 Z9 132 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2009 VL 109 IS 5 BP 1497 EP 1507 DI 10.1111/j.1471-4159.2009.06078.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 443UB UT WOS:000265935200026 PM 19344374 ER PT J AU Berman, RA Joiner, WM Cavanaugh, J Wurtz, RH AF Berman, Rebecca A. Joiner, Wilsaan M. Cavanaugh, James Wurtz, Robert H. TI Modulation of Presaccadic Activity in the Frontal Eye Field by the Superior Colliculus SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID POSTERIOR PARIETAL CORTEX; SACCADE TARGET SELECTION; BRAIN-STEM TELLS; REVERSIBLE INACTIVATION; TERMINAL FIELDS; MACAQUE MONKEY; SIGNALS SENT; NEURONS; MOVEMENTS; GENERATION AB Berman RA, Joiner WM, Cavanaugh J, Wurtz RH. Modulation of presaccadic activity in the frontal eye field by the superior colliculus. J Neurophysiol 101: 2934-2942, 2009. First published March 25, 2009; doi: 10.1152/jn.00053.2009. A cascade of neuronal signals precedes each saccadic eye movement to targets in the visual scene. In the cerebral cortex, this neuronal processing culminates in the frontal eye field (FEF), where neurons have bursts of activity before the saccade. This presaccadic activity is typically considered to drive downstream activity in the intermediate layers of the superior colliculus (SC), which receives direct projections from FEF. Consequently, the FEF activity is thought to be determined solely by earlier cortical processing and unaffected by activity in the SC. Recent evidence of an ascending path from the SC to FEF raises the possibility, however, that presaccadic activity in the FEF may also depend on input from the SC. Here we tested this possibility by recording from single FEF neurons during the reversible inactivation of SC. Our results indicate that presaccadic activity in the FEF does not require SC input: we never observed a significant reduction in FEF presaccadic activity when the SC was inactivated. Unexpectedly, in a third of experiments, SC inactivation elicited a significant increase in FEF presaccadic activity. The passive visual response of FEF neurons, in contrast, was virtually unaffected by inactivation of the SC. These findings show that presaccadic activity in the FEF does not originate in the SC but nevertheless may be influenced by modulatory signals ascending from the SC. C1 [Berman, Rebecca A.; Joiner, Wilsaan M.; Cavanaugh, James; Wurtz, Robert H.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20982 USA. RP Berman, RA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20982 USA. EM bermanr@nei.nih.gov FU National Institutes of Health FX This research was supported by the National Eye Institute Intramural Research Program of the National Institutes of Health. NR 47 TC 13 Z9 13 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUN PY 2009 VL 101 IS 6 BP 2934 EP 2942 DI 10.1152/jn.00053.2009 PG 9 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 450KD UT WOS:000266398500020 PM 19321644 ER PT J AU Bonnot, A Chub, N Pujala, A O'Donovan, MJ AF Bonnot, Agnes Chub, Nikolai Pujala, Avinash O'Donovan, Michael J. TI Excitatory Actions of Ventral Root Stimulation During Network Activity Generated by the Disinhibited Neonatal Mouse Spinal Cord SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID METABOTROPIC GLUTAMATE RECEPTORS; IN-VITRO; LOCOMOTOR NETWORK; MOTOR ROOTS; MOTONEURONS; INHIBITION; DEPOLARIZATION; MECHANISMS; EXPRESSION; PATTERNS AB Bonnot A, Chub N, Pujala A, O'Donovan MJ. Excitatory actions of ventral root stimulation during network activity generated by the disinhibited neonatal mouse spinal cord. J Neurophysiol 101: 2995-3011, 2009. First published March 25, 2009; doi: 10.1152/jn.90740.2008. To further understand the excitatory effects of motoneurons on spinal network function, we investigated the entrainment of disinhibited rhythms by ventral root (VR) stimulation in the neonatal mouse spinal cord. A brief train of stimuli applied to a VR triggered bursting reliably in 31/32 experiments. The same roots that entrained disinhibited bursting could also produce locomotor-like activity with a similar probability when the network was not disinhibited. The ability of VR stimulation to entrain the rhythm persisted in nicotinic and muscarinic cholinergic antagonists but was blocked by the AMPAR antagonist NBQX. Bath application of the type I mGluR1 receptor antagonist CPCCOEt reduced the ability of both dorsal root and VR stimulation to entrain the disinhibited rhythm and abolished the ability of either type of stimulation to evoke locomotor-like activity. Calcium imaging through the lateral aspect of the cord revealed that VR stimulation and spontaneously occurring bursts were accompanied by a wave of activity that originated ventrally and propagated dorsally. Imaging the cut transverse face of L-5 revealed that the earliest VR-evoked optical activity began ventrolaterally. The optical activity accompanying spontaneous bursts could originate ventrolaterally, ventromedially, or throughout the mediolateral extent of the ventral horn or very occasionally dorsally. Collectively, our data indicate that VR stimulation can entrain disinhibited spinal network activity and trigger locomotor-like activity through a mechanism dependent on activation of both ionotropic and metabotropic glutamate receptors. The effects of entrainment appear to be mediated by a ventrolaterally located network that is also active during spontaneously occurring bursts. C1 [Bonnot, Agnes; Chub, Nikolai; Pujala, Avinash; O'Donovan, Michael J.] NINDS, Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP O'Donovan, MJ (reprint author), NINDS, Dev Neurobiol Sect, NIH, Room 3C-1014,Bldg 35,35 Convent Dr, Bethesda, MD 20892 USA. EM odonovm@ninds.nih.gov RI o'donovan, michael/A-2357-2015 OI o'donovan, michael/0000-0003-2487-7547 FU National Institutes of Neurological Disorders and Stroke FX This work was supported by the intramural program of the National Institutes of Neurological Disorders and Stroke. NR 34 TC 10 Z9 10 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUN PY 2009 VL 101 IS 6 BP 2995 EP 3011 DI 10.1152/jn.90740.2008 PG 17 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 450KD UT WOS:000266398500025 PM 19321640 ER PT J AU Okun, E Mattson, MP AF Okun, Eitan Mattson, Mark P. TI Phosphothioated Oligodeoxynucleotides Induce Nonspecific Effects on Neuronal Cell Adhesion in a Growth Substrate-Dependent Manner SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE phosphothioate; ODN; neurons; adhesion; toll-like receptors ID TOLL-LIKE-RECEPTORS AB Synthetic phosphothioated (PTO) oligodeoxynucleotide (ODN) sequences are commonly used for a variety of applications that benefit from nuclease protection. The PTO modification is implemented mainly in antisense ODN, but also in ODN that were shown to activate members of the toll-like receptor (TLR) family such as TLR3 (poly-I:C), TLR8 (ssRNA), and TLR9 (CpG). Neurons are routinely plated on surfaces coated with either cationic substances such as poly-L-ornithine (PLO), polyethylenimine (PEI), poly-L-lysine or ECM components such as laminin, collagen, or fibronectin. We found that PTO-ODN aimed at activating TLR9 induces a non-TLR9-specific detachment phenotype in cortical neurons plated on either laminin or PEI, but not on PLO. This phenotype was correlated with decreased viability and was partially inhibited when caspase-3 was inhibited with Ac-DEVD-CMK. This finding suggests that the use of PTO-ODN can cause nonspecific effects on cell adhesion that could compromise interpretation of data from experiments using PTO-ODN. (C) 2009 Wiley-Liss, Inc. C1 [Okun, Eitan; Mattson, Mark P.] NIH, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Okun, E (reprint author), NIH, Neurosci Lab, Intramural Res Program, 251 Bayview Blvd,Suite 100,Room 5C218,5th Floor, Baltimore, MD 21224 USA. EM okune@mail.nih.gov RI Mattson, Mark/F-6038-2012; okun, eitan/K-1314-2016 OI okun, eitan/0000-0001-8474-1487 FU Intramural Research Program of the National Institute on Aging, NIH FX Contract grant sponsor: Intramural Research Program of the National Institute on Aging, NIH. NR 7 TC 4 Z9 4 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN PY 2009 VL 87 IS 8 BP 1947 EP 1952 DI 10.1002/jnr.21995 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 437CD UT WOS:000265462800023 PM 19156868 ER PT J AU Margulies, S Hicks, R AF Margulies, Susan Hicks, Ramona CA Combination Therapies Traumatic Br TI Combination Therapies for Traumatic Brain Injury: Prospective Considerations SO JOURNAL OF NEUROTRAUMA LA English DT Review DE clinical trials; head injury; injury mechanisms; intervention; in-vitro and in-vivo models ID CEREBRAL-BLOOD-FLOW; HIPPOCAMPAL ORGANOTYPIC CULTURES; RANDOMIZED CONTROLLED-TRIAL; CONTROLLED CORTICAL IMPACT; NITRIC-OXIDE SYNTHASE; NEURONAL CELL-DEATH; IN-VITRO MODEL; EXPERIMENTAL INTRACEREBRAL HEMORRHAGE; ERYTHROPOIETIN ENHANCES NEUROGENESIS; RECOMBINANT-HUMAN-ERYTHROPOIETIN AB Traumatic brain injury (TBI) initiates a cascade of numerous pathophysiological events that evolve over time. Despite the complexity of TBI, research aimed at therapy development has almost exclusively focused on single therapies, all of which have failed in multicenter clinical trials. Therefore, in February 2008 the National Institute of Neurological Disorders and Stroke, with support from the National Institute of Child Health and Development, the National Heart, Lung, and Blood Institute, and the Department of Veterans Affairs, convened a workshop to discuss the opportunities and challenges of testing combination therapies for TBI. Workshop participants included clinicians and scientists from a variety of disciplines, institutions, and agencies. The objectives of the workshop were to: (1) identify the most promising combinations of therapies for TBI; (2) identify challenges of testing combination therapies in clinical and pre-clinical studies; and (3) propose research methodologies and study designs to overcome these challenges. Several promising combination therapies were discussed, but no one combination was identified as being the most promising. Rather, the general recommendation was to combine agents with complementary targets and effects (e. g., mechanisms and time-points), rather than focusing on a single target with multiple agents. In addition, it was recommended that clinical management guidelines be carefully considered when designing pre-clinical studies for therapeutic development. To overcome the challenges of testing combination therapies it was recommended that statisticians and the U. S. Food and Drug Administration be included in early discussions of experimental design. Furthermore, it was agreed that an efficient and validated screening platform for candidate therapeutics, sensitive and clinically relevant biomarkers and outcome measures, and standardization and data sharing across centers would greatly facilitate the development of successful combination therapies for TBI. Overall there was great enthusiasm for working collaboratively to act on these recommendations. C1 [Margulies, Susan] Univ Pennsylvania, Sch Engn & Appl Sci, Dept Bioengn, Philadelphia, PA 19104 USA. [Hicks, Ramona] NINDS, Bethesda, MD 20892 USA. RP Margulies, S (reprint author), Univ Pennsylvania, Sch Engn & Appl Sci, Dept Bioengn, 240 Skirkanich Hall,210 S 33rd St, Philadelphia, PA 19104 USA. EM margulie@seas.upenn.edu RI Morrison, Barclay/B-7132-2008 OI Morrison, Barclay/0000-0001-7676-0864 FU National Institute of Neurological Disorders and Stroke; National Institute of Child Health and Development; National Institute Heart, Lung, and Blood Institute; Department of Veterans Affairs FX Beth Ansel,*double dagger Clinton Baird, Hulya Bayir, Gretchen Brophy, Ross Bullock, Tracy Chen, William Clarke, David Clifford, Guy Clifton,* Robin Conwit,*double dagger William Coplin, Ken Curley,double dagger Pramod Dash, Donald Denson, Rebecca Desrocher,double dagger Ramon Diaz-Arrastia, W. Dalton Dietrich, Billy Dunn,*double dagger Emmeline Edwards,double dagger Debra Egan,double dagger Scott Emerson, Stephanie Fertig,* Donald Fink, Candace Floyd, Natalie Getzoff, Paula Goforth, Edward D. Hall, Ramona Hicks,*double dagger David Hoyt, Scott Janis,*double dagger Melissa Kaime,*double dagger Naomi Kleitman,double dagger Steve Korn,double dagger Walter Koroshetz,*double dagger Michelle LaPlaca, Daniel Laskowitz, Henry Lew,double dagger Jonathan Lifschitz, Geoffrey Ling,double dagger Susan Margulies,* David Meaney, David Moore,double dagger Barclay Morrison, Claudia Moy, Linda Noble, John Povlishock, Ramesh Raghupathi, Claudia Robertson, Courtney Robertson, Peter Rumm,double dagger Leslie Satin, Holly Soares, George Sopko,*double dagger James Stables, Pat Sullivan, Frank Tortella,double dagger Robert Vandre,double dagger Michael Whalen, Michael Weinrich,*double dagger David Wright, and Ross Zafonte. (* Member of the organizing committee.double dagger Support for the workshop came from the National Institute of Neurological Disorders and Stroke, the National Institute of Child Health and Development, the National Institute Heart, Lung, and Blood Institute, and the Department of Veterans Affairs. The views expressed by the authors in this manuscript represent the professional opinions of the authors and are not an official document, guidance, or policy of the United States Government, the Department of Veterans Affairs, the Department of Defense, the Department of Health and Human Services, the National Institutes of Health, or the U.S. Food and Drug Administration, nor should any official endorsement be inferred. Specific recommendations made in this manuscript should not be construed in any way to represent official recommendations or opinions of the FDA). NR 174 TC 127 Z9 128 U1 1 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN PY 2009 VL 26 IS 6 BP 925 EP 939 DI 10.1089/neu.2008.0794 PG 15 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 455OV UT WOS:000266773600011 PM 19331514 ER PT J AU Sempos, CT Picciano, MF AF Sempos, Christopher T. Picciano, Mary Frances TI The Intention to Treat Principle, and the Potential Impact of Excluding Data from the Analysis of Clinical Trial Data SO JOURNAL OF NUTRITION LA English DT Letter C1 [Sempos, Christopher T.; Picciano, Mary Frances] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Sempos, CT (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. EM semposch@mail.nih.gov NR 3 TC 2 Z9 2 U1 0 U2 0 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 JUN PY 2009 VL 139 IS 6 BP 1204 EP 1204 DI 10.3945/jn.109.106799 PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 448VQ UT WOS:000266290500025 PM 19403721 ER PT J AU Korecki, CL Kuo, CK Tuan, RS Iatridis, JC AF Korecki, Casey L. Kuo, Catherine K. Tuan, Rocky S. Iatridis, James C. TI Intervertebral Disc Cell Response to Dynamic Compression Is Age and Frequency Dependent SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE intervertebral disc; aging; mechanical loading; alginate; gene expression ID NUCLEUS PULPOSUS CELLS; GENE-EXPRESSION; HYDROSTATIC-PRESSURE; IN-VITRO; MECHANICAL-PROPERTIES; ARTICULAR-CARTILAGE; CULTURE-SYSTEM; MATRIX; CHONDROCYTE; MODEL AB The maintenance of the intervertebral disc extracellular matrix is regulated by mechanical loading, nutrition, and the accumulation of matrix proteins and cytokines that are affected by both aging and degeneration. Evidence suggests that cellular aging may lead to alterations in the quantity and quality of extracellular matrix produced. The aims of this study were to examine the role of loading and maturation (a subset of aging), and the interaction between these two factors in intervertebral disc cell gene expression and biosynthesis in a controlled 3D culture environment. Cells were isolated from young (4-6 months) and mature (18-24 months) bovine caudal annulus fibrosus and nucleus pulposus tissue. Isolated cells were seeded into alginate and dynamically compressed for 7 days at either 0.1, 1, or 3 Hz or maintained as a free-swelling control. After 7 days, DNA and sulfated glycosaminoglycan contents were analyzed along with real time, quantitative reverse transcription-polymerase chain reaction analysis for collagen types I and II, aggrecan, and matrix metalloproteinase-3 gene expression. Results suggest that maturation plays an important role in intervertebral disc homeostasis and influences the cell response to mechanical loading. While isolated intervertebral disc cells responded to mechanical compression in 3D culture, the effect of loading frequency was minimal. Altered cellular phenotype and biosynthesis rates appear to be an attribute of the cell maturation process, potentially independent of changes in cellular microenvironment associated with lost nutrition and disc degeneration. Mature cells may have a decreased capacity to create or retain extracellular matrix components in response to mechanical loading compared to young cells. (C) 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:800-806, 2009 C1 [Korecki, Casey L.; Iatridis, James C.] Univ Vermont, Coll Engn & Math Sci, Spine Bioengn Lab, Burlington, VT 05405 USA. [Kuo, Catherine K.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Iatridis, JC (reprint author), Univ Vermont, Coll Engn & Math Sci, Spine Bioengn Lab, Burlington, VT 05405 USA. EM james.iatridis@uvm.edu FU NIH [R01AR051146]; Intramural Research Program; National Institute of Arthritis and Musculoskeletal and Skin Diseases [Z01 AR41131] FX This Study was sponsored by an NIH Grant (R01AR051146) and the Intramural Research Program of the NIH, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Z01 AR41131). NR 30 TC 39 Z9 42 U1 0 U2 9 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD JUN PY 2009 VL 27 IS 6 BP 800 EP 806 DI 10.1002/jor.20814 PG 7 WC Orthopedics SC Orthopedics GA 446LM UT WOS:000266123100016 PM 19058142 ER PT J AU Salzer, W Dinndorf, P Dreyer, Z Hilden, J Reaman, GH AF Salzer, Wanda Dinndorf, Patricia Dreyer, ZoAnn Hilden, Joanne Reaman, Gregory H. TI Analysis of Infectious Complications in Infants With Acute Lymphoblastic Leukemia Treated on the Children's Cancer Group Protocol 1953 A Report From the Children's Oncology Group SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE infection; infant acute lymphoblastic leukemia ID PNEUMOCYSTIS-CARINII-PNEUMONIA; INVASIVE FUNGAL-INFECTIONS; IMMUNODEFICIENCY-VIRUS-INFECTION; STEM-CELL TRANSPLANTATION; AEROSOLIZED PENTAMIDINE; PROGNOSTIC-FACTORS; CHILDHOOD-LEUKEMIA; GENE REARRANGEMENT; PROPHYLAXIS; EXPERIENCE AB Infants with acute lymphoblastic leukemia have a poor prognosis. The Children's Cancer Group (CCG) 1953 protocol tested the hypothesis that intensification of therapy would improve outcome for these patients. This intensified therapy resulted in better disease control, but resulted in greater toxicity. In this paper, we report the infectious complications associated with this intensified therapy. We retrospectively analyzed the infectious complications reported on the case report forms of all 115 patients enrolled on CCG 1953. Overall 495 infectious complications were identified in 115 patients. Bacterial infections occurred most frequently (74%), followed by viral (13%), fungal (11%), and protozoan (1%). Infection related mortality disproportionately occurred with viral (31%) and fungal (19%) infections. Twenty-three percent (n = 26) of patients died of infectious complications, with the majority occurring during induction/intensification. Lower respiratory infections contributed to death in 12 patients and were most commonly viral (n = 6) and fungal (n = 3). Intensification of therapy resulted in increased infectious complications and deaths compared with previous studies. Future studies will need to focus on: (1) decreasing intensification during the first month of therapy, (2) developing targeted therapies, and (3) improving measures designed to prevent, quickly diagnose, and appropriately treat infections. C1 [Salzer, Wanda] NCI, NIH, IRB, Bethesda, MD 20892 USA. [Dinndorf, Patricia] US FDA, Silver Spring, MD USA. [Dreyer, ZoAnn] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Hilden, Joanne] Peyton Manning Childrens Hosp St Vincent, Indianapolis, IN USA. [Reaman, Gregory H.] Childrens Oncol Grp, Arcata, CA USA. RP Salzer, W (reprint author), NCI, NIH, IRB, 9030 Old Georgetown Rd,Bldg 82,Room 215,MSC 8200, Bethesda, MD 20892 USA. EM salzerw@mail.nih.gov FU National Institutes of Health [CA13539, CA98543]; Children's Cancer Group (CCG); Pediatric Oncology Group (POG) FX Supported by grants from the National Institutes of Health (grants CA13539 and CA98543). A complete listing of grant support for research conducted by Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) before initiation of the COG grant in 2003. NR 45 TC 10 Z9 11 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD JUN PY 2009 VL 31 IS 6 BP 398 EP 405 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 455CJ UT WOS:000266733900004 PM 19648788 ER PT J AU Steigman, SA Ahmed, A Shanti, RM Tuan, RS Valim, C Fauza, DO AF Steigman, Shaun A. Ahmed, Azra Shanti, Rabie M. Tuan, Rocky S. Valim, Clarissa Fauza, Dario O. TI Sternal repair with bone grafts engineered from amniotic mesenchymal stem cells SO JOURNAL OF PEDIATRIC SURGERY LA English DT Article; Proceedings Paper CT 60th Annual Meeting of the American-Academy-of-Pediatrics CY OCT 10-12, 2008 CL Boston, MA SP Amer Acad Pediat DE Tissue engineering; Amniotic mesenchymal stem cells; Mesenchymal stem cells; Amniotic fluid; Chest wall anomalies; Sternum ID ECTOPIA CORDIS; TISSUE; SCAFFOLDS; AMNIOCYTES; RECONSTRUCTION; FLUID AB Purpose: We aimed at determining whether osseous grafts engineered from amniotic mesenchymal stem cells (aMSCs) Could be used in postnatal sternal repair. Methods: Leporine aMSCs were isolated, identified, transfected with green fluorescent protein (GFP), expanded, and seeded onto biodegradable electrospun nanofibrous scaffolds (n = 6). Constructs were dynamically maintained in an osteogenic medium and equally divided into 2 groups with respect to time in vitro as follows: 14.6 or 33.9 weeks. They were then used to repair full-thickness sternal defects spanning 2 to 3 intercostal spaces in allogeneic kits (n = 6). Grafts were Submitted to multiple analyses 2 months thereafter. Results: Chest roentgenograms showed defect closure in all animals, confirmed at necropsy. Graft density as assessed by microcomputed tomographic scans increased significantly in vivo, yet there were no differences in mineralization by extracellular calcium measurements preimplantation and postimplantation. There was a borderline increase in alkaline phosphatase activity in vivo, suggesting ongoing graft remodeling. Histologically, implants contained GFP-positive cells and few mononuclear infiltrates. There were no differences between the 2 construct groups in any comparison. Conclusions: Engineered osseous grafts derived from amniotic mesenchymal stem cells may become a viable alternative for sternal repair. The amniotic fluid can be a practical cell source for engineered chest wall reconstruction. (C) 2009 Elsevier Inc. All rights reserved. C1 [Steigman, Shaun A.; Ahmed, Azra; Shanti, Rabie M.; Valim, Clarissa; Fauza, Dario O.] Childrens Hosp, Dept Surg, Boston, MA 02115 USA. [Steigman, Shaun A.; Ahmed, Azra; Shanti, Rabie M.; Valim, Clarissa; Fauza, Dario O.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Tuan, Rocky S.] NIAMS, Cartilage Biol & Orthoped Branch, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Fauza, DO (reprint author), Childrens Hosp, Dept Surg, Boston, MA 02115 USA. EM dario.fauza@childrens.harvard.edu FU Intramural NIH HHS [ZIA AR041179-02] NR 26 TC 31 Z9 31 U1 2 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 0022-3468 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD JUN PY 2009 VL 44 IS 6 BP 1120 EP 1126 DI 10.1016/j.jpedsurg.2009.02.038 PG 7 WC Pediatrics; Surgery SC Pediatrics; Surgery GA 462HV UT WOS:000267342800018 PM 19524727 ER PT J AU Chen, C Li, GL Liao, WM Wu, J Liu, L Ma, D Zhou, JF Elbekai, RH Edin, ML Zeldin, DC Wang, DW AF Chen, Chen Li, Guiling Liao, Wanmin Wu, Jun Liu, Liu Ma, Ding Zhou, Jianfeng Elbekai, Reem H. Edin, Matthew L. Zeldin, Darryl C. Wang, Dao Wen TI Selective Inhibitors of CYP2J2 Related to Terfenadine Exhibit Strong Activity against Human Cancers in Vitro and in Vivo SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ARACHIDONIC-ACID EPOXYGENASE; HUMAN CYTOCHROME-P450 2J2; ACTIVATED PROTEIN-KINASE; HUMAN-MELANOMA CELLS; SIGNALING PATHWAYS; MOLECULAR-CLONING; EXPRESSION; METABOLISM; APOPTOSIS; PROMOTES AB The cytochrome P450 epoxygenase, CYP2J2, converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs). We found recently that this enzyme is dramatically up-regulated in a variety of established human carcinoma cell lines and in human cancerous tissue and promotes the neoplastic phenotype. In the present study, we tested the hypothesis that specific inhibitors of CYP2J2 related to the drug terfenadine are effective antitumor agents. Four of these inhibitors (compounds 4, 5, 11, and 26) were tested for effectiveness in vitro and in vivo. In Tca-8113 cells, the CYP2J2 inhibitors decreased EET production by approximately 60%, whereas they had no effect on CYP2J2 mRNA or protein expression. Compound 26 inhibited the proliferation of human tumor cells, reduced their ability to adhere, invade, and migrate, and attenuated activation of epithelial growth factor receptor signal and kinases and phosphatidylinositol 3 kinase/Akt pathways. Inhibition of CYP2J2 also significantly potentiated human tumor cell apoptosis and caused a corresponding increase in caspase-3 activity and change in expression of apoptosis-related proteins Bax and Bcl-2. In murine xenograft models using MDA-MB-435 cells, treatment with compound 26 significantly repressed tumor growth, decreased lung metastasis, and was associated with increased expression of the anticancer genes CD82 and nm23, without causing toxicity. These data suggest that CYP2J2 inhibitors hold significant promise for use in treatment of neoplastic diseases. C1 [Chen, Chen; Li, Guiling; Liao, Wanmin; Wu, Jun; Liu, Liu; Ma, Ding; Zhou, Jianfeng; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Internal Med, Tongji Hosp, Wuhan 430030, Peoples R China. [Chen, Chen; Li, Guiling; Liao, Wanmin; Wu, Jun; Liu, Liu; Ma, Ding; Zhou, Jianfeng; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Inst Hypertens, Tongji Hosp, Wuhan 430030, Peoples R China. [Elbekai, Reem H.; Edin, Matthew L.; Zeldin, Darryl C.] Natl Inst Environm Hlth Sci, Div Intramural Res, NIH, Res Triangle Pk, NC USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Internal Med, Tongji Hosp, 1095 Jiefang Ave, Wuhan 430030, Peoples R China. EM dwwang@tjh.tjmu.edu.cn OI Edin, Matthew/0000-0002-7042-500X FU China Natural Science Foundation Committee [30540087, 30430320]; International Collaboration Project [2005DFA30880]; 973 Program [2007CB512004, 2002CB513107]; National Institutes of Health National Institute of Environmental Health Sciences [Z01 ES025034] FX This work was supported in part by the China Natural Science Foundation Committee [Grants 30540087, 30430320]; the International Collaboration Project [Grant 2005DFA30880]; the 973 Program [Grants 2007CB512004, 2002CB513107]; and by the Intramural Research program of the National Institutes of Health National Institute of Environmental Health Sciences [Grant Z01 ES025034]. NR 31 TC 46 Z9 47 U1 2 U2 13 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 JUN PY 2009 VL 329 IS 3 BP 908 EP 918 DI 10.1124/jpet.109.152017 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 447QV UT WOS:000266207800008 PM 19289568 ER PT J AU Couty, JP Lupu-Meiri, M Oron, Y Gershengorn, MC AF Couty, Jean-Pierre Lupu-Meiri, Monica Oron, Yoram Gershengorn, Marvin C. TI Kaposi's Sarcoma-Associated Herpesvirus-G Protein-Coupled Receptor-Expressing Endothelial Cells Exhibit Reduced Migration and Stimulated Chemotaxis by Chemokine Inverse Agonists SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NF-KAPPA-B; HUMAN-HERPESVIRUS-8; ACTIVATION; KINASE; SECRETION; ONCOGENE; PATHWAYS AB A constitutively active G protein-coupled receptor (GPCR) encoded by Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) (KSHV) is expressed in endothelial (spindle) cells of Kaposi's sarcoma lesions. In this study, we report novel effects of basal signaling by this receptor and of inverse agonist chemokines on migration of KSHV-GPCR-expressing mouse lung endothelial cells. We show that basal signaling by KSHV-GPCR inhibits migration of endothelial cells in two systems, movement through porous filters and in vitro wound closure. Naturally occurring chemokines, interferon gamma-inducible protein-10 and stromal-derived factor-1, which act as inverse agonists at KSHV-GPCR, abrogate the inhibition of migration and stimulate directed migration (or chemotaxis) of these cells. Thus, the expression of KSHV-GPCR may allow infected endothelial cells in situ to remain in a localized environment or to directionally migrate along a gradient of specific chemokines that are inverse agonists at KSHV-GPCR. C1 [Couty, Jean-Pierre; Gershengorn, Marvin C.] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD USA. [Lupu-Meiri, Monica; Oron, Yoram] Tel Aviv Univ, Dept Physiol & Pharmacol, Sackler Fac Med, Ramat Aviv, Israel. RP Gershengorn, MC (reprint author), Bldg 50,Room 4134,50 S Dr,MSC 8029, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov FU National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [1Z01-DK047045-01] FX This work was supported by the Intramural Research program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant 1Z01-DK047045-01 CEB]. NR 33 TC 7 Z9 8 U1 0 U2 2 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 JUN PY 2009 VL 329 IS 3 BP 1142 EP 1147 DI 10.1124/jpet.108.147686 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 447QV UT WOS:000266207800035 PM 19258523 ER PT J AU Aponte, AM Phillips, D Hopper, RK Johnson, DT Harris, RA Blinova, K Boja, ES French, S Balaban, RS AF Aponte, Angel M. Phillips, Darci Hopper, Rachel K. Johnson, D. Thor Harris, Robert A. Blinova, Ksenia Boja, Emily S. French, Stephanie Balaban, Robert S. TI Use of P-32 To Study Dynamics of the Mitochondrial Phosphoproteome SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE P-32; mitochondria; protein phosphorylation; phosphate-metabolite association; 2D gel electrophoresis; Complex I; Complex V ID BOVINE HEART-MITOCHONDRIA; DEPENDENT PROTEIN-KINASE; ALPHA-KETO ACID; NUCLEAR-ENCODED SUBUNITS; COMPLEX-I; PYRUVATE-DEHYDROGENASE; CYTOCHROME-C; AQDQ SUBUNIT; MASS-SPECTROMETRY; NDUFS4 GENE AB Protein phosphorylation is a well-characterized regulatory mechanism in the cytosol, but remains poorly defined in the mitochondrion. In this study, we characterized the use of P-32-labeling to monitor the turnover of protein phosphorylation in the heart and liver mitochondria matrix. The UP labeling technique was compared and contrasted to Phos-tag protein phosphorylation fluorescent stain and 2D isoelectric focusing. Of the 64 proteins identified by MS spectroscopy in the Phos-Tag gels, over 20 proteins were correlated with (32)p labeling. The high sensitivity of (32)p incorporation detected proteins well below the mass spectrometry and even 2D gel protein detection limits. Phosphate-chase experiments revealed both turnover and phosphate associated protein pool size alterations dependent on initial incubation conditions. Extensive weak phosphate/phosphate metabolite interactions were observed using nondisruptive native gels, providing a novel approach to screen for potential allosteric interactions of phosphate metabolites with matrix proteins. We confirmed the phosphate associations in Complexes V and I due to their critical role in oxidative phosphorylation and to validate the 2D methods. These complexes were isolated by immunocapture, after (32)p labeling in the intact mitochondria, and revealed P-32-incorporation for the alpha, beta, gamma, OSCP, and d subunits in Complex V and the 75, 51, 42, 23, and 13a kDa subunits in Complex I. These results demonstrate that a dynamic and extensive mitochondrial matrix phosphoproteome exists in heart and liver. C1 [Phillips, Darci; Hopper, Rachel K.; Johnson, D. Thor; Blinova, Ksenia; Boja, Emily S.; French, Stephanie; Balaban, Robert S.] NHLBI, Cardiac Energet Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Aponte, Angel M.] NHLBI, Prote Core Facil, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Johnson, D. Thor; Harris, Robert A.] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. RP Balaban, RS (reprint author), NHLBI, Cardiac Energet Lab, NIH, Dept Hlth & Human Serv, 10 Ctr Dr,Room B1D416, Bethesda, MD 20892 USA. EM rsb@nih.gov FU Division of Intramural Research; Intramural Research Division of the NHLBI; NIH [DK47844] FX We thank Ilsa Rovira for providing guidance and oversight of the radioisotope studies and Dr. Toren Finkel for the laboratory space. These studies were funded by the Division of Intramural Research. This work was supported by the Intramural Research Division of the NHLBI and NIH grant DK47844 (RH). NR 62 TC 32 Z9 32 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD JUN PY 2009 VL 8 IS 6 BP 2679 EP 2695 DI 10.1021/pr800913j PG 17 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 454YD UT WOS:000266719400008 PM 19351177 ER PT J AU Grubb, RL Deng, JH Pinto, PA Mohler, JL Chinnaiyan, A Rubin, M Linehan, WM Liotta, LA Petricoin, EF Wulfkuhle, JD AF Grubb, Robert L., III Deng, Jianghong Pinto, Peter A. Mohler, James L. Chinnaiyan, Arul Rubin, Mark Linehan, W. Marston Liotta, Lance A. Petricoin, Emanuel F., III Wulfkuhle, Julia D. TI Pathway Biomarker Profiling of Localized and Metastatic Human Prostate Cancer Reveal Metastatic and Prognostic Signatures SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE prostate cancer; signaling; proteomics; protein microarray; reverse phase array; metastasis ID PHASE PROTEIN MICROARRAYS; MESSENGER-RNA; II TRIAL; EXPRESSION; CELLS; CARCINOMA; SURVIVAL; ACTIVATION; DOCETAXEL; THERAPY AB Reverse phase protein microarray technology was used to study key signaling pathways thought to be involved in the progression of benign epithelium to the lethal phenotype of prostate cancer. Specimens of androgen-stimulated localized prostate cancer (N = 21) and androgen-deprivation therapy-recurrent local (N = 4) or metastatic (N = 11) prostate cancer were laser capture microdissected prior to analysis. The results showed significant increases in protein expression levels in malignant epithelial cells and patient-matched stromal tissue, which included higher levels of the apoptotic proteins Bax and Smac/Diablo and increased phosphorylation of Bcl2 (S70). The mitochondrial protein Smac/Diablo and the transcription regulatory protein STAT3 (Y705) correlated with Gleason sum and differed statistically in high Gleason grade (8-10) prostate cancers. Distinct metastasis-specific pathways were activated by caspase cleavage activation, ErbB2 phosphorylation, Bax total protein and Bcl-2 phosphorylation while phosphorylation of all three members of the MAPK family, ERK, p38, and SAP/JNK, were reduced significantly in metastatic lesions compared to primary cancers. This study, the most comprehensive pathway analysis ever performed for human prostate cancer, presents evidence of specific pathway biomarkers that may be useful for assessment of prognosis and stratification for therapy if validated in larger clinical study sets. C1 [Deng, Jianghong; Liotta, Lance A.; Petricoin, Emanuel F., III; Wulfkuhle, Julia D.] George Mason Univ, Ctr Appl Proteom & Mol Med, Manassas, VA USA. [Grubb, Robert L., III; Pinto, Peter A.; Linehan, W. Marston] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. Roswell Pk Canc Inst, Dept Urol Oncol, Buffalo, NY 14263 USA. SUNY Buffalo, Dept Urol, Buffalo, NY 14260 USA. [Mohler, James L.] Univ N Carolina, Dept Surg, Div Urol, Chapel Hill, NC USA. [Mohler, James L.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Chinnaiyan, Arul] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Rubin, Mark] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Wulfkuhle, JD (reprint author), George Mason Univ, Ctr Appl Proteom & Mol Med, 10900 Univ Blvd,Discovery Hall MS 4E3, Manassas, VA USA. EM epetrico@gmu.edu; jwulfkuh@gmu.edu OI Rubin, Mark/0000-0002-8321-9950 FU Department of Life Sciences at George Mason University; [NCI-PO1-CA77739] FX We appreciate the generous support of Dr. Vikas Chandhoke and the Department of Life Sciences at George Mason University. This work was partly supported by NCI-PO1-CA77739. NR 47 TC 29 Z9 32 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD JUN PY 2009 VL 8 IS 6 BP 3044 EP 3054 DI 10.1021/pr8009337 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 454YD UT WOS:000266719400039 PM 19275204 ER PT J AU Coleman, CN Parker, GW AF Coleman, C. Norman Parker, Gerald W. TI Radiation terrorism: what society needs from the radiobiology-radiation protection and radiation oncology communities SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Article ID LINEAR NO-THRESHOLD; HEALTH-CARE-SYSTEMS; MEDICAL-MANAGEMENT; CANCER-RISKS; RECOMMENDATIONS; BIODOSIMETRY; EXPOSURE; EVENTS; MOUSE AB Society's and individuals' concerns about the adverse effects from radiation are logically amplified many times when radiological terrorism is considered. The spectrum of events include industrial sabotage, the use of an explosive or non-explosive radiological dispersal device, the placement of a radiological exposure device in a public facility and the use of an improvised nuclear device. The consequences of an event relate to the physical and medical damage of the event itself, the financial impact, and the acute and long-term medical consequences, including fear of radiation-induced cancer. The magnitude of a state-sponsored nuclear event is so great that limited detailed response planning had been done in the past, as compared to the work now ongoing. Planning is done on the basis of scenario modelling. Medical response planning includes medical triage, distribution of victims to care by experienced physicians, developing medical countermeasures to mitigate or treat radiation injury, counselling and appropriately following exposed or potentially exposed people, and helping the local community develop confidence in their own response plan. Optimal response must be based on the best available science. This requires scientists who can define, prioritise and address the gaps in knowledge with the range of expertise from basic physics to biology to translational research to systems expertise to response planning to healthcare policy to communications. Not only are there unique needs and career opportunities, but there is also the opportunity for individuals to serve their communities and country with education regarding radiation effects and by formulating scientifically based government policy. C1 [Coleman, C. Norman] US Dept HHS, Off Assistant Secretary Preparedness & Response, Off Preparedness & Emergency Response, Washington, DC 20201 USA. [Coleman, C. Norman] NCI, Radiat Res Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Coleman, CN (reprint author), US Dept HHS, Off Assistant Secretary Preparedness & Response, Off Preparedness & Emergency Response, Washington, DC 20201 USA. FU Assistant Secretary for Preparedness and Response; National Institutes of Allergy and Infectious Diseases; National Cancer Institute FX Acknowledgment to the many people in the Office of the Assistant Secretary for Preparedness and Response, the National Institutes of Allergy and Infectious Diseases and the National Cancer Institute for their contributions to the radiation response planning. NR 44 TC 8 Z9 8 U1 0 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 J9 J RADIOL PROT JI J. Radiol. Prot. PD JUN PY 2009 VL 29 IS 2A BP A159 EP A169 DI 10.1088/0952-4746/29/2A/S11 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 464BD UT WOS:000267478500011 PM 19454803 ER PT J AU Hendry, JH Simon, SL Wojcik, A Sohrabi, M Burkart, W Cardis, E Laurier, D Tirmarche, M Hayata, I AF Hendry, Jolyon H. Simon, Steven L. Wojcik, Andrzej Sohrabi, Mehdi Burkart, Werner Cardis, Elisabeth Laurier, Dominique Tirmarche, Margot Hayata, Isamu TI Human exposure to high natural background radiation: what can it teach us about radiation risks? SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Article ID DOMESTIC RADON EXPOSURE; CHROMOSOMAL-ABERRATIONS; LUNG-CANCER; INDOOR RADON; RESIDENTIAL RADON; COLLABORATIVE ANALYSIS; IONIZING-RADIATION; BLOOD-LYMPHOCYTES; HUMAN-POPULATION; SOUTHWEST COAST AB Natural radiation is the major source of human exposure to ionising radiation, and its largest contributing component to effective dose arises from inhalation of (222)Rn and its radioactive progeny. However, despite extensive knowledge of radiation risks gained through epidemiologic investigations and mechanistic considerations, the health effects of chronic low-level radiation exposure are still poorly understood. The present paper reviews the possible contribution of studies of populations living in high natural background radiation (HNBR) areas (Guarapari, Brazil; Kerala, India; Ramsar, Iran; Yangjiang, China), including radon-prone areas, to low dose risk estimation. Much of the direct information about risk related to HNBR comes from case-control studies of radon and lung cancer, which provide convincing evidence of an association between long-term protracted radiation exposures in the general population and disease incidence. The success of these studies is mainly due to the careful organ dose reconstruction (with relatively high doses to the lung), and to the fact that large-scale collaborative studies have been conducted to maximise the statistical power and to ensure the systematic collection of information on potential confounding factors. In contrast, studies in other (non-radon) HNBR areas have provided little information, relying mainly on ecological designs and very rough effective dose categorisations. Recent steps taken in China and India to establish cohorts for follow-up and to conduct nested case-control studies may provide useful information about risks in the future, provided that careful organ dose reconstruction is possible and information is collected on potential confounding factors. C1 [Hendry, Jolyon H.; Sohrabi, Mehdi; Burkart, Werner] IAEA, Dept Nucl Sci & Applicat, A-1400 Vienna, Austria. [Simon, Steven L.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wojcik, Andrzej] Inst Nucl Chem & Technol, PL-03195 Warsaw, Poland. [Wojcik, Andrzej] Jan Kochanowski Univ Humanities & Sci, Inst Biol, Kielce, Poland. [Cardis, Elisabeth] Hosp del Mar, IMIM, Municipal Inst Med Res, Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Cardis, Elisabeth] CIBERESP, Barcelona, Spain. [Laurier, Dominique; Tirmarche, Margot] Inst Radiol Protect & Nucl Safety, Radiol & Human Hlth Div, Radiobiol & Epidemiol Dept, Fontenay Aux Roses, France. [Hayata, Isamu] Natl Inst Radiol Sci, Chiba 260, Japan. [Hayata, Isamu] Cent Res Inst Elect Power Ind, Tokyo 201, Japan. RP Hendry, JH (reprint author), Adlington, Macclesfield SK10 4JU, Cheshire, England. RI Cardis, Elisabeth/C-3904-2017 FU Intramural NIH HHS [ZIA CP010132-18] NR 79 TC 58 Z9 65 U1 0 U2 14 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 J9 J RADIOL PROT JI J. Radiol. Prot. PD JUN PY 2009 VL 29 IS 2A SI SI BP A29 EP A42 DI 10.1088/0952-4746/29/2A/S03 PG 14 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 464BD UT WOS:000267478500003 PM 19454802 ER PT J AU Bixler, EO Papaliaga, MN Vgontzas, AN Lin, HM Pejovic, S Karataraki, M Vela-Bueno, A Chrousos, GP AF Bixler, Edward O. Papaliaga, Maria N. Vgontzas, Alexandros N. Lin, Hung-Mo Pejovic, Slobodanka Karataraki, Maria Vela-Bueno, Antonio Chrousos, George P. TI Women sleep objectively better than men and the sleep of young women is more resilient to external stressors: effects of age and menopause SO JOURNAL OF SLEEP RESEARCH LA English DT Article DE gender; menopause; sleep ID ESTROGEN REPLACEMENT THERAPY; POSTMENOPAUSAL WOMEN; PREVALENCE; INSOMNIA; DISORDERS; COMMUNITY; CATHETER; QUALITY; HEALTH; LIFE AB The aims of this study were to: (i) assess gender differences of objective sleep patterns in a general population sample; (ii) evaluate the effects of menopause and hormone treatment (HT) on the sleep of the same cohort; and (iii) examine gender differences in sleep resilience towards external stressors. The participants were (i) 1324 subjects without sleep complaints, recruited from the general population of Central Pennsylvania that spent one night in the sleep laboratory and (ii) 66 young, healthy volunteers whose sleep was disturbed during night four by an external stressor, i.e. 24-h blood drawing (average of nights 2 and 3 versus night 4). Women compared with men in the general population sample had significantly higher percentage of sleep time, lower percentage of stage 1, and higher percentage of slow wave sleep. Also, menopause, in the absence of HT, was associated with prolonged sleep latency and decreased deep sleep. Finally, young, healthy women compared with men experienced less sleep disturbance because of blood draws as indicated by a significantly smaller change in per cent sleep time, and percentage of stage 1 sleep. These findings suggest that women without sleep complaints sleep objectively better across age than men and the sleep of young women is more resistant to external stressors. Also, gonadal hormones exert a beneficial effect on women's sleep. This gender dimorphism in sleep regulation may have been to protect women from the demands of infant and child care, and in part, might contribute to women's lower cardiovascular risks and greater longevity. C1 [Bixler, Edward O.; Papaliaga, Maria N.; Vgontzas, Alexandros N.; Pejovic, Slobodanka; Karataraki, Maria] Penn State Coll Med, Sleep Res & Treatment Ctr, Dept Psychiat, Hershey, PA USA. [Vela-Bueno, Antonio] Autonomous Univ Madrid, Dept Psychiat, E-28049 Madrid, Spain. [Chrousos, George P.] NICHD, Reprod Biol & Med Branch, NIH, Bethesda, MD USA. [Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, GR-11527 Athens, Greece. [Chrousos, George P.] Univ Athens, Sch Med, Unit Endocrinol Metab & Diabet, GR-11527 Athens, Greece. RP Vgontzas, AN (reprint author), Penn State Univ, Dept Psychiat H073, Coll Med, 500 Univ Dr, Hershey, PA 17033 USA. EM avgontzas@psu.edu FU NIH [R01 HL40916, R01 HL51931, R01 HL64415] FX This study was supported in part by NIH Grants R01 HL40916, R01 HL51931 and R01 HL64415. NR 35 TC 32 Z9 32 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0962-1105 J9 J SLEEP RES JI J. Sleep Res. PD JUN PY 2009 VL 18 IS 2 BP 221 EP 228 DI 10.1111/j.1365-2869.2008.00713.x PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 448DS UT WOS:000266243900011 PM 19302341 ER PT J AU Tager-Flusberg, H Rogers, S Cooper, J Landa, R Lord, C Paul, R Rice, M Stoel-Gammon, C Wetherby, A Yoder, P AF Tager-Flusberg, Helen Rogers, Sally Cooper, Judith Landa, Rebecca Lord, Catherine Paul, Rhea Rice, Mabel Stoel-Gammon, Carol Wetherby, Amy Yoder, Paul TI Defining Spoken Language Benchmarks and Selecting Measures of Expressive Language Development for Young Children With Autism Spectrum Disorders SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article DE autism; autism spectrum disorders; language acquisition ID POPULATION; INVENTORY; TODDLERS; OUTCOMES AB Purpose: The aims of this article are twofold: (a) to offer a set of recommended measures that can be used for evaluating the efficacy of interventions that target spoken language acquisition as part of treatment research studies or for use in applied settings and (b) to propose and define a common terminology for describing levels of spoken language ability in the expressive modality and to set benchmarks for determining a child's language level in order to establish a framework for comparing outcomes across intervention studies. Method: The National Institute on Deafness and Other Communication Disorders assembled a group of researchers with interests and experience in the study of language development and disorders in young children with autism spectrum disorders. The group worked for 18 months through a series of conference calls and correspondence, culminating in a meeting held in December 2007 to achieve consensus on these aims. Results: The authors recommend moving away from using the term functional speech, replacing it with a developmental framework. Rather, they recommend multiple sources of information to define language phases, including natural language samples, parent report, and standardized measures. They also provide guidelines and objective criteria for defining children's spoken language expression in three major phases that correspond to developmental levels between 12 and 48 months of age. C1 [Tager-Flusberg, Helen] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Rogers, Sally] Univ Calif Davis, Med Invest Neurodev Disorders MIND Inst, Sacramento, CA 95817 USA. [Cooper, Judith] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. [Landa, Rebecca] Johns Hopkins Sch Med, Kennedy Krieger Inst, Baltimore, MD USA. [Lord, Catherine] Univ Michigan, Ann Arbor, MI 48109 USA. [Paul, Rhea] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. [Rice, Mabel] Univ Kansas, Lawrence, KS 66045 USA. [Stoel-Gammon, Carol] Univ Washington, Seattle, WA 98195 USA. [Wetherby, Amy] Florida State Univ, Tallahassee, FL 32306 USA. [Yoder, Paul] Vanderbilt Univ, Nashville, TN USA. RP Tager-Flusberg, H (reprint author), Boston Univ, Sch Med, Dept Anat & Neurobiol, 715 Albany St L-814, Boston, MA 02118 USA. EM htagerf@bu.edu RI Tager-Flusberg, Helen/D-5265-2009; OI Rice, Mabel/0000-0002-8150-5523 FU NICHD NIH HHS [P01 HD003008-397319]; NIDCD NIH HHS [K24 DC006619-06, R01 DC007462]; NIMH NIH HHS [R01 MH078165, R01 MH077730, U54 MH066494-010003] NR 48 TC 80 Z9 82 U1 4 U2 31 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 JUN 1 PY 2009 VL 52 IS 3 BP 643 EP 652 DI 10.1044/1092-4388(2009/08-0136) PG 10 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 450YW UT WOS:000266438900005 PM 19380608 ER PT J AU Deutsch, KM Farmer, SF Stephens, JA AF Deutsch, Katherine M. Farmer, Simon F. Stephens, John A. TI Developmental changes in the pulsatile control of slow hand movements SO JOURNAL OF SPORT & EXERCISE PSYCHOLOGY LA English DT Meeting Abstract C1 [Deutsch, Katherine M.] Natl Inst Hlth, Bethesda, MD USA. [Farmer, Simon F.; Stephens, John A.] UCL, London WC1E 6BT, England. [Farmer, Simon F.] Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. RI Farmer, Simon/D-1969-2012 OI Farmer, Simon/0000-0001-5193-8195 NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 0895-2779 J9 J SPORT EXERCISE PSY JI J. Sport Exerc. Psychol. PD JUN PY 2009 VL 31 BP S30 EP S31 PG 2 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 463PV UT WOS:000267445000056 ER PT J AU Hildebrand, M Kim, S Shi, D Scott, K Subramaniam, S AF Hildebrand, Mark Kim, Sang Shi, Dan Scott, Keana Subramaniam, Sriram TI 3D imaging of diatoms with ion-abrasion scanning electron microscopy SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Diatom; Ion-abrasion SEM; Biomineral structure formation; Biosilicification; 3D tomography ID SILICA SHELL FORMATION; THALASSIOSIRA-PSEUDONANA; VALVE MORPHOGENESIS; CENTRIC DIATOM; CELL-WALL; CYLINDROTHECA-FUSIFORMIS; CYCLOTELLA-CRYPTICA; MICROTUBULE CENTER; FINE-STRUCTURE; BIOSILICA AB Ion-abrasion scanning electron microscopy (IASEM) takes advantage of focused ion beams to abrade thin sections from the surface of bulk specimens, coupled with SEM to image the surface of each section, enabling 3D reconstructions of subcellular architecture at similar to 30 nm resolution. Here, we report the first application of IASEM for imaging a biomineralizing organism, the marine diatom Thalassiosira pseudonana. Diatoms have highly patterned silica-based cell wall structures that are unique models for the study and application of directed nanomaterials synthesis by biological systems. Our study provides new insights into the architecture and assembly principles of both the "hard" (siliceous) and "soft" (organic) components of the cell. From 3D reconstructions of developmentally synchronized diatoms captured at different stages, we show that both micro- and nanoscale siliceous structures can be visualized at specific stages in their formation. We show that not only are structures visualized in a whole-cell context, but demonstrate that fragile, early-stage structures are visible, and that this can be combined with elemental mapping in the exposed slice. We demonstrate that the 3D architectures of silica structures, and the cellular components that mediate their creation and positioning can be visualized simultaneously, providing new opportunities to study and manipulate mineral nanostructures in a genetically tractable system. (C) 2009 Elsevier Inc. All rights reserved. C1 [Hildebrand, Mark] Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92093 USA. [Kim, Sang; Shi, Dan; Subramaniam, Sriram] NCI, Cell Biol Lab, NIH, Bethesda, MD 20817 USA. [Scott, Keana] Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA. RP Hildebrand, M (reprint author), Univ Calif San Diego, Scripps Inst Oceanog, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM mhildebrand@ucsd.edu RI Scott, Keana/J-5717-2015 FU Air Force Office of Scientific Research Multidisciplinary University Research Initiative [RF00965521]; National Cancer Institute FX This work was supported by the Air Force Office of Scientific Research Multidisciplinary University Research Initiative Grant RF00965521 (to M.H.) and by the intramural program of the National Cancer Institute (to S.S.). NR 52 TC 41 Z9 42 U1 2 U2 30 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD JUN PY 2009 VL 166 IS 3 BP 316 EP 328 DI 10.1016/j.jsb.2009.02.014 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 445QL UT WOS:000266066500008 PM 19269330 ER PT J AU Reeb-Sutherland, BC Helfinstein, SM Degnan, KA Perez-Edgar, K Henderson, HA Lissek, S Chronis-Tuscano, A Grillon, C Pine, DS Fox, NA AF Reeb-Sutherland, Bethany C. Helfinstein, Sarah M. Degnan, Kathryn A. Perez-Edgar, Koraly Henderson, Heather A. Lissek, Shmuel Chronis-Tuscano, Andrea Grillon, Christian Pine, Daniel S. Fox, Nathan A. TI Startle Response in Behaviorally Inhibited Adolescents With a Lifetime Occurrence of Anxiety Disorders SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE anxiety; temperament; startle; risk factors; adolescence ID FEAR-POTENTIATED STARTLE; POSTTRAUMATIC-STRESS-DISORDER; ACOUSTIC STARTLE; SOCIAL ANXIETY; CHILDREN; CHILDHOOD; THREAT; RISK; ANTICIPATION; ASSOCIATION AB Objective: Behaviorally inhibited children face increased risk for anxiety disorders, although factors that predict which children develop a disorder remain poorly specified. The current study examines whether the startle reflex response may be used to differentiate between behaviorally inhibited adolescents with and without a history of anxiety. Method: Participants were assessed for behavioral inhibition during toddlerhood and early childhood. They returned to the laboratory as adolescents and completed a fear-potentiated startle paradigm and a clinical diagnostic interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version). Magnitude of the startle reflex was examined at baseline and during cues associated with safety and threat. Results: Only adolescents who showed high levels of behavioral inhibition and had a lifetime occurrence of anxiety disorders showed increased startle reactivity in the presence of safety cues. Neither behavioral inhibition nor diagnosis was related to startle reactivity during threat cues. Conclusions: These results suggest that neurobiological measures, such as the startle reflex, may be a potential risk marker for the development of anxiety disorders among behaviorally inhibited adolescents. These methods may enhance our ability to identify vulnerable individuals before the development of anxious psychopathology. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(6):610-617. C1 [Reeb-Sutherland, Bethany C.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [Perez-Edgar, Koraly] George Mason Univ, Fairfax, VA 22030 USA. [Henderson, Heather A.] Univ Miami, Coral Gables, FL 33124 USA. [Lissek, Shmuel; Grillon, Christian; Pine, Daniel S.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD USA. RP Reeb-Sutherland, BC (reprint author), Univ Maryland, Dept Human Dev, 3304 Benjamin Bldg, College Pk, MD 20742 USA. EM breeb@umd.edu OI Perez-Edgar, Koraly/0000-0003-4051-9563 FU National Institutes of Health [MH 074454, HD 17899]; Ortho-McNeil-Janssen FX Dr. Chronis-Tuscano has received support from Ortho-McNeil-Janssen. The other authors report no conflicts of interest. NR 35 TC 37 Z9 37 U1 4 U2 7 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 JUN PY 2009 VL 48 IS 6 BP 610 EP 617 DI 10.1097/CHI.0b013e31819f70fb PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 448YO UT WOS:000266298100005 PM 19454917 ER PT J AU Brotman, MA Rooney, MH Skup, M Pine, DS Leibenluft, E AF Brotman, Melissa A. Rooney, Melissa H. Skup, Martha Pine, Daniel S. Leibenluft, Ellen TI Increased Intrasubject Variability in Response Time in Youths With Bipolar Disorder and At-Risk Family Members SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE bipolar disorder; sustained attention; endophenotype ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT-HYPERACTIVITY-DISORDER; CONTINUOUS PERFORMANCE-TEST; INTRA-SUBJECT VARIABILITY; SUSTAINED ATTENTION; WORKING-MEMORY; 1ST-DEGREE RELATIVES; EXECUTIVE FUNCTIONS; EUTHYMIC PATIENTS; BRAIN-FUNCTION AB Objective: Deficits in sustained attention may represent an endophenotype for bipolar disorder (BD). One heritable measure of sustained attention is intrasubject variability in response time (ISV-RT). We tested the hypothesis that, compared with controls, both youths with BD and those at familial risk for the disorder would have increased ISV-RT. Method: Subjects were 28 patients with BID, 26 unaffected youths with a first-degree relative with BD, and 24 control youths without an affected relative, all aged 7 to 17 years. Subjects completed the Flanker Continuous Performance Test. Results: Bipolar disorder and at-risk youths had increased ISV-RT, compared with the controls. Differences were independent of comorbid psychopathology in youths with BD and present in psychiatrically healthy at-risk youths. Conclusions: Increased ISV-RT may be a risk marker for BD. Further research is needed to investigate the neural and genetic underpinnings of this deficit, as well as the specificity of the finding to BD. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(6):628-635. C1 [Brotman, Melissa A.; Rooney, Melissa H.; Skup, Martha; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rooney, Melissa H.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Skup, Martha] Yale Univ, Dept Biostat, New Haven, CT 06520 USA. RP Brotman, MA (reprint author), NIMH, Mood & Anxiety Program, 15K N Dr,Room 208, Bethesda, MD 20892 USA. EM brotmanm@mail.nih.gov RI Brotman, Melissa/H-7409-2013; OI Rooney, Melissa/0000-0001-6428-7918 FU National Institute of Mental Health; Clinical Research Training Program; National Institutes of Health (NIH); Pfizer FX Funding support for this work was provided by the Intramural Research Program of the National Institute of Mental Health. Funding support for Melissa H. Rooney was provided through the Clinical Research Training Program, a public-private partnership supported jointly by the National Institutes of Health (NIH) and Pfizer (via a grant to the Foundation for NIH from Pfizer). NR 59 TC 28 Z9 29 U1 1 U2 11 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 JUN PY 2009 VL 48 IS 6 BP 628 EP 635 DI 10.1097/CHI.0b013e3181a27527 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 448YO UT WOS:000266298100007 PM 19454918 ER PT J AU Sobanko, JF Freeman, AF Palmore, TN Mendoza, D Lee, CCR Cowen, EW AF Sobanko, Joseph F. Freeman, Alexandra F. Palmore, Tara N. Mendoza, Daniel Lee, Chyi-Chia Richard Cowen, Edward W. TI A Sri Lankan woman with rheumatoid arthritis and anesthetic plaques SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID HEART-TRANSPLANT RECIPIENT; LEPROSY; DISEASE C1 [Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Sobanko, Joseph F.] Georgetown Univ Hosp, Dept Dermatol, Washington Hosp Ctr, Washington, DC USA. [Freeman, Alexandra F.] NCI Frederick, SAIC Frederick Inc, Frederick, MD USA. [Palmore, Tara N.; Mendoza, Daniel] NCI, NIAID, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Natl Inst Hlth, Bldg 10 Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov RI Lee, Chyi-Chia/I-1938-2013; OI Lee, Chyi-Chia/0000-0002-5306-7781; Mendoza, Daniel/0000-0002-6362-0771 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 15 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 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUN PY 2009 VL 60 IS 6 BP 1018 EP 1021 DI 10.1016/j.jaad.2008.10.042 PG 4 WC Dermatology SC Dermatology GA 450QT UT WOS:000266416600015 PM 19467372 ER PT J AU Wu, DW Zhou, QF Shung, KPK Bharadwaja, SN Zhang, DS Zheng, HX AF Wu, Dawei Zhou, Qifa Shung, Koping Kirk. Bharadwaja, Srowthi N. Zhang, Dongshe Zheng, Haixing TI Dielectric and Piezoelectric Properties of PZT Composite Thick Films with Variable Solution to Powder Ratios SO JOURNAL OF THE AMERICAN CERAMIC SOCIETY LA English DT Article ID FABRICATION; TRANSDUCERS; DEPOSITION; ACTUATOR; SILICON; TAPE AB The use of PZT films in sliver-mode high-frequency ultrasonic transducers applications requires thick, dense, and crack-free films with excellent piezoelectric and dielectric properties. In this work, PZT composite solutions were used to deposit PZT films >10 mu m in thickness. It was found that the functional properties depend strongly on the mass ratio of PZT sol-gel solution to PZT powder in the composite solution. Both the remanent polarization, P(r), and transverse piezoelectric coefficient, e(31,f), increase with increasing proportion of the sol-gel solution in the precursor. Films prepared using a solution-to-powder mass ratio of 0.5 have a remanent polarization of 8 mu C/cm(2), a dielectric constant of 450 (at 1 kHz), and e(31,f) = -2.8 C/m(2). Increasing the solution-to-powder mass ratio to 6, the films were found to have remanent polarizations as large as 37 mu C/cm(2), a dielectric constant of 1250 (at 1 kHz) and e(31,f) = -5.8 C/m(2). C1 [Wu, Dawei; Zhou, Qifa; Shung, Koping Kirk.] Univ So Calif, Dept Biomed Engn, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Bharadwaja, Srowthi N.] Penn State Univ, Mat Res Inst, Dept Mat Sci & Engn, University Pk, PA 16802 USA. [Zhang, Dongshe; Zheng, Haixing] Chemat Technol Inc, Northridge, CA 91324 USA. RP Zhou, QF (reprint author), Univ So Calif, Dept Biomed Engn, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu RI wu, dawei/D-3158-2014 FU NIH [P41-EB2182, 1R43 RR014127-01A1] FX This work has been supported by NIH grants # P41-EB2182 and 1R43 RR014127-01A1. NR 27 TC 10 Z9 10 U1 0 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-7820 J9 J AM CERAM SOC JI J. Am. Ceram. Soc. PD JUN PY 2009 VL 92 IS 6 BP 1276 EP 1279 DI 10.1111/j.1551-2916.2009.03065.x PG 4 WC Materials Science, Ceramics SC Materials Science GA 456TX UT WOS:000266875400018 PM 20376196 ER PT J AU Berger, VW AF Berger, Vance W. TI CHEWING GUM AND CARIES SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Letter C1 Univ Maryland Baltimore Cty, Biometry Res Grp, NCI, Bethesda, MD 21228 USA. RP Berger, VW (reprint author), Univ Maryland Baltimore Cty, Biometry Res Grp, NCI, Bethesda, MD 21228 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUN PY 2009 VL 140 IS 6 BP 638 EP + PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 456KQ UT WOS:000266845300006 PM 19491155 ER PT J AU Kenchaiah, S Benjamin, EJ Evans, JC Aragam, J Vasan, RS AF Kenchaiah, Satish Benjamin, Emelia J. Evans, Jane C. Aragam, Jayashri Vasan, Ramachandran S. TI Epidemiology of Left Ventricular False Tendons: Clinical Correlates in the Framingham Heart Study SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article DE Left ventricular false tendons; Echocardiography; Electrocardiography; Heart murmurs; Holter; Tendons ID TWO-DIMENSIONAL ECHOCARDIOGRAPHY; APPARENTLY HEALTHY-SUBJECTS; PREVALENCE; CHILDREN; MURMUR; BANDS; TACHYCARDIA; TRABECULATIONS; HYPERTROPHY; COEXISTENCE AB Objective: The study objective was to describe the echocardiographic characteristics and investigate the clinical correlates and prognostic significance of left ventricular false tendons (LVFTs). Although LVFTs are generally considered as anatomic variants, they have been associated with innocent precordial murmurs and electrocardiographic abnormalities in small case series. The correlates of LVFTs in the community are unknown. Methods: We compared 101 Framingham Study participants with LVFTs (mean age 56 years, 45% were women) on routine two-dimensional echocardiograms with 151 referents without LVFTs (mean age 57 years, 44% were women). We examined the cross-sectional clinical, electrocardiographic (rest and ambulatory), and echocardiographic correlates of LVFTs using logistic regression models and evaluated the prospective association between LVFTs and all-cause mortality using Cox proportional hazards regression models. Results: A total of 107 LVFTs (94 simple with 2 points of attachment and 13 complex/branching type with 3 or more points of attachment) were identified in 101 participants. LVFTs were most commonly visualized in the apical 4-chamber view (81%) and predominantly localized to the apical third of the left ventricular cavity (78%). LVFTs were associated with the presence of innocent precordial murmurs (multivariable adjusted odds ratio [OR] 5.55, 95% confidence interval [CI], 1.40-21.94) and electrocardiographic left ventricular hypertrophy (OR 4.43; 95% CI, 1.08-18.25). Body mass index was inversely related to the presence of LVFTs (per kilogram/meters squared increment; OR 0.94; 95% CI, 0.88-0.99). LVFTs were not associated with QRS axis deviation, ventricular premature beats, or repolarization abnormalities (all P values > .20). During a mean (+/- standard deviation) follow-up of 7.7 (+/- 1.6) years, 15 participants with LVFTs and 19 participants without LVFTs died. In multivariable analyses, the presence of LVFTs was not associated with the risk of death (P = .92). Conclusion: In our community-based sample of middle-aged to elderly white women and men, LVFTs were more likely to be identified in individuals with lower body mass index and cross-sectionally associated with the presence of innocent precordial murmurs and electrocardiographic left ventricular hypertrophy, but they were not associated with the risk of mortality. (J Am Soc Echocardiogr 2009;22:739-745.) C1 [Kenchaiah, Satish; Benjamin, Emelia J.; Evans, Jane C.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Kenchaiah, Satish] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Kenchaiah, Satish] Harvard Univ, Sch Med, Boston, MA USA. [Aragam, Jayashri] Boston VA Healthcare Syst, W Roxbury, MA USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. RP Kenchaiah, S (reprint author), NHLBI, Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM skenchaiah@rics.bwh.harvard.edu RI Kenchaiah, Satish/A-1519-2016; OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute [N01 HC 25195]; National Heart, Lung and Blood Institute, Bethesda, Maryland [2K24 HL04334, R01HL080124] FX This work was supported in part by a contract (N01 HC 25195) with the National Heart, Lung, and Blood Institute and by a research career award (2K24 HL04334) and R01HL080124 from the National Heart, Lung and Blood Institute, Bethesda, Maryland (to Dr Vasan). NR 53 TC 16 Z9 16 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD JUN PY 2009 VL 22 IS 6 BP 739 EP 745 DI 10.1016/j.echo.2009.03.008 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 454HX UT WOS:000266674100015 PM 19423290 ER PT J AU Norris, KC Agodoa, LY AF Norris, Keith C. Agodoa, Lawrence Y. TI How Long Can We Afford to Wait for Equity in the Renal Transplant Waiting List? SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID CHRONIC KIDNEY-DISEASE; UNITED-STATES; RACIAL DISPARITIES; ACCESS; DIALYSIS; HEALTH; INSURANCE; CARE; RACE C1 [Norris, Keith C.] Charles R Drew Univ Med & Sci, Dept Med, Los Angeles, CA 90062 USA. [Norris, Keith C.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Agodoa, Lawrence Y.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Norris, KC (reprint author), Charles R Drew Univ Med & Sci, Dept Med, Los Angeles, CA 90062 USA. EM keithnorris@cdrewu.edu FU NCRR NIH HHS [G12-RR03026, U54 RR019234]; NIMHD NIH HHS [P20-MD00182] NR 20 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2009 VL 20 IS 6 BP 1168 EP 1170 DI 10.1681/ASN.2009040425 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 453NK UT WOS:000266617200006 PM 19470667 ER PT J AU Knepper, MA AF Knepper, Mark A. TI Common Sense Approaches to Urinary Biomarker Study Design SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID PROTEOMICS; EXOSOMES; KIDNEY; AQUAPORIN-2; EXCRETION C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. EM knep@helix.nih.gov NR 15 TC 32 Z9 32 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2009 VL 20 IS 6 BP 1175 EP 1178 DI 10.1681/ASN.2009030321 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 453NK UT WOS:000266617200009 PM 19470673 ER PT J AU Anderson, S Halter, JB Hazzard, WR Himmelfarb, J Horne, FM Kaysen, GA Kusek, JW Nayfield, SG Schmader, K Tian, Y Ashworth, JR Clayton, CP Parker, RP Tarver, ED Woolard, NF High, KP AF Anderson, Sharon Halter, Jeffrey B. Hazzard, William R. Himmelfarb, Jonathan Horne, Frances McFarland Kaysen, George A. Kusek, John W. Nayfield, Susan G. Schmader, Kenneth Tian, Ying Ashworth, John R. Clayton, Charles P. Parker, Ryan P. Tarver, Erika D. Woolard, Nancy F. High, Kevin P. TI Prediction, Progression, and Outcomes of Chronic Kidney Disease in Older Adults SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Review ID STAGE RENAL-DISEASE; GLOMERULAR-FILTRATION-RATE; CYCLE INHIBITOR P16(INK4A); CARDIOVASCULAR RISK-FACTOR; URINARY ALBUMIN EXCRETION; CHRONIC-HEMODIALYSIS PATIENTS; POLYUNSATURATED FATTY-ACIDS; TYPE-2 DIABETES-MELLITUS; LOW-DENSITY-LIPOPROTEIN; COGNITIVE FUNCTION AB Chronic kidney disease is a large and growing problem among aging populations. Although progression of chronic kidney disease to end-stage renal disease (ESRD) is a costly and important clinical event with substantial morbidity, it appears less frequently in aging people compared with cardiovascular mortality. The measurement of kidney function and management of kidney disease in older individuals remain challenging, partly because the pathophysiologic mechanisms underlying age-related decline in kidney function, the interactions between age and other risk factors in renal progression, and the associations of chronic kidney disease with other comorbidities in older people are understudied and poorly understood. The Association of Specialty Professors, the American Society of Nephrology, the American Geriatrics Society, the National Institute on Aging, and the National Institute of Diabetes and Digestive and Kidney Diseases held a workshop, summarized in this article, to review what is known about chronic kidney disease, identify research gaps and resources available to address them, and identify priority areas for future research. Answers to emerging research questions will support the integration of geriatrics and nephrology and thus improve care for older patients at risk for chronic kidney disease. C1 [High, Kevin P.] Wake Forest Univ, Sch Med, Dept Internal Med, Infect Dis Sect, Winston Salem, NC 27157 USA. [Anderson, Sharon] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Halter, Jeffrey B.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Hazzard, William R.] Univ Washington, Dept Med, Seattle, WA USA. [Hazzard, William R.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Himmelfarb, Jonathan] Maine Med Ctr, Dept Med, Portland, ME 04102 USA. [Horne, Frances McFarland; Ashworth, John R.; Clayton, Charles P.; Parker, Ryan P.; Tarver, Erika D.] Assoc Specialty Professors, Washington, DC USA. [Kaysen, George A.] Univ Calif Davis, Dept Internal Med, Davis, CA 95616 USA. [Kusek, John W.] NIDDKD, Kidney & Urol Branch, Bethesda, MD 20892 USA. [Nayfield, Susan G.; Tian, Ying] NIA, Geriatr & Clin Gerontol Branch, Bethesda, MD 20892 USA. [Schmader, Kenneth] Duke Univ, Dept Med, Durham, NC USA. [Schmader, Kenneth] Durham VA Med Ctr, Durham, NC USA. RP High, KP (reprint author), Wake Forest Univ, Sch Med, Dept Internal Med, Infect Dis Sect, 100 Med Ctr Blvd, Winston Salem, NC 27157 USA. EM khigh@wfubmc.edu FU John A. Hartford Foundation FX This workshop was supported by a generous grant from the John A. Hartford Foundation to the Association of Specialty Professors. For a list of the planning cornmittee and attendees of the conference, please visit http:// www.im.org/CarcerDevelopinent/Grantsand Scholarships/IGP/ExpandingResearch Efforts/ Pages/Workshoponprediction,Progression and Outcomes of Chronic Kidney Diseasein OlderAdults.aspx. NR 146 TC 77 Z9 84 U1 0 U2 9 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2009 VL 20 IS 6 BP 1199 EP 1209 DI 10.1681/ASN.2008080860 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 453NK UT WOS:000266617200012 PM 19470680 ER PT J AU Doi, K Yuen, PST Eisner, C Hu, XZ Leelahavanichkul, A Schnermann, J Star, RA AF Doi, Kent Yuen, Peter S. T. Eisner, Christoph Hu, Xuzhen Leelahavanichkul, Asada Schnermann, Juergen Star, Robert A. TI Reduced Production of Creatinine Limits Its Use as Marker of Kidney Injury in Sepsis SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACUTE-RENAL-FAILURE; GLOMERULAR-FILTRATION; HYPERDYNAMIC SEPSIS; BLOOD-FLOW; MORTALITY; MICE; ACETYLCYSTEINE; INHIBITION; PREVENTION; CLEARANCE AB Although diagnosis and staging of acute kidney injury uses serum creatinine, acute changes in creatinine lag behind both renal injury and recovery. The risk for mortality increases when acute kidney injury accompanies sepsis; therefore, we sought to explore the limitations of serum creatinine in this setting. In mice, induction of sepsis by cecal ligation and puncture in bilaterally nephrectomized mice increased markers of nonrenal organ injury and serum TNF-alpha. Serum creatinine, however, was significantly lower in septic animals than in animals subjected to bilateral nephrectomy and sham cecal ligation and puncture. Under these conditions treatment with chloroquine decreased nonrenal organ injury markers but paradoxically increased serum creatinine. Sepsis dramatically decreased production of creatinine in nephrectomized mice, without changes in body weight, hematocrit, or extracellular fluid volume. In conclusion, sepsis reduces production of creatinine, which blunts the increase in serum creatinine after sepsis, potentially limiting the early detection of acute kidney injury. This may partially explain why small absolute increases in serum creatinine levels are associated with poor clinical outcomes. These data support the need for new biomarkers that provide better measures of renal injury, especially in patients with sepsis. C1 [Doi, Kent; Yuen, Peter S. T.; Eisner, Christoph; Hu, Xuzhen; Leelahavanichkul, Asada; Schnermann, Juergen; Star, Robert A.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Star, RA (reprint author), NIDDK, Renal Diagnost & Therapeut Unit, NIH, 10 Ctr Dr,Room 3N108, Bethesda, MD 20892 USA. EM robert_star@nih.gov RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 FU Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; Japan Society for the Promotion of Science Postdoctoral Fellow for Research Abroad 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. K.D. is a Japan Society for the Promotion of Science Postdoctoral Fellow for Research Abroad. NR 34 TC 125 Z9 132 U1 3 U2 5 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2009 VL 20 IS 6 BP 1217 EP 1221 DI 10.1681/ASN.2008060617 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 453NK UT WOS:000266617200014 PM 19389851 ER PT J AU Ma, GX Toubbeh, JI Wang, MQ Shive, SE Cooper, L Pham, A AF Ma, Grace X. Toubbeh, Jamil I. Wang, Min Qi Shive, Steven E. Cooper, Leslie Pham, Anny TI Factors Associated With Cervical Cancer Screening Compliance and Noncompliance among Chinese, Korean, Vietnamese, and Cambodian Women SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE cervical cancer; compliance; Asians; women's health ID AMERICAN WOMEN; UNITED-STATES; BREAST; KNOWLEDGE; PREDICTORS; ATTITUDES; RISK AB Objective: The purpose of this study was to determine factors associated with cervical cancer screening compliance and noncompliance among Chinese, Korean, Vietnamese, and Cambodian women aged 18 years and older. Methods: A cross-sectional design was used. The sample consisted of 1049 women aged 18 or older, of whom 37.94% reported never having been screened for cervical cancer, 23.55% reported noncompliance, and 38.51% were in compliance with screening guidelines. The sample was comprised of Chinese, 50.58%; Koreans, 17.50%; Vietnamese, 16.15%; and Cambodians, 15.77%. Results: Education was significantly associated with never having been screened for cervical cancer for Cambodians. Low income (<$10000) was significantly associated with never having been screened for Cambodian and Chinese women. Not having health insurance was significantly correlated with not getting screened for all ethnic groups. Age and living in the United States less than 15 years were significantly correlated with never having been screened for Vietnamese, Korean, and Chinese women. Marital status was significantly correlated with not getting screened for Korean and Chinese women, English fluency was significantly associated with screening for Cambodians, Koreans, and Chinese. Barriers associated with women who were never screened compared to those barriers for women who were screened and were compliant included lack of knowledge, psychosocial, no insurance, language, transportation, and lack of time, but these barriers were different among the 4 ethnic groups. Conclusion: Compliance with cervical cancer screening guidelines among Asian American women can be enhanced significantly by providing culturally and linguistically appropriate educational and early intervention programs. C1 [Ma, Grace X.; Toubbeh, Jamil I.] Temple Univ, Dept Publ Hlth, Coll Hlth Profess, Philadelphia, PA 19122 USA. [Ma, Grace X.; Toubbeh, Jamil I.; Shive, Steven E.] Temple Univ, Ctr Asian Hlth, Coll Hlth Profess, Philadelphia, PA 19122 USA. [Wang, Min Qi] Univ Maryland, Dept Publ & Community Hlth, College Pk, MD 20742 USA. [Shive, Steven E.] E Stroudsburg Univ, Dept Hlth, E Stroudsburg, PA USA. [Cooper, Leslie] NCI, Ctr Reduce Hlth Care Dispar, NIH, Rockville, MD USA. RP Ma, GX (reprint author), Temple Univ, Dept Publ Hlth, Coll Hlth Profess, 1700 N Broad St,304 Vivacqua Hall, Philadelphia, PA 19122 USA. EM grace.ma@temple.edu FU National Institutes of Health; National Cancer Institute's Community Networks Program [U01 CA114582] FX This research was supported by National Institutes of Health, National Cancer Institute's Community Networks Program, grant U01 CA114582 ATECAR-Asian Community Cancer Network (Dr Ma, principal investigator). NR 32 TC 19 Z9 20 U1 2 U2 10 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD JUN PY 2009 VL 101 IS 6 BP 541 EP 551 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 462XB UT WOS:000267390400005 PM 19585922 ER PT J AU Tammemagi, MC Freedman, MT Pinsky, PF Oken, MM Hu, P Riley, TL Ragard, LR Berg, CD Prorok, PC AF Tammemagi, Martin Carl Freedman, Matthew T. Pinsky, Paul F. Oken, Martin M. Hu, Ping Riley, Thomas L. Ragard, Lawrence R. Berg, Christine D. Prorok, Philip C. TI Prediction of True Positive Lung Cancers in Individuals with Abnormal Suspicious Chest Radiographs-A Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Study SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Lung cancer; Screening; Prediction; Lung cancer risk ID SOLITARY PULMONARY NODULES; BODY-MASS INDEX; PREOPERATIVE DIAGNOSIS; RISK MODEL; COHORT; CT; ASSOCIATION; MALIGNANCY; MANAGEMENT; PROBABILITY AB Introduction: Chest radiographs are routinely employed in clinical practice. Radiographic findings that are abnormal suspicious (AS) for lung cancer occur commonly. The majority of AS radiographic abnormalities are not cancer. This study identifies predictors of true positive (TP) AS and presents models for estimating the probability of lung cancer. Methods: This is a prospective cohort study nested in the randomized National Cancer Institute's Prostate Lung Colorectal Ovarian Cancer Screening Trial (PLCO). First-time AS screens in the screening arm of the PLCO were studied. Associations between nonradiographic and radiographic factors, and TP AS were evaluated by multiple logistic regression. Results: The PLCO intervention arm had 77,465 individuals, of whom 12,314 were AS and of these 232 (1.9%) had lung cancer (were TP). Important independent predictors of TP were older age, lower education, greater pack years and duration smoking history, body mass index <30, family history of lung cancer, lung nodule, lung mass, unilateral mediastinal or hilar lymphadenopathy, lung infiltrate, and upper/middle chest AS location. The model including these variables had a receiver operator characteristic area under the curve (ROC AUC) of 86.4%. This model excluding the smoking variables had an ROC AUC of 77.1% and excluding all nonradiographic variables had an ROC AUC of 73.3% (p < 0.0001 for all these model differences). Smoking and nonsmoking nonradiographic variables significantly added to prediction. Conclusion: This study identifies important nonradiographic and radiographic predictors of lung cancer, and presents an accurate model for estimating the probability of lung cancer in individuals with suspicious radiographs. These findings may be of value for screening, research, and patient and clinician decision-making. C1 [Tammemagi, Martin Carl] Brock Univ, Dept Community Hlth Sci, St Catharines, ON L2S 3A1, Canada. [Freedman, Matthew T.] Georgetown Univ, Dept Oncol, Washington, DC USA. [Oken, Martin M.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Berg, Christine D.] NCI, Early Detect Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Riley, Thomas L.] Informat Management Serv Inc, Rockville, MD USA. [Ragard, Lawrence R.] Westat Corp, Rockville, MD USA. RP Tammemagi, MC (reprint author), Brock Univ, Dept Community Hlth Sci, 500 Glenridge Ave, St Catharines, ON L2S 3A1, Canada. EM martin.tammemagi@brocku.ca RI Pepper, John/O-1662-2013 OI Pepper, John/0000-0001-9888-0437 NR 39 TC 11 Z9 11 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD JUN PY 2009 VL 4 IS 6 BP 710 EP 721 PG 12 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 449RO UT WOS:000266347900008 PM 19404219 ER PT J AU Yabroff, KR Harlan, L Stevens, J Martin, A AF Yabroff, K. Robin Harlan, Linda Stevens, Jennifer Martin, Alison TI Patterns of Care in Adults With Renal Cell Carcinoma: Findings in a Population Based Sample SO JOURNAL OF UROLOGY LA English DT Article DE kidney; kidney neoplasms; health services research; nephrectomy; SEER program ID PARTIAL NEPHRECTOMY; KIDNEY CANCER; UNITED-STATES; TRENDS; PARTICIPATION; DISPARITIES; MORBIDITY; SURGERY AB Purpose: Treatment options in patients with renal cell carcinoma have changed in recent years. However, few studies include detailed information on patient, clinical and health system characteristics in the evaluation of surgical management and the use of systemic therapies in community practice. Materials and Methods: We evaluated surgical management and the use of systemic treatments in a national population based sample of 1,263 patients with renal cell carcinoma newly diagnosed in 2004. Patients were identified from the Surveillance, Epidemiology and End Results Program as part of the Patterns of Care studies. We used descriptive statistics to assess treatment in the entire sample and logistic regression analysis to evaluate the associations between patient demographic, clinical and health system characteristics, and surgery in the subset of 1,032 patients who were potentially eligible for partial or radical nephrectomy and an open or laparoscopic procedure. Results: Surgical treatment in 64.7% of patients (95% CI 60.0%, 69.1%) was radical nephrectomy and most underwent an. open rather than a laparoscopic procedure. Although the proportion of all patients receiving systemic treatments was small, 34.3% (95% CI 23.1, 47.5) of those with stage IV disease received systemic treatment. Few patients participated in clinical trials. On multivariate analysis patients who were female, nonwhite, with larger tumors, without comorbid conditions and treated at hospitals without a residency training program were more likely to undergo radical rather than partial nephrectomy (p <0.05). Patients with larger tumors treated at smaller hospitals were more likely to undergo an open rather than a laparoscopic procedure (p <0.05). Conclusions: In 2004 open radical nephrectomy was the most common surgical management for renal cell carcinoma. Few patients received systemic therapy. Patient demographic, clinical and health system characteristics were associated with surgery. Evaluation of the diffusion of surgical management and newer systemic agents, and trial participation in community practice will be important for future research. C1 [Yabroff, K. Robin] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Stevens, Jennifer] Informat Management Serv Inc, Silver Spring, MD USA. [Martin, Alison] Melanoma Res Alliance, Washington, DC USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 FU NCI NIH HHS [N01-PC-65107, N01-PC-65064, N01-PC-67000, N01-PC-67001, N01-PC-67005, N01-PC-67006, N01-PC-67007, N01-PC-67008, N01-PC-67009, N01-PC-67010] NR 16 TC 12 Z9 12 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 JUN PY 2009 VL 181 IS 6 BP 2462 EP 2468 DI 10.1016/j.juro.2009.02.022 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 444ZX UT WOS:000266020500018 PM 19371892 ER PT J AU Helfand, BT Mongiu, AK Roehrborn, CG Donnell, RF Bruskewitz, R Kaplan, SA Kusek, JW Coombs, L McVary, KT AF Helfand, Brian T. Mongiu, Anne K. Roehrborn, Claus G. Donnell, Robert F. Bruskewitz, Reginald Kaplan, Steven A. Kusek, John W. Coombs, Laura McVary, Kevin T. CA MIST Investigators TI Variation in Institutional Review Board Responses to a Standard Protocol for a Multicenter Randomized, Controlled Surgical Trial SO JOURNAL OF UROLOGY LA English DT Article DE ethics committees, research; randomized controlled trials as topic; surgical procedures, minimally invasive; prostate; research subjects ID HEALTH-SERVICES RESEARCH; RESEARCH-ETHICS-BOARD; MINIMAL-RISK; VARIABILITY; BARRIERS; UROLOGY AB Purpose: The primary responsibility of institutional review boards is to protect human research subjects and, therefore, ensure that studies are performed in accordance with a standard set of ethical principles. A number of groups have compared the responses of institutional review boards in multicenter clinical trials involving medical therapies. To our knowledge no such studies have been performed to date of trials investigating surgical intervention. We investigated the consistency of the recommendations issued by various institutional review boards in the Minimally Invasive Surgical Therapies study for benign prostatic hyperplasia, a multicenter trial with a uniform consent and study protocol. Materials and Methods: We obtained the institutional review board response from 6 of the 7 participating institutions after initial submission of the Minimally Invasive Surgical Therapies study protocol and classified the responses. We then redistributed the approved protocols to an institutional review board at another participating institution and analyzed that review of these protocols. Results: We found that the number and type of responses required for institutional review board approval of an identical study protocol varied significantly among participating institutions. We also found that institutional review board responses were inconsistent in the second review, although all protocols were ultimately approved. Conclusions: The current system of local institutional review board review in the context of a multicenter surgical trial is inefficient in the review process and may not provide expertise for overseeing surgical trials. Based on these results a central surgical institutional review board may be needed to improve the ethical review process in multicenter trials. C1 [Helfand, Brian T.; Mongiu, Anne K.; McVary, Kevin T.] Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA. [Roehrborn, Claus G.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Donnell, Robert F.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Bruskewitz, Reginald] Univ Wisconsin, Ctr Clin Sci, Madison, WI USA. [Kaplan, Steven A.] Weill Cornell Med Coll, New York, NY USA. [Kusek, John W.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. [Coombs, Laura] Amer Coll Radiol, Reston, VA USA. RP McVary, KT (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Urol, Tarry 16-703,303 E Chicago Ave, Chicago, IL 60611 USA. EM k-mcvary@northwestern.edu FU National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health; MIST collaborative group FX Supported by the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health and the MIST collaborative group. NR 23 TC 17 Z9 17 U1 1 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 JUN PY 2009 VL 181 IS 6 BP 2674 EP 2679 DI 10.1016/j.juro.2009.02.032 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 444ZX UT WOS:000266020500106 PM 19375101 ER PT J AU Joshi, BH Leland, P Calvo, A Green, JE Puri, RK AF Joshi, B. H. Leland, P. Calvo, A. Green, J. E. Puri, R. K. TI Human Adrenomedullin Up-Regulates Interleukin-13 Receptor Alpha2 Chain in Prostate Cancer In Vitro and In Vivo: A Novel Approach to Sensitize Prostate Cancer to Anticancer Therapy Comment SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Joshi, B. H.; Leland, P.; Calvo, A.; Green, J. E.; Puri, R. K.] NCI, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,Food & Drug Adm,NIH, Bethesda, MD 20892 USA. RP Joshi, BH (reprint author), NCI, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,Food & Drug Adm,NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUN PY 2009 VL 181 IS 6 BP 2824 EP 2825 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 444ZX UT WOS:000266020500146 ER PT J AU Joshi, A Ablan, SD Soheilian, F Nagashima, K Freed, EO AF Joshi, Anjali Ablan, Sherimay D. Soheilian, Ferri Nagashima, Kunio Freed, Eric O. TI Evidence that Productive Human Immunodeficiency Virus Type 1 Assembly Can Occur in an Intracellular Compartment SO JOURNAL OF VIROLOGY LA English DT Article ID GP41 CYTOPLASMIC TAIL; HIV-1 GAG PROTEINS; PLASMA-MEMBRANE; MATRIX PROTEIN; ENVELOPE GLYCOPROTEINS; PRIMARY MACROPHAGES; DEPENDENT MANNER; INFECTIOUS HIV-1; TERMINAL REGION; VPU PROTEIN AB Human immunodeficiency virus type 1 (HIV-1) assembly occurs predominantly at the plasma membrane of infected cells. The targeting of assembly to intracellular compartments such as multivesicular bodies (MVBs) generally leads to a significant reduction in virus release efficiency, suggesting that MVBs are a nonproductive site for HIV-1 assembly. In the current study, we make use of an HIV-1 Gag-matrix mutant, 29/31KE, that is MVB targeted. We previously showed that this mutant is severely defective for virus particle production in HeLa cells but more modestly affected in primary macrophages. To more broadly examine the consequences of MVB targeting for virus production, we investigated 29/31KE particle production in a range of cell types. Surprisingly, this mutant supported highly efficient assembly and release in T cells despite its striking MVB Gag localization. Manipulation of cellular endocytic pathways revealed that unlike Vpu-defective HIV-1, which demonstrated intracellular Gag localization as a result of Gag endocytosis from the plasma membrane, 29/31KE mutant Gag was targeted directly to an MVB compartment. The 29/31KE mutant was unable to support multiple-round replication; however, this defect could be reversed by truncating the cytoplasmic tail of the transmembrane envelope glycoprotein gp41 and by the acquisition of a 16EK change in matrix. The 16EK/29/31KE matrix mutant replicated efficiently in the MT-4 T-cell line despite maintaining an MVB-targeting phenotype. These results indicate that MVB-targeted Gag can be efficiently released from T cells and primary macrophages, suggesting that under some circumstances, late endosomal compartments can serve as productive sites for HIV-1 assembly in these physiologically relevant cell types. C1 [Joshi, Anjali; Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Soheilian, Ferri; Nagashima, Kunio] NCI, Image Anal Lab, Adv Technol Program, SAIC Frederick, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Bldg 535,Rm 108,Sultan St, Frederick, MD 21702 USA. EM efreed@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, NIH; National Cancer Institute, NIH [N01-CO-12400] FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, and by the Intramural AIDS Targeted Antiviral Program. This project was funded in part with federal funds from the National Cancer Institute, NIH, under contract number N01-CO-12400. NR 77 TC 46 Z9 47 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 JUN 1 PY 2009 VL 83 IS 11 BP 5375 EP 5387 DI 10.1128/JVI.00109-09 PG 13 WC Virology SC Virology GA 445EZ UT WOS:000266034100008 PM 19297499 ER PT J AU Ourmanov, I Kuwata, T Goeken, R Goldstein, S Iyengar, R Buckler-White, A Lafont, B Hirsch, VM AF Ourmanov, Ilnour Kuwata, Takeo Goeken, Robert Goldstein, Simoy Iyengar, Ranjani Buckler-White, Alicia Lafont, Bernard Hirsch, Vanessa M. TI Improved Survival in Rhesus Macaques Immunized with Modified Vaccinia Virus Ankara Recombinants Expressing Simian Immunodeficiency Virus Envelope Correlates with Reduction in Memory CD4(+) T-Cell Loss and Higher Titers of Neutralizing Antibody SO JOURNAL OF VIROLOGY LA English DT Review ID POLYMERASE-CHAIN-REACTION; ACUTE SIV INFECTION; HIV-INFECTION; GAG-POL; AIDS VACCINE; VIRAL REPLICATION; MONONUCLEAR-CELLS; TYPE-1 INFECTION; PASSIVE TRANSFER; DNA VACCINATION AB Previous studies demonstrated that immunization of macaques with simian immunodeficiency virus (SIV) Gag-Pol and Env recombinants of the attenuated poxvirus modified vaccinia virus Ankara (MVA) provided protection from high viremia and AIDS following challenge with a pathogenic strain of SIV. Although all animals became infected, plasma viremia was significantly reduced in animals that received the MVA-SIV recombinant vaccines compared with animals that received nonrecombinant MVA. Most importantly, the reduction in viremia resulted in a significant increase in median and cumulative survival. Continued analysis of these animals over the subsequent 9 years has shown that they maintain a survival advantage, although all but two of the macaques have progressed to AIDS. Importantly, improved survival correlated with preservation of memory CD4(+) T cells in the peripheral blood. The greatest survival advantage was observed in macaques immunized with regimens containing SIV Env, and the titer of neutralizing antibodies to the challenge virus prior to or shortly following challenge correlated with preservation of CD4(+) T cells. These data are consistent with a role for neutralizing antibodies in nonsterilizing protection from high viremia and associated memory CD4(+) T-cell loss. C1 [Ourmanov, Ilnour; Kuwata, Takeo; Goeken, Robert; Goldstein, Simoy; Iyengar, Ranjani; Buckler-White, Alicia; Lafont, Bernard; Hirsch, Vanessa M.] NIAID, LMM, NIH, Bethesda, MD 20892 USA. RP Hirsch, VM (reprint author), NIAID, LMM, NIH, Bldg 4,Room B1-41,4 Ctr Dr, Bethesda, MD 20892 USA. EM vhirsch@niaid.nih.gov RI Kuwata, Takeo/F-5809-2013; Lafont, Bernard/B-7236-2014 FU NIAID; NIH FX This work was supported by the intramural research program of NIAID, NIH. NR 108 TC 14 Z9 14 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 JUN 1 PY 2009 VL 83 IS 11 BP 5388 EP 5400 DI 10.1128/JVI.02598-08 PG 13 WC Virology SC Virology GA 445EZ UT WOS:000266034100009 PM 19321617 ER PT J AU Dunham, EJ Dugan, VG Kaser, EK Perkins, SE Brown, IH Holmes, EC Taubenberger, JK AF Dunham, Eleca J. Dugan, Vivien G. Kaser, Emilee K. Perkins, Sarah E. Brown, Ian H. Holmes, Edward C. Taubenberger, Jeffery K. TI Different Evolutionary Trajectories of European Avian-Like and Classical Swine H1N1 Influenza A Viruses SO JOURNAL OF VIROLOGY LA English DT Article ID H5N1 INFLUENZA; CODON USAGE; GENETIC REASSORTMENT; NORTH-AMERICA; PIGS; TRANSMISSION; HOST; HEMAGGLUTININ; EMERGENCE; ORIGIN AB In 1979, a lineage of avian-like H1N1 influenza A viruses emerged in European swine populations independently from the classical swine H1N1 virus lineage that had circulated in pigs since the Spanish influenza pandemic of 1918. To determine whether these two distinct lineages of swine-adapted A/H1N1 viruses evolved from avian-like A/H1N1 ancestors in similar ways, as might be expected given their common host species and origin, we compared patterns of nucleotide and amino acid change in whole genome sequences of both groups. An analysis of nucleotide compositional bias across all eight genomic segments for the two swine lineages showed a clear lineage-specific bias, although a segment-specific effect was also apparent. As such, there appears to be only a relatively weak host-specific selection pressure. Strikingly, despite each lineage evolving in the same species of host for decades, amino acid analysis revealed little evidence of either parallel or convergent changes. These findings suggest that although adaptation due to evolutionary lineages can be distinguished, there are functional and structural constraints on all gene segments and that the evolutionary trajectory of each lineage of swine A/H1N1 virus has a strong historical contingency. Thus, in the context of emergence of an influenza A virus strain via a host switch event, it is difficult to predict what specific polygenic changes are needed for mammalian adaptation. C1 [Dunham, Eleca J.; Dugan, Vivien G.; Kaser, Emilee K.; Taubenberger, Jeffery K.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Perkins, Sarah E.; Holmes, Edward C.] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16802 USA. [Brown, Ian H.] Vet Labs Agcy Weybridge, Dept Virol, Surrey, England. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Taubenberger, JK (reprint author), NIAID, Infect Dis Lab, NIH, 33 North Dr,Room 3E19A-2,MSC 3203, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov RI Perkins, Sarah/B-1817-2010; Brown, Ian/E-1119-2011; APHA, Staff publications/E-6082-2010; OI Perkins, Sarah/0000-0002-7457-2699; Holmes, Edward/0000-0001-9596-3552 FU NIAID; NIH; Alfred P. Sloan Foundation; NIH/INRO FX This work was supported in part by the intramural program of the NIAID and the NIH, by an Alfred P. Sloan Foundation graduate scholarship, and by the NIH/INRO fellowship program. NR 68 TC 78 Z9 84 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN 1 PY 2009 VL 83 IS 11 BP 5485 EP 5494 DI 10.1128/JVI.02565-08 PG 10 WC Virology SC Virology GA 445EZ UT WOS:000266034100018 PM 19297491 ER PT J AU Changotra, H Jia, YL Moore, TN Liu, GL Kahan, SM Sosnovtsev, SV Karst, SM AF Changotra, Harish Jia, Yali Moore, Tara N. Liu, Guangliang Kahan, Shannon M. Sosnovtsev, Stanislav V. Karst, Stephanie M. TI Type I and Type II Interferons Inhibit the Translation of Murine Norovirus Proteins SO JOURNAL OF VIROLOGY LA English DT Article ID ALTERNATIVE ANTIVIRAL PATHWAYS; ANTIGEN-PRESENTING CELLS; NORWALK-LIKE VIRUS; ACUTE GASTROENTERITIS; INFECTED-CELLS; MURINE-NOROVIRUS-1 INFECTION; ALPHAVIRUS REPLICATION; TARGETED DISRUPTION; STIMULATED GENE-15; CALICIVIRUS RNA AB Human noroviruses are responsible for more than 95% of nonbacterial epidemic gastroenteritis worldwide. Both onset and resolution of disease symptoms are rapid, suggesting that components of the innate immune response are critical in norovirus control. While the study of the human noroviruses has been hampered by the lack of small animal and tissue culture systems, our recent discovery of a murine norovirus (MNV) and its in vitro propagation have allowed us to begin addressing norovirus replication strategies and immune responses to norovirus infection. We have previously demonstrated that interferon responses are critical to control MNV-1 infection in vivo and to directly inhibit viral replication in vitro. We now extend these studies to define the molecular basis for interferon-mediated inhibition. Viral replication intermediates were not detected in permissive cells pretreated with type I interferon after either infection or transfection of virion-associated RNA, demonstrating a very early block to virion production that is after virus entry and uncoating. A similar absence of viral replication intermediates was observed in infected primary macrophages and dendritic cells pretreated with type I IFN. This was not due to degradation of incoming genomes in interferon-pretreated cells since similar levels of genomes were present in untreated and pretreated cells through 6 h of infection, and these genomes retained their integrity. Surprisingly, this block to the translation of viral proteins was not dependent on the well-characterized interferon-induced antiviral molecule PKR. Similar results were observed in cells pretreated with type II interferon, except that the inhibition of viral translation was dependent on PKR. Thus, both type I and type II interferon signaling inhibit norovirus translation in permissive myeloid cells, but they display distinct dependence on PKR for this inhibition. C1 [Changotra, Harish; Jia, Yali; Moore, Tara N.; Liu, Guangliang; Kahan, Shannon M.; Karst, Stephanie M.] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol & Immunol, Ctr Mol & Tumor Virol, Shreveport, LA 71130 USA. [Sosnovtsev, Stanislav V.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Karst, SM (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol & Immunol, Ctr Mol & Tumor Virol, 1501 Kings Highway, Shreveport, LA 71130 USA. EM skarst@lsuhsc.edu RI Changotra, Harish/H-2105-2011; Liu, Guangliang/I-8173-2013; OI Liu, Guangliang/0000-0001-8158-5749; Changotra, Harish/0000-0002-1465-5257 FU Center for Molecular and Tumor Virology [P20-RR018724]; National Center for Research Resources (NCRR); National Institutes of Health (NIH); Board of Regents Support Fund [LEQSF(2008-11)-RD-A-16] FX The findings presented here are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or the NIH. NR 59 TC 33 Z9 35 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN 1 PY 2009 VL 83 IS 11 BP 5683 EP 5692 DI 10.1128/JVI.00231-09 PG 10 WC Virology SC Virology GA 445EZ UT WOS:000266034100037 PM 19297466 ER PT J AU Varadhan, R Chaves, PHM Lipsitz, LA Stein, PK Tian, J Windham, BG Berger, RD Fried, LP AF Varadhan, Ravi Chaves, Paulo H. M. Lipsitz, Lewis A. Stein, Phyllis K. Tian, Jing Windham, B. Gwen Berger, Ronald D. Fried, Linda P. TI Frailty and Impaired Cardiac Autonomic Control: New Insights From Principal Components Aggregation of Traditional Heart Rate Variability Indices SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Frailty; Mortality; Homeostatic impairment; Frequency domain indices; Time-domain indices; Principal components analysis ID ACUTE MYOCARDIAL-INFARCTION; MIDDLE-AGED PERSONS; COMPLEXITY; FLUCTUATION; PHENOTYPE; DYNAMICS; HEALTHY AB Background. Age-related deterioration in homeostatic regulatory mechanisms leads to decreased complexity in their output. For example, the degradation of cardiac autonomic control results in loss of complexity in the heart rate signal. Frailty is a state of critically impaired homeostasis that results in heightened vulnerability to stressors. We propose a new measure of heart rate variability (HRV) to capture the impairment in cardiac autonomic control associated with frailty. Methods. Traditional time and frequency domain indices of HRV were obtained from 2-hour ambulatory electrocardiograms (ECGs) of 276 women (65-101 years old) in the Women's Health and Aging Study-I. Principal components analysis was conducted on the correlation matrix of HRV indices. Frailty was defined using a validated instrument. Regression models were used to evaluate associations of HRV measures with age, frailty, and 5-year mortality. Results. The first two principal components (PCs), PC1 and PC2, explained 90% of the variance in HRV indices. PC I is the mean of log-transformed HRV indices. PC2 is a linear combination of log-transformed indices, with positive weights for very low frequency (VLF), low frequency (LF), and standard deviation of N-N intervals (SDNN), and negative weights for high frequency (HF), root-mean-squared differences of successive N-N intervals (RMSSD), and proportion of all N-N intervals that are larger than 50 ms (pNN50). Decreases in SDNN, VLF, LF, and LF/HF were associated with an increased risk of frailty. PC2 was more strongly associated with age (beta = -.23, p <.001) and frailty (0 = -73. p < 10(-5)) than were the individual HRV indices and LF/HF. PC2 was also the best predictor of 5-year mortality (beta = -.60, p < 10(-6)). Conclusions. Cardiac autonomic control, as reflected by HRV, is impaired in frailty. A new measure derived from PC aggregation of traditional HRV indices provides a compact summary of this impairment. C1 [Varadhan, Ravi; Chaves, Paulo H. M.; Tian, Jing; Fried, Linda P.] Johns Hopkins Univ, Ctr Aging & Hlth, Baltimore, MD 21205 USA. [Varadhan, Ravi; Chaves, Paulo H. M.; Fried, Linda P.] Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. [Lipsitz, Lewis A.] Harvard Univ, Sch Med, Beth Deaconess Med Ctr, Boston, MA USA. [Stein, Phyllis K.] Washington Univ, Sch Med, St Louis, MO USA. [Windham, B. Gwen] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Berger, Ronald D.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD 21205 USA. RP Varadhan, R (reprint author), Johns Hopkins Univ, Ctr Aging & Hlth, 2024 E Monument St,Suite 2-700, Baltimore, MD 21205 USA. EM rvaradhan@jhmi.edu FU National Institute oil Aging [P30 AG021334]; National Institutes of Heallh-National Center [R37AGt9905] FX This research was supported by the National Institute oil Aging. Claude D. Pepper Older Americans Independence Centers. grant P30 AG021334. and National Institutes of Heallh-National Center for Research Resources grant R37AGt9905 at theJohns Hopkins University School of Medicine. NR 23 TC 20 Z9 20 U1 0 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 JUN PY 2009 VL 64 IS 6 BP 682 EP 687 DI 10.1093/gerona/glp013 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 473YB UT WOS:000268247100010 PM 19223607 ER PT J AU Williamson, JD Espeland, M Kritchevsky, SB Newman, AB King, AC Pahor, M Guralnik, JM Pruitt, LA Miller, ME AF Williamson, Jeff D. Espeland, Mark Kritchevsky, Stephen B. Newman, Anne B. King, Abby C. Pahor, Marco Guralnik, Jack M. Pruitt, Leslie A. Miller, Michael E. CA LIFE Study Investigators TI Changes in Cognitive Function in a Randomized Trial of Physical Activity: Results of the Lifestyle Interventions and Independence for Elders Pilot Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Exercise; Cognition; Aging; Prevention; LIFE Study ID LOWER-EXTREMITY FUNCTION; OLDER-ADULTS; PERFORMANCE BATTERY; ALZHEIMER-DISEASE; F344 RATS; EXERCISE; RISK; DEMENTIA; BRAIN; DECLINE AB Background Cognitive impairment is an important contributor to disability. Limited clinical trial evidence exists regarding the impact of physical exercise on cognitive function (CF). We report results of a pilot study to provide estimates of the relative impact of physical activity (PA) on 1-year changes in cognitive outcomes and to characterize relationships between changes in mobility disability and changes in cognition in older adults at increased risk for disability. Methods. Sedentary persons (102) at increased risk for disability (aged 70-89 years) were randomized to moderate-intensity PA or health education. Participants were administered the Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), modified Stroop test. and Modified Mini-Mental State Examination at baseline and 1 year. Results. Group differences were not significant but improvements in cognitive scores were associated with improvements in physical function. Specifically, the DSST significantly correlated with change in the Short Physical Performance Battery score (r=.38, p=.0002), in chair stand score (r=.26 p=.012), in balance score (r =.21 p =.046), and in 400-m gait speed (r=.15, p=.147). Change recall on the RAVLT and in the Stroop test was also positively correlated with changes in chair stand and balance. respectively. Conclusions. These results provide further support for the benefits of exercise on CF in older adults. An adequately powered clinical trial of PA involving older adults at increased risk for cognitive disability is needed to expand the indications for prescribing exercise for prevention of decline in brain function. C1 [Williamson, Jeff D.] Wake Forest Univ Hlth Sci, Roena Kulynych Ctr Memory & Cognit Res, J Paul Sticht Ctr Aging, Dept Med, Winston Salem, NC 27151 USA. [Miller, Michael E.] Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Med, Pittsburgh, PA USA. [King, Abby C.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Pahor, Marco] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. [Guralnik, Jack M.] NIA, Epidemiol & Demog Sect, Bethesda, MD 20892 USA. [Pruitt, Leslie A.] Stanford Univ, Dept Publ Hlth, Stanford, CA 94305 USA. [Espeland, Mark] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC 27103 USA. RP Williamson, JD (reprint author), Wake Forest Univ Hlth Sci, Roena Kulynych Ctr Memory & Cognit Res, J Paul Sticht Ctr Aging, Dept Med, Med Ctr Blvd, Winston Salem, NC 27151 USA. EM jwilliam@wfubmc.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institutes of Health (NIH)/National Institute oil Aging [U01 AG22376]; Pepper Older American Independence Center [11330, AG21332] FX The LIFE-P study was funded by I grant from the National Institutes of Health (NIH)/National Institute oil Aging (NIA) (U01 AG22376) and supported in pail by the Intramural Research Program, NIA, NIH. The Wake Forest Univcrsity Field Centel- was, in part, supported by the Claud', D. Pepper Older American Independence Center #11330 AG21332. J..W. and M.E.M.'s contributions are partially SLIpported by the Rocna Kulyllych Centel- lot- `Vlernory and Cognition Research, Wake Forest University Health Sciences, Winston-Salem. North Carolina. This study Was funded by a grant from tile NIA. The NIA scientists had substantial involvement in the study design, data collection analysis and interpretation, and manuscript prepaiation. NR 41 TC 63 Z9 64 U1 1 U2 10 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 JUN PY 2009 VL 64 IS 6 BP 688 EP 694 DI 10.1093/gerona/glp014 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 473YB UT WOS:000268247100011 PM 19244157 ER PT J AU Miller, FG Truog, RD AF Miller, Franklin G. Truog, Robert D. TI The Incoherence of Determining Death by Neurological Criteria: A Commentary on Controversies in the Determination of Death, A White Paper by the President's Council on Bioethics SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article ID BRAIN-DEATH C1 [Miller, Franklin G.] Georgetown Univ, Kennedy Inst Eth, Washington, DC 20057 USA. [Miller, Franklin G.] NIMH, Bethesda, MD 20892 USA. [Truog, Robert D.] Harvard Univ, Sch Med, Boston, MA USA. [Truog, Robert D.] Childrens Hosp, Boston, MA 02115 USA. [Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. NR 16 TC 23 Z9 24 U1 0 U2 1 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD JUN PY 2009 VL 19 IS 2 BP 185 EP 193 PG 9 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA 464AD UT WOS:000267475000005 PM 19623822 ER PT J AU Anderson, AH Cohen, AJ Kutner, NG Kopp, JB Kimmel, PL Muntner, P AF Anderson, Amanda H. Cohen, Andrew J. Kutner, Nancy G. Kopp, Jeffrey B. Kimmel, Paul L. Muntner, Paul TI Missed dialysis sessions and hospitalization in hemodialysis patients after Hurricane Katrina SO KIDNEY INTERNATIONAL LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the American-Society-of-Nephrology/Annual Renal Week CY OCT 31-NOV 05, 2007 CL San Francisco, CA SP Amer Soc Nephrol DE disaster; end-stage renal disease; hemodialysis; hospitalization; missed dialysis; preparedness ID RELIEF TASK-FORCE; INTERDIALYTIC WEIGHT-GAIN; PSYCHOMETRIC PROPERTIES; DISASTER; PREDICTORS; EARTHQUAKE; SURVIVAL; NONCOMPLIANCE; ORGANIZATION; PREVALENCE AB In order to evaluate the factors that contributed to missed dialysis sessions and increased hospitalizations of hemodialysis patients after Hurricane Katrina, we contacted 386 patients from 9 New Orleans hemodialysis units. Data were collected through structured telephone interviews on socio-demographics, dialysis factors, and evacuation characteristics. Overall, 44% of patients reported missing at least one and almost 17% reported missing 3 or more dialysis sessions. The likelihood of missing 3 or more sessions was greater for those whose dialysis vintage was less than 2 years compared to those for whom it was 5 or more years, who had 38 or fewer billed dialysis sessions compared to those who had 39 or more in the 3 months before the storm, who lived alone before the storm, who were unaware of their dialysis facility's emergency plans, who did not evacuate prior to hurricane landfall, and who were placed in a shelter. The adjusted odds ratio of hospitalization among patients who missed 3 or more compared to those who did not miss any dialysis sessions was 2.16 (95% CI: 1.05-4.43). These findings suggest that when preparing for future disasters more emphasis needs to be placed on patient awareness and early execution of emergency plans. Kidney International (2009) 75, 1202-1208; doi:10.1038/ki.2009.5; published online 11 February 2009 C1 [Muntner, Paul] Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY 10029 USA. [Anderson, Amanda H.; Muntner, Paul] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Anderson, Amanda H.] Univ Penn, Sch Med, Dept Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Cohen, Andrew J.] Ochsner Hlth Syst, Nephrol Sect, Dept Med, New Orleans, LA USA. [Kutner, Nancy G.] Emory Univ, US Renal Data Syst Rehabil Qual Life Special Stud, Dept Med, Atlanta, GA 30322 USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. [Kimmel, Paul L.] George Washington Univ, Dept Med, Div Renal Dis & Hypertens, Washington, DC USA. RP Muntner, P (reprint author), Mt Sinai Sch Med, Dept Community & Prevent Med, 1 Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. EM paul.muntner@mssm.edu OI Kopp, Jeffrey/0000-0001-9052-186X FU NIDDK NIH HHS [N01-DK-7-5004, N01-DK-1-2471]; PHS HHS [HHSN267200715004C] NR 31 TC 25 Z9 25 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUN PY 2009 VL 75 IS 11 BP 1202 EP 1208 DI 10.1038/ki.2009.5 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 447YK UT WOS:000266227800012 PM 19212421 ER PT J AU Su, XZ Jiang, HY Yi, M Mu, JB Stephens, RM AF Su, Xin-zhuan Jiang, Hongying Yi, Ming Mu, Jianbing Stephens, Robert M. TI Large-scale Genotyping and Genetic Mapping in Plasmodium Parasites SO KOREAN JOURNAL OF PARASITOLOGY LA English DT Review DE Plasmodium; malaria; phenotype; genotype; microsatellite; SNP ID HUMAN MALARIA PARASITE; SINGLE-NUCLEOTIDE POLYMORPHISMS; FRAGMENT LENGTH POLYMORPHISM; CHLOROQUINE-RESISTANCE LOCUS; MICROSATELLITE MARKERS; MEFLOQUINE RESISTANCE; FALCIPARUM INFECTIONS; MULTIDRUG-RESISTANCE; COMPARATIVE GENOMICS; MIXED INFECTIONS AB The completion of many malaria parasite genomes provides great opportunities for genomewide characterization of gene expression and high-throughput genotyping. Substantial progress in malaria genomics and genotyping has been made recently, particularly the development of various microarray platforms for large-scale characterization of the Plasmodium falciparum genome. Microarray has been used for gene expression analysis, detection of single nucleotide polymorphism ( SNP) and copy number variation (CNV), characterization of chromatin modifications, and other applications. Here we discuss some recent advances in genetic mapping and genomic studies of malaria parasites, focusing on the use of high-throughput arrays for the detection of SNP and CNV in the P. falciparum genome. Strategies for genetic mapping of malaria traits are also discussed. C1 [Su, Xin-zhuan; Jiang, Hongying; Mu, Jianbing] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Yi, Ming; Stephens, Robert M.] NCI, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM xsu@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 FU NCI [N01-CO-12400] FX We thank Jun Yang and Brandie Fullmer at the Laboratory of Immunopathogenesis and Bioinformatics, SAIC-Frederick, Inc. for microarray hybridizations and NIAID intramural editor Brenda Rae Marshall for assistance. This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health and the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; and in part was funded by NCI contract N01-CO-12400. NR 91 TC 4 Z9 4 U1 0 U2 2 PU KOREAN SOC PARASITOLOGY, SEOUL NATL UNIV COLL MEDI PI SEOUL PA DEPT PARASITOLOGY, SEOUL, 00000, SOUTH KOREA SN 0023-4001 J9 KOREAN J PARASITOL JI Korean J. Parasitol. PD JUN PY 2009 VL 47 IS 2 BP 83 EP 91 DI 10.3347/kjp.2009.47.2.83 PG 9 WC Parasitology SC Parasitology GA 458UI UT WOS:000267049700001 PM 19488413 ER PT J AU Brown, P Gipson, C AF Brown, Patricia Gipson, Chester TI A word from OLAW and USDA SO LAB ANIMAL LA English DT Editorial Material C1 [Brown, Patricia] NIH, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. [Gipson, Chester] USDA, APHIS, AC, Washington, DC USA. RP Brown, P (reprint author), NIH, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD JUN PY 2009 VL 38 IS 6 BP 186 EP 186 DI 10.1038/laban0609-186b PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 450OZ UT WOS:000266412000004 PM 19455159 ER PT J AU Nishiura, H Nonaka, H Revollo, IS Semba, U Li, Y Ota, Y Irie, A Harada, K Kehrl, JH Yamamoto, T AF Nishiura, Hiroshi Nonaka, Hideo Revollo, Ivette S. Semba, Umeko Li, Ying Ota, Yoshihiko Irie, Atsushi Harada, Kumiko Kehrl, John H. Yamamoto, Tetsuro TI Pro- and anti-apoptotic dual functions of the C5a receptor: involvement of regulator of G protein signaling 3 and extracellular signal-regulated kinase SO LABORATORY INVESTIGATION LA English DT Article DE apoptosis; C5a; C5a receptor; extracellular signal-regulated kinase; regulator of G protein signaling 3; ribosomal protein S19 ID S19 RIBOSOMAL-PROTEIN; MONOCYTE CHEMOTACTIC FACTOR; HISTONE DEACETYLASE INHIBITOR; PREDOMINANT INFILTRATION; HUMAN NEUTROPHILS; CELL-DEATH; NF-Y; CONSTITUTIVE ACTIVITY; MOLECULAR MECHANISM; COUPLED RECEPTORS AB When apoptosis is initiated by manganese (II) loading, hyperthermia or thapsigargin treatment, human HL-60 and AsPC-1 cells initiate de novo synthesis of the C5a receptor (C5aR) and generation of its ligand, the ribosomal protein S19 (RP S19) homodimer. The ligand-receptor interaction, in an autocrine/paracrine fashion, promotes apoptosis, which can be bypassed by exogenous administration of C5a, another ligand. The proapoptotic function of the RP S19 dimer is reproduced by a C5a/RPS19 chimera that contains the body of C5a and the C-terminal region (Ile134-His145) of RP S19. The RP S19 dimer or C5a/RPS19 and C5a inversely regulate the expression of Regulator of G protein Signaling 3 (RGS3) gene in the apoptosis-initiated cells. Namely, the RP S19-type proteins upregulate RGS3 expression, whereas the C5a reduce it. Transformation of HL-60 cells to overexpress RGS3 promotes apoptosis in association with the downregulation of the Extracellular signal-Regulated Kinase (ERK) signal, and vice versa in the RGS3 knocked-down cells. Consistent with this result, an inhibitor of ERK phosphorylation effectively enhances the apoptotic rate in wild-type HL-60 cells. Moreover, a dominant negative effect on the RP S19 dimer production encourages apoptosis-initiated HL-60 cells with a longer lifespan in mouse than the natural effect. Our data indicate that, in apoptosis-initiated cells, the ligand-dependent C5aR-mediated dual signal affects the fate of cells, either apoptosis execution or survival, through regulation of RGS3 gene expression and subsequent modulation of ERK signal. Laboratory Investigation (2009) 89, 676-694; doi:10.1038/labinvest.2009.27; published online 30 March 2009 C1 [Nishiura, Hiroshi; Nonaka, Hideo; Revollo, Ivette S.; Semba, Umeko; Li, Ying; Ota, Yoshihiko; Yamamoto, Tetsuro] Kumamoto Univ, Fac Med & Pharmaceut Sci, Dept Mol Pathol, Kumamoto, Kyushyu 8600811, Japan. [Irie, Atsushi; Harada, Kumiko] Kumamoto Univ, Fac Med & Pharmaceut Sci, Dept Immunogenet, Kumamoto, Kyushyu 8600811, Japan. [Kehrl, John H.] NIAID, Dept Cell B, Mol Immunol Sect, Lab Immunoregulat,NIH, Bethesda, MD 20892 USA. RP Nishiura, H (reprint author), Kumamoto Univ, Fac Med & Pharmaceut Sci, Dept Mol Pathol, Kumamoto, Kyushyu 8600811, Japan. EM seino@kumamoto-u.ac.jp OI Kehrl, John/0000-0002-6526-159X NR 55 TC 20 Z9 20 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD JUN PY 2009 VL 89 IS 6 BP 676 EP 694 DI 10.1038/labinvest.2009.27 PG 19 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 450OV UT WOS:000266411600008 PM 19333232 ER PT J AU Einstein, MH Schiller, JT Viscidi, RP Strickler, HD Coursaget, P Tan, T Halsey, N Jenkins, D AF Einstein, Mark H. Schiller, John T. Viscidi, Raphael P. Strickler, Howard D. Coursaget, Pierre Tan, Tina Halsey, Neal Jenkins, David TI Clinician's guide to human papillomavirus immunology: knowns and unknowns SO LANCET INFECTIOUS DISEASES LA English DT Review ID VIRUS-LIKE PARTICLES; CERVICAL INTRAEPITHELIAL NEOPLASIA; COTTONTAIL RABBIT PAPILLOMAVIRUS; P53 CODON-72 POLYMORPHISM; SUBSEQUENT HPV INFECTION; LANGERHANS CELLS; CANCER WORLDWIDE; NATURAL-HISTORY; DENDRITIC CELLS; RISK-FACTORS AB Oncogenic human papillomavirus (HPV) is a common genital infection that has the potential to develop into cervical cancer in some women. This Review summarises current knowledge on the mechanisms of host immunity that help prevent and control HPV infection and the viral factors that exist to avoid immune surveillance. Although most women clear the infection within a few months, the virus induces a shift towards immune tolerance that can facilitate persistence and permit tumorigenesis. Mechanisms used by HPV to avoid immune surveillance and control include infecting only the basal layer of the cervical epithelium, limiting expression of viral proteins until later stages of epithelial differentiation, undergoing non-lytic replication, and downregulating the expression of important receptors on cells of the innate immune system. Furthermore, HPV suppresses the expression of several proinflammatory proteins that are crucial in clearing infection and activating the cytotoxic T lymphocytes involved in killing virus-infected cells. Interestingly, neutralising antibodies, although of uncertain effectiveness in preventing infection or reinfection after natural exposure (prior infection), are highly protective after immunisation with HPV virus-like-particle-based vaccines. Understanding what is known and unknown about the interaction between the immune system and HPV is important in the assessment of the potential contribution of prophylactic vaccination in reducing the incidence of cervical cancer. However, despite our growing understanding, many aspects of the interactions between HPV and the host immune system remain unknown, and this Review draws attention to several of these unresolved issues and their implications. C1 [Einstein, Mark H.] Albert Einstein Coll Med, Div Gynecol Oncol, Bronx, NY 10461 USA. [Einstein, Mark H.] Montefiore Med Ctr, Bronx, NY 10461 USA. [Schiller, John T.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Viscidi, Raphael P.] Johns Hopkins Univ Hosp, Dept Pediat, Baltimore, MD 21287 USA. [Viscidi, Raphael P.] Johns Hopkins Univ Hosp, Stanley Div Dev Neurovirol, Baltimore, MD 21287 USA. [Strickler, Howard D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Coursaget, Pierre] Univ Tours, Vectors Viruses & Vaccines Lab, INSERM, Fac Pharm,U618, Tours, France. [Tan, Tina] Northwestern Univ, Feinberg Sch Med, Travel Immunizat Program, Chicago, IL 60611 USA. [Halsey, Neal] Johns Hopkins Univ, Dept Int Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Jenkins, David] Univ Nottingham, Dept Pathol, Nottingham NG7 2RD, England. RP Einstein, MH (reprint author), Albert Einstein Coll Med, Div Gynecol Oncol, 1695 Eastchester Rd,Suite 601, Bronx, NY 10461 USA. EM meinstei@montefiore.org NR 78 TC 81 Z9 90 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUN PY 2009 VL 9 IS 6 BP 347 EP 356 PG 10 WC Infectious Diseases SC Infectious Diseases GA 452LU UT WOS:000266542300012 PM 19467474 ER PT J AU Romagnoli, R Baraldi, PG Carrion, MD Cruz-Lopez, O Cara, CL Preti, D Tabrizi, MA Balzarini, J Hamel, E Fabbri, E Gambari, R AF Romagnoli, Romeo Baraldi, Pier Giovanni Carrion, Maria Dora Cruz-Lopez, Olga Cara, Carlota Lopez Preti, Delia Tabrizi, Mojgan Aghazadeh Balzarini, Jan Hamel, Ernest Fabbri, Enrica Gambari, Roberto TI Discovery of 8-methoxypyrazino[1,2-a]indole as a New Potent Antiproliferative Agent Against Human Leukemia K562 Cells. A Structure-Activity Relationship Study SO LETTERS IN DRUG DESIGN & DISCOVERY LA English DT Article DE Pyrazino[1,2-a]indole; Human leukemia K562 cell line; Anticancer agents ID GLOBIN MESSENGER-RNA; DIFFERENTIATION; TUBULIN; INDOLE; POLYMERIZATION; INHIBITORS; APOPTOSIS; ANALOGS AB Identification of novel and selective anticancer agents remains an important and challenging goal in pharmacological research. The indole nucleus, frequently encountered as a molecular fragment in natural products and pharmaceutically active compounds, was employed as the initial building block for the synthesis of a series of pyrazino[1,2-a]indoles 1a-k, variably substituted at the 6, 7, 8 and 9-positions. Compound 1e, bearing the methoxy group at the 8-position of the pyrazino[1,2-a]indole nucleus was identified as a novel potent antiproliferative agent against the human chronic myelogenous leukemia K562 cell line, but it was much less active against several other cancer cell lines. Comparison of positional isomers indicated that moving the methoxy group from the 8- to the 7- or 6-position, to furnish compounds 1f and 1g, respectively, yielded inactive compounds. The analysis of structure-activity relationships observed in the series of investigated compounds may represent the basis for the design of more active molecules. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Carrion, Maria Dora; Cruz-Lopez, Olga; Cara, Carlota Lopez; Preti, Delia; Tabrizi, Mojgan Aghazadeh] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Balzarini, Jan] Katholieke Univ Leuven, Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. [Hamel, Ernest] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Fabbri, Enrica; Gambari, Roberto] Univ Ferrara, Dipartmento Biochim & Biol Mol, I-44100 Ferrara, Italy. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, Via Fossato Mortara 17-19, I-44100 Ferrara, Italy. EM rmr@unife.it RI Aghazadeh Tabrizi, Mojgan/I-9169-2014; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Gambari, Roberto/F-9555-2015; Carrion, M. Dora/G-8638-2015; preti, delia/G-9916-2015; Romagnoli, Romeo/G-9887-2015; Fabbri, Enrica/O-8059-2015; Baraldi, Pier Giovanni/B-7933-2017; Cruz-Lopez, Olga /F-3060-2017 OI LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; Gambari, Roberto/0000-0001-9205-6033; Carrion, M. Dora/0000-0002-6794-3949; preti, delia/0000-0002-1075-3781; Fabbri, Enrica/0000-0002-9836-8262; FU AIRC; "Fondazione Cassa di Risparmio di Padova e Rovigo"; [GOA05/19] FX RG is supported by grants from the AIRC and the "Fondazione Cassa di Risparmio di Padova e Rovigo". The financial support (GOA05/19) was gratefully acknowledged. We thanks Mrs. Lizette van Berckelaer for excellent technical assistance. NR 25 TC 5 Z9 5 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-1808 J9 LETT DRUG DES DISCOV JI Lett. Drug Des. Discov. PD JUN PY 2009 VL 6 IS 4 BP 298 EP 303 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 458TN UT WOS:000267046500008 PM 20161090 ER PT J AU Chuang, KH Koretsky, AP AF Chuang, Kai-Hsiang Koretsky, Alan P. TI Accounting for nonspecific enhancement in neuronal tract tracing using manganese enhanced magnetic resonance imaging SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Tract tracing; Pituitary gland; Olfactory pathways; Molecular imaging; MRI ID ANTERIOR-PITUITARY-CELLS; BRAIN IN-VIVO; MOUSE-BRAIN; MRI; MNCL2; CONNECTIONS; INJURY; MEMRI; PROJECTIONS; INJECTION AB Manganese enhanced MRI (MEMRI) is an emerging technique for tracing neuronal pathways in vivo. However, manganese may leak into blood vessels or cerebrospinal fluid (CSF) after local injection and can be circulated to and taken up by brain regions that may not have connections to the targeted pathways. Comparing enhancement time courses after intranasal injection with intravenous infusion of MnCl(2) in rats, the early enhancements in the pituitary gland (Pit) and hippocampus indicate the contrasts in those regions in the olfactory tract-tracing experiment were caused by such systemic effects. Since the Pit has easy access to manganese from the blood and its signal is proportional to other brain regions after intravenous infusion, it was used as air internal reference for the systemic effects. Applying intensity normalization by the Pit signal to tract-tracing data from the olfactory bulb led to reduced contrast in the hippocampus. These results demonstrate that nonspecific enhancements in MEMRI tract-tracing studies may have to be taken into account and that normalization by the Pit signal can compensate these effects. Published by Elsevier Inc. C1 [Chuang, Kai-Hsiang; Koretsky, Alan P.] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Chuang, KH (reprint author), Singapore Bioimaging Consortium, Lab Mol Imaging, 11 Biopolis Way,Helios 02-02, Singapore 138667, Singapore. EM chuangk@ninds.nih.gov; chuang_kai_hsiang@sbic.a-star.edu.sg RI Koretsky, Alan/C-7940-2015; OI Koretsky, Alan/0000-0002-8085-4756; Chuang, Kai-Hsiang/0000-0002-8356-0657 FU Intramural Research Program of the NINDS, NIH FX This research was supported by the Intramural Research Program of the NINDS, NIH. NR 31 TC 25 Z9 26 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD JUN PY 2009 VL 27 IS 5 BP 594 EP 600 DI 10.1016/j.mri.2008.10.006 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 455WS UT WOS:000266799600002 PM 19144489 ER PT J AU Nezafat, R Ouwerkerk, R Derbyshire, AJ Stuber, M McVeigh, ER AF Nezafat, Reza Ouwerkerk, Ronald Derbyshire, Andrew J. Stuber, Matthias McVeigh, Elliot R. TI Spectrally Selective B-1-Insensitive T-2 Magnetization Preparation Sequence SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE contrast enhancement; fat saturation; high field imaging; B-1 and B-0 homogeneity; adiabatic RF ID CORONARY MRA; RESONANCE ANGIOGRAPHY; ADIABATIC PULSES; PLANE ROTATIONS; FREQUENCY; NMR; TISSUE; RELAXATION; CONTRAST; FIELDS AB A T-2 magnetization-preparation (T-2 Prep) sequence is proposed that is insensitive to B-1 field variations and simultaneously provides fat suppression without any further increase in specific absorption rate (SAR). Increased B-1 inhomogeneity at higher magnetic field strength (B-0 >= 3T) necessitates a preparation sequence that is less sensitive to B, variations. For the proposed technique, T-2 weighting in the image is achieved using a segmented B-1-insensitive rotation (BIR-4) adiabatic pulse by inserting two equally long delays, one after the initial reverse adiabatic half passage (AHP), and the other before the final AHP segment of a BIR-4 pulse. This sequence yields T-2 weighting with both B-1 and B-0 insensitivity. To simultaneously suppress fat signal (at the cost of B-0 insensitivity), the second delay is prolonged so that fat accumulates additional phase due to its chemical shift. Numerical simulations as well as phantom and in vivo image acquisitions were performed to show the efficacy of the proposed technique. Magn Reson Med 61:1326-1335, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Nezafat, Reza] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Nezafat, Reza] Harvard Univ, Sch Med, Boston, MA USA. [Ouwerkerk, Ronald; Stuber, Matthias] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Derbyshire, Andrew J.; McVeigh, Elliot R.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [McVeigh, Elliot R.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. RP Nezafat, R (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, 330 Brookline Ave, Boston, MA 02215 USA. EM rnezafat@bidmc.harvard.edu RI Stuber, Matthias/B-2949-2010 OI Stuber, Matthias/0000-0001-9843-2028 NR 20 TC 20 Z9 20 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2009 VL 61 IS 6 BP 1326 EP 1335 DI 10.1002/mrm.21742 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 450VS UT WOS:000266429900008 PM 19319903 ER PT J AU Saybasili, H Kellman, P Griswold, MA Derbyshire, JA Guttman, MA AF Saybasili, Haris Kellman, Peter Griswold, Mark A. Derbyshire, J. Andrew Guttman, Michael A. TI HTGRAPPA: Real-Time B-1-Weighted Image Domain TGRAPPA Reconstruction SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE GRAPPA; TGRAPPA; real-time MRI; parallel MRI ID PHASED-ARRAY; PARALLEL; TSENSE; GRAPPA; SENSE; MRI AB The temporal generalized autocalibrating partially parallel acquisitions (TGRAPPA) algorithm for parallel MRI was modified for real-time low latency imaging in interventional procedures using image domain, B-1-weighted reconstruction. GRAPPA coefficients were calculated in k-space, but applied in the image domain after appropriate transformation. Convolution-like operations in k-space were thus avoided, resulting in improved reconstruction speed. Image domain GRAPPA weights were combined into composite unmixing coefficients using adaptive B-1-map estimates and optimal noise weighting. Images were reconstructed by pixel-by-pixel multiplication in the image domain, rather than time-consuming convolution operations in k-space. Reconstruction and weight-set calculation computations were parallelized and implemented on a general-purpose multicore architecture. The weight calculation was performed asynchronously to the real-time image reconstruction using a dedicated parallel processing thread. The weight-set coefficients were computed in an adaptive manner with updates linked to changes in the imaging scan plane. In this implementation, reconstruction speed is not dependent on acceleration rate or GRAPPA kernel size. Magn Reson Med 61: 1425-1433, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Saybasili, Haris; Kellman, Peter; Derbyshire, J. Andrew; Guttman, Michael A.] NHLBI, NIH, DHHS, Bethesda, MD 20892 USA. [Griswold, Mark A.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Saybasili, Haris] Bogazici Univ, Inst Biomed Engn, Istanbul, Turkey. RP Saybasili, H (reprint author), NHLBI, NIH, DHHS, Bldg 10,Rm B1D416, Bethesda, MD 20892 USA. EM saybasilih@mail.nih.gov FU Intramural NIH HHS NR 16 TC 5 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2009 VL 61 IS 6 BP 1425 EP 1433 DI 10.1002/mrm.21922 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 450VS UT WOS:000266429900017 PM 19353673 ER PT J AU Lee, J Lustig, M Kim, DH Pauly, JM AF Lee, Jongho Lustig, Michael Kim, Dong-hyun Pauly, John M. TI Improved Shim Method Based on the Minimization of the Maximum Off-Resonance Frequency for Balanced Steady-State Free Precession (bSSFP) SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE min-max; minimax; least-squares; shimming; shim; SSFP ID IN-VIVO; SSFP; HOMOGENEITY; COILS AB In this work, a shim method that minimizes the maximum off-resonance frequency (min-max shim) in balanced steady-state free precession (bSSFP) is tested for brain imaging at 3T with constant and linear shim terms. The method demonstrates improvement of spatial coverage and banding artifact reduction over standard least-squares shimming. In addition, a new method (modified min-max shim) is introduced. This method reduces boundary band regions where the artifact is inevitable due to the excessive off-resonance frequency distribution. In comparison to standard least-squares shimming, the min-max based shim method either eliminates or reduces the size of banding artifacts. The method can be used to increase the signal-to-noise ratio (SNR) in bSSFP imaging or to increase the functional contrast in bSSFP functional MRI (fMRI) by allowing a longer usable repetition time(TR). Magn Reson Med 61:1500-1506, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Lee, Jongho] NINCDS, Adv MRI, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [Lee, Jongho; Lustig, Michael; Pauly, John M.] Stanford Univ, Dept Elect Engn, Magnet Resonance Syst Res Lab, Stanford, CA 94305 USA. [Kim, Dong-hyun] Yonsei Univ, Sch Elect & Elect Engn, Seoul 120749, South Korea. RP Lee, J (reprint author), 9000 Rockville Pike,Bldg 10,Room B1D723A, Bethesda, MD 20892 USA. EM jonghoyi@mail.nih.gov RI Lustig, Michael/G-7081-2012; Kim, Dong-Hyun/G-5096-2012 FU National Institutes of Health (NIH) [R01-EB006471, R21-EB002969]; GE Medical Systems FX Grant sponsor: National Institutes of Health (NIH); Grant numbers: R01-EB006471, R21-EB002969; Grant sponsor: GE Medical Systems. NR 24 TC 16 Z9 16 U1 2 U2 7 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 JUN PY 2009 VL 61 IS 6 BP 1500 EP 1506 DI 10.1002/mrm.21800 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 450VS UT WOS:000266429900026 PM 19319895 ER PT J AU Chuang, KH Koretsky, AP Sotak, CH AF Chuang, Kai-Hsiang Koretsky, Alan P. Sotak, Christopher H. TI Temporal Changes in the T-1 and T-2 Relaxation Rates (Delta R-1 and Delta R-2) in the Rat Brain Are Consistent With the Tissue-Clearance Rates of Elemental Manganese SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE T-1 relaxivity; T-2 relaxivity; r(1) relaxivity; r(2) relaxivity; manganese; bioelimination; rat brain; quantification ID ENHANCED MRI; MITOCHONDRIA; MYOCARDIUM; BINDING; IONS AB Temporal changes in the T-1 and T-2 relaxation rates (Delta R-1 and Delta R-2) in rat olfactory bulb (OB) and cortex were compared with the absolute manganese (Mn) concentrations from the corresponding excised tissue samples. In vivo T-1 and T-2 relaxation times were measured before, and at 1, 7, 28, and 35 d after intravenous infusion of 176 mg/kg MnCl2. The values of Delta R-1, Delta R-2, and absolute Mn concentration peaked at day 1 and then declined to near control levels after 28 to 35 d. The Mn bioelimination rate from the rat brain was significantly faster than that reported using radioisotope techniques. The R-1 and R-2 relaxation rates were linearly proportional to the underlying tissue Mn concentration and reflect the total absolute amount of Mn present in the tissue. The in vivo Mn r(1) and r(2) tissue relaxivities were comparable to the in vitro values for aqueous Mn2+. These results demonstrate that loss of manganese-enhanced MRI (MEMRI) contrast after systemic Mn2+ administration is due to elimination of Mn2+ from the brain. Magn Reson Med 61:1528-1532, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Sotak, Christopher H.] Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01609 USA. [Chuang, Kai-Hsiang; Koretsky, Alan P.] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [Sotak, Christopher H.] Univ Massachusetts, Sch Med, Dept Radiol, Worcester, MA USA. [Sotak, Christopher H.] Worcester Polytech Inst, Dept Chem & Biochem, Worcester, MA 01609 USA. RP Sotak, CH (reprint author), Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01609 USA. EM csotak@wpi.edu RI Koretsky, Alan/C-7940-2015; OI Koretsky, Alan/0000-0002-8085-4756; Chuang, Kai-Hsiang/0000-0002-8356-0657 FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS) FX Grant sponsors: Intramural Research Program of the National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS). NR 18 TC 41 Z9 41 U1 2 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2009 VL 61 IS 6 BP 1528 EP 1532 DI 10.1002/mrm.21962 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 450VS UT WOS:000266429900030 PM 19353652 ER PT J AU Wazen, RM Moffatt, P Zalzal, SF Yamada, Y Nanci, A AF Wazen, Rima M. Moffatt, Pierre Zalzal, Sylvia Francis Yamada, Yoshihiko Nanci, Antonio TI A mouse model expressing a truncated form of ameloblastin exhibits dental and junctional epithelium defects SO MATRIX BIOLOGY LA English DT Article DE Ameloblastin; Enamel organ; Junctional epithelium; Animal model; Mineralization ID CALCIUM-BINDING; ENAMEL FORMATION; RAT INCISORS; PROTEINS; TOOTH; AMELOGENESIS; BONE; GENE; DIFFERENTIATION; IDENTIFICATION AB Ameloblastin (AMBN) is the second most abundant extracellular matrix protein produced by the epithelial cells called ameloblasts and is found mainly in forming dental enamel. Inactivation of its expression by gene knockout results in absence of the enamel layer and its replacement by a thin layer of dysplastic mineralized matrix. The objective of this study was to further characterize the enamel organ and mineralized matrix produced in the AMBN knockout mouse. However, in the course of our study, we unexpectedly found that this mouse is in fact a mutant that does not express the full-length protein but that produces a truncated form of AMBN. Mandibles from wild type and mutant mice were processed for morphological analyses and immunolabeling. Microdissected enamel organs and associated matrix were also prepared for molecular and biochemical analyses. In incisors from mutants, ameloblasts lost their polarized organization and the enamel organ detached from the tooth surface and became disorganized. A thin layer of dysplastic mineralized material was deposited onto dentin, and mineralized masses were present within the enamel organ. These mineralized materials generated lower backscattered electron contrast than normal enamel, and immunocytochemistry with colloidal gold revealed the presence of amelogenin, bone sialoprotein and osteopontin. In addition, the height of the alveolar bone was reduced, and the junctional epithelium lost its integrity. Immunochemical and RT-PCR results revealed that the altered enamel organ in the mutant mice produced a shorter AMBN protein that is translated from truncated RNA missing exons 5 and 6. These results indicate that absence of full-length protein and/or expression of an incomplete protein have direct/indirect effects beyond structuring of mineral during enamel formation, and highlight potential functional regions on the AMBN molecule. (C) 2009 Elsevier B.V. All rights reserved. C1 [Wazen, Rima M.; Zalzal, Sylvia Francis; Nanci, Antonio] Univ Montreal, Fac Dent, Lab Study Calcified Tissues & Biomat, Stn Ctr Ville, Montreal, PQ H3C 3J7, Canada. [Moffatt, Pierre] Shriners Hosp Children, Montreal, PQ H3G 1A6, Canada. [Yamada, Yoshihiko] Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Nanci, A (reprint author), Univ Montreal, Fac Dent, Lab Study Calcified Tissues & Biomat, Stn Ctr Ville, POB 6128, Montreal, PQ H3C 3J7, Canada. EM antonio.nanci@umontreal.ca FU Canadian Institutes of Health Research (CIHR); Network for Oral and Bone Health Research (RSBO); National Institute of Dental and Craniofacial Research (NIDCR) [DE000720-02]; NIH; Shriners of North America FX This work was supported by the Canadian Institutes of Health Research (CIHR), the Network for Oral and Bone Health Research (RSBO), and the Intramural Research Program of the National Institute of Dental and Craniofacial Research (NIDCR #DE000720-02), NIH, U.S. A. Dr. Pierre Moffatt is supported by the Shriners of North America. NR 32 TC 47 Z9 49 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD JUN PY 2009 VL 28 IS 5 BP 292 EP 303 DI 10.1016/j.matbio.2009.04.004 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 475KB UT WOS:000268356100006 PM 19375505 ER PT J AU Robitaille, L Hoffer, LJ Levine, M AF Robitaille, Line Hoffer, L. John Levine, Mark TI Reply: Oxalic acid excretion after intravenous ascorbic acid administration SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Letter C1 [Robitaille, Line; Hoffer, L. John] McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. [Levine, Mark] NIDDKD, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Robitaille, L (reprint author), McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. NR 0 TC 0 Z9 0 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 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD JUN PY 2009 VL 58 IS 6 BP 888 EP 889 DI 10.1016/j.metabol.2009.02.007 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 450VU UT WOS:000266430100024 ER PT J AU Wang, J Kim, JM Donovan, DM Becker, KG Li, MD AF Wang, Ju Kim, Jong-Man Donovan, David M. Becker, Kevin G. Li, Ming D. TI Significant modulation of mitochondrial electron transport system by nicotine in various rat brain regions SO MITOCHONDRION LA English DT Article DE Nicotine; Microarray; Gene expression; Brain; Mitochondria ID INCREASES OXIDATIVE STRESS; CYTOCHROME-B GENE; ACETYLCHOLINE-RECEPTORS; PHEOCHROMOCYTOMA CELLS; PARKINSONS-DISEASE; IN-VITRO; NEURODEGENERATIVE DISEASES; NUCLEUS-ACCUMBENS; III DEFICIENCY; MATRIX VOLUME AB The mitochondrion is the organelle responsible for generation of most usable energy in a cell. It also plays an important role in a series of physiological processes such as apoptosis and proliferation. Although previous studies have demonstrated that nicotine modulates the morphology and function of mitochondria, the mechanism(s) underlying these effects is largely unknown. In this study, using a microarray consisting of 4793 clones derived from a mouse dopamine cDNA library, we profiled the gene expression patterns for six brain regions (amygdala, hippocampus, nucleus accumbens, prefrontal cortex, striatum and ventral tegmental area) of female Sprague-Dawley rats subjected to nicotine treatment for 7 days through osmotic minipump infusion. We identified a number of genes and pathways, including components of the electron transport system of mitochondria, such as cytochrome c oxidase subunit I (Mt-co1), Mt-co2, Mt-co3, cytochrome b (Mt-cyb), mitochondrial NADH dehydrogenase 4 (Mt-nd4), and Mt-nd6, that were significantly modulated by nicotine in multiple brain regions. Bioinformatics analysis provided evidence that Gene Ontology categories related to the electron transport system were overrepresented in each brain region. Finally, the results from the microarray analysis were verified by quantitative RTPCR for four representative genes. Together, our findings imply that mitochondria are involved in neuronal adaptation to chronic nicotine exposure. (C) 2009 Elsevier B.V. and Mitochondria Research Society. All rights reserved. C1 [Wang, Ju; Kim, Jong-Man; Li, Ming D.] Univ Virginia, Dept Psychiat & Neurobehav Sci, Neurobiol Sect, Charlottesville, VA 22911 USA. [Donovan, David M.] ARS, USDA, ANRI, Beltsville, MD USA. [Becker, Kevin G.] NIA, NIH, Baltimore, MD 21224 USA. [Li, Ming D.] Univ Virginia, Dept Neurosci, Charlottesville, VA USA. RP Li, MD (reprint author), Univ Virginia, Dept Psychiat & Neurobehav Sci, Neurobiol Sect, 1670 Discovery Dr,Suite 110, Charlottesville, VA 22911 USA. EM Ming_Li@virginia.edu OI Becker, Kevin/0000-0002-6794-6656 FU NIH [DA-13783] FX This project was in part supported by NIH Grant DA-13783 to Ming D. Li. The authors thank Dr. David L. Bronson for his excellent editing of this manuscript. NR 76 TC 10 Z9 11 U1 2 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD JUN PY 2009 VL 9 IS 3 BP 186 EP 195 DI 10.1016/j.mito.2009.01.008 PG 10 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 443YI UT WOS:000265946300003 PM 19460297 ER PT J AU Stuart, GR Humble, MM Strand, MK Copeland, WC AF Stuart, Gregory R. Humble, Margaret M. Strand, Micheline K. Copeland, William C. TI Transcriptional response to mitochondrial NADH kinase deficiency in Saccharomyces cerevisiae SO MITOCHONDRION LA English DT Article DE Cytoscape; Microarray; Mitochondria; NADH kinase; Oxidative stress; POS5 ID CYTOCHROME-C-OXIDASE; RESPIRATORY-CHAIN; GENE-EXPRESSION; YEAST; HAP1; ROX1; OXYGEN; STRAINS; ANAEROBIOSIS; METABOLISM AB Yeast cells lacking the mitochondrial NADH kinase encoded by POS5 display increased sensitivity to hydrogen peroxide, a slow-growth phenotype, reduced mitochondrial function and increased levels of mitochondrial protein oxidation and mtDNA mutations. Here we examined gene expression in pos5 Delta cells, comparing these data to those from cells containing deletions of superoxide dismutase-encoding genes SOD1 or SOD2. Surprisingly, stress-response genes were down-regulated in pos5 Delta, sod1 Delta and sod2 Delta cells, implying that cells infer stress levels from mitochondrial activity rather than sensing reactive oxygen species directly. Additionally, pos5 Delta, but not sod1 or sod2, cells displayed an anaerobic expression profile, indicating a defect in oxygen sensing that is specific to pos5, and is not a general stress-response. Finally, the pos5 Delta expression profile is quite similar to the hap1 Delta expression profile previously reported, which may indicate a shared mechanism. Published by Elsevier B.V. on behalf of Mitochondria Research Society. C1 [Stuart, Gregory R.; Humble, Margaret M.; Strand, Micheline K.; Copeland, William C.] NIEHS, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. [Strand, Micheline K.] USA, Res Off, Div Life Sci, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Genet Mol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov FU National Institute of Environmental Health Sciences [Z01-ES065078]; US Army Research Office [W991 NF04-D-0001, DAAG55-98-D-0002]; National Research Council Research FX We thank Astrid Haugen (NIEHS) and Leroy Worth (NIEHS) for critical reading of the manuscript. We also thank Jennifer Collins, Sherry Grissom and Jeff Tucker of the NIEHS Microarray Group for technical support, and Astrid Haugen for discussions regarding the use of Cytoscape. This work was supported by intramural funds from the National Institutes of Health, National Institute of Environmental Health Sciences (Grant No. Z01-ES065078). G.R.S. was supported by the US Army Research Office (Grant No. W991 NF04-D-0001 and DAAG55-98-D-0002), and a National Research Council Research Associateship Award. NR 38 TC 3 Z9 4 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD JUN PY 2009 VL 9 IS 3 BP 211 EP 221 DI 10.1016/j.mito.2009.02.004 PG 11 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 443YI UT WOS:000265946300006 PM 19254780 ER PT J AU Nkrumaha, LJ Riegelhaupt, PM Moura, P Johnson, DJ Patel, J Hayton, K Ferdig, MT Wellems, TE Akabas, MH Fidock, DA AF Nkrumaha, Louis J. Riegelhaupt, Paul M. Moura, Pedro Johnson, David J. Patel, Jigar Hayton, Karen Ferdig, Michael T. Wellems, Thomas E. Akabas, Myles H. Fidock, David A. TI Probing the multifactorial basis of Plasmodium falciparum quinine resistance: Evidence for a strain-specific contribution of the sodium-proton exchanger PfNHE SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Malaria; Quinine; Multidrug resistance; Transfection; Tranporters; Knockdown ID INTRAERYTHROCYTIC MALARIA PARASITE; CHLOROQUINE RESISTANCE; INFECTED ERYTHROCYTES; NA+/H+ EXCHANGER; COPY NUMBER; IN-VITRO; PH; TRANSPORTER; MUTATIONS; MEFLOQUINE AB Quinine (QN) continues to be an important treatment option for severe malaria, however resistance to this drug has emerged in field isolates of the etiologic agent Plasmodium falciparum. Quantitative trait loci investigations of QN resistance have mapped three loci of this complex trait. Two coincide with pfcrt and pfmdr1, involved in resistance to chloroquine (CQ) and other quinoline-based antimalarials. A third locus on chromosome 13 contains the sodium-proton exchanger (pfnhe) gene. Previous studies have associated pfnhe polymorphisms with reduced QN sensitivity in culture-adapted field isolates. Here, we provide direct evidence supporting the hypothesis that pfnhe contributes to QN resistance. Using allelic exchange, we reduced pfnhe expression by introducing a truncated 3' untranslated region (UTR) from pfcrt into the endogenous pfnhe 3'UTR. Transfections were performed with 1BB5 and 3BA6 (both CQ-and QN-resistant) as well as GC03 (CQ- and QN-sensitive), all progenies of the HB3 x Dd2 genetic cross. RNA and protein analyses of the ensuing recombinant clones demonstrated a similar to 50% decrease in pfnhe expression levels. A statistically significant 30% decrease in QN IC(50) values was associated with these decreased expression levels in 1BB5 and 3BA6 but not in GC03. CQ, mefloquine and lumefantrine IC50 values were unaltered. Cytosolic pH values were similar in all parental lines and recombinant clones. Our observations support a role for pfnhe in QN resistance in a strain-dependent manner, which might be contingent on pre-existing resistance to CQ and/or QN. These data bolster observations that QN resistance is a complex trait requiring the contribution of multiple transporter proteins. (C) 2009 Elsevier B.V. All rights reserved. C1 [Moura, Pedro; Fidock, David A.] Columbia Univ Coll Phys & Surg, Dept Microbiol, New York, NY 10032 USA. [Nkrumaha, Louis J.; Johnson, David J.] Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. [Riegelhaupt, Paul M.; Akabas, Myles H.] Yeshiva Univ Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA. [Patel, Jigar; Ferdig, Michael T.] Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Hayton, Karen; Wellems, Thomas E.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Fidock, David A.] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. RP Fidock, DA (reprint author), 701 W 168th St,HHSC 1502, New York, NY 10032 USA. EM df2260@columbia.edu RI Ferdig, Michael/C-6627-2016; OI Fidock, David/0000-0001-6753-8938; Akabas, Myles/0000-0001-8781-7846 FU Burroughs Wellcome Fund; NIH; Intramural Research Program of the NIH, MAID FX We thank Dr. Marcus Lee and Celeste D. Li for their kind help with the preparation of this manuscript. Funding for this work was provided in part by an Investigator in Pathogenesis Award in Infectious Diseases from the Burroughs Wellcome Fund (to D.A.F.) and from the NIH (to D.A.F., M.T.F. and M.H.A.). T.E.W. is supported by the Intramural Research Program of the NIH, MAID. NR 39 TC 47 Z9 48 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD JUN PY 2009 VL 165 IS 2 BP 122 EP 131 DI 10.1016/j.molbiopara.2009.01.011 PG 10 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 435SY UT WOS:000265364800004 PM 19428659 ER PT J AU Gondeau, C Corradin, G Heitz, F Le Peuch, C Balbo, A Schuck, P Kajava, AV AF Gondeau, Claire Corradin, Giampietro Heitz, Frederic Le Peuch, Christian Balbo, Andrea Schuck, Peter Kajava, Andrey V. TI The C-terminal domain of Plasmodium falciparum merozoite surface protein 3 self-assembles into alpha-helical coiled coil tetramer SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE alpha-Helical coiled coil; Oligomerization; Protein structure; Plasmodium falciparum ID SEDIMENTATION EQUILIBRIUM-ANALYSIS; SYSTEMATIC NOISE DECOMPOSITION; ERYTHROCYTE-MEMBRANE; ASSOCIATION; ANTIBODIES; ULTRACENTRIFUGATION; CONSERVATION; SECONDARY; PEPTIDES; INVASION AB Proteins located on the surface of the pathogenic malaria parasite Plasmodium falciparum are objects of intensive studies due to their important role in the invasion of human cells and the accessibility to host antibodies thus making these proteins attractive vaccine candidates. One of these proteins, merozoite surface protein 3 (MSP3) represents a leading component among vaccine candidates; however, little is known about its structure and function. Our biophysical studies suggest that the 40 residue C-terminal domain of MSP3 protein self-assembles into a four-stranded alpha-helical coiled coil structure where alpha-helices are packed "side-by-side". A bioinformatics analysis provides an extended list of known and putative proteins from different species of Plasmodium which have such MSP3-like C-terminal domains. This finding allowed us to extend some conclusions of our studies to a larger group of the malaria surface proteins. Possible structural and functional roles of these highly conserved oligomerization domains in the intact merozoite surface proteins are discussed. (C) 2009 Elsevier B.V. All rights reserved. C1 [Gondeau, Claire; Heitz, Frederic; Le Peuch, Christian; Kajava, Andrey V.] Univ Montpellier 1, Ctr Rech Biochim Macromol, CNRS, UMR 5237, F-34293 Montpellier 5, France. [Gondeau, Claire; Heitz, Frederic; Le Peuch, Christian; Kajava, Andrey V.] Univ Montpellier 2, Ctr Rech Biochim Macromol, CNRS, UMR 5237, F-34293 Montpellier, France. [Corradin, Giampietro] Univ Lausanne, Inst Biochem, CH-1066 Epalinges, Switzerland. [Balbo, Andrea; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Kajava, AV (reprint author), Univ Montpellier 1, Ctr Rech Biochim Macromol, CNRS, UMR 5237, 1919 Route Mende, F-34293 Montpellier 5, France. EM andrey.kajava@crbm.cnrs.fr RI Kajava, Andrey/E-1107-2014; OI Kajava, Andrey/0000-0002-2342-6886; Schuck, Peter/0000-0002-8859-6966 FU National Institutes of Health, NIBIB FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, NIBIB. NR 43 TC 14 Z9 14 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD JUN PY 2009 VL 165 IS 2 BP 153 EP 161 DI 10.1016/j.molbiopara.2009.01.015 PG 9 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 435SY UT WOS:000265364800007 PM 19428662 ER PT J AU Madesh, M Zong, WX Hawkins, BJ Ramasamy, S Venkatachalam, T Mukhopadhyay, P Doonan, PJ Irrinki, KM Rajesh, M Pacher, P Thompson, CB AF Madesh, Muniswamy Zong, Wei-Xing Hawkins, Brian J. Ramasamy, Subbiah Venkatachalam, Thilagavathi Mukhopadhyay, Partha Doonan, Patrick J. Irrinki, Krishna M. Rajesh, Mohanraj Pacher, Pal Thompson, Craig B. TI Execution of Superoxide-Induced Cell Death by the Proapoptotic Bcl-2-Related Proteins Bid and Bak SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MITOCHONDRIAL PERMEABILITY TRANSITION; CYTOCHROME-C RELEASE; FOCAL CEREBRAL-ISCHEMIA; OXIDATIVE STRESS; CYCLOPHILIN-D; INDUCED APOPTOSIS; LIVER; BCL-2; CASPASE-2; MECHANISM AB Ethanol intoxication stimulates the production of proinflammatory cytokines, increases the formation of reactive oxygen species, and induces mitochondrial impairment. However, information is limited as to the exact sequence and components involved in ethanol-induced hepatotoxicity. Acute ethanol exposure enhances mitochondrial superoxide (O(2)(center dot-)) production and impairs mitochondrial Ca(2+) handling. In turn, O(2)(center dot-) facilitates cytochrome c release and mitochondrial membrane potential loss that is not dependent upon H(2)O(2) and divalent cations and requires Bak in a Bax-independent fashion. Furthermore, triggering of Bak's proapoptotic activity requires the cytosolic presence of Bid, a BH(3)-only protein that is processed by the initiator caspase-2. Together, these studies identify an O(2)(center dot-)-driven, caspase-initiated apoptotic pathway that selectively involves the Bcl-2 family proteins Bid and Bak. This pathway manifests itself during chronic ethanol consumption in aged animals and identifies caspase-2, Bid, and Bak as essential mediators of O(2)(center dot-)-induced apoptosis that may prove effective targets for the development of therapeutics to treat alcoholic liver disease. C1 [Zong, Wei-Xing; Thompson, Craig B.] Univ Penn, Abramson Canc Res Inst, Dept Canc Biol, Philadelphia, PA 19140 USA. [Madesh, Muniswamy; Hawkins, Brian J.; Ramasamy, Subbiah; Venkatachalam, Thilagavathi; Doonan, Patrick J.; Irrinki, Krishna M.] Temple Univ, Dept Biochem, Philadelphia, PA 19140 USA. [Mukhopadhyay, Partha; Rajesh, Mohanraj; Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Labs Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Madesh, M (reprint author), Temple Univ, Dept Biochem, 627 Kresge Bldg,3440 N Broad St, Philadelphia, PA 19140 USA. EM madeshm@temple.edu; craig@mail.med.upenn.edu RI MUKHOPADHYAY, PARTHA/G-3890-2010; Pacher, Pal/B-6378-2008 OI MUKHOPADHYAY, PARTHA/0000-0002-1178-1274; Pacher, Pal/0000-0001-7036-8108 FU American Heart Association; National Institutes of Health [HL086699, 1S10RR022511]; Leukemia & Lymphoma Society and the Howard Temin Award; [K99HL094536] FX M. M. is supported by an American Heart Association-National Scientist Development grant and the National Institutes of Health (HL086699, 1S10RR022511). W.-X. Z. is supported by the Leukemia & Lymphoma Society and the Howard Temin Award (NCI). B. J. H. is supported by K99HL094536. P. P. is supported by the intramural NIH (NIAAA). C. B. T. is supported by grants from the NIH and NCI. NR 55 TC 32 Z9 33 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN 1 PY 2009 VL 29 IS 11 BP 3099 EP 3112 DI 10.1128/MCB.01845-08 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 444US UT WOS:000266006500015 PM 19332555 ER PT J AU Kurmangaliyev, YZ Gelfand, MS AF Kurmangaliyev, Y. Z. Gelfand, M. S. TI Alternative splicing tends to involve protein phosphorylation sites SO MOLECULAR BIOLOGY LA English DT Article DE alternative splicing; phosphorylation sites ID FUNCTIONAL DIVERSITY; GENOMICS C1 [Kurmangaliyev, Y. Z.; Gelfand, M. S.] Russian Acad Sci, Kharkevich Inst Informat Transmiss Problems, Moscow 127994, Russia. [Kurmangaliyev, Y. Z.] Natl Ctr Biotechnol Republ Kazakhstan, Astana 010000, Kazakhstan. [Gelfand, M. S.] Moscow MV Lomonosov State Univ, Fac Bioengn & Bioinformat, Moscow 119992, Russia. RP Kurmangaliyev, YZ (reprint author), Russian Acad Sci, Kharkevich Inst Informat Transmiss Problems, Moscow 127994, Russia. EM gelfand@iitp.ru RI Gelfand, Mikhail/F-3425-2012 FU Russian Academy of Sciences; Russian Foundation for Basic Research [07-04-00343, 08-04-90900] FX This work was supported by the program Molecular and Cell Biology of the Russian Academy of Sciences and the Russian Foundation for Basic Research (project nos. 07-04-00343 and 08-04-90900). NR 11 TC 0 Z9 0 U1 0 U2 1 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0026-8933 J9 MOL BIOL+ JI Mol. Biol. PD JUN PY 2009 VL 43 IS 3 BP 528 EP 530 DI 10.1134/S0026893309030224 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 461UE UT WOS:000267296800022 ER PT J AU McNeill, DR Lam, W DeWeese, TL Cheng, YC Wilson, DM AF McNeill, Daniel R. Lam, Wing DeWeese, Theodore L. Cheng, Yung-Chi Wilson, David M., III TI Impairment of APE1 Function Enhances Cellular Sensitivity to Clinically Relevant Alkylators and Antimetabolites SO MOLECULAR CANCER RESEARCH LA English DT Article ID BASE EXCISION-REPAIR; HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; DNA-DAMAGING AGENTS; STRAND BREAK ENDS; ABASIC ENDONUCLEASE; CANCER CELLS; 5-FLUOROURACIL; MECHANISMS; PROTEIN; CYTOTOXICITY AB Base excision repair (BER) is the major pathway for removing mutagenic and cytotoxic oxidative and alkylation DNA modifications. Using a catalytically inactive, dominant negative protein form of human APE1, termed ED, which binds with high affinity to substrate DNA and blocks subsequent repair steps, we assessed the role of BER in mediating cellular resistance to clinically relevant alkylating drugs and antimetabolites. Colony formation assays revealed that ED expression enhanced cellular sensitivity to melphalan not at all; to decarbazine, thiotepa, busulfan and carmustine moderately (1.2- to 2.4-fold); and to streptozotocin and temozolomide significantly (2.0- to 5.3-fold). The effectiveness of ED to promote enhanced cytotoxicity generally correlated with the agent's (a) monofunctional nature, (b) capacity to induce N(7)-guanine and N(3)-adenine modifications, and (c) inability to generate O(6)-guanine adducts or DNA cross-links. ED also enhanced the cell killing potency of the antimetabolite, troxacitabine, apparently by blocking the processing of DNA strand breaks, yet had no effect on the cytotoxicity of gemcitabine, results that agree well with the known efficiency of APE1 to excise these nucleoside analogues from DNA. Most impressively, ED expression produced an similar to 5- and 25-fold augmentation of the cell killing effect of 5-fluorouracil and 5-fluorodeoxyuridine, respectively, implicating BER in the cellular response to such anti metabolites; the increased 5-fluorouracil sensitivity was associated with an accumulation of abasic sites and active caspase-positive staining. Our data suggest that APE1, and BER more broadly, is a potential target for inactivation in anticancer treatment paradigms that involve select alkylating agents or anti metabolites. (Mol Cancer Res 2009;7(6):897-906) C1 [McNeill, Daniel R.; Wilson, David M., III] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [DeWeese, Theodore L.] Johns Hopkins Univ, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA. [Lam, Wing; Cheng, Yung-Chi] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, 251 Bayview Blvd,Suite 100,Room 06B117, Baltimore, MD 21224 USA. EM wilsonda@grc.nia.nih.gov FU NIH [CA63477]; National Institute on Aging FX Intramural Research Program of the NIH, National Institute on Aging, and NIH grant CA63477 (Y-C. Cheng). NR 57 TC 41 Z9 46 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD JUN PY 2009 VL 7 IS 6 BP 897 EP 906 DI 10.1158/1541-7786.MCR-08-0519 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 461YX UT WOS:000267312500013 PM 19470598 ER PT J AU Kaye, FJ AF Kaye, Frederic J. TI Mutation-associated fusion cancer genes in solid tumors SO MOLECULAR CANCER THERAPEUTICS LA English DT Review ID CELL LUNG-CANCER; ADENOID CYSTIC CARCINOMA; SALIVARY-GLAND TUMORS; MUCOEPIDERMOID CARCINOMA; MYELOID-LEUKEMIA; PROSTATE-CANCER; TYROSINE KINASE; WARTHINS TUMOR; HUMAN GENOME; CHROMOSOME-ABERRATIONS AB Chromosomal translocations; and fusion oncogenes serve as the ultimate biomarker for clinicians as they show specificity for distinct histopathologic malignancies while simultaneously encoding an etiologic mutation and a therapeutic target. Previously considered a minor mutational event in epithelial solid tumors, new methodologies that do not rely on the detection of macroscopic cytogenetic alterations, as well as access to large series of annotated clinical material, are expanding the inventory of recurrent fusion oncogenes in both common and rare solid epithelial tumors. Unexpectedly, related assays are also revealing a high number of tandem or chimeric transcripts in normal tissues including, in one provocative case, a template for a known fusion oncogene. These observations may force us to reassess long-held views on the definition of a gene. They also raise the possibility that some rearrangements might represent constitutive forms of a physiological chimeric transcript. Defining the chimeric transcriptome in both health (transcription-induced chimerism and intergenic splicing) and disease (mutation-associated fusion oncogenes) will play an increasingly important role in the diagnosis, prognosis, and therapy of patients with cancer. [Mol Cancer Ther 2009;8(6):1399-408] C1 [Kaye, Frederic J.] Natl Naval Med Ctr, Bethesda, MD 20889 USA. [Kaye, Frederic J.] NCI, Genet Branch, Bethesda, MD 20892 USA. RP Kaye, FJ (reprint author), Natl Naval Med Ctr, Bldg 8 Rm 5101, Bethesda, MD 20889 USA. EM kayef@mail.nih.go RI kaye, frederic/E-2437-2011 FU Intramural Program of the National Cancer Institute; National Institutes of Health (NIH) FX Grant support: Intramural Program of the National Cancer Institute, National Institutes of Health (NIH). NR 82 TC 25 Z9 27 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUN PY 2009 VL 8 IS 6 BP 1399 EP 1408 DI 10.1158/1535-7163.MCT-09-0135 PG 10 WC Oncology SC Oncology GA 458SF UT WOS:000267043100001 PM 19509239 ER PT J AU Miranda, TB Cortez, CC Yoo, CB Liang, GN Abe, M Kelly, TK Marquez, VE Jones, PA AF Miranda, Tina Branscombe Cortez, Connie C. Yoo, Christine B. Liang, Gangning Abe, Masanobu Kelly, Theresa K. Marquez, Victor E. Jones, Peter A. TI DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID S-ADENOSYLHOMOCYSTEINE HYDROLASE; GROUP PROTEIN EZH2; MOUSE L929 CELLS; PROSTATE-CANCER; DEACETYLASE INHIBITORS; POLYCOMB; H3; DEMETHYLATION; DISRUPTION; REPRESSION AB DNA methylation, histone modifications, and nucleosomal occupancy collaborate to cause silencing of tumor-related genes in cancer, The development of drugs that target these processes is therefore important for cancer therapy. Inhibitors of DNA methylation and histone deacetylation have been approved by the Food and Drug Administration for treatment of hematologic malignancies. However, drugs that target other mechanisms still need to be developed. Recently, 3-deazaneplanocin A (DZNep) was reported to selectively inhibit trimethylation of lysine 27 on histone H3 (H3K27me3) and lysine 20 on histone H4 (H4K20me3) as well as reactivate silenced genes in cancer cells. This finding opens the door to the pharmacologic inhibition of histone methylation. We therefore wanted to further study the mechanism of action of DZNep in cancer cells. Western blot analysis shows that DZNep globally inhibits histone methylation and is not selective. Two other drugs, sinefungin and adenosine dialdehyde, have similar effects as DZNep on H3K27me3. Intriguingly, chromatin immunoprecipitation of various histone modifications and microarray analysis show that DZNep acts through a different pathway than 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor. These observations give us interesting insight into how chromatin structure affects gene expression. We also determined the kinetics of gene activation to understand if the induced changes were somatically heritable. We found that upon removal of DZNep, gene expression is reduced to its original state. This suggests that there is a homeostatic mechanism that returns the histone modifications to their "ground state" after DZNep treatment. Our data show the strong need for further development of histone methylation inhibitors. [Mol Cancer Ther 2009;8(6):1579-88] C1 [Miranda, Tina Branscombe; Cortez, Connie C.; Yoo, Christine B.; Liang, Gangning; Abe, Masanobu; Kelly, Theresa K.; Jones, Peter A.] Univ So Calif, Norris Comprehens Canc Ctr, Dept Urol, Keck Sch Med, Los Angeles, CA 90033 USA. [Miranda, Tina Branscombe; Cortez, Connie C.; Yoo, Christine B.; Liang, Gangning; Abe, Masanobu; Kelly, Theresa K.; Jones, Peter A.] Univ So Calif, Norris Comprehens Canc Ctr, Dept Biochem & Mol Biol, Keck Sch Med, Los Angeles, CA 90033 USA. [Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MA USA. RP Jones, PA (reprint author), Univ So Calif, Norris Comprehens Canc Ctr, Dept Urol, Keck Sch Med, 1441 Eastlake Ave, Los Angeles, CA 90033 USA. EM jones_p@ccnt.usc.edu RI kelly, theresa/E-3624-2010; OI Liang, Gangning/0000-0001-8664-922X FU NIH [CA83867]; American Cancer Society Postdoctoral Fellowship FX Grant support: NIH grant CA83867 (P.A. Jones) and an American Cancer Society Postdoctoral Fellowship (T.B. Miranda). This research was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute-Frederick. NR 32 TC 238 Z9 244 U1 1 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUN PY 2009 VL 8 IS 6 BP 1579 EP 1588 DI 10.1158/1535-7163.MCT-09-0013 PG 10 WC Oncology SC Oncology GA 458SF UT WOS:000267043100018 PM 19509260 ER PT J AU Baschnagel, A Russo, A Burgan, WE Carter, D Beam, K Palmieri, D Steeg, PS Tofilon, P Camphausen, K AF Baschnagel, Andrew Russo, Andrea Burgan, William E. Carter, Donna Beam, Katie Palmieri, Diane Steeg, Patricia S. Tofilon, Philip Camphausen, Kevin TI Vorinostat enhances the radiosensitivity of a breast cancer brain metastatic cell line grown in vitro and as intracranial xenografts SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; SUBEROYLANILIDE HYDROXAMIC ACID; GAMMA-H2AX FOCI; RADIATION; PROLONGATION; MS-275; VIVO AB Vorinostat (suberoylanilide hydroxamic acid), a histone deacetylase inhibitor, is currently undergoing clinical evaluation as therapy for cancer. We investigated the effects of vorinostat on tumor cell radiosensitivity in a breast cancer brain metastasis model using MDA-MB-231-BR cells. In vitro radiosensitivity was evaluated using clonogenic assay. Cell cycle distribution and apoptosis was measured using flow cytometry. DNA damage and repair was evaluated using yH2AX. Mitotic catastrophe was measured by immunostaining. Growth delay and intracranial xenograft models were used to evaluate the in vivo tumor radiosensitivity. Cells exposed to vorinostat for 16 hours before and maintained in the medium after irradiation had an increase in radiosensitivity with a dose enhancement factor of 1.57. yH2AX, as an indicator of double-strand breaks, had significantly more foci per cell in the vorinostat plus irradiation group. Mitotic catastrophe, measured at 72 hours, was significantly increased in cells receiving vorinostat plus irradiation. Irradiation of s.c. MDA-MB-231-BR tumors in mice treated with vorinostat resulted in an increase in radiation-induced tumor growth delay. Most importantly, animals with intracranial tumor implants lived the longest after combination treatment. These results indicate that vorinostat enhances tumor cell radiosensitivity in vitro and in vivo. There was a greater than additive improvement in survival in our intracranial model. Combining vorinostat with radiation may be a potential treatment option for patients with breast cancer who develop brain metastases. [Mol Cancer Ther 2009;8(6):1589-95] C1 [Baschnagel, Andrew; Russo, Andrea; Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Burgan, William E.; Carter, Donna; Beam, Katie] NCI, Mol Radiat Therapeut Branch, Bethesda, MD 20892 USA. [Beam, Katie; Palmieri, Diane; Steeg, Patricia S.] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Burgan, William E.; Carter, Donna] NCI, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. [Tofilon, Philip] Univ S Florida, H Lee Moffitt Canc Ctr, Drug Discovery Program, Tampa, FL 33682 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr,Bldg 10,CRC,Room B2-3561, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov RI Palmieri, Diane/B-4258-2015 FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research and Department of Defense Breast Cancer Research Program [W81 XWH-062-0033]; Clinical Research Training Program; Pfizer, Inc FX Grant support: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and Department of Defense Breast Cancer Research Program grant W81 XWH-062-0033 (P.S. Steeg and K. Camphausen). A. Baschnagel was supported through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer, Inc. (via a grant to the Foundation for NIH from Pfizer, Inc.). NR 20 TC 44 Z9 44 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUN PY 2009 VL 8 IS 6 BP 1589 EP 1595 DI 10.1158/1535-7163.MCT-09-0038 PG 7 WC Oncology SC Oncology GA 458SF UT WOS:000267043100019 PM 19509253 ER PT J AU Tryndyak, VP Ross, SA Belland, FA Pogribny, IP AF Tryndyak, Volodymyr P. Ross, Sharon A. Belland, Frederick A. Pogribny, Igor P. TI Down-Regulation of the microRNAs miR-34a, miR-127, and miR-200b in Rat Liver During Hepatocarcinogenesis Induced by a Methyl-Deficient Diet SO MOLECULAR CARCINOGENESIS LA English DT Article DE microRNAs; p53; apoptosis; hepatocarcinogenesis ID HUMAN HEPATOCELLULAR-CARCINOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; TUMOR-SUPPRESSOR; GENE-EXPRESSION; FOLATE/METHYL DEFICIENCY; CELLULAR-TRANSFORMATION; DNA HYPOMETHYLATION; HUMAN CANCERS; CYCLIN G1; PROLIFERATION AB Altered expression of microRNAs (miRNAs) has been reported in diverse human cancers; however, the down-regulation or up-regulation of any particular miRNAs in cancer is not sufficient to address the role of these changes in carcinogenesis. In this study, using the rat model of liver carcinogenesis induced by a methyl-deficient diet, which is relevant to the hepatocarcinogenesis in humans associated with viral hepatitis C and B infections, alcohol exposure and metabolic liver diseases, we showed that the development of hepatocellular carcinoma (HCC) is characterized by prominent early changes in expression of miRNA genes, specifically by inhibition of expression of microRNAs miR-34a, miR-127, miR-200b, and miR-16a involved in the regulation of apoptosis, cell proliferation, cell-to-cell connection, and epithelial-mesenchymal transition. The mechanistic link between these alterations in miRNAs expression and the development of HCC was confirmed by the corresponding changes in the levels of E2F3, NOTCH1, BCL6, ZFHX1B, and BCL2 proteins targeted by these miRNAs. The significance of miRNAs expression dysregulation in respect to hepatocarcinogenesis was confirmed by the persistence of these miRNAs alterations in the livers of methyl-deficient rats re-fed a methyl-adequate diet. Altogether, the early occurrence of alterations in miRNAs expression and their persistence during the entire process of hepatocarcinogenesis indicate that the dysregulation of microRNAs expression may be an important contributing factor in the development of HCC. (C) 2008 Wiley-Liss, Inc. C1 [Tryndyak, Volodymyr P.; Belland, Frederick A.; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Ross, Sharon A.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. FU Postgraduate Research Program; Interagency Agreement between NIH-NCI and FDA-NCTR FX The authors would like to thank Dr. M.P. Waalkes for providing the rat liver TRL1215 cell line. Dr. V. Tryndyak is supported by the Postgraduate Research Program administered by the Oak Ridge Institute for Science and Education. Supported in part by Interagency Agreement between NIH-NCI and FDA-NCTR. NR 56 TC 88 Z9 98 U1 1 U2 7 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 JUN PY 2009 VL 48 IS 6 BP 479 EP 487 DI 10.1002/mc.20484 PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 451MF UT WOS:000266473600001 PM 18942116 ER PT J AU McKenna, NJ Cooney, AJ DeMayo, FJ Downes, M Glass, CK Lanz, RB Lazar, MA Mangelsdorf, DJ Moore, DD Qin, J Steffen, DL Tsai, MJ Tsai, SY Yu, R Margolis, RN Evans, RM O'Malley, BW AF McKenna, Neil J. Cooney, Austin J. DeMayo, Francesco J. Downes, Michael Glass, Christopher K. Lanz, Rainer B. Lazar, Mitchell A. Mangelsdorf, David J. Moore, David D. Qin, Jun Steffen, David L. Tsai, Ming-Jer Tsai, Sophia Y. Yu, Ruth Margolis, Ronald N. Evans, Ronald M. O'Malley, Bert W. TI Minireview: Evolution of NURSA, the Nuclear Receptor Signaling Atlas SO MOLECULAR ENDOCRINOLOGY LA English DT Review ID BILE-ACID RECEPTOR; GENE-EXPRESSION; COREGULATOR; GENOME; IDENTIFICATION; COMPLEXES; DISEASE; CELLS AB Nuclear receptors and coregulators are multifaceted players in normal metabolic and homeostatic processes in addition to a variety of disease states including cancer, inflammation, diabetes, obesity, and atherosclerosis. Over the past 7 yr, the Nuclear Receptor Signaling Atlas (NURSA) research consortium has worked toward establishing a discovery-driven platform designed to address key questions concerning the expression, organization, and function of these molecules in a variety of experimental model systems. By applying powerful technologies such as quantitative PCR, high-throughput mass spectrometry, and embryonic stem cell manipulation, we are pursuing these questions in a series of transcriptomics-, proteomics-, and metabolomics-based research projects and resources. The consortium's web site (www.nursa.org) integrates NURSA datasets and existing public datasets with the ultimate goal of furnishing the bench scientist with a comprehensive framework for hypothesis generation, modeling, and testing. We place a strong emphasis on community input into the development of this resource and to this end have published datasets from academic and industrial laboratories, established strategic alliances with Endocrine Society journals, and are developing tools to allow web site users to act as data curators. With the ongoing support of the nuclear receptor and coregulator signaling communities, we believe that NURSA can make a lasting contribution to research in this dynamic field. (Molecular Endocrinology 23: 740-746, 2009) C1 [McKenna, Neil J.; Cooney, Austin J.; DeMayo, Francesco J.; Lanz, Rainer B.; Moore, David D.; Tsai, Ming-Jer; Tsai, Sophia Y.; O'Malley, Bert W.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Qin, Jun] Baylor Coll Med, Dept Biochem, Houston, TX 77030 USA. [Steffen, David L.] Baylor Coll Med, Bioinformat Res Ctr, Houston, TX 77030 USA. [Glass, Christopher K.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Lazar, Mitchell A.] Univ Penn, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Mangelsdorf, David J.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Margolis, Ronald N.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. [Downes, Michael; Yu, Ruth; Evans, Ronald M.] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA. RP O'Malley, BW (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, 1 Baylor Plaza, Houston, TX 77030 USA. EM evans@salk.edu; berto@bcm.edu OI Margolis, Ronald/0000-0002-8956-0455; McKenna, Neil/0000-0001-6689-0104 FU Howard Hughes Medical Institute; NHLBI NIH HHS [R01 HL105278]; NICHD NIH HHS [R01 HD007857]; NIDDK NIH HHS [U19DK62434, R37 DK057978, U19 DK062434] NR 35 TC 61 Z9 62 U1 0 U2 9 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUN PY 2009 VL 23 IS 6 BP 740 EP 746 DI 10.1210/me.2009-0135 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 450MC UT WOS:000266403600002 PM 19423650 ER PT J AU Park, SK Qiao, HH Beaven, MA AF Park, Seung-Kiel Qiao, Huihong Beaven, Michael A. TI Src-like adaptor protein (SLAP) is upregulated in antigen-stimulated mast cells and acts as a negative regulator SO MOLECULAR IMMUNOLOGY LA English DT Article DE Mast cells; Antigen; Src-like adaptor protein; Inhibitory regulator; Signaling; Cytokines ID FC-EPSILON-RI; AFFINITY IGE RECEPTOR; CBL-DEPENDENT MANNER; SYK TYROSINE KINASE; C-CBL; CUTTING EDGE; MAP KINASE; ACTIVATION; SIGNALS; DEXAMETHASONE AB our studies in the RBL-2H3 mast cell line suggest that responses to antigen (Ag) are negatively modulated through upregulation of Src-like adaptor protein (SLAP). Ag stimulation of RBL-2H3 cells leads to increased levels of SLAP (but not SLAP2) transcripts and protein over a period of several hours. The effects of pharmacologic inhibitors indicate that the upregulation of SLAP is dependent on multiple signaling pathways. Knockdown of SLAP with anti-SLAP siRNA is associated with enhanced phosphorylation of Syk. the linker for activation of T cells (LAT), phospholipase C gamma, MAP kinases, and various transcription factors. Production of IL-3 and MCP-1, but not degranulation, is also enhanced. The upregulation of SLAP may thus serve to limit the duration of cytokine production in Ag-stimulated cells. Published by Elsevier Ltd. C1 [Park, Seung-Kiel; Qiao, Huihong; Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Park, Seung-Kiel] Chungnam Natl Univ, Coll Med, Res Inst Med Sci, Taejon 301130, South Korea. [Park, Seung-Kiel] Chungnam Natl Univ, Coll Med, Dept Biochem, Taejon 301130, South Korea. RP Beaven, MA (reprint author), NHLBI, Lab Mol Immunol, NIH, Room 8N109,Bldg 10, Bethesda, MD 20892 USA. EM beavenm@nhlbi.nih.gov FU Intramural Research Program of NHLBI at the National Institutes of Health FX This work was supported by the Intramural Research Program of NHLBI at the National Institutes of Health. NR 47 TC 4 Z9 4 U1 0 U2 1 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 JUN PY 2009 VL 46 IS 10 BP 2133 EP 2139 DI 10.1016/j.molimm.2009.03.013 PG 7 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 458EL UT WOS:000266997500025 PM 19371953 ER PT J AU Lawrence, KA Jewett, MW Rosa, PA Gherardini, FC AF Lawrence, Kevin A. Jewett, Mollie W. Rosa, Patricia A. Gherardini, Frank C. TI Borrelia burgdorferi bb0426 encodes a 2'-deoxyribosyltransferase that plays a central role in purine salvage SO MOLECULAR MICROBIOLOGY LA English DT Article ID BORRELIA-BURGDORFERI; INFECTIOUS CYCLE; UREAPLASMA-UREALYTICUM; ESCHERICHIA-COLI; RELAPSING FEVER; PLASMID; SPIROCHETE; PURIFICATION; POLYMORPHISM; MUTAGENESIS AB P>Borrelia burgdorferi is an obligate parasite with a limited genome that severely narrows its metabolic and biosynthetic capabilities. Thus survival of this spirochaete in an arthropod vector and mammalian host requires that it can scavenge amino acids, fatty acids and nucleosides from a blood meal or various host tissues. Additionally, the utilization of ribonucleotides for DNA synthesis is further complicated by the lack of a ribonucleotide reductase for the conversion of nucleoside-5'-diphosphates to deoxynucleosides-5'-diphosphates. The data presented here demonstrate that B. burgdorferi must rely on host-derived sources of purine bases, deoxypurines and deoxypyrimidines for the synthesis of DNA. However, if deoxyguanosine (dGuo) is limited in host tissue, the enzymatic activities of a 2'-deoxyribosyltransferase (DRTase, encoded by bb0426), IMP dehydrogenase (GuaB) and GMP synthase (GuaA) catalyse the multistep conversion of hypoxanthine (Hyp) to dGMP for DNA synthesis. This pathway provides additional biochemical flexibility for B. burgdorferi when it colonizes and infects different host tissues. C1 [Lawrence, Kevin A.; Jewett, Mollie W.; Rosa, Patricia A.; Gherardini, Frank C.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Gherardini, FC (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM fgherardini@niaid.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases FX We thank Dr Lizbeth Hedstrom at Brandeis University for providing purified recombinant IMP dehydrogenase (GuaB). We also thank Dr Tom Schwan, Sandy Stewart and Dr Jonas Pettersson for helpful discussion regarding the purine metabolic pathway of B. hermsii. In addition, we thank Dr Tom Schwan for providing B. hermsii strain DAH. We also thank Gary Hettrick and Anita Mora for graphics support. This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 35 TC 15 Z9 15 U1 0 U2 7 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 JUN PY 2009 VL 72 IS 6 BP 1517 EP 1529 DI 10.1111/j.1365-2958.2009.06740.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 456UB UT WOS:000266875800017 PM 19460093 ER PT J AU Eastwood, SL Hodgkinson, CA Harrison, PJ AF Eastwood, S. L. Hodgkinson, C. A. Harrison, P. J. TI DISC-1 Leu607Phe alleles differentially affect centrosomal PCM1 localization and neurotransmitter release SO MOLECULAR PSYCHIATRY LA English DT Letter ID SCHIZOPHRENIA; RECRUITMENT; ASSOCIATION; PROTEINS; DEPENDS C1 [Eastwood, S. L.; Harrison, P. J.] Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England. [Hodgkinson, C. A.] NIAAA, Sect Human Neurogenet, Rockville, MD 20852 USA. RP Eastwood, SL (reprint author), Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England. EM sharon.eastwood@psych.ox.ac.uk FU Medical Research Council [G0500180] NR 10 TC 19 Z9 20 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUN PY 2009 VL 14 IS 6 BP 556 EP 557 DI 10.1038/mp.2009.13 PG 2 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 448BL UT WOS:000266236300001 PM 19455170 ER PT J AU Weickert, CS Elashoff, M Richards, AB Sinclair, D Bahn, S Paabo, S Khaitovich, P Webster, MJ AF Weickert, C. S. Elashoff, M. Richards, A. B. Sinclair, D. Bahn, S. Paabo, S. Khaitovich, P. Webster, M. J. TI Transcriptome analysis of male-female differences in prefrontal cortical development SO MOLECULAR PSYCHIATRY LA English DT Letter C1 [Weickert, C. S.; Richards, A. B.] NIMH, MiNDS Unit, CBDB, IRP, Bethesda, MD 20892 USA. [Weickert, C. S.; Sinclair, D.] Univ New S Wales, Schizophrenia Res Inst, Prince Wales Med Res Inst, Sydney, NSW, Australia. [Elashoff, M.] Cardiodx, Palo Alto, CA USA. [Bahn, S.] Univ Cambridge, Inst Biotechnol, Cambridge, England. [Paabo, S.; Khaitovich, P.] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, Leipzig, Germany. [Khaitovich, P.] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Computat Biol, Shanghai, Peoples R China. [Webster, M. J.] Stanley Med Res Inst, Rockville, MD USA. RP Weickert, CS (reprint author), NIMH, MiNDS Unit, CBDB, IRP, Bethesda, MD 20892 USA. EM websterm@stanleyresearch.org RI Shannon Weickert, Cynthia/G-3171-2011; OI Sinclair, Duncan/0000-0001-5961-1007 NR 4 TC 46 Z9 46 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUN PY 2009 VL 14 IS 6 BP 558 EP 561 DI 10.1038/mp.2009.5 PG 4 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 448BL UT WOS:000266236300002 PM 19455171 ER PT J AU Sergeev, YV Smaoui, N Sui, R Stiles, D Gordiyenko, N Strunnikova, N MacDonald, IM AF Sergeev, Y. V. Smaoui, N. Sui, R. Stiles, D. Gordiyenko, N. Strunnikova, N. MacDonald, I. M. TI The functional effect of pathogenic mutations in Rab escort protein 1 SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Choroideremia; Rab escort protein 1; Missense mutation; Structural mechanism; Protein destabilization ID GERANYLGERANYL TRANSFERASE; CDNA CLONING; COMPONENT-A; CHOROIDEREMIA; GENE; DEGENERATION; OPTIMIZATION; CONFORMATION; COMPLEX AB Choroideremia (CHM) is a chorioretinal degeneration with an X-linked pattern of inheritance. Affected males experience progressive atrophy of the choroid, retinal pigment epithelium and retina leading to eventual blindness. The CHM gene encodes Rab escort protein 1 (REP-1). REP-1 is involved in trafficking of Rab proteins in the cell. To date, the majority of reported mutations in the CHM gene cause a complete loss of REP-1 function. Here we report pathogenic mutations: a novel missense mutation, L550P; a truncation c.1542T > A, STOP; and two deletions (c.525_526delAG and c.1646delC) in the CHM gene and their phenotypic effect. To analyze the effect of mutations, the 3D structure of human REP-1 and the proteins associated with REP-1 function were modeled using sequence homology with rat proteins. In silico analysis of the missense mutation L550P suggests that the proline residue at position 550 destabilizes the beta-structural elements, and the REP-1 tertiary structure. Truncation and deletion mutants are associated with a partial or total loss of the REP-1 essential activity and protein-protein interactions as predicted by the analysis of the structure and stability of these protein products. The presumptive loss of protein was confirmed by Western Blot analysis of protein from mononuclear cells and fibroblasts (FB) from CHM patients. (C) 2009 Elsevier B.V. All rights reserved. C1 [Sergeev, Y. V.; Smaoui, N.; Sui, R.; Stiles, D.; Gordiyenko, N.; Strunnikova, N.; MacDonald, I. M.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP MacDonald, IM (reprint author), Bldg 10,Rm10N226,10 Ctr Dr,MSC 1860, Bethesda, MD 20892 USA. EM macdonald@mail.nih.gov OI MacDonald, Ian/0000-0001-7472-8385 FU Intramural NIH HHS [Z99 EY999999] NR 31 TC 26 Z9 28 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 1 PY 2009 VL 665 IS 1-2 BP 44 EP 50 DI 10.1016/j.mrfmmm.2009.02.015 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 454NW UT WOS:000266690200007 PM 19427510 ER PT J AU Borojerdi, JP Ming, J Cooch, C Ward, Y Semino-Mora, C Yu, M Braun, HM Taylor, BJ Poirier, MC Olivero, OA AF Borojerdi, Jennifer P. Ming, Jessica Cooch, Catherine Ward, Yvona Semino-Mora, Cristina Yu, Mia Braun, Hannan M. Taylor, Barbara J. Poirier, Miriam C. Olivero, Ofelia A. TI Centrosomal amplification and aneuploidy induced by the antiretroviral drug AZT in hamster and human cells SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Kinetochore; Aurora A; Aurora B; Immunohistochemistry; Zidovudine; Flow cytometry; Confocal microscopy; Pericentrin ID CYCLE PROGRESSION; S-PHASE; GENOMIC STABILITY; IN-VITRO; GENOTOXICITY; ZIDOVUDINE; 3'-AZIDO-3'-DEOXYTHYMIDINE; INSTABILITY; EXPRESSION; ARREST AB The centrosome directs chromosomal migration by a complex process of tubulin-chromatin binding. In this contribution centrosomal abnormalities, including centrosomal amplification, were explored in Chinese hamster ovary (CHO) and normal human mammary epithelial cells (NHMECs) exposed to the antiretroviral drug zidovudine (3'-azido-3'-deoxythymidine, AZT). Centrosomal amplification/fragmentation was observed in both cell types and kinetochore positive micronuclei were found in AZT-exposed CHO cells in correlation with dose. Normal human mammary epithelial cell (NMHEC) strain M99005, previously identified as a strain that incorporates high levels of AZT into DNA (high incorporator, HI), showed greater centrosomal amplification when compared with a second strain, NHMEC M98040, which did not incorporate AZT into DNA (low incorporator, LI). Additionally, an abnormal tubulin distribution was observed in AZT-exposed HI cells bearing multiple centrosomes. Immunofluorescent staining of human cells with Aurora A, a kinase involved in the maturation of the centrosome, confirmed the induction of centrosomal amplification and revealed multipolar mitotic figures. Flow cytometric studies revealed that cells bearing abnormal numbers of centrosomes and abnormal tubulin distribution had similar S-phase percentages suggesting that cells bearing unbalanced chromosomal segregation could divide. Therefore, AZT induces genomic instability and clastogenicity as well as alterations in proteins involved in centrosomal activation, all of which may contribute to the carcinogenic properties of this compound. Published by Elsevier B.V. C1 [Borojerdi, Jennifer P.; Ming, Jessica; Cooch, Catherine; Yu, Mia; Braun, Hannan M.; Taylor, Barbara J.; Poirier, Miriam C.; Olivero, Ofelia A.] NCI, Lab Canc Biol & Genet, CCR, NIH, Bethesda, MD 20892 USA. [Ward, Yvona] NCI, Cell & Canc Biol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Semino-Mora, Cristina] Uniformed Serv Univ Hlth Sci, Gastrointestinal & Liver Studies Lab, Dept Med, Bethesda, MD 20814 USA. RP Olivero, OA (reprint author), NCI, Lab Canc Biol & Genet, CCR, NIH, 37 Convent Dr,MSC 4255,Bldg 37 Rm 4032, Bethesda, MD 20892 USA. EM oliveroo@exchange.nih.gov FU Laboratory of Integrative and Medical Biophysics; NICHD; NIH; National Cancer Institute; Center for Cancer Research FX The authors would like to thank Dr. Dan Sackett from the Laboratory of Integrative and Medical Biophysics, NICHD, NIH, for guidance and critical reading of the manuscript and Dr. Jean-Marie Peloponese Jr. for advise with the staining. The work was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 29 TC 20 Z9 20 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 1 PY 2009 VL 665 IS 1-2 BP 67 EP 74 DI 10.1016/j.mrfmmm.2009.03.004 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 454NW UT WOS:000266690200010 PM 19427513 ER PT J AU Sousa, AA Aronova, MA Wu, H Sarin, H Griffiths, GL Leapman, RD AF Sousa, A. A. Aronova, M. A. Wu, H. Sarin, H. Griffiths, G. L. Leapman, R. D. TI Determining molecular mass distributions and compositions of functionalized dendrimer nanoparticles SO NANOMEDICINE LA English DT Article DE dendrimer; EFTEM; energy-filtered transmission electron microscopy; gadolinium; mass measurement; scanning transmission electron microscopy; STEM ID IMAGING CONTRAST AGENTS; MAGNETIC-RESONANCE; ELECTRON-MICROSCOPY; CROSS-SECTIONS; MACROMOLECULES; QUANTIFICATION; DELIVERY; EFTEM; STEM AB This study demonstrates that a combination of unconventional electron microscopy techniques provides a quantitative means of assessing the degree of monodispersity of gadolinium (Cid) diethylenetriamine pentaacetic acid-conjugated polyamicloamine (PAMAM) dendrimers, which are designed for diagnostic imaging and delivering chemotherapeutics. Specifically, analysis of images acquired in the scanning transmission electron microscopy mode yields the distribution of molecular weights of individual dendrimers, whereas analysis of images acquired in the energy-filtering transmission electron microscopy mode yields the distribution of Gd atoms bound to the dendrimer nanoparticles. Measured compositions of Gd-conjugated G7 and G8 PAMAM dendrimers were consistent with the known synthetic chemistry. The G7 dendrimers had a mass of 330 +/- 4 kDa and 266 +/- 4 Gd atoms (standard error of the mean). The G8 dendrimers had a mass of 600 +/- 8 kDa and 350 +/- 5 Gd atoms (standard error of the mean). This approach will be particularly attractive for assessing the mass, composition and homogeneity of metal-containing organic nanoparticles used in nanomedicine. C1 [Sousa, A. A.; Aronova, M. A.; Sarin, H.; Leapman, R. D.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Wu, H.; Griffiths, G. L.] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20850 USA. [Sarin, H.] NIH, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. RP Leapman, RD (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bldg 13,Rm 3N17,13 South Dr, Bethesda, MD 20892 USA. EM leapmanr@mail.nih.gov FU Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering in the NIH; Image Probe Development Center FX This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering in the NIH, and the NIH Roadmap for Medical Research Initiative for support of the Image Probe Development Center. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 25 TC 9 Z9 9 U1 1 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1743-5889 J9 NANOMEDICINE-UK JI Nanomedicine PD JUN PY 2009 VL 4 IS 4 BP 391 EP 399 DI 10.2217/NMM.09.14 PG 9 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA 470UA UT WOS:000268005100010 PM 19505242 ER PT J AU Kobayashi, H Ogawa, M Kosaka, N Choyke, PL Urano, Y AF Kobayashi, Hisataka Ogawa, Mikako Kosaka, Nobuyuki Choyke, Petet L. Urano, Yasuteru TI Multicolor imaging of lymphatic function with two nanomaterials: quantum dot-labeled cancer cells and dendrimer-based optical agents SO NANOMEDICINE LA English DT Article DE cancer; dendrimer; fluorescence; lymphatic flow; metastasis; multicolor imaging; quantum dot ID MAGNETIC RESONANCE LYMPHANGIOGRAPHY; IN-VIVO; CONTRAST AGENTS; SENTINEL NODE; BREAST-CANCER; TUMOR-CELLS; LIVE CELLS; MICE; NANOPARTICLES; TRACKING AB Aim: The lymphatics, critical conduits of metastases, are difficult to study because of their size and location. Two approaches to lymphatic imaging have been employed; cancer cell labeling provides information on cell migration and metastasis and macromolecular contrast agents enable visualization of the lymphatic drainage and identification of sentinel lymph node. Only one of these approaches is typically employed during an imaging examination. Here, we demonstrate the combined use of both approaches. Method: In this study, we simultaneously visualize migration of quantum dot-labeled melanoma cells and the lymphatics using optically labeled dendrimers in vivo. Results: The appropriate use of two nanomaterials, quantum dots and dendrimers, enabled the simultaneous tracking of cancer cells within draining lymphatics. Conclusion: This technique could enable better understanding of lymph node metastasis. C1 [Kobayashi, Hisataka; Ogawa, Mikako; Kosaka, Nobuyuki; Choyke, Petet L.] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Urano, Yasuteru] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH Bldg 10,Room 1B40,MSC 1088,10 Ctr Dr, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov RI Urano, Yasuteru/H-1380-2012 FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer earch, USA FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer earch, USA. The authors have no other relevant affiliations orfinancial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apartfrom those disclosed. NR 33 TC 47 Z9 48 U1 0 U2 11 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1743-5889 J9 NANOMEDICINE-UK JI Nanomedicine PD JUN PY 2009 VL 4 IS 4 BP 411 EP 419 DI 10.2217/NNM.09.15 PG 9 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA 470UA UT WOS:000268005100012 PM 19505244 ER PT J AU Dobrovolskaia, MA Patri, AK Zheng, JW Clogston, JD Ayub, N Aggarwal, P Neun, BW Hall, JB McNeil, SE AF Dobrovolskaia, Marina A. Patri, Anil K. Zheng, Jiwen Clogston, Jeffrey D. Ayub, Nader Aggarwal, Parag Neun, Barry W. Hall, Jennifer B. McNeil, Scott E. TI Interaction of colloidal gold nanoparticles with human blood: effects on particle size and analysis of plasma protein binding profiles SO NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE LA English DT Article DE Nanoparticles; Gold colloids; Plasma protein binding; Hydrodynamic size; Complement ID ENHANCED RAMAN-SCATTERING; PEG-CHAIN-LENGTH; 2-DIMENSIONAL ELECTROPHORESIS; REJECTING PROPERTIES; SURFACE-DENSITY; DRUG-DELIVERY; ADSORPTION; IDENTIFICATION AB Nanoparticle size and plasma binding profile contribute to a particle's longevity in the bloodstream, which can have important consequences for therapeutic efficacy. In this study an approximate doubling in nanoparticle hydrodynamic size was observed upon in vitro incubation of 30- and 50-nm colloidal gold in human plasma. Plasma proteins that bind the surface of citrate-stabilized gold colloids have been identified. Effects of protein binding on the nanoparticle hydrodynamic size, elements of coagulation, and the complement system have been investigated. The difference in size measurements obtained from dynamic light scattering, electron microscopy, and scanning probe microscopy are also discussed. (C) 2009 Elsevier Inc. All rights reserved. C1 [Dobrovolskaia, Marina A.; Patri, Anil K.; Zheng, Jiwen; Clogston, Jeffrey D.; Ayub, Nader; Aggarwal, Parag; Neun, Barry W.; Hall, Jennifer B.; McNeil, Scott E.] SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, NCI Frederick, Frederick, MD 21702 USA. RP Dobrovolskaia, MA (reprint author), SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, NCI Frederick, POB B, Frederick, MD 21702 USA. EM marina@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute, National Institutes of Health [N01-CO-12400] FX The study was supported in whole or in part by federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. NR 23 TC 262 Z9 265 U1 11 U2 112 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1549-9634 J9 NANOMED-NANOTECHNOL JI Nanomed.-Nanotechnol. Biol. Med. PD JUN PY 2009 VL 5 IS 2 BP 106 EP 117 DI 10.1016/j.nano.2008.08.001 PG 12 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA 463GK UT WOS:000267418000002 PM 19071065 ER PT J AU Gottesman, MM Ambudkar, SV Xia, D AF Gottesman, Michael M. Ambudkar, Suresh V. Xia, Di TI Structure of a multidrug transporter SO NATURE BIOTECHNOLOGY LA English DT Editorial Material ID P-GLYCOPROTEIN; MOLECULAR-BASIS; RESISTANCE; PROTEINS; HOMOLOGY; CELLS; MDR1; GENE AB Crystal structures of a mammalian multidrug efflux pump bound to peptide inhibitors may reveal drug-binding sites. C1 [Gottesman, Michael M.; Ambudkar, Suresh V.; Xia, Di] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU Intramural NIH HHS [Z01 BC010319-09, Z01 BC010030-12, Z01 BC005598-18] NR 11 TC 45 Z9 46 U1 1 U2 9 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 JUN PY 2009 VL 27 IS 6 BP 546 EP 547 DI 10.1038/nbt0609-546 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 458AC UT WOS:000266980500023 PM 19513059 ER PT J AU Shukla, A Malik, M Cataisson, C Ho, Y Friesen, T Suh, KS Yuspa, SH AF Shukla, Anjali Malik, Mariam Cataisson, Christophe Ho, Yan Friesen, Travis Suh, Kwang S. Yuspa, Stuart H. TI TGF-beta signalling is regulated by Schnurri-2-dependent nuclear translocation of CLIC4 and consequent stabilization of phospho-Smad2 and 3 SO NATURE CELL BIOLOGY LA English DT Article ID CHLORIDE CHANNEL PROTEIN; ION CHANNEL; SMAD PROTEINS; EXPRESSION; GROWTH; KERATINOCYTES; TRANSCRIPTION; MTCLIC/CLIC4; APOPTOSIS; P53 AB CLIC4 (chloride intracellular channel 4), a multifunctional protein that traffics between the cytoplasm and nucleus, interacts with Schnurri-2, a transcription factor in the bone morphogenetic protein (BMP) signalling pathway. Here we show that transforming growth factor beta (TGF-beta) promotes the expression of CLIC4 and Schnurri-2 as well as their association in the cytoplasm and their translocation to the nucleus. In the absence of CLIC4 or Schnurri-2, TGF-beta signalling is abrogated. Direct nuclear targeting of CLIC4 enhances TGF-beta signalling and removes the requirement for Schnurri-2. Nuclear CLIC4 associates with phospho (p)-Smad2 and p-Smad3, protecting them from dephosphorylation by nuclear phosphatases. An intact TGF-beta signalling pathway is essential for CLIC4-mediated growth-arrest. These results newly identify Schnurri-2 and CLIC4 as modifiers of TGF-beta signalling through their stabilization of p-Smad2 and 3 in the nucleus. C1 [Shukla, Anjali; Malik, Mariam; Cataisson, Christophe; Ho, Yan; Friesen, Travis; Suh, Kwang S.; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM yuspas@mail.nih.gov RI Shukla, Anjali/G-4046-2014 FU National Cancer Institute, NIH FX The authors thank L. Wakefield for critically reading the manuscript, M. Anzano for help with genotyping, C. Cheng for help with immunoprecipitation assays and colleagues for providing constructive criticism throughout the study. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 25 TC 40 Z9 40 U1 0 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 JUN PY 2009 VL 11 IS 6 BP 777 EP U154 DI 10.1038/ncb1885 PG 21 WC Cell Biology SC Cell Biology GA 451XH UT WOS:000266503700024 PM 19448624 ER PT J AU Goetz, BI Wang, P Shields, HW Basu, S Grubina, R Huang, J Conradie, J Huang, Z Jeffers, A Jiang, A He, X Azarov, I Seibert, R Mehta, A Patel, R King, SB Ghosh, A Hogg, N Gladwin, MT Kim-Shapiro, DB AF Goetz, Bradley I. Wang, Pamela Shields, Howard W. Basu, Swati Grubina, Rozalina Huang, Jinming Conradie, Jeanet Huang, Zhi Jeffers, Anne Jiang, Alice He, Xiaojun Azarov, Ivan Seibert, Ryan Mehta, Atul Patel, Rakesh King, S. Bruce Ghosh, Abhik Hogg, Neil Gladwin, Mark T. Kim-Shapiro, Daniel B. TI Nitrite-methemoglobin inadequate for hypoxic vasodilation Reply SO NATURE CHEMICAL BIOLOGY LA English DT Letter ID DIETARY NITRATE; BLOOD-PRESSURE; HEMOGLOBIN; OXIDE; REDUCTION; HUMANS C1 [Goetz, Bradley I.; Wang, Pamela; Shields, Howard W.; Basu, Swati; Huang, Jinming; Jeffers, Anne; Jiang, Alice; He, Xiaojun; Azarov, Ivan; Seibert, Ryan; Mehta, Atul; King, S. Bruce; Kim-Shapiro, Daniel B.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Grubina, Rozalina] NHLBI, Bethesda, MD 20892 USA. [Grubina, Rozalina] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. [Conradie, Jeanet] Univ Tromso, Tromso, Norway. [Conradie, Jeanet] Univ Free State, Bloemfontein, South Africa. [Patel, Rakesh] Univ Alabama, Birmingham, AL USA. [Hogg, Neil] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Gladwin, Mark T.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. RP Goetz, BI (reprint author), Wake Forest Univ, Winston Salem, NC 27109 USA. EM nhogg@mcw.edu; gladwinmt@upmc.edu; shapiro@wfu.edu RI Ghosh, Abhik/G-8164-2016 OI Ghosh, Abhik/0000-0003-1161-6364 NR 12 TC 4 Z9 4 U1 0 U2 3 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 JUN PY 2009 VL 5 IS 6 BP 367 EP 367 DI 10.1038/nchembio0609-367 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 450EM UT WOS:000266383800003 ER PT J AU Hartge, P AF Hartge, Patricia TI Genetics of reproductive lifespan SO NATURE GENETICS LA English DT Editorial Material ID SECULAR TRENDS; AGE; MENARCHE; PUBERTY; GIRLS AB Five genome-wide association studies of the timing of menarche and menopause have now taken us beyond the range of candidate gene and linkage studies. The list of new genetic associations identified for these two traits should shed light on the mechanisms of ovarian aging, as well as breast cancer and other diseases associated with reproductive lifespan. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Hartge, P (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM hartgep@mail.nih.gov NR 13 TC 40 Z9 41 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2009 VL 41 IS 6 BP 637 EP 638 DI 10.1038/ng0609-637 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 450OW UT WOS:000266411700002 PM 19471299 ER PT J AU Perry, JRB Stolk, L Franceschini, N Lunetta, KL Zhai, GJ McArdle, PF Smith, AV Aspelund, T Bandinelli, S Boerwinkle, E Cherkas, L Eiriksdottir, G Estrada, K Ferrucci, L Folsom, AR Garcia, M Gudnason, V Hofman, A Karasik, D Kiel, DP Launer, LJ van Meurs, J Nalls, MA Rivadeneira, F Shuldiner, AR Singleton, A Soranzo, N Tanaka, T Visser, JA Weedon, MN Wilson, SG Zhuang, V Streeten, EA Harris, TB Murray, A Spector, TD Demerath, EW Uitterlinden, AG Murabito, JM AF Perry, John R. B. Stolk, Lisette Franceschini, Nora Lunetta, Kathryn L. Zhai, Guangju McArdle, Patrick F. Smith, Albert V. Aspelund, Thor Bandinelli, Stefania Boerwinkle, Eric Cherkas, Lynn Eiriksdottir, Gudny Estrada, Karol Ferrucci, Luigi Folsom, Aaron R. Garcia, Melissa Gudnason, Vilmundur Hofman, Albert Karasik, David Kiel, Douglas P. Launer, Lenore J. van Meurs, Joyce Nalls, Michael A. Rivadeneira, Fernando Shuldiner, Alan R. Singleton, Andrew Soranzo, Nicole Tanaka, Toshiko Visser, Jenny A. Weedon, Michael N. Wilson, Scott G. Zhuang, Vivian Streeten, Elizabeth A. Harris, Tamara B. Murray, Anna Spector, Tim D. Demerath, Ellen W. Uitterlinden, Andre G. Murabito, Joanne M. TI Meta-analysis of genome-wide association data identifies two loci influencing age at menarche SO NATURE GENETICS LA English DT Article ID SECULAR TRENDS; OBESITY; GIRLS; ADULTHOOD; HEIGHT; GROWTH; GENES AB We conducted a meta-analysis of genome-wide association data to detect genes influencing age at menarche in 17,510 women. The strongest signal was at 9q31.2 (P = 1.7 x 10(-9)), where the nearest genes include TMEM38B, FKTN, FSD1L, TAL2 and ZNF462. The next best signal was near the LIN28B gene (rs7759938; P = 7.0 x 10(-9)), which also influences adult height. We provide the first evidence for common genetic variants influencing female sexual maturation. C1 [Perry, John R. B.; Stolk, Lisette; Estrada, Karol; van Meurs, Joyce; Rivadeneira, Fernando; Visser, Jenny A.; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Perry, John R. B.; Nalls, Michael A.; Murray, Anna] Penn Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England. [Stolk, Lisette; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Franceschini, Nora] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Lunetta, Kathryn L.; Karasik, David; Kiel, Douglas P.; Murabito, Joanne M.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Lunetta, Kathryn L.; Zhuang, Vivian] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Zhai, Guangju; Cherkas, Lynn; Soranzo, Nicole; Wilson, Scott G.; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [McArdle, Patrick F.; Shuldiner, Alan R.; Streeten, Elizabeth A.] Univ Maryland, Sch Med, Div Endocrinol Diabet Clin Nutr, Baltimore, MD 21201 USA. [Smith, Albert V.; Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Ferrucci, Luigi] NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. [Folsom, Aaron R.; Demerath, Ellen W.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Garcia, Melissa; Launer, Lenore J.; Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Karasik, David; Kiel, Douglas P.] Hebrew SeniorLife Inst Aging Res, Boston, MA USA. [Karasik, David; Kiel, Douglas P.] Harvard Univ, Sch Med, Boston, MA USA. [Nalls, Michael A.; Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Soranzo, Nicole] Wellcome Trust Sanger Inst, Hinxton, Cambs, England. [Tanaka, Toshiko] NIA, Medstar Res Inst, Baltimore, MD 21224 USA. [Wilson, Scott G.] Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA 6009, Australia. [Wilson, Scott G.] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Uitterlinden, AG (reprint author), Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. EM a.g.uitterlinden@erasmusmc.nl RI Aspelund, Thor/C-5983-2008; Spector, Tim/F-6533-2012; Singleton, Andrew/C-3010-2009; Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015; Smith, Albert Vernon/K-5150-2015; Aspelund, Thor/F-4826-2011; Visser, Jenny /F-8156-2011; OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Lunetta, Kathryn/0000-0002-9268-810X; Murabito, Joanne/0000-0002-0192-7516; Murray, Anna/0000-0002-2351-2522; Smith, Albert Vernon/0000-0003-1942-5845; Soranzo, Nicole/0000-0003-1095-3852; Kiel, Douglas/0000-0001-8474-0310; Karasik, David/0000-0002-8826-0530 FU Intramural NIH HHS; NCRR NIH HHS [M01 RR 16500, M01 RR016500-02]; NHLBI NIH HHS [N01 HC025195, N01 HC055015, N01 HC055016, N01 HC055018, N01 HC055019, N01 HC055020, N01 HC055021, N01 HC055022, N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N02 HL64278, N02-HL-6-4278, U01 HL072515, U01 HL072515-06, U01 HL72515]; NIA NIH HHS [N.1-AG-1-1, N.1-AG-1-2111, N01 AG012100, N01-AG-12100, N01-AG-5-0002, R01 AR/AG 41398, R21 AG032598, R21 AG032598-02, R21AG032598, U19 AG023122, U19 AG023122-05]; NIAMS NIH HHS [R01 AR041398, R01 AR041398-15]; NIDDK NIH HHS [P30 DK072488-02, P30 DK072488]; NIMHD NIH HHS [263 MD 821336, 263 MD 9164, 263 MD821336, 263 MD9164 13]; Wellcome Trust NR 15 TC 134 Z9 141 U1 3 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2009 VL 41 IS 6 BP 648 EP 650 DI 10.1038/ng.386 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 450OW UT WOS:000266411700011 PM 19448620 ER PT J AU Newton-Cheh, C Johnson, T Gateva, V Tobin, MD Bochud, M Coin, L Najjar, SS Zhao, JH Heath, SC Eyheramendy, S Papadakis, K Voight, BF Scott, LJ Zhang, F Farrall, M Tanaka, T Wallace, C Chambers, JC Khaw, KT Nilsson, P van der Harst, P Polidoro, S Grobbee, DE Onland-Moret, NC Bots, ML Wain, LV Elliott, KS Teumer, A Luan, J Lucas, G Kuusisto, J Burton, PR Hadley, D McArdle, WL Brown, M Dominiczak, A Newhouse, SJ Samani, NJ Webster, J Zeggini, E Beckmann, JS Bergmann, S Lim, N Song, K Vollenweider, P Waeber, G Waterworth, DM Yuan, X Groop, L Orho-Melander, M Allione, A Di Gregorio, A Guarrera, S Panico, S Ricceri, F Romanazzi, V Sacerdote, C Vineis, P Barroso, I Sandhu, MS Luben, RN Crawford, GJ Jousilahti, P Perola, M Boehnke, M Bonnycastle, LL Collins, FS Jackson, AU Mohlke, KL Stringham, HM Valle, TT Willer, CJ Bergman, RN Morken, MA Doring, A Gieger, C Illig, T Meitinger, T Org, E Pfeufer, A Wichmann, HE Kathiresan, S Marrugat, J O'Donnell, CJ Schwartz, SM Siscovick, DS Subirana, I Freimer, NB Hartikainen, AL McCarthy, MI O'Reilly, PF Peltonen, L Pouta, A de Jong, PE Snieder, H van Gilst, WH Clarke, R Goel, A Hamsten, A Peden, JF Seedorf, U Syvanen, AC Tognoni, G Lakatta, EG Sanna, S Scheet, P Schlessinger, D Scuteri, A Dorr, M Ernst, F Felix, SB Homuth, G Lorbeer, R Reffelmann, T Rettig, R Volker, U Galan, P Gut, IG Hercberg, S Lathrop, GM Zelenika, D Deloukas, P Soranzo, N Williams, FM Zhai, G Salomaa, V Laakso, M Elosua, R Forouhi, NG Volzke, H Uiterwaal, CS van der Schouw, YT Numans, ME Matullo, G Navis, G Berglund, G Bingham, SA Kooner, JS Connell, JM Bandinelli, S Ferrucci, L Watkins, H Spector, TD Tuomilehto, J Altshuler, D Strachan, DP Laan, M Meneton, P Wareham, NJ Uda, M Jarvelin, MR Mooser, V Melander, O Loos, RJF Elliott, P Abecasis, GR Caulfield, M Munroe, PB AF Newton-Cheh, Christopher Johnson, Toby Gateva, Vesela Tobin, Martin D. Bochud, Murielle Coin, Lachlan Najjar, Samer S. Zhao, Jing Hua Heath, Simon C. Eyheramendy, Susana Papadakis, Konstantinos Voight, Benjamin F. Scott, Laura J. Zhang, Feng Farrall, Martin Tanaka, Toshiko Wallace, Chris Chambers, John C. Khaw, Kay-Tee Nilsson, Peter van der Harst, Pim Polidoro, Silvia Grobbee, Diederick E. Onland-Moret, N. Charlotte Bots, Michiel L. Wain, Louise V. Elliott, Katherine S. Teumer, Alexander Luan, Jian'an Lucas, Gavin Kuusisto, Johanna Burton, Paul R. Hadley, David McArdle, Wendy L. Brown, Morris Dominiczak, Anna Newhouse, Stephen J. Samani, Nilesh J. Webster, John Zeggini, Eleftheria Beckmann, Jacques S. Bergmann, Sven Lim, Noha Song, Kijoung Vollenweider, Peter Waeber, Gerard Waterworth, Dawn M. Yuan, Xin Groop, Leif Orho-Melander, Marju Allione, Alessandra Di Gregorio, Alessandra Guarrera, Simonetta Panico, Salvatore Ricceri, Fulvio Romanazzi, Valeria Sacerdote, Carlotta Vineis, Paolo Barroso, Ines Sandhu, Manjinder S. Luben, Robert N. Crawford, Gabriel J. Jousilahti, Pekka Perola, Markus Boehnke, Michael Bonnycastle, Lori L. Collins, Francis S. Jackson, Anne U. Mohlke, Karen L. Stringham, Heather M. Valle, Timo T. Willer, Cristen J. Bergman, Richard N. Morken, Mario A. Doering, Angela Gieger, Christian Illig, Thomas Meitinger, Thomas Org, Elin Pfeufer, Arne Wichmann, H. Erich Kathiresan, Sekar Marrugat, Jaume O'Donnell, Christopher J. Schwartz, Stephen M. Siscovick, David S. Subirana, Isaac Freimer, Nelson B. Hartikainen, Anna-Liisa McCarthy, Mark I. O'Reilly, Paul F. Peltonen, Leena Pouta, Anneli de Jong, Paul E. Snieder, Harold van Gilst, Wiek H. Clarke, Robert Goel, Anuj Hamsten, Anders Peden, John F. Seedorf, Udo Syvanen, Ann-Christine Tognoni, Giovanni Lakatta, Edward G. Sanna, Serena Scheet, Paul Schlessinger, David Scuteri, Angelo Doerr, Marcus Ernst, Florian Felix, Stephan B. Homuth, Georg Lorbeer, Roberto Reffelmann, Thorsten Rettig, Rainer Voelker, Uwe Galan, Pilar Gut, Ivo G. Hercberg, Serge Lathrop, G. Mark Zelenika, Diana Deloukas, Panos Soranzo, Nicole Williams, Frances M. Zhai, Guangju Salomaa, Veikko Laakso, Markku Elosua, Roberto Forouhi, Nita G. Volzke, Henry Uiterwaal, Cuno S. van der Schouw, Yvonne T. Numans, Mattijs E. Matullo, Giuseppe Navis, Gerjan Berglund, Goran Bingham, Sheila A. Kooner, Jaspal S. Connell, John M. Bandinelli, Stefania Ferrucci, Luigi Watkins, Hugh Spector, Tim D. Tuomilehto, Jaakko Altshuler, David Strachan, David P. Laan, Maris Meneton, Pierre Wareham, Nicholas J. Uda, Manuela Jarvelin, Marjo-Riitta Mooser, Vincent Melander, Olle Loos, Ruth J. F. Elliott, Paul Abecasis, Goncalo R. Caulfield, Mark Munroe, Patricia B. CA Wellcome Trust Case Control Consor TI Genome-wide association study identifies eight loci associated with blood pressure SO NATURE GENETICS LA English DT Article ID METHYLENETETRAHYDROFOLATE REDUCTASE GENE; LOW-RENIN HYPERTENSION; COMMON VARIANTS; CELL-DIFFERENTIATION; BARTTERS-SYNDROME; PUBLIC-HEALTH; RISK; POLYMORPHISM; POPULATION; MUTATIONS AB Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N <= 71,225 European ancestry, N <= 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 x 10(-24)), CYP1A2 (P = 1 x 10(-23)), FGF5 (P = 1 x 10(-21)), SH2B3 (P = 3 x 10(-18)), MTHFR (P = 2 x 10(-13)), c10orf107 (P = 1 x 10(-9)), ZNF652 (P = 5 x 10(-9)) and PLCD3 (P = 1 x 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease. C1 [Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Newton-Cheh, Christopher; Voight, Benjamin F.; Kathiresan, Sekar; Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Newton-Cheh, Christopher; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher; Voight, Benjamin F.; Crawford, Gabriel J.; Kathiresan, Sekar; Altshuler, David] Harvard & Massachusetts Inst Technol, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02138 USA. [Johnson, Toby; Beckmann, Jacques S.; Bergmann, Sven] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Johnson, Toby; Bochud, Murielle] CHU Vaudois, Univ Inst Social & Preventat Med, CH-1011 Lausanne, Switzerland. [Johnson, Toby; Bergmann, Sven] Swiss Inst Bioinformat, Lausanne, Switzerland. [Gateva, Vesela; Scott, Laura J.; Boehnke, Michael; Jackson, Anne U.; Stringham, Heather M.; Willer, Cristen J.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Gateva, Vesela; Scott, Laura J.; Boehnke, Michael; Jackson, Anne U.; Stringham, Heather M.; Willer, Cristen J.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Tobin, Martin D.; Wain, Louise V.; Burton, Paul R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Tobin, Martin D.; Wain, Louise V.; Burton, Paul R.] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. [Coin, Lachlan; Chambers, John C.; Vineis, Paolo; O'Reilly, Paul F.; Jarvelin, Marjo-Riitta; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [Najjar, Samer S.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Zhao, Jing Hua; Luan, Jian'an; Sandhu, Manjinder S.; Forouhi, Nita G.; Wareham, Nicholas J.; Loos, Ruth J. F.] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [Zhao, Jing Hua; Khaw, Kay-Tee; Barroso, Ines; Sandhu, Manjinder S.; Luben, Robert N.; Deloukas, Panos; Bingham, Sheila A.; Wareham, Nicholas J.; Loos, Ruth J. F.] Cambridge Genet Energy Metab GEM Consortium, Cambridge, England. [Heath, Simon C.; Gut, Ivo G.; Lathrop, G. Mark; Zelenika, Diana] Ctr Natl Genotypage, Evry, France. [Eyheramendy, Susana] Pontificia Univ Catolica Chile, Fac Matemat, Santiago, Chile. [Eyheramendy, Susana; Doering, Angela; Gieger, Christian; Illig, Thomas; Wichmann, H. Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Papadakis, Konstantinos; Hadley, David; Strachan, David P.] Univ London, Div Community Hlth Sci, London, England. [Zhang, Feng; Soranzo, Nicole; Williams, Frances M.; Zhai, Guangju; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Farrall, Martin; Goel, Anuj; Peden, John F.; Watkins, Hugh] Univ Oxford, Dept Cardiovasc Med, Oxford, England. [Farrall, Martin; Elliott, Katherine S.; Zeggini, Eleftheria; McCarthy, Mark I.; Goel, Anuj; Watkins, Hugh] Wellcome Trust Ctr Human Genet, Oxford, England. [Tanaka, Toshiko] Medstar Res Inst, Baltimore, MD USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Wallace, Chris; Newhouse, Stephen J.; Caulfield, Mark; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Genome Ctr, London, England. [Wallace, Chris] Univ Cambridge, Addenbrookes Hosp, Cambridge Inst Med Res, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Cambridge CB2 2QQ, England. [Khaw, Kay-Tee; Sandhu, Manjinder S.; Luben, Robert N.] Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge, England. [Nilsson, Peter; Orho-Melander, Marju; Berglund, Goran; Melander, Olle] Lund Univ, Malmo Univ Hosp, Dept Clin Sci, Malmo, Sweden. [van der Harst, Pim; van Gilst, Wiek H.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Polidoro, Silvia; Di Gregorio, Alessandra; Guarrera, Simonetta; Ricceri, Fulvio; Romanazzi, Valeria; Vineis, Paolo; Matullo, Giuseppe] ISI Fdn Inst Sci Interchange, Turin, Italy. [Grobbee, Diederick E.; Onland-Moret, N. Charlotte; Bots, Michiel L.; Uiterwaal, Cuno S.; van der Schouw, Yvonne T.; Numans, Mattijs E.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Onland-Moret, N. Charlotte] Univ Med Ctr Utrecht, Dept Med Genet DBG, Complex Genet Sect, Utrecht, Netherlands. [Teumer, Alexander; Ernst, Florian; Homuth, Georg; Voelker, Uwe] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Lucas, Gavin; Marrugat, Jaume; Subirana, Isaac; Elosua, Roberto] Inst Municipal Invest Med, E-08003 Barcelona, Spain. [Kuusisto, Johanna; Laakso, Markku] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland. [McArdle, Wendy L.] Univ Bristol, Dept Social Med, ALSPAC Lab, Bristol, Avon, England. [Brown, Morris] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge CB2 2QQ, England. [Dominiczak, Anna; Connell, John M.] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Webster, John] Aberdeen Royal Infirm, Aberdeen, Scotland. [Zeggini, Eleftheria; Barroso, Ines; Peltonen, Leena; Deloukas, Panos; Soranzo, Nicole] Wellcome Trust Sanger Inst, Cambridge, England. [Beckmann, Jacques S.] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland. [Lim, Noha; Song, Kijoung; Waterworth, Dawn M.; Yuan, Xin; Mooser, Vincent] GlaxoSmithKline Inc, Div Genet, King Of Prussia, PA USA. [Vollenweider, Peter; Waeber, Gerard] CHU Vaudois, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Groop, Leif] Univ Hosp, Diabet & Endocrinol Res Unit, Dept Clin Sci, Malmo, Sweden. [Groop, Leif] Lund Univ, Malmo, Sweden. [Di Gregorio, Alessandra; Matullo, Giuseppe] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Panico, Salvatore] Univ Naples Federico 2, Dept Clin & Expt Med, Naples, Italy. [Sacerdote, Carlotta; Peltonen, Leena] Univ Turin, Canc Epidemiol Unit, Turin, Italy. [Sacerdote, Carlotta; Peltonen, Leena] Ctr Canc Epidemiol & Prevent CPO Piemonte, Turin, Italy. [Jousilahti, Pekka; Perola, Markus; Salomaa, Veikko] Natl Inst Welf & Hlth, Helsinki, Finland. [Perola, Markus] Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00014 Helsinki, Finland. [Bonnycastle, Lori L.; Collins, Francis S.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Valle, Timo T.; Morken, Mario A.; Tuomilehto, Jaakko] Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Diabet Unit, Helsinki, Finland. [Bergman, Richard N.] Univ So Calif, Sch Med, Los Angeles, CA USA. [Meitinger, Thomas; Pfeufer, Arne] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Meitinger, Thomas; Pfeufer, Arne] Tech Univ Munich, Inst Human Genet, Munich, Germany. [Org, Elin; Laan, Maris] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Wichmann, H. Erich] Univ Munich, IBE, Chair Epidemiol, Munich, Germany. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Framingham Heart Study & Natl Heart Lung & Bloo, Framingham, MA USA. [Schwartz, Stephen M.; Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Schwartz, Stephen M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Subirana, Isaac; Elosua, Roberto] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Freimer, Nelson B.] Univ Calif Los Angeles, Gonda Ctr, Ctr Neurobehav Genet, Los Angeles, CA USA. [Hartikainen, Anna-Liisa; Pouta, Anneli] Univ Oulu, Dept Clin Sci Obstet & Gynecol, Oulu, Finland. [McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Pouta, Anneli; Jarvelin, Marjo-Riitta] Natl Publ Hlth Inst KTL, Dept Child & Adolescent Hlth, Oulu, Finland. [de Jong, Paul E.; Navis, Gerjan] Univ Groningen, Univ Med Ctr Groningen, Dept Med, Div Nephrol, Groningen, Netherlands. [Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Unit Genet Epidemiol & Bioinformat, Groningen, Netherlands. [Clarke, Robert] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Clarke, Robert] Univ Oxford, Epidemiol Studies Unit CTSU, Oxford, England. [Hamsten, Anders] Karolinska Univ, Hosp Solna, Karolinska Inst, Dept Med Solna,Atherosclerosis Res Unit, Stockholm, Sweden. [Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Tognoni, Giovanni] Ist Ric Farmacol Mario Negri, Consorzio Mario Negri Sud, I-66030 Santa Maria Imbaro, Chieti, Italy. [Sanna, Serena; Uda, Manuela] CNR, Inst Neurogenet & Neurofarmacol, Cagliari, Italy. [Scheet, Paul] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Schlessinger, David] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Scuteri, Angelo] IRCCS, INRCA, Unita Operat Geriatria, Rome, Italy. [Doerr, Marcus; Felix, Stephan B.; Reffelmann, Thorsten] Ernst Moritz Arndt Univ Greifswald, Dept Internal Med B, Greifswald, Germany. [Lorbeer, Roberto; Navis, Gerjan] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Rettig, Rainer] Ernst Moritz Arndt Univ Greifswald, Inst Physiol, Greifswald, Germany. [Galan, Pilar; Hercberg, Serge] Univ Paris 13, Inst Natl Rech Agron, Inst Natl Sante & Rech Med, U557, Bobigny, France. [Bingham, Sheila A.] Wellcome Trust Res Labs, MRC Dunn Human Nutr Unit, Cambridge, England. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Bandinelli, Stefania] ASF, Geriatr Rehabil Unit, Florence, Italy. [Tuomilehto, Jaakko] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Meneton, Pierre] Fac Med Paris Descartes, Inst Natl Sante & Rech Med, U872, Paris, France. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Seedorf, Udo] Univ Munster, Leibniz Inst Arterioskleroseforsch, Munster, Germany. RP Abecasis, GR (reprint author), Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. EM cnewtoncheh@chgr.mgh.harvard.edu; goncalo@umich.edu; m.j.caulfield@qmul.ac.uk; p.b.munroe@qmul.ac.uk RI Deloukas, Panos/B-2922-2013; Pfeufer, Arne/B-6634-2013; Colaus, PsyColaus/K-6607-2013; Grobbee, Diederick/C-7651-2014; van der Schouw, Yvonne/F-8327-2014; Worthington, Jane/M-9770-2014; Hinks, Anne/E-1853-2015; Onland-Moret, N. Charlotte/G-9185-2011; Breen, Gerome/A-5540-2010; Meitinger, Thomas/O-1318-2015; Mathew, Christopher/G-3434-2015; Burton, Paul/H-7527-2016; Matullo, Giuseppe/K-6383-2016; Panico, Salvatore/K-6506-2016; Coin, Lachlan/A-9001-2014; van Gilst, Wiek/C-3828-2008; Bochud, Murielle/A-3981-2010; Altshuler, David/A-4476-2009; Laan, Maris/A-4100-2011; Voight, Benjamin/F-1775-2011; Beckmann, Jacques S /A-9772-2008; Lucas, Gavin/D-4346-2012; Spector, Tim/F-6533-2012; Newhouse, Stephen/C-9330-2011; Hadley, David/I-6902-2012; Heath, Simon/J-4138-2012; Dominiczak, Anna/D-2262-2009; Abecasis, Goncalo/B-7840-2010; OI Deloukas, Panos/0000-0001-9251-070X; Grobbee, Diederick/0000-0003-4472-4468; van der Schouw, Yvonne/0000-0002-4605-435X; Worthington, Jane/0000-0003-0544-042X; Hinks, Anne/0000-0001-8843-3967; Breen, Gerome/0000-0003-2053-1792; Mathew, Christopher/0000-0003-4178-1838; Panico, Salvatore/0000-0002-5498-8312; Coin, Lachlan/0000-0002-4300-455X; Seedorf, Udo/0000-0003-4652-5358; Willer, Cristen/0000-0001-5645-4966; Allione, Alessandra/0000-0001-9599-309X; Lango Allen, Hana/0000-0002-7803-8688; Zeggini, Eleftheria/0000-0003-4238-659X; Williams, Frances/0000-0002-2998-2744; Simmonds, Matt/0000-0003-3154-3510; Conway, David/0000-0002-8711-3037; O'Donovan, Michael/0000-0001-7073-2379; Bochud, Murielle/0000-0002-5727-0218; Altshuler, David/0000-0002-7250-4107; Laan, Maris/0000-0002-8519-243X; Beckmann, Jacques S /0000-0002-9741-1900; Newhouse, Stephen/0000-0002-1843-9842; Barrett, Jenny/0000-0002-1720-7724; sanna, serena/0000-0002-3768-1749; Johnson, Toby/0000-0002-5998-3270; MATULLO, Giuseppe/0000-0003-0674-7757; Org, Elin/0000-0003-1451-9375; Abecasis, Goncalo/0000-0003-1509-1825; Dunger, Professor David/0000-0002-2566-9304; Luben, Robert/0000-0002-5088-6343; Symmons, Deborah/0000-0002-8625-1200; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Sacerdote, Carlotta/0000-0002-8008-5096; Bishop, Tim/0000-0002-8752-8785; Forouhi, Nita/0000-0002-5041-248X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Thomson, Wendy/0000-0002-9022-5179; Wallace, Chris/0000-0001-9755-1703; Marrugat, Jaume/0000-0003-3320-554X; Watkins, Hugh/0000-0002-5287-9016; Eyre, Stephen/0000-0002-1251-6974; Bruce, Ian/0000-0003-3047-500X; Prescott, Natalie/0000-0002-5901-7371; Evans, David/0000-0003-0663-4621; Bergmann, Sven/0000-0002-6785-9034; Wain, Louise/0000-0003-4951-1867 FU British Heart Foundation [FS/05/061/19501, PG02/128, SP/04/002]; Cancer Research UK [, 10589]; Chief Scientist Office [CZB/4/540]; Intramural NIH HHS; Medical Research Council [G0501942, 85374, G0000934, G0400874, G0401527, G0600329, G0701863, G0800675, G0800759, G0801056, G9521010, G9521010D, MC_QA137934, MC_U105630924, MC_U106188470, MC_U137686857]; NCRR NIH HHS [U54 RR020278, U54RR020278]; NHGRI NIH HHS [1Z01HG000024, Z01 HG000024]; NHLBI NIH HHS [K23 HL080025, K23 HL080025-04, K23 HL083102, K23HL083102, K23HL80025, R01 HL056931, R01 HL056931-02, R01 HL056931-03, R01 HL056931-04, R01 HL087676, R01 HL087679, R01HL056931, R01HL087676, R01HL087679]; NIA NIH HHS [N01-AG-1-2109, N01AG-821336, N01AG-916413]; NICHD NIH HHS [N01-HD-1-3107]; NIDA NIH HHS [U54 DA021519, U54DA021519]; NIDDK NIH HHS [DK062370, DK072193, R01 DK029867, R01 DK062370, R01 DK072193, R56 DK062370, U01 DK062370, U01 DK062418, U01DK062418]; NIEHS NIH HHS [P30 ES007033, P30ES007033]; NIMH NIH HHS [RL1 MH083268, RL1MH083268]; NIMHD NIH HHS [263MD821336, 263MD916413]; PHS HHS [263-MA-410953]; Wellcome Trust [061858, 068545/Z/02, 070191/Z/03/Z, 076113, 076113/B/04/Z, 077011, 077016, 077016/Z/05/Z, 079557, 079895, 088885, 089061, 090532, WT088885/Z/09/Z]; Associazione Italiana per la Ricerca sul Cancro NR 49 TC 613 Z9 642 U1 5 U2 82 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2009 VL 41 IS 6 BP 666 EP 676 DI 10.1038/ng.361 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 450OW UT WOS:000266411700015 PM 19430483 ER PT J AU Levy, D Ehret, GB Rice, K Verwoert, GC Launer, LJ Dehghan, A Glazer, NL Morrison, AC Johnson, AD Aspelund, T Aulchenko, Y Lumley, T Kottgen, A Vasan, RS Rivadeneira, F Eiriksdottir, G Guo, XQ Arking, DE Mitchell, GF Mattace-Raso, FUS Smith, AV Taylor, K Scharpf, RB Hwang, SJ Sijbrands, EJG Bis, J Harris, TB Ganesh, SK O'Donnell, CJ Hofman, A Rotter, JI Coresh, J Benjamin, EJ Uitterlinden, AG Heiss, G Fox, CS Witteman, JCM Boerwinkle, E Wang, TJ Gudnason, V Larson, MG Chakravarti, A Psaty, BM van Duijn, CM AF Levy, Daniel Ehret, Georg B. Rice, Kenneth Verwoert, Germaine C. Launer, Lenore J. Dehghan, Abbas Glazer, Nicole L. Morrison, Alanna C. Johnson, Andrew D. Aspelund, Thor Aulchenko, Yurii Lumley, Thomas Koettgen, Anna Vasan, Ramachandran S. Rivadeneira, Fernando Eiriksdottir, Gudny Guo, Xiuqing Arking, Dan E. Mitchell, Gary F. Mattace-Raso, Francesco U. S. Smith, Albert V. Taylor, Kent Scharpf, Robert B. Hwang, Shih-Jen Sijbrands, Eric J. G. Bis, Joshua Harris, Tamara B. Ganesh, Santhi K. O'Donnell, Christopher J. Hofman, Albert Rotter, Jerome I. Coresh, Josef Benjamin, Emelia J. Uitterlinden, Andre G. Heiss, Gerardo Fox, Caroline S. Witteman, Jacqueline C. M. Boerwinkle, Eric Wang, Thomas J. Gudnason, Vilmundur Larson, Martin G. Chakravarti, Aravinda Psaty, Bruce M. van Duijn, Cornelia M. TI Genome-wide association study of blood pressure and hypertension SO NATURE GENETICS LA English DT Article ID GENETIC-VARIANTS; CALCIUM-CHANNEL; COMMON VARIANTS; CELIAC-DISEASE; SUSCEPTIBILITY; EXPRESSION; MUTATIONS; POPULATION; PROJECT; HAPMAP AB Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 x 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 x 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension. C1 [Levy, Daniel; Johnson, Andrew D.; Vasan, Ramachandran S.; Hwang, Shih-Jen; O'Donnell, Christopher J.; Benjamin, Emelia J.; Fox, Caroline S.; Wang, Thomas J.; Larson, Martin G.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Levy, Daniel; Johnson, Andrew D.; Hwang, Shih-Jen; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Ehret, Georg B.; Arking, Dan E.; Ganesh, Santhi K.; Chakravarti, Aravinda] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Ehret, Georg B.] Univ Hosp Geneva, Div Cardiol, Geneva, Switzerland. [Rice, Kenneth; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Verwoert, Germaine C.; Dehghan, Abbas; Aulchenko, Yurii; Rivadeneira, Fernando; Mattace-Raso, Francesco U. S.; Hofman, Albert; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Mattace-Raso, Francesco U. S.] Erasmus MC, Dept Internal Med, Geriatr Med Sect, Rotterdam, Netherlands. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Dermog & Biometry, Bethesda, MD 20892 USA. [Glazer, Nicole L.; Bis, Joshua] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Glazer, Nicole L.; Bis, Joshua] Univ Washington, Dept Med, Seattle, WA USA. [Morrison, Alanna C.; Boerwinkle, Eric] Univ Texas Houston, Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Koettgen, Anna; Coresh, Josef; Chakravarti, Aravinda] Johns Hopkins Univ, Dept Epidemiol & Med, Baltimore, MD USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Cardiol, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Epidemiol Sect, Boston, MA USA. [Guo, Xiuqing; Taylor, Kent; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Scharpf, Robert B.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Ganesh, Santhi K.] NHGRI, Vasc Biol Sect, Bethesda, MD 20892 USA. [Heiss, Gerardo] Carolina Cardiovasc Biol Ctr, Chapel Hill, NC USA. [Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. RP Levy, D (reprint author), Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. EM levyd@nhlbi.nih.gov; c.vanduijn@erasmusmc.nl RI Aulchenko, Yurii/M-8270-2013; Gudnason, Vilmundur/K-6885-2015; Mattace- Raso, Francesco/L-2541-2015; Rivadeneira, Fernando/O-5385-2015; Smith, Albert/K-5150-2015; Aspelund, Thor/C-5983-2008; Aspelund, Thor/F-4826-2011; EHRET, Georg/A-9532-2009; Kottgen, Anna/D-2920-2012; Rice, Kenneth/A-4150-2013; Johnson, Andrew/G-6520-2013; OI Aulchenko, Yurii/0000-0002-7899-1575; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Smith, Albert/0000-0003-1942-5845; Larson, Martin/0000-0002-9631-1254; Aspelund, Thor/0000-0002-7998-5433; EHRET, Georg/0000-0002-5730-0675; Rice, Kenneth/0000-0001-5779-4495; Sijbrands, Eric/0000-0001-8857-7389; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Dehghan, Abbas/0000-0001-6403-016X FU Intramural NIH HHS; NCRR NIH HHS [UL1 RR025005, UL1 RR025005-01, UL1RR025005]; NHGRI NIH HHS [U01 HG004402, U01 HG004402-01, U01HG004402]; NHLBI NIH HHS [N01 HC025195, N01 HC-55222, N01 HC015103, N01 HC035129, N01 HC045133, N01 HC055015, N01 HC055016, N01 HC055018, N01 HC055019, N01 HC055020, N01 HC055021, N01 HC055022, N01 HC055222, N01 HC075150, N01 HC085079, N01 HC085086, N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-75150, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01HC25195, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC55222, N01HC75150, N01HC85079, N01HC85086, N02 HL64278, N02-HL-6-4278, R01 HL059367, R01 HL059367-02, R01 HL086694, R01 HL086694-01A1, R01 HL087641, R01 HL087641-01, R01 HL087652, R01 HL087652-01, R01HL086694, R01HL087641, R01HL59367, R37 HL051021, R37 HL051021-06, R37 HL051021-10, R37 HL051021-11, R37 HL051021-12, R37 HL051021-13, R37 HL051021-14, R37 HL051021-15, R37HL051021, U01 HL080295, U01 HL080295-01, U10 HL054512, U10 HL054512-05, U10HL054512]; NIA NIH HHS [N01 AG012100, N01AG12100]; NIDDK NIH HHS [P30 DK063491, P30 DK063491-019004, P30 DK063491-029004, P30 DK063491-039004, P30 DK063491-049004]; PHS HHS [HHSN268200625226C] NR 47 TC 602 Z9 634 U1 6 U2 53 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2009 VL 41 IS 6 BP 677 EP 687 DI 10.1038/ng.384 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 450OW UT WOS:000266411700016 PM 19430479 ER PT J AU Barrett, JC Clayton, DG Concannon, P Akolkar, B Cooper, JD Erlich, HA Julier, C Morahan, G Nerup, J Nierras, C Plagnol, V Pociot, F Schuilenburg, H Smyth, DJ Stevens, H Todd, JA Walker, NM Rich, SS AF Barrett, Jeffrey C. Clayton, David G. Concannon, Patrick Akolkar, Beena Cooper, Jason D. Erlich, Henry A. Julier, Cecile Morahan, Grant Nerup, Jorn Nierras, Concepcion Plagnol, Vincent Pociot, Flemming Schuilenburg, Helen Smyth, Deborah J. Stevens, Helen Todd, John A. Walker, Neil M. Rich, Stephen S. CA Type 1 Diabet Genetics Consortium TI Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes SO NATURE GENETICS LA English DT Article ID SUSCEPTIBILITY LOCUS; CHROMOSOME; DISEASE; REGION; GENES; HLA; VARIANTS; MELLITUS; PTPN22; TESTS AB Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with T1D in the meta-analysis (P < 10(-6)). After excluding previously reported associations, we further tested 27 regions in an independent set of 4,267 cases, 4,463 controls and 2,319 affected sib-pair (ASP) families. Of these, 18 regions were replicated (P < 0.01; overall P < 5 x 10(-8)) and 4 additional regions provided nominal evidence of replication (P < 0.05). The many new candidate genes suggested by these results include IL10, IL19, IL20, GLIS3, CD69 and IL27. C1 [Clayton, David G.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22903 USA. [Barrett, Jeffrey C.; Clayton, David G.; Cooper, Jason D.; Plagnol, Vincent; Schuilenburg, Helen; Smyth, Deborah J.; Stevens, Helen; Todd, John A.; Walker, Neil M.] Univ Cambridge, Addenbrookes Hosp, Cambridge Inst Med Res,Juvenile Diabet Res Fdn, Dept Med Genet,Wellcom Trust Diabet & Inflammat L, Cambridge CB2 2QQ, England. [Concannon, Patrick; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Akolkar, Beena] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD USA. [Erlich, Henry A.] Roche Mol Syst, Pleasanton, CA USA. [Julier, Cecile] INSERM, U958, Ctr Natl Genotypage, Evry, France. [Morahan, Grant] Western Australia Inst Med Res, Ctr Diabet Res, Perth, WA, Australia. [Morahan, Grant] Univ Western Australia, Med Res Ctr, Perth, WA 6009, Australia. [Nerup, Jorn; Pociot, Flemming] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Nerup, Jorn; Pociot, Flemming] Hagedorn Res Inst, Gentofte, Denmark. [Nierras, Concepcion] Juvenile Diabet Res Fdn, New York, NY USA. [Rich, Stephen S.] Univ Virginia, Dept Publ Hlth Sci, Div Biostat & Epidemiol, Charlottesville, VA USA. RP Concannon, P (reprint author), Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22903 USA. EM patcon@virginia.edu RI Altshuler, David/A-4476-2009; Tillmann, Vallo/G-8118-2012; Li, Dawei/A-3466-2011; Plagnol, Vincent/A-5667-2011; de Bakker, Paul/B-8730-2009; Argente , Jesus /K-1167-2014; Boehm, Bernhard/F-8750-2015; Mauricio, Didac/B-7951-2009; Cameron, Fergus/N-9535-2015; Skrha, Jan/C-3095-2017; OI Altshuler, David/0000-0002-7250-4107; Tillmann, Vallo/0000-0002-5279-4493; de Bakker, Paul/0000-0001-7735-7858; Argente , Jesus /0000-0001-5826-0276; Mauricio, Didac/0000-0002-2868-0250; Skrha, Jan/0000-0001-8012-8802; Brodnicki, Thomas/0000-0003-2294-315X; Corripio, Raquel/0000-0003-3344-8269; Walker, Neil/0000-0001-9796-7688; Burren, Oliver/0000-0002-3388-5760; Schofield, Ellen/0000-0003-0648-1418; smyth, deborah/0000-0002-6330-2669; Battelino, Tadej/0000-0002-0273-4732; Concannon, Patrick/0000-0002-5801-1859; Schuilenburg, Helen/0000-0002-0040-6591; Dunger, Professor David/0000-0002-2566-9304; Johannesen, Jesper/0000-0003-2772-2567; Plagnol, Vincent/0000-0002-5597-9215; McLaren, William/0000-0001-6218-1116; Cinek, Ondrej/0000-0002-0526-8714; Pociot, Flemming/0000-0003-3274-5448; Castano, Luis/0000-0003-0437-9401; Ludvigsson, Johnny/0000-0003-1695-5234 FU Medical Research Council [G0000934, ]; NIDDK NIH HHS [DK46635, K08 DK002876, K08 DK002876-06, R01 DK046635, R01 DK046635-15, U01 DK062418, U01 DK062418-06]; NIMH NIH HHS [MH 63420, MH059565, MH059571, MH059588, MH060879, MH061675, MH067257, MH59566, MH59586, MH59587, MH60870, R01 MH059565, R01 MH059566, R01 MH059571, R01 MH059586, R01 MH059587, R01 MH059588, R01 MH060870, R01 MH060879, R01 MH061675, R01 MH063420, R01 MH067257]; Wellcome Trust [061858, 076113] NR 29 TC 752 Z9 771 U1 6 U2 85 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUN PY 2009 VL 41 IS 6 BP 703 EP 707 DI 10.1038/ng.381 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 450OW UT WOS:000266411700019 PM 19430480 ER PT J AU Kottgen, A Glazer, NL Dehghan, A Hwang, SJ Katz, R Li, M Yang, Q Gudnason, V Launer, LJ Harris, TB Smith, AV Arking, DE Astor, BC Boerwinkle, E Ehret, GB Ruczinski, I Scharpf, RB Chen, YDI de Boer, IH Haritunians, T Lumley, T Sarnak, M Siscovick, D Benjamin, EJ Levy, D Upadhyay, A Aulchenko, YS Hofman, A Rivadeneira, F Uitterlinden, AG van Duijn, CM Chasman, DI Pare, G Ridker, PM Kao, WHL Witteman, JC Coresh, J Shlipak, MG Fox, CS AF Koettgen, Anna Glazer, Nicole L. Dehghan, Abbas Hwang, Shih-Jen Katz, Ronit Li, Man Yang, Qiong Gudnason, Vilmundur Launer, Lenore J. Harris, Tamara B. Smith, Albert V. Arking, Dan E. Astor, Brad C. Boerwinkle, Eric Ehret, Georg B. Ruczinski, Ingo Scharpf, Robert B. Chen, Yii-Der Ida de Boer, Ian H. Haritunians, Talin Lumley, Thomas Sarnak, Mark Siscovick, David Benjamin, Emelia J. Levy, Daniel Upadhyay, Ashish Aulchenko, Yurii S. Hofman, Albert Rivadeneira, Fernando Uitterlinden, Andre G. van Duijn, Cornelia M. Chasman, Daniel I. Pare, Guillaume Ridker, Paul M. Kao, W. H. Linda Witteman, Jacqueline C. Coresh, Josef Shlipak, Michael G. Fox, Caroline S. TI Multiple loci associated with indices of renal function and chronic kidney disease SO NATURE GENETICS LA English DT Article ID GLOMERULAR-FILTRATION-RATE; SERUM CREATININE; CARDIOVASCULAR-DISEASE; POOLED ANALYSIS; RISK-FACTOR; STANNIOCALCIN-1; HERITABILITY; PREVALENCE; STATEMENT; BIOLOGY AB Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity(1). We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 x 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein(2), and rare mutations in UMOD cause mendelian forms of kidney disease(3). Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease. C1 [Hwang, Shih-Jen; Levy, Daniel; Fox, Caroline S.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Hwang, Shih-Jen; Levy, Daniel; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Koettgen, Anna; Li, Man; Astor, Brad C.; Kao, W. H. Linda; Coresh, Josef] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Glazer, Nicole L.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, DC USA. [Siscovick, David] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Dehghan, Abbas; Aulchenko, Yurii S.; Hofman, Albert; van Duijn, Cornelia M.; Witteman, Jacqueline C.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Katz, Ronit; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Yang, Qiong] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Gudnason, Vilmundur; Smith, Albert V.] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Launer, Lenore J.; Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Arking, Dan E.; Ehret, Georg B.] Johns Hopkins Med Inst, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Houston, TX USA. [Ehret, Georg B.] Univ Hosp Geneva, Div Cardiol, Geneva, Switzerland. [Ruczinski, Ingo; Scharpf, Robert B.; Coresh, Josef] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Chen, Yii-Der Ida; Haritunians, Talin] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [de Boer, Ian H.] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [Sarnak, Mark] Tufts Univ New England Med Ctr, Boston, MA USA. [Siscovick, David] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Upadhyay, Ashish] Boston Med Ctr, Renal Sect, Boston, MA USA. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Chasman, Daniel I.; Pare, Guillaume; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco VA Med Ctr, Gen Internal Med Div, San Francisco, CA 94143 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP Fox, CS (reprint author), Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. EM j.witteman@erasmusmc.nl; coresh@jhu.edu; michael.shlipak@ucsf.edu; foxca@nhlbi.nih.gov RI EHRET, Georg/A-9532-2009; Kottgen, Anna/D-2920-2012; Aulchenko, Yurii/M-8270-2013; Yang, Qiong/G-5438-2014; Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015; Smith, Albert/K-5150-2015; OI Upadhyay, Ashish/0000-0002-0536-5776; Benjamin, Emelia/0000-0003-4076-2336; EHRET, Georg/0000-0002-5730-0675; Aulchenko, Yurii/0000-0002-7899-1575; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Smith, Albert/0000-0003-1942-5845; Dehghan, Abbas/0000-0001-6403-016X FU Intramural NIH HHS; NCATS NIH HHS [UL1 TR000423]; NCI NIH HHS [CA 047988, R01 CA047988]; NCRR NIH HHS [KL2 RR025015, KL2 RR025015-03, M01 RR000069, M01RR00069, UL1 RR025005, UL1 RR025005-01, UL1RR025005]; NHGRI NIH HHS [U01 HG004402, U01 HG004402-01, U01HG004402]; NHLBI NIH HHS [N01 HC085079, HL 043851, N01 HC015103, N01 HC025195, N01 HC035129, N01 HC045133, N01 HC055015, N01 HC055016, N01 HC055018, N01 HC055019, N01 HC055020, N01 HC055021, N01 HC055022, N01 HC055222, N01 HC075150, N01 HC085086, N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-55222, N01-HC-75150, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01HC25195, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC55222, N01HC75150, N01HC85079, N01HC85086, N02 HL64278, N02-HL-6-4278, R01 HL043851, R01 HL043851-09, R01 HL059367, R01 HL059367-02, R01 HL086694, R01 HL086694-01A1, R01 HL087641, R01 HL087641-01, R01 HL087652, R01 HL087652-01, R01HL086694, R01HL087641, R01HL59367, U01 HL080295, U01 HL080295-01]; NIA NIH HHS [N01 AG012100, N01AG12100, R01 AG027002, R01 AG027002-01]; NIDDK NIH HHS [DK063491, K01 DK067207, K01 DK067207-01A1, K01DK067207, P30 DK063491, P30 DK063491-019004, P30 DK063491-05, R01 DK076770]; PHS HHS [HHSN268200625226C] NR 30 TC 248 Z9 255 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2009 VL 41 IS 6 BP 712 EP 717 DI 10.1038/ng.377 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 450OW UT WOS:000266411700021 PM 19430482 ER PT J AU He, CY Kraft, P Chen, C Buring, JE Pare, G Hankinson, SE Chanock, SJ Ridker, PM Hunter, DJ Chasman, DI AF He, Chunyan Kraft, Peter Chen, Constance Buring, Julie E. Pare, Guillaume Hankinson, Susan E. Chanock, Stephen J. Ridker, Paul M. Hunter, David J. Chasman, Daniel I. TI Genome-wide association studies identify loci associated with age at menarche and age at natural menopause SO NATURE GENETICS LA English DT Article ID QUANTITATIVE TRAIT LOCI; REPRODUCTIVE FACTORS; LINKAGE ANALYSIS; BREAST-CANCER; SCAN; RISK; REPLICATION; PROTEIN; GENES; TWIN AB Age at menarche and age at natural menopause are associated with causes of substantial morbidity and mortality such as breast cancer and cardiovascular disease. We conducted a joint analysis of two genome-wide association studies of these two traits in a total of 17,438 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 15,151). For age at menarche, we identified ten associated SNPs (P = 1 x 10(-7)-3 x 10(-13)) clustered at 6q21 (in or near the gene LIN28B) and 9q31.2 (in an intergenic region). For age at natural menopause, we identified 13 associated SNPs (P = 1 x 10(-7)-1 x 10(-21)) clustered at 20p12.3 (in the gene MCM8), 19q13.42 (in or near the gene BRSK1), 5q35.2 (in or near genes UIMC1 and HK3) and 6p24.2 (in the gene SYCP2L). These newly identified loci might expand understanding of the biological pathways regulating these two traits. C1 [He, Chunyan; Kraft, Peter; Chen, Constance; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [He, Chunyan; Kraft, Peter; Chen, Constance; Buring, Julie E.; Hankinson, Susan E.; Ridker, Paul M.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Buring, Julie E.; Pare, Guillaume; Ridker, Paul M.; Chasman, Daniel I.] Harvard Univ, Sch Med, Donald W Reynolds Ctr Cardiovasc Res, Boston, MA 02115 USA. [Buring, Julie E.; Pare, Guillaume; Ridker, Paul M.; Chasman, Daniel I.] Harvard Univ, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Pare, Guillaume; Ridker, Paul M.; Chasman, Daniel I.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Boston, MA 02115 USA. [Hankinson, Susan E.; Hunter, David J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Channing Lab, Boston, MA 02115 USA. [Chanock, Stephen J.; Hunter, David J.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hunter, David J.] Harvard & MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP He, CY (reprint author), Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA. EM che@hsph.harvard.edu FU National Heart, Lung, and Blood Institute [HL 043851, HL69757]; National Cancer Institute [CA 047988, CA 40356, U01-CA98233]; Donald W. Reynolds Foundation; Fondation Leducq FX We thank J. Miletich and A. Parker as well as the technical staff at Amgen for their collaboration and scientific support in performing the genotyping for the WGHS. The NHS GWAS was performed as part of the Cancer Genetic Markers of Susceptibility initiative of the NCI. We particularly acknowledge the contributions of R. Hoover, A. Hutchinson, K. Jacobs and G. Thomas. We thank J. Chen for discussion of gene functions. We thank H. Ranu and P. Soule for assistance. The WGHS is supported by HL 043851 and HL69757 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. The NHS is supported by CA 40356 and U01-CA98233 from the National Cancer Institute. We acknowledge the study participants in the NHS and the WGHS for their contribution in making this study possible. NR 30 TC 171 Z9 177 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2009 VL 41 IS 6 BP 724 EP 728 DI 10.1038/ng.385 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 450OW UT WOS:000266411700023 PM 19448621 ER PT J AU Khanna, H Davis, EE Murga-Zamalloa, CA Estrada-Cuzcano, A Lopez, I den Hollander, AI Zonneveld, MN Othman, MI Waseem, N Chakarova, CF Maubaret, C Diaz-Font, A MacDonald, I Muzny, DM Wheeler, DA Morgan, M Lewis, LR Logan, CV Tan, PL Beer, MA Inglehearn, CF Lewis, RA Jacobson, SG Bergmann, C Beales, PL Attie-Bitach, T Johnson, CA Otto, EA Bhattacharya, SS Hildebrandt, F Gibbs, RA Koenekoop, RK Swaroop, A Katsanis, N AF Khanna, Hemant Davis, Erica E. Murga-Zamalloa, Carlos A. Estrada-Cuzcano, Alejandro Lopez, Irma den Hollander, Anneke I. Zonneveld, Marijke N. Othman, Mohammad I. Waseem, Naushin Chakarova, Christina F. Maubaret, Cecilia Diaz-Font, Anna MacDonald, Ian Muzny, Donna M. Wheeler, David A. Morgan, Margaret Lewis, Lora R. Logan, Clare V. Tan, Perciliz L. Beer, Michael A. Inglehearn, Chris F. Lewis, Richard A. Jacobson, Samuel G. Bergmann, Carsten Beales, Philip L. Attie-Bitach, Tania Johnson, Colin A. Otto, Edgar A. Bhattacharya, Shomi S. Hildebrandt, Friedhelm Gibbs, Richard A. Koenekoop, Robert K. Swaroop, Anand Katsanis, Nicholas TI A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies SO NATURE GENETICS LA English DT Article ID BARDET-BIEDL-SYNDROME; LINKED RETINITIS-PIGMENTOSA; LEBER CONGENITAL AMAUROSIS; JOUBERT-SYNDROME; CENTROSOMAL PROTEIN; MUTATION ANALYSIS; MECKEL-SYNDROME; EARLY-ONSET; CILIARY; GENE AB Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss-of-function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the Thr229-encoded protein significantly compromises this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect. C1 [Khanna, Hemant; Murga-Zamalloa, Carlos A.; Estrada-Cuzcano, Alejandro; Othman, Mohammad I.; Swaroop, Anand] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Davis, Erica E.; Tan, Perciliz L.; Beer, Michael A.; Katsanis, Nicholas] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Lopez, Irma; Koenekoop, Robert K.] McGill Univ, Ctr Hlth, McGill Ocular Genet Lab, Montreal, PQ, Canada. [den Hollander, Anneke I.; Zonneveld, Marijke N.] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Waseem, Naushin; Chakarova, Christina F.; Maubaret, Cecilia; Bhattacharya, Shomi S.] UCL, Inst Ophthalmol, London, England. [Diaz-Font, Anna; Beales, Philip L.] UCL, Inst Child Hlth, Mol Med Unit, London, England. [MacDonald, Ian] NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Muzny, Donna M.; Wheeler, David A.; Morgan, Margaret; Lewis, Lora R.; Gibbs, Richard A.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Logan, Clare V.; Inglehearn, Chris F.; Johnson, Colin A.] St James Univ Hosp, Leeds Inst Mol Med, Sect Ophthalmol & Neurosci, Leeds, W Yorkshire, England. [Beer, Michael A.] Johns Hopkins Univ, Dept Biomed Engn, Sch Med, Baltimore, MD USA. [Lewis, Richard A.] Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. [Lewis, Richard A.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Lewis, Richard A.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Lewis, Richard A.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Jacobson, Samuel G.] Univ Penn, Sch Med, Dept Ophthalmol, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Bergmann, Carsten] Univ Aachen, Rhein Westfal TH Aachen, Dept Human Genet, D-5100 Aachen, Germany. [Attie-Bitach, Tania] Hop Necker Enfants Malad, Dept Genet, Paris, France. [Attie-Bitach, Tania] Hop Necker Enfants Malad, INSERM, U781, Paris, France. [Otto, Edgar A.; Hildebrandt, Friedhelm; Swaroop, Anand] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Hildebrandt, Friedhelm] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. [Hildebrandt, Friedhelm] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD USA. [Katsanis, Nicholas] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Katsanis, Nicholas] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. RP Swaroop, A (reprint author), Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. EM swaroopa@nei.nih.gov; katsanis@jhmi.edu RI Beales, Philip/C-7367-2009; Katsanis, Nicholas/E-1837-2012; Chakarova, Christina/C-9479-2013; Waseem, Naushin/C-9573-2013; Hollander, Anneke/N-4911-2014; OI Swaroop, Anand/0000-0002-1975-1141; Katsanis, Nicholas/0000-0002-2480-0171; Logan, Clare/0000-0003-4323-1602; MacDonald, Ian/0000-0001-7472-8385; Otto, Edgar/0000-0002-2387-9973 FU National Eye Institute [R01EY007961]; National Institute of Child Health and Development [R01HD04260]; NRSA fellowship [R01DK072301, R01DK075972, R01DK068306, R01DK064614, R01DK069274]; National Institute of Diabetes, Digestive and Kidney disorders [F32 DK079541]; Intramural program of NEI; Macular Vision Research Foundation; Foundation for Fighting Blindness; Foundation for Fighting Blindness Canada; Le Fonds de la recherche en sante du Quebec; Research to Prevent Blindness; Harold Falls Collegiate Professorship; Midwest Eye Banks and Transplantation Center; Searle Scholars Program; Deutsche Forschungsgemeinschaft [BE 3910/4-1]; UK Medical Research Council [G0700073]; NIHR Biomedical Research Centre for Ophthalmology; EU-GENORET [LSHGCT-2005-512036]; Howard Hughes Medical Institute ( HHMI); Doris Duke Distinguished Clinical Scientist (DDCF) FX We thank the individuals affected with ciliopathies and their families for their continued support and encouragement. We also thank H. Arts for critical evaluation of the manuscript. This work was supported by grants R01EY007961 from the National Eye Institute ( H. K. and A. S.), R01HD04260 from the National Institute of Child Health and Development ( N. K.), R01DK072301, R01DK075972 ( N. K.), R01DK068306, R01DK064614, R01DK069274 ( F. H.), NRSA fellowship F32 DK079541 ( E. E. D.) from the National Institute of Diabetes, Digestive and Kidney disorders, Intramural program of NEI ( A. S.), the Macular Vision Research Foundation ( N. K.), the Foundation for Fighting Blindness ( H. K., S. S. B., A. S. and N. K.), the Foundation for Fighting Blindness Canada ( R. K. K.), Le Fonds de la recherche en sante du Quebec ( FRSQ) ( R. K. K.), Research to Prevent Blindness ( A. S.), Harold Falls Collegiate Professorship ( A. S.), the Midwest Eye Banks and Transplantation Center ( H. K.), the Searle Scholars Program ( M. A. B.), the Deutsche Forschungsgemeinschaft ( DFG grant BE 3910/4-1; C. B.) the UK Medical Research Council ( grant number G0700073; C. A. J.), NIHR Biomedical Research Centre for Ophthalmology ( S. S. B.) and EU-GENORET Grant LSHGCT-2005-512036 ( S. S. B.). F. H. is an investigator of the Howard Hughes Medical Institute ( HHMI) and a Doris Duke Distinguished Clinical Scientist (DDCF). NR 30 TC 154 Z9 158 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2009 VL 41 IS 6 BP 739 EP 745 DI 10.1038/ng.366 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 450OW UT WOS:000266411700026 PM 19430481 ER PT J AU Margulies, DH AF Margulies, David H. TI Antigen-processing and presentation pathways select antigenic HIV peptides in the fight against viral evolution SO NATURE IMMUNOLOGY LA English DT Editorial Material AB The evolution of immunodominant epitopes in HIV-1 Gag proteins correlates with quantitative measures of several antigen processing events. Thus, peptides recognized by CD8(+) cytolytic T cells are selected by their ability to pass through the antigen processing pathway, as well as by their binding to HLA molecules. C1 NIAID, Mol Biol Sect, Immunol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Margulies, DH (reprint author), NIAID, Mol Biol Sect, Immunol Lab, Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dhm@nih.gov RI Margulies, David/H-7089-2013; OI Margulies, David/0000-0001-8530-7375 NR 6 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2009 VL 10 IS 6 BP 566 EP 568 DI 10.1038/ni0609-566 PG 4 WC Immunology SC Immunology GA 450EP UT WOS:000266384100006 PM 19448656 ER PT J AU Kwong, PD Wilson, IA AF Kwong, Peter D. Wilson, Ian A. TI HIV-1 and influenza antibodies: seeing antigens in new ways SO NATURE IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CORECEPTOR-BINDING-SITE; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; TYROSINE SULFATION; B-CELLS; REPERTOIRE DEVELOPMENT; ENVELOPE GLYCOPROTEIN; VARIABLE REGIONS; CD4-BINDING SITE AB New modes of humoral recognition have been identified by studies of antibodies that neutralize human immunodeficiency virus type 1 and influenza A viruses. Understanding how such modes of antibody-antigen recognition can occur in the context of sophisticated mechanisms of humoral evasion has implications for the development of effective vaccines. Here we describe eight modes of antibody recognition first observed with human immunodeficiency virus type 1. Similarities to four of these modes have been identified with antibodies to a conserved 'stem' epitope on influenza A viruses. We outline how each of these different modes of antibody recognition is particularly suited to overcoming a specific viral evasion tactic and assess potential routes of re-elicitation in vaccine settings. C1 [Kwong, Peter D.] NIAID, Vaccine Res Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. [Wilson, Ian A.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Chiang, Vincent, Ming-Hsien/D-4312-2016 OI Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863 FU National Institutes of Health; International AIDS Vaccine Initiative FX We thank M. Elsliger, G. Nabel and L. Shapiro for comments on the manuscript; D. Ekiert for assistance with Figure 2; J. Stuckey for Figures 1-3; and members of the Structural Biology Section, Vaccine Research Center for comments on the manuscript. Supported by the National Institutes of Health (intramural program and grants) and by the International AIDS Vaccine Initiative. NR 61 TC 91 Z9 92 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2009 VL 10 IS 6 BP 573 EP 578 DI 10.1038/ni.1746 PG 6 WC Immunology SC Immunology GA 450EP UT WOS:000266384100008 PM 19448659 ER PT J AU Nemeth, K Leelahavanichkul, A Yuen, PST Mayer, B Parmelee, A Doi, K Robey, PG Leelahavanichkul, K Koller, BH Brown, JM Hu, XZ Jelinek, I Star, RA Mezey, E AF Nemeth, Krisztian Leelahavanichkul, Asada Yuen, Peter S. T. Mayer, Balazs Parmelee, Alissa Doi, Kent Robey, Pamela G. Leelahavanichkul, Kantima Koller, Beverly H. Brown, Jared M. Hu, Xuzhen Jelinek, Ivett Star, Robert A. Mezey, Eva TI Mesenchymal stem cells: another anti-inflammatory treatment for sepsis? reply SO NATURE MEDICINE LA English DT Letter C1 [Nemeth, Krisztian; Mayer, Balazs; Parmelee, Alissa; Robey, Pamela G.; Leelahavanichkul, Kantima; Mezey, Eva] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, US Natl Inst Hlth, Bethesda, MD USA. [Leelahavanichkul, Asada; Yuen, Peter S. T.; Doi, Kent; Hu, Xuzhen; Star, Robert A.] NIDDK, Renal Diagnost & Therapeut Unit, US Natl Inst Hlth, Bethesda, MD USA. [Jelinek, Ivett] NCI, Expt Immunol Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Koller, Beverly H.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Brown, Jared M.] E Carolina Univ, Dept Pharmacol & Toxicol, Greenville, NC USA. RP Nemeth, K (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, US Natl Inst Hlth, Bethesda, MD USA. EM mezeye@mail.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 4 TC 0 Z9 0 U1 0 U2 5 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 JUN PY 2009 VL 15 IS 6 BP 602 EP 602 DI 10.1038/nm0609-602a PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 455BS UT WOS:000266731600011 ER PT J AU Bell, AW Deutsch, EW Au, CE Kearney, RE Beavis, R Sechi, S Nilsson, T Bergeron, JJM AF Bell, Alexander W. Deutsch, Eric W. Au, Catherine E. Kearney, Robert E. Beavis, Ron Sechi, Salvatore Nilsson, Tommy Bergeron, John J. M. CA HUPO Test Sample Working Grp TI A HUPO test sample study reveals common problems in mass spectrometry-based proteomics SO NATURE METHODS LA English DT Article ID STATISTICAL-MODEL; DATABASE; SEARCH; RESOURCE; TANDEM; MS/MS; IDENTIFICATIONS; COLLECTION; ALGORITHMS; ACCURACY AB We performed a test sample study to try to identify errors leading to irreproducibility, including incompleteness of peptide sampling, in liquid chromatography-mass spectrometry-based proteomics. We distributed an equimolar test sample, comprising 20 highly purified recombinant human proteins, to 27 laboratories. Each protein contained one or more unique tryptic peptides of 1,250 Da to test for ion selection and sampling in the mass spectrometer. Of the 27 labs, members of only 7 labs initially reported all 20 proteins correctly, and members of only 1 lab reported all tryptic peptides of 1,250 Da. Centralized analysis of the raw data, however, revealed that all 20 proteins and most of the 1,250 Da peptides had been detected in all 27 labs. Our centralized analysis determined missed identifications (false negatives), environmental contamination, database matching and curation of protein identifications as sources of problems. Improved search engines and databases are needed for mass spectrometry-based proteomics. C1 [Bell, Alexander W.; Au, Catherine E.; Bergeron, John J. M.] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada. [Deutsch, Eric W.] Inst Syst Biol, Seattle, WA USA. [Kearney, Robert E.] McGill Univ, Dept Biomed Engn, Montreal, PQ, Canada. [Beavis, Ron] Univ British Columbia, Biomed Res Ctr, Vancouver, BC, Canada. [Sechi, Salvatore] NIDDKD, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. [Nilsson, Tommy] McGill Univ, Res Inst, Ctr Hlth, Montreal, PQ, Canada. [Nilsson, Tommy] McGill Univ, Dept Med, Montreal, PQ, Canada. RP Bergeron, JJM (reprint author), McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada. EM john.bergeron@mcgill.ca RI Martens, Lennart/E-8816-2010; Kearney, Robert/D-3917-2012; Vizcaino, Juan Antonio/C-3691-2009; Eisenacher, Martin/J-8044-2014; Yang, Bing/L-2768-2015; Elia, Giuliano/H-3438-2011; OI Martens, Lennart/0000-0003-4277-658X; Vizcaino, Juan Antonio/0000-0002-3905-4335; Eisenacher, Martin/0000-0003-2687-7444; Elia, Giuliano/0000-0001-8216-9560; Andrews, Philip/0000-0001-6843-5420; Ping, Peipei/0000-0003-3583-3881; Parker, Kenneth/0000-0002-6282-2478 FU National Heart, Lung and Blood Institute, National Institutes of Health (NIH) [N01-HV-28179]; University of California, Los Angeles Burnham Institute for Medical Research NIH [RR020843]; University of California, Los Angeles (National Heart, Lung and Blood Institute) [P01-008111]; University of Michigan, NIH [P41RR018627]; Beijing Proteome Research Center [2006CB910801, 2006AA02A308]; Science Foundation, Ireland [04/RPI/B499]; Spanish Ministry of Education and Science; EU [LSHG-CT-2006036814] FX Supported in part by Canadian Institutes of Health Research to the HUPO Head Quarters (S. Ouellette) for coordination of this HUPO test sample initiative. A. W. B. and C. E. A. were supported by Genome Quebec and McGill University. We thank D. Juncker, G. Temple, J. van Oostrum, G. Omenn, K. Colwill, J. Langridge and M. Hallett for their comments on the manuscript, and D. M. Desiderio for helpful comments on the manuscript. This test sample effort builds on pioneering efforts from several other groups and especially Association of Biomolecular Resource Facilities. This study is a HUPO test sample initiative and HUPO welcomes collaborative efforts to benefit proteomics. We acknowledge the following sources of grant support: E. W. D. is supported by the National Heart, Lung and Blood Institute, National Institutes of Health (NIH), under contract N01-HV-28179; the University of California, Los Angeles Burnham Institute for Medical Research NIH grant number RR020843; University of California, Los Angeles (National Heart, Lung and Blood Institute P01-008111); University of Michigan, NIH P41RR018627; Beijing Proteome Research Center, affiliated with The Beijing Institute of Radiation Medicine for National Key Programs for Basic Research grant 2006CB910801 and Hi-Tech Research grant 2006AA02A308. We acknowledge access and use of The University College Dublin Conway Mass Spectrometry Resource instrumentation, supported by Science Foundation, Ireland grant 04/RPI/B499. PRIDE, J. A. V. is a postdoctoral fellow of the "Especializacion en Organismos Internacionales'' program from the Spanish Ministry of Education and Science. L. M. is supported by the "ProDaC'' grant LSHG-CT-2006036814 of the EU. Samuel Lunenfeld Research Institute, Mount Sinai, Toronto is supported by Genome Canada through Ontario Genomics Institute. J. A. V. and L. M. thank H. Hermjakob and R. Apweiler for their support. A. W. B. thanks L. Roy and Z. Bencsath-Makkai for help in data submission and analysis. NR 32 TC 195 Z9 199 U1 2 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD JUN PY 2009 VL 6 IS 6 BP 423 EP U40 DI 10.1038/NMETH.1333 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 451TO UT WOS:000266493300012 PM 19448641 ER PT J AU Michino, M Abola, E Brooks, CL Dixon, JS Moult, J Stevens, RC Olson, A Jurkowski, W Elofsson, A Filipek, S Pogozheva, I Lomize, A Maigret, B Horst, J Bernard, B Iyer, S Samudrala, R Roy, A Zhang, Y Sezerman, OU Nikiforovich, GV Taylor, CM Costanzi, S Vorobjev, Y Bakulina, N Solovyev, V Kanou, K Takaya, D Terashi, G Takeda-Shitaka, M Umeyama, H Goddard, WA Li, YY Kim, SK Trzaskowski, B Abrol, R Griffith, A Katritch, V Rueda, M Davis, I Barth, P Baker, D Feig, M Brylinski, M Zhou, HY Lee, SY Skolnick, J Ostopovici-Halip, L Bologa, C Lam, P Abagyan, R Dawson, ES Kaufmann, K Woetzel, N Meiler, J Ding, F Serohijos, A Yin, SY Dokholyan, NV Rodriguez, D Gutierrez-de-Teran, H Xhaard, H AF Michino, Mayako Abola, Enrique Brooks, Charles L., III Dixon, J. Scott Moult, John Stevens, Raymond C. Olson, Arthur Jurkowski, Wiktor Elofsson, Arne Filipek, Slawomir Pogozheva, Irina Lomize, Andrei Maigret, Bernard Horst, Jeremy Bernard, Brady Iyer, Shyamala Samudrala, Ram Roy, Ambrish Zhang, Yang Sezerman, Osman Ugur Nikiforovich, Gregory V. Taylor, Christina M. Costanzi, Stefano Vorobjev, Y. Bakulina, N. Solovyev, V. Kanou, Kazuhiko Takaya, Daisuke Terashi, Genki Takeda-Shitaka, Mayuko Umeyama, Hideaki Goddard, William A., III Li, Youyong Kim, Soo-Kyung Trzaskowski, Bartosz Abrol, Ravinder Griffith, Adam Katritch, Vsevolod Rueda, Manuel Davis, Ian Barth, Patrick Baker, David Feig, Michael Brylinski, Michal Zhou, Hongyi Lee, Seung Yup Skolnick, Jeffrey Ostopovici-Halip, Liliana Bologa, Cristian Lam, Polo Abagyan, Ruben Dawson, Eric S. Kaufmann, Kristian Woetzel, Nils Meiler, Jens Ding, Feng Serohijos, Adrian Yin, Shuangye Dokholyan, Nikolay V. Rodriguez, David Gutierrez-de-Teran, Hugo Xhaard, Henri CA GPCR Dock 2008 Participants TI Community-wide assessment of GPCR structure modelling and ligand docking: GPCR Dock 2008 SO NATURE REVIEWS DRUG DISCOVERY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; A(2A) ADENOSINE RECEPTOR; DRUG DISCOVERY; STRUCTURE PREDICTION; CASP7 PREDICTIONS; RHODOPSIN; CRYSTAL; ACCURACY; INSIGHTS; TARGETS AB Recent breakthroughs in the determination of the crystal structures of G protein-coupled receptors (GPCRs) have provided new opportunities for structure-based drug design strategies targeting this protein family. With the aim of evaluating the current status of GPCR structure prediction and ligand docking, a community-wide, blind prediction assessment - GPCR Dock 2008 - was conducted in coordination with the publication of the crystal structure of the human adenosine A(2A) receptor bound to the ligand ZM241385. Twenty-nine groups submitted 206 structural models before the release of the experimental structure, which were evaluated for the accuracy of the ligand binding mode and the overall receptor model compared with the crystal structure. This analysis highlights important aspects for success and future development, such as accurate modelling of structurally divergent regions and use of additional biochemical insight such as disulphide bridges in the extracellular loops. C1 [Michino, Mayako; Abola, Enrique; Stevens, Raymond C.; Olson, Arthur; Lam, Polo; Abagyan, Ruben] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Stevens, Raymond C.] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Brooks, Charles L., III] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. [Brooks, Charles L., III] Univ Michigan, Biophys Program, Ann Arbor, MI 48109 USA. [Dixon, J. Scott] Daylight Chem Informat Syst Inc, Aliso Viejo, CA 92656 USA. [Moult, John] Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. [Jurkowski, Wiktor; Elofsson, Arne] Stockholm Univ, Ctr Biomembrane Res, Dept Biochem & Biophys, S-10691 Stockholm, Sweden. [Filipek, Slawomir] Int Inst Mol & Cell Biol, Lab Biomodelling, Warsaw, Poland. [Pogozheva, Irina; Lomize, Andrei] Univ Michigan, Peptide Synth & Mol Recognit Lab, Ann Arbor, MI 48109 USA. [Maigret, Bernard] Nancy Univ, LORIA, Orpailleur Team, Nancy, France. [Horst, Jeremy; Bernard, Brady; Iyer, Shyamala; Samudrala, Ram] Univ Washington, Computat Biol Grp, Seattle, WA 98195 USA. [Roy, Ambrish; Zhang, Yang] Univ Kansas, Dept Mol Biosci, Ctr Bioinformat, Lawrence, KS 66045 USA. [Sezerman, Osman Ugur] Sabanci Univ, Biol Sci & Bioengn, Istanbul, Turkey. [Nikiforovich, Gregory V.] MolLife Design LLC, St Louis, MO USA. [Taylor, Christina M.] Washington Univ, Dept Biochem & Mol Biophys, St Louis, MO 63130 USA. [Costanzi, Stefano] NIH, Lab Biol Modeling, NIDDKD, Bethesda, MD 20892 USA. [Vorobjev, Y.; Bakulina, N.; Solovyev, V.] Univ London, Royal Holloway, Dept Comp Sci, London TW20 0EX, England. [Vorobjev, Y.; Bakulina, N.; Solovyev, V.] Softberry Inc, Mt Kisco, NY 10549 USA. [Kanou, Kazuhiko; Takaya, Daisuke; Terashi, Genki; Takeda-Shitaka, Mayuko; Umeyama, Hideaki] Kitasato Univ, Sch Pharm, Tokyo 1088641, Japan. [Kanou, Kazuhiko; Takaya, Daisuke; Terashi, Genki; Takeda-Shitaka, Mayuko; Umeyama, Hideaki] RIKEN Syst & Struct Biol Ctr, Yokohama, Kanagawa 2300045, Japan. [Goddard, William A., III; Li, Youyong; Kim, Soo-Kyung; Trzaskowski, Bartosz; Abrol, Ravinder; Griffith, Adam] CALTECH, Mat & Proc Simulat Ctr, Pasadena, CA 91125 USA. [Katritch, Vsevolod; Rueda, Manuel; Abagyan, Ruben] Molsoft LLC, San Diego, CA USA. [Davis, Ian; Barth, Patrick; Baker, David] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Feig, Michael] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. [Brylinski, Michal; Zhou, Hongyi; Lee, Seung Yup; Skolnick, Jeffrey] Georgia Inst Technol, Ctr Study Syst Biol, Atlanta, GA 30332 USA. [Ostopovici-Halip, Liliana; Bologa, Cristian] Univ New Mexico, Div Biocomp, Albuquerque, NM 87131 USA. [Dawson, Eric S.; Kaufmann, Kristian; Woetzel, Nils; Meiler, Jens] Vanderbilt Univ, Ctr Struct Biol, Nashville, TN 37235 USA. [Ding, Feng; Serohijos, Adrian; Yin, Shuangye; Dokholyan, Nikolay V.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC USA. [Rodriguez, David; Gutierrez-de-Teran, Hugo] Complejo Hosp Univ Santiago de Compostela, Fdn Publ Galega Med Xen, Santiago De Compostela, Spain. [Xhaard, Henri] Univ Helsinki, Fac Pharm, Ctr Drug Res, FIN-00014 Helsinki, Finland. RP Stevens, RC (reprint author), Scripps Res Inst, Dept Mol Biol, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM stevens@scripps.edu; olson@scripps.edu; wiktor.jurkowski@sbc.su.se; irinap@umich.edu; bernard.maigret@loria.fr; jhorst@compbio.washington.edu; ugur@sabanciuniv.edu; gnikiforovich@gmail.com; stefanoc@mail.nih.gov; kanouk@pharm.kitasato-u.ac.jp; wag@wag.caltech.edu; iwd@u.washington.edu; barthp@u.washington.edu; feig@msu.edu; skolnick@gatech.edu; cbologa@salud.unm.edu; pololam@scripps.edu; eric.dawson@vanderbilt.edu; dokh@med.unc.edu; henri.xhaard@helsinki.fi RI Rodriguez, David/E-1412-2011; Gutierrez de Teran, Hugo/E-1391-2011; Bologa, Cristian/A-7952-2010; Trzaskowski, Bartosz/B-1881-2008; Ding, Feng/G-6029-2011; Katritch, Vsevolod/Q-8357-2016; OI Katritch, Vsevolod/0000-0003-3883-4505; Solovyev, Victor/0000-0001-8885-493X; Gutierrez de Teran, Hugo/0000-0003-0459-3491; Bologa, Cristian/0000-0003-2232-4244; Trzaskowski, Bartosz/0000-0003-2385-1476; Ding, Feng/0000-0003-1850-6336; Moult, John/0000-0002-3012-2282; Costanzi, Stefano/0000-0003-3183-7332; Dokholyan, Nikolay/0000-0002-8225-4025 FU Protein Structure Initiative [U54 GM074961]; NIH [P50 GM073197]; Multiscale Modeling Tools for Structural Biology NCRR [P41 RR012255] FX We thank M. Hanson, V.-P. Jaakola, C. Roth and V. Cherezov for help with the analysis and comments on the manuscript, and K. Kadyshevskaya and V. Cherezov for figure preparation. We are grateful to the Goddard group for providing the script to calculate the binding site contact RMSD. We thank A. Walker for data tracking and assistance with the manuscript and J. Kunken for IT help during the assessment. This work was supported in part by the Protein Structure Initiative grant U54 GM074961 (ATCG3D), the NIH Roadmap grant P50 GM073197 (JCIMPT), and the Multiscale Modeling Tools for Structural Biology NCRR via grant P41 RR012255. NR 37 TC 174 Z9 174 U1 4 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD JUN PY 2009 VL 8 IS 6 BP 455 EP 463 DI 10.1038/nrd2877 PG 9 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 452CE UT WOS:000266516500012 PM 19461661 ER PT J AU Marasa, M Kopp, JB AF Marasa, Maddalena Kopp, Jeffrey B. TI Monoclonal antibodies for podocytopathies: rationale and clinical responses SO NATURE REVIEWS NEPHROLOGY LA English DT Review ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; IDIOPATHIC NEPHROTIC SYNDROME; REGULATORY T-CELLS; GLOMERULAR-PERMEABILITY FACTOR; MINIMAL CHANGE NEPHROPATHY; NECROSIS-FACTOR-ALPHA; RITUXIMAB THERAPY; MEMBRANOUS NEPHROPATHY; KIDNEY-TRANSPLANTATION; COMPLEMENT ACTIVATION AB The podocytopathies, including minimal-change nephropathy, focal segmental glomerulosclerosis, collapsing glomerulopathy, and diffuse mesangial sclerosis, involve diverse types of injury to podocytes. These injuries can have genetic causes, or can be caused by viral infection, mechanical stress, medication or-probably-immunologic injury. several lines of evidence-including the immunosuppressive effects of standard therapies-suggest a role for immunologic injury in some cases, but the precise pathologic mechanisms are far from clear. Despite this uncertainty, newly available biologic therapies that target immune cells and cytokines have been used to treat a number of patients with different podocytopathies. Of these therapies, the greatest experience has been gained with rituximab. The data on all such therapies remain too fragmentary to provide firm conclusions, but further clinical research with such agents might help to define pathogenetic pathways and could potentially contribute to new therapies. C1 [Kopp, Jeffrey B.] NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. [Marasa, Maddalena] Osped Riuniti Bergamo, Azienda Osped, Nephrol Unit, I-24100 Bergamo, Italy. RP Kopp, JB (reprint author), NIDDKD, Kidney Dis Sect, NIH, 10 Ctr Dr,10-3N116, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU National institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA FX The authors would like to thank Dr Paolo Cravedi and Dr Meryl waldman for critical reading of the manuscript. Our work is supported by the Intramural Research Program of the National institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. NR 101 TC 13 Z9 13 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD JUN PY 2009 VL 5 IS 6 BP 337 EP 348 DI 10.1038/nrneph.2009.70 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 452VT UT WOS:000266570000009 PM 19474828 ER PT J AU Ward, MM AF Ward, Michael M. TI RHEUMATOID ARTHRITIS Guidelines for the management of RA: breadth versus depth SO NATURE REVIEWS RHEUMATOLOGY LA English DT Editorial Material ID BRITISH HEALTH-PROFESSIONALS; 1ST 2 YEARS; AMERICAN-COLLEGE; SOCIETY C1 [Ward, Michael M.] NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMS, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr,MSC 1468, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS [Z01 AR041153-04] NR 8 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4790 J9 NAT REV RHEUMATOL JI Nat. Rev. Rheumatol. PD JUN PY 2009 VL 5 IS 6 BP 302 EP 303 DI 10.1038/nrrheum.2009.90 PG 3 WC Rheumatology SC Rheumatology GA 452VE UT WOS:000266568500003 PM 19491909 ER PT J AU Kumar, J Schuck, P Jin, RS Mayer, ML AF Kumar, Janesh Schuck, Peter Jin, Rongsheng Mayer, Mark L. TI The N-terminal domain of GluR6-subtype glutamate receptor ion channels SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID LIGAND-BINDING PROPERTIES; PROTEIN STRUCTURES; MODULATORY DOMAIN; GABA(B) RECEPTOR; NMDA RECEPTOR; AMPA RECEPTOR; SUBUNIT; CONSERVATION; EXPRESSION; ULTRACENTRIFUGATION AB The amino-terminal domain (ATD) of glutamate receptor ion channels, which controls their selective assembly into AMPA, kainate and NMDA receptor subtypes, is also the site of action of NMDA receptor allosteric modulators. Here we report the crystal structure of the ATD from the kainate receptor GluR6. The ATD forms dimers in solution at micromolar protein concentrations and crystallizes as a dimer. Unexpectedly, each subunit adopts an intermediate extent of domain closure compared to the apo and ligand-bound complexes of LIVBP and G protein-coupled glutamate receptors (mGluRs), and the dimer assembly has a markedly different conformation from that found in mGluRs. This conformation is stabilized by contacts between large hydrophobic patches in the R2 domain that are absent in NMDA receptors, suggesting that the ATDs of individual glutamate receptor ion channels have evolved into functionally distinct families. C1 [Kumar, Janesh; Mayer, Mark L.] NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Schuck, Peter] Natl Inst Biomed Imaging & BioEngn, Lab Bioengn & Phys Sci, NIH, DHHS, Bethesda, MD USA. [Jin, Rongsheng] Burnham Inst Med Res, La Jolla, CA USA. RP Mayer, ML (reprint author), NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. EM mayerm@mail.nih.gov RI Mayer, Mark/H-5500-2013; Jin, Rongsheng/M-7797-2013; OI Jin, Rongsheng/0000-0003-0348-7363; Schuck, Peter/0000-0002-8859-6966 FU Intramural NIH HHS [Z01 HD000707-23]; NIGMS NIH HHS [R01 GM090023] NR 48 TC 76 Z9 76 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUN PY 2009 VL 16 IS 6 BP 631 EP U58 DI 10.1038/nsmb.1613 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 452YH UT WOS:000266576600011 PM 19465914 ER PT J AU Yin, Q Lin, SC Lamothe, B Lu, M Lo, YC Hura, G Zheng, LX Rich, RL Campos, AD Myszka, DG Lenardo, MJ Darnay, BG Wu, H AF Yin, Qian Lin, Su-Chang Lamothe, Betty Lu, Miao Lo, Yu-Chih Hura, Gregory Zheng, Lixin Rich, Rebecca L. Campos, Alejandro D. Myszka, David G. Lenardo, Michael J. Darnay, Bryant G. Wu, Hao TI E2 interaction and dimerization in the crystal structure of TRAF6 SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID NECROSIS-FACTOR RECEPTOR; NF-KAPPA-B; CONJUGATING ENZYME COMPLEX; RAY SOLUTION SCATTERING; POLYUBIQUITIN CHAIN; BIOLOGICAL MACROMOLECULES; MOLECULAR-MECHANISM; UBIQUITIN LIGASES; RING DOMAIN; U-BOX AB Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-6 mediates Lys63-linked polyubiquitination for NF-kappa B activation via its N-terminal RING and zinc finger domains. Here we report the crystal structures of TRAF6 and its complex with the ubiquitin-conjugating enzyme (E2) Ubc13. The RING and zinc fingers of TRAF6 assume a rigid, elongated structure. Interaction of TRAF6 with Ubc13 involves direct contacts of the RING and the preceding residues, and the first zinc finger has a structural role. Unexpectedly, this region of TRAF6 is dimeric both in the crystal and in solution, different from the trimeric C-terminal TRAF domain. Structure-based mutagenesis reveals that TRAF6 dimerization is crucial for polyubiquitin synthesis and autoubiquitination. Fluorescence resonance energy transfer analysis shows that TRAF6 dimerization induces higher-order oligomerization of full-length TRAF6. The mismatch of dimeric and trimeric symmetry may provide a mode of infinite oligomerization that facilitates ligand-dependent signal transduction of many immune receptors. C1 [Yin, Qian; Lin, Su-Chang; Lu, Miao; Lo, Yu-Chih; Wu, Hao] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Yin, Qian; Wu, Hao] Triinst Training Program Chem Biol, New York, NY USA. [Lamothe, Betty; Campos, Alejandro D.; Darnay, Bryant G.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Hura, Gregory] Univ Calif Berkeley, Lawrence Berkeley Lab, Adv Light Source, Berkeley, CA 94720 USA. [Zheng, Lixin; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Rich, Rebecca L.; Myszka, David G.] Univ Utah, Sch Med, Ctr Biomol Interact Anal, Salt Lake City, UT USA. RP Wu, H (reprint author), Cornell Univ, Weill Med Coll, New York, NY 10021 USA. EM haowu@med.cornell.edu OI Lin, Su-Chang/0000-0003-0687-3139 FU US National Institutes of Health [RO1 AI045937, RO1 AR053540]; US Department of Defense [DE-AC02-05CH11231]; Intramural Research Program; US National Institute of Allergy and Infectious Diseases; Cancer Research Institute; American Heart Association FX We thank T. Min and J. Y. Chung for their earlier work on the project, X. Jiang and X. Wang of the Sloan-Kettering Institute for purified E1, Z. Chen of the University of Texas Southwestern Medical School for the expression constructs of Ubc13 and Uev1A, R. Abramowitz and J. Schwanof of X4A of the National Synchrotron Light Source for data collection and J. Wu for maintaining our X-ray and computer equipment. This work was supported by the US National Institutes of Health (RO1 AI045937 to H. W. and RO1 AR053540 to B. G. D.), the US Department of Defense (DOE Contract DE-AC02-05CH11231 for G. H.), the Intramural Research Program of the US National Institute of Allergy and Infectious Diseases (to L. Z. and M. J. L.) and institutional start-up funds to B. G. D., S.-C. L. and Y.-C. L. from the Cancer Research Institute and to M. L. from the American Heart Association. NR 59 TC 138 Z9 141 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUN PY 2009 VL 16 IS 6 BP 658 EP U97 DI 10.1038/nsmb.1605 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 452YH UT WOS:000266576600015 PM 19465916 ER PT J AU Kwong, J Chan, FL Wong, KK Birrer, MJ Archibald, KM Balkwill, FR Berkowitz, RS Mok, SC AF Kwong, Joseph Chan, Franky Leung Wong, Kwong-kwok Birrer, Michael J. Archibald, Kyra M. Balkwill, Frances R. Berkowitz, Ross S. Mok, Samuel C. TI Inflammatory Cytokine Tumor Necrosis Factor alpha Confers Precancerous Phenotype in an Organoid Model of Normal Human Ovarian Surface Epithelial Cells SO NEOPLASIA LA English DT Article ID INCLUSION CYSTS; CANCER CELLS; TNF-ALPHA; RISK; METASTASIS; EXPRESSION; PATHOGENESIS; PROMOTION; MICE; CARCINOGENESIS AB In this study, we established an in vitro organoid model of normal human ovarian surface epithelial (HOSE) cells. The spheroids of these normal HOSE cells resembled epithelial inclusion cysts in human ovarian cortex, which are the cells of origin of ovarian epithelial tumor. Because there are strong correlations between chronic inflammation and the incidence of ovarian cancer, we used the organoid model to test whether protumor inflammatory cytokine tumor necrosis factor a would induce malignant phenotype in normal HOSE cells. Prolonged treatment of tumor necrosis factor a induced phenotypic changes of the HOSE spheroids, which exhibited the characteristics of precancerous lesions of ovarian epithelial tumors, including reinitiation of cell proliferation, structural disorganization, epithelial stratification, loss of epithelial polarity, degradation of basement membrane, cell invasion, and overexpression of ovarian cancer markers. The result of this study provides not only an evidence supporting the link between chronic inflammation and ovarian cancer formation but also a relevant and novel in vitro model for studying of early events of ovarian cancer. C1 [Kwong, Joseph; Berkowitz, Ross S.; Mok, Samuel C.] Harvard Univ, Brigham & Womens Hosp, Sch Med,Dept Obstet Gynecol & Reprod Biol, Lab Gynecol Oncol,Div Gynecol Oncol, Boston, MA 02115 USA. [Kwong, Joseph; Archibald, Kyra M.; Balkwill, Frances R.] Queen Mary Univ London, Ctr Canc & Inflammat, Inst Canc, Barts & London Sch Med & Dent, London EC1M 6BQ, England. [Chan, Franky Leung] Chinese Univ Hong Kong, Dept Anat, Hong Kong, Hong Kong, Peoples R China. [Wong, Kwong-kwok] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Birrer, Michael J.] Natl Canc Inst, Cell & Canc Biol Branch, Bethesda, MD USA. [Berkowitz, Ross S.; Mok, Samuel C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. RP Kwong, J (reprint author), Chinese Univ Hong Kong, Prince Wales Hosp, Dept Obstet & Gynaecol, Block E,1-F, Shatin, Hong Kong, Peoples R China. EM josephkwong@cuhk.edu.hk RI Kwong, Joseph/H-2368-2013; OI Balkwill, Frances/0000-0002-5587-9759 FU The Ovarian Cancer Fund Inc (Research Training Program of Excellence Grant); Association for International Cancer Research (AICR) [R33CA103595]; The Ovarian Cancer SPORE; National Institutes of Health, Department of Health and Human Service [P50CA165009]; The Gillette Center for Women's Cancer; Adler Foundation Inc.; The Morse Family Fund; The Natalie Pihl Fund; HEFCE; Cancer Research UK Studentship FX This study was supported by The Ovarian Cancer Fund Inc (Research Training Program of Excellence Grant) and Association for International Cancer Research (AICR) to J. K.; R33CA103595 and The Ovarian Cancer SPORE P50CA165009 from National Institutes of Health, Department of Health and Human Service; The Gillette Center for Women's Cancer; Adler Foundation Inc.; The Morse Family Fund; and The Natalie Pihl Fund (to S. C. M. and R. S. B.); HEFCE for F. R. B.; Cancer Research UK Studentship for K. M. A. NR 56 TC 13 Z9 15 U1 0 U2 1 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD JUN PY 2009 VL 11 IS 6 BP 529 EP 541 DI 10.1593/neo.09112 PG 13 WC Oncology SC Oncology GA 449WJ UT WOS:000266360800003 PM 19484142 ER PT J AU Coble, JB Dosemeci, M Stewart, PA Blair, A Bowman, J Fine, HA Shapiro, WR Selker, RG Loeffler, JS Black, PM Linet, MS Inskip, PD AF Coble, Joseph B. Dosemeci, Mustafa Stewart, Patricia A. Blair, Aaron Bowman, Joseph Fine, Howard A. Shapiro, William R. Selker, Robert G. Loeffler, Jay S. Black, Peter M. Linet, Martha S. Inskip, Peter D. TI Occupational exposure to magnetic fields and the risk of brain tumors SO NEURO-ONCOLOGY LA English DT Article DE glioma; job modules; magnetic fields; meningioma; occupation ID CENTRAL-NERVOUS-SYSTEM; RADIATION EXPOSURE; UNITED-STATES; CANCER; MORTALITY; LEUKEMIA; WORKERS; UTILITY; DESIGN; SWEDEN AB We investigated the association between occupational exposure to extremely low-frequency magnetic fields (MFs) and the risk of glioma and meningioma. Occupational exposure to MF was assessed for 489 glioma cases, 197 meningioma cases, and 799 controls enrolled in a hospital-based case-control study. Lifetime occupational history questionnaires were administered to all subjects; for 24% of jobs, these were supplemented with job-specific questionnaires, or "job modules," to obtain information on the use of electrically powered tools or equipment at work. Job-specific quantitative estimates for exposure to MF in milligauss were assigned using a previously published job exposure matrix (JEM) with modification based on the job modules. Jobs were categorized as <= 1.5 mG, >1.5 to <3.0 mG, and >= 3.0 mG. Four exposure metrics were evaluated: (1) maximum exposed job; (2) total years of exposure >1.5 mG; (3) cumulative lifetime exposure; and (4) average lifetime exposure. Odds ratios (ORs) were calculated using unconditional logistic regression with adjustment for the age, gender, and hospital site. The job modules increased the number of jobs with exposure >= 3.0 mG from 4% to 7% relative to the JEM. No statistically significant elevation in ORs or trends in ORs across exposure categories was observed using four different exposure metrics for the three tumor types analyzed. Occupational exposure to MFs assessed using job modules was not associated with an increase in the risk for glioma, glioblastoma, or meningioma among the subjects evaluated in this study. Neuro-Oncology 11, 242-249, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00200, February 20, 2009. URL http://neuro-oncology.dukejournals.org; DOI:10.1215/15228517-2009-002) C1 [Coble, Joseph B.; Dosemeci, Mustafa; Stewart, Patricia A.; Blair, Aaron] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Fine, Howard A.] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. [Linet, Martha S.; Inskip, Peter D.] NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. [Bowman, Joseph] NIOSH, Engn & Phys Hazards Branch, Div Appl Res & Technol, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. [Shapiro, William R.] St Josephs Hosp, Barrow Neurol Inst, Phoenix, AZ 85013 USA. [Shapiro, William R.] Med Ctr, Phoenix, AZ USA. [Selker, Robert G.] Western Penn Hosp, Pittsburgh, PA 15224 USA. [Loeffler, Jay S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Black, Peter M.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Coble, JB (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM jcoble@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX This project has been funded in part through an intramural program from 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 35 TC 12 Z9 15 U1 2 U2 2 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2009 VL 11 IS 3 BP 242 EP 249 DI 10.1215/15228517-2009-002 PG 8 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 459TH UT WOS:000267132300002 PM 19234232 ER PT J AU Otnaess, MK Djurovic, S Rimol, LM Kulle, B Kahler, AK Jonsson, EG Agartz, I Sundet, K Hall, H Timm, S Hansen, T Callicott, JH Melle, I Werge, T Andreassen, OA AF Otnaess, Mona K. Djurovic, Srdjan Rimol, Lars M. Kulle, Bettina Kahler, Anna K. Jonsson, Erik G. Agartz, Ingrid Sundet, Kjetil Hall, Hakan Timm, Sally Hansen, Thomas Callicott, Joseph H. Melle, Ingrid Werge, Thomas Andreassen, Ole A. TI Evidence for a possible association of neurotrophin receptor (NTRK-3) gene polymorphisms with hippocampal function and schizophrenia SO NEUROBIOLOGY OF DISEASE LA English DT Article DE NTRK3; NT-3; SNP; Schizophrenia; Memory; Hippocampus ID EXPRESSING MESSENGER-RNA; NERVOUS-SYSTEM; NEUROCOGNITIVE ENDOPHENOTYPES; SYNAPTIC PLASTICITY; DENDRITIC GROWTH; HUMAN BRAIN; IN-VIVO; TRKC; BDNF; NEURONS AB Altered neurodevelopment and plasticity are implicated in schizophrenia pathology. Based on the important role of neurotrophic factors in brain development and plasticity as well as their extensive expression in hippocampal areas, we hypothesized that a variation in the neurotrophin receptor 3 gene (NTRK-3) is associated to hippocampal function and schizophrenia. Thirty-three tagging NTRK-3 single nucleotide polymorphisms (SNPs) were genotyped in 839 schizophrenia patients and 1473 healthy controls. SNPs that were significantly associated with schizophrenia were evaluated in subgroups of the sample with neuropsychological test battery (n = 104 patients and 175 controls) and functional magnetic resonance imaging tests of hippocampal function (n = 36 controls). rs999905 was nominally significantly associated with schizophrenia and the haplotype block that included markers rs999905 and rs4887348 remained significant after permutation tests. These gene variants are also related to in vivo brain function in healthy control subjects, shown by a significant association with hippocampal activation during an encoding task. The present results, although not robust, suggest that the NTRK-3 gene influences hippocampal function and may modify the risk for schizophrenia. (C) 2009 Elsevier Inc. All rights reserved. C1 [Djurovic, Srdjan; Kahler, Anna K.] Ullevaal Univ Hosp, Dept Med Genet, N-0407 Oslo, Norway. [Otnaess, Mona K.; Djurovic, Srdjan; Rimol, Lars M.; Kahler, Anna K.; Agartz, Ingrid; Melle, Ingrid; Andreassen, Ole A.] Univ Oslo, Inst Psychiat, Oslo, Norway. [Otnaess, Mona K.; Djurovic, Srdjan; Rimol, Lars M.; Kahler, Anna K.; Melle, Ingrid; Andreassen, Ole A.] Ullevaal Univ Hosp, Dept Res & Dev, Div Psychiat, N-0407 Oslo, Norway. [Kulle, Bettina] Univ Oslo, Fac Div Akershus Univ Hosp, Oslo, Norway. [Kulle, Bettina] Univ Oslo, Dept Biostat, Oslo, Norway. [Jonsson, Erik G.; Agartz, Ingrid; Hall, Hakan] Karolinska Hosp & Inst, HUBIN Project, Dept Clin Neurosci, Stockholm, Sweden. [Agartz, Ingrid] Diakonhjemmet Hosp, Dept Psychiat Res, Oslo, Norway. [Sundet, Kjetil] Univ Oslo, Inst Psychol, Oslo, Norway. [Timm, Sally] Copenhagen Univ Hosp, Mental Hlth Ctr Frederiksberg, Frederiksberg, Denmark. [Hansen, Thomas; Werge, Thomas] Copenhagen Univ Hosp, Res Inst Biol Psychiat, Mental Hlth Ctr Sct Hans, Roskilde, Denmark. [Callicott, Joseph H.] NIMH, Bethesda, MD 20892 USA. RP Djurovic, S (reprint author), Ullevaal Univ Hosp, Dept Med Genet, Kirkeveien 166, N-0407 Oslo, Norway. EM srdjan.djurovic@medisin.uio.no RI Kahler, Anna/J-2874-2012; Callicott, Joseph/C-9102-2009; Hansen, Thomas/O-5965-2014; Melle, Ingrid /B-4858-2011; OI Andreassen, Ole A./0000-0002-4461-3568; Callicott, Joseph/0000-0003-1298-3334; Hansen, Thomas/0000-0001-6703-7762; Melle, Ingrid /0000-0002-9783-548X; Rimol, Lars M./0000-0002-1243-0396; Agartz, Ingrid/0000-0002-9839-5391; Jonsson, Erik/0000-0001-8368-6332 FU Research Council of Norway [167153/V50, 163070/V50, 175345/V50]; South-East Norway Health Authority [123-2004]; Ulleval University Hospital; University of Oslo; Copenhagen Hospital Corporation Research Fond; Danish National Psychiatric Research Foundation; Danish Agency for Science, Technology and Innovation (Centre for Pharmacogenomics); Danish Medical Research Council; Wallenberg Foundation; HUBIN; Swedish Research Council [K2007-62X-15078-04-1, K2007-62X-15078-04-3, K2008-62P20597-01-3] FX We thank patients and controls for their participation in the study, and the health professionals who facilitated our work. We also thank Drs. Per Nakstad and Andres Server for MRI assistance, Elin Inderhaug for molecular genetic technical assistance, and Kristina Larsson, Per Lundmark, Tomas Axelsson and Ann-Christine Syvinen at the SNP Technology Platform in Uppsala for performing the genotyping. The SNP Technology Platform is supported by Uppsala University, Uppsala University Hospital and by the Knut and Alice Wallenberg Foundation. The study was supported by grants from the Research Council of Norway (#167153/V50,#163070/V50, #175345/V50), South-East Norway Health Authority (#123-2004), Ulleval University Hospital and the University of Oslo in support of the Thematic Organized Psychosis Research (TOP) Study group; the Copenhagen Hospital Corporation Research Fond, the Danish National Psychiatric Research Foundation, the Danish Agency for Science, Technology and Innovation (Centre for Pharmacogenomics) and the Danish Medical Research Council in support of the Danish Group; and the Wallenberg Foundation, the HUBIN project and the Swedish Research Council (K2007-62X-15078-04-1, K2007-62X-15078-04-3, K2008-62P20597-01-3) in support of the HUBIN study, Sweden. NR 65 TC 19 Z9 19 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 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD JUN PY 2009 VL 34 IS 3 BP 518 EP 524 DI 10.1016/j.nbd.2009.03.011 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 450JN UT WOS:000266396900014 PM 19344762 ER PT J AU Kanungo, J Zheng, YL Mishra, B Pant, HC AF Kanungo, Jyotshnabala Zheng, Ya-Li Mishra, Bibhutibhushan Pant, Harish C. TI Zebrafish Rohon-Beard Neuron Development: Cdk5 in the Midst SO NEUROCHEMICAL RESEARCH LA English DT Review DE Rohon-Beard neuron; Neurogenesis; Protein kinases; Gene knockdown; Cell fate ID CYCLIN-DEPENDENT KINASE-5; PROGRAMMED CELL-DEATH; REGULATES AXONAL-TRANSPORT; XENOPUS-LAEVIS; ACTIVATOR P35; IN-VIVO; NERVOUS-SYSTEM; NEUROFILAMENT PHOSPHORYLATION; INSULIN-SECRETION; NEURITE OUTGROWTH AB Cyclin-dependent kinase 5 (cdk5) is a proline-directed serine/threonine kinase that is activated mostly by association with its activators, p35 and p39. Initially projected as a neuron-specific kinase, cdk5 is expressed ubiquitously and its kinase activity solely depends on the presence of its activators, which are also found in some non-neuronal tissues. As a multifunctional protein, cdk5 has been linked to axonogenesis, cell migration, exocytosis, neuronal differentiation and apoptosis. Cdk5 plays a critical role in functions other than normal physiology, especially in neurodegeneration. Its contribution to both normal physiological as well as pathological processes is mediated by its specific substrates. Cdk5-null mice are embryonically lethal, therefore making it difficult to study precisely what cdk5 does to the nervous system at early stages of development, be it neuron development or programmed cell death. Zebrafish model system bypasses the impediment, as it is amenable to reverse genetics studies. One of the functions that we have followed for the cdk5 ortholog in zebrafish in vivo is its effect on the Rohon-Beard (RB) neurons. RB neurons are the primary sensory spinal neurons that die during the first two days of zebrafish development eventually to be replaced by the dorsal root ganglia (DRG). Based on ours studies and others', here we discuss possible mechanisms that may be involved in cdk5's role in RB neuron development and survival. C1 [Kanungo, Jyotshnabala; Zheng, Ya-Li; Pant, Harish C.] Natl Inst Neurol Disorders & Stroke, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Mishra, Bibhutibhushan] Georgetown Univ, Sch Med, Dev Neurobiol Lab, Washington, DC 20007 USA. RP Pant, HC (reprint author), Natl Inst Neurol Disorders & Stroke, Neurochem Lab, NIH, Bldg 49,Rm 2A28, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA FX This work was supported by intramural funds from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA. We thank Drs. Ajay Chitnis and Moloy Goswami (NICHD, NIH) for providing the HuC plasmid and helpful discussions. NR 102 TC 5 Z9 5 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD JUN PY 2009 VL 34 IS 6 BP 1129 EP 1137 DI 10.1007/s11064-008-9885-4 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 430BX UT WOS:000264964900013 PM 19067160 ER PT J AU Xu, XQ Lee, DJ Antani, SK Long, LR Archibald, JK AF Xu, Xiaoqian Lee, Dah-Jye Antani, Sameer K. Long, L. Rodney Archibald, James K. TI Using relevance feedback with short-term memory for content-based spine X-ray image retrieval SO NEUROCOMPUTING LA English DT Article DE Relevance feedback; Content-based image retrieval; Spine X-ray; Shape matching; Osteophytes ID NEGATIVE EXAMPLES; SYSTEM; OSTEOPHYTES; DATABASES; FRAMEWORK; SVM AB Managing large medical image databases has become a challenging task as more medical images are produced and stored in digital format. Computer-aided decision support for content-based image retrieval (CBIR) is an essential tool for medical image management. This paper presents a novel hybrid relevance feedback (RF) system for shape-based retrieval of spine X-ray images. A new shape similarity measure that considers both whole shape and partial shape matching is presented. The proposed RF architecture includes separate retrieval and feedback modes to solicit user's opinion for refining retrieval results. A unique short-term memory approach is implemented to avoid repeated request for user's feedback on the same, already approved, and retrieved relevant images. An automatic weight updating scheme is developed to present the images on which it is best for the user to provide feedback. Incorporating all these unique features, the proposed RF retrieval system is able to reduce the gap between high-level human visual perception and low-level computerized features. Experimental results show overall retrieval accuracy improvement of 22.0% and 17.5% after the second feedback iteration for retrieving spine X-ray images with similar osteophytes severity and type, respectively. (C) 2009 Elsevier B.V. All rights reserved. C1 [Xu, Xiaoqian; Lee, Dah-Jye; Archibald, James K.] Brigham Young Univ, Dept Elect & Comp Engn, Provo, UT 84602 USA. [Antani, Sameer K.; Long, L. Rodney] NIH, Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20892 USA. RP Lee, DJ (reprint author), Brigham Young Univ, Dept Elect & Comp Engn, Provo, UT 84602 USA. EM djlee@ee.byu.edu OI Antani, Sameer/0000-0002-0040-1387 FU National Library of Medicine (NLM) [467-MZ301975, 467-MZ401638]; Lister Hill National Center for Biomedical Communications; National Library of Medicine (NLM); National Institutes of Health (NIH) FX This work research was supported in part by the National Library of Medicine (NLM) under Grant contracts #467-MZ301975 and #467-MZ401638 and intramural research funds of the Lister Hill National Center for Biomedical Communications, the National Library of Medicine (NLM), and the National Institutes of Health (NIH). NR 53 TC 13 Z9 13 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-2312 J9 NEUROCOMPUTING JI Neurocomputing PD JUN PY 2009 VL 72 IS 10-12 BP 2259 EP 2269 DI 10.1016/j.neucom.2008.12.029 PG 11 WC Computer Science, Artificial Intelligence SC Computer Science GA 454SG UT WOS:000266702300022 ER PT J AU Bruestle, DA Cutler, RG Telljohann, RS Mattson, MP AF Bruestle, Daniel A. Cutler, Roy G. Telljohann, Richard S. Mattson, Mark P. TI Decline in Daily Running Distance Presages Disease Onset in a Mouse Model of ALS SO NEUROMOLECULAR MEDICINE LA English DT Article DE ALS; Exercise; Mutant SOD1 ID AMYOTROPHIC-LATERAL-SCLEROSIS; AXONAL EXCITABILITY PROPERTIES; TRANSGENIC MODEL; EXERCISE; MICE; PROGRESSION; RESTRICTION; GEHRIG,LOU; RILUZOLE; BENEFIT AB Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of lower motor neurons resulting in paralysis and death. Epidemiological and clinical findings suggest that a decline in athletic performance may presage the clinical onset of ALS, but this possibility has not been tested in an animal model. By placing running wheels in each mouse's cage to measure their exercise activity, we show that presymptomatic G93A SOD1 ALS mice are more active runners (15-20 km/day) than control mice (7-9 km/day). The ALS mice then exhibit a sharp decline in daily running distance 10-20 days prior to the onset of clinical disease. Within the group of ALS mice, there were no significant correlations between cumulative lifetime running distance and age at clinical disease onset or age at death, suggesting that amount of exercise did not affect the course of the disease process. Our data show that presymptomatic ALS mice have a propensity for running long distances, and then dramatically reduce the amount they run prior to the appearance of clinical symptoms. The monitoring of voluntary running distance may provide a valuable biomarker to evaluate the efficacy of potential therapeutic interventions for ALS in preclinical studies. C1 [Bruestle, Daniel A.; Cutler, Roy G.; Telljohann, Richard S.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM cutlerro@mail.nih.gov; mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU Intramural Research Program of the National Institute on Aging, NIH FX This research was supported by the Intramural Research Program of the National Institute on Aging, NIH. NR 32 TC 9 Z9 9 U1 1 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD JUN PY 2009 VL 11 IS 2 BP 58 EP 62 DI 10.1007/s12017-009-8064-3 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 466TJ UT WOS:000267685400002 PM 19418268 ER PT J AU Varma, R Chai, Y Troncoso, J Gu, J Xing, H Stojilkovic, SS Mattson, MP Haughey, NJ AF Varma, R. Chai, Y. Troncoso, J. Gu, J. Xing, H. Stojilkovic, S. S. Mattson, M. P. Haughey, N. J. TI Amyloid-beta Induces a Caspase-mediated Cleavage of P2X4 to Promote Purinotoxicity SO NEUROMOLECULAR MEDICINE LA English DT Article DE Alzheimer's; Purinergic; P2X4; Receptor trafficking; Excitotoxicity ID CEREBELLAR GRANULE NEURONS; GATED ION CHANNELS; ALZHEIMERS-DISEASE; EXTRACELLULAR ATP; RECEPTOR DESENSITIZATION; CELLULAR-DISTRIBUTION; MURINE THYMOCYTES; CORTICAL-NEURONS; OXIDATIVE STRESS; DENDRITIC CELLS AB Overproduction of the beta-amyloid fragment 1-42 (A beta(1-42)) is thought to contribute to synaptic dysfunction and neuronal death in Alzheimer's disease. Mounting evidence suggests that purinergic receptors play critical roles in synaptic plasticity and neuronal survival, but the potential involvement of these receptors in A beta(1-42)-induced synaptic dysfunction and neuronal death has not been addressed. Here we report that A beta(1-42) promoted accumulation of the calcium-permeable purinergic receptor P2X4 in neurons. We also report evidence that A beta(1-42) induced a caspase-3-mediated cleavage of the receptor that slowed channel closure times and prevented agonist-induced internalization of the receptor. Molecular interference to reduce the expression of P2X4 in primary rodent neurons attenuated A beta(1-42)-induced neuronal death while induced expression of P2X4 in a neuronal cell line that does not normally express P2-receptors enhanced the toxic effect of A beta(1-42). Together these findings suggest that A beta(1-42)-induced synaptic dysfunction and neuronal death may involve perturbations in P2X4 purinergic receptors. C1 [Varma, R.; Chai, Y.; Haughey, N. J.] Univ Sch Med, Dept Neurol, Baltimore, MD 21287 USA. [Troncoso, J.] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21287 USA. [Gu, J.; Xing, H.] Univ Florida, Coll Dent Oral & Maxillofacial Surg & Diagnost Sc, Div Neurosci, Gainesville, FL USA. [Stojilkovic, S. S.] NICHD, Cellular Signalling Sect, Program Dev Neurosci, Bethesda, MD 20892 USA. [Mattson, M. P.] Johns Hopkins Univ, Dept Neurosci, Sch Med, Baltimore, MD 21205 USA. [Mattson, M. P.] NIA, Div Neurosci, NIH, Baltimore, MD 21224 USA. RP Haughey, NJ (reprint author), Univ Sch Med, Dept Neurol, Meyer 6-109,600 N Wolfe St, Baltimore, MD 21287 USA. EM nhaughe1@jhmi.edu RI Mattson, Mark/F-6038-2012 FU National Institutes of Health [R01AG023471] FX This study was funded in part by the National Institutes of Health Grants R01AG023471 to NJH. NR 60 TC 12 Z9 13 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD JUN PY 2009 VL 11 IS 2 BP 63 EP 75 DI 10.1007/s12017-009-8073-2 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 466TJ UT WOS:000267685400003 PM 19562525 ER PT J AU Martin, B Maudsley, S McNeilly, J Nicol, L Crawford, J Millar, M Sharpe, RM McNeilly, AS AF Martin, Bronwen Maudsley, Stuart McNeilly, Judith Nicol, Linda Crawford, Janet Millar, Michael Sharpe, Richard M. McNeilly, Alan S. TI Neonatal Estrogenic Effects upon the Male Rat Pituitary: Early Gonadotrophin Attenuation Precedes Long-term Recovery SO NEUROMOLECULAR MEDICINE LA English DT Article DE Neonatal; Diethylstilbestrol; Pituitary; Gonadotroph; Follicle stimulating hormone; Luteinizing hormone; Endocrine disruptors; Testosterone; Inhibin ID FOLLICLE-STIMULATING-HORMONE; WEAK ENVIRONMENTAL ESTROGENS; REPRODUCTIVE-TRACT; CELL DEVELOPMENT; RECEPTOR-ALPHA; INHIBIN-B; MARMOSET MONKEY; EXCURRENT DUCTS; SERTOLI-CELLS; ESTROUS-CYCLE AB Neonatal exposure to potent estrogenic compounds can affect multiple components of the male reproductive system causing impaired development of the epithelium and overgrowth of stromal tissue in the epididymis, vas deferens, seminal vesicles, and prostate. However, very little is known about the direct effects of estrogenic compounds on the anterior pituitary gland. In this study we have investigated the effects of neonatal estrogenic exposure upon the anterior pituitary. Both the early- and late-stage effects of exposure to a synthetic estrogenic agent, diethylstilbestrol (DES), upon pituitary gonadotroph cell function were assessed. We administered either a high dose (10 mu g) or a low dose (0.1 mu g) of DES to male rats during their neonatal period (P2-12). Gonadotroph function, cell number and morphology shortly after DES treatment (P18) and during adulthood (P90) were assessed. At P18 there was a significant decrease in follicle stimulating hormone (FSH) immunoreactivity in the pituitary gonadotroph cells in the high DES dose treated rats compared to control animals. No significant change in luteinizing hormone (LH) was observed at either DES dose. In adulthood (P90), there was no significant difference in FSH or LH gonadotroph immunoreactivity between control rats and any dose of DES-treated rats. Therefore, despite acute and selective ablation of FSH expression the gonadotrophs were able to recover in adulthood, suggesting that perinatal estrogenic exposure was only temporarily deleterious. C1 [Martin, Bronwen; Maudsley, Stuart; McNeilly, Judith; Nicol, Linda; Millar, Michael; Sharpe, Richard M.; McNeilly, Alan S.] Queens Med Res Inst, MRC Human Reprod Sci Unit, Ctr Reprod Biol, Edinburgh, Midlothian, Scotland. [Crawford, Janet] AgResearch Ltd, Reprod Grp, Wallaceville Anim Res Ctr, Upper Hutt, New Zealand. RP Martin, B (reprint author), NIA, Labs Clin Invest & Neurosci, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM martinbro@mail.nih.gov RI Pitman, Janet/B-1558-2012; OI Sharpe, Richard/0000-0003-1686-8085 FU Medical Research Council [MC_U127685843, MC_U127684422] NR 42 TC 2 Z9 2 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 EI 1559-1174 J9 NEUROMOL MED JI Neuromol. Med. PD JUN PY 2009 VL 11 IS 2 BP 76 EP 86 DI 10.1007/s12017-009-8075-0 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 466TJ UT WOS:000267685400004 PM 19565361 ER PT J AU Pinol-Ripoll, G Shatunov, A Cabello, A Larrode, P de la Puerta, I Pelegrin, J Ramos, FJ Olive, M Goldfarb, LG AF Pinol-Ripoll, Gerard Shatunov, Alexey Cabello, Ana Larrode, Pilar de la Puerta, Iris Pelegrin, Juana Ramos, Feliciano J. Olive, Montse Goldfarb, Lev G. TI Severe infantile-onset cardiomyopathy associated with a homozygous deletion in desmin SO NEUROMUSCULAR DISORDERS LA English DT Article DE Desmin mutation; Restrictive cardiomyopathy; Heart failure; Skeletal myopathy; Autosomal recessive inheritance ID SUDDEN-DEATH; GENE; MUTATIONS; MYOPATHY; DISEASE; MUSCLE AB Desminopathy is a genetically heterogeneous disorder with autosomal dominant pattern of inheritance in most affected families; the age of disease onset is on average 30 years. We studied a patient with a history of recurrent episodes of syncope from infancy who later developed second-degree AV block and restrictive cardiomyopathy; she subsequently suffered several episodes of ventricular tachyarrhythmia requiring implantation of bicameral defibrillator. Neurological examination revealed rapidly progressive bilateral facial weakness, winging of the scapulae, symmetric weakness and atrophy of the trunk muscles, shoulder girdle and distal muscles of both upper and lower extremities. Muscle biopsy demonstrated signs of myofibrillar myopathy with prominent subsarcolemmal desmin-reactive aggregates. Molecular analysis identified a homozygous deletion in DES resulting in a predicted in-frame obliteration of seven amino acids (p.R173_E179del) in the 1B domain of desmin. We describe the youngest known desminopathy patient with severe cardiomyopathy and aggressive course leading to the devastation of cardiac, skeletal and smooth musculature at an early age. Published by Elsevier B.V. C1 [Shatunov, Alexey; Goldfarb, Lev G.] NINDS, NIH, Bethesda, MD 20892 USA. [Pinol-Ripoll, Gerard; Larrode, Pilar] Hosp Clin Univ Zaragoza, Div Neurol, Zaragoza, Spain. [Cabello, Ana] Hosp 12 Octubre, Div Neuropathol, E-28041 Madrid, Spain. [de la Puerta, Iris; Pelegrin, Juana] Hosp Clin Univ Zaragoza, Div Cardiol, Zaragoza, Spain. [Ramos, Feliciano J.] Univ Zaragoza, Fac Med, Genet Unit, Hosp Clin Univ,Pediat Serv, Zaragoza, Spain. [Olive, Montse] IDIBELL Bellvitge Hosp, Inst Neuropathol, Barcelona, Spain. [Olive, Montse] CIBERNED, Barcelona, Spain. RP Goldfarb, LG (reprint author), NINDS, NIH, Room 4S06,5625 Fishers Lane,MSC 9404, Bethesda, MD 20892 USA. EM GoldfarbL@ninds.nih.gov RI Shatunov, Aleksey/E-6946-2011; OI Larrode, Pilar/0000-0002-5413-1431; Ramos Fuentes, Feliciano Jesus/0000-0002-5732-2209; Olive, Montse/0000-0001-5727-0165 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health; Gobierno de Aragon Research Groups Program [B20] FX The authors are grateful to the patient and members of her family for participation in the Study. This research was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. F.J.R. is a participant of the Gobierno de Aragon Research Groups Program (Ref. B20), Spain. MO was the recipient of the Fondo de Investigaci6n Sanitaria P108-574 Grant. NR 16 TC 20 Z9 23 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD JUN PY 2009 VL 19 IS 6 BP 418 EP 422 DI 10.1016/j.nmd.2009.04.004 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 474SV UT WOS:000268305200007 PM 19433360 ER PT J AU Basselin, M Fox, MA Chang, L Bell, JM Greenstein, D Chen, M Murphy, DL Rapoport, SI AF Basselin, Mireille Fox, Meredith A. Chang, Lisa Bell, Jane M. Greenstein, Dede Chen, Mei Murphy, Dennis L. Rapoport, Stanley I. TI Imaging Elevated Brain Arachidonic Acid Signaling in Unanesthetized Serotonin Transporter (5-HTT)-Deficient Mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE serotonin; arachidonic acid; serotonin transporter; deficient mice; phospholipase A(2); eicosanoids ID OBSESSIVE-COMPULSIVE DISORDER; CYTOSOLIC PHOSPHOLIPASE A(2); POSITRON-EMISSION-TOMOGRAPHY; MOUSE-BRAIN; PROMOTER-POLYMORPHISM; (SERT)-DEFICIENT MICE; PREFRONTAL CORTEX; RECEPTOR AGONISTS; BIPOLAR DISORDER; KNOCKOUT MOUSE AB Certain polymorphisms reduce serotonin (5-HT) reuptake transporter (5-HTT) function and increase susceptibility to psychiatric disorders. Heterozygous (5-HTT(+/-))-deficient mice, models for humans with these polymorphisms, have elevated brain 5-HT concentrations and behavioral abnormalities. As postsynaptic 5-HT(2A/2C) receptors are coupled to cytosolic phospholipase A(2) (cPLA(2)), which releases arachidonic acid (AA) from membrane phospholipid, 5-HTT-deficient mice may have altered brain AA signaling and metabolism. To test this hypothesis, signaling was imaged as an AA incorporation coefficient k* in unanesthetized homozygous knockout (5-HTT(-/-)), 5-HTT(+/-) and wild-type (5-HTT(+/+)), mice following saline (baseline) or 1.5 mg/kg s.c. DOI, a partial 5-HT(2A/2C) receptor agonist. Enzyme activities, metabolite concentrations, and head-twitch responses to DOI were also measured. Baseline k* was widely elevated by 20-70% in brains of 5-HTT(+/-) and 5-HTT(-/-) compared to 5-HTT(+/+) mice. DOI increased k* in 5-HTT(+/+) mice, but decreased k* in 5-HTT-deficient mice. Brain cPLA(2) activity was elevated in 5-HTT-deficient mice; cyclooxygenase activity and prostaglandin E(2) and F(2 alpha) and thromboxane B(2) concentrations were reduced. Head-twitch responses to DOI, although robust in 5-HTT(+/+) and 5-HTT(+/-) mice, were markedly fewer in 5-HTT(-/-) mice. Pretreatment with para-chlorophenylalanine, a 5-HT synthesis inhibitor, restored head twitches in 5-HTT(-/-) mice to levels in 5-HTT(+/+) mice. We propose that increased baseline values of k* in 5-HTT-deficient mice reflect tonic cPLA(2) stimulation through 5-HT(2A/2C) receptors occupied by excess 5-HT, and that reduced k* and head-twitch responses to DOI reflected displacement of receptor-bound 5-HT by DOI with a lower affinity. Increased baseline AA signaling in humans having polymorphisms with reduced 5-HTT function might be identified using positron emission tomography. Neuropsychopharmacology (2009) 34, 1695-1709; doi:10.1038/npp.2008.227; published online 14 January 2009 C1 [Basselin, Mireille; Chang, Lisa; Bell, Jane M.; Chen, Mei; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Fox, Meredith A.; Murphy, Dennis L.] NIH, Clin Sci Lab, Bethesda, MD USA. [Greenstein, Dede] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Basselin, M (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room ISI26, Bethesda, MD 20892 USA. EM mirvasln@mail.nih.gov FU Intramural NIH HHS [Z01 AG000134-24] NR 76 TC 17 Z9 18 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2009 VL 34 IS 7 BP 1695 EP 1709 DI 10.1038/npp.2008.227 PG 15 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 444KR UT WOS:000265980400007 PM 19145225 ER PT J AU Li, X Li, J Peng, XQ Spiller, K Gardner, EL Xi, ZX AF Li, Xia Li, Jie Peng, Xiao-Qing Spiller, Krista Gardner, Eliot L. Xi, Zheng-Xiong TI Metabotropic Glutamate Receptor 7 Modulates the Rewarding Effects of Cocaine in Rats: Involvement of a Ventral Pallidal GABAergic Mechanism SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE mGluR7; AMN082; cocaine; dopamine; GABA; self-administration ID BRAIN-STIMULATION REWARD; GAMMA-AMINOBUTYRIC-ACID; NUCLEUS-ACCUMBENS; SYNAPTIC-TRANSMISSION; INDUCED REINSTATEMENT; DOPAMINE-RECEPTORS; DORSAL STRIATUM; MESSENGER-RNA; MICE LACKING; IN-VIVO AB The metabotropic glutamate receptor 7 (mGluR7) has received much attention as a potential target for the treatment of epilepsy, major depression, and anxiety. In this study, we investigated the possible involvement of mGluR7 in cocaine reward in animal models of drug addiction. Pretreatment with the selective mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082; 1-20 mg/kg, i.p.) dose-dependently inhibited cocaine-induced enhancement of electrical brain-stimulation reward and intravenous cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement conditions, but failed to alter either basal or cocaine-enhanced locomotion or oral sucrose self-administration, suggesting a specific inhibition of cocaine reward. Microinjections of AMN082 (1-5 mu g/mu l per side) into the nucleus accumbens (NAc) or ventral pallidum (VP), but not dorsal striatum, also inhibited cocaine self-administration in a dose-dependent manner. Intra-NAc or intra-VP co-administration of 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c] pyridin-4(5H)-one (MMPIP, 5 mu g/mu l per side), a selective mGluR7 allosteric antagonist, significantly blocked AMN082's action, suggesting an effect mediated by mGluR7 in these brain regions. In vivo microdialysis demonstrated that cocaine (10 mg/kg, i.p.) priming significantly elevated extracellular DA in the NAc or VP, while decreasing extracellular GABA in VP (but not in NAc). AMN082 pretreatment selectively blocked cocaine-induced changes in extracellular GABA, but not in DA, in both naive rats and cocaine self-administration rats. These data suggest: (1) mGluR7 is critically involved in cocaine's acute reinforcement; (2) GABA-, but not DA-, dependent mechanisms in the ventral striatopallidal pathway appear to underlie AMN082's actions; and (3) AMN082 or other mGluR7-selective agonists may be useful in the treatment of cocaine addiction. Neuropsychopharmacology (2009) 34, 1783-1796; doi:10.1038/npp.2008.236; published online 21 January 2009 C1 [Li, Xia; Li, Jie; Peng, Xiao-Qing; Spiller, Krista; Gardner, Eliot L.; Xi, Zheng-Xiong] NIDA, Neuropsychopharmacol Sect, Chem Biol Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Xi, ZX (reprint author), NIDA, Neuropsychopharmacol Sect, Chem Biol Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. EM zxi@intra.nida.nih.gov OI PENG, XIAOQING/0000-0002-7272-5428 FU National Institute on Drug Abuse; National Institutes of Health; Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. NR 53 TC 42 Z9 43 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2009 VL 34 IS 7 BP 1783 EP 1796 DI 10.1038/npp.2008.236 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 444KR UT WOS:000265980400015 PM 19158667 ER PT J AU Williams, LM Gatt, JM Kuan, SA Dobson-Stone, C Palmer, DM Paul, RH Song, L Costa, PT Schofield, PR Gordon, E AF Williams, Leanne M. Gatt, Justine M. Kuan, Stacey A. Dobson-Stone, Carol Palmer, Donna M. Paul, Robert H. Song, Le Costa, Paul T. Schofield, Peter R. Gordon, Evian TI A Polymorphism of the MAOA Gene is Associated with Emotional Brain Markers and Personality Traits on an Antisocial Index SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE monoamine oxidase A (MAOA) genotype; event-related potentials (ERPs); LORETA; NEO personality factors; antisocial traits ID MONOAMINE-OXIDASE-A; CATECHOL-O-METHYLTRANSFERASE; EVENT-RELATED POTENTIALS; INTEGRATIVE NEUROSCIENCE; FUNCTIONAL POLYMORPHISM; FACIAL EXPRESSIONS; CONDUCT DISORDER; 5-FACTOR MODEL; PANIC DISORDER; LIFE STRESS AB Association studies suggest that the low activity variant of the monoamine oxidase A (MAOA)-uVNTR polymorphism confers risk for emotional disturbances associated with antisocial traits, particularly in males. Here, we assessed the low (MAOA-L) activity variant in relation to both brain function and a behavioral index of antisocial traits. From an initial sample of 290 healthy participants, 210 had low (MAOA-L) or high (MAOA-H) activity variants. Participants underwent a brief assessment of personality traits and event-related potential (ERP) recording during an emotion-processing task. Genotype differences in ERPs were localized using LORETA. The MAOA-L genotype was distinguished by elevated scores on the index of antisocial traits. These traits were related to altered ERPs elicited 120 280 ms post-stimulus, particularly for negative emotion. Altered neural processing of anger in MAOA-L genotypes was localized to medial frontal, parietal, and superior temporo-occipital regions in males, but only to the superior occipital cortex in females. The MAOA low activity variant may increase susceptibility to antisocial traits through alterations to the neural systems for processing threat-related emotion, especially for males. Monoamines such as noradrenalin and serotonin may modulate these relationships, given that their metabolism varies according to MAOA variants, and that they modulate both emotional brain systems and antisocial aggression. Neuropsychopharmacology (2009) 34, 1797-1809; doi:10.1038/npp.2009.1; published online 4 February 2009 C1 [Williams, Leanne M.; Gatt, Justine M.; Kuan, Stacey A.; Palmer, Donna M.; Gordon, Evian] Univ Sydney, Westmead Millennium Inst, Brain Dynam Ctr, Westmead Hosp, Westmead, NSW 2145, Australia. [Williams, Leanne M.; Gatt, Justine M.; Kuan, Stacey A.; Palmer, Donna M.; Gordon, Evian] Univ Sydney, Western Clin Sch, Westmead, NSW 2145, Australia. [Williams, Leanne M.; Gatt, Justine M.; Kuan, Stacey A.; Gordon, Evian] Univ Sydney, Western Clin Sch, Sydney, NSW 2006, Australia. [Dobson-Stone, Carol; Schofield, Peter R.] Prince Wales Med Res Inst, Sydney, NSW, Australia. [Dobson-Stone, Carol; Schofield, Peter R.] Univ New S Wales, Sydney, NSW, Australia. [Palmer, Donna M.] Univ Sydney, Sch Psychol, Sydney, NSW 2006, Australia. [Paul, Robert H.; Gordon, Evian] Univ Missouri, Dept Psychol, St Louis, MO 63121 USA. [Song, Le] Brain Resource Co, Ultimo, NSW, Australia. [Song, Le] Brain Resource Int Database, Ultimo, NSW, Australia. [Song, Le] Univ Sydney, NICTA, Sydney, NSW 2006, Australia. [Costa, Paul T.] Univ Sydney, Sch Informat Technol, Sydney, NSW 2006, Australia. NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. RP Williams, LM (reprint author), Univ Sydney, Westmead Millennium Inst, Brain Dynam Ctr, Westmead Hosp, Westmead, NSW 2145, Australia. EM lea_williams@wmi.usyd.edu.au RI Schofield, Peter/C-9669-2011; Song, Le/C-1496-2012; Williams, Leanne/B-4095-2012; Gatt, Justine/C-4624-2008 OI Schofield, Peter/0000-0003-2967-9662; Costa, Paul/0000-0003-4375-1712; Gatt, Justine/0000-0002-9276-6358 FU ARC-linkage Grant [LP0455104]; Intramural Research Program of the National Institute on Aging; European Molecular Biology Organisation post-doctoral Fellowship [ALTF 166-2004]; Pfizer Senior Research Fellowship; Brain Resource International Database FX This project is supported by an ARC-linkage Grant (LP0455104) with Brain Resource as industry partner. This work supported in part by the Intramural Research Program of the National Institute on Aging (PTC). CDS is supported by a European Molecular Biology Organisation post-doctoral Fellowship (ALTF 166-2004); LMW holds a Pfizer Senior Research Fellowship. The authors also thank the individuals who gave their time to take part in this study. We acknowledge the support of the Brain Resource International Database (under the auspices of Brain Resource Ltd; http://www.brainresource.com) for use of the behavioral and brain structure/function data. NR 78 TC 41 Z9 44 U1 4 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2009 VL 34 IS 7 BP 1797 EP 1809 DI 10.1038/npp.2009.1 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 444KR UT WOS:000265980400016 PM 19194374 ER PT J AU Perlis, RH Laje, G Smoller, JW Fava, M Rush, AJ McMahon, FJ AF Perlis, Roy H. Laje, Gonzalo Smoller, Jordan W. Fava, Maurizio Rush, A. John McMahon, Francis J. TI Genetic and Clinical Predictors of Sexual Dysfunction in Citalopram-Treated Depressed Patients SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE antidepressant; pharmacogenetic; serotonin; glutamate; adverse effect ID MEDIAL PREOPTIC AREA; STAR-ASTERISK-D; SEQUENCED TREATMENT ALTERNATIVES; ILLNESS RATING-SCALE; REPORT QIDS-SR; QUICK INVENTORY; NITRIC-OXIDE; ANTIDEPRESSANT TREATMENT; PSYCHOMETRIC EVALUATION; RECEPTOR ANTAGONISTS AB Sexual dysfunction is a major contributor to treatment discontinuation and nonadherence among patients treated with selective serotonin reuptake inhibitors (SSRIs). The mechanisms by which depressive symptoms in general, as well as SSRI exposure in particular, may worsen sexual function are not known. We examined genetic polymorphisms, including those of the serotonin and glutamate systems, for association with erectile dysfunction, anorgasmia, and decreased libido during citalopram treatment. Clinical data were drawn from a nested case-control cohort derived from the STAR*D study, a multicenter, prospective, effectiveness trial in outpatients with nonpsychotic major depressive disorder (MDD). Self-reports of erectile dysfunction, decreased libido, or difficulty achieving orgasm based on the Patient-Rated Inventory of Side Effects were examined among Caucasian subjects (n = 1473) for whom DNA and adverse effect measures were available, and who were treated openly with citalopram for up to 14 weeks. Of 1473 participants, 799 (54%) reported decreased libido; 525 (36%) reported difficulty achieving orgasm. Of 574 men, 211 (37%) reported erectile dysfunction. Using a set-based test for association, single nucleotide polymorphisms in glutamatergic genes were associated with decreased libido (GRIA3; GRIK2), difficulty achieving orgasm (GRIA1), and difficulty achieving erection (GRIN3A) (experiment-wide permuted p<0.05 for each). Evidence of association persisted after adjustment for baseline clinical and sociodemographic differences. Likewise, evidence of association was similar when the cohort was limited to those who did not report a given adverse event at the first post-baseline visit (ie, those whose adverse events were known to be treatment emergent). These hypothesis-generating analyses suggest the potential for glutamatergic treatment targets for sexual dysfunction during major depressive episodes. Neuropsychopharmacology (2009) 34, 1819-1828; doi:10.1038/npp.2009.4; published online 18 March 2009 C1 [Perlis, Roy H.; Smoller, Jordan W.; Fava, Maurizio] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Perlis, Roy H.; Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Laje, Gonzalo; McMahon, Francis J.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Rush, A. John] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM rperlis@partners.org RI Laje, Gonzalo/L-2654-2014; OI Laje, Gonzalo/0000-0003-2763-3329; Rush, Augustus/0000-0003-2004-2382; McMahon, Francis/0000-0002-9469-305X FU NIMH [N01 MH-90003, K23MH67060]; NARSAD Young Investigator/Sidney R Baer Jr Foundation Award; Bowman Family Foundation award FX The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study is supported by federal funds from NIMH under contract N01 MH-90003 to the University of Texas Southwestern Medical Center at Dallas (AJ Rush, principal investigator). Dr Perlis is supported by NIMH K23MH67060, a NARSAD Young Investigator/Sidney R Baer Jr Foundation Award, and a Bowman Family Foundation award. Additional support provided by NIMH Intramural program. We thank Rutgers Cell and DNA Repository for extracting DNA and providing samples. We appreciate the support of Forest Laboratories for providing citalopram at no cost to the STAR*D study. We thank Stephen Wisniewski and Heather Eng for providing the clinical data. We thank the STAR*D Research Team for conducting the clinical study and obtaining clinical data and the blood samples for these analyses. Finally, we thank the study participants without whom this study would not have been possible. NR 47 TC 53 Z9 54 U1 4 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2009 VL 34 IS 7 BP 1819 EP 1828 DI 10.1038/npp.2009.4 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 444KR UT WOS:000265980400018 PM 19295509 ER PT J AU Holmes, A Wellman, CL AF Holmes, Andrew Wellman, Cara L. TI Stress-induced prefrontal reorganization and executive dysfunction in rodents SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Prefrontal cortex; Infralimbic; Prelimbic; Orbitofrontal; Stress; Neuron; Dendrite; Executive function; Working memory; Cognitive flexibility; Attentional set-shifting; Glucocorticoid; Mouse; Rat ID DORSAL RAPHE NUCLEUS; SPATIAL WORKING-MEMORY; MEDIAL FRONTAL-CORTEX; ALTERS DENDRITIC MORPHOLOGY; ELEVATED-PLUS-MAZE; AMPHETAMINE-ELICITED PERSEVERATION; PHASEOLUS-VULGARIS-LEUKOAGGLUTININ; HIPPOCAMPAL PYRAMIDAL NEURONS; CHRONIC UNPREDICTABLE STRESS; PRELIMBIC-INFRALIMBIC AREAS AB The prefrontal cortex (PFC) mediates a range of higher order 'executive functions' that subserve the selection and processing of information in such a way that behavior can be planned, controlled and directed according to shifting environmental demands. Impairment of executive functions typifies many forms of psychopathology, including schizophrenia, mood and anxiety disorders and addiction, that are often associated with a history of trauma and stress. Recent research in animal models demonstrates that exposure to even brief periods of intense stress is sufficient to cause significant structural remodeling of the principle projection neurons within the rodent PFC. In parallel, there is growing evidence that stress-induced alterations in PFC neuronal morphology are associated with deficits in rodent executive functions such as working memory, attentional set-shifting and cognitive flexibility, as well as emotional dysregulation in the form of impaired fear extinction. Although the molecular basis of stress-induced changes in PFC morphology and function are only now being elucidated, an understanding of these mechanisms could provide important insight into the pathophysiology of executive dysfunction in neuropsychiatric disease and foster improved strategies for treatment. (C) 2009 Published by Elsevier Ltd. C1 [Holmes, Andrew] NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. [Wellman, Cara L.] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA. RP Holmes, A (reprint author), NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM holmesan@mail.nih.gov FU National Institute on Alcohol Abuse; Alcoholism Intramural Research Program; National Institute of Mental Health [MH067607] FX This work was supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program (A.H.) and National Institute of Mental Health Grant MH067607 (C.L.W.). NR 255 TC 189 Z9 194 U1 2 U2 45 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD JUN PY 2009 VL 33 IS 6 BP 773 EP 783 DI 10.1016/j.neubiorev.2008.11.005 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 446UE UT WOS:000266145900001 PM 19111570 ER PT J AU Guo, Y Wang, HL Xiang, XH Zhao, Y AF Guo, Yuan Wang, Hui-Ling Xiang, Xiao-Hui Zhao, Yan TI The role of glutamate and its receptors in mesocorticolimbic dopaminergic regions in opioid addiction SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Opioid addiction; Mesocorticolimbic dopaminergic regions; Glutamate; Glutamate receptor ID VENTRAL TEGMENTAL AREA; PROTEIN-KINASE-C; EXCITATORY AMINO-ACIDS; RAT NUCLEUS-ACCUMBENS; SIGNAL-REGULATED KINASE; CENTRAL-NERVOUS-SYSTEM; MORPHINE-WITHDRAWAL SYMPTOMS; COCAINE-SEEKING BEHAVIOR; ELEMENT-BINDING PROTEIN; LONG-TERM POTENTIATION AB Accumulating evidence suggests that glutamate, as one of the most important excitatory neurotransmitters in the brain, plays a key role in drug addiction including opioid addiction. There is substantial evidence for glutamatergic projections into mesocorticolimbic dopaminergic neurons, which are associated with opioid psychological dependence and are also the key regions of enhancement effect. Glutamate may be involved in the process of opioid addiction not only by acting on its ionotropic and metabotropic glutamate receptors that activate several signal transduction pathways, but also by interacting with other neurotransmitters or neuropeptides such as opioids, dopamine, gamma-aminobutyric acid and substance P in the mesocorticolimbic dopaminergic regions. Studies on the role of glutamate and its receptors in opioid addiction will provide a new strategy for the exploitation of drugs for the treatment of opioid addiction. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Guo, Yuan; Wang, Hui-Ling; Zhao, Yan] Xi An Jiao Tong Univ, Dept Physiol & Pathophysiol, Sch Med, Xian 710061, Shaanxi, Peoples R China. [Wang, Hui-Ling] Natl Inst Drug Abuse, Biomed Res Ctr, Intramural Res Program, Baltimore, MD 21224 USA. [Xiang, Xiao-Hui] Med Coll Chinese Peoples Armed Police Forces, Dept Physiol & Pathophysiol, Tianjin 300162, Peoples R China. RP Zhao, Y (reprint author), Xi An Jiao Tong Univ, Dept Physiol & Pathophysiol, Sch Med, Xian 710061, Shaanxi, Peoples R China. EM zhaoy502@mail.xjtu.edu.cn OI xiang, xiaohui/0000-0002-5762-5007 FU National Natural Science Foundation of China [30600219, 30772705]; Special Research Fund for the Doctoral Program of High Education [20070698101]; Research Fund of Medical College of Chinese People's Armed Police Forces [WY2006-13] FX The project was supported by the National Natural Science Foundation of China (No. 30600219 and No. 30772705), the Special Research Fund for the Doctoral Program of High Education (No. 20070698101) and Research Fund of Medical College of Chinese People's Armed Police Forces (WY2006-13). NR 213 TC 14 Z9 16 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD JUN PY 2009 VL 33 IS 6 BP 864 EP 873 DI 10.1016/j.neubiorev.2009.02.005 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 446UE UT WOS:000266145900008 PM 19428497 ER PT J AU Schatlo, B Glasker, S Zauner, A Thompson, BG Oldfield, EH Pluta, RM AF Schatlo, Bawarjan Glasker, Sven Zauner, Alois Thompson, B. Gregory Oldfield, Edward H. Pluta, Ryszard M. TI CONTINUOUS NEUROMONITORING USING TRANSCRANIAL DOPPLER REFLECTS BLOOD FLOW DURING CARBON DIOXIDE CHALLENGE IN PRIMATES WITH GLOBAL CEREBRAL ISCHEMIA SO NEUROSURGERY LA English DT Article DE Cerebral blood flow; Cerebral ischemia; Chemoregulation; Primates; Subarachnoid hemorrhage; Transcranial Doppler; Vasospasm ID ANEURYSMAL SUBARACHNOID HEMORRHAGE; CO2 REACTIVITY; CEREBROVASCULAR REACTIVITY; PARTIAL-PRESSURE; CAROTID SURGERY; AUTOREGULATION; VELOCITY; VASOSPASM; ULTRASOUND; SONOGRAPHY AB OBJECTIVE: At present, there is no consensus on the optimal monitoring method for cerebral blood flow (CBF) in neurointensive care patients. The aim of the present study was to investigate whether continuous transcranial Doppler (TCD) monitoring with modulation of partial pressure of CO(2) reflects CBF changes. This hypothesis was tested in 2 pathological settings in which cerebral ischemia can be imminent: after an episode of cerebral ischemia and during vasospasm after subarachnoid hemorrhage. METHODS: Sixteen cynomolgus monkeys were divided into 3 groups: 1) chemoregulation in control animals to assess the physiological range of CBF regulation, 2) chemoregulation during vasospasm after subarachnoid hemorrhage, and 3) chemoregulation after transient cerebral ischemia. We surgically placed a thermal CBF probe over the cortex perfused by the right middle cerebral artery. Corresponding TCD values were acquired simultaneously while partial pressure of CO(2) was changed within a range of 25 to 65 mm Hg (chemoregulation). A correlation coefficient of CBF with TCD values of greater than r equals 0.8 was considered clinically relevant. RESULTS: CBF and CBF velocity correlated strongly after cerebral ischemia (r = 0.83, P < 0.001). Correlations were poor in chemoregulation controls (r = 0.2) and in the vasospasm group (r = 0.55). CONCLUSION:The present study provides experimental support that, in clearly defined conditions, continuous TCD monitoring combined with chemoregulation testing may provide an estimate of CBF in the early postischemic period. C1 [Schatlo, Bawarjan; Glasker, Sven; Pluta, Ryszard M.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Schatlo, Bawarjan] Charite Univ Med Berlin, Dept Expt Neurol, D-13353 Berlin, Germany. [Schatlo, Bawarjan] Univ Hosp Geneva, Dept Neurosurg, Geneva, Switzerland. [Zauner, Alois] Santa Barbara Cottage Hosp, Dept Neurosurg, Santa Barbara, CA USA. [Thompson, B. Gregory] Univ Michigan, Dept Neurosurg, Ann Arbor, MI 48109 USA. [Oldfield, Edward H.] Univ Virginia, Dept Neurosurg, Charlottesville, VA USA. RP Pluta, RM (reprint author), NINDS, Surg Neurol Branch, NIH, 10 Ctr Dr,Room 5D37, Bethesda, MD 20892 USA. EM plutar@ninds.hih.gov RI SCHATLO, Bawarjan/F-4285-2010 FU Intramural NIH HHS [Z99 NS999999] NR 42 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD JUN PY 2009 VL 64 IS 6 BP 1148 EP 1154 DI 10.1227/01.NEU.0000343542.61238.DF PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 452YE UT WOS:000266576300031 PM 19487895 ER PT J AU Severson, HH Peterson, AL Andrews, JA Gordon, JS Cigrang, JA Danaher, BG Hunter, CM Barckley, M AF Severson, Herbert H. Peterson, Alan L. Andrews, Judy A. Gordon, Judith S. Cigrang, Jeffrey A. Danaher, Brian G. Hunter, Christine M. Barckley, Maureen TI Smokeless tobacco cessation in military personnel: A randomized controlled trial SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID LONGITUDINAL DATA-ANALYSIS; DECISIONAL BALANCE; ORAL-CANCER; SMOKING; POPULATION; PREVALENCE; USERS; RISK; INTERVENTIONS; VALIDATION AB Military personnel are twice as likely as civilians to use smokeless tobacco (ST). This study evaluated the efficacy of a minimal-contact ST cessation program in military personnel. Participants were recruited from 24 military dental clinics across the United States during annual dental examinations. Participants were 785 active-duty military personnel who were randomly assigned to receive a minimal-contact behavioral treatment (n = 392) or usual care (n = 393). The behavioral treatment included an ST cessation manual, a videotape cessation guide tailored for military personnel, and three 15-min telephone counseling sessions using motivational interviewing methods. Usual care consisted of standard procedures that are part of the annual dental examination, including recommendations to quit using ST and referral to extant local tobacco cessation programs. Participants were assessed at 3 and 6 months after enrollment. Participants in the ST cessation program were significantly more likely to be abstinent from all tobacco, as assessed by repeated point prevalence at both 3 and 6 months (25.0%), and were significantly more likely to be abstinent from ST use for 6 months, as assessed by prolonged abstinence (16.8%), compared with participants in usual care (7.6% and 6.4%, respectively). These results indicate that a minimal-contact behavioral treatment can significantly reduce ST use in military personnel and has the potential for widespread dissemination. If ST users were identified in dental visits and routinely referred to telephone counseling, this could have a substantial benefit for the health and well-being of military personnel. C1 [Severson, Herbert H.; Andrews, Judy A.; Gordon, Judith S.; Danaher, Brian G.; Barckley, Maureen] Oregon Res Inst, Eugene, OR 97403 USA. [Peterson, Alan L.; Cigrang, Jeffrey A.; Hunter, Christine M.] Wilford Hall USAF Med Ctr, San Antonio, TX 78236 USA. [Peterson, Alan L.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Hunter, Christine M.] Natl Inst Hlth, Bethesda, MD USA. RP Severson, HH (reprint author), Oregon Res Inst, 1715 Franklin Blvd, Eugene, OR 97403 USA. EM herb@ori.org FU Congressionally Directed Medical Research Program's Peer Review Medical Research Program to HHS [DAMD17-02-2-0] FX Congressionally Directed Medical Research Program's Peer Review Medical Research Program to HHS (DAMD17-02-2-0) NR 56 TC 11 Z9 11 U1 1 U2 4 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 JUN PY 2009 VL 11 IS 6 BP 730 EP 738 DI 10.1093/ntr/ntp057 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 454QX UT WOS:000266698600021 PM 19395686 ER PT J AU Aklin, WM Moolchan, ET Luckenbaugh, DA Ernst, M AF Aklin, Will M. Moolchan, Eric T. Luckenbaugh, David A. Ernst, Monique TI Early tobacco smoking in adolescents with externalizing disorders: Inferences for reward function SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CONDUCT DISORDER; ADULTS; DEPENDENCE; CHILDREN; BEHAVIOR; BRAIN; ABUSE; MODEL AB Tobacco smoking is the leading preventable cause of mortality in the United States, and 90% of regular smokers initiate smoking before age 18 years. Factors that confer risk for chronic smoking include psychiatric factors, such as externalizing disorders, and potentially related neurobiological substrates, such as reward function. The present study examined the relationship between the externalizing disorders and the temporal progression of smoking among adolescent smokers. Data were from 64 adolescents who requested smoking cessation treatment and included information on developmental smoking trajectory, number of cigarettes per day, and Fagerstrom Test for Nicotine Dependence score. This sample was assessed carefully for psychiatric disorders. Analyses examined the relationships between externalizing psychiatric disorders and smoking trajectory. Adolescents with an externalizing disorder consumed more tobacco in the first 2 years of smoking than those without a disorder. There were no differences in speed of progression between groups, which may index a distinct functional pattern of reward systems that confers vulnerability for tobacco dependence. These data are discussed in terms of potential predictors of early smoking behavior that can inform interventions for adolescents with externalizing behaviors and tobacco dependence. They also provide some hypotheses for how the development of chronic smoking can be influenced by specific patterns of reward responses. C1 [Ernst, Monique] NIMH, Sect Dev, Intramural Res Program, Natl Inst Hlth, Bethesda, MD 20892 USA. [Moolchan, Eric T.] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. [Aklin, Will M.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. RP Ernst, M (reprint author), NIMH, Sect Dev, Intramural Res Program, Natl Inst Hlth, 15K North Dr, Bethesda, MD 20892 USA. EM aklinwm@mail.nih.gov FU National Institute on Drug Abuse; National Institute of Mental Health of the National Institutes of Health FX Intramural research programs of National Institute on Drug Abuse and National Institute of Mental Health of the National Institutes of Health. This research was supported by National Institute on Drug Abuse Intramural Funds. NR 32 TC 7 Z9 7 U1 1 U2 4 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 JUN PY 2009 VL 11 IS 6 BP 750 EP 755 DI 10.1093/ntr/ntp059 PG 6 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 454QX UT WOS:000266698600023 PM 19454552 ER PT J AU Espey, M AF Espey, Michael TI Relationship between oxygen and nitrite's fate in tumors SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Role of Nitrite in Physiology, Pathophysiology and Therapeutics Meeting CY JUN 17-18, 2009 CL Stockholm, SWEDEN SP Karolinska Inst, Dept Physiol Pharmacol, Univ Pittsburgh, Vasc Med Inst, Univ Pittsburgh, Dept Pharmacol & Chem Biol, Hope Pharmaceut C1 [Espey, Michael] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2009 VL 20 BP S33 EP S33 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 455LL UT WOS:000266761400039 ER PT J AU Gladwin, M Tiso, M Jayaraman, T Shiva, S Wang, XD Basu, S Kato, G Kim-Shapiro, DB AF Gladwin, Mark Tiso, Mauro Jayaraman, T. Shiva, Sruti Wang, Xunde Basu, Swati Kato, Gregory Kim-Shapiro, Daniel B. TI Heme globins as six-to-five coordinate regulated nitrite reductases and primordial NO synthases SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Role of Nitrite in Physiology, Pathophysiology and Therapeutics Meeting CY JUN 17-18, 2009 CL Stockholm, SWEDEN SP Karolinska Inst, Dept Physiol Pharmacol, Univ Pittsburgh, Vasc Med Inst, Univ Pittsburgh, Dept Pharmacol & Chem Biol, Hope Pharmaceut ID MYOCARDIAL-ISCHEMIA; NEUROGLOBIN; RESPIRATION; CYTOGLOBIN; PROTECTS; INJURY; BRAIN; OXIDE C1 [Gladwin, Mark; Tiso, Mauro; Jayaraman, T.; Shiva, Sruti] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Wang, Xunde; Kato, Gregory] NHLBI, NIH, Bethesda, MD 20892 USA. [Basu, Swati; Kim-Shapiro, Daniel B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [Basu, Swati; Kim-Shapiro, Daniel B.] Wake Forest Univ, Bowman Gray Sch Med, Sch Biomed Engn & Sci, Virginia Tech, Winston Salem, NC USA. RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 11 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2009 VL 20 BP S21 EP S22 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 455LL UT WOS:000266761400003 ER PT J AU Rifkind, J Salgado, MT Cao, Z Nagababu, E AF Rifkind, Joseph Salgado, Maria T. Cao, Zeling Nagababu, Enika TI The contribution of red cells to nitrite induced vasodilation: The role of hemoglobin-membrane interactions SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Role of Nitrite in Physiology, Pathophysiology and Therapeutics Meeting CY JUN 17-18, 2009 CL Stockholm, SWEDEN SP Karolinska Inst, Dept Physiol Pharmacol, Univ Pittsburgh, Vasc Med Inst, Univ Pittsburgh, Dept Pharmacol & Chem Biol, Hope Pharmaceut C1 [Rifkind, Joseph; Salgado, Maria T.; Cao, Zeling; Nagababu, Enika] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2009 VL 20 BP S42 EP S42 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 455LL UT WOS:000266761400068 ER PT J AU Schechter, A Qazi, M Rizzatti, F Piknova, B Sibmooh, N Stroncek, D AF Schechter, Alan Qazi, Melissa Rizzatti, Fabiola Piknova, Barbora Sibmooh, Nathawut Stroncek, David TI Effect of storage on levels of nitric oxide derivatives in blood products SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Role of Nitrite in Physiology, Pathophysiology and Therapeutics Meeting CY JUN 17-18, 2009 CL Stockholm, SWEDEN SP Karolinska Inst, Dept Physiol Pharmacol, Univ Pittsburgh, Vasc Med Inst, Univ Pittsburgh, Dept Pharmacol & Chem Biol, Hope Pharmaceut C1 [Schechter, Alan; Qazi, Melissa; Piknova, Barbora; Stroncek, David] NIH, Bethesda, MD 20892 USA. [Rizzatti, Fabiola] Univ Sao Paolo, Sao Paulo, Brazil. [Sibmooh, Nathawut] Mahidol Univ, Bangkok 10700, Thailand. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2009 VL 20 BP S41 EP S42 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 455LL UT WOS:000266761400065 ER PT J AU Tiso, M Jayaraman, T Basu, S Wang, XD Kato, G Shiva, S Kim-Shapiro, D Gladwin, M AF Tiso, Mauro Jayaraman, Thottala Basu, Shati Wang Xunde Kato, Gregory Shiva, Sruti Kim-Shapiro, Daniel Gladwin, Mark TI Neuroglobin as a six-to-five coordinate regulated nitrite reductase and NO synthase SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Role of Nitrite in Physiology, Pathophysiology and Therapeutics Meeting CY JUN 17-18, 2009 CL Stockholm, SWEDEN SP Karolinska Inst, Dept Physiol Pharmacol, Univ Pittsburgh, Vasc Med Inst, Univ Pittsburgh, Dept Pharmacol & Chem Biol, Hope Pharmaceut C1 [Tiso, Mauro; Jayaraman, Thottala; Shiva, Sruti; Gladwin, Mark] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15260 USA. [Basu, Shati; Kim-Shapiro, Daniel] Wake Forest Univ, Winston Salem, NC 27109 USA. [Wang Xunde; Kato, Gregory] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2009 VL 20 BP S45 EP S46 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 455LL UT WOS:000266761400077 ER PT J AU Wood, K Liu, V Noguchi, A Wang, XD Raghavachari, N Kato, G Gladwin, M AF Wood, Katherine Liu, Virginia Noguchi, Audrey Wang, Xunde Raghavachari, Nalini Kato, Gregory Gladwin, Mark TI Nitrite homeostasis and blood pressure regulation: A role for blood cell eNOS SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Role of Nitrite in Physiology, Pathophysiology and Therapeutics Meeting CY JUN 17-18, 2009 CL Stockholm, SWEDEN SP Karolinska Inst, Dept Physiol Pharmacol, Univ Pittsburgh, Vasc Med Inst, Univ Pittsburgh, Dept Pharmacol & Chem Biol, Hope Pharmaceut C1 [Wood, Katherine; Liu, Virginia; Noguchi, Audrey; Wang, Xunde; Raghavachari, Nalini; Kato, Gregory] NHLBI, NIH, Bethesda, MD 20892 USA. [Gladwin, Mark] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15260 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 ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2009 VL 20 BP S50 EP S50 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 455LL UT WOS:000266761400090 ER PT J AU Wood, K Liu, V Noguchi, A Wang, XD Raghavachari, N Kato, G Gladwin, M AF Wood, Katherine Liu, Virginia Noguchi, Audrey Wang, Xunde Raghavachari, Nalini Kato, Gregory Gladwin, Mark TI Nitrite homeostasis and blood pressure regulation: A role for blood cell eNOS SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Role of Nitrite in Physiology, Pathophysiology and Therapeutics Meeting CY JUN 17-18, 2009 CL Stockholm, SWEDEN SP Karolinska Inst, Dept Physiol Pharmacol, Univ Pittsburgh, Vasc Med Inst, Univ Pittsburgh, Dept Pharmacol & Chem Biol, Hope Pharmaceut C1 [Wood, Katherine; Liu, Virginia; Noguchi, Audrey; Wang, Xunde; Raghavachari, Nalini; Kato, Gregory] NHLBI, NIH, Bethesda, MD 20892 USA. [Gladwin, Mark] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 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 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2009 VL 20 BP S47 EP S47 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 455LL UT WOS:000266761400082 ER PT J AU Chung, YS Brendler, T Austin, S Guarne, A AF Chung, Yu Seon Brendler, Therese Austin, Stuart Guarne, Alba TI Structural insights into the cooperative binding of SeqA to a tandem GATC repeat SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ESCHERICHIA-COLI; REPLICATION INITIATION; DNA-REPLICATION; SEQUENTIAL BINDING; CRYSTAL-STRUCTURE; CELL-DIVISION; PROTEIN; SEQUENCES; ORIGIN; SITES AB SeqA is a negative regulator of DNA replication in Escherichia coli and related bacteria that functions by sequestering the origin of replication and facilitating its resetting after every initiation event. Inactivation of the seqA gene leads to unsynchronized rounds of replication, abnormal localization of nucleoids and increased negative superhelicity. Excess SeqA also disrupts replication synchrony and affects cell division. SeqA exerts its functions by binding clusters of transiently hemimethylated GATC sequences generated during replication. However, the molecular mechanisms that trigger formation and disassembly of such complex are unclear. We present here the crystal structure of a dimeric mutant of SeqA [SeqA(4159)-A25R] bound to tandem hemimethylated GATC sites. The structure delineates how SeqA forms a high-affinity complex with DNA and it suggests why SeqA only recognizes GATC sites at certain spacings. The SeqADNA complex also unveils additional proteinprotein interaction surfaces that mediate the formation of higher ordered complexes upon binding to newly replicated DNA. Based on this data, we propose a model describing how SeqA interacts with newly replicated DNA within the origin of replication and at the replication forks. C1 [Chung, Yu Seon; Guarne, Alba] McMaster Univ, Dept Biochem & Biomed Sci, Hlth Sci Ctr, Hamilton, ON L8N 3Z5, Canada. [Brendler, Therese; Austin, Stuart] NCI, Gene Regulat & Chromosome Biol Lab, Div Basic Sci, Ctr Canc Res, Frederick, MD 21702 USA. RP Guarne, A (reprint author), McMaster Univ, Dept Biochem & Biomed Sci, Hlth Sci Ctr, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada. EM guarnea@mcmaster.ca FU Canadian Institutes of Health Research [MOP-67189]; Intramural Research Program of the National Institutes of Health FX Canadian Institutes of Health Research ( MOP-67189 to A. G.); Intramural Research Program of the National Institutes of Health ( to S. A.) in part. Funding for open access charge: Canadian Institutes of Health Research. NR 42 TC 8 Z9 10 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 JUN PY 2009 VL 37 IS 10 BP 3143 EP 3152 DI 10.1093/nar/gkp151 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 457WU UT WOS:000266966700003 PM 19304745 ER PT J AU Stone, JE Kissling, GE Lujan, SA Rogozin, IB Stith, CM Burgers, PMJ Kunkel, TA AF Stone, Jana E. Kissling, Grace E. Lujan, Scott A. Rogozin, Igor B. Stith, Carrie M. Burgers, Peter M. J. Kunkel, Thomas A. TI Low-fidelity DNA synthesis by the L979F mutator derivative of Saccharomyces cerevisiae DNA polymerase SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DEPENDENT TRANSLESION SYNTHESIS; THYMINE-THYMINE DIMER; STRAND-BREAK-REPAIR; CROSS-LINK REPAIR; EMBRYONIC LETHALITY; REV1 PROTEIN; POL-ZETA; IN-VIVO; REPLICATION FIDELITY; INDUCED MUTAGENESIS AB To probe Pol functions in vivo via its error signature, here we report the properties of Saccharomyces cerevisiae Pol in which phenyalanine was substituted for the conserved Leu-979 in the catalytic (Rev3) subunit. We show that purified L979F Pol is 30 as active as wild-type Pol when replicating undamaged DNA. L979F Pol shares with wild-type Pol the ability to perform moderately processive DNA synthesis. When copying undamaged DNA, L979F Pol is error-prone compared to wild-type Pol , providing a biochemical rationale for the observed mutator phenotype of rev3-L979F yeast strains. Errors generated by L979F Pol in vitro include single-base insertions, deletions and substitutions, with the highest error rates involving stable misincorporation of dAMP and dGMP. L979F Pol also generates multiple errors in close proximity to each other. The frequency of these events far exceeds that expected for independent single changes, indicating that the first error increases the probability of additional errors within 10 nucleotides. Thus L979F Pol , and perhaps wild-type Pol , which also generates clustered mutations at a lower but significant rate, performs short patches of processive, error-prone DNA synthesis. This may explain the origin of some multiple clustered mutations observed in vivo. C1 [Stone, Jana E.; Lujan, Scott A.; Kunkel, Thomas A.] Natl Inst Environm Hlth Sci Res, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Stone, Jana E.; Lujan, Scott A.; Kunkel, Thomas A.] Natl Inst Environm Hlth Sci Res, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] Natl Inst Environm Hlth Sci Res, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Rogozin, Igor B.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, DHHS, Bethesda, MD 20894 USA. [Stith, Carrie M.; Burgers, Peter M. J.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Kunkel, TA (reprint author), Natl Inst Environm Hlth Sci Res, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU National Institutes of Health [GM032431] FX National Institutes of Health (GM032431 to P.M.J.B, partial.); Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Project Z01 ES065070 to T. A. K, partial.); Intramural Research Program of the National Institutes of Health, National Library of Medicine (to I. B. R., partial). Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, Project Z01 ES065070 to T. A. K.. NR 67 TC 13 Z9 13 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN PY 2009 VL 37 IS 11 BP 3774 EP 3787 DI 10.1093/nar/gkp238 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 463OP UT WOS:000267441800034 PM 19380376 ER PT J AU Rothney, MP Brychta, RJ Schaefer, EV Chen, KY Skarulis, MC AF Rothney, Megan P. Brychta, Robert J. Schaefer, Emily V. Chen, Kong Y. Skarulis, Monica C. TI Body Composition Measured by Dual-energy X-ray Absorptiometry Half-body Scans in Obese Adults SO OBESITY LA English DT Article ID MINERAL-CONTENT; MUSCLE MASS; FAT MASS; WOMEN; BONE; MEN AB Dual-energy X-ray absorptiometry (DXA) has become a common measurement of human body composition. However, obese subjects have been understudied largely due to weight and scan area restrictions. Newer DXA instruments allow for heavier subjects to be supported by the DXA scanner, but the imaging area is still smaller than the body size of some obese subjects. In this study, we determined the validity of an automated half-scan methodology by comparing to the standard whole-body scans in a cohort of obese volunteers. Fifty-two subjects whose BMI > 30 kg/m(2) completed whole-body iDXA (GE Lunar) scans. The resulting scans were analyzed in three ways: the standard whole-body scan, total body estimated from the left side, and from the right side. Fat mass, nonbone lean mass, bone mineral content (BMC), and percent fat derived from each half scan were compared to the whole-body scans. Total fat mass, nonbone lean mass, or percent fat was comparable for the whole-body scans, left, and right side scans (> 97% within individuals and > 99.9% for the group). The BMC estimate using the right side scan was slightly but statistically higher than the whole-body BMC (similar to 30 g or 1%, P < 0.001), while the left side scan BMC estimate was lower than the whole-body BMC by the same magnitude. No significant magnitude bias was found for any of the composition variables. We conclude that the new iDXA half-body analysis in obese subjects appears to be closely comparable to whole-body analysis for fat mass, nonbone lean mass, and percent fat. C1 [Rothney, Megan P.; Brychta, Robert J.; Schaefer, Emily V.; Chen, Kong Y.; Skarulis, Monica C.] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Chen, KY (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. EM chenkong@niddk.nih.gov OI Chen, Kong/0000-0002-0306-1904 FU Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; Clinical Endocrinology Branch [Z01-DK071014-01] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Clinical Endocrinology Branch Z01-DK071014-01. NR 19 TC 40 Z9 41 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD JUN PY 2009 VL 17 IS 6 BP 1281 EP 1286 DI 10.1038/oby.2009.14 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 450EG UT WOS:000266383200029 PM 19584885 ER PT J AU Neumann, G Hunter, D Nevitt, M Chibnik, LB Kwoh, K Chen, H Harris, T Satterfield, S Duryea, J AF Neumann, G. Hunter, D. Nevitt, M. Chibnik, L. B. Kwoh, K. Chen, H. Harris, T. Satterfield, S. Duryea, J. CA Hlth ABC Study TI Location specific radiographic joint space width for osteoarthritis progression SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article ID KNEE OSTEOARTHRITIS; ANTEROPOSTERIOR; REPRODUCIBILITY; ARTHRITIS; VIEWS AB Objective: To establish the performance of location specific computer measures of radiographic joint space width (JSW) compared to measurements of minimum joint space width (mJSW) for the assessment of medial compartment knee osteoarthritis (OA). The study also investigated the most disease-responsive location for measuring medial compartment JSW. Methods: Serial bilateral Posterior Anterior (PA) conventional radiographs acquired with a fixed flexion protocol were obtained 36 months apart in 118 persons with knee OA participating in the Health, Aging and Body Composition (Health ABC) Study. Measurements of medial compartment mJSW and JSW at seven fixed locations were facilitated by the use of semi-automated software that delineated the femoral and tibial margins of the joint. A human reader operated custom software to verify and correct the software-drawn margins where necessary. Paired images were displayed with the reader blinded to the chronological order. The amount of joint space narrowing was measured and the standardized response mean (SRM) was used as a metric to quantify performance. Results: For all subjects, the mJSW SRM value was 0.42 while, for the most responsive location specific measure of JSW, it was SRM = 0.46. For subjects with a Kellgren-Lawrence (KL) score less than or equal to 1, mJSW (SRM = 0.40) was more responsive than the new measures (Maximum SRM = 0.30). For KL = 2 or 3, SRM = 0.49 for mJSW, and SRM = 0.74 for the most responsive location specific measure of JSW. Improved responsiveness was observed in the more central portion of the joint on the more diseased knees. Conclusions: Location specific computer measures of JSW are feasible and potentially provide a superior method to assess radiographic OA for more diseased subjects. This new measure has the potential to improve the power of clinical studies that use a fixed flexion protocol. (C) 2008 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Neumann, G.; Chibnik, L. B.; Duryea, J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Hunter, D.] Boston Univ, Boston, MA 02215 USA. [Hunter, D.] New England Baptist Hosp, Boston, MA USA. [Nevitt, M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kwoh, K.] Univ Pittsburgh, Pittsburgh, PA USA. [Chen, H.; Harris, T.] NIA, Lab Epidemiol, Demog & Biometry Program, NIH, Baltimore, MD 21224 USA. [Satterfield, S.] Univ Tennessee, Memphis, TN USA. RP Duryea, J (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, 75 Francis St, Boston, MA 02115 USA. EM jduryea@bwh.harvard.edu RI Hunter, David/A-4622-2010 OI Hunter, David/0000-0003-3197-752X FU NIH; National Institute of Aging; NIH/NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] FX We would like to thank the participants and investigators of the Health ABC study for their support of this project. The authors would also like to thank Dr. John Lynch for his valuable comments on the manuscript. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Aging and NIH/NIA contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. NR 25 TC 36 Z9 37 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD JUN PY 2009 VL 17 IS 6 BP 761 EP 765 DI 10.1016/j.joca.2008.11.001 PG 5 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 460NM UT WOS:000267194400010 PM 19073368 ER PT J AU Blitzer, A Crumley, RL Dailey, SH Ford, CN Floeter, MK Hillel, AD Hoffmann, HT Ludlow, CL Merati, A Munin, MC Robinson, LR Rosen, C Saxon, KG Sulica, L Thibeault, SL Titze, I Woo, P Woodson, GE AF Blitzer, Andrew Crumley, Roger L. Dailey, Seth H. Ford, Charles N. Floeter, Mary Kay Hillel, Allen D. Hoffmann, Henry T. Ludlow, Christy L. Merati, Albert Munin, Michael C. Robinson, Lawrence R. Rosen, Clark Saxon, Keith G. Sulica, Lucian Thibeault, Susan L. Titze, Ingo Woo, Peak Woodson, Gayle E. TI Recommendations of the Neurolaryngology Study Group on laryngeal electromyography SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article ID ABDUCTOR SPASMODIC DYSPHONIA; MUSCLE TENSION DYSPHONIA; SINGLE-FIBER ELECTROMYOGRAPHY; FINE-WIRE ELECTROMYOGRAPHY; MULTIPLE SYSTEM ATROPHY; VOCAL FOLD PARALYSIS; BOTULINUM TOXIN; MYASTHENIA-GRAVIS; QUANTITATIVE-ANALYSIS; INTERFERENCE PATTERN AB The Neurolaryngology Study Group convened a multidisciplinary panel of experts in neuromuscular physiology, electromyography, physical medicine and rehabilitation, neurology, and laryngology to meet with interested members from the American Academy of Otolaryngology Head and Neck Surgery, the Neurolaryngology Subcommittee and the Neurolaryngology Study Group to address the use of laryngeal electromyography (LEMG) for electrodiagnosis of laryngeal disorders. The panel addressed the use of LEMG for: 1) diagnosis of vocal fold paresis, 2) best practice application of equipment and techniques for LEMG, 3) estimation of time of injury and prediction of recovery of neural injuries, 4) diagnosis of neuromuscular diseases of the laryngeal muscles, and, 5) differentiation between central nervous system and behaviorally based laryngeal disorders. The panel also addressed establishing standardized techniques and methods for future assessment of LEMG sensitivity, specificity and reliability for identification, assessment and prognosis of neurolaryngeal disorders. Previously an evidence-based review of the clinical utility of LEMG published in 2004 only found evidence supported that LEMG was possibly useful for guiding injections of botulinum toxin into the laryngeal muscles. An updated traditional/narrative literature review and expert opinions were used to direct discussion and format conclusions. In current clinical practice, LEMG is a qualitative and not a quantitative examination. Specific recommendations were made to standardize electrode types, muscles to be sampled, sampling techniques, and reporting requirements. Prospective studies are needed to determine the clinical utility of LEMG. Use of the standardized methods and reporting will support future studies correlating electro-diagnostic findings with voice and upper airway function. (C) 2009 American Academy of Otolaryngology-Head and Neck Surgery Foundation. All rights reserved. C1 [Blitzer, Andrew] Head & Neck Surg Grp, New York, NY USA. [Crumley, Roger L.] Univ Calif Irvine, Dept Otolaryngol Head & Neck Surg, Irvine, CA 92717 USA. [Dailey, Seth H.; Ford, Charles N.; Thibeault, Susan L.] Univ Wisconsin, Sch Med & Publ Hlth, Div Otolaryngol Head & Neck Surg, Madison, WI USA. [Floeter, Mary Kay; Ludlow, Christy L.] NINDS, NIH, Bethesda, MD 20892 USA. [Hillel, Allen D.; Merati, Albert] Univ Washington, Sch Med, Dept Otolaryngol Head & Neck Surg, Seattle, WA USA. [Hoffmann, Henry T.] Dept Otolaryngol Head & Neck Surg, Iowa City, IA USA. [Titze, Ingo] Univ Iowa, Iowa City, IA USA. [Munin, Michael C.] Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Rosen, Clark] Univ Pittsburgh, Sch Med, Dept Otolaryngol, Pittsburgh, PA USA. [Robinson, Lawrence R.] Univ Washington, Sch Med, Dept Rehabil Med, Seattle, WA 98195 USA. [Saxon, Keith G.] Harvard Univ, Sch Med, Dept Surg, Div Otolaryngol, Boston, MA 02115 USA. [Sulica, Lucian] Cornell Univ, Weill Med Coll, Dept Otorhinolaryngol, New York, NY 10021 USA. [Woo, Peak] Mt Sinai Sch Med, Dept Otolaryngol, New York, NY USA. [Woodson, Gayle E.] So Illinois Univ, Dept Otolaryngol Head & Neck Surg, Springfield, IL USA. RP Ludlow, CL (reprint author), 10 Ctr Dr MSC 1416, Bethesda, MD 20892 USA. EM Ludlowc@ninds.nih.gov RI Robinson , Lawrence/D-8455-2013; OI Woodson, Gayle/0000-0002-0315-5329; Ludlow, Christy/0000-0002-2015-6171 FU National Institute of Neurological Disorders and Stroke, National Institutes of Health. Bethesda, MD FX Preparation of the manuscript was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. Bethesda, MD. NR 91 TC 48 Z9 49 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD JUN PY 2009 VL 140 IS 6 BP 782 EP 793 DI 10.1016/j.otohns.2009.01.026 PG 12 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 453NL UT WOS:000266617400002 PM 19467391 ER PT J AU Alexander, TH Weisman, MH Derebery, JM Espeland, MA Gantz, BJ Gulya, AJ Hammerschlag, PE Hannley, M Hughes, GB Moscicki, R Nelson, RA Niparko, JK Rauch, SD Telian, SA Brookhouser, PE Harris, JP AF Alexander, Thomas H. Weisman, Michael H. Derebery, Jennifer M. Espeland, Mark A. Gantz, Bruce J. Gulya, A. Julianna Hammerschlag, Paul E. Hannley, Maureen Hughes, Gordon B. Moscicki, Richard Nelson, Ralph A. Niparko, John K. Rauch, Steven D. Telian, Steven A. Brookhouser, Patrick E. Harris, Jeffrey P. TI Safety of High-Dose Corticosteroids for the Treatment of Autoimmune Inner Ear Disease SO OTOLOGY & NEUROTOLOGY LA English DT Article; Proceedings Paper CT 140th Annual Meeting of the American-Otological-Society CY APR 27-28, 2007 CL San Diego, CA SP Amer Otol Soc DE Adverse events; Autoimmune inner ear disease; Corticosteroids; Hearing loss; Prednisone; Toxicity ID SENSORINEURAL HEARING-LOSS; POLYMYALGIA-RHEUMATICA; INDUCED OSTEOPOROSIS; CONTROLLED-TRIAL; ADVERSE EVENTS; DOUBLE-BLIND; THERAPY; METHOTREXATE; MANAGEMENT; PLASMAPHERESIS AB Objective: To report the adverse effects associated with prolonged high-dose prednisone for the treatment of autoimmune inner ear disease (AIED). Study Design: Prospective data collected as part of a multi-center, randomized, controlled trial for the treatment of corticosteroid-responsive AIED with methotrexate. Setting: Tertiary referral centers. Patients: One hundred sixteen patients with rapidly progressive, bilateral sensorineural hearing loss. Intervention: All patients completed a 1-month course of prednisone (60 mg/d). In Phase 2, 67 patients with improvement in hearing underwent a monitored 18-week prednisone taper, resulting in 22 weeks of prednisone therapy at an average dose of 30 mg per day. Thirty-three patients were randomized to receive methotrexate in Phase 2. Thirty-four patients received prednisone and placebo. Main Outcome Measure: Adverse events (AE) in patients treated with prednisone only. Results: Of 116 patients, 7 had to stop prednisone therapy during the 1-month challenge phase due to AE. Of 34 patients, 5 were unable to complete the full 22-week course of prednisone due to AE. The most common AE was hyperglycemia, which occurred in 17.6% of patients participating in Phase 2. Weight gain was also common, with a mean increase in body mass index of 1.6 kg/m(2) (95% confidence interval, 0.77-2.3) during the 22-week steroid course. Patients entering Phase 2 were followed for a mean of 66 weeks. No fractures or osteonecrosis were reported. Conclusion: Although high-dose corticosteroids are associated with known serious side effects, prospective data in the literature are limited. The present study suggests that with appropriate patient selection, monitoring, and patient education, high-dose corticosteroids are a safe and effective treatment of AIED. C1 [Alexander, Thomas H.; Harris, Jeffrey P.] Univ Calif San Diego, Div Otolaryngol Head & Neck Surg, San Diego, CA 92103 USA. [Weisman, Michael H.] Cedars Sinai Med Ctr, Div Rheumatol, Los Angeles, CA 90048 USA. [Derebery, Jennifer M.; Nelson, Ralph A.] House Ear Res Inst, Los Angeles, CA USA. [Espeland, Mark A.] Wake Forest Univ, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. [Gantz, Bruce J.] Univ Iowa, Dept Otolaryngol Head & Neck Surg, Iowa City, IA 52242 USA. [Gulya, A. Julianna] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. [Hammerschlag, Paul E.] NYU, Dept Otolaryngol Head & Neck Surg, New York, NY USA. [Hannley, Maureen] Amer Acad Otolaryngol Head & Neck Surg, Alexandria, Egypt. [Hughes, Gordon B.] Cleveland Clin, Cleveland, OH 44106 USA. [Moscicki, Richard] Massachusetts Gen Hosp, Dept Allergy & Immunol, Boston, MA 02114 USA. [Niparko, John K.] Johns Hopkins Univ, Dept Otolaryngol, Baltimore, MD USA. [Rauch, Steven D.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Telian, Steven A.] Univ Michigan, Dept Otolaryngol Head & Neck Surg, Ann Arbor, MI 48109 USA. [Brookhouser, Patrick E.] Boystown Natl Res Hosp, Omaha, NE USA. RP Harris, JP (reprint author), Univ Calif San Diego, Div Otolaryngol Head & Neck Surg, 200 W Arbor Dr,Mail Code 8895, San Diego, CA 92103 USA. EM jpharris@ucsd.edu RI Alexander, Thomas/E-5836-2015 OI Alexander, Thomas/0000-0001-7994-7755 FU NCRR NIH HHS [M01 RR000059]; NIDCD NIH HHS [5 U01 DC03209] NR 40 TC 17 Z9 19 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD JUN PY 2009 VL 30 IS 4 BP 443 EP 448 DI 10.1097/MAO.0b013e3181a52773 PG 6 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 586QG UT WOS:000276925800002 PM 19395984 ER PT J AU Tambeli, CH Levine, JD Gear, RW AF Tambeli, Claudia H. Levine, Jon D. Gear, Robert W. TI Centralization of noxious stimulus-induced analgesia (NSIA) is related to activity at inhibitory synapses in the spinal cord SO PAIN LA English DT Article DE Pain-induced analgesia; Nucleus accumbens; Spinal cord; Rat; Antinociception; Capsaicin ID JAW-OPENING REFLEX; VENTROLATERAL ORBITAL CORTEX; ANTERIOR PRETECTAL NUCLEUS; PERIAQUEDUCTAL GRAY-MATTER; DORSAL HORN; RECEPTOR ANTAGONIST; RAT; ANTINOCICEPTION; NEURONS; STIMULATION AB The duration of noxious stimulus-induced antinociception (NSIA) has been shown to outlast the pain stimulus that elicited it, however, the mechanism that determines the duration of analgesia is unknown. We evaluated the role of spinal excitatory and inhibitory receptors (NMDA, mGluR(5), mu-opioid, GABA(A), and GABA(B)), previously implicated in NSIA initiation, in its maintenance. As in our previous studies, the supraspinal trigeminal jaw-opening reflex (JOR) in the rat was used for nociceptive testing because of its remoteness from the region of drug application, the lumbar spinal cord. NSIA was reversed by antagonists for two inhibitory receptors (GABA(B) and mu-opioid) but not by antagonists for either of the two excitatory receptors (NMDA and mGluR(5)), indicating that NSIA is maintained by ongoing activity at inhibitory synapses in the spinal cord. Furthermore, spinal administration of the GABAB agonist baclofen mimicked NSIA in that it could be blocked by prior injection of the p-opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) in nucleus accumbens. CTAP also blocked baclofen antinociception when administered in the spinal cord. We conclude that analgesia induced by noxious stimulation is maintained by activity in spinal inhibitory receptors. (C) 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Tambeli, Claudia H.; Levine, Jon D.; Gear, Robert W.] Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, NIH, Pain Ctr, San Francisco, CA 94143 USA. [Levine, Jon D.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Tambeli, Claudia H.] Univ Estadual Campinas, Fac Dent Piracicaba, Campinas, Brazil. RP Gear, RW (reprint author), Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, NIH, Pain Ctr, Rm C-522,Box 0440, San Francisco, CA 94143 USA. EM robert.gear@ucsf.edu RI Tambeli, Claudia/D-4356-2012 FU U.S. National Institutes of Health; CNPq, Brazil FX This work was supported in part by the U.S. National Institutes of Health and a post-doctoral fellowship to C.H.T. from CNPq, Brazil. NR 38 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUN PY 2009 VL 143 IS 3 BP 228 EP 232 DI 10.1016/j.pain.2009.03.005 PG 5 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 454UJ UT WOS:000266707900014 PM 19375225 ER PT J AU Parameswaran, N O'Handley, RM Grigg, ME Fenwick, SG Thompson, RCA AF Parameswaran, N. O'Handley, R. M. Grigg, M. E. Fenwick, S. G. Thompson, R. C. A. TI Seroprevalence of Toxoplasma gondii in wild kangaroos using an ELISA SO PARASITOLOGY INTERNATIONAL LA English DT Article DE Toxoplasma gondii; Marsupial; Serology; ELISA; Prevalence; Australia ID WALLABIES MACROPUS-RUFOGRISEUS; EASTERN BARRED BANDICOOTS; DIRECT AGGLUTINATION-TEST; WOMBATS VOMBATUS-URSINUS; NEOSPORA-CANINUM; CONGENITAL TRANSMISSION; ANTIBODIES; INFECTION; AUSTRALIA; SHEEP AB Infection with Toxoplasma gondii is a significant problem in Australian marsupials, and can lead to devastating disease and predispose animals to predation. T gondii infection in kangaroos is also of public health significance due to the kangaroo meat trade. A moderate seroprevalence of T.gondii was observed in a Study of western grey kangaroos located in the Perth metropolitan area in Western Australia. Or 219 kangaroos tested, 15.5% (95%CI: 10.7-20.3) were positive for T.gondii antibodies using an ELISA developed to detect T.gondii IgG in macropod Marsupials. When compared with the commercially available MAT (modified agglutination test), the ELISA developed was in absolute agreement and yielded a kappa coefficient of 1.00. Of 18 kangaroos tested for the presence of T. gondii DNA by PCR, the 9 ELISA positive kangaroos tested PCR positive and the 9 ELISA negative kangaroos tested PCR negative indicating the ELISA protocol was both highly specific and sensitive and correlated 100% with the more labour intensive PCR assay. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Parameswaran, N.; Fenwick, S. G.; Thompson, R. C. A.] Murdoch Univ, WHO Collaborating Ctr Mol Epidemiol Parasit Infec, Sch Vet & Biomed Sci, Murdoch, WA 6150, Australia. [O'Handley, R. M.] Murdoch Univ, Environm Biotechnol CRC, Murdoch, WA 6150, Australia. [Grigg, M. E.] NIAID, Mol Parasitol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Parameswaran, N (reprint author), Murdoch Univ, WHO Collaborating Ctr Mol Epidemiol Parasit Infec, Sch Vet & Biomed Sci, Murdoch, WA 6150, Australia. EM nevi.parameswaran@gmail.com FU Intramural Research Program of the NIH; NIAID (MEG) FX We wish to thank Lisa Hulme-Moir for the provision of western grey kangaroo sera for the seroprevalence study. We also wish to thank Glen Goudie and his team for their immense help with the collection of western grey kangaroo samples. Nick Smith at the University of Technology, Sydney is acknowledged for providing T gondii tachyzoites for vero cell culture. This research was Supported in part by the Intramural Research Program of the NIH and NIAID (MEG). NR 55 TC 19 Z9 24 U1 2 U2 26 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1383-5769 J9 PARASITOL INT JI Parasitol. Int. PD JUN PY 2009 VL 58 IS 2 BP 161 EP 165 DI 10.1016/j.parint.2009.01.008 PG 5 WC Parasitology SC Parasitology GA 446SU UT WOS:000266142200008 PM 19567231 ER PT J AU Tang, JS Rangayyan, R Yao, JH Yang, YY AF Tang, Jinshan Rangayyan, Raj Yao, Jianhua Yang, Yongyi TI Digital image processing and pattern recognition techniques for the detection of cancer SO PATTERN RECOGNITION LA English DT Editorial Material C1 [Tang, Jinshan] Alcorn State Univ, Dept Adv Technol, Lorman, MS USA. [Rangayyan, Raj] Univ Calgary, Dept Elect & Comp Engn, Schulich Sch Engn, Calgary, AB T2N 1N4, Canada. [Yao, Jianhua] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Yang, Yongyi] IIT, Dept Elect & Comp Engn, Chicago, IL 60616 USA. RP Tang, JS (reprint author), Alcorn State Univ, Dept Adv Technol, Lorman, MS USA. EM jtang@alcorn.edu; ranga@enel.ucalgary.ca; JYao@cc.nih.gov; yy@ece.iit.edu NR 0 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0031-3203 J9 PATTERN RECOGN JI Pattern Recognit. PD JUN PY 2009 VL 42 IS 6 BP 1015 EP 1016 DI 10.1016/j.patcog.2008.11.012 PG 2 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 417CB UT WOS:000264051600001 ER PT J AU Yao, JH Li, J Summers, RM AF Yao, Jianhua Li, Jiang Summers, Ronald M. TI Employing topographical height map in colonic polyp measurement and false positive reduction SO PATTERN RECOGNITION LA English DT Article DE CAD; Colonic polyps; Topographical height map; Range image ID COMPUTER-AIDED DETECTION; TOMOGRAPHIC VIRTUAL COLONOSCOPY; CT COLONOGRAPHY AB CT colonography (CTC) is an emerging minimally invasive technique for screening and diagnosing colon cancers. Computer aided detection (CAD) techniques can increase sensitivity and reduce false positives. Inspired by the way radiologists detect polyps via 3D virtual fly-through in CTC, we borrowed the idea from geographic information systems to employ topographical height map in colonic polyp measurement and false positive reduction. After a curvature based filtering and a 3D CT feature classifier. a height map is computed for each detection using a ray-casting algorithm. We design a concentric index to characterize the concentric pattern in polyp height map based on the fact that polyps are protrusions from the colon wall and round in shape. The height map is optimized through a multi-scale spiral spherical search to maximize the concentric index. We derive several topographic features from the map and compute texture features based on wavelet decomposition. We then send the features to a committee of support vector machines for classification. We have trained our method on 394 patients (71 polyps) and tested it on 792 patients (226 polyps). Results showed that we can achieve 95% sensitivity at 2.4 false positives per patient and the height map features can reduce false positives by more than 50%. We compute the polyp height and width Measurements and correlate them with manual measurements. The Pearson correlations are 0.74 (p = 0.11) and 0.75 (p = 0.17) for height and width, respectively. Published by Elsevier Ltd. C1 [Yao, Jianhua; Li, Jiang; Summers, Ronald M.] NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20892 USA. [Li, Jiang] Old Dominion Univ, ECE, Norfolk, VA 23529 USA. [Li, Jiang] Old Dominion Univ, VMASC, Norfolk, VA 23529 USA. RP Yao, JH (reprint author), NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20892 USA. EM jyao@cc.nih.gov FU National Institutes of Health, Clinical Center FX The authors thank Perry J. Pickhardt, William R. Schindler and Richard Choi for providing computed tomographic colonography and supporting data. We thank Suzanne Frentz for performing the manual measurement of polyp height and width. This research was supported by the Intramural Research Program of the National Institutes of Health, Clinical Center. NR 39 TC 16 Z9 17 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0031-3203 J9 PATTERN RECOGN JI Pattern Recognit. PD JUN PY 2009 VL 42 IS 6 BP 1029 EP 1040 DI 10.1016/j.patcog.2008.09.034 PG 12 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 417CB UT WOS:000264051600003 PM 19578483 ER PT J AU Narasimha, R Ouyang, H Gray, A McLaughlin, SW Subramaniam, S AF Narasimha, Rajesh Ouyang, Hua Gray, Alexander McLaughlin, Steven W. Subramaniam, Sriram TI Automatic joint classification and segmentation of whole cell 3D images SO PATTERN RECOGNITION LA English DT Article DE Mitochondria; Texture features; Segmentation; Classification; Automated techniques; Machine learning; Cancer detection AB We present a machine learning tool for automatic texton-based joint classification and segmentation of mitochondria in MNT-1 cells imaged using ion-abrasion scanning electron microscopy (IA-SEM). For diagnosing signatures that may be unique to cellular states such as cancer, automatic tools with minimal user intervention need to be developed for analysis and mining of high-throughput data from these large volume data sets (typically similar to 2 GB/cell). Challenges for such a tool in 3D electron microscopy arise due to low contrast and signal-to-noise ratios (SNR) inherent to biological imaging. Our approach is based on block-wise classification of images into a trained list of regions. Given manually labeled images, our goal is to learn models that can localize novel instances of the regions in test datasets. Since datasets obtained using electron microscopes are intrinsically noisy, we improve the SNR of the data for automatic segmentation by implementing a 2D texture-preserving filter on each slice of the 3D dataset. We investigate texton-based region features in this work. Classification is performed by k-nearest neighbor (k-NN) classifier, Support vector machines (SVMs), adaptive boosting (AdaBoost) and histogram matching using a NN classifier. In addition, we study the computational complexity vs. segmentation accuracy tradeoff of these classifiers. Segmentation results demonstrate that Our approach using minimal training data performs close to semi-automatic methods using the variational level-set method and manual segmentation carried out by an experienced user. Using our method, which we show to have minimal user intervention and high classification accuracy, we investigate quantitative parameters such as volume of the cytoplasm occupied by mitochondria, differences between the surface area of inner and outer membranes and mean mitochondrial width which are quantities potentially relevant to distinguishing cancer cells from normal cells. To test the accuracy of our approach, these quantities are compared against manually computed counterparts. We also demonstrate extension of these methods to segment 3D images obtained using electron tomography. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Narasimha, Rajesh; Subramaniam, Sriram] NCI, Canc Res Ctr, Bethesda, MD 20892 USA. [Narasimha, Rajesh; Ouyang, Hua; Gray, Alexander; McLaughlin, Steven W.] Georgia Inst Technol, Atlanta, GA 30332 USA. RP Narasimha, R (reprint author), NCI, Canc Res Ctr, Bethesda, MD 20892 USA. EM rajesh@ece.gatech.edu; houyang3@mail.gatech.edu; agray@cc.gatech.edu; swm@ace.gatech.edu; ss1@nih.gov NR 36 TC 24 Z9 24 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0031-3203 J9 PATTERN RECOGN JI Pattern Recognit. PD JUN PY 2009 VL 42 IS 6 BP 1067 EP 1079 DI 10.1016/j.patcog.2008.08.009 PG 13 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 417CB UT WOS:000264051600007 ER PT J AU Linguraru, MG Yao, J Gautam, R Peterson, J Li, ZX Linehan, WM Summers, RM AF Linguraru, Marius George Yao, Jianhua Gautam, Rabindra Peterson, James Li, Zhixi Linehan, W. Marston Summers, Ronald M. TI Renal tumor quantification and classification in contrast-enhanced abdominal CT SO PATTERN RECOGNITION LA English DT Article DE Contrast-enhanced CT; Kidney cancer; von Hippel Lindau syndrome; Hereditary papillary renal carcinoma; Segmentation; Quantification; Classification; Monitoring; Level sets; Computer-assisted radiology ID MULTIDETECTOR-ROW CT; HOGG-DUBE-SYNDROME; KIDNEY CANCER; NEPHROGRAPHIC PHASES; COMPUTED-TOMOGRAPHY; GENETIC-BASIS; MR-IMAGES; SEGMENTATION; REGISTRATION; ALGORITHM AB Kidney cancer Occurs in both hereditary (inherited) and sporadic (non-inherited) form. It is estimated that almost a quarter of a million people in the USA are living with kidney cancer and their number increases, with 51,000 diagnosed with the disease every year. In clinical practice, the response to treatment is monitored by manual measurements of tumor size, which are 21), do not reflect the 3D geometry and enhancement of tumors, and show high intra- and inter-operator variability. We propose a computer-assisted radiology too] to assess renal tumors in contrast-enhanced CT for the management Of tumor diagnoses and responses to now treatments. The algorithm employs anisotropic diffusion (for smoothing), a combination of fast-marching and geodesic level-sets (for segmentation), and a novel statistical refinement step to adapt to the shape of the lesions. It also quantifies the 3D size, volume and enhancement (If the lesion, and allows serial management over time. Tumors are robustly segmented and the comparison between manual and semi-automated quantifications shows disparity within the limits of inter-observer variability. The analysis of lesion enhancement for tumor classification shows great separation between cysts, von Hippel-Lindau syndrome lesions. and hereditary papillary renal carcinomas (HPRC) with p-values inferior to 0.004. The results on temporal evaluation of tumors from serial scans illustrate the potential of the method to become an important tool for disease monitoring, drug trials, and non-invasive clinical surveillance. (C) 2008 Published by Elsevier Ltd. C1 [Linguraru, Marius George; Yao, Jianhua; Li, Zhixi; Summers, Ronald M.] NIH, Ctr Clin, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Gautam, Rabindra; Peterson, James; Linehan, W. Marston] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Linguraru, MG (reprint author), NIH, Ctr Clin, Dept Radiol & Imaging Sci, 10 Ctr Dr, Bethesda, MD 20892 USA. EM lingorarum@mail.nih.gov FU National Institutes of Health, Clinical Center; National Cancer Institute; Center for Cancer Research FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, Clinical Center and National Cancer Institute, Center for Cancer Research. The authors would like to thank Dr. Sovira Tan from the National Institutes of Health for the constructive discussions. NR 47 TC 15 Z9 16 U1 2 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0031-3203 EI 1873-5142 J9 PATTERN RECOGN JI Pattern Recognit. PD JUN PY 2009 VL 42 IS 6 BP 1149 EP 1161 DI 10.1016/j.patcog.2008.09.018 PG 13 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 417CB UT WOS:000264051600015 PM 19492069 ER PT J AU Joseph, CLM Havstad, SL Ownby, DR Zoratti, E Peterson, EL Stringer, S Johnson, CC AF Joseph, C. L. M. Havstad, S. L. Ownby, D. R. Zoratti, E. Peterson, E. L. Stringer, S. Johnson, C. C. TI Gender differences in the association of overweight and asthma morbidity among urban adolescents with asthma SO PEDIATRIC ALLERGY AND IMMUNOLOGY LA English DT Article DE asthma; obesity; adolescents; African-American; gender ID BODY-MASS INDEX; RISK-FACTOR; CHILDREN; OBESITY; PREVALENCE; SYMPTOMS; CHILDHOOD; SEVERITY; RACE; SURVEILLANCE AB Asthma and obesity disproportionately affect US African-American youth. Among youth with asthma, obesity has been associated with poor control. The impact of gender on this association is unclear. We examined these relationships in a sample of urban, African-American adolescents with asthma. Questionnaires were used to identify high school students with asthma, and to examine the association of body mass index (BMI) to asthma morbidity, by gender. Of 5967 students completing questionnaires, 599 (10%) met criteria for asthma and 507 had data sufficient for inclusion in further analyses (46% male, mean age = 15.1 yr). Univariately, BMI > 85th percentile was significantly related only to reported emergency department visits (ED) and school days missed for any reason, Odds Ratio (95%Confidence Interval) = 1.7(1.1-2.7), p = 0.01 and 1.8(1.1-3.0), p = 0.01, respectively. A significant gender-BMI interaction (p < 0.05) was observed in multivariate models for ED visits, hospitalizations and school days missed for asthma. In gender-specific models, adjusted Risk Ratios for BMI > 85th and ED visits, hospitalizations, and school days missed because of asthma were 1.7(0.9-3.2), 6.6(3.1-14.6) and 3.6(1.8-7.2) in males. These associations were not observed in females. Gender modifies the association between BMI and asthma-related morbidity among adolescents with asthma. Results have implications for clinical management as well as future research. C1 [Joseph, C. L. M.; Havstad, S. L.; Peterson, E. L.; Johnson, C. C.] Henry Ford Hlth Syst, Dept Biostat & Res Epidemiol, Detroit, MI 48202 USA. [Ownby, D. R.] Med Coll Georgia, Augusta, GA 30912 USA. [Stringer, S.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Joseph, CLM (reprint author), Henry Ford Hlth Syst, Dept Biostat & Res Epidemiol, 1 Ford Pl,3E, Detroit, MI 48202 USA. EM cjoseph1@hfhs.org OI Johnson, Christine Cole/0000-0002-6864-6604 FU NHLBI NIH HHS [R01 HL068971] NR 43 TC 7 Z9 7 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0905-6157 J9 PEDIATR ALLERGY IMMU JI Pediatr. Allergy Immunol. PD JUN PY 2009 VL 20 IS 4 BP 362 EP 369 DI 10.1111/j.1399-3038.2008.00803.x PG 8 WC Allergy; Immunology; Pediatrics SC Allergy; Immunology; Pediatrics GA 450LC UT WOS:000266401000009 PM 18823359 ER PT J AU Harper, D Caudell, D Novak, RL Pierce, RM Slape, C Wolff, L Aplan, PD AF Harper, David Caudell, David Novak, Rachel L. Pierce, Rachel M. Slape, Christopher Wolff, Linda Aplan, Peter D. TI (PLATFORM 302D) IDENTIFICATION OF GENES THAT COLLABORATE WITH CALM-AF10 TO INDUCE LEUKEMIA BY RETROVIRAL INSERTIONAL MUTAGENESIS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Harper, David] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. [Caudell, David; Novak, Rachel L.; Aplan, Peter D.] Natl Canc Inst, Ctr Canc Res, Genet Branch, Bethesda, MD USA. [Slape, Christopher] Royal Melbourne Hosp, Bone Marrow Res Lab, Parkville, Vic 3050, Australia. RI Aplan, Peter/K-9064-2016 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 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2009 VL 52 IS 6 BP 695 EP 696 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 423SI UT WOS:000264515600016 ER PT J AU Rao, VK Price, S Perkins, K Aldridge, P Treller, J Davis, J Dowdell, K Niemela, J Brown, M Fleisher, T AF Rao, V. Koneti Price, Susan Perkins, Katie Aldridge, Patricia Treller, Jean Davis, Joie Dowdell, Kennichi Niemela, Julie Brown, Margaret Fleisher, Thomas TI USE OF MYCOPHENOLATE MOFETIL IN CHILDREN WITH CHRONIC, REFRACTORY IMMUNE CYTOPENIAS ASSOCIATED WITH AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (ALPS) SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 Natl Inst Hlth, Bethesda, MD USA. Natl Inst Allergy, Bethesda, MD USA. NR 0 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 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2009 VL 52 IS 6 BP 697 EP 697 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 423SI UT WOS:000264515600021 ER PT J AU Kumkhaek, C Liu, WL Aerbajinai, W Zhu, J Fucharoen, S Rodgers, G AF Kumkhaek, Chutima Liu, Wenli Aerbajinai, Wulin Zhu, Jianqiong Fucharoen, Suthat Rodgers, Griffin TI HUMAN 14-3-3 beta EXPRESSION IS UP-REGULATED DURING MEGAKARYOCYTIC DIFFERENTIATION SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Kumkhaek, Chutima; Liu, Wenli; Aerbajinai, Wulin; Zhu, Jianqiong; Rodgers, Griffin] NHLBI, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. [Fucharoen, Suthat] Mahidol Univ, Thalassemia Res Ctr, Nakhon Pathom, Thailand. 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 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2009 VL 52 IS 6 BP 708 EP 709 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 423SI UT WOS:000264515600054 ER PT J AU Staber, JM Burnight, E Xie, LT Kaminski, J McCray, PB AF Staber, Janice M. Burnight, Erin Xie, Litao Kaminski, Joseph McCray, Paul B., Jr. TI NONVIRAL, GENE TRANSFER TO HEPATOCYTES UTILIZING THE PIGGYBAC TRANSPOSON SYSTEM: AN APPROACH TOWARDS HEMOPHILIA A CORRECTION AND LONG TERM EXPRESSION OF FACTOR VIII SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Staber, Janice M.; Burnight, Erin; Xie, Litao; McCray, Paul B., Jr.] Univ Iowa, Childrens Hosp, Iowa City, IA USA. [Kaminski, Joseph] NIH, Bethesda, MD 20892 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 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2009 VL 52 IS 6 BP 709 EP 709 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 423SI UT WOS:000264515600055 ER PT J AU Minniti, CP Burgos, A Gordeuk, V Speller-Brown, B AF Minniti, Caterina P. Burgos, Ana Gordeuk, Victor Speller-Brown, Barbara TI HYDROXYUREA IS EFFECTIVE IN PREVENTING REOCCURRENCE OF ACUTE CHEST SYNDROME IN CHILDREN WITH SICKLE CELL ANEMIA SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Minniti, Caterina P.] NHLBI, NIH, Bethesda, MD 20892 USA. [Burgos, Ana; Speller-Brown, Barbara] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Gordeuk, Victor] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 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 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2009 VL 52 IS 6 BP 724 EP 725 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 423SI UT WOS:000264515600106 ER PT J AU Meier, ER Byrnes, C Weissman, M Noel, P Luban, NLC Miller, JL AF Meier, Emily R. Byrnes, Colleen Weissman, Maxine Noel, Pierre Luban, Naomi L. C. Miller, Jeffery L. TI AGE-DEPENDENT EFFECTS OF CHRONIC TRANSFUSION UPON FETAL HEMOGLOBIN EXPRESSION IN CHILDREN WITH SICKLE CELL DISEASE SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Meier, Emily R.; Luban, Naomi L. C.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Byrnes, Colleen; Miller, Jeffery L.] NIDDK, Mol Med Branch, NIH, Bethesda, MD USA. [Weissman, Maxine; Noel, Pierre] NIH, Dept Lab Med, Hematol Serv, 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 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2009 VL 52 IS 6 BP 727 EP 727 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 423SI UT WOS:000264515600113 ER PT J AU Prodanov, T Havekes, B Nathanson, KL Adams, KT Pacak, K AF Prodanov, Tamara Havekes, Bas Nathanson, Katherine L. Adams, Karen T. Pacak, Karel TI Malignant paraganglioma associated with succinate dehydrogenase subunit B in an 8-year-old child: the age of first screening? SO PEDIATRIC NEPHROLOGY LA English DT Article DE Succinate dehydrogenase subunit B (SDHB) mutation; Paraganglioma; Genetic screening; Pheochromocytoma; Malignant ID PHEOCHROMOCYTOMA; MANAGEMENT; PHENOTYPES; DIAGNOSIS AB Several studies have shown that patients with succinate dehydrogenase subunit B (SDHB) mutations have a very high risk for developing malignant paragangliomas. However, there is no consensus of what age screening for paragangliomas should start. We report a case of an 8-year-old white girl with a 3-year history of catecholamine excess-related complaints who was diagnosed with a malignant SDHB-associated mediastinal paraganglioma. The patient presented with intermittent sweating, headache, nausea, vomiting, fatigue and weight loss that had been present since she was 5 years of age. A large posterior mediastinal mass measuring 6.4 cm x 3.1 cm x 4.6 cm was discovered on computed tomography (CT) and magnetic resonance imaging (MRI). Laboratory data included an elevated level of urine normetanephrine of 45,400 mu g/g creatinine (upper reference limit 718 mu g/g) and elevated level of plasma normetanephrine of 62.4 nmol/l (upper reference limit < 0.90 nmol/l). She was diagnosed with a thoracic paraganglioma and subsequently underwent surgical removal of the tumor and two lymph nodes. Histopathologic examination confirmed metastatic paraganglioma. Postoperatively, her blood pressure normalized and plasma normetanephrine levels remained normal. Our patient first presented with paraganglioma-associated signs and symptoms at the young age of 5 years. This case clearly illustrates the need for increased vigilance and screening for paragangliomas in families with SDHB at a younger age than previously thought. C1 [Pacak, Karel] NICHD, Sect Med Neuroendocrinol, Reprod & Adult Endocrinol Program, NIH,CRC, Bethesda, MD 20892 USA. [Prodanov, Tamara; Havekes, Bas; Adams, Karen T.; Pacak, Karel] NICHHD, Reprod & Adult Endocrinol Program, NIH, Bethesda, MD 20892 USA. [Havekes, Bas] Leiden Univ, Med Ctr, Dept Endocrinol & Metab, Leiden, Netherlands. [Nathanson, Katherine L.] Univ Penn, Sch Med, Dept Med, Div Med Genet, Philadelphia, PA 19104 USA. RP Pacak, K (reprint author), NICHD, Sect Med Neuroendocrinol, Reprod & Adult Endocrinol Program, NIH,CRC, Bldg 10,1-East,Room 1-3140,10 Ctr Dr,MSC-1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov OI Nathanson, Katherine/0000-0002-6740-0901 FU Intramural NIH HHS [Z01 HD008735-08] NR 19 TC 7 Z9 7 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUN PY 2009 VL 24 IS 6 BP 1239 EP 1242 DI 10.1007/s00467-008-1111-8 PG 4 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 466LS UT WOS:000267664300024 PM 19189136 ER PT J AU Spence, SJ Schneider, MT AF Spence, Sarah J. Schneider, Mark T. TI The Role of Epilepsy and Epileptiform EEGs in Autism Spectrum Disorders SO PEDIATRIC RESEARCH LA English DT Review ID PERVASIVE DEVELOPMENTAL DISORDER; RETT-SYNDROME; COGNITIVE IMPAIRMENT; TUBEROUS SCLEROSIS; LANGUAGE REGRESSION; ROLANDIC EPILEPSY; SEIZURE DISORDERS; CONVULSIVE DISORDER; MENTAL-RETARDATION; CLINICAL SEIZURES AB Autism is a neurodevelopmental disorder of unknown etiology characterized by social and communication deficits and the presence of restricted interests/repetitive behaviors. Higher rates of epilepsy have long been reported, but prevalence estimates vary from as little its 5% to as much as 46%. This variation is probably the result of sample characteristics that increase epilepsy risk such as sample ascertainment, lower intelligence quotient (IQ), the inclusion of patients with nonidiopathic autism, age, and gender. However, critical review of the literature reveals that the rate in idiopathic cases with normal IQ is still significantly above the population risk suggesting that autism itself is associated with an increased risk of epilepsy. Recently, there has been interest in the Occurrence of epileptiform electroencephalograms (EEGs) even in the absence of epilepsy. Rates as high as 60% have been reported and some investigators propose that these abnormalities may play a Causal role in the autism phenotype. Although this phenomenon is still not well understood and risk factors have yet to be determined, the treatment implications are increasingly important, We review the recent literature to elucidate possible risk factors for both epilepsy and epileptiform EEGs. We then review existing data and discuss controversies surrounding treatment of EEG abnormalities. (Pediatr Res 65: 599-606, 2009) C1 [Spence, Sarah J.; Schneider, Mark T.] NIMH, Pediat & Dev Neurosci Branch, NIH, Bethesda, MD 20892 USA. RP Spence, SJ (reprint author), 10 Ctr Dr,MSC 1255,Bldg 10,Rm 4N208, Bethesda, MD 20892 USA. EM spences2@mail.nih.gov FU NIMH [XFF 80100] FX Supported by the intramural research program of the NIMH, XFF 80100. NR 91 TC 130 Z9 132 U1 2 U2 19 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 W CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD JUN PY 2009 VL 65 IS 6 BP 599 EP 606 PG 8 WC Pediatrics SC Pediatrics GA 448OL UT WOS:000266271800002 PM 19454962 ER PT J AU Cohen, JI AF Cohen, Jeffrey I. TI Optimal treatment for chronic active Epstein-Barr virus disease SO PEDIATRIC TRANSPLANTATION LA English DT Editorial Material ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; CYTOTOXIC T-LYMPHOCYTES; UMBILICAL-CORD BLOOD; EBV INFECTION; LYMPHOPROLIFERATIVE DISEASE; VIROLOGICAL CHARACTERISTICS; PATIENT; INTERFERON; EXPRESSION C1 NIH, Med Virol Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Med Virol Sect, Lab Clin Infect Dis, Bldg 10, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU Intramural NIH HHS [ZIA AI000913-08] NR 38 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1397-3142 J9 PEDIATR TRANSPLANT JI Pediatr. Transplant. PD JUN PY 2009 VL 13 IS 4 BP 393 EP 396 DI 10.1111/j.1399-3046.2008.01095.x PG 4 WC Pediatrics; Transplantation SC Pediatrics; Transplantation GA 441NC UT WOS:000265774900002 PM 19032417 ER PT J AU Hingson, RW Zha, WX AF Hingson, Ralph W. Zha, Wenxing TI Age of Drinking Onset, Alcohol Use Disorders, Frequent Heavy Drinking, and Unintentionally Injuring Oneself and Others After Drinking SO PEDIATRICS LA English DT Article DE alcohol-related disorders; unintentional injury; injury prevention; prospective study ID UNDERAGE DRINKING; PREVENTIVE INTERVENTIONS; RELATIVE RISK; UNITED-STATES; FATAL CRASHES; DRIVER AGE; FOLLOW-UP; DEPENDENCE; IV; INVOLVEMENT AB OBJECTIVE. To explore whether early age of drinking onset is prospectively associated with respondents unintentionally injuring themselves and others when respondents were under the influence of alcohol, controlling for current alcohol dependence/abuse, frequency of consuming 5 drinks per occasion, and other demographic characteristics. METHODS. From 2001 to 2002, in-person interviews were conducted with a national multistage probability sample of 43 093 adults aged 18 years older. From 2004 to 2005, of 39 959 eligible respondents, 34 653 were reinterviewed. The cumulative 2-survey response rate was 70.2%. Respondents were asked the age at which they first started drinking (not counting tastes or sips), diagnostic questions for alcohol dependence and abuse, questions about behaviors that increase risk of injury, and whether respondents, when under the influence of alcohol, injured themselves or someone else as a driver in a motor vehicle crash or in some other way. RESULTS. Logistic regression analyses revealed that the younger respondents were when they started drinking, the greater the likelihood that, between the 2 surveys, they experienced alcohol dependence/abuse, drank 5 drinks per occasion at least weekly drove under the influence of alcohol, and placed themselves in situation after drinking where they could be hurt. After controlling for those injury risk and sociodemographic characteristics, respondents who began drinking at earlier ages remained more likely between the 2 surveys to have, under the influence of alcohol, unintentionally injured themselves and someone else. More than one third of those injuries occurred when respondents 25 years of age were under the influence, although only 7% of respondents were 25 years of age. Persons other than respondents experienced 20% of those unintentional injuries, more than one third of them in traffic. CONCLUSION. Delaying drinking onset may help reduce unintentional alcohol-related injuries that drinkers may inflict on themselves and others. Pediatrics 2009; 123: 1477-1484 C1 [Hingson, Ralph W.; Zha, Wenxing] NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD 20892 USA. RP Hingson, RW (reprint author), NIAAA, Div Epidemiol & Prevent Res, 5635 Fishers Lane,Room 2077, Bethesda, MD 20892 USA. EM rhingson@mail.nih.gov NR 50 TC 117 Z9 118 U1 7 U2 21 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 JUN PY 2009 VL 123 IS 6 BP 1477 EP 1484 DI 10.1542/peds.2008-2176 PG 8 WC Pediatrics SC Pediatrics GA 449GO UT WOS:000266319000006 PM 19482757 ER PT J AU Schoch, CL Wang, Z Townsend, JP Spatafora, JW AF Schoch, C. L. Wang, Z. Townsend, J. P. Spatafora, J. W. TI Geoglossomycetes cl. nov., Geoglossales ord. nov and taxa above class rank in the Ascomycota Tree of Life SO PERSOONIA LA English DT Article DE Bayesian inference; hybrid classification; maximum likelihood ID PHYLOGENETIC CLASSIFICATION; RDNA PHYLOGENY; FUNGAL TREE; EVOLUTION; PEZIZOMYCOTINA; GENUS; ULTRASTRUCTURE; SYSTEMATICS; MORPHOLOGY; SEQUENCES AB Featuring a high level of taxon sampling across Ascomycota, we evaluate a multi-gene phylogeny and propose a novel order and class in Ascomycota. We describe two new taxa, Geoglossomycetes and Geoglossales, to host three earth tongue genera: Geoglossum, Trichoglossum and Sarcoleotia as a lineage of 'Leotiomyceta'. Correspondingly, we confirm that these genera are not closely related to the genera Neolecta, Mitrula, Cudonia, Microglossum, Thuemenidum, Spathularia and Bryoglossum, all of which have been previously placed within the Geoglossaceae. We also propose a non-hierarchical system for naming well-resolved nodes, such as 'Saccharomyceta', 'Dothideomyceta', and 'Sordariomyceta' for supraordinal nodes, within the current phylogeny, acting as rankless taxa. As part of this revision, the continued use of 'Leotiomyceta', now as a rankless taxon, is proposed. C1 [Schoch, C. L.] NIH, Natl Ctr Biol Informat GenBank, Natl Lib Med, Bethesda, MD 20892 USA. [Wang, Z.; Townsend, J. P.] Yale Univ, Dept Ecol & Evolutionary Biol, New Haven, CT 06520 USA. [Spatafora, J. W.] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. RP Schoch, CL (reprint author), NIH, Natl Ctr Biol Informat GenBank, Natl Lib Med, 45 Ctr Dr,MSC 6510, Bethesda, MD 20892 USA. EM schoch2@ncbi.nlm.nih.gov RI Wang, Zheng/A-2318-2011 OI Wang, Zheng/0000-0002-8849-8549 FU NSF [DEB 0717476]; C.L.S.; Intramural Research program of the National Institutes of Health; Yale University Anonymous Postdoctoral Fellowship FX We are grateful to Kentaro Hosaka, Dan Luoma and Zhuliang Yang for the photographs used. We acknowledge funding provided by NSF through a grant (DEB 0717476) to J.W.S. and C.L.S. (while at Oregon State). C.L.S. was also supported in part by the Intramural Research program of the National Institutes of Health, Z.W. was supported by the Yale University Anonymous Postdoctoral Fellowship. NR 62 TC 26 Z9 27 U1 0 U2 10 PU RIJKSHERBARIUM PI LEIDEN PA PO BOX 9514, 2300 RA LEIDEN, NETHERLANDS SN 0031-5850 J9 PERSOONIA JI Persoonia PD JUN PY 2009 VL 22 BP 129 EP 138 DI 10.3767/003158509X461486 PG 10 WC Mycology SC Mycology GA 469JD UT WOS:000267892600013 PM 19915689 ER PT J AU Ye, RD Boulay, F Wang, JM Dahlgren, C Gerard, C Parmentier, M Serhan, CN Murphy, PM AF Ye, Richard D. Boulay, Francois Wang, Ji Ming Dahlgren, Claes Gerard, Craig Parmentier, Marc Serhan, Charles N. Murphy, Philip M. TI International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the Formyl Peptide Receptor (FPR) Family SO PHARMACOLOGICAL REVIEWS LA English DT Review ID SERUM-AMYLOID-A; PROTEIN-COUPLED RECEPTOR; N-FORMYLPEPTIDE RECEPTOR; METHIONYL-LEUCYL-PHENYLALANINE; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; ASPIRIN-TRIGGERED LIPOXIN; NEUTROPHIL NADPH-OXIDASE; BETA-ADRENERGIC-RECEPTOR; LOCALIZED JUVENILE PERIODONTITIS; C5A CHEMOATTRACTANT RECEPTORS AB Formyl peptide receptors (FPRs) are a small group of seven-transmembrane domain, G protein-coupled receptors that are expressed mainly by mammalian phagocytic leukocytes and are known to be important in host defense and inflammation. The three human FPRs (FPR1, FPR2/ALX, and FPR3) share significant sequence homology and are encoded by clustered genes. Collectively, these receptors bind an extraordinarily numerous and structurally diverse group of agonistic ligands, including N-formyl and nonformyl peptides of different composition, that chemoattract and activate phagocytes. N-formyl peptides, which are encoded in nature only by bacterial and mitochondrial genes and result from obligatory initiation of bacterial and mitochondrial protein synthesis with N-formylmethionine, is the only ligand class common to all three human receptors. Surprisingly, the endogenous anti-inflammatory peptide annexin 1 and its N-terminal fragments also bind human FPR1 and FPR2/ALX, and the anti-inflammatory eicosanoid lipoxin A4 is an agonist at FPR2/ALX. In comparison, fewer agonists have been identified for FPR3, the third member in this receptor family. Structural and functional studies of the FPRs have produced important information for understanding the general pharmacological principles governing all leukocyte chemoattractant receptors. This article aims to provide an overview of the discovery and pharmacological characterization of FPRs, to introduce an International Union of Basic and Clinical Pharmacology (IUPHAR)-recommended nomenclature, and to discuss unmet challenges, including the mechanisms used by these receptors to bind diverse ligands and mediate different biological functions. C1 [Ye, Richard D.] Univ Illinois, Dept Pharmacol, Coll Med, Chicago, IL 60612 USA. [Boulay, Francois] CEA, Inst Rech Technol & Sci Vivant, Lab Biochim & Biophys Syst Integres, Grenoble, France. [Boulay, Francois] CNRS, UMR 5092, Grenoble, France. [Boulay, Francois] Univ Grenoble 1, Grenoble, France. [Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Dahlgren, Claes] Univ Gothenburg, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden. [Gerard, Craig] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Gerard, Craig] Childrens Hosp, Boston, MA 02115 USA. [Parmentier, Marc] Univ Libre Bruxelles, Inst Rech Interdisciplinaire Biol Humaine & Mol, Brussels, Belgium. [Serhan, Charles N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Expt Therapeut & Reperfus Injury, Boston, MA 02115 USA. [Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Ye, RD (reprint author), Univ Illinois, Dept Pharmacol, Coll Med, 835 S Wolcott Ave,M-C 868, Chicago, IL 60612 USA. EM yer@uic.edu RI TEST-GU, TEST-GU/B-5469-2010; Ye, Richard/O-5223-2016; OI Ye, Richard/0000-0002-2164-5620; Parmentier, Marc/0000-0001-8081-4685 FU Intramural NIH HHS [Z01 AI000615-17, Z01 BC010725-02]; NIAID NIH HHS [AI033503, R01 AI033503, R56 AI033503]; NIGMS NIH HHS [GM066182, R01 GM066182] NR 401 TC 308 Z9 317 U1 2 U2 25 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD JUN PY 2009 VL 61 IS 2 BP 119 EP 161 DI 10.1124/pr.109.001578 PG 43 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 461QW UT WOS:000267285000002 PM 19498085 ER PT J AU Shi, J Liu, TT Wang, X Epstein, DH Zhao, LY Zhang, XL Lu, L AF Shi, Jie Liu, Ting-Ting Wang, Xi Epstein, David H. Zhao, Li-Yan Zhang, Xiao-Li Lu, Lin TI Tetrodotoxin reduces cue-induced drug craving and anxiety in abstinent heroin addicts SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Drug cues; Heroin dependence; Tetrodotoxin; Craving ID INDUCED RESPONSES; SEEKING BEHAVIOR; COCAINE-SEEKING; ANIMAL-MODEL; RATS; REINSTATEMENT; STRESS; USERS; PAIN; INACTIVATION AB Background: Tetrodotoxin (TTX) is a neurotoxin found in Puffer fish and other marine animals. New clinical studies Suggest that low-dose TTX can safely relieve severe, treatment-resistant cancer pain. The therapeutic potential of TTX in addiction is supported by studies in laboratory animals. The purpose of this double-blind, placebo-controlled study was to assess the effect of a single intramuscular dose of TTX on cue-induced craving and anxiety in abstinent heroin addicts. Methods: Forty-five abstinent heroin addicts were randomly assigned to three treatment groups: placebo, 5 mu g TTX, or 10 mu g TTX. Participants were exposed to a neutral video or a heroin-related video. Craving. anxiety, blood pressure, and heart rate were measured pre- and post-exposure. Results: Heroin-related cues increased both craving and anxiety and had no effect on blood pressure and heart rate. A single dose of TTX dose-dependently attenuated the increases in craving and anxiety while having no effect on blood pressure or heart rate. Conclusion: The results suggest that low-dose TTX is acutely effective in reducing cue-induced increases in heroin craving and associated anxiety. (c) 2009 Elsevier Inc. All rights reserved. C1 [Shi, Jie; Liu, Ting-Ting; Wang, Xi; Zhao, Li-Yan; Zhang, Xiao-Li; Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Beijing 100083, Peoples R China. [Epstein, David H.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Lu, L (reprint author), Peking Univ, Natl Inst Drug Dependence, 38 Xue Yuan Rd, Beijing 100083, Peoples R China. EM linlu@bjmu.edu.cn FU National Basic Research Program of China [2007CB512302]; National High Technology Research and Development Program of China [2006AA02Z4D1]; China-Canada joint Health Research Program [30611120528] FX This work was supported in part by the National Basic Research Program of China (973 Program, 2007CB512302), the National High Technology Research and Development Program of China (863 Program, 2006AA02Z4D1), and the China-Canada joint Health Research Program (No: 30611120528). The authors declare that they do not have any conflicts of interest (financial or otherwise) related to the data presented in this manuscript. NR 28 TC 13 Z9 14 U1 3 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD JUN PY 2009 VL 92 IS 4 BP 603 EP 607 DI 10.1016/j.pbb.2009.02.013 PG 5 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 452KL UT WOS:000266538800007 PM 19268686 ER PT J AU Koonin, EV AF Koonin, E. V. TI The diverse routes of plant virus evolution SO PHYTOPATHOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Phytopathology-Society CY AUG 01-05, 2009 CL Portland, OR SP Amer Phytopathol Soc C1 [Koonin, E. V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0031-949X J9 PHYTOPATHOLOGY JI Phytopathology PD JUN PY 2009 VL 99 IS 6 BP S165 EP S165 PG 1 WC Plant Sciences SC Plant Sciences GA 447SY UT WOS:000266213300975 ER PT J AU Day, CP Carter, J Bonomi, C Esposito, D Crise, B Ortiz-Conde, B Hollingshead, M Merlino, G AF Day, Chi-Ping Carter, John Bonomi, Carrie Esposito, Dominic Crise, Bruce Ortiz-Conde, Betty Hollingshead, Melinda Merlino, Glenn TI Lentivirus-mediated bifunctional cell labeling for in vivo melanoma study SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE Bioluminescence; cell labeling; fluorescence-activated cell sorter; green fluorescence protein; lentiviral vectors; luciferase; syngeneic mouse model ID GREEN FLUORESCENT PROTEIN; QUANTITATIVE-EVALUATION; IMMUNE-RESPONSE; GENE-THERAPY; VECTORS; EXPRESSION; TRANSDUCTION; TUMOR; PROMOTERS; CANCER AB Lentiviral vectors (LVs) are capable of labeling a broad spectrum of cell types, achieving stable expression of transgenes. However, for in vivo studies, the duration of marker gene expression has been highly variable. We have developed a series of LVs harboring different promoters for expressing reporter gene in mouse cells. Long-term culture and colony formation of several LV-labeled mouse melanoma cells showed that promoters derived from mammalian house-keeping genes, especially those encoding RNA polymerase II (Pol2) and ferritin (FerH), provided the highest consistency for reporter expression. For in vivo studies, primary B16BL6 mouse melanoma were infected with LVs whose luciferase-green fluorescence protein fusion gene (Luc/GFP) was driven by either Pol2 or FerH promoters. When transplanted into syngeneic C57BL/6 mice, Luc/GFP-labeled B16BL6 mouse melanoma cells can be monitored by bioluminescence imaging in vivo, and GFP-positive cells can be isolated from the tumors by fluorescence-activated cell sorter. Pol2-Luc/GFP labeling, while lower in activity, was more sustainable than FerH-Luc/GFP labeling in B16BL6 over consecutive passages into mice. We conclude that Pol-2-Luc/GFP labeling allows long-term in vivo monitoring and tumor cell isolation in immunocompetent mouse melanoma models. C1 [Day, Chi-Ping; Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Carter, John; Bonomi, Carrie] NCI, Dev Therapeut Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Esposito, Dominic] NCI, Prot Express Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Crise, Bruce] NCI, Adv Technol Partnership Initiat, SAIC Frederick Inc, Frederick, MD 21701 USA. [Ortiz-Conde, Betty] NCI, Viral Technol Lab, Prot Express Lab, Adv Technol Program,SAIC Frederick Inc, Frederick, MD 21701 USA. [Hollingshead, Melinda] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. RP Merlino, G (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM gmerlino@helix.nih.gov FU Intramural Research Program of the Center for Cancer Research; National Cancer Institute (NCI), National Institutes of Health (NIH) [NO1-CO-12400]; NCI Director's Innovation Award; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis, NCI FX This research was supported by the Intramural Research Program of the Center for Cancer Research, the National Cancer Institute (NCI), National Institutes of Health (NIH), and 2007 NCI Director's Innovation Award (to C.-P. D.). This project has been funded in part with federal funds from NCI, NIH, under Contract No. NO1-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. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis, NCI. We thank Dr. Tyler Jacks (Whitehead Institute, MIT) for the generous gift of the pSico vector, Dr. Steve Hughes (National Cancer Institute, NIH) for the Pol2 promoter vector, Dr. Paul Khavari (Stanford University School of Medicine) for kindly providing the retrovirus with constitutively active N-Ras gene, and Drs. Dot Bennett and Elena Sviderskaya for the p19Arf-null mouse melanocytes. The p19NR-Mel cells were generated by Dr. Linan Ha in this laboratory. We thank Mr. Eleazar Vega-Valle for establishing the HGF-Mel cell line from melanoma derived from our HGF-transgenic mice. NR 33 TC 26 Z9 26 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 JUN PY 2009 VL 22 IS 3 BP 283 EP 295 DI 10.1111/j.1755-148X.2009.00545.x PG 13 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 444LN UT WOS:000265982600010 PM 19175523 ER PT J AU Hornyak, TJ Jiang, SL Guzman, EA Scissors, BN Tuchinda, C He, HB Neville, JD Strickland, FM AF Hornyak, Thomas J. Jiang, Shunlin Guzman, Esther A. Scissors, Beth N. Tuchinda, Chinisada He, Hongbin Neville, James D. Strickland, Faith M. TI Mitf dosage as a primary determinant of melanocyte survival after ultraviolet irradiation SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE apoptosis; melanocyte; melanoma; Mitf; ultraviolet; Fas; mice ID CULTURED HUMAN MELANOCYTES; CELL-CYCLE PROGRESSION; TRANSCRIPTION FACTOR; DOPACHROME-TAUTOMERASE; INDUCED APOPTOSIS; DNA-DAMAGE; SIGNAL-TRANSDUCTION; MALIGNANT-MELANOMA; LINEAGE SURVIVAL; GENE-EXPRESSION AB Microphthalmia-associated transcription factor (Mitf) is essential for melanocyte development and function and regulates anti-apoptotic Bcl2 expression. We hypothesized that cellular deficiency of Mitf can influence melanocyte survival in response to ultraviolet (UV) radiation. Primary melanocyte cultures were prepared from neonatal wild-type mice and congenic animals heterozygous for Mitf mutations Mitf (mi-vga9/+) and Mitf(Mi-wh/+) and exposed to UV irradiation. Wild-type melanocytes were more resistant to UV-induced apoptosis than melanocytes partially deficient in Mitf activity, as determined by relative levels of intracellular melanin and relative activation of Mitf target genes Tyr, Tyrp1, Dct, and Cdk2. Comparative experiments with wild-type cells and congenic albino melanocytes demonstrated that these differences are not due to differences in melanin content, implicating Mitf as a primary determinant of UV-dependent melanocyte survival. Mitf activity correlated directly with resistance to UV-induced apoptosis in melanocytes. Mitf was important not only for regulating the expression of anti-apoptotic Bcl-2 following UV irradiation, but also the expression of the pro-apoptotic BH3-only Bad protein and activation of the extrinsic apoptotic pathway. Hence, Mitf is a multifaceted regulator of UV-induced apoptosis in melanocytes. C1 [Hornyak, Thomas J.; Jiang, Shunlin] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Guzman, Esther A.; Scissors, Beth N.; Tuchinda, Chinisada; He, Hongbin; Neville, James D.; Strickland, Faith M.] Henry Ford Hlth Syst, Dept Dermatol, Detroit, MI USA. RP Strickland, FM (reprint author), Univ Michigan, Dept Internal Med, Rheumatol Sect, Ann Arbor, MI 48109 USA. EM fmstrick@umich.edu RI Guzman, Esther/C-9049-2013 FU National Institutes [R01-AR47951]; Department of Defense [DAMD17-01-1-1709]; NIH [K08 AR01992]; Intramural research program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Alice Croxen and Payal Shah for excellent technical assistance. We also thank Kenneth N. Barton for assistance in image analyses. We are grateful to Ronald P. Pelley for critical reading of this manuscript and Dr. Colin Goding for advice and assistance with the manuscript. We also thank Dr. Edward DeFabo for use and calibration of an ultraviolet light box. This work was supported by grants R01-AR47951 (FMS) from the National Institutes, DAMD17-01-1-1709 (FMS) from the Department of Defense, NIH K08 AR01992 (to TJH) and (in part) by the Intramural research program of the NIH, National Cancer Institute, Center for Cancer Research. NR 62 TC 18 Z9 18 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 JUN PY 2009 VL 22 IS 3 BP 307 EP 318 DI 10.1111/j.1755-148X.2009.00551.x PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 444LN UT WOS:000265982600012 PM 19192212 ER PT J AU Beltrao, P Trinidad, JC Fiedler, D Roguev, A Lim, WA Shokat, KM Burlingame, AL Krogan, NJ AF Beltrao, Pedro Trinidad, Jonathan C. Fiedler, Dorothea Roguev, Assen Lim, Wendell A. Shokat, Kevan M. Burlingame, Alma L. Krogan, Nevan J. TI Evolution of Phosphoregulation: Comparison of Phosphorylation Patterns across Yeast Species SO PLOS BIOLOGY LA English DT Article ID CYCLIN-DEPENDENT KINASE; SACCHAROMYCES-CEREVISIAE; GENETIC INTERACTION; FISSION YEAST; IN-VIVO; PROTEIN COMPLEXES; SCHIZOSACCHAROMYCES-POMBE; PHOSPHOPROTEOME ANALYSIS; SYSTEMATIC DISCOVERY; INTERACTION NETWORK AB The extent by which different cellular components generate phenotypic diversity is an ongoing debate in evolutionary biology that is yet to be addressed by quantitative comparative studies. We conducted an in vivo mass-spectrometry study of the phosphoproteomes of three yeast species (Saccharomyces cerevisiae, Candida albicans, and Schizosaccharomyces pombe) in order to quantify the evolutionary rate of change of phosphorylation. We estimate that kinase-substrate interactions change, at most, two orders of magnitude more slowly than transcription factor (TF)-promoter interactions. Our computational analysis linking kinases to putative substrates recapitulates known phosphoregulation events and provides putative evolutionary histories for the kinase regulation of protein complexes across 11 yeast species. To validate these trends, we used the E-MAP approach to analyze over 2,000 quantitative genetic interactions in S. cerevisiae and Sc. pombe, which demonstrated that protein kinases, and to a greater extent TFs, show lower than average conservation of genetic interactions. We propose therefore that protein kinases are an important source of phenotypic diversity. C1 [Beltrao, Pedro; Fiedler, Dorothea; Roguev, Assen; Lim, Wendell A.; Shokat, Kevan M.; Krogan, Nevan J.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Beltrao, Pedro; Roguev, Assen; Krogan, Nevan J.] Univ Calif San Francisco, Calif Inst Quantitat Biosci, San Francisco, CA 94143 USA. [Trinidad, Jonathan C.; Burlingame, Alma L.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. [Fiedler, Dorothea; Lim, Wendell A.; Shokat, Kevan M.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Lim, Wendell A.] Univ Calif San Francisco, Cell Prop Lab, NIH, Nanomed Dev Ctr, San Francisco, CA 94143 USA. RP Beltrao, P (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. EM pedro.beltrao@ucsf.edu; krogan@cmpmail.ucsf.edu RI Beltrao, Pedro/B-3342-2010; OI Beltrao, Pedro/0000-0002-2724-7703 FU Sandler Family Foundation; National Institutes of Health; Fundacao para Ciencia e Tecnologia [(SFRH/BDP/41583/2007)] FX This work was supported by the Sandler Family Foundation and the National Institutes of Health. PB was supported by a fellowship from the Fundacao para Ciencia e Tecnologia (SFRH/BDP/41583/2007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 121 Z9 134 U1 3 U2 15 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 JUN PY 2009 VL 7 IS 6 AR e1000134 DI 10.1371/journal.pbio.1000134 PG 12 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 475XC UT WOS:000268398600011 PM 19547744 ER PT J AU Chakicherla, A Zhou, CLE Dang, ML Rodriguez, V Hansen, JN Zemla, A AF Chakicherla, Anu Zhou, Carol L. Ecale Dang, Martha Ligon Rodriguez, Virginia Hansen, J. Norman Zemla, Adam TI SpaK/SpaR Two-component System Characterized by a Structure-driven Domain-fusion Method and in Vitro Phosphorylation Studies SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; BACTERIAL RESPONSE REGULATORS; SIGNAL-TRANSDUCTION SYSTEMS; BACILLUS-SUBTILIS; HISTIDINE-KINASE; COMPUTATIONAL METHODS; CRYSTAL-STRUCTURE; 3D STRUCTURES; PREDICTION; COMPLEXES AB Here we introduce a quantitative structure-driven computational domain-fusion method, which we used to predict the structures of proteins believed to be involved in regulation of the subtilin pathway in Bacillus subtilis, and used to predict a protein-protein complex formed by interaction between the proteins. Homology modeling of SpaK and SpaR yielded preliminary structural models based on a best template for SpaK comprising a dimer of a histidine kinase, and for SpaR a response regulator protein. Our LGA code was used to identify multi-domain proteins with structure homology to both modeled structures, yielding a set of domain-fusion templates then used to model a hypothetical SpaK/SpaR complex. The models were used to identify putative functional residues and residues at the protein-protein interface, and bioinformatics was used to compare functionally and structurally relevant residues in corresponding positions among proteins with structural homology to the templates. Models of the complex were evaluated in light of known properties of the functional residues within two-component systems involving His-Asp phosphorelays. Based on this analysis, a phosphotransferase complexed with a beryllofluoride was selected as the optimal template for modeling a SpaK/SpaR complex conformation. In vitro phosphorylation studies performed using wild type and site-directed SpaK mutant proteins validated the predictions derived from application of the structure-driven domain-fusion method: SpaK was phosphorylated in the presence of (32)P-ATP and the phosphate moiety was subsequently transferred to SpaR, supporting the hypothesis that SpaK and SpaR function as sensor and response regulator, respectively, in a two-component signal transduction system, and furthermore suggesting that the structure-driven domain-fusion approach correctly predicted a physical interaction between SpaK and SpaR. Our domain-fusion algorithm leverages quantitative structure information and provides a tool for generation of hypotheses regarding protein function, which can then be tested using empirical methods. C1 [Chakicherla, Anu; Zhou, Carol L. Ecale; Zemla, Adam] Lawrence Livermore Natl Lab, Comp Applicat & Res Dept, Livermore, CA USA. [Dang, Martha Ligon] Sacred Hearts Acad, Honolulu, HI USA. [Rodriguez, Virginia] Natl Inst Hlth, Natl Human Genome Res Inst, Genome Technol Branch, Bethesda, MD USA. [Hansen, J. Norman] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. RP Chakicherla, A (reprint author), Lawrence Livermore Natl Lab, Comp Applicat & Res Dept, Livermore, CA USA. EM zhou4@llnl.gov FU LLNL-LLNS; National Institute of Allergy and Infectious Diseases [R01-AI24454-12]; NIH; [DE-AC52-07NA27344] FX Prepared by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. The bioinformatics work was supported by an LLNL-LLNS internally funded grant to CZ and AZ through the Laboratory Directed Research and Development program, and the experimental work was supported by grant R01-AI24454-12 to NH from the National Institute of Allergy and Infectious Diseases, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 2 Z9 2 U1 0 U2 5 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 JUN PY 2009 VL 5 IS 6 AR e1000401 DI 10.1371/journal.pcbi.1000401 PG 12 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 476JK UT WOS:000268436100009 PM 19503843 ER PT J AU Bucan, M Abrahams, BS Wang, K Glessner, JT Herman, EI Sonnenblick, LI Retuerto, AIA Imielinski, M Hadley, D Bradfield, JP Kim, C Gidaya, NB Lindquist, I Hutman, T Sigman, M Kustanovich, V Lajonchere, CM Singleton, A Kim, J Wassink, TH McMahon, WM Owley, T Sweeney, JA Coon, H Nurnberger, JI Li, MY Cantor, RM Minshew, NJ Sutcliffe, JS Cook, EH Dawson, G Buxbaum, JD Grant, SFA Schellenberg, GD Geschwind, DH Hakonarson, H AF Bucan, Maja Abrahams, Brett S. Wang, Kai Glessner, Joseph T. Herman, Edward I. Sonnenblick, Lisa I. Retuerto, Ana I. Alvarez Imielinski, Marcin Hadley, Dexter Bradfield, Jonathan P. Kim, Cecilia Gidaya, Nicole B. Lindquist, Ingrid Hutman, Ted Sigman, Marian Kustanovich, Vlad Lajonchere, Clara M. Singleton, Andrew Kim, Junhyong Wassink, Thomas H. McMahon, William M. Owley, Thomas Sweeney, John A. Coon, Hilary Nurnberger, John I., Jr. Li, Mingyao Cantor, Rita M. Minshew, Nancy J. Sutcliffe, James S. Cook, Edwin H. Dawson, Geraldine Buxbaum, Joseph D. Grant, Struan F. A. Schellenberg, Gerard D. Geschwind, Daniel H. Hakonarson, Hakon TI Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes SO PLOS GENETICS LA English DT Article ID STRUCTURAL VARIANTS; SPECTRUM DISORDERS; CHROMOSOMAL REARRANGEMENTS; MENTAL-RETARDATION; HIGH-FREQUENCY; SCHIZOPHRENIA; DISRUPTION; PHENOTYPES; MUTATIONS; LINKAGE AB The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3610 239), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts. C1 [Bucan, Maja; Kustanovich, Vlad; Lajonchere, Clara M.; Cantor, Rita M.; Geschwind, Daniel H.] Autism Speaks, Autism Genet Resource Exchange, Los Angeles, CA USA. [Bucan, Maja; Wang, Kai; Hadley, Dexter; Gidaya, Nicole B.; Lindquist, Ingrid] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Bucan, Maja; Kim, Junhyong] Univ Penn, Penn Ctr Bioinformat, Philadelphia, PA 19104 USA. [Abrahams, Brett S.; Herman, Edward I.; Sonnenblick, Lisa I.; Geschwind, Daniel H.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Wang, Kai; Glessner, Joseph T.; Imielinski, Marcin; Bradfield, Jonathan P.; Kim, Cecilia; Grant, Struan F. A.; Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Retuerto, Ana I. Alvarez; Geschwind, Daniel H.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Retuerto, Ana I. Alvarez; Hutman, Ted; Sigman, Marian; Geschwind, Daniel H.] Univ Calif Los Angeles, Ctr Autism Res, Semel Inst Neurosci & Behav, Los Angeles, CA USA. [Hadley, Dexter; Kim, Junhyong] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Lajonchere, Clara M.] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Singleton, Andrew] NIA, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Wassink, Thomas H.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [McMahon, William M.; Coon, Hilary] Univ Utah, Dept Psychiat, Salt Lake City, UT USA. [Owley, Thomas; Sweeney, John A.; Cook, Edwin H.] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA. [Nurnberger, John I., Jr.] Indiana Univ, Dept Psychiat, Indianapolis, IN 46204 USA. [Li, Mingyao] Univ Penn, Dept Biostat, Philadelphia, PA 19104 USA. [Cantor, Rita M.; Geschwind, Daniel H.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. [Minshew, Nancy J.] Univ Pittsburgh, Dept Psychiat & Neurol, Pittsburgh, PA USA. [Sutcliffe, James S.] Vanderbilt Univ, Ctr Mol Neurosci, Nashville, TN USA. [Sutcliffe, James S.] Vanderbilt Univ, Vanderbilt Kennedy Ctr, Nashville, TN USA. [Dawson, Geraldine] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Seaver Autism Ctr Res & Treatment, Dept Psychiat, New York, NY USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Seaver Autism Ctr Res & Treatment, Dept Neurosci, New York, NY USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Seaver Autism Ctr Res & Treatment, Dept Genet, New York, NY USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Seaver Autism Ctr Res & Treatment, Dept Genom Sci, New York, NY USA. [Grant, Struan F. A.; Hakonarson, Hakon] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA. [Schellenberg, Gerard D.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Bucan, M (reprint author), Autism Speaks, Autism Genet Resource Exchange, Los Angeles, CA USA. EM bucan@pobox.upenn.edu; hakonarson@chop.edu RI Singleton, Andrew/C-3010-2009; Sutcliffe, James/C-1348-2012; OI Sutcliffe, James/0000-0001-5200-6007; Coon, Hilary/0000-0002-8877-5446; Nurnberger, John/0000-0002-7674-1767; Buxbaum, Joseph/0000-0001-8898-8313 FU National Institute of Mental Health [1U24MH081810]; Penn/CHOP Center for Autism Research; NIH [R01MH604687]; NARSAD Distinguished Investigator Award; Pennsylvania Commonwealth HRFF [P20-GM69012]; Intramural Research Program of the National Institute on Aging [1 Z01 AG000949-02]; Tourette Syndrome Association; Autism Center of Excellence Award [P50HD055784-01]; Autism Center of Excellence Genetics Network [MH081754]; Margaret Q. Landenberger Foundation; Cotswold Foundation [UL1-RR024134-03]; Institutional Development Award FX The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). This work is supported by a seed grant from Penn/CHOP Center for Autism Research, by NIH grant R01MH604687, and a NARSAD Distinguished Investigator Award (MB); by Pennsylvania Commonwealth HRFF and P20-GM69012 (JK); by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services (1 Z01 AG000949-02 to AS); by a fellowship from the Tourette Syndrome Association (BSA); by an Autism Center of Excellence Award (P50HD055784-01 to MS, DHG, co-PI); by an Autism Center of Excellence Genetics Network grant (MH081754 to DHG); by a Research Award from the Margaret Q. Landenberger Foundation (HH); by a Research Development Award from the Cotswold Foundation (HH and SFAG); and by UL1-RR024134-03 (HH). The genotyping and other aspects of the study were funded by an Institutional Development Award to the Center for Applied Genomics (HH) from the Children's Hospital of Philadelphia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 201 Z9 207 U1 4 U2 25 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2009 VL 5 IS 6 AR e1000536 DI 10.1371/journal.pgen.1000536 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 476MA UT WOS:000268444600011 PM 19557195 ER PT J AU Drake, JW AF Drake, John W. TI Avoiding Dangerous Missense: Thermophiles Display Especially Low Mutation Rates SO PLOS GENETICS LA English DT Article ID DNA-POLYMERASE; SACCHAROMYCES-CEREVISIAE; ESCHERICHIA-COLI; SUBSTITUTION; SELECTION; FIDELITY; REPAIR; REPLICATION; SPECIFICITY AB Rates of spontaneous mutation have been estimated under optimal growth conditions for a variety of DNA-based microbes, including viruses, bacteria, and eukaryotes. When expressed as genomic mutation rates, most of the values were in the vicinity of 0.003-0.004 with a range of less than two-fold. Because the genome sizes varied by roughly 10(4)-fold, the mutation rates per average base pair varied inversely by a similar factor. Even though the commonality of the observed genomic rates remains unexplained, it implies that mutation rates in unstressed microbes reach values that can be finely tuned by evolution. An insight originating in the 1920s and maturing in the 1960s proposed that the genomic mutation rate would reflect a balance between the deleterious effect of the average mutation and the cost of further reducing the mutation rate. If this view is correct, then increasing the deleterious impact of the average mutation should be countered by reducing the genomic mutation rate. It is a common observation that many neutral or nearly neutral mutations become strongly deleterious at higher temperatures, in which case they are called temperature-sensitive mutations. Recently, the kinds and rates of spontaneous mutations were described for two microbial thermophiles, a bacterium and an archaeon. Using an updated method to extrapolate from mutation-reporter genes to whole genomes reveals that the rate of base substitutions is substantially lower in these two thermophiles than in mesophiles. This result provides the first experimental support for the concept of an evolved balance between the total genomic impact of mutations and the cost of further reducing the basal mutation rate. C1 Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC USA. RP Drake, JW (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC USA. EM drake@niehs.nih.gov FU Intramural Research Program of the NIH [Z01 ES65016]; National Institute of Environmental Health Sciences FX This research was supported by funds allocated to project number Z01 ES65016 of the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 45 Z9 45 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2009 VL 5 IS 6 AR e1000520 DI 10.1371/journal.pgen.1000520 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 476MA UT WOS:000268444600017 PM 19543367 ER PT J AU Heard-Costa, NL Zillikens, MC Monda, KL Johansson, A Harris, TB Fu, M Haritunians, T Feitosa, MF Aspelund, T Eiriksdottir, G Garcia, M Launer, LJ Smith, AV Mitchell, BD McArdle, PF Shuldiner, AR Bielinski, SJ Boerwinkle, E Brancati, F Demerath, EW Pankow, JS Arnold, AM Chen, YDI Glazer, NL McKnight, B Psaty, BM Rotter, JI Amin, N Campbell, H Gyllensten, U Pattaro, C Pramstaller, PP Rudan, I Struchalin, M Vitart, V Gao, XY Kraja, A Province, MA Zhang, QY Atwood, LD Dupuis, J Hirschhorn, JN Jaquish, CE O'Donnell, CJ Vasan, RS White, CC Aulchenko, YS Estrada, K Hofman, A Rivadeneira, F Uitterlinden, AG Witteman, JCM Oostra, BA Kaplan, RC Gudnason, V O'Connell, JR Borecki, IB van Duijn, CM Cupples, LA Fox, CS North, KE AF Heard-Costa, Nancy L. Zillikens, M. Carola Monda, Keri L. Johansson, Asa Harris, Tamara B. Fu, Mao Haritunians, Talin Feitosa, Mary F. Aspelund, Thor Eiriksdottir, Gudny Garcia, Melissa Launer, Lenore J. Smith, Albert V. Mitchell, Braxton D. McArdle, Patrick F. Shuldiner, Alan R. Bielinski, Suzette J. Boerwinkle, Eric Brancati, Fred Demerath, Ellen W. Pankow, James S. Arnold, Alice M. Chen, Yii-Der Ida Glazer, Nicole L. McKnight, Barbara Psaty, Bruce M. Rotter, Jerome I. Amin, Najaf Campbell, Harry Gyllensten, Ulf Pattaro, Cristian Pramstaller, Peter P. Rudan, Igor Struchalin, Maksim Vitart, Veronique Gao, Xiaoyi Kraja, Aldi Province, Michael A. Zhang, Qunyuan Atwood, Larry D. Dupuis, Josee Hirschhorn, Joel N. Jaquish, Cashell E. O'Donnell, Christopher J. Vasan, Ramachandran S. White, Charles C. Aulchenko, Yurii S. Estrada, Karol Hofman, Albert Rivadeneira, Fernando Uitterlinden, Andre G. Witteman, Jacqueline C. M. Oostra, Ben A. Kaplan, Robert C. Gudnason, Vilmundur O'Connell, Jeffrey R. Borecki, Ingrid B. van Duijn, Cornelia M. Cupples, L. Adrienne Fox, Caroline S. North, Kari E. TI NRXN3 Is a Novel Locus for Waist Circumference: A Genome-Wide Association Study from the CHARGE Consortium SO PLOS GENETICS LA English DT Article ID BODY-FAT DISTRIBUTION; DEPENDENT DIABETES-MELLITUS; FTO GENE; ADULT OBESITY; MASS INDEX; EXPRESSION; LINKAGE; VARIANT; MC4R; RISK AB Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity. C1 [Heard-Costa, Nancy L.; Atwood, Larry D.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Zillikens, M. Carola; Estrada, Karol; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Monda, Keri L.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Johansson, Asa; Gyllensten, Ulf] Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden. [Harris, Tamara B.; Garcia, Melissa; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Fu, Mao; Mitchell, Braxton D.; McArdle, Patrick F.; Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Haritunians, Talin; Chen, Yii-Der Ida; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Feitosa, Mary F.; Gao, Xiaoyi; Kraja, Aldi; Province, Michael A.; Zhang, Qunyuan; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Aspelund, Thor; Eiriksdottir, Gudny; Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Heart Prevent Clin, Kopavogur, Iceland. [Aspelund, Thor; Eiriksdottir, Gudny; Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Res Inst, Kopavogur, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Bielinski, Suzette J.] Mayo Clin, Div Epidemiol, Rochester, MN USA. [Boerwinkle, Eric] Univ Texas Houston, Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Houston, Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. [Brancati, Fred] Johns Hopkins Univ, Dept Med & Epidemiol, Baltimore, MD USA. [Demerath, Ellen W.; Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Arnold, Alice M.; McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Glazer, Nicole L.] Univ Washington, Dept Internal Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol Med & Hlth Serv, Seattle, WA 98195 USA. [Amin, Najaf; Struchalin, Maksim; Aulchenko, Yurii S.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.; van Duijn, Cornelia M.] Erasmus Univ, Dept Epidemiol & Biostat, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Campbell, Harry; Rudan, Igor] Univ Edinburgh, Sch Med, Dept Publ Hlth Sci, Edinburgh, Midlothian, Scotland. [Pattaro, Cristian; Pramstaller, Peter P.] European Acad Bozen Bolzano, Inst Med Genet, Bolzano, Italy. [Pramstaller, Peter P.] Univ Lubeck, Dept Neurol, Lubeck, Germany. [Pramstaller, Peter P.] Cent Reg Hosp, Dept Neurol, Bolzano, Italy. [Rudan, Igor] Univ Split, Sch Med, Croatian Ctr Global Hlth, Split, Croatia. [Rudan, Igor] Univ Hosp Sestre Milosrdnice, Inst Clin Med Res, Zagreb, Croatia. [Vitart, Veronique] Inst Genet & Mol Med, Human Genet Unit, Edinburgh, Midlothian, Scotland. [Dupuis, Josee; White, Charles C.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Program Genom, Boston, MA USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Div Endocrinol, Boston, MA USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Div Genet, Boston, MA USA. [Jaquish, Cashell E.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Framingham Heart Study, Framingham, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Oostra, Ben A.] Erasmus Univ, Dept Clin Genet, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA USA. RP Heard-Costa, NL (reprint author), Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. EM foxca@nhlbi.nih.gov; knorth@email.unc.edu RI Aulchenko, Yurii/M-8270-2013; Pramstaller, Peter/C-2357-2008; Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015; Bielinski, Suzette/A-2238-2009; Smith, Albert/K-5150-2015; Feitosa, Mary/K-8044-2012; Kaplan, Robert/A-2526-2011; Aspelund, Thor/F-4826-2011; Rudan, Igor/I-1467-2012; Johansson, Asa/G-5270-2011; Aspelund, Thor/C-5983-2008; OI Aulchenko, Yurii/0000-0002-7899-1575; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Bielinski, Suzette/0000-0002-2905-5430; Smith, Albert/0000-0003-1942-5845; Feitosa, Mary/0000-0002-0933-2410; Rudan, Igor/0000-0001-6993-6884; Johansson, Asa/0000-0002-2915-4498; Aspelund, Thor/0000-0002-7998-5433; Heard-Costa, Nancy/0000-0001-9730-0306; Cupples, L. Adrienne/0000-0003-0273-7965; Ramachandran, Vasan/0000-0001-7357-5970; Dupuis, Josee/0000-0003-2871-3603; Mitchell, Braxton/0000-0003-4920-4744 FU NCRR NIH HHS [M01 RR 16500, M01 RR000425, M01 RR016500, M01-RR00425, UL1 RR 025005, UL1 RR025005]; NHGRI NIH HHS [U01 HG004402, U01HG004402]; NHLBI NIH HHS [N01-HC-55020, N01 HC-55222, N01 HC015103, N01 HC035129, N01 HC045133, N01-HC-15103, N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55021, N01-HC-55022, N01-HC-75150, N01-HC-85079, N01-HC-85086, N01HC25195, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC55222, N01HC75150, N01HC85079, N01HC85086, N02-HL-6-4278, R01 HL059367, R01 HL086694, R01 HL087641, R01 HL087652, R01 HL088119, R01HL086694, R01HL087641, R01HL08770003, R01HL59367, U01 HL072515, U01 HL080295, U01 HL084756, U01 HL72515, U01 HL84756]; NIA NIH HHS [N01AG12100, R01 AG018728, R01 AG18728]; NIAMS NIH HHS [R01 AR046838]; NIDDK NIH HHS [DK063491, P30 DK063491, P30 DK063491-019004, P30 DK063491-029004, P30 DK063491-039004, P30 DK063491-049004, P30 DK063491-05, P30 DK072488, P30 DK079637, R01DK06833603, R01DK07568101]; PHS HHS [HSN268200625226C] NR 32 TC 148 Z9 154 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2009 VL 5 IS 6 AR e1000539 DI 10.1371/journal.pgen.1000539 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 476MA UT WOS:000268444600014 PM 19557197 ER PT J AU Kallin, EM Cao, R Jothi, R Xia, K Cui, KR Zhao, KJ Zhang, Y AF Kallin, Eric M. Cao, Ru Jothi, Raja Xia, Kai Cui, Kairong Zhao, Keji Zhang, Yi TI Genome-Wide uH2A Localization Analysis Highlights Bmi1-Dependent Deposition of the Mark at Repressed Genes SO PLOS GENETICS LA English DT Article ID EMBRYONIC STEM-CELLS; HISTONE H2A UBIQUITINATION; POLYCOMB GROUP PROTEINS; DNA METHYLATION; DEVELOPMENTAL REGULATORS; BINDING-SITES; COMPLEXES; H3; UBIQUITYLATION; CHROMATIN AB Polycomb group (PcG) proteins control organism development by regulating the expression of developmental genes. Transcriptional regulation by PcG proteins is achieved, at least partly, through the PRC2-mediated methylation on lysine 27 of histone H3 (H3K27) and PRC1-mediated ubiquitylation on lysine 119 of histone H2A (uH2A). As an integral component of PRC1, Bmi1 has been demonstrated to be critical for H2A ubiquitylation. Although recent studies have revealed the genome-wide binding patterns of some of the PRC1 and PRC2 components, as well as the H3K27me3 mark, there have been no reports describing genome-wide localization of uH2A. Using the recently developed ChIP-Seq technology, here, we report genome-wide localization of the Bmi1-dependent uH2A mark in MEF cells. Gene promoter averaging analysis indicates a peak of uH2A just inside the transcription start site (TSS) of well-annotated genes. This peak is enriched at promoters containing the H3K27me3 mark and represents the least expressed genes in WT MEF cells. In addition, peak finding reveals regions of local uH2A enrichment throughout the mouse genome, including almost 700 gene promoters. Genes with promoter peaks of uH2A exhibit lower-level expression when compared to genes that do not contain promoter peaks of uH2A. Moreover, we demonstrate that genes with uH2A peaks have increased expression upon Bmi1 knockout. Importantly, local enrichment of uH2A is not limited to regions containing the H3K27me3 mark. We describe the enrichment of H2A ubiquitylation at high-density CpG promoters and provide evidence to suggest that DNA methylation may be linked to uH2A at these regions. Thus, our work not only reveals Bmi1-dependent H2A ubiquitylation, but also suggests that uH2A targeting in differentiated cells may employ a different mechanism from that in ES cells. C1 [Kallin, Eric M.; Cao, Ru; Xia, Kai; Zhang, Yi] Univ N Carolina, Howard Hughes Med Inst, Chapel Hill, NC 27515 USA. [Kallin, Eric M.; Cao, Ru; Xia, Kai; Zhang, Yi] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Jothi, Raja] Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Res Triangle Pk, NC USA. [Cui, Kairong; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Kallin, EM (reprint author), Univ N Carolina, Howard Hughes Med Inst, Chapel Hill, NC 27515 USA. EM yi_zhang@med.unc.edu RI Xia, Kai/B-7214-2014; Jothi, Raja/G-3780-2015 FU National Heart, Lung and Blood Institute; National Institutes of Health; National Institute of Environmental Health Sciences, NIH [GM68804]; Howard Hughes Medical Institute FX RJ, KC and KZ were supported by the intramural research programs of the National Heart, Lung and Blood Institute, National Institutes of Health. RJ was supported in part by the National Institute of Environmental Health Sciences, NIH. Others were supported by NIH (GM68804) and the Howard Hughes Medical Institute. YZ is an Investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 40 Z9 41 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2009 VL 5 IS 6 AR e1000506 DI 10.1371/journal.pgen.1000506 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 476MA UT WOS:000268444600039 PM 19503595 ER PT J AU Kolz, M Johnson, T Sanna, S Teumer, A Vitart, V Perola, M Mangino, M Albrecht, E Wallace, C Farrall, M Johansson, A Nyholt, DR Aulchenko, Y Beckmann, JS Bergmann, S Bochud, M Brown, M Campbell, H Connell, J Dominiczak, A Homuth, G Lamina, C McCarthy, MI Meitinger, T Mooser, V Munroe, P Nauck, M Peden, J Prokisch, H Salo, P Salomaa, V Samani, NJ Schlessinger, D Uda, M Volker, U Waeber, G Waterworth, D Wang-Sattler, R Wright, AF Adamski, J Whitfield, JB Gyllensten, U Wilson, JF Rudan, I Pramstaller, P Watkins, H Doering, A Wichmann, HE Spector, TD Peltonen, L Volzke, H Nagaraja, R Vollenweider, P Caulfield, M Illig, T Gieger, C AF Kolz, Melanie Johnson, Toby Sanna, Serena Teumer, Alexander Vitart, Veronique Perola, Markus Mangino, Massimo Albrecht, Eva Wallace, Chris Farrall, Martin Johansson, Asa Nyholt, Dale R. Aulchenko, Yurii Beckmann, Jacques S. Bergmann, Sven Bochud, Murielle Brown, Morris Campbell, Harry Connell, John Dominiczak, Anna Homuth, Georg Lamina, Claudia McCarthy, Mark I. Meitinger, Thomas Mooser, Vincent Munroe, Patricia Nauck, Matthias Peden, John Prokisch, Holger Salo, Perttu Salomaa, Veikko Samani, Nilesh J. Schlessinger, David Uda, Manuela Voelker, Uwe Waeber, Gerard Waterworth, Dawn Wang-Sattler, Rui Wright, Alan F. Adamski, Jerzy Whitfield, John B. Gyllensten, Ulf Wilson, James F. Rudan, Igor Pramstaller, Peter Watkins, Hugh Doering, Angela Wichmann, H. -Erich Spector, Tim D. Peltonen, Leena Voelzke, Henry Nagaraja, Ramaiah Vollenweider, Peter Caulfield, Mark Illig, Thomas Gieger, Christian CA EUROSPAN Consortium ENGAGE Consortium PROCARDIS Consortium KORA Study WTCCC TI Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; URATE-ANION EXCHANGER; TRIGLYCERIDE LEVELS; FASTING GLUCOSE; SERUM URATE; CARNITINE; GOUT; TRANSPORTER; PROTEIN; SLC2A9 AB Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels. C1 [Kolz, Melanie; Albrecht, Eva; Lamina, Claudia; Wang-Sattler, Rui; Doering, Angela; Wichmann, H. -Erich; Illig, Thomas; Gieger, Christian] Natl Res Ctr Environm & Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Johnson, Toby; Beckmann, Jacques S.; Bergmann, Sven] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Johnson, Toby; Bergmann, Sven] Swiss Inst Bioinformat, Lausanne, Switzerland. [Johnson, Toby; Bochud, Murielle] CHU Vaudois, Univ Inst Social & Prevent Med, Vaudois, Switzerland. [Sanna, Serena; Uda, Manuela] Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Teumer, Alexander; Homuth, Georg; Voelker, Uwe] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Vitart, Veronique; Wright, Alan F.] Western Gen Hosp, MRC, Human Genet Unit, IGMM, Edinburgh EH4 2XU, Midlothian, Scotland. [Perola, Markus; Salo, Perttu; Salomaa, Veikko] Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Perola, Markus; Salo, Perttu; Peltonen, Leena] Inst Mol Med, FIMM, Helsinki, Finland. [Mangino, Massimo; Spector, Tim D.] Kings Coll London, DTR Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Wallace, Chris] Univ Cambridge, Diabet Inflammat Lab, Cambridge Inst Med Res, Cambridge, England. [Farrall, Martin; Peden, John; Watkins, Hugh] Univ Oxford, Dept Cardiovasc Med, Oxford, England. [Johansson, Asa; McCarthy, Mark I.; Peden, John; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Johansson, Asa; Gyllensten, Ulf] Uppsala Univ, Dept Genet & Pathol, Rudbeck Lab, Uppsala, Sweden. [Nyholt, Dale R.; Whitfield, John B.] Queensland Inst Med Res, Genet Epidemiol Unit, Brisbane, Qld 4006, Australia. [Aulchenko, Yurii] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Beckmann, Jacques S.] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland. [Brown, Morris] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge CB2 2QQ, England. [Campbell, Harry; Wilson, James F.; Rudan, Igor] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Connell, John; Dominiczak, Anna] Univ Glasgow, Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Lamina, Claudia] Innsbruck Med Univ, Div Genet Epidemiol, Dept Med Genet Mol & Clin Pharmacol, Innsbruck, Austria. [McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [McCarthy, Mark I.] Univ Oxford, Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford, England. [Meitinger, Thomas; Prokisch, Holger] Natl Res Ctr Environm & Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Mooser, Vincent; Waterworth, Dawn] GlaxoSmithKline Inc, Div Genet, King Of Prussia, PA USA. [Munroe, Patricia; Caulfield, Mark] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Nauck, Matthias] Ernst Moritz Arndt Univ Greifswald, Inst Klin Chem, Greifswald, Germany. [Nauck, Matthias] Ernst Moritz Arndt Univ Greifswald, Labs Med, Greifswald, Germany. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Leicester, Leics, England. [Schlessinger, David; Nagaraja, Ramaiah] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Waeber, Gerard; Pramstaller, Peter] CHU Vaudois, Dept Med & Internal Med, CH-1011 Lausanne, Switzerland. [Adamski, Jerzy] Natl Res Ctr Environm & Hlth, Helmholtz Zentrum Munchen, Genome Anal Ctr, Inst Expt Genet, Neuherberg, Germany. [Rudan, Igor] Univ Split, Croatian Ctr Global Hlth, Fac Med, Split, Croatia. [Rudan, Igor] Gen Info, Zagreb, Croatia. [Pramstaller, Peter] European Acad Bozen Bolzano EURAC, Inst Med Genet, Bolzano, Italy. [Pramstaller, Peter] Med Univ Lubeck, Affiliated Inst, Dept Neurol, Cent Hosp, Bolzano, Italy. [Wichmann, H. -Erich] Univ Munich, IBE, Chair Epidemiol, D-80539 Munich, Germany. [Peltonen, Leena] Wellcome Trust Sanger Inst, Cambridge, England. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. RP Kolz, M (reprint author), Natl Res Ctr Environm & Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. EM christian.gieger@helmholtz-muenchen.de RI Dominiczak, Anna/D-2262-2009; Bochud, Murielle/A-3981-2010; Beckmann, Jacques S /A-9772-2008; Rudan, Igor/I-1467-2012; Colaus, PsyColaus/K-6607-2013; turton, miranda/F-4682-2011; Johansson, Asa/G-5270-2011; Spector, Tim/F-6533-2012; Lamina, Claudia/F-7608-2010; Nyholt, Dale/C-8384-2013; Prokisch, Holger/N-8964-2013; Waldenberger, Melanie/B-5355-2014; Pramstaller, Peter/C-2357-2008; Wilson, James F/A-5704-2009; Meitinger, Thomas/O-1318-2015; mangino, massimo/F-5134-2011; OI Bochud, Murielle/0000-0002-5727-0218; Beckmann, Jacques S /0000-0002-9741-1900; Rudan, Igor/0000-0001-6993-6884; Johansson, Asa/0000-0002-2915-4498; Wallace, Chris/0000-0001-9755-1703; Watkins, Hugh/0000-0002-5287-9016; Wang-Sattler, Rui/0000-0002-8794-8229; Waldenberger, Melanie/0000-0003-0583-5093; Wilson, James F/0000-0001-5751-9178; mangino, massimo/0000-0002-2167-7470; sanna, serena/0000-0002-3768-1749; Johnson, Toby/0000-0002-5998-3270; Gieger, Christian/0000-0001-6986-9554; Aulchenko, Yurii/0000-0002-7899-1575 FU Medical Research Council of Great Britain [G9521010D]; British Heart Foundation [PG02/128, FS/05/061/19501]; Wellcome Trust [076113/B/04/Z]; The Barts and The London Charity; GlaxoSmithKline; Faculty of Biology and Medicine of Lausanne; Swiss National Science Foundation [33CSCO-122661, 3200BO-111361/2, 3100AO-116323/1]; Giorgi-Cavaglieri Foundation; European Framework Project 6; EUROSPAN; European Commission [018947, LSHG-CT-2006-01947]; Medical Research Council UK; Ministry of Science, Education and Sport of the Republic of Croatia [108-1080315-0302, 196-1962766-2751, 196-1962766-2763, 196-1962766-2747]; Helmholtz Zentrum Munchen; German Federal Ministry of Education and Research; German National Genome Research Network (NGFN); LMUinnovativ; Ministry of Health of the Autonomous Province of Bolzano; South Tyrolean Sparkasse Foundation; The Swedish Natural Sciences Research Council; The Foundation for Strategic Research; Scottish Executive Health Department; Royal Society; EC Sixth Framework Programme [LSHM-CT-2007-037273]; AstraZeneca AB; Knut and Alice Wallenberg Foundation; National Institute on Aging [NO1-AG-1-2109]; National Institute on Aging (NIH); Ministry of Cultural Affairs (Germany); Social Ministry of the Federal State of Mecklenburg-Western Pomerania; Siemens Healthcare; Australian National Health and Medical Research Council (NHMRC); US National Institutes of Health [AA007535]; European Union FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]; Arthritis Research Campaign; Chronic Disease Research Foundation; National Institute for Health Research (NIHR); European Community's Seventh Framework Programme [FP7/2007-2013]; ENGAGE [HEALTH-F4-2007-201413] FX Major funding for the work described in this manuscript comes from the Medical Research Council of Great Britain (G9521010D), the British Heart Foundation (PG02/128, FS/05/061/19501), the Wellcome Trust (076113/B/04/Z), The Barts and The London Charity, GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, the Swiss National Science Foundation (33CSCO-122661, 3200BO-111361/2, 3100AO-116323/1), the Giorgi-Cavaglieri Foundation, the European Framework Project 6 (EuroDia, AnEuploidy and Hypergenes projects), the EUROSPAN (European Special Populations Research Network) project funded by the European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947), the Medical Research Council UK, the Ministry of Science, Education and Sport of the Republic of Croatia (108-1080315-0302, 196-1962766-2751, 196-1962766-2763, 196-1962766-2747), the Helmholtz Zentrum Munchen, the German Federal Ministry of Education and Research, the German National Genome Research Network (NGFN), LMUinnovativ, the Ministry of Health of the Autonomous Province of Bolzano, the South Tyrolean Sparkasse Foundation, The Swedish Natural Sciences Research Council, The Foundation for Strategic Research, the Scottish Executive Health Department, the Royal Society, the EC Sixth Framework Programme (LSHM-CT-2007-037273), AstraZeneca AB, the Knut and Alice Wallenberg Foundation, the National Institute on Aging (NO1-AG-1-2109 to the "SardiNIA-ProgeNIA'' team), the Intramural research funding at the National Institute on Aging (NIH), the Ministry of Cultural Affairs (Germany), the Social Ministry of the Federal State of Mecklenburg-Western Pomerania, Siemens Healthcare, the Federal State of Mecklenburg-West Pomerania, the Australian National Health and Medical Research Council (NHMRC), the US National Institutes of Health (AA007535), the European Union FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), the Arthritis Research Campaign, the Chronic Disease Research Foundation, the National Institute for Health Research (NIHR) and the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 285 Z9 309 U1 4 U2 33 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2009 VL 5 IS 6 AR e1000504 DI 10.1371/journal.pgen.1000504 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 476MA UT WOS:000268444600037 PM 19503597 ER PT J AU Lindgren, CM Heid, IM Randall, JC Lamina, C Steinthorsdottir, V Qi, L Speliotes, EK Thorleifsson, G Willer, CJ Herrera, BM Jackson, AU Lim, N Scheet, P Soranzo, N Amin, N Aulchenko, YS Chambers, JC Drong, A Luan, JA Lyon, HN Rivadeneira, F Sanna, S Timpson, NJ Zillikens, MC Zhao, JH Almgren, P Bandinelli, S Bennett, AJ Bergman, RN Bonnycastle, LL Bumpstead, SJ Chanock, SJ Cherkas, L Chines, P Coin, L Cooper, C Crawford, G Doering, A Dominiczak, A Doney, ASF Ebrahim, S Elliott, P Erdos, MR Estrada, K Ferrucci, L Fischer, G Forouhi, NG Gieger, C Grallert, H Groves, CJ Grundy, S Guiducci, C Hadley, D Hamsten, A Havulinna, AS Hofman, A Holle, R Holloway, JW Illig, T Isomaa, B Jacobs, LC Jameson, K Jousilahti, P Karpe, F Kuusisto, J Laitinen, J Lathrop, GM Lawlor, DA Mangino, M McArdle, WL Meitinger, T Morken, MA Morris, AP Munroe, P Narisu, N Nordstrom, A Nordstrom, P Oostra, BA Palmer, CNA Payne, F Peden, JF Prokopenko, I Renstrom, F Ruokonen, A Salomaa, V Sandhu, MS Scott, LJ Scuteri, A Silander, K Song, KJ Yuan, X Stringham, HM Swift, AJ Tuomi, T Uda, M Vollenweider, P Waeber, G Wallace, C Walters, GB Weedon, MN Witteman, JCM Zhang, CL Zhang, WH Caulfield, MJ Collins, FS Smith, GD Day, INM Franks, PW Hattersley, AT Hu, FB Jarvelin, MR Kong, A Kooner, JS Laakso, M Lakatta, E Mooser, V Morris, AD Peltonen, L Samani, NJ Spector, TD Strachan, DP Tanaka, T Tuomilehto, J Uitterlinden, AG van Duijn, CM Wareham, NJ Watkins, H Waterworth, DM Boehnke, M Deloukas, P Groop, L Hunter, DJ Thorsteinsdottir, U Schlessinger, D Wichmann, HE Frayling, TM Abecasis, GR Hirschhorn, JN Loos, RJF Stefansson, K Mohlke, KL Barroso, IS McCarthy, MI AF Lindgren, Cecilia M. Heid, Iris M. Randall, Joshua C. Lamina, Claudia Steinthorsdottir, Valgerdur Qi, Lu Speliotes, Elizabeth K. Thorleifsson, Gudmar Willer, Cristen J. Herrera, Blanca M. Jackson, Anne U. Lim, Noha Scheet, Paul Soranzo, Nicole Amin, Najaf Aulchenko, Yurii S. Chambers, John C. Drong, Alexander Luan, Jian'an Lyon, Helen N. Rivadeneira, Fernando Sanna, Serena Timpson, Nicholas J. Zillikens, M. Carola Zhao, Jing Hua Almgren, Peter Bandinelli, Stefania Bennett, Amanda J. Bergman, Richard N. Bonnycastle, Lori L. Bumpstead, Suzannah J. Chanock, Stephen J. Cherkas, Lynn Chines, Peter Coin, Lachlan Cooper, Cyrus Crawford, Gabriel Doering, Angela Dominiczak, Anna Doney, Alex S. F. Ebrahim, Shah Elliott, Paul Erdos, Michael R. Estrada, Karol Ferrucci, Luigi Fischer, Guido Forouhi, Nita G. Gieger, Christian Grallert, Harald Groves, Christopher J. Grundy, Scott Guiducci, Candace Hadley, David Hamsten, Anders Havulinna, Aki S. Hofman, Albert Holle, Rolf Holloway, John W. Illig, Thomas Isomaa, Bo Jacobs, Leonie C. Jameson, Karen Jousilahti, Pekka Karpe, Fredrik Kuusisto, Johanna Laitinen, Jaana Lathrop, G. Mark Lawlor, Debbie A. Mangino, Massimo McArdle, Wendy L. Meitinger, Thomas Morken, Mario A. Morris, Andrew P. Munroe, Patricia Narisu, Narisu Nordstrom, Anna Nordstroem, Peter Oostra, Ben A. Palmer, Colin N. A. Payne, Felicity Peden, John F. Prokopenko, Inga Renstroem, Frida Ruokonen, Aimo Salomaa, Veikko Sandhu, Manjinder S. Scott, Laura J. Scuteri, Angelo Silander, Kaisa Song, Kijoung Yuan, Xin Stringham, Heather M. Swift, Amy J. Tuomi, Tiinamaija Uda, Manuela Vollenweider, Peter Waeber, Gerard Wallace, Chris Walters, G. Bragi Weedon, Michael N. Witteman, Jacqueline C. M. Zhang, Cuilin Zhang, Weihua Caulfield, Mark J. Collins, Francis S. Smith, George Davey Day, Ian N. M. Franks, Paul W. Hattersley, Andrew T. Hu, Frank B. Jarvelin, Marjo-Riitta Kong, Augustine Kooner, Jaspal S. Laakso, Markku Lakatta, Edward Mooser, Vincent Morris, Andrew D. Peltonen, Leena Samani, Nilesh J. Spector, Timothy D. Strachan, David P. Tanaka, Toshiko Tuomilehto, Jaakko Uitterlinden, Andre G. van Duijn, Cornelia M. Wareham, Nicholas J. Watkins, Hugh Waterworth, Dawn M. Boehnke, Michael Deloukas, Panos Groop, Leif Hunter, David J. Thorsteinsdottir, Unnur Schlessinger, David Wichmann, H. -Erich Frayling, Timothy M. Abecasis, Goncalo R. Hirschhorn, Joel N. Loos, Ruth J. F. Stefansson, Kari Mohlke, Karen L. Barroso, Ine S. McCarthy, Mark I. CA Wellcome Trust Case Control Consor PROCARDIS Consortia GIANT Consortium TI Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution SO PLOS GENETICS LA English DT Article ID FTO GENE; WAIST CIRCUMFERENCE; ADULT OBESITY; ENVIRONMENTAL-CONDITIONS; INSULIN-RESISTANCE; SEQUENCE VARIANTS; COMMON VARIANTS; EXPRESSION; IMPUTATION; HEIGHT AB To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity. C1 [Lindgren, Cecilia M.; Randall, Joshua C.; Herrera, Blanca M.; Drong, Alexander; Morris, Andrew P.; Peden, John F.; Prokopenko, Inga; Watkins, Hugh; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Heid, Iris M.; Lamina, Claudia; Doering, Angela; Fischer, Guido; Gieger, Christian; Grallert, Harald; Holle, Rolf; Meitinger, Thomas; Wichmann, H. -Erich] Natl Res Ctr Environm & Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Heid, Iris M.] Univ Regensburg, Inst Epidemiol & Prevent Med, Regensburg, Germany. [Lamina, Claudia] Innsbruck Med Univ, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, Innsbruck, Austria. [Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Walters, G. Bragi; Kong, Augustine; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Qi, Lu; Hu, Frank B.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Qi, Lu; Hu, Frank B.; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Speliotes, Elizabeth K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Gastroenterol, Boston, MA USA. [Speliotes, Elizabeth K.; Lyon, Helen N.; Hirschhorn, Joel N.] Broad Inst MIT & Harvard, Metab Initiat & Program Med & Populat Genet, Boston, MA USA. [Willer, Cristen J.; Jackson, Anne U.; Scheet, Paul; Scott, Laura J.; Stringham, Heather M.; Boehnke, Michael; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Herrera, Blanca M.; Bennett, Amanda J.; Groves, Christopher J.; Karpe, Fredrik; McCarthy, Mark I.] Univ Oxford, Dept Endocrinol & Metab, Oxford Ctr Diabet, Oxford, England. [Lim, Noha; Scheet, Paul; Song, Kijoung; Yuan, Xin; Mooser, Vincent; Waterworth, Dawn M.] Clin Pharmacol & Discovery Med, Med Genet, King Of Prussia, PA USA. [Soranzo, Nicole; Cherkas, Lynn; Mangino, Massimo; Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Soranzo, Nicole; Bumpstead, Suzannah J.; Payne, Felicity; Peltonen, Leena; Barroso, Ine S.] Wellcome Trust Sanger Inst, Cambridge, England. [Amin, Najaf; Aulchenko, Yurii S.; Rivadeneira, Fernando; Hofman, Albert; Witteman, Jacqueline C. M.; Uitterlinden, Andre G.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [Luan, Jian'an; Zhao, Jing Hua; Sandhu, Manjinder S.; Wareham, Nicholas J.; Loos, Ruth J. F.] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England. [Lyon, Helen N.; Hirschhorn, Joel N.] Childrens Hosp, Div Genet & Endocrinol, Program Genom, Boston, MA 02115 USA. [Rivadeneira, Fernando; Zillikens, M. Carola; Estrada, Karol; Jacobs, Leonie C.; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Sanna, Serena; Uda, Manuela] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Timpson, Nicholas J.; Lawlor, Debbie A.; Smith, George Davey] Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Bristol, Avon, England. [Almgren, Peter; Lawlor, Debbie A.; Smith, George Davey; Groop, Leif] Lund Univ, Malmo Univ Hosp, Diabet & Endocrinol Res Unit, Dept Clin Sci, Malmo, Sweden. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Bergman, Richard N.] Univ So Calif, Sch Med, Los Angeles, CA USA. [Bonnycastle, Lori L.; Chines, Peter; Erdos, Michael R.; Morken, Mario A.; Narisu, Narisu; Swift, Amy J.; Collins, Francis S.] NHGRI, Bethesda, MD 20892 USA. [Chanock, Stephen J.] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Coin, Lachlan; Elliott, Paul; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [Cooper, Cyrus; Holloway, John W.; Jameson, Karen] Univ Southampton, MRC, Epidemiol Resource Ctr, Southampton, Hants, England. [Crawford, Gabriel; Guiducci, Candace; Peltonen, Leena] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Dominiczak, Anna] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Doney, Alex S. F.; Morris, Andrew D.] Univ Dundee, Ninewells Hosp & Med Sch, Div Med & Therapeut, Diabet Res Grp, Dundee DD1 9SY, Scotland. [Ebrahim, Shah; Lawlor, Debbie A.; McArdle, Wendy L.; Smith, George Davey] Univ Bristol, Dept Social Med, Bristol, Avon, England. [Ferrucci, Luigi; Tanaka, Toshiko] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Grundy, Scott] Univ Texas SW Med Ctr Dallas, Ctr Human Nutr, Dallas, TX 75390 USA. [Hadley, David; Strachan, David P.] St Georges Univ London, Div Community Hlth Sci, London, England. [Hamsten, Anders] Karolinska Inst, Dept Med, Atherosclerosis Res Unit, Stockholm, Sweden. [Havulinna, Aki S.; Jousilahti, Pekka; Salomaa, Veikko] KTL Natl Publ Hlth Inst, Helsinki, Finland. [Holloway, John W.] Univ Southampton, Div Human Genet, Southampton, Hants, England. [Isomaa, Bo] Malmska Municipal Hlth Ctr & Hosp, Folkhalsan Res Ctr, Pietarsaari, Finland. [Kuusisto, Johanna; Tuomi, Tiinamaija; Laakso, Markku; Groop, Leif] Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland. [Laitinen, Jaana] Finnish Inst Occpat Hlth, Oulu, Finland. [Lathrop, G. Mark] Ctr Natl Genotypage, Evry, France. [Munroe, Patricia; Wallace, Chris; Caulfield, Mark J.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Nordstrom, Anna; Nordstroem, Peter] Umea Univ, Dept Surg & Perioperat Sci, Sect Sports Med, Umea, Sweden. [Nordstrom, Anna; Nordstroem, Peter] Umea Univ Hosp, Dept Community Med & Rehabil, Sect Geriatr, S-90185 Umea, Sweden. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Populat Pharmacogenet Grp, Dundee DD1 9SY, Scotland. [Peden, John F.; Watkins, Hugh; PROCARDIS Consortia] Univ Oxford, Dept Cardiovasc Med, Oxford, England. [Renstroem, Frida; Franks, Paul W.] Umea Univ Hosp, Med Sect, Dept Publ Hlth & Clin Med, Genet Epidemiol & Clin Res Grp, S-90185 Umea, Sweden. [Ruokonen, Aimo] Univ Oulu, Dept Clin Chem, Oulu, Finland. [Sandhu, Manjinder S.] Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge, England. [Scuteri, Angelo] IRCCS, INRCA, Unita Operat Geriatr, Rome, Italy. [Silander, Kaisa] Natl Publ Hlth Inst, Dept Mol Med, Helsinki, Finland. [Tuomi, Tiinamaija] Univ Helsinki, Res Program Mol Med, Helsinki, Finland. [Waeber, Gerard] CHU Vaudois, Dept Med & Internal Med, CH-1011 Lausanne, Switzerland. [Weedon, Michael N.; Hattersley, Andrew T.; Frayling, Timothy M.] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England. [Zhang, Cuilin] NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Zhang, Weihua] Ealing Gen Hosp, Natl Hlth Serv Trust, Southall, Middx, England. [Day, Ian N. M.] Univ Bristol, Dept Social Med, Bristol Genet Epidemiol Labs, Bristol, Avon, England. [Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, Umea Med Biobank, Sect Nutr Res, Umea, Sweden. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Bioctr Oulu, Oulu, Finland. [Jarvelin, Marjo-Riitta] Natl Publ Hlth Inst, Dept Child & Adolescent Hlth, Oulu, Finland. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England. [Lakatta, Edward; Schlessinger, David] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Tanaka, Toshiko] Medstar Res Inst, Baltimore, MD USA. [Tuomilehto, Jaakko] Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Diabet Unit, Helsinki, Finland. [Deloukas, Panos] Addenbrookes Hosp, Inst Metab Sci, Cambridge, England. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [McCarthy, Mark I.; GIANT Consortium] Univ Oxford, Oxford Biomed Res Ctr, Natl Inst Hlth Res, Oxford, England. RP Lindgren, CM (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. EM goncalo@umich.edu; joelh@broad.mit.edu; rjfl2@medschl.cam.ac.uk; kari.stefansson@decode.is; mohlke@med.unc.edu; ib1@sanger.ac.uk; mark.mccarthy@drl.ox.ac.uk RI Morris, Andrew/C-2837-2009; Dominiczak, Anna/D-2262-2009; Abecasis, Goncalo/B-7840-2010; Spector, Tim/F-6533-2012; Lamina, Claudia/F-7608-2010; Hadley, David/I-6902-2012; Deloukas, Panos/B-2922-2013; Palmer, Colin/C-7053-2008; Holloway, John/B-5424-2009; Colaus, PsyColaus/K-6607-2013; Aulchenko, Yurii/M-8270-2013; Grallert, Harald/B-3424-2013; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Holle, Rolf/D-9333-2013; Study, GoDARTS/K-9448-2016; mangino, massimo/F-5134-2011; Coin, Lachlan/A-9001-2014; Fox, Laura /C-6249-2016; Davey Smith, George/A-7407-2013; OI Forouhi, Nita/0000-0002-5041-248X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Tuomi, Tiinamaija/0000-0002-8306-6202; Wallace, Chris/0000-0001-9755-1703; Karpe, Fredrik/0000-0002-2751-1770; Watkins, Hugh/0000-0002-5287-9016; Nordstrom, Anna/0000-0003-3534-456X; Timpson, Nicholas/0000-0002-7141-9189; Lawlor, Debbie A/0000-0002-6793-2262; Payne, Felicity/0000-0003-4228-581X; Deloukas, Panos/0000-0001-9251-070X; Palmer, Colin/0000-0002-6415-6560; Holloway, John/0000-0001-9998-0464; Aulchenko, Yurii/0000-0002-7899-1575; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Holle, Rolf/0000-0001-5395-2695; mangino, massimo/0000-0002-2167-7470; Coin, Lachlan/0000-0002-4300-455X; Davey Smith, George/0000-0002-1407-8314; Nordstrom, Peter/0000-0003-2924-508X; Willer, Cristen/0000-0001-5645-4966; sanna, serena/0000-0002-3768-1749; Monsalve, Beatriz Elena/0000-0002-5994-866X; Abecasis, Goncalo/0000-0003-1509-1825; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554 FU Academy of Finland [104781, 124243]; ADA Smith Family Foundation Pinnacle Program; American Diabetes Association, Arthritis Research Campaign, AstraZeneca AB; The Barts; The London Charity, Biocentrum Helsinki, Biotechnology and Biological Sciences Research Council (UK), British Heart Foundation, Camstrad, Cancer Research UK, CIDR [N01-HG-65403]; European Commission [LSHG-CT-2004-518153, LSHG-CT-2004-512066, LSHM-CT-2006-037197, LSHM-CT-2003-503041, QL46-CT-2002-02629, LSHM-CT-2007-037273, HEALTH-F4-2007-201413]; Faculty of Biology and Medicine of Lausanne, Switzerland; Swiss National Science Foundation [33CSCO-122661]; Finnish Heart Association; Finnish Cultural Foundation, Folkhalsan Research Foundation; German National Genome Research Net, GlaxoSmithKline; Sigrid Juselius Foundation; Karolinska Institute, Kings College London; Knut and AliceWallenberg Foundation; Medical Research Council UK [G0000934, G0000649, G0601261, G0500539, G9521010D, G0600705]; MedStar Research Institute, Munich Center of Health Sciences, National Institutes of Health [1Z01-HG000024]; National Institute on Aging; NHLBI [HL087679, HL084729]; NIDDK [DK062370, DK072193, DK075787, DK079466, DK080145, DK067288, DK07191]; NHGRI [HG02651]; Netherlands Organization for Scientific Research; Netherlands Center of Medical Systems Biology; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Novartis, Peninsula Medical School, Scottish Executive Chief Scientist's Office, Stockholm County Council [560183]; Swedish Heart-Lung Foundation; Swedish Medical Research Council [8691]; UK National Institute of Health Research; UK Department of Health Policy Research Programme; University of Oxford; Vandervell Foundation; Wellcome Trust [068545/Z/02, GR072960, GR076113, GR069224, 086596/Z/08/Z] FX Major project or personal funding for the work described in this paper comes from the Academy of Finland (104781, 124243), ADA Smith Family Foundation Pinnacle Program, the American Diabetes Association, Arthritis Research Campaign, AstraZeneca AB, The Barts and The London Charity, Biocentrum Helsinki, Biotechnology and Biological Sciences Research Council (UK), British Heart Foundation, Camstrad, Cancer Research UK, CIDR (NIH Contract Number N01-HG-65403), Diabetes UK, the European Commission (Framework VI: LSHG-CT-2004-518153 [EURODIA]; LSHG-CT-2004-512066 [MolPAGE]; LSHM-CT-2006-037197; LSHM-CT-2003-503041; QL46-CT-2002-02629 [GENOMOS]; LSHM-CT-2007-037273; Framework VII: HEALTH-F4-2007-201413 [ENGAGE]), the Faculty of Biology and Medicine of Lausanne, Switzerland, the Swiss National Science Foundation (Grant 33CSCO-122661, the Finnish Heart Association, the Finnish Cultural Foundation, Folkhalsan Research Foundation, the German National Genome Research Net, GlaxoSmithKline, the Sigrid Juselius Foundation, the Karolinska Institute, Kings College London, the Knut and AliceWallenberg Foundation, the Medical Research Council UK (G0000934, G0000649, G0601261, G0500539, G9521010D, G0600705), MedStar Research Institute, Munich Center of Health Sciences, National Institutes of Health (US: intramural programs (1Z01-HG000024), National Institute on Aging; NHLBI (HL087679 [STAMPEED], HL084729), NIDDK (DK062370; DK072193; DK075787; DK079466; DK080145; DK067288; DK07191), NHGRI (HG02651), the Netherlands Organization for Scientific Research, the Netherlands Center of Medical Systems Biology, the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) (050-060-810), Novartis, Peninsula Medical School, Scottish Executive Chief Scientist's Office, Stockholm County Council (560183), Support for Science Funding (UK); Swedish Heart-Lung Foundation, the Swedish Medical Research Council (8691), UK National Institute of Health Research, UK Department of Health Policy Research Programme, University of Oxford, Vandervell Foundation and Wellcome Trust (068545/Z/02, GR072960, GR076113, GR069224, 086596/Z/08/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 285 Z9 294 U1 3 U2 28 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2009 VL 5 IS 6 AR e1000508 DI 10.1371/journal.pgen.1000508 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 476MA UT WOS:000268444600004 PM 19557161 ER PT J AU Price, AL Tandon, A Patterson, N Barnes, KC Rafaels, N Ruczinski, I Beaty, TH Mathias, R Reich, D Myers, S AF Price, Alkes L. Tandon, Arti Patterson, Nick Barnes, Kathleen C. Rafaels, Nicholas Ruczinski, Ingo Beaty, Terri H. Mathias, Rasika Reich, David Myers, Simon TI Sensitive Detection of Chromosomal Segments of Distinct Ancestry in Admixed Populations SO PLOS GENETICS LA English DT Article ID NUCLEOTIDE-POLYMORPHISM PANEL; MULTILOCUS GENOTYPE DATA; ADMIXTURE MAP; HAPLOTYPE; INFERENCE AB Identifying the ancestry of chromosomal segments of distinct ancestry has a wide range of applications from disease mapping to learning about history. Most methods require the use of unlinked markers; but, using all markers from genome-wide scanning arrays, it should in principle be possible to infer the ancestry of even very small segments with exquisite accuracy. We describe a method, HAPMIX, which employs an explicit population genetic model to perform such local ancestry inference based on fine-scale variation data. We show that HAPMIX outperforms other methods, and we explore its utility for inferring ancestry, learning about ancestral populations, and inferring dates of admixture. We validate the method empirically by applying it to populations that have experienced recent and ancient admixture: 935 African Americans from the United States and 29 Mozabites from North Africa. HAPMIX will be of particular utility for mapping disease genes in recently admixed populations, as its accurate estimates of local ancestry permit admixture and case-control association signals to be combined, enabling more powerful tests of association than with either signal alone. C1 [Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Price, Alkes L.; Tandon, Arti; Patterson, Nick; Reich, David; Myers, Simon] Broad Inst Harvard & MIT, Cambridge, MA USA. [Tandon, Arti; Reich, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Barnes, Kathleen C.; Rafaels, Nicholas] Johns Hopkins Allergy & Asthma Ctr, Div Clin Immunol, Dept Med, Sch Med, Baltimore, MD USA. [Ruczinski, Ingo; Beaty, Terri H.] Johns Hopkins Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Mathias, Rasika] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Myers, Simon] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Myers, Simon] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. RP Price, AL (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM reich@genetics.med.harvard.edu; myers@stats.ox.ac.uk RI Myers, Simon/A-6792-2015 OI Myers, Simon/0000-0002-2585-9626 FU NIH [U01-HG004168, R01-HL087699]; Ruth Kirschstein National Research Service Award from the National Institutes of Health; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; Mary Beryl Patch Turnbull Scholar Program; Burroughs Wellcome Career Development Award in the Biomedical Sciences FX This work was supported by NIH grants U01-HG004168 to ALP, AT, NP, and DR and by R01-HL087699 (to KCB, THB, IR, RM, and NR). ALP was supported by a Ruth Kirschstein National Research Service Award from the National Institutes of Health; RM was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; KCB was supported in part by the Mary Beryl Patch Turnbull Scholar Program; and DR was supported by a Burroughs Wellcome Career Development Award in the Biomedical Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 225 Z9 229 U1 1 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2009 VL 5 IS 6 AR e1000519 DI 10.1371/journal.pgen.1000519 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA 476MA UT WOS:000268444600016 PM 19543370 ER PT J AU Simeonov, A Kulkarni, A Dorjsuren, D Jadhav, A Shen, M McNeill, DR Austin, CP Wilson, DM AF Simeonov, Anton Kulkarni, Avanti Dorjsuren, Dorjbal Jadhav, Ajit Shen, Min McNeill, Daniel R. Austin, Christopher P. Wilson, David M., III TI Identification and Characterization of Inhibitors of Human Apurinic/apyrimidinic Endonuclease APE1 SO PLOS ONE LA English DT Article AB APE1 is the major nuclease for excising abasic (AP) sites and particular 3'-obstructive termini from DNA, and is an integral participant in the base excision repair (BER) pathway. BER capacity plays a prominent role in dictating responsiveness to agents that generate oxidative or alkylation DNA damage, as well as certain chain-terminating nucleoside analogs and 5-fluorouracil. We describe within the development of a robust, 1536-well automated screening assay that employs a deoxyoligonucleotide substrate operating in the red-shifted fluorescence spectral region to identify APE1 endonuclease inhibitors. This AP site incision assay was used in a titration-based high-throughput screen of the Library of Pharmacologically Active Compounds (LOPAC(1280)), a collection of well-characterized, drug-like molecules representing all major target classes. Prioritized hits were authenticated and characterized via two high-throughput screening assays - a Thiazole Orange fluorophore-DNA displacement test and an E. coli endonuclease IV counterscreen - and a conventional, gel-based radiotracer incision assay. The top, validated compounds, i.e. 6-hydroxy-DL-DOPA, Reactive Blue 2 and myricetin, were shown to inhibit AP site cleavage activity of whole cell protein extracts from HEK 293T and HeLa cell lines, and to enhance the cytotoxic and genotoxic potency of the alkylating agent methylmethane sulfonate. The studies herein report on the identification of novel, small molecule APE1-targeted bioactive inhibitor probes, which represent initial chemotypes towards the development of potential pharmaceuticals. RP Simeonov, A (reprint author), NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. EM wilsonda@mail.nih.gov FU Intramural NIH HHS; NIMH NIH HHS [1 R03 MH086444] NR 55 TC 58 Z9 62 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 1 PY 2009 VL 4 IS 6 AR e5740 DI 10.1371/journal.pone.0005740 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 452GL UT WOS:000266528200002 PM 19484131 ER PT J AU Ashok, A Hegde, RS AF Ashok, Aarthi Hegde, Ramanujan S. TI Selective Processing and Metabolism of Disease-Causing Mutant Prion Proteins SO PLOS PATHOGENS LA English DT Article ID ENDOPLASMIC-RETICULUM; QUALITY-CONTROL; WILD-TYPE; PATHOGENIC MUTATIONS; PLASMA-MEMBRANE; NEURODEGENERATIVE DISEASE; SECRETORY PATHWAY; CULTURED-CELLS; E200K MUTATION; LIVE CELLS AB Prion diseases are fatal neurodegenerative disorders caused by aberrant metabolism of the cellular prion protein (PrP(C)). In genetic forms of these diseases, mutations in the globular C-terminal domain are hypothesized to favor the spontaneous generation of misfolded PrP conformers (including the transmissible PrP(Sc) form) that trigger downstream pathways leading to neuronal death. A mechanistic understanding of these diseases therefore requires knowledge of the quality control pathways that recognize and degrade aberrant PrPs. Here, we present comparative analyses of the biosynthesis, trafficking, and metabolism of a panel of genetic disease-causing prion protein mutants in the C-terminal domain. Using quantitative imaging and biochemistry, we identify a misfolded subpopulation of each mutant PrP characterized by relative detergent insolubility, inaccessibility to the cell surface, and incomplete glycan modifications. The misfolded populations of mutant PrPs were neither recognized by ER quality control pathways nor routed to ER-associated degradation despite demonstrable misfolding in the ER. Instead, mutant PrPs trafficked to the Golgi, from where the misfolded subpopulation was selectively trafficked for degradation in acidic compartments. Surprisingly, selective re-routing was dependent not only on a mutant globular domain, but on an additional lysine-based motif in the highly conserved unstructured N-terminus. These results define a specific trafficking and degradation pathway shared by many disease-causing PrP mutants. As the acidic lysosomal environment has been implicated in facilitating the conversion of PrP(C) to PrP(Sc), our identification of a mutant-selective trafficking pathway to this compartment may provide a cell biological basis for spontaneous generation of PrP(Sc) in familial prion disease. C1 [Ashok, Aarthi; Hegde, Ramanujan S.] Eunice Kennedy Shriver NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Ashok, A (reprint author), Eunice Kennedy Shriver NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM hegder@mail.nih.gov OI Hegde, Ramanujan/0000-0001-8338-852X FU Intramural NIH HHS NR 54 TC 58 Z9 58 U1 1 U2 3 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 JUN PY 2009 VL 5 IS 6 AR e1000479 DI 10.1371/journal.ppat.1000479 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 476LZ UT WOS:000268444500012 PM 19543376 ER PT J AU Chang, TH Kubota, T Matsuoka, M Jones, S Bradfute, SB Bray, M Ozato, K AF Chang, Tsung-Hsien Kubota, Toru Matsuoka, Mayumi Jones, Steven Bradfute, Steven B. Bray, Mike Ozato, Keiko TI Ebola Zaire Virus Blocks Type I Interferon Production by Exploiting the Host SUMO Modification Machinery SO PLOS PATHOGENS LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; DOUBLE-STRANDED-RNA; TOLL-LIKE RECEPTORS; NF-KAPPA-B; VP35 PROTEIN; MEDIATED DEGRADATION; HEMORRHAGIC-FEVER; ADAPTIVE IMMUNITY; BINDING-PROTEIN; GENE-EXPRESSION AB Ebola Zaire virus is highly pathogenic for humans, with case fatality rates approaching 90% in large outbreaks in Africa. The virus replicates in macrophages and dendritic cells (DCs), suppressing production of type I interferons (IFNs) while inducing the release of large quantities of proinflammatory cytokines. Although the viral VP35 protein has been shown to inhibit IFN responses, the mechanism by which it blocks IFN production has not been fully elucidated. We expressed VP35 from a mouse-adapted variant of Ebola Zaire virus in murine DCs by retroviral gene transfer, and tested for IFN transcription upon Newcastle Disease virus (NDV) infection and toll-like receptor signaling. We found that VP35 inhibited IFN transcription in DCs following these stimuli by disabling the activity of IRF7, a transcription factor required for IFN transcription. By yeast two-hybrid screens and coimmunoprecipitation assays, we found that VP35 interacted with IRF7, Ubc9 and PIAS1. The latter two are the host SUMO E2 enzyme and E3 ligase, respectively. VP35, while not itself a SUMO ligase, increased PIAS1-mediated SUMOylation of IRF7, and repressed Ifn transcription. In contrast, VP35 did not interfere with the activation of NFkB, which is required for induction of many proinflammatory cytokines. Our findings indicate that Ebola Zaire virus exploits the cellular SUMOylation machinery for its advantage and help to explain how the virus overcomes host innate defenses, causing rapidly overwhelming infection to produce a syndrome resembling fulminant septic shock. C1 [Chang, Tsung-Hsien; Kubota, Toru; Matsuoka, Mayumi; Ozato, Keiko] Eunice Kennedy Shriver NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Jones, Steven] Canadian Sci Ctr Human & Anim Hlth, Natl Microbiol Lab, Populat & Publ Hlth Branch, Winnipeg, MB, Canada. [Bradfute, Steven B.] USA, Med Inst Infect Dis, Ft Detrick, MD USA. [Bray, Mike] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD USA. RP Chang, TH (reprint author), Eunice Kennedy Shriver NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM ozatok@nih.gov FU Intramural NIH HHS NR 72 TC 103 Z9 106 U1 1 U2 19 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 JUN PY 2009 VL 5 IS 6 AR e1000493 DI 10.1371/journal.ppat.1000493 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 476LZ UT WOS:000268444500009 PM 19557165 ER PT J AU Peters, NC Kimblin, N Secundino, N Kamhawi, S Lawyer, P Sacks, DL AF Peters, Nathan C. Kimblin, Nicola Secundino, Nagila Kamhawi, Shaden Lawyer, Phillip Sacks, David L. TI Vector Transmission of Leishmania Abrogates Vaccine-Induced Protective Immunity SO PLOS PATHOGENS LA English DT Article ID AMERICAN CUTANEOUS LEISHMANIASIS; MEMORY T-CELLS; SAND FLIES; PLUS BCG; MAJOR VACCINE; VISCERAL LEISHMANIASIS; AMAZONENSIS VACCINE; HUMAN VOLUNTEERS; CONTROLLED-TRIAL; APOPTOTIC CELL AB Numerous experimental vaccines have been developed to protect against the cutaneous and visceral forms of leishmaniasis caused by infection with the obligate intracellular protozoan Leishmania, but a human vaccine still does not exist. Remarkably, the efficacy of anti-Leishmania vaccines has never been fully evaluated under experimental conditions following natural vector transmission by infected sand fly bite. The only immunization strategy known to protect humans against natural exposure is "leishmanization,'' in which viable L. major parasites are intentionally inoculated into a selected site in the skin. We employed mice with healed L. major infections to mimic leishmanization, and found tissue-seeking, cytokine-producing CD4+ T cells specific for Leishmania at the site of challenge by infected sand fly bite within 24 hours, and these mice were highly resistant to sand fly transmitted infection. In contrast, mice vaccinated with a killed vaccine comprised of autoclaved L. major antigen (ALM)+ CpG oligodeoxynucleotides that protected against needle inoculation of parasites, showed delayed expression of protective immunity and failed to protect against infected sand fly challenge. Two-photon intra-vital microscopy and flow cytometric analysis revealed that sand fly, but not needle challenge, resulted in the maintenance of a localized neutrophilic response at the inoculation site, and removal of neutrophils following vector transmission led to increased parasite-specific immune responses and promoted the efficacy of the killed vaccine. These observations identify the critical immunological factors influencing vaccine efficacy following natural transmission of Leishmania. C1 [Peters, Nathan C.; Kimblin, Nicola; Secundino, Nagila; Kamhawi, Shaden; Lawyer, Phillip; Sacks, David L.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Peters, NC (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM dsacks@nih.gov FU NIH FX This research was supported by the Intramural Research Program of the NIH, NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 78 Z9 79 U1 0 U2 7 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 JUN PY 2009 VL 5 IS 6 AR e1000484 DI 10.1371/journal.ppat.1000484 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 476LZ UT WOS:000268444500015 PM 19543375 ER PT J AU Sorin, M Cano, J Das, S Mathew, S Wu, XH Davies, KP Shi, XL Cheng, SWG Ott, D Kalpana, GV AF Sorin, Masha Cano, Jennifer Das, Supratik Mathew, Sheeba Wu, Xuhong Davies, Kelvin P. Shi, Xuanling Cheng, S. -W. Grace Ott, David Kalpana, Ganjam V. TI Recruitment of a SAP18-HDAC1 Complex into HIV-1 Virions and Its Requirement for Viral Replication SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CHROMATIN-REMODELING COMPLEX; TAT-ACTIVATED TRANSCRIPTION; CELL-CYCLE ARREST; REVERSE TRANSCRIPTION; RHABDOID TUMORS; C-MYC; INTEGRASE; INI1/HSNF5; MUTATIONS AB HIV-1 integrase (IN) is a virally encoded protein required for integration of viral cDNA into host chromosomes. INI1/hSNF5 is a component of the SWI/SNF complex that interacts with HIV-1 IN, is selectively incorporated into HIV-1 (but not other retroviral) virions, and modulates multiple steps, including particle production and infectivity. To gain further insight into the role of INI1 in HIV-1 replication, we screened for INI1-interacting proteins using the yeast two-hybrid system. We found that SAP18 (Sin3a associated protein 18 kD), a component of the Sin3a-HDAC1 complex, directly binds to INI1 in yeast, in vitro and in vivo. Interestingly, we found that IN also binds to SAP18 in vitro and in vivo. SAP18 and components of a Sin3A-HDAC1 complex were specifically incorporated into HIV-1 (but not SIV and HTLV-1) virions in an HIV-1 IN-dependent manner. Using a fluorescence-based assay, we found that HIV-1 (but not SIV) virion preparations harbour significant deacetylase activity, indicating the specific recruitment of catalytically active HDAC into the virions. To determine the requirement of virion-associated HDAC1 to HIV-1 replication, an inactive, transdominant negative mutant of HDAC1 (HDAC1(H141A)) was utilized. Incorporation of HDAC1(H141A) decreased the virion-associated histone deacetylase activity. Furthermore, incorporation of HDAC1(H141A) decreased the infectivity of HIV-1 (but not SIV) virions. The block in infectivity due to virion-associated HDAC1(H141A) occurred specifically at the early reverse transcription stage, while entry of the virions was unaffected. RNA-interference mediated knock-down of HDAC1 in producer cells resulted in decreased virion-associated HDAC1 activity and a reduction in infectivity of these virions. These studies indicate that HIV-1 IN and INI1/hSNF5 bind SAP18 and selectively recruit components of Sin3a-HDAC1 complex into HIV-1 virions. Furthermore, HIV-1 virion-associated HDAC1 is required for efficient early post-entry events, indicating a novel role for HDAC1 during HIV-1 replication. C1 [Sorin, Masha; Cano, Jennifer; Das, Supratik; Mathew, Sheeba; Wu, Xuhong; Davies, Kelvin P.; Cheng, S. -W. Grace; Kalpana, Ganjam V.] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA. [Shi, Xuanling; Kalpana, Ganjam V.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Ott, David] NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Sorin, M (reprint author), Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA. EM kalpana@aecom.yu.edu FU National Institutes of Health [R01 AI30051-01, T32-AI007501, AI-51519, NO1-CO-12400] FX This work was supported by the National Institutes of Health grant R01 AI30051-01, and by an Irma T. Hirschl scholar award to GVK. MS, JC, and SM wish to acknowledge Institutional AIDS training grant T32-AI007501. This work was supported in part by the Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center funded by the National Institutes of Health ( NIH AI-51519). This project was funded in part by NIH under contract NO1-CO-12400 to DO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 31 Z9 32 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 JUN PY 2009 VL 5 IS 6 AR e1000463 DI 10.1371/journal.ppat.1000463 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 476LZ UT WOS:000268444500025 PM 19503603 ER PT J AU Haaga, JG AF Haaga, John G. TI What's Next for the Demography of Aging? A Symposium SO POPULATION AND DEVELOPMENT REVIEW LA English DT Article ID UNITED-STATES; POPULATION; EVOLUTION; SENESCENCE; LONGEVITY AB This is an expanded version of comments on the future of the demography of aging at an invited session of the 2008 annual meeting of the Population Association of America. In an introduction, John Haaga offers reasons for a revival of interest in population aging, including greater realization of plasticity in aging trajectories at both individual and societal levels. Linda Martin proposes that population scientists working in aging emulate those studying fertility and family planning in previous decades, learning from interventions (in this case, aimed at increasing retirement savings and reducing disability at older ages). Changes in family structure will increasingly affect new cohorts of the elderly, and Linda Waite speculates on the ways in which changes in the economy, medicine, and the legal environment could affect the social context for aging. Research on mortality at older ages is "alive and well" asserts James Vaupel, who sets out six large questions on mortality trends and differentials over time and across species. Lastly, Wolfgang Lutz expands the scope of projections, showing the considerable uncertainty about the timing and pace of population aging in the developing world and the effects on future elderly of the increases in educational attainment in much of the world during the second half of the twentieth century. C1 NIA, Div Behav & Social Sci, Bethesda, MD 20892 USA. RP Haaga, JG (reprint author), NIA, Div Behav & Social Sci, Bethesda, MD 20892 USA. NR 21 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0098-7921 J9 POPUL DEV REV JI Popul. Dev. Rev. PD JUN PY 2009 VL 35 IS 2 BP 323 EP + PG 9 WC Demography; Sociology SC Demography; Sociology GA 458AH UT WOS:000266981200005 ER PT J AU Varmus, H AF Varmus, Harold TI Science Publishing and Science Libraries in the Internet Age SO PROCEEDINGS OF THE AMERICAN PHILOSOPHICAL SOCIETY LA English DT Article C1 [Varmus, Harold] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Varmus, Harold] NIH, Bethesda, MD 20892 USA. RP Varmus, H (reprint author), Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 7 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 JUN PY 2009 VL 153 IS 2 BP 160 EP 184 PG 25 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA 507JO UT WOS:000270849500005 ER PT J AU Lee, HJ Macbeth, AH Pagani, JH Young, WS AF Lee, Heon-Jin Macbeth, Abbe H. Pagani, Jerome H. Young, W. Scott, III TI Oxytocin: The great facilitator of life SO PROGRESS IN NEUROBIOLOGY LA English DT Review DE Vasopressin; Social recognition; Stress; Anxiety; Autism; Schizophrenia; Aggression; Sexual behavior; Bonding ID VOLES MICROTUS-OCHROGASTER; FEMALE PRAIRIE VOLES; OBSESSIVE-COMPULSIVE DISORDER; RECEPTOR GENE-EXPRESSION; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; MESSENGER-RIBONUCLEIC-ACID; MEDIAL PREOPTIC AREA; MATERNAL AGGRESSIVE-BEHAVIOR; VASOPRESSIN-BINDING-SITES; ANXIETY-RELATED BEHAVIOR AB Oxytocin (Oxt) is a nonapeptide hormone best known for its role in lactation and parturition. Since 1906 when its uteri ne-contracting properties were described until 50 years later when its sequence was elucidated, research has focused on its peripheral roles in reproduction. only over the past several decades have researchers focused on what functions Oxt might have in the brain, the subject of this review. Immunohistochemical studies revealed that magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei are the neurons of origin for the Oxt released from the posterior pituitary. Smaller cells in various parts of the brain. as well as release from magnocellular dendrites, provide the Oxt responsible for modulating various behaviors at its only identified receptor. Although Oxt is implicated in a variety of "non-social" behaviors, such as learning, anxiety, feeding and pain perception, it is Oxt's roles in various social behaviors that have come to the fore recently. Oxt is important for social memory and attachment, sexual and maternal behavior, and aggression. Recent work implicates Oxt in human bonding and trust as well. Human disorders characterized by aberrant social interactions, such as autism and schizophrenia, may also involve Oxt expression. Many, if not most, of Oxt's functions, from social interactions (affiliation, aggression) and sexual behavior to eventual parturition, lactation and maternal behavior, may be viewed as specifically facilitating species propagation. Published by Elsevier Ltd. C1 [Lee, Heon-Jin; Macbeth, Abbe H.; Pagani, Jerome H.; Young, W. Scott, III] NIMH, Sect Neural Gene Express, NIH, DHHS, Bethesda, MD 20892 USA. RP Young, WS (reprint author), 9000 Rockville Pike,Bldg 49,Room 5A60, Bethesda, MD 20892 USA. EM wsy@mail.nih.gov RI Young, W Scott/A-9333-2009; OI Young, W Scott/0000-0001-6614-5112; , Heon-Jin/0000-0002-1911-5014 FU NIMH [Z01-MH-002498-20] FX This work was supported by the NIMH Intramural Research Program (Z01-MH-002498-20). NR 448 TC 364 Z9 373 U1 19 U2 153 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD JUN PY 2009 VL 88 IS 2 BP 127 EP 151 DI 10.1016/j.pneurobio.2009.04.001 PG 25 WC Neurosciences SC Neurosciences & Neurology GA 463ZO UT WOS:000267473100004 PM 19482229 ER PT J AU Kawasaki, BT Hurt, EM Kalathur, M Duhagon, MA Milner, JA Kim, YS Farrar, WL AF Kawasaki, Brian T. Hurt, Elaine M. Kalathur, Madhuri Duhagon, Maria Ana Milner, John A. Kim, Young S. Farrar, William L. TI Effects of the Sesquiterpene Lactone Parthenolide on Prostate Tumor-Initiating Cells: An Integrated Molecular Profiling Approach SO PROSTATE LA English DT Article DE prostate; cancer stem cells; parthenolide; phytonutrient ID MYELOGENOUS LEUKEMIA STEM; NF-KAPPA-B; CANCER CELLS; PROGENITOR CELLS; ANDROGEN RECEPTOR; DOWN-REGULATION; BREAST-CANCER; EXPRESSION; MODEL; SRC AB Recent evidence suggests tumor-initating cells (TICs), also called cancer stem cells, are responsible for tumor initiation and progression; therefore, they represent an important cell population for development of future anti-cancer therapies. In this study, we show that the sesquiterpene lactone parthenolide (PTL) is cytotoxic to prostate TICs isolated from prostate cancer cell lines: DU145, PC3, VCAP, and LAPC4, as well as primary prostate TICs. Furthermore, PTL inhibited TIC-driven tumor formation in mouse xenografts. Using an integrated molecular profiling approach encompassing proteomics, profiles of activated transcription factors and genomics we ascertained the effects of PTL on prostate cancer cells. In addition to the previously described effects of PTL, we determined that the non-receptor tyrosine kinase src, and many src signaling components, including: Csk, FAK, beta 1-arrestin, FGFR2, PKC, MEK/MAPK, CaMK, ELK-1, and ELK-1-dependent genes are novel targets of PTL action. Furthermore, PTL altered the binding of transcription factors important in prostate cancer including: C/EBP-alpha, fos related antigen-1 (FRA-1), HOXA-4, c-MYB, SNAIL, SP1, serum response factor (SRF), STAT3, X-box binding protein-1 (XBP1), and p53. In summary, we show PTL is cytotoxic to prostate TICs and describe the molecular events of PTL-mediated cytotoxicity. Therefore, PTL represents a promising therapeutic for prostate cancer treatment. Prostate 69: 827-837, 2009. (c) 2009 Wiley-Liss, Inc. C1 [Kawasaki, Brian T.; Hurt, Elaine M.; Kalathur, Madhuri; Duhagon, Maria Ana; Farrar, William L.] NCI Frederick, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Duhagon, Maria Ana] Univ Republica, LIM F Ciencias, Montevideo, Uruguay. [Milner, John A.; Kim, Young S.] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Farrar, WL (reprint author), NCI Frederick, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, 1050 Boyles St,Bldg 560,Room 21-78, Frederick, MD 21702 USA. EM farrar@mail.ncifcrf.gov OI kalathur, madhuri/0000-0002-1534-5664 FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; Office of Dietary Supplements, National Institutes of Health; National Cancer Institute, National Institutes of Health [N01CO-12400] FX We would like to acknowledge Kathleen Noer, Roberta Matthai, and Samantha Baucherio for their technical assistance in FACS separation of cells. We also thank all the members of the Farrar laboratory for their helpful discussions. Grant support: This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. In addition, this work was funded in part by the Office of Dietary Supplements, National Institutes of Health. This work has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract no. N01CO-12400. The content of this paper 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 35 TC 51 Z9 57 U1 1 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD JUN 1 PY 2009 VL 69 IS 8 BP 827 EP 837 DI 10.1002/pros.20931 PG 11 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 449ZC UT WOS:000266368700004 PM 19204913 ER PT J AU Wang, MH Helzlsouer, KJ Smith, MW Hoffman-Bolton, JA Clipp, SL Grinberg, V De Marzo, AM Isaacs, WB Drake, CG Shugart, YY Platz, EA AF Wang, Ming-Hsi Helzlsouer, Kathy J. Smith, Michael W. Hoffman-Bolton, Judith A. Clipp, Sandra L. Grinberg, Viktoriya De Marzo, Angelo M. Isaacs, William B. Drake, Charles G. Shugart, Yin Yao Platz, Elizabeth A. TI Association of IL10 and Other Immune Response- and Obesity-Related Genes With Prostate Cancer in CLUE II SO PROSTATE LA English DT Article DE prostate cancer; single nucleotide polymorphism; inflammation; obesity ID ACTIVATED-RECEPTOR-GAMMA; C-REACTIVE PROTEIN; TRANSCRIPTION-FACTOR-7-LIKE-2 TCF7L2 GENE; TOLL-LIKE RECEPTOR-4; PRO12ALA POLYMORPHISM; CYTOKINE PRODUCTION; SEQUENCE VARIANTS; RISK; DISEASE; INTERLEUKIN-10 AB BACKGROUND. Chronic intra-prostatic inflammation and obesity are thought to influence prostate carcinogenesis. Thus, variants in genes in these pathways could be associated with prostate cancer risk. METHODS. We genotyped 17 common single nucleotide polymorphisms (SNPs) in RNASEL, TLR4, IL1B, IL6, IL8, IL10, TNF, CRP, ADIPOQ, LEP, PPARG, and TCF7L2 in 258 white prostate cancer cases and 258 matched controls nested in CLUE II. Single-locus analyses were conducted using conditional logistic regression. TagSNPs were selected in IL10, CRP, and TLR4 and haplotype analyses were done. RESULTS. The A allele of IL10 -1.082G > A (rs1800896), known to result in lower levels of this anti-inflammatory cytokine, was positively associated with risk (AG vs. GG, OR = 1.69, 95% CI: 1.10-2.60; AA vs. GG, OR = 1.81, 95% CI: 1.11-2.96; P(trend) = 0.02). Associations of IL10 haplotypes with prostate cancer were explained by high linkage disequilibrium between two tagSNPs (rs1800890 and rs3024496) and -1082G > A. A TLR4 candidate SNP (rs4986790; AG/GG vs. AA, OR = 0.60, 95% CI: 0.33-1.08; P(trend) = 0.09), known to have decreased expression and be associated with lower circulating levels of inflammatory mediators, and tagSNP (rs10116253; CC vs. TT, OR = 3.05, 95% CI: 1.11-8.41), but not haplotypes, were associated with risk. None of the other candidate SNPs or haplotypes was statistically significantly associated with risk. CONCLUSION. Our prospective study suggests that genetic variation in IL10 and possibly TLR4 is associated with prostate cancer risk. Although none of the SNPs in the obesity genes tested was associated, this does not rule out a complex role of obesity and its metabolic consequences in prostate cancer etiology. Prostate 69: 874-885, 2009. (c) 2009 Wiley-Liss, Inc. C1 [Wang, Ming-Hsi; Helzlsouer, Kathy J.; Hoffman-Bolton, Judith A.; Clipp, Sandra L.; Shugart, Yin Yao; Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Helzlsouer, Kathy J.] St Johns Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Helzlsouer, Kathy J.; Hoffman-Bolton, Judith A.; Clipp, Sandra L.] George W Comstock Ctr Publ Hlth Res & Prevent, Hagerstown, MD USA. [Helzlsouer, Kathy J.; De Marzo, Angelo M.; Isaacs, William B.; Drake, Charles G.; Platz, Elizabeth A.] Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Smith, Michael W.; Grinberg, Viktoriya] NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21701 USA. [Smith, Michael W.; Grinberg, Viktoriya] NCI, Lab Genom Div, Adv Technol Program, Frederick, MD 21701 USA. [De Marzo, Angelo M.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [De Marzo, Angelo M.; Isaacs, William B.; Drake, Charles G.; Platz, Elizabeth A.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Drake, Charles G.] Johns Hopkins Med Inst, Dept Immunol, Baltimore, MD 21205 USA. RP Platz, EA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Room E6132,615 N Wolfe St, Baltimore, MD 21205 USA. EM eplatz@jhsph.edu RI Smith, Michael/B-5341-2012 FU National Cancer Institute, Prostate Cancer Specialized Program of Research Excellence [P50 CA58236]; National Cancer Institute, Early Detection Research Network [U01 CA86308]; National Cancer Institute [N01 C012400]; National Institute of Aging [U01 AG18033]; American Institute for Cancer Research FX Grant sponsor: National Cancer Institute, Prostate Cancer Specialized Program of Research Excellence (Career Development Award); Grant number: P50 CA58236; Grant sponsor: National Cancer Institute, Early Detection Research Network; Grant number: U01 CA86308; Grant sponsor: National Cancer Institute; Contract number: N01 C012400; Grant sponsor: National Institute of Aging; Grant number: U01 AG18033; Grant sponsor: American Institute for Cancer Research. NR 57 TC 74 Z9 77 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD JUN 1 PY 2009 VL 69 IS 8 BP 874 EP 885 DI 10.1002/pros.20933 PG 12 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 449ZC UT WOS:000266368700008 PM 19267370 ER PT J AU FitzGerald, LM Karlins, E Karyadi, DM Kwon, EM Koopmeiners, JS Stanford, JL Ostrander, EA AF FitzGerald, L. M. Karlins, E. Karyadi, D. M. Kwon, E. M. Koopmeiners, J. S. Stanford, J. L. Ostrander, E. A. TI Association of FGFR4 genetic polymorphisms with prostate cancer risk and prognosis SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article DE population-based association analysis; FGFR4; radical prostatectomy ID GLY388ARG POLYMORPHISM; OVER-EXPRESSION; BREAST-CANCER; INTRAEPITHELIAL NEOPLASIA; ARG(388) ALLELE; GROWTH; RECEPTOR; ADENOCARCINOMA; THERAPY; PROGRESSION AB The fibroblast growth factor receptor 4 (FGFR4) is thought to be involved in many critical cellular processes and has been associated with prostate cancer risk. Four single nucleotide polymorphisms (SNPs) within or near FGFR4 were analyzed in a population-based study of 1458 prostate cancer patients and 1352 age-matched controls. We found no evidence to suggest that any of the FGFR4 SNP genotypes were associated with prostate cancer risk or with disease aggressiveness, Gleason score or stage. A weak association was seen between rs351855 and prostate cancer-specific mortality. Subset analysis of cases that had undergone radical prostatectomy revealed an association between rs351855 and prostate cancer risk. Although our results confirm an association between FGFR4 and prostate cancer risk in radical prostatectomy cases, they suggest that the role of FGFR4 in disease risk and outcomes at a population-based level appears to be minor. Prostate Cancer and Prostatic Diseases (2009) 12, 192-197; doi:10.1038/pcan.2008.46; published online 2 September 2008 C1 [Karlins, E.; Karyadi, D. M.; Kwon, E. M.; Ostrander, E. A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [FitzGerald, L. M.; Koopmeiners, J. S.; Stanford, J. L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Stanford, J. L.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. RP Ostrander, EA (reprint author), NHGRI, Canc Genet Branch, NIH, 50 S Dr,Bldg 50,Room 5351, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU National Cancer Institute [RO1 CA56678, RO1 CA82664, RO1 CA092579, P50 CA97186]; Fred Hutchinson Cancer Research Center; National Human Genome Research Institute FX We thank all the men who participated in this study for their time, effort and cooperation. This work was supported by grants RO1 CA56678, RO1 CA82664, RO1 CA092579 and P50 CA97186 from the National Cancer Institute; additional support was provided by the Fred Hutchinson Cancer Research Center and the Intramural Program of the National Human Genome Research Institute. NR 30 TC 14 Z9 16 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD JUN PY 2009 VL 12 IS 2 BP 192 EP 197 DI 10.1038/pcan.2008.46 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 444KT UT WOS:000265980600015 PM 18762813 ER PT J AU Sharma, D Masison, DC AF Sharma, Deepak Masison, Daniel C. TI Hsp70 Structure, Function, Regulation and Influence on Yeast Prions SO PROTEIN AND PEPTIDE LETTERS LA English DT Review DE Hsp70; chaperone; co-chaperone; prion ID MOLECULAR CHAPERONE DNAK; HEAT-SHOCK PROTEINS; NUCLEOTIDE EXCHANGE FACTOR; TRANSMEMBRANE CONDUCTANCE REGULATOR; ESCHERICHIA-COLI DNAJ; BETA-SHEET STRUCTURE; SACCHAROMYCES-CEREVISIAE; ENDOPLASMIC-RETICULUM; SUBSTRATE-BINDING; ATPASE ACTIVITY AB Heat shock proteins protect cells from various conditions of stress. Hsp70, the most ubiquitous and highly conserved Hsp, helps proteins adopt native conformation or regain function after misfolding. Various co-chaperones specify Hsp70 function and broaden its substrate range. We discuss Hsp70 structure and function, regulation by co-factors and influence on propagation of yeast prions. C1 [Sharma, Deepak; Masison, Daniel C.] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Masison, DC (reprint author), LBG NIDDK, NIH, Bldg 8,Room 407, Bethesda, MD 20892 USA. EM masisond@helix.nih.gov FU Intramural NIH HHS [Z01 DK024946-10] NR 116 TC 36 Z9 45 U1 0 U2 22 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8665 J9 PROTEIN PEPTIDE LETT JI Protein Pept. Lett. PD JUN PY 2009 VL 16 IS 6 BP 571 EP 581 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 458UH UT WOS:000267049500002 PM 19519514 ER PT J AU Greene, LE Park, YN Masison, DC Eisenberg, E AF Greene, Lois E. Park, Yang-Nim Masison, Daniel C. Eisenberg, Evan TI Application of GFP-Labeling to Study Prions in Yeast SO PROTEIN AND PEPTIDE LETTERS LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; SACCHAROMYCES-CEREVISIAE; PSI+ PRION; URE3 PRION; PROTEIN; PROPAGATION; HSP104; CHAPERONE; CELLS; SEEDS AB Fluorescent live cell imaging has recently been used in numerous studies to examine prions in yeast. These fluorescence studies take advantage of the fact that unlike the normally folded form, the misfolded amyloid form of the prion protein is aggregated. The studies have used fluorescence to identify new prions, to study the transmission of prion from mother to daughter, and to understand the role of molecular chaperones in this transmission. The use of fluorescence imaging complements the more standard methods used to study prion propagation. This review discusses the various studies that have taken advantage of fluorescence imaging technique particularly in regard to understanding the transmission and curing of the [PSI(+)], the prion form of the translation termination factor Sup35p. C1 [Greene, Lois E.; Park, Yang-Nim; Eisenberg, Evan] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Masison, Daniel C.] NIDDKD, Lab Biochem & Genet, Bethesda, MD 20892 USA. RP Greene, LE (reprint author), NHLBI, Cell Biol Lab, NIH, 50 S Dr Rm 2537 MSC 8017, Bethesda, MD 20892 USA. EM greenel@helix.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 39 TC 6 Z9 7 U1 0 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8665 J9 PROTEIN PEPTIDE LETT JI Protein Pept. Lett. PD JUN PY 2009 VL 16 IS 6 BP 635 EP 641 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 458UH UT WOS:000267049500010 PM 19519522 ER PT J AU Pang, J Zeng, XK Xiao, RP Lakatta, EG Lin, L AF Pang, John Zeng, Xiaokun Xiao, Rui-ping Lakatta, Edward G. Lin, Li TI Design, generation, and testing of mammalian expression modules that tag membrane proteins SO PROTEIN SCIENCE LA English DT Article DE membrane protein expression module; epitope tag; RAGE signal peptide; multicloning sites; western blotting; immunoprecipitation; immunohistochemistry ID CELL-SURFACE EXPRESSION; RECOMBINANT PROTEINS; QUALITY-CONTROL; AT(1) RECEPTOR; GLYCOSYLATION; LOCALIZATION; TRAFFICKING; INSERTION; PEPTIDE; ALPHA AB The expression of mammalian membrane proteins in laboratory cell lines allows their biological functions to be characterized and carefully dissected. However, it is often difficult to design and generate effective antibodies for membrane proteins in the desired studies. As a result, expressed membrane proteins cannot be detected or characterized via common biochemical approaches such as western blotting, immunoprecipitation, or immunohistochemical analysis, and their cellular behaviors cannot be sufficiently investigated. To circumvent such roadblocks, we designed and generated two sets of expression modules that consist of sequences encoding for three essential components: (1) a signal peptide from human receptor for advanced glycation end products that targets the intended protein to the endoplasmic reticulum for cell surface expression; (2) an antigenic epitope tag that elicits specific antibody recognition; and (3) a series of restriction sites that facilitate subcloning of the target membrane protein. The modules were designed with the flexibility to change the epitope tag to suit the specific tagging needs. The modules were subcloned into expression vectors, and were successfully tested with both Type I and Type III human membrane proteins: the receptor for advanced glycation end products, the Toll-like receptor 4, and the angiotensin II receptor 1. These expressed membrane proteins are readily detected by western blotting, and are immunoprecipitated by antibodies to their relative epitope tags. Immunohistochemical and biochemical analyses also show that the expressed proteins are located at cell surface, and maintain their modifications and biological functions. Thus, the designed modules serve as an effective tool that facilitates biochemical studies of membrane proteins. C1 [Pang, John; Xiao, Rui-ping; Lakatta, Edward G.; Lin, Li] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Zeng, Xiaokun; Lin, Li] MedStar Res Inst, Hyattsville, MD 20783 USA. RP Lin, L (reprint author), NIA, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM linli@mail.nih.gov FU NIH [RO1CA104912]; National Institute on Aging; Medstar Research Institute [NIA 2008] FX Grant sponsor: NIH; Grant number: RO1CA104912; Grant sponsors: National Institute on Aging (NIA) Intramural Research Program; Medstar Research Institute; NIA 2008 Summer Student Internship Program NR 26 TC 7 Z9 7 U1 0 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD JUN PY 2009 VL 18 IS 6 BP 1261 EP 1271 DI 10.1002/pro.136 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 469FU UT WOS:000267882100014 PM 19472344 ER PT J AU Burroughs, AM Iyer, LM Aravind, L AF Burroughs, A. Maxwell Iyer, Lakshminarayan M. Aravind, L. TI Natural history of the E1-like superfamily: Implication for adenylation, sulfur transfer, and ubiquitin conjugation SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE ubiquitin; evolution; E1; Uba; microcin; secondary metabolism; cysteinyl tRNA synthetase; goadsporin; TBP; sulphur transfer ID MULTIPLE SEQUENCE ALIGNMENT; RHODANESE-LIKE DOMAIN; IN-VITRO SYNTHESIS; ESCHERICHIA-COLI; MOLYBDENUM COFACTOR; MOLYBDOPTERIN SYNTHASE; CRYSTAL-STRUCTURE; GENE-CLUSTER; STRUCTURE PREDICTION; COMPARATIVE GENOMICS AB The E1-like superfamily is central to ubiquitin (Ub) conjugation, biosynthesis of cysteine, thiamine, and MoCo, and several secondary metabolites. Yet, its functional diversity and evolutionary history is not well understood. We develop a natural classification of this superfamily and use it to decipher the major adaptive trends occurring in the evolution of the El-like superfamily. Within the Rossmann fold, El-like proteins are closest to NAD(P)/FAD-dependent dehydrogenases and S-AdoMet-dependent methyltransferases. Hence, their phosphotransfer activity is an independent catalytic "invention" with respect to such activities seen in other Rossmannoid folds. Sequence and structure analysis reveals a striking diversity of residues and structures involved in adenylation, sulfotransfer, and substrate binding between different El-like families, allowing us to predict previously uncharacterized functional adaptations. E1-like proteins are fused to several previously undetected domains, such as a predicted sulfur transfer domain containing a novel superfamily of the TATA-binding protein fold, different types of catalytic domains, a novel winged helix-turn-helix domain and potential adaptor domains related to Ub conjugation. On the basis of these fusions, we develop a generalized model for the linking of E1 catalyzed adenylation/thiolation with further downstream reactions. This is likely to involve a dynamic interplay between the El active sites and diverse fused C-terminal domains. We also predict participation of El-like domains in previously uncharacterized bacterial secondary metabolism pathways, new cysteine biosynthesis systems, such as those associated with archaeal O-phosphoseryl tRNA, metal-sulfur cluster assembly (e.g., in nitrogen fixation) and Ub-conjugation. Evolutionary reconstructions suggest that the last universal common ancestor contained a single El-like domain possessing both phosphotransfer and thiolating activities and participating in multiple sulfotransfer reactions. The E1-like superfamily subsequently expanded to include 26 families clustering into three major radiations. These are broadly involved in Ub activation, cofactor and cysteine biosynthesis, and biosynthesis of secondary metabolites. In light of this, we present evidence that in eukaryotes other El-like enzymes such as Urm1 were independently recruited for Ub1 conjugation, probably functioning without conventional E2-like enzymes. C1 [Burroughs, A. Maxwell; Iyer, Lakshminarayan M.; Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Burroughs, A. Maxwell] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM aravind@mail.nih.gov FU Intramural NIH HHS [Z99 LM999999, Z01 LM594244-01] NR 72 TC 47 Z9 48 U1 1 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUN PY 2009 VL 75 IS 4 BP 895 EP 910 DI 10.1002/prot.22298 PG 16 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 446PM UT WOS:000266133600010 PM 19089947 ER PT J AU Amstadter, AB Nugent, NR Koenen, KC AF Amstadter, Ananda B. Nugent, Nicole R. Koenen, Karestan C. TI Genetics of PTSD: Fear Conditioning as a Model for Future Research SO PSYCHIATRIC ANNALS LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; PITUITARY-ADRENAL AXIS; ENVIRONMENTAL-INFLUENCES; VAL66MET POLYMORPHISM; PSYCHOLOGICAL TRAUMA; HIPPOCAMPAL VOLUME; MAJOR DEPRESSION; INJURED CHILDREN; TRANSPORTER GENE; COMBAT VETERANS C1 [Koenen, Karestan C.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Koenen, Karestan C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Amstadter, Ananda B.] Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. [Amstadter, Ananda B.] Med Univ S Carolina, Dept Behav Sci, Charleston, SC 29425 USA. [Nugent, Nicole R.] Brown Univ, Sch Med, NIMH, Inst Res Training Program, Providence, RI 02912 USA. RP Koenen, KC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, 677 Huntington Ave,Kresge 613, Boston, MA 02115 USA. EM kkoenen@hsph.harvard.edu FU NIMH NIH HHS [T32 MH078788-02, F32 MH083469-01, K01 MH087240, K08 MH070627, F32 MH083469, K08 MH070627-05, R01 MH078928, R01 MH078928-01A1, T32 MH078788] NR 74 TC 60 Z9 62 U1 6 U2 16 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD JUN PY 2009 VL 39 IS 6 BP 358 EP + DI 10.3928/00485713-20090526-01 PG 13 WC Psychiatry SC Psychiatry GA 458GY UT WOS:000267004900008 PM 19779593 ER PT J AU Vasic, N Walter, H Sambataro, F Wolf, RC AF Vasic, N. Walter, H. Sambataro, F. Wolf, R. C. TI Aberrant functional connectivity of dorsolateral prefrontal and cingulate networks in patients with major depression during working memory processing SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Cingulate gyrus; fMRI; independent component analysis; major depression; prefrontal cortex; working memory ID N-BACK TASK; INDEPENDENT COMPONENT ANALYSIS; BOLD SIGNAL FLUCTUATIONS; EVENT-RELATED FMRI; DEFAULT-MODE; RESTING-STATE; UNIPOLAR DEPRESSION; EXECUTIVE FUNCTIONS; BRAIN-FUNCTION; ACTIVATION AB Background. In patients with major depressive disorder (MDD), functional neuroimaging studies have reported an increased activation of the dorsolateral prefrontal cortex (DLPFC) during executive performance and working memory (WM) processing, and also an increased activation of the anterior cingulate cortex (ACC) during baseline conditions. However, the functional coupling of these cortical networks during WM processing is less clear. Method. In this study, we used a verbal WM paradigm, event-related functional magnetic resonance imaging (fMRI) and multivariate statistical techniques to explore patterns of functional coupling of temporally dissociable dorsolateral prefrontal and cingulate networks. By means of independent component analyses (ICAs), two components of interest were identified that showed either a positive or a negative temporal correlation with the delay period of the cognitive activation task in both healthy controls and MDD patients. Results. In a prefronto-parietal network, a decreased functional connectivity pattern was identified in depressed patients comprising inferior parietal, superior prefrontal and frontopolar regions. Within this cortical network, MDD patients additionally revealed a pattern of increased functional connectivity in the left DLPFC and the cerebellum compared to healthy controls. In a second, temporally anti-correlated network, healthy controls exhibited higher connectivity in the ACC, the ventrolateral and the superior prefrontal cortex compared to MDD patients. Conclusions. These results complement and expand previous functional neuroimaging findings by demonstrating a dysconnectivity of dissociable prefrontal and cingulate regions in MDD patients. A disturbance of these dynamic networks is characterized by a simultaneously increased connectivity of the DLPFC during task-induced activation and increased connectivity of the ACC during task-induced deactivation. C1 [Vasic, N.; Wolf, R. C.] Univ Ulm, Dept Psychiat & Psychotherapy 3, D-89075 Ulm, Germany. [Walter, H.] Univ Bonn, Dept Psychiat, Div Med Psychol, D-5300 Bonn, Germany. [Sambataro, F.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. RP Vasic, N (reprint author), Univ Ulm, Dept Psychiat & Psychotherapy, Leimgrubenweg 12-14, D-89075 Ulm, Germany. EM nenad.vasic@uni-ulm.de RI Sambataro, Fabio/E-3426-2010; Walter, Henrik/O-2612-2013 OI Sambataro, Fabio/0000-0003-2102-416X; FU Sanofi-Synthelabo [D 1218] FX This study was partly financially supported by a grant (no. D 1218) from Sanofi-Synthelabo. NR 52 TC 66 Z9 69 U1 2 U2 14 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 JUN PY 2009 VL 39 IS 6 BP 977 EP 987 DI 10.1017/S0033291708004443 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 455GI UT WOS:000266746000010 PM 18845009 ER PT J AU Ren, ZY Shi, J Epstein, DH Wang, J Lu, L AF Ren, Zhen-Yu Shi, Jie Epstein, David H. Wang, Jun Lu, Lin TI Abnormal pain response in pain-sensitive opiate addicts after prolonged abstinence predicts increased drug craving SO PSYCHOPHARMACOLOGY LA English DT Article DE Craving; Heroin; Addiction; Pain ID CUE-INDUCED RESPONSES; METHADONE-MAINTENANCE; HEROIN USERS; SMOKING CUES; COCAINE; REACTIVITY; HYPERALGESIA; TOLERANCE; ABUSERS; STRESS AB Craving is a primary feature of opiate addiction and is clinically significant because of its potential to trigger opiate use and relapse. Opiate use can also produce abnormal pain perception. We predicted that for opiate addicts (OAs), there may be an association between these two major features of addiction (drug craving and abnormal pain responses). To examine pain responses in abstinent opiate addicts in comparison with healthy controls using a cold-pressor test (CPT) and investigate the correlations of cue-induced drug craving with pain responses. Fifty-four abstinent OAs and 46 healthy subjects participated in the CPT, and the OAs were also exposed to heroin-related cues the day before the pain test. Outcome measures included pain-tolerance time, VAS ratings of pain intensity and distress, and (in the cue-exposure procedure) VAS ratings of heroin craving and anxiety. In the CPT, abstinent addicts showed shorter pain-tolerance time (85.1 +/- 14.1 s vs. 133.7 +/- 16.7 s, p < 0.05) and higher ratings of pain distress (61 +/- 3.2 vs. 45.6 +/- 3.2, p < 0.01) compared to healthy controls. When we divided the addicts and controls into pain-sensitive (PS) and pain-tolerant (PT) groups by dichotomizing each group in terms of pain-tolerance time, we again found differences between the two PS groups (37.3 +/- 3.5 s vs. 57.4 +/- 5.1 s, p < 0.01 for pain-tolerance time; 66.7 +/- 3.2 vs. 52.4 +/- 3.3, p < 0.01 for distress ratings). For all participants, pain-tolerance time was negatively correlated with VAS ratings for pain intensity and distress. More importantly, the PS addicts reported greater cue-induced craving than the PT addicts (17.8 +/- 2.2 vs. 4.5 +/- 4.2, p < 0.05). For the addict group as a whole, pain distress (the affective aspect of pain) was positively correlated with intensity of cue-induced craving measured on a different day (r = 0.33, p = 0.01). A hyperalgesic state persists for at least 5 months in abstinent OAs and is predictive of cue-induced craving. Longitudinal research is needed to clarify the direction of causation between hyperalgesia and opiate addiction. C1 [Ren, Zhen-Yu; Shi, Jie; Wang, Jun; Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Beijing 100083, Peoples R China. [Epstein, David H.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Lu, L (reprint author), Peking Univ, Natl Inst Drug Dependence, 38 Xue Yuan Rd, Beijing 100083, Peoples R China. EM linlu@bjmu.edu.cn FU National Basic Research Program of China [2007CB512302, 2009CB522004]; National High Technology Research and Development Program of China [2006AA02Z4D1]; China-Canada Joint Health Research Program [30611120528] FX This work was supported in part by the grant from the National Basic Research Program of China (973 Program, 2007CB512302 and 2009CB522004), the National High Technology Research and Development Program of China (863 Program, 2006AA02Z4D1), and the China-Canada Joint Health Research Program (No: 30611120528). We thank Xiaoli Zhang, Jingjie Yu, and Tangying Lu for technical assistant and Yu Liu for helpful comments on an early version of the manuscript. NR 46 TC 33 Z9 33 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 2009 VL 204 IS 3 BP 423 EP 429 DI 10.1007/s00213-009-1472-0 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 445XV UT WOS:000266085700005 PM 19172249 ER PT J AU Vasa, RA Pine, DS Masten, CL Vythilingam, M Collin, C Charney, DS Neumeister, A Mogg, K Bradley, BP Bruck, M Monk, CS AF Vasa, Roma A. Pine, Daniel S. Masten, Carrie L. Vythilingam, Meena Collin, Carlos Charney, Dennis S. Neumeister, Alexander Mogg, Karin Bradley, Brendan P. Bruck, Maggie Monk, Christopher S. TI Effects of yohimbine and hydrocortisone on panic symptoms, autonomic responses, and attention to threat in healthy adults SO PSYCHOPHARMACOLOGY LA English DT Article DE Yohimbine; Hydrocortisone; Panic symptoms; Attention; Threat cues; Adults ID POSTTRAUMATIC-STRESS-DISORDER; PRECONSCIOUS SELECTIVE ATTENTION; GENERALIZED ANXIETY DISORDER; PITUITARY-ADRENAL AXIS; CORTICOTROPIN-RELEASING-FACTOR; SALIVARY CORTISOL-LEVELS; NORADRENERGIC FUNCTION; EMOTIONAL FACES; SOCIAL ANXIETY; ANGRY FACES AB Research in rodents and non-human primates implicates the noradrenergic system and hypothalamic-pituitary-adrenal axis in stress, anxiety, and attention to threat. Few studies examine how these two neurochemical systems interact to influence anxiety and attention in humans. The objective of this paper is to examine the effects of exogenous yohimbine and hydrocortisone, as well as their combination (Y + H), on panic symptoms and attention to social threat cues. Thirty-two healthy adults underwent a pharmacological challenge in which they were blindly randomized to either yohimbine, hydrocortisone, Y + H, or placebo. Thirty minutes after drug infusion, attention to threat was measured using the dot probe task, a visual attention task that presents angry, happy, and neutral faces and measures the degree of attention allocated towards or away from the emotional faces. Panic and autonomic measures were assessed before and 30 min after drug infusion. There was a significant increase in panic symptoms in the yohimbine and Y + H groups, but not in the hydrocortisone or placebo groups. Yohimbine resulted in a greater increase in panic symptoms than Y + H. On the dot probe task, the placebo group exhibited an attention bias to angry faces, whereas this bias was absent after yohimbine. When collapsing across groups, increased panic symptoms was associated with less attention to angry faces. Exogenous hydrocortisone may attenuate noradrenergic-induced panic symptoms. The inverse relationship between panic symptoms and attention to angry faces extends prior research demonstrating attention modulation by stressful conditions. C1 [Vasa, Roma A.] Johns Hopkins Univ, Sch Med, Kennedy Krieger Inst, Dept Psychiat, Baltimore, MD 21211 USA. [Pine, Daniel S.; Vythilingam, Meena; Collin, Carlos] Natl Inst Mental Hlth, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Dev, Bethesda, MD 20892 USA. [Masten, Carrie L.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Charney, Dennis S.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Charney, Dennis S.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Charney, Dennis S.] Mt Sinai Sch Med, Dept Pharmacol & Biol Chem, New York, NY 10029 USA. [Neumeister, Alexander] Yale Univ, Sch Med, Clin Neurosci Div, West Haven, CT 06516 USA. [Mogg, Karin; Bradley, Brendan P.] Univ Southampton, Sch Psychol, Southampton SO17 1BJ, Hants, England. [Bruck, Maggie] Johns Hopkins Med Inst, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Monk, Christopher S.] Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. RP Vasa, RA (reprint author), Johns Hopkins Univ, Sch Med, Kennedy Krieger Inst, Dept Psychiat, Baltimore, MD 21211 USA. EM vasa@kennedykrieger.org RI Mogg, Karin/C-1181-2008; Bradley, Brendan/B-9724-2008; Monk, Christopher/J-1805-2014; OI Mogg, Karin/0000-0002-2738-7378; Bradley, Brendan/0000-0003-2801-4271 FU Intramural NIH HHS; NIMH NIH HHS [K23 MH071567-03, K23 MH071567-04, K23 MH071567] NR 81 TC 26 Z9 27 U1 11 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 2009 VL 204 IS 3 BP 445 EP 455 DI 10.1007/s00213-009-1475-x PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 445XV UT WOS:000266085700007 PM 19266185 ER PT J AU Wen, H Bennett, EE Hegedus, MM Rapacchi, S AF Wen, Han Bennett, Eric E. Hegedus, Monica M. Rapacchi, Stanislas TI Fourier X-ray Scattering Radiography Yields Bone Structural Information SO RADIOLOGY LA English DT Article ID GRATING INTERFEROMETER; BREAST-CANCER; DIFFRACTION; MICROSCOPE; SPECTRA; CT AB Purpose: To characterize certain aspects of the microscopic structures of cortical and trabecular bone by using Fourier x-ray scattering imaging. Materials and Methods: Protocols approved by the National Institutes of Health Animal Care and Use Committee were used to examine ex vivo the hind limb of a rat and the toe of a pig. The Fourier x-ray scattering imaging technique involves the use of a grid mask to modulate the cone beam and Fourier spectral filters to isolate the harmonic images. The technique yields attenuation, scattering, and phase-contrast (PC) images from a single exposure. In the rat tibia cortical bone, the scattering signals from two orthogonal grid orientations were compared by using Wilcoxon signed rank tests. In the pig toe, the heterogeneity of scattering and PC signals was compared between trabecular and compact bone regions of uniform attenuation by using F tests. Results: In cortical bone, the scattering signal was significantly higher (P < 10(-15)) when the grid was parallel to the periosteal surface. Trabecular bone, as compared with cortical bone, appeared highly heterogeneous on the scattering (P < 10(-34)) and PC (P < 10(-27)) images. Conclusion: The ordered alignment of the mineralized collagen fibrils in compact bone was reflected in the anisotropic scattering signal in this bone. In trabecular bone, the porosity of the mineralized matrix accounted for the granular pattern seen on the scattering and PC images. (C) RSNA, 2009 C1 [Wen, Han; Bennett, Eric E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Hegedus, Monica M.] Thomas Jefferson Med Coll, Philadelphia, PA USA. [Rapacchi, Stanislas] Ctr Rech & Applicat Traitement Image, Lyon, France. [Rapacchi, Stanislas] Inst Natl Sci Appl Lyon, Signal Lab Resonance Magnet Nucl, Lyon, France. RP Wen, H (reprint author), NHLBI, NIH, Bldg 10,B1D416,10 Ctr Dr, Bethesda, MD 20892 USA. EM wenh@nhlbi.nih.gov RI Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 FU Intramural NIH HHS NR 32 TC 61 Z9 61 U1 2 U2 12 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUN PY 2009 VL 251 IS 3 BP 910 EP 918 DI 10.1148/radiol.2521081903 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 475MD UT WOS:000268362700035 PM 19403849 ER PT J AU Vestergaard, S Patel, KV Bandinelli, S Ferrucci, L Guralnik, JM AF Vestergaard, Sonja Patel, Kushang V. Bandinelli, Stefania Ferrucci, Luigi Guralnik, Jack M. TI Characteristics of 400-Meter Walk Test Performance and Subsequent Mortality in Older Adults SO REJUVENATION RESEARCH LA English DT Article ID INCIDENT MOBILITY DISABILITY; LOWER-EXTREMITY FUNCTION; DISTANCE CORRIDOR WALK; GAIT VARIABILITY; CARDIORESPIRATORY FITNESS; INCHIANTI; BATTERY; ASSOCIATION; LIMITATION; ABILITY AB The purpose was to examine the relationship between performance in the 400-meter walking test and mortality. Data are from a population-based sample of 948 Italian men and women >= 65 years. The main outcome measures that were assessed comprised time to complete the 400-meter walk, 20-meter lap time coefficient of variation, need to rest during the test, and ability to complete the walk. All-cause mortality was ascertained over a 6-year follow-up period. Data were analyzed with proportional hazard logistic and linear regression analyses. In age- and sex-adjusted analyses, all 400-meter walking test variables except need to rest were associated with mortality. After further adjusting for the Mini-Mental State Examination, symptoms of depression, education, smoking, body mass index, being sedentary / minimally active, disease burden, and lower extremity performance (Short Physical Performance Battery score), both time to complete the 400-meter walk and lap time coefficient of variation were significant independent predictors of mortality. We conclude that multiple aspects of performance in the 400-meter walk test provide complementary information on mortality prognosis in older persons. C1 [Vestergaard, Sonja; Patel, Kushang V.; Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Patel, Kushang V.] MedStar Res Inst, Hyattsville, MD USA. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Bethesda, MD 20892 USA. RP Vestergaard, S (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, 7201 Wisconsin Ave,Suite 3C309, Bethesda, MD 20892 USA. EM vestergaards@mail.nih.gov FU Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1/N.1-AG-1-2111, N01-AG-5-0002] FX The InCHIANTI baseline study was supported as a targeted project (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (contracts 263 MD 9164 and 263 MD 821336). The InCHIANTI Follow-up 1 and 2 were funded by the U.S. National Institute on Aging (contracts N.1-AG-1-1/N.1-AG-1-2111 and N01-AG-5-0002, respectively) and supported in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. The granting institutions named above did not interfere in any way with the design, methods, participants' recruitment, data collection, or analysis and preparation of the manuscript. NR 18 TC 36 Z9 38 U1 0 U2 2 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 JUN PY 2009 VL 12 IS 3 BP 177 EP 184 DI 10.1089/rej.2009.0853 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 469VT UT WOS:000267929500003 PM 19594326 ER PT J AU Beydoun, HA Stadtmauer, L Beydoun, MA Russell, H Zhao, YQ Oehninger, S AF Beydoun, Hind A. Stadtmauer, Laurel Beydoun, May A. Russell, Helena Zhao, Yueqin Oehninger, Sergio TI Polycystic ovary syndrome, body mass index and outcomes of assisted reproductive technologies SO REPRODUCTIVE BIOMEDICINE ONLINE LA English DT Article DE body mass index; infertility; obesity; polycystic ovary syndrome; pregnancy; reproduction ID ANTI-MULLERIAN HORMONE; IN-VITRO FERTILIZATION; METABOLIC SYNDROME; INSULIN-RESISTANCE; WOMEN; HYPERSTIMULATION; PREVALENCE; IVF; IMPACT; METAANALYSIS AB The purpose of this study was to examine the effects of polycystic ovary syndrome (PCOS) and body mass index (BMI) oil selected indicators of IVF or intracytoplasmic sperm injection (ICSI) treatment success. A retrospective cohort study was conducted using existing data on 69 IVF/ICSI treatment cycles undergone by PCOS women and an individually matched sample of 69 IVF/ICSI treatment cycles undergone by non-PCOS women at a major fertility treatment Centre. BMI (kg/m(2)) was analysed as a continuous and categorical (<25, 25-29.9,>= 30) variable. Results indicated that PCOS was directly associated with the number of oocytes retrieved. Irrespective of PCOS status. continuous BMI was inversely associated with total and mature oocytes retrieved. Multiple linear regression analyses indicated no significant effects of PCOS or continuous BMI oil the number of mature oocytes fertilized per mature oocyte retrieved or inseminated. Similarly, multiple logistic regression analyses suggested no significant effect of PCOS and continuous BMI on the odds of pregnancy, miscarriage or live birth. Furthermore, categorical BMI did not influence process and outcome measures of IVF/ICSI treatment success. PCOS and continuous BMI appear to have significant and distinct effects oil early stages. but not Oil later stages. of IVF/ICSI treatment. C1 [Beydoun, Hind A.; Zhao, Yueqin] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Beydoun, Hind A.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [Stadtmauer, Laurel; Russell, Helena; Oehninger, Sergio] Eastern Virginia Med Sch, Jones Inst Reprod Med, Norfolk, VA 23501 USA. [Beydoun, May A.] NIA, Baltimore, MD 21224 USA. RP Beydoun, HA (reprint author), Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. EM baydouha@evms.edu FU Intramural NIH HHS [Z01 AG000185-18] NR 34 TC 16 Z9 16 U1 0 U2 6 PU REPRODUCTIVE HEALTHCARE LTD PI CAMBRIDGE PA DUCK END FARM, DRY DRAYTON, CAMBRIDGE, CB3 8DB, ENGLAND SN 1472-6483 J9 REPROD BIOMED ONLINE JI Reprod. Biomed. Online PD JUN PY 2009 VL 18 IS 6 BP 856 EP 863 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 455HV UT WOS:000266750300017 PM 19490792 ER PT J AU Tudor-Locke, C McClain, JJ Hart, TL Sisson, SB Washington, TL AF Tudor-Locke, Catrine McClain, James J. Hart, Teresa L. Sisson, Susan B. Washington, Tracy L. TI Expected Values for Pedometer-Determined Physical Activity in Youth SO RESEARCH QUARTERLY FOR EXERCISE AND SPORT LA English DT Article DE assessment; children; exercise; motion sensors ID BODY-MASS INDEX; SCHOOL-CHILDREN; ACTIVITY LEVEL; ADOLESCENTS; OBESITY; OVERWEIGHT; EDUCATION; SWEDEN; ADULTS; FAT AB The review assembles pedometry literature focused on youth, with particular attention to expected values for habitual, school day, physical education class, recess, lunch break, out-of-school, weekend, and vacation activity. From 31 studies published since 1999, we constructed a youth habitual activity step-curve that indicates: (a) from ages 6 to 18 years, boys typically take more steps per day than girls; (c) for both sexes the youngest age groups appear to take fewer steps per day than those immediately older; and (C) from a young age, boys decline more in steps per day to become more consistent with girls at older ages. Additional studies revealed that boys take approximately 42-49% of daily steps during the school day; girls take 41-47%. Steps taken during physical education class contribute to total steps per day by 8.7-23.7% in boys and 11.4-17.2% in girls. Recess represents 8-11% and lunch break represents 15-16% of total steps per day. After-school activity contributes approximately 47-56% of total steps per day for boys and 47-59% for girls. Weekdays range from approximately 12,000 to 16,000 steps per day in boys and 10,000 to 14,000 steps per day in girls. The corresponding values for weekend days are 12,000-13,000 steps per day in boys and 10,000-12,000 steps per day in girls. C1 [Tudor-Locke, Catrine] Pennington Biomed Res Ctr, Walking Behav Lab, Baton Rouge, LA 70808 USA. [McClain, James J.] Natl Canc Inst, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Hart, Teresa L.] Univ Wisconsin, Coll Hlth Sci, Milwaukee, WI USA. [Sisson, Susan B.] Univ Oklahoma, Hlth Sci Ctr, Dept Nutr Sci, Norman, OK 73019 USA. [Washington, Tracy L.] Arizona State Univ, Dept Exercise & Wellness, Tempe, AZ 85287 USA. RP Tudor-Locke, C (reprint author), Pennington Biomed Res Ctr, Walking Behav Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM Tudor-Locke@pbrc.edu OI Washington, Tracy L./0000-0002-0959-7320 NR 63 TC 58 Z9 58 U1 1 U2 9 PU AMER ALLIANCE HEALTH PHYS EDUC REC & DANCE PI RESTON PA 1900 ASSOCIATION DRIVE, RESTON, VA 22091 USA SN 0270-1367 J9 RES Q EXERCISE SPORT JI Res. Q. Exerc. Sport PD JUN PY 2009 VL 80 IS 2 BP 164 EP 174 PG 11 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 466TI UT WOS:000267685300006 PM 19650381 ER PT J AU Tudor-Locke, C McClain, JJ Hart, TL Sisson, SB Washington, TL AF Tudor-Locke, Catrine McClain, James J. Hart, Teresa L. Sisson, Susan B. Washington, Tracy L. TI Pedometry Methods for Assessing Free-Living Youth SO RESEARCH QUARTERLY FOR EXERCISE AND SPORT LA English DT Article DE measurement; motion sensors; physical activity; protocols ID QUANTIFYING PHYSICAL-ACTIVITY; AEROBIC FITNESS; SCHOOL-CHILDREN; HEART-RATE; RELIABILITY; VALIDITY; ACCURACY; OBESITY; ACCELEROMETER; REACTIVITY AB The purpose of this review is to integrate and summarize specific measurement topics (instrument and metric choice, validity, reliability, how many and what types of days, reactivity, and data treatment) appropriate to the study of youth physical activity. Research quality pedometers are necessary to aid interpretation of steps per day collected in a range of young populations under a variety of circumstances. Steps per day is the most appropriate metric choice, but steps per minute can be used to interpret time-in-intensity in specifically delimited time periods (e.g., physical education class). Reported intraclass correlations (ICC) have ranged from .65 over 2 days. (although higher values also have been reported for 2 days) to .87 over 8 days (although higher values have been reported for fewer days). Reported ICCs are lower on weekend days (.59) versus weekdays (.75) and lower over vacation days (.69) versus school days (.74). There is no objective evidence of reactivity at this time. Data treatment includes (a) identifying and addressing missing values, (b) identifying outliers and reducing data appropriately if necessary, and (c) transforming the data as required in preparation for inferential analysis. As more pedometry studies in young populations are published, these preliminary methodological recommendations should be modified and refined. C1 [Tudor-Locke, Catrine] Pennington Biomed Res Ctr, Walking Behav Lab, Baton Rouge, LA 70808 USA. [McClain, James J.] Natl Canc Inst, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Hart, Teresa L.] Univ Wisconsin, Coll Hlth Sci, Milwaukee, WI USA. [Sisson, Susan B.] Univ Oklahoma, Hlth Sci Ctr, Dept Nutr Sci, Norman, OK 73019 USA. [Washington, Tracy L.] Arizona State Univ, Dept Exercise & Wellness, Tempe, AZ 85287 USA. RP Tudor-Locke, C (reprint author), Pennington Biomed Res Ctr, Walking Behav Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM Tudor-Locke@pbrc.edu OI Washington, Tracy L./0000-0002-0959-7320 NR 62 TC 29 Z9 29 U1 1 U2 8 PU AMER ALLIANCE HEALTH PHYS EDUC REC & DANCE PI RESTON PA 1900 ASSOCIATION DRIVE, RESTON, VA 22091 USA SN 0270-1367 J9 RES Q EXERCISE SPORT JI Res. Q. Exerc. Sport PD JUN PY 2009 VL 80 IS 2 BP 175 EP 184 PG 10 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 466TI UT WOS:000267685300007 PM 19650382 ER PT J AU Sugarman, J Sitlani, C Andrusiek, D Aufderheide, T Bulger, EM Davis, DP Hoyt, DB Idris, A Kerby, JD Powell, J Schmidt, T Slutsky, AS Sopko, G Stephens, S Williams, C Nichol, G AF Sugarman, Jeremy Sitlani, Colleen Andrusiek, Dug Aufderheide, Tom Bulger, Eileen M. Davis, Daniel P. Hoyt, David B. Idris, Ahamed Kerby, Jeffrey D. Powell, Judy Schmidt, Terri Slutsky, Arthur S. Sopko, George Stephens, Shannon Williams, Carolyn Nichol, Graham CA Resuscitation Outcomes Consortium TI Is the enrollment of racial and ethnic minorities in research in the emergency setting equitable? SO RESUSCITATION LA English DT Article DE Research in the emergency setting; Exemption from consent; Research ethics; Subject selection; Clinical trials; Trauma; Race and ethnicity ID AFRICAN-AMERICANS; MEDICAL-RESEARCH; BRAIN-INJURY; RESUSCITATION; OUTCOMES; TRAUMA; IMPLEMENTATION; EPIDEMIOLOGY; WILLINGNESS; PARTICIPATE AB Background: Concerns have been raised about the enrollment of racial and ethnic minorities in research in the emergency setting when it is not possible to obtain informed consent. However, there is a paucity of data related to the validity of such claims. Methods: Retrospective comparison of registry enrollment (4/1/2006-3/31/2007) and trial enrollment (4/1/2007-3/31/2008) from three sites in the Resuscitation Outcomes Consortium. Subjects compared met the following Criteria: (I) shock, defined by blunt or penetrating force to the body with either systolic blood pressure (SBP) <= 70 mmHg or SBP 71-90 mmHg and heart rate >= 108 beats/min and/or (2) traumatic brain injury (TBI), defined by blunt force to the head with out-of-hospital Glasgow Coma Score <= 8. Results: Overall, compared to a registry there were no differences in the percent of racial or ethnic groups enrolled in the clinical trial [odds ratio (OR) for Blacks versus Whites: 0.87, 95% confidence interval (Cl) 0.65-1.16, p = .34; OR for Hispanics versus Whites 1.04; 95% CI 0.72-1.49, p =.85]. However, Blacks were less likely than Whites to be enrolled in the TBI cohort [OR 0.58 (0.34-0.97), p =.04]. Conclusions: Despite some discordance in subgroups, there was no overall difference in the racial and ethnic distribution of subjects enrolled in a multi-center clinical trial of severe trauma compared to a registry accounting for study entry criteria. These findings help address justice concerns about enrollment of racial and ethnic minorities in trauma research performed using an exception from informed consent under emergency circumstances. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Sugarman, Jeremy] Johns Hopkins Univ, Berman Inst Bioeth, Baltimore, MD 21205 USA. [Sugarman, Jeremy] Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. [Sitlani, Colleen; Powell, Judy; Nichol, Graham] Univ Washington, Dept Biostat, Resuscitat Outcomes Consortium Clin Trial Ctr, Seattle, WA 98195 USA. [Andrusiek, Dug] Univ British Columbia, Program Med, Emergency & Hlth Serv Commiss, Vancouver, BC V5Z 1M9, Canada. [Andrusiek, Dug] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Aufderheide, Tom] Med Coll Wisconsin, Dept Emergency Med, Milwaukee, WI 53226 USA. [Bulger, Eileen M.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Davis, Daniel P.] Univ Calif San Diego, Dept Emergency Med, La Jolla, CA 92093 USA. [Hoyt, David B.] Univ Calif Irvine, Dept Surg, Irvine, CA 92717 USA. [Idris, Ahamed] Univ Texas SW Med Ctr Dallas, Dept Surg, Dallas, TX 75390 USA. [Kerby, Jeffrey D.] Univ Alabama, Dept Surg, Sect Trauma Burns & Surg Crit Care, Birmingham, AL 35294 USA. [Schmidt, Terri] Oregon Hlth & Sci Univ, Sch Med, Dept Emergency Med, Portland, OR 97201 USA. [Schmidt, Terri] Oregon Hlth & Sci Univ, Sch Med, Ctr Eth Hlth Care, Portland, OR 97201 USA. [Slutsky, Arthur S.] Univ Toronto, Toronto, CA USA. [Slutsky, Arthur S.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto, CA USA. [Sopko, George] NHLBI, Div Cardiovasc Dis, NIH, Bethesda, MD 20892 USA. [Stephens, Shannon; Williams, Carolyn] Univ Alabama, Dept Emergency Med, Alabama Resuscitat Ctr, Birmingham, AL USA. [Nichol, Graham] Univ Washington, Dept Med, Harborview Ctr Prehosp Emergency Care, Seattle, WA USA. RP Sugarman, J (reprint author), Johns Hopkins Univ, Berman Inst Bioeth, Hampton House 351,624 N Broadway, Baltimore, MD 21205 USA. EM jsugarml@jhm1.edu OI Idris, Ahamed/0000-0001-7113-6499; Stephens, Shannon/0000-0001-5898-5170 FU NHLBI NIH HHS [HL077873, HL077885, U01 HL077867, U01 HL077885, HL077867, HL077871, HL077865, U01 HL077908, 5U01 HL077863, HL077866, HL077872, HL077881, HL077887, HL077908, U01 HL077863, U01 HL077863-05, U01 HL077866, U01 HL077872, U01 HL077881] NR 29 TC 8 Z9 8 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-9572 J9 RESUSCITATION JI Resuscitation PD JUN PY 2009 VL 80 IS 6 BP 644 EP 649 DI 10.1016/j.resuscitation.2009.03.015 PG 6 WC Critical Care Medicine; Emergency Medicine SC General & Internal Medicine; Emergency Medicine GA 459ID UT WOS:000267094100008 PM 19395144 ER PT J AU Forooghian, F Cukras, C Meyerle, CB Chew, EY Wong, WT AF Forooghian, Farzin Cukras, Catherine Meyerle, Catherine B. Chew, Emily Y. Wong, Wai T. TI TACHYPHYLAXIS AFTER INTRAVITREAL BEVACIZUMAB FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE age-related macular degeneration; anti-angiogenic treatment; bevacizumab; intravitreal injection; neovascularization; optical coherence tomography; tachyphylaxis; vascular endothelial growth factor ID EXPERIMENTAL CHOROIDAL NEOVASCULARIZATION; OPTICAL COHERENCE TOMOGRAPHY; PHOTODYNAMIC THERAPY; INFLAMMATION; RANIBIZUMAB; MACROPHAGE; ANTIBODIES; EXPRESSION; AVASTIN; DISEASE AB Purpose: To describe tachyphylaxis to intravitreal bevacizumab (IVB) in patients with exudative age-related macular degeneration (AMD). Methods: We retrospectively reviewed the records of 59 consecutive patients treated with IVB at the National Eye Institute over a 14-month period and identified cases demonstrating loss of treatment efficacy as revealed by spectral domain optical coherence tomography. We defined tachyphylaxis as a loss of therapeutic response to IVB 28 7 days after administration in an eye that had previously demonstrated a therapeutic response in the same time interval. Results: Five patients (six eyes) were identified as developing tachyphylaxis after repeated treatment with IVB. High-dose IVB (2.50 mg) did not restore therapeutic response in these patients. Bilateral tachyphylaxis to IVB was seen after an episode of unilateral postinjection anterior uveitis. After the first treatment of IVB, the median time taken to develop tachyphylaxis was 100 weeks (range: 31-128 weeks), and the median number of IVB treatments to the development of tachyphylaxis was 8 treatments (range: 5-10 treatments). Conclusion: Tachyphylaxis can occur after long-term intravitreal use of bevacizumab in patients with AMD. The precise mechanism of tachyphylaxis is unclear, but both local and/or systemic factors may be involved. RETINA 29:723-731, 2009 C1 [Wong, Wai T.] NEI, Off Sci Director, NIH, Bethesda, MD 20892 USA. [Forooghian, Farzin; Cukras, Catherine; Meyerle, Catherine B.; Chew, Emily Y.] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), NEI, Off Sci Director, NIH, 7 Mem Dr,Bldg 7,Room 217, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute Intramural Research Program FX Supported by the National Eye Institute Intramural Research Program. NR 18 TC 80 Z9 82 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD JUN PY 2009 VL 29 IS 6 BP 723 EP 731 PG 9 WC Ophthalmology SC Ophthalmology GA 464HS UT WOS:000267496600001 PM 19516114 ER PT J AU Cidlowski, JA AF Cidlowski, John A. TI GLUCOCORTICOIDS AND THEIR ACTIONS IN CELLS SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE glucocorticoids; inflammation; receptors; steroid resistance AB The biologic responses to the administration of exogenous glucocorticoids (GCs) appear to be specific to cell type. As a result, progress in understanding how to improve the benefit-to-risk ratio of GC therapies for the eye will depend on better characterization of both the receptors and the proteins induced when these receptors are stimulated. The complexity and diversity of the GC receptors in human tissue is underscored by evidence that up to 6,000 genes are expressed or suppressed within hours of GC exposure. The enormous potential to use exogenous GC agents to clownregulate processes involved in age-related macular degeneration must be balanced against a similar potential for counterproductive effects. Recent progress predicts an increasing precision with which GC steroids can be used to influence biologic functions. RETINA 29:S18-S20, 2009 C1 NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov NR 3 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD JUN PY 2009 VL 29 IS 6 BP S18 EP S20 PG 3 WC Ophthalmology SC Ophthalmology GA 464HT UT WOS:000267496700007 ER PT J AU Linnstaedt, SD Kasprzak, WK Shapiro, BA Casey, JL AF Linnstaedt, Sarah D. Kasprzak, Wojciech K. Shapiro, Bruce A. Casey, John L. TI The fraction of RNA that folds into the correct branched secondary structure determines hepatitis delta virus type 3 RNA editing levels SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE RNA editing; RNA structural dynamics; hepatitis delta virus; ADAR1; RNA folding ID PARALLEL GENETIC ALGORITHM; GENOTYPE-III; ADENOSINE DEAMINASES; LARGE FORM; REPLICATION; SEQUENCE; ANTIGEN; ADAR2; EXPRESSION; INHIBITION AB RNA editing by the host RNA adenosine deaminase ADAR1 at the amber/W site of hepatitis delta virus RNA plays a central role in the viral replication cycle by affecting the balance between viral RNA synthesis and packaging. Previously, we found that HDV genotype III (HDV-3) RNA can form two secondary structures following transcription: an unbranched rod structure, which is characteristic of HDV, and a metastable branched structure that serves as the substrate for editing. The unstable nature of the branched editing substrate structure raised the possibility that structural dynamics of the RNA following transcription could determine the rate at which editing occurs. Here, editing and its control are examined in two HDV-3 isolates, from Peru and Ecuador. Analysis of editing in vitro by ADAR1 indicated that the branched structure formed by RNA derived from the Peruvian isolate is edited more efficiently than that from the Ecuadorian isolate. In contrast, in the context of replication, Peruvian RNA is edited less efficiently than RNA containing Ecuadorian sequences. Computational analyses of RNA folding using the massively parallel genetic algorithm (MPGAfold) indicated that the Peruvian RNA is less likely to form the branched structure required for editing than the Ecuadorian isolate. This difference was confirmed by in vitro transcription of these RNAs. Overall, our data indicate that HDV-3 controls RNA editing levels via ( 1) the fraction of the RNA that folds, during transcription, into the metastable branched structure required for editing and ( 2) the efficiency with which ADAR1 edits this branched substrate RNA. C1 [Linnstaedt, Sarah D.; Casey, John L.] Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20007 USA. [Kasprzak, Wojciech K.] NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Shapiro, Bruce A.] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. RP Casey, JL (reprint author), Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, 3900 Reservoir Rd NW, Washington, DC 20007 USA. EM caseyj@georgetown.edu FU National Institute of Allergy and Infectious Diseases [R01-AI42324]; National Institutes of Health; National Cancer Institute; National Institutes of Health [NO1-CO-12400]; Intramural Research Program of the NIH; Center for Cancer Research FX This work was supported by grant R01-AI42324 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-12400. 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 48 TC 15 Z9 16 U1 1 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD JUN PY 2009 VL 15 IS 6 BP 1177 EP 1187 DI 10.1261/rna.1504009 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 452CC UT WOS:000266516200018 PM 19383766 ER PT J AU Wu, DY Pollock, JD Shurtleff, D AF Wu, Da-Yu Pollock, Jonathan D. Shurtleff, David TI The Molecular and Cellular Mechanisms in the Development of Addiction SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Editorial Material C1 [Wu, Da-Yu; Pollock, Jonathan D.; Shurtleff, David] Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. RP Wu, DY (reprint author), Natl Inst Drug Abuse, NIH, 6001 Execut Blvd,Room 4249,MSC 9555, Bethesda, MD 20892 USA. EM wudy@nida.nih.gov RI Pollock, Jonathan/B-1554-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD JUN PY 2009 VL 20 IS 4 BP 377 EP 377 DI 10.1016/j.semcdb.2009.03.002 PG 1 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 503XY UT WOS:000270576700001 PM 19560041 ER PT J AU Klar, AJS AF Klar, Amar J. S. TI Scalp hair-whorl orientation of Japanese individuals is random; hence, the trait's distribution is not genetically determined SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Human handedness trait; Scalp hair-whorl orientation; Brain laterality development; Human genetic variation ID HEMISPHERIC LANGUAGE DOMINANCE; HANDEDNESS; DIRECTION; LATERALIZATION; SCHIZOPHRENIA; ASSOCIATION; PREFERENCE; MECHANISM; HUMANS AB Because the features of clockwise versus anti-clockwise orientation of hair-whorl coiling developed on a person's scalp is (partially, albeit significantly) correlated with that individual's right-versus left-hand-use preference (i.e., handedness) in the US and British subjects, these traits have been recently suggested to be determined biologically and through a common genetic mechanism. Here I report results of a serendipitously made observation with the Japanese population that helps to scrutinize validity of partial correlation between these attributes and to ascertain whether the underlying gene's frequency variations exist in different gene pools. Surprisingly, the whorl orientation in the Japanese individuals was found to be random, although their handedness variation is similar to that of the US population. Therefore, the whorl orientation trait is not genetically determined in the Japanese population. This result supports the idea that separate decisions must be made during embryogenesis for developing handedness and hair-whorl features at least in Japanese individuals. A recent study found the lack of association between whorl orientation and handedness in the German population, yet previous studies suggested that their scalp hair orientation is genetically determined. Therefore, pronounced genetic variation for the hair-whorl trait exists between individuals of different geographical regions. As hand preference exhibits "complex correlation" with brain hemispheric functional specialization, implications of these findings are discussed here with the goal to define biology of brain hemispheric laterality determination. Published by Elsevier Ltd. C1 NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Klar, AJS (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, POB B,Bldg 539, Frederick, MD 21702 USA. EM klar@ncifcrf.gov FU Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research at Frederick, USA FX Dr. Charanjit S. Aulakh is thanked for reviewing the manuscript. The Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research at Frederick, USA, has supported this research. NR 20 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD JUN PY 2009 VL 20 IS 4 BP 510 EP 513 DI 10.1016/j.semcdb.2008.11.003 PG 4 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 503XY UT WOS:000270576700018 PM 19049888 ER PT J AU Pacher, P Steffens, S AF Pacher, Pal Steffens, Sabine TI The emerging role of the endocannabinoid system in cardiovascular disease SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review ID CB2 CANNABINOID RECEPTOR; CARDIOMETABOLIC RISK-FACTORS; ACID AMIDE HYDROLASE; RAT ISOLATED HEARTS; HEPATIC ISCHEMIA/REPERFUSION INJURY; DENSITY-LIPOPROTEIN RECEPTOR; ISCHEMIA-REPERFUSION INJURY; RANDOMIZED CONTROLLED-TRIAL; CORONARY-ARTERY-DISEASE; DIET-INDUCED OBESITY AB Endocannabinoids are endogenous bioactive lipid mediators present both in the brain and various peripheral tissues, which exert their biological effects via interaction with specific G-protein-coupled cannabinoid receptors, the CB(1) and CB(2). Pathological overactivation of the endocannabinoid system (ECS) in various forms of shock and heart failure may contribute to the underlying pathology and cardiodepressive state by the activation of the cardiovascular CB(1) receptors. Furthermore, tonic activation of CB(1) receptors by endocannabinoids has also been implicated in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes, such as plasma lipid alterations, abdominal obesity, hepatic steatosis, inflammation, and insulin and leptin resistance. In contrast, activation of CB(2) receptors in immune cells exerts various immunomodulatory effects, and the CB(2) receptors in endothelial and inflammatory cells appear to limit the endothelial inflammatory response, chemotaxis, and inflammatory cell adhesion and activation in atherosclerosis and reperfusion injury. Here, we will overview the cardiovascular actions of endocannabinoids and the growing body of evidence implicating the dysregulation of the ECS in a variety of cardiovascular diseases. We will also discuss the therapeutic potential of the modulation of the ECS by selective agonists/antagonists in various cardiovascular disorders associated with inflammation and tissue injury, ranging from myocardial infarction and heart failure to atherosclerosis and cardiometabolic disorders. C1 [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Steffens, Sabine] Univ Hosp Geneva, Div Cardiol, Dept Internal Med, Fdn Med Res, CH-1211 Geneva, Switzerland. RP Pacher, P (reprint author), NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, 5625 Fishers Lane,MSC 9413, Bethesda, MD 20892 USA. EM pacher@mail.nih.gov; Sabine.Steffens@unige.ch RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Swiss National Science Foundation; Novartis Foundation for Biomedical Research, Prevot and Wolfermann-Naegeli Foundation; NIH/NIAAA FX S. S. is supported by grants from the Swiss National Science Foundation, the Novartis Foundation for Biomedical Research, Prevot and Wolfermann-Naegeli Foundation. P. P. is supported by the Intramural research program of the NIH/NIAAA. NR 162 TC 55 Z9 56 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1863-2297 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD JUN PY 2009 VL 31 IS 1 BP 63 EP 77 DI 10.1007/s00281-009-0145-8 PG 15 WC Immunology; Pathology SC Immunology; Pathology GA 456WV UT WOS:000266884000006 PM 19357846 ER PT J AU Thurman, AR Holden, AEC Shain, RN Perdue, S Piper, JM AF Thurman, Andrea Ries Holden, Alan E. C. Shain, Rochelle N. Perdue, Sondra Piper, Jeanna M. TI Effect of Acculturation on the Acceptability of Potential Microbicides and Sexual Risk-Taking SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID CARRAGUARD VAGINAL GEL; CONTROLLED-TRIAL; UNITED-STATES; EPIDEMIOLOGIC PARADOX; HIV PREVENTION; CONDOM USE; US WOMEN; HISPANICS; BEHAVIOR; COMPENSATION AB Background: The objective was to determine the acceptability and use patterns of potential microbicides among African American (AA), acculturated Hispanic (AH), and less acculturated Hispanic (LAH) women. We Measured baseline sexual risk-taking and the likelihood of behavioral change, given effective microbicides. Methods: Interview of 506 Mexican-American and AA women, all of whom have a sexually transmitted infection enrolled in Project Sexual Awareness for Everyone. Results: The 3 groups reported similarly high acceptance of potential microbicides (76%-83% P = 0.24). LAHs were most likely to report they would use microbicides covertly (P = 0.03). Given the possibility of effective microbicides, AHs were consistently more likely to report risk disinhibition. AHs, as compared to LAHs and AAs, respectively, were most likely to report that they would not use condoms, (53% vs. 33% vs. 30% P <0.001), would have a 1-night stand (18% vs. 8% vs. 6% P = 0.02), or would have sex with humans before they got to know them (18% vs. 8% vs. 6% P = 0.01). AHs were also most likely to say they would or probably would change from baseline safe sexual practices to unsafe sexual behaviors if potential microbicides were available. Age was controlled for in the analysis as AHs were younger than AAs and LAHs. Conclusions: Future microbicides were acceptable among this at risk cohort. Acculturation was a predictor of risk disinhibition and should be considered when tailoring sexually transmitted infection prevention messages, given the advent of effective microbicides. C1 [Thurman, Andrea Ries; Holden, Alan E. C.; Shain, Rochelle N.; Perdue, Sondra] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. [Piper, Jeanna M.] NIAID, NIH, Bethesda, MD 20892 USA. RP Thurman, AR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, 7703 Floyd Curl Dr,Mail Code 7836, San Antonio, TX 78229 USA. EM thurmana@uthscsa.edu FU National Institute of Allergy and Infectious Diseases [U01 A140029] FX Supported by a grant (U01 A140029) from the National Institute of Allergy and Infectious Diseases. NR 37 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD JUN PY 2009 VL 36 IS 6 BP 387 EP 394 DI 10.1097/OLQ.0b013e318198d90c PG 8 WC Infectious Diseases SC Infectious Diseases GA 449WR UT WOS:000266361700012 PM 19556933 ER PT J AU Platt, AB Field, SH Asch, DA Chen, Z Patel, NP Gupta, R Roche, DF Gurubhagavatula, I Christie, JD Kuna, ST AF Platt, Alec B. Field, Samuel H. Asch, David A. Chen, Zhen Patel, Nirav P. Gupta, Rajesh Roche, Dominic F. Gurubhagavatula, Indira Christie, Jason D. Kuna, Samuel T. TI Neighborhood of Residence is Associated with Daily Adherence to CPAP Therapy SO SLEEP LA English DT Article DE Obstructive sleep apnea; continuous positive airway pressure; adherence; socioeconomic status ID POSITIVE AIRWAY PRESSURE; OBSTRUCTIVE SLEEP-APNEA; CORONARY HEART-DISEASE; CHARLSON COMORBIDITY INDEX; SOCIOECONOMIC-STATUS; ADMINISTRATIVE DATABASES; PRACTICE PARAMETERS; NASAL CPAP; HEALTH; RISK AB Study Objectives: Adherence to continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea is poor. Risk factors for nonadherence are not well understood but may reflect individual or neighborhood socioeconomic factors. We sought to determine the association of socioeconomic status and initial CPAP adherence. Design: Retrospective cohort study, 2005 to 2006. Setting: Philadelphia VA Medical Center. Participants: Of 330 consecutive veterans who met study criteria for initiation of CPAP therapy for newly diagnosed sleep apnea, 266 had complete data for study inclusion. Interventions: N/A. Measurements: Through a multivariable logistic regression model, using an outcome of objectively measured CPAP use ! 4 h daily during the first week of treatment, we tested whether patients from higher socioeconomic neighborhoods had higher CPAP adherence. We measured neighborhood socioeconomic status with an index derived from the 2000 U.S. Census at the block group-level composed of median household income, male and female employment, adult high school completion, married households, and minority composition. Results: CPAP adherence : >= 4 h occurred on 48.9% of 1,805 patient-days observed for the 266 subjects. After adjustment for individual sociodemographic characteristics and medical comorbidity, the probability of daily CPAP use >= 4 h ranged from 34.1% (95% CI, 26.4-42.7) for subjects from a low socioeconomic neighborhood (5th percentile) to 62.3% (95% CI, 53.8-70.1) for subjects from a high (95th percentile) neighborhood. Conclusions: In a retrospective cohort of veterans, initial CPAP adherence was closely associated with higher neighborhood socioeconomic factors. Future investigation should target specific impediments to adherence in the home and neighborhood environment. C1 [Platt, Alec B.; Field, Samuel H.; Asch, David A.; Roche, Dominic F.; Kuna, Samuel T.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Platt, Alec B.] Reading Hosp Med Ctr, Reading, PA USA. [Field, Samuel H.] Univ N Carolina, Frank Porter Graham Child Dev Inst, Chapel Hill, NC USA. [Asch, David A.; Patel, Nirav P.; Gurubhagavatula, Indira; Christie, Jason D.; Kuna, Samuel T.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Asch, David A.; Christie, Jason D.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Chen, Zhen] NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Patel, Nirav P.; Gupta, Rajesh; Gurubhagavatula, Indira; Kuna, Samuel T.] Philadelphia VA Med Ctr, Pulm Crit Care & Sleep Sect, Philadelphia, PA USA. RP Platt, AB (reprint author), 2608 Keiser Blvd, Wyomissing, PA 19610 USA. EM alecplatt@gmail.com FU NHLBI NIH HHS [T-32 HL07713-14, T32 HL007713]; NIOSH CDC HHS [R01-OH-009149-01, R01 OH009149] NR 52 TC 53 Z9 53 U1 1 U2 6 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 JUN 1 PY 2009 VL 32 IS 6 BP 799 EP 806 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 452WE UT WOS:000266571100014 PM 19544757 ER PT J AU Sarno, RJ Gonzalez, BA Bonacic, C Zapata, B O'Brien, SJ Johnson, WE AF Sarno, Ronald J. Gonzalez, Benito A. Bonacic, Cristian Zapata, Beatriz O'Brien, Stephen J. Johnson, Warren E. TI Molecular genetic evidence for social group disruption of wild vicunas Vicugna vicugna captured for wool harvest in Chile SO SMALL RUMINANT RESEARCH LA English DT Article DE Camelid; Capture; Microsatellites; Parentage; Ungulate; Vicuna ID SUSTAINABLE USE; CONSEQUENCES; POPULATIONS; CONSERVATION; MANAGEMENT; EVOLUTION; CAMELIDAE; COLLAPSE; ALLELES; MARKERS AB Since 1994 wild vicunas have been captured and shorn for their wool, yet, there remains a noticeable lack of data regarding the possible influence of capture and shearing upon vicuna biology. Therefore, we assessed post-capture group composition, genetic relatedness, and paternity among animals that were captured for live shearing and release. We captured twenty-six groups (134 animals) on the Chilean Altiplano. Seventy-three percent of Male Groups (designated prior to chase) contained exclusively adult males upon capture,whereas remaining "Male Groups" contained crias and/or adult females and crias. Forty-seven percent of Family Groups (designated prior to chase) contained I adult male, adult females, and the number of crias <= the number of adult females. Remaining Family Groups contained no or multiple adult males, and more crias than adult females. Average relatedness among all vicunas was -0.007. Paternity analysis revealed that 35% of crias were captured with their biological mother and that only 1 cria was captured with both biological parents. Based on previous observations of group composition in the wild, animals from different groups may separate and/or mix during the chasing stage. Improvement of the chasing technique and instituting a post-capture monitoring program may aid in the detection of medium- and long-term impacts regarding group stability, cria survival, and ultimately wool production. (C) 2009 Elsevier B.V. All rights reserved. C1 [Sarno, Ronald J.] 114 Hofstra Univ, Dept Biol, Hempstead, NY 11549 USA. [Gonzalez, Benito A.] Univ Chile, Fac Ciencias Forestales, Lab Ecol Vida Silvestre, Santiago 11315, Chile. [Bonacic, Cristian] Pontificia Univ Catolica Chile, Fac Agron & Ingn, Santiago, Chile. [Zapata, Beatriz] Univ Chile, Fac Cs Vet Pecuarias, Dept Fomento Prod Anim, Santiago 11735, Chile. [O'Brien, Stephen J.; Johnson, Warren E.] NCI, Lab Genom Divers, Frederick, MD 21702 USA. RP Sarno, RJ (reprint author), 114 Hofstra Univ, Dept Biol, Hempstead, NY 11549 USA. EM ronald.sarno@hofstra.edu; bengonza@uchile.cl; bona@uc.cl; bzapata@uchile.cl; obrien@ncifcrf.gov; johnsonw@ncifcrf.gov RI Gonzalez, Benito/I-9570-2014; Johnson, Warren/D-4149-2016 OI Gonzalez, Benito/0000-0001-8201-8789; Johnson, Warren/0000-0002-5954-186X FU Centro de Estudios Internacionales PUC, MACS, CFTWI; Wildlife Trust; US Fish & Wildlife Service [99US834015/9]; USDA [PER-743, 44100]; Programa de Doctorado en Ciencias Silvoagropecuarias y Veterinarias of the Universidad de Chile.; NIH FX We thank Agustin Iriarte of the Servicio Agricola y Canadero, Chile who provided assistance in obtaining CITES exportation permits from Chile. Thanks to CONAF personnel in Arica and Parinacota, especially Jose Luis Galaz and park guards who organized and captured vicuhas in Surire and Paquiza. Carla Ferris, Jason Grove, Amanda Garfinkel, Amy Snyder, Stan Cevario, Victor David, Eduardo Eizirik, Jill Slattery, Bill Murphy, and Al Roca provided advice and/or technical assistance. Adam Jones and Tristan Marshall provided helpful comments regarding data analysis and interpretation. This project was partially supported by Centro de Estudios Internacionales PUC, MACS, CFTWI, and Wildlife Trust. Permits were issued by the US Fish & Wildlife Service (CITES permit # 99US834015/9) and USDA (permit # PER-743 and permit #44100) to Ronald J. Sarno for the importation of vicuha samples into the United States. Capture permitswere issued by Servicio Agricola y Ganadero and Corporacion Nacional Forestal (Chile) and the Direccion General de Biodiversidad, Ministerio del Medio Ambiente (Bolivia) to Cristian Bonacic. Benito A. GonzAlez and Beatriz Zapata were supported by a CONICYT Dissertation Fellowship through the Programa de Doctorado en Ciencias Silvoagropecuarias y Veterinarias of the Universidad de Chile. The project was approved by the Ethical Committee, Department of Animal Science, Pontificia Universidad Catolica de Chile. The content of this publication does not reflect the views or policies of the NIH, nor does the mention of trade names, commercial products, or organization imply endorsement by the US Government. NR 54 TC 5 Z9 5 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0921-4488 J9 SMALL RUMINANT RES JI Small Ruminant Res. PD JUN PY 2009 VL 84 IS 1-3 BP 28 EP 34 DI 10.1016/j.smallrumres.2009.05.001 PG 7 WC Agriculture, Dairy & Animal Science SC Agriculture GA 490MS UT WOS:000269505700005 ER PT J AU Beydoun, MA Wang, YF AF Beydoun, May A. Wang, Youfa TI Parent-child dietary intake resemblance in the United States: Evidence from a large representative survey SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE USA; Dietary; Diet; Dietary quality; Ethnicity; Food intake; Familial aggregation; Child; CSFII; Gender ID NUTRITION INTERVENTION; FAMILY RESEMBLANCE; SCHOOL-CHILDREN; INTAKE PATTERNS; US ADULTS; SOCIOECONOMIC-STATUS; GENDER-DIFFERENCES; MEXICAN-AMERICAN; NUTRIENT INTAKE; WEIGHT STATUS AB We studied the association in dietary intakes and patterns between parents (aged 20-65 years) and their children (aged 2-18 years), using nationally representative data collected by the US Department of Agriculture (USDA) in the Continuing Survey of Food Intake by Individuals 1994-96. We analyzed two 24-h recall dietary data for 1061 fathers, 1230 mothers, 1370 sons and 1322 daughters. All analyses adjusted for sampling design complexity. We assessed multivariate-adjusted parent-child correlations in selected nutrients, food groups and overall dietary quality assessed using the new USDA 2005 Healthy Eating Index score (HEI(n)). The parent-child correlations were weak or moderate (0.20-0.33) for most intake measures. There were clear patterns of interaction with gender dyads in the intakes of calcium and dairy products (P < 0.05 for dyad x parental intake), whereby multivariate-adjusted correlations in mother-daughter or mother-child dyads were significantly stronger compared to their father-child counterparts. The reverse was true for multivariate-adjusted correlations in HEI(n). Hispanics and other ethnic groups had significantly stronger resemblance than Non-Hispanic whites and blacks in soft drinks and HEI(n). Resemblance in general was stronger among older children, though the reverse was true when considering agreement in HEI(n)'s upper quintile. The influence of family income and parental education on the resemblance was small. In conclusion, parent-child dietary resemblance in the US is relatively weak, and varies by nutrients and food groups, and by the types of parent-child dyad and population groups. Factors other than parental eating behaviors seem to play an important role in affecting American young people's dietary intake. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Beydoun, May A.; Wang, Youfa] Johns Hopkins Sch Publ Hlth, Ctr Human Nutr, Dept Int Hlth, Baltimore, MD 21205 USA. [Beydoun, May A.] NIA, NIH, IRP, Bethesda, MD 20892 USA. RP Wang, YF (reprint author), Johns Hopkins Sch Publ Hlth, Ctr Human Nutr, Dept Int Hlth, 615 N Wolfe St,Room E2546, Baltimore, MD 21205 USA. EM ywang@jhsph.edu FU Intramural NIH HHS [Z99 AG999999]; NICHD NIH HHS [1R03HD058077-01A1, R03 HD056073, R03 HD058077, R03HD056073]; NIDDK NIH HHS [R01 DK063383, R01 DK63383] NR 51 TC 55 Z9 55 U1 2 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD JUN PY 2009 VL 68 IS 12 BP 2137 EP 2144 DI 10.1016/j.socscimed.2009.03.029 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 472KE UT WOS:000268128700006 PM 19375837 ER PT J AU Guthrie, LC Butler, SC Ward, MM AF Guthrie, Lori C. Butler, Stephen C. Ward, Michael M. TI Time perspective and socioeconomic status: A link to socioeconomic disparities in health? SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE USA; Time perspective; Socioeconomic status; Health disparities ID SOCIAL-CLASS; FUTURE CONSEQUENCES; SUBSTANCE USE; ALL-CAUSE; CHILDHOOD; MORTALITY; INEQUALITIES; ADULTHOOD; DETERMINANTS; ORIENTATION AB Time perspective is a measure of the degree to which one's thinking is motivated by considerations of the future, present, or past. Time perspective has been proposed as a potential mediator of socioeconomic disparities in health because it has been associated with health behaviors and is presumed to vary with socioeconomic status. In this cross-sectional community-based survey of respondents recruited from hair salons and barber shops in a suburb of Washington DC, we examined the association between time perspective and both education level and occupation. We asked participants (N = 525) to complete a questionnaire that included three subscales (future, present-fatalistic, and present-hedonistic) of the Zimbardo Time Perspective Inventory. Participants with more formal education and those with professional occupations had higher scores on the future time perspective subscale, and lower scores on the present-fatalistic subscale, than participants with less formal education or a non-professional occupation. Present-fatalistic scores were also higher among participants whose parents had less formal education. Present-hedonistic scores were not associated with either education level or professional occupation. Time perspective scores were not independently associated with the likelihood of obesity, smoking, or exercise. In this community sample, future time perspective was associated with current socioeconomic status, and past-fatalistic time perspective was associated with both current and childhood socioeconomic status. Published by Elsevier Ltd. C1 [Ward, Michael M.] NIAMS, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMS, NIH, Bldg 10,Room 4-1339, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS [Z01 AR041153-03] NR 44 TC 45 Z9 45 U1 3 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD JUN PY 2009 VL 68 IS 12 BP 2145 EP 2151 DI 10.1016/j.socscimed.2009.04.004 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 472KE UT WOS:000268128700007 PM 19394738 ER PT J AU Aliotta, JM Keaney, PJ Warburton, RR DelTatto, M Dooner, MS Passero, MA Quesenberry, PJ Klinger, JR AF Aliotta, Jason M. Keaney, Patrick J. Warburton, Rod R. DelTatto, Michael Dooner, Mark S. Passero, Michael A. Quesenberry, Peter J. Klinger, James R. TI Marrow Cell Infusion Attenuates Vascular Remodeling in a Murine Model of Monocrotaline-Induced Pulmonary Hypertension SO STEM CELLS AND DEVELOPMENT LA English DT Article ID ACUTE LUNG INJURY; BONE-MARROW; STEM-CELLS; PROGENITOR CELLS; G-CSF; MYOCARDIAL-INFARCTION; GENE-THERAPY; IN-VIVO; MICE; ENGRAFTMENT AB There have been reports of marrow cells converting into pulmonary epithelial cells after marrow transplantation in irradiated mice. We evaluated the impact of whole bone marrow (WBM) infusion in mice, with or without total body irradiation (TBI), treated with saline or monocrotaline (MCT), which induces pulmonary hypertension (PH). C57BL/6 mice were injected with MCT or saline weekly for 4 weeks. Cohorts were then infused with saline vehicle ( vehicle) or WBM from C57BL/-Tg(UBC-GFP)30Scha/J mice, with or without previous TBI ( WBM or WBM/TBI). Four weeks later, right ventricular peak pressures (RVPP), right ventricular free wall-to-body weight ratios (RV/BW), and pulmonary vessel wall thickness-to-blood vessel diameter ratios (PVWT/D) were determined. WBM infusion and WBM following TBI induced increases in RVPP and RV/BW in saline-treated mice, while only TBI-exposed mice showed additional increases in PVWT/D. MCT increased RVPP, RV/BW, and PVWT/D in mice given vehicle or WBM alone, but not in mice given WBM/TBI. RVPP and RV/BW were not significantly lower in MCT mice given WBM/TBI than in MCT mice treated with vehicle, but MCT-treated mice given WBM or TBI/WBM had significantly lower PVWT/D compared to MCT-treated mice given saline vehicle. No donor WBM-derived pulmonary vascular cells were detected, suggesting that the observed effects of WBM infusion may be due to paracrine effects separate from cell conversions. The observation of PH after marrow infusion suggests an additional mechanism for lung toxicity seen in marrow transplantation. In conclusion, WBM alone appears to increase RVPP and RV/BW in normal mice but the combination of WBM and TBI attenuates MCT-induced PH. C1 [Aliotta, Jason M.; DelTatto, Michael; Dooner, Mark S.; Quesenberry, Peter J.] Brown Univ, Warren Alpert Med Sch, Rhode Isl Hosp, Div Hematol & Oncol, Providence, RI 02903 USA. [Aliotta, Jason M.; Keaney, Patrick J.; Klinger, James R.] Brown Univ, Warren Alpert Med Sch, Rhode Isl Hosp, Div Pulm Sleep & Crit Care Med, Providence, RI 02903 USA. [Warburton, Rod R.] Tufts Med Ctr, Boston, MA USA. [Passero, Michael A.] COBRE, Roger Williams Med Ctr, Providence, RI USA. RP Aliotta, JM (reprint author), Brown Univ, Warren Alpert Med Sch, Rhode Isl Hosp, Div Hematol & Oncol, 7th Floor APC Bldg,593 Eddy St, Providence, RI 02903 USA. EM jason_aliotta@brown.edu FU [1 K08 HL086868-01A1]; [R01 HL088328-01]; [7R01HL073749-05]; [1 P20 RR018757-02] FX This publication was made possible by support from the following grants: 1 K08 HL086868-01A1 (J.M.A.), R01 HL088328-01 (J.R.K.), 7R01HL073749-05 (P.J.Q.), 1 P20 RR018757-02. NR 32 TC 10 Z9 10 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 JUN PY 2009 VL 18 IS 5 BP 773 EP 781 DI 10.1089/scd.2008.0237 PG 9 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 448BQ UT WOS:000266237000011 PM 19072290 ER PT J AU Famakin, BM Chimowitz, MI Lynn, MJ Stern, BJ George, MG AF Famakin, Bolanle M. Chimowitz, Marc I. Lynn, Michael J. Stern, Barney J. George, Mary G. CA WASID Trial Investigators TI Causes and Severity of Ischemic Stroke in Patients With Symptomatic Intracranial Arterial Stenosis SO STROKE LA English DT Article DE acute stroke; intracranial stenosis; lacunar infarcts; severity; WASID ID ATRIAL-FIBRILLATION; WARFARIN; ASPIRIN; PREVENTION; RECURRENCE; PROGNOSIS; RISK; MECHANISMS; SUBTYPES; DISEASE AB Background and Purpose-There are limited data on the causes and severity of subsequent stroke in patients presenting initially with TIA or stroke attributed to intracranial arterial stenosis. Methods-We evaluated the location, type (lacunar vs nonlacunar), cause, and severity of stroke in patients who had an ischemic stroke endpoint in the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial. Results-Of the 569 patients enrolled in the WASID trial, 106 patients (18.6%) had an ischemic stroke during a mean follow-up of 1.8 years. Stroke occurred in the territory of the symptomatic artery in 77 (73%) of 106 patients. Among the 77 strokes in the territory, 70 (91%) were nonlacunar and 34 (44%) were disabling. Stroke out of the territory of the symptomatic artery occurred in 29 (27%) of 106 patients. Among these 29 strokes, 24 (83%) were nonlacunar, 14 (48%) were attributed to previously asymptomatic intracranial stenosis, and 9 (31%) were disabling. Conclusions-Most subsequent strokes in patients with symptomatic intracranial artery stenosis are in the same territory and nonlacunar, and nearly half of the strokes in the territory are disabling. The most commonly identified cause of stroke out of the territory was a previously asymptomatic intracranial stenosis. Penetrating artery disease was responsible for a low number of strokes. (Stroke. 2009; 40: 1999-2003.) C1 [Lynn, Michael J.; George, Mary G.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA 30322 USA. [Famakin, Bolanle M.; Chimowitz, Marc I.; Stern, Barney J.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. RP Famakin, BM (reprint author), NINDS, NIH, Stroke Branch, 49 Convent Dr,Bldg 49,Room 2A51,MSC 4476, Bethesda, MD 20892 USA. EM famakinb@ninds.nih.gov FU US Public Health Service, NINDS [1R01 NS36643]; NIH [M01 RR00039]; Case Western University, Metro Health Medical Center [5M01 RR00080]; San Francisco General Hospital [M01 RR00083-42]; Johns Hopkins University School of Medicine [M01 RR000052]; Indiana University School of Medicine [5M01 RR000750-32]; Cedars-Sinai Hospital [M01 RR00425]; University of Maryland [M01 RR165001] FX This study was funded by a research grant ( 1R01 NS36643; Principal Investigator Dr Chimowitz) from the US Public Health Service, NINDS. In addition, the following General Clinical Research centers, funded by the NIH, provided local support for the evaluation of patients in the trial: Emory University ( M01 RR00039), Case Western University, Metro Health Medical Center ( 5M01 RR00080), San Francisco General Hospital ( M01 RR00083-42), Johns Hopkins University School of Medicine ( M01 RR000052), Indiana University School of Medicine ( 5M01 RR000750-32), Cedars-Sinai Hospital ( M01 RR00425), and the University of Maryland ( M01 RR165001). NR 22 TC 34 Z9 35 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2009 VL 40 IS 6 BP 1999 EP 2003 DI 10.1161/STROKEAHA.108.546150 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 449AD UT WOS:000266302200012 PM 19407228 ER PT J AU Skinbjerg, M Namkung, Y Halldin, C Innis, RB Sibley, DR AF Skinbjerg, Mette Namkung, Yoon Halldin, Christer Innis, Robert B. Sibley, David R. TI Pharmacological Characterization of 2-Methoxy-N-Propylnorapomorphine's Interactions with D(2) and D(3) Dopamine Receptors SO SYNAPSE LA English DT Article DE MNPA; dopamine; receptor; agonist; internalization; PET ID POSITRON-EMISSION-TOMOGRAPHY; BETA-ADRENERGIC-RECEPTORS; HIGH-AFFINITY STATES; G-PROTEIN; IN-VIVO; D2 RECEPTOR; AGONIST RADIOTRACER; ENDOGENOUS DOPAMINE; INTACT-CELLS; BINDING CHARACTERISTICS AB Dopaminergic signaling pathways have been extensively investigated using PET imaging, primarily with antagonist radioligands of D(2) and D(3) dopamine receptors (DARs). Recently, agonist radioligands of D(2)/D(3) DARs have begun to be developed and employed. One such agonist is (R)-2-(11)CH(3)O-N-n-propylnorapomorphine (MNPA). Here, we perform a pharmacological characterization of MNPA using recombinant D(2) and D(3) DARs expressed in HEK293 cells. MNPA was found to robustly inhibit forskolin-stimulated cAMP accumulation to the same extent as dopamine in D(2) or D(3) DAR-transfected cells, indicating that it is a full agonist at both receptors. MNPA is similar to 50-fold more potent than dopamine at the D(2) DAR, but equally potent as dopamine at the D(3) DAR. MNPA competition binding curves in membrane preparations expressing D(2) DARs revealed two binding states of high and low-affinity. In the presence of GTP, only one binding state of low affinity was observed. Direct saturation binding assays using [(3)H]MNPA revealed similar results as with the competition experiments leading to the conclusion that MNPA binds to the D(2) DAR in an agonist-specific fashion. In contrast to membrane preparations, using intact cell binding assays, only one site of low affinity was observed for MNPA and other agonists binding to the D(2) DAR. MNPA was also found to induce D(2) DAR internalization to an even greater extent than dopamine as determined using both cell surface receptor binding assays and confocal fluorescence microscopy. Taken together, our data indicate that the PET tracer, MNPA, is a full and potent agonist at both D(2) and D(3) receptors. Synapse 63:462-475, 2009. (C)2009 Wiley-Liss, Inc. C1 [Sibley, David R.] NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. [Skinbjerg, Mette; Halldin, Christer] Karolinska Inst, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden. [Skinbjerg, Mette; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Sibley, DR (reprint author), NINDS, Mol Neuropharmacol Sect, NIH, 5625 Fishers Lane,Room 4S-04,MSC 9405, Bethesda, MD 20892 USA. EM sibley@helix.nih.gov FU Intramural NIH HHS [Z01 NS002263-31] NR 61 TC 17 Z9 17 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JUN PY 2009 VL 63 IS 6 BP 462 EP 475 DI 10.1002/syn.20626 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 435EQ UT WOS:000265326900002 PM 19217026 ER PT J AU Mueller, M Kolbrich, EA Peters, FT Maurer, HH McCann, UD Huestis, MA Ricaurte, GA AF Mueller, Melanie Kolbrich, Erin A. Peters, Frank T. Maurer, Hans H. McCann, Una D. Huestis, Marilyn A. Ricaurte, George A. TI Direct Comparison of (+/-) 3,4-Methylenedioxymethamphetamine ("Ecstasy") Disposition and Metabolism in Squirrel Monkeys and Humans SO THERAPEUTIC DRUG MONITORING LA English DT Article DE MDMA; nonlinear pharmacokinetics; MDMA metabolites; neurotoxicity; serotonin; squirrel monkey ID NONLINEAR PHARMACOKINETICS; MDMA; PHARMACOLOGY; BRAIN; METHYLENEDIOXYMETHAMPHETAMINE; TOXICITY; CYP2D6 AB The present study compared the disposition and metabolism of the recreational drug (+/-) 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in squirrel monkeys and humans because the squirrel monkey has been extensively studied for MDMA neurotoxicity. A newly developed liquid chromatography-mass spectrometric procedure for simultaneous measurement of MDMA, 3,4-dihydroxymethamphetamine, 4-hydroxy-3-methoxymethamphetamine, and 3,4-methylenedioxyamphetamine was employed. In both humans and squirrel monkeys, a within-subject design permitted testing of different doses in the same subjects. Humans and squirrel monkeys were found to metabolize MDMA in similar, but not identical, pathways and proportions. In particular, amounts of 3,4-dihydroxymethamphetamine (after conjugate cleavage) and 3,4-methylenedioxyamphetamine were similar in the 2 species, but formation of 4-hydroxy-3-methoxymethamphetamine was greater in squirrel monkeys than in humans. Both species demonstrated nonlinear MDMA pharmacokinetics at comparable plasma MDMA concentrations (125-150 ng/mL and above). The elimination half-life of MDMA was considerably shorter in squirrel monkeys than in humans (2-3 versus 6-9 hours). In both species, there was substantial individual variability. These results suggest that the squirrel monkey may be a useful model for predicting outcomes of MDMA exposure in humans, although this will also depend on the degree to which MDMA pharmacodynamics in the squirrel monkey parallels that in humans. C1 [Ricaurte, George A.] Johns Hopkins Univ, Sch Med, Johns Hopkins Med Inst, Dept Neurol, Baltimore, MD 21224 USA. [Mueller, Melanie; Peters, Frank T.; Maurer, Hans H.] Univ Saarland, Inst Expt & Clin Pharmacol & Toxicol, Dept Expt & Clin Toxicol, D-6650 Homburg, Saar, Germany. [Kolbrich, Erin A.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. [McCann, Una D.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21224 USA. RP Ricaurte, GA (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Med Inst, Dept Neurol, 5501 Hopkins Bayview Circle,Room 5B71 E, Baltimore, MD 21224 USA. EM ricaurte@jhmi.edu FU PHS [DA05707, DA017964]; National Institutes of Health; Intramural Research Program; National Institute on Drug Abuse FX Supported by PHS Grants DA05707 and DA017964 (G.A.R.) and the National Institutes of Health, Intramural Research Program, National Institute on Drug Abuse. NR 19 TC 14 Z9 14 U1 0 U2 2 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 JUN PY 2009 VL 31 IS 3 BP 367 EP 373 PG 7 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 450WG UT WOS:000266431400009 PM 19417716 ER PT J AU Brenta, G Celi, FS Pisarev, M Schnitman, M Sinay, I Arias, P AF Brenta, Gabriela Celi, Francesco S. Pisarev, Mario Schnitman, Marta Sinay, Isaac Arias, Pablo TI Acute Thyroid Hormone Withdrawal in Athyreotic Patients Results in a State of Insulin Resistance SO THYROID LA English DT Letter ID TRANSPORTER GENE-EXPRESSION; SKELETAL-MUSCLE; GLUCOSE-HOMEOSTASIS; HYPOTHYROIDISM; METABOLISM; RATS; SENSITIVITY; HYPERTHYROIDISM; TOLERANCE; THYROTOXICOSIS C1 [Brenta, Gabriela] Cesar Milstein Hosp, Dept Endocrinol & Metab, RA-1221 Buenos Aires, DF, Argentina. [Celi, Francesco S.] NIDDK, Clin Endocrinol Branch, Natl Inst Hlth, Bethesda, MD USA. [Pisarev, Mario] Univ Buenos Aires, Sch Med, Dept Biochem, Buenos Aires, DF, Argentina. [Pisarev, Mario] CNEA, Dept Radiol, Buenos Aires, DF, Argentina. [Schnitman, Marta] Cesar Milstein Hosp, Dept Endocrinol & Metab, RA-1221 Buenos Aires, DF, Argentina. [Sinay, Isaac] Cardiovasc Inst Buenos Aires, Diabet Sect, Buenos Aires, DF, Argentina. [Arias, Pablo] Univ Buenos Aires, Sch Med, Dept Physiol, Buenos Aires, DF, Argentina. RP Brenta, G (reprint author), Cesar Milstein Hosp, Dept Endocrinol & Metab, La Rioja 951, RA-1221 Buenos Aires, DF, Argentina. EM gbrenta@gmail.com FU Intramural NIH HHS NR 31 TC 12 Z9 12 U1 1 U2 3 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 JUN PY 2009 VL 19 IS 6 BP 665 EP 669 DI 10.1089/thy.2009.0108 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 455BF UT WOS:000266729700016 PM 19499994 ER PT J AU Mauck, RL Baker, BM Nerurkar, NL Burdick, JA Li, WJ Tuan, RS Elliott, DM AF Mauck, Robert L. Baker, Brendon M. Nerurkar, Nandan L. Burdick, Jason A. Li, Wan-Ju Tuan, Rocky S. Elliott, Dawn M. TI Engineering on the Straight and Narrow: The Mechanics of Nanofibrous Assemblies for Fiber-Reinforced Tissue Regeneration SO TISSUE ENGINEERING PART B-REVIEWS LA English DT Review ID ANTERIOR CRUCIATE LIGAMENT; NORMAL HUMAN KERATINOCYTES; AMORPHOUS DRUG DISPERSIONS; LUMBAR ANULUS FIBROSUS; MESENCHYMAL STEM-CELLS; SMOOTH-MUSCLE-CELLS; IN-VITRO EVALUATION; HUMAN KNEE-JOINT; ELECTROSPUN NANOFIBERS; CELLULAR INFILTRATION AB Tissue engineering of fibrous tissues of the musculoskeletal system represents a considerable challenge because of the complex architecture and mechanical properties of the component structures. Natural healing processes in these dense tissues are limited as a result of the mechanically challenging environment of the damaged tissue and the hypocellularity and avascular nature of the extracellular matrix. When healing does occur, the ordered structure of the native tissue is replaced with a disorganized fibrous scar with inferior mechanical properties, engendering sites that are prone to re-injury. To address the engineering of such tissues, we and others have adopted a structurally motivated approach based on organized nanofibrous assemblies. These scaffolds are composed of ultrafine polymeric fibers that can be fabricated in such a way to recreate the structural anisotropy typical of fiber-reinforced tissues. This straight-and-narrow topography not only provides tailored mechanical properties, but also serves as a 3D biomimetic micropattern for directed tissue formation. This review describes the underlying technology of nanofiber production and focuses specifically on the mechanical evaluation and theoretical modeling of these structures as it relates to native tissue structure and function. Applying the same mechanical framework for understanding native and engineered fiber-reinforced tissues provides a functional method for evaluating the utility and maturation of these unique engineered constructs. We further describe several case examples where these principles have been put to test, and discuss the remaining challenges and opportunities in forwarding this technology toward clinical implementation. C1 [Mauck, Robert L.; Baker, Brendon M.; Nerurkar, Nandan L.; Elliott, Dawn M.] Univ Penn, McKay Orthopaed Res Lab, Dept Orthopaed Surg, Philadelphia, PA 19104 USA. [Mauck, Robert L.; Baker, Brendon M.; Burdick, Jason A.; Elliott, Dawn M.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Nerurkar, Nandan L.] Univ Penn, Dept Mech Engn, Philadelphia, PA 19104 USA. [Li, Wan-Ju] Univ Wisconsin, Dept Orthopaed & Rehabil & Biomed Engn, Madison, WI USA. [Tuan, Rocky S.] Natl Inst Musculoskeletal & Skin Disorders, Dept Hlth & Human Serv, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD USA. RP Mauck, RL (reprint author), Univ Penn, McKay Orthopaed Res Lab, Dept Orthopaed Surg, 36th St & Hamilton Walk, Philadelphia, PA 19104 USA. EM lemauck@mail.med.upenn.edu RI Elliott, Dawn/E-8862-2012 FU National Institutes of Health [RO1 EB02425]; Aircast Foundation; NFL charities; Penn Center of Musculoskeletal Disorders [P30 AR050950] FX Funding for this work was provided by the National Institutes of Health (RO1 EB02425), the Aircast Foundation, The NFL charities, and the Penn Center of Musculoskeletal Disorders (P30 AR050950). The authors would like to acknowledge Ms. Lara Ionescu for provision of the fetal and adult meniscus images and Mr. Ashwin Nathan for strain maps of deformed scaffolds. NR 147 TC 101 Z9 103 U1 6 U2 30 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3368 J9 TISSUE ENG PART B-RE JI Tissue Eng. Part B-Rev. PD JUN PY 2009 VL 15 IS 2 BP 171 EP 193 DI 10.1089/ten.teb.2008.0652 PG 23 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 452XH UT WOS:000266574000006 PM 19207040 ER PT J AU Cohen, JE Zeller, M Eissenberg, T Parascandola, M O'Keefe, R Planinac, L Leischow, S AF Cohen, J. E. Zeller, M. Eissenberg, T. Parascandola, M. O'Keefe, R. Planinac, L. Leischow, S. TI Criteria for evaluating tobacco control research funding programs and their application to models that include financial support from the tobacco industry SO TOBACCO CONTROL LA English DT Article ID CONFLICTS-OF-INTEREST; CLINICAL-TRIAL AGREEMENTS; NATIONAL-CANCER-INSTITUTE; EXTERNAL-RESEARCH-PROGRAM; PHILIP-MORRIS; SECONDHAND SMOKE; MEDICAL-SCHOOLS; HARM REDUCTION; SCIENCE; SCIENTISTS C1 [Cohen, J. E.] Univ Toronto, Toronto, ON M5S 2S1, Canada. [Cohen, J. E.; Planinac, L.] Ontario Tobacco Res Unit, Toronto, ON, Canada. [Zeller, M.] Pinney Associates, Bethesda, MD USA. [Eissenberg, T.] Virginia Commonwealth Univ, Richmond, VA USA. [Parascandola, M.] NCI, Bethesda, MD 20892 USA. [O'Keefe, R.] Hlth Effects Inst, Boston, MA USA. [Leischow, S.] Univ Arizona, Tucson, AZ USA. RP Cohen, JE (reprint author), Univ Toronto, 33 Russell St,T5, Toronto, ON M5S 2S1, Canada. EM Joanna_cohen@camh.net FU USPHS [R01CA103827] FX The 2007 Workshop that led to this manuscript was funded through the strategic initiative Advancing the Science to Reduce Tobacco Abuse and Nicotine Addiction. This initiative is a partnership of government and non-profit organisations under the coordination of the Canadian Tobacco Control Research Initiative (CTCRI). TE's effort on this project was supported in part by USPHS grant R01CA103827. NR 50 TC 4 Z9 4 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 JUN PY 2009 VL 18 IS 3 BP 228 EP 234 DI 10.1136/tc.2008.027623 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 448PE UT WOS:000266273700012 PM 19240229 ER PT J AU Savolainen, SM Foley, JF Elmore, SA AF Savolainen, Saija M. Foley, Julie F. Elmore, Susan A. TI Histology Atlas of the Developing Mouse Heart with Emphasis on E11.5 to E18.5 SO TOXICOLOGIC PATHOLOGY LA English DT Review DE heart; embryo; mouse; in utero lethality ID CARDIAC NEURAL CREST; PROGRAMMED CELL-DEATH; OUTFLOW TRACT; CARDIOVASCULAR DEVELOPMENT; CORONARY-ARTERIES; GENE-EXPRESSION; CHICK-EMBRYO; SEPTATION; MICE; APOPTOSIS AB In humans, congenital heart diseases are common. Since the rapid progression of transgenic technologies, the mouse has become the major animal model of defective cardiovascular development. Moreover, genetically modified mice frequently die in utero, commonly due to abnormal cardiovascular development. A variety of publications address specific developmental stages or structures of the mouse heart, but a single reference reviewing and describing the anatomy and histology of cardiac developmental events, stage by stage, has not been available. The aim of this color atlas, which demonstrates embryonic/fetal heart development, is to provide a tool for pathologists and biomedical scientists to use for detailed histological evaluation of hematoxylin and eosin (H&E)-stained sections of the developing mouse heart with emphasis on embryonic days (E) 11.5-18.5. The selected images illustrate the main structures and developmental events at each stage and serve as reference material for the confirmation of the chronological age of the embryo/early fetus and assist in the identification of any abnormalities. An extensive review of the literature covering cardiac development pre-E11.5 is summarized in the introduction. Although the focus of this atlas is on the descriptive anatomic and histological development of the normal mouse heart from E11.5 to E18.5, potential embryonic cardiac lesions are discussed with a list of the most common transgenic pre- and perinatal heart defects. Representative images of hearts at E11.5-15.5 and E18.5 are provided in Figures 2-4, 6, 8, and 9. A complete set of labeled images (Figures E11.5-18.5) is available on the CD enclosed in this issue of Toxicologic Pathology. All digital images can be viewed online at https://niehsimages.epl-inc.com with the username "ToxPath'' and the password "embryohearts.'' C1 [Savolainen, Saija M.; Foley, Julie F.; Elmore, Susan A.] NIEHS, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. RP Elmore, SA (reprint author), NIEHS, Cellular & Mol Pathol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM elmore@niehs.nih.gov FU Academy of Finland; Emil Aaltonen's Foundation; Finnish Culture Foundation; National Institutes of Health, National Institute of Environmental Health Sciences FX Competing Interest: Financial support was provided to Dr. Savolainen by the Academy of Finland, Emil Aaltonen's Foundation, and Finnish Culture Foundation. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The author has not declared any other competing interests. NR 74 TC 51 Z9 52 U1 1 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2009 VL 37 IS 4 BP 395 EP 414 DI 10.1177/0192623309335060 PG 20 WC Pathology; Toxicology SC Pathology; Toxicology GA 463YW UT WOS:000267471200001 PM 19359541 ER PT J AU Morrison, JP Ton, TV Collins, JB Switzer, RC Little, PB Morgan, DL Sills, RC AF Morrison, James P. Ton, Thai-Vu Collins, Jennifer B. Switzer, Robert C. Little, Peter B. Morgan, Daniel L. Sills, Robert C. TI Gene Expression Studies Reveal That DNA Damage, Vascular Perturbation, and Inflammation Contribute to the Pathogenesis of Carbonyl Sulfide Neurotoxicity SO TOXICOLOGIC PATHOLOGY LA English DT Article DE gene expression; carbonyl sulfide; posterior colliculus; brain; neurotoxicity; neuropathology; transcriptome ID COLONY-STIMULATING FACTOR; CENTRAL-NERVOUS-SYSTEM; TISSUE GROWTH-FACTOR; NEURONAL CELL-DEATH; REACTIVE ASTROCYTES; C/EBP-DELTA; APOPTOSIS; RAT; DIFFERENTIATION; DISEASE AB Carbonyl sulfide (COS) is an odorless gas that produces highly reproducible lesions in the central nervous system. In the present study, the time course for the development of the neurotoxicological lesions was defined and the gene expression changes occurring in the posterior colliculus upon exposure to COS were characterized. Fischer 344 rats were exposed to 0 or 500 ppm COS for one, two, three, four, five, eight, or ten days, six hours per day. On days 1 and 2, no morphological changes were detected; on day 3, 10/10 (100%) rats had necrosis in the posterior colliculi; and on day 4 and later, necrosis was observed in numerous areas of the brain. Important gene expression changes occurring in the posterior colliculi after one or two days of COS exposure that were predictive of the subsequent morphological findings included up-regulation of genes associated with DNA damage and G1/S checkpoint regulation (KLF4, BTG2, GADD45g), apoptosis (TGM2, GADD45g, RIPK3), and vascular mediators (ADAMTS, CTGF, CYR61, VEGFC). Proinflammatory mediators (CCL2, CEBPD) were up-regulated prior to increases in expression of the astrocytic marker GFAP and macrophage marker CSF2rb1. These gene expression findings were predictive of later CNS lesions caused by COS exposure and serve as a model for future investigations into the mechanisms of disease in the central nervous system. C1 [Ton, Thai-Vu; Sills, Robert C.] NIEHS, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Morrison, James P.; Little, Peter B.] Pathol Associates Inc, Charles River Labs, Durham, NC 27703 USA. [Collins, Jennifer B.; Morgan, Daniel L.] NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Switzer, Robert C.] Neurosci Associates, Knoxville, TN 37934 USA. RP Sills, RC (reprint author), NIEHS, Cellular & Mol Pathol Branch, MD B3-06,POB 12233, Res Triangle Pk, NC 27709 USA. EM sills@niehs.nih.gov FU National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 48 TC 8 Z9 8 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2009 VL 37 IS 4 BP 502 EP 511 DI 10.1177/0192623309335631 PG 10 WC Pathology; Toxicology SC Pathology; Toxicology GA 463YW UT WOS:000267471200011 PM 19395590 ER PT J AU Chaturvedi, A Pierce, SK AF Chaturvedi, Akanksha Pierce, Susan K. TI How Location Governs Toll-Like Receptor Signaling SO TRAFFIC LA English DT Article DE Toll-like receptors; B cells; macrophages; dendritic cells ID DOUBLE-STRANDED-RNA; ACTIVATE B-CELLS; CPG-DNA; ANTIGEN PRESENTATION; CRYSTAL-STRUCTURE; IMMUNE-RESPONSES; TLR9; ENDOCYTOSIS; RECOGNITION; AUTOPHAGY AB Toll-like receptors (TLRs) are a family of innate immune system receptors responsible for recognizing conserved pathogen-associated molecular patterns (PAMPs). PAMP binding to TLRs initiates intracellular signaling pathways that lead to the upregulation of a variety of costimulatory molecules and the synthesis and secretion of various cytokines and interferons by cells of the innate immune system. TLR-induced innate immune responses are a prerequisite for the generation of most adaptive immune responses, and in the case of B cells, TLRs directly regulate signaling from the antigen-specific B-cell receptor. The outcome of TLR signaling is determined, in part, by the cells in which they are expressed and by the selective use of signaling adaptors. Recent studies suggest that, in addition, both the ligand recognition by TLRs and the functional outcome of ligand binding are governed by the subcellular location of the TLRs and their signaling adaptors. In this review we describe what is known about the intracellular trafficking and compartmentalization of TLRs in innate system's dendritic cells and macrophages and in adaptive system's B cells, highlighting how location regulates TLR function. C1 [Chaturvedi, Akanksha; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Chaturvedi, A (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM achaturvedi@nih.gov; spierce@nih.gov FU Intramural NIH HHS [Z01 AI000899-07] NR 50 TC 44 Z9 47 U1 0 U2 5 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 JUN PY 2009 VL 10 IS 6 BP 621 EP 628 DI 10.1111/j.1600-0854.2009.00899.x PG 8 WC Cell Biology SC Cell Biology GA 446HP UT WOS:000266113000002 PM 19302269 ER PT J AU Gaines, AR Lee-Stroka, H Byrne, K Scott, DE Uhl, L Lazarus, E Stroncek, DF AF Gaines, Ann Reed Lee-Stroka, Hallie Byrne, Karen Scott, Dorothy E. Uhl, Lynne Lazarus, Ellen Stroncek, David F. TI Investigation of whether the acute hemolysis associated with Rh-o(D) immune globulin intravenous (human) administration for treatment of immune thrombocytopenic purpura is consistent with the acute hemolytic transfusion reaction model SO TRANSFUSION LA English DT Article ID ANTI-D TREATMENT; ACUTE-RENAL-FAILURE; INTRAVASCULAR HEMOLYSIS; D IMMUNOGLOBULIN; AUTOIMMUNE THROMBOCYTOPENIA; RANDOMIZED-TRIAL; WINRHO; HEMOGLOBINURIA; CHILDREN; EFFICACY AB Immune thrombocytopenic purpura and secondary thrombocytopenia patients treated with Rh-o(D) immune globulin intravenous (human; anti-D IGIV) have experienced acute hemolysis, which is inconsistent with the typical presentation of extravascular hemolysis-the presumed mechanism of action of anti-D IGIV. Although the mechanism of anti-D-IGIV-associated acute hemolysis has not been established, the onset, signs/symptoms, and complications appear consistent with the intravascular hemolysis of acute hemolytic transfusion reactions (AHTRs). In transfusion medicine, the red blood cell (RBC) antigen-antibody incompatibility(-ies) that precipitate AHTRs can be detected in vitro with compatibility testing. Under the premise that anti-D-IGIV-associated acute hemolysis results from RBC antigen-antibody-mediated complement activation, this study evaluated whether the incompatibility(-ies) could be detected in vitro with a hemolysin assay, which would support the AHTR model as the hemolytic mechanism. Seven anti-D IGIV lots were tested to determine the RBC antibody identities in those lots, including four lots that had been implicated in acute hemolytic episodes. Hemolysin assays were performed that tested each of 73 RBC specimens against each lot, including the RBCs of one patient who had experienced acute hemolysis after anti-D IGIV administration. Only two anti-D IGIV lots contained RBC antibodies beyond those expected. No hemolysis endpoint was observed in any of the hemolysin assays. Although the findings did not support the AHTR model, the results are reported to contribute knowledge about the mechanism of anti-D-IGIV-associated acute hemolysis and to prompt continued investigation into cause(s), prediction, and prevention of this potentially serious adverse event. C1 [Gaines, Ann Reed] US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, Off Blood Res & Review, Rockville, MD 20852 USA. US FDA, Ctr Biol Evaluat & Res, Off Cellular Tissue & Gene Therapies, Rockville, MD 20852 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Div Lab & Transfus Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Gaines, AR (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, Off Blood Res & Review, 1401 Rockville Pike, Rockville, MD 20852 USA. EM ann.gaines@fda.hhs.gov FU Robert Wise and M. Miles Braun, Office of Biostatistics and Epidemiology, and Susan Abbondanzo, Office of Blood Research and Review; Center for Biologics Evaluation and Research, FDA FX The authors express their appreciation to the patient who experienced acute hemolysis after WinRho SDF administration and who agreed to provide us with blood specimens for this study. The authors would also express our appreciation to Robert Wise and M. Miles Braun, Office of Biostatistics and Epidemiology, and Susan Abbondanzo, Office of Blood Research and Review, Center for Biologics Evaluation and Research, FDA, for their review of the manuscript. The authors declare no competing financial interests. NR 51 TC 8 Z9 10 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUN PY 2009 VL 49 IS 6 BP 1050 EP 1058 DI 10.1111/j.1537-2995.2008.02083.x PG 9 WC Hematology SC Hematology GA 453IB UT WOS:000266603000006 PM 19220820 ER PT J AU Klein, HG Glynn, SA Ness, PM Blajchman, MA AF Klein, Harvey G. Glynn, Simone A. Ness, Paul M. Blajchman, Morris A. CA NHLBI Working Grp Res Opportunitie TI Research opportunities for pathogen reduction/inactivation of blood components: summary of an NHLBI workshop SO TRANSFUSION LA English DT Editorial Material ID WAVELENGTH ULTRAVIOLET-LIGHT; PHOTOCHEMICAL TREATMENT; INACTIVATION TREATMENT; CONSENSUS CONFERENCE; AMOTOSALEN HCL; SPRINT TRIAL; PLASMA; CELLS; HEMOVIGILANCE; PLATELETS AB In July 2008, a workshop sponsored by the Division of Blood Diseases and Resources of the National Heart, Lung, and Blood Institute (NHLBI) was convened to identify potential research opportunities that could advance our understanding of both the biologic and the clinical impact of the various available pathogen reduction/inactivation (PR/PI) methods of blood components (platelets [PLTs], red blood cells, and plasma) intended for allogeneic transfusion. These discussions resulted in consensus that, even though several PR/PI technologies have already been licensed and are being used in Europe and elsewhere for PLTs and plasma, concerns about possible side effects, particularly component quality and pulmonary toxicity, have impeded regulatory approval in North America (United States and Canada). Such concerns thus threaten to stall further development of these technologies. As a consequence, the NHLBI workshop participants focused on formulating a series of research-related recommendations to better understand, mitigate, and prevent these adverse effects. Other important issues identified included the need for a single method to inactivate pathogens in whole blood without damaging the various blood components; new ways to monitor the efficacy of treated components, including animal models to screen for safety; a better understanding of the effect of PR/PI-treated products on recipient alloimmunization, tolerance, and immune modulation; understanding the impact of PR/PI on various other noninfectious hazards of transfusion; and establishing methods to evaluate risk-benefit and cost-effectiveness, in particular with reference to emerging pathogens. The working group also discussed issues related to specific blood components, such as improving the process of clinical evaluation, investigating the impact of PR/PI on component storage lesions, understanding mechanisms that reduce component viability, and addressing the underlying resistance to the adoption of PR/PI-treated components. This communication summarizes the opinions of workshop participants on these issues and concludes with a list of areas for possible research that could advance the application of PR/PI methods to enhance the safety of the world's blood supplies. C1 [Blajchman, Morris A.] McMaster Univ, Dept Pathol, Hamilton, ON L8N 3Z5, Canada. NHLBI, NIH, Bethesda, MD 20892 USA. NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. RP Blajchman, MA (reprint author), McMaster Univ, Dept Pathol, 1200 Main St W,HSC 4N67, Hamilton, ON L8N 3Z5, Canada. EM blajchma@mcmaster.ca NR 33 TC 18 Z9 18 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUN PY 2009 VL 49 IS 6 BP 1262 EP 1268 DI 10.1111/j.1537-2995.2009.02210.x PG 7 WC Hematology SC Hematology GA 453IB UT WOS:000266603000031 PM 19392769 ER PT J AU Chakrabarti, O Ashok, A Hegde, RS AF Chakrabarti, Oishee Ashok, Aarthi Hegde, Ramanujan S. TI Prion protein biosynthesis and its emerging role in neurodegeneration SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID CREUTZFELDT-JAKOB-DISEASE; ENDOPLASMIC-RETICULUM; TRANSMEMBRANE FORM; PROTEASOMAL DEGRADATION; TRANSLOCATION CHANNEL; SIGNAL SEQUENCES; PRIMARY NEURONS; QUALITY-CONTROL; CULTURED-CELLS; CYTOSOLIC PRP AB Various fatal neurodegenerative disorders are caused by altered metabolism of the prion protein (PrP). These diseases are typically transmissible by an unusual 'protein-only' mechanism in which a misfolded isomer, PrP(Sc), confers its aberrant conformation onto normal cellular PrP. An impressive range of studies has investigated nearly every aspect of this fascinating event; yet, our understanding of how PrP(Sc) accumulation might lead to cellular dysfunction and neurodegeneration is trifling. Recent advances in our understanding of normal PrP biosynthesis and degradation might have unexpectedly shed new light on this complex problem. Indeed, our current understanding of normal PrP cell biology, coupled with a growing appreciation of its complex metabolism, is providing new hypotheses for PrP-mediated neurodegeneration. C1 [Chakrabarti, Oishee; Ashok, Aarthi; Hegde, Ramanujan S.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Hegde, RS (reprint author), NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM hegder@mail.nih.gov OI Hegde, Ramanujan/0000-0001-8338-852X FU National Institute of Child Health and Human Development (www.nichd.nih.gov) at the National Institutes of Health FX Work in our laboratory is supported by the Intramural Research Program of the National Institute of Child Health and Human Development (www.nichd.nih.gov) at the National Institutes of Health. NR 80 TC 36 Z9 36 U1 0 U2 14 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 JUN PY 2009 VL 34 IS 6 BP 287 EP 295 DI 10.1016/j.tibs.2009.03.001 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 467DN UT WOS:000267717200003 PM 19447626 ER PT J AU Hasko, G Csoka, B Nemeth, ZH Vizi, ES Pacher, P AF Hasko, Gyoergy Csoka, Balazs Nemeth, Zoltan H. Vizi, E. Sylvester Pacher, Pal TI A(2B) adenosine receptors in immunity and inflammation SO TRENDS IN IMMUNOLOGY LA English DT Review ID INTESTINAL EPITHELIAL-CELLS; HUMAN MAST-CELLS; INDUCED VASCULAR LEAK; SMOOTH-MUSCLE-CELLS; HIF-1-DEPENDENT REPRESSION; ECTO-5'-NUCLEOTIDASE CD73; PULMONARY INFLAMMATION; DEPENDENT INDUCTION; THERAPEUTIC TARGETS; MACROPHAGE FUNCTION AB A(2B) adenosine receptors are increasingly recognized as important orchestrators of inflammation. A(2B) receptor activation promotes the inflammatory response of mast cells, epithelial cells, smooth muscle cells and fibroblasts, thereby contributing to the pathophysiology of asthma and colitis. A(2B) receptor stimulation limits endothelial cell inflammatory responses and permeability and suppresses macrophage activation thereby preventing tissue injury after episodes of hypoxia and ischemia. A(2B) receptor stimulation also promotes the production of angiogenic cytokines by endothelial cells, mast cells and dendritic cells, aiding granuloma tissue formation and inflammatory resolution, but can also contribute to tumor growth. A(2B) receptors are, thus, potentially important pharmacological targets in treating immune system dysfunction and inflammation. C1 [Hasko, Gyoergy; Csoka, Balazs; Nemeth, Zoltan H.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Hasko, Gyoergy; Vizi, E. Sylvester] Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, H-1083 Budapest, Hungary. [Nemeth, Zoltan H.] Morristown Mem Hosp, Dept Surg, Morristown, NJ 07960 USA. [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, Bethesda, MD 20892 USA. RP Hasko, G (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. EM haskoge@umdnj.edu RI Pacher, Pal/B-6378-2008; OI Pacher, Pal/0000-0001-7036-8108; Csoka, Balazs/0000-0002-7562-1130 FU National Institutes of Health [R01 GM66189]; Intramural Research Program of NIH, National Institute on Alcohol Abuse and Alcoholism,; Hungarian Research Fund OTKA [K73110]; Marie Curie Grant [PIRG02-GA-2007-224767] FX This work was supported by the National Institutes of Health Grant R01 GM66189 and the Intramural Research Program of NIH, National Institute on Alcohol Abuse and Alcoholism, as well as Hungarian Research Fund OTKA (K73110) and Marie Curie Grant PIRG02-GA-2007-224767. NR 84 TC 99 Z9 101 U1 0 U2 10 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 JUN PY 2009 VL 30 IS 6 BP 263 EP 270 DI 10.1016/j.it.2009.04.001 PG 8 WC Immunology SC Immunology GA 470EL UT WOS:000267957600003 PM 19427267 ER PT J AU Ahlers, JD Belyakov, IM AF Ahlers, Jeffrey D. Belyakov, Igor M. TI Strategies for recruiting and targeting dendritic cells for optimizing HIV vaccines SO TRENDS IN MOLECULAR MEDICINE LA English DT Review ID CD8(+) T-CELLS; SIMIAN IMMUNODEFICIENCY VIRUS; ANTIGEN-PRESENTING CELLS; IN-VIVO ELECTROPORATION; FC-GAMMA-RIIB; IMMUNE-RESPONSES; DNA VACCINES; GM-CSF; CROSS-PRESENTATION; CUTTING EDGE AB The natural immune response against HIV and other pathogens that cause chronic infection is insufficient for protection. Novel vaccine design and delivery strategies for optimization of HIV vaccines are urgently needed. These will require a better understanding of a number of factors including: the interplay between dendritic cells (DCs) and multiple cell types in linking innate signals that orchestrate subsequent adaptive immune responses; the regulation of DC function by viral and bacterial vectors, adjuvants and immunomodulatory molecules; and the temporal and synergistic relationships between C-type lectins, Toll-like receptors, NOD-like receptors and RIG-1-like receptors, chemokines and cytokines in enhancing immune responses. Here, we discuss current vaccine strategies for optimizing the induction of immune responses by the recruitment of DCs and the targeting of vaccine antigens to DCs. C1 [Ahlers, Jeffrey D.] NIAID, Div Aids, NIH, Bethesda, MD 20817 USA. [Belyakov, Igor M.] Midwest Res Inst, Frederick, MD 21702 USA. RP Ahlers, JD (reprint author), NIAID, Div Aids, NIH, 6700 Rockledge Dr, Bethesda, MD 20817 USA. EM JAhlers@niaid.nih.gov NR 107 TC 20 Z9 20 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 J9 TRENDS MOL MED JI Trends Mol. Med PD JUN PY 2009 VL 15 IS 6 BP 263 EP 274 DI 10.1016/j.molmed.2009.04.003 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 471JO UT WOS:000268053800004 PM 19487159 ER PT J AU Onaivi, ES AF Onaivi, Emmanuel S. TI Drug Addiction - A Global Problem for the Rich and Poor SO TROPICAL JOURNAL OF PHARMACEUTICAL RESEARCH LA English DT Editorial Material ID HYPOTHESIS; DOPAMINE; REWARD C1 [Onaivi, Emmanuel S.] William Paterson Univ, Dept Biol, Wayne, NJ 07470 USA. [Onaivi, Emmanuel S.] NIDA, NIH, Bethesda, MD USA. RP Onaivi, ES (reprint author), William Paterson Univ, Dept Biol, 300 Pompton Rd, Wayne, NJ 07470 USA. EM Onaivie@wpunj.edu NR 7 TC 0 Z9 0 U1 1 U2 1 PU PHARMACOTHERAPY GROUP PI BENIN CITY PA UNIV BENIN, FACULTY PHARMACY, BENIN CITY, 00000, NIGERIA SN 1596-5996 J9 TROP J PHARM RES JI Trop. J. Pharm. Res. PD JUN PY 2009 VL 8 IS 3 BP 191 EP 192 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 486KJ UT WOS:000269194600001 ER PT J AU Yeo, L Romero, R AF Yeo, L. Romero, R. TI What is the best transperineal ultrasound parameter for predicting success of vacuum extraction? Reply SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Letter ID INTRAPARTUM TRANSLABIAL ULTRASOUND; FETAL HEAD; LABOR; 2ND-STAGE C1 [Romero, R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. Wayne State Univ, Detroit, MI USA. RP Romero, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. EM prbchiefstaff@med.wayne.edu NR 7 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 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD JUN PY 2009 VL 33 IS 6 BP 736 EP 736 DI 10.1002/uog.6399 PG 1 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 461UY UT WOS:000267298900023 ER PT J AU Sarma, AV Kanaya, A Nyberg, LM Kusek, JW Vittinghoff, E Rutledge, B Cleary, PA Gatcomb, P Brown, JS AF Sarma, Aruna V. Kanaya, Alka Nyberg, Leroy M. Kusek, John W. Vittinghoff, Eric Rutledge, Brandy Cleary, Patricia A. Gatcomb, Patricia Brown, Jeanette S. CA Diabet Control & Complications Tri TI Risk Factors for Urinary Incontinence Among Women With Type 1 Diabetes: Findings From the Epidemiology of Diabetes Interventions and Complications Study SO UROLOGY LA English DT Article ID POSTMENOPAUSAL WOMEN; PREVALENCE; MELLITUS; TRIAL; THERAPY; WEIGHT AB OBJECTIVES To determine risk factors for, and long-term effects of, glycemic control on urinary incontinence among women with type I diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications study. METHODS The Diabetes Control and Complications Trial (1982-1993) cohort follow-up, Epidemiology of Diabetes Interventions and Complications trial, began in 1994. In 2004, the female participants (n = 550) completed a self-administered questionnaire on incontinence. Our primary outcome was weekly or greater incontinence, overall and by type. Multivariate regression models were used to determine independent predictors of weekly urinary incontinence, both overall and by type. RESULTS Overall, 38% of women reported any incontinence and 17% reported weekly or greater incontinence. An increasing body mass index (odds ratio 1.1, 95% confidence interval 1.1-1.2) was significantly associated with weekly incontinence, overall and by type. Advancing age and >= 2 urinary tract infections in the previous year were associated with weekly urge incontinence (odds ratio 1.4, 95% confidence interval 1.0-2.0 per 5 years, and odds ratio 4.9, 95% confidence interval 1.8-13.5, respectively). Weaker evidence was seen for increased risk with age for overall weekly incontinence (22% per 5 years, P = .06) and stress incontinence (21% per 5 years, P = .08). CONCLUSIONS Urinary incontinence is common among Women with type l diabetes and the risk factors, including advancing age, increased weight, and previous urinary tract infection, are important. Weight reduction and the treatment of urinary tract infections might have the additional benefit of preventing incontinence or reducing its severity. UROLOGY 73: 1203-1209, 2009. (C) 2009 Elsevier Inc. C1 [Sarma, Aruna V.] Univ Michigan, Dept Urol, Ann Arbor, MI 48105 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Yale Univ, Sch Med, Dept Paediat, New Haven, CT USA. RP Sarma, AV (reprint author), Univ Michigan, Dept Urol, Michigan House,Room 1025, Ann Arbor, MI 48105 USA. EM asarma@umich.edu FU National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health [K-24]; Mid-career Investigator Award in Patient Oriented Research [PA-98-053] FX This research was supported in part by a National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health K-24 Mid-career Investigator Award in Patient Oriented Research (PA-98-053) to J. S. Brown; and by contracts with the Division of Diabetes, Endocrinology, and Metabolic Disease of the National Institute of Diabetes, Digestive, and Kidney Diseases anti the General Clinical Research Center Program, National Center for Research Resources. NR 25 TC 16 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD JUN PY 2009 VL 73 IS 6 BP 1203 EP 1209 DI 10.1016/j.urology.2008.11.009 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 457YA UT WOS:000266972100014 PM 19362350 ER PT J AU Beaumier, CM Rothman, AL AF Beaumier, Coreen M. Rothman, Alan L. TI Cross-Reactive Memory CD4(+) T Cells Alter the CD8(+) T-Cell Response to Heterologous Secondary Dengue Virus Infections in Mice in a Sequence-Specific Manner SO VIRAL IMMUNOLOGY LA English DT Article ID SEROTYPES; GLYCOPROTEIN; THAILAND; EPITOPES AB Secondary dengue virus (DENV) infection is a major factor contributing to the risk for severe disease, an effect that depends upon the sequence of infection with different DENV serotypes. We previously reported sequence-dependent effects of secondary DENV infection on CD8(+) T-cell responses in mice. To further evaluate the effect of infection sequence, we analyzed DENV-specific CD4(+) T-cell responses and their relationship to the CD8(+) T-cell response. Serotype cross-reactivity of CD4(+) T-cell responses also depended upon the sequence of serotypes in this model. Furthermore, adoptive transfer of memory CD4(+) T cells altered the response of memory CD8(+) T cells to secondary infection. These data demonstrate the interaction of different components of the T-cell response in determining the immunological outcome of secondary DENV infection. C1 [Beaumier, Coreen M.; Rothman, Alan L.] Univ Massachusetts, Sch Med, Ctr Infect Dis & Vaccine Res, Worcester, MA 01655 USA. [Beaumier, Coreen M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Rothman, AL (reprint author), Univ Massachusetts, Sch Med, Ctr Infect Dis & Vaccine Res, 55 Lake Ave N,Room S6-862, Worcester, MA 01655 USA. EM Alan.Rothman@umassmed.edu FU National Institutes of Health [U19 AI57319] FX This work was supported by the National Institutes of Health grant U19 AI57319. NR 14 TC 13 Z9 13 U1 1 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0882-8245 J9 VIRAL IMMUNOL JI Viral Immunol. PD JUN PY 2009 VL 22 IS 3 BP 215 EP 219 DI 10.1089/vim.2008.0089 PG 5 WC Immunology; Virology SC Immunology; Virology GA 444MG UT WOS:000265984500009 PM 19435418 ER PT J AU Bengali, Z Townsley, AC Moss, B AF Bengali, Zain Townsley, Alan C. Moss, Bernard TI Vaccinia virus strain differences in cell attachment and entry SO VIROLOGY LA English DT Article DE Poxviruses; Membrane fusion; Endocytosis; Bafilomycin A1; Glycosaminoglycans ID INTRACELLULAR MATURE VIRION; SURFACE HEPARAN-SULFATE; MEMBRANE-PROTEIN; FUSION COMPLEX; ESSENTIAL COMPONENT; L1 PROTEIN; GENE; BINDS; GLYCOSAMINOGLYCANS; PATHWAY AB Vaccinia virus (VACV) strain WR can enter cells by a low pH endosomal pathway or direct fusion with the plasma membrane at neutral pH. Here, we compared attachment and entry of five VACV strains in six cell lines and discovered two major patterns. Only WR exhibited pH 5-enhanced rate of entry following neutral pH adsorption to cells, which correlated with sensitivity to bafilomycin A1, an inhibitor of endosomal acidification. Entry of IHD-J, Copenhagen and Elstree strains were neither accelerated by pH 5 treatment nor prevented by bafilomycin A1. Entry of the Wyeth strain, although not augmented by pH 5, was inhibited by bafilomycin A1. WR and Wyeth were both relatively resistant to the negative effects of heparin on entry, whereas the other strains were extremely sensitive due to inhibition of cell binding. The relative sensitivities of individual vaccinia virus strains to heparin correlated inversely with their abilities to bind to and enter glycosaminoglycan-deficient sog9 cells but not other cell lines tested. These results suggested that that IHD-J, Copenhagen and Elstree have a more limited ability than WR and Wyeth to use the low pH endosomal pathway and are more dependent on binding to glycosaminoglycans for cell attachment. Published by Elsevier Inc. C1 [Bengali, Zain; Townsley, Alan C.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 33 N Dr, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Norman Cooper and Catherine Cotter for providing cells and virus stocks, and Timothy R. Wagenaar, Subbian Sathesh Kumar Panayampalli, Amanda Howard, and Jason Laliberte for helpful discussions. This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 33 TC 43 Z9 44 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN-JUL PY 2009 VL 389 IS 1-2 BP 132 EP 140 DI 10.1016/j.virol.2009.04.012 PG 9 WC Virology SC Virology GA 457RA UT WOS:000266948800015 PM 19428041 ER PT J AU Samuel, AS Kumar, S Madhuri, S Collins, PL Samal, SK AF Samuel, Arthur S. Kumar, Sachin Madhuri, Subbiah Collins, Peter L. Samal, Siba K. TI Complete sequence of the genome of avian paramyxovirus type 9 and comparison with other paramyxoviruses SO VIRUS RESEARCH LA English DT Article DE APMV; Avian paramyxovirus; Paramyxoviridae; Paramyxovirinae; Genome sequence ID NEWCASTLE-DISEASE VIRUS; COMPLETE NUCLEOTIDE-SEQUENCE; L-PROTEINS; RNA; REPLICATION; REVEALS; TRAILER; RULE AB The complete genome consensus sequence was determined for avian paramyxovirus (APMV) serotype 9 prototype strain PMV-9/domestic Duck/New York/22/78. The genome is 15,438 nucleotides (nt) long and encodes six non-overlapping genes in the order of 3'-N-P/V/W-M-F-HN-L-5' with intergenic regions of 0-30 nt. The genome length follows the "rule of six" and contains a 55-nt leader sequence at the 3' end and a 47-nt trailer sequence at the 5' end. The cleavage site of the F protein is I-R-E-G-R-I down arrow F, which does not conform to the conventional cleavage site of the ubiquitous cellular protease furin. The virus required exogenous protease for in vitro replication and grew only in a few established cell lines, indicating a restricted host range. Alignment and phylogenetic analysis of the predicted amino acid sequences of APMV-9 proteins with the cognate proteins of viruses of all five genera of family Paramyxoviridae showed that APMV-9 is more closely related to APMV-1 than to other APMVs. The mean death time in embryonated chicken eggs was found to be more than 120 h, indicating APMV-9 to be avirulent for chickens. (C) 2009 Elsevier B.V. All rights reserved. C1 [Samuel, Arthur S.; Kumar, Sachin; Madhuri, Subbiah; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu FU MAID [N01A060009]; NIH FX We thank Daniel Rockemann and all our laboratory members for their excellent technical assistance and help. We also thank Hamp Edwards for performing electron microscopy and Ireen Dryburgh-Barry for proofreading the manuscript. "This research was supported by MAID contract no.N01A060009 (85% support) and MAID, NIH Intramural Research Program (15% support). The views expressed herein do not necessarily reflect the official policies of the Department of Health and Human Services: nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government." NR 30 TC 30 Z9 30 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD JUN PY 2009 VL 142 IS 1-2 BP 10 EP 18 DI 10.1016/j.virusres.2008.12.016 PG 9 WC Virology SC Virology GA 449YI UT WOS:000266366600002 PM 19185593 ER PT J AU Paldurai, A Subbiah, M Kumar, S Collins, PL Samal, SK AF Paldurai, Anandan Subbiah, Madhuri Kumar, Sachin Collins, Peter L. Samal, Siba K. TI Complete genome sequences of avian paramyxovirus type 8 strains goose/Delaware/1053/76 and pintail/Wakuya/20/78 SO VIRUS RESEARCH LA English DT Article DE APMV-8; Delaware strain; Wakuya strain; Avulavirus; Paramyxovindae; Complete genome sequence ID NEWCASTLE-DISEASE VIRUS; COMPLETE NUCLEOTIDE-SEQUENCE; L-PROTEIN; FAMILY PARAMYXOVIRIDAE; MATRIX PROTEIN; HENDRA VIRUS; IN-VITRO; GENE; RNA; REPLICATION AB Complete consensus genome sequences were determined for avian paramyxovirus type 8 (APMV-8) strains goose/Delaware/1053/76 (prototype strain) and pintail/Wakuya/20/78. The genome of each strain is 15,342 nucleotides (nt) long, which follows the "rule of six". The genome consists of six genes in the order of 3'-N-P/V/W-M-F-HN-L-5'. The genes are flanked on either side by conserved transcription start and stop signals, and have intergenic regions ranging from 1 to 30 nt. The genome contains a 55 nt leader region at the 3'-end and a 171 nt trailer region at the 5'-end. Comparison of sequences of strains Delaware and Wakuya showed nucleotide identity of 96.8% at the genome level and amino acid identities of 99.3%, 96.5%, 98.6%, 99.4%, 98.6% and 99.1% for the predicted N, P, M, F, HN and L proteins, respectively. Both strains grew in embryonated chicken eggs and in primary chicken embryo kidney cells, and 293T cells. Both strains contained only a single basic residue at the cleavage activation site of the F protein and their efficiency of replication in vitro depended on and was augmented by, the presence of exogenous protease in most cell lines. Sequence alignment and phylogenic analysis of the predicted amino acid sequence of APMV-8 strain Delaware proteins with the cognate proteins of other available APMV serotypes showed that APMV-8 is more closely related to APMV-2 and -6 than to APMV-1, -3 and -4. (C) 2009 Elsevier B.V. All rights reserved. C1 [Paldurai, Anandan; Subbiah, Madhuri; Kumar, Sachin; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu FU MAID [N01A060009]; NIH FX We thank Daniel Rockemann, Flavia Militino Dias and all our laboratory members for their excellent technical assistance and help. Special thanks to Ireen Dryburgh-Barry for proofreading the manuscript. "This research was supported by MAID contract no. N01A060009 (85% support) and MAID, NIH Intramural Research Program (15% support). The views expressed herein do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government." NR 44 TC 33 Z9 33 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD JUN PY 2009 VL 142 IS 1-2 BP 144 EP 153 DI 10.1016/j.virusres.2009.02.003 PG 10 WC Virology SC Virology GA 449YI UT WOS:000266366600019 PM 19341613 ER PT J AU Freed, EO AF Freed, Eric O. TI Welcome to Viruses: A New Open-Access, Multidisciplinary Forum for Virology SO VIRUSES-BASEL LA English DT Editorial Material C1 NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM efreed@mail.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 4 PU MDPI AG PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD JUN PY 2009 VL 1 IS 1 BP 1 EP 2 DI 10.3390/v1010001 PG 2 WC Virology SC Virology GA 631HH UT WOS:000280336800001 PM 21994533 ER PT J AU Nam, JM Kwon, D AF Nam, Jun-mo Kwon, Deukwoo TI Non-inferiority tests for clustered matched-pair data SO STATISTICS IN MEDICINE LA English DT Article DE adjusted score test; adjusted Wald-type test; clustered matched pair; method of moments estimate; non-inferiority ID INTRACLASS CORRELATION; BINARY DATA; CORRELATED PROPORTIONS; SAMPLE-SIZE; EQUIVALENCE; DESIGN AB Non-inferiority tests for matched-pair data where pairs are mutually independent may not be appropriate when pairs are clustered. The tests may require an adjustment to account for the correlation within a cluster. We consider the adjusted score and Wald-type tests, and a modification of Obuchowski's method for non-inferiority and compare them with the non-inferiority test based on a method of moments estimate in terms of Type I error rate and power by simulations for a small cluster size under various correlation structures. In general, the score test adjusted by an inflation factor and the modified Obuchowski's method perform as good as the test based on moments estimate in the accuracy of Type I error rates. The latter does not provide reasonably close Type I error rates to the nominal level when the number of clusters is 25 or smaller and a positive response rate for the standard procedure is 20 per cent or lower. The adjusted score test, the method based on moments estimate and the modified test are comparable in power. The adjusted Wald-type test is too anti-conservative and we should caution use of the test. Since number of clusters is strongly related to the accuracy of empirical Type I error rate and power, it is very important to have a sufficiently large number Of Clusters in designing a clustered matched-pair study for non-inferiority. Published in 2009 by John Wiley & Sons, Ltd. C1 [Nam, Jun-mo] NCI, NIH, Biostat Branch, DCEG,DHHS, Rockville, MD 20852 USA. [Kwon, Deukwoo] NCI, NIH, Radiat Epidemiol Branch, DCEG,DHHS, Rockville, MD 20852 USA. RP Nam, JM (reprint author), NCI, NIH, Biostat Branch, DCEG,DHHS, 6120 Execut Blvd, Rockville, MD 20852 USA. EM namj@mail.nih.gov FU NIH National Cancer Institute FX The authors thank two reviewers and an associate editor for their helpful suggestions and constructive comments that improved the manuscript. This research was supported by the Intramural Research Program of the NIH National Cancer Institute. NR 25 TC 11 Z9 11 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAY 30 PY 2009 VL 28 IS 12 BP 1668 EP 1679 DI 10.1002/sim.3580 PG 12 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 450JD UT WOS:000266395900002 PM 19326387 ER PT J AU Peterson, TR Laplante, M Thoreen, CC Sancak, Y Kang, SA Kuehl, WM Gray, NS Sabatini, DM AF Peterson, Timothy R. Laplante, Mathieu Thoreen, Carson C. Sancak, Yasemin Kang, Seong A. Kuehl, W. Michael Gray, Nathanael S. Sabatini, David M. TI DEPTOR Is an mTOR Inhibitor Frequently Overexpressed in Multiple Myeloma Cells and Required for Their Survival SO CELL LA English DT Article ID UNFOLDED PROTEIN RESPONSE; C-MAF; PHOSPHORYLATION; KINASE; RAPAMYCIN; COMPLEX; AKT; PROTEASOME; CANCER; GROWTH AB The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Surprisingly, DEPTOR is highly overexpressed in a subset of multiple myelomas harboring cyclin D1/D3 or c-MAF/MAFB translocations. In these cells, high DEPTOR expression is necessary to maintain PI3K and Akt activation and a reduction in DEPTOR levels leads to apoptosis. Thus, we identify a novel MTOR-interacting protein whose deregulated overexpression in multiple myeloma cells represents a mechanism for activating PI3K/Akt signaling and promoting cell survival. C1 [Peterson, Timothy R.; Laplante, Mathieu; Thoreen, Carson C.; Sancak, Yasemin; Kang, Seong A.; Sabatini, David M.] Nine Cambridge Ctr, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Peterson, Timothy R.; Laplante, Mathieu; Thoreen, Carson C.; Sancak, Yasemin; Kang, Seong A.; Sabatini, David M.] MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Sabatini, David M.] MIT, Koch Ctr Integrat Canc Res, Cambridge, MA 02139 USA. [Kuehl, W. Michael] NCI, Bethesda, MD 20814 USA. [Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Sabatini, DM (reprint author), Nine Cambridge Ctr, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. EM sabatini@wi.mit.edu FU National Institutes of Health [R01 AI47389, R01 CA103866]; Keck Foundation; LAM Foundation; American Diabetes Association; Canadian Institutes of Health Research; American Cancer Society; Intramural Research Program; National Cancer Institute; Center for Cancer Research; Dana Farber Cancer Institute High-Tech Research Fund; Howard Hughes Medical Institute FX The authors thank Thijn Brummelkamp for reviewing the manuscript and the following for technical assistance: Leslie Brents, Stephen Carr, Jake Jaffe, Xana Frias, Heather Keys, Stephanie Kinkel, Doug McMillin, Jan Reiling, Eric Spooner, Ed Van Veen, and Marcel Van Vugt. We thank members of the Sabatini lab for helpful discussions. This work was supported by grants from the National Institutes of Health ( NIH; R01 AI47389 and R01 CA103866) to D. M. S.; awards from the Keck Foundation and LAM Foundation to D. M. S.; a fellowship from the American Diabetes Association to T. R. P.; a fellowship from the Canadian Institutes of Health Research to M. L.; and a fellowship from the American Cancer Society to S. A. K. W. M. K was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. N. S. G. is funded in part by the Dana Farber Cancer Institute High-Tech Research Fund. D. M. S. is an investigator of the Howard Hughes Medical Institute. NR 47 TC 472 Z9 487 U1 5 U2 54 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAY 29 PY 2009 VL 137 IS 5 BP 873 EP 886 DI 10.1016/j.cell.2009.03.046 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 451EZ UT WOS:000266454800018 PM 19446321 ER PT J AU Vadaparampil, ST Moser, RP Loud, J Peters, JA Greene, MH Korde, L AF Vadaparampil, Susan T. Moser, Richard P. Loud, Jennifer Peters, June A. Greene, Mark H. Korde, Larissa TI Factors associated with testicular self-examination among unaffected men from multiple-case testicular cancer families SO HEREDITARY CANCER IN CLINICAL PRACTICE LA English DT Article ID HEALTH BELIEF MODEL; OF-THE-LITERATURE; MALIGNANT-MELANOMA; PROSTATE-CANCER; SUN PROTECTION; PREVALENCE; BREAST; WOMEN; RISK; SUSCEPTIBILITY AB Background: The lifetime testicular cancer (TC) risk in the general population is relatively low (similar to 1 in 250), but men with a family history of TC are at 4 to 9 times greater risk than those without. Some health and professional organizations recommend consideration of testicular self-examination (TSE) for certain high-risk groups (e.g. men with a family history of TC). Yet little is known about factors associated with TSE behaviors in this at-risk group. Methods: We collected information on this subject during an on-going NCI multidisciplinary, etiologically-focused, cross-sectional Familial Testicular Cancer (FTC) study. We present the first report specifically targeting TSE behaviors among first- and second-degree relatives (n = 99) of affected men from families with = 2 TC cases. Demographic, medical, knowledge, health belief, and psychological factors consistent with the Health Belief Model (HBM) were evaluated as variables related to TSE behavior, using chi-square tests of association for categorical variables, and t-tests for continuous variables. Results: For men in our sample, 46% (n = 46) reported performing TSE regularly and 51% (n = 50) reported not regularly performing TSE. Factors associated (p < .05) with regularly performing TSE in multivariate analysis were physician recommendation and testicular cancer worry. This is the first study to examine TSE in unaffected men from FTC families. Conclusion: The findings suggest that, even in this high-risk setting, TSE practices are sub-optimal. Our data provide a basis for further exploring psychosocial issues that are specific to men with a family history of TC, and formulating intervention strategies aimed at improving adherence to TSE guidelines. C1 [Vadaparampil, Susan T.] Univ S Florida, H Lee Moffitt Canc Ctr, Div Populat Sci, Tampa, FL 33682 USA. [Moser, Richard P.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Loud, Jennifer; Peters, June A.; Greene, Mark H.; Korde, Larissa] NCI, DCEG, Clin Genet Branch, Rockville, MD USA. RP Vadaparampil, ST (reprint author), Univ S Florida, H Lee Moffitt Canc Ctr, Div Populat Sci, Tampa, FL 33682 USA. EM susan.vadaparampil@moffitt.org; moserr@mail.nih.gov; loudj@mail.nih.gov; petersju@mail.nih.gov; greenem@mail.nih.gov; kordel@mail.nih.gov FU National Cancer Institute; Westat, Inc. [NO2-CP-11019, N02-CP65504] FX This research was supported in part by funding from the Intramural Research Program of the National Cancer Institute to NCI's Clinical Genetics Branch, and by support services contracts NO2-CP-11019 and N02-CP65504 with Westat, Inc. The authors gratefully acknowledge the invaluable technical and programmatic support of Ann Carr, Janet Bracci and Jennifer Restrepo in the conduct of the study, Doug Banks and the Testicular Cancer Resource Center for their efforts in raising awareness of the research protocol in the familial testicular cancer community and facilitating referral of families, and the invaluable contributions made by study participants, without whom this work could not have been done. NR 52 TC 9 Z9 9 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1731-2302 J9 HERED CANCER CLIN PR JI Hered. Cancer Clin. Pract. PD MAY 29 PY 2009 VL 7 AR 11 DI 10.1186/1897-4287-7-11 PG 10 WC Oncology SC Oncology GA 490SL UT WOS:000269524600001 PM 19480691 ER PT J AU Hoffert, JD Chou, CL Knepper, MA AF Hoffert, Jason D. Chou, Chung-Lin Knepper, Mark A. TI Aquaporin-2 in the "-omics" Era SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID MEDULLARY COLLECTING DUCT; VASOPRESSIN-STIMULATED INCREASE; CAMP-DEPENDENT PHOSPHORYLATION; WATER CHANNEL; PLASMA-MEMBRANE; CYCLIC-AMP; INTRACELLULAR CA2+; AQP2 TRAFFICKING; RENAL-CELLS; RAT-KIDNEY AB Vasopressin controls renal water excretion largely through actions to regulate the water channel aquaporin-2 in collecting duct principal cells. Our knowledge of the mechanisms involved has increased markedly in recent years with the advent of methods for large-scale systems-level profiling such as protein mass spectrometry, yeast two-hybrid analysis, and oligonucleotide microarrays. Here we review this progress. C1 [Hoffert, Jason D.; Chou, Chung-Lin; Knepper, Mark A.] NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM knep@helix.nih.gov NR 50 TC 17 Z9 19 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 29 PY 2009 VL 284 IS 22 BP 14683 EP 14687 DI 10.1074/jbc.R900006200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 448UT UT WOS:000266288200003 PM 19193633 ER PT J AU Namkung, Y Dipace, C Javitch, JA Sibley, DR AF Namkung, Yoon Dipace, Concetta Javitch, Jonathan A. Sibley, David R. TI G Protein-coupled Receptor Kinase-mediated Phosphorylation Regulates Post-endocytic Trafficking of the D-2 Dopamine Receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AGONIST-INDUCED DESENSITIZATION; HAMSTER OVARY CELLS; D2 RECEPTORS; ADENYLATE-CYCLASE; ARRESTIN BINDING; BETA-ARRESTINS; INTERNALIZATION; SENSITIZATION; ISOFORMS; RESPONSIVENESS AB We investigated the role of G protein-coupled receptor kinase (GRK)-mediated phosphorylation in agonist-induced desensitization, arrestin association, endocytosis, and intracellular trafficking of the D-2 dopamine receptor (DAR). Agonist activation of D-2 DARs results in rapid and sustained receptor phosphorylation that is solely mediated by GRKs. A survey of GRKs revealed that only GRK2 or GRK3 promotes D-2 DAR phosphorylation. Mutational analyses resulted in the identification of eight serine/threonine residues within the third cytoplasmic loop of the receptor that are phosphorylated by GRK2/3. Simultaneous mutation of these eight residues results in a receptor construct, GRK(-), that is completely devoid of agonist-promoted GRK-mediated receptor phosphorylation. We found that both wild-type (WT) and GRK(-) receptors underwent a similar degree of agonist-induced desensitization as assessed using [S-35]GTP gamma S binding assays. Similarly, both receptor constructs internalized to the same extent in response to agonist treatment. Furthermore, using bioluminescence resonance energy transfer assays to directly assess receptor association with arrestin3, we found no differences between the WT and GRK(-) receptors. Thus, phosphorylation is not required for arrestin-receptor association or agonist-induced desensitization or internalization. In contrast, when we examined recycling of the D-2 DARs to the cell surface, subsequent to agonist-induced endocytosis, the GRK(-) construct exhibited less recycling in comparison with the WT receptor. This impairment appears to be due to a greater propensity of the GRK(-) receptors to down-regulate once internalized. In contrast, if the receptor is highly phosphorylated, then receptor recycling is promoted. These results reveal a novel role for GRK-mediated phosphorylation in regulating the post-endocytic trafficking of a G protein-coupled receptor. C1 [Namkung, Yoon; Sibley, David R.] NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. [Dipace, Concetta; Javitch, Jonathan A.] Columbia Univ, Coll Phys & Surg, Ctr Mol Recognit, New York, NY 10032 USA. [Dipace, Concetta; Javitch, Jonathan A.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Dipace, Concetta; Javitch, Jonathan A.] Columbia Univ, Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA. RP Sibley, DR (reprint author), NINDS, Mol Neuropharmacol Sect, NIH, 5625 Fishers Ln,Rm 4S-04,MSC 9405, Bethesda, MD 20892 USA. EM sibley@helix.nih.gov FU NINDS FX work was supported, in whole or in part, by a National Institutes of Health grant from NINDS (Intramural Research Program). NR 55 TC 48 Z9 53 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 29 PY 2009 VL 284 IS 22 BP 15038 EP 15051 DI 10.1074/jbc.M900388200 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 448UT UT WOS:000266288200040 PM 19332542 ER PT J AU Mushinski, JF Nguyen, P Stevens, LM Khanna, C Lee, S Chung, EJ Lee, MJ Kim, YS Linehan, WM Horisberger, MA Trepel, JB AF Mushinski, J. Frederic Nguyen, PhuongMai Stevens, Lisa M. Khanna, Chand Lee, Sunmin Chung, Eun Joo Lee, Min-Jung Kim, Yeong Sang Linehan, W. Marston Horisberger, Michel A. Trepel, Jane B. TI Inhibition of Tumor Cell Motility by the Interferon-inducible GTPase MxA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN PROSTATE-CANCER; GENE-EXPRESSION; ANTIVIRAL ACTIVITY; CARCINOMA-CELLS; DYNAMIN FAMILY; MESSENGER-RNA; PROTEIN MXA; METASTASIS; GROWTH; INVOLVEMENT AB To identify pathways controlling prostate cancer metastasis we performed differential display analysis of the human prostate carcinoma cell line PC-3 and its highly metastatic derivative PC-3M. This revealed that a 78-kDa interferon-inducible GTPase, MxA, was expressed in PC-3 but not in PC-3M cells. The gene encoding MxA, MX1, is located in the region of chromosome 21 deleted as a consequence of fusion of TMPRSS2 and ERG, which has been associated with aggressive, invasive prostate cancer. Stable exogenous MxA expression inhibited in vitro motility and invasiveness of PC-3M cells. In vivo exogenous MxA expression decreased the number of hepatic metastases following intrasplenic injection. Exogenous MxA also reduced motility and invasiveness of highly metastatic LOX melanoma cells. A mutation in MxA that inactivated its GTPase reversed inhibition of motility and invasion in both tumor cell lines. Co-immunoprecipitation studies demonstrated that MxA associated with tubulin, but the GTPase-inactivating mutation blocked this association. Because MxA is a highly inducible gene, an MxA-targeted drug discovery screen was initiated by placing the MxA promoter upstream of a luciferase reporter. Examination of the NCI diversity set of small molecules revealed three hits that activated the promoter. In PC-3M cells, these drugs induced MxA protein and inhibited motility. These data demonstrate that MxA inhibits tumor cell motility and invasion, and that MxA expression can be induced by small molecules, potentially offering a new approach to the prevention and treatment of metastasis. C1 [Nguyen, PhuongMai; Lee, Sunmin; Chung, Eun Joo; Lee, Min-Jung; Kim, Yeong Sang; Trepel, Jane B.] NCI, NIH, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, NIH, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Khanna, Chand] NCI, NIH, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Linehan, W. Marston] NCI, NIH, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Horisberger, Michel A.] Aivogen AG, CH-4052 Basel, Switzerland. RP Trepel, JB (reprint author), NCI, NIH, Med Oncol Branch, Ctr Canc Res, Bldg 10,Rm 12N230,10 Ctr Dr, Bethesda, MD 20892 USA. EM trepel@helix.nih.gov FU National Institutes of Health NCI Intramural Program FX This work was supported, in whole or in part, by the National Institutes of Health NCI Intramural Program. NR 59 TC 24 Z9 26 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 29 PY 2009 VL 284 IS 22 BP 15206 EP 15214 DI 10.1074/jbc.M806324200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 448UT UT WOS:000266288200055 PM 19297326 ER PT J AU Grice, EA Kong, HH Conlan, S Deming, CB Davis, J Young, AC Bouffard, GG Blakesley, RW Murray, PR Green, ED Turner, ML Segre, JA AF Grice, Elizabeth A. Kong, Heidi H. Conlan, Sean Deming, Clayton B. Davis, Joie Young, Alice C. Bouffard, Gerard G. Blakesley, Robert W. Murray, Patrick R. Green, Eric D. Turner, Maria L. Segre, Julia A. CA NISC Comparative Sequencing Progra TI Topographical and Temporal Diversity of the Human Skin Microbiome SO SCIENCE LA English DT Article ID BACTERIAL BIOTA AB Human skin is a large, heterogeneous organ that protects the body from pathogens while sustaining microorganisms that influence human health and disease. Our analysis of 16S ribosomal RNA gene sequences obtained from 20 distinct skin sites of healthy humans revealed that physiologically comparable sites harbor similar bacterial communities. The complexity and stability of the microbial community are dependent on the specific characteristics of the skin site. This topographical and temporal survey provides a baseline for studies that examine the role of bacterial communities in disease states and the microbial interdependencies required to maintain healthy skin. C1 [Grice, Elizabeth A.; Conlan, Sean; Deming, Clayton B.; Segre, Julia A.] NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Kong, Heidi H.; Turner, Maria L.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Davis, Joie] NHGRI, Off Translat Res, Bethesda, MD 20892 USA. [Young, Alice C.; Bouffard, Gerard G.; Blakesley, Robert W.; Green, Eric D.; NISC Comparative Sequencing Progra] NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Bouffard, Gerard G.; Blakesley, Robert W.; Green, Eric D.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Murray, Patrick R.] NIH, Clin Microbiol Lab, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov RI Conlan, Sean/B-4401-2008; OI Conlan, Sean/0000-0001-6848-3465; Kong, Heidi/0000-0003-4424-064X; Grice, Elizabeth/0000-0003-3939-2200 FU NIGMS Pharmacology Research Associate Training Fellowship; NHGRI; NCI Center for Cancer Research Intramural Research Programs; NCBI Genome Project [30125] FX We thank the volunteers who participated in this study; E. Bassett for assistance with sample collection; members of the Segre laboratory for their underlying contributions; M. Udey, N. Salafsky, and E. Lander for critical reading of the manuscript; and J. Fekecs and D. Leja for graphical assistance. Supported by a NIGMS Pharmacology Research Associate Training Fellowship (E.A.G.) and by the NHGRI and NCI Center for Cancer Research Intramural Research Programs. All sequences are deposited under NCBI Genome Project 30125, GenBank accession numbers GQ000001 to GQ116391. NR 11 TC 675 Z9 695 U1 27 U2 223 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 29 PY 2009 VL 324 IS 5931 BP 1190 EP 1192 DI 10.1126/science.1171700 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 450OG UT WOS:000266410100043 PM 19478181 ER PT J AU Gregoriou, GG Gotts, SJ Zhou, HH Desimone, R AF Gregoriou, Georgia G. Gotts, Stephen J. Zhou, Huihui Desimone, Robert TI High-Frequency, Long-Range Coupling Between Prefrontal and Visual Cortex During Attention SO SCIENCE LA English DT Article ID MACAQUE AREA V4; NEURONAL SYNCHRONIZATION; NEURAL MECHANISMS; TOP-DOWN; GAMMA OSCILLATIONS; CORTICAL NETWORK; CONNECTIONS; ENTRAINMENT; TOPOGRAPHY; SELECTION AB Electrical recordings in humans and monkeys show attentional enhancement of evoked responses and gamma synchrony in ventral stream cortical areas. Does this synchrony result from intrinsic activity in visual cortex or from inputs from other structures? Using paired recordings in the frontal eye field (FEF) and area V4, we found that attention to a stimulus in their joint receptive field leads to enhanced oscillatory coupling between the two areas, particularly at gamma frequencies. This coupling appeared to be initiated by FEF and was time-shifted by about 8 to 13 milliseconds across a range of frequencies. Considering the expected conduction and synaptic delays between the areas, this time-shifted coupling at gamma frequencies may optimize the postsynaptic impact of spikes from one area upon the other, improving cross-area communication with attention. C1 [Gregoriou, Georgia G.; Zhou, Huihui; Desimone, Robert] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Gotts, Stephen J.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Desimone, R (reprint author), MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM desimone@mit.edu RI Gregoriou, Georgia/F-7759-2011; Gotts, Stephen/J-4842-2012 OI Gregoriou, Georgia/0000-0002-4002-6657; FU NIH [MH64445]; [EY017292]; [EY017921] FX We thank G. Pielli, D. Stock, and C. Alfes for help with the animal training and Z.-X. Liu for help with the Granger causality analysis. We also thank N. Bichot, R. Landman, G. Mulliken, and A. Mitz for helpful discussions. Supported by grants EY017292 and EY017921 to R.D. S.J.G. was supported in part by grant MH64445 from NIH (USA). NR 27 TC 468 Z9 470 U1 9 U2 63 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 29 PY 2009 VL 324 IS 5931 BP 1207 EP 1210 DI 10.1126/science.1171402 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 450OG UT WOS:000266410100048 PM 19478185 ER PT J AU Landgren, O Kyle, RA Pfeiffer, RM Katzmann, JA Caporaso, NE Hayes, RB Dispenzieri, A Kumar, S Clark, RJ Baris, D Hoover, R Rajkumar, SV AF Landgren, Ola Kyle, Robert A. Pfeiffer, Ruth M. Katzmann, Jerry A. Caporaso, Neil E. Hayes, Richard B. Dispenzieri, Angela Kumar, Shaji Clark, Raynell J. Baris, Dalsu Hoover, Robert Rajkumar, S. Vincent TI Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study SO BLOOD LA English DT Article ID LONG-TERM; PROGRESSION; PROGNOSIS; TRIAL; RISK AB Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma-cell proliferative disorder associated with a life-long risk of progression to multiple myeloma (MM). It is not known whether MM is always preceded by a premalignant asymptomatic MGUS stage. Among 77 469 healthy adults enrolled in the nationwide population-based prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 71 subjects who developed MM during the course of the study in whom serially collected (up to 6) prediagnostic serum samples obtained 2 to 9.8 years prior to MM diagnosis were available. Using assays for monoclonal (M)- proteins (electrophoresis/immunofixation) and kappa-lambda free light chains (FLCs), we determined longitudinally the prevalence of MGUS and characterized patterns of monoclonal immunoglobulin abnormalities prior to MM diagnosis. MGUS was present in 100.0% (87.2%-100.0%), 98.3% (90.8%-100.0%), 97.9% (88.9%-100.0%), 94.6% (81.8%-99.3%), 100.0% (86.3%-100.0%), 93.3% (68.1%-99.8%), and 82.4% (56.6%-96.2%) at 2, 3, 4, 5, 6, 7, and 8+ years prior to MM diagnosis, respectively. In approximately half the study population, the M-protein concentration and involved FLC-ratio levels showed a yearly increase prior to MM diagnosis. In the present study, an asymptomatic MGUS stage consistently preceded MM. Novel molecular markers are needed to better predict progression to MM in patients with MGUS. (Blood. 2009; 113: 5412-5417) C1 [Landgren, Ola] NCI, NIH, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. [Landgren, Ola; Pfeiffer, Ruth M.; Caporaso, Neil E.; Hayes, Richard B.; Baris, Dalsu; Hoover, Robert] NCI, NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kyle, Robert A.; Katzmann, Jerry A.; Dispenzieri, Angela; Kumar, Shaji; Rajkumar, S. Vincent] Mayo Clin, Div Hematol & Internal Med, Rochester, MN USA. [Kyle, Robert A.; Katzmann, Jerry A.; Dispenzieri, Angela; Clark, Raynell J.] Mayo Clin, Div Clin Biochem & Immunol, Rochester, MN USA. [Kyle, Robert A.; Katzmann, Jerry A.; Dispenzieri, Angela; Clark, Raynell J.] Mayo Clin, Lab Med & Pathol, Rochester, MN USA. RP Landgren, O (reprint author), NCI, NIH, Ctr Canc Res, Med Oncol Branch, Bldg 10,Room 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; Kumar, Shaji/A-9853-2008; OI Kumar, Shaji/0000-0001-5392-9284; Rajkumar, S. Vincent/0000-0002-5862-1833; Hayes, Richard/0000-0002-0918-661X; Dispenzieri, Angela/0000-0001-8780-9512 FU National Cancer Institute [CA 62242, CA 107-476-03]; National Institutes of Health (Bethesda, MD);; National Cancer Institute Director's Intramural Innovation Award (O.L.); FX The authors thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute; the Screening Center investigators and staff of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Mr Tom Riley and staff, Information Management Services (Rockville, MD); and Ms Barbara O'Brien and staff, Westat (Rockville, MD). Most importantly, we acknowledge the study participants for their contributions to making this study possible.; This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (Bethesda, MD); the National Cancer Institute Director's Intramural Innovation Award (O.L.); the grants CA 62242 and CA 107-476-03 from the National Cancer Institute; and the facilities and resources of the Divisions of Hematology, Biostatistics, Clinical Biochemistry and Immunology, and Epidemiology at the Mayo Clinic. The study sponsors did not have any role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the paper; or the decision to submit the paper for publication. NR 22 TC 337 Z9 341 U1 3 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 28 PY 2009 VL 113 IS 22 BP 5412 EP 5417 DI 10.1182/blood-2008-12-194241 PG 6 WC Hematology SC Hematology GA 453TD UT WOS:000266634700011 PM 19179464 ER PT J AU Weiss, BM Abadie, J Verma, P Howard, RS Kuehl, WM AF Weiss, Brendan M. Abadie, Jude Verma, Pramvir Howard, Robin S. Kuehl, W. Michael TI A monoclonal gammopathy precedes multiple myeloma in most patients SO BLOOD LA English DT Article ID UNDETERMINED SIGNIFICANCE MGUS; INDEPENDENT RISK-FACTOR; LIGHT-CHAIN RATIO; LONG-TERM; FOLLOW-UP; PROGRESSION; PROGNOSIS; SURVIVAL AB Preexisting plasma cell disorders, monoclonal gammopathy of undetermined significance, or smoldering myeloma are present in at least one-third of multiple myeloma patients. However, the proportion of patients with a preexisting plasma cell disorder has never been determined by laboratory testing on prediagnostic sera. We cross-referenced our autologous stem cell transplantation database with the Department of Defense Serum Repository. Serum protein electrophoresis, immunofixation electrophoresis, and serum free light-chain analysis were performed on all sera collected 2 or more years before diagnosis to detect a monoclonal gammopathy (M-Ig). In 30 of 90 patients, 110 prediagnostic samples were available from 2.2 to 15.3 years before diagnosis. An M-Ig was detected initially in 27 of 30 patients (90%, 95% confidence interval, 74%-97%); by serum protein electrophoresis and/or immunofixation electrophoresis in 21 patients (77.8%), and only by serum free lightchain analysis in 6 patients (22.2%). Four patients had only one positive sample within 4 years before diagnosis, with all preceding sera negative. All 4 patients with light-chain/nonsecretory myeloma evolved from a light-chain M-Ig. A preexisting M-Ig is present in most multiple myeloma patients before diagnosis. Some patients progress rapidly through a premalignant phase. Light-chain detected M-Ig is a new entity that requires further study. (Blood. 2009; 113: 5418-5422) C1 [Weiss, Brendan M.] Walter Reed Army Med Ctr, Hematol Oncol Serv, Dept Med, Washington, DC 20307 USA. [Abadie, Jude] Walter Reed Army Med Ctr, Dept Pathol, Washington, DC 20307 USA. [Abadie, Jude] Walter Reed Army Med Ctr, Area Lab Serv, Washington, DC 20307 USA. [Verma, Pramvir] Womack Army Med Ctr, Hematol Oncol Serv, Dept Med, Ft Bragg, NC USA. [Howard, Robin S.] Walter Reed Army Med Ctr, Dept Clin Invest, Washington, DC 20307 USA. [Kuehl, W. Michael] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Weiss, BM (reprint author), Walter Reed Army Med Ctr, Hematol Oncol Serv, Dept Med, 6900 Georgia Ave NW, Washington, DC 20307 USA. EM brendan.weiss@us.army.mil FU Walter Reed Army Medical Center; Armed Forces Health Surveillance Agency (Silver Spring, MD);; National Institutes of Health; National Cancer Institute; Center for Cancer Research FX The authors thank Dr Karen van Hoeven of The Binding Site Inc.; Drs Angelia Eick and Mark Rubertone at the Armed Forces Health Surveillance Agency; and Ms Debra Marks and Ms Sue Vernigor in the Department of Pathology and Area Laboratory Services, Walter Reed Army Medical Center.; This work was supported by the facilities and resources of the Walter Reed Army Medical Center; the Armed Forces Health Surveillance Agency (Silver Spring, MD); the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; and a gift of laboratory supplies from The Binding Site Inc. These sponsors had no role in the study design, data analysis, data interpretation, manuscript writing, or the decision to submit for publication. NR 23 TC 208 Z9 212 U1 2 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 28 PY 2009 VL 113 IS 22 BP 5418 EP 5422 DI 10.1182/blood-2008-12-195008 PG 5 WC Hematology SC Hematology GA 453TD UT WOS:000266634700012 PM 19234139 ER PT J AU Kim, YJ Kim, YS Larochelle, A Renaud, G Wolfsberg, TG Adler, R Donahue, RE Hematti, P Hong, BK Roayaei, J Akagi, K Riberdy, JM Nienhuis, AW Dunbar, CE Persons, DA AF Kim, Yoo-Jin Kim, Yoon-Sang Larochelle, Andre Renaud, Gabriel Wolfsberg, Tyra G. Adler, Rima Donahue, Robert E. Hematti, Peiman Hong, Bum-Kee Roayaei, Jean Akagi, Keiko Riberdy, Janice M. Nienhuis, Arthur W. Dunbar, Cynthia E. Persons, Derek A. TI Sustained high-level polyclonal hematopoietic marking and transgene expression 4 years after autologous transplantation of rhesus macaques with SIV lentiviral vector-transduced CD34(+) cells SO BLOOD LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; CHRONIC GRANULOMATOUS-DISEASE; BONE-MARROW-TRANSPLANTATION; RETROVIRAL GENE MARKING; STEM-CELLS; INSERTIONAL MUTAGENESIS; STABLE TRANSDUCTION; NONDIVIDING CELLS; PROGENITOR CELLS; ACIDIC CLUSTER AB We previously reported that lentiviral vectors derived from the simian immunodeficiency virus (SIV) were efficient at transducing rhesus hematopoietic re-populating cells. To evaluate the persistence of vector-containing and -expressing cells long term, and the safety implications of SIV lentiviral vector-mediated gene transfer, we followed 3 rhesus macaques for more than 4 years after transplantation with transduced CD34(+) cells. All 3 animals demonstrated significant vector marking and expression of the GFP transgene in T cells, B cells, and granulocytes, with mean GFP(+) levels of 6.7% (range, 3.3%-13.0%), 7.4% (4.2%-13.4%), and 5.6% (3.1%-10.5%), respectively. There was no vector silencing in hematopoietic cells over time. Vector insertion site analysis of granulocytes demonstrated sustained highly polyclonal reconstitution, with no evidence for progression to oligoclonality. A significant number of clones were found to contribute at both 1-year and 3- or 4-year time points. No vector integrations were detected in the MDS1/EVI1 region, in contrast to our previous findings with a gamma-retroviral vector. These data show that lentiviral vectors can mediate stable and efficient long-term expression in the progeny of transduced hematopoietic stem cells, with an integration profile that may be safer than that of standard Moloney murine leukemia virus (MLV) derived retroviral vectors. (Blood. 2009; 113: 5434-5443) C1 [Kim, Yoo-Jin; Larochelle, Andre; Adler, Rima; Donahue, Robert E.; Hematti, Peiman; Hong, Bum-Kee; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20852 USA. [Kim, Yoon-Sang; Nienhuis, Arthur W.; Persons, Derek A.] St Jude Childrens Hosp, Dept Hematol, Memphis, TN 38105 USA. [Renaud, Gabriel; Wolfsberg, Tyra G.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Roayaei, Jean; Akagi, Keiko] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Riberdy, Janice M.] St Jude Childrens Hosp, Dept Immunol, Memphis, TN 38105 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, CRC Bldg 10,Rm 4E-5132,10 Ctr Dr, Bethesda, MD 20852 USA. EM dunbarc@nhlbi.nih.gov RI Kim, Yoon-Sang/A-5303-2013 FU National Heart, Lung, and Blood Institute; National Human Genome Research Institute, National Institutes of Health FX We thank Stephanie Sellers for skilled laboratory assistance, Colin Wu for statistical advice, Lauren Brinster, DVM, and the pathology staff of the Division of Veterinary Resources for histopathology processing and interpretation, and Allen Krouse and Mark Metzger and the rest of the 5 Research Court staff for providing excellent animal care.; This research was supported in part by the Intramural Research Programs of the National Heart, Lung, and Blood Institute and the National Human Genome Research Institute, National Institutes of Health. NR 65 TC 33 Z9 35 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 28 PY 2009 VL 113 IS 22 BP 5434 EP 5443 DI 10.1182/blood-2008-10-185199 PG 10 WC Hematology SC Hematology GA 453TD UT WOS:000266634700014 PM 19339698 ER PT J AU Horman, SR Velu, CS Chaubey, A Bourdeau, T Zhu, JF Paul, WE Gebelein, B Grimes, HL AF Horman, Shane R. Velu, Chinavenmeni S. Chaubey, Aditya Bourdeau, Tristan Zhu, Jinfang Paul, William E. Gebelein, Brian Grimes, H. Leighton TI Gfi1 integrates progenitor versus granulocytic transcriptional programming SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; BONE-MARROW-CELLS; ZINC-FINGER PROTEIN; ONCOGENIC K-RAS; MYELOID-LEUKEMIA; MYELOPROLIFERATIVE DISEASE; SELF-RENEWAL; C-MYC; HOXA9; GENE AB In patients with severe congenital neutropenia (SCN) and mice with growth factor independent-1 (Gfi1) loss of function, arrested myeloid progenitors accumulate, whereas terminal granulopoiesis is blocked. One might assume that Gfi-null progenitors accumulate because they lack the ability to differentiate. Instead, our data indicate that Gfi1 loss of function deregulates 2 separable transcriptional programs, one of which controls the accumulation and lineage specification of myeloid progenitors, but not terminal granulopoiesis. We demonstrate that Gfi1 directly represses HoxA9, Pbx1, and Meis1 during normal myelopoiesis. Gfi1(-/-) progenitors exhibit elevated levels of HoxA9, Pbx1 and Meis1, exaggerated HoxA9-Pbx1-Meis1 activity, and progenitor transformation in collaboration with oncogenic K-Ras. Limiting HoxA9 alleles corrects, in a dose-dependent manner, in vivo and in vitro phenotypes observed with loss of Gfi1 in myeloid progenitor cells but did not rescue Gfi1(-/-) blocked granulopoiesis. Thus, Gfi1 integrates 2 events during normal myeloid differentiation; the suppression of a HoxA9-Pbx1-Meis1 progenitor program and the induction of a granulopoietic transcription program. (Blood. 2009; 113: 5466-5475) C1 [Horman, Shane R.; Velu, Chinavenmeni S.; Chaubey, Aditya; Bourdeau, Tristan; Grimes, H. Leighton] Cincinnati Childrens Hosp, Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA. [Horman, Shane R.; Velu, Chinavenmeni S.; Chaubey, Aditya; Bourdeau, Tristan; Grimes, H. Leighton] Cincinnati Childrens Hosp, Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Zhu, Jinfang; Paul, William E.] NIAID, NIH, Bethesda, MD 20892 USA. [Gebelein, Brian] Cincinnati Childrens Hosp, Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA. RP Grimes, HL (reprint author), Cincinnati Childrens Hosp, Med Ctr, Div Immunobiol, 3333 Burnet Ave,MLC7038, Cincinnati, OH 45229 USA. EM lee.grimes@cchmc.org RI Zhu, Jinfang/B-7574-2012; Nakafuku, Masato/J-3068-2013; OI Grimes, H. Leighton/0000-0001-8162-6758 FU Division of Intramural Research; NIAID; NIH [CA105152, HL079574]; Cancerfree Kids (Loveland, OH), FX This work was supported by the Division of Intramural Research, NIAID, NIH (J.Z. and W.E.P.), by a grant from Cancerfree Kids (Loveland, OH), and by NIH (CA105152 and HL079574; H.L.G.). NR 49 TC 42 Z9 42 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 28 PY 2009 VL 113 IS 22 BP 5466 EP 5475 DI 10.1182/blood-2008-09-179747 PG 10 WC Hematology SC Hematology GA 453TD UT WOS:000266634700016 PM 19346496 ER PT J AU Berezhkovskii, A Hummer, G Szabo, A AF Berezhkovskii, Alexander Hummer, Gerhard Szabo, Attila TI Reactive flux and folding pathways in network models of coarse-grained protein dynamics SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE biochemistry; master equation; molecular biophysics; proteins; reaction rate constants ID TRANSITION-STATES; MASTER EQUATION; KINETICS; PEPTIDE; SIMULATIONS; KRAMERS; HAIRPIN; REGIME; RATES AB The reactive flux between folded and unfolded states of a two-state protein, whose coarse-grained dynamics is described by a master equation, is expressed in terms of the commitment or splitting probabilities of the microstates in the bottleneck region. This allows one to determine how much each transition through a dividing surface contributes to the reactive flux. By repeating the analysis for a series of dividing surfaces or, alternatively, by partitioning the reactive flux into contributions of unidirectional pathways that connect reactants and products, insight can be gained into the mechanism of protein folding. Our results for the flux in a network with complex connectivity, obtained using the discrete counterpart of Kramers' theory of activated rate processes, show that the number of reactive transitions is typically much smaller than the total number of transitions that cross a dividing surface at equilibrium. C1 [Berezhkovskii, Alexander] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Hummer, Gerhard; Szabo, Attila] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Berezhkovskii, A (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM berezh@helix.nih.gov RI Szabo, Attila/H-3867-2012; Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Intramural Research Program of the NIH; Center for Information Technology; National Institute of Diabetes and Digestive and Kidney Diseases FX This study was supported by the Intramural Research Program of the NIH, Center for Information Technology and National Institute of Diabetes and Digestive and Kidney Diseases. NR 39 TC 83 Z9 83 U1 2 U2 20 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 28 PY 2009 VL 130 IS 20 AR 205102 DI 10.1063/1.3139063 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 451VY UT WOS:000266500200054 PM 19485483 ER PT J AU Minh, DDL AF Minh, David D. L. TI Density-dependent analysis of nonequilibrium paths improves free energy estimates SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE entropy; free energy; nonequilibrium thermodynamics ID COMPUTER-SIMULATIONS; FLUCTUATION THEOREM; EQUILIBRIUM; BOUNDS; WORK; TRAJECTORIES; EQUALITY; SYSTEMS; ERROR; BIAS AB When a system is driven out of equilibrium by a time-dependent protocol that modifies the Hamiltonian, it follows a nonequilibrium path. Samples of these paths can be used in nonequilibrium work theorems to estimate equilibrium quantities such as free energy differences. Here, we consider analyzing paths generated with one protocol using another one. It is posited that analysis protocols which minimize the lag, the difference between the nonequilibrium and the instantaneous equilibrium densities, will reduce the dissipation of reprocessed trajectories and lead to better free energy estimates. Indeed, when minimal lag analysis protocols based on exactly soluble propagators or relative entropies are applied to several test cases, substantial gains in the accuracy and precision of estimated free energy differences are observed. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Minh, DDL (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM daveminh@gmail.com RI Minh, David/A-4655-2009 OI Minh, David/0000-0002-4802-2618 FU NIH; NIDDK FX The author thanks Artur Adib, Christopher Jarzynski, Attila Szabo, and Suriyanarayanan Vaikuntanathan for pertinent discussions and Gerhard Hummer for suggesting that he considers the lag. He also thanks Artur Adib for supporting a postdoctoral fellowship. This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 36 TC 5 Z9 5 U1 0 U2 2 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 28 PY 2009 VL 130 IS 20 AR 204102 DI 10.1063/1.3139189 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 451VY UT WOS:000266500200003 PM 19485432 ER PT J AU Hall, MD Salam, NK Hellawell, JL Fales, HM Kensler, CB Ludwig, JA Szakacs, G Hibbs, DE Gottesman, MM AF Hall, Matthew D. Salam, Noeris K. Hellawell, Jennifer L. Fales, Henry M. Kensler, Caroline B. Ludwig, Joseph A. Szakacs, Gergely Hibbs, David E. Gottesman, Michael M. TI Synthesis, Activity, and Pharmacophore Development for Isatin-beta-thiosemicarbazones with Selective Activity toward Multidrug-Resistant Cells SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PRIMARY CYTOTOXICITY EVALUATION; RIBONUCLEOTIDE REDUCTASE; 3-AMINOPYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONE; IRON CHELATORS; PHASE-I; CANCER; INHIBITOR; DISCOVERY; TRANSPORTERS; DERIVATIVES AB We have recently identified a new class of compounds that selectively kill cells that express P-glycoprotein (P-gp, MDR1), the ATPase efflux pump that confers multidrug resistance on cancer cells. Several isatin-beta-thiosemicarbazones from our initial study have been validated and a range of analogues synthesized and tested. A number demonstrated improved MDR1-selective activity over the lead, NSC73306 (1). Pharmacophores for cytotoxicity and MDR1 selectivity were generated to delineate the structural features required for activity. The MDR1-selective pharmacophore highlights the importance of aromatic/hydrophobic features at the N4 position of the thiosemicarbazone and the reliance on the isatin moiety as key bioisosteric contributors. Additionally, a quantitative structure-activity relationship (QSAR) model that yielded a cross-validated correlation coefficient of 0.85 effectively predicts the cytotoxicity of untested thiosemicarbazones. Together, the models serve as effective approaches for predicting structures with MDR1-selective activity and aid in directing the search for the mechanism of action of 1. C1 [Hall, Matthew D.; Hellawell, Jennifer L.; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Salam, Noeris K.; Hibbs, David E.] Univ Sydney, Fac Pharm, Pharmaceut Chem Div, Grp Biomol Struct & Informat, Sydney, NSW 2006, Australia. [Fales, Henry M.; Kensler, Caroline B.] NHLBI, Lab Appl Mass Spectrometry, NIH, Bethesda, MD 20892 USA. [Ludwig, Joseph A.] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX 77030 USA. [Szakacs, Gergely] Hungarian Acad Sci, Inst Enzymol, H-1113 Budapest, Hungary. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM gottesmm@mail.nih.gov RI Szakacs, Gergely/A-2580-2009; Hall, Matthew/B-2132-2010 OI Szakacs, Gergely/0000-0002-9311-7827; FU Australian Research Council; University of Sydney; Howard Hughes Medical Institute; National Institutes of Health; National Cancer Institute FX D.E.H. acknowledges Australian Research Council for funding. N.K.S. acknowledges Faculty of Pharmacy, University of Sydney, for award of a scholarship. J.L.H. acknowledges the Howard Hughes Medical Institute for award of a HHMI Fellowship. G.S. is an EMBO SDIG fellow and a Special Fellow of the Leukemia and Lymphoma Society. The authors thank Edward Sokoloslci and Noel Whittaker for assistance in obtaining NMR and mass spectra. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 44 TC 87 Z9 89 U1 2 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 28 PY 2009 VL 52 IS 10 BP 3191 EP 3204 DI 10.1021/jm800861c PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 448XV UT WOS:000266296200009 PM 19397322 ER PT J AU Comin, MJ Czifra, G Kedei, N Telek, A Lewin, NE Kolusheva, S Velasquez, JF Kobylarz, R Jelinek, R Blumberg, PM Marquez, VE AF Comin, Maria J. Czifra, Gabriella Kedei, Noemi Telek, Andrea Lewin, Nancy E. Kolusheva, Sofiya Velasquez, Julia F. Kobylarz, Ryan Jelinek, Raz Blumberg, Peter M. Marquez, Victor E. TI Conformationally Constrained Analogues of Diacylglycerol (DAG). 31. Modulation of the Biological Properties of Diacylgycerol Lactones (DAG-lactones) Containing Rigid-Rod Acyl Groups Separated from the Core Lactone by Spacer Units of Different Lengths SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; DELTA; CANCER; POTENT; DERIVATIVES; DISCOVERY; MEMBRANES; ISOZYMES; ISOFORM; BINDING AB Diacylglycerol lactones built with a rigid 4-[(methylphenyl)ethynyl]phenyl rod that is separated from the exocyclic acylcarbonyl of the DAG-lactone core by a spacer unit of variable length were synthesized and studied. Binding affinities for a panel of classical and novel PKC isozymes in two different phospholipid environments, one corresponding to the plasma membrane of cells, were determined. The kinetics and site of translocation for the PKC isozymes alpha and delta upon treatment with the compounds were also studied as well as the early response of ERK phosphorylation and the late response of induction of apoptosis in the human prostatic carcinoma cell line LNCaP. Finally, the compounds were evaluated in terms of their interaction with biomimetic lipid/polydiacetylene membranes by the associated chromatic response. The different spatial disposition of the rigid structural motif on the DAG-lactones contributes to differential activity. C1 [Comin, Maria J.; Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Czifra, Gabriella; Kedei, Noemi; Telek, Andrea; Lewin, Nancy E.; Velasquez, Julia F.; Kobylarz, Ryan; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kolusheva, Sofiya; Jelinek, Raz] Ben Gurion Univ Negev, Dept Chem, IL-84105 Beer Sheva, Israel. [Kolusheva, Sofiya; Jelinek, Raz] Ben Gurion Univ Negev, Ilse Katz Inst Nanotechnol, IL-84105 Beer Sheva, Israel. RP Marquez, VE (reprint author), NCI, Med Chem Lab, Ctr Canc Res, NIH, 376 Boyles St, Frederick, MD 21702 USA. EM marquezv@dc37a.nci.nih.gov RI JELINEK, RAZ/F-2023-2012; OI jelinek, raz/0000-0002-0336-1384 FU Intramural Research Program of the NIH; National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We also thank Drs. James A. Kelley and Chris Lai for HRMS measurements and Dr. Dina M. Sigano for help with the calculations of log P values and assembling the manuscript. NR 37 TC 7 Z9 7 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 28 PY 2009 VL 52 IS 10 BP 3274 EP 3283 DI 10.1021/jm900186m PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 448XV UT WOS:000266296200017 PM 19379015 ER PT J AU Ivanov, AA Barak, D Jacobson, KA AF Ivanov, Andrei A. Barak, Dov Jacobson, Kenneth A. TI Evaluation of Homology Modeling of G-Protein-Coupled Receptors in Light of the A(2A) Adenosine Receptor Crystallographic Structure SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SITE-DIRECTED MUTAGENESIS; LIGAND RECOGNITION; BINDING-SITE; A(3)-ADENOSINE RECEPTOR; CRYSTAL-STRUCTURE; DISTAL REGIONS; ANTAGONISTS; AGONISTS; NUCLEOSIDES; PHARMACOLOGY AB Homology modeling of the human A(2A) adenosine receptor (AR) based on bovine rhodopsin predicted a protein structure that was very similar to the recently determined crystallographic structure. The discrepancy between the experimentally observed orientation of the antagonist and those obtained by previous antagonist docking is related to the loop structure of rhodopsin being carried over to the model of the A(2A) AR and was rectified when the beta(2)-adrenergic receptor was used as a template for homology modeling. Docking of the triazolotriazine antagonist ligand ZM241385 1 was greatly improved by including water molecules of the X-ray structure or by using a constraint from mutagenesis. Automatic agonists docking to both a new homology modeled receptor and the A(2A) AR crystallographic structure produced similar results. Heterocyclic nitrogen atoms closely corresponded when the docked adenine moiety of agonists and 1 were overlaid. The cumulative mutagenesis data, which support the proposed mode of agonist docking, can be reexamined in light of the crystallographic structure. Thus, homology modeling of GPCRs remains a useful technique in probing the structure of the protein and predicting modes of ligand docking. C1 [Ivanov, Andrei A.; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, NIH, LBC, Bethesda, MD 20892 USA. [Barak, Dov] Israel Inst Biol Res, IL-70450 Ness Ziona, Israel. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, NIH, LBC, Bldg 8A,Room B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. We thank Dr. Stefano Costanzi (NIDDK) and Dr. Soo-Kyung Kim (California Institute of Technology) for helpful discussions. NR 40 TC 67 Z9 67 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 28 PY 2009 VL 52 IS 10 BP 3284 EP 3292 DI 10.1021/jm801533x PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 448XV UT WOS:000266296200018 PM 19402631 ER PT J AU Chung, HW Lee, SG Kim, H Hong, DJ Chung, JB Stroncek, D Lim, JB AF Chung, Hye Won Lee, Sang-Guk Kim, Heejung Hong, Duck Jin Chung, Jae Bock Stroncek, David Lim, Jong-Baeck TI Serum high mobility group box-1 (HMGB1) is closely associated with the clinical and pathologic features of gastric cancer SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID GLYCATION END-PRODUCTS; CARCINOEMBRYONIC ANTIGEN; EXPRESSION; RECEPTOR; RAGE; CARCINOMA; PROTEIN; CELLS; EPIDEMIOLOGY; INFLAMMATION AB Background: High mobility group box-1 (HMGB1) is a newly recognized factor regulating cancer cell tumorigenesis, expansion and invasion. We investigated the correlation between the serum HMGB1 levels and the clinical and pathologic features of gastric cancer and evaluated the validity of HMGB1 as a potential biomarker for the early diagnosis of gastric cancer. Methods: A total of 227 subjects were classified into 5 disease groups according to the 'gastritisdysplasia-carcinoma' sequence of gastric carcinogenesis and their serum levels of HMGB1 were analyzed by an enzyme-linked immunosorbent assay (ELISA) method. Clinical parameters, International Union Against Cancer (UICC) TNM stage, cancer size, differentiation or lymphatic invasion, vascular or perineural invasion and prognosis were used as analysis variables. Results: The serum HMGB1 levels were significantly different among disease groups (ANOVA, p < 0.05) and HMGB1 levels tended to increase according to the progression of gastric carcinogenesis. Serum HMGB1 levels were significantly associated with depth of invasion, lymph node metastasis, tumor size, and poor prognosis (p < 0.05). However, HMGB1 levels were not associated with patient gender or age, differentiation of tumor cells, or lymphatic, vascular and perineural invasion, or the existence of distant metastasis in advanced cancer (p > 0.05). The sensitivity and specificity of serum HMGB1 was 71% and 67% (cut-off value of 5 ng/ml) for the diagnosis of early gastric cancer, and 70% and 64% (cut-off value of 4 ng/ ml) for the diagnosis of high-risk lesions, respectively. These values were greater than those for carcinoembryonic antigen (CEA) (30-40% of sensitivity). Conclusion: HMGB1 appears to be a useful serological biomarker for early diagnosis as well as evaluating the tumorigenesis, stage, and prognosis of gastric cancer. C1 [Lee, Sang-Guk; Kim, Heejung; Hong, Duck Jin; Lim, Jong-Baeck] Yonsei Univ, Coll Med, Dept Lab Med, Seoul, South Korea. [Chung, Hye Won; Chung, Jae Bock] Yonsei Univ, Coll Med, Dept Internal Med, Seoul, South Korea. [Stroncek, David] NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Lim, JB (reprint author), Yonsei Univ, Coll Med, Dept Lab Med, Seoul, South Korea. EM hwchungmd@yumc.yonsei.ac.kr; COMFORTER6@yumc.yonsei.ac.kr; hjkim12@yumc.yonsei.ac.kr; dududuckt@yumc.yonsei.ac.kr; jbchung@yumc.yonsei.ac.kr; Dstroncek@cc.nih.gov; jlim@yumc.yonsei.ac.kr FU KOSEF through National Core Research Center for Nanomedical Technology [R15-2004024-01001-0] FX This work was supported by KOSEF through National Core Research Center for Nanomedical Technology (R15-2004024-01001-0) NR 32 TC 62 Z9 78 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAY 28 PY 2009 VL 7 AR 38 DI 10.1186/1479-5876-7-38 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 461CK UT WOS:000267241800002 PM 19476625 ER PT J AU Chen, BS Roche, KW AF Chen, Bo-Shiun Roche, Katherine W. TI Growth Factor-Dependent Trafficking of Cerebellar NMDA Receptors via Protein Kinase B/Akt Phosphorylation of NR2C SO NEURON LA English DT Article ID METHYL-D-ASPARTATE; NEURONAL SURVIVAL; POTASSIUM DEPOLARIZATION; ENDOPLASMIC-RETICULUM; SYNAPTIC PLASTICITY; MEMBRANE-PROTEINS; FACTOR-I; B-GAMMA; INSULIN; AKT AB NMDA receptor subunit composition varies throughout the brain, providing molecular diversity in NMDA receptor function. The NR2 subunits (NR2A-D) in large part dictate the distinct functional properties of NMDA receptors and differentially regulate receptor trafficking. Although the NR2C subunit is highly enriched in cerebellar granule cells and plays aunique role in cerebellar function, little is known about NR2C-specific regulation of NMDA receptors. Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3 epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. Both growth factor stimulation and NMDA receptor activity lead to a robust increase in both phosphorylation of NR2C on S1096 and surface expression of cerebellar NMDA receptors. Finally, we find that NR2C expression, unlike NR2A and NR2B, supports neuronal survival. Thus, our data provide a direct mechanistic link between growth factor stimulation and regulation of cerebellar NMDA receptors. C1 [Chen, Bo-Shiun; Roche, Katherine W.] NINDS, NIH, Bethesda, MD 20892 USA. RP Chen, BS (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM chenbos@ninds.nih.gov; rochek@ninds.nih.gov RI Chen, Bo-Shiun/E-2736-2010; Chen, Bo-Shiun/H-4633-2012; OI Roche, Katherine/0000-0001-7282-6539 FU NINDS FX We thank John D. Badger II, Viren Vasudeva and Eleanor Thomas for technical assistance and John T.R. Isaac for critical reading of the manuscript. We also thank the NINDS sequencing facility, light imaging facility and FACS facility, in particular Dragan Maric and Carolyn Smith for their expertise and advice. This research was supported by the NINDS Intramural Research Program (B.-S.C. and K.W.R.) and a NINDS Career Transition Award (B.-S.C.). NR 42 TC 33 Z9 34 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAY 28 PY 2009 VL 62 IS 4 BP 471 EP 478 DI 10.1016/j.neuron.2009.04.015 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 453OH UT WOS:000266619700005 PM 19477150 ER PT J AU Resnik, DB AF Resnik, David B. TI Parent-Investigators A Dilemma SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Box 12233 Mail Drop CR 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-02] NR 9 TC 0 Z9 0 U1 0 U2 2 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 MAY 27 PY 2009 VL 301 IS 20 BP 2159 EP 2161 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 449KF UT WOS:000266328800030 PM 19470993 ER PT J AU Ferreira, P Gatehouse, P Kellman, P Bucciarelli-Ducci, C Firmin, D AF Ferreira, Pedro Gatehouse, Peter Kellman, Peter Bucciarelli-Ducci, Chiara Firmin, David TI Variability of myocardial perfusion dark rim Gibbs artifacts due to sub-pixel shifts SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article ID CARDIOVASCULAR MAGNETIC-RESONANCE; CORONARY-ARTERY-DISEASE; NONINVASIVE DETECTION; 1ST PASS; ANGIOGRAPHY AB Background: Gibbs ringing has been shown as a possible source of dark rim artifacts in myocardial perfusion studies. This type of artifact is usually described as transient, lasting a few heart beats, and localised in random segments of the myocardial wall. Dark rim artifacts are known to be unpredictably variable. This article aims to illustrate that a sub-pixel shift, i.e. a small displacement of the pixels with respect to the endocardial border, can result in different Gibbs ringing and hence different artifacts. Therefore a hypothesis for one cause of dark rim artifact variability is given based on the sub-pixel position of the endocardial border. This article also demonstrates the consequences for Gibbs artifacts when two different methods of image interpolation are applied (post-FFT interpolation, and pre-FFT zero-filling). Results: Sub-pixel shifting of in vivo perfusion studies was shown to change the appearance of Gibbs artifacts. This effect was visible in the original uninterpolated images, and in the post-FFT interpolated images. The same shifted data interpolated by pre-FFT zero-filling exhibited much less variability in the Gibbs artifact. The in vivo findings were confirmed by phantom imaging and numerical simulations. Conclusion: Unless pre-FFT zero-filling interpolation is performed, Gibbs artifacts are very dependent on the position of the subendocardial wall within the pixel. By introducing sub-pixel shifts relative to the endocardial border, some of the variability of the dark rim artifacts in different myocardial segments, in different patients and from frame to frame during first-pass perfusion due to cardiac and respiratory motion can be explained. Image interpolation by zero-filling can be used to minimize this dependency. C1 [Ferreira, Pedro; Gatehouse, Peter; Bucciarelli-Ducci, Chiara; Firmin, David] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Gatehouse, Peter; Bucciarelli-Ducci, Chiara; Firmin, David] Royal Brompton Hosp, London SW3 6LY, England. [Kellman, Peter] NIH, Bethesda, MD 20892 USA. RP Ferreira, P (reprint author), Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. EM p.f.ferreira05@imperial.ac.uk; P.Gatehouse@rbht.nhs.uk; kellmanp@nhlbi.nih.gov; C.Bucciarelli-Ducci@rbht.nhs.uk; D.Firmin@rbht.nhs.uk OI Gatehouse, Peter/0000-0002-0260-4719; Ferreira, Pedro/0000-0002-0436-3496 FU British Heart Foundation; National Health Service, UK; National Institutes of Health, USA; CORDA, UK FX Sources of funding: PF - British Heart Foundation, UK; PG - National Health Service, UK; PK - National Institutes of Health, USA; CBD - CORDA, UK; DF - National Health Service, UK NR 17 TC 10 Z9 10 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD MAY 27 PY 2009 VL 11 AR 17 DI 10.1186/1532-429X-11-17 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 460FW UT WOS:000267174600001 PM 19473492 ER PT J AU Je, HS Lu, Y Yang, F Nagappan, G Zhou, JZ Jiang, ZH Nakazawa, K Lu, B AF Je, Hyun-Soo Lu, Yuan Yang, Feng Nagappan, Guhan Zhou, Jianzheng Jiang, Zhihong Nakazawa, Kazu Lu, Bai TI Chemically Inducible Inactivation of Protein Synthesis in Genetically Targeted Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GENE-EXPRESSION; MOUSE-BRAIN; MAP KINASE; PLASTICITY; MEMORY; LONG; LTP; CA1; MANIPULATION; DIMERIZATION C1 [Lu, Bai] NICHHD, Porter Neurosci Res Ctr, Lab Cellular & Synapt Neurophysiol, NIH,Sect Neural Dev & Plast, Bethesda, MD 20892 USA. [Lu, Yuan; Lu, Bai] NIH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Jiang, Zhihong; Nakazawa, Kazu] NIH, Mood & Anxiety Program, Bethesda, MD 20892 USA. RP Lu, B (reprint author), NICHHD, Porter Neurosci Res Ctr, Lab Cellular & Synapt Neurophysiol, NIH,Sect Neural Dev & Plast, 35 Lincoln Dr,MSC 3714,Bldg 35,Room 1C1004 Off, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Yang, Feng/C-9530-2011; Lu, Bai/A-4018-2012; Nakazawa, Kazutoshi/J-6195-2015; OI Nakazawa, Kazutoshi/0000-0001-5699-9093; Je, hyunsoo/0000-0002-2924-5621 FU Intramural Research Program of the National Institutes of Health FX H.-S.J. and Y.L. contributed equally to this work. NR 25 TC 7 Z9 7 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 MAY 27 PY 2009 VL 29 IS 21 BP 6761 EP 6766 DI 10.1523/JNEUROSCI.1280-09.2009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 450YV UT WOS:000266438800001 PM 19474302 ER PT J AU Eriksen, J Rasmussen, SGF Rasmussen, TN Vaegter, CB Cha, JH Zou, MF Newman, AH Gether, U AF Eriksen, Jacob Rasmussen, Sren G. F. Rasmussen, Trine Nygaard Vaegter, Christian Bjerggaard Cha, Joo Hwan Zou, Mu-Fa Newman, Amy Hauck Gether, Ulrik TI Visualization of Dopamine Transporter Trafficking in Live Neurons by Use of Fluorescent Cocaine Analogs SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PROTEIN-KINASE-C; AMINOBUTYRIC-ACID TRANSPORTER; LENTIVIRAL VECTOR; MONOAMINE TRANSPORTERS; IN-VIVO; DEPENDENT ENDOCYTOSIS; MEDIATED ENDOCYTOSIS; SURFACE EXPRESSION; GENE DELIVERY; MEMBRANE AB The dopamine transporter (DAT) mediates reuptake of dopamine from the synaptic cleft and is a target for widely abused psychostimulants such as cocaine and amphetamine. Nonetheless, little is known about the cellular distribution and trafficking of natively expressed DAT. Here we use novel fluorescently tagged cocaine analogs to visualize DAT and DAT trafficking in cultured live midbrain dopaminergic neurons. The fluorescent tags were extended from the tropane N-position of 2 beta-carbomethoxy-3 beta-(3,4-dichlorophenyl) tropane using an ethylamino-linker. The rhodamine-, OR Green-, or Cy3-labeled ligands had high binding affinity for DAT and enabled specific labeling of DAT in live neurons and visualization by confocal imaging. In the dopaminergic neurons, DAT was uniformly distributed in the plasma membrane of the soma, the neuronal extensions, and varicosities along these extensions. FRAP (fluorescence recovery after photobleaching) experiments demonstrated bidirectional movement of DAT in the extensions and indicated that DAT is highly mobile both in the extensions and in the varicosities (immobile fraction less than similar to 30%). DAT was constitutively internalized into vesicular structures likely representing intracellular transporter pools. The internalization was blocked by lentiviral-mediated expression of dominant-negative dynamin and internalized DAT displayed partial colocalization with the early endosomal marker EGFP-Rab5 and with the transferrin receptor. DAT internalization and function was not affected by activation of protein kinase C (PKC) with phorbol-12-myristate-13-acetate (PMA) or by inhibition with staurosporine or GF109203X. These data are in contrast to findings for DAT in transfected heterologous cells and challenge the paradigm that trafficking and cellular distribution of endogenous DAT is subject to regulation by PKC. C1 [Eriksen, Jacob; Rasmussen, Sren G. F.; Rasmussen, Trine Nygaard; Vaegter, Christian Bjerggaard; Gether, Ulrik] Univ Copenhagen, Mol Neuropharmacol Grp, DK-2200 Copenhagen N, Denmark. [Eriksen, Jacob; Rasmussen, Sren G. F.; Rasmussen, Trine Nygaard; Vaegter, Christian Bjerggaard; Gether, Ulrik] Univ Copenhagen, Ctr Pharmacogenom, Dept Neurosci & Pharmacol, Panum Inst, DK-2200 Copenhagen, Denmark. [Cha, Joo Hwan; Zou, Mu-Fa; Newman, Amy Hauck] Natl Inst Drug Abuse, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gether, U (reprint author), Univ Copenhagen, Mol Neuropharmacol Grp, DK-2200 Copenhagen N, Denmark. EM gether@sund.ku.dk RI Vaegter, Christian/A-7909-2008; OI Vaegter, Christian/0000-0001-6573-146X; Eriksen, Jacob/0000-0003-0726-9769; Rasmussen, Soren/0000-0002-1853-1841; Gether, Ulrik/0000-0002-0020-3807 FU National Institutes of Health (NIH) [P01 DA 12408]; Lundbeck Foundation; Danish Medical Research Councils; "Fabrikant Vilhelm Pedersen og Hustrus Mindelegat"; National Institute on Drug Abuse Intramural Research Program (NIDA-IRP) FX This work was supported in part by National Institutes of Health (NIH) Grant P01 DA 12408 (U. G.), the Lundbeck Foundation (U. G.), the Danish Medical Research Councils (U. G.), "Fabrikant Vilhelm Pedersen og Hustrus Mindelegat" (U. G.), and National Institute on Drug Abuse Intramural Research Program (NIDA-IRP), NIH (A.H.N.). We thank Dr. Erika Adkins for critical advice on the FRAP measurements and Dr. Alexandra Newton for providing the cDNA encoding CKAR. We thank Donna Czerny and Nabeela Khadim for excellent technical assistance. The MALDI-TOF spectra were obtained by Dr. Amina Woods, NIDA-IRP. NR 56 TC 43 Z9 43 U1 3 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 27 PY 2009 VL 29 IS 21 BP 6794 EP 6808 DI 10.1523/JNEUROSCI.4177-08.2009 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 450YV UT WOS:000266438800006 PM 19474307 ER PT J AU Isaac, JTR Buchanan, KA Muller, RU Mellor, JR AF Isaac, John T. R. Buchanan, Katherine A. Muller, Robert U. Mellor, Jack R. TI Hippocampal Place Cell Firing Patterns Can Induce Long-Term Synaptic Plasticity In Vitro SO JOURNAL OF NEUROSCIENCE LA English DT Article ID TIMING-DEPENDENT PLASTICITY; NMDA-RECEPTOR BLOCKADE; METHYL-D-ASPARTATE; PYRAMIDAL CELLS; RAT HIPPOCAMPUS; PATH-INTEGRATION; THETA-FREQUENCY; SPATIAL MAP; POTENTIATION; CA1 AB In the hippocampus, synaptic strength between pyramidal cells is modifiable by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD), both of which require coincident presynaptic and postsynaptic activity. In vivo, many pyramidal cells exhibit location-specific activity patterns and are known as "place cells." The combination of these factors suggests that synaptic plasticity will be induced at synapses connecting place cells with overlapping firing fields, because such cells fire coincidentally when the rat is in a specific part of the environment. However, this prediction, which is important for models of how long-term synaptic plasticity can be used to encode space in the hippocampal network, has not been tested. To investigate this, action potential time series recorded simultaneously from place cells in freely moving rats were replayed concurrently into postsynaptic CA1 pyramidal cells and presynaptic inputs during perforated patch-clamp recordings from adult hippocampal slices. Place cell firing patterns induced large, pathway-specific, NMDAR-dependent LTP that was rapidly expressed within a few minutes. However, place-cell LTP was induced only if the two place cells had overlapping firing fields and if the cholinergic tone present in the hippocampus during exploration was restored by bath application of the cholinergic agonist carbachol. LTD was never observed in response to place cell firing patterns. Our findings demonstrate that spike patterns from hippocampal place cells can robustly induce NMDAR-dependent LTP, providing important evidence in support of a model in which spatial distance is encoded as the strength of synaptic connections between place cells. C1 [Isaac, John T. R.; Buchanan, Katherine A.; Muller, Robert U.; Mellor, Jack R.] Univ Bristol, MRC, Ctr Synapt Plast, Dept Anat, Bristol BS8 1TD, Avon, England. [Isaac, John T. R.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Buchanan, Katherine A.] UCL, Dept Neurosci Physiol & Pharmacol, London WC1E 6BT, England. [Muller, Robert U.] SUNY, Hlth Sci Ctr Brooklyn, Brooklyn, NY 11203 USA. RP Mellor, JR (reprint author), Univ Bristol, MRC, Ctr Synapt Plast, Dept Anat, Bristol BS8 1TD, Avon, England. EM jack.mellor@bristol.ac.uk RI yu, yan/C-2322-2012 FU Wellcome Trust; Medical Research Council; European Union Network of European Neuroscience Institutes; GlaxoSmithKline; National Institutes of Health extramural [NS20686]; National Institute of Neurological Disorders and Stroke intramural FX We are grateful to the Wellcome Trust (J.R.M., J.T.R.I.), the Medical Research Council (J.R.M., R.U.M.), the European Union Network of European Neuroscience Institutes (J.R.M.), GlaxoSmithKline (K. A. B.), and National Institutes of Health extramural (Grant NS20686 to R.U.M.) and National Institute of Neurological Disorders and Stroke intramural (J.T.R.I.) programs for financial support. We thank Y. Li for converting in vivo recorded data into timestamp format for replay. NR 54 TC 43 Z9 44 U1 0 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 27 PY 2009 VL 29 IS 21 BP 6840 EP 6850 DI 10.1523/JNEUROSCI.0731-09.2009 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 450YV UT WOS:000266438800010 PM 19474311 ER PT J AU Mars, RB Klein, MC Neubert, FX Olivier, E Buch, ER Boorman, ED Rushworth, MFS AF Mars, Rogier B. Klein, Miriam C. Neubert, Franz-Xaver Olivier, Etienne Buch, Ethan R. Boorman, Erie D. Rushworth, Matthew F. S. TI Short-Latency Influence of Medial Frontal Cortex on Primary Motor Cortex during Action Selection under Conflict SO JOURNAL OF NEUROSCIENCE LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; SUBTHALAMIC NUCLEUS; MOVEMENT; PREMOTOR; NEURONS; MONKEY; AREAS; FMRI AB Medial frontal cortex (MFC) is crucial when actions have to be inhibited, reprogrammed, or selected under conflict, but the precise mechanism by which it operates is unclear. Importantly, how and when the MFC influences the primary motor cortex (M1) during action selection is unknown. Using paired-pulse transcranial magnetic stimulation, we investigated functional connectivity between the presupplementary motor area (pre-SMA) part of MFC and M1. We found that functional connectivity increased in a manner dependent on cognitive context: pre-SMA facilitated the motor evoked-potential elicited by M1 stimulation only during action reprogramming, but not when otherwise identical actions were made in the absence of conflict. The effect was anatomically specific to pre-SMA; it was not seen when adjacent brain regions were stimulated. We discuss implications for the anatomical pathways mediating the observed effects. C1 [Mars, Rogier B.; Klein, Miriam C.; Neubert, Franz-Xaver; Buch, Ethan R.; Boorman, Erie D.; Rushworth, Matthew F. S.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Mars, Rogier B.; Boorman, Erie D.; Rushworth, Matthew F. S.] Univ Oxford, John Radcliffe Hosp, Ctr Funct Magnet Resonance Imaging Brain, Oxford OX3 9DU, England. [Olivier, Etienne] Univ Catholique Louvain, Inst Neurosci, B-1200 Brussels, Belgium. [Buch, Ethan R.] Natl Inst Neurol Disorders & Stroke, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Mars, RB (reprint author), Univ Oxford, Dept Expt Psychol, Tinbergen Bldg,S Parks Rd, Oxford OX1 3UD, England. EM rogier.mars@psy.ox.ac.uk RI Buch, Ethan/G-1981-2011; OI Klein-Flugge, Miriam/0000-0002-5156-9833 FU Medical Research Council; Marie Curie Intra-European Fellowship within the 6th European Community Framework Programme; Royal Society International Incoming Short Visits FX This study was supported by the Medical Research Council. R.B.M. was supported by a Marie Curie Intra-European Fellowship within the 6th European Community Framework Programme. E.O. was supported by a Royal Society International Incoming Short Visits grant awarded to M.F.R.S. and E.O. NR 15 TC 91 Z9 91 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 27 PY 2009 VL 29 IS 21 BP 6926 EP 6931 DI 10.1523/JNEUROSCI.1396-09.2009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 450YV UT WOS:000266438800018 PM 19474319 ER PT J AU Wallace, GL Happe, F Giedd, JN AF Wallace, Gregory L. Happe, Francesca Giedd, Jay N. TI A case study of a multiply talented savant with an autism spectrum disorder: neuropsychological functioning and brain morphometry SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Joint Discussion Meeting of the Royal-Society/British Academy on Autism and Talent CY 2008 CL Royal Soc, London, ENGLAND SP British Acad HO Royal Soc DE autism; savant; weak central coherence; implicit learning; neuroanatomy; magnetic resonance imaging ID CALENDRICAL CALCULATORS; INTELLIGENCE; CHILDREN; SKILLS; ANNOTATION; ABILITY; MEMORY; IQ AB Neuropsychological functioning and brain morphometry in a savant (case GW) with an autism spectrum disorder (ASD) and both calendar calculation and artistic skills are quantified and compared with small groups of neurotypical controls. Good memory, mental calculation and visuospatial processing, as well as (implicit) knowledge of calendar structure and 'weak' central coherence characterized the cognitive profile of case GW. Possibly reflecting his savant skills, the superior parietal region of GW's cortex was the only area thicker (while areas such as the superior and medial prefrontal, middle temporal and motor cortices were thinner) than that of a neurotypical control group. Taken from the perspective of learning/practice-based models, skills in domains (e. g. calendars, art, music) that capitalize upon strengths often associated with ASD, such as detail-focused processing, are probably further enhanced through over-learning and massive exposure, and reflected in atypical brain structure. C1 [Wallace, Gregory L.; Happe, Francesca] Univ London, Kings Coll, Social Genet & Dev Psychiat Ctr, Inst Psychiat, London WC2R 2LS, England. [Wallace, Gregory L.; Giedd, Jay N.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Wallace, GL (reprint author), Univ London, Kings Coll, Social Genet & Dev Psychiat Ctr, Inst Psychiat, London WC2R 2LS, England. EM gregwallace@mail.nih.gov RI Giedd, Jay/A-3080-2008; Happe, Francesca/D-5544-2012; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Happe, Francesca/0000-0001-9226-4000; Wallace, Gregory/0000-0003-0329-5054 FU Intramural NIH HHS NR 44 TC 24 Z9 25 U1 6 U2 26 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAY 27 PY 2009 VL 364 IS 1522 BP 1425 EP 1432 DI 10.1098/rstb.2008.0330 PG 8 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 432AH UT WOS:000265105400011 PM 19528026 ER PT J AU Sandebring, A Thomas, KJ Beilina, A van der Brug, M Cleland, MM Ahmad, R Miller, DW Zambrano, I Cowburn, RF Behbahani, H Cedazo-Minguez, A Cookson, MR AF Sandebring, Anna Thomas, Kelly Jean Beilina, Alexandra van der Brug, Marcel Cleland, Megan M. Ahmad, Rili Miller, David W. Zambrano, Ibardo Cowburn, Richard F. Behbahani, Homira Cedazo-Minguez, Angel Cookson, Mark R. TI Mitochondrial Alterations in PINK1 Deficient Cells Are Influenced by Calcineurin-Dependent Dephosphorylation of Dynamin-Related Protein 1 SO PLOS ONE LA English DT Article AB PTEN-induced novel kinase 1 (PINK1) mutations are associated with autosomal recessive parkinsonism. Previous studies have shown that PINK1 influences both mitochondrial function and morphology although it is not clearly established which of these are primary events and which are secondary. Here, we describe a novel mechanism linking mitochondrial dysfunction and alterations in mitochondrial morphology related to PINK1. Cell lines were generated by stably transducing human dopaminergic M17 cells with lentiviral constructs that increased or knocked down PINK1. As in previous studies, PINK1 deficient cells have lower mitochondrial membrane potential and are more sensitive to the toxic effects of mitochondrial complex I inhibitors. We also show that wild-type PINK1, but not recessive mutant or kinase dead versions, protects against rotenone-induced mitochondrial fragmentation whereas PINK1 deficient cells show lower mitochondrial connectivity. Expression of dynamin-related protein 1 (Drp1) exaggerates PINK1 deficiency phenotypes and Drp1 RNAi rescues them. We also show that Drp1 is dephosphorylated in PINK1 deficient cells due to activation of the calcium-dependent phosphatase calcineurin. Accordingly, the calcineurin inhibitor FK506 blocks both Drp1 dephosphorylation and loss of mitochondrial integrity in PINK1 deficient cells but does not fully rescue mitochondrial membrane potential. We propose that alterations in mitochondrial connectivity in this system are secondary to functional effects on mitochondrial membrane potential. RP Sandebring, A (reprint author), NIA, Neurogenet Lab, Bethesda, MD 20892 USA. EM Cookson@mail.nih.gov RI Cedazo-Minguez, Angel/C-6707-2012; OI Cedazo-Minguez, Angel/0000-0003-4626-4864; Harwig, Megan/0000-0003-2140-5739 FU Intramural NIH HHS NR 67 TC 128 Z9 128 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 MAY 27 PY 2009 VL 4 IS 5 AR e5701 DI 10.1371/journal.pone.0005701 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 450QD UT WOS:000266415000013 PM 19492085 ER PT J AU Watanabe, S Ito, T Sasaki, T Li, SS Uchiyama, I Kishii, K Kikuchi, K Skov, RL Hiramatsu, K AF Watanabe, Shinya Ito, Teruyo Sasaki, Takashi Li, Shanshuang Uchiyama, Ikuo Kishii, Kozue Kikuchi, Ken Skov, Robert Leo Hiramatsu, Keiichi TI Genetic Diversity of Staphylocoagulase Genes (coa): Insight into the Evolution of Variable Chromosomal Virulence Factors in Staphylococcus aureus SO PLOS ONE LA English DT Article AB Background: The production of staphylocoagulase (SC) causing the plasma coagulation is one of the important characteristics of Staphylococcus aureus. Although SCs have been classified into 10 serotypes based on the differences in the antigenicity, genetic bases for their diversities and relatedness to chromosome types are poorly understood. Methodology/Principal Findings: We compared the nucleotide sequences of 105 SC genes (coa), 59 of which were determined in this study. D1 regions, which contain prothrombin-activating and -binding domains and are presumed to be the binding site of each type-specific antiserum, were classified into twelve clusters having more than 90% nucleotide identities, resulting to create two novel SC types, XI and XII, in addition to extant 10 types. Nine of the twelve SC types were further subdivided into subtypes based on the differences of the D2 or the central regions. The phylogenetical relations of the D1 regions did not correlate exactly with either one of agr types and multilocus sequence types (STs). In addition, genetic analysis showed that recombination events have occurred in and around coa. So far tested, STs of 126 S. aureus strains correspond to the combination of SC type and agr type except for the cases of CC1 and CC8, which contained two and three different SC types, respectively. Conclusion: The data suggested that the evolution of coa was not monophyletic in the species. Chromosomal recombination had occurred at coa and agr loci, resulting in the carriage of the combinations of allotypically different important virulence determinants in staphylococcal chromosome. RP Watanabe, S (reprint author), NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM teruybac@juntendo.ac.jp RI Watanabe, Shinya/B-7008-2009 OI Watanabe, Shinya/0000-0001-6542-6502 NR 55 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 MAY 27 PY 2009 VL 4 IS 5 AR e5714 DI 10.1371/journal.pone.0005714 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 450QD UT WOS:000266415000021 PM 19492076 ER PT J AU Yao, B Liu, JZ Brown, RW Sahgal, V Yue, GH AF Yao, Bing Liu, Jing Z. Brown, Robert W. Sahgal, Vinod Yue, Guang H. TI Nonlinear features of surface EEG showing systematic brain signal adaptations with muscle force and fatigue SO BRAIN RESEARCH LA English DT Article DE Chaos; Neuromuscular; Lyapunov exponent ID PRINCIPAL LYAPUNOV EXPONENT; OPTIMAL EMBEDDING DIMENSION; TIME-SERIES; SENSORIMOTOR CORTEX; FUNCTIONAL MRI; SLEEP EEG; EPILEPTIC SEIZURES; ALZHEIMERS-DISEASE; FRACTAL DIMENSION; SPECTRAL-ANALYSIS AB Nonlinear dynamics has been introduced to the analysis of biological data and increasingly recognized to be functionally relevant. The purpose of this study was to examine chaotic properties of human scalp EEG signals associated with voluntary motor tasks using the largest Lyapunov exponent (L1). 64-channel scalp EEG data were recorded from eight healthy subjects in two tasks: (1) intermittent handgrip contractions at 20, 40, 60, and 80% of maximal voluntary contraction (MVC) with 20 trials at each level. No significant fatigue were induced; (2) intermittent handgrip MVCs (100 trials) that resulted in significant fatigue. The L1 values of all EEG channels were calculated in each trial first then averaged across the 20 trials at each force level (Task 1) or over each of the S-trial blocks (Task 2) before the group means were obtained. A multivariate statistical model was used to examine the effect of force and fatigue on L1. L1 values were greater with higher force (Task 1), and decreased significantly with fatigue (Task 2). The L1 of the EEG signals changes systematically and correlates significantly with muscle force and fatigue. The results suggest that nonlinear chaotic index L1 may serve as a quantitative measure for motor control-related cortical signal adaptations. Published by Elsevier B.V. C1 [Yao, Bing] NINDS, NIH, LFMI, Bethesda, MD 20892 USA. [Liu, Jing Z.; Yue, Guang H.] Cleveland Clin, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44195 USA. [Sahgal, Vinod; Yue, Guang H.] Cleveland Clin, Dept Phys Med & Rehabil, Cleveland, OH 44195 USA. [Liu, Jing Z.; Brown, Robert W.] Case Western Reserve Univ, Dept Phys, Cleveland, OH 44106 USA. RP Yao, B (reprint author), NINDS, NIH, LFMI, 10 Ctr Dr,Bldg 10,Room B1D728,MSC 1065, Bethesda, MD 20892 USA. EM yaob@mail.nih.gov FU Department of Defense [DAMD17-01-1-0665]; NIH [NS-37400] FX This work was partially supported by NIH grants NS-37400 and a Department of Defense grant DAMD17-01-1-0665. NR 55 TC 4 Z9 4 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 26 PY 2009 VL 1272 BP 89 EP 98 DI 10.1016/j.brainres.2009.03.042 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 457CG UT WOS:000266902400011 PM 19332036 ER PT J AU Lagiou, P Hsieh, CC Lipworth, L Samoli, E Okulicz, W Troisi, R Xu, B Hall, P Ekbom, A Adami, HO Trichopoulos, D AF Lagiou, P. Hsieh, C. C. Lipworth, L. Samoli, E. Okulicz, W. Troisi, R. Xu, B. Hall, P. Ekbom, A. Adami, H. O. Trichopoulos, D. TI Insulin-like growth factor levels in cord blood, birth weight and breast cancer risk SO BRITISH JOURNAL OF CANCER LA English DT Article DE insulin-like growth factor; IGF-1; IGF-2; breast cancer; birth weight; birth length ID FACTOR BINDING PROTEIN-3; FACTOR-I; AMERICAN WOMEN; HORMONE-LEVELS; IGF-II; SERUM; SIZE; STEM; ETIOLOGY; LEPTIN AB Breast cancer incidence and birth weight are higher among Caucasian than Asian women, and birth size has been positively associated with breast cancer risk. Pregnancy hormone levels, however, have been generally lower in Caucasian than Asian women. We studied components of the insulin-like growth factor (IGF) system in cord blood from 92 singleton babies born in Boston, USA, and 110 born in Shanghai, China, in 1994-1995. Cord blood IGF-1 was significantly higher among Caucasian compared with Chinese babies (P < 10(-6)). The opposite was noted for IGF-2 (P similar to 10(-4)). IGF-1 was significantly positively associated with birth weight and birth length in Boston, but not Shanghai. In contrast, stronger positive, though statistically non-significant, associations of IGF-2 with birth size were only evident in Shanghai. The associations of birth weight and birth length were positive and significant in taller women (for IGF-1 in Boston P similar to 0.003 and 0.03, respectively; for IGF-2 in Shanghai P similar to 0.05 and similar to 0.04, respectively), among whom maternal anthropometry does not exercise strong constraints in foetal growth. The documentation of higher cord blood levels of IGF-1, a principal growth hormone that does not cross the placenta, among Caucasian than in Asian newborns is concordant with breast cancer incidence in these populations. British Journal of Cancer (2009) 100, 1794-1798. doi: 10.1038/sj.bjc.6605074 www.bjcancer.com Published online 5 May 2009 (C) 2009 Cancer Research UK C1 [Lagiou, P.; Hsieh, C. C.; Adami, H. O.; Trichopoulos, D.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lagiou, P.; Samoli, E.] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Lagiou, P.; Hsieh, C. C.; Hall, P.; Adami, H. O.; Trichopoulos, D.] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Hsieh, C. C.] Univ Massachusetts, Sch Med, Div Biostat & Epidemiol, UMass Canc Ctr, Worcester, MA 01605 USA. [Lipworth, L.] Int Epidemiol Inst, Rockville, MD 20850 USA. [Okulicz, W.] Univ Massachusetts, Sch Med, Dept Physiol, ILAT Steroid RIA Lab, Worcester, MA 01605 USA. [Troisi, R.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Xu, B.] Fudan Univ, Sch Publ Hlth, Dept Epidemiol, Shanghai 200023, Peoples R China. [Ekbom, A.] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Clin Epidemiol Unit, SE-17176 Stockholm, Sweden. RP Trichopoulos, D (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM dtrichop@hsph.harvard.edu FU Innovator Award, US Department of Defense Breast Cancer Research Program, Office of the Congressionally Directed Medical Research Programs [W81XWH-05-1-0314] FX The study was funded by the W81XWH-05-1-0314 Innovator Award, US Department of Defense Breast Cancer Research Program, Office of the Congressionally Directed Medical Research Programs. NR 33 TC 15 Z9 15 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 26 PY 2009 VL 100 IS 11 BP 1794 EP 1798 DI 10.1038/sj.bjc.6605074 PG 5 WC Oncology SC Oncology GA 452CP UT WOS:000266517600013 PM 19417744 ER PT J AU Azzato, EM Greenberg, D Shah, M Blows, F Driver, KE Caporaso, NE Pharoah, PDP AF Azzato, E. M. Greenberg, D. Shah, M. Blows, F. Driver, K. E. Caporaso, N. E. Pharoah, P. D. P. TI Prevalent cases in observational studies of cancer survival: do they bias hazard ratio estimates? SO BRITISH JOURNAL OF CANCER LA English DT Article DE survival analysis; prevalent cases; left truncation; breast cancer ID GERMLINE GENETIC-VARIATION; BREAST-CANCER; DISEASE AB Observational epidemiological studies often include prevalent cases recruited at various times past diagnosis. This left truncation can be dealt with in non-parametric (Kaplan-Meier) and semi-parametric (Cox) time-to-event analyses, theoretically generating an unbiased hazard ratio (HR) when the proportional hazards (PH) assumption holds. However, concern remains that inclusion of prevalent cases in survival analysis results inevitably in HR bias. We used data on three well-established breast cancer prognosticators - clinical stage, histopathological grade and oestrogen receptor (ER) status - from the SEARCH study, a population-based study including 4470 invasive breast cancer cases (incident and prevalent), to evaluate empirically the effectiveness of allowing for left truncation in limiting HR bias. We found that HRs of prognostic factors changed over time and used extended Cox models incorporating time-dependent covariates. When comparing Cox models restricted to subjects ascertained within six months of diagnosis (incident cases) to models based on the full data set allowing for left truncation, we found no difference in parameter estimates (P = 0.90, 0.32 and 0.95, for stage, grade and ER status respectively). Our results show that use of prevalent cases in an observational epidemiological study of breast cancer does not bias the HR in a left truncation Cox survival analysis, provided the PH assumption holds true. British Journal of Cancer (2009) 100, 1806-1811. doi: 10.1038/sj.bjc.6605062 www.bjcancer.com Published online 28 April 2009 (C) 2009 Cancer Research UK C1 [Azzato, E. M.; Shah, M.; Blows, F.; Driver, K. E.; Pharoah, P. D. P.] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Cambridge CB1 8RN, England. [Azzato, E. M.; Caporaso, N. E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Greenberg, D.] Eastern Canc Registrat & Informat Ctr, Unit C, Cambridge CB22 3AD, England. RP Azzato, EM (reprint author), Univ Cambridge, Strangeways Res Lab, Dept Oncol, Cambridge CB1 8RN, England. EM azzatoe2@mail.nih.gov FU NIH; NCI; DCEG; Cancer Research UK FX We thank the women who have taken part in the study, the SEARCH study team, the consultants and general practitioners throughout East Anglia for their help in recruiting patients, the staff of ECRIC and North Thames Cancer Registry for providing outcome and clinical data. EA was supported by the Intramural Research Program of the NIH, NCI, DCEG and the NIH-Cambridge Graduate Partnership Program. NC is a senior investigator in the National Cancer Institute (DCEG). PP is a Cancer Research UK Senior Clinical Research Fellow and SEARCH is funded by a programme grant from Cancer Research UK. This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. NR 15 TC 38 Z9 38 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 26 PY 2009 VL 100 IS 11 BP 1806 EP 1811 DI 10.1038/sj.bjc.6605062 PG 6 WC Oncology SC Oncology GA 452CP UT WOS:000266517600015 PM 19401693 ER PT J AU Rosenberger, LR Zeck, J Berl, MM Moore, EN Ritzl, EK Shamim, S Weinstein, SL Conry, JA Pearl, PL Sato, S Vezina, LG Theodore, WH Gaillard, WD AF Rosenberger, L. R. Zeck, J. Berl, M. M. Moore, E. N. Ritzl, E. K. Shamim, S. Weinstein, S. L. Conry, J. A. Pearl, P. L. Sato, S. Vezina, L. G. Theodore, W. H. Gaillard, W. D. TI Interhemispheric and intrahemispheric language reorganization in complex partial epilepsy SO NEUROLOGY LA English DT Article ID TEMPORAL-LOBE EPILEPSY; FUNCTIONAL MRI; ATYPICAL LANGUAGE; RIGHT-HEMISPHERE; FOCAL EPILEPSY; EARLY-ONSET; FMRI; LATERALIZATION; ACTIVATION; DOMINANCE AB Objective: To investigate interhemispheric and intrahemispheric reorganization in patients with localization-related epilepsy. Method: We studied 50 patients with a left hemispheric focus and 20 normal right-handed controls with a 3T echoplanar imaging blood oxygen level dependent functional MRI auditory-based word definition decision task. Data were analyzed using SPM 2. Using region of interest for Broca and Wernicke areas and an asymmetry index (AI), patients were categorized as left language (LL; AI >= 0.20) or atypical language (AL; AI<0.20) for region. The point maxima activation for normal controls (p<0.05 corrected FDR) was identified in Broca and midtemporal regions and then used as a point of reference for individual point maxima identified at p<0.001, uncorrected. Results: Patient groups showed increased frequency of having activation in right homologues. Activation in AL groups occurred in homologous right regions; distances for point maxima activation in homologous regions were the same as point maxima distances in normal control activation in left regions. Distances for LL patient in left regions showed a trend for differences for midtemporal gyrus (6 mm posterior, 3 mm superior) but variability around mean difference distance was significant. There was no effect of age at epilepsy onset, duration, or pathology on activation maxima. Conclusions: Right hemisphere language regions in patients with left hemispheric focus are homologues of left hemisphere Broca and broadly defined Wernicke areas. We found little evidence for intrahemispheric reorganization in patients with left hemisphere epilepsy who remain left language dominant by these methods. Neurology (R) 2009; 72: 1830-1836 C1 [Rosenberger, L. R.; Zeck, J.; Berl, M. M.; Moore, E. N.; Weinstein, S. L.; Conry, J. A.; Pearl, P. L.; Vezina, L. G.; Gaillard, W. D.] George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurosci, Washington, DC 20010 USA. [Vezina, L. G.] George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Radiol, Washington, DC 20010 USA. [Rosenberger, L. R.; Zeck, J.; Moore, E. N.; Ritzl, E. K.; Shamim, S.; Sato, S.; Theodore, W. H.; Gaillard, W. D.] NINDS, Clin Epilepsy Sect, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Gaillard, W. D.] Georgetown Univ, Sch Med, Dept Neurol, Washington, DC USA. [Ritzl, E. K.] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. RP Gaillard, WD (reprint author), George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurosci, 111 Michigan Ave NW, Washington, DC 20010 USA. EM wgaillar@cnmc.org FU NINDS [R01 NS44280]; American Academy of Neurology; NINDS Division of Intramural Research FX Supported by NINDS R01 NS44280, the American Academy of Neurology Summer fellowship award (J.Z.), and the NINDS Division of Intramural Research. NR 38 TC 30 Z9 31 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 26 PY 2009 VL 72 IS 21 BP 1830 EP 1836 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 450ZA UT WOS:000266439300007 PM 19470965 ER PT J AU Therapontos, C Erskine, L Gardner, ER Figg, WD Vargesson, N AF Therapontos, Christina Erskine, Lynda Gardner, Erin R. Figg, William D. Vargesson, Neil TI Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE blood vessels; chick limb development; thalidomide analog; angiogensis; zebrafish ID PRODUCTION-INHIBITORY ACTIVITY; ENDOTHELIAL-CELLS; ANALOGS; EMBRYOPATHY; TERATOGENESIS; MALFORMATIONS; METABOLITES; HYPOTHESIS; MECHANISM; PATHWAY AB Thalidomide is a potent teratogen that induces a range of birth defects, most commonly of the developing limbs. The mechanisms underpinning the teratogenic effects of thalidomide are unclear. Here we demonstrate that loss of immature blood vessels is the primary cause of thalidomide-induced teratogenesis and provide an explanation for its action at the cell biological level. Antiangiogenic but not antiinflammatory metabolites/analogues of thalidomide induce chick limb defects. Both in vitro and in vivo, outgrowth and remodeling of more mature blood vessels is blocked temporarily, whereas newly formed, rapidly developing, angiogenic vessels are lost. Such vessel loss occurs upstream of changes in limb morphogenesis and gene expression and, depending on the timing of drug application, results in either embryonic death or developmental defects. These results explain both the timing and relative tissue specificity of thalidomide embryopathy and have significant implications for its use as a therapeutic agent. C1 [Therapontos, Christina; Vargesson, Neil] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Fac Med, London SW7 2AZ, England. [Therapontos, Christina; Erskine, Lynda; Vargesson, Neil] Univ Aberdeen, Inst Med Sci, Sch Med Sci, Aberdeen AB25 2ZD, Scotland. [Gardner, Erin R.] NCI, Clin Pharmacol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Figg, William D.] NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Vargesson, N (reprint author), Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Fac Med, Sir Alexander Fleming Bldg,Exhibit Rd, London SW7 2AZ, England. EM n.vargesson@abdn.ac.uk RI Figg Sr, William/M-2411-2016; OI Erskine, Lynda/0000-0001-6538-9406; Vargesson, Neil/0000-0001-8027-114X FU Royal Society and University of London Central Research Fund; National Cancer Institute, National Institutes of Health [N01-CO-12400]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Colin McCaig for comments on the manuscript; Grahame Nixon and Alix McDowell for advice on the mouse aortic ring; Matthew L. Danish and Haihao Sun for technical help on the rat aortic ring; and Elizabeth Kilby and Caroline Lim for technical support with Fig. S1. C. T. was an Imperial College London funded PhD student. This work was funded by grants from the Royal Society and University of London Central Research Fund (to N. V.) and federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 (E. R. G.) and was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (E. R. G. and W. D. F.). NR 34 TC 86 Z9 90 U1 6 U2 27 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 26 PY 2009 VL 106 IS 21 BP 8573 EP 8578 DI 10.1073/pnas.0901505106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 450WS UT WOS:000266432700031 PM 19433787 ER PT J AU Swanton, C Nicke, B Schuett, M Eklund, AC Ng, C Li, QY Hardcastle, T Lee, A Roy, R East, P Kschischo, M Endesfelder, D Wylie, P Kim, SN Chen, JG Howell, M Ried, T Habermann, JK Auer, G Brenton, JD Szallasi, Z Downward, J AF Swanton, Charles Nicke, Barbara Schuett, Marion Eklund, Aron C. Ng, Charlotte Li, Qiyuan Hardcastle, Thomas Lee, Alvin Roy, Rajat East, Philip Kschischo, Maik Endesfelder, David Wylie, Paul Kim, Se Nyun Chen, Jie-Guang Howell, Michael Ried, Thomas Habermann, Jens K. Auer, Gert Brenton, James D. Szallasi, Zoltan Downward, Julian TI Chromosomal instability determines taxane response SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemotherapy; drug resistance ID SPINDLE ASSEMBLY CHECKPOINT; GENE-EXPRESSION; CANCER-CELLS; MITOTIC ARREST; MULTIDRUG-RESISTANCE; INDUCED APOPTOSIS; PACLITAXEL; DRUGS; IDENTIFICATION; REASSORTMENTS AB Microtubule-stabilizing (MTS) agents, such as taxanes, are important chemotherapeutics with a poorly understood mechanism of action. We identified a set of genes repressed in multiple cell lines in response to MTS agents and observed that these genes are overexpressed in tumors exhibiting chromosomal instability (CIN). Silencing 22/50 of these genes, many of which are involved in DNA repair, caused cancer cell death, suggesting that these genes are involved in the survival of aneuploid cells. Overexpression of these "CIN-survival'' genes is associated with poor outcome in estrogen receptor-positive breast cancer and occurs frequently in basal-like and Her2-positive cases. In diploid cells, but not in chromosomally unstable cells, paclitaxel causes repression of CIN-survival genes, followed by cell death. In the OV01 ovarian cancer clinical trial, a high level of CIN was associated with taxane resistance but carboplatin sensitivity, indicating that CIN may determine MTS response in vivo. Thus, pretherapeutic assessment of CIN may optimize treatment stratification and clinical trial design using these agents. C1 [Ng, Charlotte; Hardcastle, Thomas; Brenton, James D.] Canc Res UK, Cambridge Res Inst, Li Ka Shing Ctr, Cambridge CB2 0RE, England. [Swanton, Charles; Nicke, Barbara; Schuett, Marion; Lee, Alvin; Roy, Rajat; East, Philip; Howell, Michael; Downward, Julian] Canc Res UK, London Res Inst, London WC2A 3PX, England. [Swanton, Charles] Royal Marsden Hosp, Dept Med, Sutton SM2 5PT, Surrey, England. [Schuett, Marion; Kschischo, Maik; Endesfelder, David] Univ Appl Sci Koblenz, D-53424 Remagen, Germany. [Eklund, Aron C.; Li, Qiyuan; Szallasi, Zoltan] Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Ng, Charlotte; Hardcastle, Thomas] Univ Cambridge, Dept Oncol, Cambridge CB2 0XZ, England. [Kim, Se Nyun] Digital Genom Inc, Seoul 120749, South Korea. [Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Habermann, Jens K.] Univ Hosp Schleswig Holstein, Dept Surg, D-23538 Lubeck, Germany. [Auer, Gert; Brenton, James D.] Karolinska Inst, S-17176 Stockholm, Sweden. [Szallasi, Zoltan] Harvard Univ, Sch Med, Harvard Mit Div Hlth Sci & Technol, Childrens Hosp Informat Program, Boston, MA 02115 USA. RP Brenton, JD (reprint author), Canc Res UK, Cambridge Res Inst, Li Ka Shing Ctr, Cambridge CB2 0RE, England. EM james.brenton@cancer.org.uk; zoltan.szallasi@childrens.harvard.edu; julian.downward@cancer.org.uk RI Habermann, Jens/E-2968-2010; Lee, Alvin/A-1047-2017; OI Downward, Julian/0000-0002-2331-4729; Lee, Alvin/0000-0002-7427-9142; East, Philip/0000-0001-5801-5713; Szallasi, Zoltan/0000-0001-5395-7509; Brenton, James/0000-0002-5738-6683; Hardcastle, Thomas/0000-0002-9328-5011; Eklund, Aron Charles/0000-0003-0861-1001 FU Cancer Research UK; Medical Research Council; National Institutes of Health [NCI SPORE P50 CA 89393, R21LM008823-01A1]; Breast Cancer Research Foundation; Medical Research Council funded senior clinical research fellow FX This work was funded by Cancer Research UK, the Medical Research Council, the National Institutes of Health (Grants NCI SPORE P50 CA 89393 and R21LM008823-01A1), and the Breast Cancer Research Foundation (Z. S.). C. S. is a Medical Research Council funded senior clinical research fellow. We thank Drs. Moreno, Bani, and Horwitz for microarray data sets; Professor Vogelstein and Drs. Jallepalli and Benezra for hSecurin-/- and Mad2-/- cells; and Professor Berres, Aengus Stewart, and Gavin Kelly for statistical support. We also thank the patients and the clinical staff at Adden-brookes and the Karolinska University Hospital. NR 33 TC 116 Z9 118 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 MAY 26 PY 2009 VL 106 IS 21 BP 8671 EP 8676 DI 10.1073/pnas.0811835106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 450WS UT WOS:000266432700048 PM 19458043 ER PT J AU Cantarella, G Liniger, M Zuniga, A Schiller, JT Billeter, M Naim, HY Glueck, R AF Cantarella, Giuseppina Liniger, Matthias Zuniga, Armando Schiller, John T. Billeter, Martin Naim, Hussein Y. Glueck, Reinhard TI Recombinant measles virus-HPV vaccine candidates for prevention of cervical carcinoma SO VACCINE LA English DT Article; Proceedings Paper CT 6th World Congress on Vaccines, Immunisation and Immunotherapy CY SEP 23-25, 2008 CL Milan, ITALY DE Recombinant MV; Reverse genetics; HPV-L1 ID GENETICALLY-MODIFIED MICE; HUMAN-PAPILLOMAVIRUS; IMMUNE-RESPONSES; PROTEIN; RECEPTOR; CANCER; VECTOR; DNA AB Cervical cancer is mainly associated with HPV genotype 16 infection. Recombinant measles virus (rMV) expressing HPV genotype 16 L1 capsid protein was generated by Construction of an antigenomic plasmid, followed by rescue using the human "helper" cell line 293-3-46. In cell cultures the recombinant MV-L1 virus replicated practically as efficiently as the standard attenuated MV established as commercial vaccine, devoid of the transgene. The high genetic stability of MVb2-L1 was confirmed by 10 serial viral transfers in cell Culture. In transgenic mice expressing the MV receptor CD46 the recombinant induced strong humoral immune responses against both MV and HPV the antibodies against L1 exhibited mainly neutralizing capacity. Our data Suggest that MV is a promising vehicle for development of inexpensive and efficient vaccines protecting from HPV infection. (c) 2009 Elsevier Ltd. All rights reserved. C1 [Liniger, Matthias; Zuniga, Armando; Naim, Hussein Y.; Glueck, Reinhard] Crucell Berna Biotech, CH-3018 Bern, Switzerland. [Cantarella, Giuseppina; Glueck, Reinhard] Etna Biotech Srl, Catania, Italy. [Schiller, John T.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Billeter, Martin] Univ Zurich, Inst Mol Biol, Zurich, Switzerland. RP Naim, HY (reprint author), Crucell Berna Biotech, Rehhagstr 79, CH-3018 Bern, Switzerland. EM hussein.naim@crucell.ch; reinhard.glueck@crucell.ch FU Intramural NIH HHS [Z01 BC009052-18]; NIAID NIH HHS [P01 AI046007, AI46007] NR 23 TC 19 Z9 22 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAY 26 PY 2009 VL 27 IS 25-26 BP 3385 EP 3390 DI 10.1016/j.vaccine.2009.01.061 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 457QT UT WOS:000266947900027 PM 19200837 ER PT J AU Newbold, RR Padilla-Banks, E Jefferson, WN AF Newbold, Retha R. Padilla-Banks, Elizabeth Jefferson, Wendy N. TI Environmental estrogens and obesity SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 16th European Congress on Obesity CY MAY 14-17, 2008 CL Geneva, SWITZERLAND DE Metabolic disease; Diabetes; Xenoestrogens; Developmental exposure; Endocrine disruptor; Bisphenol A ID BISPHENOL-A; DEVELOPMENTAL EXPOSURE; ENDOCRINE DISRUPTORS; PERINATAL EXPOSURE; INSULIN-RESISTANCE; FETAL ORIGINS; 3T3-L1 CELLS; DIETHYLSTILBESTROL; EPIDEMIC; ADIPOCYTES AB Many chemicals in the environment, in particular those with estrogenic activity, can disrupt the programming of endocrine signaling pathways that are established during development and result in adverse consequences that may not be apparent until much later in life. Most recently, obesity and diabetes join the growing list of adverse consequences that have been associated with developmental exposure to environmental estrogens during critical stages of differentiation. These diseases are quickly becoming significant public health issues and are fast reaching epidemic proportions worldwide. In this review, we summarize the literature from experimental animal studies documenting an association of environmental estrogens and the development of obesity, and further describe an animal model of exposure to diethylstilbestrol (DES) that has proven useful in studying mechanisms involved in abnormal programming of various differentiating estrogen-target tissues. Other examples of environmental estrogens including the phytoestrogen genistein and the environmental contaminant Bisphenol A are also discussed. Together, these data suggest new targets (i.e., adipocyte differentiation and molecular mechanisms involved in weight homeostasis) for abnormal programming by estrogenic chemicals, and provide evidence that support the scientific hypothesis termed "the developmental origins of adult disease". The proposal of an association of environmental estrogens with obesity and diabetes expands the focus on the diseases from intervention/treatment to include prevention/avoidance of chemical modifiers especially during critical windows of development. Published by Elsevier Ireland Ltd. C1 [Newbold, Retha R.; Padilla-Banks, Elizabeth; Jefferson, Wendy N.] NIEHS, Dev Endocrinol & Endocrine Disruptor Sect, Mol Toxicol Lab, NIH,DHHS, Res Triangle Pk, NC 27709 USA. RP Newbold, RR (reprint author), NIEHS, Dev Endocrinol & Endocrine Disruptor Sect, Mol Toxicol Lab, NIH,DHHS, Mail Drop E4-02, Res Triangle Pk, NC 27709 USA. EM newbold1@niehs.nih.gov FU Intramural NIH HHS [Z01 ES070060-34] NR 43 TC 141 Z9 148 U1 3 U2 26 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAY 25 PY 2009 VL 304 IS 1-2 SI SI BP 84 EP 89 DI 10.1016/j.mce.2009.02.024 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 455HR UT WOS:000266749800012 PM 19433252 ER PT J AU Heindel, JJ vom Saal, FS AF Heindel, Jerrold J. vom Saal, Frederick S. TI Role of nutrition and environmental endocrine disrupting chemicals during the perinatal period on the aetiology of obesity SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 16th European Congress on Obesity CY 2008 CL Geneva, SWITZERLAND DE Endocrine disrupting chemicals; Intrauterine growth restriction; Macrosomia; Fetal growth; Bisphenol A; Tributyltin; DES; Cadmium ID BISPHENOL-A; DEVELOPMENTAL ORIGINS; ADIPOSE-TISSUE; NEONATAL EXPOSURE; DIABETES-MELLITUS; MATERNAL SMOKING; RISK-ASSESSMENT; MAMMARY-GLAND; ADULT DISEASE; FETAL AB The basis for the current obesity epidemic remains controversial. However, the simplistic idea that obesity can be explained by two factors: energy intake and energy expenditure, is now being challenged due to the lack of success in decreasing obesity based on a focus on only these two factors. In this article we propose an emerging hypothesis that the recent dramatic increase in obesity could be due to developmental nutrition, developmental exposure to environmental chemicals or the interaction of nutrition and environmental chemical exposures during development. Indeed, developmental exposure to environmental chemicals in animal studies has been shown to increase the susceptibility to a number of diseases including obesity. Obesity is thus one of many diseases shown to have a developmental origin. We show that factors that impact growth during fetal and neonatal life, such as placental blood flow and nutrient transport to fetuses, as well as components of the maternal and infant diets, can influence weight gain later in life. In addition, we show that developmental exposure to endocrine disrupting chemicals can create abnormalities in homeostatic control systems required to maintain a normal body weight throughout life. Eliminating exposures to these chemicals and improving nutrition during development offer the potential for reducing obesity and associated diseases. Published by Elsevier Ireland Ltd. C1 [Heindel, Jerrold J.] NIEHS, Div Extramural Res & Training, NIH, DHHS,Cellular Organs & Syst Pathobiol Branch, Res Triangle Pk, NC 27709 USA. [vom Saal, Frederick S.] Univ Missouri, Div Biol Sci, Columbia, MO 65201 USA. RP Heindel, JJ (reprint author), NIEHS, Div Extramural Res & Training, NIH, DHHS,Cellular Organs & Syst Pathobiol Branch, POB 12233,104 Alexander Dr,Ky3-15, Res Triangle Pk, NC 27709 USA. EM heindelj@niehs.nih.gov FU NIEHS NIH HHS [ES11283] NR 66 TC 95 Z9 97 U1 1 U2 24 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAY 25 PY 2009 VL 304 IS 1-2 BP 90 EP 96 DI 10.1016/j.mce.2009.02.025 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 455HR UT WOS:000266749800013 PM 19433253 ER PT J AU Kim, SB Cai, C Trenkle, WC Sweigart, DA AF Kim, Sang Bok Cai, Chen Trenkle, William C. Sweigart, Dwight A. TI Immobilization of a Quinonoid Rhodium Catalyst on Silica Gel by the Surface Sol-Gel Process and Catalytic Activity for Phenylacetylene Polymerization SO ORGANOMETALLICS LA English DT Article ID COMPLEX; ACIDS; PHOSPHINES; OXIDATION; ALDEHYDES; LIGANDS AB A metal alkoxide monolayer was formed on the surface of silica gel by the SSG process (surface sol-gel). Quinonoid rhodium complexes possessing an acidic -OH group were immobilized on the alkoxide layer by deprotonation and subsequent formation of strong M-O (quinonoid) bonds (M = Ti, Zr). The silica-gel-supported rhodium catalyst shows a high reactivity for the stereospecific polymerization of phenylacetylene to cis-transoidal polyphenylacetylene. C1 [Kim, Sang Bok; Cai, Chen; Sweigart, Dwight A.] Brown Univ, Dept Chem, Providence, RI 02912 USA. [Trenkle, William C.] NIDDK, NIH, DHHS, Bethesda, MD 20814 USA. RP Sweigart, DA (reprint author), Brown Univ, Dept Chem, Providence, RI 02912 USA. EM Dwight_Sweigart@brown.edu FU American Chemical Society; NIH; National Science Foundation [CHE-0308640]; Dean Peder Estrup Graduate Student Research Fellowship FX We are grateful to the donors of the Petroleum Research Fund, administered by the American Chemical Society, the intramural research program at the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (W.C.T.), to the National Science Foundation (CHE-0308640), and to Dean Peder Estrup Graduate Student Research Fellowship for support of this research. NR 32 TC 3 Z9 3 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0276-7333 J9 ORGANOMETALLICS JI Organometallics PD MAY 25 PY 2009 VL 28 IS 10 BP 3000 EP 3003 DI 10.1021/om900085q PG 4 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic SC Chemistry GA 446YD UT WOS:000266156900009 ER PT J AU Ramos, E Rotimi, C AF Ramos, Edward Rotimi, Charles TI The A's, G's, C's, and T's of health disparities SO BMC MEDICAL GENOMICS LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; CHRONIC HEART-FAILURE; CANCER RISK VARIANTS; MODERN HUMAN ORIGINS; PROSTATE-CANCER; WHITE PATIENTS; MODERN HUMANS; 8Q24; DISEASE; GENOME AB In order to eliminate health disparities in the United States, more efforts are needed to address the breadth of social issues directly contributing to the healthy divide observed across racial and ethnic groups. Socioeconomic status, education, and the environment are intimately linked to health outcomes. However, with the tremendous advances in technology and increased investigation into human genetic variation, genomics is poised to play a valuable role in bolstering efforts to find new treatments and preventions for chronic conditions and diseases that disparately affect certain ethnic groups. Promising studies focused on understanding the genetic underpinnings of diseases such as prostate cancer or beta-blocker treatments for heart failure are illustrative of the positive contribution that genomics can have on improving minority health. C1 [Ramos, Edward; Rotimi, Charles] Natl Human Genome Res Inst, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Rotimi, C (reprint author), Natl Human Genome Res Inst, Ctr Res Genom & Global Hlth, NIH, 12 South Dr, Bethesda, MD 20892 USA. EM ramose@mail.nih.gov; rotimic@mail.nih.gov NR 39 TC 19 Z9 20 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD MAY 22 PY 2009 VL 2 AR 29 DI 10.1186/1755-8794-2-29 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 532VL UT WOS:000272778100001 PM 19463148 ER PT J AU Shevach, EM AF Shevach, Ethan M. TI Mechanisms of Foxp3(+) T Regulatory Cell-Mediated Suppression SO IMMUNITY LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; DENDRITIC CELLS; TGF-BETA; IN-VIVO; CUTTING EDGE; AUTOIMMUNE-DISEASE; IMMUNE SUPPRESSION; GRANZYME-B; ACTIVATION; TOLERANCE AB Foxp3(+) T regulatory (Treg) cells control all aspects of the immune response. Here, I will review the in vitro model systems that have been developed to define the mechanisms used by Treg cells to suppress a large number of distinct target cell types. These mechanisms can be broadly divided into those that target T cells (suppressor cytokines, IL-2 consumption, cytolysis) and those that primarily target antigen-presenting cells (decreased costimulation or decreased antigen presentation). Although multiple mechanisms for Treg cell suppression have been shown in vitro, it is unclear whether the same or different mechanisms are used by Treg cells in vivo. An increase in our understanding of Treg cell suppressor mechanisms will offer an insight into how Treg cell function can be manipulated either positively or negatively in vivo. C1 NIAID, Immunol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov NR 67 TC 872 Z9 916 U1 15 U2 98 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD MAY 22 PY 2009 VL 30 IS 5 BP 636 EP 645 DI 10.1016/j.immuni.2009.04.010 PG 10 WC Immunology SC Immunology GA 449UX UT WOS:000266356900004 PM 19464986 ER PT J AU Gong, R Vu, BK Feng, Y Prieto, DA Dyba, MA Walsh, JD Prabakaran, P Veenstra, TD Tarasov, SG Ishima, R Dimitrov, DS AF Gong, Rui Vu, Bang K. Feng, Yang Prieto, DaRue A. Dyba, Marzena A. Walsh, Joseph D. Prabakaran, Ponraj Veenstra, Timothy D. Tarasov, Sergey G. Ishima, Rieko Dimitrov, Dimiter S. TI Engineered Human Antibody Constant Domains with Increased Stability SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BINDING-PROTEINS; DISULFIDE BOND; CRYSTAL-STRUCTURE; VARIABLE DOMAINS; NMR; STABILIZATION; RECOGNITION; SENSITIVITY; SCAFFOLDS; FRAGMENTS AB The immunoglobulin (Ig) constant CH2 domain is critical for antibody effector functions. Isolated CH2 domains are promising as scaffolds for construction of libraries containing diverse binders that could also confer some effector functions. However, previous work has shown that an isolated murine CH2 domain is relatively unstable to thermally induced unfolding. To explore unfolding mechanisms of isolated human CH2 and increase its stability gamma 1 CH2 was cloned and a panel of cysteine mutants was constructed. Human gamma 1 CH2 unfolded at a higher temperature (T(m) = 54.1 degrees C, as measured by circular dichroism) than that previously reported for a mouse CH2 (41 degrees C). One mutant (m01) was remarkably stable (T(m) = 73.8 degrees C). Similar results were obtained by differential scanning calorimetry. This mutant was also significantly more stable than the wild-type CH2 against urea induced unfolding (50% unfolding at urea concentration of 6.8 M versus 4.2 M). The m01 was highly soluble and monomeric. The existence of the second disulfide bond in m01 and its correct position were demonstrated by mass spectrometry and nuclear magnetic resonance spectroscopy, respectively. The loops were on average more flexible than the framework in both CH2 and m01, and the overall secondary structure was not affected by the additional disulfide bond. These data suggest that a human CH2 domain is relatively stable to unfolding at physiological temperature, and that both CH2 and the highly stable mutant m01 are promising new scaffolds for the development of therapeutics against human diseases. C1 [Gong, Rui; Vu, Bang K.; Feng, Yang; Prabakaran, Ponraj; Dimitrov, Dimiter S.] NCI Frederick, Prot Interact Grp, CCRNP, CCR,NIH, Frederick, MD 21702 USA. [Tarasov, Sergey G.] NCI Frederick, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. [Prieto, DaRue A.; Veenstra, Timothy D.] NCI Frederick, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. [Dyba, Marzena A.] NCI Frederick, Struct Biophys Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Walsh, Joseph D.; Ishima, Rieko] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA. RP Dimitrov, DS (reprint author), NCI Frederick, Prot Interact Grp, CCRNP, CCR,NIH, Bldg 469,Rm 150B, Frederick, MD 21702 USA. EM dimitrov@ncifcrf.gov RI Ponraj, Prabakaran/D-6325-2011 FU National Institutes of Health; NCI [N01-CO-12400]; Center for Cancer Research Intramural Research Program; Gates Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grants from the Intramural AIDS Targeted Antiviral Program (IATAP), the NIAID Intramural Biodefense Program, the NCI, Center for Cancer Research Intramural Research Program (to D. S. D.) and Contract N01-CO-12400 from the NCI. This work was also supported by the Gates Foundation. NR 29 TC 57 Z9 58 U1 5 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 22 PY 2009 VL 284 IS 21 BP 14203 EP 14210 DI 10.1074/jbc.M900769200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 448TY UT WOS:000266286100026 PM 19307178 ER PT J AU Bonini, MG Gabel, SA Ranguelova, K Stadler, K DeRose, EF London, RE Mason, RP AF Bonini, Marcelo G. Gabel, Scott A. Ranguelova, Kalina Stadler, Krisztian DeRose, Eugene F. London, Robert E. Mason, Ronald P. TI Direct Magnetic Resonance Evidence for Peroxymonocarbonate Involvement in the Cu,Zn-Superoxide Dismutase Peroxidase Catalytic Cycle SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; ZINC SUPEROXIDE-DISMUTASE; CARBONATE-RADICAL-ANION; HYDROGEN-PEROXIDE; HYDROPEROXIDE ANION; NITROGEN-DIOXIDE; AQUEOUS-SOLUTION; ALPHA-SYNUCLEIN; MOTOR-NEURONS; HUMAN COPPER AB Cu,Zn-superoxide dismutase (SOD1) is a copper- and zinc-dependent enzyme. The main function of SOD1 is believed to be the scavenging and detoxification of superoxide radicals. Nevertheless, the last 30 years have seen a rapid accumulation of evidence indicating that SOD1 may also act as a peroxidase, an alternative function that was implicated in the onset and progression of familial amyotrophic lateral sclerosis. Although SOD1 peroxidase activity and its dependence on carbon dioxide have been well described, the molecular basis of the SOD1 peroxidase cycle remains obscure, because none of the proposed catalytic intermediates have so far been identified. In view of recent observations, we hypothesized that the SOD1 peroxidase cycle relies on two steps: 1) reduction of SOD-Cu(II) by hydrogen peroxide followed by 2) oxidation of SOD-Cu(I) by peroxy-monocarbonate, the product of the spontaneous reaction of bicarbonate with hydrogen peroxide, to produce SOD-Cu(II) and carbonate radical anion. This hypothesis has been investigated through electron paramagnetic resonance and nuclear magnetic resonance to provide direct evidence for a peroxycarbonate-driven, SOD1-catalyzed carbonate radical production. The results gathered herein indicate that peroxymonocarbonate (HOOCO(2)(-)) is a key intermediate in the SOD1 peroxidase cycle and identify this species as the precursor of carbonate radical anions. C1 [Bonini, Marcelo G.; Ranguelova, Kalina; Stadler, Krisztian; Mason, Ronald P.] NIEHS, Pharmacol Lab, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. [Gabel, Scott A.; DeRose, Eugene F.; London, Robert E.] NIEHS, Struct Biol Lab, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. RP Bonini, MG (reprint author), NIEHS, Pharmacol Lab, Natl Inst Hlth, MD F0-02,POB 12233, Res Triangle Pk, NC 27709 USA. EM bonini@niehs.nih.gov FU National Institutes of Health; NIEHS; Intramural Research Program FX This work was supported, in whole or in part, by the National Institutes of Health, NIEHS, Intramural Research Program. NR 55 TC 16 Z9 17 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 22 PY 2009 VL 284 IS 21 BP 14618 EP 14627 DI 10.1074/jbc.M804644200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 448TY UT WOS:000266286100067 PM 19286663 ER PT J AU Riazuddin, SA Amiri-Kordestani, L Kaul, H Butt, T Jiao, XD Riazuddin, S Hejtmancik, JF AF Riazuddin, S. Amer Amiri-Kordestani, Laleh Kaul, Haiba Butt, Tariq Jiao, Xiaodong Riazuddin, Sheikh Hejtmancik, J. Fielding TI Novel SIL1 mutations in consanguineous Pakistani families mapping to chromosomes 5q31 SO MOLECULAR VISION LA English DT Article ID MARINESCO-SJOGREN-SYNDROME; CATARACT; PROTEIN; BIP AB Purpose: To investigate the genetic basis of Marinesco-Sjogren syndrome (MSS) in consanguineous Pakistani families. Methods: Two consanguineous Pakistani families with congenital cataract and muscular dystrophy were enrolled for this study. Detailed ophthalmic and systemic examination including slit lamp microscopy, electromyogram and computed tomography scans were performed to characterize the syndrome. Blood samples were collected from affected and unaffected individuals and a genome wide scan consisting of 382 polymorphic microsatellite markers was performed. Coding exons, exon-intron boundaries, 5' UTR, and 3' UTR of the candidate gene SIL1 residing in the linkage interval was sequenced bi-directionally. Results: Clinical examination of the affected members of families 60067 and 60078 revealed features of MSS. The linked interval at chromosome 5q31 harbors SIL1. Sequencing of SIL1 in family 60067 revealed a homozygous substitution; c1240C>T, leading to a premature substitution; p.Q414X. Similarly, sequencing of SIL1 in family 60078 identified a homozygous change; c.274C>T, leading to a non conservative substitution; p.R92W. Conclusion: In conclusion, our data report two novel missense mutations in two consanguineous Pakistani families affected with MSS. C1 [Riazuddin, S. Amer; Kaul, Haiba; Butt, Tariq; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 53700, Pakistan. [Amiri-Kordestani, Laleh; Jiao, Xiaodong; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Riazuddin, SA (reprint author), Univ Punjab, Natl Ctr Excellence Mol Biol, 87 W Canal Bank Rd, Lahore 53700, Pakistan. EM amerriazuddin@ncemb.org FU Higher Education Commission, Islamabad, Pakistan; Ministry of Science and Technology, Islamabad, Pakistan FX The authors are grateful to all members for their participation in this study. We are also thankful to members of the staff of Layton Rehmatullah Benevolent Trust (LRBT) hospital for clinical evaluation of affected individuals. This study was supported, in part, by Higher Education Commission, Islamabad, Pakistan and Ministry of Science and Technology, Islamabad, Pakistan. NR 15 TC 8 Z9 8 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD MAY 22 PY 2009 VL 15 IS 111 BP 1050 EP 1056 PG 7 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 459UN UT WOS:000267136200001 PM 19471582 ER PT J AU Tishkoff, SA Reed, FA Friedlaender, FR Ehret, C Ranciaro, A Froment, A Hirbo, JB Awomoyi, AA Bodo, JM Doumbo, O Ibrahim, M Juma, AT Kotze, MJ Lema, G Moore, JH Mortensen, H Nyambo, TB Omar, SA Powell, K Pretorius, GS Smith, MW Thera, MA Wambebe, C Weber, JL Williams, SM AF Tishkoff, Sarah A. Reed, Floyd A. Friedlaender, Francoise R. Ehret, Christopher Ranciaro, Alessia Froment, Alain Hirbo, Jibril B. Awomoyi, Agnes A. Bodo, Jean-Marie Doumbo, Ogobara Ibrahim, Muntaser Juma, Abdalla T. Kotze, Maritha J. Lema, Godfrey Moore, Jason H. Mortensen, Holly Nyambo, Thomas B. Omar, Sabah A. Powell, Kweli Pretorius, Gideon S. Smith, Michael W. Thera, Mahamadou A. Wambebe, Charles Weber, James L. Williams, Scott M. TI The Genetic Structure and History of Africans and African Americans SO SCIENCE LA English DT Article ID Y-CHROMOSOME; HUMAN-POPULATIONS; COMPLEX DISEASE; MTDNA VARIATION; DIVERSITY; GENOME; ORIGINS; SOUTH; POLYMORPHISMS; PROPORTIONS AB Africa is the source of all modern humans, but characterization of genetic variation and of relationships among populations across the continent has been enigmatic. We studied 121 African populations, four African American populations, and 60 non-African populations for patterns of variation at 1327 nuclear microsatellite and insertion/deletion markers. We identified 14 ancestral population clusters in Africa that correlate with self-described ethnicity and shared cultural and/or linguistic properties. We observed high levels of mixed ancestry in most populations, reflecting historical migration events across the continent. Our data also provide evidence for shared ancestry among geographically diverse hunter-gatherer populations (Khoesan speakers and Pygmies). The ancestry of African Americans is predominantly from Niger-Kordofanian (similar to 71%), European (similar to 13%), and other African (similar to 8%) populations, although admixture levels varied considerably among individuals. This study helps tease apart the complex evolutionary history of Africans and African Americans, aiding both anthropological and genetic epidemiologic studies. C1 [Tishkoff, Sarah A.; Reed, Floyd A.; Ranciaro, Alessia; Hirbo, Jibril B.; Awomoyi, Agnes A.; Mortensen, Holly; Powell, Kweli] Univ Maryland, Dept Biol, College Pk, MD 20742 USA. [Tishkoff, Sarah A.; Ranciaro, Alessia; Hirbo, Jibril B.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Tishkoff, Sarah A.; Ranciaro, Alessia; Hirbo, Jibril B.] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Ehret, Christopher] Univ Calif Los Angeles, Dept Hist, Los Angeles, CA 90095 USA. [Ranciaro, Alessia] Univ Ferrara, Dipartimento Biol & Evoluz, I-44100 Ferrara, Italy. [Froment, Alain] Musee Homme Paris, IRD MNHN, UMR 208, F-75116 Paris, France. [Bodo, Jean-Marie] Minist Rech Sci & Innovat, Yaounde, Cameroon. [Doumbo, Ogobara; Thera, Mahamadou A.] Univ Bamako, Malaria Res & Training Ctr, Bamako, Mali. [Ibrahim, Muntaser; Juma, Abdalla T.] Univ Khartoum, Inst Endem Dis, Dept Mol Biol, Khartoum 1513, Sudan. [Kotze, Maritha J.] Univ Stellenbosch, Fac Hlth Sci, Dept Pathol, ZA-7505 Tygerberg, South Africa. [Lema, Godfrey; Nyambo, Thomas B.] Muhimbili Univ Hlth & Allied Sci, Dept Biochem, Dar Es Salaam, Tanzania. [Moore, Jason H.] Dartmouth Med Sch, Dept Genet, Lebanon, NH 03756 USA. [Moore, Jason H.] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH 03756 USA. [Omar, Sabah A.] Ctr Biotechnol Res & Dev, Kenya Med Res Inst, Nairobi 5484000200, Kenya. [Pretorius, Gideon S.] Univ Stellenbosch, Fac Hlth Sci, Div Human Genet, ZA-7505 Tygerberg, South Africa. [Smith, Michael W.] NCI, Lab Genom Div, Frederick, MD 21702 USA. [Wambebe, Charles] Int Biomed Res Africa, Abuja, Nigeria. [Weber, James L.] Marshfield Clin Res Fdn, Marshfield, WI 54449 USA. [Williams, Scott M.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. RP Tishkoff, SA (reprint author), Univ Maryland, Dept Biol, College Pk, MD 20742 USA. EM tishkoff@mail.med.upenn.edu RI Smith, Michael/B-5341-2012; Williams, Scott/B-9491-2012 FU L. S. B. Leakey and Wenner Gren Foundation; NSF [BCS-0196183, BSC-0552486, BCS-0827436]; NIH [R01GM076637, 1R01GM083606-01, F32HG03801, R01 HL65234]; NHLBI Mammalian Genotyping Service; National Cancer Institute [N01-CO-12400] FX We thank the thousands of people who donated DNA samples used in this study. We thank D. Bygott, S. J. Deo, D. Guracha, J. Hanby, D. Kariuki, P. Lufungulo, A. Mabulla, A. A. Mohamed, W. Ntandu, L. A. Nyindodo, C. Plowe, and A. Tibwitta for assisting with sample collection; K. Panchapakesan and L. Pfeiffer for assistance in sample preparation; S. Dobrin for assistance with genotyping; J. Giles, J. Bartlett, N. Kodaman, and J. Jarvis for assistance with analyses; and N. Rosenberg, J. Pritchard, A. Brooks, J. S. Friedlaender, J. Jarvis, C. Lambert, B. Payseur, N. Patterson, and J. Plotkin for helpful suggestions and discussions. Conducted in part using the ACCRE computing facility at Vanderbilt University, Nashville, TN. Supported by L. S. B. Leakey and Wenner Gren Foundation grants, NSF grants BCS-0196183, BSC-0552486, and BCS-0827436, NIH grants R01GM076637 and 1R01GM083606-01, and David and Lucile Packard and Burroughs Wellcome Foundation Career Awards (S.A.T.); NIH grant F32HG03801 (F.A.R.); and NIH grant R01 HL65234 (S.M.W. and J.H.M.). Genotyping was supported by the NHLBI Mammalian Genotyping Service. 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. The project included in this manuscript has been funded in part with federal funds from the National Cancer Institute under contract N01-CO-12400. Original genotype data are available at http://research.marshfieldclinic.org/genetics/genotypingData_Statistics/ humanDiversityPanel.asp. Data used for analyses in the current manuscript are available at www.med.upenn.edu/tishkoff/Supplemental/files.html and at http://chgr.mc.vanderbilt.edu/page/supplementary-data. NR 63 TC 574 Z9 588 U1 12 U2 88 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 22 PY 2009 VL 324 IS 5930 BP 1035 EP 1044 DI 10.1126/science.1172257 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 448EU UT WOS:000266246700033 PM 19407144 ER PT J AU Bradford, PT Devesa, SS Anderson, WF Toro, JR AF Bradford, Porcia T. Devesa, Susan S. Anderson, William F. Toro, Jorge R. TI Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases SO BLOOD LA English DT Article ID B-CELL LYMPHOMA; WHO-EORTC CLASSIFICATION; MYCOSIS-FUNGOIDES; T-CELL; PROGNOSTIC-FACTORS; CLINICOPATHOLOGICAL FEATURES; FOLLICULAR LYMPHOMA; SEZARY-SYNDROME; SURVEILLANCE; SURVIVAL AB There have been no prior large population-based studies focusing on cutaneous lymphomas (CL) in the United States. Using the Surveillance, Epidemiology and End Results (SEER) program data, we analyzed age-adjusted CL incidence rates (IRs) and survival rates by sex and race/ethnicity. There were 3884 CLs diagnosed during 2001-2005. Cutaneous T-cell lymphomas(CTCLs) accounted for 71% (age-adjusted incidence rate [IR] = 7.7/1 000 000 person-years), whereas cutaneous B-cell lymphomas (CBCLs) accounted for 29% (IR = 3.1/1 000 000 person-years). Males had a statistically significant higher IR of CL than females (14.0 vs 8.2/1 000 000 person-years, respectively; male-female IR ratio [M/F IRR] = 1.72; P <.001). CL IRs were highest among blacks and non-Hispanic whites (both 11.5/1 000 000 person-years), followed by Hispanic whites (7.9) and Asian/Pacific Islanders (7.1). The CTCL IR was highest amongblacks (10.0/1 000 000 person-years), whereas the CBCL IR was highest among (non-Hispanic whites (3.5). Over the past 25 years, the CLIR increased from 5.0/1 000 000 person-years during 1980-1982 to 14.3 during 2001-2003. During 2004-2005, the CL IR was 12.7. This recent apparent change could be incomplete case ascertainment or potential leveling off of IRs. CLs rates vary markedly by race and sex, supporting the notion that they represent distinct disease entities. (Blood. 2009; 113: 5064-5073) C1 [Bradford, Porcia T.; Toro, Jorge R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Natl Inst Hlth,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Devesa, Susan S.; Anderson, William F.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Natl Inst Hlth,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Toro, JR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Natl Inst Hlth,Dept Hlth & Human Serv, 6120 Executive Blvd,Executive Plaza S,Rm 7012, Bethesda, MD 20892 USA. EM toroj@mail.nih.gov FU Intramural Program of Division of Cancer Epidemiology and Genetics; National Cancer Institute, National Institutes of Health FX This research was supported in part by the Intramural Program of Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 55 TC 192 Z9 196 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 MAY 21 PY 2009 VL 113 IS 21 BP 5064 EP 5073 DI 10.1182/blood-2008-10-184168 PG 10 WC Hematology SC Hematology GA 450ML UT WOS:000266404500010 PM 19279331 ER PT J AU Throm, RE Ouma, AA Zhou, S Chandrasekaran, A Lockey, T Greene, M De Ravin, SS Moayeri, M Malech, HL Sorrentino, BP Gray, JT AF Throm, Robert E. Ouma, Annastasia A. Zhou, Sheng Chandrasekaran, Anantharaman Lockey, Timothy Greene, Michael De Ravin, Suk See Moayeri, Morvarid Malech, Harry L. Sorrentino, Brian P. Gray, John T. TI Efficient construction of producer cell lines for a SIN lentiviral vector for SCID-X1 gene therapy by concatemeric array transfection SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; SEVERE COMBINED IMMUNODEFICIENCY; IN-VIVO; TRANSGENE EXPRESSION; SYSTEM; GENERATION; RETROVIRUS; INSULATOR; GENOTOXICITY; PROMOTERS AB Retroviral vectors containing internal promoters, chromatin insulators, and self-inactivating (SIN) long terminal repeats (LTRs) may have significantly reduced genotoxicity relative to the conventional retroviral vectors used in recent, otherwise successful clinical trials. Largescale production of such vectors is problematic, however, as the introduction of SIN vectors into packaging cells cannot be accomplished with the traditional method of viral transduction. We have derived a set of packaging cell lines for HIV-based lentiviral vectors and developed a novel concatemeric array transfection technique for the introduction of SIN vector genomes devoid of enhancer and promoter sequences in the LTR. We used this method to derive a producer cell clone for a SIN lentiviral vector expressing green fluorescent protein, which when grown in a bioreactor generated more than 20 L of supernatant with titers above 107 transducing units (TU) per milliliter. Further refinement of our technique enabled the rapid generation of whole populations of stably transformed cells that produced similar titers. Finally, we describe the construction of an insulated, SIN lentiviral vector encoding the human interleukin 2 receptor common gamma chain (IL2RG) gene and the efficient derivation of cloned producer cells that generate supernatants with titers greater than 5 x 10(7) TU/mL and that are suitable for use in a clinical trial for X-linked severe combined immunodeficiency (SCID-X1). (Blood. 2009; 113: 5104-5110) C1 [Throm, Robert E.; Ouma, Annastasia A.; Zhou, Sheng; Chandrasekaran, Anantharaman; Greene, Michael; Sorrentino, Brian P.; Gray, John T.] St Jude Childrens Hosp, Div Expt Hematol, Dept Hematol, Memphis, TN 38105 USA. [Lockey, Timothy] St Jude Childrens Hosp, Dept Therapeut Prod & Qual, Memphis, TN 38105 USA. [De Ravin, Suk See; Moayeri, Morvarid; Malech, Harry L.] NIAID, Host Def Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Gray, JT (reprint author), St Jude Childrens Hosp, Div Expt Hematol, Dept Hematol, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM john.gray@stjude.org OI Malech, Harry/0000-0001-5874-5775 FU National Heart, Lung, and Blood Institute [5 PO1 HL-53749, 2V54HL070590-06]; Assisi Foundation of Memphis; American Lebanese Syrian Associated Charities; National Institute of Allergy and Infectious Diseases FX This work was supported by National Heart, Lung, and Blood Institute grant 5 PO1 HL-53749, 2V54HL070590-06, the Assisi Foundation of Memphis, the American Lebanese Syrian Associated Charities, and in part by the intramural program of the National Institute of Allergy and Infectious Diseases. NR 33 TC 58 Z9 60 U1 3 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 21 PY 2009 VL 113 IS 21 BP 5104 EP 5110 DI 10.1182/blood-2008-11-191049 PG 7 WC Hematology SC Hematology GA 450ML UT WOS:000266404500015 PM 19286997 ER PT J AU Tran, DQ Andersson, J Hardwick, D Bebris, L Illei, GG Shevach, EM AF Tran, Dat Q. Andersson, John Hardwick, Donna Bebris, Lolita Illei, Gabor G. Shevach, Ethan M. TI Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I/II (CD121a/CD121b) on activated human FOXP3(+) regulatory T cells allows for their purification from expansion cultures SO BLOOD LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; VERSUS-HOST-DISEASE; IN-VITRO EXPANSION; SUPPRESSOR FUNCTION; MULTIPLE-SCLEROSIS; AUTOIMMUNE-DISEASE; APLASTIC-ANEMIA; TOLERANCE; TRANSPLANTATION; RAPAMYCIN AB Although adoptive transfer of regulatory T cells (Foxp3(+) Tregs) has proven to be efficacious in the prevention and treatment of autoimmune diseases and graft-versus-host disease in rodents, a major obstacle for the use of Treg immunotherapy in humans is the difficulty of obtaining a highly purified preparation after ex vivo expansion. We have identified latency-associated peptide (LAP) and IL-1 receptor type I and II (CD121a/CD121b) as unique cell-surface markers that distinguish activated Tregs from activated FOXP3(+) and FOXP3(+) non-Tregs. We show that it is feasible to sort expanded FOXP3(+) Tregs from non-Tregs with the use of techniques for magnetic bead cell separation based on expression of these 3 markers. After separation, the final product contains greater than 90% fully functional FOXP3(+) Tregs. This novel protocol should facilitate the purification of Tregs for both cell-based therapies as well as detailed studies of human Treg function in health and disease. (Blood. 2009; 113: 5125-5133) C1 [Tran, Dat Q.; Andersson, John; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Hardwick, Donna; Bebris, Lolita; Illei, Gabor G.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Tran, DQ (reprint author), NIAID, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 11N256 11N315,MSC 1892, Bethesda, MD 20892 USA. EM dtran@niaid.nih.gov; eshevach@niaid.nih.gov RI Andersson, John/A-4436-2009; OI Andersson, John/0000-0003-2799-6349 FU Intramural Research Program of the NIAID, NIH (Bethesda, MD) FX This work was supported by the Intramural Research Program of the NIAID, NIH (Bethesda, MD). NR 38 TC 108 Z9 111 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 21 PY 2009 VL 113 IS 21 BP 5125 EP 5133 DI 10.1182/blood-2009-01-199950 PG 9 WC Hematology SC Hematology GA 450ML UT WOS:000266404500018 PM 19299332 ER PT J AU Lambert, S Bouttier, M Vassy, R Seigneuret, M Petrow-Sadowski, C Janvier, S Heveker, N Ruscetti, FW Perret, G Jones, KS Pique, C AF Lambert, Sophie Bouttier, Manuella Vassy, Roger Seigneuret, Michel Petrow-Sadowski, Cari Janvier, Sebastien Heveker, Nikolaus Ruscetti, Francis W. Perret, Gerrard Jones, Kathryn S. Pique, Claudine TI HTLV-1 uses HSPG and neuropilin-1 for entry by molecular mimicry of VEGF(165) SO BLOOD LA English DT Article ID LEUKEMIA-VIRUS TYPE-1; ENDOTHELIAL GROWTH-FACTOR; HEPARAN-SULFATE PROTEOGLYCANS; GLUCOSE-TRANSPORTER GLUT-1; EXON 7-ENCODED DOMAIN; TO-CELL TRANSMISSION; DENDRITIC CELLS; ENVELOPE GLYCOPROTEINS; STRUCTURAL BASIS; TUMOR-CELLS AB Human T-cell lymphotropic virus type 1 (HTLV-1) entry involves the interaction between the surface (SU) subunit of the Env proteins and cellular receptor(s). Previously, our laboratories demonstrated that heparan sulfate proteoglycans (HSPGs) and neuropilin-1 (NRP-1), a receptor of VEGF(165), are essential for HTLV-1 entry. Here we investigated whether, as when binding VEGF(165), HSPGs and NRP-1 work in concert during HTLV-1 entry. VEGF(165) binds to the b domain of NRP-1 through both HSPG-dependent and -independent interactions, the latter involving its exon 8. We show that VEGF(165) is a selective competitor of HTLV-1 entry and that HTLV-1 mimics VEGF(165) to recruit HSPGs and NRP-1: (1) the NRP-1 b domain is required for HTLV-1 binding; (2) SU binding to target cells is blocked by the HSPG-binding domain of VEGF(165); (3) the formation of Env/NRP-1 complexes is enhanced by HSPGs; and (4) the HTLV SU contains a motif homologous to VEGF(165) exon 8. This motif directly binds to NRP-1 and is essential for HTLV-1 binding to, internalization into, and infection of CD4(+) T cells and dendritic cells. These findings demonstrate that HSPGs and NRP-1 function as HTLV-1 receptors in a cooperative manner and reveal an unexpected mimicry mechanism that may have major implications in vivo. (Blood. 2009; 113: 5176-5185) C1 [Petrow-Sadowski, Cari; Jones, Kathryn S.] NCI, SAIC Frederick, Basic Sci Program, Frederick, MD 21702 USA. [Lambert, Sophie; Bouttier, Manuella; Seigneuret, Michel; Pique, Claudine] Univ Paris 05, CNRS, UMR 8104, Inserm U567, Paris, France. [Vassy, Roger; Perret, Gerrard] Univ Paris 13, UMR 7033, Bobigny, France. [Janvier, Sebastien; Heveker, Nikolaus] Univ Montreal, Hop St Justine, Ctr Rech 6737, Montreal, PQ H3T 1C5, Canada. [Janvier, Sebastien; Heveker, Nikolaus] Univ Montreal, Dept Biochim, Montreal, PQ H3C 3J7, Canada. [Ruscetti, Francis W.] NCI, Canc & Inflammat Program, Ctr Canc Res, Expt Immunol Lab, Frederick, MD 21702 USA. RP Jones, KS (reprint author), NCI, SAIC Frederick, Basic Sci Program, Bldg 567,Rm 253, Frederick, MD 21702 USA. EM joneska@mail.nih.gov; claudine.pique@inserm.fr RI PERRET, gerard/A-7379-2008; Heveker, Nikolaus/G-5306-2012 OI PERRET, gerard/0000-0003-0645-3337; FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 46 TC 56 Z9 56 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 21 PY 2009 VL 113 IS 21 BP 5176 EP 5185 DI 10.1182/blood-2008-04-150342 PG 10 WC Hematology SC Hematology GA 450ML UT WOS:000266404500023 PM 19270265 ER PT J AU Dixit, VD Yang, HW Cooper-Jenkins, A Giri, BB Patel, K Taub, DD AF Dixit, Vishwa D. Yang, Hyunwon Cooper-Jenkins, Anthony Giri, Banabihari B. Patel, Kalpesh Taub, Dennis D. TI Reduction of T cell-derived ghrelin enhances proinflammatory cytokine expression: implications for age-associated increases in inflammation SO BLOOD LA English DT Article ID SECRETAGOGUE RECEPTOR; LEPTIN; PROLIFERATION; ACTIVATION; SECRETION AB Ghrelin (Grln) is a peptide hormone that is predominantly produced in the stomach and stimulates appetite and induces growth hormone (GH) release. We have previously reported that ghrelin is also expressed in T cells and exerts prothymic and anti-inflammatory effects. However, the biologic relevance of T cell-derived ghrelin remains to be determined. Here, we report that acylated-bioactive ghrelin is expressed in human T cells and preferentially segregates within the lipid raft domains upon TCR ligation. The RNA interference (RNAi)-mediated down-regulation of ghrelin in primary human T cells activates IkB, and increases Th1 cytokines and IL-17 secretion. Ghrelin expression declines with increasing age in spleen and T cells and exogenous ghrelin administration in old mice reduces proinflammatory cytokines. These findings demonstrate that ghrelin functions in an autocrine and paracrine capacity to regulate proinflammatory cytokine expression in human and murine T cells and may contribute in regulating "inflamm-aging." (Blood. 2009; 113: 5202-5205) C1 [Taub, Dennis D.] NIA, Clin Immunol Sect, Immunol Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Taub, DD (reprint author), NIA, Clin Immunol Sect, Immunol Lab, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM taubd@grc.nia.nih.gov RI Patel, Kalpesh/G-6685-2012 OI Patel, Kalpesh/0000-0002-2952-6773 FU NIA, National Institutes of Health FX This research was entirely supported by the Intramural Research Program of the NIA, National Institutes of Health. NR 21 TC 36 Z9 38 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 MAY 21 PY 2009 VL 113 IS 21 BP 5202 EP 5205 DI 10.1182/blood-2008-09-181255 PG 4 WC Hematology SC Hematology GA 450ML UT WOS:000266404500026 PM 19324904 ER PT J AU Huestis, DL Oppert, B Marshall, JL AF Huestis, Diana L. Oppert, Brenda Marshall, Jeremy L. TI Geographic distributions of Idh-1 alleles in a cricket are linked to differential enzyme kinetic performance across thermal environments SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID PHOSPHOGLUCOSE ISOMERASE PGI; ALLONEMOBIUS-SOCIUS; NATURAL-SELECTION; BALANCING SELECTION; ISOCITRATE DEHYDROGENASE; DROSOPHILA PSEUDOOBSCURA; REPRODUCTIVE ISOLATION; GENIC HETEROZYGOSITY; TEMPERATURE OPTIMA; METABOLIC ENZYMES AB Background: Geographic clines within species are often interpreted as evidence of adaptation to varying environmental conditions. However, clines can also result from genetic drift, and these competing hypotheses must therefore be tested empirically. The striped ground cricket, Allonemobius socius, is widely-distributed in the eastern United States, and clines have been documented in both life-history traits and genetic alleles. One clinally-distributed locus, isocitrate dehydrogenase (Idh-1), has been shown previously to exhibit significant correlations between allele frequencies and environmental conditions (temperature and rainfall). Further, an empirical study revealed a significant genotype-by-environmental interaction (GxE) between Idh-1 genotype and temperature which affected fitness. Here, we use enzyme kinetics to further explore GxE between Idh-1 genotype and temperature, and test the predictions of kinetic activity expected under drift or selection. Results: We found significant GxE between temperature and three enzyme kinetic parameters, providing further evidence that the natural distributions of Idh-1 allele frequencies in A. socius are maintained by natural selection. Differences in enzyme kinetic activity across temperatures also mirror many of the geographic patterns observed in allele frequencies. Conclusion: This study further supports the hypothesis that the natural distribution of Idh-1 alleles in A. socius is driven by natural selection on differential enzymatic performance. This example is one of several which clearly document a functional basis for both the maintenance of common alleles and observed clines in allele frequencies, and provides further evidence for the non-neutrality of some allozyme alleles. C1 [Huestis, Diana L.; Oppert, Brenda; Marshall, Jeremy L.] Kansas State Univ, Dept Entomol, Manhattan, KS 66506 USA. [Huestis, Diana L.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Oppert, Brenda] USDA ARS, Grain Mkt & Prod Res Ctr, Manhattan, KS 66502 USA. RP Huestis, DL (reprint author), Kansas State Univ, Dept Entomol, Manhattan, KS 66506 USA. EM dhuestis@ksu.edu; bso@ksu.edu; cricket@ksu.edu RI Marshall, Jeremy/D-1436-2013; OI Huestis, Diana/0000-0001-6649-4785 NR 61 TC 6 Z9 6 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD MAY 21 PY 2009 VL 9 AR 113 DI 10.1186/1471-2148-9-113 PG 12 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 454DK UT WOS:000266661700001 PM 19460149 ER PT J AU Walley, NM Julg, B Dickson, SP Fellay, J Ge, D Walker, BD Carrington, M Cohen, MS de Bakker, PIW Goldstein, DB Shianna, KV Haynes, BF Letvin, NL McMichael, AJ Michael, NL Weintrob, AC AF Walley, Nicole M. Julg, Boris Dickson, Samuel P. Fellay, Jacques Ge, Dongliang Walker, Bruce D. Carrington, Mary Cohen, Myron S. de Bakker, Paul I. W. Goldstein, David B. Shianna, Kevin V. Haynes, Barton F. Letvin, Norman L. McMichael, Andrew J. Michael, Nelson L. Weintrob, Amy C. TI The Duffy Antigen Receptor for Chemokines Null Promoter Variant Does Not Influence HIV-1 Acquisition or Disease Progression SO CELL HOST & MICROBE LA English DT Letter ID GENOME-WIDE ASSOCIATION C1 [Weintrob, Amy C.] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20307 USA. [Walley, Nicole M.; Dickson, Samuel P.; Fellay, Jacques; Ge, Dongliang; Goldstein, David B.; Shianna, Kevin V.] Duke Univ, Ctr Human Genome Variat, Inst Genome Sci & Policy, Durham, NC 27710 USA. [Walley, Nicole M.] Duke Univ, Dept Biol, Durham, NC 27710 USA. [Haynes, Barton F.] Duke Univ, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Julg, Boris; Walker, Bruce D.] Massachusetts Gen Hosp E, Charlestown, MA 02129 USA. [Julg, Boris; Walker, Bruce D.] MIT, Ragon Inst, Charlestown, MA 02129 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Carrington, Mary] NCI Frederick, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Cohen, Myron S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [de Bakker, Paul I. W.] Broad Inst MIT & Harvard, Program Med & Populat Genet & Genet Anal Platform, Cambridge, MA 02142 USA. [de Bakker, Paul I. W.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Letvin, Norman L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02215 USA. [McMichael, Andrew J.] John Radcliffe Hosp, Weatherall Inst Mol Med, Human Immunol Unit, Med Res Council, Oxford OX3 9DS, England. [Michael, Nelson L.] Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD 20850 USA. RP Weintrob, AC (reprint author), Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20307 USA. EM amy.weintrob@us.army.mil RI Ge, Dongliang/A-2073-2010; de Bakker, Paul/B-8730-2009; Fellay, Jacques/A-6681-2009 OI de Bakker, Paul/0000-0001-7735-7858; Fellay, Jacques/0000-0002-8240-939X FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS; Medical Research Council [MC_U137884177]; NCI NIH HHS [HHSN261200800001E]; NIAID NIH HHS [HU0001-05-2-0011]; PHS HHS [HHSN261200800001E] NR 6 TC 21 Z9 21 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAY 21 PY 2009 VL 5 IS 5 BP 408 EP 410 DI 10.1016/j.chom.2009.04.011 PG 3 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 450RZ UT WOS:000266419800002 PM 19454339 ER PT J AU Winkler, CA An, P Johnson, R Nelson, GW Kirk, G AF Winkler, Cheryl A. An, Ping Johnson, Randall Nelson, George W. Kirk, Gregory TI Expression of Duffy Antigen Receptor for Chemokines (DARC) Has No Effect on HIV-1 Acquisition or Progression to AIDS in African Americans SO CELL HOST & MICROBE LA English DT Letter ID INJECTION-DRUG USERS; GENE C1 [Winkler, Cheryl A.; An, Ping; Johnson, Randall; Nelson, George W.] Natl Canc Inst, Lab Genom Divers, SAIC Frederick, Ft Detrick, MD 21702 USA. [Kirk, Gregory] Johns Hopkins Univ, Sch Publ Hlth & Med, Dept Epidemiol, Baltimore, MD 21205 USA. RP Winkler, CA (reprint author), Natl Canc Inst, Lab Genom Divers, SAIC Frederick, Ft Detrick, MD 21702 USA. EM winkler@ncifcrf.gov RI Johnson, Randall/B-1517-2014 OI Johnson, Randall/0000-0001-7754-0847 FU NCI NIH HHS [N01-CO-12400, N02-CP-55504] NR 11 TC 23 Z9 23 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAY 21 PY 2009 VL 5 IS 5 BP 411 EP 413 DI 10.1016/j.chom.2009.04.010 PG 3 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 450RZ UT WOS:000266419800003 PM 19454340 ER PT J AU Julg, B Reddy, S van der Stok, M Kulkarni, S Qi, Y Bass, S Gold, B Nalls, MA Nelson, GW Walker, BD Carrington, M Ndung'u, T AF Julg, Boris Reddy, Shabashini van der Stok, Mary Kulkarni, Smita Qi, Ying Bass, Sara Gold, Bert Nalls, Michael A. Nelson, George W. Walker, Bruce D. Carrington, Mary Ndung'u, Thumbi TI Lack of Duffy Antigen Receptor for Chemokines: No Influence on HIV Disease Progression in an African Treatment-Naive Population SO CELL HOST & MICROBE LA English DT Letter ID LOCUS C1 [Julg, Boris; Reddy, Shabashini; van der Stok, Mary; Walker, Bruce D.; Ndung'u, Thumbi] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. [Julg, Boris; Walker, Bruce D.] MIT & Harvard, Ragon Inst MGH, Boston, MA 02114 USA. [Nelson, George W.] NCI Frederick, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21702 USA. [Nalls, Michael A.] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Ndung'u, T (reprint author), Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. EM ndungu@ukzn.ac.za OI Ndung'u, Thumbi/0000-0003-2962-3992 FU Howard Hughes Medical Institute; NIAID NIH HHS [R01 AI067073, R01 AI067073-04] NR 6 TC 20 Z9 20 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAY 21 PY 2009 VL 5 IS 5 BP 413 EP 415 DI 10.1016/j.chom.2009.04.009 PG 3 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 450RZ UT WOS:000266419800004 PM 19454341 ER PT J AU Gupta, L Molina-Cruz, A Kumar, S Rodrigues, J Dixit, R Zamora, RE Barillas-Mury, C AF Gupta, Lalita Molina-Cruz, Alvaro Kumar, Sanjeev Rodrigues, Janneth Dixit, Rajnikant Zamora, Rodolfo E. Barillas-Mury, Carolina TI The STAT Pathway Mediates Late-Phase Immunity against Plasmodium in the Mosquito Anopheles gambiae SO CELL HOST & MICROBE LA English DT Article ID COMPLEMENT-LIKE PROTEIN; NITRIC-OXIDE; MALARIA PARASITES; AEDES-AEGYPTI; IN-VITRO; DROSOPHILA; BERGHEI; GENES; STEPHENSI; RESPONSES AB The STAT family of transcription factors activates expression of immune system genes in vertebrates. The ancestral STAT gene (AgSTAT-A) appears to have duplicated in the mosquito Anopheles gambiae, giving rise to a second intronless STAT gene (AgSTAT-B), which we show regulates AgSTAT-A expression in adult females. AgSTAT-A participates in the transcriptional activation of nitric oxide synthase (NOS) in response to bacterial and plasmodial infection. Activation of this pathway, however, is not essential for mosquitoes to survive a bacterial challenge. AgSTAT-A silencing reduces the number of early Plasmodium oocysts in the midgut, but nevertheless enhances the overall infection by increasing oocyst survival. Silencing of SOCS, a STAT suppressor, has the opposite effect, reducing Plasmodium infection by increasing NOS expression. Chemical inhibition of mosquito NOS activity after oocyte formation increases oocyte survival. Thus, the AgSTAT-A pathway mediates a late-phase antiplasmodial response that reduces oocyst survival in A. gambiae. C1 [Gupta, Lalita; Molina-Cruz, Alvaro; Kumar, Sanjeev; Rodrigues, Janneth; Dixit, Rajnikant; Zamora, Rodolfo E.; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, Natl Inst Hlth, Rockville, MD 20892 USA. RP Barillas-Mury, C (reprint author), NIAID, Lab Malaria & Vector Res, Natl Inst Hlth, Rockville, MD 20892 USA. EM cbarillas@niaid.nih.gov RI DIXIT, RAJNIKANT/D-2566-2009 OI DIXIT, RAJNIKANT/0000-0002-3536-8329 FU National Institutes of Health FX We thank Andre Laughinghouse, Kevin Lee, Tovi Lehman, and Robert Gwadz for insectary support and Juraj Kabat from the NIH Biological Imaging Section for his assistance with confocal imaging. We are also grateful to Jose Ribeiro and Jesus Valenzuela for their comments and insight. This research was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 36 TC 76 Z9 78 U1 2 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAY 21 PY 2009 VL 5 IS 5 BP 498 EP 507 DI 10.1016/j.chom.2009.04.003 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 450RZ UT WOS:000266419800016 PM 19454353 ER PT J AU Liu, J Cao, L Chen, JC Song, SW Lee, IH Quijano, C Liu, HJ Keyvanfar, K Chen, HQ Cao, LY Ahn, BH Kumar, NG Rovira, II Xu, XL van Lohuizen, M Motoyama, N Deng, CX Finkel, T AF Liu, Jie Cao, Liu Chen, Jichun Song, Shiwei Lee, In Hye Quijano, Celia Liu, Hongjun Keyvanfar, Keyvan Chen, Haoqian Cao, Long-Yue Ahn, Bong-Hyun Kumar, Neil G. Rovira, Ilsa I. Xu, Xiao-Ling van Lohuizen, Maarten Motoyama, Noboru Deng, Chu-Xia Finkel, Toren TI Bmi1 regulates mitochondrial function and the DNA damage response pathway SO NATURE LA English DT Article ID HEMATOPOIETIC STEM-CELLS; SELF-RENEWAL; BMI1-DEFICIENT MICE; CELLULAR SENESCENCE; OXIDATIVE STRESS; PROLIFERATION; REPAIR; P16(INK4A); CANCER; INK4A AB Mice deficient in the Polycomb repressor Bmi1 develop numerous abnormalities including a severe defect in stem cell self-renewal, alterations in thymocyte maturation and a shortened lifespan. Previous work has implicated de-repression of the Ink4a/Arf (also known as Cdkn2a) locus as mediating many of the aspects of the Bmi1(-/-) phenotype. Here we demonstrate that cells derived from Bmi1(-/-) mice also have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species and subsequent engagement of the DNA damage response pathway. Furthermore, many of the deficiencies normally observed in Bmi1(-/-) mice improve after either pharmacological treatment with the antioxidant N-acetylcysteine or genetic disruption of the DNA damage response pathway by Chk2 (also known as Chek2) deletion. These results demonstrate that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis and indicate that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function. C1 [Liu, Jie; Cao, Liu; Song, Shiwei; Lee, In Hye; Quijano, Celia; Liu, Hongjun; Chen, Haoqian; Cao, Long-Yue; Ahn, Bong-Hyun; Kumar, Neil G.; Rovira, Ilsa I.; Finkel, Toren] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Cao, Liu; Keyvanfar, Keyvan] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Kumar, Neil G.] NIH, Howard Hughes Med Inst, Res Scholar Program, Bethesda, MD 20892 USA. [Xu, Xiao-Ling; Deng, Chu-Xia] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [van Lohuizen, Maarten] Netherlands Canc Inst, Div Mol Genet, NL-1066 CX Amsterdam, Netherlands. [Motoyama, Noboru] Natl Ctr Geriatr & Gerontol, Natl Inst Longev Sci, Dept Geriatr Med, Aichi 4748522, Japan. RP Finkel, T (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Liu.Cao@nih.gov; finkelt@nih.gov RI deng, chuxia/N-6713-2016 FU Howard Hughes Medical Institute; Intramural NIH HHS [Z01 HL005012-11]; NIA NIH HHS [R00 AG032356] NR 38 TC 234 Z9 243 U1 3 U2 31 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 21 PY 2009 VL 459 IS 7245 BP 387 EP U100 DI 10.1038/nature08040 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 448DQ UT WOS:000266243700037 PM 19404261 ER PT J AU Dixon, BS Beck, GJ Vazquez, MA Greenberg, A Delmez, JA Allon, M Dember, LM Himmelfarb, J Gassman, JJ Greene, T Radeva, MK Davidson, IJ Ikizler, TA Braden, GL Fenves, AZ Kaufman, JS Cotton, JR Martin, KJ McNeil, JW Rahman, A Lawson, JH Whiting, JF Hu, B Meyers, CM Kusek, JW Feldman, HI AF Dixon, Bradley S. Beck, Gerald J. Vazquez, Miguel A. Greenberg, Arthur Delmez, James A. Allon, Michael Dember, Laura M. Himmelfarb, Jonathan Gassman, Jennifer J. Greene, Tom Radeva, Milena K. Davidson, Ingemar J. Ikizler, T. Alp Braden, Gregory L. Fenves, Andrew Z. Kaufman, James S. Cotton, James R., Jr. Martin, Kevin J. McNeil, James W. Rahman, Asif Lawson, Jeffery H. Whiting, James F. Hu, Bo Meyers, Catherine M. Kusek, John W. Feldman, Harold I. CA DAC Study Grp TI Effect of Dipyridamole plus Aspirin on Hemodialysis Graft Patency SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; MUSCLE CELL-PROLIFERATION; VASCULAR ACCESS SURVIVAL; UNITED-STATES; ARTERIOVENOUS GRAFTS; PRACTICE PATTERNS; FAILURE; PREVENTION; FISTULAS; OUTCOMES AB BACKGROUND Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity. METHODS We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates. RESULTS At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups. CONCLUSIONS Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.) C1 [Dixon, Bradley S.] Univ Iowa, Coll Med, Iowa City, IA 52242 USA. [Dixon, Bradley S.] Vet Affairs Med Ctr, Iowa City, IA 52242 USA. [Beck, Gerald J.; Gassman, Jennifer J.; Radeva, Milena K.; Hu, Bo] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Vazquez, Miguel A.; Davidson, Ingemar J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Fenves, Andrew Z.] Baylor Med Ctr, Dallas, TX USA. [Cotton, James R., Jr.] Tyler Nephrol Associates, Tyler, TX USA. [Greenberg, Arthur; Lawson, Jeffery H.] Duke Univ, Durham, NC USA. [Delmez, James A.] Washington Univ, St Louis, MO 63130 USA. [Martin, Kevin J.] St Louis Univ, St Louis, MO 63103 USA. [Allon, Michael] Univ Alabama, Birmingham, AL USA. [Dember, Laura M.] Boston Univ, Boston, MA 02215 USA. [Himmelfarb, Jonathan; Whiting, James F.] Maine Med Ctr, Portland, ME USA. [Greene, Tom] Univ Utah, Salt Lake City, UT USA. [Ikizler, T. Alp] Vanderbilt Univ, Nashville, TN USA. [Braden, Gregory L.] Baystate Med Ctr, Springfield, MA USA. [McNeil, James W.] Vasc Surg Associates, Baton Rouge, LA USA. [Rahman, Asif] Charleston Area Med Ctr, Charleston, WV USA. [Meyers, Catherine M.; Kusek, John W.] NIDDK, NIH, Bethesda, MD USA. [Feldman, Harold I.] Univ Penn, Philadelphia, PA 19104 USA. RP Dixon, BS (reprint author), Univ Iowa, Coll Med, E-300D GH,200 Hawkins Dr, Iowa City, IA 52242 USA. EM bradley-dixon@uiowa.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health [U01DK058981, U01DK058982, U01DK058973, U01DK058985, U01DK058978, U01DK058968, U01DK058986, U01DK058966]; Boehringer Ingelheim Pharmaceuticals FX Supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (under cooperative agreements U01DK058981, U01DK058982, U01DK058973, U01DK058985, U01DK058978, U01DK058968, U01DK058986, and U01DK058966) and Boehringer Ingelheim Pharmaceuticals, which also provided the extended- release dipyridamole plus aspirin and matched placebo. NR 35 TC 128 Z9 131 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 21 PY 2009 VL 360 IS 21 BP 2191 EP 2201 DI 10.1056/NEJMoa0805840 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 447QI UT WOS:000266206000006 PM 19458364 ER PT J AU Sacks, FM Bray, GA Loria, C AF Sacks, Frank M. Bray, George A. Loria, Catherine TI Comparison of Weight-Loss Diets REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID LOW-FAT DIET; LOW-CARBOHYDRATE; OBESITY C1 [Sacks, Frank M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bray, George A.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Loria, Catherine] NHLBI, Bethesda, MD 20892 USA. RP Sacks, FM (reprint author), Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. EM fsacks@hsph.harvard.edu NR 5 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 21 PY 2009 VL 360 IS 21 BP 2247 EP 2248 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 447QI UT WOS:000266206000017 ER PT J AU Allikmets, R Bergen, AA Dean, M Guymer, RH Hageman, GS Klaver, CC Stefansson, K Weber, BH AF Allikmets, Rando Bergen, Arthur A. Dean, Michael Guymer, Robyn H. Hageman, Gregory S. Klaver, Caroline C. Stefansson, Kari Weber, Bernhard H. CA Int Age Related Macular Degenerati TI Geographic Atrophy in Age-Related Macular Degeneration and TLR3 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Allikmets, Rando] Columbia Univ, New York, NY 10032 USA. [Bergen, Arthur A.] Netherlands Inst Neurosci, NL-1105 BA Amsterdam, Netherlands. [Dean, Michael] NCI, Frederick, MD 21702 USA. [Guymer, Robyn H.] Ctr Eye Res Australia, Melbourne, Vic 3002, Australia. [Hageman, Gregory S.] Univ Iowa, Iowa City, IA 52240 USA. [Klaver, Caroline C.] Erasmus MC, NL-3000 CA Rotterdam, Netherlands. [Stefansson, Kari] DeCODE Genet, IS-101 Reykjavik, Iceland. [Weber, Bernhard H.] Univ Regensburg, D-93053 Regensburg, Germany. RP Allikmets, R (reprint author), Columbia Univ, New York, NY 10032 USA. EM rla22@columbia.edu RI Dean, Michael/G-8172-2012; Klaver, Caroline/A-2013-2016 OI Dean, Michael/0000-0003-2234-0631; FU NEI NIH HHS [R24 EY017404] NR 1 TC 22 Z9 22 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 21 PY 2009 VL 360 IS 21 BP 2252 EP 2254 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 447QI UT WOS:000266206000026 PM 19469038 ER PT J AU Edwards, AO Swaroop, A Seddon, JM AF Edwards, Albert O. Swaroop, Anand Seddon, Johanna M. TI Geographic Atrophy in Age-Related Macular Degeneration and TLR3 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Edwards, Albert O.] Mayo Clin, Rochester, MN 55904 USA. [Swaroop, Anand] NEI, Bethesda, MD 20892 USA. [Seddon, Johanna M.] Tufts Med Ctr, Boston, MA 02111 USA. RP Edwards, AO (reprint author), Mayo Clin, Rochester, MN 55904 USA. EM edwardslab@mayo.edu OI Swaroop, Anand/0000-0002-1975-1141 NR 4 TC 14 Z9 14 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 21 PY 2009 VL 360 IS 21 BP 2254 EP 2255 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 447QI UT WOS:000266206000027 PM 19469037 ER PT J AU Rotunno, M Yu, K Lubin, JH Consonni, D Pesatori, AC Goldstein, AM Goldin, LR Wacholder, S Welch, R Burdette, L Chanock, SJ Bertazzi, PA Tucker, MA Caporaso, NE Chatterjee, N Bergen, AW Landi, MT AF Rotunno, Melissa Yu, Kai Lubin, Jay H. Consonni, Dario Pesatori, Angela C. Goldstein, Alisa M. Goldin, Lynn R. Wacholder, Sholom Welch, Robert Burdette, Laurie Chanock, Stephen J. Bertazzi, Pier Alberto Tucker, Margaret A. Caporaso, Neil E. Chatterjee, Nilanjan Bergen, Andrew W. Landi, Maria Teresa TI Phase I Metabolic Genes and Risk of Lung Cancer: Multiple Polymorphisms and mRNA Expression SO PLOS ONE LA English DT Article AB Polymorphisms in genes coding for enzymes that activate tobacco lung carcinogens may generate inter-individual differences in lung cancer risk. Previous studies had limited sample sizes, poor exposure characterization, and a few single nucleotide polymorphisms (SNPs) tested in candidate genes. We analyzed 25 SNPs (some previously untested) in 2101 primary lung cancer cases and 2120 population controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study from six phase I metabolic genes, including cytochrome P450s, microsomal epoxide hydrolase, and myeloperoxidase. We evaluated the main genotype effects and genotype-smoking interactions in lung cancer risk overall and in the major histology subtypes. We tested the combined effect of multiple SNPs on lung cancer risk and on gene expression. Findings were prioritized based on significance thresholds and consistency across different analyses, and accounted for multiple testing and prior knowledge. Two haplotypes in EPHX1 were significantly associated with lung cancer risk in the overall population. In addition, CYP1B1 and CYP2A6 polymorphisms were inversely associated with adenocarcinoma and squamous cell carcinoma risk, respectively. Moreover, the association between CYP1A1 rs2606345 genotype and lung cancer was significantly modified by intensity of cigarette smoking, suggesting an underling dose-response mechanism. Finally, increasing number of variants at CYP1A1/A2 genes revealed significant protection in never smokers and risk in ever smokers. Results were supported by differential gene expression in non-tumor lung tissue samples with down-regulation of CYP1A1 in never smokers and up-regulation in smokers from CYP1A1/A2 SNPs. The significant haplotype associations emphasize that the effect of multiple SNPs may be important despite null single SNP-associations, and warrants consideration in genome-wide association studies (GWAS). Our findings emphasize the necessity of post-GWAS fine mapping and SNP functional assessment to further elucidate cancer risk associations. RP Rotunno, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Tucker, Margaret/B-4297-2015; bertazzi, pietro alberto/D-5039-2017; OI bertazzi, pietro alberto/0000-0003-3475-2449; Bergen, Andrew/0000-0002-1237-7644; pesatori, angela/0000-0002-0261-3252 FU Intramural NIH HHS; NIDA NIH HHS [U01 DA020830] NR 61 TC 52 Z9 56 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 MAY 21 PY 2009 VL 4 IS 5 AR e5652 DI 10.1371/journal.pone.0005652 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 449LB UT WOS:000266331000011 PM 19479063 ER PT J AU Furchtgott, LA Chow, CC Periwal, V AF Furchtgott, Leon A. Chow, Carson C. Periwal, Vipul TI A Model of Liver Regeneration SO BIOPHYSICAL JOURNAL LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; TUMOR-NECROSIS-FACTOR; FLUID SHEAR-STRESS; PARTIAL-HEPATECTOMY; ENDOTHELIAL-CELLS; HUMORAL AGENT; RAT LIVER; HEPATOCYTES; EXPRESSION; PROLIFERATION AB The network of interactions underlying liver regeneration is robust and precise with liver resections resulting in controlled hyperplasia (cell proliferation) that terminates when the liver regains its lost mass. The interplay of cytokines and growth factors responsible for the inception and termination of this hyperplasia is not well understood. A model is developed for this network of interactions based on the known data of liver resections. This model reproduces the relevant published data on liver regeneration and provides geometric insights into the experimental observations. The predictions of this model are used to suggest two novel strategies for speeding up liver mass recovery and a strategy for enabling liver mass recovery in cases where a resection leaves <20% of the liver that would otherwise result in complete loss of liver mass. C1 [Chow, Carson C.; Periwal, Vipul] NIDDK, Lab Biol Modeling, Natl Inst Hlth, Bethesda, MD 20892 USA. [Furchtgott, Leon A.] Princeton Univ, Dept Phys, Princeton, NJ 08544 USA. RP Periwal, V (reprint author), NIDDK, Lab Biol Modeling, Natl Inst Hlth, Bethesda, MD 20892 USA. EM vipulp@mail.nih.gov RI Chow, Carson/A-7970-2009; Periwal, Vipul/I-1728-2012; OI Furchtgott, Leon/0000-0002-4258-0950 FU Intramural Research Program of the U.S. 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 U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 49 TC 21 Z9 21 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY 20 PY 2009 VL 96 IS 10 BP 3926 EP 3935 DI 10.1016/j.bpj.2009.01.061 PG 10 WC Biophysics SC Biophysics GA 449EF UT WOS:000266312900006 PM 19450465 ER PT J AU Chaudhry, C Weston, MC Schuck, P Rosenmund, C Mayer, ML AF Chaudhry, Charu Weston, Matthew C. Schuck, Peter Rosenmund, Christian Mayer, Mark L. TI Stability of ligand-binding domain dimer assembly controls kainate receptor desensitization SO EMBO JOURNAL LA English DT Article DE analytical ultracentrifugation; crystallography; desensitization; glutamate receptors; synaptic transmission ID IONOTROPIC GLUTAMATE-RECEPTOR; AMINO-ACID-RESIDUES; AMPA RECEPTOR; CRYSTAL-STRUCTURES; AGONIST-BINDING; POTASSIUM CHANNEL; POINT MUTATION; CONCANAVALIN-A; SUBUNIT GLUR6; MODULATION AB AMPA and kainate receptors mediate fast synaptic transmission. AMPA receptor ligand-binding domains form dimers, which are key functional units controlling ion-channel activation and desensitization. Dimer stability is inversely related to the rate and extent of desensitization. Kainate and AMPA receptors share common structural elements, but functional measurements suggest that subunit assembly and gating differs between these subtypes. To investigate this, we constructed a library of GluR6 kainate receptor mutants and directly measured changes in kainate receptor dimer stability by analytical ultracentrifugation, which, combined with electrophysiological experiments, revealed an inverse correlation between dimer stability and the rate of desensitization. We solved crystal structures for a series of five GluR6 mutants, to understand the molecular mechanisms for dimer stabilization. We demonstrate that the desensitized state of kainate receptors acts as a deep energy well offsetting the stabilizing effects of dimer interface mutants, and that the deactivation of kainate receptor responses is dominated by entry into desensitized states. Our results show how neurotransmitter receptors with similar structures and gating mechanisms can exhibit strikingly different functional properties. The EMBO Journal (2009) 28, 1518-1530. doi:10.1038/emboj.2009.86; Published online 2 April 2009 C1 [Chaudhry, Charu; Mayer, Mark L.] NICHD, Porter Neurosci Res Ctr, NIH, Lab Cellular & Mol Neurophysiol,DHHS, Bethesda, MD 20892 USA. [Weston, Matthew C.; Rosenmund, Christian] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. [Weston, Matthew C.; Rosenmund, Christian] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Schuck, Peter] NIBIB, Lab Bioengn & Phys Sci, NIH, DHHS, Bethesda, MD USA. RP Mayer, ML (reprint author), NICHD, Porter Neurosci Res Ctr, NIH, Lab Cellular & Mol Neurophysiol,DHHS, Bldg 35 Room 3B 1002,35 Lincoln Dr, Bethesda, MD 20892 USA. EM mlm@helix.nih.gov RI Mayer, Mark/H-5500-2013; OI Schuck, Peter/0000-0002-8859-6966; Rosenmund, Christian/0000-0002-3905-2444 FU NICHD; NIH; DHHS; NIBIB; Helen Hay Whitney Foundation; [RO1 NS 050655] FX We thank Carla Glasser for preparing cDNAs; Andrea Balbo for technical assistance with AUC experiments; the NINDS DNA sequencing facility; Drs S Heinemann and P Seeburg for the gift of wild-type cDNAs; and Dr Andrew Plested for discussion. Synchrotron diffraction data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source (APS), Argonne National Laboratory. Use of APS was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. This work was supported by the intramural research programs of NICHD, NIH, DHHS (MLM) and NIBIB, NIH, DHHS (PS); RO1 NS 050655 (CR); and the Helen Hay Whitney Foundation (CC). NR 48 TC 39 Z9 39 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 20 PY 2009 VL 28 IS 10 BP 1518 EP 1530 DI 10.1038/emboj.2009.86 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 448EV UT WOS:000266246800014 PM 19339989 ER PT J AU Anderson, SJ Wapnir, I Dignam, JJ Fisher, B Mamounas, EP Jeong, JH Geyer, CE Wickerham, DL Costantino, JP Wolmark, N AF Anderson, Stewart J. Wapnir, Irene Dignam, James J. Fisher, Bernard Mamounas, Eleftherios P. Jeong, Jong-Hyeon Geyer, Charles E., Jr. Wickerham, D. Lawrence Costantino, Joseph P. Wolmark, Norman TI Prognosis After Ipsilateral Breast Tumor Recurrence and Locoregional Recurrences in Patients Treated by Breast-Conserving Therapy in Five National Surgical Adjuvant Breast and Bowel Project Protocols of Node-Negative Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 41st Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 13-17, 2005 CL Orlando, FL SP Amer Soc Clin Oncol ID RANDOMIZED CLINICAL-TRIAL; COMPARING TOTAL MASTECTOMY; RECEPTOR-POSITIVE TUMORS; LOCAL RECURRENCE; CONSERVATIVE SURGERY; SEQUENTIAL METHOTREXATE; RADIATION-THERAPY; FOLLOW-UP; CHEMOTHERAPY; TAMOXIFEN AB Purpose Locoregional failure (LRF) after breast-conserving therapy (BCT) is associated with increased risk of distant disease and death. The magnitude of this risk has not been adequately characterized in patients with lymph node-negative disease. Patients and Methods Our study population included 3,799 women randomly assigned to five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative disease (ie, B-13, B-14, B-19, B-20, and B-23) who underwent lumpectomy and whole breast irradiation with or without adjuvant systemic therapy. Cumulative incidences of ipsilateral breast tumor recurrence (IBTR) and other locoregional recurrence (oLRR) were calculated, along with distant-disease-free interval (DDFI) and overall survival ( OS) after these events. Cox models were employed to model mortality by using clinical and pathologic factors jointly with these events. Results Four hundred nineteen patients (11.0%) experienced LRF: 342 (9.0%) experienced IBTR, and 77 (2.0%) experienced oLRR. The 12-year cumulative incidences of IBTR and oLRR in patients treated with adjuvant systemic therapy were 6.6% and 1.8%, respectively. Overall, 37.1% of IBTRs and 72.7% of oLRRs occurred within 5 years of diagnosis. Older age, black race, higher body mass index (BMI), larger tumors, and occurrence of IBTR or oLRR were significantly associated with increased mortality. The 5-year OS after IBTR and oLRR were 76.6% and 34.9%, respectively. Adjusted hazard ratios for mortality associated with IBTR and oLRR were significantly higher in estrogen receptor (ER)-negative patients than in ER-positive patients (P = .002 and P < .0001, respectively). Patients with early LRF had worse OS and DDFI than those with later-occurring LRF. Conclusion Although LRF is uncommon in patients with node-negative breast cancer who are treated with lumpectomy, radiation, and adjuvant systemic therapy, those who do develop LRF have substantially worse OS and DDFI. C1 [Anderson, Stewart J.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. Ctr Biostat, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15261 USA. Operat Ctr, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Stanford Univ, Sch Med, Dept Surg, Stanford, CA 94305 USA. Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. Univ Chicago, Canc Res Ctr, Chicago, IL 60637 USA. NE Ohio State Univ, Aultman Canc Ctr, Canton, OH USA. RP Anderson, SJ (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, 130 DeSoto St,302 Parran Hall, Pittsburgh, PA 15261 USA. EM sja@pitt.edu OI Anderson, Stewart/0000-0001-8948-0650; Jeong, Jong/0000-0003-0596-2201 FU NCI NIH HHS [U10-CA-69651, U10 CA012027, U10 CA037377, U10 CA069651, U10 CA069974, U10-CA-12027, U10-CA-37377, U10-CA-69974] NR 44 TC 172 Z9 175 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 BP 2466 EP 2473 DI 10.1200/JCO.2008.19.8424 PG 8 WC Oncology SC Oncology GA 447MO UT WOS:000266195400011 PM 19349544 ER PT J AU Dai, Q Gao, YT Shu, XO Yang, G Milne, G Cai, QY Wen, WQ Rothman, N Cai, H Li, HL Xiang, YB Chow, WH Zheng, W AF Dai, Qi Gao, Yu-Tang Shu, Xiao-Ou Yang, Gong Milne, Ginger Cai, Qiuyin Wen, Wanqing Rothman, Nathaniel Cai, Hui Li, Honglan Xiang, Yongbing Chow, Wong-Ho Zheng, Wei TI Oxidative Stress, Obesity, and Breast Cancer Risk: Results From the Shanghai Women's Health Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GAS CHROMATOGRAPHY/MASS SPECTROMETRY; LIPID-PEROXIDATION; OXIDANT STRESS; IN-VIVO; PHYSICAL-ACTIVITY; TGF-BETA; F-2-ISOPROSTANES; QUANTIFICATION; ISOPROSTANES; EXERCISE AB Purpose Increased reactive oxygen species may exhaust the antioxidant capability of human defense systems, leading to oxidative stress and cancer development. Urinary F2-isoprostanes, secondary end products of lipid peroxidation, are more accurate markers of oxidative stress than other available biomarkers. No prospective study has investigated whether levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP) and its metabolite 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (15-F(2t)-IsoPM) are related to breast cancer risk. Patients and Methods We conducted a nested case-control study within the Shanghai Women's Health Study, a population-based cohort study of 74,942 Chinese women between 40 and 70 years of age. Prediagnostic urinary 15-F(2t)-IsoP and 15-F(2t)-IsoPM were measured by gas chromatography mass spectrometry for 436 breast cancer cases and 852 individually matched controls. Results Urinary excretion of isoprostanes was not significantly different between cases and controls. However, among overweight women, levels of isoprostanes were positively associated with breast cancer risk, which became stronger with increasing body mass index (BMI). Among women with a BMI >= 29, the odds ratio (OR) increased to 10.27 (95% CI, 2.41 to 43.80) for the highest compared with the lowest tertile of 15-F(2t)-IsoPM (P for trend = .003; P for interaction = .0004). In contrast, 15-F(2t)-IsoP and 15-F(2t)-IsoPM were inversely associated with breast cancer risk among nonoverweight women. Among women with a BMI <= 23, breast cancer risk was reduced with increasing 15-F(2t)-IsoP levels in a dose-response manner (P for trend = .006), with an OR of 0.46 ( 95% CI, 0.26 to 0.80) for the highest tertile versus the lowest (P for interaction = .006). Conclusion Our results suggest that the role of oxidative stress in breast cancer development may depend on adiposity. C1 [Dai, Qi] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr, Dept Med,Inst Med & Publ Hlth,Sch Med, Nashville, TN 37203 USA. Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr, Dept Pharmacol,Sch Med, Nashville, TN 37203 USA. Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Dai, Q (reprint author), Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr, Dept Med,Inst Med & Publ Hlth,Sch Med, 2525 W End Ave,6th Floor,Suite 600, Nashville, TN 37203 USA. EM qi.dai@vanderbilt.edu RI Milne, Ginger/D-7648-2014 OI Milne, Ginger/0000-0003-3890-151X FU National Institutes of Health [R01CA106591, R01CA70867]; National Institutes of Health Intramural Program [N02 CP1101066] FX Supported by Grant No. R01CA106591 from the National Institutes of Health ( Q. D.) as well as Grants No. R01CA70867 from the National Institutes of Health ( W. Z.) and N02 CP1101066 from the National Institutes of Health Intramural Program ( X. O. S.) for the parent study. NR 56 TC 56 Z9 56 U1 1 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 BP 2482 EP 2488 DI 10.1200/JCO.2008.19.7970 PG 7 WC Oncology SC Oncology GA 447MO UT WOS:000266195400013 PM 19380446 ER PT J AU Albouy, B Billemont, B Massard, C Gross-Goupil, M Rixe, O Escudier, B AF Albouy, B. Billemont, B. Massard, C. Gross-Goupil, M. Rixe, O. Escudier, B. TI Pancreatic metastasis from renal cell carcinoma: Presentation, recurrence, survival, and response to antiangiogenic therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Inst Gustave Roussy, Villejuif, France. Hop Cochin, CERIA, F-75674 Paris, France. Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e16137 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606604176 PM 27963352 ER PT J AU Anderson, WF Pfeiffer, RM Tucker, MA Rosenberg, PS AF Anderson, W. F. Pfeiffer, R. M. Tucker, M. A. Rosenberg, P. S. TI Divergent cancer pathways for early-onset and late-onset cutaneous malignant melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 NCI, DHHS, NIH, DCEG, Darnestown, MD USA. Natl Canc Inst, Bethesda, MD USA. RI Pfeiffer, Ruth /F-4748-2011; Tucker, Margaret/B-4297-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 9079 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606606094 PM 27962183 ER PT J AU Azad, NS Henning, R Yu, M Davidson, B Figg, WD Calvo, K Venkatasen, A Annunziata, C Meltzer, P Kohn, E AF Azad, N. S. Henning, R. Yu, M. Davidson, B. Figg, W. D. Calvo, K. Venkatasen, A. Annunziata, C. Meltzer, P. Kohn, E. TI Translational proof of mechanism (PoM) for sorafenib with bevacizumab: Endpoint analysis and clinical activity SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Azad, N. S.; Henning, R.; Yu, M.; Davidson, B.; Figg, W. D.; Calvo, K.; Venkatasen, A.; Annunziata, C.; Meltzer, P.; Kohn, E.] NCI, Bethesda, MD 20892 USA. RI Annunziata, Christina/L-3219-2016; Figg Sr, William/M-2411-2016 OI Annunziata, Christina/0000-0003-2033-6532; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 3574 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602464 PM 27961719 ER PT J AU Berkowitz, JL Fernandez, A Dichmann, RA Kennedy, KA DiCarlo, B AF Berkowitz, J. L. Fernandez, A. Dichmann, R. A. Kennedy, K. A. DiCarlo, B. TI Clinical trials networks and enrollment of historically underrepresented populations in medical oncology trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Natl Canc Inst, Rockville, MD USA. Cent Coast Med Oncol, Santa Maria, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e20598 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606606351 PM 27961158 ER PT J AU Bible, KC Smallridge, RC Maples, WJ Molina, JR Menefee, ME Suman, VJ Burton, JK Bieber, CC Ivy, SP Erlichman, C AF Bible, K. C. Smallridge, R. C. Maples, W. J. Molina, J. R. Menefee, M. E. Suman, V. J. Burton, J. K. Bieber, C. C. Ivy, S. P. Erlichman, C. CA Endocrine Malignancies Dis Oriente TI Phase II trial of pazopanib in progressive, metastatic, iodine-insensitive differentiated thyroid cancers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Mayo Clin, Rochester, MN USA. Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 7 Z9 8 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 MAY 20 PY 2009 VL 27 IS 15 SU S MA 3521 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602411 PM 27961328 ER PT J AU Bishop, MR Kwak, LW Fowler, DH Giralt, S Steinberg, SM Bryant, K Neelapu, SS AF Bishop, M. R. Kwak, L. W. Fowler, D. H. Giralt, S. Steinberg, S. M. Bryant, K. Neelapu, S. S. TI Sibling donor immunization with patient-derived Id-KLH vaccine prior to reduced-intensity allogeneic hematopoietic cell transplantation for multiple myeloma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. MD Anderson Canc Ctr, Houston, TX USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 7024 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606605015 PM 27961397 ER PT J AU Bleyer, A Friedman, S Finnegan, S Montello, M Budd, T Anderson, B Trimble, EL AF Bleyer, A. Friedman, S. Finnegan, S. Montello, M. Budd, T. Anderson, B. Trimble, E. L. TI Association of adolescent and young adult cancer treatment trial activity with a national mortality reduction benefit in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 CureSearch Natl Childhood Canc Fdn, St Charles Med Ctr, Bend, OR USA. Natl Canc Inst, Bethesda, MD USA. Theradex, Princeton Jct, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 6605 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606604453 PM 27961733 ER PT J AU Bonanni, B Guerrieri-Gonzaga, A Radice, D Serrano, D Varricchio, C Ferretti, S Johansson, H Szabo, E Decensi, A Veronesi, G AF Bonanni, B. Guerrieri-Gonzaga, A. Radice, D. Serrano, D. Varricchio, C. Ferretti, S. Johansson, H. Szabo, E. Decensi, A. Veronesi, G. TI Randomized phase II trial of budesonide versus placebo in high-risk population with screening-detected lung nodules: Update on secondary endpoints SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Bonanni, B.; Guerrieri-Gonzaga, A.; Radice, D.; Serrano, D.; Varricchio, C.; Ferretti, S.; Johansson, H.; Szabo, E.; Decensi, A.; Veronesi, G.] European Inst Oncol, Milan, Italy. [Bonanni, B.; Guerrieri-Gonzaga, A.; Radice, D.; Serrano, D.; Varricchio, C.; Ferretti, S.; Johansson, H.; Szabo, E.; Decensi, A.; Veronesi, G.] NCI, NIH, Bethesda, MD 20892 USA. [Bonanni, B.; Guerrieri-Gonzaga, A.; Radice, D.; Serrano, D.; Varricchio, C.; Ferretti, S.; Johansson, H.; Szabo, E.; Decensi, A.; Veronesi, G.] EO Osped Galliera, Genoa, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 1518 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602113 PM 27964329 ER PT J AU Bottomley, A Coens, C King, M Osoba, D Taphoorn, MJ Reeve, B Ringash, J Schmucker-Von Koch, J Weis, J Quinten, C AF Bottomley, A. Coens, C. King, M. Osoba, D. Taphoorn, M. J. Reeve, B. Ringash, J. Schmucker-Von Koch, J. Weis, J. Quinten, C. TI Is patient self-reporting more accurate than clinician reporting of symptoms for predicting survival in patients with cancer? Meta-analysis of 30 closed EORTC randomized controlled trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 EORTC, Brussels, Belgium. Univ Sydney, Sydney, NSW 2006, Australia. Qual Life Consulting, W Vancouver, BC, Canada. VU Med Center, Amsterdam, Netherlands. Med Ctr Haaglanden, The Hague, Netherlands. NCI, NIH, Bethesda, MD 20892 USA. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Univ Regensburg, Regensburg, Germany. Univ Freiburg, Freiburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 9597,47 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606606215 PM 27963749 ER PT J AU Brown, AB Rudin, C Rizvi, N Travis, W Takebe, N James, LP Subzwari, S Tyson, L Markus, S Krug, LM AF Brown, A. B. Rudin, C. Rizvi, N. Travis, W. Takebe, N. James, L. P. Subzwari, S. Tyson, L. Markus, S. Krug, L. M. TI Phase I study of obatoclax mesylate (GX15-070MS), a bcl-2 antagonist, plus topotecan in relapsed small cell lung carcinoma and other solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Brown, A. B.; Rudin, C.; Rizvi, N.; Travis, W.; Takebe, N.; James, L. P.; Subzwari, S.; Tyson, L.; Markus, S.; Krug, L. M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Brown, A. B.; Rudin, C.; Rizvi, N.; Travis, W.; Takebe, N.; James, L. P.; Subzwari, S.; Tyson, L.; Markus, S.; Krug, L. M.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Brown, A. B.; Rudin, C.; Rizvi, N.; Travis, W.; Takebe, N.; James, L. P.; Subzwari, S.; Tyson, L.; Markus, S.; Krug, L. M.] Natl Canc Inst, Bethesda, MD USA. NR 0 TC 1 Z9 1 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 MAY 20 PY 2009 VL 27 IS 15 SU S MA 3504 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602394 PM 27961280 ER PT J AU Buetow, K AF Buetow, K. TI caBIG: Proof of concept platform for personalized cancer care SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Buetow, K.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e20712 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606606460 PM 27961970 ER PT J AU Cabell, C Bates, S Piekarz, R Whittaker, S Kim, Y Godfrey, C Schoonmaker, C McCulloch, W Nichols, J Burris, HA AF Cabell, C. Bates, S. Piekarz, R. Whittaker, S. Kim, Y. Godfrey, C. Schoonmaker, C. McCulloch, W. Nichols, J. Burris, H. A. TI Systematic assessment of potential cardiac effects of the novel histone deacetylase (HDAC) inhibitor romidepsin SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Cabell, C.; Bates, S.; Piekarz, R.; Whittaker, S.; Kim, Y.; Godfrey, C.; Schoonmaker, C.; McCulloch, W.; Nichols, J.; Burris, H. A.] Quintiles Transnatl Corp, Res Triangle Pk, NC USA. [Cabell, C.; Bates, S.; Piekarz, R.; Whittaker, S.; Kim, Y.; Godfrey, C.; Schoonmaker, C.; McCulloch, W.; Nichols, J.; Burris, H. A.] Natl Canc Inst, Bethesda, MD USA. [Cabell, C.; Bates, S.; Piekarz, R.; Whittaker, S.; Kim, Y.; Godfrey, C.; Schoonmaker, C.; McCulloch, W.; Nichols, J.; Burris, H. A.] Guys & St Thomas Hosp, London SE1 9RT, England. [Cabell, C.; Bates, S.; Piekarz, R.; Whittaker, S.; Kim, Y.; Godfrey, C.; Schoonmaker, C.; McCulloch, W.; Nichols, J.; Burris, H. A.] Stanford Canc Ctr, Stanford, CA USA. [Cabell, C.; Bates, S.; Piekarz, R.; Whittaker, S.; Kim, Y.; Godfrey, C.; Schoonmaker, C.; McCulloch, W.; Nichols, J.; Burris, H. A.] Anoixis Corp, Natick, MA USA. [Cabell, C.; Bates, S.; Piekarz, R.; Whittaker, S.; Kim, Y.; Godfrey, C.; Schoonmaker, C.; McCulloch, W.; Nichols, J.; Burris, H. A.] Veristat Inc, Holliston, MA USA. [Cabell, C.; Bates, S.; Piekarz, R.; Whittaker, S.; Kim, Y.; Godfrey, C.; Schoonmaker, C.; McCulloch, W.; Nichols, J.; Burris, H. A.] Gloucester Pharmaceut, Cambridge, MA USA. [Cabell, C.; Bates, S.; Piekarz, R.; Whittaker, S.; Kim, Y.; Godfrey, C.; Schoonmaker, C.; McCulloch, W.; Nichols, J.; Burris, H. A.] Sarah Cannon Res Inst, Nashville, TN USA. NR 0 TC 1 Z9 1 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 MAY 20 PY 2009 VL 27 IS 15 SU S MA e19533 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606605545 PM 27961029 ER PT J AU Cappuzzo, F Ciuleanu, T Stelmakh, L Cicenas, S Szczesna, A Juhasz, E Gonzalez, EE Molinier, O Klingelschmitt, G Giaccone, G AF Cappuzzo, F. Ciuleanu, T. Stelmakh, L. Cicenas, S. Szczesna, A. Juhasz, E. Gonzalez, E. Esteban Molinier, O. Klingelschmitt, G. Giaccone, G. CA SATURN Investigators TI SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 IRCCS, Ist Clin Humanitas, Rozzano, Italy. Inst Oncol Ion Chiricuta, Cluj Napoca, Romania. Pavlov State Med Univ, St Petersburg, Russia. Vilnius Univ, Inst Oncol, Vilnius, Lithuania. Mazowieckie Ctr Leczenia Chorob Pluc Gruzlic, Otwock, Poland. Koranyi Natl Inst Pulmonol, Budapest, Hungary. Hosp Univ Cent Asturias, Oviedo, Spain. Ctr Hosp Le Mans, Le Mans, France. F Hoffmann La Roche, Basel, Switzerland. NCI, NIH, CCR, Bethesda, MD 20892 USA. RI Ciuleanu, Tudor Eliade/C-3996-2011 NR 0 TC 14 Z9 21 U1 2 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 8001 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606605206 PM 27962767 ER PT J AU Chang, SM Kuhn, J Lamborn, K Cloughesy, T Robins, I Lieberman, F Yung, A Dancey, J Prados, M Wen, P AF Chang, S. M. Kuhn, J. Lamborn, K. Cloughesy, T. Robins, I. Lieberman, F. Yung, A. Dancey, J. Prados, M. Wen, P. TI Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas (MG) (NABTC 04-02) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Chang, S. M.; Kuhn, J.; Lamborn, K.; Cloughesy, T.; Robins, I.; Lieberman, F.; Yung, A.; Dancey, J.; Prados, M.; Wen, P.] UCSF, Neuro Onc Svc, San Francisco, CA USA. [Chang, S. M.; Kuhn, J.; Lamborn, K.; Cloughesy, T.; Robins, I.; Lieberman, F.; Yung, A.; Dancey, J.; Prados, M.; Wen, P.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Chang, S. M.; Kuhn, J.; Lamborn, K.; Cloughesy, T.; Robins, I.; Lieberman, F.; Yung, A.; Dancey, J.; Prados, M.; Wen, P.] Univ Calif Los Angeles, Los Angeles, CA USA. [Chang, S. M.; Kuhn, J.; Lamborn, K.; Cloughesy, T.; Robins, I.; Lieberman, F.; Yung, A.; Dancey, J.; Prados, M.; Wen, P.] Univ Wisconsin, Madison, WI USA. [Chang, S. M.; Kuhn, J.; Lamborn, K.; Cloughesy, T.; Robins, I.; Lieberman, F.; Yung, A.; Dancey, J.; Prados, M.; Wen, P.] Univ Pittsburgh, Pittsburgh, PA USA. [Chang, S. M.; Kuhn, J.; Lamborn, K.; Cloughesy, T.; Robins, I.; Lieberman, F.; Yung, A.; Dancey, J.; Prados, M.; Wen, P.] MD Anderson Canc Ctr, Houston, TX USA. [Chang, S. M.; Kuhn, J.; Lamborn, K.; Cloughesy, T.; Robins, I.; Lieberman, F.; Yung, A.; Dancey, J.; Prados, M.; Wen, P.] NCI, Bethesda, MD 20892 USA. [Chang, S. M.; Kuhn, J.; Lamborn, K.; Cloughesy, T.; Robins, I.; Lieberman, F.; Yung, A.; Dancey, J.; Prados, M.; Wen, P.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 4 Z9 4 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 MAY 20 PY 2009 VL 27 IS 15 SU S MA 2004 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602152 PM 27964561 ER PT J AU Cheng, S Dietrich, M Finnigan, S Sandler, A Crites, J Ferranti, L Wu, A Dilts, D AF Cheng, S. Dietrich, M. Finnigan, S. Sandler, A. Crites, J. Ferranti, L. Wu, A. Dilts, D. TI A sense of urgency: Evaluating the link between clinical trial development time and the accrual performance of CTEP-sponsored studies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Cheng, S.; Dietrich, M.; Finnigan, S.; Sandler, A.; Crites, J.; Ferranti, L.; Wu, A.; Dilts, D.] Vanderbilt Univ, Nashville, TN USA. [Cheng, S.; Dietrich, M.; Finnigan, S.; Sandler, A.; Crites, J.; Ferranti, L.; Wu, A.; Dilts, D.] NCI, Bethesda, MD 20892 USA. [Cheng, S.; Dietrich, M.; Finnigan, S.; Sandler, A.; Crites, J.; Ferranti, L.; Wu, A.; Dilts, D.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA CRA6509 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606604358 PM 27960770 ER PT J AU Chi, AS Gerstner, ER Eichler, AF Chea, HK Drappatz, J Wen, PY Ivy, SP Loeffler, JS Sorensen, AG Jain, RK Batchelor, TT AF Chi, A. S. Gerstner, E. R. Eichler, A. F. Chea, H. K. Drappatz, J. Wen, P. Y. Ivy, S. P. Loeffler, J. S. Sorensen, A. G. Jain, R. K. Batchelor, T. T. TI Phase Ib study of cediranib in combination with daily temozolomide and radiation in patients with newly diagnosed glioblastoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Chi, A. S.; Gerstner, E. R.; Eichler, A. F.; Chea, H. K.; Drappatz, J.; Wen, P. Y.; Ivy, S. P.; Loeffler, J. S.; Sorensen, A. G.; Jain, R. K.; Batchelor, T. T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Chi, A. S.; Gerstner, E. R.; Eichler, A. F.; Chea, H. K.; Drappatz, J.; Wen, P. Y.; Ivy, S. P.; Loeffler, J. S.; Sorensen, A. G.; Jain, R. K.; Batchelor, T. T.] BWH Canc Ctr, Dana Farber Canc Inst, Boston, MA USA. [Chi, A. S.; Gerstner, E. R.; Eichler, A. F.; Chea, H. K.; Drappatz, J.; Wen, P. Y.; Ivy, S. P.; Loeffler, J. S.; Sorensen, A. G.; Jain, R. K.; Batchelor, T. T.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e13010 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602239 PM 27962847 ER PT J AU Costello, MR Meropol, NJ Denlinger, CS Engstrom, PF Wright, JJ Li, T Mclaughlin, S Beard, M Cimildoro, R Cohen, SJ AF Costello, M. R. Meropol, N. J. Denlinger, C. S. Engstrom, P. F. Wright, J. J. Li, T. Mclaughlin, S. Beard, M. Cimildoro, R. Cohen, S. J. TI A phase II trial of the proteasome inhibitor bortezomib in patients with recurrent or metastatic adenocarcinoma of the bile duct or gallbladder (NCI #6135) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. NIH, CTEP, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e15605 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606603323 PM 27962683 ER PT J AU Croswell, JM Baker, SG Marcus, PM Clapp, JD Kramer, BS AF Croswell, J. M. Baker, S. G. Marcus, P. M. Clapp, J. D. Kramer, B. S. TI Cumulative risk for a false-positive test using low-dose computed tomography in lung cancer screening SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Croswell, J. M.; Baker, S. G.; Marcus, P. M.; Clapp, J. D.; Kramer, B. S.] Natl Inst Hlth, Bethesda, MD USA. [Croswell, J. M.; Baker, S. G.; Marcus, P. M.; Clapp, J. D.; Kramer, B. S.] Natl Canc Inst, Bethesda, MD USA. [Croswell, J. M.; Baker, S. G.; Marcus, P. M.; Clapp, J. D.; Kramer, B. S.] IMS Inc, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA CRA1502 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606602099 PM 27962438 ER PT J AU Davis, DW Liu, W Kurzrock, R Naing, A Wheler, J Ricks, LW Ivy, S Hong, D AF Davis, D. W. Liu, W. Kurzrock, R. Naing, A. Wheler, J. Ricks, L. W. Ivy, S. Hong, D. TI Circulating tumor and endothelial cells as pharmacodynamic biomarkers in a phase I clinical trial of intravenous bevacizumab in combination with escalating doses of oral cediranib for patients with advanced malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 ApoCell Inc, Houston, TX USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NCI, DCTD, CTEP, IDB, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 3525 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602415 PM 27961324 ER PT J AU Demierre, M Whittaker, S Kim, Y Kim, E Piekarz, R Prince, M Nichols, J Balser, J Prentice, A Bates, S AF Demierre, M. Whittaker, S. Kim, Y. Kim, E. Piekarz, R. Prince, M. Nichols, J. Balser, J. Prentice, A. Bates, S. TI Pooled analyses of two international, multicenter clinical studies of romidepsin in 167 patients with cutaneous T-cell lymphoma (CTCL) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Demierre, M.; Whittaker, S.; Kim, Y.; Kim, E.; Piekarz, R.; Prince, M.; Nichols, J.; Balser, J.; Prentice, A.; Bates, S.] Boston Med Ctr, Boston SE1 9RT, MA USA. [Demierre, M.; Whittaker, S.; Kim, Y.; Kim, E.; Piekarz, R.; Prince, M.; Nichols, J.; Balser, J.; Prentice, A.; Bates, S.] Guys & St Thomas Hosp, London, England. [Demierre, M.; Whittaker, S.; Kim, Y.; Kim, E.; Piekarz, R.; Prince, M.; Nichols, J.; Balser, J.; Prentice, A.; Bates, S.] Stanford Canc Ctr, Stanford, CA USA. [Demierre, M.; Whittaker, S.; Kim, Y.; Kim, E.; Piekarz, R.; Prince, M.; Nichols, J.; Balser, J.; Prentice, A.; Bates, S.] Univ Penn Hlth Syst, Philadelphia, PA 20892 USA. [Demierre, M.; Whittaker, S.; Kim, Y.; Kim, E.; Piekarz, R.; Prince, M.; Nichols, J.; Balser, J.; Prentice, A.; Bates, S.] NCI, Bethesda, MD USA. [Demierre, M.; Whittaker, S.; Kim, Y.; Kim, E.; Piekarz, R.; Prince, M.; Nichols, J.; Balser, J.; Prentice, A.; Bates, S.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Demierre, M.; Whittaker, S.; Kim, Y.; Kim, E.; Piekarz, R.; Prince, M.; Nichols, J.; Balser, J.; Prentice, A.; Bates, S.] Gloucester Pharmaceut, Cambridge, MA USA. [Demierre, M.; Whittaker, S.; Kim, Y.; Kim, E.; Piekarz, R.; Prince, M.; Nichols, J.; Balser, J.; Prentice, A.; Bates, S.] Veristat Inc, Holliston NW3 2QG, PA USA. [Demierre, M.; Whittaker, S.; Kim, Y.; Kim, E.; Piekarz, R.; Prince, M.; Nichols, J.; Balser, J.; Prentice, A.; Bates, S.] Royal Free Hosp, London, England. NR 0 TC 2 Z9 2 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 MAY 20 PY 2009 VL 27 IS 15 SU S MA 8546 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606605455 PM 27960961 ER PT J AU Dennis, PA Blumenthal, G Ballas, M Gardner, E Kawabata, S LoPiccolo, J Helsabeck, C Root, H Figg, WD Bernstein, W AF Dennis, P. A. Blumenthal, G. Ballas, M. Gardner, E. Kawabata, S. LoPiccolo, J. Helsabeck, C. Root, H. Figg, W. D. Bernstein, W. TI A phase I study of nelfinavir, an FDA approved HIV protease inhibitor, in adults with refractory solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Dennis, P. A.; Blumenthal, G.; Ballas, M.; Gardner, E.; Kawabata, S.; LoPiccolo, J.; Helsabeck, C.; Root, H.; Figg, W. D.; Bernstein, W.] NCI, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 2583 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602349 PM 27961900 ER PT J AU Fakih, MG Pendyala, L Egorin, MJ Fetterly, G Espinoza-Delgado, I Ross, M Phelan, J Kramer, Z Yirinec, B Diasio, R AF Fakih, M. G. Pendyala, L. Egorin, M. J. Fetterly, G. Espinoza-Delgado, I. Ross, M. Phelan, J. Kramer, Z. Yirinec, B. Diasio, R. TI A phase I clinical trial of vorinostat in combination with sFULV2 in patients with refractory solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Fakih, M. G.; Pendyala, L.; Egorin, M. J.; Fetterly, G.; Espinoza-Delgado, I.; Ross, M.; Phelan, J.; Kramer, Z.; Yirinec, B.; Diasio, R.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Fakih, M. G.; Pendyala, L.; Egorin, M. J.; Fetterly, G.; Espinoza-Delgado, I.; Ross, M.; Phelan, J.; Kramer, Z.; Yirinec, B.; Diasio, R.] Univ Pittsburgh, Pittsburgh, PA USA. [Fakih, M. G.; Pendyala, L.; Egorin, M. J.; Fetterly, G.; Espinoza-Delgado, I.; Ross, M.; Phelan, J.; Kramer, Z.; Yirinec, B.; Diasio, R.] NCI, Bethesda, MD 20892 USA. [Fakih, M. G.; Pendyala, L.; Egorin, M. J.; Fetterly, G.; Espinoza-Delgado, I.; Ross, M.; Phelan, J.; Kramer, Z.; Yirinec, B.; Diasio, R.] Rochester Gen Hosp, Rochester, NY 14621 USA. [Fakih, M. G.; Pendyala, L.; Egorin, M. J.; Fetterly, G.; Espinoza-Delgado, I.; Ross, M.; Phelan, J.; Kramer, Z.; Yirinec, B.; Diasio, R.] Pluta Canc Ctr, Rochester, NY USA. [Fakih, M. G.; Pendyala, L.; Egorin, M. J.; Fetterly, G.; Espinoza-Delgado, I.; Ross, M.; Phelan, J.; Kramer, Z.; Yirinec, B.; Diasio, R.] Mayo Clin, Rochester, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 4083 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606601025 PM 27961640 ER PT J AU Fox, E Widemann, BC Whitcomb, PO Aikin, A Dombi, E Lodish, M Stratakis, CA Steinberg, S Wells, SA Balis, FM AF Fox, E. Widemann, B. C. Whitcomb, P. O. Aikin, A. Dombi, E. Lodish, M. Stratakis, C. A. Steinberg, S. Wells, S. A., Jr. Balis, F. M. TI Phase I/II trial of vandetanib in children and adolescents with hereditary medullary thyroid carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. NICHD, Bethesda, MD USA. Washington Univ, Sch Med, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 10014 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606606512 ER PT J AU Freedman, AN Slattery, ML Ballard-Barbash, R Willis, G Cann, BJ Pee, D Gail, MH Pfeiffer, RM AF Freedman, A. N. Slattery, M. L. Ballard-Barbash, R. Willis, G. Cann, B. J. Pee, D. Gail, M. H. Pfeiffer, R. M. TI Colorectal cancer risk prediction tool for men and women without known susceptibility SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Freedman, A. N.; Slattery, M. L.; Ballard-Barbash, R.; Willis, G.; Cann, B. J.; Pee, D.; Gail, M. H.; Pfeiffer, R. M.] NCI, Rockville, MD USA. [Freedman, A. N.; Slattery, M. L.; Ballard-Barbash, R.; Willis, G.; Cann, B. J.; Pee, D.; Gail, M. H.; Pfeiffer, R. M.] Univ Utah, Salt Lake City, UT USA. [Freedman, A. N.; Slattery, M. L.; Ballard-Barbash, R.; Willis, G.; Cann, B. J.; Pee, D.; Gail, M. H.; Pfeiffer, R. M.] NCI, Bethesda, MD 20892 USA. [Freedman, A. N.; Slattery, M. L.; Ballard-Barbash, R.; Willis, G.; Cann, B. J.; Pee, D.; Gail, M. H.; Pfeiffer, R. M.] Kaiser Permanente Med Grp, Oakland, CA USA. [Freedman, A. N.; Slattery, M. L.; Ballard-Barbash, R.; Willis, G.; Cann, B. J.; Pee, D.; Gail, M. H.; Pfeiffer, R. M.] IMS, Silver Spring, MD USA. RI Pfeiffer, Ruth /F-4748-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e15002 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606601076 PM 27964384 ER PT J AU Gerber, NL Diao, G Stout, N Soballe, P McGarvey, C Pfalzer, L Springer, B Shieh, C AF Gerber, N. L. Diao, G. Stout, N. Soballe, P. McGarvey, C. Pfalzer, L. Springer, B. Shieh, C. TI Correlates of clinically significant fatigue in women with newly diagnosed breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 George Mason Univ, Fairfax, VA 22030 USA. Natl Naval Med Ctr, Bethesda, MD USA. Univ Michigan, Flint, MI 48503 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. Natl Inst Hlth, Bethesda, MD USA. RI Diao, Guoqing/B-9513-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e20517 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606606274 PM 27960913 ER PT J AU Giaccone, G Rajan, A Carter, C Kelly, R Berman, A Spittler, J Espinoza-Delgado, I Lee, M Trepel, J Loehrer, P AF Giaccone, G. Rajan, A. Carter, C. Kelly, R. Berman, A. Spittler, J. Espinoza-Delgado, I. Lee, M. Trepel, J. Loehrer, P. TI Phase II study of the histone deacetylase inhibitor belinostat in thymic malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Natl Canc Inst, Bethesda, MD USA. Indiana Univ, Med Ctr, Indianapolis, IN 46204 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 7589 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606605190 PM 27963413 ER PT J AU Gibson, MK Kies, M Kim, S Savvides, P Kotsakis, A Blumenschein, G Worden, F Chen, H Grandis, J Argiris, A AF Gibson, M. K. Kies, M. Kim, S. Savvides, P. Kotsakis, A. Blumenschein, G. Worden, F. Chen, H. Grandis, J. Argiris, A. TI Cetuximab (C) and bevacizumab (B) in patients with recurrent or metastatic head and neck squamous cell carcinoma: An updated report SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Univ Pittsburgh, Pittsburgh, PA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Case Western Univ, Cleveland, OH USA. Univ Michigan, Ann Arbor, MI 48109 USA. Natl Canc Inst, CTEP, Bethesda, MD USA. RI Kotsakis, Athanasios/Q-4600-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 6049 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606604255 ER PT J AU Grimley, PM Matsuno, R Anderson, WF AF Grimley, P. M. Matsuno, R. Anderson, W. F. TI Population profiles of extra-ovarian and ovarian serous adenocarcinomas: Comparisons with grade stratification SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Grimley, P. M.; Matsuno, R.; Anderson, W. F.] F Edward Herbert Sch Med, Bethesda, MD USA. [Grimley, P. M.; Matsuno, R.; Anderson, W. F.] Natl Canc Inst, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e16506 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606600103 PM 27960765 ER PT J AU Grossi, F Belvedere, O Defferrari, C Brianti, A Follador, A Rijavec, E Ceschia, T Pronzato, P Fasola, G Aita, M AF Grossi, F. Belvedere, O. Defferrari, C. Brianti, A. Follador, A. Rijavec, E. Ceschia, T. Pronzato, P. Fasola, G. Aita, M. TI Optimal duration of chemotherapy (CT) for advanced non-small cell lung cancer (NSCLC) in the first- and second-line settings SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Grossi, F.; Belvedere, O.; Defferrari, C.; Brianti, A.; Follador, A.; Rijavec, E.; Ceschia, T.; Pronzato, P.; Fasola, G.; Aita, M.] Natl Canc Inst, Genoa, Italy. [Grossi, F.; Belvedere, O.; Defferrari, C.; Brianti, A.; Follador, A.; Rijavec, E.; Ceschia, T.; Pronzato, P.; Fasola, G.; Aita, M.] Inst Mol Med, Leeds, W Yorkshire, England. [Grossi, F.; Belvedere, O.; Defferrari, C.; Brianti, A.; Follador, A.; Rijavec, E.; Ceschia, T.; Pronzato, P.; Fasola, G.; Aita, M.] Univ Hosp Udine, Udine, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e19037 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606605345 PM 27962120 ER PT J AU Grubbs, SS Gonzalez, M Krasna, M Siegel, R Bryant, D Tschetter, L Hayenga, L Duggan, B St Germaine, D Denicoff, A AF Grubbs, S. S. Gonzalez, M. Krasna, M. Siegel, R. Bryant, D. Tschetter, L. Hayenga, L. Duggan, B. St. Germaine, D. Denicoff, A. TI Tracking clinical trial accrual strategies and barriers via a Web-based screening tool SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Helen F Graham Canc Ctr, Newark, DE USA. St Joseph Hosp, Orange, CA USA. St Joseph Med Ctr, Towson, MD USA. Hartford Hosp, Hartford, CT 06115 USA. Our Lady Lake Reg Med Ctr, Baton Rouge, LA USA. Sanford USD Med Ctr, Sioux Falls, SD USA. St Vincent Indianapolis Hosp, Indianapolis, IN USA. CBIIT, NCI, Commun Informat Programs, Rockville, MD USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, CTEP, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 6586 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606604434 PM 27963861 ER PT J AU Gutierrez, M Murgo, AJ Allen, D Turkbey, I Gardner, ER Trepel, J Chen, H Giaccone, G Doroshow, JH Kummar, S AF Gutierrez, M. Murgo, A. J. Allen, D. Turkbey, I. Gardner, E. R. Trepel, J. Chen, H. Giaccone, G. Doroshow, J. H. Kummar, S. TI Phase I study of vandetanib (V) and bevacizumab (B) combination therapy evaluating the VEGF and EGF signal transduction pathways in adults with solid tumors and NHL SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Gutierrez, M.; Murgo, A. J.; Allen, D.; Turkbey, I.; Gardner, E. R.; Trepel, J.; Chen, H.; Giaccone, G.; Doroshow, J. H.; Kummar, S.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 3522 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602412 PM 27961325 ER PT J AU Harford, J AF Harford, J. TI The UICC Cervical Cancer Initiative: A comprehensive program for cervical cancer prevention worldwide including a fellowship program SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Harford, J.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 1547 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602142 PM 27964072 ER PT J AU Jamshed, S Fowler, D Neelapu, S Dean, RM Steinberg, SM Snow, K Odom, J Gress, RE Bishop, M AF Jamshed, S. Fowler, D. Neelapu, S. Dean, R. M. Steinberg, S. M. Snow, K. Odom, J. Gress, R. E. Bishop, M. TI EPOCH-F: A salvage regimen for multiple myeloma prior to reduced intensity allogenic hematopoietic stem cell transplantation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Jamshed, S.; Fowler, D.; Neelapu, S.; Dean, R. M.; Steinberg, S. M.; Snow, K.; Odom, J.; Gress, R. E.; Bishop, M.] Georgetown Univ, Washington, DC USA. [Jamshed, S.; Fowler, D.; Neelapu, S.; Dean, R. M.; Steinberg, S. M.; Snow, K.; Odom, J.; Gress, R. E.; Bishop, M.] Natl Canc Inst, Bethesda, MD USA. [Jamshed, S.; Fowler, D.; Neelapu, S.; Dean, R. M.; Steinberg, S. M.; Snow, K.; Odom, J.; Gress, R. E.; Bishop, M.] MD Anderson Canc Ctr, Houston, TX USA. [Jamshed, S.; Fowler, D.; Neelapu, S.; Dean, R. M.; Steinberg, S. M.; Snow, K.; Odom, J.; Gress, R. E.; Bishop, M.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Jamshed, S.; Fowler, D.; Neelapu, S.; Dean, R. M.; Steinberg, S. M.; Snow, K.; Odom, J.; Gress, R. E.; Bishop, M.] Natl Canc Inst, NIH, Bethesda, MD USA. [Jamshed, S.; Fowler, D.; Neelapu, S.; Dean, R. M.; Steinberg, S. M.; Snow, K.; Odom, J.; Gress, R. E.; Bishop, M.] Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 8592 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606605500 PM 27962289 ER PT J AU Janne, PA Reckamp, K Koczywas, M Engelman, JA Camidge, DR Rajan, A Khuri, F Liang, JQ O'Connell, J Giaccone, G AF Janne, P. A. Reckamp, K. Koczywas, M. Engelman, J. A. Camidge, D. R. Rajan, A. Khuri, F. Liang, J. Q. O'Connell, J. Giaccone, G. TI Efficacy and safety of PF-00299804 (PF299) in patients (pt) with advanced NSCLC after failure of at least one prior chemotherapy regimen and prior treatment with erlotinib (E): A two-arm, phase II trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Janne, P. A.; Reckamp, K.; Koczywas, M.; Engelman, J. A.; Camidge, D. R.; Rajan, A.; Khuri, F.; Liang, J. Q.; O'Connell, J.; Giaccone, G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Janne, P. A.; Reckamp, K.; Koczywas, M.; Engelman, J. A.; Camidge, D. R.; Rajan, A.; Khuri, F.; Liang, J. Q.; O'Connell, J.; Giaccone, G.] City Hope Natl Med Ctr, Duarte, CA USA. [Janne, P. A.; Reckamp, K.; Koczywas, M.; Engelman, J. A.; Camidge, D. R.; Rajan, A.; Khuri, F.; Liang, J. Q.; O'Connell, J.; Giaccone, G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Janne, P. A.; Reckamp, K.; Koczywas, M.; Engelman, J. A.; Camidge, D. R.; Rajan, A.; Khuri, F.; Liang, J. Q.; O'Connell, J.; Giaccone, G.] Univ Colorado, Denver, CO 80202 USA. [Janne, P. A.; Reckamp, K.; Koczywas, M.; Engelman, J. A.; Camidge, D. R.; Rajan, A.; Khuri, F.; Liang, J. Q.; O'Connell, J.; Giaccone, G.] Natl Canc Inst, Bethesda, MD USA. [Janne, P. A.; Reckamp, K.; Koczywas, M.; Engelman, J. A.; Camidge, D. R.; Rajan, A.; Khuri, F.; Liang, J. Q.; O'Connell, J.; Giaccone, G.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Janne, P. A.; Reckamp, K.; Koczywas, M.; Engelman, J. A.; Camidge, D. R.; Rajan, A.; Khuri, F.; Liang, J. Q.; O'Connell, J.; Giaccone, G.] Pfizer Oncol, New London, CT USA. NR 0 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 8063 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606605265 PM 27962636 ER PT J AU Jessup, JM Dobbin, K Hamilton, S Thibodeau, S Redston, M Taube, S Wang, Z Benedetti, J AF Jessup, J. M. Dobbin, K. Hamilton, S. Thibodeau, S. Redston, M. Taube, S. Wang, Z. Benedetti, J. CA Program Assessment Clin Canc Test TI Interlaboratory assay reproducibility study for loss of heterozygosity on chromosome 18 (18q LOH) in colon cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Jessup, J. M.; Dobbin, K.; Hamilton, S.; Thibodeau, S.; Redston, M.; Taube, S.; Wang, Z.; Benedetti, J.] NCI, Rockville, MD USA. [Jessup, J. M.; Dobbin, K.; Hamilton, S.; Thibodeau, S.; Redston, M.; Taube, S.; Wang, Z.; Benedetti, J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Jessup, J. M.; Dobbin, K.; Hamilton, S.; Thibodeau, S.; Redston, M.; Taube, S.; Wang, Z.; Benedetti, J.] Mayo Clin, Rochester, MN USA. [Jessup, J. M.; Dobbin, K.; Hamilton, S.; Thibodeau, S.; Redston, M.; Taube, S.; Wang, Z.; Benedetti, J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Jessup, J. M.; Dobbin, K.; Hamilton, S.; Thibodeau, S.; Redston, M.; Taube, S.; Wang, Z.; Benedetti, J.] IMS, Silver Spring, MD USA. [Jessup, J. M.; Dobbin, K.; Hamilton, S.; Thibodeau, S.; Redston, M.; Taube, S.; Wang, Z.; Benedetti, J.; Program Assessment Clin Canc Test] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 4052 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606600292 PM 27961569 ER PT J AU Joseph, RW Prieto, VG Papadopolus, N Papadopolus, N Bedikian, A Colevas, AD Kim, K AF Joseph, R. W., Jr. Prieto, V. G. Papadopolus, N. Papadopolus, N. Bedikian, A. Colevas, A. D. Kim, K. TI In vivo molecular changes in patients (pts) with metastatic melanoma treated with EMD121974 (selective antagonist of av beta 3 integrin) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 MD Anderson Canc Ctr, Houston, TX USA. Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 9058 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606606073 PM 27962156 ER PT J AU Kadia, TM Faderl, S Estrov, Z Konopleva, M George, S Lee, W Puzanov, I Chen, A Kantarjian, H Ravandi, F AF Kadia, T. M. Faderl, S. Estrov, Z. Konopleva, M. George, S. Lee, W. Puzanov, I. Chen, A. Kantarjian, H. Ravandi, F. TI Final results of phase I and pharmacokinetic study of SJG-136 administered on a daily x 5 schedule SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Kentucky, Lexington, KY USA. Vanderbilt Univ, Nashville, TN USA. NCI, Canc Therapy Evaluat Program, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e13506 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606602355 PM 27961262 ER PT J AU Kantoff, PW Schuetz, T Blumenstein, BA Glode, MM Bilhartz, D Gulley, J Schlom, J Laus, R Godfrey, W AF Kantoff, P. W. Schuetz, T. Blumenstein, B. A. Glode, M. M. Bilhartz, D. Gulley, J. Schlom, J. Laus, R. Godfrey, W. TI Overall survival (OS) analysis of a phase II randomized controlled trial (RCT) of a poxviral-based PSA targeted immunotherapy in metastatic castration-resistant prostate cancer (mCRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Trial Architecture Consulting, Washington, DC USA. Univ Colorado, Aurora, CO USA. Urol Associates, Nashville, TN USA. Natl Canc Inst, Bethesda, MD USA. BN Immunotherapeut, Mountain View, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 5013 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606603417 PM 27962903 ER PT J AU Karakunnel, JJ Gulley, JL Arlen, P Mulquin, M Wright, J Turkbey, IB Choyke, P Figg, WD Dahut, W AF Karakunnel, J. J. Gulley, J. L. Arlen, P. Mulquin, M. Wright, J. Turkbey, I. B. Choyke, P. Figg, W. D. Dahut, W. TI Cediranib (AZD2171) in docetaxel-resistant, castration-resistant prostate cancer (CRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Karakunnel, J. J.; Gulley, J. L.; Arlen, P.; Mulquin, M.; Wright, J.; Turkbey, I. B.; Choyke, P.; Figg, W. D.; Dahut, W.] NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 5141 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606604014 PM 27964432 ER PT J AU Kerr, D Gray, R Quirke, P Watson, D Yothers, G Lavery, IC Lee, M O'Connell, MJ Shak, S Wolmark, N AF Kerr, D. Gray, R. Quirke, P. Watson, D. Yothers, G. Lavery, I. C. Lee, M. O'Connell, M. J. Shak, S. Wolmark, N. CA Genomic Health QUASAR Colon Teams TI A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Kerr, D.; Gray, R.; Quirke, P.; Watson, D.; Yothers, G.; Lavery, I. C.; Lee, M.; O'Connell, M. J.; Shak, S.; Wolmark, N.] Univ Oxford, Oxford, England. [Kerr, D.; Gray, R.; Quirke, P.; Watson, D.; Yothers, G.; Lavery, I. C.; Lee, M.; O'Connell, M. J.; Shak, S.; Wolmark, N.] Birmingham Clin Trials Unit, Birmingham, W Midlands, England. [Kerr, D.; Gray, R.; Quirke, P.; Watson, D.; Yothers, G.; Lavery, I. C.; Lee, M.; O'Connell, M. J.; Shak, S.; Wolmark, N.] Leeds Inst Mol Med, Leeds, W Yorkshire, England. [Kerr, D.; Gray, R.; Quirke, P.; Watson, D.; Yothers, G.; Lavery, I. C.; Lee, M.; O'Connell, M. J.; Shak, S.; Wolmark, N.] Genomic Hlth Inc, Redwood City, CA USA. [Kerr, D.; Gray, R.; Quirke, P.; Watson, D.; Yothers, G.; Lavery, I. C.; Lee, M.; O'Connell, M. J.; Shak, S.; Wolmark, N.] NSABP, Pittsburgh, PA USA. [Kerr, D.; Gray, R.; Quirke, P.; Watson, D.; Yothers, G.; Lavery, I. C.; Lee, M.; O'Connell, M. J.; Shak, S.; Wolmark, N.; Genomic Health QUASAR Colon Teams] Cleveland Clin Fdn, Cleveland, OH 44195 USA. NR 0 TC 21 Z9 22 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 4000 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606600249 PM 27961827 ER PT J AU Kim, HK Choi, IJ Kim, CG Oshima, A Green, JE AF Kim, H. K. Choi, I. J. Kim, C. G. Oshima, A. Green, J. E. TI Gene expression signatures to predict the response of gastric cancer to cisplatin and fluorouracil SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Kim, H. K.; Choi, I. J.; Kim, C. G.; Oshima, A.; Green, J. E.] NCI, Bethesda, MD 20892 USA. [Kim, H. K.; Choi, I. J.; Kim, C. G.; Oshima, A.; Green, J. E.] Natl Canc Ctr, Goyang, South Korea. NR 0 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 4628 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606603216 PM 27964202 ER PT J AU Kim, KB Davies, MA Papadopoulos, NE Bedikian, AY Hwu, W Woodard, K Washington, EW Dancey, JE Wright, J Hwu, P AF Kim, K. B. Davies, M. A. Papadopoulos, N. E. Bedikian, A. Y. Hwu, W. Woodard, K. Washington, E. W. Dancey, J. E. Wright, J. Hwu, P. TI Phase I/II study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 9026 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606606042 PM 27962093 ER PT J AU Kolesar, J Brundage, R Pomplun, M Jiang, Z Schelman, W Alberti, D Holen, K Traynor, A Ivy, P Wilding, G AF Kolesar, J. Brundage, R. Pomplun, M. Jiang, Z. Schelman, W. Alberti, D. Holen, K. Traynor, A. Ivy, P. Wilding, G. TI Population pharmacokinetics of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in cancer patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Univ Wisconsin, Madison, WI USA. Univ Minnesota, Minneapolis, MN USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 2508 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602274 PM 27961965 ER PT J AU Libutti, SK Paciotti, GF Myer, L Haynes, R Gannon, W Walker, M Seidel, G Byrnes, A Yuldasheva, N Tamarkin, L AF Libutti, S. K. Paciotti, G. F. Myer, L. Haynes, R. Gannon, W. Walker, M. Seidel, G. Byrnes, A. Yuldasheva, N. Tamarkin, L. TI Results of a completed phase I clinical trial of CYT-6091: A pegylated colloidal gold-TNF nanomedicine SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Libutti, S. K.; Paciotti, G. F.; Myer, L.; Haynes, R.; Gannon, W.; Walker, M.; Seidel, G.; Byrnes, A.; Yuldasheva, N.; Tamarkin, L.] NCI, Bethesda, MD USA. [Libutti, S. K.; Paciotti, G. F.; Myer, L.; Haynes, R.; Gannon, W.; Walker, M.; Seidel, G.; Byrnes, A.; Yuldasheva, N.; Tamarkin, L.] CytImmune Sci Inc, Rockville, MD USA. NR 0 TC 10 Z9 10 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 3586 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606602476 PM 27961746 ER PT J AU Macdonald, JS Benedetti, J Smalley, S Haller, D Hundahl, S Jessup, J Ajani, J Gunderson, L Goldman, B Martenson, J AF Macdonald, J. S. Benedetti, J. Smalley, S. Haller, D. Hundahl, S. Jessup, J. Ajani, J. Gunderson, L. Goldman, B. Martenson, J. TI Chemoradiation of resected gastric cancer: A 10-year follow-up of the phase III trial INT0116 (SWOG 9008) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Aptium Oncol Inc, Los Angeles, CA USA. Univ Washington, Seattle, WA 98195 USA. Radiat Oncol Ctr Olathe, Olathe, KS USA. Univ Penn, Philadelphia, PA 19104 USA. UC Davis, Mather, CA USA. NCI, Bethesda, MD 20892 USA. MD Anderson Canc Ctr, Houston, TX USA. Mayo Clin, Rochester, MN USA. NR 0 TC 6 Z9 9 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 4515 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606603106 PM 27962700 ER PT J AU Martinelli, F Quinten, C Coens, C Flechtner, H Gotay, C Mendoza, T Osoba, D Reeve, B Wang, X Bottomley, A AF Martinelli, F. Quinten, C. Coens, C. Flechtner, H. Gotay, C. Mendoza, T. Osoba, D. Reeve, B. Wang, X. Bottomley, A. TI Relationships among health-related quality of life indicators in cancer patients: A pooled study of baseline EORTC QLQ-C30 data from 6,739 patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 EORTC, Brussels, Belgium. Otto Von Guericke Univ, Magdeburg, Germany. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Qual Life Consulting, W Vancouver, BC, Canada. Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 9612 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606606230 PM 27963865 ER PT J AU Mohebtash, M Madan, RA Arlen, PM Rauckhorst, M Tsang, KY Cereda, V Vergati, M Poole, DJ Dahut, WL Schlom, J Gulley, JL AF Mohebtash, M. Madan, R. A. Arlen, P. M. Rauckhorst, M. Tsang, K. Y. Cereda, V. Vergati, M. Poole, D. J. Dahut, W. L. Schlom, J. Gulley, J. L. TI Phase I trial of targeted therapy with PSA-TRICOM vaccine (V) and ipilimumab (ipi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Mohebtash, M.; Madan, R. A.; Arlen, P. M.; Rauckhorst, M.; Tsang, K. Y.; Cereda, V.; Vergati, M.; Poole, D. J.; Dahut, W. L.; Schlom, J.; Gulley, J. L.] NCI, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 5144 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606604017 PM 27964446 ER PT J AU Naing, A LoRusso, P Mills, G Berry, D Doyle, L Rohren, E Burger, A Chen, H Busaidy, NL Kurzrock, R AF Naing, A. LoRusso, P. Mills, G. Berry, D. Doyle, L. Rohren, E. Burger, A. Chen, H. Busaidy, N. L. Kurzrock, R. TI Phase I study combining an IGFR inhibitor (IMC-A12) and an mTOR inhibitor (temsirolimus) in patients with solid tumors or lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 MD Anderson Canc Ctr, Houston, TX USA. Karmanos Canc Inst, Detroit, MI USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e14535 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602509 PM 27963555 ER PT J AU Ninan, JA Bailey, H Kolesar, J Marnocha, R Eickhoff, J Wright, J Espinoza-Delgado, I Alberti, D Wilding, G Schelman, W AF Ninan, J. A. Bailey, H. Kolesar, J. Marnocha, R. Eickhoff, J. Wright, J. Espinoza-Delgado, I. Alberti, D. Wilding, G. Schelman, W. TI A phase I study of vorinostat in combination with bortezomib in refractory solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Ninan, J. A.; Bailey, H.; Kolesar, J.; Marnocha, R.; Eickhoff, J.; Wright, J.; Espinoza-Delgado, I.; Alberti, D.; Wilding, G.; Schelman, W.] UW Carbone Comprehens Canc Ctr, Madison, WI USA. [Ninan, J. A.; Bailey, H.; Kolesar, J.; Marnocha, R.; Eickhoff, J.; Wright, J.; Espinoza-Delgado, I.; Alberti, D.; Wilding, G.; Schelman, W.] Natl Canc Inst, Bethesda, MD USA. NR 0 TC 2 Z9 2 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 MAY 20 PY 2009 VL 27 IS 15 SU S MA 2531 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606602297 PM 27961857 ER PT J AU O'Mara, AM Denicoff, AM Reeve, B Burns, R Trimble, T AF O'Mara, A. M. Denicoff, A. M. Reeve, B. Burns, R. Trimble, T. TI A comparison of patient-reported outcomes (PROs) in National Cancer Institute-sponsored cancer treatment trials conducted during two time periods: 1999-2003 and 2003-2008 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Natl Canc Inst, Bethesda, MD USA. EMMES Corp, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 6618 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606604466 PM 27961778 ER PT J AU Oza, AM Kollmannsberger, C Hirte, H Welch, S Siu, L Mazurka, J Sederias, J Doyle, LA Eisenhauer, E AF Oza, A. M. Kollmannsberger, C. Hirte, H. Welch, S. Siu, L. Mazurka, J. Sederias, J. Doyle, L. A. Eisenhauer, E. CA NCIC Clinical Trials Grp TI Phase I study of temsirolimus (CCI-779), carboplatin, and paclitaxel in patients (pts) with advanced solid tumors: NCIC CTG IND 179 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Oza, A. M.; Kollmannsberger, C.; Hirte, H.; Welch, S.; Siu, L.; Mazurka, J.; Sederias, J.; Doyle, L. A.; Eisenhauer, E.] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Oza, A. M.; Kollmannsberger, C.; Hirte, H.; Welch, S.; Siu, L.; Mazurka, J.; Sederias, J.; Doyle, L. A.; Eisenhauer, E.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Oza, A. M.; Kollmannsberger, C.; Hirte, H.; Welch, S.; Siu, L.; Mazurka, J.; Sederias, J.; Doyle, L. A.; Eisenhauer, E.] Juravinski Canc Ctr, NCIC Clin Trials Grp, Hamilton, ON, Canada. [Oza, A. M.; Kollmannsberger, C.; Hirte, H.; Welch, S.; Siu, L.; Mazurka, J.; Sederias, J.; Doyle, L. A.; Eisenhauer, E.] London Hlth Sci Ctr, London, ON, Canada. [Oza, A. M.; Kollmannsberger, C.; Hirte, H.; Welch, S.; Siu, L.; Mazurka, J.; Sederias, J.; Doyle, L. A.; Eisenhauer, E.] NCIC Clin Trials Grp, Kingston, ON, Canada. [Oza, A. M.; Kollmannsberger, C.; Hirte, H.; Welch, S.; Siu, L.; Mazurka, J.; Sederias, J.; Doyle, L. A.; Eisenhauer, E.; NCIC Clinical Trials Grp] Natl Canc Inst, CTEP, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 3558 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602448 PM 27961362 ER PT J AU Pejovic, T Gaile, DP Darcy, KM Liu, S Shepherd, L Rodgers, WH Kohn, E Mannel, R Birrer, MJ Nowak, N AF Pejovic, T. Gaile, D. P. Darcy, K. M. Liu, S. Shepherd, L. Rodgers, W. H. Kohn, E. Mannel, R. Birrer, M. J. Nowak, N. TI A Gynecologic Oncology Group study of frequent copy number aberrations in DNA repair genes and other genomic regions in stage I serous ovarian cancers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Pejovic, T.; Gaile, D. P.; Darcy, K. M.; Liu, S.; Shepherd, L.; Rodgers, W. H.; Kohn, E.; Mannel, R.; Birrer, M. J.; Nowak, N.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Pejovic, T.; Gaile, D. P.; Darcy, K. M.; Liu, S.; Shepherd, L.; Rodgers, W. H.; Kohn, E.; Mannel, R.; Birrer, M. J.; Nowak, N.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Pejovic, T.; Gaile, D. P.; Darcy, K. M.; Liu, S.; Shepherd, L.; Rodgers, W. H.; Kohn, E.; Mannel, R.; Birrer, M. J.; Nowak, N.] Lenox Hill Hosp, New York, NY 10021 USA. [Pejovic, T.; Gaile, D. P.; Darcy, K. M.; Liu, S.; Shepherd, L.; Rodgers, W. H.; Kohn, E.; Mannel, R.; Birrer, M. J.; Nowak, N.] Natl Inst Hlth, Bethesda, MD USA. [Pejovic, T.; Gaile, D. P.; Darcy, K. M.; Liu, S.; Shepherd, L.; Rodgers, W. H.; Kohn, E.; Mannel, R.; Birrer, M. J.; Nowak, N.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Pejovic, T.; Gaile, D. P.; Darcy, K. M.; Liu, S.; Shepherd, L.; Rodgers, W. H.; Kohn, E.; Mannel, R.; Birrer, M. J.; Nowak, N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e16504 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606600101 PM 27960763 ER PT J AU Piao, Y Heymach, JV Bekele, B Camphausen, K Wen, PY Liu, J Yung, WK De Groot, J AF Piao, Y. Heymach, J. V. Bekele, B. Camphausen, K. Wen, P. Y. Liu, J. Yung, W. K. De Groot, J. TI Circulating cytokine and angiogenic factors as predictive biomarkers of glioblastoma response to aflibercept (VEGF Trap) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Piao, Y.; Heymach, J. V.; Bekele, B.; Camphausen, K.; Wen, P. Y.; Liu, J.; Yung, W. K.; De Groot, J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Piao, Y.; Heymach, J. V.; Bekele, B.; Camphausen, K.; Wen, P. Y.; Liu, J.; Yung, W. K.; De Groot, J.] NCI, Bethesda, MD 20892 USA. [Piao, Y.; Heymach, J. V.; Bekele, B.; Camphausen, K.; Wen, P. Y.; Liu, J.; Yung, W. K.; De Groot, J.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 2029 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602177 PM 27964597 ER PT J AU Pistollato, F Abbadi, S Rampazzo, E Viola, G Della Puppa, A Cavallini, L Panchision, DM te Kronnie, G Basso, G AF Pistollato, F. Abbadi, S. Rampazzo, E. Viola, G. Della Puppa, A. Cavallini, L. Panchision, D. M. te Kronnie, G. Basso, G. TI Glioblastoma-derived cells exhibit differential responses to glycolysis inhibition under hypoxia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Pistollato, F.; Abbadi, S.; Rampazzo, E.; Viola, G.; Della Puppa, A.; Cavallini, L.; Panchision, D. M.; te Kronnie, G.; Basso, G.] Univ Padua, Padua, Italy. [Pistollato, F.; Abbadi, S.; Rampazzo, E.; Viola, G.; Della Puppa, A.; Cavallini, L.; Panchision, D. M.; te Kronnie, G.; Basso, G.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e13031 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602258 PM 27962877 ER PT J AU Ramalingam, SS Maitland, M Frankel, P Argiris, AE Koczywas, M Gitlitz, B Espinoza-Delgado, I Vokes, EE Gandara, DR Belani, CP AF Ramalingam, S. S. Maitland, M. Frankel, P. Argiris, A. E. Koczywas, M. Gitlitz, B. Espinoza-Delgado, I. Vokes, E. E. Gandara, D. R. Belani, C. P. TI Randomized, double-blind, placebo-controlled phase II study of carboplatin and paclitaxel with or without vorinostat, a histone deacetylase inhibitor (HDAC), for first-line therapy of advanced non-small cell lung cancer (NCI 7863) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Emory Univ, Atlanta, GA 30322 USA. Univ Chicago, Chicago, IL 60637 USA. City Hope Comprehens Canc Ctr, Duarte, CA USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ So Calif, Los Angeles, CA USA. NCI, Bethesda, MD 20892 USA. Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. Penn State Hershey Canc Inst, Hershey, PA USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 8004 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606605207 PM 27962784 ER PT J AU Ramanathan, M Srinivasan, R Geller, N Donohue, T Goodwin, R Cook, L Ramos, C Barrett, J Childs, R AF Ramanathan, M. Srinivasan, R. Geller, N. Donohue, T. Goodwin, R. Cook, L. Ramos, C. Barrett, J. Childs, R. TI Combined tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) blockade in acute steroid refractory graft-versus-host disease (SR-GVHD) following allogeneic hematopoietic stem cell transplantation (HCT) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Ramanathan, M.; Srinivasan, R.; Geller, N.; Donohue, T.; Goodwin, R.; Cook, L.; Ramos, C.; Barrett, J.; Childs, R.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 7023 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606605014 PM 27961396 ER PT J AU Ramaswamy, B Phelps, M Baiocchi, R Bekaii-Saab, T Wilkins, D Arbogast, D Campbell, A Doyle, AL Grever, M Shah, M AF Ramaswamy, B. Phelps, M. Baiocchi, R. Bekaii-Saab, T. Wilkins, D. Arbogast, D. Campbell, A. Doyle, A. L. Grever, M. Shah, M. TI A phase I study of flavopiridol using an alternative schedule in patients (pts) with advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Ramaswamy, B.; Phelps, M.; Baiocchi, R.; Bekaii-Saab, T.; Wilkins, D.; Arbogast, D.; Campbell, A.; Doyle, A. L.; Grever, M.; Shah, M.] Ohio State Univ, Columbus, OH 43210 USA. [Ramaswamy, B.; Phelps, M.; Baiocchi, R.; Bekaii-Saab, T.; Wilkins, D.; Arbogast, D.; Campbell, A.; Doyle, A. L.; Grever, M.; Shah, M.] NCI, CTEP, Bethesda, MD 20892 USA. RI Phelps, Mitch/H-3941-2013; Bekaii-Saab, Tanios/E-2733-2011; Ramaswamy, Bhuvaneswari/E-3919-2011 OI Phelps, Mitch/0000-0002-1615-5280; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 2580 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606602346 PM 27961903 ER PT J AU Rastogi, P Buyse, M Swain, S Jacobs, S Robidoux, A Liepman, M Dy, P Geyer, C Wolmark, N AF Rastogi, P. Buyse, M. Swain, S. Jacobs, S. Robidoux, A. Liepman, M. Dy, P. Geyer, C., Jr. Wolmark, N. TI Bevacizumab beginning concurrently with a sequential regimen of doxorubicin and cyclophosphamide followed by docetaxel and capecitabine as neoadjuvant therapy followed by postoperative bevacizumab alone for women with HER2-negative locally advanced breast cancer (LABC): A phase II trial of the NSABP Foundation Research Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Rastogi, P.; Buyse, M.; Swain, S.; Jacobs, S.; Robidoux, A.; Liepman, M.; Dy, P.; Geyer, C., Jr.; Wolmark, N.] NSABP, Pittsburgh, PA USA. [Rastogi, P.; Buyse, M.; Swain, S.; Jacobs, S.; Robidoux, A.; Liepman, M.; Dy, P.; Geyer, C., Jr.; Wolmark, N.] Univ Pittsburgh, Pittsburgh, PA USA. [Rastogi, P.; Buyse, M.; Swain, S.; Jacobs, S.; Robidoux, A.; Liepman, M.; Dy, P.; Geyer, C., Jr.; Wolmark, N.] IDDI, Louvain, Belgium. [Rastogi, P.; Buyse, M.; Swain, S.; Jacobs, S.; Robidoux, A.; Liepman, M.; Dy, P.; Geyer, C., Jr.; Wolmark, N.] Washington Hosp Ctr, Washington, DC 20010 USA. [Rastogi, P.; Buyse, M.; Swain, S.; Jacobs, S.; Robidoux, A.; Liepman, M.; Dy, P.; Geyer, C., Jr.; Wolmark, N.] Univ Montreal, Ctr Hosp, Montreal, PQ, Canada. [Rastogi, P.; Buyse, M.; Swain, S.; Jacobs, S.; Robidoux, A.; Liepman, M.; Dy, P.; Geyer, C., Jr.; Wolmark, N.] W Michigan Canc Ctr, Kalamazoo, MI USA. [Rastogi, P.; Buyse, M.; Swain, S.; Jacobs, S.; Robidoux, A.; Liepman, M.; Dy, P.; Geyer, C., Jr.; Wolmark, N.] Canc Care Specialists Cent Illinois, Effingham, IL USA. [Rastogi, P.; Buyse, M.; Swain, S.; Jacobs, S.; Robidoux, A.; Liepman, M.; Dy, P.; Geyer, C., Jr.; Wolmark, N.] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 584 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606601292 PM 27960695 ER PT J AU Reeves, DM Helton, E Speakman, J Ness, E Komatsoulis, G AF Reeves, D. M. Helton, E. Speakman, J. Ness, E. Komatsoulis, G. TI Creation of a library of harmonized standard research variables and case report forms (CRFs) for oncology research SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 NCI, Rockville, MD USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e17512 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606604492 PM 27963273 ER PT J AU Rixe, O Dutcher, J Motzer, R Wilding, G Stadler, WM Garrett, M Pithavala, Y Kim, S Tarazi, J Rini, BI AF Rixe, O. Dutcher, J. Motzer, R. Wilding, G. Stadler, W. M. Garrett, M. Pithavala, Y. Kim, S. Tarazi, J. Rini, B. I. TI Diastolic blood pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib efficacy in metastatic renal cell cancer (mRCC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. New York Med Coll, New York, NY USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Wisconsin, Madison, WI USA. Univ Chicago, Chicago, IL 60637 USA. Pfizer Oncol, San Diego, CA USA. Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. NR 0 TC 7 Z9 7 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 MAY 20 PY 2009 VL 27 IS 15 SU S MA 5045 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606603446 PM 27962952 ER PT J AU Roberts, AW Wilson, W Gandhi, L O'Connor, OA Rudin, CM Brown, JR Xiong, H Chiu, Y Enschede, S Krivoshik, AP AF Roberts, A. W. Wilson, W. Gandhi, L. O'Connor, O. A. Rudin, C. M. Brown, J. R. Xiong, H. Chiu, Y. Enschede, S. Krivoshik, A. P. TI Ongoing phase I studies of ABT-263: Mitigating Bcl-X-L induced thrombocytopenia with lead-in and continuous dosing SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Roberts, A. W.; Wilson, W.; Gandhi, L.; O'Connor, O. A.; Rudin, C. M.; Brown, J. R.; Xiong, H.; Chiu, Y.; Enschede, S.; Krivoshik, A. P.] Royal Melbourne Hosp, Parkville, Vic 3050, Australia. [Roberts, A. W.; Wilson, W.; Gandhi, L.; O'Connor, O. A.; Rudin, C. M.; Brown, J. R.; Xiong, H.; Chiu, Y.; Enschede, S.; Krivoshik, A. P.] Natl Canc Inst, Bethesda, MD USA. [Roberts, A. W.; Wilson, W.; Gandhi, L.; O'Connor, O. A.; Rudin, C. M.; Brown, J. R.; Xiong, H.; Chiu, Y.; Enschede, S.; Krivoshik, A. P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Roberts, A. W.; Wilson, W.; Gandhi, L.; O'Connor, O. A.; Rudin, C. M.; Brown, J. R.; Xiong, H.; Chiu, Y.; Enschede, S.; Krivoshik, A. P.] Columbia Univ, New York, NY USA. [Roberts, A. W.; Wilson, W.; Gandhi, L.; O'Connor, O. A.; Rudin, C. M.; Brown, J. R.; Xiong, H.; Chiu, Y.; Enschede, S.; Krivoshik, A. P.] Johns Hopkins Univ, Baltimore, MD USA. [Roberts, A. W.; Wilson, W.; Gandhi, L.; O'Connor, O. A.; Rudin, C. M.; Brown, J. R.; Xiong, H.; Chiu, Y.; Enschede, S.; Krivoshik, A. P.] Abbott Labs, Abbott Pk, IL 60064 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 3505 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602395 PM 27961281 ER PT J AU Sargent, DJ Yothers, G Van Cutsem, E Cassidy, J Saltz, L Wolmark, N Shi, Q Buyse, M de Gramont, A AF Sargent, D. J. Yothers, G. Van Cutsem, E. Cassidy, J. Saltz, L. Wolmark, N. Shi, Q. Buyse, M. de Gramont, A. CA ACCENT Grp TI Use of two-year disease-free survival (DFS) as a primary endpoint in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: New data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, NSAPB C-06 and C-07, and C89803 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Sargent, D. J.; Yothers, G.; Van Cutsem, E.; Cassidy, J.; Saltz, L.; Wolmark, N.; Shi, Q.; Buyse, M.; de Gramont, A.] Mayo Clin, Rochester, MN USA. [Sargent, D. J.; Yothers, G.; Van Cutsem, E.; Cassidy, J.; Saltz, L.; Wolmark, N.; Shi, Q.; Buyse, M.; de Gramont, A.] NSABP, Ctr Biostat, Pittsburgh, PA USA. [Sargent, D. J.; Yothers, G.; Van Cutsem, E.; Cassidy, J.; Saltz, L.; Wolmark, N.; Shi, Q.; Buyse, M.; de Gramont, A.] Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Sargent, D. J.; Yothers, G.; Van Cutsem, E.; Cassidy, J.; Saltz, L.; Wolmark, N.; Shi, Q.; Buyse, M.; de Gramont, A.] Univ Hosp Leuven, Louvain, Belgium. [Sargent, D. J.; Yothers, G.; Van Cutsem, E.; Cassidy, J.; Saltz, L.; Wolmark, N.; Shi, Q.; Buyse, M.; de Gramont, A.] Canc Res UK, Glasgow, Lanark, Scotland. [Sargent, D. J.; Yothers, G.; Van Cutsem, E.; Cassidy, J.; Saltz, L.; Wolmark, N.; Shi, Q.; Buyse, M.; de Gramont, A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Sargent, D. J.; Yothers, G.; Van Cutsem, E.; Cassidy, J.; Saltz, L.; Wolmark, N.; Shi, Q.; Buyse, M.; de Gramont, A.] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Sargent, D. J.; Yothers, G.; Van Cutsem, E.; Cassidy, J.; Saltz, L.; Wolmark, N.; Shi, Q.; Buyse, M.; de Gramont, A.] IDDI, Louvian La Neuve, Belgium. [Sargent, D. J.; Yothers, G.; Van Cutsem, E.; Cassidy, J.; Saltz, L.; Wolmark, N.; Shi, Q.; Buyse, M.; de Gramont, A.; ACCENT Grp] Hosp St Antoine, Paris, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 4011 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606600253 ER PT J AU Sarkaria, JN Galanis, E Wu, W Giannini, C Jaeckle, KA Doyle, L Uhm, J Brown, P Dietz, AB Buckner, J AF Sarkaria, J. N. Galanis, E. Wu, W. Giannini, C. Jaeckle, K. A. Doyle, L. Uhm, J. Brown, P. Dietz, A. B. Buckner, J. TI NCCTG phase I trial of temsirolimus (CCI-779) and temozolomide (TMZ) in combination with radiation therapy (RT) in newly diagnosed glioblastoma multiforme (GBM) patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Sarkaria, J. N.; Galanis, E.; Wu, W.; Giannini, C.; Jaeckle, K. A.; Doyle, L.; Uhm, J.; Brown, P.; Dietz, A. B.; Buckner, J.] Mayo Clin, Rochester, MN USA. [Sarkaria, J. N.; Galanis, E.; Wu, W.; Giannini, C.; Jaeckle, K. A.; Doyle, L.; Uhm, J.; Brown, P.; Dietz, A. B.; Buckner, J.] Mayo Clin, Jacksonville, FL 32224 USA. [Sarkaria, J. N.; Galanis, E.; Wu, W.; Giannini, C.; Jaeckle, K. A.; Doyle, L.; Uhm, J.; Brown, P.; Dietz, A. B.; Buckner, J.] NCI, CTEP, Bethesda, MD 20892 USA. RI Dietz, Allan/H-7414-2015 OI Dietz, Allan/0000-0003-3410-9621 NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 2019 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602167 PM 27964576 ER PT J AU Schroen, AT Petroni, GR Wang, H Djulbegovic, B Slingluff, CL Wang, XF Gray, R Sargent, DJ Cronin, W Benedetti, J AF Schroen, A. T. Petroni, G. R. Wang, H. Djulbegovic, B. Slingluff, C. L., Jr. Wang, X. F. Gray, R. Sargent, D. J. Cronin, W. Benedetti, J. CA Oncology Clinical Trial Accrual St TI Challenges to accrual predictions to phase III cancer clinical trials: A survey of study chairs and lead statisticians of 248 NCI-sponsored trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Univ Virginia, Charlottesville, VA USA. Univ S Florida, Tampa, FL USA. Canc & Leukemia Grp B, Durham, NC USA. Eastern Cooperat Oncol Grp, Boston, MA USA. NCCTG, Rochester, MN USA. NSABP, Pittsburgh, PA USA. SW Oncol Grp, Seattle, WA USA. RI Djulbegovic, Benjamin/I-3661-2012 OI Djulbegovic, Benjamin/0000-0003-0671-1447 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 6562 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606604410 PM 27963800 ER PT J AU Schuster, SJ Neelapu, SS Gause, BL Muggia, FM Gockerman, JP Sotomayor, EM Winter, JN Flowers, CR Stergiou, AM Kwak, LW AF Schuster, S. J. Neelapu, S. S. Gause, B. L. Muggia, F. M. Gockerman, J. P. Sotomayor, E. M. Winter, J. N. Flowers, C. R. Stergiou, A. M. Kwak, L. W. CA BiovaxID Phase III Study TI Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: Phase III clinical trial results SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Schuster, S. J.; Neelapu, S. S.; Gause, B. L.; Muggia, F. M.; Gockerman, J. P.; Sotomayor, E. M.; Winter, J. N.; Flowers, C. R.; Stergiou, A. M.; Kwak, L. W.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Schuster, S. J.; Neelapu, S. S.; Gause, B. L.; Muggia, F. M.; Gockerman, J. P.; Sotomayor, E. M.; Winter, J. N.; Flowers, C. R.; Stergiou, A. M.; Kwak, L. W.] MD Anderson Canc Ctr, Houston, TX USA. [Schuster, S. J.; Neelapu, S. S.; Gause, B. L.; Muggia, F. M.; Gockerman, J. P.; Sotomayor, E. M.; Winter, J. N.; Flowers, C. R.; Stergiou, A. M.; Kwak, L. W.] Natl Canc Inst, Bethesda, MD USA. [Schuster, S. J.; Neelapu, S. S.; Gause, B. L.; Muggia, F. M.; Gockerman, J. P.; Sotomayor, E. M.; Winter, J. N.; Flowers, C. R.; Stergiou, A. M.; Kwak, L. W.] NYU, Med Ctr, New York, NY 10016 USA. [Schuster, S. J.; Neelapu, S. S.; Gause, B. L.; Muggia, F. M.; Gockerman, J. P.; Sotomayor, E. M.; Winter, J. N.; Flowers, C. R.; Stergiou, A. M.; Kwak, L. W.] Duke Univ, Med Ctr, Durham, NC USA. [Schuster, S. J.; Neelapu, S. S.; Gause, B. L.; Muggia, F. M.; Gockerman, J. P.; Sotomayor, E. M.; Winter, J. N.; Flowers, C. R.; Stergiou, A. M.; Kwak, L. W.] Moffit Canc Ctr & Res Inst, Tampa, FL USA. [Schuster, S. J.; Neelapu, S. S.; Gause, B. L.; Muggia, F. M.; Gockerman, J. P.; Sotomayor, E. M.; Winter, J. N.; Flowers, C. R.; Stergiou, A. M.; Kwak, L. W.] Northwestern Univ, Chicago, IL 60611 USA. [Schuster, S. J.; Neelapu, S. S.; Gause, B. L.; Muggia, F. M.; Gockerman, J. P.; Sotomayor, E. M.; Winter, J. N.; Flowers, C. R.; Stergiou, A. M.; Kwak, L. W.] Emory Univ, Atlanta, GA 30322 USA. [Schuster, S. J.; Neelapu, S. S.; Gause, B. L.; Muggia, F. M.; Gockerman, J. P.; Sotomayor, E. M.; Winter, J. N.; Flowers, C. R.; Stergiou, A. M.; Kwak, L. W.; BiovaxID Phase III Study] Biovest Int, New York, NY USA. RI Flowers, Christopher/F-1953-2010 OI Flowers, Christopher/0000-0002-9524-3990 NR 0 TC 11 Z9 12 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 2 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606600181 PM 27961278 ER PT J AU Seruga, B Hertz, PC Wang, L Booth, CM Krzyzanowska, M Cescon, DW Tannock, IF AF Seruga, B. Hertz, P. C. Wang, L. Booth, C. M. Krzyzanowska, M. Cescon, D. W. Tannock, I. F. TI Absolute benefits of experimental medical therapies in phase III randomized clinical trials (RCTs) in breast and colorectal cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. NCI, Kingston, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 6513 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606604362 PM 27964019 ER PT J AU Smith, JW Buyse, M Rastogi, P Geyer, C Jacobs, S Patocskai, E Wolmark, N AF Smith, J. W. Buyse, M. Rastogi, P. Geyer, C., Jr. Jacobs, S. Patocskai, E. Wolmark, N. TI Epirubicin plus cyclophosphamide followed by docetaxel plus trastuzumab and bevacizumab as neoadjuvant therapy for HER2-positive locally advanced breast cancer (LABC) or as adjuvant therapy for HER2-positive pathologic stage III breast cancer (PS3BC): A phase II trial of the NSABP Foundation Research Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Smith, J. W.; Buyse, M.; Rastogi, P.; Geyer, C., Jr.; Jacobs, S.; Patocskai, E.; Wolmark, N.] Columbia River Oncol Program, Portland, OR USA. [Smith, J. W.; Buyse, M.; Rastogi, P.; Geyer, C., Jr.; Jacobs, S.; Patocskai, E.; Wolmark, N.] IDDI, Louvain, Belgium. [Smith, J. W.; Buyse, M.; Rastogi, P.; Geyer, C., Jr.; Jacobs, S.; Patocskai, E.; Wolmark, N.] NSABP, Pittsburgh, PA USA. [Smith, J. W.; Buyse, M.; Rastogi, P.; Geyer, C., Jr.; Jacobs, S.; Patocskai, E.; Wolmark, N.] UPCI, Magee Womens Hosp, Womens Canc Clin, Pittsburgh, PA USA. [Smith, J. W.; Buyse, M.; Rastogi, P.; Geyer, C., Jr.; Jacobs, S.; Patocskai, E.; Wolmark, N.] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Smith, J. W.; Buyse, M.; Rastogi, P.; Geyer, C., Jr.; Jacobs, S.; Patocskai, E.; Wolmark, N.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Smith, J. W.; Buyse, M.; Rastogi, P.; Geyer, C., Jr.; Jacobs, S.; Patocskai, E.; Wolmark, N.] Univ Montreal, Ctr Hosp, Montreal, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 580 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606601288 PM 27960693 ER PT J AU Springer, B Danoff, J Levy, E Stout, N Pfalzer, L McGarvey, C Gerber, L Soballe, P AF Springer, B. Danoff, J. Levy, E. Stout, N. Pfalzer, L. McGarvey, C. Gerber, L. Soballe, P. TI Functional recovery after surgery in patients with breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Off Surgeon Gen, Falls Church, VA USA. Natl Inst Hlth, Bethesda, MD USA. Natl Naval Med Ctr, Bethesda, MD USA. Univ Michigan, Bethesda, MD USA. CLM Consulting Serv LLC, Rockville, MD USA. George Mason Univ, Fairfax, VA 22030 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e20539 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606606296 PM 27960969 ER PT J AU Srinivasan, R Linehan, WM Vaishampayan, U Logan, T Shankar, SM Sherman, LJ Liu, Y Choueiri, TK AF Srinivasan, R. Linehan, W. M. Vaishampayan, U. Logan, T. Shankar, S. M. Sherman, L. J. Liu, Y. Choueiri, T. K. TI A phase II study of two dosing regimens of GSK 1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in patients (pts) with papillary renal carcinoma (PRC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Indiana Univ, Sch Med, Indianapolis, IN 46204 USA. GlaxoSmithKline Inc, Collegeville, PA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 5103 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606603502 ER PT J AU Stathis, A Hotte, S Hirte, H Chen, EX Webster, S Iacobucci, A McGill, S Wang, L Espinoza-Delgado, I Siu, LL AF Stathis, A. Hotte, S. Hirte, H. Chen, E. X. Webster, S. Iacobucci, A. McGill, S. Wang, L. Espinoza-Delgado, I. Siu, L. L. TI Phase I study of intravenous decitabine in combination with oral vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas (NHL) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Princess Margaret Hosp, Phase Consortium 1, Toronto, ON M4X 1K9, Canada. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 3528 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602418 PM 27961316 ER PT J AU Tay, K Shapiro, G Disinski, M Chirieac, LR Pittaluga, S Jaffe, ES Janik, JE Wiestner, A Wilson, WH Dunleavy, K AF Tay, K. Shapiro, G. Disinski, M. Chirieac, L. R. Pittaluga, S. Jaffe, E. S. Janik, J. E. Wiestner, A. Wilson, W. H. Dunleavy, K. TI Phase I/II study of a hybrid schedule of flavopiridol in relapsed/refractory mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 8563 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606605472 PM 27961020 ER PT J AU Taylor, SK Chia, S Dent, S Clemons, M Grenci, P Wang, L Oza, AM Ivy, P Pritchard, K Leighl, N AF Taylor, S. K. Chia, S. Dent, S. Clemons, M. Grenci, P. Wang, L. Oza, A. M. Ivy, P. Pritchard, K. Leighl, N. TI A phase II study of GW786034 (pazopanib) in patients with recurrent or metastatic invasive breast carcinoma: Results after completion of stage I: A trial of the Princess Margaret Hospital Phase II Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Taylor, S. K.; Chia, S.; Dent, S.; Clemons, M.; Grenci, P.; Wang, L.; Oza, A. M.; Ivy, P.; Pritchard, K.; Leighl, N.] Princess Margaret Hosp Phase II Consortium, Toronto, ON, Canada. [Taylor, S. K.; Chia, S.; Dent, S.; Clemons, M.; Grenci, P.; Wang, L.; Oza, A. M.; Ivy, P.; Pritchard, K.; Leighl, N.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 1133 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602066 ER PT J AU Townsley, C Hirte, H Hoskins, P Buckanovich, R Mackay, H Welch, S Wang, L Polintan, R Chen, A Oza, AM AF Townsley, C. Hirte, H. Hoskins, P. Buckanovich, R. Mackay, H. Welch, S. Wang, L. Polintan, R. Chen, A. Oza, A. M. TI A phase II study of aflibercept (VEGF trap) in recurrent or metastatic gynecologic soft-tissue sarcomas: A study of the Princess Margaret Hospital Phase II Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Townsley, C.; Hirte, H.; Hoskins, P.; Buckanovich, R.; Mackay, H.; Welch, S.; Wang, L.; Polintan, R.; Chen, A.; Oza, A. M.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Townsley, C.; Hirte, H.; Hoskins, P.; Buckanovich, R.; Mackay, H.; Welch, S.; Wang, L.; Polintan, R.; Chen, A.; Oza, A. M.] Juravinski Canc Ctr, Hamilton, ON, Canada. [Townsley, C.; Hirte, H.; Hoskins, P.; Buckanovich, R.; Mackay, H.; Welch, S.; Wang, L.; Polintan, R.; Chen, A.; Oza, A. M.] BC Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Townsley, C.; Hirte, H.; Hoskins, P.; Buckanovich, R.; Mackay, H.; Welch, S.; Wang, L.; Polintan, R.; Chen, A.; Oza, A. M.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Townsley, C.; Hirte, H.; Hoskins, P.; Buckanovich, R.; Mackay, H.; Welch, S.; Wang, L.; Polintan, R.; Chen, A.; Oza, A. M.] NCI, CTEP, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 5591 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606600092 PM 27962397 ER PT J AU Vidaurre, T Wilkerson, J Bates, SE Simon, R Fojo, AT AF Vidaurre, T. Wilkerson, J. Bates, S. E. Simon, R. Fojo, A. T. TI Value of stable disease (SD) in drug development of targeted therapies (TGT) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Vidaurre, T.; Wilkerson, J.; Bates, S. E.; Simon, R.; Fojo, A. T.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 2509 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606602275 PM 27961963 ER PT J AU Vourganti, S Stovsky, M Ponsky, L Siroky, M Kipnis, V Fedotoff, O Mikheeva, L Zaslavsky, B Chait, A Jones, JS AF Vourganti, S. Stovsky, M. Ponsky, L. Siroky, M. Kipnis, V. Fedotoff, O. Mikheeva, L. Zaslavsky, B. Chait, A. Jones, J. S. TI Evaluation of the prostate-specific antigen/solvent interaction analysis (PSA/SIA) assay for prostate cancer (CaP) diagnosis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Hosp Case Med Ctr, Cleveland, OH USA. Vet Affairs Boston Healthcare Syst, Boston, MA USA. Natl Canc Inst, Bethesda, MD USA. AnalizaDx LLC, Cleveland, OH USA. Cleveland Clin, Cleveland, OH 44106 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 5053 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606603453 PM 27962955 ER PT J AU Welch, S Mackay, HJ Hirte, H Fleming, GF Morgan, R Wang, L Blattler, C Ivy, SP Oza, AM AF Welch, S. Mackay, H. J. Hirte, H. Fleming, G. F. Morgan, R. Wang, L. Blattler, C. Ivy, S. P. Oza, A. M. TI A phase II study of sunitinib in recurrent or metastatic endometrial carcinoma: A trial of the PMH Phase II Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Welch, S.; Mackay, H. J.; Hirte, H.; Fleming, G. F.; Morgan, R.; Wang, L.; Blattler, C.; Ivy, S. P.; Oza, A. M.] Princess Margaret Hosp, Phase II Consortium, Toronto, ON M4X 1K9, Canada. [Welch, S.; Mackay, H. J.; Hirte, H.; Fleming, G. F.; Morgan, R.; Wang, L.; Blattler, C.; Ivy, S. P.; Oza, A. M.] Juravinski Canc Ctr, Hamilton, ON, Canada. [Welch, S.; Mackay, H. J.; Hirte, H.; Fleming, G. F.; Morgan, R.; Wang, L.; Blattler, C.; Ivy, S. P.; Oza, A. M.] Univ Chicago Consortium, Chicago, IL USA. [Welch, S.; Mackay, H. J.; Hirte, H.; Fleming, G. F.; Morgan, R.; Wang, L.; Blattler, C.; Ivy, S. P.; Oza, A. M.] Calif Canc Consortium, Duarte, CA USA. [Welch, S.; Mackay, H. J.; Hirte, H.; Fleming, G. F.; Morgan, R.; Wang, L.; Blattler, C.; Ivy, S. P.; Oza, A. M.] Natl Canc Inst, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 5576 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606600077 PM 27962603 ER PT J AU Wen, PY Cloughesy, T Kuhn, J Lamborn, K Abrey, LE Lieberman, F Robins, HI Wright, J Prados, MD Gilbert, M AF Wen, P. Y. Cloughesy, T. Kuhn, J. Lamborn, K. Abrey, L. E. Lieberman, F. Robins, H. I. Wright, J. Prados, M. D. Gilbert, M. TI Phase I/II study of sorafenib and temsirolimus for patients with recurrent glioblastoma (GBM) (NABTC 05-02) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Wen, P. Y.; Cloughesy, T.; Kuhn, J.; Lamborn, K.; Abrey, L. E.; Lieberman, F.; Robins, H. I.; Wright, J.; Prados, M. D.; Gilbert, M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wen, P. Y.; Cloughesy, T.; Kuhn, J.; Lamborn, K.; Abrey, L. E.; Lieberman, F.; Robins, H. I.; Wright, J.; Prados, M. D.; Gilbert, M.] Univ Calif Los Angeles, Los Angeles, CA USA. [Wen, P. Y.; Cloughesy, T.; Kuhn, J.; Lamborn, K.; Abrey, L. E.; Lieberman, F.; Robins, H. I.; Wright, J.; Prados, M. D.; Gilbert, M.] UT San Antonio, San Antonio, TX USA. [Wen, P. Y.; Cloughesy, T.; Kuhn, J.; Lamborn, K.; Abrey, L. E.; Lieberman, F.; Robins, H. I.; Wright, J.; Prados, M. D.; Gilbert, M.] UCSF, San Francisco, CA USA. [Wen, P. Y.; Cloughesy, T.; Kuhn, J.; Lamborn, K.; Abrey, L. E.; Lieberman, F.; Robins, H. I.; Wright, J.; Prados, M. D.; Gilbert, M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Wen, P. Y.; Cloughesy, T.; Kuhn, J.; Lamborn, K.; Abrey, L. E.; Lieberman, F.; Robins, H. I.; Wright, J.; Prados, M. D.; Gilbert, M.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Wen, P. Y.; Cloughesy, T.; Kuhn, J.; Lamborn, K.; Abrey, L. E.; Lieberman, F.; Robins, H. I.; Wright, J.; Prados, M. D.; Gilbert, M.] Univ Wisconsin, Madison, WI USA. [Wen, P. Y.; Cloughesy, T.; Kuhn, J.; Lamborn, K.; Abrey, L. E.; Lieberman, F.; Robins, H. I.; Wright, J.; Prados, M. D.; Gilbert, M.] NCI, Bethesda, MD 20892 USA. [Wen, P. Y.; Cloughesy, T.; Kuhn, J.; Lamborn, K.; Abrey, L. E.; Lieberman, F.; Robins, H. I.; Wright, J.; Prados, M. D.; Gilbert, M.] MD Anderson Canc Ctr, Houston, TX USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 2006 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606602154 PM 27964559 ER PT J AU Widemann, BC Fox, E Adamson, PC Baruchel, S Kim, A Ingle, AM Bender, JG Stempak, D Balis, FM Blaney, SM AF Widemann, B. C. Fox, E. Adamson, P. C. Baruchel, S. Kim, A. Ingle, A. M. Bender, J. Glade Stempak, D. Balis, F. M. Blaney, S. M. TI Phase I study of sorafenib in children with refractory solid tumors: A Children's Oncology Group Phase I Consortium trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Natl Canc Inst, Bethesda, MD USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Childrens Oncol Grp, Arcadia, CA USA. Columbia Presbytarian Coll Physicians & Surg, New York, NY USA. Texas Childrens Canc Ctr, Houston, TX USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 10012 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606606510 PM 27962524 ER PT J AU Wilson, W O'Connor, OO Roberts, AW Czuczman, M Brown, J Xiong, H Xiong, H Chiu, Y Krivoshik, A Enschede, S Humerickhouse, R AF Wilson, W. O'Connor, O. O. Roberts, A. W. Czuczman, M. Brown, J. Xiong, H. Xiong, H. Chiu, Y. Krivoshik, A. Enschede, S. Humerickhouse, R. TI ABT-263 activity and safety in patients with relapsed or refractory lymphoid malignancies in particular chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. Columbia Univ, New York, NY USA. Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Abbott Labs, Abbott Pk, IL 60064 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 8574 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606605483 ER PT J AU Wolmark, N Yothers, G O'Connell, MJ Sharif, S Atkins, JN Seay, TE Feherenbacher, L O'Reilly, S Allegra, CJ AF Wolmark, N. Yothers, G. O'Connell, M. J. Sharif, S. Atkins, J. N. Seay, T. E. Feherenbacher, L. O'Reilly, S. Allegra, C. J. TI A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 NSABP, Pittsburgh, PA USA. Univ Florida, Gainesville, FL USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. SE Canc Control Consortium CCOP, Goldsboro, NC USA. Atlanta Canc Care, Atlanta, GA USA. Kaiser Permanente No Calif, Vallejo, CA USA. All Ireland Cooperat Oncol Res Grp, Dublin, Ireland. NR 0 TC 15 Z9 15 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 MAY 20 PY 2009 VL 27 IS 15 SU S MA LBA4 PG 1 WC Oncology SC Oncology GA 582OF UT WOS:000276606600299 PM 27964154 ER PT J AU Yang, SX Costantino, JP Nguyen, D Jeong, J Mamounas, EP Wolmark, N Kim, C Kidwell, K Paik, S Swain, SM AF Yang, S. X. Costantino, J. P. Nguyen, D. Jeong, J. Mamounas, E. P. Wolmark, N. Kim, C. Kidwell, K. Paik, S. Swain, S. M. TI Correlation of levels of Akt phosphorylation at Ser473 with benefit from paclitaxel chemotherapy in NSABP B-28 patients with node-positive breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 [Yang, S. X.; Costantino, J. P.; Nguyen, D.; Jeong, J.; Mamounas, E. P.; Wolmark, N.; Kim, C.; Kidwell, K.; Paik, S.; Swain, S. M.] NCI, Bethesda, MD 20892 USA. [Yang, S. X.; Costantino, J. P.; Nguyen, D.; Jeong, J.; Mamounas, E. P.; Wolmark, N.; Kim, C.; Kidwell, K.; Paik, S.; Swain, S. M.] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Yang, S. X.; Costantino, J. P.; Nguyen, D.; Jeong, J.; Mamounas, E. P.; Wolmark, N.; Kim, C.; Kidwell, K.; Paik, S.; Swain, S. M.] Aultman Hlth Fdn, Canton, OH USA. [Yang, S. X.; Costantino, J. P.; Nguyen, D.; Jeong, J.; Mamounas, E. P.; Wolmark, N.; Kim, C.; Kidwell, K.; Paik, S.; Swain, S. M.] Washington Hosp Ctr, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA 537 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606601247 PM 27960687 ER PT J AU Zeldis, JB Heller, C Seidel, G Yuldasheva, N Stirling, D Shutack, Y Libutti, SK AF Zeldis, J. B. Heller, C. Seidel, G. Yuldasheva, N. Stirling, D. Shutack, Y. Libutti, S. K. TI A randomized phase II trial comparing two doses of lenalidomide for the treatment of stage IV ocular melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Celgene Corp, Summit, NJ USA. Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2009 VL 27 IS 15 SU S MA e20012 PG 2 WC Oncology SC Oncology GA 582OF UT WOS:000276606606111 PM 27962565 ER PT J AU Beane Freeman, LE Blair, A Lubin, JH Stewart, PA Hayes, RB Hoover, RN Hauptmann, M AF Beane Freeman, Laura E. Blair, Aaron Lubin, Jay H. Stewart, Patricia A. Hayes, Richard B. Hoover, Robert N. Hauptmann, Michael TI Mortality From Lymphohematopoietic Malignancies Among Workers in Formaldehyde Industries: The National Cancer Institute Cohort SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID OCCUPATIONAL EXPOSURE; LYMPHOCYTES; EMBALMERS; ABERRATIONS; ENVIRONMENT; RESINS; DEATH AB Formaldehyde exposure is associated with leukemia in some epidemiological studies. In the National Cancer Institute's formaldehyde cohort, previously followed through December 31, 1979, and updated through December 31, 1994, formaldehyde exposure was associated with an increased risk for leukemia, particularly myeloid leukemia, that increased with peak and average intensity of exposure. We extended follow-up through December 31, 2004 (median follow-up = 42 years), for 25 619 workers employed at one of 10 formaldehyde-using or formaldehyde-producing plants before 1966. We used Poisson regression to calculate relative risk (RR) estimates and 95% confidence intervals (CIs) to examine associations between quantitative formaldehyde exposure estimates (peak exposure, average intensity and cumulative exposure) and death from lymphohematopoietic malignancies. All statistical tests were two-sided and considered to be significant at P = .05. When follow-up ended in 2004, there were statistically significant increased risks for the highest vs lowest peak formaldehyde exposure category (>= 4 parts per million [ppm] vs > 0 to < 2.0 ppm) and all lymphohematopoietic malignancies (RR = 1.37; 95% CI = 1.03 to 1.81, P trend = .02) and Hodgkin lymphoma (RR = 3.96; 95% CI = 1.31 to 12.02, P trend = .01). Statistically nonsignificant associations were observed for multiple myeloma (RR = 2.04; 95% CI = 1.01 to 4.12, P trend > .50), all leukemia (RR = 1.42; 95% CI = 0.92 to 2.18, P trend = .12), and myeloid leukemia (RR = 1.78; 95% CI = 0.87 to 3.64, P trend = .13). There was little evidence of association for any lymphohematopoietic malignancy with average intensity or cumulative exposure at the end of follow-up in 2004. However, disease associations varied over time. For peak exposure, the highest formaldehyde-related risks for myeloid leukemia occurred before 1980, but trend tests attained statistical significance in 1990 only. After the mid-1990s, the formaldehyde-related risk of myeloid leukemia declined. Evaluation of risks over time suggests a possible link between formaldehyde exposure and lymphohematopoietic malignancies, particularly myeloid leukemia but also perhaps Hodgkin lymphoma and multiple myeloma. Observed patterns could be due to chance but are also consistent with a causal association within the relatively short induction-incubation periods characteristic of leukemogenesis. Further epidemiological study and exploration of potential molecular mechanisms are warranted. C1 [Beane Freeman, Laura E.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Rockville, MD 20892 USA. RP Beane Freeman, LE (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, 6120 Execut Blvd,EPS 8112, Rockville, MD 20892 USA. EM freemala@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015 OI Beane Freeman, Laura/0000-0003-1294-4124 FU Intramural Research Program; Division of Cancer Epidemiology and Genetics, National Cancer Institute; National Institutes of Health FX Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health NR 51 TC 17 Z9 18 U1 1 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 20 PY 2009 VL 101 IS 10 BP 751 EP 761 DI 10.1093/jnci/djp096 PG 11 WC Oncology SC Oncology GA 449TE UT WOS:000266352100012 PM 19436030 ER PT J AU Lacey, JV Chia, VM AF Lacey, James V., Jr. Chia, Victoria M. TI Endometrial hyperplasia and the risk of progression to carcinoma SO MATURITAS LA English DT Review DE Uterine cancer; WHO; Complex atypical hyperplasia; Cancer precursor; Progression risk ID WELL-DIFFERENTIATED CARCINOMA; K-RAS MUTATIONS; MICROSATELLITE INSTABILITY; ATYPICAL HYPERPLASIA; TRANSVAGINAL ULTRASONOGRAPHY; INTRAEPITHELIAL NEOPLASIA; CURETTAGE SPECIMENS; PTEN EXPRESSION; LONG-TERM; CANCER AB The primary presenting symptom of endometrial neoplasia is abnormal uterine bleeding, which typically prompts an endometrial biopsy to rule out carcinoma. Approximately 70% of women with abnormal uterine bleeding are diagnosed with benign findings and 15% are diagnosed with carcinoma. The remaining 15% receive a diagnosis of endometrial hyperplasia (EH), which includes a broad range of lesions, from mild, reversible proliferations to the immediate precursors of carcinoma. The widely used World Health Organization (WHO) system classifies EH according to four combinations of glandular crowding and nuclear atypia: simple (SH), complex (CH), simple atypical (SAH), or complex atypical hyperplasia (CAH), although the two forms of atypical hyperplasia (AH) are often collapsed into one category. Diagnoses of EH raise three issues. First, the low interobserver reproducibility-less than 50% in almost all studies-hinders the ability of WHO-based classification to effectively guide clinical management. Second, approximately 50% of women diagnosed with AH have concurrent carcinoma. Not surprisingly, most women with AH undergo hysterectomy as primary treatment, but non-surgical management can be effective. Third, data on progression risks for women with EH who retain their uterus are extremely limited. Emerging data indicate the long-term risk among women with SH or CH is less than 5%, but the risk among women with AH is approximately 30%. These data highlight priority areas for future research, such as increasing the diagnostic reproducibility of EH, improving the discrimination between AH and carcinoma, and identifying biomarkers to stratify risks or serve as indicators of response to clinical treatment. (C) 2009 Published by Elsevier Ireland Ltd. C1 [Lacey, James V., Jr.; Chia, Victoria M.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Lacey, JV (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd MSC 7234, Rockville, MD 20852 USA. EM jimlacey@nih.gov NR 58 TC 42 Z9 47 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-5122 J9 MATURITAS JI Maturitas PD MAY 20 PY 2009 VL 63 IS 1 BP 39 EP 44 DI 10.1016/j.maturitas.2009.02.005 PG 6 WC Geriatrics & Gerontology; Obstetrics & Gynecology SC Geriatrics & Gerontology; Obstetrics & Gynecology GA 463VY UT WOS:000267462300008 PM 19285814 ER PT J AU Sapsford, KE Farrell, D Sun, S Rasooly, A Mattoussi, H Medintz, IL AF Sapsford, Kim E. Farrell, Dorothy Sun, Steven Rasooly, Avraham Mattoussi, Hedi Medintz, Igor L. TI Monitoring of enzymatic proteolysis on a electroluminescent-CCD microchip platform using quantum dot-peptide substrates SO SENSORS AND ACTUATORS B-CHEMICAL LA English DT Article; Proceedings Paper CT 9th European Conference on Optical Chemical Sensors and Biosensors (EUROPT(R) ODE 9) CY MAR 30-APR 02, 2008 CL Dublin, IRELAND DE Electroluminescent excitation; CCD; Resonance energy transfer; FRET; Quantum dots; Peptides; Protease sensor; Trypsin; Microfabricated device; Biosensor ID RESONANCE ENERGY-TRANSFER; TRYPSIN INHIBITION; PROTEASES; PROTEIN; KINETICS; DEVICES; NANOCRYSTALLITES; FLUOROPHORES; LIGANDS; SYSTEMS AB Microfabricated devices will have a large impact on many aspects of analytical chemistry from clinical diagnostics to security applications due to their small size, ease of fabrication, portability and low sample volumes. In this report we compare quantum dot (QD)-peptide fluorescence resonance energy transfer (FRET) and Subsequent FRET-based monitoring of enzymatic proteolysis on both a conventional laboratory fluorescent assay plate reader and an electroluminescent-charged-coupled device (EL-CCD) microchip detection platform. The EL-CCD setup combines the spatial detection of CCD with the simple illumination provided by EL strips to measure fluorescence from multi-well credit card-sized sample chips. Data on FRET between a QD donor and a dye-labeled peptide acceptor along with their usage as a substrate for trypsin proteolysis were collected on both platforms and analyzed. Despite a greater than 12-fold reduction in assay volumes in the microchip format and simplification of excitation/emission monitoring, the data reflected a general agreement including an analysis of the QD donor-dye acceptor FRET efficiency and the determination of proteolytic kinetic parameters such as enzymatic velocity V(max) and the Michaelis constant Km. The EL-CCD was further utilized to monitor specific ovomucoid inhibition of trypsin activity. The results suggest that the unique properties inherent to QDs can be combined with the reduced-scale nature of microfabricated devices to make them suitable fora variety of focused bioanalytical applications. including point-of-care diagnostics and global healthcare applications. (C) 2008 Elsevier B.V. All rights reserved. C1 [Sapsford, Kim E.; Sun, Steven; Rasooly, Avraham] US FDA, Div Biol, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Farrell, Dorothy; Mattoussi, Hedi] USN, Div Opt Sci Code 5611, Res Lab, Washington, DC 20375 USA. [Sun, Steven] Univ Maryland Baltimore Cty, Ctr Adv Sensor Technol, Baltimore, MD 21227 USA. [Rasooly, Avraham] NCI, Bethesda, MD 20892 USA. [Medintz, Igor L.] USN, Ctr Biol Mol Sci & Engn Code 6900, Res Lab, Washington, DC 20375 USA. RP Sapsford, KE (reprint author), US FDA, Div Biol, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM Kim.sapsford@fda.hhs.gov; Igor.Medintz@nrl.navy.mil NR 50 TC 64 Z9 64 U1 3 U2 36 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0925-4005 J9 SENSOR ACTUAT B-CHEM JI Sens. Actuator B-Chem. PD MAY 20 PY 2009 VL 139 IS 1 BP 13 EP 21 DI 10.1016/j.snb.2008.07.026 PG 9 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA 450VO UT WOS:000266429400004 ER PT J AU Klusak, V Barinka, C Plechanovova, A Mlcochova, P Konvalinka, J Rulisek, L Lubkowski, J AF Klusak, Vojtech Barinka, Cyril Plechanovova, Anna Mlcochova, Petra Konvalinka, Jan Rulisek, Lubomir Lubkowski, Jacek TI Reaction Mechanism of Glutamate Carboxypeptidase II Revealed by Mutagenesis, X-ray Crystallography, and Computational Methods SO BIOCHEMISTRY LA English DT Article ID AEROMONAS-PROTEOLYTICA AMINOPEPTIDASE; STREPTOMYCES-GRISEUS AMINOPEPTIDASE; LENS LEUCINE AMINOPEPTIDASE; SITE-DIRECTED MUTAGENESIS; MEMBRANE ANTIGEN; ACTIVE-SITE; BASIS-SETS; PEPTIDE HYDROLYSIS; TRANSITION-STATE; ANGSTROM RESOLUTION AB Glutamate carboxypeptidase II (GCPII, EC 3.4.17.21) is a zinc-dependent exopeptidase and an important therapeutic target for neurodegeneration and prostate cancer. The hydrolysis of N-acetyl-L-aspartyl-L-glutamate (N-Ac-Asp-Glu), the natural dipeptidic substrate of the GCPII, is intimately involved in cellular signaling within the mammalian nervous system, but the exact mechanism of this reaction has not yet been determined. To investigate peptide hydrolysis by GCPII in detail, we constructed a mutant of human GCPII [GCPII(E424A)], in which Glu424, a putative proton shuttle residue, is substituted with alanine. Kinetic analysis of GCPII(E424A) using N-Ac-Asp-Glu as substrate revealed a complete loss of catalytic activity, suggesting the direct involvement of Glu424 in peptide hydrolysis. Additionally, we determined the crystal structure of GCPII(E424A) in complex with N-Ac-Asp-Glu at 1.70 angstrom resolution. The presence of the intact substrate in the GCPII(E424A) binding cavity substantiates our kinetic data and allows a detailed analysis of GCPII/N-Ac-Asp-Glu interactions. The experimental data are complemented by the combined quantum mechanics/molecular mechanics calculations (QM/MM) which enabled us to characterize the transition states, including the associated reaction barriers, and provided detailed information concerning the GCPII reaction mechanism. The best estimate of the reaction barrier was calculated to be Delta G double dagger approximate to 22(+/- 5) kcal.mol(-1), which is in a good agreement with the experimentally observed reaction rate constant (kcat approximate to 1 s(-1)). Combined together, our results provide a detailed and consistent picture of the reaction mechanism of this highly interesting enzyme at the atomic level. C1 [Klusak, Vojtech; Plechanovova, Anna; Mlcochova, Petra; Konvalinka, Jan; Rulisek, Lubomir] Acad Sci Czech Republic, Inst Organ Chem & Biochem, Gilead Sci Res Ctr, CR-16610 Prague 6, Czech Republic. [Klusak, Vojtech; Plechanovova, Anna; Mlcochova, Petra; Konvalinka, Jan; Rulisek, Lubomir] Acad Sci Czech Republic, IOCB, CR-16610 Prague 6, Czech Republic. [Mlcochova, Petra; Konvalinka, Jan] Charles Univ Prague, Fac Sci, Dept Biochem, Prague 2, Czech Republic. [Barinka, Cyril; Lubkowski, Jacek] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Rulisek, L (reprint author), Acad Sci Czech Republic, Inst Organ Chem & Biochem, Gilead Sci Res Ctr, Flemingovo Nam 2, CR-16610 Prague 6, Czech Republic. EM lubos@uochb.cas.cz; jacek@ncifcrf.gov RI Rulisek, Lubomir/G-5277-2014; Konvalinka, Jan/G-7518-2014; Barinka, Cyril/G-9803-2014; OI Konvalinka, Jan/0000-0003-0695-9266 FU National Institutes of Health; National Cancer Institute; Center for Cancer Research; Ministry of Education, Youth, and Sports of the Czech Republic [1M0508, Z40550506, LC512]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This project was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (C.B. and J.L.) and the Ministry of Education, Youth, and Sports of the Czech Republic (Projects 1M0508, Z40550506, and LC512). Use of the APS 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 50 TC 33 Z9 34 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 19 PY 2009 VL 48 IS 19 BP 4126 EP 4138 DI 10.1021/bi900220s PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 445JP UT WOS:000266047400012 PM 19301871 ER PT J AU Ng, CL Waterman, DG Koonin, EV Walters, AD Chong, JPJ Isupov, MN Lebedev, AA Bunka, DHJ Stockley, PG Ortiz-Lombardia, M Antson, AA AF Ng, C. Leong Waterman, David G. Koonin, Eugene V. Walters, Alison D. Chong, James P. J. Isupov, Michail N. Lebedev, Andrey A. Bunka, David H. J. Stockley, Peter G. Ortiz-Lombardia, Miguel Antson, Alfred A. TI Conformational flexibility and molecular interactions of an archaeal homologue of the Shwachman-Bodian-Diamond syndrome protein SO BMC STRUCTURAL BIOLOGY LA English DT Article ID MACROMOLECULAR STRUCTURES; GLOBAL ANALYSIS; WEB SERVER; SBDS GENE; YEAST; RNA; MUTATIONS; SEQUENCE; FAMILY; REPLACEMENT AB Background: Defects in the human Shwachman-Bodian-Diamond syndrome (SBDS) protein-coding gene lead to the autosomal recessive disorder characterised by bone marrow dysfunction, exocrine pancreatic insufficiency and skeletal abnormalities. This protein is highly conserved in eukaryotes and archaea but is not found in bacteria. Although genomic and biophysical studies have suggested involvement of this protein in RNA metabolism and in ribosome biogenesis, its interacting partners remain largely unknown. Results: We determined the crystal structure of the SBDS orthologue from Methanothermobacter thermautotrophicus (mthSBDS). This structure shows that SBDS proteins are highly flexible, with the N-terminal FYSH domain and the C-terminal ferredoxin-like domain capable of undergoing substantial rotational adjustments with respect to the central domain. Affinity chromatography identified several proteins from the large ribosomal subunit as possible interacting partners of mthSBDS. Moreover, SELEX (Systematic Evolution of Ligands by EXponential enrichment) experiments, combined with electrophoretic mobility shift assays (EMSA) suggest that mthSBDS does not interact with RNA molecules in a sequence specific manner. Conclusion: It is suggested that functional interactions of SBDS proteins with their partners could be facilitated by rotational adjustments of the N-terminal and the C-terminal domains with respect to the central domain. Examination of the SBDS protein structure and domain movements together with its possible interaction with large ribosomal subunit proteins suggest that these proteins could participate in ribosome function. C1 [Ng, C. Leong] MRC, Mol Biol Lab, Struct Studies Div, Cambridge CB2 0QH, England. [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Walters, Alison D.; Chong, James P. J.] Univ York, Dept Biol, York YO10 5YW, N Yorkshire, England. [Isupov, Michail N.] Univ Exeter, Sch Biosci, Exeter EX4 4QD, Devon, England. [Bunka, David H. J.; Stockley, Peter G.] Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England. [Ng, C. Leong; Waterman, David G.; Lebedev, Andrey A.; Ortiz-Lombardia, Miguel; Antson, Alfred A.] Univ York, Dept Chem, York Struct Biol Lab, York YO10 5YW, N Yorkshire, England. RP Ortiz-Lombardia, M (reprint author), Architecture & Fonct Macromol Biol UMR 9068, Case 932,163 Ave Luminy, F-13288 Marseille 9, France. EM clng@mrc-lmb.cam.ac.uk; david.waterman@diamond.ac.uk; koonin@ncbi.nlm.nih.gov; adw501@york.ac.uk; jpjc1@york.ac.uk; M.Isupov@exeter.ac.uk; lebedev@ysbl.york.ac.uk; bmbdhjb@bmb.leeds.ac.uk; P.G.Stockley@leeds.ac.uk; miguel.ortiz-lombardia@afmb.univ-mrs.fr; fred@ysbl.york.ac.uk RI Ng, Chyan Leong/E-9689-2014; Antson, Alfred/N-2551-2016; OI Ng, Chyan Leong/0000-0001-8590-7418; Antson, Alfred/0000-0002-4533-3816; Chong, James/0000-0001-9447-7421; Isupov, Michail/0000-0001-6842-4289 FU Wellcome Trust [081916] FX This work was supported by the Wellcome Trust (fellowship 081916 to AAA). We thank M. Chechik for her technical assistance and Martin Walsh for help during the data collection at the ESRF BM14 beamline (Grenoble, France). We also thank Alan Warren for critically reading the manuscript and useful suggestions. NR 39 TC 16 Z9 17 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2237 J9 BMC STRUCT BIOL JI BMC Struct. Biol. PD MAY 19 PY 2009 VL 9 AR 32 DI 10.1186/1472-6807-9-32 PG 15 WC Biophysics SC Biophysics GA 458BQ UT WOS:000266987800001 PM 19454024 ER PT J AU Thompson, KE Wang, YL Madej, T Bryant, SH AF Thompson, Kenneth Evan Wang, Yanli Madej, Tom Bryant, Stephen H. TI Improving protein structure similarity searches using domain boundaries based on conserved sequence information SO BMC STRUCTURAL BIOLOGY LA English DT Article ID STRUCTURE ALIGNMENT; 3-DIMENSIONAL STRUCTURE; GAMMAG-IMMUNOGLOBULIN; COVALENT STRUCTURE; DATABASE; CLASSIFICATION; MOLECULE; TOOLS; CATH; CDD AB Background: The identification of protein domains plays an important role in protein structure comparison. Domain query size and composition are critical to structure similarity search algorithms such as the Vector Alignment Search Tool (VAST), the method employed for computing related protein structures in NCBI Entrez system. Currently, domains identified on the basis of structural compactness are used for VAST computations. In this study, we have investigated how alternative definitions of domains derived from conserved sequence alignments in the Conserved Domain Database (CDD) would affect the domain comparisons and structure similarity search performance of VAST. Results: Alternative domains, which have significantly different secondary structure composition from those based on structurally compact units, were identified based on the alignment footprints of curated protein sequence domain families. Our analysis indicates that domain boundaries disagree on roughly 8% of protein chains in the medium redundancy subset of the Molecular Modeling Database (MMDB). These conflicting sequence based domain boundaries perform slightly better than structure domains in structure similarity searches, and there are interesting cases when structure similarity search performance is markedly improved. Conclusion: Structure similarity searches using domain boundaries based on conserved sequence information can provide an additional method for investigators to identify interesting similarities between proteins with known structures. Because of the improvement in performance of structure similarity searches using sequence domain boundaries, we are in the process of implementing their inclusion into the VAST search and MMDB resources in the NCBI Entrez system. C1 [Thompson, Kenneth Evan; Wang, Yanli; Madej, Tom; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Bryant, SH (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike,Bldg 38A, Bethesda, MD 20892 USA. EM EvanThompson@jhu.edu; ywang@ncbi.nlm.nih.gov; madej@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov FU NIH FX This research was supported by the Intramural Research Program of the NIH. NR 34 TC 2 Z9 3 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2237 J9 BMC STRUCT BIOL JI BMC Struct. Biol. PD MAY 19 PY 2009 VL 9 AR 33 DI 10.1186/1472-6807-9-33 PG 10 WC Biophysics SC Biophysics GA 458BQ UT WOS:000266987800002 PM 19454035 ER PT J AU Gladwin, MT Aletras, AH Cannon, RO Arai, AE AF Gladwin, Mark T. Aletras, Anthony H. Cannon, Richard O., III Arai, Andrew E. TI Letter by Tsikas and Rossi Regarding Article, "Nitrite Anion Provides Potent Cytoprotective and Antiapoptotic Effects as Adjunctive Therapy to Reperfusion for Acute Myocardial Infarction" Response SO CIRCULATION LA English DT Letter ID SYNTHASE; OXIDASE; BLOOD C1 [Gladwin, Mark T.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. [Aletras, Anthony H.; Cannon, Richard O., III; Arai, Andrew E.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. NR 5 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 19 PY 2009 VL 119 IS 19 BP E532 EP E532 DI 10.1161/CIRCULATIONAHA.108.814699 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 447NY UT WOS:000266199400019 ER PT J AU Hummel, FC Steven, B Hoppe, J Heise, K Thomalla, G Cohen, LG Gerloff, C AF Hummel, F. C. Steven, B. Hoppe, J. Heise, K. Thomalla, G. Cohen, L. G. Gerloff, C. TI Deficient intracortical inhibition (SICI) during movement preparation after chronic stroke SO NEUROLOGY LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; UNAFFECTED HEMISPHERE; INTERHEMISPHERIC INHIBITION; CORTICAL DISINHIBITION; HAND FUNCTION; RECOVERY; EXCITABILITY; BRAIN; FACILITATION AB Background: In healthy subjects, preparation to move is accompanied by motor cortical disinhibition. Poor control of intracortical inhibitory function in the primary motor cortex (M1) might contribute to persistent abnormal motor behavior in the paretic hand after chronic stroke. Methods: Here, we studied GABAergic short intracortical inhibition (SICI) in the ipsilesional M1 in well-recovered chronic stroke patients (n = 14; 63.8 +/- 3.0 years) engaged in preparation to move the impaired hand in a reaction time paradigm. Results: The main finding was an abnormal persistence of SICI in the ipsilesional M1 during movement preparation that was absent in age-matched controls (n = 14). Additionally, resting SICI was reduced in the patient group relative to controls. Conclusions: Our findings document a deficit of dynamic premovement modulation of intracortical inhibition in the ipsilesional primary motor cortex of patients with chronic stroke. This abnormality might contribute to deficits in motor control of the paretic hand, presenting a possible target for correction in the framework of developing novel therapeutic interventions after chronic stroke. Neurology (R) 2009; 72: 1766-1772 C1 [Hummel, F. C.; Steven, B.; Hoppe, J.; Heise, K.; Thomalla, G.; Gerloff, C.] Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Brain Imaging & Neurostimulat Lab, D-20246 Hamburg, Germany. [Hummel, F. C.; Cohen, L. G.] Natl Inst Neurol Disorders & Stroke, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD USA. RP Hummel, FC (reprint author), Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Brain Imaging & Neurostimulat Lab, D-20246 Hamburg, Germany. EM f.hummel@uke.uni-hamburg.de OI Heise, Kirstin-Friederike/0000-0003-3666-8531 FU Alexander von Humboldt Foundation; Deutsche Forschungsgemeinschaft [SFB 550 A13]; FFM of the University of Hamburg [NWF04/07]; intramural National Institute of Neurological Disorders and Stroke program, NIH FX Supported by a grant from the Alexander von Humboldt Foundation (Feodor-Lynen) to F. H., by the Deutsche Forschungsgemeinschaft (SFB 550 A13 to F. H.), by the FFM of the University of Hamburg (NWF04/07 to F. H.), and by the intramural National Institute of Neurological Disorders and Stroke program, NIH. NR 39 TC 29 Z9 29 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 19 PY 2009 VL 72 IS 20 BP 1766 EP 1772 DI 10.1212/WNL.0b013e3181a609c5 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 447EB UT WOS:000266173300010 PM 19451532 ER PT J AU Ellison, DW Clark, TR Sturdevant, DE Virtaneva, K Hackstadt, T AF Ellison, Damon W. Clark, Tina R. Sturdevant, Daniel E. Virtaneva, Kimmo Hackstadt, Ted TI Limited Transcriptional Responses of Rickettsia rickettsii Exposed to Environmental Stimuli SO PLOS ONE LA English DT Article AB Rickettsiae are strict obligate intracellular pathogens that alternate between arthropod and mammalian hosts in a zoonotic cycle. Typically, pathogenic bacteria that cycle between environmental sources and mammalian hosts adapt to the respective environments by coordinately regulating gene expression such that genes essential for survival and virulence are expressed only upon infection of mammals. Temperature is a common environmental signal for upregulation of virulence gene expression although other factors may also play a role. We examined the transcriptional responses of Rickettsia rickettsii, the agent of Rocky Mountain spotted fever, to a variety of environmental signals expected to be encountered during its life cycle. R. rickettsii exposed to differences in growth temperature (25 degrees C vs. 37 degrees C), iron limitation, and host cell species displayed nominal changes in gene expression under any of these conditions with only 0, 5, or 7 genes, respectively, changing more than 3-fold in expression levels. R. rickettsii is not totally devoid of ability to respond to temperature shifts as cold shock (37 degrees C vs. 4 degrees C) induced a change greater than 3-fold in up to 56 genes. Rickettsiae continuously occupy a relatively stable environment which is the cytosol of eukaryotic cells. Because of their obligate intracellular character, rickettsiae are believed to be undergoing reductive evolution to a minimal genome. We propose that their relatively constant environmental niche has led to a minimal requirement for R. rickettsii to respond to environmental changes with a consequent deletion of non-essential transcriptional response regulators. A minimal number of predicted transcriptional regulators in the R. rickettsii genome is consistent with this hypothesis. RP Ellison, DW (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. EM thackstadt@niaid.nih.gov FU Intramural NIH HHS NR 60 TC 18 Z9 18 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 19 PY 2009 VL 4 IS 5 AR e5612 DI 10.1371/journal.pone.0005612 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 446ZK UT WOS:000266161200013 PM 19440298 ER PT J AU Caldas-Lopes, E Cerchietti, L Ahn, JH Clement, CC Robles, AI Rodina, A Moulick, K Taldone, T Gozman, A Guo, YK Wu, N de Stanchina, E White, J Gross, SS Ma, YL Varticovski, L Melnick, A Chiosis, G AF Caldas-Lopes, Eloisi Cerchietti, Leandro Ahn, James H. Clement, Cristina C. Robles, Ana I. Rodina, Anna Moulick, Kamalika Taldone, Tony Gozman, Alexander Guo, Yunke Wu, Nian de Stanchina, Elisa White, Julie Gross, Steven S. Ma, Yuliang Varticovski, Lyuba Melnick, Ari Chiosis, Gabriela TI Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE targeted therapy; triple-negative breast tumors; heat shock protein 90; purine-scaffold Hsp90 inhibitor PU-H71; basal-like breast cancer ID NF-KAPPA-B; HEAT-SHOCK-PROTEIN-90 INHIBITOR; AKT; METASTASIS; KINASE; GROWTH; CELLS; PHOSPHORYLATION; XENOGRAFTS; ACTIVATION AB Triple-negative breast cancers (TNBCs) are defined by a lack of expression of estrogen, progesterone, and HER2 receptors. Because of the absence of identified targets and targeted therapies, and due to a heterogeneous molecular presentation, treatment guidelines for patients with TNBC include only conventional chemotherapy. Such treatment, while effective for some, leaves others with high rates of early relapse and is not curative for any patient with metastatic disease. Here, we demonstrate that these tumors are sensitive to the heat shock protein 90 (Hsp90) inhibitor PU-H71. Potent and durable anti-tumor effects in TNBC xenografts, including complete response and tumor regression, without toxicity to the host are achieved with this agent. Notably, TNBC tumors respond to retreatment with PU-H71 for several cycles extending for over 5 months without evidence of resistance or toxicity. Through a proteomics approach, we show that multiple oncoproteins involved in tumor proliferation, survival, and invasive potential are in complex with PU-H71-bound Hsp90 in TNBC. PU-H71 induces efficient and sustained downregulation and inactivation, both in vitro and in vivo, of these proteins. Among them, we identify downregulation of components of the Ras/Raf/MAPK pathway and G(2)-M phase to contribute to its anti-proliferative effect, degradation of activated Akt and Bcl-xL to induce apoptosis, and inhibition of activated NF-kappa B, Akt, ERK2, Tyk2, and PKC to reduce TNBC invasive potential. The results identify Hsp90 as a critical and multimodal target in this most difficult to treat breast cancer subtype and support the use of the Hsp90 inhibitor PU-H71 for clinical trials involving patients with TNBC. C1 [Caldas-Lopes, Eloisi; Ahn, James H.; Clement, Cristina C.; Rodina, Anna; Moulick, Kamalika; Taldone, Tony; Gozman, Alexander; Guo, Yunke; Wu, Nian; de Stanchina, Elisa; White, Julie; Chiosis, Gabriela] Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol & Chem, New York, NY 10021 USA. [Caldas-Lopes, Eloisi; Ahn, James H.; Clement, Cristina C.; Rodina, Anna; Moulick, Kamalika; Taldone, Tony; Gozman, Alexander; Guo, Yunke; Wu, Nian; de Stanchina, Elisa; White, Julie; Chiosis, Gabriela] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Cerchietti, Leandro; Gross, Steven S.; Ma, Yuliang; Melnick, Ari] Weill Cornell Med Coll, Dept Med, Div Hematol & Med Oncol, New York, NY 10065 USA. [Cerchietti, Leandro; Gross, Steven S.; Ma, Yuliang; Melnick, Ari] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10065 USA. [Robles, Ana I.; Varticovski, Lyuba] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Chiosis, G (reprint author), Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol & Chem, New York, NY 10021 USA. EM chiosisg@mskcc.org OI Cerchietti, Leandro/0000-0003-0608-1350 FU Manhasset Women's Coalition Against Breast Cancer; Byrne Fund; Geoffrey Beene Cancer Research Center of Memorial Sloan-Kettering Cancer Center; Susan G. Komen Breast Cancer Foundation; Commonwealth Cancer Foundation for Research; National Cancer Institute FX This work was supported in part by the Manhasset Women's Coalition Against Breast Cancer (G. C.), the Byrne Fund, the Geoffrey Beene Cancer Research Center of Memorial Sloan-Kettering Cancer Center (MSKCC) (G. C.), the Susan G. Komen Breast Cancer Foundation (G. C.), the Translational and Integrative Medicine Research Fund of MSKCC (G. C.), Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Cancer Foundation for Research and the Experimental Therapeutics Center of MSKCC (G. C., E. C.-L., and C. C. C.), and the intramural program of the National Cancer Institute (A. I. R. and L. V.). We thank Danuta Zatorska for the synthesis of Hsp90 inhibitors. NR 30 TC 156 Z9 160 U1 1 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 19 PY 2009 VL 106 IS 20 BP 8368 EP 8373 DI 10.1073/pnas.0903392106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 447RH UT WOS:000266209000051 PM 19416831 ER PT J AU Pise-Masison, CA Marriott, SJ Marriott, S Masison, C Howley, P Jeang, KT Khalili, K Lairmore, M Gitlin, S Maheiux, R Semmes, OJ Shuh, M Lindholm, P Morris, C Munger, K Giam, CZ Derse, D Price, D Kashanchi, F Boris-Lawrie, K Chevalier, S AF Pise-Masison, Cynthia A. Marriott, Susan J. Marriott, Susan Masison, Cynthia Howley, Peter Jeang, Kuan-Teh Khalili, Kamel Lairmore, Michael Gitlin, Scott Maheiux, Renaud Semmes, O. John Shuh, Maureen Lindholm, Paul Morris, Cindy Munger, Karl Giam, Chou-Zen Derse, David Price, David Kashanchi, Fatah Boris-Lawrie, Kathleen Chevalier, Sebastien TI Memories of John N. Brady: scientist, mentor and friend SO RETROVIROLOGY LA English DT Biographical-Item AB Friends and colleagues remember John N. Brady, Ph.D., Chief of the Virus Tumor Biology Section of the Laboratory of Cellular Oncology, who died much too young at the age of 57 on April 27, 2009 of colon cancer. John grew up in Illinois and received his Ph.D. with Dr. Richard Consigli at Kansas State University studying the molecular structure of polyomavirus. In 1984 John came to the National Institutes of Health as a Staff Fellow in the laboratory of Dr. Norman Salzman, Laboratory of Biology of Viruses NIAID, where he was among the first to analyze SV40 transcription using in vitro transcription systems and to analyze regulatory sequences for SV40 late transcription. He then trained with Dr. George Khoury in the Laboratory of Molecular Virology NCI, where he identified SV40 T-antigen as a transcriptional activator protein. His research interests grew to focus on the human retroviruses: human T-cell lymphotropic virus type I (HTLV-1) and human immunodeficiency virus (HIV), analyzing how interactions between these viruses and the host cell influence viral gene regulation, viral pathogenesis and viral transformation. His research also impacted the fields of eukaryotic gene regulation and tumor suppressor proteins. John is survived by his wife, Laraine, and two sons, Matt and Kevin. C1 [Marriott, Susan J.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Pise-Masison, Cynthia A.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Howley, Peter; Munger, Karl] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Jeang, Kuan-Teh] NIAID, NIH, Bethesda, MD USA. [Khalili, Kamel] Temple Univ, Philadelphia, PA 19122 USA. [Lairmore, Michael; Boris-Lawrie, Kathleen] Ohio State Univ, Columbus, OH 43210 USA. [Gitlin, Scott] Univ Michigan, Ann Arbor, MI 48109 USA. [Maheiux, Renaud] ENS Lyon, Lyon, France. [Shuh, Maureen] Xavier Univ, Cincinnati, OH USA. [Lindholm, Paul] Northwestern Univ, Evanston, IL 60208 USA. [Morris, Cindy] Tulane Univ, New Orleans, LA 70118 USA. [Giam, Chou-Zen] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Price, David] Univ Iowa, Iowa City, IA 52242 USA. [Kashanchi, Fatah] George Washington Univ, Washington, DC 20052 USA. RP Marriott, SJ (reprint author), Baylor Coll Med, Dept Mol Virol & Microbiol, MS-385,1 Baylor Plaza, Houston, TX 77030 USA. EM masisonc@dce41.nci.nih.gov; susanm@bcm.edu RI Jeang, Kuan-Teh/A-2424-2008 FU NIAID NIH HHS [P30 AI036211] NR 1 TC 2 Z9 2 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD MAY 19 PY 2009 VL 6 AR 48 DI 10.1186/1742-4690-6-48 PG 8 WC Virology SC Virology GA 463KI UT WOS:000267430400001 PM 19454030 ER PT J AU Mackem, S Lewandoski, M AF Mackem, Susan Lewandoski, Mark TI Limb Development Takes a Measured Step Toward Systems Analysis SO SCIENCE SIGNALING LA English DT Article ID APICAL ECTODERMAL RIDGE; FEEDBACK LOOP; SONIC-HEDGEHOG; VERTEBRATE LIMB; REDUCTIONISM REDUX; BUD; ROBUSTNESS; EXPRESSION; EVOLUTION; GREMLIN AB Growth and patterning of the embryonic vertebrate limb is regulated by feedback loops signaling between the epithelium and mesenchyme of the limb bud. Fibroblast growth factor (FGF) signaling from the epithelium regulates Sonic hedgehog (Shh) expression in the mesenchyme. In turn, SHH activity maintains the expression of Gremlin1, which encodes a bone morphogenetic protein (BMP) antagonist; the interaction between BMP and Gremlin1 regulates Fgf gene expression. A computational model using data from complex genetic analysis and quantitative measurements of gene induction kinetics demonstrates that limb development is robust and thus buffered against certain mutational alterations and epigenetic changes because of these feedback loops. C1 [Mackem, Susan; Lewandoski, Mark] NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. RP Mackem, S (reprint author), NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. EM mackems@mail.nih.gov; mlewandoski@mail.ncifcrf.gov NR 35 TC 4 Z9 4 U1 1 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAY 19 PY 2009 VL 2 IS 71 AR pe33 DI 10.1126/scisignal.271pe33 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 567VK UT WOS:000275474700002 PM 19454648 ER PT J AU Satyanarayana, A Kaldis, P AF Satyanarayana, Ande Kaldis, Philipp TI A dual role of Cdk2 in DNA damage response SO CELL DIVISION LA English DT Article ID CYCLIN-DEPENDENT KINASES; CELL-CYCLE; PROTEIN; PHOSPHORYLATION; CHECKPOINTS; REPAIR; P21; CYCLIN-DEPENDENT-KINASE-2; ACTIVATION; INHIBITORS AB Once it was believed that Cdk2 was the master regulator of S phase entry. Gene knockout mouse studies of cell cycle regulators revealed that Cdk2 is dispensable for S phase initiation and progression whereby Cdk1 can compensate for the loss of Cdk2. Nevertheless, recent evidence indicates that Cdk2 is involved in cell cycle independent functions such as DNA damage repair. Whether these properties are unique to Cdk2 or also being compensated by other Cdks in the absence of Cdk2 is under extensive investigation. Here we review the emerging new role of Cdk2 in DNA damage repair and also discuss how the loss of Cdk2 impacts the G(1)/S phase DNA damage checkpoint. C1 [Satyanarayana, Ande] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Kaldis, Philipp] Proteos, IMCB, Singapore 138673, Singapore. RP Satyanarayana, A (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Bldg 560-22-69,1050 Boyles St, Frederick, MD 21702 USA. EM satya@ncifcrf.gov; kaldis@imcb.a-star.edu.sg RI Kaldis, Philipp/G-2714-2010; ASTAR, IMCB/E-2320-2012 OI Kaldis, Philipp/0000-0002-7247-7591; FU Kaldis laboratory; A*STAR of Singapore; NIH, National Cancer Institute, Center for Cancer Research FX The authors thank members of the Kaldis laboratory for discussions and support. This research was supported by A*STAR of Singapore (P. K.) and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (A. S). NR 27 TC 11 Z9 13 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1747-1028 J9 CELL DIV JI Cell Div. PD MAY 18 PY 2009 VL 4 AR 9 DI 10.1186/1747-1028-4-9 PG 4 WC Cell Biology SC Cell Biology GA 674WI UT WOS:000283780700001 PM 19445729 ER PT J AU Yang, F Je, HS Ji, YY Nagappan, G Hempstead, B Lu, B AF Yang, Feng Je, Hyun-Soo Ji, Yuanyuan Nagappan, Guhan Hempstead, Barbara Lu, Bai TI Pro-BDNF-induced synaptic depression and retraction at developing neuromuscular synapses SO JOURNAL OF CELL BIOLOGY LA English DT Article ID MATRIX METALLOPROTEINASES MMP-2; LONG-TERM DEPRESSION; HETEROSYNAPTIC SUPPRESSION; CORTICAL CIRCUITS; NEUROTROPHINS; POTENTIATION; PROBDNF; PLASTICITY; P75(NTR); RECEPTOR AB Postsynaptic cells generate positive and negative signals that retrogradely modulate presynaptic function. At developing neuromuscular synapses, prolonged stimulation of muscle cells induces sustained synaptic depression. We provide evidence that pro-brain-derived neurotrophic factor (BDNF) is a negative retrograde signal that can be converted into a positive signal by metalloproteases at the synaptic junctions. Application of pro-BDNF induces a dramatic decrease in synaptic efficacy followed by a retraction of presynaptic terminals, and these effects are mediated by presynaptic pan-neurotrophin receptor p75 (p75(NTR)), the pro-BDNF receptor. A brief stimulation of myocytes expressing cleavable or uncleavable pro-BDNF elicits synaptic potentiation or depression, respectively. Extracellular application of metalloprotease inhibitors, which inhibits the cleavage of endogenous pro-BDNF, facilitates the muscle stimulation-induced synaptic depression. Inhibition of presynaptic p75(NTR) or postsynaptic BDNF expression also blocks the activity-dependent synaptic depression and retraction. These results support a model in which postsynaptic secretion of a single molecule, pro-BDNF, may stabilize or eliminate presynaptic terminals depending on its proteolytic conversion at the synapses. C1 [Yang, Feng; Je, Hyun-Soo; Ji, Yuanyuan; Nagappan, Guhan; Lu, Bai] NICHHD, Sect Neural Dev & Plast, Bethesda, MD 20892 USA. [Yang, Feng; Je, Hyun-Soo; Ji, Yuanyuan; Nagappan, Guhan; Lu, Bai] NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Hempstead, Barbara] Cornell Univ, Weill Cornell Med Coll, Dept Med, Div Hematol & Med Oncol, New York, NY 10021 USA. RP Lu, B (reprint author), NICHHD, Sect Neural Dev & Plast, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Yang, Feng/C-9530-2011; Lu, Bai/A-4018-2012; OI Je, hyunsoo/0000-0002-2924-5621 FU National Institute of Mental Health; National Institute of Child Health and Human Development; National Institutes of Health FX The study was supported by the National Institute of Mental Health and National Institute of Child Health and Human Development intramural research programs to B. Lu and National Institutes of Health grants to B. Hempstead. NR 50 TC 53 Z9 55 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAY 18 PY 2009 VL 185 IS 4 BP 727 EP 741 DI 10.1083/jcb.200811147 PG 15 WC Cell Biology SC Cell Biology GA 448RO UT WOS:000266279900016 PM 19451278 ER PT J AU Kobrinsky, E Abrahimi, P Duong, SQ Thomas, S Harry, JB Patel, C Lao, QZ Soldatov, NM AF Kobrinsky, Evgeny Abrahimi, Parwiz Duong, Son Q. Thomas, Sam Harry, Jo Beth Patel, Chirag Lao, Qi Zong Soldatov, Nikolai M. TI Effect of Ca-v beta Subunits on Structural Organization of Ca(v)1.2 Calcium Channels SO PLOS ONE LA English DT Article AB Background: Voltage-gated Ca(v)1.2 calcium channels play a crucial role in Ca2+ signaling. The pore-forming alpha(1C) subunit is regulated by accessory Ca-v beta subunits, cytoplasmic proteins of various size encoded by four different genes (Ca-v beta(1) - beta(4)) and expressed in a tissue-specific manner. Methods and Results: Here we investigated the effect of three major Ca-v beta types, beta(1b), beta(2d) and beta(3), on the structure of Ca(v)1.2 in the plasma membrane of live cells. Total internal reflection fluorescence microscopy showed that the tendency of Ca(v)1.2 to form clusters depends on the type of the Ca-v beta subunit present. The highest density of Ca(v)1.2 clusters in the plasma membrane and the smallest cluster size were observed with neuronal/cardiac beta(1b) present. Ca(v)1.2 channels containing beta(3), the predominant Ca-v beta subunit of vascular smooth muscle cells, were organized in a significantly smaller number of larger clusters. The inter- and intramolecular distances between alpha(1C) and Ca-v beta in the plasma membrane of live cells were measured by three-color FRET microscopy. The results confirm that the proximity of Ca(v)1.2 channels in the plasma membrane depends on the Ca-v beta type. The presence of different Ca-v beta subunits does not result in significant differences in the intramolecular distance between the termini of alpha(1C), but significantly affects the distance between the termini of neighbor alpha(1C) subunits, which varies from 67 angstrom with beta(1b) to 79 A with beta(3). Conclusions: Thus, our results show that the structural organization of Ca(v)1.2 channels in the plasma membrane depends on the type of Ca-v beta subunits present. RP Kobrinsky, E (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM soldatovN@grc.nia.nih.gov FU Intramural NIH HHS; NIA NIH HHS [Z01 AG000294] NR 65 TC 6 Z9 6 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 18 PY 2009 VL 4 IS 5 AR e5587 DI 10.1371/journal.pone.0005587 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 446FZ UT WOS:000266107500016 PM 19492014 ER PT J AU Johnson, TR Rao, S Seder, RA Chen, M Graham, BS AF Johnson, Teresa R. Rao, Srinivas Seder, Robert A. Chen, Man Graham, Barney S. TI TLR9 agonist, but not TLR7/8, functions as an adjuvant to diminish FI-RSV vaccine-enhanced disease, while either agonist used as therapy during primary RSV infection increases disease severity SO VACCINE LA English DT Article DE RSV; Toll-like receptors; Eosinophil; Adjuvant; Pathogenesis; Immunization; Pathology ID RESPIRATORY-SYNCYTIAL-VIRUS; TOLL-LIKE RECEPTORS; T-CELL RESPONSES; G-GLYCOPROTEIN; DENDRITIC CELLS; STRAIN DIFFERENCES; NONHUMAN-PRIMATES; IMMUNE-RESPONSE; INNATE IMMUNITY; BALB/C MICE AB Agonists for TLR7, TLR8, and TLR9 have been shown to enhance vaccine immunogenicity. We evaluated the impact of TLR activation on RSV disease in a murine model by administering TLR7/8 and TLR9 agonists during FI-RSV immunization or RSV infection. CpG administered during immunization reduced disease following challenge as evidenced by decreased lung pathology, illness, and cytokines. In marked contrast, TLR7/8 agonist had little impact. To evaluate potential therapeutic use, TLR agonists were administered during primary infection. Although type 2 cytokine responses decreased and type 1 cytokines and MIP-1-alpha/beta increased, both TLR7/8 and TLR9 agonists increased clinical symptoms and pulmonary inflammation when administered during primary infection. Thus, TLR9-induced signaling during FI-RSV immunization reduced vaccine-enhanced disease whereas immunostimulatory properties of TLR agonists enhanced disease severity when used during RSV infection. Immunomodulation elicited by TLR9 agonist confirms the adjuvant potential of TLR agonists during RSV immunization. However, in contrast to work done with HIV-1 vaccines, the inability of TLR7/8 agonist to boost type 1 vaccine-induced RSV immunity demonstrates pathogen-TLR specificity. These data reveal that the timing of administration of immunomodulatory agents is critical. Furthermore, these data underscore that amplification of anti-viral immune responses may result in immunopathology rather than immune-mediated protection. Published by Elsevier Ltd. C1 [Johnson, Teresa R.; Chen, Man; Graham, Barney S.] NIAID, NIH, Vaccine Res Ctr, Viral Pathogenesis Lab, Bethesda, MD 20892 USA. [Rao, Srinivas] NIAID, NIH, Vaccine Res Ctr, Off Lab Anim Med, Bethesda, MD 20892 USA. [Seder, Robert A.] NIAID, NIH, Vaccine Res Ctr, Cellular Immunol Sect, Bethesda, MD 20892 USA. RP Johnson, TR (reprint author), Bldg 40Rm 2614,40Convent Dr,MSC3017, Bethesda, MD 20892 USA. EM teresaj@nih.gov FU Intramural NIH HHS [, NIH0010719202]; PHS HHS [NIH0010719202] NR 57 TC 22 Z9 23 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAY 18 PY 2009 VL 27 IS 23 BP 3045 EP 3052 DI 10.1016/j.vaccine.2009.03.026 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 450WM UT WOS:000266432100006 PM 19428918 ER PT J AU Sagara, I Dicko, A Ellis, RD Fay, MP Diawara, SI Assadou, MH Sissoko, MS Kone, M Diallo, AI Saye, R Guindo, MA Kante, O Niambele, MB Miura, K Mullen, GED Pierce, M Martin, LB Dolo, A Diallo, DA Doumbo, OK Miller, LH Saul, A AF Sagara, Issaka Dicko, Alassane Ellis, Ruth D. Fay, Michael P. Diawara, Sory I. Assadou, Mahamadoun H. Sissoko, Mahamadou S. Kone, Mamady Diallo, Abdoulbaki I. Saye, Renion Guindo, Merepen A. Kante, Ousmane Niambele, Mohamed B. Miura, Kazutoyo Mullen, Gregory E. D. Pierce, Mark Martin, Laura B. Dolo, Amagana Diallo, Dapa A. Doumbo, Ogobara K. Miller, Louis H. Saul, Allan TI A randomized controlled phase 2 trial of the blood stage AMA1-C1/Alhydrogel malaria vaccine in children in Mali SO VACCINE LA English DT Article DE Malaria; Vaccine; AMA1 ID APICAL MEMBRANE ANTIGEN-1; PLASMODIUM-FALCIPARUM MALARIA; ANTIBODY-RESPONSES; CLINICAL MALARIA; AMA1 VACCINE; CANDIDATE; MEROZOITES; PROTECTION; DIVERSITY; EFFICACY AB A double blind, randomized, controlled Phase 2 clinical trial was conducted to assess the safety, immunogenicity, and biologic impact of the vaccine candidate Apical Membrane Antigen 1-Combination 1 (AMA1-C1), adjuvanted with Alhydrogel (R) Participants were healthy children 2-3 years old living in or near the village of Bancoumana. Mali. A total of 300 children received either the study vaccine or the comparator. No impact of vaccination was seen on the primary endpoint, the frequency of parasitemia measured as episodes >3000/mu L/day at risk. There was a negative impact of vaccination on the hemoglobin level during clinical malaria, and mean incidence of hemoglobin <8.5 g/dL, in the direction of lower hemoglobin in the children who received AMA1-C1, although these differences were not significant after correction for multiple tests. These differences were not seen in the second year of transmission. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Sagara, Issaka; Dicko, Alassane; Diawara, Sory I.; Assadou, Mahamadoun H.; Sissoko, Mahamadou S.; Kone, Mamady; Diallo, Abdoulbaki I.; Saye, Renion; Guindo, Merepen A.; Kante, Ousmane; Niambele, Mohamed B.; Dolo, Amagana; Diallo, Dapa A.; Doumbo, Ogobara K.] Univ Bamako, Malaria Res & Training Ctr, Fac Med Pharm & Dent, Mali, Malaysia. [Ellis, Ruth D.; Miura, Kazutoyo; Mullen, Gregory E. D.; Pierce, Mark; Martin, Laura B.; Miller, Louis H.; Saul, Allan] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD USA. [Martin, Laura B.; Saul, Allan] Novartis Vaccines Inst Global Hlth Srl, Siena, Italy. [Pierce, Mark] Cookeville Reg Med Ctr, Cookeville, TN 38506 USA. [Mullen, Gregory E. D.] St Thomas Hosp, Rayne Inst, Div Imaging Sci, Sch Med,Kings Coll London, London SE1 7EH, England. RP Sagara, I (reprint author), Univ Bamako, Malaria Res & Training Ctr, Fac Med Pharm & Dent, BP 1805 Bamako, Mali, Malaysia. EM isagara@mrtcbko.org; ellisru@niaid.nih.gov RI Saul, Allan/I-6968-2013; Martin, Laura/N-1789-2013; OI Saul, Allan/0000-0003-0665-4091; Martin, Laura/0000-0002-4431-4381; Fay, Michael P./0000-0002-8643-9625 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank Janet Wittes, Tatiana Keita, Lawrence Yamuah, NIAID DSMB, Etsegenet Meshesha, Dick Sakai, Drissa Sow, and the volunteers in the villages for their cooperation. NR 35 TC 96 Z9 99 U1 0 U2 25 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAY 18 PY 2009 VL 27 IS 23 BP 3090 EP 3098 DI 10.1016/j.vaccine.2009.03.014 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 450WM UT WOS:000266432100011 PM 19428923 ER PT J AU Craig, AT Gavrilova, O Dwyer, NK Jou, W Pack, S Liu, E Pechhold, K Schmidt, M McAlister, VJ Chiorini, JA Blanchette-Mackie, EJ Harlan, DM Owens, RA AF Craig, Anthony T. Gavrilova, Oksana Dwyer, Nancy K. Jou, William Pack, Stephanie Liu, Eric Pechhold, Klaus Schmidt, Michael McAlister, Victor J. Chiorini, John A. Blanchette-Mackie, E. Joan Harlan, David M. Owens, Roland A. TI Transduction of rat pancreatic islets with pseudotyped adeno-associated virus vectors SO VIROLOGY JOURNAL LA English DT Article ID BETA GENE-TRANSFER; VIRAL VECTORS; AMPHIPATHIC HELIX; RODENT ISLETS; TRANSPLANTATION; EFFICIENT; SURVIVAL; RECEPTOR; GENOME; PURIFICATION AB Background: Pancreatic islet transplantation is a promising treatment for type I diabetes mellitus, but current immunosuppressive strategies do not consistently provide long-term survival of transplanted islets. We are therefore investigating the use of adeno-associated viruses (AAVs) as gene therapy vectors to transduce rat islets with immunosuppressive genes prior to transplantation into diabetic mice. Results: We compared the transduction efficiency of AAV2 vectors with an AAV2 capsid (AAV2/2) to AAV2 vectors pseudotyped with AAV5 (AAV2/5), AAV8 (AAV2/8) or bovine adeno-associated virus (BAAV) capsids, or an AAV2 capsid with an insertion of the low density lipoprotein receptor ligand from apolipoprotein E (AAV2apoE), on cultured islets, in the presence of helper adenovirus infection to speed expression of a GFP transgene. Confocal microscopy and flow cytometry were used. The AAV2/5 vector was superior to AAV2/2 and AAV2/8 in rat islets. Flow cytometry indicated AAV2/5-mediated gene expression in approximately 9% of rat islet cells and almost 12% of insulin-positive cells. The AAV2/8 vector had a higher dependence on the helper virus multiplicity of infection than the AAV 2/5 vector. In addition, the BAAV and AAV2apoE vectors were superior to AAV2/2 for transducing rat islets. Rat islets ( 300 per mouse) transduced with an AAV2/5 vector harboring the immunosuppressive transgene, tgf beta 1, retain the ability to correct hyperglycemia when transplanted into immunedeficient diabetic mice. Conclusion: AAV2/5 vectors may therefore be useful for pre-treating donor islets prior to transplantation. C1 [Craig, Anthony T.; McAlister, Victor J.; Owens, Roland A.] NIDDK, Mol & Cellular Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Craig, Anthony T.; Owens, Roland A.] Howard Univ, Grad Sch, Dept Genet & Human Genet, Washington, DC 20059 USA. [Gavrilova, Oksana; Jou, William; Pack, Stephanie] NIDDK, Mouse Metab Core Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Dwyer, Nancy K.; Blanchette-Mackie, E. Joan] NIDDK, Lab Cell Biochem & Biol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Liu, Eric; Pechhold, Klaus; Harlan, David M.] NIDDK, Diabet Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Schmidt, Michael; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Owens, RA (reprint author), NIDDK, Mol & Cellular Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM anthonycraig3@gmail.com; oksanag@intra.niddk.nih.gov; nancyd@bdg8.niddk.nih.gov; williaj@intra.niddk.nih.gov; spack@ocme.nyc.gov; ericliu2007@gmail.com; klausp@intra.niddk.nih.gov; mschmidt@mail.nih.gov; mcalisterv@niddk.nih.gov; jchiorini@dir.nidcr.nih.gov; joanbm@bdg8.niddk.nih.gov; davidmh@intra.niddk.nih.gov; owensrol@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Dental and Craniofacial Research; National Heart, Lung and Blood Institute 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, National Institute of Dental and Craniofacial Research, and National Heart, Lung and Blood Institute. NR 35 TC 3 Z9 3 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD MAY 18 PY 2009 VL 6 AR 61 DI 10.1186/1743-422X-6-61 PG 10 WC Virology SC Virology GA 452JF UT WOS:000266535600001 PM 19450275 ER PT J AU Thanos, PK Bermeo, C Wang, GJ Volkow, ND AF Thanos, Panayotis K. Bermeo, Carlos Wang, Gene-Jack Volkow, Nora D. TI D-Cycloserine accelerates the extinction of cocaine-induced conditioned place preference in C57bL/c mice SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Learning; Glutamate; Withdrawal; Abstinence; Drug abuse; NMDA; Addiction; Substance abuse ID FACILITATES EXTINCTION; NMDA; RECEPTORS; MEMORY; RATS; FEAR; REINSTATEMENT; ANTAGONISM; BEHAVIORS; CONTEXT AB Recently, it was shown that D-cycloserine (DCS, a NMDA partial agonist) facilitated extinction of fear as well as cocaine conditioned place preference (CPP) in rats. Methods: The present study examined the effects of DIES (115 mg/kg i.p. and 30 mg/kg i.p.) on extinction and renewal of cocaine-induced CPP in C57bL/c mice. In parallel, we examined the effects of DCS on locomotor activity. Results: Extinction to cocaine CPP was significantly faster with DCS than with vehicle treatment (three versus six sessions, respectively). After extinction was achieved, mice were retested for CPP 1 and 2 weeks later. All animals maintained extinction to CPP 1 week later, but at 2 weeks, the vehicle and the 15 mg/kg DCS-treated animals maintained the extinction, but the 30 mg/kg DCS-treated mice had renewed CPP. During induction of cocaine CPP mice displayed enhanced locomotor activity following treatment with cocaine, as expected, based on previous literature. During extinction, there were no differences in locomotor activity between the vehicle and the 15 mg/kg DCS-treated mice, whereas the 30 mg/kg DCS-treated animal showed significant locomotor activity inhibition. These results corroborate in mice the previously reported acceleration of extinction to cocaine-induced CPP by DCS in rats. However, we also show that the higher DCS doses facilitated CPP reestablishment after extinction. Thus, while DCS could be beneficial in accelerating the extinction to conditioned responses in addiction it could, at higher doses, increase the risk of relapse. Thus, studies evaluating the beneficial therapeutic effects of DCS should assess not only the short-term effects but also the potential of longer lasting undesirable effects. Published by Elsevier B.V. C1 [Thanos, Panayotis K.; Wang, Gene-Jack] Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol & Neuroimaging Lab, Upton, NY 11973 USA. [Thanos, Panayotis K.; Bermeo, Carlos; Volkow, Nora D.] NIAAA, Neuroimaging Lab, Intramural Program, NIH, Bethesda, MD USA. [Thanos, Panayotis K.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Bermeo, Carlos] SUNY Stony Brook, Sch Social Welf, Stony Brook, NY 11794 USA. RP Thanos, PK (reprint author), Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol & Neuroimaging Lab, Bldg 490, Upton, NY 11973 USA. EM thanos@bnl.gov FU National Institute of Health (NIH); U.S. Department of Energy [DE-AC02-98CH108886]; NIDA FX This work was supported by the Intramural Research Program of NIAAA at the National Institute of Health (NIH), the U.S. Department of Energy under contract DE-AC02-98CH108886 and the Behavioral Pharmacology and Neuroimaging Lab (http://www.bnl.gov/thanoslab). Carlos Bermeo was partially supported by the NIDA summer research program. NR 19 TC 44 Z9 47 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAY 16 PY 2009 VL 199 IS 2 BP 345 EP 349 DI 10.1016/j.bbr.2008.12.025 PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 429XP UT WOS:000264953700024 PM 19152811 ER PT J AU Engels, EA AF Engels, Eric A. TI Non-AIDS-defining malignancies in HIV-infected persons: etiologic puzzles, epidemiologic perils, prevention opportunities SO AIDS LA English DT Review DE cancer; hepatitis C virus; HIV/AIDS; human papillomavirus; immunodeficiency; tobacco use ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; SQUAMOUS INTRAEPITHELIAL LESIONS; HEPATITIS-C VIRUS; HEPATOCELLULAR-CARCINOMA; LUNG-CANCER; HUMAN-PAPILLOMAVIRUS; HODGKIN-LYMPHOMA; ANAL CANCER; CELL-CARCINOMA C1 NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Engels, EA (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7076, Rockville, MD 20852 USA. EM engelse@exchange.nih.gov FU Intramural Research Program of the National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. The views expressed are those of the author and should not be considered as reflecting views or policy of the National Cancer Institute. NR 97 TC 45 Z9 45 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 15 PY 2009 VL 23 IS 8 BP 875 EP 885 DI 10.1097/QAD.0b013e328329216a PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 446MH UT WOS:000266125200001 PM 19349851 ER PT J AU Johansen, AMW Wilcox, AJ Lie, RT Andersen, LF Drevon, CA AF Johansen, Anne Marte W. Wilcox, Allen J. Lie, Rolv T. Andersen, Lene F. Drevon, Christian A. TI Maternal Consumption of Coffee and Caffeine-containing Beverages and Oral Clefts: A Population-based Case-Control Study in Norway SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE caffeine; cleft lip; cleft palate; coffee; pregnancy ID PLASMA HOMOCYSTEINE; HEALTHY-VOLUNTEERS; OROFACIAL CLEFTS; RISK; ALCOHOL; SMOKING; COHORT; TRIAL; GENES AB A large, population-based case-control study of facial clefts was carried out in Norway between 1996 and 2001. The study included 573 cases-025EF377 with cleft lip with or without cleft palate and 196 with cleft palate only-025EFand 763 randomly selected controls. Maternal consumption of coffee and other caffeine-containing beverages in early pregnancy was recorded shortly after birth. Compared with that for no coffee consumption, the adjusted odds ratios for cleft lip with or without cleft palate were 1.39 (95% confidence interval: 1.01, 1.92) for less than 3 cups a day and 1.59 (95% confidence interval: 1.05, 2.39) for 3 cups or more. Coffee consumption was not associated with risk of cleft palate only (for >= 3 cups vs. none, adjusted odds ratio = 0.96, 95% confidence interval: 0.55, 1.67). Tea consumption was associated with a reduced odds ratio of both cleft lip with or without cleft palate and cleft palate only. There was little evidence of an association between caffeine exposure and clefts when all sources of caffeine were considered. Adjustment for known confounding factors in general had minor effects on risk estimates. Still, the authors could not rule out the possibility of uncontrolled confounding by factors associated with the habit of drinking coffee. C1 [Johansen, Anne Marte W.; Andersen, Lene F.; Drevon, Christian A.] Univ Oslo, Inst Basic Med Sci, Dept Nutr, N-0316 Oslo, Norway. [Wilcox, Allen J.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Durham, NC USA. [Lie, Rolv T.] Univ Bergen, Sect Epidemiol & Med Stat, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway. [Lie, Rolv T.] Norwegian Inst Publ Hlth, Med Birth Registry Norway, Bergen, Norway. RP Johansen, AMW (reprint author), Univ Oslo, Inst Basic Med Sci, Dept Nutr, POB 1046, N-0316 Oslo, Norway. EM a.m.w.johansen@medisin.uio.no RI Drevon, Christian /F-6012-2010; OI Wilcox, Allen/0000-0002-3376-1311 FU Research Council of Norway [166026/V50]; Freia Medical Foundation; Throne-Holst Foundation for Nutrition Research; Faculty of Medicine, University of Oslo, Oslo, Norway; Nutrigenomics, Network of Excellence, FP6, Food Quality and Safety [NuGO FP6-506360]; Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences FX This work was supported by the Research Council of Norway (grant 166026/V50); the Freia Medical Foundation; the Throne-Holst Foundation for Nutrition Research; the thematic area of perinatal nutrition, Faculty of Medicine, University of Oslo, Oslo, Norway; and Nutrigenomics, Network of Excellence, FP6, Food Quality and Safety (NuGO FP6-506360). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 23 TC 12 Z9 13 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 15 PY 2009 VL 169 IS 10 BP 1216 EP 1222 DI 10.1093/aje/kwp040 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 440ZX UT WOS:000265739600007 PM 19342400 ER PT J AU Duncan, AJ Bitner-Glindzicz, M Meunier, B Costello, H Hargreaves, IP Lopez, LC Hirano, M Quinzii, CM Sadowski, MI Hardy, J Singleton, A Clayton, PT Rahman, S AF Duncan, Andrew J. Bitner-Glindzicz, Maria Meunier, Brigitte Costello, Harry Hargreaves, Iain P. Lopez, Luis C. Hirano, Michio Quinzii, Catarina M. Sadowski, Michael I. Hardy, John Singleton, Andrew Clayton, Peter T. Rahman, Shamima TI A Nonsense Mutation in COQ9 Causes Autosomal-Recessive Neonatal-Onset Primary Coenzyme Q(10) Deficiency: A Potentially Treatable Form of Mitochondrial Disease SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CEREBELLAR-ATAXIA; SACCHAROMYCES-CEREVISIAE; UBIQUINONE DEFICIENCY; MUSCLE; GENE; ENCEPHALOMYOPATHY; HOMOZYGOSITY; NEPHROPATHY; POPULATIONS; MYOPATHY AB Coenzyme Q(10) is a mobile lipophilic electron carrier located in the inner mitochondrial membrane. Defects of coenzyme Q(10) biosynthesis represent one of the few treatable mitochondrial diseases. We genotyped a patient with primary coenzyme Q(10) deficiency who presented with neonatal lactic acidosis and later developed multisytem disease including intractable seizures, global developmental delay, hypertrophic cardiomyopathy, and renal tubular dysfunction. Cultured skin fibroblasts from the patient had a coenzyme Q(10) biosynthetic rate of 11% of normal controls and accumulated an abnormal metabolite that we believe to be a biosynthetic intermediate. In view of the rarity of coenzyme Q(10) deficiency, we hypothesized that the disease-causing gene might lie in a region of ancestral homozygosity by descent. Data from an Illumina HumanHap550 array were analyzed with BeadStudio software. Sixteen regions of homozygosity > 1.5 Mb were identified in the affected infant. Two of these regions included the loci of two of 16 candidate genes implicated in human coenzyme Q(10) biosynthesis. Sequence analysis demonstrated a homozygous stop mutation affecting a highly conserved residue of COQ9, leading to the truncation of 75 amino acids. Site-directed mutagenesis targeting the equivalent residue in the yeast Saccharomyces cerevisiae abolished respiratory growth. C1 [Duncan, Andrew J.; Bitner-Glindzicz, Maria; Costello, Harry; Clayton, Peter T.; Rahman, Shamima] UCL, Inst Child Hlth, Mitochondrial Res Grp, Clin & Mol Genet Unit, London WC1N 1EH, England. [Meunier, Brigitte] CNRS, Ctr Genet Mol, FRC3115, F-91198 Gif Sur Yvette, France. [Hargreaves, Iain P.] Natl Hosp Neurol, Neurometab Unit, London WC1N 3BG, England. [Lopez, Luis C.; Hirano, Michio; Quinzii, Catarina M.] Columbia Univ, Med Ctr, New York, NY 10032 USA. [Sadowski, Michael I.] Natl Inst Med Res, Div Math Biol, London NW7 1AA, England. [Hardy, John] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Hardy, John] Inst Neurol, Reta Lila Western Labs, London WC1N 3BG, England. [Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Clayton, Peter T.; Rahman, Shamima] Great Ormond St Hosp Sick Children, Metab Unit, London WC1N 3JH, England. [Rahman, Shamima] MRC Ctr Neuromuscular Dis, London WC1N 3BG, England. RP Rahman, S (reprint author), UCL, Inst Child Hlth, Mitochondrial Res Grp, Clin & Mol Genet Unit, London WC1N 1EH, England. EM s.rahman@ich.ucl.ac.uk RI Singleton, Andrew/C-3010-2009; Sadowski, Michael/F-4475-2010; Clayton, Peter/C-1523-2008; Bitner-Glindzicz, Maria/A-4231-2009; Hardy, John/C-2451-2009; Rahman, Shamima/C-5232-2008; Lopez, Luis Carlos/L-5129-2014; OI Sadowski, Michael/0000-0002-4546-2159; Rahman, Shamima/0000-0003-2088-730X; Lopez, Luis Carlos/0000-0003-3355-0298; Meunier, Brigitte/0000-0002-6988-4663 FU Department of Health's NIHR Biomedical Research Centres; UK Medical Research Council [G0200335]; European Commission [LSHG-CT-2003-503265]; National Institutes of Health, Department of Health and Human Services [AG000932-01] FX This work was undertaken at GOSH/UCL Institute of Child Health, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. We gratefully acknowledge funding from the UK Medical Research Council (grant number G0200335); the Biosapiens Network of Excellence (funded by the European Commission within its FP6 Programme, under the thematic area Life sciences, Genomics and Biotechnology for Health, contract number LSHG-CT-2003-503265); and the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project AG000932-01. We also thank Tabitha Owen for her excellent technical assistance. NR 42 TC 94 Z9 100 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 15 PY 2009 VL 84 IS 5 BP 558 EP 566 DI 10.1016/j.ajhg.2009.03.018 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 449OB UT WOS:000266338800001 PM 19375058 ER PT J AU Himes, BE Hunninghake, GM Baurley, JW Rafaels, NM Sleiman, P Strachan, DP Wilk, JB Willis-Owen, SAG Klanderman, B Lasky-Su, J Lazarus, R Murphy, AJ Soto-Quiros, ME Avila, L Beaty, T Mathias, RA Ruczinski, I Barnes, KC Celedon, JC Cookson, WOC Gauderman, WJ Gilliland, FD Hakonarson, H Lange, C Moffatt, MF O'Connor, GT Raby, BA Silverman, EK Weiss, ST AF Himes, Blanca E. Hunninghake, Gary M. Baurley, James W. Rafaels, Nicholas M. Sleiman, Patrick Strachan, David P. Wilk, Jemma B. Willis-Owen, Saffron A. G. Klanderman, Barbara Lasky-Su, Jessica Lazarus, Ross Murphy, Amy J. Soto-Quiros, Manuel E. Avila, Lydiana Beaty, Terri Mathias, Rasika A. Ruczinski, Ingo Barnes, Kathleen C. Celedon, Juan C. Cookson, William O. C. Gauderman, W. James Gilliland, Frank D. Hakonarson, Hakon Lange, Christoph Moffatt, Miriam F. O'Connor, George T. Raby, Benjamin A. Silverman, Edwin K. Weiss, Scott T. TI Genome-wide Association Analysis Identifies PDE4D as an Asthma-Susceptibility Gene SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID FAMILY-BASED ASSOCIATION; OBSTRUCTIVE PULMONARY-DISEASE; PHOSPHODIESTERASE 4D GENE; CHILDHOOD ASTHMA; MANAGEMENT PROGRAM; ORMDL3 EXPRESSION; COSTA-RICA; POLYMORPHISM; RISK; POPULATION AB Asthma, a chronic airway disease with known heritability, affects more than 300 million people around the world. A genome-wide association (GWA) study of asthma with 359 cases from the Childhood Asthma Management Program (CAMP) and 846 genetically matched controls from the Illumina ICONdb public resource was performed. The strongest region of association seen was on chromosome 5q12 in PDE4D. The phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila) gene (PDE4D) is a regulator of airway smooth-muscle contractility, and PDE4 inhibitors have been developed as medications for asthma. Allelic p values for top SNPs in this region were 4.3 x 10(-07) for rs1588265 and 9.7 x 10(-07) for rs1544791. Replications were investigated in ten independent populations with different ethnicities, study designs, and definitions of asthma. In seven white and Hispanic replication populations, two PDE4D SNPs had significant results with p values less than 0.05, and five had results in the same direction as the original population but had p values greater than 0.05. Combined p values for 18,891 white and Hispanic individuals (4,342 cases) in our replication populations were 4.1 x 10(-04) for rs1588265 and 9.2 x 10(-04) for rs1544791. In three black replication populations, which had different linkage disequilibrium patterns than the other populations, original findings were not replicated. Further study of PDE4D variants might lead to improved understanding of the role of PDE4D in asthma pathophysiology and the efficacy of PDE4 inhibitor medications. C1 [Himes, Blanca E.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02138 USA. [Himes, Blanca E.; Hunninghake, Gary M.; Klanderman, Barbara; Lasky-Su, Jessica; Lazarus, Ross; Murphy, Amy J.; Celedon, Juan C.; Lange, Christoph; Silverman, Edwin K.; Weiss, Scott T.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Himes, Blanca E.; Hunninghake, Gary M.; Klanderman, Barbara; Lasky-Su, Jessica; Lazarus, Ross; Murphy, Amy J.; Celedon, Juan C.; Lange, Christoph; Raby, Benjamin A.; Silverman, Edwin K.; Weiss, Scott T.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Himes, Blanca E.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Himes, Blanca E.] Partners Ctr Personalized Genet Med, Boston, MA 02115 USA. [Baurley, James W.; Gauderman, W. James; Gilliland, Frank D.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90089 USA. [Rafaels, Nicholas M.; Beaty, Terri; Ruczinski, Ingo; Barnes, Kathleen C.] Johns Hopkins Univ, Johns Hopkins Asthma & Allergy Ctr, Baltimore, MD 21224 USA. [Sleiman, Patrick; Hakonarson, Hakon] Univ Philadelphia, Childrens Hosp Philadelphia, Ctr Appl Genom, Div Human Genet,Sch Med, Philadelphia, PA 19104 USA. [Strachan, David P.] Univ London, London SW17 0RE, England. [Wilk, Jemma B.; O'Connor, George T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Willis-Owen, Saffron A. G.; Cookson, William O. C.; Moffatt, Miriam F.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England. [Soto-Quiros, Manuel E.; Avila, Lydiana] Hosp Nacl Ninos Dr Carlos Saenz Herrera, Div Pediat Pulmonol, San Jose, Costa Rica. [Mathias, Rasika A.] NHGRI, Inherited Dis Res Inst, NIH, Baltimore, MD 21224 USA. RP Himes, BE (reprint author), Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02138 USA. EM blanca_himes@hms.harvard.edu OI O'Connor, George/0000-0002-6476-3926; lazarus, ross/0000-0003-3939-1961 FU NHLBI National Institutes of Health (NIH) [U01 HL075419, U01 HL65899, P01 HL083069, R01 HL086601, T32 HL07427]; NIH [R37 HL066289, 5R01HL087680, 5P01ES011627, 5P30ES007048, 2T15LM007092-16]; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02] FX We thank all CAMP subjects for their ongoing participation in this study. We acknowledge the CAMP investigators and research team, supported by the National Heart, Lung, and Blood Institute (NHLBI), for collection of CAMP Genetic Ancillary Study data. All work on data collected from the CAMP Genetic Ancillary Study was conducted at the Charming Laboratory of the Brigham and Women's Hospital under appropriate CAMP policies and human subject protections. The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, p01 HL083069, R01 HL086601, and T32 HL07427 from the NHLBI National Institutes of Health (NIH). Additional support was provided by the following NIH grants: R37 HL066289, 5R01HL087680 (NHLBI); 5P01ES011627, and 5P30ES007048 (National Institute of Environmental Health Sciences); and 2T15LM007092-16 (National Library of Medicine). We acknowledge use of genotype data from the B58C DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. We are grateful to John Todd, Diabetes & Inflammation Laboratory, University of Cambridge, and Panos Deloukas, Wellcome Trust Sanger Institute, for depositing genotype data on the B58C. K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. R.A.M. was supported by the Intramural Research Program of the National Human Genoine Research Institute, NIH. We thank Georgia Dunston and Mezbah Faruque from Howard University, Washington, DC, for their vital contribution in the recruitment of the GRAADI cohort. NR 50 TC 178 Z9 184 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 15 PY 2009 VL 84 IS 5 BP 581 EP 593 DI 10.1016/j.ajhg.2009.04.006 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 449OB UT WOS:000266338800003 PM 19426955 ER PT J AU Ali, M McKibbin, M Booth, A Parry, DA Jain, P Riazuddin, SA Hejtmancik, JF Khan, SN Firasat, S Shires, M Gilmour, DF Towns, K Murphy, AL Azmanov, D Tournev, I Cherninkova, S Jafri, H Raashid, Y Toomes, C Craig, J Mackey, DA Kalaydjieva, L Riazuddin, S Inglehearn, CF AF Ali, Manir McKibbin, Martin Booth, Adam Parry, David A. Jain, Payal Riazuddin, S. Amer Hejtmancik, J. Fielding Khan, Shaheen N. Firasat, Sabika Shires, Mike Gilmour, David F. Towns, Katherine Murphy, Anna-Louise Azmanov, Dimitar Tournev, Ivailo Cherninkova, Sylvia Jafri, Hussain Raashid, Yasmin Toomes, Carmel Craig, Jamie Mackey, David A. Kalaydjieva, Luba Riazuddin, Sheikh Inglehearn, Chris F. TI Null Mutations in LTBP2 Cause Primary Congenital Glaucoma SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID OPEN-ANGLE GLAUCOMA; LATENT TGF-BETA; GENOME-WIDE SCAN; BINDING-PROTEIN; DEVELOPMENTAL EXPRESSION; GENETIC-HETEROGENEITY; CYTOCHROME P4501B1; MOLECULAR-CLONING; MARFAN-SYNDROME; CYP1B1 AB Primary congenital glaucoma (PCG) is an autosomal-recessive condition characterized by high intraocular pressure (IOP), usually within the first year of life, which potentially could lead to optic nerve damage, globe enlargement, and permanent loss of vision. To date, PCG has been linked to three loci: 2p21 (GLC3A), for which the responsible gene is CYP1B1, and 1p36 (GLC3B) and 14q24 (GLC3C), for which the genes remain to be identified. Here we report that null mutations in LTBP2 cause PCG in four consanguineous families from Pakistan and in patients of Gypsy ethnicity. LTBP2 maps to chromosome 14q24.3 but is around 1.3 Mb proximal to the documented GLC3C locus. Therefore, it remains to be determined whether LTBP2 is the GLC3C gene or whether a second adjacent gene is also implicated in PCG. LTBP2 is the largest member of the latent transforming growth factor (TGF)-beta binding protein family, which are extracellular matrix proteins with multidomain structure. It has homology to fibrillins and may have roles in cell adhesion and as a structural component of microfibrils. We confirmed localization of LTBP2 in the anterior segment of the eye, at the ciliary body, and particularly the ciliary process. These findings reveal that LTBP2 is essential for normal development of the anterior chamber of the eye, where it may have a structural role in maintaining ciliary muscle tone. C1 [Ali, Manir; McKibbin, Martin; Booth, Adam; Parry, David A.; Jain, Payal; Shires, Mike; Gilmour, David F.; Towns, Katherine; Murphy, Anna-Louise; Toomes, Carmel; Inglehearn, Chris F.] Univ Leeds, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England. [McKibbin, Martin; Gilmour, David F.] St James Univ Hosp, Eye Dept, Leeds LS9 7TF, W Yorkshire, England. [Booth, Adam] Peninsula Med Sch, Plymouth PL6 8BU, Devon, England. [Riazuddin, S. Amer; Khan, Shaheen N.; Firasat, Sabika; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 53700, Pakistan. [Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Azmanov, Dimitar; Kalaydjieva, Luba] Univ Western Australia, Med Res Ctr, Perth, WA 6009, Australia. [Mackey, David A.] Univ Western Australia, Lions Eye Inst, Perth, WA 6009, Australia. [Tournev, Ivailo; Cherninkova, Sylvia] Med Univ, Dept Neurol, Sofia 1431, Bulgaria. [Jafri, Hussain] Gene Tech Lab, Lahore 54000, Pakistan. [Raashid, Yasmin] King Edward Med Univ, Dept Obstet & Gynaecol, Lahore 54000, Pakistan. [Craig, Jamie] Flinders Med Ctr, Dept Ophthalmol, Bedford Pk, SA 5042, Australia. RP Ali, M (reprint author), Univ Leeds, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England. EM medma@leeds.ac.uk RI Nasim Khan, Shaheen/F-2135-2015; Mackey, David/H-5340-2014; OI Mackey, David/0000-0001-7914-4709; Parry, David/0000-0003-0376-7736 FU MRC [G0501050]; Yorkshire Eye Research [009]; Higher Education Commission (Islamabad, Pakistan); Ministry of Science and Technology (Islamabad, Pakistan); Australia India Strategic Research Fund [BF020055]; COMSTECH.EMRO project of the World Health Organization [GH 06-0724] FX We thank the families for their support and cooperation in this work. This research was supported by the MRC (grant G0501050), the Yorkshire Eye Research (grant 009), the Higher Education Commission (Islamabad, Pakistan), the Ministry of Science and Technology (Islamabad, Pakistan), the Australia India Strategic Research Fund (grant BF020055), and the COMSTECH.EMRO project of the World Health Organization (No., RAB and GH 06-0724). C.T. is a Royal Society University Research Fellow. NR 41 TC 108 Z9 115 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 15 PY 2009 VL 84 IS 5 BP 664 EP 671 DI 10.1016/j.ajhg.2009.03.017 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 449OB UT WOS:000266338800011 PM 19361779 ER PT J AU Periasamy, S Chalmers, NI Du-Thumm, L Kolenbrander, PE AF Periasamy, Saravanan Chalmers, Natalia I. Du-Thumm, Laurence Kolenbrander, Paul E. TI Fusobacterium nucleatum ATCC 10953 Requires Actinomyces naeslundii ATCC 43146 for Growth on Saliva in a Three-Species Community That Includes Streptococcus oralis 34 SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID DENTAL PLAQUE; BIOFILM; COLONIZATION; BACTERIA; ENAMEL AB Formation of dental plaque is a developmental process involving initial and late colonizing species that form polymicrobial communities. Fusobacteria are the most numerous gram-negative bacteria in dental plaque, but they become prevalent after the initial commensal colonizers, such as streptococci and actinomyces, have established communities. The unusual ability of these bacteria to coaggregate with commensals, as well as pathogenic late colonizers, has been proposed to facilitate colonization by the latter organisms. We investigated the integration of Fusobacterium nucleatum into multispecies communities by employing two in vitro models with saliva as the sole nutritional source. In flow cell biofilms, numbers of cells were quantified using fluorescently conjugated antibodies against each species, and static biofilms were analyzed by quantitative real-time PCR (q-PCR) using species-specific primers. Unable to grow as single-species biofilms, F. nucleatum grew in two-species biofilms with Actinomyces naeslundii but not with Streptococcus oralis. However, enhanced growth of fusobacteria was observed in three-species biofilms, indicating that there was multispecies cooperation. Importantly, these community dynamics yielded an 18-fold increase in the F. nucleatum biomass between 4 h and 18 h in the flow cell inoculated with three species. q-PCR analysis of static biofilms revealed that maximum growth of the three species occurred at 24 h to 36 h. Lower numbers of cells were observed at 48 h, suggesting that saliva could not support higher cell densities as the sole nutrient. Integration of F. nucleatum into multispecies commensal communities was evident from the interdigitation of fusobacteria in coaggregates with A. naeslundii and S. oralis and from the improved growth of fusobacteria, which was dependent on the presence of A. naeslundii. C1 [Periasamy, Saravanan; Chalmers, Natalia I.; Kolenbrander, Paul E.] NIDCR, NIH, Bethesda, MD 20892 USA. [Du-Thumm, Laurence] Colgate Palmol Co, Piscataway, NJ 08855 USA. RP Kolenbrander, PE (reprint author), NIDCR, NIH, Bldg 30,Room 310,30 Convent Dr,MSC 4350, Bethesda, MD 20892 USA. EM pkolenbrander@dir.nidrc.nih.gov FU National Institute of Dental and Craniofacial Research, National Institutes of Health; Colgate-Palmolive Co. FX We thank R. J. Palmer, Jr., for his assistance with the CLSM and for helpful comments on the manuscript. NR 23 TC 38 Z9 41 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD MAY 15 PY 2009 VL 75 IS 10 BP 3250 EP 3257 DI 10.1128/AEM.02901-08 PG 8 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 443KL UT WOS:000265908500031 PM 19286780 ER PT J AU Mitra, PS Basu, NK Owens, IS AF Mitra, Partha S. Basu, Nikhil K. Owens, Ida S. TI Src supports UDP-glucuronosyltransferase-2B7 detoxification of catechol estrogens associated with breast cancer SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE UDP-glucuronosyltransferase (UGT); Catechol estrogen; 4-Hydroxy estrone; Phosphorylation; Src; Tyrosine kinase; Curcumin; PP2; Genistein; Colocalization ID BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE; AROMATASE ACTIVITIES; PHOSPHORYLATION; ESTRADIOL; ESTRONE; EXPRESSION; CELLS; LIVER; IDENTIFICATION; METABOLITES AB Mammary gland-distributed and ER-bound UDP-glucuronosyltransferase (UGT)-2B7 metabolizes genotoxic catechol-estrogens (CE) associated with breast cancer initiation. Although UGT2B7 has 3 PKC- and 2 tyrosine kinase (TK)-sites, its inhibition by genistein, herbimycin-A and PP2 with parallel losses in phospho-tyrosine and phospho-Y438-2B7 content indicated it requires tyrosine phosphorylation, unlike required PKC phosphorylation of UGT1A isozymes. 2B7 mutants at PKC-sites had essentially normal activity, while its TK-sites mutants, Y236F- and Y438F-2B7, were essentially inactive. Overexpression of regular or active Src, but not dominant-negative Src, in 2B7-transfected COS-1 cells increased 2B7 activity and phospho-Y438-2B7 by 50%. Co-localization of 2B7 and regular SrcTK in COS-1 cells that was dissociated by pretreatment with Src-specific PP2-inhibitor provided strong evidence Src supports 2B7 activity. Consistent with these findings, evidence indicates an appropriate set of ER proteins with Src-homology binding-domains, including 2B7 and well-known multi-functional Src-engaged AKAP12 scaffold, supports Src-dependent phosphorylation of CE-metabolizing 2B7 enabling it to function as a tumor suppressor. Published by Elsevier Inc. C1 [Mitra, Partha S.; Basu, Nikhil K.; Owens, Ida S.] NICHHD, Sect Genet Disorders Drug Metab, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Owens, IS (reprint author), NICHHD, Sect Genet Disorders Drug Metab, Program Dev Endocrinol & Genet, NIH, Bldg 10,Room 9D-42, Bethesda, MD 20892 USA. EM basun@mail.nih.gov; owensi@mail.nih.gov FU National Institutes of Health MCHD Intramural Research Program FX This work was supported in whole or in part by the National Institutes of Health MCHD Intramural Research Program. NR 28 TC 10 Z9 10 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 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 15 PY 2009 VL 382 IS 4 BP 651 EP 656 DI 10.1016/j.bbrc.2009.03.054 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 444OB UT WOS:000265989200003 PM 19289110 ER PT J AU Zappala, G Rechler, MM AF Zappala, Giovanna Rechler, Matthew M. TI IGFBP-3, hypoxia and TNF-alpha inhibit adiponectin transcription SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Insulin-like growth factor binding protein-3 (IGFBP-3); Adiponectin; Retinoid X receptor-alpha (RXR-alpha); Hypoxia; Tumor necrosis factor-alpha (TNF-alpha) ID FACTOR-BINDING PROTEIN-3; NECROSIS-FACTOR-ALPHA; PROSTATE-CANCER CELLS; X-RECEPTOR-ALPHA; INSULIN-RESISTANCE; ADIPOSE-TISSUE; METABOLIC SYNDROME; PPAR-GAMMA; IN-VITRO; GROWTH AB The thiazolidinedione rosiglitazone, an agonist ligand for the nuclear receptor PPAR-gamma, improves insulin sensitivity in part by stimulating transcription of the insulin-sensitizing adipokine adiponectin. It activates PPAR-gamma-RXR-alpha heterodimers bound to PPAR-gamma response elements in the adiponectin promoter. Rosiglitazone-stimulated adiponectin protein synthesis in 3T3-L1 mouse adipocytes has been shown to be inhibited by IGFBP-3, which can be induced by hypoxia and the proinflammatory cytokine, TNF-alpha, two inhibitors of adiponectin transcription. The present study demonstrates that IGFBP-3, the hypoxia mimetic agent cobalt chloride, and TNF-alpha inhibit rosiglitazone-induced adiponectin transcription in mouse embryo fibroblasts that stably express PPAR-gamma 2. Native IGFBP-3 can bind RXR-alpha and inhibited rosiglitazone stimulated promoter activity, whereas an IGFBP-3 mutant that does not bind RXR-alpha did not. These results suggest that IGFBP-3 may mediate the inhibition of adiponectin transcription by hypoxia and TNF-alpha, and that IGFBP-3 binding to RXR-alpha may be required for the observed inhibition. Published by Elsevier Inc. C1 [Zappala, Giovanna; Rechler, Matthew M.] NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. [Rechler, Matthew M.] NIDDKD, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Zappala, G (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, 10 Ctr Dr,CRC Bldg 10,Rm3-3288, Bethesda, MD 20892 USA. EM zappalag@mail.nih.gov FU NIDDK, NIH FX This research was supported by the Intramural Research Program of the NIDDK, NIH. NR 38 TC 28 Z9 28 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 15 PY 2009 VL 382 IS 4 BP 785 EP 789 DI 10.1016/j.bbrc.2009.03.112 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 444OB UT WOS:000265989200028 PM 19324019 ER PT J AU de Wit, H Shaham, Y AF de Wit, Harriet Shaham, Yavin TI Incentive Motivation, Conditioning, Stress, and Neuropsychiatric Disorders: A Tribute to Jane Stewart SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID INDUCED SENSITIZATION; DOPAMINE; RATS; REINFORCEMENT; REINSTATEMENT; OPIATES; LIGHT C1 [de Wit, Harriet] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Shaham, Yavin] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. RP de Wit, H (reprint author), Univ Chicago, Dept Psychiat, 5841 S Maryland Ave MC3077, Chicago, IL 60637 USA. EM hdew@uchicago.edu RI shaham, yavin/G-1306-2014; OI de Wit, Harriet/0000-0002-7211-8994 FU Intramural NIH HHS [Z01 DA000434-08] NR 19 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2009 VL 65 IS 10 BP 827 EP 828 DI 10.1016/j.biopsych.2008.12.012 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 442AE UT WOS:000265811300001 PM 19398047 ER PT J AU Wang, B You, ZB Wise, RA AF Wang, Bin You, Zhi-Bing Wise, Roy A. TI Reinstatement of Cocaine Seeking by Hypocretin (Orexin) in the Ventral Tegmental Area: Independence from the Local Corticotropin-Releasing Factor Network SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Addiction; cocaine; hypocretin; orexin; relapse; ventral tegmental area ID ACETYLCHOLINE-RELEASE; EXTRACELLULAR DOPAMINE; NUCLEUS-ACCUMBENS; RAT-BRAIN; NEURONS; RECEPTOR; REWARD; STRESS; HYPOTHALAMUS; STIMULATION AB Background: Hypocretin (Hcrt), an arousal- and feeding-associated peptide, is expressed in lateral hypothalamic neurons that project to the ventral tegmental area (VTA). Intra-VTA Hcrt reinstates morphine-conditioned place preferences, and intracerebroventricular and intra-VTA corticotropin-releasing factor (CRF) reinstate cocaine seeking. Each is presumed to act, at least in part, through actions local to the VTA. Here, we examined the possibility that VTA perfusion of Hcrt reinstates cocaine seeking and, if so, whether it does so through the VTA mechanism that is implicated in reinstatement by CRF. Methods: Rats were trained to lever-press for intravenous cocaine (2 weeks) and then underwent extinction training (saline substituted for cocaine: 3 weeks). Reinstatement behavior was tested and VTA dialysates were collected and assayed for glutamate or dopamine following footshock or perfusion of Hcrt or CRF, with or without Hcrt or CRF antagonists, into the VTA. Results: Ventral tegmental area perfusion of Hcrt-1 or footshock stress reinstated cocaine seeking and caused release of VTA glutamate and dopamine. The effects of Hcrt-1 were blocked by a selective Hcrt-1 antagonist, but not a CRF antagonist, and were not mimicked by Hcrt-2. The Hcrt-1 antagonist did not block CRF-dependent footshock-induced reinstatement or glutamate or dopamine release. The behavioral and neurochemical effects of Hcrt-1 were attenuated but not blocked by kynurenic acid, an ionotropic glutamate antagonist that blocks foots hock-induced reinstatement and glutamate release. Conclusions: While Hcrt and CRF are known to interact in some area of the brain, in the VTA proper they appear to have largely independent actions on the mesolimbic dopamine mechanisms of cocaine seeking. C1 [Wang, Bin; You, Zhi-Bing; Wise, Roy A.] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Wise, RA (reprint author), Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM rwise@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse; National Institutes of Health; Department of Health and Human Services FX This work. tuns supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. NR 31 TC 64 Z9 64 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2009 VL 65 IS 10 BP 857 EP 862 DI 10.1016/j.biopsych.2009.01.018 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 442AE UT WOS:000265811300007 PM 19251246 ER PT J AU Pickens, CL Golden, SA Adams-Deutsch, T Nair, SG Shaham, Y AF Pickens, Charles L. Golden, Sam A. Adams-Deutsch, Tristan Nair, Sunila G. Shaham, Yavin TI Long-Lasting Incubation of Conditioned Fear in Rats SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Animal models; anxiety; fear conditioning; incubation; posttraumatic stress disorder; stress ID POSTTRAUMATIC-STRESS-DISORDER; CENTRAL AMYGDALA INJECTIONS; AGONIST LY379268 ATTENUATE; SIGNALING PATHWAY; ANXIETY; EXTINCTION; MEMORY; INHIBITION; CONTEXT; MODEL AB Background: In 1937, Diven reported that human fear responses to cues previously paired with shock progressively increase or incubate over 24 hours. Since then, fear incubation has been demonstrated in both humans and nonhumans. However, the difficulty of demonstrating long-lasting fear incubation in rodents has hampered the study of the underlying mechanisms of this incubation. Here, we describe a rat procedure where fear reliably incubates over time. Methods: We trained food-restricted rats to lever-press for food pellets in daily 90-min sessions. We then gave each rat 100 30-sec tones co-terminating with a.5-sec.5-mA footshock over 10 days (10 pairings/day). Groups of rats (n = 10-15) were then given four presentations of the tone (the fear cue) 2, 15, 31, or 61 days after fear conditioning training and were assessed for conditioned suppression of lever-pressing. Results: We found that conditioned fear responses were significantly higher 31 and 61 days after fear training than after 2 or 15 days. In control experiments, we showed that extensive tone-shock pairing is necessary for the emergence of fear incubation and that it is unlikely that non-associative factors contribute to this incubation. Conclusions: We describe a procedure for generating reliable and long-lasting conditioned fear incubation. Our procedure can be used to study mechanisms of fear incubation and might provide a model for studying the mechanisms of delayed-onset posttraumatic stress disorder that occur in a sub-population of people previously exposed to chronic stressors. C1 [Pickens, Charles L.; Golden, Sam A.; Adams-Deutsch, Tristan; Nair, Sunila G.; Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM yshaham@intra.nida.nih.gov RI Pickens, Charles/E-8984-2010; shaham, yavin/G-1306-2014; OI Golden, Sam/0000-0002-2104-2272 FU National Institute on Drug Abuse; Intramural Research Program FX Research was supported by the National Institute on Drug Abuse, Intramural Research Program. The authors report no biomedical financial interests or potential conflicts of interest. We thank Drs. Mark: Bouton, Brian Wiltgen, Gonzalo Urcelay, and Darn Wheeler for helpful comments on issues related to experimental procedures and data interpretation and Drs. Roger Pitman and Markus Heilig for helpful discussions on the applicability of the fear incubation model to posttraumatic stress disorder. NR 53 TC 49 Z9 51 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2009 VL 65 IS 10 BP 881 EP 886 DI 10.1016/j.biopsych.2008.12.010 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 442AE UT WOS:000265811300011 PM 19167702 ER PT J AU Li, SX Shi, J Epstein, DH Wang, X Zhang, XL Bao, YP Zhang, D Zhang, XY Kosten, TR Lu, L AF Li, Su-xia Shi, Jie Epstein, David H. Wang, Xi Zhang, Xiao-li Bao, Yan-ping Zhang, Dai Zhang, Xiang-yang Kosten, Thomas R. Lu, Lin TI Circadian Alteration in Neurobiology During 30 Days of Abstinence in Heroin Users SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Circadian rhythms; clock genes; cytokines; heroin addiction; hormones; peptides; spontaneous withdrawal ID BLOOD-BRAIN-BARRIER; METHADONE-INDUCED HYPOADRENALISM; STRESS-INDUCED RELAPSE; NEUROPEPTIDE-Y; CLOCK GENES; INDUCED IMMUNOSUPPRESSION; DIACETYLMORPHINE HEROIN; COCAINE SENSITIZATION; MAINTENANCE TREATMENT; CEREBROSPINAL-FLUID AB Background: Previous studies have shown that individuals withdrawn from chronic opiate administration undergo substantial elevations of cortisol levels with blunted corticotropin (ACTH) rhythms and that these changes persist beyond the 7-10 days of acute withdrawal symptoms. However, there are no published studies of changes in expression of clock genes or of other neuropeptides related to circadian-rhythm regulation, which may influence relapse susceptibility. Methods: Blood samples were collected from 8 healthy control subjects and 16 heroin addicts during pharmacologically unassisted withdrawal on the 3rd, 10th, and 30th days of abstinence at 3-hour intervals for 24 hours. Outcome measures were the relative expression of clock gene mRNA (hperiod1, hperiod2, hclock) and the levels of serum cortisol, plasma ACTH, beta-endorphin (beta-EP), leptin, neuropeptide Y, interleukin-2 (IL-2), and tumor necrosis factor (TNF) in these subjects. Results: Compared with healthy volunteers, abstinent addicts showed disruptions in diurnal rhythms of hPER1 and hPER2 mRNA expression, along with disruptions in diurnal rhythms of cortisol, ACTH, beta-endorphin, leptin, and IL-2 release. Several of these disruptions (hPER1, hPER2, ACTH, beta-endorphin, and IL-2) persisted for the 30-day testing period, as did elevation of 24-hour levels of cortisol and decreases in 24-hour IL-2 and TNF levels. Conclusions: These prolonged neurobiological changes may play a role in protracted opiate withdrawal symptoms and contribute to relapse vulnerability. C1 [Li, Su-xia; Shi, Jie; Wang, Xi; Zhang, Xiao-li; Bao, Yan-ping; Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Beijing 100083, Peoples R China. [Epstein, David H.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. [Zhang, Dai] Peking Univ, Inst Mental Hlth, Beijing 100083, Peoples R China. [Zhang, Xiang-yang; Kosten, Thomas R.] Baylor Coll Med, Div Alcohol & Addict Disorders, Houston, TX 77030 USA. RP Lu, L (reprint author), Peking Univ, Natl Inst Drug Dependence, 38 Xue Yuan Rd, Beijing 100083, Peoples R China. EM linlu@bjmu.edu.cn FU The National Basic Research Program of China [2007013512302, 2009013522004]; The National High Technology Research and Development Program of China [2006AA02Z4D1]; Natural Science Foundation of China [30670773, 30725016] FX This work was supported in part by The National Basic Research Program of China (973 Program, Grant Nos. 2007013512302 and 2009013522004), The National High Technology Research and Development Program of China (86,3 Program, Grant No. 2006AA02Z4D1), and the Natural Science Foundation of China (Grant Nos. 30670773 and 30725016). NR 78 TC 25 Z9 27 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2009 VL 65 IS 10 BP 905 EP 912 DI 10.1016/j.biopsych.2008.11.025 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 442AE UT WOS:000265811300015 PM 19135652 ER PT J AU Pal, S Choi, WJ Choe, SA Heller, CL Gao, ZG Chinn, MS Jacobson, KA Hou, XY Lee, SK Kim, HO Jeong, LS AF Pal, Shantanu Choi, Won Jun Choe, Seung Ah Heller, Cara L. Gao, Zhan-Guo Chinn, Moshe Jacobson, Kenneth A. Hou, Xiyan Lee, Sang Kook Kim, Hea Ok Jeong, Lak Shin TI Structure-activity relationships of truncated adenosine derivatives as highly potent and selective human A(3) adenosine receptor antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE A(3) Adenosine receptor; Antagonists; Truncated adenosine; Structure-activity relationships ID LIGANDS; CELLS; INHIBITION AB On the basis of potent and selective binding affinity of truncated 4'-thioadenosine derivatives at the human A(3) adenosine receptor (AR), their bioisosteric 4'-oxo derivatives were designed and synthesized from commercially available 2,3-O-isopropylidene-D-erythrono lactone. The derivatives tested in AR binding assays were substituted at the C2 and N-6 positions. All synthesized nucleosides exhibited potent and selective binding affinity at the human A(3) AR. They were less potent than the corresponding 4'-thio analogues, but showed still selective to other subtypes. The 2-Cl series generally were better than the 2-H series in view of binding affinity and selectivity. Among compounds tested, compound 5d (X=Cl, R=3-bromobenzyl) showed the highest binding affinity (K-i = 13.0 +/- 6.9 nM) at the hA(3) AR with high selectivity (at least 88-fold) in comparison to other AR subtypes. Like the corresponding truncated 4'-thio series, compound 5d antagonized the action of an agonist to inhibit forskolin-stimulated adenylate cyclase in hA(3) AR-expressing CHO cells. Although the 4'-oxo series were less potent than the 4'-thio series, this class of human A(3) AR antagonists is also regarded as another good template for the design of A(3) AR antagonists and for further drug development. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Pal, Shantanu; Choi, Won Jun; Choe, Seung Ah; Hou, Xiyan; Lee, Sang Kook; Kim, Hea Ok; Jeong, Lak Shin] Ewha Womans Univ, Coll Pharm, Med Chem Lab, Dept Bioinspired Sci, Seoul 120750, South Korea. [Pal, Shantanu; Choi, Won Jun; Choe, Seung Ah; Hou, Xiyan; Lee, Sang Kook; Kim, Hea Ok; Jeong, Lak Shin] Ewha Womans Univ, Coll Pharm, Med Chem Lab, Div Life & Pharmaceut Sci, Seoul 120750, South Korea. [Heller, Cara L.; Gao, Zhan-Guo; Chinn, Moshe; Jacobson, Kenneth A.] NIDDKD, NIH, Mol Recognit Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Jeong, LS (reprint author), Ewha Womans Univ, Coll Pharm, Med Chem Lab, Dept Bioinspired Sci, Seoul 120750, South Korea. EM lakjeong@ewha.ac.kr RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Korea Research Foundation Grant [KRF-2008-E00304]; Ministry of Education and Science, Korea [R31-2008-000-10010-0]; Intramural Research Program of NIDDK; NIH, Bethesda, MD, USA FX This work was supported by the Korea Research Foundation Grant (KRF-2008-E00304), the Grant from the World Class University (WCU) Project from Ministry of Education and Science, Korea (R31-2008-000-10010-0), and the Intramural Research Program of NIDDK, NIH, Bethesda, MD, USA. NR 21 TC 15 Z9 15 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAY 15 PY 2009 VL 17 IS 10 BP 3733 EP 3738 DI 10.1016/j.bmc.2009.03.034 PG 6 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 440ET UT WOS:000265683800026 PM 19375920 ER PT J AU Jiang, S Liao, CZ Bindu, L Yin, BL Worthy, KW Fisher, RJ Burke, TR Nicklaus, MC Roller, PP AF Jiang, Sheng Liao, Chenzhong Bindu, Lakshman Yin, Biaolin Worthy, Karen W. Fisher, Robert J. Burke, Terrence R., Jr. Nicklaus, Marc C. Roller, Peter P. TI Discovery of thioether-bridged cyclic pentapeptides binding to Grb2-SH2 domain with high affinity SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Grb2-SH2 domain; Cyclic peptides; G1TE analogs; Phosphotyrosine; Grb2-SH2 antagonist ID STRUCTURE-BASED DESIGN; PHOSPHOTYROSINE-CONTAINING PEPTIDE; SH2 DOMAIN; NONPHOSPHORYLATED INHIBITOR; ABSOLUTE-CONFIGURATION; SIGNAL-TRANSDUCTION; POTENT INHIBITORS; ACCURATE DOCKING; STRUCTURAL BASIS; BREAST-CANCER AB Blocking the interaction between phosphotyrosine (pTyr)-containing activated receptors and the Src homology 2 (SH2) domain of the growth factor receptor-bound protein 2 (Grb 2) is considered to be an effective and non-cytotoxic strategy to develop new anti-proliferate agents due to its potential to shut down the Ras activation pathway. In this study, a series of phosphotyrosine containing cyclic pentapeptides were designed and synthesized based upon the phage library derived cyclopeptide, G1TE. A comprehensive SAR study was also carried out to develop potent Grb2-SH2 domain antagonists based upon this novel template. With both the peptidomimetic optimization of the amino acid side-chains and the constraint of the backbone conformation guided by molecular modeling, we developed several potent antagonists with low micromolar range binding affinity, such as cyclic peptide 15 with an K(d) = 0.359 mu M, which is providing a novel template for the development of Grb2-SH2 domain antagonists as potential therapeutics for certain cancers. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Jiang, Sheng; Yin, Biaolin] Chinese Acad Sci, Lab Regenerat Biol, Guangzhou Inst Biomed & Hlth, Guangzhou 510663, Guangdong, Peoples R China. [Liao, Chenzhong; Burke, Terrence R., Jr.; Nicklaus, Marc C.; Roller, Peter P.] NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. [Bindu, Lakshman; Worthy, Karen W.; Fisher, Robert J.] SAIC Frederick, Prot Chem Lab, Frederick, MD 21702 USA. RP Jiang, S (reprint author), Chinese Acad Sci, Lab Regenerat Biol, Guangzhou Inst Biomed & Hlth, Guangzhou 510663, Guangdong, Peoples R China. EM jiang_sheng@gibh.ac.cn RI Nicklaus, Marc/N-4183-2014; Burke, Terrence/N-2601-2014; OI Nicklaus, Marc/0000-0002-4775-7030 FU National Natural Science Foundation [20802078]; National Basic Research Program of China [2009CB940900]; Guangdong Natural Science Foundation [8151066302000008]; NIH, National Cancer Institute, Center for Cancer Research FX This project was supported by the National Natural Science Foundation (Grant no. 20802078), National Basic Research Program of China (973 Program, Grant no. 2009CB940900), the Guangdong Natural Science Foundation (Grant no. 8151066302000008) and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 11 Z9 12 U1 2 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD MAY 15 PY 2009 VL 19 IS 10 BP 2693 EP 2698 DI 10.1016/j.bmcl.2009.03.134 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 439LE UT WOS:000265627800017 PM 19362470 ER PT J AU Zhao, XZ Maddali, K Vu, BC Marchand, C Hughes, SH Pommier, Y Burke, TR AF Zhao, Xue Zhi Maddali, Kasthuraiah Vu, B. Christie Marchand, Christophe Hughes, Stephen H. Pommier, Yves Burke, Terrence R., Jr. TI Examination of halogen substituent effects on HIV-1 integrase inhibitors derived from 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-ones and 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE HIV integrase; Inhibitor; AIDS; Structure-activity relationship ID POTENT; RALTEGRAVIR; PYRIMIDONES; DISCOVERY; DESIGN; SAR AB Using 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one and 4,5-dihydroxy-1H-isoindole-1,3(2H)-dione based HIV-1 integrase inhibitors as display platforms, we undertook a thorough examination of the effects of modifying the halogen substituents on a key benzyl ring that is hypothesized to bind in a hydrophobic pocket of the integrase. DNA complex. Data from this study suggest that in general dihalo-substituted analogues have higher potency than monohalo-substituted compounds, but that further addition of halogens is not beneficial. Published by Elsevier Ltd. C1 [Zhao, Xue Zhi; Burke, Terrence R., Jr.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Maddali, Kasthuraiah; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Vu, B. Christie; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Zhao, Xue Zhi/N-9594-2014; Burke, Terrence/N-2601-2014 OI Zhao, Xue Zhi/0000-0003-1006-6364; FU NIH, Center for Cancer Research, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute. NR 16 TC 26 Z9 30 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD MAY 15 PY 2009 VL 19 IS 10 BP 2714 EP 2717 DI 10.1016/j.bmcl.2009.03.122 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 439LE UT WOS:000265627800022 PM 19364649 ER PT J AU Nandurdikar, RS Maciag, AE Citro, ML Shami, PJ Keefer, LK Saavedra, JE Chakrapani, H AF Nandurdikar, Rahul S. Maciag, Anna E. Citro, Michael L. Shami, Paul J. Keefer, Larry K. Saavedra, Joseph E. Chakrapani, Harinath TI Synthesis and evaluation of piperazine and homopiperazine analogues of JS-K, an anti-cancer lead compound SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Nitric oxide; JS-K; Cancer; Prodrug; Glutathione; Glutathione S-transferase; Homopiperazine; Diazeniumdiolate ID NITRIC-OXIDE PRODRUGS; IN-VITRO; CELLS; PATHWAYS; VIVO AB Here we report a number of novel JS-K structural analogues with sub-micromolar anti-proliferative activities against human leukemia cell lines HL-60 and U937; JS-K is the anti-cancer lead compound O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate. The ability of these compounds to generate intracellular nitric oxide correlated well with their observed anti-proliferative effects: analogues that had potent inhibitory activity against leukemia cells formed elevated levels of intracellular nitric oxide. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Maciag, Anna E.; Citro, Michael L.; Saavedra, Joseph E.] NCI, Basic Sci Program, SAIC Frederick, Frederick, MD 21702 USA. [Nandurdikar, Rahul S.; Keefer, Larry K.; Chakrapani, Harinath] NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. [Shami, Paul J.] Univ Utah, Div Oncol, Dept Internal Med, Salt Lake City, UT 84112 USA. RP Saavedra, JE (reprint author), NCI, Basic Sci Program, SAIC Frederick, Frederick, MD 21702 USA. EM saavj@ncifcrf.gov; chakrah@ncifcrf.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NIH, National Cancer Institute, Center for Cancer Research [NO1-CO-2008-00001] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, as well as by National Cancer Institute contract NO1-CO-2008-00001 to SAIC-Frederick. NR 14 TC 11 Z9 11 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD MAY 15 PY 2009 VL 19 IS 10 BP 2760 EP 2762 DI 10.1016/j.bmcl.2009.03.115 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 439LE UT WOS:000265627800033 PM 19364650 ER PT J AU Pelotte, AL Smith, RM Ayestas, M Dersch, CM Bilsky, EJ Rothman, RB Deveau, AM AF Pelotte, Andrea L. Smith, Ryan M. Ayestas, Mario Dersch, Christina M. Bilsky, Edward J. Rothman, Richard B. Deveau, Amy M. TI Design, synthesis, and characterization of 6 beta-naltrexol analogs, and their selectivity for in vitro opioid receptor subtypes SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Synthesis; Opioid; Antagonism; Naltrexol; Naltrexamide; MOR ID AGONIST DELTA-ANTAGONIST; NEUTRAL ANTAGONISTS; NARCOTIC DEPENDENCE; INVERSE AGONISTS; NALTREXONE; NALOXONE; ADDICTION; LIGANDS; PAIN; MICE AB Since the mu opioid receptor (MOR) is known to be involved in the therapeutically relevant pathways leading to the manifestation of pain and addiction, we are currently studying the specific structural characteristics that promote antagonism at the MOR. The opiates 6 beta-naltrexol and 6 beta-naltrexamide function as neutral antagonists in in vitro and in vivo systems previously exposed to morphine, and are under investigation as improved treatments for narcotic dependence. In this research, we synthesized and characterized carbamate and sulfonate ester derivates of 6 beta-naltrexol that do not contain a protic group at C(6), and evaluated these compounds for opioid receptor affinity. In vitro receptor subtype (mu, kappa, and delta opioid receptors) binding data of the carbamate and sulfonate derivatives is reported. All four compounds synthesized exhibited affinity for the MOR better than the standard 6 beta-naltrexol HCl. Based on K(i) data, the order of MOR affinity is as follows: 9 > 13 > 14 > 10 > 6 beta-naltrexol HCl. Carbamate 9 and tosylate 13 displayed subnanomolar affinity for the MOR, while 10 was the most mu-selective compound synthesized. In conclusion, our data indicate that the absence of a hydrogen-bond donor on the C(6) oxygen enhances rather than impedes the in vitro affinity of naltrexol derivatives for the MOR. Additionally, data also suggest that increasing the bulk around C(6) may allow control of subtype selectivity within these compound series. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Pelotte, Andrea L.; Smith, Ryan M.; Deveau, Amy M.] Univ New England, Coll Arts & Sci, Dept Chem & Phys, Biddeford, ME 04005 USA. [Smith, Ryan M.; Bilsky, Edward J.] Univ New England, Dept Pharmacol, Coll Osteopath Med, Biddeford, ME 04005 USA. [Ayestas, Mario; Dersch, Christina M.; Rothman, Richard B.] Natl Inst Drug Abuse, Clin Psychopharmacol Sect, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Deveau, AM (reprint author), Univ New England, Coll Arts & Sci, Dept Chem & Phys, Biddeford, ME 04005 USA. EM adeveau@une.edu OI Bilsky, Edward/0000-0002-4664-5256 FU University of New England (UNE) for University and College of Arts & Sciences (CAS) Mini-Grants; Chemistry & Physics Department; American Society for Experimental Therapeutics (ASPET); UNE's College Of Osteopathic Medicine; CAS Dean's Office; Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS FX M. D. gratefully acknowledges the support of the University of New England (UNE) for University and College of Arts & Sciences (CAS) Mini-Grants and the Chemistry & Physics Department for monies to support research & conference travel. A. M. D. also thanks the American Society for Experimental Therapeutics (ASPET) for a Young Investigator Award. R. M. S. thanks ASPET and UNE's College Of Osteopathic Medicine for fellowship support. A. L. P. thanks the CAS Dean's Office for summer research grant support. The authors thank Mallinckrodt, Inc. for the generous donation of naltrexol free base and naltrexone. Portions of this work were supported by the Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS. NR 26 TC 8 Z9 9 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD MAY 15 PY 2009 VL 19 IS 10 BP 2811 EP 2814 DI 10.1016/j.bmcl.2009.03.095 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 439LE UT WOS:000265627800046 PM 19364645 ER PT J AU Atkins, MB Bukowski, RM Escudier, BJ Figlin, RA Hudes, GH Kaelin, WG Linehan, WM McDermott, DF Mier, JW Pedrosa, I Rini, BI Signoretti, S Sosman, JA Teh, BT Wood, CG Zurita, AJ King, L AF Atkins, Michael B. Bukowski, Ronald M. Escudier, Bernard J. Figlin, Robert A. Hudes, Gary H. Kaelin, William G., Jr. Linehan, W. Marston McDermott, David F. Mier, James W. Pedrosa, Ivan Rini, Brian I. Signoretti, Sabina Sosman, Jeffrey A. Teh, Bin Tean Wood, Christopher G. Zurita, Amado J. King, Laura TI Innovations and Challenges in Renal Cancer: Summary Statement From the Third Cambridge Conference SO CANCER LA English DT Article; Proceedings Paper CT 3rd International Conference on the Innovations and Challenges in Renal Cancer CY JUN 27-28, 2008 CL Cambridge, ENGLAND DE renal cancer; genetics; vascular endothelial growth factor; immunotherapy; biomarkers ID CELL CARCINOMA; IDENTIFICATION; INTERLEUKIN-2 AB The Third Cambridge Conference on Innovations and Challenges in Renal Cancer, a symposium held in Cambridge, Massachusetts, June 27-28, 2008, and chaired by Michael B. Atkins, was convened to discuss the current state of knowledge in the field, critique new data, stimulate communication among those involved in basic and clinical research, and offer recommendations for further study. Four main topics were discussed: genetics and molecular biology of renal cell cancer, staging and prognosis, systemic therapy, and correlative science and biomarkers in stage IV disease. The conference format combined brief presentations with extended periods of discussion. The conclusions and recommendations are summarized in this paper and presented in more detail in the individual papers that follow. Cancer 2009;115(10 suppl):2247-51. (C) 2009 American Cancer Society. C1 [Atkins, Michael B.; McDermott, David F.; Mier, James W.; Pedrosa, Ivan] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Bukowski, Ronald M.; Rini, Brian I.] Cleveland Clin Fdn, Taussig Canc Inst, Cleveland, OH 44195 USA. [Escudier, Bernard J.] Inst Gustave Roussy, Unite Immunotherapie, Villejuif, France. [Figlin, Robert A.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Hudes, Gary H.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Kaelin, William G., Jr.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Linehan, W. Marston] NCI, Bethesda, MD 20892 USA. [Signoretti, Sabina] Brigham & Womens Hosp, Boston, MA 02115 USA. [Sosman, Jeffrey A.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Teh, Bin Tean] Van Andel Res Inst, Grand Rapids, MI USA. [Wood, Christopher G.; Zurita, Amado J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [King, Laura] InforMED Commun Inc, Carlisle, MA USA. RP Atkins, MB (reprint author), 300 Brookline Ave, Boston, MA 02115 USA. EM matkins@bidmc.harvard.edu FU Intramural NIH HHS [Z01 SC006659-25] NR 15 TC 12 Z9 13 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 15 PY 2009 VL 115 IS 10 BP 2247 EP 2251 DI 10.1002/cncr.24229 PG 5 WC Oncology SC Oncology GA 438YC UT WOS:000265591600001 PM 19402064 ER PT J AU Linehan, WM Pinto, PA Bratslavsky, G Pfaffenroth, E Merino, M Vocke, CD Toro, JR Bottaro, D Neckers, L Schmidt, LS Srinivasan, R AF Linehan, W. Marston Pinto, Peter A. Bratslavsky, Gennady Pfaffenroth, Elizabeth Merino, Maria Vocke, Cathy D. Toro, Jorge R. Bottaro, Donald Neckers, Len Schmidt, Laura S. Srinivasan, Ramaprasad TI Hereditary Kidney Cancer Unique Opportunity for Disease-based Therapy SO CANCER LA English DT Article; Proceedings Paper CT 3rd International Conference on the Innovations and Challenges in Renal Cancer CY JUN 27-28, 2008 CL Cambridge, ENGLAND DE kidney; neoplasm; von Hippel-Lindau; MET; Birt-Hogg-Dube; fumarate hydratase ID RENAL-CELL CARCINOMA; HIPPEL-LINDAU-DISEASE; HOGG-DUBE-SYNDROME; PARENCHYMAL SPARING SURGERY; TUMOR-SUPPRESSOR GENE; TUBEROUS SCLEROSIS COMPLEX; MET PROTOONCOGENE; SPONTANEOUS PNEUMOTHORAX; GERMLINE MUTATIONS; FUMARATE-HYDRATASE AB Kidney cancer is not a single disease; it is comprised of several different types of cancer, each with a different histology, with a different clinical course, caused by a different gene, and responding differently to therapy. The VHL gene is the gene for the hereditary cancer syndrome, von Hippel-Lindau, as well as for the common form of sporadic, noninherited, clear cell kidney cancer. Understanding the VHL-hypoxia inducible factor (HIF) pathway has provided the foundation for the development of several agents targeting this pathway, such as sunitinib, sorafenib, and temsirolimus. Hereditary papillary renal carcinoma (HPRC) is a hereditary renal cancer syndrome in which affected individuals are at risk for the development of bilateral, multi-focal, type I papillary renal cell carcinoma. The genetic defect underlying HPRC is MET, the cell surface receptor for hepatocyte growth factor. Mutations of MET also have been identified in a subset of tumors from patients with sporadic type 1 papillary renal cell carcinoma (RCC). Clinical trials targeting the MET pathway are currently underway in patients with HPRC and in patients with sporadic (nonhereditary) papillary kidney cancer. The BHD gene (also known as folliculin or FLCN) is the gene for Birt-Hogg-Dube syndrome, an autosomal-dominant genodermatosis associated with a hereditary form of chromophobe and oncocytic, hybrid RCC. Preclinical studies are underway targeting the BHD gene pathway in preparation for clinical trials in Birt-Hogg-Dube and sporadic chromophobe RCC. Patients with hereditary leiomyomatosis RCC (HLRCC) are at risk for developing cutaneous and uterine leiomyomas and a very aggressive type of RCC. HLRCC is characterized by germline mutation of the Krebs cycle enzyme, fumarate hydratase (FH). Studies of the tricarboxylic acid cycle and the VHL-HIF pathways have provided the foundation for therapeutic approaches in patients with HLRCC-associated kidney cancer as well as other hereditary and sporadic forms of RCC. Cancer 2009;115(10 suppl):2252-61. Published 2009 by the American Cancer Society.(dagger) C1 [Linehan, W. Marston; Pinto, Peter A.; Bratslavsky, Gennady; Pfaffenroth, Elizabeth; Vocke, Cathy D.; Bottaro, Donald; Neckers, Len; Schmidt, Laura S.; Srinivasan, Ramaprasad] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Merino, Maria] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Toro, Jorge R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Schmidt, Laura S.] SAIC Frederick Inc, Basic Res Program, NCI, Frederick, MD 21701 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bldg 10 CRC,Room 1-5940, Bethesda, MD 20892 USA. EM wml@nih.gov RI Bottaro, Donald/F-8550-2010 OI Bottaro, Donald/0000-0002-5057-5334 FU Intramural NIH HHS [Z01 SC006659-25]; NCI NIH HHS [N01-CO-12,400, N01CO12400] NR 66 TC 55 Z9 55 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD MAY 15 PY 2009 VL 115 IS 10 SU S BP 2252 EP 2261 DI 10.1002/cncr.24230 PG 10 WC Oncology SC Oncology GA 438YC UT WOS:000265591600002 PM 19402075 ER PT J AU Wolfe, ME Yagoda, D Thurman, PW Luna, JM Figg, WD AF Wolfe, Margaret E. Yagoda, Daniel Thurman, Paul W. Luna, Jorge M. Figg, William D. TI NCI designated cancer center funding not influenced by organizational structure SO CANCER BIOLOGY & THERAPY LA English DT Article DE cancer center; organizational structure AB Background: National Cancer Institutes (NCI) designated cancer centers use one of three organizational structures. The hypothesis of this study is that there are differences in the amount of annual NCI funding per faculty member based on a cancer center's organizational structure. The study also considers the impact of secondary factors (i.e., the existence of a clinical program, the region and the size of the city in which the cancer center is located) on funding and the number of Howard Hughes Medical Institute (HHMI) investigators at each cancer center. Results: Of the 63 cancer centers, 44 use a matrix structure, 16 have a freestanding structure, and three have a Department of Oncology structure. Kruskal-Wallis tests reveal no statistically significant differences in the amount of funding per faculty member or the number of HHMI investigators between centers with a matrix, freestanding or Department of Oncology structure. Methods: Online research and telephone interviews with each cancer center were used to gather information, including: organizational structure, the presence of a clinical program, the number of faculty members, and the number of Howard Hughes Medical Institute investigators. Statistical tests were used to assess the impact which organizational structure has on the amount of funding per faculty member and number of HHMI investigators. Conclusion: While the results seem to suggest that the organizational structure of a given cancer center does not impact the amount of NCI funding or number of HHMI investigators which it attracts, the existence of this relationship is likely masked by the small sample size in this study. Further studies may be appropriate to examine the effect organizational structure has on other measurements which are relevant to cancer centers, such as quality and quantity of research produced. C1 [Figg, William D.] NCI, Med Oncol Branch, Natl Canc Ctr, Bethesda, MD 20892 USA. [Wolfe, Margaret E.; Yagoda, Daniel; Thurman, Paul W.; Luna, Jorge M.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. RP Figg, WD (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bldg 10 Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 5 TC 0 Z9 0 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAY 15 PY 2009 VL 8 IS 10 BP 869 EP 873 DI 10.4161/cbt.8.10.8120 PG 5 WC Oncology SC Oncology GA 475WD UT WOS:000268393300004 PM 19270497 ER PT J AU Zang, GX Miao, LY Mu, YB Qiao, CY Liu, JZ Ke, XL Zheng, CY Sun, HC AF Zang, Guangxiang Miao, Leiying Mu, Yabing Qiao, Chunyan Liu, Jinzhong Ke, Xiaoliang Zheng, Changyu Sun, Hongchen TI Adenoviral mediated transduction of adenoid cystic carcinoma by human TRAIL gene driven with hTERT tumor specific promoter induces apoptosis SO CANCER BIOLOGY & THERAPY LA English DT Article DE hTERT promoter; TRAIL; gene therapy; adenoid cystic carcinoma ID REVERSE-TRANSCRIPTASE PROMOTER; HUMAN HEPATOCELLULAR-CARCINOMA; VECTOR EXPRESSING TRAIL; CYTOTOXIC LIGAND TRAIL; CELL LUNG-CANCER; ONCOLYTIC ADENOVIRUS; ANTITUMOR-ACTIVITY; TUMORICIDAL ACTIVITY; HUMAN HEPATOCYTES; RECEPTOR AB Adenoid cystic carcinoma (ACC) is a common malignant tumor in salivary glands. Unfortunately, current treatment modalities which include surgery, radiation and chemotherapy have limited success rates. To develop new treatment strategies we hypothesized that a cancer-specific apoptotic ligand driven by a tumor specific promoter would specifically induce apoptosis in ACC. To test this concept, we selected tumor necrosis factor-related apoptosis-inducing ligand ( TRAIL) and the human telomerase reverse transcriptase (hTERT) promoter. The latter is highly active in 85% of human cancer cells while it is mostly inactive in somatic cells. Using immunohistochemistry we confirmed that ACC samples but not normal salivary cells were positive for hTERT. Similar results were also seen in an ACC cell line, SACC-83. We then constructed first generation Ad5 vectors which used the hTERT promoter to drive TRAIL (AdTERT-TRAIL). Transduction of SACC-83, but not of control human embryo-fibrocyte lung (HEL) cells, led to apoptosis as measured by MTT assay and flow cytomerty. We used the SACC-83 cells for a subcutaneous tumor model in vivo. Intratumoral injections of AdTERT-TRAIL (5 x 10(9) particles/tumor) but not of AdTERT-EGFP or PBS resulted in significant (p < 0.01) reduction in tumor sizes, which demonstrated that the human TRAIL driven by tumor-specific promoter could efficiently induce apoptosis in SACC-83 cells in vitro and in vivo. These results suggest that a novel gene therapy strategy can also be used in the treatment of ACC in the near future. C1 [Zang, Guangxiang; Miao, Leiying; Mu, Yabing; Qiao, Chunyan; Liu, Jinzhong; Ke, Xiaoliang; Sun, Hongchen] Jilin Univ, Dept Oral Pathol, Sch Stomotol, Changchun 130023, Peoples R China. [Zheng, Changyu] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, DHHS, Bethesda, MD USA. RP Sun, HC (reprint author), Jilin Univ, Dept Oral Pathol, Sch Stomotol, Changchun 130023, Peoples R China. EM hcsun@mail.jlu.edu.cn FU National Natural Science Foundation of China [30672338, 30740420551] FX This work was supported by grants from the National Natural Science Foundation of China (No: 30672338 and 30740420551). We thank Dr. Shengli Li for a gift of SACC-83 cell line, Peking University, China. NR 52 TC 7 Z9 9 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAY 15 PY 2009 VL 8 IS 10 BP 966 EP 972 DI 10.4161/cbt.8.10.8117 PG 7 WC Oncology SC Oncology GA 475WD UT WOS:000268393300016 PM 19587531 ER PT J AU Raimondi, AR Molinolo, A Gutkind, JS AF Raimondi, Ana R. Molinolo, Alfredo Gutkind, J. Silvio TI Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model SO CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; NECK-CANCER; CONDITIONAL EXPRESSION; MOUSE SKIN; KINASE PHOSPHATASE; MAMMALIAN TARGET; KERATIN GENE; STEM-CELLS; HEAD; GROWTH AB Head and neck squamous cell carcinomas (HNSCC), the majority of which occur in the oral cavity, remain a significant cause of morbidity and mortality worldwide. A major limitation in HNSCC research has been the paucity of animal models to test the validity of current genetic paradigms of tumorigenesis and to explore the effectiveness of new treatment modalities and chemopreventive strategies. Here, we have developed an inducible oral-specific animal tumor model system, which consists in the expression of a tamoxifen-inducible Cre recombinase (CreER(tam)) under the control of the cytokeratin 14 (K14) promoter (K14-CreER(tam)) and mice in which the endogenous K-ras locus is targeted (LSL-K-ras(G12D)), thereby causing the expression of endogenous levels of oncogenic K-ras(G12D) following removal of a stop element. Surprisingly, whereas K14-CreER(tam) can also target the skin, K14-CreER(tam)/LSL-K-ras(G12D) mice developed papillomas exclusively in the oral mucosa within 1 month after tamoxifen treatment. These lesions were highly proliferative but never progressed to carcinoma. However, when crossed with p53 conditional knockout (p53(flox/flox)) mice, mice developed SCCs exclusively on the tongue as early as 2 weeks after tamoxifen induction, concomitant with at remarkable activation of the mammalian target of rapamycin (mTOR) signaling pathway. The availability of this ras and p53 two-hit animal model system recapitulating HNSCC progression may provide a suitable platform for exploring novel molecular targeted approaches for the treatment of this devastating disease. Indeed, we show here that. mTOR inhibition by the use of rapamycin is sufficient to halt tumor progression in this genetically defined oral cancer model system, thereby prolonging animal survival. [Cancer Res 2009;69(10):4159-66] C1 [Raimondi, Ana R.; Molinolo, Alfredo; Gutkind, J. Silvio] Natl Inst Craniofacial & Dent Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Craniofacial & Dent Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 211, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009 FU Intramural Research program of NIH; National Institute of Dental and Craniofacial Research FX Grant support: Intramural Research program of NIH, National Institute of Dental and Craniofacial Research. NR 39 TC 50 Z9 50 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2009 VL 69 IS 10 BP 4159 EP 4166 DI 10.1158/0008-5472.CAN-08-4645 PG 8 WC Oncology SC Oncology GA 447TJ UT WOS:000266214400011 PM 19435901 ER PT J AU Embree, LJ Azuma, M Hickstein, DD AF Embree, Lisa J. Azuma, Mizuki Hickstein, Dennis D. TI Ewing Sarcoma Fusion Protein EWSR1/FLI1 Interacts with EWSR1 Leading to Mitotic Defects in Zebrafish Embryos and Human Cell Lines SO CANCER RESEARCH LA English DT Article ID RNA-POLYMERASE-II; TRANSCRIPTION FACTOR; TARGET GENES; FAMILY; CANCER; TUMORS; EXPRESSION; TRANSLOCATION; ONCOPROTEINS; EWS-FLI-1 AB The mechanism whereby the fusion of EWSR1 with the ETS transcription factor FLI1 contributes to malignant transformation in Ewing sarcoma remains unclear. We show that injection of human or zebrafish EWSR1/FLI1 mRNA into developing zebrafish embryos leads to mitotic defects with multipolar and disorganized mitotic spindles. Expression of human EWSR1/FLI1 in HeLa cells also results in mitotic defects, along with mislocalization of Aurora kinase B, a key regulator of mitotic progression. Because these mitotic abnormalities mimic those observed with the knockdown of EWSR1 in zebrafish embryos and HeLa cells, we investigated whether EWSR1/FLI1 interacts with EWSR1 and interferes with its function. EWSR1 coimmunoprecipitates with EWSR1/FLI1, and overexpression of EWSR1 rescues the mitotic defects in EWSR1/FLI1-transfected HeLa cells. This interaction between EWSR1/FLI1 and EWSR1 in Ewing sarcoma may induce mitotic defects leading to genomic instability and subsequent malignant transformation. [Cancer Res 2009;69(10):4363-71] C1 [Embree, Lisa J.; Azuma, Mizuki; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hickstein, DD (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bldg 10 CRC,Room 3-3264,MSC 1203,10 Ctr Dr, Bethesda, MD 20892 USA. EM hicksted@mail.nih.gov FU NIH Intramural Research program; National Cancer Institute; Center for Cancer Research FX NIH Intramural Research program, National Cancer Institute, Center for Cancer Research. NR 41 TC 13 Z9 14 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2009 VL 69 IS 10 BP 4363 EP 4371 DI 10.1158/0008-5472.CAN-08-3229 PG 9 WC Oncology SC Oncology GA 447TJ UT WOS:000266214400035 PM 19417137 ER PT J AU Rahrmann, EP Collier, LS Knutson, TP Doyal, ME Kuslak, SL Green, LE Malinowski, RL Roethe, L Akagi, K Waknitz, M Huang, W Largaespada, DA Marker, PC AF Rahrmann, Eric P. Collier, Lara S. Knutson, Todd P. Doyal, Meghan E. Kuslak, Sheri L. Green, Laura E. Malinowski, Rita L. Roethe, Laura Akagi, Keiko Waknitz, Michelle Huang, Wei Largaespada, David A. Marker, Paul C. TI Identification of PDE4D as a Proliferation Promoting Factor in Prostate Cancer Using a Sleeping Beauty Transposon-Based Somatic Mutagenesis Screen SO CANCER RESEARCH LA English DT Article ID RETROVIRAL INSERTIONAL MUTAGENESIS; CHRONIC LYMPHOCYTIC-LEUKEMIA; GROWTH-FACTOR RECEPTOR; CYCLIC-AMP; PHOSPHODIESTERASE PDE4D; PROTEIN EXPRESSION; GENE-EXPRESSION; MESSENGER-RNAS; CELLS; TRANSCRIPTION AB Retroviral and transposon-based mutagenesis screens in mice have been useful for identifying candidate cancer genes for some tumor types. However, many of the organs that exhibit the highest cancer rates in humans, including the prostate, have not previously been amenable to these approaches. This study shows for the first time that the Sleeping Beauty transposon system can be used to identify candidate prostate cancer genes in mice. Somatic mobilization of a mutagenic transposon resulted in focal epithelial proliferation and hyperplasia in the prostate. Efficient methods were established to identify transposon insertion sites in these lesions, and analysis of transposon insertions identified candidate prostate cancer genes at common insertion sites, including Pde4d. PDE4D was also overexpressed in human prostate cancer patient samples and cell lines, and changes in PDE4D mRNA isoform expression were observed in human prostate cancers. Furthermore, knockdown of PDE4D reduced the growth and migration of prostate cancer cells in vitro, and knockdown of PDE4D reduced the growth and proliferation rate of prostate cancer xenografts in vivo. These data indicate that PDE4D functions as a proliferation promoting factor in prostate cancer, and the Sleeping Beauty transposon system is a useful tool for identifying candidate prostate cancer genes. [Cancer Res 2009;69(10):4388-97] C1 [Collier, Lara S.; Malinowski, Rita L.; Roethe, Laura; Marker, Paul C.] Univ Wisconsin, Sch Pharm, Div Pharmaceut Sci, Madison, WI 53705 USA. [Rahrmann, Eric P.; Knutson, Todd P.; Doyal, Meghan E.; Kuslak, Sheri L.; Green, Laura E.; Largaespada, David A.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN USA. [Rahrmann, Eric P.; Knutson, Todd P.; Doyal, Meghan E.; Kuslak, Sheri L.; Green, Laura E.; Largaespada, David A.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Collier, Lara S.; Malinowski, Rita L.; Roethe, Laura; Marker, Paul C.] Univ Wisconsin, Carbone Comprehens Canc Ctr, Madison, WI 53705 USA. [Waknitz, Michelle; Huang, Wei] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53705 USA. [Akagi, Keiko] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Marker, PC (reprint author), Univ Wisconsin, Sch Pharm, Div Pharmaceut Sci, 777 Highland Ave, Madison, WI 53705 USA. EM marker@wisc.edu RI Knutson, Todd/H-8304-2012; Largaespada, David/C-9832-2014 FU Department of Defense Congressionally Mandated Research Program award [W81XWH-05-1-053]; NIH/National Institute on Aging [AG024278]; National Cancer Institute/NIH [CA118600, CA122183, CA09138]; American Cancer Society postdoctoral fellowship [PF-05-153-01] FX Department of Defense Congressionally Mandated Research Program award W81XWH-05-1-053 (proposal PC050617) and NIH/National Institute on Aging grant AG024278 (P.C. Marker), National Cancer Institute/NIH grant CA118600 (D.A. Largaespada), American Cancer Society postdoctoral fellowship PF-05-153-01 (MGO) and National Cancer Institute/NIH CA122183 (L.S. Collier), and National Cancer Institute/NIH training grant CA09138 (E.P. Rahrmann and S.L. Kuslak). NR 50 TC 41 Z9 42 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2009 VL 69 IS 10 BP 4388 EP 4397 DI 10.1158/0008-5472.CAN-08-3901 PG 10 WC Oncology SC Oncology GA 447TJ UT WOS:000266214400038 PM 19401450 ER PT J AU Wan, XH O'Quinn, RP Pierce, HL Joglekar, AP Gall, WE DeLuca, JG Carroll, CW Liu, ST Yen, TJ McEwen, BF Stukenberg, T Desai, A Salmon, ED AF Wan, Xiaohu O'Quinn, Ryan P. Pierce, Heather L. Joglekar, Ajit P. Gall, Walt E. DeLuca, Jennifer G. Carroll, Christopher W. Liu, Song-Tao Yen, Tim J. McEwen, Bruce F. Stukenberg, Todd Desai, Arshad Salmon, E. D. TI Protein Architecture of the Human Kinetochore Microtubule Attachment Site SO CELL LA English DT Article ID SPINDLE-ASSEMBLY CHECKPOINT; CENP-E; OUTER PLATE; MOLECULAR ARCHITECTURE; CHROMOSOME CONGRESSION; HIGH-RESOLUTION; NDC80 COMPLEX; LIVING CELLS; LOCALIZATION; SEGREGATION AB Chromosome segregation requires assembly of kinetochores on centromeric chromatin to mediate interactions with spindle microtubules and control cell-cycle progression. To elucidate the protein architecture of human kinetochores, we developed a two-color fluorescence light microscopy method that measures average label separation, Delta, at < 5 nm accuracy. Delta analysis of 16 proteins representing core structural complexes spanning the centromeric chromatin-microtubule interface, when correlated with mechanical states of spindle-attached kinetochores, provided a nanometer-scale map of protein position and mechanical properties of protein linkages. Treatment with taxol, which suppresses microtubule dynamics and activates the spindle checkpoint, revealed a specific switch in kinetochore architecture. Cumulatively, Delta analysis revealed that compliant linkages are restricted to the proximity of chromatin, suggested a model for how the KMN (KNL1/Mis12 complex/Ndc80 complex) network provides microtubule attachment and generates pulling forces from depolymerization, and identified an intrakinetochore molecular switch that may function in controlling checkpoint activity. C1 [Wan, Xiaohu; O'Quinn, Ryan P.; Pierce, Heather L.; Joglekar, Ajit P.; Gall, Walt E.; Salmon, E. D.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Wan, Xiaohu] Univ N Carolina, Dept Biomed Engn, Chapel Hill, NC 27599 USA. [O'Quinn, Ryan P.] NIH, NIH UNC Grad Partnerships Program Cytoskeleton &, Bethesda, MD 20892 USA. [DeLuca, Jennifer G.] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. [Carroll, Christopher W.] Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. [Liu, Song-Tao; Yen, Tim J.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [McEwen, Bruce F.] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA. [Stukenberg, Todd] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. [Desai, Arshad] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Desai, Arshad] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. RP Salmon, ED (reprint author), Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. EM tsalmon@email.unc.edu OI Stukenberg, Todd/0000-0002-6788-2111; Yen, Tim/0000-0003-2159-0997; Joglekar, Ajit/0000-0002-0607-5332 FU NIH [GM24364, GM60678, GM06627, GM86877, GM44762, GM074215]; Burroughs-Wellcome Fund; Leukemia and Lymphoma Society [CA06927]; PA Tobacco Fund FX We are very grateful to a number of scientists who provided well-characterized reagents including Dr. Steve Taylor, Dr. Mitsuhiro Yanagida, Dr. Tomomi Kiyomitsu, Dr. Aaron Straight, and Dr. Jan Ellenberg. The authors would like to thank J. Hittle for expert technical assistance in generating antibodies. We also thank Dr. Kerry Bloom, Dr. Andrea Musacchio, and members of the Salmon and Desai labs for their critiques of early versions of this manuscript. Funded by NIH GM24364 and GM60678 (E. D. S.); GM06627 (B. F. M.); GM86877 and GM44762 (T. J. Y.); and GM074215 (A. D.). A. P. J. holds a Career Award at the Scientific Interface from the Burroughs-Wellcome Fund. T. J. Y. is also supported by the Leukemia and Lymphoma Society, a core grant (CA06927), the PA Tobacco Fund, and an appropriation from the Commonwealth of Pennsylvania. NR 59 TC 198 Z9 200 U1 2 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAY 15 PY 2009 VL 137 IS 4 BP 672 EP 684 DI 10.1016/j.cell.2009.03.035 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 446IA UT WOS:000266114100016 PM 19450515 ER PT J AU Ullah, Z Lee, CY Lilly, MA DePamphilis, ML AF Ullah, Zakir Lee, Chrissie Y. Lilly, Mary A. DePamphilis, Melvin L. TI Developmentally programmed endoreduplication in animals SO CELL CYCLE LA English DT Article DE drosophila; trophoblast stem cell; trophoblast giant cell; endocycle; endoreduplication; endomitosis; DNA rereplication; p21; p57; APC ID DROSOPHILA FOLLICLE CELLS; ORIGIN RECOGNITION COMPLEX; TROPHOBLAST GIANT-CELLS; S-PHASE-CONTROL; CYCLE PROGRESSION; DNA-REPLICATION; CHECKPOINT; ENDOCYCLE; KINASE; ENDOREPLICATION AB Development of a fertilized egg into an adult human requires trillions of cell divisions, the vast majority of which duplicate their genome once and only once. Nevertheless, trophoblast giant cells and megakaryocytes in mammals circumvent this rule by duplicating their genome multiple times without undergoing cell division, a process generally referred to as 'endoreduplication'. In contrast, arthropods such as Drosophila endoreduplicate their genome in most larval tissues, as well as in many adult tissues. Endoreduplication requires that cells prevent entrance into or completion of mitosis and cytokinesis under conditions that permit assembly of prereplication complexes. In addition, cells must prevent induction of apoptosis in response to incomplete DNA replication or DNA damage that may occur during the ensuing sequence of 'endocycles'. Thus, developmentally regulated endoreduplication results in terminal cell differentiation. Recent progress has revealed both differences and similarities in the mechanisms employed by flies and mammals to change from mitotic cell cycles to 'endocycles'. The critical step, however, appears to be switching from a CDK-dependent form of the anaphase promoting complex (APC) to one that functions only in the absence of CDK activity. C1 [Ullah, Zakir; Lee, Chrissie Y.; DePamphilis, Melvin L.] NICHHD, Genom Differentiat Program, NIH, Bethesda, MD 20892 USA. [Lilly, Mary A.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP DePamphilis, ML (reprint author), NICHHD, Genom Differentiat Program, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mlilly@helix.nih.gov; depamphm@mail.nih.gov OI Lilly, Mary/0000-0003-1564-619X FU National Institute of Child Health and Human Development FX This work was supported by the intramural program of the National Institute of Child Health and Human Development. NR 57 TC 45 Z9 45 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY 15 PY 2009 VL 8 IS 10 BP 1501 EP 1509 PG 9 WC Cell Biology SC Cell Biology GA 446IP UT WOS:000266115600015 PM 19372757 ER PT J AU Kapetanovic, IM Bauer, KS Tessier, DM Lindeblad, MO Zakharov, AD Lubet, R Lyubimov, A AF Kapetanovic, Izet M. Bauer, Kenneth S. Tessier, Daniel M. Lindeblad, Matthew O. Zakharov, Alexander D. Lubet, Ronald Lyubimov, Alexander TI Comparison of pharmacokinetic and pharmacodynamic profiles of aspirin following oral gavage and diet dosing in rats SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Aspirin; Salicylate; Pharmacokinetics; Pharmacodynamics; Colon; Thromboxane B(2); Prostaglandin E(2); Chemoprevention ID SALICYLATE INHIBITS PROLIFERATION; PROSTAGLANDIN E-2 LEVELS; KAPPA-B ACTIVATION; CANCER CELL-LINES; COLORECTAL-CANCER; CYCLE ARREST; COLON; CHEMOPREVENTION; CARCINOGENESIS; EXPRESSION AB Aspirin is one Of the oldest drugs and has been purported to have multiple beneficial effects, including prevention of cardiovascular disease and cancer, in addition to its original indication for treatment of inflammation, fever and pain. In cancer chemoprevention studies using animal models, two methods of aspirin administration have been employed: oral gavage and diet. The untested assumption was that exposure and the resultant pharmacological effects are similar for these two administration methods when dosing is normalized on the basis of mg/kg body weight/day. This study examined and compared time-dependent plasma and colon mucosal concentrations of aspirin metabolite salicylate (aspirin concentrations were below level of quantification), plasma thromboxane B(2) concentrations, and colon mucosal prostaglandin E(2) concentration following these two different dosing paradigms in rats. Diet dosing yielded relatively constant plasma and colon salicylate concentration vs. time profiles. On the other hand, oral gavage dosing led to a rapid peak followed by a fast decline in salicylate concentration in both plasma and colon. Nevertheless, the exposure as measured by the area under plasma or colon concentration-time curve of salicylate was linearly related to dose irrespective of the dosing method. Linear relationships were also observed between colon and plasma salicylate areas under the curve and between colon prostaglandin E(2) and plasma thromboxane B(2) areas under the curve. Therefore, more easily accessible plasma salicylate and thromboxane B(2) concentrations were representative of the salicylate exposure and prostaglandin E(2) pharmacodynamic biomarker in the target colon, respectively. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Kapetanovic, Izet M.; Lubet, Ronald] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Bauer, Kenneth S.] Univ Maryland, Sch Pharm, Dept Pharm Practice & Sci, Baltimore, MD 21201 USA. [Tessier, Daniel M.; Lindeblad, Matthew O.; Zakharov, Alexander D.; Lyubimov, Alexander] Univ Illinois, Dept Pharmacol, Toxicol Res Lab, Chicago, IL 60612 USA. RP Kapetanovic, IM (reprint author), NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, 6130 Execut Blvd,Rm 2116, Bethesda, MD 20892 USA. EM kapetani@mail.nih.gov FU NCI [N01-CN-43306] FX This research was supported by NCI contract N01-CN-43306. NR 30 TC 12 Z9 12 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD MAY 15 PY 2009 VL 179 IS 2-3 BP 233 EP 239 DI 10.1016/j.cbi.2008.10.008 PG 7 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 435SW UT WOS:000265364600021 PM 18992230 ER PT J AU Jackson, JP Kabirov, KK Kapetanovic, IM Lyubimov, A AF Jackson, Jonathan P. Kabirov, Kasim K. Kapetanovic, Izet M. Lyubimov, Alexander TI In vitro assessment of P450 induction potential of novel chemopreventive agents SR13668, 9-cis-UAB30, and pentamethychromanol in primary cultures of human hepatocytes SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Chemoprevention; SR13668; 9-cis-UAB30; Pentamethylchromanol; Human hepatocytes; CYP1A2; CYP2B6; CYP3A4 ID CONSTITUTIVE ANDROSTANE RECEPTOR; CYTOCHROME-P450 EXPRESSION; MAMMARY CANCERS; X-RECEPTOR; VITAMIN-E; PREVENTION; EFFICACY; 9CUAB30; GENES; CELLS AB Several compounds, including 2,10-dicarbethoxy-6-methoxy-5,7-dihydroindolo[2,3-b]carbazole (SR13668), (2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-napthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid (9-cis-UAB30), and 2,2,5,7,8-pentamethyl-6-chromanol (PMCol), were selected as promising chemopreventive agents and have entered preclinical trials for cancer prevention. The potential for adverse drug events resulting from interactions with other administered drugs, food components, or food additives presents an important question. Among the most important drug-drug interactions (DDI) is the potential of a new chemical entity (NCE) to induce cytochrome P450 enzymes (1:1450). Drug induction of P450 enzymes can lead to adverse drug interactions by increasing the metabolism of other drugs that are substrates for the induced isoform. Currently, sandwich cultured primary human hepatocytes are the standard for predicting human P450 enzyme induction in vitro as these cells retain the ability to respond to prototypical P450 inducers with the same specificity and potency exhibited in vivo. Therefore, a select panel of inducible P450 target genes (CYP1A2, CYP2B6, and CYP3A4) and their induction activity (measured by LC-MS/MS of respective marker substrate metabolites) were monitored in cultured hepatocytes following treatment with SR13668,9-cis-UAB30, or PMCol to predict clinically significant drug-induced expression. The concentration ranges of the NCE used were selected to maximize the clinical relevance of these results. All responses were evaluated according to major prototypical P450 inducers (i.e., 3-methylcholanthrene, 3-MC: phenobarbital, PB; rifampicin, RIF) and increases >= 40% of the respective positive control(s) were considered an indication of demonstrable induction. Herein, we report that there is low potential for DDI with SR13668 and PMCol due to enzyme induction of CYP1A2, CYP2B6, and CYP3A4 expression at the concentrations examined. Similarly, the study results suggested that 9-cis-UAB30 has low potential to induce CYP1A2 and CYP3A4 expression at the concentrations examined. However. 9-cis-UAB30 was shown to significantly induce CYP2B6 enzyme activity at 10 mu M suggesting the potential for DDI as a result. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Lyubimov, Alexander] Univ Illinois, Dept Pharmacol, Toxicol Res Lab, Coll Med, Chicago, IL 60612 USA. [Jackson, Jonathan P.] CellzDirect Invitrogen Corp, Austin, TX 78754 USA. [Kapetanovic, Izet M.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Lyubimov, A (reprint author), Univ Illinois, Dept Pharmacol, Toxicol Res Lab, Coll Med, 808 S Wood St, Chicago, IL 60612 USA. EM lyubimov@uic.edu FU National Cancer Institute [N-01-CN-43306] FX The study was supported by Contract No. N-01-CN-43306 from the National Cancer Institute. NR 29 TC 8 Z9 8 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD MAY 15 PY 2009 VL 179 IS 2-3 BP 263 EP 272 DI 10.1016/j.cbi.2008.12.005 PG 10 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 435SW UT WOS:000265364600025 PM 19135037 ER PT J AU Zhang, FJ Yang, JY Mou, YH Sun, BS Ping, YF Wang, JM Bian, XW Wu, CF AF Zhang, Feng-Jiao Yang, Jing-Yu Mou, Yan-Hua Sun, Bao-Shan Ping, Yi-Fang Wang, Ji-Ming Bian, Xiu-Wu Wu, Chun-Fu TI Inhibition of U-87 human glioblastoma cell proliferation and formyl peptide receptor function by oligomer procyanidins (F2) isolated from grape seeds SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Grape seed extract; Oligomer procyanidins; Glioma; Formyl peptide receptor; Chemotaxis; U-87 ID CARCINOMA DU145 CELLS; PROANTHOCYANIDIN EXTRACT; FORMYLPEPTIDE RECEPTOR; POLYPHENOLIC FRACTION; CHEMOTACTIC AGONIST; DNA-DAMAGE; ACTIVATION; CANCER; GROWTH; MITOCHONDRIA AB Gliomas are the most common and lethal tumor type in the brain. The present study investigated the effect of oligomer procyanidins (F2) (F2, degree of polymerization 2-15), a natural fraction isolated from grape seeds on the biological behavior of glioblastoma cells. We found that F2 significantly inhibited the glioblastoma growth, with little cytotoxicity on normal cells, induced G2/M arrest and decreased mitochondrial membrane potential in U-87 cells. It also induced a non-apoptotic cell death phenotype resembling paraptosis in U-87 cells. In addition, it was found for the first time that F2 in non-cytotoxic concentrations selectively inhibited U-87 cell chemotaxis mediated by a G-protein coupled receptor formyl peptide receptor FPR, which is implicated in tumor cell invasion and metastasis. Further experiments indicated that F2 inhibited fMLF-induced U-87 cell calcium mobilization and MAP kinases ERK1/2 phosphorylation. Moreover, F2 attenuated the glioblastoma FPR expression, a new molecular target for glioma therapeutics, which has been shown to play important roles in glioma cells chemotaxis, proliferation and angiogenesis in addition to its promotion to tumor progression, but did not affect FPR mRNA expression in U-87 cells. Taken together, our results suggest that F2 may be a promising candidate for the development of novel anti-tumor therapeutics. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Zhang, Feng-Jiao; Yang, Jing-Yu; Mou, Yan-Hua; Wu, Chun-Fu] Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Peoples R China. [Sun, Bao-Shan] Estacao Vitivinicola Nacl, Inst Nacl Recursos Biol, P-2565191 Dois Portos, Portugal. [Ping, Yi-Fang; Bian, Xiu-Wu] Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing 400038, Peoples R China. [Wang, Ji-Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Wu, CF (reprint author), Shenyang Pharmaceut Univ, Dept Pharmacol, 103 Wenhua Rd, Shenyang 110016, Peoples R China. EM chunfuw@gmail.com RI Bian, Xiuwu/F-1569-2011; Bian, Xiu-wu/D-4736-2017 OI Bian, Xiu-wu/0000-0003-4383-0197 FU Liaoning Province FX This research is partially supported by the Project of Key Laboratory for New Drug Screening of Liaoning Province. The authors are grateful to Dr. Youhong Cui for his technical assistance. NR 39 TC 16 Z9 17 U1 0 U2 15 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD MAY 15 PY 2009 VL 179 IS 2-3 BP 419 EP 429 DI 10.1016/j.cbi.2008.12.017 PG 11 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 435SW UT WOS:000265364600045 PM 19167369 ER PT J AU Abraham, J Edgerly, M Wilson, R Chen, C Rutt, A Bakke, S Robey, R Dwyer, A Goldspiel, B Balis, F Van Tellingen, O Bates, SE Fojo, T AF Abraham, Jame Edgerly, Maureen Wilson, Richard Chen, Clara Rutt, Ann Bakke, Susan Robey, Rob Dwyer, Andrew Goldspiel, Barry Balis, Frank Van Tellingen, Olaf Bates, Susan E. Fojo, Tito TI A Phase I Study of the P-Glycoprotein Antagonist Tariquidar in Combination with Vinorelbine SO CLINICAL CANCER RESEARCH LA English DT Article ID HEMATOPOIETIC STEM-CELLS; MULTIDRUG-RESISTANCE; DRUG EFFLUX; TRIHYDROCHLORIDE LY335979; MYELOID-LEUKEMIA; SOLID TUMORS; INHIBITOR; XR9576; REVERSAL; CANCER AB Purpose: P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine. Experimental Design: Patients first received tariquidar alone to assess effects on the accumulation of (99m)Tc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine. Results: Twenty-six patients were enrolled. Vinorelbine 20 mg/m(2) on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver (99m)Tc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased (99m)Tc-sestamibi retention in a majority of tumor masses visible by (99m)Tc-sestamibi; and (3) blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission. Conclusions: Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers. C1 [Edgerly, Maureen; Rutt, Ann; Bakke, Susan; Robey, Rob; Bates, Susan E.; Fojo, Tito] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Abraham, Jame] W Virginia Univ, Mary Babb Canc Ctr, Morgantown, WV 26506 USA. [Chen, Clara] NCI, Dept Nucl Med, Bethesda, MD 20892 USA. [Dwyer, Andrew] NCI, Dept Radiol, Bethesda, MD 20892 USA. [Goldspiel, Barry] NCI, Clin Ctr Pharm, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. [Balis, Frank] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Wilson, Richard] Queens Univ Belfast, Sch Biomed Sci, Ctr Canc Res & Cell Biol, Dept Oncol, Belfast, Antrim, North Ireland. [Van Tellingen, Olaf] Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Clin Chem, Amsterdam, Netherlands. RP Fojo, T (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov NR 34 TC 58 Z9 59 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAY 15 PY 2009 VL 15 IS 10 BP 3574 EP 3582 DI 10.1158/1078-0432.CCR-08-0938 PG 9 WC Oncology SC Oncology GA 448SP UT WOS:000266282600037 PM 19417029 ER PT J AU Baar, J Silverman, P Lyons, J Fu, PF Abdul-Karim, F Ziats, N Wasman, J Hartman, P Jesberger, J Dumadag, L Hohler, E Leeming, R Shenk, R Chen, H McCrae, K Dowlati, A Remick, SC Overmoyer, B AF Baar, Joseph Silverman, Paula Lyons, Janice Fu, Pingfu Abdul-Karim, Fadi Ziats, Nicholas Wasman, Jay Hartman, Paul Jesberger, John Dumadag, Leda Hohler, Erin Leeming, Rosemary Shenk, Robert Chen, Helen McCrae, Keith Dowlati, Afshin Remick, Scot C. Overmoyer, Beth TI A Vasculature-Targeting Regimen of Preoperative Docetaxel with or without Bevacizumab for Locally Advanced Breast Cancer: Impact on Angiogenic Biomarkers SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; CELL-ADHESION MOLECULE-1; PHASE-II TRIAL; E-SELECTIN; NEOADJUVANT CHEMOTHERAPY; TUMOR ANGIOGENESIS; RECEPTORS; CARCINOMA; REGRESSION; ICAM-1 AB Purpose: Taxanes have effects on angiogenesis causing difficulties in separating biological effects of chemotherapy from those due to angiogenesis inhibitors. This randomized phase 11 trial was designed to evaluate the additional biomarker effect on angiogenesis when bevacizumab is added to docetaxel. Experimental Design: Patients with inoperable breast cancer were randomized to either 2 cycles of preoperative docetaxel (D) 35 mg/m(2) i.v. weekly for 6 weeks, followed by a 2-week break; or docetaxel with bevacizumab 10 mg/kg i.v. every other week for a total of 16 weeks (DB). Plasma and serum markers of endothelial damage, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and tumor microvessel density were assessed before treatment and at the end of each preoperative cycle. Results: Forty-nine patients were randomized (DB, 24; D, 25). There was no difference in overall clinical response, progression-free survival, or overall survival. Vascular endothelial growth factor increased during treatment; more so with DB (P < 0.0001). Vascular cell adhesion molecule-1 (VCAM-1) also increased (P < 0.0001); more so with DB (P = 0.069). Intercellular adhesion molecule increased (P = 0.018) and E-selectin decreased (P = 0.006) overall. Baseline levels of VCAM-1 and E-selectin correlated with clinical response by univariate analysis. DCE-MRI showed a greater decrease in tumor perfusion calculated by initial area under the curve for the first 90 seconds in DB (P = 0.024). DCE-MRI also showed an overall decrease in tumor volume (P = 0.012). Conclusion: Bevacizumab plus docetaxel caused a greater increase in vascular endothelial growth factor and VCAM-1, and a greater reduction in tumor perfusion by DCE-MRI compared with docetaxel. Clinical outcomes of inoperable breast cancer were predicted by changes in VCAM-1 and E-selectin. C1 [Overmoyer, Beth] Dana Farber Canc Inst, Boston, MA 02115 USA. [Baar, Joseph; Silverman, Paula; Lyons, Janice; Fu, Pingfu; Abdul-Karim, Fadi; Ziats, Nicholas; Wasman, Jay; Hartman, Paul; Jesberger, John; Dumadag, Leda; Hohler, Erin; Leeming, Rosemary; Shenk, Robert; McCrae, Keith; Dowlati, Afshin] Univ Hosp Case Med Ctr, Dev Therapeut Program, Cleveland, OH USA. [Hartman, Paul; Hohler, Erin] Univ Hosp Case Med Ctr, Case Comprehens Canc Ctr, Cleveland, OH USA. [Baar, Joseph; Silverman, Paula; McCrae, Keith; Dowlati, Afshin] Univ Hosp Case Med Ctr, Dept Med, Cleveland, OH USA. [Lyons, Janice] Univ Hosp Case Med Ctr, Dept Radiat Oncol, Cleveland, OH USA. [Fu, Pingfu] Univ Hosp Case Med Ctr, Dept Biostat & Epidemiol, Cleveland, OH USA. [Abdul-Karim, Fadi; Ziats, Nicholas; Wasman, Jay] Univ Hosp Case Med Ctr, Dept Pathol, Cleveland, OH USA. [Jesberger, John] Univ Hosp Case Med Ctr, Dept Radiol, Cleveland, OH USA. [Leeming, Rosemary; Shenk, Robert] Univ Hosp Case Med Ctr, Dept Surg, Cleveland, OH USA. [Chen, Helen] NCI, Bethesda, MD 20892 USA. [Remick, Scot C.] W Virginia Univ, Sch Med, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA. RP Overmoyer, B (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM Beth_Overmoyer@DFCI.HARVARD.EDU FU NIH [K23 CA87725, P30 CA43703]; Avon Supplement [P30 C143703, U01 CA62502]; National Cancer Institute Translational Research Initiative [M01 RR00080]; Sanofi Aventis FX NIH grants: K23 CA87725 (B. Overmoyer); P30 CA43703, Avon Supplement to P30 C143703 (B. Overmoyer), U01 CA62502 and National Cancer Institute Translational Research Initiative; M01 RR00080; Sanofi Aventis. NR 46 TC 64 Z9 68 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAY 15 PY 2009 VL 15 IS 10 BP 3583 EP 3590 DI 10.1158/1078-0432.CCR-08-2917 PG 8 WC Oncology SC Oncology GA 448SP UT WOS:000266282600038 PM 19417018 ER PT J AU Kreisl, TN Kim, L Moore, K Duic, P Kotliarova, S Walling, J Musib, L Thornton, D Albert, PS Fine, HA AF Kreisl, Teri N. Kim, Lyndon Moore, Kraig Duic, Paul Kotliarova, Svetlana Walling, Jennifer Musib, Luna Thornton, Donald Albert, Paul S. Fine, Howard A. TI A Phase I Trial of Enzastaurin in Patients with Recurrent Gliomas SO CLINICAL CANCER RESEARCH LA English DT Article ID PROTEIN-KINASE-C; ANTIEPILEPTIC DRUGS; SIGNALING PATHWAY; BETA-II; INHIBITOR; EXPRESSION; LY333531; CRITERIA; CANCER; AKT AB Purpose: Enzastaurin is a selective inhibitor of protein kinase C beta. Prior phase I studies did not show increased drug exposures with escalating once daily administration. Limits from gastrointestinal absorption may be overcome by twice daily dosing, potentially improving antitumor effects. Experimental Design: We conducted a phase I dose escalation study in 26 patients with recurrent malignant glioma, stratified by use of enzyme-inducing antiepileptic drugs, to investigate whether divided twice daily dosing results in higher exposures compared with once daily dosing. Phosphorylated glycogen synthase 3 beta was analyzed as a potential biomarker of enzastaurin activity. Results: Enzastaurin was poorly tolerated at all dose levels evaluated (500, 800, and 1,000 mg total daily), with thrombocytopenia and prolonged QTc as dose-limiting toxicities. The average drug concentration of enzastaurin under steady-state conditions was doubled by twice daily dosing compared with daily dosing [1.990; 90% confidence interval (CI), 1.450-2.730]. Additionally, geometric mean ratios doubled with 800 versus 500 mg dosing for both daily (2.687; 90% CI, 1.232-5.860) and twice daily regimens (1.852; 90% CI, 0.799-4.292). Two patients achieved long-term benefit (over 150 weeks progression free). Conclusions: Higher and more frequent dosing of enzastaurin resulted in improved drug exposure but with unacceptable toxicity at the doses tested. Phosphorylated glycogen synthase 3 beta may be a useful biomarker of the biological activity of enzastaurin. Enzastaurin has activity in a subset of malignant glioma patients and warrants continued study in combination with other agents using a maximal once daily dose of 500 mg. C1 [Kreisl, Teri N.; Kim, Lyndon; Moore, Kraig; Duic, Paul; Kotliarova, Svetlana; Walling, Jennifer; Fine, Howard A.] NINDS, Neurooncol Branch, NCI, NIH, Bethesda, MD 20892 USA. [Albert, Paul S.] NINDS, Biometr Res Branch, NCI, NIH, Bethesda, MD 20892 USA. [Musib, Luna; Thornton, Donald] Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Fine, HA (reprint author), NINDS, Neurooncol Branch, NCI, NIH, Bloch Bldg 82,Room 225,9030 Old Georgetown Rd, Bethesda, MD 20892 USA. EM hfine@mail.nih.gov FU Eli Lilly; Company Cooperative Research and Development Agreement [01364] FX Eli Lilly and Company Cooperative Research and Development Agreement (CRADA #01364). NR 19 TC 32 Z9 34 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAY 15 PY 2009 VL 15 IS 10 BP 3617 EP 3623 DI 10.1158/1078-0432.CCR-08-3071 PG 7 WC Oncology SC Oncology GA 448SP UT WOS:000266282600042 PM 19417015 ER PT J AU Powers, JH AF Powers, John H. TI Risk Perception and Inappropriate Antimicrobial Use: Yes, It Can Hurt SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID TRIALS C1 [Powers, John H.] NIAID, Sci Applicat Int Corp, Collaborat Clin Res Branch, NIH, Bethesda, MD 20892 USA. [Powers, John H.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Powers, John H.] George Washington Univ, Sch Med, Washington, DC USA. RP Powers, JH (reprint author), NIAID, Sci Applicat Int Corp, Collaborat Clin Res Branch, NIH, 6700B Rockledge Dr,Rm 1123, Bethesda, MD 20892 USA. EM powersjohn@mail.nih.gov FU PHS HHS [HHSN261200800001E] NR 18 TC 9 Z9 9 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2009 VL 48 IS 10 BP 1350 EP 1353 DI 10.1086/598184 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 441DK UT WOS:000265749300003 PM 19361305 ER PT J AU Cohen, JI AF Cohen, Jeffrey I. TI Rheumatoid Arthritis and the Incidence of Herpes Zoster: Risky Business SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID NECROSIS-FACTOR-ALPHA; FACTOR ANTAGONISTS; INFECTIONS; AGENTS; THERAPY C1 NIH, Med Virol Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Med Virol Sect, Lab Clin Infect Dis, Bldg 10,Room 11N234,10 Ctr Dr, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov NR 23 TC 2 Z9 2 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2009 VL 48 IS 10 BP 1372 EP 1374 DI 10.1086/598332 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 441DK UT WOS:000265749300007 PM 19368500 ER PT J AU Manabe, YC Jacob, ST Thomas, D Quinn, TC Ronald, A Coutinho, A Mayanja-Kizza, H Merry, C AF Manabe, Yukari C. Jacob, Shevin T. Thomas, David Quinn, Thomas C. Ronald, Allan Coutinho, Alex Mayanja-Kizza, Harriet Merry, Concepta TI Resurrecting the Triple Threat: Academic Social Responsibility in the Context of Global Health Research SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material AB As a result of the pandemic of human immunodeficiency virus infection, more academic physicians involved in research are working in resource-limited settings, especially in the field of infectious diseases. These researchers are often located in close proximity to health care facilities with serious workforce shortages. Because institutions and funders support global health research, they have the opportunity to make a lasting impact on the health system by training local health workers where the research is being conducted. Academic researchers who spend clinical time in local health care centers and who teach and mentor students as part of academic social responsibility will build capacity, an investment that will yield dividends for future generations. C1 [Manabe, Yukari C.; Coutinho, Alex; Merry, Concepta] Makerere Univ, Sch Med, Infect Dis Inst, Kampala, Uganda. [Mayanja-Kizza, Harriet] Makerere Univ, Sch Med, Dept Med, Kampala, Uganda. [Manabe, Yukari C.; Thomas, David; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. [Manabe, Yukari C.; Thomas, David; Quinn, Thomas C.] Johns Hopkins Univ, Johns Hopkins Ctr Global Hlth, Baltimore, MD 21205 USA. [Quinn, Thomas C.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Jacob, Shevin T.] Univ Washington, Dept Med, Div Allergy & Infect Dis, Seattle, WA USA. [Ronald, Allan] Univ Manitoba, Dept Med, Winnipeg, MB, Canada. [Merry, Concepta] Trinity Coll Dublin, Dublin, Ireland. RP Manabe, YC (reprint author), 2190 Kampala Pl, Dulles, VA 20189 USA. EM ymanabe@mu-jhu.idi.co.ug OI Mayanja-Kizza, Harriet/0000-0002-9297-6208; Ronald, Allan/0000-0002-5746-3490 FU Intramural NIH HHS [Z01 AI000361-25]; NHLBI NIH HHS [R01 HL090312, 1R01HL090312-01] NR 8 TC 13 Z9 13 U1 0 U2 9 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2009 VL 48 IS 10 BP 1420 EP 1422 DI 10.1086/598199 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 441DK UT WOS:000265749300014 PM 19368501 ER PT J AU Huang, J Dattilo, LK Rajagopal, R Liu, Y Kaartinen, V Mishina, Y Deng, CX Umans, L Zwijsen, A Roberts, AB Beebe, DC AF Huang, Jie Dattilo, Lisa K. Rajagopal, Ramya Liu, Ying Kaartinen, Vesa Mishina, Yuji Deng, Chu-Xia Umans, Lieve Zwijsen, An Roberts, Anita B. Beebe, David C. TI FGF-regulated BMP signaling is required for eyelid closure and to specify conjunctival epithelial cell fate SO DEVELOPMENT LA English DT Article DE Eyelid closure; Conjunctival cell fate; c-Jun nuclear transport; BMP signaling; FGF signaling; Mouse ID LYMPHEDEMA-DISTICHIASIS SYNDROME; FORKHEAD/WINGED-HELIX GENE; CONDITIONAL KNOCKOUT MICE; TRANSCRIPTION FACTORS; TGF-BETA; C-JUN; FUNCTIONAL-CHARACTERIZATION; HAIR FOLLICLE; LEADING-EDGE; NEURAL CREST AB There are conflicting reports about whether BMP signaling is required for eyelid closure during fetal development. This question was addressed using mice deficient in BMP or TGF beta signaling in prospective eyelid and conjunctival epithelial cells. Genes encoding two type I BMP receptors, the type II TGF beta receptor, two BMP- or two TGF beta-activated R-Smads or the co-Smad Smad4 were deleted from the ocular surface ectoderm using Cre recombinase. Only mice with deletion of components of the BMP pathway had an 'eyelid open at birth' phenotype. Mice lacking Fgf10 or Fgfr2 also have open eyelids at birth. To better understand the pathways that regulate BMP expression and function during eyelid development, we localized BMPs and BMP signaling intermediates in Fgfr2 and Smad4 conditional knockout (CKO) mice. We found that Fgfr2 was required for the expression of Bmp4, the normal distribution of Shh signaling and for preserving the differentiation of the conjunctival epithelium. FGF signaling also promoted the expression of the Wnt antagonist Sfrp1 and suppressed Wnt signaling in the prospective eyelid epithelial cells, independently of BMP function. Transcripts encoding Foxc1 and Foxc2, which were previously shown to be necessary for eyelid closure, were not detectable in Smad4(CKO) animals. c-Jun, another key regulator of eyelid closure, was present and phosphorylated in eyelid periderm cells at the time of fusion, but failed to translocate to the nucleus in the absence of BMP function. Smad4(CKO) mice also showed premature differentiation of the conjunctival epithelium, conjunctival hyperplasia and the acquisition of epidermal characteristics, including formation of an ectopic row of hair follicles in place of the Meibomian glands. A second row of eyelashes is a feature of human lymphedema-distichiasis syndrome, which is associated with mutations in FOXC2. C1 [Huang, Jie; Dattilo, Lisa K.; Rajagopal, Ramya; Liu, Ying; Beebe, David C.] Washington Univ, Dept Ophthalmol & Visual Sci, St Louis, MO 63130 USA. [Beebe, David C.] Washington Univ, Dept Cell Biol & Physiol, St Louis, MO 63130 USA. [Kaartinen, Vesa] Univ So Calif, Childrens Hosp Los Angeles, Keck Sch Med, Dev Biol Program,Dept Pathol, Los Angeles, CA 90027 USA. [Kaartinen, Vesa] Univ So Calif, Childrens Hosp Los Angeles, Keck Sch Med, Dev Biol Program,Dept Surg, Los Angeles, CA 90027 USA. [Mishina, Yuji] Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, Mol Dev Biol Grp, Res Triangle Pk, NC 27709 USA. [Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Umans, Lieve; Zwijsen, An] Dept Mol & Dev Genet, Lab Mol Biol Celgen, B-3000 Louvain, Belgium. [Umans, Lieve; Zwijsen, An] Katholieke Univ Leuven, Ctr Human Genet, Lab Mol Biol Celgen, B-3000 Louvain, Belgium. [Roberts, Anita B.] NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Beebe, DC (reprint author), Washington Univ, Dept Ophthalmol & Visual Sci, St Louis, MO 63130 USA. EM Beebe@vision.wustl.edu RI Huang, Jie/D-7728-2014; deng, chuxia/N-6713-2016; OI Kaartinen, Vesa/0000-0002-9432-510X FU NIH [EY04853, EY02687]; Prevent Blindness to the Department of Ophthalmology and Visual Sciences FX The authors are indebted to Drs Zhen Mahoney and Jeff Miner for generously sharing reagents, for many suggestions on the technical aspects of this work and for assistance in editing. Belinda McMahan and Jean Jones prepared the histological sections and Dr Claudia Garcia provided guidance with the Fgfr2 conditional knockouts, which were generously provided by Dr David Ornitz, Washington University, St Louis. The Psen1 and Psen2 floxed and mutant mice were generously provided by Dr J. Shen, Brigham and Women's Hospital, Boston, MA and Dr Raphael Kopan, Washington University, St Louis. Drs Peter Gruss and Ruth Ashery-Padan generated and provided the Le-Cre mice. Research was supported by NIH grant EY04853 (D. C. B.) and NIH Core Grant P30 EY02687 and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology and Visual Sciences. Deposited in PMC for release after 12 months. NR 52 TC 48 Z9 52 U1 0 U2 14 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAY 15 PY 2009 VL 136 IS 10 BP 1741 EP 1750 DI 10.1242/dev.034082 PG 10 WC Developmental Biology SC Developmental Biology GA 438AV UT WOS:000265529200016 PM 19369394 ER PT J AU Covassin, LD Siekmann, AF Kacergis, MC Laver, E Moore, JC Villefranc, JA Weinstein, BM Lawson, ND AF Covassin, L. D. Siekmann, A. F. Kacergis, M. C. Laver, E. Moore, J. C. Villefranc, J. A. Weinstein, B. M. Lawson, N. D. TI A genetic screen for vascular mutants in zebrafish reveals dynamic roles for Vegf/Plcg1 signaling during artery development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Zebrafish; Vascular; Genetic screen; Vegf ID ENDOTHELIAL-GROWTH-FACTOR; RECEPTOR TYROSINE KINASE; PHOSPHOLIPASE-C-GAMMA; CARDIOVASCULAR DEVELOPMENT; TRANSGENIC ZEBRAFISH; NOTCH PATHWAY; TIE2 RECEPTOR; VEGF; ANGIOGENESIS; MICE AB In this work we describe a forward genetic approach to identify mutations that affect blood vessel development in the zebrafish. By applying a haploid screening strategy in a transgenic background that allows direct visualization of blood vessels, it was possible to identify several classes of mutant vascular phenotypes. Subsequent characterization of mutant lines revealed that defects in Vascular endothelial growth factor (Vegf) signaling specifically affected artery development. Comparison of phenotypes associated with different mutations within a functional zebrafish Vegf receptor-2 ortholog (referred to as kdr-like, kdr1) revealed surprisingly varied effects on vascular development. In parallel, we identified an allelic series of mutations in phospholipase c gamma 1 (p1cg1). Together with in vivo structure-function analysis, our results suggest a requirement for Plcg1 catalytic activity downstream of receptor tyrosine kinases. We further find that embryos lacking both maternal and zygotic plcg1 display more severe defects in artery differentiation but are otherwise similar to zygotic mutants. Finally, we demonstrate through mosaic analysis that plcg1 functions autonomously in endothelial cells. Together our genetic analyses Suggest that Vegf/Plcg1 signaling acts at multiple time points and in different signaling contexts to mediate distinct aspects of artery development. (C) 2009 Elsevier Inc. All rights reserved. C1 [Covassin, L. D.; Siekmann, A. F.; Kacergis, M. C.; Laver, E.; Moore, J. C.; Villefranc, J. A.; Lawson, N. D.] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. [Weinstein, B. M.] NICHD, Mol Genet Lab, NIH, Bethesda, MD USA. [Covassin, L. D.] Univ Massachusetts, Sch Med, Div Diabet, Worcester, MA 01605 USA. [Siekmann, A. F.] Max Planck Inst Mol Biomed, Lab Cardiovasc Patterning, Munster, Germany. RP Lawson, ND (reprint author), Univ Massachusetts, Sch Med, Program Gene Funct & Express, Lazare Res Bldg,Room 617,364 Plantat St, Worcester, MA 01605 USA. EM nathan.lawson@umassmed.edu FU National Cancer Institute [R01CA107454]; Ruth Kirchstein Minority Predoctoral Fellowship [F31HL081927] FX We would like to thank the members of the NIH and UMass Screen Teams: NIH - Brianne Lo, josh Mugford, Michael Tsang, Neil Hukriede and Sue Lyons; UMass - Letitiah Etheridge, Seong-Kyu Choe, Kristen Alexa, Nicolas Hirsch and Charles Sagerstrom. We thank John Polli for outstanding fish care. We thank Fumihiko Urano, Roger Davis, Alex Schier, Erez Raz, and Chi-Bin Chien for generously providing plasmids used in this study. This work was supported by R01CA107454 (National Cancer Institute) awarded to N. D. L. and a Ruth Kirchstein Minority Predoctoral Fellowship (F31HL081927; National Heart, Lung, and Blood Institute) awarded to J.A.V. NR 72 TC 67 Z9 67 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAY 15 PY 2009 VL 329 IS 2 BP 212 EP 226 DI 10.1016/j.ydbio.2009.02.031 PG 15 WC Developmental Biology SC Developmental Biology GA 445JY UT WOS:000266048300005 PM 19269286 ER PT J AU Grieder, NC Morata, G Affolter, M Gehring, WJ AF Grieder, Nicole C. Morata, Gines Affolter, Markus Gehring, Walter J. TI Spalt major controls the development of the notum and of wing hinge primordia of the Drosophila melanogaster wing imaginal disc SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Spalt major; Spalt related; Notum; Wing hinge; Imaginal disc patterning; Wing disc ID GENE-FUNCTION; CELL FATE; ADULT DROSOPHILA; DUAL ROLE; COMPLEX; DORSAL; EXPRESSION; BODY; SPECIFICATION; MECHANISMS AB The Drosophila wing and the dorsal thorax develop from primordia within the wing imaginal disc. Here we show that spalt major (salm) is expressed within the presumptive dorsal body wall primordium early in wing disc development to specify notum and wing hinge tissue. Upon ectopic salm expression, dorsally located second leg disc cells develop notum and wing hinge tissue instead of sternopleural tissue. Similarly, by salm over-expression within the wing disc, wing blade formation is suppressed and a mirror-image duplication of the notum and wing hinge is formed. in large dorsal clones, which lack saint and its neighboring paralogue spalt related (salr), the cells of the notum primordium do not grow; these dorsal cells are not specified as notum, hence no notum outgrowth develops. These results suggest that the zinc finger factors encoded by the salm/salr complex play important roles in defining cells of the early wing disc as dorsal body wall cells, which develop into a large dorsal body wall territory and form mesonotum and some wing hinge tissue, and in delimiting the wing primordium. We also find that salm activity is down-regulated by its own product and by that of the Pax gene eyegone. (C) 2009 Elsevier Inc. All rights reserved. C1 [Grieder, Nicole C.; Affolter, Markus; Gehring, Walter J.] Univ Basel, Biozentrum, Abt Zellbiol, CH-4056 Basel, Switzerland. [Morata, Gines] Univ Autonoma Madrid, Ctr Biol Mol, E-28049 Madrid, Spain. RP Grieder, NC (reprint author), NICHD, NIH, 18 Lib Dr,Bldg 32,Rm 103, Bethesda, MD 20892 USA. EM griedern@gmail.nih.gov OI Affolter, Markus/0000-0002-5171-0016 FU Kantons Basel-Stadt and Basel-Land; Swiss National Science Foundation; Treubel-Fonds, Basel FX We thank Natalia Azpiazu and Reinhard Schuh for antibodies. The monoclonal antibody against Wg developed by S.M. Cohen was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa. We thank David del Alamo Rodriguez, Konrad Basler, Bruno Bello, Clemens Cabernard, Sean Carroll, Stephen Cohen, Susanne Flister, George Haider, Richard Mann, Juan Modolell, Mark Neumann, Pernille Rorth Ulrich Schafer, Reinhard Schuh, Y. Henry Sun and the Bloomington Stock Center for many fly lines or plasmids. We thank Paul Baumgartner for advice on construction of the phage library. We thank Veronique Charpignon and Salome Rock for comments on the manuscript. This work was supported by the Kantons Basel-Stadt and Basel-Land, the Swiss National Science Foundation and the Treubel-Fonds, Basel. NR 58 TC 9 Z9 10 U1 0 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD MAY 15 PY 2009 VL 329 IS 2 BP 315 EP 326 DI 10.1016/j.ydbio.2009.03.006 PG 12 WC Developmental Biology SC Developmental Biology GA 445JY UT WOS:000266048300013 PM 19298807 ER PT J AU Kunisada, M Cui, CY Piao, YL Ko, MSH Schlessinger, D AF Kunisada, Makoto Cui, Chang-Yi Piao, Yulan Ko, Minoru S. H. Schlessinger, David TI Requirement for Shh and Fox family genes at different stages in sweat gland development SO HUMAN MOLECULAR GENETICS LA English DT Article ID HAIR FOLLICLE MORPHOGENESIS; SONIC-HEDGEHOG; TRANSCRIPTION FACTORS; ECTODERMAL DYSPLASIA; SKIN; MICE; ECTODYSPLASIN; EXPRESSION; CELL; INVOLVEMENT AB Sweat glands play a fundamental role in thermal regulation in man, but the molecular mechanism of their development remains unknown. To initiate analyses, we compared the model of Eda mutant Tabby mice, in which sweat glands were not formed, with wild-type (WT) mice. We inferred developmental stages and critical genes based on observations at seven time points spanning embryonic, postnatal and adult life. In WT footpads, sweat gland germs were detected at E17.5. The coiling of secretory portions started at postnatal day 1 (P1), and sweat gland formation was essentially completed by P5. Consistent with a controlled morphological progression, expression profiling revealed stage-specific gene expression changes. Similar to the development of hair follicles-025EFthe other major skin appendage controlled by EDA-025EFsweat gland induction and initial progression were accompanied by Eda-dependent up-regulation of the Shh pathway. During the further development of sweat gland secretory portions, Foxa1 and Foxi1, not at all expressed in hair follicles, were progressively up-regulated in WT but not in Tabby footpads. Upon completion of WT development, Shh declined to Tabby levels, but Fox family genes remained at elevated levels in mature sweat glands. The results provide a framework for the further analysis of phased down-stream regulation of gene action, possibly by a signaling cascade, in response to Eda. C1 [Kunisada, Makoto; Cui, Chang-Yi; Piao, Yulan; Ko, Minoru S. H.; Schlessinger, David] NIA, Genet Lab, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. RP Cui, CY (reprint author), NIA, Genet Lab, NIH, NIH Biomed Res Ctr, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM cuic@grc.nia.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU IRP of the NIH; National Institute on Aging FX This work was supported entirely by the IRP of the NIH, National Institute on Aging. NR 36 TC 21 Z9 21 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2009 VL 18 IS 10 BP 1769 EP 1778 DI 10.1093/hmg/ddp089 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 437ZJ UT WOS:000265525400004 PM 19270025 ER PT J AU Stanford, JL FitzGerald, LM McDonnell, SK Carlson, EE McIntosh, LM Deutsch, K Hood, L Ostrander, EA Schaid, DJ AF Stanford, Janet L. FitzGerald, Liesel M. McDonnell, Shannon K. Carlson, Erin E. McIntosh, Laura M. Deutsch, Kerry Hood, Lee Ostrander, Elaine A. Schaid, Daniel J. TI Dense genome-wide SNP linkage scan in 301 hereditary prostate cancer families identifies multiple regions with suggestive evidence for linkage SO HUMAN MOLECULAR GENETICS LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; SUSCEPTIBILITY GENES; AGGRESSIVENESS LOCI; INTERNATIONAL CONSORTIUM; PROGNOSTIC-SIGNIFICANCE; GENETICS PROJECT; CHROMOSOME 19Q; RISK; VARIANTS; DISEASE AB The search for susceptibility loci in hereditary prostate cancer (HPC) has proven challenging due to genetic and disease heterogeneity. Multiple risk loci have been identified to date, however few loci have been replicated across independent linkage studies. In addition, most previous analyses have been hampered by the relatively poor information content provided by microsatellite scans. To overcome these issues, we have performed linkage analyses on members of 301 HPC families genotyped using the Illumina SNP linkage panel IVb. The information content for this panel, averaged over all pedigrees and all chromosomes, was 86% (range 83-87% over chromosomes). Analyses were also stratified on families according to disease aggressiveness, age at diagnosis and number of affected individuals to achieve more genetically homogeneous subsets. Suggestive evidence for linkage was identified at 7q21 (HLOD = 1.87), 8q22 (KCLOD = 1.88) and 15q13-q14 (HLOD = 1.99) in 289 Caucasian families, and nominal evidence for linkage was identified at 2q24 (LOD = 1.73) in 12 African American families. Analysis of more aggressive prostate cancer phenotypes provided evidence for linkage to 11q25 (KCLOD = 2.02), 15q26 (HLOD = 1.99) and 17p12 (HLOD = 2.13). Subset analyses according to age at diagnosis and number of affected individuals also identified several regions with suggestive evidence for linkage, including a KCLOD of 2.82 at 15q13-q14 in 128 Caucasian families with younger ages at diagnosis. The results presented here provide further evidence for a prostate cancer susceptibility locus on chromosome 15q and demonstrate the power of utilizing high information content SNP scans in combination with homogenous collections of large prostate cancer pedigrees. C1 [Stanford, Janet L.; FitzGerald, Liesel M.; McIntosh, Laura M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [McDonnell, Shannon K.; Carlson, Erin E.; Schaid, Daniel J.] Mayo Clin, Div Biostat, Rochester, MN 55905 USA. [Deutsch, Kerry; Hood, Lee] Inst Syst Biol, Seattle, WA 98103 USA. [Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Stanford, JL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. EM jstanfor@fhcrc.org OI Ostrander, Elaine/0000-0001-6075-9738 FU National Cancer Institute [RO1 CA080122, P50-CA097186]; Fred Hutchinson Cancer Research Center. Genotyping; National Institutes of Health [N01-HG-65403] FX This work was supported by the National Cancer Institute [grant numbers RO1 CA080122 and P50-CA097186] with additional support from the Fred Hutchinson Cancer Research Center. Genotyping services provided by the Center for Inherited Disease Research at Johns Hopkins University were supported by the National Institutes of Health [ contract number N01-HG-65403]. NR 54 TC 18 Z9 18 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2009 VL 18 IS 10 BP 1839 EP 1848 DI 10.1093/hmg/ddp100 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 437ZJ UT WOS:000265525400010 PM 19251732 ER PT J AU Kabat, GC Cross, AJ Park, Y Schatzkin, A Hollenbeck, AR Rohan, TE Sinha, R AF Kabat, Geoffrey C. Cross, Amanda J. Park, Yikyung Schatzkin, Arthur Hollenbeck, Albert R. Rohan, Thomas E. Sinha, Rashmi TI Meat intake and meat preparation in relation to risk of postmenopausal breast cancer in the NIH-AARP diet and health study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE meat mutagens; high temperature cooking; heterocyclic amines; breast neoplasms ID FOOD FREQUENCY QUESTIONNAIRE; HETEROCYCLIC AMINE CONTENT; GENETIC-POLYMORPHISM; NATIONAL-INSTITUTES; VARYING DEGREES; COOKED MEAT; CONSUMPTION; COHORT; COOKING; FAT AB A number of studies have reported that intake of red meat or meat cooked at high temperatures is associated with increased risk of breast cancer, but other studies have shown no association. We assessed the association between meat, meat-cooking methods, and meat-mutagen intake and postmenopausal breast cancer in the NIH-AARP Diet and Health Study cohort of 120,755 postmenopausal women who completed a food frequency questionnaire at baseline (1995-1996) as well as a detailed ineat-cooking module within 6 months following baseline. During 8 years of follow-up, 3,818 cases of invasive breast cancer were identified in this cohort. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). After adjusting for covariates, intake of total meat, red meat, meat cooked at high temperatures, and meat mutagens showed no association with breast cancer risk. This large prospective study with detailed information on meat preparation methods provides no support for a role of meat mutagens in the development of postmenopausal breast cancer. (C) 2008 Wiley-Liss. Inc. C1 [Kabat, Geoffrey C.; Rohan, Thomas E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Health, Bronx, NY 10461 USA. [Cross, Amanda J.; Park, Yikyung; Schatzkin, Arthur; Sinha, Rashmi] NCI, Nutr Epidemiol Branch, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC 20049 USA. RP Kabat, GC (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Health, Bronx, NY 10461 USA. EM gkabat@aecom.yu.edu RI Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Park, Yikyung/0000-0002-6281-489X FU Intramural NIH HHS [ZIA CP010196-05] NR 34 TC 28 Z9 28 U1 2 U2 5 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 MAY 15 PY 2009 VL 124 IS 10 BP 2430 EP 2435 DI 10.1002/ijc.24203 PG 6 WC Oncology SC Oncology GA 435OM UT WOS:000265353200021 PM 19165862 ER PT J AU Andreotti, G Freeman, LEB Hou, LF Coble, J Rusiecki, J Hoppin, JA Silverman, DT Alavanja, MCR AF Andreotti, Gabriella Freeman, Laura E. Beane Hou, Lifang Coble, Joseph Rusiecki, Jennifer Hoppin, Jane A. Silverman, Debra T. Alavanja, Michael C. R. TI Agricultural pesticide use and pancreatic cancer risk in the Agricultural Health Study Cohort SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE pancreatic cancer; pesticides; agriculture ID EXPOSURE; APPLICATORS; TUMORS; LUNG AB Pancreatic cancer is a rapidly fatal disease that has been linked with pesticide use. Previous studies have reported excess risks of pancreatic cancer with organochlorines such as DDT, however, many other commonly used pesticides have not been examined. To further examine the potential associations between the use of a number of pesticides and pancreatic cancer, we conducted a case-control analysis in the Agricultural Health Study, one of the largest prospective cohorts with over 89,000 participants including pesticide applicators and their spouses in Iowa and North Carolina. This analysis included 93 incident pancreatic cancer cases (64 applicators, 29 spouses) and 82,503 cancer-free controls who completed an enrollment questionnaire providing detailed pesticide use, demographic and lifestyle information. Ever use of 24 pesticides and intensity-weighted lifetime days [(lifetime exposure days) X (exposure intensity score)] of 13 pesticides was assessed. Risk estimates were calculated using unconditional logistic regression controlling for age, smoking, and diabetes. Among pesticide applicators, 2 herbicides (EPTC and pendimethalin) of the 13 pesticides examined for intensity-weighted lifetime use showed a statistically significant exposure-response association with pancreatic cancer. Applicators in the top half of lifetime pendimethalin use had a 3.0-fold (95% CI 1.3-7.2, p-trend = 0.01) risk compared with never users, and those in the top half of lifetime EPTC use had a 2.56-fold (95% CI = 1.1-5.4, p-trend = 0.01) risk compared with never users. Organochlorines were not associated with an excess risk of pancreatic cancer in this study. These findings suggest that herbicides, particularly pendimethalin and EPTC, may be associated with pancreatic cancer. (C) 2008 Wiley-Liss, Inc. C1 [Andreotti, Gabriella; Freeman, Laura E. Beane; Coble, Joseph; Silverman, Debra T.; Alavanja, Michael C. R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Rusiecki, Jennifer] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Hoppin, Jane A.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Andreotti, G (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 8011,MSC 7240, Bethesda, MD 20892 USA. EM andreotg@mail.nih.gov FU National Cancer Institute; NIH [Z01 CP010119]; National Institute of Environmental Health Sciences [Z01-ES049030-11] FX Grant sponsor: National Cancer Institute, NIH; Grant number Z01 CP010119; Grant sponsor National Institute of Environmental Health Sciences; Grant number: Z01-ES049030-11. NR 25 TC 32 Z9 34 U1 1 U2 9 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 MAY 15 PY 2009 VL 124 IS 10 BP 2495 EP 2500 DI 10.1002/ijc.24185 PG 6 WC Oncology SC Oncology GA 435OM UT WOS:000265353200029 PM 19142867 ER PT J AU Dawid, IB AF Dawid, Igor B. TI Differential Gene Expression in Vertebrate Embryos SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Editorial Material ID XENOPUS-LAEVIS; MESSENGER-RNA; DROSOPHILA-MELANOGASTER; ZEBRAFISH EMBRYOGENESIS; SYNTHESIZE HYALURONAN; POLYADENYLATED RNA; RIBOSOMAL-RNA; CDNA LIBRARY; DG42 GENE; DNA C1 Eunice Kennedy Shriver NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Dawid, IB (reprint author), Eunice Kennedy Shriver NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM idawid@nih.gov FU Intramural NIH HHS NR 76 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 15 PY 2009 VL 284 IS 20 BP 13277 EP 13283 DI 10.1074/jbc.X800018200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 442YL UT WOS:000265877300001 PM 19158075 ER PT J AU Seo, JH Lim, JC Lee, DY Kim, KS Piszczek, G Nam, HW Kim, YS Ahn, T Yun, CH Kim, K Chock, PB Chae, HZ AF Seo, Jae Ho Lim, Jung Chae Lee, Duck-Yeon Kim, Kyung Seok Piszczek, Grzegorz Nam, Hyung Wook Kim, Yu Sam Ahn, Taeho Yun, Chul-Ho Kim, Kanghwa Chock, P. Boon Chae, Ho Zoon TI Novel Protective Mechanism against Irreversible Hyperoxidation of Peroxiredoxin N-alpha-TERMINAL ACETYLATION OF HUMAN PEROXIREDOXIN II SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYSTEINE-SULFINIC ACID; ACTIVE-SITE CYSTEINE; THIOL-SPECIFIC ANTIOXIDANT; OXIDATIVE STRESS; MAMMALIAN PEROXIREDOXIN; 2-CYS PEROXIREDOXIN; HYDROGEN-PEROXIDE; IN-VIVO; DIFFERENTIAL EXPRESSION; REDUCE PEROXIDES AB Peroxiredoxins (Prxs) are a group of peroxidases containing a cysteine thiol at their catalytic site. During peroxidase catalysis, the catalytic cysteine, referred to as the peroxidatic cysteine (C-P), cycles between thiol (C-P-SH) and disulfide (-S-S-) states via a sulfenic (C-P-SOH) intermediate. Hyperoxidation of the CP thiol to its sulfinic (C-P-SO2H) derivative has been shown to be reversible, but its sulfonic (C-P-SO3H) derivative is irreversible. Our comparative study of hyperoxidation and regeneration of Prx I and Prx II in HeLa cells revealed that Prx II is more susceptible than Prx I to hyperoxidation and that the majority of the hyperoxidized Prx II formation is reversible. However, the hyperoxidized Prx I showed much less reversibility because of the formation of its irreversible sulfonic derivative, as verified with C-P-SO3H-specific antiserum. In an attempt to identify the multiple hyperoxidized spots of the Prx I on two-dimensional PAGE analysis, an N-acetylated Prx I was identified as part of the total Prx I using anti-acetylated Lys antibody. Using peptidyl-Asp metalloendopeptidase (EC 3.4.24.33) peptide fingerprints, we found that N-alpha-terminal acetylation (N-alpha-Ac) occurred exclusively on Prx II after demethionylation. N-alpha-Ac of Prx II blocks Prx II from irreversible hyperoxidation without altering its affinity for hydrogen peroxide. A comparative study of non-N-alpha-acetylated and N-alpha-terminal acetylated Prx II revealed that N-alpha-Ac of Prx II induces a significant shift in the circular dichroism spectrum and elevation of T-m from 59.6 to 70.9 degrees C. These findings suggest that the structural maintenance of Prx II by N-alpha-Ac may be responsible for preventing its hyperoxidation to form C-P-SO3H. C1 [Lee, Duck-Yeon; Piszczek, Grzegorz; Chock, P. Boon; Chae, Ho Zoon] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. [Seo, Jae Ho; Lim, Jung Chae; Kim, Kyung Seok; Yun, Chul-Ho] Chonnam Natl Univ, Sch Biol Sci & Technol, Kwangju 500757, South Korea. [Kim, Kanghwa] Chonnam Natl Univ, Dept Food & Nutr, Kwangju 500757, South Korea. [Kim, Kanghwa] Chonnam Natl Univ, Coll Vet Med, Kwangju 500757, South Korea. [Ahn, Taeho] Chonnam Natl Univ, Dept Biochem, Kwangju 500757, South Korea. [Nam, Hyung Wook; Kim, Yu Sam] Yonsei Univ, Res Ctr, Prot Network, Coll Sci,Dept Biochem, Seoul 120749, South Korea. RP Chae, HZ (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3, Bethesda, MD 20892 USA. EM hzchae@chonnam.ac.kr FU Korea Research Foundation [KRF2005-070-C00081]; Chonnam National University [CNU-2008-1005]; Korea Science and Engineering Foundation [R01-2008-000-2107202008]; Ministry of Education, Science and Technology of Korea FX This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported by Korea Research Foundation Grant KRF2005-070-C00081, Chonnam National University Grant CNU-2008-1005, Korea Science and Engineering Foundation Grant R01-2008-000-2107202008 (to H. Z. C.), and Second Stage BK21 Project from the Ministry of Education, Science and Technology of Korea. NR 60 TC 28 Z9 28 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 15 PY 2009 VL 284 IS 20 BP 13455 EP 13465 DI 10.1074/jbc.M900641200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 442YL UT WOS:000265877300021 PM 19286652 ER PT J AU Webster, M Witkin, KL Cohen-Fix, O AF Webster, Micah Witkin, Keren L. Cohen-Fix, Orna TI Sizing up the nucleus: nuclear shape, size and nuclear-envelope assembly SO JOURNAL OF CELL SCIENCE LA English DT Review DE ER membrane; Reticulons; ER tubules; ER sheets; Lamina; Nuclear envelope assembly; Nuclear pore complex; Lipin ID HUTCHINSON-GILFORD-PROGERIA; CELL-CYCLE PROGRESSION; LAMIN-B RECEPTOR; ENDOPLASMIC-RETICULUM; PORE COMPLEXES; CAENORHABDITIS-ELEGANS; DE-NOVO; MEMBRANE PROTEIN; FISSION YEAST; INHIBITING FARNESYLATION AB The nucleus is one of the most prominent cellular organelles, yet surprisingly little is known about how it is formed, what determines its shape and what defines its size. As the nuclear envelope (NE) disassembles in each and every cell cycle in metazoans, the process of rebuilding the nucleus is crucial for proper development and cell proliferation. In this Commentary, we summarize what is known about the regulation of nuclear shape and size, and highlight recent findings that shed light on the process of building a nucleus, including new discoveries related to NE assembly and the relationship between the NE and the endoplasmic reticulum (ER). Throughout our discussion, we note interesting aspects of nuclear structure that have yet to be resolved. Finally, we present an idea-which we refer to as 'the limited flat membrane hypothesis'-to explain the formation of a single nucleus that encompasses of all of the cell's chromosomes following mitosis. C1 [Webster, Micah; Witkin, Keren L.; Cohen-Fix, Orna] NIDDK, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Cohen-Fix, O (reprint author), NIDDK, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM ornacf@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney diseases FX We thank Will Prinz, Paula Fearon, Daphna Joseph-Strauss (National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD), and Donald Olins and Ada Olins (Bowdoin College, Brunswick ME) for comments on the manuscript. We also thank Tom Misteli and Paola Scaffidi (National Cancer Institute, Bethesda, MD) for generously providing the images in Fig. 3D, and Ada Olins and Donald Olins for allowing us to use the image in Fig. 3B. M. W., K. L. W. and O. C. F. are funded by an intramural grant from the National Institute of Diabetes and Digestive and Kidney diseases. NR 112 TC 129 Z9 134 U1 5 U2 33 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAY 15 PY 2009 VL 122 IS 10 BP 1477 EP 1486 DI 10.1242/jcs.037333 PG 10 WC Cell Biology SC Cell Biology GA 442PC UT WOS:000265852100002 PM 19420234 ER PT J AU Kapoor, V Hakim, FT Rehman, N Gress, RE Telford, WG AF Kapoor, Veena Hakim, Fran T. Rehman, Najibah Gress, Ronald E. Telford, William G. TI Quantum dots thermal stability improves simultaneous phenotype-specific telomere length measurement by FISH-flow cytometry SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE FISH-flow cytometry; Quantum dots; Telomere length ID STEM-CELLS; LYMPHOCYTES; TURNOVER; DYNAMICS; SUBSETS AB Telomere length analysis has been greatly simplified by the quantitative flow cytometry technique FISH-flow. In this method, a fluorescein-labeled synthetic oligonucleotide complementary to the telomere terminal repeat sequence is hybridized to the telomere sequence and the resulting fluorescence measured by flow cytometry. This technique has supplanted the traditional laborious Southern blot telomere length measurement techniques in many laboratories, and allows single cell analysis of telomere length in high-throughput sample formats. Nevertheless, the harsh conditions required for telomere probe annealing (82 degrees C) has made it difficult to successfully combine this technique with simultaneous immunolabeling. Most traditional organic fluorescent probes (i.e. fluorescein, phycoerythrin, etc.) have limited thermal stability and do not survive the high temperature annealing process, despite efforts to covalently crosslink the antigen-antibody-fluorophore complex. This loss of probe fluorescence has made it difficult to measure FISH-flow in complex lymphocyte populations, and has generally forced investigators to use fluorescent-activated cell sorting to pre-separate their populations, a laborious technique that requires prohibitively large numbers of cells. In this study, we have substituted quantum dots (nanoparticles) for traditional fluorophores in FISH-flow. Quantum dots were demonstrated to possess much greater thermal stability than traditional low molecular weight and phycobiliprotein fluorophores. Quantum dot antibody conjugates directed against monocyte and T cell antigens were found to retain most of their fluorescence following the high temperature annealing step, allowing simultaneous fluorescent immunophenotyping and telomere length measurement. Since quantum dots have very narrow emission bandwidths, we were able to analyze multiple quantum dot antibody conjugates (Qdot 605, 655 and 705) simultaneously with FISH-flow measurement to assess the age-associated decline in telomere length in both human monocytes and T cell subsets. With quantum dot immunolabeling, the mean decrease rate in telomere length for CD4+ cells was calculated at 41.8 bp/year, very close to previously reported values using traditional flow-FISH and Southern blotting. This modification to the traditional flow-FISH technique should therefore allow simultaneous fluorescent immunophenotyping and telomere length measurement, permitting complex cell subset-specific analysis in small numbers of cells without the requirement for prior cell sorting. Published by Elsevier B.V. C1 [Kapoor, Veena] NCI, Expt Transplantat & Immunol Branch, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. RP Kapoor, V (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Clin Res Ctr, Bldg 10,Room 3-3330,9000 Rockville Pike, Bethesda, MD 20892 USA. EM veenak@helix.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 24 TC 12 Z9 13 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD MAY 15 PY 2009 VL 344 IS 1 BP 6 EP 14 DI 10.1016/j.jim.2009.02.004 PG 9 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 452WW UT WOS:000266572900002 PM 19268672 ER PT J AU Zhu, DM Huang, SH Gebregeorgis, E McClellan, H Dai, WL Miller, L Sau, A AF Zhu, Daming Huang, Shuhui Gebregeorgis, Elizabeth McClellan, Holly Dai, Weili Miller, Louis Sau, Allan TI Development of a Direct Alhydrogel Formulation Immunoassay (DAFIA) SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE DAFIA; Alhydrogel; Vaccine; Antigen content; Plasmodium falciparum apical membrane antigen 1 ID APICAL MEMBRANE ANTIGEN-1; ALUMINUM HYDROXIDE ADJUVANT; VACCINE ADJUVANTS; ASSAY AB Alhydrogel (R) (aluminum hydroxide) is a widely used adjuvant in the US. Regulatory authorities require that vaccines be tested to determine the antigen content in the final vaccine product. The level of formulated antigen is currently determined in our laboratory by the o-Phthalaldehyde (OPA) fluorescent protein assay, and antigen identity and integrity are determined by Western blot and SDS-PAGE. However, OPA assay is non-specific and only limited to detection of total protein content, and it is often not sensitive enough to detect antigens in low dose formulations. Furthermore, antigens used in identity and integrity tests must be extracted from vaccines using an extraction procedure which is time-consuming and may not completely recover antigens for analysis or may alter the structures of antigens during extraction. The present study developed a Direct Alum Formulation Immunoassay (DAFIA) which was designed to directly (without antigen extraction), accurately, and sensitively determine the antigen content, identity and integrity on alum. The AMA1-C1/Alhydrogel formulation was used as a model vaccine in assay development and validation. The results showed that the DAFIA is highly antigen-specific, accurate (87-100%), sensitive (0.16 mu g/ml), reproducible, and simple with a linear detection range of 0.16-10 mu g/ml. These results demonstrate that DAFIA is an excellent assay to determine antigen content, identity and integrity of antigens bound to alum and may be used in routine vaccine quality control for testing antigens in Alhydrogel-based vaccines. Published by Elsevier B.V. C1 [Zhu, Daming; Huang, Shuhui; Gebregeorgis, Elizabeth; McClellan, Holly; Dai, Weili; Miller, Louis; Sau, Allan] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. RP Zhu, DM (reprint author), NIAID, Malaria Vaccine Dev Branch, NIH, 5640 Fishers Lane,Twinbrook 1 Room 1118, Rockville, MD 20852 USA. EM dzhu@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank David Narum and Richard Shimp, Jr. for making AMA1-FVO and AMA1-3D7 available, and this work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 17 TC 13 Z9 14 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD MAY 15 PY 2009 VL 344 IS 1 BP 73 EP 78 DI 10.1016/j.jim.2009.03.005 PG 6 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 452WW UT WOS:000266572900009 PM 19328804 ER PT J AU Sundstrom, JB Hair, GA Ansari, AA Secor, WE Gilfillan, AM Metcalfe, DD Kirshenbaum, AS AF Sundstrom, J. Bruce Hair, Gregory A. Ansari, Aftab A. Secor, W. Evan Gilfillan, Alasdair M. Metcalfe, Dean D. Kirshenbaum, Arnold S. TI IgE-Fc epsilon RI Interactions Determine HIV Coreceptor Usage and Susceptibility to Infection during Ontogeny of Mast Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN T-LYMPHOCYTES; CLADE-C INFECTION; SCHISTOSOMA-MANSONI; ANTIRETROVIRAL THERAPY; CHEMOKINE RECEPTORS; CXCR4 EXPRESSION; RHESUS MACAQUES; GASTROINTESTINAL-TRACT; SURFACE EXPRESSION AB Progenitor mast cells (prMCs), derived from CD34(+) precursors are CD4(+)/CCR5(+)/CXCR4(+) and susceptible to CCR5(R5)-tropic virus but only marginally susceptible to CXCR4(X4)-tropic HIV. As infected prMCs mature within extravascular compartments, they become both latently infected and HIV-infection resistant, and thus capable of establishing an inducible reservoir of CCR5-tropic infectious clones. In this report we provide the first evidence that IgE-Fc epsilon RI interactions, occurring during a unique period of mast cell (MC) ontogeny, enhance prMC susceptibility to X4 and R5X4 virus. IgE-Fc epsilon RI interactions significantly increased expression of CXCR4 mRNA (similar to 400- to 1800-fold), enhanced prMC susceptibility to X4 and R5X4 virus (similar to 3000- to 16,000-fold), but had no significant effect on CD4, CCR3, or CCR5 expression, susceptibility to R5 virus, or degranulation. Enhanced susceptibility to infection with X4 virus occurred during the first 3-5 wk of MC ontogeny and was completely inhibited by CXCR4-specific peptide antagonists and omalizumab, a drug that inhibits IgE-Fc epsilon RI interactions. IgE-Fc epsilon RI coaggregation mediated by HIVgp120 or Schistosoma mansoni soluble egg Ag accelerated maximal CXCR4 expression and susceptibility to X4 virus by prMCs. Our findings suggest that for HIV-positive individuals with atopic or helminthic diseases, elevated IgE levels could potentially influence the composition of CXCR4-tropic and R5X4-tropic variants archived within the long-lived tissue MC reservoir created during infection. The Journal of Immunology, 2009, 182: 6401-6409. C1 [Sundstrom, J. Bruce; Hair, Gregory A.; Ansari, Aftab A.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Secor, W. Evan] Ctr Dis Control & Prevent, Div Parasit Dis, Atlanta, GA 30341 USA. [Gilfillan, Alasdair M.; Metcalfe, Dean D.; Kirshenbaum, Arnold S.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Sundstrom, JB (reprint author), NIAID, Sci Review Program, Div Extramural Activ, NIH, Bethesda, MD 20892 USA. EM sundstromj@niaid.nih.gov FU National Institutes of Health [R01A1062383]; Division of Intramural Research; National Institute of Allergy and Infectious Diseases/National Institutes of Health; Animal Resources Program of the National Institutes of Health [RR-00165] FX This work was supported in part by Grant R01A1062383 from the National Institutes of Health (to J.B.S.), in part by the Division of Intramural Research. National Institute of Allergy and Infectious Diseases/National Institutes of Health. and in part by base Grant RR-00165 from the Animal Resources Program of the National Institutes of Health awarded to the Yerkes National Primate Research Center at Emory University. NR 52 TC 12 Z9 13 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2009 VL 182 IS 10 BP 6401 EP 6409 DI 10.4049/jimmunol.0801481 PG 9 WC Immunology SC Immunology GA 443HC UT WOS:000265899800058 PM 19414793 ER PT J AU Singh, A Zarember, KA Kuhns, DB Gallin, JI AF Singh, Anjali Zarember, Kol A. Kuhns, Douglas B. Gallin, John I. TI Impaired Priming and Activation of the Neutrophil NADPH Oxidase in Patients with IRAK4 or NEMO Deficiency SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECURRENT BACTERIAL-INFECTIONS; B ESSENTIAL MODULATOR; PHOSPHORYLATION-INDUCED ACTIVATION; POLYMORPHONUCLEAR LEUKOCYTES; KINASE-4 DEFICIENCY; IMMUNE-DEFICIENCY; GENE-EXPRESSION; REACTIVE OXYGEN; MOLECULAR-BASIS; IKK-GAMMA/NEMO AB The NADPH oxidase (NOX), an oligomeric enzyme, plays a key role in polymorphonuclear neutrophil (PMN)-mediated host defense by producing cytotoxic superoxide anion (O(2)((center dot) over bar)). Whereas in vitro and biochemical studies have examined the assembly and activation of this important host immune defense system, few studies have examined the function of NOX in human patients with primary immunodeficiency other than chronic granulomatous disease. We studied the activation of NOX in PMN from patients with two distinct immunodeficiencies, IL-1R-associated kinase (IRAK)4 deficiency and NF-kappa B essential modulator (NEMO or I kappa B kinase gamma) deficiency. We observed impaired O(2)((center dot) over bar) generation by LPS-treated and fMLP-activated IRAK4-deficient PMN that correlated with decreased phosphorylation of p47(phox) and subnormal translocation of p47(phox), p67(phox), Rac2, and gp91(phox)/Nox2 to the membranes indicating that TLR4 signaling to the NOX activation pathway requires IRAK4. NEMO-deficient PMN generated significantly less O(2)((center dot) over bar) in response to LPS-primed fMLP and translocated less p67(phox) than normal PMN, although p47(phox) and Rac2 2 translocation were normal. Generally, responses of NEMO-deficient cells were intermediate between IRAK4-deficient cells and normal cells. Decreased LPS- and fMLP-induced phosphorylation of p38 MAPK in both IRAK4- and NEMO-deficient PMN implicates additional signal transduction pathways in regulating PMN activation by LPS and fMLP. Decreased activation of NOX may contribute to the increased risk of infection seen in patients with IRAK4 and NEMO deficiency. The Journal of Immunology, 2009, 182: 6410-6417. C1 [Singh, Anjali; Zarember, Kol A.; Gallin, John I.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Kuhns, Douglas B.] Natl Canc Inst, Clin Serv Program, SAIC Frederick, Frederick, MD 21702 USA. RP Gallin, JI (reprint author), NIAID, Host Def Lab, NIH, 10 Ctr Dr,Room 6-2551,MSC 1504, Bethesda, MD 20892 USA. EM jgallin@cc.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Disease; National Institutes of Health; National Institutes of Health Clinical Center FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Disease, National Institutes of Health and the National Institutes of Health Clinical Center. NR 43 TC 26 Z9 29 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2009 VL 182 IS 10 BP 6410 EP 6417 DI 10.4049/jimmunol.0802512 PG 8 WC Immunology SC Immunology GA 443HC UT WOS:000265899800059 PM 19414794 ER PT J AU Ramalingam, TR Pesce, JT Mentink-Kane, MM Madala, S Cheever, AW Comeau, MR Ziegler, SF Wynn, TA AF Ramalingam, Thirumalai R. Pesce, John T. Mentink-Kane, Margaret M. Madala, Satish Cheever, Allen W. Comeau, Michael R. Ziegler, Steven F. Wynn, Thomas A. TI Regulation of Helminth-Induced Th2 Responses by Thymic Stromal Lymphopoietin SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN EPITHELIAL-CELLS; SCHISTOSOMA-MANSONI; DENDRITIC CELLS; T-CELLS; HEPATIC-FIBROSIS; MURINE SCHISTOSOMIASIS; ALLERGIC INFLAMMATION; IN-VITRO; AIRWAY INFLAMMATION; GRANULOMA-FORMATION AB Thymic stromal lymphopoietin was recently identified as a master switch for the development of allergen-driven Th2 responses. However, the role of thymic stromal lymphopoietin (TSLP) in the development of helminth-induced Th2 responses is unclear. Here, using TSLPR(-/-) mice, we show that while TSLPR signaling participates in the development of Schistosoma mansoni egg-induced CD4(+) Th2 responses, it plays only a transient role in the development of Th2-dependent pathology in the lung, liver, and intestine. Studies conducted in a pulmonary granuloma model showed that while a reduction in IL-4/IL-13-dependent granulomatous inflammation and tissue eosinophilia was observed in TSLPR(-/-) mice undergoing a primary response, lesion formation was not affected during a secondary granulomatous response, even though IL-5 and IL-13 were modestly reduced in the knockout mice. To evaluate the importance of TSLPR signaling in the development of a chronic Th2-dependent response, TSLPR(-/-) mice were also infected with S. mansoni cercariae. Here, the only significant difference noted in TSLPR(-/-) mice was a modest decrease in liver fibrosis in acutely infected animals. The transient decrease in fibrosis was associated with increased production of the antifibrotic cytokine IFN-gamma and decreased production of the profibrotic cytokine IL-13. Although the altered cytokine response persisted in chronically infected TSLPR(-/-) mice, it failed to reduce granuloma formation or fibrosis, confirming that TSLPR signaling plays a limited role in the development of chronic Th2-dependent pathology. Collectively, these findings suggest that while TSLPR signaling serves a key role in allergen-driven Th2 responses, it exerts minor regulatory activity during this chronic helminth infection. The Journal of Immunology, 2009, 182: 6452-6459. C1 [Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Ziegler, Steven F.] Benaroya Res Inst, Program Immunol, Seattle, WA 98101 USA. [Comeau, Michael R.] Amgen Inc, Dept Inflammat, Seattle, WA 98119 USA. [Cheever, Allen W.] Biomed Res Inst, Rockville, MD 20852 USA. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH,Dept Hlth & Human Serv, 50 S Dr,Room 6154,Mail Stop Code 8003, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU Intramural Research Program of the National Institutes of Health; National Institute of Allergy and Infectious Diseases; National Institutes of Health Grants [A1068731, AR056113] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (to T.A.W.) and by National Institutes of Health Grants A1068731 and AR056113 (to S.F.Z.). NR 62 TC 37 Z9 38 U1 0 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2009 VL 182 IS 10 BP 6452 EP 6459 DI 10.4049/jimmunol.0900181 PG 8 WC Immunology SC Immunology GA 443HC UT WOS:000265899800064 PM 19414799 ER PT J AU de Sanjose, S Mbisa, G Perez-Alvarez, S Benavente, Y Sukvirach, S Nguyen, TH Shin, HR Pham, THA Thomas, J Lazcano, E Matos, E Herrero, R Munoz, N Molano, M Franceschi, S Whitby, D AF de Sanjose, Silvia Mbisa, Georgina Perez-Alvarez, Susana Benavente, Yolanda Sukvirach, Sukhon Nguyen Trong Hieu Shin, Hai-Rim Pham Thi Hoang Anh Thomas, Jaiyeola Lazcano, Eduardo Matos, Elena Herrero, Rolando Munoz, Nubia Molano, Monica Franceschi, Silvia Whitby, Denise TI Geographic Variation in the Prevalence of Kaposi Sarcoma-Associated Herpesvirus and Risk Factors for Transmission SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 11th International Workshop on KSHV and Related Agents CY JUL 22-26, 2008 CL Birmingham, ENGLAND ID TO-CHILD TRANSMISSION; HUMAN-HERPESVIRUS-8 INFECTION; SEXUAL TRANSMISSION; DNA-SEQUENCES; NONSEXUAL TRANSMISSION; HUMAN-PAPILLOMAVIRUS; POOLED ANALYSIS; BLOOD-DONORS; SEROPREVALENCE; HHV-8 AB Background. The aim of the present study was to estimate the prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) in the female general population, to define geographic variation in and heterosexual transmission of the virus. Methods. The study included 10,963 women from 9 countries for whom information on sociodemographic characteristics and reproductive, sexual, and smoking behaviors were available. Antibodies against KSHV that encoded lytic antigen K8.1 and latent antigen ORF73 were determined. Results. The range of prevalence of KSHV (defined as detection of any antigen) was 3.81%-46.02%, with significant geographic variation noted. In Nigeria, the prevalence was 46.02%; in Colombia, 13.32%; in Costa Rica, 9.81%; in Argentina, 6.40%; in Ho Chi Minh City, Vietnam, 15.50%; in Hanoi, Vietnam, 11.26%; in Songkla, Thailand, 10%; in Lampang, Thailand, 8.63%; in Korea, 4.93%; and in Spain, 3.65%. The prevalence of KSHV slightly increased with increasing age among subjects in geographic areas where the prevalence of KSHV was high, such as Nigeria and Colombia, and it significantly decreased with increases in the educational level attained by subjects in those areas. KSHV was not statistically associated with age at first sexual intercourse, number of sex partners, number of children, patterns of oral contraceptive use, presence of cervical human papillomavirus DNA, or smoking status. Conclusions. The study provides comparable estimates of KSHV prevalence in diverse cultural settings across 4 continents and provides evidence that sexual transmission of KSHV is not a major source of infection in the general population. C1 [de Sanjose, Silvia] Inst Catala Oncol, Unit Infect & Canc, Program Res Canc Epidemiol, IDIBELL,CIBERESP, Barcelona 08907, Spain. [de Sanjose, Silvia; Benavente, Yolanda] Ctr Invest Biomed Red Epidemiol & Salud Publ, Barcelona, Spain. [Sukvirach, Sukhon] Natl Canc Inst, Div Res, Bangkok, Thailand. [Nguyen Trong Hieu; Pham Thi Hoang Anh] Hung Vuong Hosp, Dept Neonatol, Ho Chi Minh City, Vietnam. [Shin, Hai-Rim; Franceschi, Silvia] Int Agcy Res Canc, F-69372 Lyon, France. [Thomas, Jaiyeola] Univ Ibadan, Coll Med, Ibadan, Nigeria. [Lazcano, Eduardo] Inst Nacl Salud Publ, Cuernavaca, Morelos, Mexico. [Matos, Elena] Univ Buenos Aires, Inst Oncol Angel H Roffo, Buenos Aires, DF, Argentina. [Herrero, Rolando] Fdn Inst Costarricense Invest & Ensenanza Nutr &, San Jose, Costa Rica. [Munoz, Nubia; Molano, Monica] Inst Nacl Cancerol, Bogota, Colombia. [Shin, Hai-Rim] Natl Canc Ctr, Goyang, South Korea. [Mbisa, Georgina; Whitby, Denise] NCI, Viral Oncol Sect, AIDS & Canc Virus Program, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. RP de Sanjose, S (reprint author), Inst Catala Oncol, Unit Infect & Canc, Program Res Canc Epidemiol, IDIBELL,CIBERESP, Gran Via Km 2-7, Barcelona 08907, Spain. EM s.sanjose@iconcologia.net RI de Sanjose Llongueras, Silvia/H-6339-2014; Benavente, Yolanda/H-9810-2014 FU NCI NIH HHS [N01-CO-12400] NR 32 TC 28 Z9 28 U1 1 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2009 VL 199 IS 10 BP 1449 EP 1456 DI 10.1086/598523 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 437TK UT WOS:000265509600007 PM 19351262 ER PT J AU Veazey, RS Ling, BH Green, LC Ribka, EP Lifson, JD Piatak, M Lederman, MM Mosier, D Offord, R Hartley, O AF Veazey, Ronald S. Ling, Binhua Green, Linda C. Ribka, Erin P. Lifson, Jeffrey D. Piatak, Michael, Jr. Lederman, Michael M. Mosier, Donald Offord, Robin Hartley, Oliver TI Topically Applied Recombinant Chemokine Analogues Fully Protect Macaques from Vaginal Simian-Human Immunodeficiency Virus Challenge SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Microbicides 2008 Conference CY FEB 24-27, 2008 CL New Delhi, INDIA ID HIGHLY POTENT; VIRAL LOAD; HIV; MICROBICIDES; AIDS; CCR5; TRANSMISSION; PREVENTION; INHIBITORS; INFECTION AB Effective strategies for preventing human immunodeficiency virus infection are urgently needed, but recent failures in key clinical trials of vaccines and microbicides highlight the need for new approaches validated in relevant animal models. Here, we show that 2 new chemokine (C-C motif) receptor 5 inhibitors, 5P12-RANTES (regulated on activation, normal T cell expressed and secreted) and 6P4-RANTES, fully protect against infection in the rhesus vaginal challenge model. These highly potent molecules, which are amenable to low-cost production, represent promising new additions to the microbicides pipeline. C1 [Lederman, Michael M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Veazey, Ronald S.; Ling, Binhua; Green, Linda C.; Ribka, Erin P.] Tulane Natl Primate Res Ctr, Covington, LA USA. [Lifson, Jeffrey D.; Piatak, Michael, Jr.] NCI, AIDS & Canc Virus Program, SAIC Frederick, Frederick, MD 21701 USA. [Mosier, Donald] Scripps Res Inst, La Jolla, CA USA. [Offord, Robin] Univ Geneva, Fac Med, Mintaka Fdn Med Res, Geneva, Switzerland. [Hartley, Oliver] Univ Geneva, Fac Med, Dept Struct Biol & Bioinformat, Geneva, Switzerland. RP Lederman, MM (reprint author), Case Western Reserve Univ, 2061 Cornell Rd, Cleveland, OH 44106 USA. EM lederman.michael@clevelandactu.org FU NCRR NIH HHS [P51 RR000164]; NIAID NIH HHS [AI-51649, P01 AI051649] NR 18 TC 46 Z9 48 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 MAY 15 PY 2009 VL 199 IS 10 BP 1525 EP 1527 DI 10.1086/598685 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 437TK UT WOS:000265509600016 PM 19331577 ER PT J AU Steiger, C Finnema, SJ Raus, L Schou, M Nakao, R Suzuki, K Pike, VW Wikstrom, HV Halldin, C AF Steiger, C. Finnema, S. J. Raus, L. Schou, M. Nakao, R. Suzuki, K. Pike, V. W. Wikstrom, H. V. Halldin, C. TI A two-step one-pot radiosynthesis of the potent dopamine D-2/D-3 agonist PET radioligand [C-11]MNPA SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE PET; MNPA; dopamine D-2/D-3 agonist; radiosynthesis; LC-MS/MS analysis ID ENDOGENOUS DOPAMINE; RECEPTOR AGONIST; RADIOTRACER; ANTAGONIST; BINDING; MNPA AB (R)-(-)-2-[C-11]Methoxy-N-n-propylnorapomorphine ([C-11]MNPA ([C-11]2)) is an agonist radioligand of interest for imaging D-2/D-3 receptors in vivo. Here we sought to develop an improved radiosynthesis of this radioligand. Reference 2 was synthesized in nine steps with an overall yield of about 5%, starting from codeine. Trimethylsilyldiazomethane proved to be a practical improvement in comparison to diazomethane in the penultimate methylation step. A protected precursor for radiolabeling ((R)-(-)-2-hydroxy-10,11-acetonide-N-n-propylnoraporphine, 4) was prepared from (R)-(-)-2-hydroxy-N-n-propylnorapomorphine (1) in 30% yield. [C-11]2 was prepared from 4 via a two-step one-pot radiosynthesis. The first step, methylation of 4 with [C-11]methyl triflate, occurred in quantitative radiochemical yield. The second step, deprotection of the catechol moiety with HCl and heat, yielded 60-90% of [C-11]2 giving an overall incorporation yield from [C-11]methyl triflate of 60-90%. In a typical run more than 1 GBq of [C-11]2, was produced from carbon-11 generated from a 10-min proton irradiation (16MeV; 35 mu A) of nitrogen-hydrogen target gas. The radiochemical purity of [C-11]2 was > 99% and specific radioactivity at the time of injection was 901 +/- 342 GBq/mu mol (n = 10). The total synthesis time was 35-38 min from the end of radionuclide production. The identity of [C-11]2 was confirmed by comparing its LC-MS/MS spectrum with those of reference 2 and (R)-(-)-10-methoxy-2,11-dihydroxy-N-n-propylnoraporphine. C1 [Steiger, C.; Finnema, S. J.; Schou, M.; Halldin, C.] Karolinska Univ Hosp, Dept Clin Neurosci, Karolinska Inst, Psychiat Sect, S-17176 Stockholm, Sweden. [Raus, L.] Univ Tartu, Inst Chem, EE-50090 Tartu, Estonia. [Raus, L.] Pharmasynth AS, Tartu, Estonia. [Nakao, R.; Suzuki, K.] Natl Inst Radiol Sci, Mol Imaging Ctr, Inage Ku, Chiba 2638555, Japan. [Pike, V. W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Wikstrom, H. V.] Allbay AB, S-45070 Hamburgsund, Sweden. RP Steiger, C (reprint author), Karolinska Univ Hosp, Dept Clin Neurosci, Karolinska Inst, Psychiat Sect, Bldg R5-U1, S-17176 Stockholm, Sweden. EM carsten.steiger@ki.se FU NIH (NIMH) FX The authors would like to thank Mr Jinsoo Hong and Dr H. Umesha Shetty (Molecular Imaging Branch, NIMH) for useful discussions. We also would like to thank Mr Ithamar Brinkman for his help during his internship at the PET centre at the Karolinska Institutet. Also, the authors would like to thank Mr Guennadi Jogolev, Dr Zhi Sjeng Jia and Mr Arsalan Amir for technical assistance. Dr Victor W. Pike was supported by the Intramural Research Program of NIH (NIMH). NR 14 TC 6 Z9 6 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2009 VL 52 IS 5-6 BP 158 EP 165 DI 10.1002/jlcr.1583 PG 8 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 461DA UT WOS:000267243600004 ER PT J AU Lebiedowska, MK Fisk, JR AF Lebiedowska, Maria K. Fisk, John R. TI Knee resistance during passive stretch in patients with hypertonia SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Spasticity; Hypertonia; Resistance; Cerebral palsy ID CEREBRAL-PALSY; SPASTICITY-ASSESSMENT; FLEXOR SPASTICITY; REFLEX THRESHOLD; MUSCLE; STIFFNESS; CHILDREN; JOINT; PATHOPHYSIOLOGY; RELIABILITY AB The aims of the study were to determine by a portable method (1) whether velocity-dependent changes in knee resistance in patients with spastic paresis differ from those in non-disabled subjects, and (2) whether biomechanical measures of resistance can differentiate between neural and other factors that contribute to hypertonia (increased resistance). Biomechanical (hand-hold dynamometer, electrogoniometer) and bioelectrical (EMG) measures of resistance were evaluated under static (slow stretch) and dynamic (fast stretch) conditions in twenty patients with hypertonia and 19 non-disabled subjects. Measures calculated for non-disabled subjects (control limbs) were compared to those calculated for patients (spastic limbs). Biomechanical measures of resistance did not differ strongly between groups of spastic and control limbs and between spastic limbs having different origins of knee hypertonia (neural vs. other), due to substantial variability. In contrary the static and dynamic bioelectrical measures of muscles activation were substantially larger in spastic limbs than in control limbs (p < 0.05). The variability of biomechanical measures of resistance was due to varied patterns of muscle activation in response to stretch. We concluded that the biomechanical measures of hypertonia did not discriminate spastic patients from non-disabled subjects. To classify various types of knee hypertonia, the portable method should include not only analysis of biomechanical but also EMG characteristics of hypertonia. It is expected that the functional status of patients would be better predicted using clinical and quantitative measures of impairment if different classes of hypertonia (defined by different patterns of activation) were analyzed separately rather than analyzing the heterogeneous patient population as a whole. Published by Elsevier B.V. C1 [Lebiedowska, Maria K.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, CRC, Bethesda, MD 20892 USA. [Fisk, John R.] So Illinois Univ, Sch Med, Dept Surg, Springfield, IL 62794 USA. RP Lebiedowska, MK (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, CRC, BLDG 10,RM 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM lebiedowskam@cc.nih.gov; jfisk@siumed.edu FU Central Research Committee, SIU, School of Medicine, Springfield, Illinois, USA. FX Supported in part by a grant from Central Research Committee, SIU, School of Medicine, Springfield, Illinois, USA. The authors wish to thank Dr. Richard Burns, Dr. Deborah Spira-Gaebler and Dr. Jean-Michel Gracies for insightful comments at the early stage of preparation of the manuscript. The authors thank Michelle A. Mattera, M.B.E. for her pointed editing of the paper. NR 49 TC 12 Z9 13 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD MAY 15 PY 2009 VL 179 IS 2 BP 323 EP 330 DI 10.1016/j.jneumeth.2009.02.005 PG 8 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 438VZ UT WOS:000265585400023 PM 19428544 ER PT J AU DeHaven, WI Jones, BF Petranka, JG Smyth, JT Tomita, T Bird, GS Putney, JW AF DeHaven, Wayne I. Jones, Bertina F. Petranka, John G. Smyth, Jeremy T. Tomita, Takuro Bird, Gary S. Putney, James W., Jr. TI TRPC channels function independently of STIM1 and Orai1 SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID OPERATED CA2+ ENTRY; SMOOTH-MUSCLE-CELLS; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; TRANSIENT-RECEPTOR; PLASMA-MEMBRANE; CATION CHANNELS; CALCIUM-ENTRY; STORE DEPLETION; CRAC CHANNEL; HEK293 CELLS AB Recent studies have defined roles for STIM1 and Orai1 as calcium sensor and calcium channel, respectively, for Ca(2+)-release activated Ca(2+) (CRAC) channels, channels underlying store-operated Ca(2+) entry (SOCE). In addition, these proteins have been suggested to function in signalling and constructing other channels with biophysical properties distinct from the CRAC channels. Using the human kidney cell line, HEK293, we examined the hypothesis that STIM1 can interact with and regulate members of a family of non-selective cation channels (TRPC) which have been suggested to also function in SOCE pathways under certain conditions. Our data reveal no role for either STIM1 or Orai1 in signalling of TRPC channels. Specifically, Ca(2+) entry seen after carbachol treatment in cells transiently expressing TRPC1, TRPC3, TRPC5 or TRPC6 was not enhanced by the co-expression of STIM1. Further, knockdown of STIM1 in cells expressing TRPC5 did not reduce TRPC5 activity, in contrast to one published report. We previously reported in stable TRPC7 cells a Ca(2+) entry which was dependent on TRPC7 and appeared store-operated. However, we show here that this TRPC7-mediated entry was also not dependent on either STIM1 or Orai1, as determined by RNA interference (RNAi) and expression of a constitutively active mutant of STIM1. Further, we determined that this entry was not actually store-operated, but instead TRPC7 activity which appears to be regulated by SERCA. Importantly, endogenous TRPC activity was also not regulated by STIM1. In vascular smooth muscle cells, arginine-vasopressin (AVP) activated non-selective cation currents associated with TRPC6 activity were not affected by RNAi knockdown of STIM1, while SOCE was largely inhibited. Finally, disruption of lipid rafts significantly attenuated TRPC3 activity, while having no effect on STIM1 localization or the development of I(CRAC). Also, STIM1 punctae were found to localize in regions distinct from lipid rafts. This suggests that TRPC signalling and STIM1/Orai1 signalling occur in distinct plasma membrane domains(.) Thus, TRPC channels appear to be activated by mechanisms dependent on phospholipase C which do not involve the Ca(2+) sensor, STIM1. C1 [DeHaven, Wayne I.; Jones, Bertina F.; Petranka, John G.; Smyth, Jeremy T.; Tomita, Takuro; Bird, Gary S.; Putney, James W., Jr.] NIEHS, Lab Signal Transduct, 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 RI chen, xuanlan/H-4158-2011 FU Intramural Research Program; National Institute of Environmental Health Sciences; National Institutes of Health [Z01 ES090087] FX This work was supported in part by the Intramural Research Program, National Institute of Environmental Health Sciences, National Institutes of Health, project number Z01 ES090087. NR 99 TC 149 Z9 152 U1 2 U2 8 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAY 15 PY 2009 VL 587 IS 10 BP 2275 EP 2298 DI 10.1113/jphysiol.2009.170431 PG 24 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 451SU UT WOS:000266491300016 PM 19332491 ER PT J AU Zhong, SZ Ge, QH Li, Q Qu, R Ma, SP AF Zhong, Shu-Zhi Ge, Qing-Hua Li, Qiao Qu, Rong Ma, Shi-Ping TI Peoniflorin attentuates A beta((1-42))-mediated neurotoxicity by regulating calcium homeostasis and ameliorating oxidative stress in hippocampus of rats SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Alzheimer's disease; Beta-amyloid; Calcium; Morris water maze test; Neuroprotective effect; Peoniflorin ID AMYLOID-BETA; NITRIC-OXIDE; ALZHEIMERS-DISEASE; CORTICAL-NEURONS; IN-VIVO; LIPID-PEROXIDATION; PROTEIN OXIDATION; BRAIN; GLUTATHIONE; MEMORY AB Peoniflorin (PEF), a monoterpene glycoside isolated from the aqueous extract of the dry root of Paeonia, possesses wide pharmacological effects in nervous system. In this study, by using a developed rat model of hippocampal dysfunction induced by intrahippocampal injection of A beta((1-42)) oligomers, we investigated whether PEF exerted protection against A beta-induced neurotoxicity. A stereotactic intrahippocampal bilateral injection of A beta((1-42)) (5 mu g per side) was performed in Sprague-Dawley rats (250-280 g). A beta((1-42))-exposed rats showed remarkable memory impairment in Morris water maze test and neuronal apoptosis by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling in hippocampus. Chronic treatment with PEF (7.5, 15 and 30 mg/(kg day), for 20 days, intraperitoneally) significantly and dose-dependently attenuated cognitive deficit, ameliorated cell apoptosis in A beta((1-42))-treated rats. The neuroprotective effect of PEF was closely associated with its activities of maintenance of [Ca2(+)](i) homeostasis, increase of reduced glutathione (GSH) content, suppression of NOS activity and nitric oxide (NO) level, decrease of carbonyl protein (CP) and malondialdehyde (MDA) levels. These results suggested that PEF possessed the activity of prevention of the neurotoxicity induced by A beta((1-42)) and might exert beneficial action for the treatment of Alzheimer's disease (AD). (C) 2009 Elsevier B.V. All rights reserved. C1 [Zhong, Shu-Zhi; Li, Qiao; Ma, Shi-Ping] China Pharmaceut Univ, Dept Pharmacol Chinese Mat Med, Nanjing 210009, Peoples R China. [Ge, Qing-Hua] NCI, NIH, Bethesda, MD 20892 USA. [Qu, Rong] Nanjing Univ Tradit Chinese Med, Dept Pharmacol Tradit Chinese Med Formulae, Nanjing 210009, Peoples R China. RP Ma, SP (reprint author), China Pharmaceut Univ, Dept Pharmacol Chinese Mat Med, Nanjing 210009, Peoples R China. EM shipingma2006@sohu.com NR 56 TC 54 Z9 65 U1 0 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD MAY 15 PY 2009 VL 280 IS 1-2 BP 71 EP 78 DI 10.1016/j.jns.2009.01.027 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 441IJ UT WOS:000265762200012 PM 19268972 ER PT J AU Adamson, CS Waki, K Ablan, SD Salzwedel, K Freed, EO AF Adamson, Catherine S. Waki, Kayoko Ablan, Sherimay D. Salzwedel, Karl Freed, Eric O. TI Impact of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Evolution of Resistance to the Maturation Inhibitor Bevirimat (PA-457) SO JOURNAL OF VIROLOGY LA English DT Article ID BETULINIC ACID; CLEAVAGE SITES; GAG PRECURSOR; HIV-1 MATURATION; ANTIRETROVIRAL THERAPY; VIROLOGICAL RESPONSE; PARTICLE MATURATION; TREATED PATIENTS; VIRAL FITNESS; LIFE-CYCLE AB The maturation inhibitor bevirimat [3-O-(3',3'dimethysuccinyl) betulinic acid; BVM; also known as PA-457 or DSB] potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking protease (PR)-mediated cleavage at the junction between capsid (CA) and spacer peptide 1 (SP1) in Gag. We previously isolated a panel of single-amino-acid substitutions that confer resistance to BVM in vitro (C.S. Adamson, S. D. Ablan, I. Boeras, R. Goila-Gaur, F. Soheilian, K. Nagashima, F. Li, K. Salzwedel, M. Sakalian, C. T. Wild, and E.O. Freed, J. Virol. 80: 10957-10971, 2006). The BVM resistance mutations cluster at or near the CA-SP1 cleavage site. Because BVM likely will be used clinically in patients harboring viruses resistant to PR inhibitors (PIs), in this study we evaluated the interplay between a PI-resistant (PIR) PR and the BVM resistance mutations in Gag. As expected, the PIR mutations had no effect on inhibition by BVM; however, we observed general processing defects and a slight delay in viral replication in Jurkat T cells associated with the PIR mutations, even in the absence of compound. When combined, most BVM resistance and PIR mutations acted additively to impair viral replication, particularly in the presence of BVM. The BVM-resistant mutant SP1-A1V was an exception, as it supported robust replication in the context of either wild-type (WT) or PIR PR, even at high BVM concentrations. Significantly, the emergence of BVM resistance was delayed in the context of the PIR PR, and the SP1-A1V mutation was acquired most frequently with either WT or PIR PR. These results suggest that resistance to BVM is less likely to emerge in patients who have failed PIs than in patients who are PI naive. We predict that the SP1-A1V substitution is the most likely to emerge in vivo, as this mutant replicates robustly independently of PR mutations or BVM. These findings offer insights into the effect of PIR mutations on the evolution of BVM resistance in PI-experienced patients. C1 [Adamson, Catherine S.; Waki, Kayoko; Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Salzwedel, Karl] Panacos Pharmaceut Inc, Gaithersburg, MD 20877 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM efreed@nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; Intramural AIDS Targeted Antiviral Program FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the Intramural AIDS Targeted Antiviral Program. NR 49 TC 36 Z9 36 U1 0 U2 4 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 MAY 15 PY 2009 VL 83 IS 10 BP 4884 EP 4894 DI 10.1128/JVI.02659-08 PG 11 WC Virology SC Virology GA 436IS UT WOS:000265407700016 PM 19279107 ER PT J AU Li, XJ Hanson, C Cmarik, JL Ruscetti, S AF Li, Xiujie Hanson, Charlotte Cmarik, Joan L. Ruscetti, Sandra TI Neurodegeneration Induced by PVC-211 Murine Leukemia Virus Is Associated with Increased Levels of Vascular Endothelial Growth Factor and Macrophage Inflammatory Protein 1 alpha and Is Inhibited by Blocking Activation of Microglia SO JOURNAL OF VIROLOGY LA English DT Article ID TISSUE-PLASMINOGEN ACTIVATOR; CENTRAL-NERVOUS-SYSTEM; MULTIPLE-SCLEROSIS; CELL TROPISM; SPONGIFORM NEURODEGENERATION; CHEMOKINE RECEPTORS; BRAIN; EXPRESSION; DEGENERATION; DEPLETION AB PVC-211 murine leukemia virus (MuLV) is a neuropathogenic retrovirus that has undergone genetic changes from its nonneuropathogenic parent, Friend MuLV, that allow it to efficiently infect rat brain capillary endothelial cells (BCEC). To clarify the mechanism by which PVC-211 MuLV expression in BCEC induces neurological disease, we examined virus-infected rats at various times during neurological disease progression for vascular and inflammatory changes. As early as 2 weeks after virus infection and before any marked appearance of spongiform neurodegeneration, we detected vessel leakage and an increase in size and number of vessels in the areas of the brain that eventually become diseased. Consistent with these findings, the amount of vascular endothelial growth factor (VEGF) increased in the brain as early as 1 to 2 weeks postinfection. Also detected at this early disease stage was an increased level of macrophage inflammatory protein 1 alpha (MIP-1 alpha), a cytokine involved in recruitment of microglia to the brain. This was followed at 3 weeks postinfection by a marked accumulation of activated microglia in the spongiform areas of the brain accompanied by an increase in tissue plasminogen activator, a product of microglia implicated in neurodegeneration. Pathological observations at the end stage of the disease included loss of neurons, decreased myelination, and mild muscle atrophy. Treatment of PVC-211 MuLV-infected rats with clodronate-containing liposomes, which specifically kill microglia, significantly blocked neurodegeneration. Together, these results suggest that PVC-211 MuLV infection of BCEC results in the production of VEGF and MIP-1 alpha, leading to the vascular changes and microglial activation necessary to cause neurodegeneration. C1 [Li, Xiujie; Hanson, Charlotte; Cmarik, Joan L.; Ruscetti, Sandra] Natl Canc Inst, Lab Canc Prevent, Frederick, MD 21702 USA. RP Ruscetti, S (reprint author), Natl Canc Inst, Lab Canc Prevent, Bldg 567,Room 152, Frederick, MD 21702 USA. EM ruscetti@ncifcrf.gov FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research FX We thank Peter Kaczmarek for his generosity in helping us to prepare clodronate-containing liposomes. We also thank Chris Perella for excellent technical assistance with our animal studies. NR 49 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY 15 PY 2009 VL 83 IS 10 BP 4912 EP 4922 DI 10.1128/JVI.02343-08 PG 11 WC Virology SC Virology GA 436IS UT WOS:000265407700018 PM 19279110 ER PT J AU Liu, J Ruckwardt, TJ Chen, M Johnson, TR Graham, BS AF Liu, Jie Ruckwardt, Tracy J. Chen, Man Johnson, Teresa R. Graham, Barney S. TI Characterization of Respiratory Syncytial Virus M- and M2-Specific CD4 T Cells in a Murine Model SO JOURNAL OF VIROLOGY LA English DT Article ID IN-VIVO; EXPRESSION PATTERNS; PRIMARY INFECTION; EFFECTOR ACTIVITY; FLOW-CYTOMETRY; BALB/C MICE; SUBSETS; EPITOPE; INTERLEUKIN-4; CHALLENGE AB CD4 T cells have been shown to play an important role in the immunity and immunopathogenesis of respiratory syncytial virus (RSV) infection. We identified two novel CD4 T-cell epitopes in the RSV M and M2 proteins with core sequences M(213-223) (FKYIKPQSQFI) and M2(27-37) (YFEWPPHALLV). Peptides containing the epitopes stimulated RSV-specific CD4 T cells to produce gamma interferon (IFN-gamma), interleukin 2 (IL-2), and other Th1- and Th2-type cytokines in an I-A(b)-restricted pattern. Construction of fluorochrome-conjugated peptide-I-A(b) class II tetramers revealed RSV M- and M2-specific CD4 T-cell responses in RSV-infected mice in a hierarchical pattern. Peptide-activated CD4 T cells from lungs were more activated and differentiated, and had greater IFN-gamma expression, than CD4 T cells from the spleen, which, in contrast, produced greater levels of IL-2. In addition, M(209-223) peptide-activated CD4 T cells reduced IFN-gamma and IL-2 production in M- and M2-specific CD8 T-cell responses to Db-M(187-195) and Kd-M(282-90) peptides more than M(225-39) peptide-stimulated CD4 T cells. This correlated with the fact that I-A(b)-M(209-223) tetramer-positive cells responding to primary RSV infection had a much higher frequency of FoxP3 expression than I-A(b)-M(226-39) tetramer-positive CD4 T cells, suggesting that the M- specific CD4 T-cell response has greater regulatory function. Characterization of epitope-specific CD4 T cells by novel fluorochrome-conjugated peptide-I-A(b) tetramers allows detailed analysis of their roles in RSV pathogenesis and immunity. C1 [Liu, Jie; Ruckwardt, Tracy J.; Chen, Man; Johnson, Teresa R.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU NIAID FX This work was supported entirely by intramural NIAID funding. NR 51 TC 15 Z9 16 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 MAY 15 PY 2009 VL 83 IS 10 BP 4934 EP 4941 DI 10.1128/JVI.02140-08 PG 8 WC Virology SC Virology GA 436IS UT WOS:000265407700020 PM 19264776 ER PT J AU Faumont, N Durand-Panteix, S Schlee, M Gromminger, S Schuhmacher, M Holzel, M Laux, G Mailhammer, R Rosenwald, A Staudt, LM Bornkamm, GW Feuillard, J AF Faumont, Nathalie Durand-Panteix, Stephanie Schlee, Martin Groemminger, Sebastian Schuhmacher, Marino Hoelzel, Michael Laux, Gerhard Mailhammer, Reinhard Rosenwald, Andreas Staudt, Louis M. Bornkamm, Georg W. Feuillard, Jean TI c-Myc and Rel/NF-kappa B Are the Two Master Transcriptional Systems Activated in the Latency III Program of Epstein-Barr Virus-Immortalized B Cells SO JOURNAL OF VIROLOGY LA English DT Article ID BURKITTS-LYMPHOMA CELLS; NON-HODGKINS-LYMPHOMAS; NUCLEAR ANTIGEN-2; LYMPHOPROLIFERATIVE DISORDERS; LYMPHOBLASTOID-CELLS; DOWN-REGULATION; CYCLE ARREST; APOPTOSIS; EXPRESSION; EBNA2 AB The Epstein-Barr virus (EBV) latency III program imposed by EBNA2 and LMP1 is directly responsible for immortalization of B cells in vitro and is thought to mediate most immunodeficiency-related posttransplant lymphoproliferative diseases in vivo. To answer the question whether and how this proliferation program is related to c-Myc, we have established the transcriptome of both c-Myc and EBV latency III proliferation programs using a Lymphochip specialized microarray. In addition to EBV-positive latency I Burkitt lymphoma lines and lymphoblastoid cell lines (LCLs), we used an LCL expressing an estrogen-regulatable EBNA2 fusion protein (EREB2-5) and derivative B-cell lines expressing a constitutively active or tetracycline-regulatable c-myc gene. A total of 897 genes were found to be fourfold or more up- or downregulated in either one or both proliferation programs compared to the expression profile of resting EREB2-5 cells. A total of 661 (74%) of these were regulated similarly in both programs. Numerous repressed genes were known targets of STAT1, and most induced genes were known to be upregulated by c-Myc and to be involved in cell proliferation. In keeping with the gene expression patterns, inactivation of c-Myc by a chemical inhibitor or by conditional expression of dominant-negative c-Myc and Max mutants led to proliferation arrest of LCLs. Most genes differently regulated in both proliferation programs corresponded to genes induced by NF-kappa B in LCLs, and many of them coded for immunoregulatory and/or antiapoptotic molecules. Thus, c-Myc and NF-kappa B are the two main transcription factors responsible for the phenotype, growth pattern, and biological properties of cells driven into proliferation by EBV. C1 [Faumont, Nathalie; Durand-Panteix, Stephanie; Feuillard, Jean] Univ Limoges, Ctr Hosp Univ Dupuytren, Unite Mixte Rech 6101, CNRS,Lab Hematol, F-87025 Limoges, France. [Schlee, Martin; Groemminger, Sebastian; Hoelzel, Michael; Laux, Gerhard; Mailhammer, Reinhard; Bornkamm, Georg W.] Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Clin Mol Biol & Tumor Genet, D-81377 Munich, Germany. [Schlee, Martin] Univ Bonn, Inst Clin Chem & Pharmacol, D-5300 Bonn, Germany. [Schuhmacher, Marino] GPC Biotech AG, D-82152 Martinsried, Germany. [Rosenwald, Andreas] Univ Wurzburg, Inst Pathol, D-8700 Wurzburg, Germany. [Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Feuillard, J (reprint author), Univ Limoges, Ctr Hosp Univ Dupuytren, Unite Mixte Rech 6101, CNRS,Lab Hematol, 2 Rue Docteur Marcland, F-87025 Limoges, France. EM jean.feuillard@unilim.fr RI Durand-Panteix, Stephanie/O-8718-2016; OI Durand-Panteix, Stephanie/0000-0003-4730-0070; FAUMONT, NATHALIE/0000-0002-6118-3168 FU Institut National du Cancer; Canceropole Grand-Sud-Ouest; Ligue Nationale contre le Cancer; Conseil Regional du Limousin; Association pour la Recherche sur le Cancer; Canceropole GSO; Ministere de l'Enseignement Superieur et de la Recherche; Wilhelm Sander foundation FX This work was supported by the Institut National du Cancer, Canceropole Grand-Sud-Ouest, Ligue Nationale contre le Cancer, Conseil Regional du Limousin, and Association pour la Recherche sur le Cancer. UMR-CNRS 6101 is a Laboratoire Labelise Ligue Nationale contre le Cancer. N.F. was successively supported by the Conseil Regional du Limousin, Canceropole GSO, and Comite Orientation Recherche Cancer en Limousin. S. D. P. was successively supported by the Ministere de l'Enseignement Superieur et de la Recherche and by the Association pour la Recherche contre le Cancer. G. W. B. was supported by a grant from the Wilhelm Sander foundation. NR 60 TC 30 Z9 30 U1 1 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 MAY 15 PY 2009 VL 83 IS 10 BP 5014 EP 5027 DI 10.1128/JVI.02264-08 PG 14 WC Virology SC Virology GA 436IS UT WOS:000265407700028 PM 19264782 ER PT J AU Wu, L Zhou, TQ Yang, ZY Svehla, K O'Dell, S Louder, MK Xu, L Mascola, JR Burton, DR Hoxie, JA Doms, RW Kwong, PD Nabel, GJ AF Wu, Lan Zhou, Tongqing Yang, Zhi-yong Svehla, Krisha O'Dell, Sijy Louder, Mark K. Xu, Ling Mascola, John R. Burton, Dennis R. Hoxie, James A. Doms, Robert W. Kwong, Peter D. Nabel, Gary J. TI Enhanced Exposure of the CD4-Binding Site to Neutralizing Antibodies by Structural Design of a Membrane-Anchored Human Immunodeficiency Virus Type 1 gp120 Domain SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; CD4 BINDING-SITE; ENVELOPE GLYCOPROTEIN; HIV-1 GP120; FAB FRAGMENTS; AIDS VACCINE; V3 LOOP; EPITOPE; TRIAL; RECOGNITION AB The broadly neutralizing antibody immunoglobulin G1 (IgG1) b12 binds to a conformationally conserved surface on the outer domain of the human immunodeficiency virus type 1 (HIV-1) gp120 envelope (Env) glycoprotein. To develop outer domain proteins (ODs) that could be recognized selectively by CD4-binding- site (CD4-BS) antibodies, membrane-anchored ODs were generated from an HIV-1 clade B virus, TA1 R3A, which was highly sensitive to neutralization by the IgG1 b12 antibody. A 231-residue fragment of gp120 (residues 252 to 482) linked to transmembrane regions from CD4 showed b12 binding comparable to that of the native Env spike as measured by flow cytometry. Truncation of the beta 20-beta 21 hairpin (residues 422 to 436 to Gly-Gly) improved overall protein expression. Replacement of the immunodominant central 20 amino acids of the V3 loop (residues 302 to 323) with a basic hexapeptide (NTRGRR) increased b12 reactivity further. Surface calculations indicated that the ratio of b12 epitope to exposed immunogenic surface in the optimized OD increased to over 30%. This OD variant [OD(GSL)(Delta beta 20-21)(hCD4-TM)] was recognized by b12 and another CD4-BS-reactive antibody, b13, but not by eight other CD4-BS antibodies with limited neutralization potency. Furthermore, optimized membrane-anchored OD selectively absorbed neutralizing activity from complex antisera and b12. Structurally designed membrane-anchored ODs represent candidate immunogens to elicit or to allow the detection of broadly neutralizing antibodies to the conserved site of CD4 binding on HIV-1 gp120. C1 [Wu, Lan; Zhou, Tongqing; Yang, Zhi-yong; Svehla, Krisha; O'Dell, Sijy; Louder, Mark K.; Xu, Ling; Mascola, John R.; Kwong, Peter D.; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Hoxie, James A.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Doms, Robert W.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Bldg 40,Room 4502,MSC-3005,40 Convent Dr, Bethesda, MD 20892 USA. EM gnabel@nih.gov RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Intramural Research Program, Vaccine Research Center, NIAID, NIH FX This research was supported by the Intramural Research Program, Vaccine Research Center, NIAID, NIH. NR 39 TC 37 Z9 39 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY 15 PY 2009 VL 83 IS 10 BP 5077 EP 5086 DI 10.1128/JVI.02600-08 PG 10 WC Virology SC Virology GA 436IS UT WOS:000265407700034 PM 19264769 ER PT J AU Jones, KS Huang, YK Chevalier, SA Afonso, PV Petrow-Sadowski, C Bertolette, DC Gessain, A Ruscetti, FW Mahieux, R AF Jones, Kathryn S. Huang, Ying K. Chevalier, Sebastien A. Afonso, Philippe V. Petrow-Sadowski, Cari Bertolette, Daniel C. Gessain, Antoine Ruscetti, Francis W. Mahieux, Renaud TI The Receptor Complex Associated with Human T-Cell Lymphotropic Virus Type 3 (HTLV-3) Env-Mediated Binding and Entry Is Distinct from, but Overlaps with, the Receptor Complexes of HTLV-1 and HTLV-2 SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; HEPARAN-SULFATE PROTEOGLYCANS; TROPICAL SPASTIC PARAPARESIS; DENDRITIC CELLS; ENVELOPE PROTEIN; MOLECULAR CHARACTERIZATION; MACACA-ARCTOIDES; II INFECTION; SURFACE; NEUROPILIN-1 AB Little is known about the transmission or tropism of the newly discovered human retrovirus, human T-cell lymphotropic virus type 3 (HTLV-3). Here, we examine the entry requirements of HTLV-3 using independently expressed Env proteins. We observed that HTLV-3 surface glycoprotein (SU) binds efficiently to both activated CD4(+) and CD8(+) T cells. This contrasts with both HTLV-1 SU, which primarily binds to activated CD4(+) T cells, and HTLV-2 SU, which primarily binds to activated CD8(+) T cells. Binding studies with heparan sulfate proteoglycans (HSPGs) and neuropilin-1 (NRP-1), two molecules important for HTLV-1 entry, revealed that these molecules also enhance HTLV-3 SU binding. However, unlike HTLV-1 SU, HTLV-3 SU can bind efficiently in the absence of both HSPGs and NRP-1. Studies of entry performed with HTLV-3 Env-pseudotyped viruses together with SU binding studies revealed that, for HTLV-1, glucose transporter 1 (GLUT-1) functions at a postbinding step during HTLV-3 Env-mediated entry. Further studies revealed that HTLV-3 SU binds efficiently to naOve CD4(+) T cells, which do not bind either HTLV-1 or HTLV-2 SU and do not express detectable levels of HSPGs, NRP-1, and GLUT-1. These results indicate that the complex of receptor molecules used by HTLV-3 to bind to primary T lymphocytes differs from that of both HTLV-1 and HTLV-2. C1 [Jones, Kathryn S.; Petrow-Sadowski, Cari] NCI, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Huang, Ying K.; Bertolette, Daniel C.; Ruscetti, Francis W.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Chevalier, Sebastien A.; Afonso, Philippe V.; Gessain, Antoine] Inst Pasteur, Dept Virol, Unite Epidemiol & Physiopathol Virus Oncogenes, Paris, France. [Mahieux, Renaud] George Washington Univ, Med Ctr, Washington, DC 20037 USA. RP Jones, KS (reprint author), NCI, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM joneska@mail.nih.gov; renaud.mahieux@ens-lyon.fr RI Afonso, Philippe/D-2234-2014 OI Afonso, Philippe/0000-0002-4828-3797 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 56 TC 9 Z9 9 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY 15 PY 2009 VL 83 IS 10 BP 5244 EP 5255 DI 10.1128/JVI.02285-08 PG 12 WC Virology SC Virology GA 436IS UT WOS:000265407700049 PM 19279090 ER EF