FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Matsunobu, T Torigoe, K Ishikawa, M de Vega, S Kulkarni, AB Iwamoto, Y Yamada, Y AF Matsunobu, Tomoya Torigoe, Kiyoyuki Ishikawa, Masaki de Vega, Susana Kulkarni, Ashok B. Iwamoto, Yukihide Yamada, Yoshihiko TI Critical roles of the TGF-beta type I receptor ALK5 in perichondrial formation and function, cartilage integrity, and osteoblast differentiation during growth plate development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE ALK5 (TGF-beta type I receptor); Skeletal progenitor cells; Osteoblasts; Chondrocytes; Growth plate; Perichondrium; Conditional knockout mice ID ACTIVATED PROTEIN-KINASE; BONE-FORMATION; TRANSCRIPTION FACTOR; CHONDROCYTE DIFFERENTIATION; EMBRYONIC-DEVELOPMENT; EXTRACELLULAR-MATRIX; TARGETED DISRUPTION; EXPRESSION PATTERNS; SIGNAL-TRANSDUCTION; MOUSE DEVELOPMENT AB TGF-beta has been implicated in the proliferation and differentiation of chondrocytes and osteoblasts. However, the in vivo function of TGF-beta in skeletal development is unclear. In this study, we investigated the role of TGF-beta signaling in growth plate development by creating mice with a conditional knockout of the TGF-beta type I receptor ALK5 (ALK5(CKO)) in skeletal progenitor cells using Dermo1-Cre mice. ALK5(CKO) mice had short and wide long bones, reduced bone collars, and trabecular bones. In ALK5(CKO) growth plates, chondrocytes proliferated and differentiated, but ectopic cartilaginous tissues protruded into the perichondrium. In normal growth plates, ALK5 protein was strongly expressed in perichondrial progenitor cells for osteoblasts, and in a thin chondrocyte layer located adjacent to the perichondrium in the peripheral cartilage. ALK5CKO growth plates had an abnormally thin perichondrial cell layer and reduced proliferation and differentiation of osteoblasts. These defects in the perichondrium likely caused the short bones and ectopic cartilaginous protrusions. Using tamoxifen-inducible Cre-ER (TM)-mediated ALK5-deficient primary calvarial cell cultures, we found that TGF-beta signaling promoted osteoprogenitor proliferation, early differentiation, and commitment to the osteoblastic lineage through the selective MAPKs and Smad2/3 pathways. These results demonstrate the important roles of TGF-beta signaling in perichondrium formation and differentiation, as well as in growth plate integrity during skeletal development. (C) Published by Elsevier Inc. C1 [Matsunobu, Tomoya; Torigoe, Kiyoyuki; Ishikawa, Masaki; de Vega, Susana; Kulkarni, Ashok B.; Yamada, Yoshihiko] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Matsunobu, Tomoya; Torigoe, Kiyoyuki; Iwamoto, Yukihide] Kyushu Univ, Grad Sch Med Sci, Dept Orthopaed Surg, Fukuoka 812, Japan. RP Yamada, Y (reprint author), NIDCR, Lab Cell & Dev Biol, NIH, Bldg 30,Rm 407,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM yoshi.yamada@nih.gov FU Intramural Program of the NIDCR; National Institutes of Health; Japan Society for the Promotion of Science FX We thank Drs. Stefan Karlsson, David M. Ornitz, and Andrew McMahon for ALK5-floxed mice, Dermo1-Cre mice, and CAGG-Cre-ER (TM) mice, respectively. This work was supported by the Intramural Program of the NIDCR, National Institutes of Health. Tomoya Matsunobu was supported in part by a Fellowship from the Japan Society for the Promotion of Science. NR 57 TC 36 Z9 43 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 15 PY 2009 VL 332 IS 2 BP 325 EP 338 DI 10.1016/j.ydbio.2009.06.002 PG 14 WC Developmental Biology SC Developmental Biology GA 480LQ UT WOS:000268736600012 PM 19501582 ER PT J AU Skuntz, S Mankoo, B Nguyen, MTT Hustert, E Nakayama, A Tournier-Lasserve, E Wright, CVE Pachnis, V Bharti, K Arnheiter, H AF Skuntz, Susan Mankoo, Baljinder Nguyen, Minh-Thanh T. Hustert, Elisabeth Nakayama, Atsuo Tournier-Lasserve, Elisabeth Wright, Christopher V. E. Pachnis, Vassilis Bharti, Kapil Arnheiter, Heinz TI Lack of the mesodermal homeodomain protein MEOX1 disrupts sclerotome polarity and leads to a remodeling of the cranio-cervical joints of the axial skeleton SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Cranio-cervical fusion; Vertebral fusion; Hemivertebrae; Tbx18; Uncx; Bapx1; Chromatin immunoprecipitation ID TARGETED DISRUPTION; MOUSE EMBRYO; CERVICAL-VERTEBRAE; PROXIMAL RIBS; GENE; TRANSCRIPTION; EXPRESSION; TBX18; BAPX1; MICE AB Meox1 and Meox2 are two related homeodomain transcription factor genes that together are essential for the development of all somite compartments. Here we show that mice homozygous for Meox1 mutations alone have abnormalities that are restricted to the sclerotome and its derivatives. A prominent and consistent phenotype of these mutations is a remodeling of the cranio-cervical joints whose major feature is the assimilation of the atlas into the basioccipital bone so that the skull rests on the axis. These abnormalities can be traced back to changes in the relative rates of cell proliferation in the rostral and caudal sclerotome compartments, and they are associated with alterations in the expression of at least three transcription factor genes, Tbx18, Uncx, and Bapx1. As previously observed for Bapx1, MEOX1 protein occupies evolutionarily conserved promoter regions of Tbx18 and Uncx, suggesting that Meox1 regulates these genes at least in part directly. Hence, Meox1 is part of a regulatory circuit that serves an essential, non-redundant function in the maintenance of rostro-caudal sclerotome polarity and axial skeleton formation. (C) Published by Elsevier Inc. C1 [Skuntz, Susan; Nguyen, Minh-Thanh T.; Nakayama, Atsuo; Tournier-Lasserve, Elisabeth; Bharti, Kapil; Arnheiter, Heinz] NINDS, MDS, NIH, Bethesda, MD 20892 USA. [Mankoo, Baljinder] Kings Coll London, Randall Div Cell & Mol Biophys, Sch Biomed & Hlth Sci, London SE1 1UL, England. [Hustert, Elisabeth] Inst Humangenet & Anthropol, Freiburg, Germany. [Wright, Christopher V. E.] Vanderbilt Univ, Med Ctr, Program Dev Biol, Nashville, TN USA. [Pachnis, Vassilis] Natl Inst Med Res, Div Mol Neurobiol, London NW7 1AA, England. RP Arnheiter, H (reprint author), NINDS, MDS, NIH, Bldg 35,Room 2A-201,35 Convent Dr,MSC 3706, Bethesda, MD 20892 USA. EM ha3p@nih.gov FU Medical Research Council; NIH; NINDS FX We thank Drs. B. Condie, B. Hogan, R. Hill and A. Kispert for reagents, Dr. E. Meier for invaluable help during the molecular characterization and Dr. Rudi Balling during the phenotypic characterization of the transgene insertion, and Drs. Lynn Hudson and Dubois-Dalcq for comments on the manuscript. We also thank Keith Rogers for preparing H&E sections, and the staff of the NINDS animal facility for excellent animal care. This work was supported in part by the Medical Research Council (BM and VP) and by the intramural research program of the NIH, NINDS. NR 36 TC 10 Z9 11 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 AUG 15 PY 2009 VL 332 IS 2 BP 383 EP 395 DI 10.1016/j.ydbio.2009.06.006 PG 13 WC Developmental Biology SC Developmental Biology GA 480LQ UT WOS:000268736600017 PM 19520072 ER PT J AU Marczak, ED Jinsmaa, Y Myers, PH Blankenship, T Wilson, R Balboni, G Salvadori, S Lazarus, LH AF Marczak, Ewa D. Jinsmaa, Yunden Myers, Page H. Blankenship, Terry Wilson, Ralph Balboni, Gianfranco Salvadori, Severo Lazarus, Lawrence H. TI Orally administered H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2), a potent mu-/delta-opioid receptor antagonist, regulates obese-related factors in mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article; Proceedings Paper CT International Narcotics Research Conference CY JUL 13-18, 2008 CL Charleston, SC DE Obesity; Bone mineral density; Insulin; Glucose; Dmt-Tic pharmacophore; Dual mu-/delta-opioid receptor antagonist; (ob/ob mouse) ID BODY-WEIGHT; BETA-ENDORPHIN; DEFICIENT MICE; FAT OXIDATION; FOOD-INTAKE; RATS; NALOXONE; NALTREXONE; MORPHINE; EXERCISE AB Orally active dual mu-/delta-opioid receptor antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2) was applied to study body weight gain, fat content, bone mineral density, serum insulin. cholesterol and glucose levels in female ob/ob (B6.V-Lep < ob >/J homozygous) and lean wild mice with or without voluntary exercise on wheels for three weeks, and during a two week post-treatment period under the same conditions. MZ-2 (10 mg/kg/day, p.o.) exhibited the following actions: (1) reduced body weight gain in sedentary obese mice that persisted beyond the treatment period without effect on lean mice; (2) stimulated voluntary running on exercise wheels of both groups of mice; (3) decreased fat content, enhanced bone mineral density (BMD), and decreased serum insulin and glucose levels in obese mice; and (4) MZ-2 (30 mu M) increased BMD in human osteoblast cells (MG-63) comparable to naltrexone, while morphine inhibited mineral nodule formation. Thus, MZ-2 has potential application in the clinical management of obesity, insulin and glucose levels, and the amelioration of osteoporosis. Published by Elsevier B.V. C1 [Marczak, Ewa D.; Jinsmaa, Yunden; Lazarus, Lawrence H.] Natl Inst Environm Hlth Sci, Med Chem Grp, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. [Myers, Page H.; Blankenship, Terry] Natl Inst Environm Hlth Sci, Vet Med Branch, Res Triangle Pk, NC 27709 USA. [Wilson, Ralph] Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Balboni, Gianfranco] Univ Cagliari, Dept Toxicol, I-09126 Cagliari, Italy. [Salvadori, Severo] Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. [Salvadori, Severo] Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. RP Marczak, ED (reprint author), Natl Inst Environm Hlth Sci, Med Chem Grp, Pharmacol Lab, POB 12233,MD C304, Res Triangle Pk, NC 27709 USA. EM marczake@niehs.nih.gov FU Intramural NIH HHS [Z01 ES100472-06, NIH0011846955, Z01 ES090053-20] NR 46 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD AUG 15 PY 2009 VL 616 IS 1-3 BP 115 EP 121 DI 10.1016/j.ejphar.2009.06.041 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 495YT UT WOS:000269933100018 PM 19576206 ER PT J AU Samuni, Y Flores-Santana, W Krishna, MC Mitchell, JB Wink, DA AF Samuni, Yuval Flores-Santana, Wilmarie Krishna, Murali C. Mitchell, James B. Wink, David A. TI The inhibitors of histone deacetylase suberoylanilide hydroxamate and trichostatin A release nitric oxide upon oxidation SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE HDAC; SAHA; Oxidation; NO; EPR; Free radicals ID SUPEROXIDE-DISMUTASE; NITROXYL HNO; BIOLOGICAL-ACTIVITY; HYDROGEN-PEROXIDE; ANTICANCER AGENT; IN-VIVO; HYDROXYUREA; NO; DONORS; VORINOSTAT AB Suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) is the lead compound of a new class of histone deacetylase (HDAC) inhibitors used as anticancer drugs that have been shown to affect multiple proteins associated with gene expression, cell proliferation, and migration. Studies have also demonstrated the essential role of the hydroxamate moiety of SAHA in HDAC inhibition. The ability of SAHA and its structural analog trichostatin A (TSA) to generate NO upon oxidation was tested directly, by spin trapping of NO using electron paramagnetic resonance spectroscopy, and also indirectly, via the determination of nitrite using the Griess assay. H(2)O(2)/metmyoglobin was used to oxidize SAHA and TSA. These studies demonstrate, for the first time, the release of NO from SAHA and its Structural analog TSA. We tested the protective effects of SAHA, TSA, and valproic acid (VPA) in mammalian Chinese hamster V79 cells exposed to a bolus of H(2)O(2) for 1 h and monitored the clonogenic cell Survival. Both SAHA and TSA afforded significant cytoprotection when co-incubated with H(2)O(2), whereas VPA was ineffective. These studies provide evidence for the release of NO by hydroxamate-containing HDAC inhibitors and their antioxidant effects. Such roles may be an added advantage of this class of HDAC agents used for epigenetic therapies in cancer. (C) Published by Elsevier Inc. C1 [Samuni, Yuval; Flores-Santana, Wilmarie; Krishna, Murali C.; Mitchell, James B.; Wink, David A.] NCI, Radiat Biol Branch, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. EM murali@helix.nih.gov FU Intramural NIH HHS [Z01 BC010478-05] NR 42 TC 20 Z9 20 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG 15 PY 2009 VL 47 IS 4 BP 419 EP 423 DI 10.1016/j.freeradbiomed.2009.05.011 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 475UF UT WOS:000268386100010 PM 19447172 ER PT J AU Roy, SW Weedall, GD da Silva, RL Polley, SD Ferreira, MU AF Roy, Scott W. Weedall, Gareth D. da Silva, Rogerio L. Polley, Spencer D. Ferreira, Marcelo U. TI Sequence diversity and evolutionary dynamics of the dimorphic antigen merozoite surface protein-6 and other Msp genes of Plasmodium falciparum SO GENE LA English DT Article DE Malaria; Plasmodium falciparum; Allelic dimorphism; Evolution; Merozoite surface proteins; Vaccine; MSP-6; MSP-7; MSP-9 ID ANTIBODY RECOGNITION; CROSS-CONTAMINATION; BALANCING SELECTION; ALLELIC DIMORPHISM; MALARIA PARASITES; BRAZILIAN AMAZON; AMINO-TERMINUS; COMPLEX; RECOMBINATION; VACCINE AB Immune evasion by Plasmodium falciparum is favored by extensive allelic diversity of surface antigens. Some of them, most notably the vaccine-candidate merozoite surface protein (MSP)-1, exhibit a poorly understood pattern of allelic dimorphism, in which all observed alleles group into two highly diverged allelic families with few or no inter-family recombinants. Here we describe contrasting levels and patterns of sequence diversity in genes encoding three MSP-1-associated surface antigens of P. falciparum, ranging from an ancient allelic dimorphism in the Msp-6 gene to a near lack of allelic divergence in Msp-9 to a more classical multi-allele polymorphism in Msp-7 Other members of the Msp-7 gene family exhibit very little polymorphism in non-repetitive regions. A comparison of P. falciparum Msp-6 sequences to an orthologous sequence from P. reichenowi provided evidence for distinct evolutionary histories of the 5' and 3' segments of the dimorphic region in PfMsp-6, consistent with one dimorphic lineage having arisen from recombination between now-extinct ancestral alleles. In addition. we uncovered two surprising patterns of evolution in repetitive sequence. Firsts in Msp-6, large deletions are associated with (nearly) identical sequence motifs at their borders. Second, a comparison of PfMsp-9 with the P. reichenowi ortholog indicated retention of a significant inter-unit diversity within an 18-base pair repeat within the coding region of P. falciparum, but homogenization in P. reichenowi. (C) 2009 Elsevier B.V. All rights reserved. C1 [Roy, Scott W.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Weedall, Gareth D.; Polley, Spencer D.] Univ London London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London WC1E 7HT, England. [Weedall, Gareth D.] Univ Liverpool, Sch Biol Sci, Liverpool LE9 7ZB, Merseyside, England. [da Silva, Rogerio L.; Ferreira, Marcelo U.] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, BR-05508900 Sao Paulo, Brazil. RP Roy, SW (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A, Bethesda, MD 20894 USA. EM royscott@ncbi.nlm.nih.gov; muferrei@usp.br RI Ferreira, Marcelo/G-8289-2011; Polley, Spencer/F-7766-2013 OI Ferreira, Marcelo/0000-0002-5293-9090; NR 58 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD AUG 15 PY 2009 VL 443 IS 1-2 BP 12 EP 21 DI 10.1016/j.gene.2009.05.007 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 471UP UT WOS:000268084100002 PM 19463923 ER PT J AU Shi, YB Ghosh, MC Tong, WH Rouault, TA AF Shi, Yanbo Ghosh, Manik C. Tong, Wing-Hang Rouault, Tracey A. TI Human ISD11 is essential for both iron-sulfur cluster assembly and maintenance of normal cellular iron homeostasis SO HUMAN MOLECULAR GENETICS LA English DT Article ID IN-VITRO BIOSYNTHESIS; COLI TRANSFER-RNA; ESCHERICHIA-COLI; SCAFFOLD PROTEIN; CYSTEINE DESULFURASE; REGULATORY PROTEINS; DNA-REPAIR; BIOGENESIS; ISCU; 4-THIOURIDINE AB The LYR family consists of proteins of diverse functions that contain the conserved tripeptide 'LYR' near the N-terminus, and it includes Isd11, which was previously observed to have an important role in iron-sulfur (Fe-S) cluster biogenesis in Saccharomyces cerevisiae. Here, we have cloned and characterized human ISD11 and shown that human ISD11 forms a stable complex in vivo with the human cysteine desulfurase (ISCS), which generates the inorganic sulfur needed for Fe-S protein biogenesis. Similar to ISCS, we have found that ISD11 localizes to the mitochondrial compartment, as expected, but also to the nucleus of mammalian cells. Using RNA-interference techniques, we have shown that suppression of human ISD11 inactivated mitochondrial and cytosolic aconitases. In addition, ISD11 suppression activated iron-responsive element-binding activity of iron regulatory protein 1, increased protein levels of iron regulatory protein 2, and resulted in abnormal punctate ferric iron accumulations in cells. These results indicate that ISD11 is important in the biogenesis of Fe-S clusters in mammalian cells, and its loss disrupts normal mitochondrial and cytosolic iron homeostasis. C1 [Shi, Yanbo; Ghosh, Manik C.; Tong, Wing-Hang; Rouault, Tracey A.] NICHHD, Program Mol Med, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Program Mol Med, Bethesda, MD 20892 USA. EM trou@helix.nih.gov FU National Institute of Child Health and Human Development FX This work was supported by the Intramural Program of National Institute of Child Health and Human Development. NR 30 TC 62 Z9 67 U1 0 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 AUG 15 PY 2009 VL 18 IS 16 BP 3014 EP 3025 DI 10.1093/hmg/ddp239 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 475BN UT WOS:000268330900008 PM 19454487 ER PT J AU Yang, MH Kostov, Y Bruck, HA Rasooly, A AF Yang, Minghui Kostov, Yordan Bruck, Hugh A. Rasooly, Avraham TI Gold nanoparticle-based enhanced chemiluminescence immunosensor for detection of Staphylococcal Enterotoxin B (SEB) in food SO INTERNATIONAL JOURNAL OF FOOD MICROBIOLOGY LA English DT Article DE Staphylococcal enterotoxins; Enhanced chemiluminescence; Food safety; CCD point-of-care detector; Gold nanoparticles ID BIOMOLECULAR IMMOBILIZATION METHOD; ASSAY KIT TECRA; POTENTIOMETRIC IMMUNOSENSOR; ATOPIC-DERMATITIS; REAL-TIME; ELECTROCHEMICAL IMMUNOSENSOR; RHEUMATOID-ARTHRITIS; CYCLIC VOLTAMMETRY; CARBON NANOTUBES; SOL-GEL AB Staphylococcal enterotoxins (SEs) are major cause of foodborne diseases, so sensitive detection (<1 ng/ml) methods are needed for SE detection in food, The surface area, geometric and physical properties of gold nanoparticles make them well-suited for enhancing interactions with biological molecules in assays. To take advantage of the properties of gold nanoparticles for immunodetection, we have developed a gold nanoparticle-based enhanced chemiluminescence (ECL) immunosensor for detection of Staphylococcal Enterotoxin B (SEB) in food. Anti-SEB primary antibodies were immobilized onto a gold nanoparticle surface through physical adsorption and then the antibody-gold nanoparticle mixture was immobilized onto a polycarbonate surface. SEB was detected by a "sandwich-type" ELISA assay on the polycarbonate surface with a secondary antibody and ECL detection. The signal from ECL was read using a point-of-care detector based on a cooled charge-coupled device (CCD) sensor or a plate reader. The system was used to test for SEB in buffer and various foods (mushrooms, tomatoes, and baby food meat). The limit of detection was found to be similar to 0.01 ng/ml, which is similar to 10 times more sensitive than traditional ELISA. The gold nanoparticles were relatively easy to use for antibody immobilization because of their physical adsorption mechanism; no other reagents were required for immobilization. The use of our simple and inexpensive detector combined with the gold nanoparticle-based ECL method described here is adaptable to simplify and increase sensitivity of any immunological assay and for point-of-care diagnostics. Published by Elsevier B.V. C1 [Rasooly, Avraham] FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Yang, Minghui; Kostov, Yordan] Univ Maryland Baltimore Cty, Ctr Adv Sensor Technol, Baltimore, MD 21250 USA. [Bruck, Hugh A.] UMCP, College Pk, MD 20742 USA. [Rasooly, Avraham] NCI, Bethesda, MD 20892 USA. RP Rasooly, A (reprint author), FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. EM rasoolya@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 53 TC 51 Z9 56 U1 2 U2 34 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1605 J9 INT J FOOD MICROBIOL JI Int. J. Food Microbiol. PD AUG 15 PY 2009 VL 133 IS 3 BP 265 EP 271 DI 10.1016/j.ijfoodmicro.2009.05.029 PG 7 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA 485IT UT WOS:000269115200008 PM 19540011 ER PT J AU Pomerantsev, AP Camp, A Leppla, SH AF Pomerantsev, Andrei P. Camp, Andrew Leppla, Stephen H. TI A New Minimal Replicon of Bacillus anthracis Plasmid pXO1 SO JOURNAL OF BACTERIOLOGY LA English DT Article ID COMPLETE SEQUENCE; GENOME SEQUENCE; CEREUS-GROUP; TOXIN GENES; REPLICATION; PROTEIN; IDENTIFICATION; ORGANIZATION; REVEALS AB An 8,883-bp mini-pXO1 plasmid containing a replicon from Bacillus anthracis pXO1 (181.6 kb) was identified by making large deletions in the original plasmid using a newly developed Cre-loxP system. Portions of the truncated mini-pXO1 were cloned into an Escherichia coli vector unable to replicate in B. anthracis. A 5.95-kb region encompassing three putative genes was identified as the minimal pXO1 fragment required for replication of the resulting recombinant shuttle plasmid (named pMR) in B. anthracis. Deletion analysis showed that the only genes essential for replication were the pXO1-14 and pXO1-16 genes, which are transcribed in opposite directions and encode predicted proteins of 66.5 and 67.1 kDa, respectively. The ORF14 protein contains a helix-turn-helix motif, while the ORF16 upstream region contains attributes of a theta-replicating plasmid origin of replication (Ori), namely, an exclusively A + T-containing segment, five 9-bp direct repeats, an inverted repeat, and a sigma(A)-dependent promoter for the putative replication initiator Rep protein (ORF16). Spontaneous mutations generated in the ORF14, ORF16, and Ori regions of pMR during PCR amplification produced a temperature-sensitive plasmid that is unable to replicate in B. anthracis at 37 degrees C. The efficacy of transformation of plasmid-free B. anthracis Ames and Sterne strains by the original pMR was similar to 10(3) CFU/mu g, while Bacillus cereus strains 569 and ATCC 10987 were transformed with efficiencies of 104 and 102 CFU/mu g, respectively. Around 95% of B. anthracis cells retained pMR after one round of sporulation and germination. C1 [Pomerantsev, Andrei P.; Camp, Andrew; Leppla, Stephen H.] NIAID, Bacterial Toxins & Therapeut Sect, NIH, Bethesda, MD 20892 USA. RP Leppla, SH (reprint author), NIAID, Bacterial Toxins & Therapeut Sect, NIH, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov FU NIH; National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 24 TC 16 Z9 17 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD AUG 15 PY 2009 VL 191 IS 16 BP 5134 EP 5146 DI 10.1128/JB.00422-09 PG 13 WC Microbiology SC Microbiology GA 475UJ UT WOS:000268386600013 PM 19502400 ER PT J AU Rosner, JL Martin, RG AF Rosner, Judah L. Martin, Robert G. TI An Excretory Function for the Escherichia coli Outer Membrane Pore TolC: Upregulation of marA and soxS Transcription and Rob Activity Due to Metabolites Accumulated in tolC Mutants SO JOURNAL OF BACTERIOLOGY LA English DT Article ID MULTIPLE-ANTIBIOTIC-RESISTANCE; ORGANIC-SOLVENT TOLERANCE; EFFLUX PUMPS; BINDING-PROTEIN; OMPF PORIN; ACTIVATION; GENES; SUPEROXIDE; EXPRESSION; PROMOTER AB Efflux pumps function to rid bacteria of xenobiotics, including antibiotics, bile salts, and organic solvents. TolC, which forms an outer membrane channel, is an essential component of several efflux pumps in Escherichia coli. We asked whether TolC has a role during growth in the absence of xenobiotics. Because tolC transcription is activated by three paralogous activators, MarA, SoxS, and Rob, we examined the regulation of these activators in tolC mutants. Using transcriptional fusions, we detected significant upregulation of marRAB and soxS transcription and Rob protein activity in tolC mutants. Three mechanisms could be distinguished: (i) activation of marRAB transcription was independent of marRAB, soxR, and rob functions; (ii) activation of soxS transcription required SoxR, a sensor of oxidants; and (iii) Rob protein was activated posttranscriptionally. This mechanism is similar to the mechanisms of upregulation of marRAB, soxS, and Rob by treatment with certain phenolics, superoxides, and bile salts, respectively. The transcription of other marA/soxS/rob regulon promoters, including tolC itself, was also elevated in tolC mutants. We propose that TolC is involved in the efflux of certain cellular metabolites, not only xenobiotics. As these metabolites accumulate during growth, they trigger the upregulation of MarA, SoxS, and Rob, which in turn upregulate tolC and help rid the bacteria of these metabolites, thereby restoring homeostasis. C1 [Rosner, Judah L.; Martin, Robert G.] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Rosner, JL (reprint author), Bldg 5,Rm 333,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jlrosner@helix.nih.gov FU National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health. NR 62 TC 32 Z9 35 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD AUG 15 PY 2009 VL 191 IS 16 BP 5283 EP 5292 DI 10.1128/JB.00507-09 PG 10 WC Microbiology SC Microbiology GA 475UJ UT WOS:000268386600027 PM 19502391 ER PT J AU Honda, M Wang, R Kong, WP Kanekiyo, M Akahata, W Xu, L Matsuo, K Natarajan, K Robinson, H Asher, TE Price, DA Douek, DC Margulies, DH Nabel, GJ AF Honda, Mitsuo Wang, Rui Kong, Wing-Pui Kanekiyo, Masaru Akahata, Wataru Xu, Ling Matsuo, Kazuhiro Natarajan, Kannan Robinson, Howard Asher, Tedi E. Price, David A. Douek, Daniel C. Margulies, David H. Nabel, Gary J. TI Different Vaccine Vectors Delivering the Same Antigen Elicit CD8(+) T Cell Responses with Distinct Clonotype and Epitope Specificity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MHC CLASS-I; RHESUS-MONKEYS; ENVELOPE GLYCOPROTEIN; HLA-B27 SUBTYPE; AIDS VACCINE; HIV-1 GP120; DNA PRIME; PEPTIDE; PROTECTION AB Prime-boost immunization with gene-based vectors has been developed to generate more effective vaccines for AIDS, malaria, and tuberculosis. Although these vectors elicit potent T cell responses, the mechanisms by which they stimulate immunity are not well understood. In this study, we show that immunization by a single gene product, HIV-1 envelope, with alternative vector combinations elicits CD8(+) cells with different fine specificities and kinetics of mobilization. Vaccine-induced CD8(+) T cells recognized overlapping third V region loop peptides. Unexpectedly, two anchor variants bound H-2D(d) better than the native sequences, and clones with distinct specificities were elicited by alternative vectors. X-ray crystallography revealed major differences in solvent exposure of MHC-bound peptide epitopes, suggesting that processed HIV-1 envelope gave rise to MHC-I/peptide conformations recognized by distinct CD8(+) T cell populations. These findings suggest that different gene-based vectors generate peptides with alternative conformations within MHC-I that elicit distinct T cell responses after vaccination. The Journal of Immunology, 2009, 183: 2425-2434. C1 [Honda, Mitsuo; Kong, Wing-Pui; Kanekiyo, Masaru; Akahata, Wataru; Xu, Ling; Asher, Tedi E.; Price, David A.; Douek, Daniel C.; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Honda, Mitsuo; Matsuo, Kazuhiro] Natl Inst Infect Dis, AIDS Res Ctr, Tokyo, Japan. [Wang, Rui; Natarajan, Kannan; Margulies, David H.] NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Robinson, Howard] Brookhaven Natl Lab, Upton, NY 11973 USA. [Price, David A.] Cardiff Univ, Sch Med, Dept Med Microbiol & Immunol, Cardiff, S Glam, Wales. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40,Room 4502, Bethesda, MD 20892 USA. EM gnabel@nih.gov RI Margulies, David/H-7089-2013; Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Margulies, David/0000-0001-8530-7375 FU U.S. Department of Energy; National Center for Research Resources of the National Institutes of Health; Medical Research Council, United Kingdom FX This work was supported by the intramural research program of the Vaccine Research Center and the Laboratory, of Immunology, National Institute of Allergy and Infections Diseases, National Institutes of Health. Support for beamline X29 of the National Synchrotron Light Source comes principally from the Offices of Biological and Environmental Research and of Basic Energy Sciences of the U.S. Department of Energy, and from the National Center for Research Resources of the National Institutes of Health. D.A.P. is a Medical Research Council (United Kingdom) Senior Clinical Fellow. NR 51 TC 15 Z9 16 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2009 VL 183 IS 4 BP 2425 EP 2434 DI 10.4049/jimmunol.0900581 PG 10 WC Immunology SC Immunology GA 482RN UT WOS:000268906500029 PM 19620307 ER PT J AU Wang, R Natarajan, K Margulies, DH AF Wang, Rui Natarajan, Kannan Margulies, David H. TI Structural Basis of the CD8 alpha beta/MHC Class I Interaction: Focused Recognition Orients CD8 beta to a T Cell Proximal Position SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-I; COMPLEX CLASS-I; ENHANCED ANTITUMOR-ACTIVITY; THYMIC LEUKEMIA ANTIGEN; CD8 BETA-CHAIN; HLA CLASS-I; CORECEPTOR FUNCTION; ALPHA-3 DOMAIN; CRYSTAL-STRUCTURE; RECEPTOR INTERACTION AB In the immune system, B cells, dendritic cells, NK cells, and T lymphocytes all respond to signals received via ligand binding to receptors and coreceptors. Although the specificity of T cell recognition is determined by the interaction of T cell receptors with MHC/peptide complexes, the development of T cells in the thymus and their sensitivity to Ag are also dependent on coreceptor molecules CD8 (for MHC class I (MHCI)) and CD4 (for MHCII). The CD8 alpha beta heterodimer is a potent coreceptor for T cell activation, but efforts to understand its function fully have been hampered by ignorance of the structural details of its interactions with MHCI. In this study we describe the structure of CD8 alpha beta in complex with the murine MHCI molecule H-2D(d) at 2.6 angstrom resolution. The focus of the CD8 alpha beta interaction is the acidic loop (residues 222-228) of the alpha 3 domain of H-2D(d). The beta subunit occupies a T cell membrane proximal position, defining the relative positions of the CD8 alpha and CD8 beta subunits. Unlike the CD8 alpha homodimer, CD8 alpha beta does not contact the MHCI alpha(2)- or beta(2)-microglobulin domains. Movements of the CD8 alpha CDR2 and CD8 beta CDR1 and CDR2 loops as well as the flexibility of the H-2D(d) CD loop facilitate the monovalent interaction. The structure resolves inconclusive data on the topology of the CD8 alpha beta/MHCI interaction, indicates that CD8 beta is crucial in orienting the CD8 alpha beta heterodimer, provides a framework for understanding the mechanistic role of CD8 alpha beta in lymphoid cell signaling, and offers a tangible context for design of structurally altered coreceptors for tumor and viral immunotherapy. The Journal of Immunology, 2009, 183: 2554-2564. C1 [Wang, Rui; Natarajan, Kannan; Margulies, David H.] NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Natarajan, K (reprint author), NIAID, Mol Biol Sect, Immunol Lab, NIH, Bldg 10,Room 11N311,10 Ctr Dr, Bethesda, MD 20892 USA. EM knatarajan@niaid.nih.gov RI Margulies, David/H-7089-2013; OI Margulies, David/0000-0001-8530-7375 FU National Institute of Allergy and Infectious Diseases; National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 83 TC 42 Z9 42 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2009 VL 183 IS 4 BP 2554 EP 2564 DI 10.4049/jimmunol.0901276 PG 11 WC Immunology SC Immunology GA 482RN UT WOS:000268906500043 PM 19625641 ER PT J AU Beigel, JH Voell, J Huang, CY Burbelo, PD Lane, HC AF Beigel, John H. Voell, Jocelyn Huang, Chiung-yu Burbelo, Peter D. Lane, H. Clifford TI Safety and Immunogenicity of Multiple and Higher Doses of an Inactivated Influenza A/H5N1 Vaccine SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID A H5N1 INFECTION; NEUTRALIZING ACTIVITY; MONOCLONAL-ANTIBODY; VIRUS; MICE; HEMAGGLUTININ; OSELTAMIVIR; RESISTANCE; PNEUMONIA; RESPONSES AB Background. H5N1 avian influenza represents an episodic zoonotic disease with the potential to cause a pandemic, and antiviral resistance is of considerable concern. We sought to generate high-titer H5N1 antibodies in healthy volunteers for the purpose of developing hyperimmune intravenous immunoglobulin. Methods. We conducted a dose-escalating, unblinded clinical trial involving 75 subjects aged 18-59 years. Three cohorts of twenty-five subjects were enrolled sequentially and received 90, 120, or 180 mg of H5N1 A/Vietnam/1203/04 vaccine in 4 doses administered similar to 28 days apart. Results. No statistically significant dose-related increases in the geometric mean titers (GMTs) of serum hemagglutination inhibition antibody were observed when the 90-mg, 120-mg, and 180-mg cohorts were compared. When the cohorts were analyzed together to determine the effect of additional vaccinations, the GMTs of hemagglutination inhibition antibody after the first, second, third, and fourth vaccinations were 1:15.7, 1:22.2, 1:36.0, and 1:32.0, respectively (first vaccination vs. baseline, P < .001; second vs. first vaccination, P = .02; and third vs. second vaccination, P < .001). The microneutralization GMTs after the first, second, third, and fourth vaccinations were 1: 7.5, 1:33.1, 1:55.7, and 1:68.4, respectively (P < .001 for all comparisons). Conclusion. The results of our study suggest that a third and fourth dose of the H5N1 A/Vietnam/1203/04 vaccine may result in higher hemagglutination inhibition and microneutralization GMTs, compared with the GMTs resulting from fewer doses. There was no benefit to increasing the dose of the vaccine. C1 [Beigel, John H.; Voell, Jocelyn; Huang, Chiung-yu; Lane, H. Clifford] NIAID, NIH, Bethesda, MD 20892 USA. [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Beigel, JH (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbeigel@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 20 TC 24 Z9 26 U1 0 U2 1 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 AUG 15 PY 2009 VL 200 IS 4 BP 501 EP 509 DI 10.1086/599992 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 470VN UT WOS:000268009700004 PM 19569973 ER PT J AU Hudgens, MG Gilbert, PB Mascola, JR Wu, CD Barouch, DH Self, SG AF Hudgens, Michael G. Gilbert, Peter B. Mascola, John R. Wu, Chih-Da Barouch, Dan H. Self, Steven G. TI Power to Detect the Effects of HIV Vaccination in Repeated Low-Dose Challenge Experiments SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFECTION; TENOFOVIR; VACCINES; MACAQUES; STRATEGY AB Simulation studies were conducted to estimate the statistical power of repeated low-dose challenge experiments performed in nonhuman primates to detect the effect of a candidate human immunodeficiency virus vaccine. The effect of various design parameters on power was explored. Results of simulation studies indicate that repeated low-dose challenge studies with a total sample of size 50 (25 animals/arm) typically provide adequate power to detect a 50% reduction in the per-exposure probability of infection resulting from vaccination. Power generally increases with the maximum number of allowable challenges per animal, the per-exposure risk of infection in control animals, and the proportion of animals susceptible to infection. C1 [Hudgens, Michael G.] Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC 27599 USA. [Barouch, Dan H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Vaccine Res, Boston, MA 02215 USA. [Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gilbert, Peter B.; Self, Steven G.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Gilbert, Peter B.; Self, Steven G.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Hudgens, MG (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC 27599 USA. EM mhudgens@bios.unc.edu FU Intramural NIH HHS [Z99 AI999999]; NIAID NIH HHS [R01 AI054165, R01 AI054165-04] NR 13 TC 27 Z9 27 U1 0 U2 1 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 AUG 15 PY 2009 VL 200 IS 4 BP 609 EP 613 DI 10.1086/600891 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 470VN UT WOS:000268009700017 PM 19591571 ER PT J AU Allison, RD Katsounas, A Koziol, DE Kleiner, DE Alter, HJ Lempicki, RA Wood, B Yang, J Fullmer, B Cortez, KJ Polis, MA Kottilil, S AF Allison, Robert D. Katsounas, Antonios Koziol, Deloris E. Kleiner, David E. Alter, Harvey J. Lempicki, Richard A. Wood, Brad Yang, Jun Fullmer, Brandie Cortez, Karoll J. Polis, Michael A. Kottilil, Shyam TI Association of Interleukin-15-Induced Peripheral Immune Activation with Hepatic Stellate Cell Activation in Persons Coinfected with Hepatitis C Virus and HIV SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SMOOTH-MUSCLE ACTIN; ANTIRETROVIRAL THERAPY; FIBROSIS PROGRESSION; SUPPRESSION; EXPRESSION; INFECTION; ANTIBODY AB Hepatic stellate cells (HSCs) mediate hepatitis C virus (HCV)-related liver fibrosis, and increased HSC activation in human immunodeficiency virus (HIV)/HCV coinfection may be associated with accelerated fibrosis. We examined the level of HSC activation in HIV/HCV-coinfected and HCV-monoinfected subjects and its relationship to the level of activation and gene expression of peripheral immune cells in coinfected subjects. HSC activation levels positively correlated with peripheral CD4(+) and CD8(+) T cell immune activation and were associated with enhanced interleukin-15 (IL-15) gene expression, suggesting a pathogenic role for IL-15-driven immunomediated hepatic fibrosis. Future strategies that reduce immune activation and HSC activation may delay progression of liver fibrosis. C1 [Katsounas, Antonios; Polis, Michael A.; Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Allison, Robert D.; Alter, Harvey J.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wood, Brad] NIH Clin Ctr, Div Radiol, Bethesda, MD USA. [Lempicki, Richard A.; Yang, Jun; Fullmer, Brandie] SAIC Frederick, Frederick, MD USA. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 11N204, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Allison, Robert/0000-0001-8458-5250; Polis, Michael/0000-0002-9151-2268; Kleiner, David/0000-0003-3442-4453 FU National Institute of Allergy and Infectious Diseases; National Institutes of Health (NIH) FX Financial support: Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), and NIH Clinical Center. NR 14 TC 14 Z9 16 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 AUG 15 PY 2009 VL 200 IS 4 BP 619 EP 623 DI 10.1086/600107 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 470VN UT WOS:000268009700019 PM 19594300 ER PT J AU Pollock, JD Koustova, E Hoffman, A Shurtleff, D Volkow, ND AF Pollock, Jonathan D. Koustova, Elena Hoffman, Allison Shurtleff, David Volkow, Nora D. TI Treatments for nicotine addiction should be a top priority SO LANCET LA English DT Editorial Material C1 [Pollock, Jonathan D.; Koustova, Elena; Hoffman, Allison; Shurtleff, David; Volkow, Nora D.] NIDA, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Pollock, JD (reprint author), NIDA, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM jpollock@mail.nih.gov RI Pollock, Jonathan/B-1554-2009 FU Intramural NIH HHS [Z99 DA999999] NR 8 TC 14 Z9 14 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD AUG 15 PY 2009 VL 374 IS 9689 BP 513 EP 514 DI 10.1016/S0140-6736(09)60352-4 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 484BX UT WOS:000269019400010 PM 19394686 ER PT J AU de Souza-Pinto, NC Maynard, S Hashiguchi, K Hu, JP Muftuoglu, M Bohr, VA AF de Souza-Pinto, Nadja C. Maynard, Scott Hashiguchi, Kazunari Hu, Jingping Muftuoglu, Meltem Bohr, Vilhelm A. TI The Recombination Protein RAD52 Cooperates with the Excision Repair Protein OGG1 for the Repair of Oxidative Lesions in Mammalian Cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DNA-DAMAGE; SACCHAROMYCES-CEREVISIAE; LUNG-CANCER; 8-OXOGUANINE-DNA GLYCOSYLASE; STRAND EXCHANGE; BASE DAMAGE; SUSCEPTIBILITY; LOCALIZATION; MECHANISMS; RESISTANT AB Oxidized bases are common types of DNA modifications. Their accumulation in the genome is linked to aging and degenerative diseases. These modifications are commonly repaired by the base excision repair (BER) pathway. Oxoguanine DNA glycosylase (OGG1) initiates BER of oxidized purine bases. A small number of protein interactions have been identified for OGG1, while very few appear to have functional consequences. We report here that OGG1 interacts with the recombination protein RAD52 in vitro and in vivo. This interaction has reciprocal functional consequences as OGG1 inhibits RAD52 catalytic activities and RAD52 stimulates OGG1 incision activity, likely increasing its turnover rate. RAD52 colocalizes with OGG1 after oxidative stress to cultured cells, but not after the direct induction of double-strand breaks by ionizing radiation. Human cells depleted of RAD52 via small interfering RNA knockdown, and mouse cells lacking the protein via gene knockout showed increased sensitivity to oxidative stress. Moreover, cells depleted of RAD52 show higher accumulation of oxidized bases in their genome than cells with normal levels of RAD52. Our results indicate that RAD52 cooperates with OGG1 to repair oxidative DNA damage and enhances the cellular resistance to oxidative stress. Our observations suggest a coordinated action between these proteins that may be relevant when oxidative lesions positioned close to strand breaks impose a hindrance to RAD52 catalytic activities. C1 [de Souza-Pinto, Nadja C.; Maynard, Scott; Hashiguchi, Kazunari; Hu, Jingping; Muftuoglu, Meltem; Bohr, Vilhelm A.] NIA IRP, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [de Souza-Pinto, Nadja C.] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-01498 Sao Paulo, Brazil. RP Bohr, VA (reprint author), NIA IRP, Lab Mol Gerontol, NIH, 251 Bayview Blvd,Ste 100, Baltimore, MD 21224 USA. EM vbohr@nih.gov RI Souza-Pinto, Nadja/C-3462-2013; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013; OI Souza-Pinto, Nadja/0000-0003-4206-964X; Maynard, Scott/0000-0001-5625-936X FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX We thank Marie Rossi and Yie Liu for the critical reading of the manuscript and Xiufen Sui and Regina Knight for technical help. RAD52 transgenic mouse tails were kindly provided by Maria Jasin, Memorial Sloan-Kettering Cancer Center, New York, NY. We also thank Miral Dizdaroglu, National Institute of Standards and Technology, Gaithersburg, MD, for the use of the GC-MS equipment. NR 41 TC 21 Z9 21 U1 1 U2 2 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 AUG 15 PY 2009 VL 29 IS 16 BP 4441 EP 4454 DI 10.1128/MCB.00265-09 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 474UP UT WOS:000268310000009 PM 19506022 ER PT J AU Sun, CH Nakatake, Y Akagi, T Ura, H Matsuda, T Nishiyama, A Koide, H Ko, MSH Niwa, H Yokota, T AF Sun, Chuanhai Nakatake, Yuhki Akagi, Tadayuki Ura, Hiroki Matsuda, Takahiko Nishiyama, Akira Koide, Hiroshi Ko, Minoru S. H. Niwa, Hitoshi Yokota, Takashi TI Dax1 Binds to Oct3/4 and Inhibits Its Transcriptional Activity in Embryonic Stem Cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ORPHAN NUCLEAR RECEPTOR; ES CELLS; MOUSE EMBRYOS; SELF-RENEWAL; GATA FACTORS; EXPRESSION; PLURIPOTENCY; OCT-3/4; NANOG; DIFFERENTIATION AB Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of blastocysts. Transcription factor Oct3/4 is an indispensable factor in the self-renewal of ES cells. In this study, we searched for a protein that would interact with Oct3/4 in ES cells and identified an orphan nuclear hormone receptor, Dax1. The association of Dax1 with Oct3/4 was mediated through the POU-specific domain of Oct3/4. Ectopic expression of Dax1 inhibited Oct3/4-mediated activation of an artificial Oct3/4-responsive promoter. Expression of Dax1 in ES cells also reduced the activities of Nanog and Rex1 promoters, while knockdown of Dax1 increased these activities. Pulldown and gel shift assays revealed that the interaction of Dax1 with Oct3/4 abolished the DNA binding activity of Oct3/4. Chromatin immunoprecipitation assay results showed that Dax1 inhibited Oct3/4 binding to the promoter/enhancer regions of Oct3/4 and Nanog. Furthermore, overexpression of Dax1 resulted in ES cell differentiation. Taken together, these data suggest that Dax1, a novel molecule interacting with Oct3/4, functions as a negative regulator of Oct3/4 in ES cells. C1 [Niwa, Hitoshi] RIKEN, Ctr Dev Biol, Lab Pluripotent Cell Studies, Chu O Ku, Kobe, Hyogo 6500047, Japan. [Sun, Chuanhai; Akagi, Tadayuki; Ura, Hiroki; Koide, Hiroshi; Yokota, Takashi] Kanazawa Univ, Dept Stem Cell Biol, Grad Sch Med Sci, Kanazawa, Ishikawa 9208640, Japan. [Matsuda, Takahiko] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, Boston, MA 02115 USA. [Nakatake, Yuhki; Nishiyama, Akira; Ko, Minoru S. H.] NIA, Genet Lab, Dev Genom & Aging Sect, Baltimore, MD 21224 USA. RP Niwa, H (reprint author), RIKEN, Ctr Dev Biol, Lab Pluripotent Cell Studies, Chu O Ku, 2-2-3 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan. EM niwa@cdb.riken.jp; tyokota@med.kanazawa-u.ac.jp RI Akagi, Tadayuki/E-1078-2011; Koide, Hiroshi/E-9000-2011; Yokota, Takashi/F-6021-2011; Ko, Minoru/B-7969-2009; Nakatake, Yuhki/K-5405-2013; Yokota, Takashi/J-8483-2015; OI Ko, Minoru/0000-0002-3530-3015; Koide, Hiroshi/0000-0001-5916-3179 FU Naito Foundation; Ministry of Education, Culture, Sports, Science, and Technology of Japan; NIH; National Institute on Aging FX This work was supported in part by the Naito Foundation, Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and the Intramural Research Program of the NIH, National Institute on Aging. NR 38 TC 45 Z9 46 U1 0 U2 7 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 AUG 15 PY 2009 VL 29 IS 16 BP 4574 EP 4583 DI 10.1128/MCB.01863-08 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 474UP UT WOS:000268310000020 PM 19528230 ER PT J AU Fernandes, AF Bian, QN Jiang, JK Thomas, CJ Taylor, A Pereira, P Shang, F AF Fernandes, Alexandre F. Bian, Qingning Jiang, Jian-Kang Thomas, Craig J. Taylor, Allen Pereira, Paulo Shang, Fu TI Proteasome Inactivation Promotes p38 Mitogen-activated Protein Kinase-dependent Phosphatidylinositol 3-kinase Activation and Increases Interleukin-8 Production in Retinal Pigment Epithelial Cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID RECEPTOR TYROSINE KINASES; HYPOXIA-INDUCIBLE FACTOR; MACULAR DEGENERATION; OXIDATIVE STRESS; PROTEOLYTIC PATHWAY; CYTOKINE EXPRESSION; ENDOTHELIAL-CELLS; GENE-EXPRESSION; KAPPA-B; UBIQUITIN AB Oxidative stress and inflammation are implicated in the pathogenesis of many age-related diseases. We have demonstrated previously that oxidative inactivation of the proteasome is a molecular link between oxidative stress and overexpression of interleukin (IL)-8. Here, we elucidated a novel signaling cascade that leads to up-regulation of IL-8 in response to proteasome inactivation. The sequence of events in this cascade includes proteasome inactivation, activation of mitogen-activated protein kinase kinase (MKK) 3/MKK6, activation of p38 mitogen-activated protein kinase (MAPK), epidermal growth factor receptor phosphorylation, phosphatidylinositol 3-kinase (PI3K) activation and increased IL-8 expression. Blocking any of these signaling pathways abolished the up-regulation of IL-8 induced by proteasome inhibition. Although Akt is also activated in response to proteasome inactivation, we found that the PI3K-dependent up-regulation of IL-8 is independent of 3-phosphoinositide-dependent protein kinase (PDK)1 and Akt. Inhibition of PDK1 and Akt with chemical inhibitors or expression of constitutive active Akt had little effects on IL-8 expression in response to proteasome inactivation. In contrast, inhibition of interleukin 2-inducible T cell kinase, a kinase downstream of PI3K, significantly reduced the expression and secretion of IL-8 in response to proteasome inactivation. Together, these data elucidate a novel signaling network that leads to increased IL-8 production in response to proteasome inactivation. C1 [Fernandes, Alexandre F.; Bian, Qingning; Taylor, Allen; Shang, Fu] Tufts Univ, Jean Mayer USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Fernandes, Alexandre F.; Pereira, Paulo] Univ Coimbra, Ctr Ophthalmol, Inst Biomed Res Light & Image, Fac Med, P-3004548 Coimbra, Portugal. [Jiang, Jian-Kang; Thomas, Craig J.] NHGRI, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. RP Shang, F (reprint author), Tufts Univ, Jean Mayer USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. EM fu.shang@tufts.edu OI Fernandes, Alexandre/0000-0001-9489-6167; Pereira, Paulo/0000-0002-9908-2290 FU National Institutes of Health [EY11717, EY13250]; Portuguese Foundation for Science and Technology [PTDC/SAU-OSM/67498/2006, SFRH/BD/19039/2004]; USDA/Current Research Information System [1950-51000-060-02S]; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research FX We thank Drs. Alex Toker and Jiahuai Han for providing the plasmids. This work was supported by National Institutes of Health grants EY11717 (to F.S.) and EY13250 (to A.T.); a grant from the Portuguese Foundation for Science and Technology, PTDC/SAU-OSM/67498/2006 (to P.P.); and USDA/Current Research Information System 1950-51000-060-02S (to A.T.) and by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research (to J.-K.J. and C.J.T.). A.F.F. is a recipient of a Fellowship from the Portuguese Foundation for Science and Technology (SFRH/BD/19039/2004). NR 69 TC 20 Z9 22 U1 0 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG 15 PY 2009 VL 20 IS 16 BP 3690 EP 3699 DI 10.1091/mbc.E08-10-1068 PG 10 WC Cell Biology SC Cell Biology GA 483TW UT WOS:000268992100008 PM 19570915 ER PT J AU Liu, JL Yue, P Artym, VV Mueller, SC Guo, W AF Liu, Jianglan Yue, Peng Artym, Vira V. Mueller, Susette C. Guo, Wei TI The Role of the Exocyst in Matrix Metalloproteinase Secretion and Actin Dynamics during Tumor Cell Invadopodia Formation SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID EXTRACELLULAR-MATRIX; EXO70 INTERACTS; PLASMA-MEMBRANE; COMPLEX; MIGRATION; INVASION; EXOCYTOSIS; PODOSOMES; DEGRADATION; MMP-9 AB Invadopodia are actin-rich membrane protrusions formed by tumor cells that degrade the extracellular matrix for invasion. Invadopodia formation involves membrane protrusions driven by Arp2/3-mediated actin polymerization and secretion of matrix metalloproteinases (MMPs) at the focal degrading sites. The exocyst mediates the tethering of post-Golgi secretory vesicles at the plasma membrane for exocytosis and has recently been implicated in regulating actin dynamics during cell migration. Here, we report that the exocyst plays a pivotal role in invadopodial activity. With RNAi knockdown of the exocyst component Exo70 or Sec8, MDA-MB-231 cells expressing constitutively active c-Src failed to form invadopodia. On the other hand, overexpression of Exo70 promoted invadopodia formation. Disrupting the exocyst function by siEXO70 or siSEC8 treatment or by expression of a dominant negative fragment of Exo70 inhibited the secretion of MMPs. We have also found that the exocyst interacts with the Arp2/3 complex in cells with high invasion potential; blocking the exocyst-Arp2/3 interaction inhibited Arp2/3-mediated actin polymerization and invadopodia formation. Together, our results suggest that the exocyst plays important roles in cell invasion by mediating the secretion of MMPs at focal degrading sites and regulating Arp2/3-mediated actin dynamics. C1 [Liu, Jianglan; Yue, Peng; Guo, Wei] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Artym, Vira V.; Mueller, Susette C.] Georgetown Univ, Dept Oncol, Sch Med, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Artym, Vira V.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Guo, W (reprint author), Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. EM guowei@sas.upenn.edu RI Liu, Jianglan/M-7861-2013 FU National Institute of General Medical Sciences; Pew Scholars Program in Biomedical Sciences FX We are grateful to Drs. Kenneth Yamada (National Institutes of Health), Henning Birkedal-Hansen (National Institutes of Health), Toshiyuki Yoneda (Osaka University), Shu-Chan Hsu (Rutgers University), Margaret Chou (University of Pennsylvania), Rytis Prekeris (University of Colorado), Jian Jing (University of Colorado), and Bing He (University of Pennsylvania) for reagents and constructive suggestions. This work is supported by grants from National Institute of General Medical Sciences and the Pew Scholars Program in Biomedical Sciences to W.G. NR 39 TC 54 Z9 57 U1 0 U2 7 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG 15 PY 2009 VL 20 IS 16 BP 3763 EP 3771 DI 10.1091/mbc.E08-09-0967 PG 9 WC Cell Biology SC Cell Biology GA 483TW UT WOS:000268992100014 PM 19535457 ER PT J AU Abu-Amero, KK Hellani, A Bender, P Spaeth, GL Myers, J Katz, LJ Moster, M Bosley, TM AF Abu-Amero, Khaled K. Hellani, Ali Bender, Patrick Spaeth, George L. Myers, Jonathan Katz, L. Jay Moster, Marlene Bosley, Thomas M. TI High-resolution analysis of DNA copy number alterations in patients with primary open-angle glaucoma SO MOLECULAR VISION LA English DT Article ID HEREDITARY OPTIC NEUROPATHY; BALTIMORE EYE SURVEY; VISUAL-FIELD DAMAGE; MITOCHONDRIAL ABNORMALITIES; IRIS HYPOPLASIA; ANOMALIES; GENE; 6P25; WORLDWIDE; PEOPLE AB Purpose: To determine whether patients with isolated primary open-angle glaucoma (POAG) have evidence of chromosomal copy number alterations. Methods: Twenty-seven Caucasian and African-American POAG patients and 12 ethnically matched controls were carefully screened for possible glaucoma and tested for chromosomal copy number alterations using high resolution array comparative genomic hybridization. Results: No POAG patient had evidence of chromosomal copy number alterations when compared to normal ethnically matched controls. Additionally, there was no evidence of somatic mosaicism in any tested POAG patient. Conclusions: Chromosomal deletions and/or duplications were not detected in POAG patients as compared to controls. Other chromosomal imbalances such as translocations, inversions, and some ploidies cannot be detected by current array comparative genomic hybridization technology, and other nuclear genetic, mitochondrial abnormalities, or epigenetic factors cannot be excluded as a possible contributing factor to POAG pathogenesis. C1 [Abu-Amero, Khaled K.; Bosley, Thomas M.] King Saud Univ, Ophthalm Genet Lab, Dept Ophthalmol, Coll Med, Riyadh 11411, Saudi Arabia. [Hellani, Ali] Saad Specialist Hosp, PGD Lab, Al Khobar, Saudi Arabia. [Bender, Patrick] NIMH, Rochville, MD USA. [Spaeth, George L.; Myers, Jonathan; Katz, L. Jay; Moster, Marlene] Thomas Jefferson Univ Hosp, William & Anna Goldberg Glaucoma Serv, Philadelphia, PA 19107 USA. [Bosley, Thomas M.] Cooper Univ Hosp, Div Neurol, Camden, NJ USA. RP Abu-Amero, KK (reprint author), King Saud Univ, Ophthalm Genet Lab, Dept Ophthalmol, Coll Med, POB 245, Riyadh 11411, Saudi Arabia. EM abuamero@gmail.com FU Glaucoma Research Chair of the Department of Ophthalmology, College of Medicine; King Saud University ( Riyadh, Saudi Arabia); Saad Specialist Hospital ( Al-Khobar, Saudi Arabia) FX The authors thank Ahmed Mousa, Ph.D., for statistical assistance. K. K. A. and T. M. B. are supported by a grant from the Glaucoma Research Chair of the Department of Ophthalmology, College of Medicine, King Saud University ( Riyadh, Saudi Arabia). This research was also supported by a grant from the Saad Specialist Hospital ( Al-Khobar, Saudi Arabia). NR 30 TC 6 Z9 6 U1 0 U2 2 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 AUG 15 PY 2009 VL 15 IS 170-72 BP 1594 EP 1598 PG 5 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 501OF UT WOS:000270390500001 PM 19693294 ER PT J AU DePaolo, J Goker-Alpan, O Samaddar, T Lopez, G Sidransky, E AF DePaolo, John Goker-Alpan, Ozlem Samaddar, Ted Lopez, Grisel Sidransky, Ellen TI The Association Between Mutations in the Lysosomal Protein Glucocerebrosidase and Parkinsonism SO MOVEMENT DISORDERS LA English DT Review DE parkinsonism; synucleinopathies; Gaucher disease; glucocerebrosidase; risk factor ID MUTANT ALPHA-SYNUCLEIN; LEWY BODY DISORDERS; GAUCHER-DISEASE; GENE-MUTATIONS; EARLY-ONSET; RISK-FACTOR; ASHKENAZI-JEWS; MANIFESTATIONS; GBA; POPULATION AB A body of work has emerged over the past decade demonstrating it relationship between mutations in glucocerebrosidase gene (GBA), the gene implicated in Gaucher disease (GD), and the development of parkinsonism. Several different lines of research Support this relationship. First, patients Willi GD who are homozygous for Mutations in GBA have a higher than expected propensity to develop Parkinson's disease (PD). Furthermore, carriers of GBA mutations, particularly family members of patients with GD. have displayed all increased rate of parkinsonism. Subsequently, investigators from centers around the world screened cohorts of patients with parkinsonism for GBA mutations and found that overall, subjects with PD, as well as other Lewy body disorders. have at least a fivefold increase in the number of carriers of GBA Mutations as compared to age-matched controls. In addition. neuropathologic Studies of Subjects with parkinsonism carrying GBA Mutations demonstrate Lewy bodies. depletion of neurons of the substantia nigra, and involvement of hippocampal layers CA2-4. Although the basis for this association has yet to be elucidated, evidence continues to support the role of GBA as a PD risk factor across different centers, synucleinopathies, and ethnicities. Further studies of the association between GD and parkinsonism will stimulate new insights into the pathophysiology of the two disorders and will prove crucial for both genetic counseling of patients and family members and the design of relevant therapeutic strategies for specific patients with parkinsonism. (C) 2009 Movement Disorder Society C1 [DePaolo, John; Goker-Alpan, Ozlem; Samaddar, Ted; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Lopez, Grisel] NINDS, Off Clin Director, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU National Human Genome Research Institute; National Institutes of Health FX This work was Supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 51 TC 33 Z9 34 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2009 VL 24 IS 11 BP 1571 EP 1578 DI 10.1002/mds.22538 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 495YL UT WOS:000269931800002 PM 19425057 ER PT J AU Meltzer, JA Postman-Caucheteux, WA McArdle, JJ Braun, AR AF Meltzer, Jed A. Postman-Caucheteux, Whitney A. McArdle, Joseph J. Braun, Allen R. TI Strategies for longitudinal neuroimaging studies of overt language production SO NEUROIMAGE LA English DT Article ID TEST-RETEST RELIABILITY; LEXICAL ACCESS; FUNCTIONAL MRI; HEMODYNAMIC-RESPONSE; POSTSTROKE APHASIA; NONFLUENT APHASIA; SPEECH PRODUCTION; RIGHT-HEMISPHERE; ANOMIA TREATMENT; FRONTAL-CORTEX AB Longitudinal fMRI studies of language production are of interest for evaluating recovery from post-stroke aphasia, but numerous methodological issues remain unresolved, particularly regarding strategies for evaluating single subjects at multiple timepoints. To address these issues, we studied overt picture naming in eleven healthy subjects, scanned four times each at one-month intervals. To evaluate the natural variability present across repeated sessions, repeated scans were directly contrasted in a unified statistical framework on a per-voxel basis. The effect of stimulus familiarity was evaluated using explicitly overtrained pictures, novel pictures, and untrained pictures that were repeated across sessions. For untrained Pictures, we found that activation declined across multiple sessions, equally for both novel and repeated stimuli. Thus, no repetition priming for individual stimuli at one-month intervals was found, but rather a general effect of task habituation was present. Using a set of overtrained pictures identical in each session, no decline was found, but activation was minimized and produced less consistent patterns across participants, as measured by intra-class correlation coefficients. Subtraction of a baseline task, in which subjects produced a stereotyped utterance to scrambled pictures, resulted in specific activations in the left inferior frontal gyrus and other language areas for untrained items, while overlearned stimuli relative to pseudo pictures activated only the fusiform gyrus and supplementary motor area. These findings indicate that longitudinal fMRI is an effective means of detecting changes in neural activation magnitude over time, as long as the effect of task habituation is taken into account. Published by Elsevier Inc. C1 [Meltzer, Jed A.; McArdle, Joseph J.; Braun, Allen R.] Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. [Postman-Caucheteux, Whitney A.] Temple Univ, Dept Commun Sci & Disorders, Philadelphia, PA 19122 USA. RP Meltzer, JA (reprint author), Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 5C410, Bethesda, MD 20892 USA. EM jed.meltzer@aya.yale.edu OI Meltzer, Jed/0000-0002-4301-1901 FU National Institutes of Health FX This work was Supported by the Intramural Research Program of the National Institute for Deafness and Other Communication Disorders, National Institutes of Health. We thank Vladimir Nechaev for preparation of the pseudo picture stimuli, and Carla Wettig for technical assistance. NR 58 TC 21 Z9 21 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2009 VL 47 IS 2 BP 745 EP 755 DI 10.1016/j.neuroimage.2009.04.089 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 467QK UT WOS:000267756900035 PM 19427907 ER PT J AU Sepulcre, J Masdeu, JC Pastor, MA Goni, J Barbosa, C Bejarano, B Villoslada, P AF Sepulcre, Jorge Masdeu, Joseph C. Pastor, Maria A. Goni, Joaquin Barbosa, Carla Bejarano, Bartolome Villoslada, Pablo TI Brain pathways of verbal working memory A lesion-function correlation study SO NEUROIMAGE LA English DT Article DE Verbal working memory; White matter pathways; White matter lesions; Gray matter atrophy; Multiple sclerosis; Voxel-based morphometry ID PROGRESSIVE MULTIPLE-SCLEROSIS; MAGNETIC-RESONANCE; ACTIVATION PATTERNS; CORTICAL NETWORKS; MATTER DAMAGE; MRI; MS; NEUROPSYCHOLOGY; TRACTOGRAPHY; PERFORMANCE AB Working memory relies on information processing by several well-identified gray matter regions. However, the white matter regions and pathways involved in this cognitive process remain unknown. An attractive and underexplored approach to study white matter connectivity in cognitive functions is through the use of nonaprioristic models, which specifically search disrupted white matter pathways. For this purpose, we used voxel-based lesion-function mapping to correlate white matter lesions on the magnetic resonance images of 54 multiple sclerosis patients with their performance on a verbal working memory task. With this approach, we have identified critical white matter regions involved in verbal working memory in humans. They are located in the cingulum, parieto-frontal pathways and thalamo-cortical projections, with a left-sided predominance, as well as the right cerebellar white matter. Our study provides direct evidence on the white matter pathways subserving verbal working memory in the human brain. (C) 2009 Elsevier Inc. All rights reserved. C1 [Villoslada, Pablo] Hosp Clin Barcelona, IDIBAPS, Dept Neurosci, E-08036 Barcelona, Spain. [Sepulcre, Jorge; Masdeu, Joseph C.; Pastor, Maria A.; Barbosa, Carla; Bejarano, Bartolome; Villoslada, Pablo] Univ Navarra, Dept Neurol & Neurosurg, E-31080 Pamplona, Spain. [Sepulcre, Jorge; Masdeu, Joseph C.; Pastor, Maria A.; Goni, Joaquin; Villoslada, Pablo] Univ Navarra, Dept Neurosci, E-31080 Pamplona, Spain. [Masdeu, Joseph C.; Pastor, Maria A.] Univ Navarra, Neuroimaging Lab, E-31080 Pamplona, Spain. [Masdeu, Joseph C.; Pastor, Maria A.] Univ Navarra, Ctr Appl Med Res, E-31080 Pamplona, Spain. [Masdeu, Joseph C.] NIMH, Sect Integrat Neuroimaging, CBDB, NIH, Bethesda, MD 20892 USA. RP Villoslada, P (reprint author), Hosp Clin Barcelona, IDIBAPS, Dept Neurosci, Villarroel 170, E-08036 Barcelona, Spain. EM pvilloslada@clinic.ub.es OI Villoslada, Pablo/0000-0002-8735-6119 FU European Union [LSHB-CT-2005-512146]; Spanish Ministry of Health [05/00222, PI052520, PI051201]; Spanish Ministry of Education and Science [SAF200-07813]; Navarra Government; Basque Country Government; UTE project CIMA; Fundocion Uriach FX We wish to thank Prof. Joaquin Fuster (University of California in Los Angeles, USA), and Dra. Herminia Peraita (UNED, Spain), for their helpful comments. Prof. Alan J. Thompson and Dra. Mara Cercignam (Institute of Neurology, London, UIO for their help in the development of the VBM protocol for MS, and the Multiple Sclerosis Society of Navarra for their help with patient recruitment. The authors would like to acknowledge the support of the European Union (JM, FP6-project DiMl, LSHB-CT-2005-512146), the Spanish Ministry of Health (JS, CM#05/00222; JM, FIS#PI052520; and PV, FIS#PI051201), the Spanish Ministry of Education and Science (MAP, SAF200-07813), the Navarra Government (JG, MAP and JM), the Basque Country Government (NVM), the foundation "UTE project CIMA" (JS, JM, MAP and PV) and the Fundocion Uriach (PV). NR 53 TC 28 Z9 28 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2009 VL 47 IS 2 BP 773 EP 778 DI 10.1016/j.neuroimage.2009.04.054 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 467QK UT WOS:000267756900038 PM 19393745 ER PT J AU Minang, JT Trivett, MT Coren, LV Barsov, EV Piatak, M Ott, DE Ohlen, C AF Minang, Jacob T. Trivett, Matthew T. Coren, Lori V. Barsov, Eugene V. Piatak, Michael, Jr. Ott, David E. Ohlen, Claes TI Nef-mediated MHC class I down-regulation unmasks clonal differences in virus suppression by SIV-specific CD8(+) T cells independent of IFN-gamma and CD107a responses SO VIROLOGY LA English DT Article DE AIDS; Cytotoxic T cells; MHC class I; Nef; Virus suppression ID SIMIAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED CELLS; RHESUS-MONKEYS; LYMPHOCYTE RESPONSES; DISEASE PROGRESSION; HIV-1-SPECIFIC CTLS; VIRAL REPLICATION; TYPE-1 INFECTION; ESCAPE MUTATION; AIDS VACCINE AB CD8(+) T lymphocytes (CTL) play a role in controlling HIV/SIV infection. CTL antiviral activity is dependent on recognition of antigenic peptides associated with MHC class I molecules on infected target cells, and CTL activation can be impaired by Nef-mediated down-regulation of MHC class I molecules. We tested the ability of a series of rhesus macaque CD8(+) T-cell clones specific for the SIV Gag CM9 peptide to suppress SIV infection of autologous CD4(+) T cells. We used a set of SIV(mac)239 viruses with either wild-type Nef or Nef mutations that impair MHC class I down-regulation. All CTL clones efficiently suppressed virus replication in cells infected with mutant Viruses with altered Nef function, phenotypically MHC class I-high or MHC class I-intermediate. However, the ability of the clones to Suppress virus replication was variably reduced in the presence of wildtype Nef (MHC class I-low) despite the observations that all CTL clones showed similar IFN-gamma responses to titrated amounts of cognate peptide as well as to SIV-infected cells. In addition, the CTL clones showed variable CD107a (CTL degranulation marker) responses that did not Correlate with their capacity to suppress virus replication. Thus, the clonal differences are not attributable to TCR avidity or typical effector responses, and point to a potential as yet unknown mechanism for CTL-mediated suppression of viral replication. These data emphasize that current assays for evaluating CTL responses in infected or vaccinated individuals do not fully capture the complex requirements for effective CTL-mediated control of virus replication. (C) 2009 Elsevier Inc. All rights reserved. C1 [Minang, Jacob T.; Trivett, Matthew T.; Coren, Lori V.; Barsov, Eugene V.; Piatak, Michael, Jr.; Ott, David E.; Ohlen, Claes] NCI, SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick, MD 21702 USA. RP Ohlen, C (reprint author), NCI, SAIC Frederick Inc, AIDS & Canc Virus Program, POB B, Frederick, MD 21702 USA. EM cohlen@ncifcrf.gov FU National Institutes of Health [N01-CO-12400, HHSN261200800001E] FX The authors thank Dr. Jeffrey Lifson for the helpful discussions. The authors also thank Kelli Oswald and Lakeisha Galloway for their help with the viral load (QPCR) analyzes. The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, MAID, NIH: IL-2 from Hoffman-La Roche Inc., NJ SIVmac p27 Hybridoma (55-2F12) from Dr. Niels Pedersen. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, Under contract numbers N01-CO-12400 and HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. NR 66 TC 11 Z9 11 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD AUG 15 PY 2009 VL 391 IS 1 BP 130 EP 139 DI 10.1016/j.virol.2009.06.008 PG 10 WC Virology SC Virology GA 482DA UT WOS:000268863000016 PM 19555986 ER PT J AU Torimiro, JN Javanbakht, H Diaz-Griffero, F Kim, J Carr, JK Carrington, M Sawitzke, J Burke, DS Wolfe, ND Dean, M Sodroski, J AF Torimiro, Judith N. Javanbakht, Hassan Diaz-Griffero, Felipe Kim, Jonghwa Carr, Jean K. Carrington, Mary Sawitzke, Julie Burke, Donald S. Wolfe, Nathan D. Dean, Michael Sodroski, Joseph TI A rare null allele potentially encoding a dominant-negative TRIM5 alpha protein in Baka pygmies SO VIROLOGY LA English DT Article DE HIV-1; Susceptibility; Restriction factor; Cross-species transmission; Polymorphism; Mutant; Africa ID SIMIAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; RESTRICTION FACTOR TRIM5-ALPHA; HIV-1 GROUP-O; RETROVIRAL RESTRICTION; GENETIC DIVERSITY; SOOTY MANGABEYS; OLD-WORLD; B30.2(SPRY) DOMAIN; B30.2/SPRY DOMAIN AB The global acquired immunodeficiency syndrome (AIDS) pandemic is thought to have arisen by the transmission of human immunodeficiency virus (HIV-1)-like viruses from chimpanzees in southeastern Cameroon to humans. TRIM5 alpha is a restriction factor that can decrease the susceptibility of cells of particular mammalian species to retrovirus infection. A survey of TRIM5 genes in 127 indigenous individuals from southeastern Cameroon revealed that approximately 4% of the Baka pygmies studied were heterozygous for a rare variant with a stop codon in exon 8. The predicted product Of this allele, TRIM5 R332X, is truncated in the functionally important B30.2(SPRY) domain, does not restrict retrovirus infection, and acts as a dominant-negative inhibitor of wild-type human TRIM5 alpha. Thus, some indigenous African forest dwellers potentially exhibit diminished TRIM5 alpha function; such genetic factors, along with the high frequency of exposure to chimpanzee body fluids, may have predisposed to the initial cross-species transmission of HIV-1-like viruses. (C) 2009 Elsevier Inc. All rights reserved. C1 [Dean, Michael] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Torimiro, Judith N.] Univ Yaounde 1, Fac Med & Biomed Sci, Dept Biochem & Physiol Sci, Yaounde, Cameroon. [Torimiro, Judith N.] Chantal Biya Int Reference Ctr, Yaounde, Cameroon. [Javanbakht, Hassan; Diaz-Griffero, Felipe; Kim, Jonghwa; Sodroski, Joseph] Harvard Univ, Sch Med, Div AIDS, Dana Farber Canc Inst,Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Carr, Jean K.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Carrington, Mary; Sawitzke, Julie] NCI, SAIC Frederick Inc, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. [Burke, Donald S.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Wolfe, Nathan D.] Global Viral Forecasting Initiat, San Francisco, CA 94105 USA. [Wolfe, Nathan D.] Stanford Univ, Program Human Biol, Stanford, CA 94305 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Dean, M (reprint author), NCI, Canc & Inflammat Program, Bldg 560,Room 21-18, Frederick, MD 21702 USA. EM dean@ncifcrf.gov RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU Fogarty International Center/USNIH [2 D 43 TW000010-16 - AITRP]; National Institutes of Health [AI063987, AI076094, AI067854]; Center for AIDS Research Award [AI060354]; International AIDS Vaccine Initiative; Global Viral Forecasting Initiative; William F. McCarty-Cooper; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank Ms. Yvette McLaughlin and Ms. Elizabeth Carpelan for the preparation of the manuscript. This work has been Supported, in part, by a Fellowship/Grant from the Fogarty International Center/USNIH: Grant # 2 D 43 TW000010-16 - AITRP; by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center, for Cancer Research: by the National Institutes of Health (AI063987,AI076094, AI067854 and a Center for AIDS Research Award AI060354); by the International AIDS Vaccine Initiative; by the Global Viral Forecasting Initiative; and by the late William F. McCarty-Cooper. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 83 TC 5 Z9 5 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD AUG 15 PY 2009 VL 391 IS 1 BP 140 EP 147 DI 10.1016/j.virol.2009.05.038 PG 8 WC Virology SC Virology GA 482DA UT WOS:000268863000017 PM 19577266 ER PT J AU Zivna, M Hulkova, H Matignon, M Hodanova, K Vylet'al, P Kalbacova, M Baresova, V Sikora, J Blazkova, H Zivny, J Ivanek, R Stranecky, V Sovova, J Claes, K Lerut, E Fryns, JP Hart, PS Hart, TC Adams, JN Pawtowski, A Clemessy, M Gasc, JM Gubler, MC Antignac, C Elleder, M Kapp, K Grimbert, P Bleyer, AJ Kmoch, S AF Zivna, Martina Hulkova, Helena Matignon, Marie Hodanova, Katerina Vylet'al, Petr Kalbacova, Marie Baresova, Veronika Sikora, Jakub Blazkova, Hana Zivny, Jan Ivanek, Robert Stranecky, Viktor Sovova, Jana Claes, Kathleen Lerut, Evelyne Fryns, Jean-Pierre Hart, P. Suzanne Hart, Thomas C. Adams, Jeremy N. Pawtowski, Audrey Clemessy, Maud Gasc, Jean-Marie Guebler, Marie-Claire Antignac, Corinne Elleder, Milan Kapp, Katja Grimbert, Philippe Bleyer, Anthony J. Kmoch, Stanislav TI Dominant Renin Gene Mutations Associated with Early-Onset Hyperuricemia, Anemia, and Chronic Kidney Failure SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CARBONIC-ANHYDRASE-IV; GLOMERULAR-FILTRATION-RATE; SIGNAL SEQUENCE MUTATION; ENDOPLASMIC-RETICULUM; RETINITIS-PIGMENTOSA; ANGIOTENSIN SYSTEM; MOLECULAR-BASIS; APOPTOSIS; DISEASE; PROTEIN AB Through linkage analysis and candidate gene sequencing, we identified three unrelated families with the autosomal-dominant inheritance of early onset anemia, hypouricosuric hyperuricemia, progressive kidney failure, and mutations resulting either in the deletion (p.Leu16del) or the amino acid exchange (p.Leu16Arg) of a single leucine residue in the signal sequence of renin. Both mutations decrease signal sequence hydrophobicity and are predicted by bioinformatic analyses to damage targeting and cotranslational translocation of preprorenin into the endoplasmic reticulum (ER). Transfection and in vitro studies confirmed that both mutations affect ER translocation and processing of nascent preprorenin, resulting either in reduced (p.Leu16del) or abolished (p.Leu16Arg) prorenin and renin biosynthesis and secretion. Expression of renin and other components of the renin-angiotensin system was decreased accordingly in kidney biopsy specimens from affected individuals. Cells stably expressing the p.Leu16del protein showed activated ER stress, unfolded protein response, and reduced growth rate. It is likely that expression of the mutant proteins has a dominant toxic effect gradually reducing the viability of renin-expressing cells. This alters the intrarenal renin-angiotensin system and the juxtaglomerular apparatus functionality and leads to nephron dropout and progressive kidney failure. Our findings provide insight into the functionality of renin-angiotensin system and stress the importance of renin analysis in families and individuals with early onset hyperuricemia, anemia, and progressive kidney failure. C1 [Zivna, Martina; Hodanova, Katerina; Vylet'al, Petr; Kalbacova, Marie; Baresova, Veronika; Ivanek, Robert; Stranecky, Viktor; Elleder, Milan; Kmoch, Stanislav] Charles Univ Prague, Fac Med 1, Ctr Appl Genom, Prague 12000, Czech Republic. [Zivna, Martina; Hulkova, Helena; Hodanova, Katerina; Vylet'al, Petr; Kalbacova, Marie; Baresova, Veronika; Sikora, Jakub; Blazkova, Hana; Ivanek, Robert; Stranecky, Viktor; Sovova, Jana; Elleder, Milan; Kmoch, Stanislav] Charles Univ Prague, Fac Med 1, Inst Inherited Metab Disorders, Prague 12000, Czech Republic. [Zivny, Jan] Charles Univ Prague, Fac Med 1, Inst Pathophysiol, Prague 12000, Czech Republic. [Matignon, Marie; Grimbert, Philippe] Hop Henri Mondor, AP HP, Nephrol & Transplantat Unit, F-94010 Creteil, France. [Matignon, Marie; Grimbert, Philippe] Univ Paris 12, F-94010 Creteil, France. [Claes, Kathleen; Lerut, Evelyne] Univ Hosp Gasthuisberg, Dept Nephrol, B-3000 Louvain, Belgium. [Fryns, Jean-Pierre] Univ Leuven, Ctr Human Genet, B-3000 Leuven, Belgium. [Hart, P. Suzanne; Adams, Jeremy N.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Hart, Thomas C.] Natl Inst Dent & Craniofacial Res, Human Craniofacial Genet Sect, NIH, Bethesda, MD 20892 USA. [Pawtowski, Audrey; Antignac, Corinne] Hop Necker Enfants Malad, AP HP, Dept Genet, F-75015 Paris, France. [Guebler, Marie-Claire; Antignac, Corinne] Hop Necker Enfants Malad, INSERM, U574, F-75015 Paris, France. [Clemessy, Maud; Gasc, Jean-Marie] Coll France, INSERM, U833, F-75005 Paris, France. [Guebler, Marie-Claire; Antignac, Corinne] Univ Paris 05, Fac Med, F-75006 Paris, France. [Kapp, Katja] Univ Heidelberg, ZMBH Ctr Mol Biol Heidelberg, D-69120 Heidelberg, Germany. [Bleyer, Anthony J.] Wake Forest Univ, Bowman Gray Sch Med, Nephrol Sect, Winston Salem, NC 27157 USA. RP Kmoch, S (reprint author), Charles Univ Prague, Fac Med 1, Ctr Appl Genom, Prague 12000, Czech Republic. EM skmoch@lf1.cuni.cz RI Ivanek, Robert/A-8852-2008; Kmoch, Stanislav/C-1575-2010; Hanzlikova, Hana/G-6183-2014; Vyletal, Petr/F-4771-2017; Sikora, Jakub /F-4842-2017 OI Vyletal, Petr/0000-0002-9357-1237; Sikora, Jakub /0000-0003-4104-2023 FU Novartis Pharma [R3-36-16]; Grant Agency of Charles University of Prague [257672, 257750]; Ministry of Education of the Czech Republic [MSM0021620806, IM6837805002] FX We thank Gert Matthijs, Elly Pijkels, Vicki Robins, Sharon Moe, Concei ao Mota, and Fatima Torres for collection of biological materials and patient data, Olivier Gribouval for contribution to the genetic analysis, Maria Leidenberger and Klaus Meese for in vitro translation experiments, Zdena VernerovA for nephropathologic expertise, Novartis Pharma for R3-36-16 renin antibody, and Pierre Corvol and Genevieve Nguyen for pro/renin antibody. The authors report no conflict of interest. This work was supported by the Grant Agency of Charles University of Prague (projects 257672 and 257750). Institutional support was provided by the Ministry of Education of the Czech Republic (projects MSM0021620806 and IM6837805002). NR 36 TC 41 Z9 48 U1 1 U2 15 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 AUG 14 PY 2009 VL 85 IS 2 BP 204 EP 213 DI 10.1016/j.ajhg.2009.07.010 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 488EV UT WOS:000269332900009 PM 19664745 ER PT J AU Riazuddin, S Anwar, S Fischer, M Ahmed, ZM Khan, SY Janssen, AGH Zafar, AU Scholl, U Husnain, T Belyantseva, IA Friedman, PL Riazuddin, S Friedman, TB Fahlke, C AF Riazuddin, Saima Anwar, Saima Fischer, Martin Ahmed, Zubair M. Khan, Shahid Y. Janssen, Audrey G. H. Zafar, Ahmad U. Scholl, Ute Husnain, Tayyab Belyantseva, Inna A. Friedman, Penelope L. Riazuddin, Sheikh Friedman, Thomas B. Fahlke, Christoph TI Molecular Basis of DFNB73: Mutations of BSND Can Cause Nonsyndromic Deafness or Bartter Syndrome SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CLC-K CHANNELS; SENSORINEURAL DEAFNESS; CHLORIDE CHANNELS; BETA-SUBUNIT; MECHANISMS; FAILURE; DISEASE; VARIANT; IV AB BSND encodes barttin, an accessory Subunit of renal and inner ear chloride channels. To date, all Mutations of BSND have been shown to cause Bartter syndrome type IV, characterized by significant renal abnormalities and deafness. We identified a BSND mutation (p.I12T) in four kindreds segregating nonsyndromic deafness linked to a 4.04-cM interval on chromosome 1p32.3. The functional consequences of p.I12T differ from BSND Mutations that cause renal failure and deafness in Bartter syndrome type IV. p.I12T leaves chloride channel function unaffected and only interferes with chaperone function of barttin in intracellular trafficking. This study provides functional data implicating a hypomorphic allele of BSND as a cause of apparent nonsyndromic deafness. We demonstrate that BSND mutations with different functional consequences are the basis for either syndromic or nonsyndromic deafness. C1 [Fischer, Martin; Janssen, Audrey G. H.; Scholl, Ute; Fahlke, Christoph] Hannover Med Sch, Inst Neurophysiol, D-30625 Hannover, Germany. [Riazuddin, Saima; Ahmed, Zubair M.; Belyantseva, Inna A.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD 20850 USA. [Riazuddin, Saima; Ahmed, Zubair M.] Childrens Hosp Res Fdn, Div Pediat Otolaryngol Head & Neck Surg, Cincinnati, OH 45229 USA. [Riazuddin, Saima; Ahmed, Zubair M.] Childrens Hosp Res Fdn, Div Ophthalmol, Cincinnati, OH 45229 USA. [Anwar, Saima; Khan, Shahid Y.; Zafar, Ahmad U.; Husnain, Tayyab; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 54700, Pakistan. [Friedman, Penelope L.] NIH, Internal Med Consult Serv, Hatfield Clin Res Ctr, Bethesda, MD 21224 USA. [Fahlke, Christoph] Zentrum Syst Neurowissensch Hannover ZSN, D-30559 Hannover, Germany. RP Fahlke, C (reprint author), Hannover Med Sch, Inst Neurophysiol, D-30625 Hannover, Germany. EM fahlke.christoph@mh-hannover.de RI Fahlke, Christoph/G-3635-2013; Husnain, Tayyab/G-3805-2015; Anwar, Saima/C-7477-2016 OI Fahlke, Christoph/0000-0001-8602-9952; FU Higher Education Commission; Ministry of Science and Technology in Pakistan; Intramural Program of the NICD/National Institutes of Health [1 ZO1 DC000039-12]; DFG [301/8, 301/10] FX We thank the families for their participation and J. Ehrich, D. Ewers, E. Miranda, D. Nothmann, and D. Wojchiechowski, for helpful discussions. This study was supported by the Higher Education Commission and the Ministry of Science and Technology in Pakistan to S.R., the Intramural Program of the NICD/National Institutes of Health 1 ZO1 DC000039-12 to T.B.F. and the DFG (FA 301/8 and FA 301/10) to C.F. NR 21 TC 32 Z9 32 U1 0 U2 10 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 AUG 14 PY 2009 VL 85 IS 2 BP 273 EP 280 DI 10.1016/j.ajhg.2009.07.003 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 488EV UT WOS:000269332900016 PM 19646679 ER PT J AU Kanungo, J Zheng, YL Amin, ND Kaur, S Ramchandran, R Pant, HC AF Kanungo, Jyotshnabala Zheng, Ya-Li Amin, Niranjana D. Kaur, Sukhbir Ramchandran, Ramani Pant, Harish C. TI Specific inhibition of cyclin-dependent kinase 5 activity induces motor neuron development in vivo SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Motor neuron; Neurogenesis; Protein kinase; Morpholino knockdown; Zebrafish ID ADULT ZEBRAFISH BRAIN; SPINAL-CORD; NEURITE OUTGROWTH; NERVOUS-SYSTEM; STEM-CELLS; EXPRESSION; NEUROGENESIS; CDK5; DIFFERENTIATION; PROLIFERATION AB Cyclin-dependent kinase 5 (cdk5) is a ubiquitous protein activated by specific activators, p35 and p39. Cdk5 regulates neuronal migration, differentiation, axonogenesis, synaptic transmission and apoptosis. However, its role in motor neuron development remains unexplored. Here, using gain and loss-of-function analyses in developing zebrafish embryos, we report that cdk5 plays a critical role in spinal and cranial motor neuron development. Cdk5 knockdown results in supernumerary spinal and cranial motor neurons. While a dominant negative, kinase-dead cdk5 promotes the generation of supernumerary motor neurons; over-expression of cdk5 suppresses motor neuron development. Thus, modulating cdk5 activity seems promising in inducing motor neuron development in vivo. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kanungo, Jyotshnabala; Zheng, Ya-Li; Amin, Niranjana D.; Pant, Harish C.] NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Kaur, Sukhbir; Ramchandran, Ramani] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Ramchandran, Ramani] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. RP Kanungo, J (reprint author), NINDS, Neurochem Lab, NIH, 49 Convent Dr,Rm 2A35, Bethesda, MD 20892 USA. EM kanungoj@mail.nih.gov FU NIH (NINDS); NCI FX This work was supported by NIH (NINDS) intramural funds. R.R. is a recipient of the NCI Scholar Award. NR 32 TC 5 Z9 6 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 14 PY 2009 VL 386 IS 1 BP 263 EP 267 DI 10.1016/j.bbrc.2009.06.038 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 469BB UT WOS:000267868800050 PM 19523926 ER PT J AU De Souza, RF Iyer, LM Aravind, L AF De Souza, Robson F. Iyer, Lakshminarayan M. Aravind, L. TI The Anabaena sensory rhodopsin transducer defines a novel superfamily of prokaryotic small-molecule binding domains SO BIOLOGY DIRECT LA English DT Article ID STRUCTURE PREDICTION; DATABASE; SERVER AB The Anabaena sensory rhodopsin transducer (ASRT) is a small protein that has been claimed to function as a signaling molecule downstream of the cyanobacterial sensory rhodopsin. However, orthologs of ASRT have been detected in several bacteria that lack rhodopsin, raising questions about the generality of this function. Using sequence profile searches we show that ASRT defines a novel superfamily of beta-sandwich fold domains. Through contextual inference based on domain architectures and predicted operons and structural analysis we present strong evidence that these domains bind small molecules, most probably sugars. We propose that the intracellular versions like ASRT probably participate as sensors that regulate a diverse range of sugar metabolism operons or even the light sensory behavior in Anabaena by binding sugars or related metabolites. We also show that one of the extracellular versions define a predicted sugar-binding structure in a novel cell-surface lipoprotein found across actinobacteria, including several pathogens such as Tropheryma, Actinomyces and Thermobifida. The analysis of this superfamily also provides new data to investigate the evolution of carbohydrate binding modes in beta-sandwich domains with very different topologies. C1 [De Souza, Robson F.; Iyer, Lakshminarayan M.; Aravind, L.] Natl Ctr Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Ctr Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD 20894 USA. EM desouza@ncbi.nlm.nih.gov; lakshmin@ncbi.nlm.nih.gov; aravind@ncbi.nlm.nih.gov FU National Library of Medicine at the National Institutes of Health, USA. FX Work by the authors is supported by the intramural funds of the National Library of Medicine at the National Institutes of Health, USA. NR 17 TC 7 Z9 7 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD AUG 14 PY 2009 VL 4 AR 25 DI 10.1186/1745-6150-4-25 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 499LY UT WOS:000270223000001 PM 19682383 ER PT J AU Stoeckel, LE Kim, J Weller, RE Cox, JE Cook, EW Horwitz, B AF Stoeckel, Luke E. Kim, Jieun Weller, Rosalyn E. Cox, James E. Cook, Edwin W., III Horwitz, Barry TI Effective connectivity of a reward network in obese women SO BRAIN RESEARCH BULLETIN LA English DT Article DE Connectivity; Food cues; Obesity; Reward system ID POSITRON-EMISSION-TOMOGRAPHY; VENTRAL TEGMENTAL AREA; ORBITOFRONTAL CORTEX; NUCLEUS-ACCUMBENS; NEURAL SYSTEMS; BASOLATERAL AMYGDALA; TALAIRACH ATLAS; BASAL FOREBRAIN; SUBSTANCE-ABUSE; FOOD-INTAKE AB Exaggerated reactivity to food cues in obese women appears to be mediated in part by a hyperactive reward system that includes the nucleus accumbens, amygdala, and orbitofrontal cortex. The present study used functional magnetic resonance imaging (fMRI) to investigate whether differences between 12 obese and 12 normal-weight women in reward-related brain activation in response to food images can be explained by changes in the functional interactions between key reward network regions. A two-step path analysis/General Linear Model approach was used to test whether there were group differences in network connections between nucleus accumbens, amygdala, and orbitofrontal cortex in response to high- and low-calorie food images. There was abnormal connectivity in the obese group in response to both high- and low-calorie food cues compared to normal-weight controls. Compared to controls, the obese group had a relative deficiency in the amygdala's modulation of activation in both orbitofirontal cortex and nucleus accumbens, but excessive influence of orbitofrontal cortex's modulation of activation in nucleus accumbens. The deficient projections from the amygdala might relate to suboptimal modulation of the affective/emotional aspects of a food's reward value or an associated cue's motivational salience, whereas increased orbitofrontal cortex to nucleus accumbens connectivity might contribute to a heightened drive to eat in response to a food cue. Thus, it is possible that not only greater activation of the reward system, but also differences in the interaction of regions in this network may contribute to the relatively increased motivational value of foods in obese individuals. (C) 2009 Elsevier Inc. All rights reserved. C1 [Stoeckel, Luke E.; Weller, Rosalyn E.; Cox, James E.; Cook, Edwin W., III] Univ Alabama, Dept Psychol, Birmingham, AL 35294 USA. [Stoeckel, Luke E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Stoeckel, Luke E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kim, Jieun; Horwitz, Barry] NIDCD, Brain Imaging & Modeling Sect, NIH, Bethesda, MD USA. RP Stoeckel, LE (reprint author), 1 Bowdoin Sq,Suite 701,7th Floor, Boston, MA 02114 USA. EM lstoeckel@partners.org; kimjieun@nidcd.nih.gov; reweller@uab.edu; jecox@uab.edu; ecook@uab.edu; horwitzb@nidcd.nih.gov FU NIH-NIDCD Intramural Research Program; GCRC [M01 RR-00032]; National Center for Research Resources; Procter and Gamble Co.; UAB's Center for the Development of Functional Imaging (CDFI) FX Supported by the NIH-NIDCD Intramural Research Program, the GCRC grant M01 RR-00032 from the National Center for Research Resources, the Procter and Gamble Co., and resources of UAB's Center for the Development of Functional Imaging (CDFI). NR 85 TC 78 Z9 78 U1 2 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD AUG 14 PY 2009 VL 79 IS 6 BP 388 EP 395 DI 10.1016/j.brainresbull.2009.05.016 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 478UR UT WOS:000268614400008 PM 19467298 ER PT J AU Adams, P Kandiah, E Effantin, G Steven, AC Ehrenfeld, E AF Adams, Peter Kandiah, Eaazhisai Effantin, Gregory Steven, Alasdair C. Ehrenfeld, Ellie TI Poliovirus 2C Protein Forms Homo-oligomeric Structures Required for ATPase Activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSMISSION ELECTRON-MICROSCOPY; REPLICATIVE HEXAMERIC HELICASE; LARGE TUMOR-ANTIGEN; RNA REPLICATION; LINKAGE MAP; NONSTRUCTURAL PROTEINS; GUANIDINE-RESISTANT; AMPHIPATHIC HELIX; ESCHERICHIA-COLI; MEMBRANE-BINDING AB The poliovirus protein 2C plays an essential role in viral RNA replication, although its precise biochemical activities or structural requirements have not been elucidated. The protein has several distinctive properties, including ATPase activity and membrane and RNA binding, that are conserved among orthologs of many positive-strand RNA viruses. Sequence alignments have placed these proteins in the SF3 helicase family, a subset of the AAA+ ATPase superfamily. A feature common to AAA+ proteins is the formation of oligomeric rings that are essential for their catalytic functions. Here we show that a recombinant protein, MBP-2C, in which maltose-binding protein was fused to 2C, formed soluble oligomers and that ATPase activity was restricted to oligomer-containing fractions from gel-filtration chromatography. The active fraction was visualized by negative-staining electron microscopy as ring-like particles composed of 5-8 protomers. This conclusion was confirmed by mass measurements obtained by scanning transmission electron microscopy. Mutation of amino acid residues in the 2C nucleotide-binding domain demonstrated that loss of the ability to bind or hydrolyze ATP did not affect oligomerization. Co-expression of active MBP-2C and inactive mutant proteins generated mixed oligomers that exhibited little ATPase activity, suggesting that incorporation of inactive subunits eliminates the function of the entire particle. Finally, deletion of the N-terminal 38 amino acids blocked oligomerization of the fusion protein and eliminated ATPase activity, despite retention of an unaltered nucleotide-binding domain. C1 [Adams, Peter; Ehrenfeld, Ellie] NIAID, NIH, Bethesda, MD 20892 USA. [Kandiah, Eaazhisai; Effantin, Gregory; Steven, Alasdair C.] NIAMS, NIH, Bethesda, MD 20892 USA. RP Ehrenfeld, E (reprint author), NIAID, NIH, 50 South Dr,Room 6120, Bethesda, MD 20892 USA. EM eehrenfeld@niaid.nih.gov FU Intramural Research Programs of the NIAID; NIAMS; National Institutes of Health; NIH [5 P41 EB2181]; Department of Energy and Office of Biological and Environmental Research FX This work was supported by the Intramural Research Programs of the NIAID and NIAMS, National Institutes of Health. The Brookhaven National Laboratory STEM is a National Institutes of Health supported resource center, NIH 5 P41 EB2181, with additional support provided by the Department of Energy and Office of Biological and Environmental Research. NR 68 TC 21 Z9 23 U1 10 U2 35 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 14 PY 2009 VL 284 IS 33 BP 22012 EP 22021 DI 10.1074/jbc.M109.031807 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 481CE UT WOS:000268783700025 PM 19520852 ER PT J AU Mazar, J Thomas, M Bezrukov, L Chanturia, A Pekkurnaz, G Yin, SR Kuznetsov, SA Robey, PG Zimmerberg, J AF Mazar, Julia Thomas, Molly Bezrukov, Ludmila Chanturia, Alexander Pekkurnaz, Gulcin Yin, Shurong Kuznetsov, Sergei A. Robey, Pamela G. Zimmerberg, Joshua TI Cytotoxicity Mediated by the Fas Ligand (FasL)-activated Apoptotic Pathway in Stem Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BONE-MARROW CELLS; IMMUNE PRIVILEGE; IN-VITRO; LYMPHOCYTE-PROLIFERATION; T-CELLS; DIFFERENTIATION; DONOR; MECHANISM; SURVIVAL; LEUKEMIA AB Whereas it is now clear that human bone marrow stromal cells (BMSCs) can be immunosuppressive and escape cytotoxic lymphocytes (CTLs) in vitro and in vivo, the mechanisms of this phenomenon remain controversial. Here, we test the hypothesis that BMSCs suppress immune responses by Fas-mediated apoptosis of activated lymphocytes and find both Fas and FasL expression by primary BMSCs. Jurkat cells or activated lymphocytes were each killed by BMSCs after 72 h of co-incubation. In comparison, the cytotoxic effect of BMSCs on non-activated lymphocytes and on caspase-8(-/-) Jurkat cells was extremely low. Fas/Fc fusion protein strongly inhibited BMSC-induced lymphocyte apoptosis. Although we detected a high level of Fas expression in BMSCs, stimulation of Fas with anti-Fas antibody did not result in the expected BMSC apoptosis, regardless of concentration, suggesting a disruption of the Fas activation pathway. Thus BMSCs may have an endogenous mechanism to evade Fas-mediated apoptosis. Cumulatively, these data provide a parallel between adult stem/progenitor cells and cancer cells, consistent with the idea that stem/progenitor cells can use FasL to prevent lymphocyte attack by inducing lymphocyte apoptosis during the regeneration of injured tissues. C1 [Mazar, Julia; Thomas, Molly; Bezrukov, Ludmila; Chanturia, Alexander; Pekkurnaz, Gulcin; Yin, Shurong; Zimmerberg, Joshua] NICHD, Program Phys Biol, Bethesda, MD 20892 USA. [Kuznetsov, Sergei A.; Robey, Pamela G.] NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), NICHD, Program Phys Biol, Bethesda, MD 20892 USA. EM joshz@helix.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU NICHD; NIDCR; Department of Health and Human Services and Breast Cancer FX This work was supported, in whole or in part, by the National Institutes of Health intramural programs of the NICHD and NIDCR. This work was also supported by Department of Health and Human Services and Breast Cancer Stamp funds. NR 30 TC 24 Z9 25 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 14 PY 2009 VL 284 IS 33 BP 22022 EP 22028 DI 10.1074/jbc.M109.032235 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 481CE UT WOS:000268783700026 PM 19531476 ER PT J AU MacDonald, CJ Cheng, RYS Roberts, DD Wink, DA Yeh, GC AF MacDonald, Christopher J. Cheng, Robert Y. S. Roberts, David D. Wink, David A. Yeh, Grace Chao TI Modulation of Carcinogen Metabolism by Nitric Oxide-Aspirin 2 Is Associated with Suppression of DNA Damage and DNA Adduct Formation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ARYL-HYDROCARBON RECEPTOR; POLYCYCLIC AROMATIC-HYDROCARBONS; HUMAN GLUTATHIONE TRANSFERASES; CANCER CELL-LINES; DONATING ASPIRIN; IN-VITRO; HUMAN COLON; CARDIOVASCULAR EVENTS; MECHANISTIC ASSAYS AB Nitric oxide (NO)-donating non-steroidal anti-inflammatory drugs (NSAIDs) represent a promising new class of drugs developed to provide a safer alternative than their conventional NSAID counterparts in chemoprevention. We tested the effects of NO-aspirin 2 on Phase I and Phase II carcinogen-metabolizing enzymes. In HepG2 human hepatoma cells and in LS180 colonic adenocarcinoma cells, NO-aspirin 2 inhibited 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD)-induced cytochrome P450 (CYP) enzyme activity and CYP1A1 and CYP1A2 mRNA expression. These effects were further characterized as being mediated through transcriptional regulation: NO-aspirin 2 inhibited binding of ligand (TCDD)-activated aryl hydrocarbon receptor to the CYP1A1 enhancer sequence; additionally, NO-aspirin 2 suppressed carcinogen-induced expression of CYP1A heterogeneous nuclear RNA. The fate of carcinogen metabolites depends not only on activation by CYP enzymes but also detoxification by Phase II enzymes. Both HepG2 and LS180 cells treated with NO-aspirin 2 showed an increase in glutathione S-transferase-P1 (GST-P1), glutamate-cysteine ligase (GCL), and NAD(P)H:quinone oxidoreductase-1 (NQO1) expression. Compared with two other NO-releasing compounds, diethylenetriamine-NO and the organic nitrate, isosorbide dinitrate, the inhibitory effects of NO-aspirin 2 on TCDD-induced CYP activity and mRNA expression were considerably more potent. Furthermore, aspirin alone had no inhibitory effect on TCDD-induced CYP activity, nor did aspirin up-regulate GCL, GST-P1, or NQO1 expression. Consequent to the effects on carcinogen-metabolizing enzymes, NO-aspirin 2 inhibited [(3)H] benzo[ a] pyrene-DNA adduct formation and DNA damage elicited by TCDD or benzo[a] pyrene. Our results demonstrate that NO-aspirin 2 may be an effective chemopreventive agent by favorably affecting the inhibitory and enhancing effects of Phase I and Phase II carcinogen metabolism, thereby protecting DNA from carcinogenic insult. C1 [MacDonald, Christopher J.; Cheng, Robert Y. S.; Yeh, Grace Chao] NCI, Cellular Def & Carcinogenesis Sect, Lab Metab, NIH, Frederick, MD 21702 USA. [Roberts, David D.] NCI, Pathol Lab, NIH, Frederick, MD 21702 USA. [Wink, David A.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Yeh, GC (reprint author), NCI, NIH, Bldg 31,Rm 3A11,31 Ctr Dr, Bethesda, MD 20892 USA. EM yeh@ncifcrf.gov RI Roberts, David/A-9699-2008; OI Roberts, David/0000-0002-2481-2981; Cheng, Robert/0000-0003-0287-6439 NR 63 TC 14 Z9 14 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 14 PY 2009 VL 284 IS 33 BP 22099 EP 22107 DI 10.1074/jbc.M109.021063 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 481CE UT WOS:000268783700034 PM 19542225 ER PT J AU Duda, RL Ross, PD Cheng, NQ Firek, BA Hendrix, RW Conway, JF Steven, AC AF Duda, Robert L. Ross, Philip D. Cheng, Naiqian Firek, Brian A. Hendrix, Roger W. Conway, James F. Steven, Alasdair C. TI Structure and Energetics of Encapsidated DNA in Bacteriophage HK97 Studied by Scanning Calorimetry and Cryo-electron Microscopy SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE 3D image reconstruction; DNA condensation; head-full packaging; conformational changes; mechanosensor ID CROSS-LINKING; CRYO-EM; ANGSTROM RESOLUTION; VIRUS MATURATION; PORTAL PROTEIN; LAMBDA DNA; VISUALIZATION; TRANSITION; PARTICLES; DYNAMICS AB Encapsidation of duplex DNA by bacteriophages represents an extreme case of genome condensation, reaching near-crystalline concentrations of DNA. The HK97 system is well suited to study this phenomenon in view of the detailed knowledge of its capsid structure. To characterize the interactions involved, we combined calorimetry with cryo-electron microscopy and native gel electrophoresis. We found that, as in other phages, HK97 DNA is organized in coaxially wound nested shells. When DNA-filled capsids (heads) are scanned in buffer containing 1 mm Mg(2+), DNA melting and capsid denaturation both contribute to the complex thermal profile between 82 degrees C and 96 degrees C. In other conditions (absence of Mg(2+) and lower ionic strength), DNA melting shifts to lower temperatures and the two events are resolved. Heads release their DNA at temperatures well below the onset of DNA melting or capsid denaturation. We suggest that, on heating, the internal pressure increases, causing the DNA to exit-probably via the portal vertex-while the capsid, although largely intact, sustains local damage that leads to an earlier onset of thermal denaturation. Heads differ structurally from empty capsids in the curvature of their protein shell, a change attributable to outwards pressure exerted by the DNA. We propose that this transition is sensed by the portal that is embedded in the capsid wall, whereupon the structure of the portal and its interactions with terminase, the packaging enzyme, are altered, thus signaling that packaging is at or approaching completion. Published by Elsevier Ltd. C1 [Cheng, Naiqian; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, Bethesda, MD 20892 USA. [Duda, Robert L.; Firek, Brian A.; Hendrix, Roger W.] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. [Ross, Philip D.] NIDDKD, Mol Biol Lab, Bethesda, MD 20892 USA. [Conway, James F.] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov RI Conway, James/A-2296-2010 OI Conway, James/0000-0002-6581-4748 FU NIAMS; NIDDK; NIH [R01 GM47795] FX We thank Crystal Moyer for preparing capsids, Cassandra Edwards for help with the electrophoresis experiments, and Lih You for help with the figures. This work was supported by the Intramural Research Programs of NIAMS and NIDDK, and by NIH grant R01 GM47795 (to R.W.H.). NR 61 TC 27 Z9 27 U1 0 U2 9 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD AUG 14 PY 2009 VL 391 IS 2 BP 471 EP 483 DI 10.1016/j.jmb.2009.06.035 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 486VE UT WOS:000269227300018 PM 19540242 ER PT J AU Kang, H Jung, JW Kim, MK Chung, JH AF Kang, Hyeog Jung, Jae-Won Kim, Myung K. Chung, Jay H. TI CK2 Is the Regulator of SIRT1 Substrate-Binding Affinity, Deacetylase Activity and Cellular Response to DNA-Damage SO PLOS ONE LA English DT Article ID PROTEIN-KINASE CK2; DEPENDENT HISTONE DEACETYLASE; SACCHAROMYCES-CEREVISIAE; CALORIE RESTRICTION; GAMMA-RADIATION; P53; PHOSPHORYLATION; SURVIVAL; NAD; TUMORIGENESIS AB SIRT1, an NAD(+) (nicotinamide adenine dinucleotide)-dependent deacetylase, protects cells from stress-induced apoptosis, and its orthologues delay aging in lower eukaryotes. SIRT1 increases survival in response to stress such as DNA damage by deacetylating a number of substrates including pro-apoptotic protein p53. The molecular mechanism by which DNA-damage activates SIRT1 is not known. By screening a kinase inhibitor library, we identified CK2 as a SIRT1 kinase. CK2 is a pleiotropic kinase with more than 300 substrates and well-known anti-apoptotic and pro-growth activities. We find that CK2 is recruited to SIRT1 after ionizing radiation (IR) and phosphorylates conserved residues Ser 154, 649, 651 and 683 in the Nand C-terminal domains of mouse SIRT1. Phosphorylation of SIRT1 increases its deacetylation rate but not if the four Ser residues are mutated. In addition, phosphorylation of SIRT1 increases its substrate-binding affinity. CK2-mediated phosphorylation increases the ability of SIRT1 to deacetylate p53 and protect cells from apoptosis after DNA damage. Based on these findings, we propose that CK2 protects against IR-induced apoptosis partly by phosphorylating and activating SIRT1. Thus, this work suggests that SIRT1 is a component of the expansive anti-apoptotic network controlled by CK2. Since expression of both CK2 and SIRT1 is upregulated with tumorigenesis and downregulated with senescence, the CK2-SIRT1 link sheds new light on how CK2 may regulate cancer development and aging. C1 [Kang, Hyeog; Jung, Jae-Won; Kim, Myung K.; Chung, Jay H.] NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Kang, H (reprint author), NHLBI, Lab Biochem Genet, NIH, Bldg 10, Bethesda, MD 20892 USA. EM chungj@nhlbi.nih.gov FU National Heart Lung and Blood Institute, National Institutes of Health FX This work was supported by the Intramural Research Program, National Heart Lung and Blood Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 69 Z9 71 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2009 VL 4 IS 8 AR e6611 DI 10.1371/journal.pone.0006611 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 483BG UT WOS:000268936200001 PM 19680552 ER PT J AU Sharma, D Martineau, CN Le Dall, MT Reidy, M Masison, DC Kabani, M AF Sharma, Deepak Martineau, Celine N. Le Dall, Marie-Therese Reidy, Michael Masison, Daniel C. Kabani, Mehdi TI Function of SSA Subfamily of Hsp70 Within and Across Species Varies Widely in Complementing Saccharomyces cerevisiae Cell Growth and Prion Propagation SO PLOS ONE LA English DT Article ID HEAT-SHOCK-PROTEIN; TRANSMEMBRANE CONDUCTANCE REGULATOR; NUCLEOTIDE EXCHANGE FACTORS; ENDOPLASMIC-RETICULUM; MOLECULAR CHAPERONE; TRANSGENIC MICE; CYTOSOLIC HSP70; YEAST PRIONS; PSI+ PRION; IN-VITRO AB Background: The cytosol of most eukaryotic cells contains multiple highly conserved Hsp70 orthologs that differ mainly by their spatio-temporal expression patterns. Hsp70s play essential roles in protein folding, transport or degradation, and are major players of cellular quality control processes. However, while several reports suggest that specialized functions of Hsp70 orthologs were selected through evolution, few studies addressed systematically this issue. Methodology/Principal Findings: We compared the ability of Ssa1p-Ssa4p from Saccharomyces cerevisiae and Ssa5p-Ssa8p from the evolutionary distant yeast Yarrowia lipolytica to perform Hsp70-dependent tasks when expressed as the sole Hsp70 for S. cerevisiae in vivo. We show that Hsp70 isoforms (i) supported yeast viability yet with markedly different growth rates, (ii) influenced the propagation and stability of the [PSI(+)] and [URE3] prions, but iii) did not significantly affect the proteasomal degradation rate of CFTR. Additionally, we show that individual Hsp70 orthologs did not induce the formation of different prion strains, but rather influenced the aggregation properties of Sup35 in vivo. Finally, we show that [URE3] curing by the overexpression of Ydj1p is Hsp70-isoform dependent. Conclusion/Significance: Despite very high homology and overlapping functions, the different Hsp70 orthologs have evolved to possess distinct activities that are required to cope with different types of substrates or stress situations. Yeast prions provide a very sensitive model to uncover this functional specialization and to explore the intricate network of chaperone/co-chaperone/substrates interactions. C1 [Sharma, Deepak; Reidy, Michael; Masison, Daniel C.] Natl Inst Diabet Digest & Kidney Dis, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Martineau, Celine N.; Kabani, Mehdi] Ctr Natl Rech Sci, Lab Enzymol & Biochim Struct, Gif Sur Yvette, France. [Le Dall, Marie-Therese] AgroParisTech, Lab Microbiol & Genet Mol, Ctr Natl Rech Sci, Inst Natl Rech Agron, Thiverval Grignon, France. RP Sharma, D (reprint author), Natl Inst Diabet Digest & Kidney Dis, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM masisond@helix.nih.gov; Mehdi.Kabani@lebs.cnrs-gif.fr RI Kabani, Mehdi/G-7456-2012; OI Kabani, Mehdi/0000-0001-7440-6394; Reidy, Michael/0000-0002-9290-7595 FU Centre National de la Recherche Scientifique; National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health; French Cystic Fibrosis Foundation 'Vaincre la Mucoviscidose' [FC0518]; French Ministry of National Education, Research and Technology FX This work was supported by grants from the Centre National de la Recherche Scientifique (M. K.), the intramural program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health (D. C. M.), and by the French Cystic Fibrosis Foundation 'Vaincre la Mucoviscidose' research grant FC0518 (M. K.). C.N.M. is the beneficiary of a doctoral grant from the French Ministry of National Education, Research and Technology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 81 TC 21 Z9 22 U1 2 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 AUG 14 PY 2009 VL 4 IS 8 AR e6644 DI 10.1371/journal.pone.0006644 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 483BG UT WOS:000268936200010 PM 19680550 ER PT J AU Paukner, A Suomi, SJ Visalberghi, E Ferrari, PF AF Paukner, Annika Suomi, Stephen J. Visalberghi, Elisabetta Ferrari, Pier F. TI Capuchin Monkeys Display Affiliation Toward Humans Who Imitate Them SO SCIENCE LA English DT Article ID MIMICRY; RECOGNITION; SYNCHRONY; BEHAVIOR; RAPPORT AB During social interactions, humans often unconsciously and unintentionally imitate the behaviors of others, which increases rapport, liking, and empathy between interaction partners. This effect is thought to be an evolutionary adaptation that facilitates group living and may be shared with other primate species. Here, we show that capuchin monkeys, a highly social primate species, prefer human imitators over non-imitators in a variety of ways: The monkeys look longer at imitators, spend more time in proximity to imitators, and choose to interact more frequently with imitators in a token exchange task. These results demonstrate that imitation can promote affiliation in nonhuman primates. Behavior matching that leads to prosocial behaviors toward others may have been one of the mechanisms at the basis of altruistic behavioral tendencies in capuchins and in other primates, including humans. C1 [Paukner, Annika; Suomi, Stephen J.; Ferrari, Pier F.] Eunice Kennedy Shriver NICHHD, Comparat Ethol Lab, NIH, Anim Ctr, Poolesville, MD 20837 USA. [Visalberghi, Elisabetta] CNR, Ist Sci & Tecnol Cogniz, I-00197 Rome, Italy. [Ferrari, Pier F.] Univ Parma, Dipartimento Biol Evolut & Funz, I-43100 Parma, Italy. RP Paukner, A (reprint author), Eunice Kennedy Shriver NICHHD, Comparat Ethol Lab, NIH, Anim Ctr, POB 529, Poolesville, MD 20837 USA. EM pauknera@mail.nih.gov OI Visalberghi, Elisabetta/0000-0001-7407-5468 FU Division of Intramural Research; National Institute of Child Health and Human Development; ECT ESF The Evolution of Cooperation and Trading European Science Foundation project SOCCOP FX This research was supported by the Division of Intramural Research, National Institute of Child Health and Human Development, and the TECT ESF The Evolution of Cooperation and Trading European Science Foundation project SOCCOP The Social and Mental Dynamics of Cooperation. NR 21 TC 75 Z9 77 U1 2 U2 30 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 14 PY 2009 VL 325 IS 5942 BP 880 EP 883 DI 10.1126/science.1176269 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 487AK UT WOS:000269242400048 PM 19679816 ER PT J AU Hakim, FT AF Hakim, Frances T. TI TRECing long-term success in SCID SO BLOOD LA English DT Editorial Material ID STEM-CELL TRANSPLANTATION; SEVERE COMBINED IMMUNODEFICIENCY; RECONSTITUTION C1 NCI, Bethesda, MD 20892 USA. RP Hakim, FT (reprint author), NCI, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 13 PY 2009 VL 114 IS 7 BP 1287 EP 1288 DI 10.1182/blood-2009-06-223495 PG 4 WC Hematology SC Hematology GA 482XT UT WOS:000268924700005 PM 19679699 ER PT J AU Ghosh, MC Collins, GD Vandanmagsar, B Patel, K Brill, M Carter, A Lustig, A Becker, KG Wood, WW Emeche, CD French, AD O'Connell, MP Xu, M Weeraratna, AT Taub, DD AF Ghosh, Manik C. Collins, Gary D. Vandanmagsar, Bolormaa Patel, Kalpesh Brill, Margaret Carter, Arnell Lustig, Ana Becker, Kevin G. Wood, William W., III Emeche, Chineye D. French, Amanda D. O'Connell, Michael P. Xu, Mai Weeraratna, Ashani T. Taub, Dennis D. TI Activation of Wnt5A signaling is required for CXC chemokine ligand 12-mediated T-cell migration SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; TUMOR-SUPPRESSOR; PATHWAY; RECEPTORS; MELANOMA; HEMATOPOIESIS; MALIGNANCIES; METASTASIS; EXPRESSION; MOTILITY AB Chemokines mediate the signaling and migration of T cells, but little is known about the transcriptional events involved therein. Microarray analysis of CXC chemokine ligand (CXCL) 12-treated T cells revealed that Wnt ligands are significantly up-regulated during CXCL12 treatment. Real-time polymerase chain reaction and Western blot analysis confirmed that the expression of noncanonical Wnt pathway members (eg, Wnt5A) was specifically up-regulated during CXCL12 stimulation, whereas beta-catenin and canonical Wnt family members were selectively down-regulated. Wnt5A augmented signaling through the CXCL12-CXCR4 axis via the activation of protein kinase C. Moreover, Wnt5A expression was required for CXCL12-mediated T-cell migration, and rWnt5A sensitized human T cells to CXCL12-induced migration. Furthermore, Wnt5A expression was also required for the sustained expression of CXCR4. These results were further supported in vivo using EL4 thymoma metastasis as a model of T-cell migration. Together, these data demonstrate that Wnt5A is a critical mediator of CXCL12-CXCR4 signaling and migration in human and murine T cells. (Blood. 2009;114:1366-1373) C1 [Weeraratna, Ashani T.] NIA, Immunol Lab, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Becker, Kevin G.; Wood, William W., III] NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. RP Weeraratna, AT (reprint author), NIA, Immunol Lab, NIH, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM weerarat@grc.nia.nih.gov; taubd@grc.nia.nih.gov RI Patel, Kalpesh/G-6685-2012; OI Patel, Kalpesh/0000-0002-2952-6773; Becker, Kevin/0000-0002-6794-6656 FU National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 26 TC 26 Z9 26 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 13 PY 2009 VL 114 IS 7 BP 1366 EP 1373 DI 10.1182/blood-2008-08-175869 PG 8 WC Hematology SC Hematology GA 482XT UT WOS:000268924700015 PM 19520808 ER PT J AU Munayco, CV Gomez, J Laguna-Torres, VA Arrasco, J Kochel, TJ Fiestas, V Garcia, J Perez, J Torres, I Condori, F Nishiura, H Chowell, G AF Munayco, C. V. Gomez, J. Laguna-Torres, V. A. Arrasco, J. Kochel, T. J. Fiestas, V. Garcia, J. Perez, J. Torres, I. Condori, F. Nishiura, H. Chowell, G. TI EPIDEMIOLOGICAL AND TRANSMISSIBILITY ANALYSIS OF INFLUENZA A(H1N1)V IN A SOUTHERN HEMISPHERE SETTING: PERU SO EUROSURVEILLANCE LA English DT Article AB We present a preliminary analysis of 1,771 confirmed cases of influenza A(H1N1)v reported in Peru by 17 July 2009 including the frequency of the clinical characteristics, the spatial and age distribution of the cases and the estimate of the transmission potential. Age-specific frequency of cases was highest among school age children and young adults, with the lowest frequency of cases among seniors, a pattern that is consistent with reports from other countries. Estimates of the reproduction number lie in the range of 1.2 to 1.7, which is broadly consistent with previous estimates for this pandemic in other regions. Validation of these estimates will be possible as additional data become available. C1 [Munayco, C. V.; Gomez, J.; Arrasco, J.] Peru Minist Hlth, Direcc Gen Epidemiol, Lima, Peru. [Laguna-Torres, V. A.; Kochel, T. J.; Garcia, J.; Perez, J.] USN, Med Res Ctr Detachment, Lima, Peru. [Fiestas, V.; Torres, I.; Condori, F.] NIH, Lima, Peru. [Nishiura, H.] Univ Utrecht, Utrecht, Netherlands. [Chowell, G.] Arizona State Univ, Sch Human Evolut & Social Change, Math & Computat Modeling Sci Ctr, Tempe, AZ USA. [Chowell, G.] NIH, Div Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Munayco, CV (reprint author), Peru Minist Hlth, Direcc Gen Epidemiol, Lima, Peru. EM cmunayco@dge.gob.pe RI Munayco, Cesar/G-9990-2013; Chowell, Gerardo/F-5038-2012 OI Munayco, Cesar/0000-0001-7872-8913; Chowell, Gerardo/0000-0003-2194-2251 NR 13 TC 20 Z9 21 U1 2 U2 6 PU EUR CENTRE DIS PREVENTION & CONTROL PI STOCKHOLM PA TOMTEBODAVAGEN 11A, STOCKHOLM, 171 83, SWEDEN SN 1560-7917 J9 EUROSURVEILLANCE JI Eurosurveillance PD AUG 13 PY 2009 VL 14 IS 32 BP 6 EP 10 AR 19299 PG 5 WC Infectious Diseases SC Infectious Diseases GA 515IG UT WOS:000271462800002 ER PT J AU Chang, YH Hsu, MH Wang, SH Huang, LJ Qian, K Morris-Natschke, SL Hamel, E Kuo, SC Lee, KH AF Chang, Yu-Hsun Hsu, Mei-Hua Wang, Sheng-Hung Huang, Li-Jiau Qian, Keduo Morris-Natschke, Susan L. Hamel, Ernest Kuo, Sheng-Chu Lee, Kuo-Hsiung TI Design and Synthesis of 2-(3-Benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one Analogues as Potent Antitumor Agents that Inhibit Tubulin Assembly SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BIOLOGICAL EVALUATION; ANTIMITOTIC AGENTS; ANTIMICROTUBULE AGENTS; POLYMERIZATION; CYTOTOXICITY; CELLS; 2-PHENYL-4-QUINOLONE; DERIVATIVES; COLCHICINE; APOPTOSIS AB As part of our continuing investigation of azo-flavonoid derivatives as potential anticancer drug candidates, a series of 2-aryl-6,7-methylenedioxyquinolin-4-one analogues was designed and synthesized. The design combined structural features of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-1), a previously discovered compound with potent in vivo antitumor activity, and 2-arylquinolin-4-ones, identified by CoMFA models, The newly synthesized analogues were evaluated for cytotoxicity against seven human cancer cell lines, and structure-activity relationship (SAR) correlations were established. Analogues 1, 37, and 39 showed potent cytotoxicity against different cancer cell lines. Compound I demonstrated selective cytotoxicity against Hep 3B (hepatoma) cells. Compound 37 was cytotoxic against HL-60 (leukemia), HCT-116 (colon cancer), Hep 3B (hepatoma), and SK-MEL-5 (melanoma) cells. Compound 39 exhibited broad cytotoxicity against all seven cancer cell lines, with IC(50) values between 0.07and 0.19 mu M. Results from mechanism of action studies revealed that these new quinolone derivatives function as antitubulin agents. C1 [Chang, Yu-Hsun; Hsu, Mei-Hua; Huang, Li-Jiau; Kuo, Sheng-Chu] China Med Univ, Grad Inst Pharmaceut Chem, Taichung, Taiwan. [Wang, Sheng-Hung] Acad Sinica, Inst Cellular & Organism Biol, Taipei 115, Taiwan. [Qian, Keduo; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung] Univ N Carolina, Sch Pharm, UNC Eshelman, Nat Prod Res Labs, Chapel Hill, NC 27599 USA. [Hamel, Ernest] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Kuo, SC (reprint author), China Med Univ, Grad Inst Pharmaceut Chem, Taichung, Taiwan. EM sckuo@mail.cmu.edu.tw; khlee@email.unc.edu FU National Science Council of the Republic of China [NSC 96-2323-B-039-001, NSC 97-2323-B-039-001]; National Cancer Institute, NIH [CA 17625] FX We acknowledge special appreciation and esteern for support received from Wen-Chill Chang, who passed away because of nasopharyngeal carcinoma before this paper was completed. The investigation was supported by research grants frorn the National Science Council of the Republic of China (NSC 96-2323-B-039-001 and NSC 97-2323-B-039-001) awarded to S. C. Kuo. Thanks are also due to support (in part) by grant CA 17625 from the National Cancer Institute, NIH (K. H. Lee). NR 29 TC 19 Z9 25 U1 2 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 13 PY 2009 VL 52 IS 15 BP 4883 EP 4891 DI 10.1021/jm900456w PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 479LT UT WOS:000268661600031 PM 19719238 ER PT J AU Cheng, N Tsunenari, T Yau, KW AF Cheng, Ning Tsunenari, Takashi Yau, King-Wai TI Intrinsic light response of retinal horizontal cells of teleosts SO NATURE LA English DT Article ID SUSTAINED CALCIUM CURRENT; GAMMA-AMINOBUTYRIC-ACID; GANGLION-CELLS; MELANOPSIN; OPSIN; MODULATION; RECEPTORS; ZEBRAFISH; GOLDFISH; TISSUE AB The discovery of intrinsically photosensitive retinal ganglion cells has overthrown the long-held belief that rods and cones are the exclusive retinal photoreceptors(1,2). Intrinsically photosensitive retinal ganglion cells use melanopsin(3) as the photopigment, and mediate non-image-forming visual functions such as circadian photoentrainment. In fish, in situ hybridization studies indicated that melanopsin is present in retinal horizontal cells(4-6)-lateral association neurons critical for creating the centre-surround receptive fields of visual neurons. This raises the question of whether fish horizontal cells are intrinsically photosensitive. This notion was examined previously in flat-mount roach retina, but all horizontal-cell light response disappeared after synaptic transmission was blocked(6), making any conclusion difficult to reach. To examine this question directly, we have now recorded from single, acutely dissociated horizontal cells from catfish and goldfish. We found that light induced a response in catfish cone horizontal cells, but not rod horizontal cells, consisting of a modulation of the nifedipine-sensitive, voltage-gated calcium current. The light response was extremely slow, lasting for many minutes. Similar light responses were observed in a high percentage of goldfish horizontal cells. We have cloned two melanopsin genes and one vertebrate ancient (VA) opsin gene from catfish. In situ hybridization indicated that melanopsin, but less likely VA opsin, was expressed in the horizontal-cell layer of catfish retina. This intrinsic light response may serve to modulate, over a long time-scale, lateral inhibition mediated by these cells. Thus, at least in some vertebrates, there are retinal non-rod/non-cone photoreceptors involved primarily in image-forming vision. C1 [Cheng, Ning; Tsunenari, Takashi; Yau, King-Wai] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. [Cheng, Ning; Tsunenari, Takashi; Yau, King-Wai] Johns Hopkins Univ, Sch Med, Ctr Sensory Biol, Baltimore, MD 21205 USA. [Yau, King-Wai] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. RP Cheng, N (reprint author), NINDS, Unit Dev Neural Plast, NIH, Bethesda, MD 20892 USA. EM chengn2@mail.nih.gov; kwyau@mail.jhmi.edu FU NIH; Antonio Champalimaud Vision Award (Portugal) FX This work was supported by an NIH grant and the Antonio Champalimaud Vision Award (Portugal) to K.-W. Y. We thank R. Johnson, C. Liu and D. Liu for advice on molecular cloning and in situ hybridization staining, Y. Shen, C. Linn and G. Matthews for suggestions on retinal dissociation. D. Bergles, P. Fuchs and J. Nathans offered comments throughout the work. L. Belluscio let N. C. take a brief leave of absence from her postdoctoral work to return to Hopkins in order to complete some experiments. Members of the Yau laboratory, especially M. Do and D.-G. Luo, as well as K. Murari, have provided comments on the manuscript. NR 30 TC 29 Z9 30 U1 1 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 13 PY 2009 VL 460 IS 7257 BP 899 EP U139 DI 10.1038/nature08175 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 483CB UT WOS:000268938300040 PM 19633653 ER PT J AU Palazzolo, I Stack, C Kong, LL Musaro, A Adachi, H Katsuno, M Sobue, G Taylor, JP Sumner, CJ Fischbeck, KH Pennuto, M AF Palazzolo, Isabella Stack, Conor Kong, Lingling Musaro, Antonio Adachi, Hiroaki Katsuno, Masahisa Sobue, Gen Taylor, J. Paul Sumner, Charlotte J. Fischbeck, Kenneth H. Pennuto, Maria TI Overexpression of IGF-1 in Muscle Attenuates Disease in a Mouse Model of Spinal and Bulbar Muscular Atrophy SO NEURON LA English DT Article ID GROWTH-FACTOR-I; FOXO TRANSCRIPTION FACTORS; ANDROGEN RECEPTOR; SKELETAL-MUSCLE; KENNEDY-DISEASE; INSULIN; EXPRESSION; HYPERTROPHY; SURVIVAL; DEGRADATION AB Expansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We previously showed that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the mutant AR toxicity. Here, we show that in culture insulin-like growth factor 1 (IGF-1) reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome system through phosphorylation of AR by Akt. In vivo, SBMA transgenic mice overexpressing a muscle-specific isoform of IGF-1 selectively in skeletal muscle show evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescues behavioral and histopathological abnormalities, extends the life span, and reduces both muscle and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated inactivation of mutant AR as a strategy to counteract disease in vivo and demonstrates that skeletal muscle is a viable target tissue for therapeutic intervention in SBMA. C1 [Pennuto, Maria] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Palazzolo, Isabella; Stack, Conor; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Palazzolo, Isabella] Univ Milan, Ist Endocrinol, I-20133 Milan, Italy. [Kong, Lingling; Sumner, Charlotte J.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Musaro, Antonio] Univ Roma La Sapienza, Inst Pasteur Cenci Bolognetti, Dept Histol & Med Embryol, IIM, I-00161 Rome, Italy. [Adachi, Hiroaki; Katsuno, Masahisa; Sobue, Gen] Nagoya Univ, Grad Sch Med, Dept Neurol, Nagoya, Aichi 4668550, Japan. [Katsuno, Masahisa] Nagoya Univ, Inst Adv Res, Nagoya, Aichi 4668550, Japan. [Taylor, J. Paul] St Jude Childrens Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. [Pennuto, Maria] Italian Inst Technol, Dept Neurosci & Brain Technol, I-16163 Genoa, Italy. RP Pennuto, M (reprint author), Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. EM maria.pennuto@iit.it RI Adachi, Hiroaki/I-2669-2012; Katsuno, Masahisa/I-7502-2014; Musaro, Antonio/K-9598-2016; OI Adachi, Hiroaki/0000-0002-9302-4663; Musaro, Antonio/0000-0002-2944-9739; Pennuto, Maria/0000-0001-8634-0767 FU NINDS; Telethon-Italy [GFP04005]; Kennedy's Disease Association; Muscular Dystrophy Association; NIH [NS053825] FX We thank G. Harmison for skillful technical assistance, Dr. S. Ranganathan and the other members of Dr. Fischbeck's lab for advice and discussion, Dr. A. Lieberman for providing us with control tissue samples, Dr. J. Crawley for advice about mouse behavioral studies, Drs. L. Wrabetz and S. Previtali for kindly providing us with muscle samples from denervated mice, Dr A. Antignani for instructions for size-exclusion chromatography, and Dr. F. Sambataro for statistical analysis. This work was supported by NINDS intramural funds and by grants from Telethon-Italy (GFP04005, M.P.; A.M.), the Kennedy's Disease Association (M.P.), Muscular Dystrophy Association (Development Grant, M.P.; Research Grant, J.P.T.), and the NIH (NS053825, J.P.T.). NR 50 TC 101 Z9 101 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 13 PY 2009 VL 63 IS 3 BP 316 EP 328 DI 10.1016/j.neuron.2009.07.019 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 487OY UT WOS:000269285500007 PM 19679072 ER PT J AU Chowell, G Bertozzi, SM Colchero, MA Lopez-Gatell, H Alpuche-Aranda, C Hernandez, M Miller, MA AF Chowell, Gerardo Bertozzi, Stefano M. Colchero, M. Arantxa Lopez-Gatell, Hugo Alpuche-Aranda, Celia Hernandez, Mauricio Miller, Mark A. TI Severe Respiratory Disease Concurrent with the Circulation of H1N1 Influenza SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID EPIDEMIOLOGIC EVIDENCE; UNITED-STATES; MORTALITY; ENGLAND; WALES; WAVE AB Background In the spring of 2009, an outbreak of severe pneumonia was reported in conjunction with the concurrent isolation of a novel swine-origin influenza A (H1N1) virus (S-OIV), widely known as swine flu, in Mexico. Influenza A (H1N1) subtype viruses have rarely predominated since the 1957 pandemic. The analysis of epidemic pneumonia in the absence of routine diagnostic tests can provide information about risk factors for severe disease from this virus and prospects for its control. Methods From March 24 to April 29, 2009, a total of 2155 cases of severe pneumonia, involving 821 hospitalizations and 100 deaths, were reported to the Mexican Ministry of Health. During this period, of the 8817 nasopharyngeal specimens that were submitted to the National Epidemiological Reference Laboratory, 2582 were positive for S-OIV. We compared the age distribution of patients who were reported to have severe pneumonia with that during recent influenza epidemics to document an age shift in rates of death and illness. Results During the study period, 87% of deaths and 71% of cases of severe pneumonia involved patients between the ages of 5 and 59 years, as compared with average rates of 17% and 32%, respectively, in that age group during the referent periods. Features of this epidemic were similar to those of past influenza pandemics in that circulation of the new influenza virus was associated with an off-season wave of disease affecting a younger population. Conclusions During the early phase of this influenza pandemic, there was a sudden increase in the rate of severe pneumonia and a shift in the age distribution of patients with such illness, which was reminiscent of past pandemics and suggested relative protection for persons who were exposed to H1N1 strains during childhood before the 1957 pandemic. If resources or vaccine supplies are limited, these findings suggest a rationale for focusing prevention efforts on younger populations. C1 [Chowell, Gerardo; Miller, Mark A.] NIH, Fogarty Int Ctr, Div Epidemiol & Populat Studies, Bethesda, MD 20892 USA. [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Tempe, AZ USA. [Bertozzi, Stefano M.; Colchero, M. Arantxa] Inst Nacl Salud Publ, Ctr Evaluat Res & Surveys, Cuernavaca 62100, Morelos, Mexico. [Bertozzi, Stefano M.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Lopez-Gatell, Hugo; Alpuche-Aranda, Celia; Hernandez, Mauricio] Mexican Minist Hlth, Mexico City, DF, Mexico. RP Bertozzi, SM (reprint author), Inst Nacl Salud Publ, Ctr Evaluat Res & Surveys, Av Univ 655, Cuernavaca 62100, Morelos, Mexico. EM sbertozzi@correo.insp.mx RI Chowell, Gerardo/A-4397-2008; Chowell, Gerardo/F-5038-2012 OI Chowell, Gerardo/0000-0003-2194-2251 FU Ministry of Health of Mexico; Mexican National Institute of Public Health; Fogarty International Center of the National Institutes of Health FX Supported by the Ministry of Health of Mexico, the Mexican National Institute of Public Health, and the Fogarty International Center of the National Institutes of Health. NR 22 TC 410 Z9 446 U1 5 U2 49 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 13 PY 2009 VL 361 IS 7 BP 674 EP 679 DI 10.1056/NEJMoa0904023 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 482JX UT WOS:000268884100007 PM 19564633 ER PT J AU Koenigs, M Grafman, J AF Koenigs, Michael Grafman, Jordan TI The functional neuroanatomy of depression: Distinct roles for ventromedial and dorsolateral prefrontal cortex SO BEHAVIOURAL BRAIN RESEARCH LA English DT Review DE Depression; Ventromedial prefrontal cortex; Dorsolateral prefrontal cortex ID STEREOTACTIC SUBCAUDATE TRACTOTOMY; ORBITOFRONTAL CORTEX; UNIPOLAR DEPRESSION; MAJOR DEPRESSION; VOLUNTARY SUPPRESSION; RESISTANT DEPRESSION; NEGATIVE AFFECT; EMOTION; DAMAGE; DISTURBANCES AB A primary aim in the neuroscientific study of depression is to identify the brain areas involved in the pathogenesis of symptoms. In this review, we describe evidence from studies employing various experimental approaches in humans (functional imaging, lesion method, and brain stimulation) that converge to implicate the ventromedial and dorsolateral sectors of prefrontal cortex as critical neural substrates for depression, albeit with distinct functional contributions. The putative roles of ventromedial and dorsolateral prefrontal cortex in depression are discussed in light of the results. (C) 2009 Elsevier B.V. All rights reserved. C1 [Koenigs, Michael] Univ Wisconsin, Dept Psychiat, Madison, WI 53719 USA. [Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Koenigs, M (reprint author), Univ Wisconsin, Dept Psychiat, 6001 Res Pk Blvd, Madison, WI 53719 USA. EM mrkoenigs@wisc.edu; grafmanj@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457; Koenigs, Michael/0000-0002-5799-4881 FU National Institute of Neurological Disorders and Stroke intramural research program [DAMD17-01-1-0675] FX This work was supported in part by the National Institute of Neurological Disorders and Stroke intramural research program, DAMD17-01-1-0675 (J.G.). NR 40 TC 233 Z9 244 U1 7 U2 35 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 AUG 12 PY 2009 VL 201 IS 2 BP 239 EP 243 DI 10.1016/j.bbr.2009.03.004 PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 452BG UT WOS:000266514000001 PM 19428640 ER PT J AU Stone, B Lipkowitz, S AF Stone, Brandon Lipkowitz, Stanley TI Pumpfrage redivivus SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID ART C1 [Stone, Brandon] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. [Lipkowitz, Stanley] NCI, Bethesda, MD 20892 USA. RP Stone, B (reprint author), Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. EM lipkowis@mail.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 12 PY 2009 VL 302 IS 6 BP 626 EP 626 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 481ZI UT WOS:000268852300019 PM 19671903 ER PT J AU Morens, DM Taubenberger, JK AF Morens, David M. Taubenberger, Jeffery K. TI Understanding Influenza Backward SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID VIRUS C1 [Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Morens, David M.] NIAID, Off Director, NIH, Bethesda, MD 20892 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, 33 North Dr, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU Intramural NIH HHS [ZIA AI000995-03] NR 10 TC 20 Z9 20 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 AUG 12 PY 2009 VL 302 IS 6 BP 679 EP 680 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 481ZI UT WOS:000268852300027 PM 19671909 ER PT J AU Vogel-Claussen, J Skrok, J Fishman, EK Lima, JAC Shah, AS Bluemke, DA AF Vogel-Claussen, Jens Skrok, Jan Fishman, Elliot K. Lima, Joao A. C. Shah, Ashish S. Bluemke, David A. TI Cardiac CT and MRI guide surgery in impending left ventricular rupture after acute myocardial infarction SO JOURNAL OF CARDIOTHORACIC SURGERY LA English DT Article ID SUBEPICARDIAL ANEURYSM; PSEUDOANEURYSM AB We report the case of a 67 year-old patient who presented with worsening chest pain and shortness of breath, four days post acute myocardial infarction. Contrast enhanced computed tomography of the chest ruled out a pulmonary embolus but revealed an unexpected small subepicardial aneurysm (SEA) in the lateral left ventricular wall which was confirmed on cardiac magnetic resonance imaging. Intraoperative palpation of the left lateral wall was guided by the cardiac MRI and CT findings and confirmed the presence of focally thinned and weakened myocardium, covered by epicardial fat. An aneurysmorrhaphy was subsequently performed in addition to coronary bypass surgery and a mitral valve repair. The patient was discharged home on post operative day eight in good condition and is feeling well 2 years after surgery. C1 [Vogel-Claussen, Jens; Skrok, Jan; Fishman, Elliot K.] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21218 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Dept Cardiol, Baltimore, MD USA. [Shah, Ashish S.] Johns Hopkins Univ, Sch Med, Dept Surg, Div Cardiac Surg, Baltimore, MD USA. [Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Vogel-Claussen, J (reprint author), Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21218 USA. EM jclauss1@jhmi.edu; jskrok1@jhmi.edu; efishman@jhmi.edu; jlima@jhmi.edu; ashah29@jhmi.edu; bluemked@cc.nih.gov OI Shah, Ashish/0000-0002-1821-9110; Bluemke, David/0000-0002-8323-8086 FU Radiological Society of North America Research and Education Foundation FX J.V.C. was supported by the Radiological Society of North America Research and Education Foundation. NR 16 TC 2 Z9 2 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1749-8090 J9 J CARDIOTHORAC SURG JI J. Cardiothorac. Surg. PD AUG 12 PY 2009 VL 4 AR 42 DI 10.1186/1749-8090-4-42 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 494QD UT WOS:000269828500001 PM 19674451 ER PT J AU Kocaturk, O Saikus, CE Guttman, MA Faranesh, AZ Ratnayaka, K Ozturk, C McVeigh, ER Lederman, RJ AF Kocaturk, Ozgur Saikus, Christina E. Guttman, Michael A. Faranesh, Anthony Z. Ratnayaka, Kanishka Ozturk, Cengizhan McVeigh, Elliot R. Lederman, Robert J. TI Whole shaft visibility and mechanical performance for active MR catheters using copper-nitinol braided polymer tubes SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article ID PARALLEL RESONANT CIRCUITS; REAL-TIME; MAGNETIC-RESONANCE; STENT PLACEMENT; INTERVENTIONAL DEVICES; TRACKING; VISUALIZATION; FEASIBILITY; GUIDANCE; SWINE AB Background: Catheter visualization and tracking remains a challenge in interventional MR. Active guidewires can be made conspicuous in "profile" along their whole shaft exploiting metallic core wire and hypotube components that are intrinsic to their mechanical performance. Polymer-based catheters, on the other hand, offer no conductive medium to carry radio frequency waves. We developed a new "active" catheter design for interventional MR with mechanical performance resembling braided X-ray devices. Our 75 cm long hybrid catheter shaft incorporates a wire lattice in a polymer matrix, and contains three distal loop coils in a flexible and torquable 7Fr device. We explored the impact of braid material designs on radiofrequency and mechanical performance. Results: The incorporation of copper wire into in a superelastic nitinol braided loopless antenna allowed good visualization of the whole shaft (70 cm) in vitro and in vivo in swine during real-time MR with 1.5 T scanner. Additional distal tip coils enhanced tip visibility. Increasing the copper: nitinol ratio in braiding configurations improved flexibility at the expense of torquability. We found a 16-wire braid of 1:1 copper: nitinol to have the optimum balance of mechanical (trackability, flexibility, torquability) and antenna (signal attenuation) properties. With this configuration, the temperature increase remained less than 2 degrees C during real-time MR within 10 cm horizontal from the isocenter. The design was conspicuous in vitro and in vivo. Conclusion: We have engineered a new loopless antenna configuration that imparts interventional MR catheters with satisfactory mechanical and imaging characteristics. This compact loopless antenna design can be generalized to visualize the whole shaft of any general-purpose polymer catheter to perform safe interventional procedures. C1 [Kocaturk, Ozgur; Saikus, Christina E.; Guttman, Michael A.; Faranesh, Anthony Z.; Ratnayaka, Kanishka; McVeigh, Elliot R.; Lederman, Robert J.] NHLBI, Translat Med Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Ozturk, Cengizhan] Bogazici Univ, Inst Biomed Engn, Istanbul, Turkey. RP Kocaturk, O (reprint author), NHLBI, Translat Med Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM kocaturko@nhlbi.nih.gov; saikusc@nhlbi.nih.gov; guttmanm@nhlbi.nih.gov; faranesa@nhlbi.nih.gov; ratnayakak@nhlbi.nih.gov; cozturk@boun.edu.tr; mcveighe@nhlbi.nih.gov; ledermar@nhlbi.nih.gov RI Ozturk, Cengizhan/A-6177-2016; OI Ozturk, Cengizhan/0000-0002-6966-0774; lederman, robert/0000-0003-1202-6673 FU Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health [Z01-HL005062-07] FX Supported by the Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health (Z01-HL005062-07). NR 43 TC 9 Z9 9 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD AUG 12 PY 2009 VL 11 AR 29 DI 10.1186/1532-429X-11-29 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 494QI UT WOS:000269829100001 PM 19674464 ER PT J AU Bhangoo, SK Ripsch, MS Buchanan, DJ Miller, RJ White, FA AF Bhangoo, Sonia K. Ripsch, Matthew S. Buchanan, David J. Miller, Richard J. White, Fletcher A. TI Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy SO MOLECULAR PAIN LA English DT Article ID DORSAL-ROOT GANGLION; MONOCYTE CHEMOATTRACTANT PROTEIN-1; HIV-1 ENVELOPE GLYCOPROTEIN; CHRONIC COMPRESSION; SENSORY NEURONS; PAIN HYPERSENSITIVITY; ENHANCED EXCITABILITY; THERMAL HYPERALGESIA; NOCICEPTIVE NEURONS; NERVOUS-SYSTEM AB Painful distal sensory polyneuropathy (DSP) is the most common neurological complication of HIV1 infection. Although infection with the virus itself is associated with an incidence of DSP, patients are more likely to become symptomatic following initiation of nucleoside reverse transcriptase inhibitor (NRTI) treatment. The chemokines monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal derived factor-1 (SDF1/CXCL12) and their respective receptors, CCR2 and CXCR4, have been implicated in HIV1 related neuropathic pain mechanisms including NRTI treatment in rodents. Utilizing a rodent model that incorporates the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC), we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the resultant chronic hypernociceptive behavior. We observed that following unilateral gp120 sciatic nerve administration, rats developed profound tactile hypernociception in the hindpaw ipsilateral to gp120 treatment. Behavioral changes were also present in the hindpaw contralateral to the injury, albeit delayed and less robust. Using immunohistochemical studies, we demonstrated that MCP1 and CCR2 were upregulated by primary sensory neurons in lumbar ganglia by post-operative day (POD) 14. The functional nature of these observations was confirmed using calcium imaging in acutely dissociated lumbar dorsal root ganglion (DRG) derived from gp120 injured rats at POD 14. Tactile hypernociception in gp120 treated animals was reversed following treatment with a CCR2 receptor antagonist at POD 14. Some groups of animals were subjected to gp120 sciatic nerve injury in combination with an injection of ddC at POD 14. This injury paradigm produced pronounced bilateral tactile hypernociception from POD 14-48. More importantly, functional MCP1/CCR2 and SDF1/CXCR4 signaling was present in sensory neurons. In contrast to gp120 treatment alone, the hypernociceptive behavior associated with the injury plus drug combination was only effectively reversed using the CXCR4 antagonist AMD3100. These studies indicate that the functional upregulation of CCR2 and CXCR4 signaling systems following a combination of gp120 and an NRTI are likely to be of central importance to associated DSP and may serve as potential therapeutic targets for treatment of this syndrome. C1 [Buchanan, David J.; White, Fletcher A.] Loyola Univ, Grad Program Neurosci, Maywood, IL 60153 USA. [Bhangoo, Sonia K.; Miller, Richard J.] Northwestern Univ, Chicago, IL 60611 USA. [Bhangoo, Sonia K.] Natl Inst Dent & Cranial Res, NIH, Bethesda, MD USA. RP White, FA (reprint author), Loyola Univ, Grad Program Neurosci, Maywood, IL 60153 USA. EM bhangoos@nidcr.nih.gov; mripsch@lumc.edu; dbuchanan@lumc.edu; r-miller10@northwestern.edu; fwhite@lumc.edu RI White, Fletcher/F-2895-2012; White, Fletcher/F-3203-2015 OI White, Fletcher/0000-0002-8408-9262 FU National Institutes of Health [NS049136, DA026040, NS043095, DA013141, MH040165] FX This work was supported by National Institutes of Health Grant NS049136 and DA026040 (to F. A. W.); and National Institutes of Health Grants NS043095, DA013141, and MH040165 (to R. J. M.). NR 55 TC 60 Z9 64 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD AUG 12 PY 2009 VL 5 AR 48 DI 10.1186/1744-8069-5-48 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 496FB UT WOS:000269953800001 PM 19674450 ER PT J AU Mravinac, B Sullivan, LL Reeves, JW Yan, CM Kopf, KS Farr, CJ Schueler, MG Sullivan, BA AF Mravinac, Brankica Sullivan, Lori L. Reeves, Jason W. Yan, Christopher M. Kopf, Kristen S. Farr, Christine J. Schueler, Mary G. Sullivan, Beth A. TI Histone Modifications within the Human X Centromere Region SO PLOS ONE LA English DT Article ID ALPHA-SATELLITE DNA; CHROMOSOME CENTROMERE; HUMAN CANCER; DROSOPHILA CENTROMERE; METHYLATION STATES; HETEROCHROMATIN; CHROMATIN; KINETOCHORE; CELLS; MINICHROMOSOME AB Human centromeres are multi-megabase regions of highly ordered arrays of alpha satellite DNA that are separated from chromosome arms by unordered alpha satellite monomers and other repetitive elements. Complexities in assembling such large repetitive regions have limited detailed studies of centromeric chromatin organization. However, a genomic map of the human X centromere has provided new opportunities to explore genomic architecture of a complex locus. We used ChIP to examine the distribution of modified histones within centromere regions of multiple X chromosomes. Methylation of H3 at lysine 4 coincided with DXZ1 higher order alpha satellite, the site of CENP-A localization. Heterochromatic histone modifications were distributed across the 400-500 kb pericentromeric regions. The large arrays of alpha satellite and gamma satellite DNA were enriched for both euchromatic and heterochromatic modifications, implying that some pericentromeric repeats have multiple chromatin characteristics. Partial truncation of the X centromere resulted in reduction in the size of the CENP-A/Cenp-A domain and increased heterochromatic modifications in the flanking pericentromere. Although the deletion removed similar to 1/3 of centromeric DNA, the ratio of CENP-A to alpha satellite array size was maintained in the same proportion, suggesting that a limited, but defined linear region of the centromeric DNA is necessary for kinetochore assembly. Our results indicate that the human X centromere contains multiple types of chromatin, is organized similarly to smaller eukaryotic centromeres, and responds to structural changes by expanding or contracting domains. C1 [Mravinac, Brankica; Sullivan, Lori L.; Reeves, Jason W.; Yan, Christopher M.; Kopf, Kristen S.; Sullivan, Beth A.] Duke Univ, Inst Genome Sci & Policy, Durham, NC USA. [Reeves, Jason W.] Duke Univ, Univ Program Genet & Genom, Durham, NC USA. [Farr, Christine J.; Schueler, Mary G.] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. NHGRI, NIH, Bethesda, MD 20892 USA. [Yan, Christopher M.; Sullivan, Beth A.] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC USA. RP Mravinac, B (reprint author), Rudjer Boskovic Inst, Zagreb, Croatia. EM beth.sullivan@duke.edu OI Sullivan, Beth/0000-0001-5216-4603 FU NIH NIGMS [R01 GM069514]; March of Dimes Research Foundation [1-FY06-377] FX This work was supported by NIH NIGMS R01 GM069514 and March of Dimes Research Foundation grant #1-FY06-377 (both to B.A.S). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 16 Z9 16 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 12 PY 2009 VL 4 IS 8 AR e6602 DI 10.1371/journal.pone.0006602 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 483BD UT WOS:000268935900015 PM 19672304 ER PT J AU Vazin, T Becker, KG Chen, J Spivak, CE Lupica, CR Zhang, YQ Worden, L Freed, WJ AF Vazin, Tandis Becker, Kevin G. Chen, Jia Spivak, Charles E. Lupica, Carl R. Zhang, Yongqing Worden, Lila Freed, William J. TI A Novel Combination of Factors, Termed SPIE, which Promotes Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells SO PLOS ONE LA English DT Article ID HEPARAN-SULFATE PROTEOGLYCANS; GENE-EXPRESSION PROFILE; CENTRAL-NERVOUS-SYSTEM; GROWTH-FACTOR; NEUROTROPHIC FACTOR; PROGENITOR CELLS; IN-VIVO; SUBSTANTIA-NIGRA; RAT-BRAIN; ES CELLS AB Background: Stromal-Derived Inducing Activity (SDIA) is one of the most efficient methods of generating dopaminergic (DA) neurons from embryonic stem cells (ESC). DA neuron induction can be achieved by co-culturing ESC with the mouse stromal cell lines PA6 or MS5. The molecular nature of this effect, which has been termed "SDIA" is so far unknown. Recently, we found that factors secreted by PA6 cells provided lineage-specific instructions to induce DA differentiation of human ESC (hESC). Methodology/Principal Findings: In the present study, we compared PA6 cells to various cell lines lacking the SDIA effect, and employed genome expression analysis to identify differentially-expressed signaling molecules. Among the factors highly expressed by PA6 cells, and known to be associated with CNS development, were stromal cell-derived factor 1 (SDF1/CXCL12), pleiotrophin (PTN), insulin-like growth factor 2 (IGF2), and ephrin B1 (EFNB1). When these four factors, the combination of which was termed SPIE, were applied to hESC, they induced differentiation to TH-positive neurons in vitro. RT-PCR and western blot analysis confirmed the expression of midbrain specific markers, including engrailed 1, Nurr1, Pitx3, and dopamine transporter (DAT) in cultures influenced by these four molecules. Electrophysiological recordings showed that treatment of hESC with SPIE induced differentiation of neurons that were capable of generating action potentials and forming functional synaptic connections. Conclusions/Significance: The combination of SDF-1, PTN, IGF2, and EFNB1 mimics the DA phenotype-inducing property of SDIA and was sufficient to promote differentiation of hESC to functional midbrain DA neurons. These findings provide a method for differentiating hESC to form DA neurons, without a requirement for the use of animal-derived cell lines or products. C1 [Vazin, Tandis; Chen, Jia; Spivak, Charles E.; Lupica, Carl R.; Worden, Lila; Freed, William J.] NIDA, Cellular Neurobiol Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. [Becker, Kevin G.; Zhang, Yongqing] NIA, Gene Express & Genom Unit, Intramural Res Program, DHHS, Baltimore, MD 21224 USA. [Vazin, Tandis] AlbaNova Univ Ctr, KTH Royal Inst Technol, Sch Biotechnol, Div Gene Technol, Stockholm, Sweden. RP Vazin, T (reprint author), NIDA, Cellular Neurobiol Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. EM vazint@mail.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU IRPs of NIDA; NIA; NIH; DHHS FX Research was supported by the IRPs of NIDA and NIA, NIH, DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 39 Z9 42 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 12 PY 2009 VL 4 IS 8 AR e6606 DI 10.1371/journal.pone.0006606 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 483BD UT WOS:000268935900017 PM 19672298 ER PT J AU del Sol, A Tsai, CJ Ma, BY Nussinov, R AF del Sol, Antonio Tsai, Chung-Jung Ma, Buyong Nussinov, Ruth TI The Origin of Allosteric Functional Modulation: Multiple Pre-existing Pathways SO STRUCTURE LA English DT Review ID PROTEIN ALLOSTERY; SIGNAL-TRANSDUCTION; BINDING CASCADES; PLAUSIBLE MODEL; PDZ DOMAIN; ACTIVATION; SITE; RECEPTOR; SCAFFOLD; UBIQUITINATION AB Although allostery draws increasing attention, not much is known about allosteric mechanisms. Here we argue that in all proteins, allosteric signals transmit through multiple, pre-existing pathways; which pathways dominate depend on protein topologies, specific binding events, covalent modifications, and cellular (environmental) conditions. Further, perturbation events at any site on the protein surface (or in the interior) will not create new pathways but only shift the pre-existing ensemble of pathways. Drugs binding at different sites or mutational events in disease shift the ensemble toward the same conformations; however, the relative populations of the different states will change. Consequently the observed functional, conformational, and dynamic effects will be different. This is the origin of allosteric functional modulation in dynamic proteins: allostery does not necessarily need to invoke conformational rearrangements to control protein activity and pre-existing pathways are always defaulted to during allostery regardless of the stimulant and perturbation site in the protein. C1 [Tsai, Chung-Jung; Ma, Buyong; Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program, Frederick, MD 21702 USA. [del Sol, Antonio] Fujirebio Inc, Div Res & Dev, Bioinformat Res Unit, Hachioji, Tokyo 1920031, Japan. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 77 TC 201 Z9 201 U1 1 U2 29 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD AUG 12 PY 2009 VL 17 IS 8 BP 1042 EP 1050 DI 10.1016/j.str.2009.06.008 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 486VR UT WOS:000269229100005 PM 19679084 ER PT J AU Oramasionwu, CU Hunter, JM Skinner, J Ryan, L Lawson, KA Brown, CM Makos, BR Frei, CR AF Oramasionwu, Christine U. Hunter, Jonathan M. Skinner, Jeff Ryan, Laurajo Lawson, Kenneth A. Brown, Carolyn M. Makos, Brittany R. Frei, Christopher R. TI Black race as a predictor of poor health outcomes among a national cohort of HIV/AIDS patients admitted to US hospitals: a cohort study SO BMC INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; SEXUALLY-TRANSMITTED-DISEASES; HIV-INFECTED PATIENTS; CD4 CELL COUNTS; UNITED-STATES; DRUG-USE; EPIDEMIOLOGIC SYNERGY; RACIAL DISPARITIES; SAN-FRANCISCO AB Background: In general, the Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) population has begun to experience the benefits of highly active antiretroviral therapy (HAART); unfortunately, these benefits have not extended equally to Blacks in the United States, possibly due to differences in patient comorbidities and demographics. These differences include rates of hepatitis B and C infection, substance use, and socioeconomic status. To investigate the impact of these factors, we compared hospital mortality and length of stay (LOS) between Blacks and Whites with HIV/AIDS while adjusting for differences in these key characteristics. Methods: The 1996-2006 National Hospital Discharge Surveys were used to identify HIV/AIDS patients admitted to US hospitals. Survey weights were incorporated to provide national estimates. Patients < 18 years of age, those who left against medical advice, those with an unknown discharge disposition and those with a LOS < 1 day were excluded. Patients were stratified into subgroups by race (Black or White). Two multivariable logistic regression models were constructed with race as the independent variable and outcomes (mortality and LOS > 10 days) as the dependent variables. Factors that were significantly different between Blacks and Whites at baseline via bivariable statistical tests were included as covariates. Results: In the general US population, there are approximately 5 times fewer Blacks than Whites. In the present study, 1.5 million HIV/AIDS hospital discharges were identified and Blacks were 6 times more likely to be hospitalized than Whites. Notably, Blacks had higher rates of substance use (30% vs. 24%; P < 0.001), opportunistic infections (27% vs. 26%; P < 0.001) and cocaine use (13% vs. 5%; P < 0.001). Conversely, fewer Blacks were co-infected with hepatitis C virus (8% vs. 12%; P < 0.001). Hepatitis B virus was relatively infrequent (3% for both groups). Crude mortality rates were similar for both cohorts (5%); however, a greater proportion of Blacks had a LOS > 10 days (21% vs. 19%; P < 0.001). Black race, in the presence of comorbidities, was correlated with a higher odds of LOS > 10 days (OR, 95% CI = 1.20 [1.10-1.30]), but was not significantly correlated with a higher odds of mortality (OR, 95% CI = 1.07 [0.93-1.25]). Conclusion: Black race is a predictor of LOS > 10 days, but not mortality, among HIV/AIDS patients admitted to US hospitals. It is possible that racial disparities in hospital outcomes may be closing with time. C1 [Oramasionwu, Christine U.; Ryan, Laurajo; Lawson, Kenneth A.; Brown, Carolyn M.; Makos, Brittany R.; Frei, Christopher R.] Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. [Oramasionwu, Christine U.; Hunter, Jonathan M.; Ryan, Laurajo; Makos, Brittany R.; Frei, Christopher R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Skinner, Jeff] NIAID, NIH, Bethesda, MD 20892 USA. RP Frei, CR (reprint author), Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. EM chrorams@mail.utexas.edu; jonathan.hunter@gmail.com; skinnerj@niaid.nih.gov; ryanl@uthscsa.edu; kenlawson@mail.utexas.edu; cmbrown@mail.utexas.edu; brittany.rose@gmail.com; freic@uthscsa.edu OI Skinner, Jeff/0000-0001-5697-0442 NR 57 TC 14 Z9 14 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD AUG 11 PY 2009 VL 9 AR 127 DI 10.1186/1471-2334-9-127 PG 12 WC Infectious Diseases SC Infectious Diseases GA 491EI UT WOS:000269560000001 PM 19671170 ER PT J AU Matt, P Schoenhoff, F Habashi, J Holm, T Van Erp, C Loch, D Carlson, OD Griswold, BF Fu, Q De Backer, J Loeys, B Huso, DL McDonnell, NB Van Eyk, JE Dietz, HC AF Matt, Peter Schoenhoff, Florian Habashi, Jennifer Holm, Tammy Van Erp, Christel Loch, David Carlson, Olga D. Griswold, Benjamin F. Fu, Qin De Backer, Julie Loeys, Bart Huso, David L. McDonnell, Nazli B. Van Eyk, Jennifer E. Dietz, Harry C. CA GenTAC Consortium TI Circulating Transforming Growth Factor-beta in Marfan Syndrome SO CIRCULATION LA English DT Article DE aneurysm; biomarkers; losartan; Marfan syndrome; TGF-beta ID RECEPTOR BLOCKADE; AORTIC-ANEURYSM; MOUSE MODEL; PATHOGENESIS; ACTIVATION; LOSARTAN; GENE AB Background-Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor-beta (TGF-beta). Recent evidence suggests that losartan, an angiotensin II type 1 blocker that blunts TGF-beta activation, may be an effective treatment for MFS. We hypothesized that dysregulation of TGF-beta might be mirrored in circulating TGF-beta concentrations. Methods and Results-Serum obtained from MFS mutant mice (Fbn1(C1039G/+)) treated with losartan was analyzed for circulating TGF-beta 1 concentrations and compared with those from placebo-treated and wild-type mice. Aortic root size was measured by echocardiography. Data were validated in patients with MFS and healthy individuals. In mice, circulating total TGF-beta 1 concentrations increased with age and were elevated in older untreated Fbn1(C1039G/+) mice compared with wild-type mice (P = 0.01; n = 16; mean +/- SEM, 115 +/- 8 ng/mL versus n = 17; mean +/- SEM, 92 +/- 4 ng/mL). Losartan-treated Fbn1(C1039G/+) mice had lower total TGF-beta 1 concentrations compared with age-matched Fbn1(C1039G/+) mice treated with placebo (P = 0.01; n = 18; 90 +/- 5 ng/mL), and circulating total TGF-beta 1 levels were indistinguishable from those of age-matched wild-type mice (P = 0.8). Correlation was observed between circulating TGF-beta 1 levels and aortic root diameters in Fbn1(C1039G/+) and wild-type mice (P = 0.002). In humans, circulating total TGF-beta 1 concentrations were elevated in patients with MFS compared with control individuals (P < 0.0001; n = 53; 15 +/- 1.7 ng/mL versus n = 74; 2.5 +/- 0.4 ng/mL). MFS patients treated with losartan (n = 55) or beta-blocker (n = 80) showed significantly lower total TGF-beta 1 concentrations compared with untreated MFS patients (P <= 0.05). Conclusions-Circulating TGF-beta 1 concentrations are elevated in MFS and decrease after administration of losartan, beta-blocker therapy, or both and therefore might serve as a prognostic and therapeutic marker in MFS. (Circulation. 2009;120:526-532.) C1 [Van Eyk, Jennifer E.] Johns Hopkins Univ, Johns Hopkins Prote Ctr, Baltimore, MD 21239 USA. [Matt, Peter; Schoenhoff, Florian; Habashi, Jennifer; Holm, Tammy; Van Erp, Christel; Loch, David; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21239 USA. [Matt, Peter; Schoenhoff, Florian; Habashi, Jennifer; Holm, Tammy; Van Erp, Christel; Loch, David; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21239 USA. [Matt, Peter] Univ Hosp, Div Cardiac Surg, Basel, Switzerland. [Schoenhoff, Florian] Univ Bern, Dept Cardiovasc Surg, CH-3012 Bern, Switzerland. [Carlson, Olga D.; Griswold, Benjamin F.] NIA, Clin Invest Lab, Bethesda, MD 20892 USA. [De Backer, Julie; Loeys, Bart] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium. [Huso, David L.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21239 USA. [McDonnell, Nazli B.] NIA, Clin Res Branch, Bethesda, MD 20892 USA. RP Van Eyk, JE (reprint author), Johns Hopkins Univ, Johns Hopkins Prote Ctr, 602 Mason F Lord Bldg,Ctr Tower, Baltimore, MD 21239 USA. EM pmatt@uhbs.ch; jvaneyk1@jhmi.edu OI Loeys, Bart/0000-0003-3703-9518 FU Swiss National Foundation; Novartis Foundation; Hippocrate Foundation Basel; National Heart, Lung, and Blood Institute Proteomic Initiative [NO-HV-28120]; Daniel P. Amos Family Foundation; Institute for Clinical and Translational Science Award [1U54RR023561-01A1]; National Institutes of Health; Howard Hughes Medical Institute; William S. Smilow Center for Marfan Syndrome Research; National Marfan Foundation FX Dr Matt is supported by the Swiss National Foundation, the Novartis Foundation, and the Hippocrate Foundation Basel. Dr Van Eyk is supported by grants from the National Heart, Lung, and Blood Institute Proteomic Initiative (contract NO-HV-28120), the Daniel P. Amos Family Foundation, and the Institute for Clinical and Translational Science Award (grant NO 1U54RR023561-01A1). Dr Dietz is supported by the National Institutes of Health, the Howard Hughes Medical Institute, the William S. Smilow Center for Marfan Syndrome Research, and the National Marfan Foundation. Dr McDonnell, Ben Griswold, and Dr Carlson are supported by intramural funds originating at the National Institute on Aging/National Institutes of Health. Dr Schoenhoff is supported by the Swiss National Foundation and the Novartis Foundation. NR 22 TC 113 Z9 118 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 11 PY 2009 VL 120 IS 6 BP 526 EP 532 DI 10.1161/CIRCULATIONAHA.108.841981 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 481LT UT WOS:000268813300010 PM 19635970 ER PT J AU Fushan, AA Simons, CT Slack, JP Manichaikul, A Drayna, D AF Fushan, Alexey A. Simons, Christopher T. Slack, Jay P. Manichaikul, An Drayna, Dennis TI Allelic Polymorphism within the TAS1R3 Promoter Is Associated with Human Taste Sensitivity to Sucrose SO CURRENT BIOLOGY LA English DT Article ID SWEET TASTE; RECEPTOR GENE; UMAMI TASTE; LOCUS; EXPRESSION; PREFERENCE; PATTERNS; IDENTIFICATION; PERCEPTION; PROTEINS AB Human sweet taste perception is mediated by the heterodimeric G protein-coupled receptor encoded by the TAS1R2 and TAS1R3 genes [1-7]. Variation in these genes has been characterized [8], but the functional consequences of such variation for sweet perception are unknown. We found that two C/T single-nucleotide polymorphisms (SNPs) located at positions -1572 (rs307355) and -1266 (rs35744813) upstream of the TAS1R3 coding sequence strongly correlate with human taste sensitivity to sucrose and explain 16% of population variability in perception. By using a luciferase reporter assay, we demonstrated that the T allele of each SNP results in reduced promoter activity in comparison to the C alleles, consistent with the phenotype observed in humans carrying T alleles. We also found that the distal region of the TAS1R3 promoter harbors a composite cis-acting element that has a strong silencing effect on promoter activity. We conclude that the rs307355 and rs35744813 SNPs affect gene transcription by altering the function of this regulatory element. A worldwide population survey reveals that the T alleles of rs307355 and rs35744813 occur at lowest frequencies in European populations. We propose that inherited differences in TAS1R3 transcription account for a substantial fraction of worldwide differences in human sweet taste perception. C1 [Fushan, Alexey A.; Drayna, Dennis] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20850 USA. [Simons, Christopher T.; Slack, Jay P.] Givaudan Flavors Corp, Cincinnati, OH 45216 USA. [Manichaikul, An] Univ Virginia, Charlottesville, VA 22904 USA. RP Drayna, D (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20850 USA. EM drayna@nidcd.nih.gov RI Manichaikul, Ani/B-7726-2009; Simons, Christopher/B-3036-2013; Marion-Poll, Frederic/D-8882-2011; OI Marion-Poll, Frederic/0000-0001-6824-0180; Manichaikul, Ani/0000-0002-5998-795X FU NIDCD/NIH [Z01-000046-09]; Givaudan Flavors Corporation [CRADA DC-CR-06-01] FX We thank the research volunteers for their participation and J. Kleinman and Lindsay Bellegia for assistance with administration of taste tests. This research was supported by NIDCD/NIH funding Z01-000046-09 and by CRADA DC-CR-06-01 from Givaudan Flavors Corporation. C.T.S. and J.P.S. note they are employees of Givaudan Flavors Corporation. NR 36 TC 65 Z9 67 U1 5 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 11 PY 2009 VL 19 IS 15 BP 1288 EP 1293 DI 10.1016/j.cub.2009.06.015 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 482WT UT WOS:000268921900025 PM 19559618 ER PT J AU Kim, JH Kocaturk, O Ozturk, C Faranesh, AZ Sonmez, M Sampath, S Saikus, CE Kim, AH Raman, VK Phd, JAD Schenke, WH Wright, VJ Berry, C McVeigh, ER Lederman, RJ AF Kim, June-Hong Kocaturk, Ozgur Ozturk, Cengizhan Faranesh, Anthony Z. Sonmez, Merdim Sampath, Smita Saikus, Christina E. Kim, Ann H. Raman, Venkatesh K. Phd, J. Andrew Derbyshire Schenke, William H. Wright, Victor J. Berry, Colin McVeigh, Elliot R. Lederman, Robert J. TI Mitral Cerclage Annuloplasty, A Novel Transcatheter Treatment for Secondary Mitral Valve Regurgitation Initial Results in Swine SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE image-guided intervention; catheter-based intervention; noncoronary; magnetic resonance imaging; multimodality image fusion ID RING SELECTION IMPLICATIONS; SHORT-TERM EFFICACY; CORONARY-SINUS; HEART-FAILURE; MYOCARDIAL-INFARCTION; MAGNETIC-RESONANCE; ANNULAR REDUCTION; CLINICAL-TRIAL; PORCINE MODEL; ANIMAL-MODEL AB Objectives We developed and tested a novel transcatheter circumferential annuloplasty technique to reduce mitral regurgitation in porcine ischemic cardiomyopathy. Background Catheter-based annuloplasty for secondary mitral regurgitation exploits the proximity of the coronary sinus to the mitral annulus, but is limited by anatomic variants and coronary artery entrapment. Methods The procedure, "cerclage annuloplasty," is guided by magnetic resonance imaging (MRI) roadmaps fused with live X-ray. A coronary sinus guidewire traverses a short segment of the basal septal myocardium to re-enter the right heart where it is exchanged for a suture. Tension is applied interactively during imaging and secured with a locking device. Results We found 2 feasible suture pathways from the great cardiac vein across the interventricular septum to create cerclage. Right ventricular septal re-entry required shorter fluoroscopy times than right atrial re-entry, which entailed a longer intramyocardial traversal but did not cross the tricuspid valve. Graded tension progressively reduced septal-lateral annular diameter, but not end-systolic elastance or regional myocardial function. A simple arch-like device protected entrapped coronary arteries from compression even during supratherapeutic tension. Cerclage reduced mitral regurgitation fraction ( from 22.8 +/- 12.7% to 7.2 +/- 4.4%, p = 0.04) by slice tracking velocity-encoded MRI. Flexible cerclage reduced annular size but preserved annular motion. Cerclage also displaced the posterior annulus toward the papillary muscles. Cerclage introduced reciprocal constraint to the left ventricular outflow tract and mitral annulus that enhanced leaflet coaptation. A sample of human coronary venograms and computed tomography angiograms suggested that most have suitable venous anatomy for cerclage. Conclusions Transcatheter mitral cerclage annuloplasty acutely reduces mitral regurgitation in porcine ischemic cardiomyopathy. Entrapped coronary arteries can be protected. MRI provided insight into the mechanism of cerclage action. (J Am Coll Cardiol 2009; 54: 638-51) (C) 2009 by the American College of Cardiology Foundation C1 [Kim, June-Hong; Kocaturk, Ozgur; Ozturk, Cengizhan; Faranesh, Anthony Z.; Sonmez, Merdim; Sampath, Smita; Saikus, Christina E.; Kim, Ann H.; Raman, Venkatesh K.; Phd, J. Andrew Derbyshire; Schenke, William H.; Wright, Victor J.; Berry, Colin; McVeigh, Elliot R.; Lederman, Robert J.] NHLBI, Translat Med Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Kim, June-Hong] Pusan Natl Univ, Div Cardiol, Pusan, South Korea. [Ozturk, Cengizhan; Sonmez, Merdim] Bogazici Univ, Dept Biomed Engn, Istanbul, Turkey. RP Lederman, RJ (reprint author), NHLBI, Translat Med Branch, Div Intramural Res, NIH, Bldg 10,Room 2C713, Bethesda, MD 20892 USA. EM ledermar@nhlbi.nih.gov RI Kocaturk, Ozgur/A-1419-2016; Ozturk, Cengizhan/A-6177-2016 OI Ozturk, Cengizhan/0000-0002-6966-0774 FU Intramural NIH HHS [Z01 HL005062-05] NR 57 TC 28 Z9 28 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 11 PY 2009 VL 54 IS 7 BP 638 EP 651 DI 10.1016/j.jacc.2009.03.071 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 480UA UT WOS:000268761100010 PM 19660696 ER PT J AU Pearl, PL Gibson, KM Quezado, Z Dustin, I Taylor, J Trzcinski, S Schreiber, J Forester, K Reeves-Tyer, P Liew, C Shamim, S Herscovitch, P Carson, R Butman, J Jakobs, C Theodore, W AF Pearl, P. L. Gibson, K. M. Quezado, Z. Dustin, I. Taylor, J. Trzcinski, S. Schreiber, J. Forester, K. Reeves-Tyer, P. Liew, C. Shamim, S. Herscovitch, P. Carson, R. Butman, J. Jakobs, C. Theodore, W. TI Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency SO NEUROLOGY LA English DT Article ID TEMPORAL-LOBE EPILEPSY; POSITRON-EMISSION-TOMOGRAPHY; TANDEM MASS-SPECTROMETRY; SSADH DEFICIENCY; IN-VIVO; 4-HYDROXYBUTYRIC ACIDURIA; CEREBROSPINAL-FLUID; RECEPTOR BINDING; MOUSE; INHIBITION AB Objective: Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of GABA metabolism characterized by elevated levels of GABA and gamma-hydroxybutyric acid. Clinical findings include intellectual impairment, hypotonia, hyporeflexia, hallucinations, autistic behaviors, and seizures. Autoradiographic labeling and slice electrophysiology studies in the murine model demonstrate use-dependent downregulation of GABA(A) receptors. We studied GABA(A) receptor activity in human SSADH deficiency utilizing [(11)C]-flumazenil (FMZ)-PET. Methods: FMZ binding was measured in 7 patients, 10 unaffected parents, and 8 healthy controls. Data analysis was performed using a reference region compartmental model, with time-activity curve from pons as the input function. Relative parametric binding potential (BP(ND)) was derived, with MRI-based pixel by pixel partial volume correction, in regions of interest drawn on coregistered MRI. Results: In amygdala, hippocampus, cerebellar vermis, frontal, parietal, and occipital cortex, patients with SSADH deficiency had significant reductions in FMZ BP(ND) compared to parents and controls. Mean cortical values were 6.96 +/- 0.79 (controls), 6.89 +/- 0.71 (parents), and 4.88 +/- 0.77 (patients) (F ratio 16.1; p < 0.001). There were no differences between controls and parents in any cortical region. Conclusions: Succinic semialdehyde dehydrogenase (SSADH) deficient patients show widespread reduction in BZPR binding on [(11)C]-flumazenil-PET. Our results suggest that high endogenous brain GABA levels in SSADH deficiency downregulate GABA(A)-BZPR binding site availability. This finding suggests a potential mechanism for neurologic dysfunction in a serious neurodevelopmental disorder, and suggests that PET may be useful to translate studies in animal models to human disease. Neurology(R) 2009; 73: 423-429 C1 [Pearl, P. L.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Pearl, P. L.; Dustin, I.; Reeves-Tyer, P.; Liew, C.; Shamim, S.; Theodore, W.] NINDS, Clin Epilepsy Sect, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Quezado, Z.] NIH, Dept Anesthesia, Ctr Clin, Bethesda, MD 20892 USA. [Quezado, Z.] NIH, Surg Serv, Positron Emiss Tomog Dept, Ctr Clin, Bethesda, MD 20892 USA. [Herscovitch, P.; Carson, R.; Butman, J.] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Gibson, K. M.] Univ Pittsburgh, Sch Med, Div Med Genet, Dept Pediat, Pittsburgh, PA 15260 USA. [Gibson, K. M.] Univ Pittsburgh, Sch Med, Div Med Genet, Dept Pathol, Pittsburgh, PA 15260 USA. [Gibson, K. M.] Univ Pittsburgh, Sch Med, Div Med Genet, Dept Human Genet, Pittsburgh, PA 15260 USA. [Jakobs, C.] Vrije Univ Amsterdam Med Ctr, Dept Clin Chem, Amsterdam, Netherlands. RP Pearl, PL (reprint author), Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave,NW, Washington, DC 20010 USA. EM ppearl@cnmc.org RI Butman, John/A-2694-2008; Carson, Richard/H-3250-2011; Quezado, Zenaide/O-4860-2016; OI Carson, Richard/0000-0002-9338-7966; Quezado, Zenaide/0000-0001-9793-4368; Butman, John/0000-0002-1547-9195 FU Intramural NIH HHS [ZIA CL009009-02]; NICHD NIH HHS [R01 HD058553]; NINDS NIH HHS [5R01NS058360, NS40270, R01 NS040270] NR 39 TC 30 Z9 31 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 11 PY 2009 VL 73 IS 6 BP 423 EP 429 DI 10.1212/WNL.0b013e3181b163a5 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 481LV UT WOS:000268813500004 PM 19667317 ER PT J AU Lin, BY Wang, J Hong, X Yan, XW Hwang, D Cho, JH Yi, D Utleg, AG Fang, XF Schones, DE Zhao, KJ Omenn, GS Hood, L AF Lin, Biaoyang Wang, Jun Hong, Xu Yan, Xiaowei Hwang, Daehee Cho, Ji-Hoon Yi, Danielle Utleg, Angelita G. Fang, Xuefeng Schones, Dustin E. Zhao, Keji Omenn, Gilbert S. Hood, Leroy TI Integrated Expression Profiling and ChIP-seq Analyses of the Growth Inhibition Response Program of the Androgen Receptor SO PLOS ONE LA English DT Article ID PROSTATE-CANCER CELLS; HUMAN GENOME; TRANSCRIPTION-FACTOR; TUMOR-SUPPRESSOR; BINDING-SITES; TARGET GENES; LINE PC-3; DNA; AMPLIFICATION; PROMOTER AB Background: The androgen receptor (AR) plays important roles in the development of male phenotype and in different human diseases including prostate cancers. The AR can act either as a promoter or a tumor suppressor depending on cell types. The AR proliferative response program has been well studied, but its prohibitive response program has not yet been thoroughly studied. Methodology/Principal Findings: Previous studies found that PC3 cells expressing the wild-type AR inhibit growth and suppress invasion. We applied expression profiling to identify the response program of PC3 cells expressing the AR (PC3-AR) under different growth conditions (i.e. with or without androgens and at different concentration of androgens) and then applied the newly developed ChIP-seq technology to identify the AR binding regions in the PC3 cancer genome. A surprising finding was that the comparison of MOCK-transfected PC3 cells with AR-transfected cells identified 3,452 differentially expressed genes (two fold cutoff) even without the addition of androgens (i.e. in ethanol control), suggesting that a ligand independent activation or extremely low-level androgen activation of the AR. ChIP-Seq analysis revealed 6,629 AR binding regions in the cancer genome of PC3 cells with an FDR (false discovery rate) cut off of 0.05. About 22.4% (638 of 2,849) can be mapped to within 2 kb of the transcription start site (TSS). Three novel AR binding motifs were identified in the AR binding regions of PC3-AR cells, and two of them share a core consensus sequence CGAGCTCTTC, which together mapped to 27.3% of AR binding regions (1,808/ 6,629). In contrast, only about 2.9% (190/ 6,629) of AR binding sites contains the canonical AR matrix M00481, M00447 and M00962 (from the Transfac database), which is derived mostly from AR proliferative responsive genes in androgen dependent cells. In addition, we identified four top ranking co-occupancy transcription factors in the AR binding regions, which include TEF1 (Transcriptional enhancer factor), GATA (GATA transcription factors), OCT (octamer transcription factors) and PU1 (PU.1 transcription factor). Conclusions/Significance: Our data provide a valuable data set in understanding the molecular basis for growth inhibition response program of the AR in prostate cancer cells, which can be exploited for developing novel prostate cancer therapeutic strategies. C1 [Lin, Biaoyang; Fang, Xuefeng] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Lin, Biaoyang; Wang, Jun; Hong, Xu] Zhejiang Univ, Zhejiang California Int NanoSyst Inst, Hangzhou 310003, Zhejiang, Peoples R China. [Lin, Biaoyang] Swedish Med Ctr, Seattle, WA USA. [Yan, Xiaowei; Yi, Danielle; Utleg, Angelita G.; Hood, Leroy] Inst Syst Biol, Seattle, WA USA. [Hwang, Daehee; Cho, Ji-Hoon] Pohang Univ Sci & Technol, Bio Program 1, Pohang, Kyungbuk, South Korea. [Hwang, Daehee; Cho, Ji-Hoon] Pohang Univ Sci & Technol, Dept Chem Engn, Pohang, Kyungbuk, South Korea. [Schones, Dustin E.; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Omenn, Gilbert S.] Univ Michigan, Ctr Computat Med & Biol, Ann Arbor, MI 48109 USA. RP Lin, BY (reprint author), Univ Washington, Dept Urol, Seattle, WA 98195 USA. EM biaoylin@gmail.com OI Omenn, Gilbert S./0000-0002-8976-6074 FU MOST, China [2006AA02A303, 2006AA02Z4A2, 2006DFA32950, 2007DFC30360]; NIH, USA [5P50GM076547, 5U54CA119347, U54DA021519]; Korean Ministry of Education, Science and Technology (MEST), Korea [M1AN29-2007-03990, FPR08A1-050] FX This work was supported by grants 2006AA02A303, 2006AA02Z4A2, 2006DFA32950 and 2007DFC30360 from the MOST (http://www.most.gov.cn/eng/), China, and grants 5P50GM076547, 5U54CA119347, U54DA021519 from NIH (www.nih.gov/), USA, and grants M1AN29-2007-03990 and FPR08A1-050 from the Korean Ministry of Education, Science and Technology (MEST) (http://www.mest.go.kr/), Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 51 Z9 55 U1 1 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 AUG 11 PY 2009 VL 4 IS 8 AR e6589 DI 10.1371/journal.pone.0006589 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 483BA UT WOS:000268935600015 PM 19668381 ER PT J AU Bethoney, KA King, MC Hinshaw, JE Ostap, EM Lemmon, MA AF Bethoney, Kelley A. King, Megan C. Hinshaw, Jenny E. Ostap, E. Michael Lemmon, Mark A. TI A possible effector role for the pleckstrin homology (PH) domain of dynamin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE endocytosis; phosphoinositide; vesicle; GTPase; actin ID CLATHRIN-MEDIATED ENDOCYTOSIS; COATED VESICLE FORMATION; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; ACTIN DYNAMICS; MEMBRANE FISSION; PLASMA-MEMBRANE; GTPASE ACTIVITY; PHOSPHOINOSITIDES; CONSTRICTION; PROTEIN AB The large GTPase dynamin plays a key role in clathrin-mediated endocytosis in animal cells, although its mechanism of action remains unclear. Dynamins 1, 2, and 3 contain a pleckstrin homology (PH) domain that binds phosphoinositides with a very low affinity (K(D) > 1 mM), and this interaction appears to be crucial for function. These observations prompted the suggestion that an array of PH domains drives multivalent binding of dynamin oligomers to phosphoinositide-containing membranes. Although in vitro experiments reported here are consistent with this hypothesis, we find that PH domain mutations that abolish dynamin function do not alter localization of the protein in transfected cells, indicating that the PH domain does not play a simple targeting role. An alternative possibility is suggested by the geometry of dynamin helices resolved by electron microscopy. Even with one phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P(2)] molecule bound per PH domain, these dynamin assemblies will elevate the concentration of PtdIns(4,5)P(2) at coated pit necks, and effectively cluster (or sequester) this phosphoinositide. In vitro fluorescence quenching studies using labeled phosphoinositides are consistent with dynamin-induced PtdIns(4,5)P(2) clustering. We therefore propose that the ability of dynamin to alter the local distribution of PtdIns(4,5)P(2) could be crucial for the role of this GTPase in promoting membrane scission during clathrin-mediated endocytosis. PtdIns(4,5)P(2) clustering could promote vesicle scission through direct effects on membrane properties, or might play a role in dynamin's ability to regulate actin polymerization. C1 [Bethoney, Kelley A.; King, Megan C.; Lemmon, Mark A.] Univ Penn, Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. [Hinshaw, Jenny E.] NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. [Ostap, E. Michael] Univ Penn, Sch Med, Penn Muscle Inst, Philadelphia, PA 19104 USA. [Ostap, E. Michael] Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. RP Lemmon, MA (reprint author), Univ Penn, Sch Med, Dept Biochem & Biophys, 809C Stellar Chance Labs,422 Curie Blvd, Philadelphia, PA 19104 USA. EM mlemmon@mail.med.upenn.edu OI Lemmon, Mark/0000-0002-3379-5319 FU National Institutes of Health (NIH) [R01-GM57247, R01-GM078345]; U.S. Army Breast Cancer Research Program [DAMD17 -02-1-0546]; Great Rivers Affiliate of the American Heart Association; National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Stuart McLaughlin (Stony Brook University, Stony Brook, NY) for kindly providing the MARCKS (151-175) peptide, Jim Keen (Thomas Jefferson University, Philadelphia) for the GFP-clathrin construct, and Sandra Schmid (Scripps Research Institute, La Jolla, CA) for dynamin1 constructs. We also thank Kate Ferguson and members of the Lemmonlaboratory for valuable discussions and Jason Mears for help with Fig. 5A. This work was supported in part by National Institutes of Health (NIH) Grants R01-GM57247 (to E. M. O.) and R01-GM078345 (to M. A. L.), Predoctoral Fellowship DAMD17 -02-1-0546 from the U.S. Army Breast Cancer Research Program (to M. C. K.), a Predoctoral Fellowship from the Great Rivers Affiliate of the American Heart Association (to K. A. B.), and the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (J. E. H). NR 46 TC 32 Z9 33 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 11 PY 2009 VL 106 IS 32 BP 13359 EP 13364 DI 10.1073/pnas.0906945106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 482IA UT WOS:000268877300040 PM 19666604 ER PT J AU Tran, DQ Andersson, J Wang, R Ramsey, H Unutmaz, D Shevach, EM AF Tran, Dat Q. Andersson, John Wang, Rui Ramsey, Heather Unutmaz, Derya Shevach, Ethan M. TI GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3(+) regulatory T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE transforming growth factor beta; Tregs; latency-associated peptide ID COMPARATIVE GENOMIC HYBRIDIZATION; SUPPRESSOR FUNCTION; DEPENDENT MANNER; CUTTING EDGE; GENE; PEPTIDE; INDUCTION; ABSENCE; CANCER; IDENTIFICATION AB TGF-beta family members are highly pleiotropic cytokines with diverse regulatory functions. TGF-beta is normally found in the latent form associated with latency-associated peptide (LAP). This latent complex can associate with latent TGF beta-binding protein (LTBP) to produce a large latent form. Latent TGF-beta is also found on the surface of activated FOXP3(+) regulatory T cells (Tregs), but it is unclear how it is anchored to the cell membrane. We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-beta to the cell surface. We demonstrate that platelets and activated Tregs co-express latent TGF-beta and GARP on their membranes. The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta 1 is able to bind directly with GARP. Confocal microscopy and immunoprecipitation strongly support their interactions. The role of TGF-beta on Tregs appears to have dual functions, both for Treg-mediated suppression and infectious tolerance mechanism. C1 [Tran, Dat Q.; Andersson, John; Ramsey, Heather; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Rui; Unutmaz, Derya] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. RP Tran, DQ (reprint author), NIAID, Immunol Lab, NIH, 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 National Institute of Allergy and Infectious Diseases Intramural Research Program; National Institutes of Health [R01 AI065303] FX We thank Carol Henry, Tom Moyer, and Calvin Eigsti in the National Institute of Allergy and Infectious Diseases Flow Cytometry Section for sorting our cells; Cynthia Matthews in the Department of Transfusion Medicine for the leukapheresis; and Lily Koo in the National Institute of Allergy and Infectious Diseases Biological Imaging Facility for performing the confocal microscopy. This work was supported by the National Institute of Allergy and Infectious Diseases Intramural Research Program and National Institutes of Health Grant R01 AI065303 (to D. U.). NR 34 TC 161 Z9 167 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 11 PY 2009 VL 106 IS 32 BP 13445 EP 13450 DI 10.1073/pnas.0901944106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 482IA UT WOS:000268877300055 PM 19651619 ER PT J AU Guo, LY Wei, G Zhu, JF Liao, W Leonard, WJ Zhao, KJ Paul, W AF Guo, Liying Wei, Gang Zhu, Jinfang Liao, Wei Leonard, Warren J. Zhao, Keji Paul, William TI IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE IL-33; TSLP; IL-18; STAT5; T1ST2 ID NF-KAPPA-B; INTERFERON-GAMMA PRODUCTION; RECEPTOR ACCESSORY PROTEIN; CD4(+) T-CELLS; IMMUNE-RESPONSES; MAST-CELLS; EXPRESSION; DIFFERENTIATION; INTERLEUKIN-13; T1/ST2 AB Expression of T1ST2, the IL-33R, by Th2 cells requires GATA3. Resting Th2 cells express little GATA3, which is increased by IL-33 and a STAT5 activator, in turn increasing T1ST2 from its low-level expression on resting Th2 cells. Th2 cells that have upregulated T1ST2 produce IL-13, but not IL-4, in response to IL-33 plus a STAT5 activator in an antigen-independent, NF-kappa B-dependent, cyclosporin A (CsA)-resistant manner. Similarly, Th17 cells produce IL-17A in response to IL-1 beta and a STAT3 activator and Th1 cells produce IFN gamma in response to IL-18 and a STAT4 inducer. Thus, each effector Th cell produces cytokines without antigenic stimulation in response to an IL-1 family member and a specific STAT activator, implying an innate mechanism through which memory CD4 T cells are recruited by an induced cytokine environment. C1 [Guo, Liying; Zhu, Jinfang; Paul, William] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wei, Gang; Liao, Wei; Leonard, Warren J.; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Paul, W (reprint author), NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM wpaul@niaid.nih.gov RI Wei, Gang/A-3291-2011; Zhu, Jinfang/B-7574-2012 FU National Institutes of Health; National Institute of Allergy and Infectious Diseases (NIAID) FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID). We thank John O'Shea and Arian Laurence for providing us with Stat5a/Stat5b fl/fl mice prepared in Lothar Hennighausen's laboratory in the National Institute of Diabetes and Digestive and Kidney Diseases, Sarah Tanksley (Laboratory of Immunology, NIAID) for cell sorting, and Shirley Starnes for editorial assistance. NR 35 TC 177 Z9 182 U1 1 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 11 PY 2009 VL 106 IS 32 BP 13463 EP 13468 DI 10.1073/pnas.0906988106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 482IA UT WOS:000268877300058 PM 19666510 ER PT J AU Chen, ZC Moayeri, M Zhao, HY Crown, D Leppla, SH Purcell, RH AF Chen, Zhaochun Moayeri, Mahtab Zhao, Huaying Crown, Devorah Leppla, Stephen H. Purcell, Robert H. TI Potent neutralization of anthrax edema toxin by a humanized monoclonal antibody that competes with calmodulin for edema factor binding SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROTECTIVE ANTIGEN; BACILLUS-ANTHRACIS; LETHAL FACTOR; ADENYLYL-CYCLASE; INHALATIONAL ANTHRAX; GENETIC IMMUNIZATION; KINASE-KINASE; IN-VIVO; IMMUNITY; PROTEIN AB This study describes the isolation and characterization of a neutralizing monoclonal antibody (mAb) against anthrax edema factor, EF13D. EF13D neutralized edema toxin (ET)-mediated cyclic AMP (cAMP) responses in cells and protected mice from both ET-induced footpad edema and systemic ET-mediated lethality. The antibody epitope was mapped to domain IV of EF. The mAb was able to compete with calmodulin (CaM) for EF binding and displaced CaM from EF-CaM complexes. EF-mAb binding affinity (0.05-0.12 nM) was 50- to 130-fold higher than that reported for EF-CaM. This anti-EF neutralizing mAb could potentially be used alone or with an anti-PA mAb in the emergency prophylaxis and treatment of anthrax infection. C1 [Chen, Zhaochun; Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Moayeri, Mahtab; Crown, Devorah; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. [Zhao, Huaying] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Chen, ZC (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM zchen@niaid.nih.gov; rpurcell@niaid.nih.gov RI Zhao, Huaying/F-5716-2012 FU Intramural Research Program of the National Institutes of Health; National Institute of Allergy and Infectious Diseases FX We thank Rasem Fattah for producing the PA, EF, FP119, and other toxin proteins, Michelle Makayi for producing EF13D Fab, and Drs. Susan Emerson and Peter Shuck for helpful discussion. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 43 TC 27 Z9 28 U1 2 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 11 PY 2009 VL 106 IS 32 BP 13487 EP 13492 DI 10.1073/pnas.0906581106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 482IA UT WOS:000268877300062 PM 19651602 ER PT J AU Chen, JB Nikolaitchik, O Singh, J Wright, A Bencsics, CE Coffin, JM Ni, N Lockett, S Pathak, VK Hu, WS AF Chen, Jianbo Nikolaitchik, Olga Singh, Jatinder Wright, Andrew Bencsics, Craig E. Coffin, John M. Ni, Na Lockett, Stephen Pathak, Vinay K. Hu, Wei-Shau TI High efficiency of HIV-1 genomic RNA packaging and heterozygote formation revealed by single virion analysis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Bgl; MS2; dimerization; DIS; fluorescent protein ID IMMUNODEFICIENCY-VIRUS TYPE-1; GENETIC-RECOMBINATION; RETROVIRUS PARTICLES; VIRAL REPLICATION; LIVE CELLS; DIMERIZATION; PROTEIN; PLASMA; RATES AB A long-standing question in retrovirus biology is how RNA genomes are distributed among virions. In the studies presented in this report, we addressed this issue by directly examining HIV-1 RNAs in virions using a modified HIV-1 genome that contained recognition sites for BglG, an antitermination protein in the Escherichia coli bgl operon, which was coexpressed with a fragment of BglG RNA binding protein fused to a fluorescent protein. Our results demonstrate that the majority of virions (>90%) contain viral RNAs. We also coexpressed HIV-1 genomes containing binding sites for BglG or the bacteriophage MS2 coat protein along with 2 fluorescent protein-tagged RNA binding proteins. This method allows simultaneously labeling and discrimination of 2 different RNAs at single-RNA-detection sensitivity. Using this strategy, we obtained physical evidence that virions contain RNAs derived from different parental viruses (heterozygous virion) at ratios expected from a random distribution, and we found that this ratio can be altered by changing the dimerization sequences. Our studies of heterozygous virions also support a generally accepted but unproven assumption that most particles contain 1 dimer. This study provides answers to long-standing questions in HIV-1 biology and illustrates the power and sensitivity of the 2-RNA labeling method, which can also be adapted to analyze various issues of RNA biogenesis including the detection of different RNAs in live cell imaging. C1 [Singh, Jatinder; Wright, Andrew; Bencsics, Craig E.; Coffin, John M.] Tufts Univ, Dept Microbiol, Boston, MA 02111 USA. [Chen, Jianbo; Nikolaitchik, Olga; Ni, Na; Pathak, Vinay K.; Hu, Wei-Shau] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Lockett, Stephen] Sci Applicat Int Corp, Opt Microscopy & Anal Lab, Frederick, MD 21702 USA. RP Coffin, JM (reprint author), Tufts Univ, Dept Microbiol, Boston, MA 02111 USA. EM john.coffin@tufts.edu; whu@ncifcrf.gov RI Chen, Jianbo/N-3737-2014 OI Chen, Jianbo/0000-0001-6491-6577 FU National Institutes of Health [GM38035, R37 CA089441, HHSN261200800001E]; National Cancer Institute; Center for Cancer Research; George Kirby Foundation FX We thank Anne Arthur for her expert editorial help; Drs. Steve Hughes and Eric Freed for suggestions, discussions, and critical reading of the manuscript; Delft University, The Netherlands, for providing DIPimage program; and Dr. Vitaly Boyko for assistance in setting up epifluorescence microscopy. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, National Institutes of Health Grants GM38035 (to A. W.) and R37 CA089441 (to J. M. C.), and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. J. M. C. was a Research Professor of the American Cancer Society, with support from the George Kirby Foundation. NR 23 TC 96 Z9 97 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 11 PY 2009 VL 106 IS 32 BP 13535 EP 13540 DI 10.1073/pnas.0906822106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 482IA UT WOS:000268877300070 PM 19628694 ER PT J AU Androutsellis-Theotokis, A Rueger, MA Park, DM Mkhikian, H Korb, E Poser, SW Walbridge, S Munasinghe, J Koretsky, AP Lonser, RR Mckay, RD AF Androutsellis-Theotokis, Andreas Rueger, Maria A. Park, Deric M. Mkhikian, Haik Korb, Erica Poser, Steve W. Walbridge, Stuart Munasinghe, Jeeva Koretsky, Alan P. Lonser, Russel R. McKay, Ronald D. TI Targeting neural precursors in the adult brain rescues injured dopamine neurons SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neural stem cell; vascular system ID EMBRYONIC STEM-CELLS; PARKINSONS-DISEASE; IN-VIVO; ENDOTHELIAL-CELLS; MOUSE BRAIN; NEURODEGENERATION; TRANSPLANTATION; NEUROGENESIS; ANGIOGENESIS; NICHE AB In Parkinson's disease, multiple cell types in many brain regions are afflicted. As a consequence, a therapeutic strategy that activates a general neuroprotective response may be valuable. We have previously shown that Notch ligands support neural precursor cells in vitro and in vivo. Here we show that neural precursors express the angiopoietin receptor Tie2 and that injections of angiopoietin2 activate precursors in the adult brain. Signaling downstream of Tie2 and the Notch receptor regulate blood vessel formation. In the adult brain, angiopoietin2 and the Notch ligand Dll4 activate neural precursors with opposing effects on the density of blood vessels. A model of Parkinson's disease was used to show that angiopoietin2 and Dll4 rescue injured dopamine neurons with motor behavioral improvement. A combination of growth factors with little impact on the vasculature retains the ability to stimulate neural precursors and protect dopamine neurons. The cellular and pharmacological basis of the neuroprotective effects achieved by these single treatments merits further analysis. C1 [Androutsellis-Theotokis, Andreas; Rueger, Maria A.; Park, Deric M.; Mkhikian, Haik; Korb, Erica; Poser, Steve W.; McKay, Ronald D.] Natl Inst Neurol Disorders & Stroke, Mol Biol Lab, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Walbridge, Stuart; Lonser, Russel R.] Natl Inst Neurol Disorders & Stroke, Clin Neurosurg Sect, Bethesda, MD 20892 USA. [Munasinghe, Jeeva; Koretsky, Alan P.] NIH, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. RP Mckay, RD (reprint author), Natl Inst Neurol Disorders & Stroke, Mol Biol Lab, Porter Neurosci Res Ctr, Bldg 35,Room 3A-201,35 Convent Dr,MSC 3703, Bethesda, MD 20892 USA. EM ronmckay@mail.nih.gov RI Park, Deric/C-5675-2013; Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke; National Institutes of Health; Michael J. Fox Foundation; National Parkinson's Foundation; Tuchman Foundation FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, the Michael J. Fox Foundation, the National Parkinson's Foundation, and the Tuchman Foundation. NR 40 TC 55 Z9 55 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 11 PY 2009 VL 106 IS 32 BP 13570 EP 13575 DI 10.1073/pnas.0905125106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 482IA UT WOS:000268877300076 PM 19628689 ER PT J AU Salzwedel, K Berger, EA AF Salzwedel, Karl Berger, Edward A. TI Complementation of diverse HIV-1 Env defects through cooperative subunit interactions: a general property of the functional trimer SO RETROVIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEIN TRIMERS; MEDIATED MEMBRANE-FUSION; T-CELL LINES; TYPE-1 ENVELOPE; ENTRY INHIBITORS; VACCINIA VIRUS; PRIMARY MACROPHAGES; DEPENDENT FUSION; ATOMIC-STRUCTURE AB Background: The HIV-1 Env glycoprotein mediates virus entry by catalyzing direct fusion between the virion membrane and the target cell plasma membrane. Env is composed of two subunits: gp120, which binds to CD4 and the coreceptor, and gp41, which is triggered upon coreceptor binding to promote the membrane fusion reaction. Env on the surface of infected cells is a trimer consisting of three gp120/gp41 homo-dimeric protomers. An emerging question concerns cooperative interactions between the protomers in the trimer, and possible implications for Env function. Results: We extended studies on cooperative subunit interactions within the HIV-1 Env trimer, using analysis of functional complementation between coexpressed inactive variants harboring different functional deficiencies. In assays of Env-mediated cell fusion, complementation was observed between variants with a wide range of defects in both the gp120 and gp41 subunits. The former included gp120 subunits mutated in the CD4 binding site or incapable of coreceptor interaction due either to mismatched specificity or V3 loop mutation. Defective gp41 variants included point mutations at different residues within the fusion peptide or heptad repeat regions, as well as constructs with modifications or deletions of the membrane proximal tryptophan-rich region or the transmembrane domain. Complementation required the defective variants to be coexpressed in the same cell. The observed complementation activities were highly dependent on the assay system. The most robust activities were obtained with a vaccinia virus-based expression and reporter gene activation assay for cell fusion. In an alternative system involving Env expression from integrated provirus, complementation was detected in cell fusion assays, but not in virus particle entry assays. Conclusion: Our results indicate that Env function does not require every subunit in the trimer to be competent for all essential activities. Through cross-talk between subunits, the functional determinants on one defective protomer can cooperatively interact to trigger the functional determinants on an adjacent protomer(s) harboring a different defect, leading to fusion. Cooperative subunit interaction is a general feature of the Env trimer, based on complementation activities observed for a highly diverse range of functional defects. C1 [Salzwedel, Karl; Berger, Edward A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Berger, EA (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM salzwedelkd@niaid.nih.gov; edward_berger@nih.gov FU Intramural NIH HHS NR 62 TC 11 Z9 11 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD AUG 11 PY 2009 VL 6 AR 75 DI 10.1186/1742-4690-6-75 PG 11 WC Virology SC Virology GA 498MP UT WOS:000270145300003 PM 19671162 ER PT J AU Prins, KW Humston, JL Mehta, A Tate, V Ralston, E Ervasti, JM AF Prins, Kurt W. Humston, Jill L. Mehta, Amisha Tate, Victoria Ralston, Evelyn Ervasti, James M. TI Dystrophin is a microtubule-associated protein SO JOURNAL OF CELL BIOLOGY LA English DT Article ID COLCHICINE-INDUCED RHABDOMYOLYSIS; DUCHENNE MUSCULAR-DYSTROPHY; SKELETAL-MUSCLE; ALPHA-TUBULIN; GLYCOPROTEIN COMPLEX; TERMINAL DOMAIN; GOLGI-COMPLEX; MDX MICE; F-ACTIN; ORGANIZATION AB Cytolinkers are giant proteins that can stabilize cells by linking actin filaments, intermediate filaments, and microtubules (MTs) to transmembrane complexes. Dystrophin is functionally similar to cytolinkers, as it links the multiple components of the cellular cytoskeleton to the transmembrane dystroglycan complex. Although no direct link between dystrophin and MTs has been documented, costamere-associated MTs are disrupted when dystrophin is absent. Using tissue-based cosedimentation assays on mice expressing endogenous dystrophin or truncated transgene products, we find that constructs harboring spectrinlike repeat 24 through the first third of the WW domain cosediment with MTs. Purified Dp260, a truncated isoform of dystrophin, bound MTs with a Kd of 0.66 mu M, a stoichiometry of 1 Dp260/1.4 tubulin heterodimer at saturation, and stabilizes MTs from cold-induced depolymerization. Finally, alpha- and beta-tubulin expression is increased. 2.5-fold in mdx skeletal muscle without altering the tubulin-MT equilibrium. Collectively, these data suggest dystrophin directly organizes and/or stabilizes costameric MTs and classifies dystrophin as a cytolinker in skeletal muscle. C1 [Prins, Kurt W.; Ervasti, James M.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Humston, Jill L.; Ervasti, James M.] Univ Wisconsin, Mol & Cellular Pharmacol Training Program, Madison, WI 53706 USA. [Mehta, Amisha; Tate, Victoria; Ralston, Evelyn] NIAMSD, Light Imaging Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. RP Ervasti, JM (reprint author), Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. EM jervasti@umn.edu FU National Institutes of Health Training Program in Muscle Research [AR007612]; National Institutes of Health [AR042423]; Gregory Marzolf Muscular Dystrophy Fellowships FX This work was supported by the National Institutes of Health Training Program in Muscle Research (AR007612), a grant from the National Institutes of Health (AR042423), and Gregory Marzolf Muscular Dystrophy Fellowships to J. L. Humston and K. W. Prins. K. W. Prins is a member of the Medical Scientist Training Program at the University of Minnesota. E. Ralston, V. Tate, and A. Mehta NR 39 TC 71 Z9 73 U1 0 U2 5 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 AUG 10 PY 2009 VL 186 IS 3 BP 363 EP 369 DI 10.1083/jcb.200905048 PG 7 WC Cell Biology SC Cell Biology GA 481TR UT WOS:000268835300010 PM 19651889 ER PT J AU Linehan, WM AF Linehan, W. Marston TI Genetic Basis of Bilateral Renal Cancer: Implications for Evaluation and Management SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID HOGG-DUBE-SYNDROME; HIPPEL-LINDAU-DISEASE; CELL CARCINOMA; HEREDITARY LEIOMYOMATOSIS; TUBEROUS SCLEROSIS; KIDNEY TUMORS; MUTATIONS; FAMILIES; PARAGANGLIOMA; IDENTIFICATION C1 NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 SC006659-25] NR 35 TC 14 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 EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2009 VL 27 IS 23 BP 3731 EP 3733 DI 10.1200/JCO.2009.23.0045 PG 3 WC Oncology SC Oncology GA 480XF UT WOS:000268769900002 PM 19597019 ER PT J AU Decensi, A Robertson, C Guerrieri-Gonzaga, A Serrano, D Cazzaniga, M Mora, S Gulisano, M Johansson, H Galimberti, V Cassano, E Moroni, SM Formelli, F Lien, EA Pelosi, G Johnson, KA Bonanni, B AF Decensi, Andrea Robertson, Chris Guerrieri-Gonzaga, Aliana Serrano, Davide Cazzaniga, Massimiliano Mora, Serena Gulisano, Marcella Johansson, Harriet Galimberti, Viviana Cassano, Enrico Moroni, Simona M. Formelli, Franca Lien, Ernst A. Pelosi, Giuseppe Johnson, Karen A. Bonanni, Bernardo TI Randomized Double-Blind 2 X 2 Trial of Low-Dose Tamoxifen and Fenretinide for Breast Cancer Prevention in High-Risk Premenopausal Women SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 30-JUN 03, 2008 CL Chicago, IL SP Amer Soc Clin Oncol ID GROWTH-FACTOR-I; SYNTHETIC RETINOID FENRETINIDE; N-(4-HYDROXYPHENYL) RETINAMIDE; BINDING PROTEIN-3; CLINICAL-TRIAL; PHASE-I; THERAPY; INHIBITION; EXPRESSION; AROMATASE AB Purpose Tamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial. Patients and Methods A total of 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), or intraepithelial neoplasia (IEN, n = 160), or 5-year Gail risk >= 1.3% (n = 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years. Results During the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n = 48) was 3.5% +/- 1.0%, 2.1% +/- 0.8%, 4.7% +/- 1.3%, and 5.2% +/- 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen X fenretinide adverse interaction P = .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density. Conclusion Despite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated. C1 [Decensi, Andrea] EO Osped Galliera, Div Med Oncol, I-16128 Genoa, Italy. European Inst Oncol, Div Canc Prevent & Genet, Milan, Italy. European Inst Oncol, Div Breast Surg, Milan, Italy. European Inst Oncol, Div Breast Diagnost, Milan, Italy. European Inst Oncol, Div Gynaecol Surg, Milan, Italy. European Inst Oncol, Div Pathol, Milan, Italy. Univ Milan, Sch Med, I-20122 Milan, Italy. Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Chemoprevent Unit, I-20133 Milan, Italy. Osped S Bortolo, Vicenza, Italy. Univ Strathclyde, Glasgow, Lanark, Scotland. Univ Bergen, Haukeland Univ Hosp, Hormone Lab, Endocrinol Sect,Inst Med, Bergen, Norway. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Decensi, A (reprint author), EO Osped Galliera, Div Med Oncol, Mura Cappuccine 14, I-16128 Genoa, Italy. EM andrea.decensi@galliera.it FU NCI NIH HHS [CA-77183]; Associazione Italiana per la Ricerca sul Cancro NR 43 TC 54 Z9 56 U1 0 U2 10 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2009 VL 27 IS 23 BP 3749 EP 3756 DI 10.1200/JCO.2008.19.3797 PG 8 WC Oncology SC Oncology GA 480XF UT WOS:000268769900006 PM 19597031 ER PT J AU Roy, SW AF Roy, Scott W. TI Intronization, de-intronization and intron sliding are rare in Cryptococcus SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID EUKARYOTIC EVOLUTION; EXON DUPLICATION; HUMAN GENES; GAIN; POSITIONS; GENOME; NEOFORMANS; SELECTION; ORIGIN; CONSERVATION AB Background: Eukaryotic pre-mRNA gene transcripts are processed by the spliceosome to remove portions of the transcript, called spliceosomal introns. The spliceosome recognizes intron boundaries by the presence of sequence signals (motifs) contained in the actual transcript, thus sequence changes in the genome that affect existing splicing signals or create new signals may lead to changes in transcript splicing patterns. Such changes may lead to previously excluded (intronic) transcript regions being included (exonic) or vice versa. Such changes can affect the encoded protein sequence and/or post-transcriptional regulation, and are thus a potentially important source of genomic and phenotypic novelty. Two recent papers suggest that such changes may be a major force in remodeling of eukaryotic gene structures, however the rate of occurrence of such changes has not been assessed at the genomic level. Results: I studied four closely related species of Cryptoccocus fungi. Among 28,256 studied introns, canonical GT/C...AG boundaries are nearly universally conserved across all four species. Among only 40 observed cases of cDNA-confirmed non-conserved intron boundaries, most are likely to involve alternative splicing. I find only five cases of "intronization," intron creation from an internal exonic region by de novo emergence of new splicing boundaries, and no cases of the reverse process, "de-intronization." I find no more than ten clear cases of true movement of an intron boundary of a possibly constitutively spliced intron, and no clear cases of true " intron sliding," in which changes in the positions of both intron boundaries could lead to a movement of the intron position along the coding sequence. Conclusion: These results suggest that intronization, de-intronization, and intron boundary movement are rare events in evolution. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Roy, SW (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM royscott@ncbi.nlm.nih.gov FU Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS FX This research was supported by the Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS. I thank Manuel Irimia and Eugene Koonin for helpful discussions. NR 43 TC 12 Z9 12 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD AUG 7 PY 2009 VL 9 AR 192 DI 10.1186/1471-2148-9-192 PG 10 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 501CG UT WOS:000270356300001 PM 19664208 ER PT J AU Mwinga, K Vermund, SH Chen, YQ Mwatha, A Read, JS Urassa, W Carpenetti, N Valentine, M Goldenberg, RL AF Mwinga, Kasonde Vermund, Sten H. Chen, Ying Q. Mwatha, Anthony Read, Jennifer S. Urassa, Willy Carpenetti, Nicole Valentine, Megan Goldenberg, Robert L. TI Selected hematologic and biochemical measurements in African HIV-infected and uninfected pregnant women and their infants: the HIV Prevention Trials Network 024 protocol SO BMC PEDIATRICS LA English DT Article ID PLATELET COUNTS; HEALTHY; TRANSMISSION; PARAMETERS; CHILDREN; VALUES; BLOOD; SUPPLEMENTATION; BIRTH; RISK AB Background: Reference values for hematological and biochemical assays in pregnant women and in newborn infants are based primarily on Caucasian populations. Normative data are limited for populations in sub-Saharan Africa, especially comparing women with and without HIV infection, and comparing infants with and without HIV infection or HIV exposure. Methods: We determined HIV status and selected hematological and biochemical measurements in women at 20-24 weeks and at 36 weeks gestation, and in infants at birth and 4-6 weeks of age. All were recruited within a randomized clinical trial of antibiotics to prevent chorioamnionitis-associated mother-to-child transmission of HIV (HPTN024). We report nearly complete laboratory data on 2,292 HIV-infected and 367 HIV-uninfected pregnant African women who were representative of the public clinics from which the women were recruited. Nearly all the HIV-infected mothers received nevirapine prophylaxis at the time of labor, as did their infants after birth (always within 72 hours of birth, but typically within just a few hours at the four study sites in Malawi (2 sites), Tanzania, and Zambia. Results: HIV-infected pregnant women had lower red blood cell counts, hemoglobin, hematocrit, and white blood cell counts than HIV-uninfected women. Platelet and monocyte counts were higher among HIV-infected women at both time points. At the 4-6-week visit, HIV-infected infants had lower hemoglobin, hematocrit and white blood cell counts than uninfected infants. Platelet counts were lower in HIV-infected infants than HIV-uninfected infants, both at birth and at 4-6 weeks of age. At 4-6 weeks, HIV-infected infants had higher alanine aminotransferase measures than uninfected infants. Conclusion: Normative data in pregnant African women and their newborn infants are needed to guide the large-scale HIV care and treatment programs being scaled up throughout the continent. These laboratory measures will help interpret clinical data and assist in patient monitoring in a sub-Saharan Africa context. C1 [Vermund, Sten H.] Vanderbilt Univ, Sch Med, Inst Global Hlth, Nashville, TN 37212 USA. [Vermund, Sten H.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. [Mwinga, Kasonde] Univ Teaching Hosp, Dept Paediat, Lusaka, Zambia. [Mwinga, Kasonde] Univ Zambia, Sch Med, Lusaka, Zambia. [Mwinga, Kasonde] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Chen, Ying Q.; Mwatha, Anthony] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. [Read, Jennifer S.] NICHHD, NIH, Bethesda, MD 20892 USA. [Urassa, Willy] Muhimbili Univ, Dar Es Salaam, Tanzania. [Carpenetti, Nicole] Johns Hopkins Univ, Coll Med, Res Project, Blantyre, Malawi. [Valentine, Megan] Family Hlth Int, Chapel Hill, NC USA. [Goldenberg, Robert L.] Drexel Univ, Dept Obstet & Gynecol, Coll Med, Philadelphia, PA 19104 USA. RP Vermund, SH (reprint author), Vanderbilt Univ, Sch Med, Inst Global Hlth, Nashville, TN 37212 USA. EM mwingak@zm.afro.who.int; sten.vermund@vanderbilt.edu; ying@scharp.org; amwatha@scharp.org; readj@exchange.nih.gov; w_urassa@yahoo.co.uk; ncarpenetti@jhu.medcol.mw; mvalentine@hvrc.org; robert.l.goldenberg@drexel.edu OI Vermund, Sten/0000-0001-7289-8698 FU NIAID NIH HHS [U01-AI-048006, N01 AI035173, N01 AI045200, N01-AI-035173, N01-AI-035173-117/412, N01-AI-045200, U01 AI047972, U01 AI048005, U01 AI048006, U01 AI068619, U01-AI-047972, U01-AI-048005, U01-AI-068619] NR 28 TC 7 Z9 7 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2431 J9 BMC PEDIATR JI BMC Pediatr. PD AUG 7 PY 2009 VL 9 AR 49 DI 10.1186/1471-2431-9-49 PG 14 WC Pediatrics SC Pediatrics GA 505RI UT WOS:000270712000001 PM 19664210 ER PT J AU Hu, JJ Shibata, Y Zhu, PP Voss, C Rismanchi, N Prinz, WA Rapoport, TA Blackstone, C AF Hu, Junjie Shibata, Yoko Zhu, Peng-Peng Voss, Christiane Rismanchi, Neggy Prinz, William A. Rapoport, Tom A. Blackstone, Craig TI A Class of Dynamin-like GTPases Involved in the Generation of the Tubular ER Network SO CELL LA English DT Article ID HEREDITARY SPASTIC PARAPLEGIA; ENDOPLASMIC-RETICULUM; MITOCHONDRIAL FUSION; MEMBRANE-PROTEINS; BINDING PARTNERS; GOLGI-APPARATUS; LIVING CELLS; ATLASTIN; GENE; YEAST AB The endoplasmic reticulum ( ER) consists of tubules that are shaped by the reticulons and DP1/Yop1p, but how the tubules form an interconnected network is unknown. Here, we show that mammalian atlastins, which are dynamin-like, integral membrane GTPases, interact with the tubule-shaping proteins. The atlastins localize to the tubular ER and are required for proper network formation in vivo and in vitro. Depletion of the atlastins or overexpression of dominant-negative forms inhibits tubule interconnections. The Sey1p GTPase in S. cerevisiae is likely a functional ortholog of the atlastins; it shares the same signature motifs and membrane topology and interacts genetically and physically with the tubule-shaping proteins. Cells simultaneously lacking Sey1p and a tubule-shaping protein have ER morphology defects. These results indicate that formation of the tubular ER network depends on conserved dynamin-like GTPases. Since atlastin-1 mutations cause a common form of hereditary spastic paraplegia, we suggest ER-shaping defects as a neuropathogenic mechanism. C1 [Hu, Junjie; Shibata, Yoko; Rapoport, Tom A.] Harvard Univ, Sch Med, Dept Cell Biol, Howard Hughes Med Inst, Boston, MA 02115 USA. [Zhu, Peng-Peng; Rismanchi, Neggy; Blackstone, Craig] NINDS, Cellular Neurol Unit, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Voss, Christiane; Prinz, William A.] NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Rapoport, TA (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Howard Hughes Med Inst, 240 Longwood Ave, Boston, MA 02115 USA. EM tom_rapoport@hms.harvard.edu RI Hu, Junjie/F-9713-2013 FU American Heart Association; Intramural Research Programs of the NINDS; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health; Howard Hughes Medical Institute investigator FX We thank H. Jaffe ( National Institute of Neurological Disorders and Stroke; NINDS) for MALDI-TOF analysis, F. Yang ( National Institute of Child Health and Human Development) for providing Xenopus eggs, L. Dreier and G. Voeltz for advice, and P. Carvalho for generating some yeast deletion strains. We thank S. Schulman, A. Palazzo, and D. Pellman for critical reading of the manuscript. Y. S. was supported by the American Heart Association, and C. B. and W. A. P. by the Intramural Research Programs of the NINDS and National Institute of Diabetes and Digestive and Kidney Diseases, respectively, National Institutes of Health. T. A. R. is a Howard Hughes Medical Institute investigator. NR 42 TC 219 Z9 241 U1 1 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 7 PY 2009 VL 138 IS 3 BP 549 EP 561 DI 10.1016/j.cell.2009.05.025 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 480XZ UT WOS:000268771900019 PM 19665976 ER PT J AU Chrispell, JD Feathers, KL Kane, MA Kim, CY Brooks, M Khanna, R Kurth, I Hubner, CA Gal, A Mears, AJ Swaroop, A Napoli, JL Sparrow, JR Thompson, DA AF Chrispell, Jared D. Feathers, Kecia L. Kane, Maureen A. Kim, Chul Y. Brooks, Matthew Khanna, Ritu Kurth, Ingo Huebner, Christian A. Gal, Andreas Mears, Alan J. Swaroop, Anand Napoli, Joseph L. Sparrow, Janet R. Thompson, Debra A. TI Rdh12 Activity and Effects on Retinoid Processing in the Murine Retina SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LEBER CONGENITAL AMAUROSIS; ALL-TRANS-RETINOL; HUMAN RETINOL-DEHYDROGENASE-12 RDH12; SHORT-CHAIN DEHYDROGENASE/REDUCTASE; PERFORMANCE LIQUID-CHROMATOGRAPHY; MANGANESE SUPEROXIDE-DISMUTASE; PHOTORECEPTOR OUTER SEGMENTS; LIGHT-INDUCED DEGENERATION; FALSE DISCOVERY RATE; VISUAL CYCLE AB RDH12 mutations are responsible for early-onset autosomal recessive retinal dystrophy, which results in profound retinal pathology and severe visual handicap in patients. To investigate the function of RDH12 within the network of retinoid dehydrogenases/reductases (RDHs) present in retina, we studied the retinal phenotype of Rdh12-deficient mice. In vivo rates of all-trans-retinal reduction and 11-cis-retinal formation during recovery from bleaching were similar in Rdh12-deficient and wild-type mice matched for an Rpe65 polymorphism that impacts visual cycle efficiency. However, retinal homogenates from Rdh12-deficient mice exhibited markedly decreased capacity to reduce exogenous retinaldehydes in vitro. Furthermore, in vivo levels of the bisretinoid compound diretinoid-pyridinium-ethanolamine (A2E) were increased in Rdh12-deficient mice of various genetic backgrounds. Conversely, in vivo levels of retinoic acid and total retinol were significantly decreased. Rdh12 transcript levels in wild-type mice homozygous for the Rpe65-Leu(450) polymorphism were greater than in Rpe65-Met(450) mice and increased during postnatal development in wild-type mice and Nrl-deficient mice having an all-cone retina. Rdh12-deficient mice did not exhibit increased retinal degeneration relative to wild-type mice at advanced ages, when bred on the light-sensitive BALB/c background, or when heterozygous for a null allele of superoxide dismutase 2 (Sod2(+/-)). Our findings suggest that a critical function of RDH12 is the reduction of all-trans-retinal that exceeds the reductive capacity of the photoreceptor outer segments. C1 Univ Michigan, Sch Med, Dept Biol Chem, Ann Arbor, MI 48105 USA. [Feathers, Kecia L.; Brooks, Matthew; Khanna, Ritu; Mears, Alan J.; Swaroop, Anand; Thompson, Debra A.] Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. [Kane, Maureen A.; Napoli, Joseph L.] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Kim, Chul Y.; Sparrow, Janet R.] Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA. [Kim, Chul Y.; Sparrow, Janet R.] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Kurth, Ingo; Gal, Andreas] Univ Hamburg Eppendorf, Inst Human Genet, D-20251 Hamburg, Germany. [Huebner, Christian A.] Univ Jena, Dept Clin Chem, D-07747 Jena, Germany. [Mears, Alan J.] Univ Ottawa, Inst Eye, Ottawa, ON K1Y 4E9, Canada. [Mears, Alan J.] Ottawa Hlth Res Inst, Ottawa, ON K1Y 4E9, Canada. [Brooks, Matthew; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. RP Thompson, DA (reprint author), Kellogg Eye Ctr, Ann Arbor, MI 48105 USA. EM dathom@med.umich.edu RI Hubner, Christian/A-2950-2017; OI Hubner, Christian/0000-0002-1030-4943; Kurth, Ingo/0000-0002-5642-8378; Swaroop, Anand/0000-0002-1975-1141 FU National Institutes of Health [P30-EY07003, P60-DK-20572, EY11115, AG13566, EY12951]; Functional Genomics of the Retina in Health and Disease (EVI-GENORET) [LSHG-CT-2005-512036]; Foundation Fighting Blindness; Research to Prevent Blindness; Midwest Eye Banks; Kaplan Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grants P30-EY07003 (Michigan Vision Core Grant) and P60-DK-20572 (Michigan Diabetes Research and Training Center). EY11115 (to A. S.), AG13566 (to J. L. N.), and EY12951 (to J. R. S.). This work was also supported by Functional Genomics of the Retina in Health and Disease (EVI-GENORET) Grant LSHG-CT-2005-512036 (to A. G.), the Foundation Fighting Blindness (to D. A. T. and A. S.), Research to Prevent Blindness (to D. A. T. and A. S.), Midwest Eye Banks (to J. D. C.), and the Kaplan Foundation (to J. R. S.). NR 58 TC 25 Z9 25 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 7 PY 2009 VL 284 IS 32 BP 21468 EP 21477 DI 10.1074/jbc.M109.020966 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 478CC UT WOS:000268564400041 PM 19506076 ER PT J AU Tchesnokov, EP Obikhod, A Massud, I Lisco, A Vanpouille, C Brichacek, B Balzarini, J McGuigan, C Derudas, M Margolis, L Schinazi, RF Gotte, M AF Tchesnokov, Egor P. Obikhod, Aleksandr Massud, Ivana Lisco, Andrea Vanpouille, Christophe Brichacek, Beda Balzarini, Jan McGuigan, Christopher Derudas, Marco Margolis, Leonid Schinazi, Raymond F. Goette, Matthias TI Mechanisms Associated with HIV-1 Resistance to Acyclovir by the V75I Mutation in Reverse Transcriptase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HERPES-SIMPLEX-VIRUS; MOLECULAR-MECHANISMS; DRUG-RESISTANCE; DOUBLE-BLIND; POLYMERASE TRANSLOCATION; MULTIDRUG-RESISTANCE; CONFERS RESISTANCE; NUCLEOTIDE ANALOGS; PRIMER UNBLOCKING; INHIBITORS NRTIS AB It has recently been demonstrated that the anti-herpetic drug acyclovir (ACV) also displays antiviral activity against the human immunodeficiency virus type 1 (HIV-1). The triphosphate form of ACV is accepted by HIV-1 reverse transcriptase (RT), and subsequent incorporation leads to classical chain termination. Like all approved nucleoside analogue RT inhibitors (NRTIs), the selective pressure of ACV is associated with the emergence of resistance. The V75I mutation in HIV-1 RT appears to be dominant in this regard. By itself, this mutation is usually not associated with resistance to currently approved NRTIs. Here we studied the underlying biochemical mechanism. We demonstrate that V75I is also selected under the selective pressure of a monophosphorylated prodrug that was designed to bypass the bottleneck in drug activation to the triphosphate form (ACV-TP). Pre-steady-state kinetics reveal that V75I discriminates against the inhibitor at the level of catalysis, whereas binding of the inhibitor remains largely unaffected. The incorporated ACV-monophosphate (ACV-MP) is vulnerable to excision in the presence of the pyrophosphate donor ATP. V75I compromises binding of the next nucleotide that can otherwise provide a certain degree of protection from excision. Collectively, the results of this study suggest that ACV is sensitive to two different resistance pathways, which warrants further investigation regarding the detailed resistance profile of ACV. Such studies will be crucial in assessing the potential clinical utility of ACV and its derivatives in combination with established NRTIs. C1 [Goette, Matthias] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada. [Obikhod, Aleksandr; Massud, Ivana; Schinazi, Raymond F.] Emory Univ, Sch Med & Vet Affairs Med Res, Dept Pediat, Ctr AIDS Res, Atlanta, GA 30322 USA. [Lisco, Andrea; Vanpouille, Christophe; Brichacek, Beda; Margolis, Leonid] Eunice Kennedy Shriver NICHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Balzarini, Jan] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. [McGuigan, Christopher; Derudas, Marco] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales. RP Gotte, M (reprint author), McGill Univ, Dept Microbiol & Immunol, Duff Med Bldg D-6,3775 Univ St, Montreal, PQ H3A 2B4, Canada. EM matthias.gotte@mcgill.ca RI McGuigan, Chris/P-1580-2014 OI McGuigan, Chris/0000-0001-8409-710X FU National Institutes of Health [5R37-AI-041980, 4R37-AI-025899, 5P30-AI-50409]; NICHD; Canadian Institutes for Health Research FX This work was supported, in whole or in part, by National Institutes of Health Grants 5R37-AI-041980, 4R37-AI-025899, and 5P30-AI-50409 (Centers for AIDS Research; to R. F. S.) and by the NICHD Intramural Program (to A. L., C. V., B. B., and L. M.). This study was also supported by the Canadian Institutes for Health Research. NR 62 TC 16 Z9 16 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 AUG 7 PY 2009 VL 284 IS 32 BP 21496 EP 21504 DI 10.1074/jbc.M109.024026 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 478CC UT WOS:000268564400044 PM 19509419 ER PT J AU Liang, GQ Bansal, G Xie, ZH Druey, KM AF Liang, Genqing Bansal, Geetanjali Xie, Zhihui Druey, Kirk M. TI RGS16 Inhibits Breast Cancer Cell Growth by Mitigating Phosphatidylinositol 3-Kinase Signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE PHOSPHORYLATION; PLASMA-MEMBRANE; ACTIVATION; AKT; MUTATIONS; THERAPY; PATHWAY; P110-ALPHA/P85-ALPHA; PROLIFERATION; ASSOCIATION AB Aberrant activity of the phosphatidylinositol 3-kinase (PI3K) pathway supports growth of many tumors including those of breast, lung, and prostate. Resistance of breast cancer cells to targeted chemotherapies including tyrosine kinase inhibitors (TKI) has been linked to persistent PI3K activity, which may in part be due to increased membrane expression of epidermal growth factor (EGF) receptors (HER2 and HER3). Recently we found that proteins of the RGS (regulator of (G) under bar protein signaling) family suppress PI3K activity downstream of the receptor by sequestering its p85 alpha subunit from signaling complexes. Because a substantial percentage of breast tumors have RGS16 mutations and reduced RGS16 protein expression, we investigated the link between regulation of PI3K activity by RGS16 and breast cancer cell growth. RGS16 overexpression in MCF7 breast cancer cells inhibited EGF-induced proliferation and Akt phosphorylation, whereas shRNA-mediated extinction of RGS16 augmented cell growth and resistance to TKI treatment. Exposure to TKI also reduced RGS16 expression in MCF7 and BT474 cell lines. RGS16 bound the amino-terminal SH2 and inter-SH2 domains of p85 alpha and inhibited its interaction with the EGF receptor-associated adapter protein Gab1. These results suggest that the loss of RGS16 in some breast tumors enhances PI3K signaling elicited by growth factors and thereby promotes proliferation and TKI evasion downstream of HER activation. C1 [Liang, Genqing; Bansal, Geetanjali; Xie, Zhihui; Druey, Kirk M.] NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Druey, KM (reprint author), NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, 10 Ctr Dr,Rm 11N242, Bethesda, MD 20892 USA. EM kdruey@niaid.nih.gov RI Bansal, Geetanjali/C-3854-2009; Liang, Genqing/B-7180-2011 FU Intramural Research funding from NIAID, National Institutes of Health FX This work was supported, in whole or in part, by Intramural Research funding from NIAID, National Institutes of Health. NR 35 TC 30 Z9 31 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 7 PY 2009 VL 284 IS 32 BP 21719 EP 21727 DI 10.1074/jbc.M109.028407 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 478CC UT WOS:000268564400064 PM 19509421 ER PT J AU Dagdug, L Berezhkovskii, AM AF Dagdug, Leonardo Berezhkovskii, Alexander M. TI Drift and diffusion in periodic potentials: Upstream and downstream step times are distributed identically SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE diffusion; electric potential; random processes AB This note deals with particles diffusing in one dimension in the presence of a periodic potential and a uniform driving force. We show that (i) the probabilities for the particle to make a step of the length L, where L is the period, in the upstream and downstream directions are independent of the periodic potential, and (ii) the distributions of the step time are independent of the step direction. These two characteristics are used to derive expressions for the effective drift velocity and diffusion coefficient. C1 [Dagdug, Leonardo] Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Dagdug, L (reprint author), Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. EM dll@xanum.uam.mx FU Intramural NIH HHS NR 8 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 AUG 7 PY 2009 VL 131 IS 5 AR 056101 DI 10.1063/1.3179679 PG 3 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 481KT UT WOS:000268809800043 PM 19673587 ER PT J AU Lu, SY Lepore, SD Li, SY Mondal, D Cohn, PC Bhunia, AK Pike, VW AF Lu, Shuiyu Lepore, Salvatore D. Li, Song Ye Mondal, Deboprosad Cohn, Pamela C. Bhunia, Anjan K. Pike, Victor W. TI Nucleophile Assisting Leaving Groups: A Strategy for Aliphatic F-18-Fluorination SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID FLUORINATION; COMPLEXES; MOLECULES; CHEMISTRY; FLUORIDE; ION AB A series of arylsulfonate nucleophile assisting leaving groups (NALGs) were prepared in which the metal chelating unit is attached to the aryl ring via an ether linker. These NALGs exhibited significant rate enhancements in halogenation reactions using metal halides. Studies with a NALG containing a macrocyclic ether unit suggest that rate enhancements of these nucleophilic halogenation reactions are facilitated by stabilization of charge in the transition state rather than through strong precomplexation with metal cation. In several cases, a primary substrate containing one of the new leaving groups rivaled or surpassed the reactivity of triflates when exposed to nucleophile but was otherwise highly stable and isolable. These and previously disclosed chelating leaving groups were used in F-18-fluorination reactions using no-carrier-added [F-18]fluoride ion (t(1/2) = 109.7 min, beta(+) = 97%) in CH3CN. Under microwave irradiation and without the assistance of a cryptand, such as K2.2.2, primary Substrates with select NALGs led to a substantial improvement (2-3-fold) in radiofluorination yields over traditional leaving groups. C1 [Lu, Shuiyu; Pike, Victor W.] Natl Inst Mental Hlth, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Lepore, Salvatore D.; Li, Song Ye; Mondal, Deboprosad; Cohn, Pamela C.; Bhunia, Anjan K.] Florida Atlantic Univ, Dept Chem, Boca Raton, FL 33431 USA. RP Lu, SY (reprint author), Natl Inst Mental Hlth, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. EM shuiyu.lu@mail.nih.gov; slepore@fau.edu OI Lu, Shuiyu/0000-0003-0310-4318 FU National Institute of Mental Health [66963-01]; General Medical Science [073621-01]; NSF [0311369]; Intramural Research Program [Z01-MH-002793] FX We thank the National Institute of Mental Health (66963-01), General Medical Science (073621-01), and NSF (0311369) for financial support. Research by S.Y.L. and VW.P. was supported by the Intramural Research Program (Project Z01-MH-002793) of the NIMH, NTH. We also thank Prof. Predrag Cudic for helpful discussions. NR 33 TC 14 Z9 14 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD AUG 7 PY 2009 VL 74 IS 15 BP 5290 EP 5296 DI 10.1021/jo900700j PG 7 WC Chemistry, Organic SC Chemistry GA 476XO UT WOS:000268480300020 PM 19572583 ER PT J AU Koenigs, M Grafman, J AF Koenigs, Michael Grafman, Jordan TI Prefrontal asymmetry in depression? The long-term effect of unilateral brain lesions SO NEUROSCIENCE LETTERS LA English DT Article DE Depression; Prefrontal cortex; Emotion; Lesion; Laterality ID POSTSTROKE DEPRESSION; MOOD DISORDERS; LOCATION; VETERANS; STROKE AB The proposal that a functional asymmetry in prefrontal cortex (PFC) may play a role in the pathophysiology of depression has sparked vigorous debate and investigation. One particularly contentious issue of clinical and theoretical importance is whether left PFC lesions are associated with the development of depression, and whether any such lesion-depression association is stable over time. To address this issue, we assessed the long-term depressive symptomotology of Vietnam veterans who had acquired left PFC lesions (n = 21), right PFC lesions (n = 18), non-PFC lesions (n = 38), or no brain lesions (n = 31) during the Vietnam War. Depressive symptoms were assessed at two different timepoints, approximately 15 and 35 years after lesion onset, respectively. There was no significant effect of PFC lesion laterality on overall depression severity at either timepoint. These data converge with previous stroke studies to suggest that PFC lesion laterality has no long-term systematic effect on vulnerability to depression. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Koenigs, Michael] Univ Wisconsin, Dept Psychiat, Madison, WI 53719 USA. [Grafman, Jordan] Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Koenigs, M (reprint author), Univ Wisconsin, Dept Psychiat, 6001 Res Pk Blvd, Madison, WI 53719 USA. EM mrkoenigs@wisc.edu; grafmanj@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457; Koenigs, Michael/0000-0002-5799-4881 FU National Institute of Neurological Disorders and Stroke [DAMD17-01-1-0675] FX This work was supported by the National Institute of Neurological Disorders and Stroke intramural research program, DAMD17-01-1-0675 (J.G.). NR 16 TC 6 Z9 6 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD AUG 7 PY 2009 VL 459 IS 2 BP 88 EP 90 DI 10.1016/j.neulet.2009.04.063 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 461GZ UT WOS:000267254100010 PM 19422881 ER PT J AU Rahman, F Pittaluga, S AF Rahman, Fahd Pittaluga, Stefania TI Intravascular lymphoma SO BLOOD LA English DT Editorial Material C1 [Rahman, Fahd; Pittaluga, Stefania] Natl Inst Hlth, Natl Cancer Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 6 PY 2009 VL 114 IS 6 BP 1140 EP 1140 DI 10.1182/blood-2009-01-195149 PG 1 WC Hematology SC Hematology GA 480XI UT WOS:000268770200026 ER PT J AU Suh, HC Ji, M Gooya, J Lee, M Klarmann, KD Keller, JR AF Suh, Hyung Chan Ji, Ming Gooya, John Lee, Michael Klarmann, Kimberly D. Keller, Jonathan R. TI Cell-nonautonomous function of Id1 in the hematopoietic progenitor cell niche SO BLOOD LA English DT Article ID BONE MORPHOGENETIC PROTEIN; EMBRYONIC STEM-CELLS; ENDOTHELIAL-CELLS; TRANSCRIPTIONAL REPRESSION; ERYTHROID-DIFFERENTIATION; REPLICATIVE SENESCENCE; SELF-RENEWAL; EXPRESSION; ANGIOGENESIS; MICE AB Development of hematopoietic stem cells (HSCs) and their immediate progeny is maintained by the interaction with cells in the microenvironment. We found that hematopoiesis was dysregulated in Id1(-/-) mice. Although the frequency of HSCs in Id1(-/-) bone marrow was increased, their total numbers remained unchanged as the result of decreased bone marrow cellularity. In addition, the ability of Id1(-/-) HSCs to self-renew was normal, suggesting Id1 does not affect HSC function. Id1(-/-) progenitors showed increased cycling in vivo but not in vitro, suggesting cell nonautonomous mechanisms for the increased cycling. Id1(-/-) HSCs developed normally when transplanted into Id1(-/-) mice, whereas the development of Id1(-/-) HSCs was impaired in Id1(-/-) recipients undergoing transplantation and reproduced the hematologic features of Id1(-/-) mice, indicating that the Id1(-/-) microenvironment cannot support normal hematopoietic development. Id1(-/-) stromal cells showed altered production of cytokines in vitro, and cytokine levels were deregulated in vivo, which could account for the Id1(-/-) hematopoietic phenotypes. Thus, Id1 is required for regulating the hematopoietic progenitor cell niche but is dispensable for maintaining HSCs. (Blood. 2009; 114: 1186-1195) C1 [Suh, Hyung Chan; Ji, Ming; Gooya, John; Lee, Michael; Klarmann, Kimberly D.; Keller, Jonathan R.] SAIC Frederick Inc, Ctr Canc Res, Natl Canc Inst Frederick, Basic Res Program, Frederick, MD 21702 USA. RP Keller, JR (reprint author), SAIC Frederick Inc, Ctr Canc Res, Natl Canc Inst Frederick, Basic Res Program, Bldg 560,Rm 12-03, Frederick, MD 21702 USA. EM kellerj@ncifcrf.gov RI Ji, Ming/C-2795-2011 FU National Cancer Institute, National Institutes of Health [NO1-CO-12 400] FX We gratefully acknowledge the technical support of Steve Stull, Kathleen Noer, Roberta Matthai, and Samantha Bauchiero. We thank Dr Robert Benezra for his gift of Id1-/- mice. We also thank Drs Nancy Colburn, Sandra Ruscetti, Francis Ruscetti, Peter Johnson, Kristbjorn Gudmundsson, and the National Institutes of Health Fellows Editorial Board for their critical review of the manuscript.; This work was supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number NO1-CO-12 400. NR 47 TC 13 Z9 13 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 6 PY 2009 VL 114 IS 6 BP 1186 EP 1195 DI 10.1182/blood-2008-09-179788 PG 10 WC Hematology SC Hematology GA 480XI UT WOS:000268770200012 PM 19478045 ER PT J AU Rouault, TA Tong, WH AF Rouault, Tracey A. Tong, Wing-Hang TI Tangled Up In Red: Intertwining of the Heme and Iron-Sulfur Cluster Biogenesis Pathways SO CELL METABOLISM LA English DT Editorial Material ID HOMEOSTASIS; DISEASES; PROTEINS AB A large-scale computational and genetic analysis study by Nilsson et al. (2009) has identified five genes that coexpress with heme biosynthetic enzymes and are required for normal heme synthesis. Several are implicated in iron-sulfur cluster biogenesis, and malfunction of these genes may repress heme synthesis by activating the IRE/IRP posttranscriptional regulatory system. C1 [Rouault, Tracey A.; Tong, Wing-Hang] NICHHD, Program Mol Med, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Program Mol Med, Bethesda, MD 20892 USA. EM trou@helix.nih.gov; tongw@mail.nih.gov NR 11 TC 5 Z9 6 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD AUG 6 PY 2009 VL 10 IS 2 BP 80 EP 81 DI 10.1016/j.cmet.2009.07.007 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 480DB UT WOS:000268711200003 PM 19656484 ER PT J AU Kamerlin, SCL Cao, J Rosta, E Warshel, A AF Kamerlin, Shina C. L. Cao, Jie Rosta, Edina Warshel, Arieh TI On Unjustifiably Misrepresenting the EVB Approach While Simultaneously Adopting It SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID MULTICONFIGURATION MOLECULAR-MECHANICS; FREE-ENERGY SIMULATIONS; ENZYMATIC-REACTIONS; CHEMICAL-REACTIONS; DIHYDROFOLATE-REDUCTASE; ELECTROSTATIC ENERGIES; TEMPERATURE-DEPENDENCE; AQUEOUS-SOLUTION; PROTON-TRANSFER; S(N)2 REACTION AB In recent years, the EVB has become a widely used tool in the QM/MM modeling of reactions in condensed phases and in biological systems, with ever increasing popularity. However, despite the fact that its power and validity have been repeatedly established since 1980, a recent work (Valero, R.; et al. J. Chem. Theory Comput. 2009, 5, 1) has strongly criticized this approach, while not discussing the fact that one of the authors is effectively using it himself for both gas-phase and solution studies. Here, we have responded to the most serious unjustified assertions of that paper, covering both the more problematic aspects of that work and the more complex scientific aspects. Additionally, we have demonstrated that the poor EVB results shown in Valero et al. which where presented as verification of the unreliability of the EVB model were in fact obtained by the use of incorrect parameters, without comparing to the correct surface obtained by our program. C1 [Kamerlin, Shina C. L.; Cao, Jie; Warshel, Arieh] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. [Rosta, Edina] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Kamerlin, SCL (reprint author), Univ So Calif, Dept Chem, 3620 McClintock Ave, Los Angeles, CA 90089 USA. EM L.Kamerlin@gmx.at; warshel@usc.edu RI Kamerlin, Shina/G-9554-2011; OI Kamerlin, Shina/0000-0002-3190-1173; Rosta, Edina/0000-0002-9823-4766 FU NIH [GM24492]; University of Southern California High Performance Computing and Communication Centre (HPCC) FX This work was supported by NIH Grant GM24492. All computational work was supported by the University of Southern California High Performance Computing and Communication Centre (HPCC). NR 47 TC 20 Z9 20 U1 1 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD AUG 6 PY 2009 VL 113 IS 31 BP 10905 EP 10915 DI 10.1021/jp901709f PG 11 WC Chemistry, Physical SC Chemistry GA 476XB UT WOS:000268479000045 PM 19606825 ER PT J AU Gopich, IV Szabo, A AF Gopich, Irina V. Szabo, Attila TI Decoding the Pattern of Photon Colors in Single-Molecule FRET SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID RESONANCE ENERGY-TRANSFER; MAXIMUM-LIKELIHOOD-ESTIMATION; CONFORMATIONAL DYNAMICS; CHANNEL KINETICS; FLUORESCENCE; PROTEIN; TRAJECTORIES; DISTRIBUTIONS; SPECTROSCOPY; STATES AB Conformational dynamics of a single molecule can be studied using Forster resonance energy transfer (FRET) by recording a sequence of photons emitted by a donor and an acceptor dye attached to the molecule. We describe a simple and robust method to estimate the rates of transitions between different conformational states and the FRET efficiencies associated with these states. For a photon trajectory with measured interphoton times, the pattern of colors is decoded by maximizing the appropriate likelihood function, This approach can be used to analyze bursts of photons from diffusing molecules as well as photon trajectories generated by immobilized molecules. The procedure is illustrated using simulated photon trajectories corresponding to two-state and three-state molecules. The method works even when the photon colors appear to be scrambled because of high background noise, the photophysical properties of the conformers are similar, or the conformational and photon count rates are comparable. The consistency of the model with the data can be checked by recoloring the photon trajectories and comparing the predicted and observed FRET efficiency histograms. C1 [Gopich, Irina V.; Szabo, Attila] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Gopich, IV (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012 FU National Institutes of Health, NIDDK FX We thank A. M. Berezhkovskii, H. S. Chung, W. A. Eaton, D. Nettels, and B. Schuler for helpful comments and the NIH Fellows Editorial Board for editorial assistance. This work was supported by the Intramural Research Program of the National Institutes of Health, NIDDK. NR 35 TC 68 Z9 68 U1 2 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD AUG 6 PY 2009 VL 113 IS 31 BP 10965 EP 10973 DI 10.1021/jp903671p PG 9 WC Chemistry, Physical SC Chemistry GA 476XB UT WOS:000268479000052 PM 19588948 ER PT J AU Watts, JM Dang, KK Gorelick, RJ Leonard, CW Bess, JW Swanstrom, R Burch, CL Weeks, KM AF Watts, Joseph M. Dang, Kristen K. Gorelick, Robert J. Leonard, Christopher W. Bess, Julian W., Jr. Swanstrom, Ronald Burch, Christina L. Weeks, Kevin M. TI Architecture and secondary structure of an entire HIV-1 RNA genome SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SELECTIVE 2'-HYDROXYL ACYLATION; SINGLE NUCLEOTIDE RESOLUTION; PRIMER EXTENSION SHAPE; CONTEXT-FREE GRAMMARS; REVERSE TRANSCRIPTION; THERMODYNAMIC PARAMETERS; STRUCTURE PREDICTION; PROTEIN EXPRESSION; CODING REGIONS AB Single-stranded RNA viruses encompass broad classes of infectious agents and cause the common cold, cancer, AIDS and other serious health threats. Viral replication is regulated at many levels, including the use of conserved genomic RNA structures. Most potential regulatory elements in viral RNA genomes are uncharacterized. Here we report the structure of an entire HIV-1 genome at single nucleotide resolution using SHAPE, a high-throughput RNA analysis technology. The genome encodes protein structure at two levels. In addition to the correspondence between RNA and protein primary sequences, a correlation exists between high levels of RNA structure and sequences that encode inter-domain loops in HIV proteins. This correlation suggests that RNA structure modulates ribosome elongation to promote native protein folding. Some simple genome elements previously shown to be important, including the ribosomal gag-pol frameshift stem-loop, are components of larger RNA motifs. We also identify organizational principles for unstructured RNA regions, including splice site acceptors and hypervariable regions. These results emphasize that the HIV-1 genome and, potentially, many coding RNAs are punctuated by previously unrecognized regulatory motifs and that extensive RNA structure constitutes an important component of the genetic code. C1 [Watts, Joseph M.; Leonard, Christopher W.; Weeks, Kevin M.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. [Dang, Kristen K.] Univ N Carolina, Dept Biomed Engn, Chapel Hill, NC 27599 USA. [Swanstrom, Ronald] Univ N Carolina, Lineberger Canc Ctr, Chapel Hill, NC 27599 USA. [Burch, Christina L.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Gorelick, Robert J.; Bess, Julian W., Jr.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Weeks, KM (reprint author), Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA. EM weeks@unc.edu OI Burch, Christina/0000-0001-7830-0124 FU US National Institutes of Health [AI068462]; National Cancer Institute [N01-CO-12400, HHSN261200800001E]; National Institutes of Health (NIH) [AI44667, T32 AI07419] FX This project was supported by the US National Institutes of Health (AI068462 to K. M. W.) and by the National Cancer Institute, under contracts N01-CO-12400 and HHSN261200800001E (to R. J. G. and J. W. B.). J. M. W. was supported as a Fellow of the UNC Lineberger Cancer Center and a National Institutes of Health (NIH) Kirschstein Postdoctoral Fellowship. R. S. and K. K. D. were supported by NIH grants AI44667 and T32 AI07419, respectively. We are indebted to D. Mathews and J. Low for assistance with the RNA structure program and genome secondary structure analysis, respectively. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations indicate endorsement by the US Government. NR 53 TC 376 Z9 383 U1 6 U2 79 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 6 PY 2009 VL 460 IS 7256 BP 711 EP U87 DI 10.1038/nature08237 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 479OO UT WOS:000268670300032 PM 19661910 ER PT J AU Frein, JD Taylor, RE Sackett, DL AF Frein, Jeffrey D. Taylor, Richard E. Sackett, Dan L. TI New Sources of Chemical Diversity Inspired by Biosynthesis: Rational Design of a Potent Epothilone Analogue SO ORGANIC LETTERS LA English DT Article ID CONFORMATION-ACTIVITY RELATIONSHIPS; POLYKETIDE NATURAL-PRODUCTS; ALDOL REACTION; ALDEHYDES; CHLORIDE; REAGENTS; ALCOHOLS; TUBULIN; BINDING AB A concise total synthesis of (S)-14-methoxyepothilone D has been accomplished. (S)-14-Methoxyepothilone D represents a conceptually novel example of polyketide analogue design based on an alternative biogenetic pattern of extender units. The significant biological activity observed for this compound provides a foundation to support studies designed to prepare derivatives of this type through fermentation of genetically engineered organisms expressing the epothilone PKS gene cluster. C1 [Frein, Jeffrey D.; Taylor, Richard E.] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. [Frein, Jeffrey D.; Taylor, Richard E.] Univ Notre Dame, Walther Canc Res Ctr, Notre Dame, IN 46556 USA. [Sackett, Dan L.] NICHHD, Lab Integrated & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Taylor, RE (reprint author), Univ Notre Dame, Dept Chem & Biochem, 251 Nieuwland Sci Hall, Notre Dame, IN 46556 USA. EM taylor.61@nd.edu FU National Institutes of General Medical Sciences [GM077683]; Walther Cancer Research Center; Eunice Kennedy Shriver National Institute for Child Health and Human Development FX Dr. Bandaru Sreenivasulu (Notre Dame) is acknowledged for preliminary Studies. Support provided by the National Institutes of General Medical Sciences (GM077683) is gratefully acknowledged. J.D.F. thanks the Walther Cancer Research Center (Notre Darne) for fellowship support. This work was supported in part by intramural funds of the Eunice Kennedy Shriver National Institute for Child Health and Human Development. NR 25 TC 11 Z9 12 U1 1 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD AUG 6 PY 2009 VL 11 IS 15 BP 3186 EP 3189 DI 10.1021/ol900971r PG 4 WC Chemistry, Organic SC Chemistry GA 476XK UT WOS:000268479900007 PM 19572566 ER PT J AU Rollenhagen, JE Kalsy, A Saksena, R Sheikh, A Alam, MM Qadri, F Calderwood, SB Kovac, P Ryan, ET AF Rollenhagen, Julianne E. Kalsy, Anuj Saksena, Rina Sheikh, Alaullah Alam, Mohammad Murshid Qadri, Firdausi Calderwood, Stephen B. Kovac, Pavol Ryan, Edward T. TI Transcutaneous immunization with a synthetic hexasaccharide-protein conjugate induces anti-Vibrio cholerae lipopolysaccharide responses in mice SO VACCINE LA English DT Article DE Cholera; Transcutaneous immunization; Conjugate ID ADP-RIBOSYLATING EXOTOXINS; RURAL EAST PAKISTAN; INFLUENZAE TYPE-B; FIELD-TRIAL AREA; FREE MOUSE MODEL; PROTECTIVE IMMUNITY; ORAL IMMUNIZATION; IN-VIVO; ATTENUATED VACCINE; SEROLOGICAL SURVEY AB Antibodies specific for Vibrio cholerae lipopolysaccaricle (LPS) are common in humans recovering from cholera, and constitute a primary component of the vibriocidal response, a serum complement-mediated bacteriocidal response correlated with protection against cholera. In order to determine whether transcutaneous immunization (TCI) with a V cholerae neoglycoconjugate (CHO-BSA) comprised of a synthetic terminal hexasaccharide of the O-specific polysaccharide of V. cholerae O1 (Ogawa) conjugated with bovine serum albumin (BSA) could induce anti-V. cholerae LPS and vibriocidal responses, we applied CHO-BSA transcutaneously in the presence or absence of the immune adjuvant cholera toxin (CT) to mice. Transcutaneously applied neoglycoconjugate elicited prominent V cholerae specific LPS IgG responses in the presence of CT, but not IgM or IgA responses. CT applied on the skin induced strong IgG and IgA serum responses. TCI with neoglycoconjugate did not elicit detectable vibriocidal responses, protection in a mouse challenge assay, or stool anti-V. cholerae IgA responses, irrespective of the presence or absence of CT. Our results suggest that transcutaneously applied synthetic V. cholerae neoglycoconjugate is safe and immunogenic, but predominantly induces systemic LPS responses of the IgG isotype. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Rollenhagen, Julianne E.; Kalsy, Anuj; Sheikh, Alaullah; Calderwood, Stephen B.; Ryan, Edward T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Rollenhagen, Julianne E.; Calderwood, Stephen B.; Ryan, Edward T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Saksena, Rina; Kovac, Pavol] NIDDK, LBC, Sect Carbohydrates, NIH, Bethesda, MD USA. [Sheikh, Alaullah; Alam, Mohammad Murshid; Qadri, Firdausi] Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh. [Calderwood, Stephen B.] Harvard Univ, Sch Med, Dept Microbiol & Mol Ctr, Boston, MA USA. [Ryan, Edward T.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Ryan, ET (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Jackson 504,55 Fruit St, Boston, MA 02114 USA. EM julianne.rollenhagen@med.navy.mil; etryan@partners.org FU National Institutes of Health; National Institute of Allergy & Infectious Diseases [AI067342, AI40725, AI058935]; Vaccine Development from the Fogarty International Center [TW05572] FX This work was supported by grants from the National Institutes of Health, including the National Institute of Allergy & Infectious Diseases (AI067342 [ETR], AI40725 [ETRI. AI058935 [SBC]), and a Training Grant in Vaccine Development from the Fogarty International Center (TW05572 [AS, FQ]). The authors would like to thank William F. Wade for helpful input. NR 43 TC 10 Z9 10 U1 0 U2 0 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 AUG 6 PY 2009 VL 27 IS 36 BP 4917 EP 4922 DI 10.1016/j.vaccine.2009.06.040 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 484UA UT WOS:000269071800008 PM 19563890 ER PT J AU Karron, RA Talaat, K Luke, C Callahan, K Thumar, B DiLorenzo, S McAuliffe, J Schappell, E Suguitan, A Mills, K Chen, G Lamirande, E Coelingh, K Jin, H Murphy, BR Kemble, G Subbarao, K AF Karron, Ruth A. Talaat, Kawsar Luke, Catherine Callahan, Karen Thumar, Bhagvanji DiLorenzo, Susan McAuliffe, Josephine Schappell, Elizabeth Suguitan, Amorsolo Mills, Kimberly Chen, Grace Lamirande, Elaine Coelingh, Kathleen Jin, Hong Murphy, Brian R. Kemble, George Subbarao, Kanta TI Evaluation of two live attenuated cold-adapted H5N1 influenza virus vaccines in healthy adults SO VACCINE LA English DT Article DE Influenza; Vaccine; Pandemic; H5N1; Clinical trial ID RANDOMIZED CONTROLLED-TRIAL; MF59-ADJUVANTED INFLUENZA; PHASE-I; ANTIBODY-RESPONSES; YOUNG-CHILDREN; SAFETY; IMMUNOGENICITY; CANDIDATE; REASSORTANT; TRIVALENT AB Background: Development of live attenuated influenza vaccines (LAIV) against avian viruses with pandemic potential is an important public health strategy. Methods and findings: We performed open-label trials to evaluate the safety, infectivity, and immunogenicity of H5N1 VN 2004 AA ca and H5N1 HK 2003 AA ca. Each of these vaccines contains a modified H5 hemagglutinin and unmodified N1 neuraminidase from the respective wild-type (wt) parent virus and the six internal protein gene segments of the A/Ann Arbor/6/60 cold-adapted (ca) master donor virus. The H5N1 VN 2004 AA ca vaccine virus was evaluated at dosages of 10(6.7) TCID(50) and 10(7.5) TCID50, and the H5N1 HK 2003 AA ca vaccine was evaluated at a dosage of 10(7.5) TCID(50). Two doses were administered intranasally to healthy adults in isolation at 4-8 week intervals. Vaccine safety was assessed through daily examinations and infectivity was assessed by viral culture and by realtime reverse transcription-polymerase chain reaction testing of nasal wash (NW) specimens. Immunogenicity was assessed by measuring hemagglutination-inhibition (HI) antibodies, neutralizing antibodies, and IgG or IgA antibodies to recombinant (r)H5 VN 2004 hemagglutinin (HA) in serum or NW. Fifty-nine participants were enrolled: 21 received 10(6.7) TCID(50) and 21 received 10(6.7) TCID(50) of H5N1 VN 2004 AA ca and 17 received H5N1 HK 2003 AA ca. Shedding of vaccine virus was minimal, as were HI and neutralizing antibody responses. Fifty-two percent of recipients of 10(7.5) TCID(50) of H5N1 VN 2004 AA ca developed a serum IgA response to rH5 VN 2004 HA. Conclusions: The live attenuated H5N1 VN 2004 and HK 2003 AA ca vaccines bearing avian H5 HA antigens were very restricted in replication and were more attenuated than seasonal LAIV bearing human H1, H3 or B HA antigens. The H5N1 AA ca LAW elicited serum ELISA antibody but not HI or neutralizing antibody responses in healthy adults. (ClinicalTrials.gov Identifiers: NCT00347672 and NC700488046). (C) 2009 Published by Elsevier Ltd. C1 [Karron, Ruth A.; Talaat, Kawsar; Callahan, Karen; Thumar, Bhagvanji; DiLorenzo, Susan; Schappell, Elizabeth] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Baltimore, MD 21205 USA. [Luke, Catherine; McAuliffe, Josephine; Suguitan, Amorsolo; Mills, Kimberly; Chen, Grace; Lamirande, Elaine; Murphy, Brian R.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Coelingh, Kathleen; Jin, Hong; Kemble, George] Medimmune Inc, Gaithersburg, MD 20878 USA. RP Karron, RA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Hampton House 217,624 N Broadway, Baltimore, MD 21205 USA. EM rkarron@jhsph.edu OI Schappell, Elizaeth/0000-0003-2142-5318 FU National Institutes of Health [N01-AI-15444]; MAID Intramural Program FX Financial support: National Institutes of Health N01-AI-15444; Medimmune; MAID Intramural Program. NR 40 TC 70 Z9 73 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 6 PY 2009 VL 27 IS 36 BP 4953 EP 4960 DI 10.1016/j.vaccine.2009.05.099 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 484UA UT WOS:000269071800013 PM 19540952 ER PT J AU Ivanov, V Li, M Mizuuchi, K AF Ivanov, Vassili Li, Min Mizuuchi, Kiyoshi TI Impact of Emission Anisotropy on Fluorescence Spectroscopy and FRET Distance Measurements SO BIOPHYSICAL JOURNAL LA English DT Article ID HEXAGONAL LIPID PHASES; ENERGY-TRANSFER; SINGLE-MOLECULE; STRUCTURAL DYNAMICS; ORIENTATION FACTOR; LATERAL DIFFUSION; POLARIZATION; ARCHITECTURE; JUNCTION; COMPLEX AB The objective of this report is to provide a practical and improved method for estimating Forster resonance energy transfer distance measurement error due to unknown angles in the dipole orientation factor based on emission anisotropy measurements. We improve on the method of Dale et al. (1979), which has minor mistakes and is frequently interpreted in overly optimistic ways in the literature. To facilitate proper fluorescence intensity measurements, we also evaluated instrument parameters that could impact the measurement. The apparent fluorescence intensity of isotropic samples depends on the sample emission anisotropy, fluorometer geometry, and optical apertures. We separate parameters of the sample, and those of the cylindrically symmetric illumination source and detector in the equations describing results of unpolarized and polarized fluorescence intensity measurements. This approach greatly simplifies calculations compared with the more universal method of Axelrod (1989). We provide a full computational method for calculating the Forster resonance energy transfer distance error and present a graph describing distance error in the simplest case. C1 [Ivanov, Vassili; Li, Min; Mizuuchi, Kiyoshi] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ivanov, V (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM ivanovv@niddk.nih.gov FU NIDDK, NIH FX This work was supported by the Intramural Research Program of the NIDDK, NIH. NR 23 TC 26 Z9 26 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG 5 PY 2009 VL 97 IS 3 BP 922 EP 929 DI 10.1016/j.bpj.2009.05.025 PG 8 WC Biophysics SC Biophysics GA 482YK UT WOS:000268926500027 PM 19651051 ER PT J AU Gao, Y Hu, N Han, XY Giffen, C Ding, T Goldstein, A Taylor, P AF Gao, Ying Hu, Nan Han, XiaoYou Giffen, Carol Ding, Ti Goldstein, Alisa Taylor, Philip TI Family history of cancer and risk for esophageal and gastric cancer in Shanxi, China SO BMC CANCER LA English DT Article ID SQUAMOUS-CELL CARCINOMA; UPPER GASTROINTESTINAL-TRACT; HIGH-INCIDENCE AREA; UPPER AERODIGESTIVE TRACT; STOMACH-CANCER; CLINICOPATHOLOGICAL CHARACTERISTICS; GENETIC POLYMORPHISMS; SEGREGATION ANALYSIS; YANGCHENG COUNTY; CARDIA CANCER AB Background: Family history (FH) by different relative types and risk of upper gastrointestinal (UGI) cancers has been only rarely reported; the data on UGI cancer survival are sparse. Methods: 600 esophageal squamous cell carcinoma (ESCC) cases, 598 gastric cardia adenocarcinoma cases, and 316 gastric non-cardia adenocarcinoma cases, and 1514 age-, gender-, and neighborhood-matched controls were asked for FH in first degree relatives and non-blood relatives. Odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regressions, and hazard ratios (HRs) from Cox proportional hazard regressions were estimated. Results: Increased ESCC risk was associated with FH of any cancer (OR = 1.72, 95% CI = 1.39-2.12), FH of any UGI cancer (OR = 2.28, 95% CI = 1.77-2.95) and FH of esophageal cancer (OR = 2.84, 95% CI = 2.09-3.86), but not FH of non-UGI cancer. Individuals with two or more affected first-degree relatives had 10-fold increased ESCC risk. FH of gastric cardia cancer was associated with an increased risk of all three cancers. Cancer in non-blood relatives was not associated with risk of any UGI cancer. FH of UGI cancer was associated with a poorer survival rate among younger ESCC cases (HR = 1.82, 95% CI = 1.01-3.29). Conclusion: These data provide strong evidence that shared susceptibility is involved in esophageal carcinogenesis and also suggest a role in prognosis. C1 [Gao, Ying; Hu, Nan; Goldstein, Alisa; Taylor, Philip] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. [Han, XiaoYou; Ding, Ti] Shanxi Canc Hosp, Taiyuan 030013, Shanxi, Peoples R China. [Giffen, Carol] Informat Management Serv Inc, Silver Spring, MD 20904 USA. RP Gao, Y (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. EM gaoying@mail.nih.gov; nhu@mail.nih.gov; han_xiaoyou@yahoo.com.cn; giffenc@imsweb.com; dingti@yahoo.com; goldstea@mail.nih.gov; ptaylor@mail.nih.gov FU Intramural Research Program of National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This study was supported by the Intramural Research Program of National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The funding unit had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 48 Z9 50 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD AUG 5 PY 2009 VL 9 AR 269 DI 10.1186/1471-2407-9-269 PG 10 WC Oncology SC Oncology GA 489UC UT WOS:000269447300001 PM 19656375 ER PT J AU Greenberg, SJ AF Greenberg, Stephen J. TI Lincoln Logged Incorrectly Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Natl Lib Med, Hist Med Div, Bethesda, MD USA. RP Greenberg, SJ (reprint author), Natl Lib Med, Hist Med Div, Bethesda, MD USA. EM greenbes@mail.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 5 PY 2009 VL 302 IS 5 BP 489 EP 489 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 479DS UT WOS:000268640500011 ER PT J AU Fojo, T Grady, C AF Fojo, Tito Grady, Christine TI How Much Is Life Worth: Cetuximab, Non-Small Cell Lung Cancer, and the $440 Billion Question SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID METASTATIC COLORECTAL-CANCER; PHASE-III TRIAL; HER2-POSITIVE BREAST-CANCER; GROWTH-FACTOR RECEPTOR; ADJUVANT CHEMOTHERAPY; 1ST-LINE TREATMENT; PLUS GEMCITABINE; BEVACIZUMAB; CARCINOMA; THERAPY AB The spiraling cost of cancer care, in particular the cost of cancer therapeutics that achieve only marginal benefits, is under increasing scrutiny. Although health-care professionals avoid putting a value on a life, our limited resources require that society address what counts as a benefit, the extent to which cost should factor in deliberations, and who should be involved in these decisions. Professional societies, such as the American Society of Clinical Oncology, government agencies, including the Food and Drug Administration, and insurance companies should be involved. However, no segment of society is better qualified to address these issues than the oncology community. Oncologists must offer clear guidance for the conduct of research, interpretation of results, and prescription of chemotherapies. We review recent drug approvals and clinical trials and comment on their relevance to the issue of the spiraling cost of oncology therapeutics. We suggest some standards that would serve as a starting point for addressing these issues. C1 [Fojo, Tito] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Fojo, T (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Rm 12 N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov NR 29 TC 186 Z9 188 U1 0 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG 5 PY 2009 VL 101 IS 15 BP 1044 EP 1048 DI 10.1093/jnci/djp177 PG 5 WC Oncology SC Oncology GA 481LQ UT WOS:000268812900005 PM 19564563 ER PT J AU Wang, JB Zuo, XB Yu, P Byeon, IJL Jung, JW Wang, XX Dyba, M Seifert, S Schwieters, CD Qin, J Gronenborn, AM Wang, YX AF Wang, Jinbu Zuo, Xiaobing Yu, Ping Byeon, In-Ja L. Jung, Jinwon Wang, Xiaoxia Dyba, Marzena Seifert, Soenke Schwieters, Charles D. Qin, Jun Gronenborn, Angela M. Wang, Yun-Xing TI Determination of Multicomponent Protein Structures in Solution Using Global Orientation and Shape Restraints SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID INTEGRIN-LINKED KINASE; RESIDUAL DIPOLAR COUPLINGS; NUCLEAR-MAGNETIC-RESONANCE; X-RAY-SCATTERING; SMALL-ANGLE SCATTERING; BIOLOGICAL MACROMOLECULES; SECONDARY STRUCTURE; NMR; COMPLEXES; SPECTROSCOPY AB Determining architectures of multicomponent proteins or protein complexes in solution is a challenging problem. Here we report a methodology that simultaneously uses residual dipolar couplings (RDC) and the small-angle X-ray scattering (SAXS) restraints to mutually orient subunits and define the global shape of multicomponent proteins and protein complexes. Our methodology is implemented in an efficient algorithm and demonstrated using five examples. First, we demonstrate the general approach with simulated data for the HIV-1 protease, a globular homodimeric protein. Second, we use experimental data to determine the structures of the two-domain proteins L11 and gamma D-Crystallin, in which the linkers between the domains are relatively rigid. Finally, complexes with K(d) values in the high micro- to millimolar range (weakly associating proteins), such as a homodimeric GB1 variant, and with K(d) values in the nanomolar range (tightly bound), such as the heterodimeric complex of the ILK ankyrin repeat domain (ARD) and PINCH LIM1 domain, respectively, are evaluated. Furthermore, the proteins or protein complexes that were determined using this method exhibit better solution structures than those obtained by either NMR or X-ray crystallography alone as judged based on the pair-distance distribution functions (PDDF) calculated from experimental SAXS data and back-calculated from the structures. C1 [Wang, Jinbu; Zuo, Xiaobing; Yu, Ping; Wang, Yun-Xing] NCI, Prot Nucle Acid Interact Sect, NIH, Frederick, MD 21702 USA. [Yu, Ping; Dyba, Marzena] NCI, SAIC Frederick Inc, NIH, Frederick, MD 21702 USA. [Byeon, In-Ja L.; Jung, Jinwon; Gronenborn, Angela M.] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15261 USA. [Seifert, Soenke] Argonne Natl Lab, Adv Photon Source, Xray Sci Div, Argonne, IL 60439 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat, Bethesda, MD 20892 USA. [Wang, Xiaoxia; Qin, Jun] Lerner Res Inst, Struct Biol Program, Dept Mol Cardiol, Cleveland, OH 44195 USA. [Dyba, Marzena] NCI, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. RP Wang, YX (reprint author), NCI, Prot Nucle Acid Interact Sect, NIH, Frederick, MD 21702 USA. EM wangyu@ncifcrf.gov RI Zuo, Xiaobing/F-1469-2010; Jung, Jinwon/F-6038-2010; Qin, Jun/D-5559-2009; OI Zuo, Xiaobing/0000-0002-0134-4804; Gronenborn, Angela M/0000-0001-9072-3525 FU NCI of NIH; CIT Intramural Research Program of the NIH; NIH [GM082251, HL58758, GM62823, N01-CO-12400]; National Cancer Institute FX We thank Dr. Xinhua Ji for insightful discussions about the crystallography of weakly associated multisubunit proteins and Dr. David M. Tiede for useful discussion and allowing us using his software for X-ray scattering 2D image processing. This project has been funded in part with federal funds from an intramural grant from the NCI of NIH to Y.X.W., the CIT Intramural Research Program of the NIH to C.D.S., and NIH grants GM082251 and HL58758, GM62823 to A.M.G. and J.Q., respectively. This research was also supported in whole or in part with federal funds from the National Cancer Institute, National Institues of health, under under contract N01-CO-12400. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 41 TC 31 Z9 31 U1 1 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD AUG 5 PY 2009 VL 131 IS 30 BP 10507 EP 10515 DI 10.1021/ja902528f PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 479FF UT WOS:000268644400045 PM 19722627 ER PT J AU Krueger, F Spampinato, MV Barbey, AK Huey, ED Morland, T Grafman, J AF Krueger, Frank Spampinato, Maria Vittoria Barbey, Aron K. Huey, Edward D. Morland, Thomas Grafman, Jordan TI The frontopolar cortex mediates event knowledge complexity: a parametric functional MRI study SO NEUROREPORT LA English DT Article DE frontopolar cortex; hierarchy; humans; prefrontal cortex; sequence ID PREFRONTAL CORTEX; SEQUENCE; FMRI; SPECIALIZATION; ACTIVATION; SCRIPTS; MEMORY AB Event knowledge is organized on the basis of goals that enable the selection of specific event sequences to organize everyday life activities. Although the medial prefrontal cortex represents event knowledge, little is known about its role in mediating event knowledge complexity. We used functional MRI to investigate the patterns of brain activation while healthy volunteers were engaged in the task of evaluating the complexity (i.e. numbers of events) of daily life activities selected on the basis of normative data. Within a left frontoparietal network, we isolated the medial frontopolar cortex as the only region that showed a linear relationship between changes in the blood oxygen level-dependent signal and changes in event knowledge complexity. Our results specify the importance of the medial frontopolar cortex in subserving event knowledge that is required to build and execute complex behavior. NeuroReport 20:1093-1097 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Krueger, Frank; Barbey, Aron K.; Grafman, Jordan] Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Krueger, Frank] George Mason Univ, Krasnow Inst Adv Study, Fairfax, VA 22030 USA. [Spampinato, Maria Vittoria] Med Univ S Carolina, Dept Radiol, Charleston, SC USA. [Huey, Edward D.] Litwin Zucker Res Ctr Study Alzheimers Dis & Memo, Manhasset, NY USA. [Morland, Thomas] Yale Univ, Dept Neurol, New Haven, CT USA. [Morland, Thomas] Yale Univ, Dept Neurosurg, New Haven, CT USA. RP Grafman, J (reprint author), Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bldg 10,Room 7D49,MSC 1440, Bethesda, MD 20892 USA. EM GrafmanJ@ninds.nih.gov RI Barbey, Aron/L-7312-2015; OI Barbey, Aron/0000-0002-6092-0912; Grafman, Jordan H./0000-0001-8645-4457 FU Intramural Research Program of the NIH/NINDS/CNS FX The authors are grateful to Eric Wassermann for his help with performing the neurological exams. This research was supported by the Intramural Research Program of the NIH/NINDS/CNS. NR 25 TC 11 Z9 11 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 5 PY 2009 VL 20 IS 12 BP 1093 EP 1097 DI 10.1097/WNR.0b013e32832e7ea5 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 472VS UT WOS:000268161300011 PM 19590392 ER PT J AU Yoshizawa, K Jelezcova, E Brown, AR Foley, JF Nyska, A Cui, XL Hofseth, LJ Maronpot, RM Wilson, SH Sepulveda, AR Sobol, RW AF Yoshizawa, Katsuhiko Jelezcova, Elena Brown, Ashley R. Foley, Julie F. Nyska, Abraham Cui, Xiangli Hofseth, Lorne J. Maronpot, Robert M. Wilson, Samuel H. Sepulveda, Antonia R. Sobol, Robert W. TI Gastrointestinal Hyperplasia with Altered Expression of DNA Polymerase beta SO PLOS ONE LA English DT Article AB Background: Altered expression of DNA polymerase beta (Pol beta) has been documented in a large percentage of human tumors. However, tumor prevalence or predisposition resulting from Pol beta over-expression has not yet been evaluated in a mouse model. Methodology/Principal Findings: We have recently developed a novel transgenic mouse model that over-expresses Pol beta. These mice present with an elevated incidence of spontaneous histologic lesions, including cataracts, hyperplasia of Brunner's gland and mucosal hyperplasia in the duodenum. In addition, osteogenic tumors in mice tails, such as osteoma and osteosarcoma were detected. This is the first report of elevated tumor incidence in a mouse model of Pol beta overexpression. These findings prompted an evaluation of human gastrointestinal tumors with regard to Pol beta expression. We observed elevated expression of Pol beta in stomach adenomas and thyroid follicular carcinomas, but reduced Pol beta expression in esophageal adenocarcinomas and squamous carcinomas. Conclusions/Significance: These data support the hypothesis that balanced and proficient base excision repair protein expression and base excision repair capacity is required for genome stability and protection from hyperplasia and tumor formation. RP Yoshizawa, K (reprint author), NIEHS, Cellular & Mol Pathol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM rws9@pitt.edu RI Sobol, Robert/E-4125-2013 OI Sobol, Robert/0000-0001-7385-3563 FU Intramural NIH HHS; NCI NIH HHS [1 P20 CA132385-01, 1P50 CA 097190 01A1, P20 CA103730, P20 CA132385, P50 CA097190]; NIA NIH HHS [1 R01 AG24364-01, R01 AG024364]; NIEHS NIH HHS [Z01 ES050158, Z01 ES050159] NR 87 TC 9 Z9 9 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2009 VL 4 IS 8 AR e6493 DI 10.1371/journal.pone.0006493 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 480MN UT WOS:000268739100004 PM 19654874 ER PT J AU Hong, SY Nandurdikar, RS Keefer, LK Saavedra, JE Chakrapani, H AF Hong, Sam Y. Nandurdikar, Rahul S. Keefer, Larry K. Saavedra, Joseph E. Chakrapani, Harinath TI An improved synthesis of V-PROLI/NO, a cytochrome P450-activated nitric oxide prodrug SO TETRAHEDRON LETTERS LA English DT Article ID INDUCED HEPATOTOXICITY; DONOR PRODRUG; PYRRO/NO; LIVER; PROTECTS; MICE; TOXICITY; APOPTOSIS; DESIGN; CELLS AB An improved synthesis of V-PROLI/NO, a cytochrome P450-activated nitric oxide (NO) prodrug, in an overall yield of 26% in four steps from prolinol is reported: the previously published yield of this transformation was 1%. Using this revised strategy, the sarcosine analogue (14) of V-PROLI/NO was prepared. Finally, the methyl ester of V-PROLI/NO (15) was found to be an esterase-activated prodrug form of V-PROLI/NO. Published by Elsevier Ltd. C1 [Saavedra, Joseph E.] NCI, Basic Sci Program, SAIC Frederick, Frederick, MD 21702 USA. [Hong, Sam Y.; Nandurdikar, Rahul S.; Keefer, Larry K.; Chakrapani, Harinath] NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 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; National Cancer Institute [NO1-CO-2008-00001] FX This research was supported in part by the Intramural Research Programme of the NIH, National Cancer Institute, Center for Cancer Research, as well as National Cancer Institute contract NO1-CO-2008-00001 to SAIC. NR 27 TC 1 Z9 1 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD AUG 5 PY 2009 VL 50 IS 31 BP 4545 EP 4548 DI 10.1016/j.tetlet.2009.05.089 PG 4 WC Chemistry, Organic SC Chemistry GA 466OV UT WOS:000267672700039 ER PT J AU Phillips, D Aponte, AM French, SA Chess, DJ Balaban, RS AF Phillips, Darci Aponte, Angel M. French, Stephanie A. Chess, David J. Balaban, Robert S. TI Succinyl-CoA Synthetase Is a Phosphate Target for the Activation of Mitochondrial Metabolism SO BIOCHEMISTRY LA English DT Article ID COENZYME-A SYNTHETASE; HUMAN SKELETAL-MUSCLE; OXIDATIVE-PHOSPHORYLATION; INORGANIC-PHOSPHATE; PERMEABILITY TRANSITION; PROTEIN-PHOSPHORYLATION; HEART-MITOCHONDRIA; P-31 NMR; LIVER-MITOCHONDRIA; TRANSPORT PROTEIN AB Succinyl-CoA synthetase (SCS) is the only mitochondrial enzyme capable of ATP production via substrate level phosphorylation in the absence of oxygen, but it also plays a key role in the citric acid cycle, ketone metabolism, and heme synthesis. Inorganic phosphate (P(i)) is a signaling molecule capable of activating oxidative phosphorylation at several sites, including NADH generation and as a substrate for ATP formation. In this study, it was shown that P(i) binds the porcine heart SCS alpha-subunit (SCS alpha) in a noncovalent manner and enhances its enzymatic activity, thereby providing a new target for P(i) activation in mitochondria. Coupling (32)P labeling of intact mitochondria with SDS gel electrophoresis revealed that (32)P labeling of SCS alpha was enhanced in substrate-depleted mitochondria. Using mitochondrial extracts and purified bacterial SCS (BSCS), we showed that this enhanced (32)P labeling resulted from a simple binding (32)P, not covalent protein phosphorylation. The ability of SCS alpha to retain its (32)P throughout the SDS denaturing gel process was unique over the entire mitochondrial proteome. In vitro studies also revealed a P(i)-induced activation of SCS activity by more than 2-fold when mitochondrial extracts and purified BSCS were incubated with millimolar concentrations of P(i). Since the level of (32)P binding to SCS alpha was increased in subs trate-depleted mitochondria, where the matrix P(i) concentration is increased, we conclude that SCS activation by P(i) binding represents another mitochondrial target for the P(i)-induced activation of oxidative phosphorylation and anaerobic ATP production in energy-limited mitochondria. C1 [Phillips, Darci; French, Stephanie A.; Chess, David J.; 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. 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 National Institutes of Health Division of Intramural Research FX These studies were funded by the National Institutes of Health Division of Intramural Research. NR 59 TC 40 Z9 41 U1 2 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 4 PY 2009 VL 48 IS 30 BP 7140 EP 7149 DI 10.1021/bi900725c PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473TG UT WOS:000268231800007 PM 19527071 ER PT J AU Ma, ZW Piszczek, G Wingfield, PT Sergeev, YV Hejtmancik, JF AF Ma, Zhiwei Piszczek, Grzegorz Wingfield, Paul T. Sergeev, Yuri V. Hejtmancik, J. Fielding TI The G18V CRYGS Mutation Associated with Human Cataracts Increases gamma S-Crystallin Sensitivity to Thermal and Chemical Stress SO BIOCHEMISTRY LA English DT Article ID PROTEIN SECONDARY STRUCTURE; CIRCULAR-DICHROISM SPECTRA; HUMAN EYE LENS; CORTICAL CATARACT; BETA-CRYSTALLIN; JUVENILE-ONSET; GENE; STABILITY; FAMILY; AGE AB gamma S-Crystallin, important in maintaining lens transparency, is a monomeric beta y-crystallin comprising two paired homologous domains, each with two Greek key motifs. An autosomal dominant cortical progressive cataract has been associated with a G18V mutation in human gamma S-crystallin. To investigate the molecular mechanism of this cataract and confirm the causative nature of the G18V mutation, we examined resultant changes in conformation and stability. Human gamma S-crystallin cDNA was cloned into pET-20b(+), and the G18V mutant was generated by site-directed mutagenesis. Recombinant H gamma S-crystallins were expressed in Escherichia coli and purified by ion-exchange and size-exclusion chromatography. By analytical ultracentrifugation wild-type and mutant H gamma S-crystallins are monomers of about 21.95 +/- 0.21 and 20.89 +/- 0.18 kDa, respectively, and have similar secondary structures by far-UV CD. In increasing levels of guanidine hydrochloride (GuHCl), a sharp red shift in fluorescence lambda(max) and increase in emission correlating with exposure of tryptophans to the protein surface are detected earlier in the mutant protein. Under thermal stress, the G18V mutant begins to show changes in tryptophan fluorescence above 42 degrees C and shows a T(m) of 65 degrees C as monitored by CD at 218 nm, while wild-type H gamma S-crystallin is very stable with T(m) values of 75.5 and 75.0 degrees C as measured by fluorescence and CD, respectively. Equilibrium unfolding/refolding experiments as a function of GuHCl confirm the relative instability of the G18V mutant. Wild-type H gamma S-crystallin exhibits a two-state transition and reversible refolding above 1.0 M GuHCl, but the unfolding transition of mutant HyS-crystallin shows an intermediate state. The first transition (N -> I) shows a [GuHCl](1/2) of 0.5 M while the second transition (I -> U) has the same [GuHCl](1/2) as wild-type HyS-crystallin, about 2.0 M. Our present study confirms the high stability of wild-type HyS-crystallin and demonstrates that the G18V mutation destabilizes the protein toward heat and GuHCl-induced unfolding. These biophysical characteristics are consistent with the progressive cataract formation seen in the family members carrying this mutation. C1 [Ma, Zhiwei; Sergeev, Yuri V.; Hejtmancik, J. Fielding] NEI, Bethesda, MD 20892 USA. [Piszczek, Grzegorz] NHLBI, Bethesda, MD 20892 USA. [Wingfield, Paul T.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Hejtmancik, JF (reprint author), NEI, MOGS, OGVFB, NIH, Room 1120,5635 Fishers Lane, Rockville, MD 20852 USA. EM f3h@nei.nih.gov FU Intramural NIH HHS [Z01 EY000272-17, Z01 EY000281-15, Z99 EY999999] NR 35 TC 20 Z9 21 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 4 PY 2009 VL 48 IS 30 BP 7334 EP 7341 DI 10.1021/bi900467a PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 473TG UT WOS:000268231800027 PM 19558189 ER PT J AU Xiao, WB Hong, H Kawakami, Y Kato, Y Wu, DQ Yasudo, H Kimura, A Kubagawa, H Bertoli, LF Davis, RS Chau, LA Madrenas, J Hsia, CC Xenocostas, A Kipps, TJ Hennighausen, L Iwama, A Nakauchi, H Kawakami, T AF Xiao, Wenbin Hong, Hong Kawakami, Yuko Kato, Yuko Wu, Dianqing Yasudo, Hiroki Kimura, Akiko Kubagawa, Hiromi Bertoli, Luigi F. Davis, Randall S. Chau, Luan A. Madrenas, Joaquin Hsia, Cyrus C. Xenocostas, Anargyros Kipps, Thomas J. Hennighausen, Lothar Iwama, Atsushi Nakauchi, Hiromitsu Kawakami, Toshiaki TI Tumor Suppression by Phospholipase C-beta 3 via SHP-1-Mediated Dephosphorylation of Stat5 SO CANCER CELL LA English DT Article ID TYROSINE-PHOSPHATASE SHP-1; COLONY-STIMULATING FACTOR; HEMATOPOIETIC STEM-CELLS; CHRONIC MYELOID-LEUKEMIA; BETA-GAMMA-SUBUNITS; MYELOPROLIFERATIVE DISORDERS; POLYCYTHEMIA-VERA; JAK-STAT5 PATHWAY; SIGNAL TRANSDUCER; SELF-RENEWAL AB Given its catalytic activity to generate diacylglycerol and inositol 1,4,5-trisphosphate, phospholipase C (PLC) is implicated in promoting cell growth. However, we found that PLC-beta 3-deficient mice develop myeloproliferative disease, lymphoma, and other tumors. The mutant mice have increased numbers of hematopoietic stem cells with increased proliferative, survival, and myeloid-differentiative abilities. These properties are dependent on Stat5 and can be antagonized by the protein phosphatase SHP-1. Stat5-dependent cooperative transformation by activec-Myc and PLC-beta 3 deficiency was suggested in mouse lymphomas in PLC-beta 3(-/-) and in E mu-myc;PLC-beta 3(+/-) mice and human Burkitt's lymphoma cells. The same mechanism for malignant transformation seems to be operative in other human lymphoid and myeloid malignancies. Thus, PLC-beta 3 is likely a tumor suppressor. C1 [Xiao, Wenbin; Hong, Hong; Kawakami, Yuko; Yasudo, Hiroki; Kawakami, Toshiaki] La Jolla Inst Allergy & Immunol, Div Cell Biol, La Jolla, CA 92037 USA. [Kato, Yuko; Iwama, Atsushi] Chiba Univ, Grad Sch Med, Dept Cellular & Mol Med, Chiba 2608670, Japan. [Wu, Dianqing] Yale Univ, Sch Med, Program Vasc Biol & Therapeut, New Haven, CT 06520 USA. [Wu, Dianqing] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA. [Kimura, Akiko; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Kubagawa, Hiromi] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. [Davis, Randall S.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Bertoli, Luigi F.] Brookwood Med Ctr, Birmingham, AL 35209 USA. [Chau, Luan A.; Madrenas, Joaquin] Univ Western Ontario, Dept Microbiol & Immunol, London, ON N6A 5K8, Canada. [Hsia, Cyrus C.; Xenocostas, Anargyros] Univ Western Ontario, Dept Med, London, ON N6A 4G5, Canada. [Kipps, Thomas J.] Univ Calif San Diego, Dept Internal Med, La Jolla, CA 92093 USA. [Nakauchi, Hiromitsu] Univ Tokyo, Inst Med Sci, Ctr Med Expt, Lab Stem Cell Therapy, Tokyo 1088639, Japan. RP Kawakami, T (reprint author), La Jolla Inst Allergy & Immunol, Div Cell Biol, La Jolla, CA 92037 USA. EM toshi@liai.org RI Kawakami, Toshiaki/O-1616-2015 FU National Institutes of Health; Diabetes and Immune Disease National Research Institute FX We thank Federico Caligaris-Cappio, James N. Ihle, Toshio Kitamura, John Ryan, Reuben P. Siraganian, Jean Y.J. Wang, and Kirin Pharma for kindly providing reagents; and Shuji Ueda for making some constructs. We are grateful to Michael Poderycki and Yu Kawakami for critical reading of the manuscript. This study was supported in part by grants from the National Institutes of Health to T.K. W.X. was supported in part by funds from the Diabetes and Immune Disease National Research Institute. This is Publication 769 from the La Jolla Institute for Allergy and Immunology. W.X., H.H., Y. Kato, and H.Y. performed experiments; D.W., A.K., and L.H. provided critical reagents; H.K., L.F.B., R.S.D., L.A.C., J.M., C.C.H., A.X., and T.J.K. pi ovided human samples; W.X., Y. Kawakami, A.I., H.N., and T.K. designed experiments and analyzed results; W.X. and T.K. wrote the manuscript. The authors declare that they have no competing financial interests. NR 53 TC 36 Z9 38 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG 4 PY 2009 VL 16 IS 2 BP 161 EP 171 DI 10.1016/j.ccr.2009.05.018 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 480UM UT WOS:000268762400012 PM 19647226 ER PT J AU Davis, BR Simpson, LM Ford, CE Kostis, JB Black, HR Cushman, WC Einhorn, PT Farber, MA Levy, D Massie, BM Nawaz, S AF Davis, Barry R. Simpson, Lara M. Ford, Charles E. Kostis, John B. Black, Henry R. Cushman, William C. Einhorn, Paula T. Farber, Michael A. Levy, Daniel Massie, Barry M. Nawaz, Shah CA ALLHAT Collaborative Res Grp TI Letter by Barrios et al Regarding Article, "Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" Response SO CIRCULATION LA English DT Letter ID CARDIOVASCULAR EVENTS; BLOCKER; ALLHAT C1 [Davis, Barry R.; Simpson, Lara M.; Ford, Charles E.] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Houston, TX USA. [Kostis, John B.] UMDNJ Robert Wood Johnson Med Sch, New Brunswick, NJ USA. [Black, Henry R.] NYU, Sch Med, New York, NY USA. [Cushman, William C.] Memphis Vet Affairs Med Ctr, Memphis, TN USA. [Einhorn, Paula T.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Farber, Michael A.] Crozer Keystone Hlth Network, Upland, PA USA. [Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Massie, Barry M.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Davis, BR (reprint author), Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Houston, TX USA. NR 4 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 AUG 4 PY 2009 VL 120 IS 5 BP E32 EP E32 DI 10.1161/CIRCULATIONAHA.109.854562 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 479DA UT WOS:000268638700020 ER PT J AU Pemberton, VL Kaltman, JR Pearson, GD AF Pemberton, Victoria L. Kaltman, Jonathan R. Pearson, Gail D. TI Children and Clinical Studies: The National Heart, Lung, and Blood Institute's New Multimedia Resource for Pediatric Research SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE pediatrics; clinical trials; informed consent; online educational tool ID ATTITUDES; PARENTS; TRIALS C1 [Pemberton, Victoria L.; Kaltman, Jonathan R.; Pearson, Gail D.] NHLBI, Div Cardiovasc Dis, Bethesda, MD 20892 USA. RP Pemberton, VL (reprint author), NHLBI, Div Cardiovasc Dis, 6701 Rockledge Dr,Room 8202, Bethesda, MD 20892 USA. EM pembertonv@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 13 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 4 PY 2009 VL 54 IS 6 BP 502 EP 504 DI 10.1016/j.jacc.2009.04.041 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 475WY UT WOS:000268397400003 PM 19643309 ER PT J AU Horkay, F Lin, DC AF Horkay, Ferenc Lin, David C. TI Mapping the Local Osmotic Modulus of Polymer Gels SO LANGMUIR LA English DT Article ID ATOMIC-FORCE MICROSCOPY; HUMAN ARTICULAR-CARTILAGE; MECHANICAL-PROPERTIES; ELASTIC PROPERTIES; SWELLING BEHAVIOR; COLLAGEN NETWORK; SCALING CONCEPT; SOFT; PRESSURE; SURFACES AB Polymer gels undergo volume phase transition in a thermodynamically poor solvent as a result of changes in molecular interactions. The osmotic pressure of gels, both synthetic and biological in nature, induces swelling and imparts the materials with the capacity to resist compressive loads. We have investigated the mechanical and swelling properties of poly(vinyl alcohol) (PVA) gels brought into the unstable state by changing the composition of the solvent. Chemically cross-linked PVA gels were prepared and initially swollen in water at 25 degrees C, and then n-propyl alcohol (nonsolvent) was gradually added to the equilibrium liquid. AFM imaging and force-indentation measurements were made in water/n-propyl alcohol mixtures of different composition. It has been found that the elastic modulus of the gels exhibits simple scaling behavior as a function of the polymer concentration in each solvent mixture over the entire concentration range investigated. The power law exponent n obtained for the concentration dependence of the shear modulus increases from 2.3 (in pure water) to 7.4 (in 35% (v/v) water + 65% (v/v) n-propyl alcohol mixture). In the vicinity of the Theta-solvent composition (59% (v/v) water + 41% (v/v) n-propyl alcohol) n approximate to 2.9. Shear and osmotic modulus maps of the phase separating gels have been constructed. It is demonstrated that the latter sensitively reflects the changes both in the topography and thermodynamic interactions occurring in the course of volume phase transition. C1 [Horkay, Ferenc; Lin, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Horkay, F (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov FU NIH; NICHD FX This work was supported by the Intramural Research Program of the NIH, NICHD. NR 58 TC 5 Z9 5 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD AUG 4 PY 2009 VL 25 IS 15 BP 8735 EP 8741 DI 10.1021/la900103j PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 473TD UT WOS:000268231500056 PM 20050048 ER PT J AU Sherrin, T Blank, T Saravana, R Rayner, M Spiess, J Todorovic, C AF Sherrin, T. Blank, T. Saravana, R. Rayner, M. Spiess, J. Todorovic, C. TI REGION SPECIFIC GENE EXPRESSION PROFILE IN MOUSE BRAIN AFTER CHRONIC CORTICOTROPIN RELEASING FACTOR RECEPTOR 1 ACTIVATION: THE NOVEL ROLE FOR DIAZEPAM BINDING INHIBITOR IN CONTEXTUAL FEAR CONDITIONING SO NEUROSCIENCE LA English DT Article DE CRF; priming; prefrontal cortex; hippocampus; anxiety; fear ID PROTEIN-PROTEIN INTERACTIONS; MESSENGER-RNA EXPRESSION; PANIC DISORDER; MICE; ANXIETY; STRESS; EXTINCTION; AMYGDALA; DBI; IDENTIFICATION AB We have previously reported that repeated central administration of sub-anxiogenic doses of the corticotropin releasing factor 1 (CRF(1)) agonist Cortagine, termed "priming," elicits a phenotype of increased anxiety-like behaviors in the elevated plus maze (EPM) and open-field test, and enhanced retention of contextual conditioned fear in C57BL/6J mice. Observed behavioral changes were functionally coupled to CRF(1)-mediated elevated central cholecystokinin (CCK) tone in discrete brain regions. However, the changes in gene expression that mediated "priming"-induced behavioral and concurrent molecular changes in specific brain regions remained unknown. In the present study, a complementary DNA microarray analysis was used to investigate gene expression profiles in the hippocampus and prefrontal cortex (PFC) of C57BL/6J mice following the "priming" procedure. Here, we report that chronic stimulation of CRF(1), by i.c.v. administration of 10 ng Cortagine for five days, brought about alterations in the expression of a wide range of hippocampal (31 genes) and PFC (18 genes) genes, implicated in anxiety and aversive memory formation. These expression changes involved genes associated with signal transduction, neurotransmitter secretion, synaptic transmission, myelination, and others involved in the transport, biosynthesis, and binding of proteins. In particular, several genes of the protein kinase A (PKA) and protein kinase C (PKC) signaling cascades, known to be involved in synaptic plasticity, such as neurogranin, calmodulin 3, and the PKA regulatory subunit 1 b were found to be upregulated in the PFC and hippocampus of CRF, agonist "primed" mice. Moreover, we show pharmacologically that one of the newly implicated memory regulatory elements, diazepam-binding inhibitor (DBI) is functionally involved in hippocampus-dependent enhancement of contextual fear, a cardinal phenotypic feature of the "primed" mice. Finally, an interaction network mapping of the altered genes and their known interacting partners identified additional molecular candidates responsible for CRF(1)-mediated hypersensitive fear circuitry. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Sherrin, T.; Blank, T.; Rayner, M.; Spiess, J.; Todorovic, C.] Univ Hawaii, Specialized Neurosci Res Project 2, John A Burns Sch Med, Honolulu, HI 96813 USA. [Blank, T.; Rayner, M.; Todorovic, C.] Univ Hawaii, Dept Cell & Mol Biol, John A Burns Sch Med, Honolulu, HI 96813 USA. [Sherrin, T.; Spiess, J.] Univ Hawaii, Mol Neuroendocrinol Lab, John A Burns Sch Med, Max Planck Inst Expt Med, Honolulu, HI 96813 USA. [Saravana, R.] NICHD, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Sherrin, T (reprint author), Univ Hawaii, Specialized Neurosci Res Project 2, John A Burns Sch Med, 651 Ilalo St, Honolulu, HI 96813 USA. EM tessi@hawaii.edu FU NIH [5U54NS039406-08]; Max Planck Society FX This work was supported by NIH grant 5U54NS039406-08 and the Max Planck Society. NR 37 TC 8 Z9 8 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD AUG 4 PY 2009 VL 162 IS 1 BP 14 EP 22 DI 10.1016/j.neuroscience.2009.04.012 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 460PT UT WOS:000267200300003 PM 19362130 ER PT J AU Bago, AG Dimitrov, E Saunders, R Seress, L Palkovits, M Usdin, TB Dobolyi, A AF Bago, A. G. Dimitrov, E. Saunders, R. Seress, L. Palkovits, M. Usdin, T. B. Dobolyi, A. TI PARATHYROID HORMONE 2 RECEPTOR AND ITS ENDOGENOUS LIGAND TUBEROINFUNDIBULAR PEPTIDE OF 39 RESIDUES ARE CONCENTRATED IN ENDOCRINE, VISCEROSENSORY AND AUDITORY BRAIN REGIONS IN MACAQUE AND HUMAN SO NEUROSCIENCE LA English DT Article DE tuberoinfundibular peptide; neuroendocrine modulator; primate hypothalamus; subparafascicular area; medial paralemniscal nucleus; in situ hybridization in monkey brain ID MALE SEXUAL-BEHAVIOR; PTH2 RECEPTOR; MESSENGER-RNA; PARAVENTRICULAR NUCLEUS; NERVOUS-SYSTEM; MOUSE-BRAIN; RAT-BRAIN; EXPRESSION; HYPOTHALAMUS; NEURONS AB Parathyroid hormone receptor 2 (PTH2R) and its ligand, tuberoinfundibular peptide of 39 residues (TIP39) constitute a neuromodulator system implicated in endocrine and nociceptive regulation. We now describe the presence and distribution of the PTH2R and TIP39 in the brain of primates using a range of tissues and ages from macaque and human brain. In situ hybridization histochemistry of TIP39 mRNA, studied in young macaque brain, due to its possible decline beyond late postnatal ages, was present only in the thalamic subparafascicular area and the pontine medial paralemniscal nucleus. In contrast, in situ hybridization histochemistry in macaque identified high levels of PTH2R expression in the central amygdaloid nucleus, medial preoptic area, hypothalamic paraventricular and periventricular nuclei, medial geniculate, and the Pontine tegmentum. PTH2R mRNA was also detected in several human brain areas by RT-PCR. The distribution of PTH2R-immunoreactive fibers in human, determined by immunocytochemistry, was similar to that in rodents, including dense fiber networks in the medial preoptic area, hypothalamic paraventricular, periventricular and infundibular (arcuate) nuclei, lateral hypothalamic area, median eminence, thalamic paraventricular nucleus, periaqueductal gray, lateral parabrachial nucleus, nucleus of the solitary tract, sensory trigeminal nuclei, medullary dorsal reticular nucleus, and dorsal horn of the spinal cord. Co-localization suggested that PTH2R fibers are glutamatergic, and that TIP39 may directly influence hypophysiotropic somatostatin containing and indirectly influence corticotropin releasing-hormone containing neurons. The results demonstrate that TIP39 and the PTH2R are expressed in the brain of primates in locations that suggest involvement in regulation of fear, anxiety, reproductive behaviors, release of pituitary hormones, and nociception. Published by Elsevier Ltd on behalf of IBRO. C1 [Dimitrov, E.; Usdin, T. B.] NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. [Bago, A. G.; Palkovits, M.; Dobolyi, A.] Semmelweis Univ, Neuromorphol & Neuroendocrine Res Lab, Dept Anat Histol & Endocrinol, H-1094 Budapest, Hungary. [Bago, A. G.; Palkovits, M.; Dobolyi, A.] Hungarian Acad Sci, H-1094 Budapest, Hungary. [Bago, A. G.] Natl Inst Neurosurg, Budapest, Hungary. [Saunders, R.] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. [Seress, L.] Univ Pecs, Cent Elect Microscop Lab, Pecs, Hungary. RP Usdin, TB (reprint author), NIMH, Sect Fundamental Neurosci, Bldg 35,Room 1B-215,35 Convent Dr,MSC 3728, Bethesda, MD 20892 USA. EM usdint@mail.nih.gov; dobolyi@ana.sote.hu RI Palkovits, Miklos/F-2707-2013; OI Palkovits, Miklos/0000-0003-0578-0387 FU Hungarian Science Foundation [NKTH-OTKA K67646]; EU [LSHM-CT-2004-503039]; NIH, National Institute of Mental Health; Bolyai Janos Scholarship FX We thank Dr. Robert Edwards for providing the antiserum against VGLUT2. The technical assistance of Dorottya Kezdi and Eva Rebeka Szabo is appreciated. The work was supported by the Hungarian Science Foundation NKTH-OTKA K67646 grant for A.D. the Consortial FP6 EU Grant BrainNet II LSHM-CT-2004-503039 for M.P., and the Intramural Research Program of the NIH, National Institute of Mental Health for T.B.U. Arpad Dobolyi is grantee of the Bolyai Janos Scholarship. NR 57 TC 16 Z9 17 U1 0 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD AUG 4 PY 2009 VL 162 IS 1 BP 128 EP 147 DI 10.1016/j.neuroscience.2009.04.054 PG 20 WC Neurosciences SC Neurosciences & Neurology GA 460PT UT WOS:000267200300014 PM 19401215 ER PT J AU Topisirovic, I Gutierrez, GJ Chen, MF Appella, E Borden, KLB Ronai, ZA AF Topisirovic, Ivan Gutierrez, Gustavo J. Chen, Meifan Appella, Ettore Borden, Katherine L. B. Ronai, Ze'ev A. TI Control of p53 multimerization by Ubc13 is JNK-regulated SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE polysomes; ubiquitin ID RIBOSOMAL-PROTEIN L26; PHOSPHORYLATION; LOCALIZATION; TRANSLATION; MUTATIONS; MDM2 AB The p53 tumor suppressor protein is a key regulator of cellular proliferation and survival whose function is tightly regulated at the levels of transcription and protein stability. Here, we unveil the fine control of p53 on translationally active polysomes. We have previously reported that Ubc13, an E2 ubiquitin-conjugating enzyme, directly regulates p53 localization and transcriptional activity. We now demonstrate that the association of p53 and Ubc13 on polysomes requires ongoing translation and results in p53 ubiquitination that interferes with its tetramerization. JNK phosphorylation of p53 at Threonine 81 occurring on polysomes is required for the dissociation of Ubc13 from p53, leading to p53 multimerization and transcriptional activation. Inhibition of JNK activity or expression of a nonphosphorylatable mutant of p53 maintains an Ubc13-p53 complex that inhibits p53 multimerization. Our findings reveal a layer in the regulation of p53 multimerization that requires the concerted action of JNK and Ubc13 on polysome-bound p53. C1 [Topisirovic, Ivan; Borden, Katherine L. B.] Univ Montreal, IRIC, Montreal, PQ H3T 1J4, Canada. [Borden, Katherine L. B.] Univ Montreal, Dept Pathol & Cell Biol, Montreal, PQ H3T 1J4, Canada. [Gutierrez, Gustavo J.; Chen, Meifan; Ronai, Ze'ev A.] Burnham Inst Med Res, Ctr Canc, Signal Transduct Program, La Jolla, CA 92037 USA. [Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Borden, KLB (reprint author), Univ Montreal, IRIC, Montreal, PQ H3T 1J4, Canada. EM katherine.borden@umontreal.ca; ronai@burnham.org RI Gutierrez, Gustavo/B-6771-2013; Topisirovic, Ivan/A-9426-2008; OI Gutierrez, Gustavo/0000-0003-4133-5002; Topisirovic, Ivan/0000-0002-5510-9762; RONAI, ZEEV/0000-0002-3859-0400 FU National Cancer Institute ( NCI) [CA138143, CA078419, CA077109]; National Institutes of Health (NIH) [RO1-80728] FX We thank Ryan Dowling for experimental assistance and members of the Ronai and Borden laboratories for advice; Benoit Grondin and Mathieu Tremblay for help with the luciferase assays; Craig Hauser and Alexy Eroshkin forprofilingarrayandbioinformatic analyses; andMichaelKarin for JNK constructs. This work was supported by National Cancer Institute ( NCI) Grants CA138143, CA078419 ( to Z.R.), and Training Grant CA077109 ( to M. C.); National Institutes of Health (NIH) Grant RO1-80728 ( to K. B.); and a fellowship from the Sass Foundation (G.J.G.). I. T. is a Special Fellow of the Leukemia and Lymphoma Society, USA. M. C. is a member of the Molecular Pathology Graduate Program at the University of California, San Diego (UCSD). NR 18 TC 30 Z9 30 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 4 PY 2009 VL 106 IS 31 BP 12676 EP 12681 DI 10.1073/pnas.0900596106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 479NT UT WOS:000268667600023 PM 19651615 ER PT J AU Hollingsworth, PM Forrest, LL Spouge, JL Hajibabaei, M Ratnasingham, S van der Bank, M Chase, MW Cowan, RS Erickson, DL Fazekas, AJ Graham, SW James, KE Kim, KJ Kress, WJ Schneider, H van AlphenStahl, J Barrett, SCH van den Berg, C Bogarin, D Burgess, KS Cameron, KM Carine, M Chacon, J Clark, A Clarkson, JJ Conrad, F Devey, DS Ford, CS Hedderson, TAJ Hollingsworth, ML Husband, BC Kelly, LJ Kesanakurti, PR Kim, JS Kim, YD Lahaye, R Lee, HL Long, DG Madrinan, S Maurin, O Meusnier, I Newmaster, SG Park, CW Percy, DM Petersen, G Richardson, JE Salazar, GA Savolainen, V Seberg, O Wilkinson, MJ Yi, DK Little, DP AF Hollingsworth, Peter M. Forrest, Laura L. Spouge, John L. Hajibabaei, Mehrdad Ratnasingham, Sujeevan van der Bank, Michelle Chase, Mark W. Cowan, Robyn S. Erickson, David L. Fazekas, Aron J. Graham, Sean W. James, Karen E. Kim, Ki-Joong Kress, W. John Schneider, Harald van AlphenStahl, Jonathan Barrett, Spencer C. H. van den Berg, Cassio Bogarin, Diego Burgess, Kevin S. Cameron, Kenneth M. Carine, Mark Chacon, Juliana Clark, Alexandra Clarkson, James J. Conrad, Ferozah Devey, Dion S. Ford, Caroline S. Hedderson, Terry A. J. Hollingsworth, Michelle L. Husband, Brian C. Kelly, Laura J. Kesanakurti, Prasad R. Kim, Jung Sung Kim, Young-Dong Lahaye, Renaud Lee, Hae-Lim Long, David G. Madrinan, Santiago Maurin, Olivier Meusnier, Isabelle Newmaster, Steven G. Park, Chong-Wook Percy, Diana M. Petersen, Gitte Richardson, James E. Salazar, Gerardo A. Savolainen, Vincent Seberg, Ole Wilkinson, Michael J. Yi, Dong-Keun Little, Damon P. CA CBOL Plant Working Grp TI A DNA barcode for land plants SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE matK; rbcL; species identification ID REGIONS; LOCI AB DNA barcoding involves sequencing a standard region of DNA as a tool for species identification. However, there has been no agreement on which region(s) should be used for barcoding land plants. To provide a community recommendation on a standard plant barcode, we have compared the performance of 7 leading candidate plastid DNA regions (atpF-atpH spacer, matK gene, rbcL gene, rpoB gene, rpoC1 gene, psbK-psbI spacer, and trnH-psbA spacer). Based on assessments of recoverability, sequence quality, and levels of species discrimination, we recommend the 2-locus combination of rbcL + matK as the plant barcode. This core 2-locus barcode will provide a universal framework for the routine use of DNA sequence data to identify specimens and contribute toward the discovery of overlooked species of land plants. C1 [Hollingsworth, Peter M.; Forrest, Laura L.; Clark, Alexandra; Hollingsworth, Michelle L.; Kelly, Laura J.; Long, David G.; Richardson, James E.] Royal Bot Garden Edinburgh, Edinburgh EH3 5LR, Midlothian, Scotland. [Spouge, John L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Computat Biol Branch, Bethesda, MD 20894 USA. [Hajibabaei, Mehrdad; Ratnasingham, Sujeevan; Meusnier, Isabelle] Univ Guelph, Biodivers Inst Ontario, Dept Integrat Biol, Guelph, ON N1G 2W1, Canada. [van der Bank, Michelle; Lahaye, Renaud; Maurin, Olivier] Univ Johannesburg, Dept Bot & Plant Biotechnol, ZA-2006 Johannesburg, South Africa. [Chase, Mark W.; Cowan, Robyn S.; van AlphenStahl, Jonathan; Clark, Alexandra; Clarkson, James J.; Devey, Dion S.; Kelly, Laura J.; Savolainen, Vincent] Royal Bot Gardens, Richmond TW9 3DS, Surrey, England. [Erickson, David L.; Kress, W. John] Smithsonian Inst, Dept Bot, Washington, DC 20013 USA. [Fazekas, Aron J.; Husband, Brian C.; Kesanakurti, Prasad R.; Newmaster, Steven G.] Univ Guelph, Dept Integrat Biol, Guelph, ON N1G 2W1, Canada. [Graham, Sean W.; Percy, Diana M.] Univ British Columbia, UBC Bot Garden & Ctr Plant Res, Fac Land & Food Syst, Vancouver, BC V6T 1Z4, Canada. [Graham, Sean W.; Percy, Diana M.] Univ British Columbia, Dept Bot, Vancouver, BC V6T 1Z4, Canada. [James, Karen E.; Schneider, Harald; Carine, Mark] Nat Hist Museum, Dept Bot, London SW7 5BD, England. [Kim, Ki-Joong; Kim, Jung Sung; Lee, Hae-Lim; Yi, Dong-Keun] Korea Univ, Sch Life Sci & Biotechnol, Seoul 136701, South Korea. [Barrett, Spencer C. H.; Burgess, Kevin S.] Univ Toronto, Dept Ecol & Evolutionary Biol, Toronto, ON M5S 3B2, Canada. [van den Berg, Cassio] Univ Estadual Feira de Santana, Lab Sistemat Mol Plantas, Dept Ciencias Biol, BR-44031460 Feira De Santana, Bahia, Brazil. [Burgess, Kevin S.] Columbus State Univ, Dept Biol, Columbus, GA 31907 USA. [Bogarin, Diego] Univ Costa Rica, Cartago, Costa Rica. [Cameron, Kenneth M.] Univ Wisconsin, Dept Bot, Madison, WI 53508 USA. [Chacon, Juliana; Madrinan, Santiago] Univ Los Andes, Bogota, DC, Colombia. [Conrad, Ferozah] Kirstenbosch Res Ctr, Leslie Hill Mol Systemat Lab, SANBI, ZA-7735 Cape Town, South Africa. [Ford, Caroline S.; Wilkinson, Michael J.] Aberystwyth Univ, Inst Biol Environm & Rural Sci, Aberystwyth SY23 3DA, Dyfed, Wales. [Hedderson, Terry A. J.] Univ Cape Town, Dept Bot, ZA-7700 Rondebosch, South Africa. [Kim, Young-Dong] Hallym Univ, Dept Life Sci, Chunchon 200702, South Korea. [Park, Chong-Wook] Seoul Natl Univ, Sch Biol Sci, Seoul 151742, South Korea. [Petersen, Gitte; Seberg, Ole] Univ Copenhagen, Nat Hist Museum Denmark, DK-1307 Copenhagen K, Denmark. [Salazar, Gerardo A.] Univ Nacl Autonoma Mexico, Inst Biol, Mexico City 04510, DF, Mexico. [Savolainen, Vincent] Imperial Coll London, Ascot SL5 7PY, Berks, England. [Little, Damon P.] New York Bot Garden, Cullman Program Mol Systemat, Bronx, NY 10458 USA. RP Hollingsworth, PM (reprint author), Royal Bot Garden Edinburgh, Edinburgh EH3 5LR, Midlothian, Scotland. EM P.Hollingsworth@rbge.org.uk RI Madrinan, Santiago/A-1149-2010; Chase, Mark /A-6642-2011; Petersen, Gitte/H-1903-2011; Schneider, Harald/B-6681-2008; Seberg, Ole/A-5111-2013; van den Berg, Cassio/B-8968-2008; Herbario Virtual, Inct/J-8725-2013; Barrett, Spencer/M-3751-2013; Ratnasingham, Sujeevan/G-9103-2014; Graham, Sean/L-3944-2014; Chacon Pinilla, Juliana/N-1123-2015; Richardson, James-Edward/L-2768-2016; OI Madrinan, Santiago/0000-0002-0807-6523; Petersen, Gitte/0000-0002-2325-0059; Schneider, Harald/0000-0002-4548-7268; Seberg, Ole/0000-0001-9675-4090; van den Berg, Cassio/0000-0001-5028-0686; Graham, Sean/0000-0001-8209-5231; Chacon Pinilla, Juliana/0000-0003-3993-2553; Richardson, James-Edward/0000-0001-9014-4865; Forrest, Laura/0000-0002-0235-9506; Hollingsworth, Peter/0000-0003-0602-0654; Yi, Dong-Keun/0000-0002-3988-323X NR 24 TC 637 Z9 710 U1 29 U2 235 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 4 PY 2009 VL 106 IS 31 BP 12794 EP 12797 DI 10.1073/pnas.0905845106 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 479NT UT WOS:000268667600043 ER PT J AU Wang, HL Lu, ML Tang, MS Van Houten, B Ross, JBA Weinfeld, M Le, XC AF Wang, Hailin Lu, Meiling Tang, Moon-Shong Van Houten, Bennett Ross, J. B. Alexander Weinfeld, Michael Le, X. Chris TI DNA wrapping is required for DNA damage recognition in the Escherichia coli DNA nucleotide excision repair pathway SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE capillary electrophoresis; laser induced fluorescence polarization; Bacillus caldotenax; fluorescence resonance energy transfer ID UVRAB PROTEIN COMPLEX; CRYSTAL-STRUCTURE; CAPILLARY-ELECTROPHORESIS; FLUORESCENCE POLARIZATION; (A)BC EXCINUCLEASE; BINDING; RESIDUES; SUBUNITS; IDENTIFICATION; INCISION AB Localized DNA melting may provide a general strategy for recognition of the wide array of chemically and structurally diverse DNA lesions repaired by the nucleotide excision repair (NER) pathway. However, it is not clear what causes such DNA melting and how it is driven. Here, we show a DNA wrapping-melting model supported by results from dynamic monitoring of the key DNA-protein and protein-protein interactions involved in the early stages of the Escherichia coli NER process. Using an analytical technique involving capillary electrophoresis coupled with laser-induced fluorescence polarization, which combines a mobility shift assay with conformational analysis, we demonstrate that DNA wrapping around UvrB, mediated by UvrA, is an early event in the damage-recognition process during E. coli NER. DNA wrapping of UvrB was confirmed by Forster resonance energy transfer and fluorescence lifetime measurements. This wrapping did not occur with readily denaturable damaged DNA substrates ("bubble" DNA), suggesting that DNA wrapping of UvrB plays an important role in the induction of DNA melting around the damage site. Analysis of DNA wrapping of mutant UvrB Y96A further suggests that a cooperative interaction between DNA wrapping of UvrA(2)B and contact of the beta-hairpin of UvrB with the bulky damage moiety may be involved in the local DNA melting at the damage site. C1 [Weinfeld, Michael] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Wang, Hailin; Lu, Meiling; Le, X. Chris] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB T6G 2G3, Canada. [Wang, Hailin] Chinese Acad Sci, State Key Lab Environm Chem & Ecotoxicol, Ecoenvironm Sci Res Ctr, Beijing 100085, Peoples R China. [Tang, Moon-Shong] NYU, Dept Environm Med, Tuxedo Pk, NY 10987 USA. [Van Houten, Bennett] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Ross, J. B. Alexander] Univ Montana, Dept Chem & Biochem, Missoula, MT 59812 USA. [Ross, J. B. Alexander] Univ Montana, BioSpect Core Res Lab, Missoula, MT 59812 USA. RP Weinfeld, M (reprint author), Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. EM michaelw@cancerboard.ab.ca; xc.le@ualberta.ca RI Wang, Hong/F-3164-2014; Le, X. Chris/O-4947-2015 OI Wang, Hong/0000-0003-0165-3559; Le, X. Chris/0000-0002-7690-6701 FU Canadian Institutes of Health Research; National Cancer Institute of Canada; Canadian Water Network; Alberta Water Research Institute; Alberta Health and Wellness FX We thank Dr. Oleg Kovalsky (Johns Hopkins University, Baltimore, MD) for providing reagents, Dr. Xing-FangLi (University of Alberta) for valuable discussion and suggestions, and Dr. Sue Edelstein (National Institute of Environmental Health Sciences) for preparing Fig. 5. This work was supported by the Canadian Institutes of Health Research, the National Cancer Institute of Canada(X.C.L. and M.W.), the Natural Sciences and Engineering Research Council of Canada, the Canada Research Chairs Program, the Canadian Water Network, Alberta Water Research Institute, and Alberta Health and Wellness (X.C.L.), 973 Project Grant 2008CB417201 (to H.W.), Natural Science Foundation of China Grants 20677066 and 20621703 (to H.W.), National Institutes of Health Grant P20 RR-15583 (to J.B.A.R.), National Science Foundation Grant MCB-0517644 (to J.B.A.R.), and the National Institutes of Health National Institute of Environmental Health Sciences Intramural Program (B. V. H.). NR 38 TC 31 Z9 32 U1 6 U2 18 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 4 PY 2009 VL 106 IS 31 BP 12849 EP 12854 DI 10.1073/pnas.0902281106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 479NT UT WOS:000268667600053 PM 19549864 ER PT J AU Radtke, I Mullighan, CG Ishii, M Su, XP Cheng, JJ Ma, J Ganti, R Cai, ZL Goorha, S Pounds, SB Cao, XY Obert, C Armstrong, J Zhang, JH Song, GC Ribeiro, RC Rubnitz, JE Raimondi, SC Shurtleff, SA Downing, JR AF Radtke, Ina Mullighan, Charles G. Ishii, Masami Su, Xiaoping Cheng, Jinjun Ma, Jing Ganti, Ramapriya Cai, Zhongling Goorha, Salil Pounds, Stanley B. Cao, Xueyuan Obert, Caroline Armstrong, Jianling Zhang, Jinghui Song, Guangchun Ribeiro, Raul C. Rubnitz, Jeffrey E. Raimondi, Susana C. Shurtleff, Sheila A. Downing, James R. TI Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE copy number alterations; single-nucleotide-polymorphism (SNP); microarray; candidate gene resequencing; loss-of-heterozygosity (LOH) ID ACQUIRED UNIPARENTAL DISOMY; LYMPHOBLASTIC-LEUKEMIA; HOMOZYGOUS DELETIONS; COLORECTAL CANCERS; SNP ARRAYS; MUTATIONS; AML; PATHWAYS; BREAST; TRIALS AB Pediatric de novo acute myeloid leukemia (AML) is an aggressive malignancy with current therapy resulting in cure rates of only 60%. To better understand the cause of the marked heterogeneity in therapeutic response and to identify new prognostic markers and therapeutic targets a comprehensive list of the genetic mutations that underlie the pathogenesis of AML is needed. To approach this goal, we examined diagnostic leukemic samples from a cohort of 111 children with de novo AML using single-nucleotide-polymorphism microarrays and candidate gene resequencing. Our data demonstrate that, in contrast to pediatric acute lymphoblastic leukemia (ALL), de novo AML is characterized by a very low burden of genomic alterations, with a mean of only 2.38 somatic copy-number alterations per leukemia, and less than 1 nonsynonymous point mutation per leukemia in the 25 genes analyzed. Even more surprising was the observation that 34% of the leukemias lacked any identifiable copy-number alterations, and 28% of the leukemias with recurrent translocations lacked any identifiable sequence or numerical abnormalities. The only exception to the presence of few mutations was acute megakaryocytic leukemias, with the majority of these leukemias being characterized by a high number of copy-number alterations but rare point mutations. Despite the low overall number of lesions across the patient cohort, novel recurring regions of genetic alteration were identified that harbor known, and potential new cancer genes. These data reflect a remarkably low burden of genomic alterations within pediatric de novo AML, which is in stark contrast to most other human malignancies. C1 [Radtke, Ina; Mullighan, Charles G.; Ishii, Masami; Su, Xiaoping; Cheng, Jinjun; Ganti, Ramapriya; Cai, Zhongling; Goorha, Salil; Song, Guangchun; Raimondi, Susana C.; Shurtleff, Sheila A.; Downing, James R.] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA. [Pounds, Stanley B.; Cao, Xueyuan] St Jude Childrens Hosp, Dept Biostat, Memphis, TN 38105 USA. [Ribeiro, Raul C.; Rubnitz, Jeffrey E.] St Jude Childrens Hosp, Dept Oncol, Memphis, TN 38105 USA. [Ma, Jing; Obert, Caroline; Armstrong, Jianling] St Jude Childrens Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA. [Zhang, Jinghui] NCI, Ctr Biomed Informat & Informat Technol, NIH, Rockville, MD 20892 USA. RP Downing, JR (reprint author), St Jude Childrens Hosp, Dept Pathol, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM james.downing@stjude.org OI Pounds, Stanley/0000-0002-9167-2114; Mullighan, Charles/0000-0002-1871-1850 FU Cancer Center Core [21765] FX This study was supported by a Cancer Center Core Grant 21765 from the National Cancer Institute, a Leukemia and Lymphoma Society Specialized Center of Research Grant (LLS7015, to J. R. D.), a grant from the National Health and Medical Research Council of Australia ( C. G. M.), and the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital. We thank Claire Boltz, Letha Phillips, and James Dalton for technical assistance. NR 41 TC 91 Z9 94 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 4 PY 2009 VL 106 IS 31 BP 12944 EP 12949 DI 10.1073/pnas.0903142106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 479NT UT WOS:000268667600069 PM 19651601 ER PT J AU Margolis, RN Moore, DD Willson, TM Guy, RK AF Margolis, Ronald N. Moore, David D. Willson, Timothy M. Guy, R. Kip TI Chemical Approaches to Nuclear Receptors in Metabolism SO SCIENCE SIGNALING LA English DT Article ID THYROID-HORMONE; MOLECULAR-BASIS; INHIBITORS; EVOLUTION; SF-1; DNA AB The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a workshop, "Chemical Approaches to Nuclear Receptors and Metabolism," in April 2009 to explore how chemical and molecular biology and physiology can be exploited to further our understanding of nuclear receptor structure, function, and role in disease. Signaling cascades involving nuclear receptors are more complex and interrelated than once thought. Nuclear receptors continue to be attractive targets for drug discovery. The overall goal of this workshop was to identify gaps in our understanding of the complexity of ligand activities and begin to address them by (i) increasing the collaboration of investigators from different disciplines, (ii) developing a better understanding of chemical modulation of nuclear receptor action, and (iii) identifying opportunities and roadblocks in the path of translating basic research to discovery of new therapeutics. C1 [Margolis, Ronald N.] NIDDKD, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. [Moore, David D.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Willson, Timothy M.] GlaxoSmithKline Inc, Dept Exploratory Chem, Res Triangle Pk, NC 27709 USA. [Guy, R. Kip] St Jude Childrens Hosp, Chem Biol & Therapeut Dept, Memphis, TN 38105 USA. RP Margolis, RN (reprint author), NIDDKD, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. EM rm76f@nih.gov RI Guy, Rodney/J-7107-2013 OI Guy, Rodney/0000-0002-9638-2060 FU Intramural NIH HHS [Z99 DK999999] NR 27 TC 2 Z9 2 U1 0 U2 2 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 AUG 4 PY 2009 VL 2 IS 82 AR mr5 DI 10.1126/scisignal.282mr5 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 569MN UT WOS:000275601300001 PM 19654413 ER PT J AU Bolland, S Garcia-Sastre, A AF Bolland, Silvia Garcia-Sastre, Adolfo TI Vicious circle: systemic autoreactivity in Ro52/TRIM21-deficient mice SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID AICARDI-GOUTIERES-SYNDROME; INTERFERON-INDUCIBLE GENE; LUPUS-ERYTHEMATOSUS; I INTERFERON; DENDRITIC CELLS; CYTOKINE EXPRESSION; SJOGRENS-SYNDROME; FAMILY PROTEINS; UP-REGULATION; IFN-ALPHA AB Dysregulated innate responses, particularly excessive activation of interferon (IFN) pathways, have been implicated in the development of autoimmune pathologies. Autoreactivity frequently targets IFN-inducible genes such as the Ro autoantigens, which ubiquitinate and inhibit interferon regulatory factors (IRFs). A new study validates the role of these common autoantigens in preventing autoimmunity. The findings reveal that injury-induced systemic autoimmune disease is exacerbated in the absence of Ro52/Trim21 and is driven by the IL-23-Th17 pathway. C1 [Bolland, Silvia] NIAID, NIH, Immunogenet Lab, Rockville, MD 20852 USA. [Garcia-Sastre, Adolfo] Mt Sinai Sch Med, Pathogens Inst, New York, NY 10029 USA. RP Bolland, S (reprint author), NIAID, NIH, Immunogenet Lab, Rockville, MD 20852 USA. EM SBolland@niaid.nih.gov OI Garcia-Sastre, Adolfo/0000-0002-6551-1827 FU Intramural NIH HHS; NIAID NIH HHS [U01AI070469, P01 AI082325, U19AI083025, R01AI46954, P01AI082325, P01AI058113, P01 AI058113, HHSN266200700010C, U19 AI083025, R01 AI046954, U54 AI057158, U01 AI070469]; PHS HHS [HHSN266200700010C] NR 50 TC 15 Z9 17 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 3 PY 2009 VL 206 IS 8 BP 1647 EP 1651 DI 10.1084/jem.20091507 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 478OY UT WOS:000268598800003 PM 19635865 ER PT J AU Steinfelder, S Andersen, JF Cannons, JL Feng, CG Joshi, M Dwyer, D Caspar, P Schwartzberg, PL Sher, A Jankovic, D AF Steinfelder, Svenja Andersen, John F. Cannons, Jennifer L. Feng, Carl G. Joshi, Manju Dwyer, Dennis Caspar, Pat Schwartzberg, Pamela L. Sher, Alan Jankovic, Dragana TI The major component in schistosome eggs responsible for conditioning dendritic cells for Th2 polarization is a T2 ribonuclease (omega-1) SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID MOLECULAR CHARACTERIZATION; CUTTING EDGE; MANSONI EGGS; ALLERGEN; ACTIVATION; MECHANISM; PHENOTYPE; PATHWAY; MICE AB Schistosoma mansoni eggs contain factors that trigger potent Th2 responses in vivo and condition mouse dendritic cells (DCs) to promote Th2 lymphocyte differentiation. Using an in vitro bystander polarization assay as the readout, we purified and identified the major Th2-inducing component from soluble egg extract (SEA) as the secreted T2 ribonuclease, omega-1. The Th2-promoting activity of omega-1 was found to be sensitive to ribonuclease inhibition and did not require MyD88/TRIF signaling in DCs. In common with unfractioned SEA, the purified native protein suppresses lipopolysaccharide-induced DC activation, but unlike SEA, it fails to trigger interleukin 4 production from basophils. Importantly, omega-1-exposed DCs displayed pronounced cytoskeletal changes and exhibited decreased antigen-dependent conjugate formation with CD4(+) T cells. Based on this evidence, we hypothesize that S. mansoni omega-1 acts by limiting the interaction of DCs with CD4(+) T lymphocytes, thereby lowering the strength of the activation signal delivered. C1 [Steinfelder, Svenja; Feng, Carl G.; Caspar, Pat; Sher, Alan; Jankovic, Dragana] NIAID, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. [Joshi, Manju; Dwyer, Dennis] NIAID, Cell Biol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Andersen, John F.] NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Cannons, Jennifer L.; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Jankovic, D (reprint author), NIAID, Immunobiol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ASher@niaid.nih.gov; DJankovic@niaid.nih.gov FU Intramural Research Program of the NIAID; National Institutes of Health; German Academic Exchange Service and the Karl-Enigk Foundation FX The authors have no conflicting financial interests. NR 35 TC 165 Z9 174 U1 1 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 3 PY 2009 VL 206 IS 8 BP 1681 EP 1690 DI 10.1084/jem.20082462 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 478OY UT WOS:000268598800007 PM 19635859 ER PT J AU Cadera, EJ Wan, FY Amin, RH Nolla, H Lenardo, MJ Schlissel, MS AF Cadera, Emily J. Wan, Fengyi Amin, Rupesh H. Nolla, Hector Lenardo, Michael J. Schlissel, Mark S. TI NF-kappa B activity marks cells engaged in receptor editing SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID V(D)J RECOMBINATION; BONE-MARROW; LYMPHOCYTE DEVELOPMENT; NUCLEAR-FACTOR; TRANSCRIPTION FACTORS; REGULATORY FACTOR-4; ANTIBODY REPERTOIRE; CHAIN; ACTIVATION; GENE AB Because of the extreme diversity in immunoglobulin genes, tolerance mechanisms are necessary to ensure that B cells do not respond to self-antigens. One such tolerance mechanism is called receptor editing. If the B cell receptor (BCR) on an immature B cell recognizes self-antigen, it is down-regulated from the cell surface, and light chain gene rearrangement continues in an attempt to edit the autoreactive specificity. Analysis of a heterozygous mutant mouse in which the NF-kappa B-dependent I kappa B alpha gene was replaced with a lacZ (beta-gal) reporter complementary DNA (cDNA; I kappa B alpha(+/lacZ)) suggests a potential role for NF-kappa B in receptor editing. Sorted beta-gal(+) pre-B cells showed increased levels of various markers of receptor editing. In I kappa B alpha(+/lacZ) reporter mice expressing either innocuous or self-specific knocked in BCRs, beta-gal was preferentially expressed in pre-B cells from the mice with self-specific BCRs. Retroviral-mediated expression of a cDNA encoding an I kappa B alpha. superrepressor in primary bone marrow cultures resulted in diminished germline kappa and rearranged lambda transcripts but similar levels of RAG expression as compared with controls. We found that IRF4 transcripts were up-regulated in beta-gal(+) pre-B cells. Because IRF4 is a target of NF-kappa B and is required for receptor editing, we suggest that NF-kappa B could be acting through IRF4 to regulate receptor editing. C1 [Cadera, Emily J.; Amin, Rupesh H.; Nolla, Hector; Schlissel, Mark S.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Wan, Fengyi; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Schlissel, MS (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. EM mss@berkeley.edu FU National Institutes of Health [R01 HL48702] FX This work was supported by a grant from the National Institutes of Health (R01 HL48702) to M. S. Schlissel. NR 50 TC 21 Z9 23 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 3 PY 2009 VL 206 IS 8 BP 1803 EP 1816 DI 10.1084/jem.20082815 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 478OY UT WOS:000268598800017 PM 19581408 ER PT J AU Quaia, C Ying, HS Optican, LM AF Quaia, Christian Ying, Howard S. Optican, Lance M. TI The Viscoelastic Properties of Passive Eye Muscle in Primates. II: Testing the Quasi-Linear Theory SO PLOS ONE LA English DT Article AB We have extensively investigated the mechanical properties of passive eye muscles, in vivo, in anesthetized and paralyzed monkeys. The complexity inherent in rheological measurements makes it desirable to present the results in terms of a mathematical model. Because Fung's quasi-linear viscoelastic (QLV) model has been particularly successful in capturing the viscoelastic properties of passive biological tissues, here we analyze this dataset within the framework of Fung's theory. We found that the basic properties assumed under the QLV theory ( separability and superposition) are not typical of passive eye muscles. We show that some recent extensions of Fung's model can deal successfully with the lack of separability, but fail to reproduce the deviation from superposition. While appealing for their elegance, the QLV model and its descendants are not able to capture the complex mechanical properties of passive eye muscles. In particular, our measurements suggest that in a passive extraocular muscle the force does not depend on the entire length history, but to a great extent is only a function of the last elongation to which it has been subjected. It is currently unknown whether other passive biological tissues behave similarly. RP Quaia, C (reprint author), NEI, Sensorimotor Res Lab, Bldg 10, Bethesda, MD 20892 USA. EM quaiac@nei.nih.gov FU NEI NIH HHS [K12 EY015025, R01 EY019347, EY15025, EY19347] NR 54 TC 9 Z9 9 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 3 PY 2009 VL 4 IS 8 AR e6480 DI 10.1371/journal.pone.0006480 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 479CV UT WOS:000268637700006 PM 19649257 ER PT J AU Raghavachari, N Xu, XL Munson, PJ Gladwin, MT AF Raghavachari, Nalini Xu, Xiuli Munson, Peter J. Gladwin, Mark T. TI Characterization of Whole Blood Gene Expression Profiles as a Sequel to Globin mRNA Reduction in Patients with Sickle Cell Disease SO PLOS ONE LA English DT Article AB Global transcriptome analysis of whole blood RNA using microarrays has been proven to be challenging due to the high abundance of globin transcripts that constitute 70% of whole blood mRNA. This is a particular problem in patients with sickle cell disease, secondary to the high abundance of globin-expressing nucleated red blood cells and reticulocytes in the circulation. In order to accurately measure the steady state blood transcriptome in sickle cell patients we evaluated the efficacy of reducing globin transcripts in PAXgene stabilized RNA for genome-wide transcriptome analyses using microarrays. We demonstrate here by both microarrays and Q-PCR that the globin mRNA depletion method resulted in 5565 fold reduction in globin transcripts in whole blood collected from healthy volunteers and sickle cell disease patients. This led to an improvement in microarray data quality by reducing data variability, with increased detection rate of expressed genes and improved overlap with the expression signatures of isolated peripheral blood mononuclear (PBMC) preparations. Analysis of differences between the whole blood transcriptome and PBMC transcriptome revealed important erythrocyte genes that participate in sickle cell pathogenesis and compensation. The combination of globin mRNA reduction after whole-blood RNA stabilization represents a robust clinical research methodology for the discovery of biomarkers for hematologic diseases. RP Raghavachari, N (reprint author), NHLBI, NIH, Pulm & Vasc Med Branch, Bldg 10, Bethesda, MD 20892 USA. EM nraghavachari@nhlbi.nih.gov NR 13 TC 21 Z9 21 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 AUG 3 PY 2009 VL 4 IS 8 AR e6484 DI 10.1371/journal.pone.0006484 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 479CV UT WOS:000268637700009 PM 19649296 ER PT J AU Ahlborn, GJ Nelson, GM Grindstaff, RD Waalkes, MP Diwan, BA Allen, JW Kitchin, KT Preston, RJ Hernandez-Zavala, A Adair, B Thomas, DJ Delker, DA AF Ahlborn, Gene J. Nelson, Gail M. Grindstaff, Rachel D. Waalkes, Michael P. Diwan, Bhalchandra A. Allen, James W. Kitchin, Kirk T. Preston, R. Julian Hernandez-Zavala, Araceli Adair, Blakely Thomas, David J. Delker, Don A. TI Impact of life stage and duration of exposure on arsenic-induced proliferative lesions and neoplasia in C3H mice SO TOXICOLOGY LA English DT Article DE Arsenic; Carcinogenesis; Life stage; Age susceptibility; Urinary bladder; C3H mice ID MALE F344 RATS; DRINKING-WATER; DIMETHYLARSINIC ACID; IN-UTERO; INTERNAL CANCERS; LUNG-CANCER; MOUSE SKIN; CARCINOGENESIS; METABOLISM; MORTALITY AB Epidemiological studies suggest that chronic exposure to inorganic arsenic is associated with cancer of the skin, urinary bladder and lung as well as the kidney and liver. Previous experimental studies have demonstrated increased incidence of liver, lung, ovary, and uterine tumors in mice exposed to 85 ppm (similar to 8 mg/kg) inorganic arsenic during gestation. To further characterize age susceptibility to arsenic carcinogenesis we administered 85 ppm inorganic arsenic in drinking water to C3H mice during gestation, prior to pubescence and post-pubescence to compare proliferative lesion and tumor outcomes over a one-year exposure period. Inorganic arsenic significantly increased the incidence of hyperplasia in urinary bladder (48%) and oviduct (36%) in female mice exposed prior to pubescence (beginning on postnatal day 21 and extending through one year) compared to control mice (19 and 5%, respectively). Arsenic also increased the incidence of hyperplasia in urinary bladder (28%) of female mice continuously exposed to arsenic (beginning on gestation day 8 and extending though one year) compared to gestation only exposed mice (0%). In contrast, inorganic arsenic significantly decreased the incidence of tumors in liver (0%) and adrenal glands (0%) of male mice continuously exposed from gestation through one year, as compared to levels in control (30 and 65%, respectively) and gestation only (33 and 55%, respectively) exposed mice. Together, these results suggest that continuous inorganic arsenic exposure at 85 ppm from gestation through one year increases the incidence and severity of urogenital proliferative lesions in female mice and decreases the incidence of liver and adrenal tumors in male mice. The paradoxical nature of these effects may be related to altered lipid metabolism, the effective dose in each target organ, and/or the shorter one-year observational period. Published by Elsevier Ireland Ltd. C1 [Ahlborn, Gene J.; Nelson, Gail M.; Grindstaff, Rachel D.; Allen, James W.; Kitchin, Kirk T.; Preston, R. Julian; Adair, Blakely; Thomas, David J.; Delker, Don A.] US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Ahlborn, Gene J.] N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC USA. [Waalkes, Michael P.] NIEHS, NCI, Lab Comparat Carcinogenesis, Res Triangle Pk, NC 27709 USA. [Diwan, Bhalchandra A.] SAIC, Basic Res Program, Fredericksburg, MD USA. [Hernandez-Zavala, Araceli] Univ N Carolina, Ctr Environm Med Asthma & Lung Biol, Chapel Hill, NC USA. RP Delker, DA (reprint author), Univ Utah, Sch Med, 30 N 1900 E SOM 4R118, Salt Lake City, UT 84132 USA. EM don.delker@hsc.utah.edu FU NCSU/EPA [CT826512010]; UNC/EPA [282952201]; Intramural Research Program of the NIH; National Cancer Institute FX This research was supported by a NCSU/EPA cooperative grant (Agreement CT826512010) and a UNC/EPA cooperative grant (Agreement 282952201). This research was also supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We gratefully acknowledge Dr. Sheau-Fung Thai and Dr. Michael Hughes for their comments and assistance in reviewing this paper. NR 40 TC 17 Z9 17 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD AUG 3 PY 2009 VL 262 IS 2 BP 106 EP 113 DI 10.1016/j.tox.2009.05.003 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 483DF UT WOS:000268941500003 PM 19450653 ER PT J AU Sun, Y Pi, JB Wang, XQ Tokar, EJ Liu, J Waalkes, MP AF Sun, Yang Pi, Jingbo Wang, Xueqian Tokar, Erik J. Liu, Jie Waalkes, Michael P. TI Aberrant cytokeratin expression during arsenic-induced acquired malignant phenotype in human HaCaT keratinocytes consistent with epidermal carcinogenesis SO TOXICOLOGY LA English DT Article DE Cytokeratins; Arsenic; Skin cancer; HaCaT cells ID GROWTH-FACTOR RECEPTOR; SKIN-CANCER; STEM-CELLS; INTERMEDIATE FILAMENTS; EPITHELIAL-CELLS; ENDEMIC AREA; TRANSFORMATION; EXPOSURE; DISEASES; TUMORS AB Inorganic arsenic is a known human skin carcinogen. Chronic arsenic exposure results in various human skin lesions, including hyperkeratosis and squamous cell carcinoma (SCC). both characterized by distorted cytokeratin (CK) production. Prior work shows the human skin keratinocyte HaCaT cell line, when exposed chronically for >25 weeks to a low level of inorganic arsenite (100 nM) results in cells able to produce aggressive SCC upon inoculation into nude mice. In the present study, CK expression analysis was performed in arsenic-exposed HaCaT cells during the progressive acquisition of this malignant phenotype (0-20 weeks) to further validate this model as relevant to epidermal carcinogenesis induced by arsenic in humans. Indeed, we observed clear evidence of acquired cancer phenotype by 20 weeks of arsenite exposure including the formation of giant cells, a >4-fold increase in colony formation in soft agar and a similar to 2.5-fold increase in matrix metalloproteinase-9 secretion, an enzyme often secreted by cancer cells to help invade through the local extra-cellular matrix. During this acquired malignant phenotype, various CK genes showed markedly altered expression at the transcript and protein levels in a time-dependent manner. For example, CK1, a marker of hyperkeratosis, increased up to 34-fold during arsenic-induced transformation, while CK13, a marker for dermal cancer progression, increased up to 45-fold. The stem cell marker, CK15, increased up to 7-fold, particularly during the later stages of arsenic exposure, indicating a potential emergence of cancer stem-like cells with arsenic-induced acquired malignant phenotype. The expression of involucrin and loricrin, markers for keratinocyte differentiation, increased up to 9-fold. Thus, during arsenic-induced acquired cancer phenotype in human keratinocytes. dramatic and dynamic alterations in CK expression occur which are consistent with the process of epidermal carcinogenesis helping validate this as an appropriate model for the study of arsenic-induced skin cancer. Published by Elsevier Ireland Ltd. C1 [Sun, Yang; Tokar, Erik J.; Liu, Jie; Waalkes, Michael P.] NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI,NIH, Res Triangle Pk, NC 27709 USA. [Pi, Jingbo] Hamner Inst Hlth Sci, Div Translat Biol, Res Triangle Pk, NC 27709 USA. [Wang, Xueqian] NIEHS, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI,NIH, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU NIH; National Cancer Institute; NIEHS FX This research was supported in part by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research and by the NIEHS. NR 45 TC 10 Z9 13 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD AUG 3 PY 2009 VL 262 IS 2 BP 162 EP 170 DI 10.1016/j.tox.2009.06.003 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 483DF UT WOS:000268941500010 PM 19524636 ER PT J AU Henrich, CJ Robey, RW Takada, K Bokesch, HR Bates, SE Shukla, S Ambudkar, SV McMahon, JB Gustafson, KR AF Henrich, Curtis J. Robey, Robert W. Takada, Kentaro Bokesch, Heidi R. Bates, Susan E. Shukla, Suneet Ambudkar, Suresh V. McMahon, James B. Gustafson, Kirk R. TI Botryllamides: Natural Product Inhibitors of ABCG2 SO ACS CHEMICAL BIOLOGY LA English DT Article ID MULTIDRUG-RESISTANCE; TYROSINE DERIVATIVES; ANTICANCER DRUGS; FUMITREMORGIN-C; P-GLYCOPROTEIN; STEM-CELLS; CANCER; TRANSPORTER; PROTEIN; ASSAY AB ABCG2 is a membrane-localized, human transporter protein that has been demonstrated to reduce the intracellular accumulation of substrates through ATP-dependent efflux. Highly expressed in placental syncytiotrophoblasts, brain microvasculature, and the gastrointestinal tract, ABCG2 has been shown to mediate normal tissue protection as well as limit oral bioavailability of substrate compounds. Development of ABCG2 Inhibitors for clinical use may allow increased penetration of therapeutic agents into sanctuary sites and increased gastrointestinal absorption. Previously identified inhibitors have lacked potency or specificity or were toxic at concentrations needed to inhibit ABCG2; none are in clinical development A previously developed high-throughput assay measuring inhibition of ABCG2-mediated pheophorbide a transport was applied to natural product extract libraries. Among the active samples were extracts from the marine ascidian Botryllus tyreus. Bioassay-guided fractionation resulted in purification of a series of botryllamides. Ten botryllamides were obtained, two of which (designated I and J) were novel. Activity against ABCG2 was confirmed by assessing the ability of the compounds to inhibit ABC62-mediated BODIPY-prazosin transport in ABCG2-transfected HEK293 cells, compete with [(125)I]-iodoarylazidoprazosin (IAAP) labeling of ABCG2, stimulate ABCG2-associated ATPase activity and reverse ABCG2-mediated resistance. C1 [Henrich, Curtis J.; Bokesch, Heidi R.] SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. [Henrich, Curtis J.; Takada, Kentaro; Bokesch, Heidi R.; McMahon, James B.; Gustafson, Kirk R.] NCI Frederick, Mol Targets Dev Program, Frederick, MD USA. [Robey, Robert W.; Bates, Susan E.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Henrich, CJ (reprint author), SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. EM henrichc@ncifcrf.gov RI shukla, suneet/B-4626-2012 FU National Cancer Institute; National Institutes of Health [N01-CO-12400] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 24 TC 30 Z9 31 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD AUG PY 2009 VL 4 IS 8 BP 637 EP 647 DI 10.1021/cb900134c PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 484YR UT WOS:000269087500006 PM 19555120 ER PT J AU Hoh, F Cave, A Strub, MP Baneres, JL Padilla, A AF Hoh, Francois Cave, Adrien Strub, Marie-Paule Baneres, Jean-Louis Padilla, Andre TI Removing the invariant salt bridge of parvalbumin increases flexibility in the AB-loop structure SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID CALCIUM-BINDING PROTEIN; RAT ALPHA-PARVALBUMIN; EF-HAND PROTEINS; MOLECULAR-REPLACEMENT; BETA-PARVALBUMIN; CRYSTAL-STRUCTURE; ONCOMODULIN; STABILITY; DYNAMICS; DOMAINS AB Parvalbumins (PVs) are calcium-buffer proteins that belong to the EF-hand family. Their N-terminal domain consists of two antiparallel helices A and B that make up a flat hydrophobic surface that is associated with the opposite side of the CD and EF binding sites. A single conserved Arg75-Glu81 salt bridge is buried in this hydrophobic interface. The structure of a rat PV mutant in which Arg75 was replaced by alanine was solved by molecular replacement. Unexpectedly, a large distance deviation of 7.8 angstrom was observed for the AB loop but not for the residues that flank the R75A mutation. The thermal stability of the calcium-loaded form is lower (T(m) = 352.0 K; Delta T(m) = -11.4 K) than that of the wild-type protein and the apo mutant is unfolded at room temperature. Weaker calcium or magnesium affinities were also measured for the R75A mutant (Ca(2+): K(1) = 4.21 x 10(7) M(-1), K(2) = 6.18 x 10(6) M(-1); Mg(2+): K(1) = 2.98 x 10(4) M(-1), K(2) = 3.09 x 10(3) M(-1)). Finally, comparison of the B factors showed an increase in the flexibility of the AB loop that is consistent with this region being more exposed to solvent in the mutant. The mutant structure therefore demonstrates the role of the salt bridge in attaching the nonbinding AB domain to the remaining protein core. Normal-mode analysis indeed indicated an altered orientation of the AB domain with regard to the CD-EF binding domains. C1 [Hoh, Francois; Cave, Adrien; Padilla, Andre] Univ Montpellier 1, CNRS, UMR 5048, INSERM,U554,Ctr Biochim Struct, F-34090 Montpellier, France. [Hoh, Francois; Cave, Adrien; Padilla, Andre] Univ Montpellier 2, CNRS, UMR 5048, INSERM,U554,Ctr Biochim Struct, F-34090 Montpellier, France. [Strub, Marie-Paule] NIH, Bethesda, MD 20892 USA. [Baneres, Jean-Louis] Univ Montpellier 1, CNRS, IBMM, UMR 5247,Fac Pharm, F-34093 Montpellier, France. [Baneres, Jean-Louis] Univ Montpellier 2, CNRS, IBMM, UMR 5247,Fac Pharm, F-34093 Montpellier, France. RP Padilla, A (reprint author), Univ Montpellier 1, CNRS, UMR 5048, INSERM,U554,Ctr Biochim Struct, 29 Rue Navacelles, F-34090 Montpellier, France. EM andre.padilla@cbs.cnrs.fr NR 64 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD AUG PY 2009 VL 65 BP 733 EP 743 DI 10.1107/S0907444909011482 PN 8 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 472MT UT WOS:000268136800001 PM 19622856 ER PT J AU Dawson, DA AF Dawson, Deborah A. TI [Commentary] LOW-RISK DRINKING LIMITS: ABSOLUTE VERSUS RELATIVE RISK SO ADDICTION LA English DT Editorial Material DE Age; gender; guidelines; low-risk drinking limits ID ALCOHOL-CONSUMPTION; GENDER-DIFFERENCES; CONSEQUENCES; INJURY C1 NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. RP Dawson, DA (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Lane,Room 3071 MSC 9403, Bethesda, MD 20892 USA. EM ddawson@mail.nih.gov FU Intramural NIH HHS [Z99 AA999999] NR 14 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD AUG PY 2009 VL 104 IS 8 BP 1303 EP 1304 PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 471BN UT WOS:000268028000011 PM 19624322 ER PT J AU Swendsen, J Conway, KP Degenhardt, L Dierker, L Glantz, M Jin, R Merikangas, KR Sampson, N Kessler, RC AF Swendsen, Joel Conway, Kevin P. Degenhardt, Louisa Dierker, Lisa Glantz, Meyer Jin, Robert Merikangas, Kathleen R. Sampson, Nancy Kessler, Ronald C. TI Socio-demographic risk factors for alcohol and drug dependence: the 10-year follow-up of the national comorbidity survey SO ADDICTION LA English DT Article DE Alcohol dependence; demographic factors; drug dependence; epidemiology; prospective; substance-related disorders; risk ID AGE-OF-ONSET; INTERNATIONAL DIAGNOSTIC INTERVIEW; SUBSTANCE USE DISORDERS; MALE-FEMALE DIFFERENCES; UNITED-STATES; EPIDEMIOLOGIC SURVEY; SEX-DIFFERENCES; YOUNG-ADULTS; LONGITUDINAL COMMUNITY; SURVEY REPLICATION AB Aims Continued progress in etiological research and prevention science requires more precise information concerning the specific stages at which socio-demographic variables are implicated most strongly in transition from initial substance use to dependence. The present study examines prospective associations between socio-demographic variables and the subsequent onset of alcohol and drug dependence using data from the National Comorbidity Survey (NCS) and the NCS Follow-up survey (NCS-2). Design The NCS was a nationally representative survey of the prevalence and correlates of DSM-III-R mental and substance disorders in the United States carried out in 1990-2002. The NCS-2 re-interviewed a probability subsample of NCS respondents a decade after the baseline survey. Baseline NCS socio-demographic characteristics and substance use history were examined as predictors of the first onset of DSM-IV alcohol and drug dependence in the NCS-2. Participants A total of 5001 NCS respondents were re-interviewed in the NCS-2 (87.6% of baseline sample). Findings Aggregate analyses demonstrated significant associations between some baseline socio-demographic variables (young age, low education, non-white ethnicity, occupational status) but not others (sex, number of children, residential area) and the subsequent onset of DSM-IV alcohol or drug dependence. However, conditional models showed that these risk factors were limited to specific stages of baseline use. Moreover, many socio-demographic variables that were not significant in the aggregate analyses were significant predictors of dependence when examined by stage of use. Conclusions The findings underscore the potential for socio-demographic risk factors to have highly specific associations with different stages of the substance use trajectory. C1 [Swendsen, Joel] Univ Bordeaux 2, CNRS 5231, F-33076 Bordeaux, France. [Conway, Kevin P.; Glantz, Meyer] NIDA, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. [Degenhardt, Louisa] Univ NSW, Natl Drug & Alcohol Res Ctr, Sydney, NSW, Australia. [Dierker, Lisa] Wesleyan Univ, Dept Psychol, Middletown, CT USA. [Jin, Robert; Sampson, Nancy; Kessler, Ronald C.] Harvard Univ, Dept Hlth Policy, Boston, MA 02115 USA. [Merikangas, Kathleen R.] NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Swendsen, J (reprint author), Univ Bordeaux 2, CNRS 5231, 146 Rue Leo Saignat, F-33076 Bordeaux, France. EM joel.swendsen@u-bordeaux2.fr RI Degenhardt, Louisa/D-4515-2012; OI Degenhardt, Louisa/0000-0002-8513-2218; Conway, Kevin/0000-0002-7638-339X FU National Institute of Mental Health [R01MH46376, R01MH070884]; National Institute on Drug Abuse [R01DA012058]; NIMH [R01MH070884, R01MH077883, U01MH060220]; Robert Wood Johnson Foundation [044780]; John W. Alden Trust; US Public Health Service [R13MH066849, R01MH069864, R01DA016558]; Fogarty International Center [FIRCA R03TW006481]; Pan American Health Organization; Eli Lilly and Company; Ortho-McNeil Pharmaceutical, Inc.; GlaxoSmithKline; Bristol-Myers Squibb FX The NCS data collection was supported by the National Institute of Mental Health (NIMH; R01MH46376). The NCS-2 data collection was supported by the National Institute on Drug Abuse (NIDA; R01DA012058). Data analysis for this paper was additionally supported by NIMH grants R01MH070884, R01MH077883 and U01MH060220, with supplemental support from the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; Grant 044780) and the John W. Alden Trust. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or US government. A complete list of NCS and NCS-2 publications can be found at http://www.hcp.med.harvard.edu/ncs/. Send correspondence to ncs@hcp.med.harvard.edu. The NCS-2 is carried out in conjunction with the World Health Organization World Mental Health (WMH) Survey Initiative. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation, fieldwork and consultation on data analysis. These activities were supported by the National Institute of Mental Health (R01MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the US Public Health Service (R13MH066849, R01MH069864 and R01DA016558), the Fogarty International Center (FIRCA R03TW006481), the Pan American Health Organization, Eli Lilly and Company, Ortho-McNeil Pharmaceutical, Inc., GlaxoSmithKline and Bristol-Myers Squibb. A complete list of WMH publications can be found at http://www.hcp.med.harvard.edu/wmh/. NR 67 TC 40 Z9 42 U1 7 U2 20 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD AUG PY 2009 VL 104 IS 8 BP 1346 EP 1355 DI 10.1111/j.1360-0443.2009.02622.x PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 471BN UT WOS:000268028000017 PM 19549055 ER PT J AU Ajdacic-Gross, V Landolt, K Angst, J Gamma, A Merikangas, KR Gutzwiller, F Rossler, W AF Ajdacic-Gross, Vladeta Landolt, Karin Angst, Jules Gamma, Alex Merikangas, Kathleen R. Gutzwiller, Felix Roessler, Wulf TI Adult versus adolescent onset of smoking: how are mood disorders and other risk factors involved? SO ADDICTION LA English DT Article DE Adolescence; depression; epidemiology; mood disorders; risk factors; tobacco use; young adulthood ID SUBSTANCE USE DISORDERS; CIGARETTE-SMOKING; PSYCHIATRIC-DISORDERS; YOUNG-ADULTS; NICOTINE DEPENDENCE; MAJOR DEPRESSION; DEVELOPMENTAL TRAJECTORIES; PROSPECTIVE COMMUNITY; PROSPECTIVE COHORT; MENTAL-HEALTH AB Aims To examine the strength of association between smoking and mood disorders and the association between smoking and its traditional risk factors, comparing those who started smoking in adolescence with those who started smoking in early adulthood. Design and participants The analyses relied on prospective data from the Zurich Study. This longitudinal community study started in 1979 with a stratified sample of 591 participants aged 20/21 years, weighted towards those with mental disorders. Follow-up interviews were conducted at ages 23, 28, 30, 35 and 41. Measurements In this analysis the adult versus adolescent onset of smoking was regressed on the cumulative prevalence of mood disorders, personality characteristics measured by the Freiburg Personality Inventory, common risk factors such as parental smoking, conduct and school problems, troubles with the family and basic socio-demographic variables (sex, education). Findings In the Zurich Study cohort we found that 61.6% were former or current smokers, of whom 87% started smoking before the age of 20 and 13% after the age of 20. Adolescent onset of smoking was associated strongly with later major depression, dysthymia or bipolar disorders and, furthermore, with parental smoking, extroverted personality and discipline problems and rebelliousness in youth. However, only depression and dysthymia were associated with adult onset smoking and other risk factors associated with smoking were not so associated in this group. Conclusions Correlates of smoking onset in adolescence are mainly not applicable to the onset of smoking in young adulthood. Smoking onset beyond adolescence is an open research issue. C1 [Ajdacic-Gross, Vladeta; Landolt, Karin; Angst, Jules; Gamma, Alex; Roessler, Wulf] Univ Zurich, Psychiat Univ Hosp Zurich, Res Unit Clin & Social Psychiat, CH-8021 Zurich, Switzerland. [Merikangas, Kathleen R.] NIMH, Bethesda, MD 20892 USA. [Gutzwiller, Felix] Univ Zurich, Inst Social & Prevent Med, CH-8021 Zurich, Switzerland. RP Ajdacic-Gross, V (reprint author), Univ Zurich, Psychiat Univ Hosp Zurich, Res Unit Clin & Social Psychiat, Militarstr 8,POB 1930, CH-8021 Zurich, Switzerland. EM vajdacic@dgsp.uzh.ch OI Ajdacic-Gross, Vladeta/0000-0002-7032-9237 FU Swiss National Science Foundation [32-50881.97]; Swiss Cancer League/Swiss Federation Against Cancer [01649-02-2005] FX The study was supported by the Swiss National Science Foundation (grant no. 32-50881.97), and the Swiss Cancer League/Swiss Federation Against Cancer (grant no. 01649-02-2005). NR 53 TC 15 Z9 15 U1 5 U2 9 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD AUG PY 2009 VL 104 IS 8 BP 1411 EP 1419 DI 10.1111/j.1360-0443.2009.02640.x PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 471BN UT WOS:000268028000025 PM 19624327 ER PT J AU Mirabello, L Huang, WY Wong, JY Chatterjee, N Reding, D Crawford, ED De Vivo, I Hayes, RB Savage, SA AF Mirabello, Lisa Huang, Wen-Yi Wong, Jason Y. Y. Chatterjee, Nilanjan Reding, Douglas Crawford, E. David De Vivo, Immaculata Hayes, Richard B. Savage, Sharon A. TI The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer SO AGING CELL LA English DT Article DE epidemiology; lifestyle; prostate cancer; risk; telomere ID GENOME-WIDE ASSOCIATION; OXIDATIVE STRESS; CARDIOVASCULAR-DISEASE; PREDISPOSITION FACTOR; BLADDER-CANCER; BLOOD-CELLS; DNA-CONTENT; INFLAMMATION; DYSFUNCTION; OBESITY AB P>Telomeres consist of nucleotide repeats and a protein complex at chromosome ends that are essential to maintaining chromosomal integrity. Several studies have suggested that subjects with shorter telomeres are at increased risk of bladder and lung cancer. In comparison to normal tissues, telomeres are shorter in high-grade intraepithelial neoplasia and prostate cancer. We examined prostate cancer risk associated with relative telomere length as determined by quantitative PCR on prediagnostic buffy coat DNA isolated from 612 advanced prostate cancer cases and 1049 age-matched, cancer-free controls from the PLCO Cancer Screening Trial. Telomere length was analyzed as both a continuous and a categorical variable with adjustment for potential confounders. Statistically significant inverse correlations between telomere length, age and smoking status were observed in cases and controls. Telomere length was not associated with prostate cancer risk (at the median, OR = 0.85, 95% CI: 0.67, 1.08); associations were similar when telomere length was evaluated as a continuous variable or by quartiles. The relationships between telomere length and inflammation-related factors, diet, exercise, body mass index, and other lifestyle variables were explored since many of these have previously been associated with shorter telomeres. Healthy lifestyle factors (i.e., lower BMI, more exercise, tobacco abstinence, diets high in fruit and vegetables) tended to be associated with greater telomere length. This study found no statistically significant association between leukocyte telomere length and advanced prostate cancer risk. However, correlations of telomere length with healthy lifestyles were noted, suggesting the role of these factors in telomere biology maintenance and potentially impacting overall health status. C1 [Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Wong, Jason Y. Y.; De Vivo, Immaculata] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Wong, Jason Y. Y.; De Vivo, Immaculata] Harvard Univ, Sch Med, Boston, MA USA. [Reding, Douglas] Marshfield Med Res & Educ Fdn, Marshfield, WI USA. [Crawford, E. David] Univ Colorado, Hlth Sci Ctr, Div Urol Oncol, Denver, CO USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7018, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015; OI Savage, Sharon/0000-0001-6006-0740; Wong, Jason/0000-0002-8167-540X FU Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services; National Institutes of Health [CA82838]; American Cancer Society [RSG-00-061-04-CCE] 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 (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services, Inc., Ms. Barbara O'Brien and staff, Westat, Inc., and the staff of the telomere testing laboratory. We thank Dr. Mark Greene, National Cancer Institute, for helpful discussions. Most importantly, we acknowledge the study participants for their contributions to making this study possible. This work was supported [in part] by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services; National Institutes of Health (grant CA82838); and American Cancer Society (grant RSG-00-061-04-CCE). NR 70 TC 107 Z9 112 U1 0 U2 15 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD AUG PY 2009 VL 8 IS 4 BP 405 EP 413 DI 10.1111/j.1474-9726.2009.00485.x PG 9 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 473NH UT WOS:000268213300006 PM 19493248 ER PT J AU Masuda, K Marasa, B Martindale, JL Halushka, MK Gorospe, M AF Masuda, Kiyoshi Marasa, Bernard Martindale, Jennifer L. Halushka, Marc K. Gorospe, Myriam TI Tissue- and age-dependent expression of RNA-binding proteins that influence mRNA turnover and translation SO AGING-US LA English DT Article DE HuR; AUF1; TIA-1; TTP; TTR-RBPs; senescence ID AU-RICH ELEMENT; NECROSIS-FACTOR-ALPHA; 3'-UNTRANSLATED REGION; CELLULAR SENESCENCE; ABERRANT REGULATION; GENE-EXPRESSION; SIGNATURE MOTIF; TNF-ALPHA; HUR; TRISTETRAPROLIN AB Gene expression patterns vary dramatically in a tissue-specific and age-dependent manner. RNA-binding proteins that regulate mRNA turnover and/or translation (TTR-RBPs) critically affect the subsets of expressed proteins. However, very little is known regarding the tissue- and age-dependent expression of TTR-RBPs in humans. Here, we use human tissue arrays containing a panel of organ biopsies from donors of different ages, to study the distribution and abundance of four TTR-RBPs: HuR, AUF1, TIA-1, and TTP. HuR and AUF1 were expressed with remarkably similar patterns. Both TTR-RBPs were present in high percentages of cells and displayed elevated intensities in many age groups and tissues, most notably in the gastrointestinal and reproductive systems; they were moderately expressed in the urinary and immune systems, and were almost undetectable in muscle and brain. TIA-1 was also abundant in many tissues and age groups; TIA-1 was expressed at high levels in the gastrointestinal, immune, urinary, and reproductive systems, and at low levels in brain and muscle. By contrast, TTP-expressing cells, as well as TTP signal intensities declined with advancing age, particularly in the immune, nervous, and muscular systems; however, TTP levels remained elevated in the gastrointestinal tract. The widespread abundance of HuR, AUF1, and TIA-1 throughout the body and in all age groups was in stark contrast with their declining levels in human diploid fibroblasts (HDFs) undergoing replicative senescence, a cultured-cell model of aging. Conversely, TTP levels increased in senescent HDFs, while TTP levels decreased with advancing age. Our studies provide a framework for the study of human TTR-RBP function in different tissues, throughout the human life span. C1 [Masuda, Kiyoshi; Marasa, Bernard; Martindale, Jennifer L.; Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, IRP, NIH, Baltimore, MD 21224 USA. [Halushka, Marc K.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21231 USA. RP Gorospe, M (reprint author), NIA, Cellular & Mol Biol Lab, IRP, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov OI Halushka, Marc/0000-0002-7112-7389 FU Intramural NIH HHS NR 75 TC 33 Z9 33 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD AUG PY 2009 VL 1 IS 8 BP 681 EP 698 PG 18 WC Cell Biology SC Cell Biology GA 579US UT WOS:000276401800002 PM 20157551 ER PT J AU Martin, S Elliott-DeSorbo, DK Calabrese, S Wolters, PL Roby, G Brennan, T Wood, LV AF Martin, Staci Elliott-DeSorbo, Deborah K. Calabrese, Sarah Wolters, Pamela L. Roby, Gregg Brennan, Tara Wood, Lauren V. TI A Comparison of Adherence Assessment Methods Utilized in the United States: Perspectives of Researchers, HIV-Infected Children, and their Caregivers SO AIDS PATIENT CARE AND STDS LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; SELF-REPORTED ADHERENCE; IMMUNODEFICIENCY-VIRUS-INFECTION; MEDICATION ADHERENCE; VIROLOGICAL RESPONSE; PROTEASE INHIBITORS; DRUG-RESISTANCE; POSITIVE ADULTS; VIRAL LOAD; PREDICTORS AB This study sought to elucidate methodological issues in adherence research by comparing multiple methods of assessing adherence to antiretroviral medication. From 2003 to 2004, 24 youths with vertically infected HIV disease (mean age = 14.0 years; range, 8-18) and their caregivers participated in a 6-month study. These children were all on highly active antiretroviral therapy (HAART) and were relatively healthy (mean CD4 absolute count = 711.8 +/- 604.5). Adherence was assessed with the Medication Event Monitoring System (MEMS), pill counts, and interviews. Patients and caregivers completed the Perceptions of Adherence Study Participation (PASP) questionnaire. MEMS provided the most detailed adherence information, and good reliability was indicated by significant correlations with medical markers. Pill counts provided similar adherence rates, while patients and caregivers reported nearly perfect adherence in interviews. Problems were experienced with each method: MEMS were expensive, had cap malfunctions, and lack a consistent guiding principle for data interpretation. With pill counts, families forgot to bring all medication bottles to clinic, and interviews were compromised by social desirability and difficulty reaching families by telephone. Most patients and caregivers believed study participation improved the child's adherence, although PASP ratings were unrelated to adherence at the study endpoint. While MEMS may be most reliable, pill counts offer comparable data and are less costly, while interviews seemed least accurate in this study. Most participants reported positive perceptions of their research experience. A consensus among researchers is needed for defining and measuring adherence, and specific recommendations are offered for achieving this goal. C1 [Martin, Staci; Elliott-DeSorbo, Deborah K.; Calabrese, Sarah; Wolters, Pamela L.; Roby, Gregg; Brennan, Tara; Wood, Lauren V.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Martin, Staci; Wolters, Pamela L.] Med Illness Counseling Ctr, Chevy Chase, MD USA. [Elliott-DeSorbo, Deborah K.] USAF Acad, Colorado Springs, CO 80840 USA. [Roby, Gregg] NIAID, Intramural Clin Management & Operat Branch, Bethesda, MD 20892 USA. [Brennan, Tara] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Wood, Lauren V.] Ctr Canc Res, Vaccine Branch, Bethesda, MD USA. RP Martin, S (reprint author), 9030 Old Georgetown Rd,Room 107, Bethesda, MD 20892 USA. EM martins@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and by federal contracts N01-SC-07006 and HHSN261200477004C. NR 47 TC 20 Z9 21 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD AUG PY 2009 VL 23 IS 8 BP 593 EP 601 DI 10.1089/apc.2009.0021 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 484RC UT WOS:000269063600003 PM 19591601 ER PT J AU Garg, H Joshi, A Blumenthal, R AF Garg, Himanshu Joshi, Anjali Blumenthal, Robert TI Altered Bystander Apoptosis Induction and Pathogenesis of Enfuvirtide-Resistant HIV Type 1 Env Mutants SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4 T-CELLS; HIV-1-INFECTED PATIENTS; RECEIVING ENFUVIRTIDE; VIROLOGICAL FAILURE; BASE-LINE; IN-VITRO; GP41; ENVELOPE; MUTATIONS AB In previous studies on mechanisms of HIV-1-mediated pathogenesis we showed that bystander apoptosis mediated by cell surface-expressed HIV-1 Env correlated with the fusogenic properties of the gp41 subunit of Env. A crucial step in HIV gp41-mediated fusion is the refolding of the protein into a six-helix bundle along the N- and C-terminal coiled-coil domains. These domains have been targeted by peptide inhibitors that inhibit gp41-mediated fusion. One of these inhibitors, enfuvirtide, is the first such drug approved for therapy. More recently, clinical data suggest that the beneficial effects of enfuvirtide extend beyond virus suppression and are associated with certain resistance mutations in gp41. In this study we characterized the bystander apoptosis-inducing potential of mutants associated with increased CD4 counts that arise during enfuvirtide therapy. Whereas all mutant clones were reduced in both cell-to-cell fusion activity and apoptosis induction there was limited effect on virus infection or replication. The viruses were found to have apoptosis-inducing activity in the order WT > V38M > V38A > G36D > V38E, which correlated with cell-to-cell fusion but not infection. Interestingly, the level of resistance as determined by the IC(50) of enfuvirtide also correlated inversely with both cell fusion and apoptosis in that the most resistant Envs were the least fusogenic and pathogenic. This suggests the beneficial effects of enfuvirtide therapy beyond virus suppression may be mediated by selecting less pathogenic HIV isolates over time. C1 [Garg, Himanshu; Blumenthal, Robert] NCI, Membrane Struct & Funct Sect, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. [Joshi, Anjali] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI, Membrane Struct & Funct Sect, Ctr Canc Res, Nanobiol Program, POB B,Bldg 469 Room 152,Miller Dr, Frederick, MD 21702 USA. EM blumenthalr@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Eric Freed for his support in performing the replication experiments and insightful comments. We are grateful to the NIH AIDS Research and Reference Reagent Program for supplying valuable reagents. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 33 TC 13 Z9 13 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD AUG PY 2009 VL 25 IS 8 BP 811 EP 817 DI 10.1089/aid.2009.0010 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 483BR UT WOS:000268937300010 PM 19619009 ER PT J AU Moss, HB Kirby, SD Donodeo, F AF Moss, Howard B. Kirby, Susan D. Donodeo, Fred TI Characterizing and Reaching High-Risk Drinkers Using Audience Segmentation SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Audience Segmentation; Marketing Research; High-Risk Drinking; Public Health ID DRUG-ABUSE PREVENTION; ALCOHOL-USE; MASS-MEDIA; STRATEGIES; SCHOOL; INTERVENTIONS; CONSUMPTION; ADOLESCENTS AB Background: Market or audience segmentation is widely used in social marketing efforts to help planners identify segments of a population to target for tailored program interventions. Market-based segments are typically defined by behaviors, attitudes, knowledge, opinions, or lifestyles. They are more helpful to health communication and marketing planning than epidemiologically defined groups because market-based segments are similar in respect to how they behave or might react to marketing and communication efforts. However, market segmentation has rarely been used in alcohol research. As an illustration of its utility, we employed commercial data that describes the sociodemographic characteristics of high-risk drinkers as an audience segment, including where they tend to live, lifestyles, interests, consumer behaviors, alcohol consumption behaviors, other health-related behaviors, and cultural values. Such information can be extremely valuable in targeting and planning public health campaigns, targeted mailings, prevention interventions, and research efforts. Methods: We described the results of a segmentation analysis of those individuals who self-reported to consume 5 or more drinks per drinking episode at least twice in the last 30 days. The study used the proprietary PRIZM TM (Claritas, Inc., San Diego, CA) audience segmentation database merged with the Center for Disease Control and Prevention's (CDC) Behavioral Risk Factor Surveillance System (BRFSS) database. The top 10 of the 66 PRIZM TM audience segments for this risky drinking pattern are described. For five of these segments we provided additional in-depth details about consumer behavior and the estimates of the market areas where these risky drinkers resided. Results: The top 10 audience segments (PRIZM clusters) most likely to engage in high-risk drinking are described. The cluster with the highest concentration of binge-drinking behavior is referred to as the "Cyber Millenials.'' This cluster is characterized as "the nation's tech-savvy singles and couples living in fashionable neighborhoods on the urban fringe.'' Almost 65% of Cyber Millenials households are found in the Pacific and Middle Atlantic regions of the United States. Additional consumer behaviors of the Cyber Millenials and other segments are also described. Conclusions: Audience segmentation can assist in identifying and describing target audience segments, as well as identifying places where segments congregate on-or offline. This information can be helpful for recruiting subjects for alcohol prevention research as well as planning health promotion campaigns. Through commercial data about high-risk drinkers as "consumers,'' planners can develop interventions that have heightened salience in terms of opportunities, perceptions, and motivations, and have better media channel identification. C1 [Kirby, Susan D.] Kirby Mkt Solut, San Diego, CA USA. [Moss, Howard B.; Donodeo, Fred] NIAAA, Bethesda, MD USA. RP Moss, HB (reprint author), NIAAA OD, 5635 Fishers Lane,MSC 9304, Bethesda, MD 20892 USA. EM mossh@mail.nih.gov FU NIAAA FX This research was supported by internal NIAAA funds. NR 24 TC 15 Z9 16 U1 0 U2 15 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2009 VL 33 IS 8 BP 1336 EP 1345 DI 10.1111/j.1530-0277.2009.00963.x PG 10 WC Substance Abuse SC Substance Abuse GA 473NL UT WOS:000268213800005 PM 19413650 ER PT J AU Liu, LJ Nettleton, JA Bertoni, AG Bluemke, DA Lima, JA Szklo, M AF Liu, Longjian Nettleton, Jennifer A. Bertoni, Alain G. Bluemke, David A. Lima, Joao A. Szklo, Moyses TI Dietary pattern, the metabolic syndrome, and left ventricular mass and systolic function: the Multi-Ethnic Study of Atherosclerosis SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID CONGESTIVE-HEART-FAILURE; INSULIN-RESISTANCE; RISK; MICRONUTRIENTS; ASSOCIATIONS; POPULATION; PREVENTION; MESA; SEX AB Background: Little is known about the relations between dietary patterns, metabolic dysfunction, and left ventricular (LV) function. Objective: The objective was to examine associations of dietary patterns with LV mass and function and to explore the potential role of metabolic dysfunction in the association between diet and LV function. Design: Dietary patterns that maximally explained the variation in metabolic syndrome (MetSyn) components were derived by using reduced rank regression (RRR). LV mass, stroke volume, and LV ejection fraction (LVEF) were measured by magnetic resonance imaging. Associations between dietary pattern and LV indexes were analyzed cross-sectionally. Results: A total of 4601 participants aged 45-84 y and free of clinical cardiovascular disease were studied. The primary RRR dietary pattern score was positively correlated with intake of foods with a high glycemic index, high-fat meats, cheeses, and processed foods and negatively correlated with low intakes of vegetables, soy, fruit, green and black tea, low-fat dairy desserts, seeds and nuts, and fish. Multivariate analyses showed that each 1-unit increase in the RRR dietary pattern score was associated with a 0.32-g/m(2) increase in LV mass/body surface area, a 0.43-mL/m(2) decrease in stroke volume/body surface area, and a 0.21% decrease in LVEF. The associations of the RRR dietary pattern score with LV mass and stroke indexes were attenuated and became nonsignificant after adjustment for all MetSyn components (P>0.05). Conclusions: The results suggest that the RRR dietary pattern is significantly associated with unfavorable LV function, and this association might be mediated by metabolic dysfunction. Given the cross-sectional nature of our study, these results must be confirmed with the use of longitudinal data. Am J Clin Nutr 2009;90:362-8 C1 [Liu, Longjian] Drexel Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Philadelphia, PA 19102 USA. [Nettleton, Jennifer A.] Univ Texas Hlth Sci Ctr, Dept Epidemiol, Houston, TX USA. [Bertoni, Alain G.] Wake Forest Univ Hlth Sci, Dept Publ Hlth Sci, Winston Salem, NC USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Lima, Joao A.] Johns Hopkins Univ, Dept Cardiol, Baltimore, MD USA. [Szklo, Moyses] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. RP Liu, LJ (reprint author), Drexel Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, 1505 Race St, Philadelphia, PA 19102 USA. EM longjian.liu@drexel.edu OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95166, N01-HC-95168, N01-HC-95169] FX Supported by contracts N01-HC-95159 through N01-HC-95166, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute. NR 29 TC 28 Z9 29 U1 0 U2 3 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG 1 PY 2009 VL 90 IS 2 BP 362 EP 368 DI 10.3945/ajcn.2009.27538 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 472SI UT WOS:000268152000017 PM 19515735 ER PT J AU Kaushal, A Curran, WJ AF Kaushal, Aradhana Curran, Walter J., Jr. TI For Whom the Bell's Palsy Tolls? SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Editorial Material DE acoustic neuroma; facial neuroma; aseptic meningitis; stereotactic fractionated radiation therapy C1 [Kaushal, Aradhana; Curran, Walter J., Jr.] Thomas Jefferson Univ Hosp, Dept Radiat Oncol, Bodine Canc Ctr, Philadelphia, PA 19107 USA. RP Kaushal, A (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10 CRC,Room B2-3500,10 Ctr Dr, Bethesda, MD 20892 USA. EM aradhanakaushal@yahoo.com FU Intramural NIH HHS [Z99 CA999999] 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 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2009 VL 32 IS 4 BP 450 EP 451 DI 10.1097/01.coc.0000239141.22916.22 PG 2 WC Oncology SC Oncology GA 480UF UT WOS:000268761600023 PM 19657241 ER PT J AU Khoury, MJ Bertram, L Boffetta, P Butterworth, AS Chanock, SJ Dolan, SM Fortier, I Garcia-Closas, M Gwinn, M Higgins, JPT Janssens, ACJW Ostell, J Owen, RP Pagon, RA Rebbeck, TR Rothman, N Bernstein, JL Burton, PR Campbell, H Chockalingam, A Furberg, H Little, J O'Brien, TR Seminara, D Vineis, P Winn, DM Yu, W Ioannidis, JPA AF Khoury, Muin J. Bertram, Lars Boffetta, Paolo Butterworth, Adam S. Chanock, Stephen J. Dolan, Siobhan M. Fortier, Isabel Garcia-Closas, Montserrat Gwinn, Marta Higgins, Julian P. T. Janssens, A. Cecile J. W. Ostell, James Owen, Ryan P. Pagon, Roberta A. Rebbeck, Timothy R. Rothman, Nathaniel Bernstein, Jonine L. Burton, Paul R. Campbell, Harry Chockalingam, Anand Furberg, Helena Little, Julian O'Brien, Thomas R. Seminara, Daniela Vineis, Paolo Winn, Deborah M. Yu, Wei Ioannidis, John P. A. TI Genome-Wide Association Studies, Field Synopses, and the Development of the Knowledge Base on Genetic Variation and Human Diseases SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE association; database; encyclopedias; epidemiologic methods; genome; human; genome-wide association study; genomics; meta-analysis ID SYSTEMATIC METAANALYSES; BLADDER-CANCER; EPIDEMIOLOGY; VARIANTS; COMMON; SUSCEPTIBILITY; REPLICATION; DATABASE; FALSE; LOCI AB Genome-wide association studies (GWAS) have led to a rapid increase in available data on common genetic variants and phenotypes and numerous discoveries of new loci associated with susceptibility to common complex diseases. Integrating the evidence from GWAS and candidate gene studies depends on concerted efforts in data production, online publication, database development, and continuously updated data synthesis. Here the authors summarize current experience and challenges on these fronts, which were discussed at a 2008 multidisciplinary workshop sponsored by the Human Genome Epidemiology Network. Comprehensive field synopses that integrate many reported gene-disease associations have been systematically developed for several fields, including Alzheimer's disease, schizophrenia, bladder cancer, coronary heart disease, preterm birth, and DNA repair genes in various cancers. The authors summarize insights from these field synopses and discuss remaining unresolved issues-especially in the light of evidence from GWAS, for which they summarize empirical P-value and effect-size data on 223 discovered associations for binary outcomes (142 with P < 10(-7)). They also present a vision of collaboration that builds reliable cumulative evidence for genetic associations with common complex diseases and a transparent, distributed, authoritative knowledge base on genetic variation and human health. As a next step in the evolution of Human Genome Epidemiology reviews, the authors invite investigators to submit field synopses for possible publication in the American Journal of Epidemiology. C1 [Khoury, Muin J.; Gwinn, Marta; Yu, Wei] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Bertram, Lars] Massachusetts Gen Hosp, Genet & Aging Res Unit, Charlestown, MA USA. [Boffetta, Paolo] Int Agcy Res Canc, F-69372 Lyon, France. [Butterworth, Adam S.; Higgins, Julian P. T.] Univ Cambridge, Mol Epidemiol Unit, Cambridge, England. [Chanock, Stephen J.; Garcia-Closas, Montserrat; Rothman, Nathaniel; O'Brien, Thomas R.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Dolan, Siobhan M.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Fortier, Isabel] McGill Univ, Quebec Innovat Ctr, Montreal, PQ, Canada. [Higgins, Julian P. T.] Univ Cambridge, MRC, Biostat Unit, Cambridge, England. [Janssens, A. Cecile J. W.] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Ostell, James] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Owen, Ryan P.] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Pagon, Roberta A.] Univ Washington, Sch Med, Seattle, WA USA. [Rebbeck, Timothy R.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Bernstein, Jonine L.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Burton, Paul R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Campbell, Harry] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Chockalingam, Anand] Univ Calif Berkeley, Div Epidemiol, Berkeley, CA 94720 USA. [Furberg, Helena] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Little, Julian] Univ Ottawa, Dept Epidemiol & Community Hlth, Ottawa, ON, Canada. [Seminara, Daniela; Winn, Deborah M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol, London, England. [Ioannidis, John P. A.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Ioannidis, John P. A.] Tufts Univ, Tufts Clin & Translat Sci Inst, Boston, MA 02111 USA. [Ioannidis, John P. A.] Tufts Med Ctr, Ctr Genet Epidemiol & Modeling, Boston, MA USA. RP Khoury, MJ (reprint author), Ctr Dis Control & Prevent, Off Publ Hlth Genom, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Highway NE, Atlanta, GA 30341 USA. EM mukl@cdc.gov RI Ioannidis, John/G-9836-2011; Higgins, Julian/H-4008-2011; Garcia-Closas, Montserrat /F-3871-2015; Burton, Paul/H-7527-2016; Bertram, Lars/K-3889-2015; OI Higgins, Julian/0000-0002-8323-2514; Garcia-Closas, Montserrat /0000-0003-1033-2650; Bertram, Lars/0000-0002-0108-124X; Janssens, A Cecile/0000-0002-6153-4976 FU British Heart Foundation [RG/08/014/24067]; Medical Research Council [MC_U105285807]; NCI NIH HHS [K07 CA118412, K07 CA118412-04]; NCRR NIH HHS [UL1 RR025752] NR 53 TC 81 Z9 82 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2009 VL 170 IS 3 BP 269 EP 279 DI 10.1093/aje/kwp119 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 475BH UT WOS:000268330300001 PM 19498075 ER PT J AU Wang, PS Schoenbaum, M AF Wang, Philip S. Schoenbaum, Michael TI Invited Commentary: Assessing Treatment Effects by Using Observational Analyses-Opportunities and Limitations SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE bias (epidemiology); depression; observation; research design; treatment outcome ID PRIMARY-CARE; DEPRESSION; RECURRENCE; RELAPSE AB Making decisions about medical treatments based upon valid evidence is critical to improve health-care quality, outcomes, and value. Although such research commonly connotes the use of randomized controlled trials, experimental methods are not always feasible, and research using observational, quasi-experimental, and other nonexperimental methods may also be important. At the same time, nonexperimental methods are inherently susceptible to various types of bias and thus present special challenges in the search for valid and generalizable evidence. The study by Gardarsdottir et al. (Am J Epidemiol. 2009;170(3):280-285), on which this commentary is based, addresses a key potential source of bias-mismeasurement of patients' duration of treatment-in previous research on pharmacotherapy for depression. However, the authors' study is unlikely to address other potential sources of bias, which may make interpretation of their findings more difficult. C1 [Wang, Philip S.; Schoenbaum, Michael] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Wang, PS (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM wangphi@mail.nih.gov NR 7 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2009 VL 170 IS 3 BP 286 EP 287 DI 10.1093/aje/kwp137 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 475BH UT WOS:000268330300003 PM 19498072 ER PT J AU Lew, JQ Freedman, ND Leitzmann, MF Brinton, LA Hoover, RN Hollenbeck, AR Schatzkin, A Park, Y AF Lew, Jasmine Q. Freedman, Neal D. Leitzmann, Michael F. Brinton, Louise A. Hoover, Robert N. Hollenbeck, Albert R. Schatzkin, Arthur Park, Yikyung TI Alcohol and Risk of Breast Cancer by Histologic Type and Hormone Receptor Status in Postmenopausal Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcohol drinking; breast neoplasms; carcinoma; ductal; breast; carcinoma; lobular; receptors; estrogen; receptors; progesterone ID HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; END RESULTS DATABASE; FOLATE INTAKE; NATIONAL-INSTITUTES; PROSPECTIVE COHORT; ESTROGEN; CONSUMPTION; EPIDEMIOLOGY; SURVEILLANCE AB Little is known about the association between alcohol and breast cancer by different tumor characteristics. The study consisted of 184,418 postmenopausal women aged 50-71 years in the National Institutes of Health-AARP Diet and Health Study (1995-2003). Alcohol use, diet, and potential risk factors for cancer were assessed with a mailed questionnaire at baseline. The relative risks and 95% confidence intervals were estimated by using Cox proportional hazards regression. Breast cancer cases and estrogen receptor and progesterone receptor status were identified through linkage to state cancer registries. During an average of 7 years of follow-up, 5,461 breast cancer cases were identified. Alcohol was significantly positively associated with total breast cancer: Even a moderate amount of alcohol (> 10 g/day) significantly increased breast cancer risk. In a comparison of > 35 g versus 0 g/day, the multivariate relative risks were 1.35 (95% confidence interval (CI): 1.17, 1.56) for total breast cancer, 1.46 (95% CI: 1.22, 1.75) for ductal tumors, and 1.52 (95% CI: 0.95, 2.44) for lobular tumors. The multivariate relative risks for estrogen receptor-positive/progesterone receptor-positive, estrogen receptor-positive/progesterone receptor-negative, and estrogen receptor-negative/progesterone receptor-negative tumors were 1.46 (95% CI: 1.12, 1.91) for > 35 g versus 0 g/day, 1.13 (95% CI: 0.73, 1.77) for > 20 g versus 0 g/day, and 1.21 (95% CI: 0.79, 1.84) for > 20 g versus 0 g/day, respectively. Moderate consumption of alcohol was associated with breast cancer, specifically hormone receptor-positive tumors. C1 [Lew, Jasmine Q.; Freedman, Neal D.; Schatzkin, Arthur; Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Brinton, Louise A.] NCI, Hormone & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Hoover, Robert N.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Lew, Jasmine Q.] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. [Leitzmann, Michael F.] Univ Regensburg, Inst Epidemiol & Prevent Med, Regensburg, Germany. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Park, Y (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20852 USA. EM parkyik@mail.nih.gov RI Brinton, Louise/G-7486-2015; Freedman, Neal/B-9741-2015; OI Brinton, Louise/0000-0003-3853-8562; Freedman, Neal/0000-0003-0074-1098; Park, Yikyung/0000-0002-6281-489X FU Intramural NIH HHS NR 36 TC 52 Z9 54 U1 1 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 AUG 1 PY 2009 VL 170 IS 3 BP 308 EP 317 DI 10.1093/aje/kwp120 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 475BH UT WOS:000268330300007 PM 19541857 ER PT J AU Kistner, EO Shi, M Weinberg, CR AF Kistner, Emily O. Shi, Min Weinberg, Clarice R. TI Using Cases and Parents to Study Multiplicative Gene-by-Environment Interaction SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; epidemiologic methods; genetic epidemiology; genetic markers; genotype-environment interaction; logistic models ID QUANTITATIVE TRAIT; OFFSPRING TRIOS; ASSOCIATION; TRIADS; GENOTYPE; SIBLINGS; DESIGN; JOINT; POWER AB With case-parent triads, one can estimate genotype relative risks by measuring the apparent overtransmission of susceptibility genotypes from parents to affected offspring. Results obtained using such designs, properly analyzed, resist both bias due to population structure and bias due to self-selection. Most diseases are not purely genetic, and environmental cofactors can also be important. In this paper, the authors describe how a polytomous logistic regression method previously developed for studying genetic effects on a quantitative trait can be used with case-parent data to study multiplicative gene-by-environment interaction. The idea is that if the joint effect of exposure and genotype on risk is submultiplicative or supermultiplicative, then, conditional on the parental genotypes, inheritance of a susceptibility genotype by affected offspring will appear to have been influenced by the offspring's exposure level. The authors' approach tolerates exposure-complicated genetic population structure, and simulations suggest power and Type I error rates comparable to those of competitors. With this approach, one can estimate the usual interaction parameters under a much less stringent assumption than gene-environment independence in the source population. Incompletely genotyped triads can contribute through an expectation-maximization algorithm. To illustrate, the authors consider polymorphisms in detoxification pathway genes and maternal smoking in relation to the birth defect oral cleft. C1 [Kistner, Emily O.] Univ Chicago, Dept Hlth Studies, Div Biol Sci, Chicago, IL 60637 USA. [Shi, Min; Weinberg, Clarice R.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Kistner, EO (reprint author), Univ Chicago, Dept Hlth Studies, Div Biol Sci, 5841 S Maryland Ave,MC2007, Chicago, IL 60637 USA. EM ekistner@uchicago.edu FU NIEHS NIH HHS [Z01-ES04007-12] NR 26 TC 8 Z9 8 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2009 VL 170 IS 3 BP 393 EP 400 DI 10.1093/aje/kwp118 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 475BH UT WOS:000268330300016 PM 19483188 ER PT J AU Gopal, L Forbes, J Uzel, G Holland, SM Heller, T AF Gopal, Lakshmi Forbes, Joanne Uzel, Gulbu Holland, Steven M. Heller, Theo TI Gastrointestinal Fistulae in Chronic Granulomatous Disease SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Letter C1 [Gopal, Lakshmi; Forbes, Joanne; Heller, Theo] NIDDK, Digest & Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Uzel, Gulbu; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Heller, T (reprint author), NIDDK, Digest & Liver Dis Branch, NIH, CRC Bldg 10 9B16, Bethesda, MD 20892 USA. EM theoh@intra.niddk.nih.gov FU Intramural NIH HHS [ZIA DK075008-04] NR 2 TC 4 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD AUG PY 2009 VL 104 IS 8 BP 2112 EP 2113 DI 10.1038/ajg.2009.181 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 483KW UT WOS:000268965300034 PM 19436280 ER PT J AU Olnes, M Chi, A Haney, C May, R Minniti, C Taylor, J Kato, GJ AF Olnes, Matthew Chi, Amy Haney, Carissa May, Rose Minniti, Caterina Taylor, James Kato, Gregory J. TI Improvement in hemolysis and pulmonary arterial systolic pressure in adult patients with sickle cell disease during treatment with hydroxyurea SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter ID ENDOTHELIAL-CELLS; HYPERTENSION; DEATH; CHILDREN; ANEMIA; RISK AB Elevated pulmonary arterial systolic pressure is strongly associated with mortality in patients with sickle cell disease (SCD). A tricuspid regurgitant velocity (TRV) of 2.5 m/s or greater by trans-thoracic echo-cardiogram is a key marker of risk [1-3]. The pathophysiologic mechanism involves release from the red cell during intravascular hemolysis of cell-free plasma hemoglobin and arginase [4]. Hydroxyurea is the only drug approved by the Food and Drug Administrations specifically for SCD. It acts by increasing levels of fetal hemoglobin, which inhibits sickling, and has been shown to reduce the incidence of vaso-occlusive crisis (VOC), and prolong survival in patients with sickle cell disease [5,6]. Because fetal hemoglobin also reduces the rate of hemolysis in SCID, hypothetically, hydroxyurea might also reduce the severity of hemolysis-linked vascular dysfunction and pulmonary hypertension. Herein, we describe five patients with sickle cell disease having elevated pulmonary arterial systolic pressure who exhibited improvement In their baseline laboratory parameters of hemolysis, accompanied by reduced TRV, during treatment with hydroxyurea. Hydroxyurea may have a role in the management of selected patients with elevated TRV. C1 [Olnes, Matthew; Chi, Amy; Haney, Carissa; May, Rose; Minniti, Caterina; Taylor, James; Kato, Gregory J.] NHLBI, Pulm & Vasc Med Branch, Dept Crit Care Med, Ctr Clin,NIH, Bethesda, MD 20892 USA. RP Kato, GJ (reprint author), NHLBI, Pulm & Vasc Med Branch, Dept Crit Care Med, Ctr Clin,NIH, 10 Ctr Dr,MSC 1476,Bldg 10 CRC, Bethesda, MD 20892 USA. EM gkato@mail.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [Z01 CL008070-04, ZIA HL005802-04, ZIA HL005802-05, ZIA HL006014-01, ZIA HL006014-02] NR 16 TC 20 Z9 20 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2009 VL 84 IS 8 BP 530 EP 532 DI 10.1002/ajh.21446 PG 3 WC Hematology SC Hematology GA 479WR UT WOS:000268693000015 PM 19536844 ER PT J AU Kawauchi, S Santos, R Lopez-Burks, ME Hoang, MP Kitzes, LM Lao, TT Lechner, MS Hallgrimsson, B Daniel, J Nussenzweig, A Lander, AD Calof, AL AF Kawauchi, Shimako Santos, Rosaysela Lopez-Burks, Martha E. Hoang, Michelle P. Kitzes, Leonard M. Lao, Taotao Lechner, Mark S. Hallgrimsson, Benedikt Daniel, JeremyA. Nussenzweig, Andre Lander, Arthur D. Calof, Anne L. TI Insights Into Cornelia de Lange Syndrome From the Nipbl-Mutant Mouse SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 3rd Scientific Cornelia de Lange Syndrome Symposium CY JUN, 2008 CL Chicago, IL C1 [Kawauchi, Shimako; Santos, Rosaysela; Kitzes, Leonard M.] Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92717 USA. [Kawauchi, Shimako; Lopez-Burks, Martha E.; Hoang, Michelle P.; Lander, Arthur D.; Calof, Anne L.] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92717 USA. [Kawauchi, Shimako; Santos, Rosaysela; Lopez-Burks, Martha E.; Hoang, Michelle P.; Lander, Arthur D.; Calof, Anne L.] Univ Calif Irvine, Ctr Dev Biol, Irvine, CA 92717 USA. [Kawauchi, Shimako; Santos, Rosaysela; Kitzes, Leonard M.; Calof, Anne L.] Univ Calif Irvine, Ctr Hearing Res, Irvine, CA 92717 USA. [Lander, Arthur D.; Calof, Anne L.] Univ Calif Irvine, Ctr Complex Biol Syst, Irvine, CA 92717 USA. [Lao, Taotao; Lechner, Mark S.] Drexel Univ, Dept Biosci & Biotechnol, Philadelphia, PA 19104 USA. [Hallgrimsson, Benedikt] Univ Calgary, Dept Cell Biol & Anat, Calgary, AB, Canada. [Daniel, JeremyA.; Nussenzweig, Andre] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RI Calof, Anne/A-8644-2013; Hallgrimsson, Benedikt/A-9616-2008 OI Calof, Anne/0000-0003-3676-2499; Hallgrimsson, Benedikt/0000-0002-7192-9103 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 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2009 VL 149A IS 8 BP 1620 EP 1621 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 481GR UT WOS:000268796000015 ER PT J AU Biesecker, LG AF Biesecker, Leslie G. TI A Silent Majority? SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Editorial Material C1 NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, Genet Dis Res Branch, 49 Convent Dr Room 4A56, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov NR 1 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 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2009 VL 149A IS 8 BP 1623 EP 1623 DI 10.1002/ajmg.a.32832 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 481GR UT WOS:000268796000021 PM 19449406 ER PT J AU Macaya, D Katsanis, SH Hefferon, TW Audlin, S Mendelsohn, NJ Roggenbuck, J Cutting, GR AF Macaya, D. Katsanis, S. H. Hefferon, T. W. Audlin, S. Mendelsohn, N. J. Roggenbuck, J. Cutting, G. R. TI A Synonymous Mutation in TCOF1 Causes Treacher Collins Syndrome Due to Mis-Splicing of a Constitutive Exon SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE mandibulofacial dysostosis; TCOF1 protein; RNA splicing; silent mutation; exonic splice enhancer; clinical molecular diagnostics ID SPLICING ENHANCERS; GENETIC-LINKAGE; IDENTIFICATION; REVEALS AB Interpretation of the pathogenicity of sequence alterations in disease-associated genes is challenging. This is especially true for novel alterations that lack obvious functional consequences. We report here on a patient with Treacher Collins syndrome (TCS) found to carry a previously reported mutation, c.122C > T, which predicts p.A41V, and a novel synonymous mutation, c.3612A > C. Pedigree analysis showed that the c.122C > T mutation segregated with normal phenotypes in multiple family members while the c.3612A > C was de novo in the patient. Analysis of TCOF1 RNA in lymphocytes showed a transcript missing exon 22. These results show that TCS in the patient is due to haploinsufficiency of TCOF1 caused by the synonymous de novo c.3612A > C mutation. This study highlights the importance of clinical and pedigree evaluation in the interpretation of known and novel sequence alterations. (C) 2009 Wiley-Liss, Inc. C1 [Macaya, D.; Katsanis, S. H.; Audlin, S.; Cutting, G. R.] Johns Hopkins Univ, Inst Med Genet, DNA Diagnost Lab, Baltimore, MD USA. [Hefferon, T. W.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Mendelsohn, N. J.; Roggenbuck, J.] Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. RP Cutting, GR (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, 733 N Broadway,Broadway Res Bldg 559, Baltimore, MD 21218 USA. EM gcutting@jhmi.edu NR 19 TC 15 Z9 15 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2009 VL 149A IS 8 BP 1624 EP 1627 DI 10.1002/ajmg.a.32834 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 481GR UT WOS:000268796000022 PM 19572402 ER PT J AU Tovar-Moll, F Evangelou, IE Chiu, AW Richert, ND Ostuni, JL Ohayon, JM Auh, S Ehrmantraut, M Talagala, SL McFarland, HF Bagnato, F AF Tovar-Moll, F. Evangelou, I. E. Chiu, A. W. Richert, N. D. Ostuni, J. L. Ohayon, J. M. Auh, S. Ehrmantraut, M. Talagala, S. L. McFarland, H. F. Bagnato, F. TI Thalamic Involvement and Its Impact on Clinical Disability in Patients with Multiple Sclerosis: A Diffusion Tensor Imaging Study at 3T SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article; Proceedings Paper CT 92nd Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America CY NOV 26-DEC 01, 2006 CL Chicago, IL SP Radiol Soc N Amer ID GRAY-MATTER INVOLVEMENT; NORMAL-APPEARING WHITE; STATUS SCALE EDSS; MAGNETIZATION-TRANSFER; CORTICAL-LESIONS; BASAL GANGLIA; HEAD-INJURY; MRI; GREY; MS AB BACKGROUND AND PURPOSE: Several studies suggest that grey matter involvement may play a role in multiple sclerosis (MS) pathology. Diffusion tensor imaging (DTI) at 3T was used to investigate the presence of damage to the normal-appearing thalamus in MS and its relationship with disability. MATERIALS AND METHODS: Twenty-four patients with relapsing-remitting (FIR, n = 13, age = 41.7 +/- 6.1, Expanded Disability Status Scale [EDSSI score = 2.2 +/- 1.2) and secondary-progressive (n = 11, age = 46.9 +/- 9.6, EDSS = 5.9 +/- 1.0) MS and 24 age- and sex-matched healthy volunteers were studied. Fractional anisotropy (FA) and mean diffusivity (MD) were measured in regions of interest of normal-appearing thalamus. We examined group differences in MD and FA and correlations between DTI-derived metrics and clinical or imaging measures of disease. RESULTS: Patients with MS had higher thalamic FA (P < .0001) and MID (P = .035) than volunteers. MD values correlated with the Paced Auditory Serial Addition Task V = -0.43, P = .034) and motor EDSS (r = 0.47, P = .021) scores. In patients with RRMS, MID values correlated with global EDSS (r = 0.75, P = .003) and motor EDSS V = 0.68, P = .010). Correlations were found between MID values and T1 and T2 lesion load V = 0.58, P < .05) and brain parenchymal fraction V = -0.46, P < .05). CONCLUSIONS: DTI was able to detect abnormalities in normal-appearing thalamus of patients with MS. The strength of association between thalamic DTI measures and functional impairment was in the same range as those seen with standard MR imaging disease measures. The assessment of the integrity of the thalamus with DTI is a promising metric as a marker of disease for future studies. C1 [Tovar-Moll, F.; Evangelou, I. E.; Chiu, A. W.; Richert, N. D.; Ostuni, J. L.; Ohayon, J. M.; Ehrmantraut, M.; McFarland, H. F.; Bagnato, F.] NINDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Auh, S.] NINDS, NIH, Off Clin Director, Bethesda, MD 20892 USA. [Talagala, S. L.] NINDS, NIH, NIH MRI Res Facil, Bethesda, MD 20892 USA. RP Bagnato, F (reprint author), Bldg 10,Room 5C103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM bagnatof@ninds.nih.gov RI Neurociencia, Inct/I-1011-2013 FU Intramural NIH HHS NR 47 TC 42 Z9 43 U1 1 U2 2 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD AUG PY 2009 VL 30 IS 7 BP 1380 EP 1386 DI 10.3174/ajnr.A1564 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 486BE UT WOS:000269169600022 PM 19369608 ER PT J AU Riva, M Ikonomidou, VN Ostuni, JJ van Gelderen, P Auh, S Ohayon, JM Tovar-Moll, F Richert, ND Duyn, JH Bagnato, F AF Riva, M. Ikonomidou, V. N. Ostuni, J. J. van Gelderen, P. Auh, S. Ohayon, J. M. Tovar-Moll, F. Richert, N. D. Duyn, J. H. Bagnato, F. TI Tissue-Specific Imaging Is a Robust Methodology to Differentiate In Vivo T1 Black Holes with Advanced Multiple Sclerosis-Induced Damage SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article; Proceedings Paper CT 58th Annual Meeting of the American-Academy-of-Neurology CY APR 01-08, 2006 CL San Diego, CA SP Amer Acad Neurol ID SPIN-ECHO MRI; HYPOINTENSE LESIONS; INTERFERON BETA-1B; ENHANCING LESIONS; AXONAL LOSS; BRAIN; MS; DISABILITY; CONTRAST; RECOVERY AB BACKGROUND AND PURPOSE: Brains of patients with multiple sclerosis (MS) characteristically have "black holes" (BHs), hypointense lesions on T1-weighted (T1W) spin-echo (SE) images. Although conventional MR imaging can disclose chronic BHs (CBHs), it cannot stage the degree of their pathologic condition. Tissue-specific imaging (TSI), a recently introduced MR imaging technique, allows selective visualization of white matter (WM), gray matter (GM), and CSF on the basis of T1 values of classes of tissue. We investigated the ability of TSI-CSF to separate CBHs with longer T1 values, which likely represent lesions containing higher levels of destruction and unbound water. MATERIALS AND METHODS: Eighteen patients with MS, who had already undergone MR imaging twice (24 months apart) on a 1.5T scanner, underwent a 3T MR imaging examination. Images acquired at 1.5T included sequences of precontrast and postcontrast T1W SE, T2-weighted (T2W) SE, and magnetization transfer (MT). Sequences obtained at 3T included precontrast and postcontrast T1W SE, T2W SE, T1 inversion recovery prepared fast spoiled gradient recalled-echo (IR-FSPGR) and TSI. A BH on the 3T-IR-FSPGR was defined as a CBH if seen as a hypointense, nonenhancing lesion with a corresponding T2 abnormality for at least 24 months. CBHs were separated into 2 groups: those visible as hyperintensities on TSI-CSF (group A), and those not appearing on the TSI-CSF (group B). RESULTS: Mean MT ratios of group-A lesions (0.22 +/- 0.06, 0.13-0.35) were lower (F(1,) (13) = 60.39; P < .0001) than those of group-B lesions (0.32 +/- 0.03, 0.27-0.36). CONCLUSIONS: Group-A lesions had more advanced tissue damage; thus, TSI is a potentially valuable method for qualitative and objective identification. C1 [Riva, M.; Ikonomidou, V. N.; Ostuni, J. J.; Ohayon, J. M.; Tovar-Moll, F.; Richert, N. D.; Bagnato, F.] NINDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Ikonomidou, V. N.; van Gelderen, P.; Duyn, J. H.] NINDS, NIH, Adv MRI Sect, LFMI, Bethesda, MD 20892 USA. [Auh, S.] NINDS, NIH, Off Clin Director, Bethesda, MD 20892 USA. RP Bagnato, F (reprint author), NINDS, NIH, Neuroimmunol Branch, Bldg 10,Room 5C103,10 Ctr Dr, Bethesda, MD 20892 USA. EM bagnatof@ninds.nih.gov RI Duyn, Jozef/F-2483-2010; Neurociencia, Inct/I-1011-2013; OI Riva, Marco/0000-0003-4643-6451 NR 42 TC 13 Z9 13 U1 0 U2 2 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD AUG PY 2009 VL 30 IS 7 BP 1394 EP 1401 DI 10.3174/ajnr.A1573 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 486BE UT WOS:000269169600025 PM 19406765 ER PT J AU Salomao, SR Soares, FS Berezovsky, A Araujo, A Mitsuhiro, MRKH Watanabe, SES Carvalho, AV Pokharel, GP Belfort, R Ellwein, LB AF Salomao, Solange R. Soares, Francisco S. Berezovsky, Adriana Araujo-Filho, Arnaud Mitsuhiro, Marcia R. K. H. Watanabe, Sung E. S. Carvalho, Alisson V. Pokharel, Gopal P. Belfort, Rubens, Jr. Ellwein, Leon B. TI Prevalence and Outcomes of Cataract Surgery in Brazil: The Sao Paulo Eye Study SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID VISUAL IMPAIRMENT; OLDER ADULTS; BLINDNESS; POPULATION; DISTRICT; COUNTY; CHINA AB PURPOSE: To investigate the prevalence and visual acuity (VA) outcomes of cataract surgery in a low- to middle-income population in Sao Paulo, Brazil. DESIGN: Population-based, cross-sectional study. METHODS: Cluster sampling was used in randomly selecting those >= 50 years old for VA measurement, refraction, and ocular examination. Participants were queried as to the year and type of facility for previous cataract surgery. Surgical procedure and evidence of surgical complications were noted. Main outcome measures were presenting and best corrected vision, and the principal cause for eyes presenting with VA >= 20/40. RESULTS: A total of 4,224 eligible persons were enumerated and 3,678 (87.1%) were examined. The prevalence of cataract surgery was 6.28% (95% confidence interval [CI], 5.29% to 7.27%). Surgical coverage for presenting VA <20/63 in both eyes because of cataract was 61.4%. Unoperated cataract impairment/blindness was associated with older age and lack of schooling. Among the 352 cataract-operated eyes, 41.2% presented with VA >20/40, 28.1% with VA 20/40 to 20/63, 14.2% with VA <20/63 to 20/200, and 16.5% with VA <20/200. With best correction, the percentages were 61.9%, 17.6%, 8.2%, and 12.2%. Intraocular lenses were found in 90.6% of cataract-ope rated eyes; half appeared to have been operated by phacoemulsification. Refractive error and retinal disorders were the main cause of vision impairment/blindness in operated eyes. CONCLUSIONS: Cataract surgery has increased in Sao Paulo, but many remain visually impaired/blind because of cataract. Refractive error and other causes of impairment are common in cataract-operated eyes. Emphasis on the quality of VA outcomes and sustained government subsidy to provide access to affordable modern cataract surgery are needed. (Am J Ophthalmol 2009;148: 199-206. (C) 2009 by Elsevier Inc. All rights reserved.) C1 [Salomao, Solange R.; Soares, Francisco S.; Berezovsky, Adriana; Araujo-Filho, Arnaud; Mitsuhiro, Marcia R. K. H.; Watanabe, Sung E. S.; Carvalho, Alisson V.; Belfort, Rubens, Jr.] Univ Fed Sao Paulo, Vis Inst, Dept Ophthalmol, BR-04023062 Sao Paulo, Brazil. [Pokharel, Gopal P.] World Hlth Org, Geneva, Switzerland. [Ellwein, Leon B.] NEI, NIH, Bethesda, MD 20892 USA. RP Salomao, SR (reprint author), Univ Fed Sao Paulo, Vis Inst, Dept Ophthalmol, R Botucatu 822, BR-04023062 Sao Paulo, Brazil. EM ssalomao@oftalmo.epm.br RI Salomao, Solange/G-9500-2012; Belfort Jr, Rubens/E-2252-2012; Berezovsky, Adriana/F-2341-2013; Mitsuhiro, Marcia/H-7872-2013 OI Salomao, Solange/0000-0002-3436-5599; Belfort Jr, Rubens/0000-0002-8422-3898; FU NEI NIH HHS [N01-EY-2103] NR 18 TC 13 Z9 15 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD AUG PY 2009 VL 148 IS 2 BP 199 EP 206 DI 10.1016/j.ajo.2009.02.019 PG 8 WC Ophthalmology SC Ophthalmology GA 477SZ UT WOS:000268540300007 PM 19406378 ER PT J AU Wang, XY Demelash, A Kim, H Jensen-Taubman, S Dakir, EH Ozbun, L Birrer, MJ Linnoila, RI AF Wang, Xiao-Yang Demelash, Abeba Kim, Heungnam Jensen-Taubman, Sandra Dakir, El Habib Ozbun, Laurent Birrer, Michael J. Linnoila, R. Ilona TI Matrilysin-1 Mediates Bronchiolization of Alveoli, a Potential Premalignant Change in Lung Cancer SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID MATRIX METALLOPROTEINASE-7; SIGNALING PATHWAY; TUMOR-CELLS; EXPRESSION; APOPTOSIS; RESISTANCE; EPITHELIUM; CARCINOMA; INVASION; TUMORIGENESIS AB Matrilysin-1 (also called matrix metalloproteinase-7) is expressed in injured lung and in cancer but not in normal epithelia. Bronchiolization of the alveoli (BOA), a potential precursor of lung cancer, is a histologically distinct type of metaplasia that is composed of cells resembling airway epithelium in the alveolar compartment. We demonstrate that there is increased expression of matrilysin-1 in human lesions and BOA in the CC10-human achaete-scute homolog-1 transgenic mouse model. Forced expression of the matrilysin-1 gene in immortalized human normal airway epithelial BEAS-2B and HPLD1 cells, which do not normally express matrilysin-1, promoted cellular migration, suggesting a functional link for BOA formation via bronchiolar cell migration. In addition, matrilysin-1 stimulated proliferation and inhibited Fas-induced apoptosis, while a knockdown by RNA interference decreased cell growth, migration, and increased sensitivity to apoptosis. Western blotting demonstrated increased levels of phospho-P38 and phospho-Erk1/2 kinases after matrilysin-1 expression. Gene expression analysis uncovered several genes that were related to cell growth, migration/movement, and death, which could potentially facilitate bronchiolization. In vivo, the formation of BOA lesions was reduced when CC10-human achaete-scute homolog-1 mice were crossed with matrilysin-1 null mice and was correlated with reduced matrilysin-1 expression in BOA. We conclude that matrilysin-1 may play an important role in the bronchiolization of alveoli by promoting proliferation, migration, and attenuation of apoptosis involving multiple genes in the MAP kinase pathway. (Am J Pathol 2009, 175:592-604; DOI: 10.2353/ajpatb.2009.080461) C1 [Linnoila, R. Ilona] NCI, NIH, Expt Pathol Sect, Cell & Canc Biol Branch,Ctr Canc Res, Bethesda, MD 20892 USA. RP Linnoila, RI (reprint author), NCI, NIH, Expt Pathol Sect, Cell & Canc Biol Branch,Ctr Canc Res, 37 Convent Dr,Room 1056B, Bethesda, MD 20892 USA. EM linnoila@mail.nih.gov RI 2009, Secribsal/A-1266-2012; DAKIR, EL HABIB/O-1383-2015 FU NIH, National Cancer Institute FX Supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 39 TC 3 Z9 4 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2009 VL 175 IS 2 BP 592 EP 604 DI 10.2353/ajpath.2009.080461 PG 13 WC Pathology SC Pathology GA 477GZ UT WOS:000268508500013 PM 19608871 ER PT J AU Yu, WH Dorado, B Figueroa, HY Wang, LL Planel, E Cookson, MR Clark, LN Duff, KE AF Yu, Wai Haung Dorado, Beatriz Figueroa, Helen Yvette Wang, Lili Planel, Emmanuel Cookson, Mark R. Clark, Lorraine N. Duff, Karen E. TI Metabolic Activity Determines Efficacy of Macroautophagic Clearance of Pathological Oligomeric alpha-Synuclein SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CHAPERONE-MEDIATED AUTOPHAGY; AGGREGATE-PRONE PROTEINS; GLUCOCEREBROSIDASE GENE-MUTATIONS; ONSET PARKINSONS-DISEASE; MULTIPLE SYSTEM ATROPHY; LEWY BODIES; ALZHEIMERS-DISEASE; DEGRADATION; DEMENTIA; PATHWAY AB Macroautophagy is an essential degradative pathway that can be induced to clear aggregated proteins, such as those found in Parkinson's disease and dementia with Lewy bodies, a form of Parkinsonism. This study found that both LC3-II and beclin were significantly increased in brains from humans with Dementia with Lewy bodies and transgenic mice overexpressing mutant a-synuclein, as compared with respective controls, suggesting that macroautophagy is induced to remove alpha-syn, particularly oligomeric or mutant forms. Aged mutant animals had higher autophagy biomarker levels relative to younger animals, suggesting that with aging, autophagy is less efficient and requires more stimulation to achieve die same outcome. Disruption of autophagy by RNA interference significantly increased alpha-syn oligomer accumulation in vitro, confirming the significance of autophagy in alpha-syn clearance. Finally, rotenone-induced alpha-syn aggregates were cleared following rapamycin stimulation of autophagy. Chronic rotenone exposure and commensurate reduction of metabolic activity limited the efficacy of rapamycin to promote autophagy, suggesting that cellular metabolism is critical for determining autophagic activity. Cumulatively, these findings support the concept that neuronal autophagy is essential for protein homeostasis and, in our system, reduction of autophagy increased the accumulation of potentially pathogenic alpha-synuclein oligomers. Aging and metabolic state were identified as important determinants of autophagic activity. This study provides therapeutic and pathological implications for both syncleinopathy and Parkinson's disease, identifying conditions in which autophagy may be insufficient to degrade alpha-syn aggregates. (Am J Patbol 2009, 175:736-747; DOI: 10.2353/ajpath.2009.080928) C1 [Duff, Karen E.] Columbia Univ, Med Ctr, Dept Pathol, New York, NY 10032 USA. [Yu, Wai Haung; Dorado, Beatriz; Figueroa, Helen Yvette; Wang, Lili; Clark, Lorraine N.; Duff, Karen E.] Columbia Univ, Taub Inst, New York, NY 10032 USA. [Clark, Lorraine N.] Columbia Univ, Ctr Human Genet, New York, NY 10032 USA. [Planel, Emmanuel] CHU Laval Neurosci, Quebec City, PQ, Canada. [Cookson, Mark R.] NIH, Gene Express Unit, Bethesda, MD 20892 USA. RP Duff, KE (reprint author), Columbia Univ, Med Ctr, Dept Pathol, 630 W168th St,Rm 12-461, New York, NY 10032 USA. EM ked2115@columbia.edu FU National Institute of Neurological Disorders and Stroke [NS050487]; Parkinson's Disease Foundation; Intramural Research Program of the National Institutes of Health; National Institute on Aging [Z01-AG000948] FX Supported by grants from the National Institute of Neurological Disorders and Stroke (NS050487, to L.C.), the Parkinson's Disease Foundation (L.C.), and the Intramural Research Program of the National Institutes of Health, National Institute on Aging (Project Z01-AG000948, to M.R.C.). NR 71 TC 80 Z9 83 U1 1 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2009 VL 175 IS 2 BP 736 EP 747 DI 10.2353/ajpath.2009.080928 PG 12 WC Pathology SC Pathology GA 477GZ UT WOS:000268508500026 PM 19628769 ER PT J AU Tuo, JS Ross, RJ Herzlich, AA Shen, DF Ding, XY Zhou, M Coon, SL Hussein, N Salem, N Chan, CC AF Tuo, Jingsheng Ross, Robert J. Herzlich, Alexandra A. Shen, Defen Ding, Xiaoyan Zhou, Min Coon, Steven L. Hussein, Nahed Salem, Norman, Jr. Chan, Chi-Chao TI A High Omega-3 Fatty Acid Diet Reduces Retinal Lesions in a Murine Model of Macular Degeneration SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; DOCOSAHEXAENOIC ACID; PIGMENT EPITHELIUM; PROSTAGLANDIN D-2; GENE-EXPRESSION; GROWTH-FACTOR; INFLAMMATION; RAT; MACROPHAGES; MICE AB Age-related macular degeneration (AMD) is one of the leading cause of blindness among the elderly; however, current therapy options are limited. Epidemiological studies have shown that a diet that is high in omega-3 polyunsaturated (n-3) fatty acids can slow disease progression in patients with advanced AMD. In this study, we evaluated the effect of such a diet on the retinas of Ccl2(-1-1)/Cx3cr1(-/-) mice, a model that develops AMD-like retinal lesions that Include focal deep retinal lesions, abnormal retinal pigment epithelium, photoreceptor degeneration, and A2E accumulation. Ccl2(-/-)/Cx3crl(-/-) mice that ingested a high n-3 fatty acid diet showed a slower progression of retinal lesions compared with the low n-3 fatty acids group. Some mice that were given high levels of n-3 fatty acids had lesion reversion. We found a shunted arachidonic acid metabolism that resulted in decreased pro-inflammatory derivatives (prostaglandin E(2) and leukotriene B(4) ) and an increased anti-inflammatory derivative (prostaglandin D(2)). We also measured lower ocular TNF-alpha and IL-6 transcript levels in the mice fed a diet of high n-3 fatty acids. Our findings in these mice are in line with human studies of AMD risk reduction by long-chain n-3 fatty acids. This murine model provides a useful tool to evaluate therapies that might delay the development of AMD. (Am J Pathol 2009, 175:799-807; DOI: 10.2353/ajpath.2009.090089) C1 [Chan, Chi-Chao] NEI, NIH, Immunopathol Sect, Immunol Lab, Bethesda, MD 20892 USA. [Coon, Steven L.] NICHHD, Sect Neuroendocrinol, Bethesda, MD 20892 USA. [Hussein, Nahed; Salem, Norman, Jr.] NIAAA, NIH, Bethesda, MD USA. [Hussein, Nahed; Salem, Norman, Jr.] Lab Membrane Biochem & Biophys, Bethesda, MD USA. RP Chan, CC (reprint author), NEI, NIH, Immunopathol Sect, Immunol Lab, 10-10N 103,10 Ctr Dr, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov OI Tuo, Jingsheng/0000-0002-1372-7810 FU Intramural Research Program of the National Eye Institute; National Institutes of Health; American Health Assistance Foundation FX Supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health and the American Health Assistance Foundation. NR 45 TC 37 Z9 39 U1 0 U2 6 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2009 VL 175 IS 2 BP 799 EP 807 DI 10.2353/ajpath.2009.090089 PG 9 WC Pathology SC Pathology GA 477GZ UT WOS:000268508500031 PM 19608872 ER PT J AU Demers, L Fuhrer, MJ Jutai, J Lenker, J Depa, M De Ruyter, F AF Demers, Louise Fuhrer, Marcus J. Jutai, Jeffrey Lenker, James Depa, Malgorzata De Ruyter, Frank TI A Conceptual Framework of Outcomes for Caregivers of Assistive Technology Users SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article; Proceedings Paper CT International Conference on Aging, Disability and Independence CY FEB, 2008 CL St Petersburg, FL DE Self-Help Devices; Outcome Assessment; Caregiver; Theoretical Model ID LONG-TERM-CARE; PERSONAL ASSISTANCE; SOCIAL SUPPORT; OLDER-ADULTS; DEVICES; IMPACT; HOME; DISABILITY; STRESS; BURDEN AB Objective: To develop and validate the content of a conceptual framework concerning outcomes for caregivers whose recipients are assistive technology users. Design: The study was designed in four stages. First, a list of potential key variables relevant to the caregivers of assistive technology users was generated from a review of the existing literature and semistructured interviews with caregivers. Second, the variables were analyzed, regrouped, and partitioned, using a conceptual mapping approach. Third, the key areas were anchored in a general stress model of caregiving. Finally, the judgments of rehabilitation experts were used to evaluate the conceptual framework. Results: An important result of this study is the identification of a complex set of variables that need to be considered when examining the experience of caregivers of assistive technology users. Stressors, such as types of assistance, number of tasks, and physical effort, are predominant contributors to caregiver outcomes along with caregivers' personal resources acting as mediating factors (intervening variables) and assistive technology acting as a key moderating factor (effect modifier variable). Conclusions: Recipients' use of assistive technology can enhance caregivers' well being because of its potential for alleviating a number of stressors associated with caregiving. Viewed as a whole, this work demonstrates that the assistive technology experience of caregivers has many facets that merit the attention of outcomes researchers. C1 [Demers, Louise; Depa, Malgorzata] Inst Univ Geriatr Montreal, Res Ctr, Montreal, PQ H3W 1W5, Canada. [Demers, Louise] Univ Montreal, Fac Med, Sch Rehabil, Montreal, PQ H3C 3J7, Canada. [Fuhrer, Marcus J.] NICHHD, NIH, Bethesda, MD 20892 USA. [Jutai, Jeffrey] Univ Ottawa, Fac Hlth Sci, Ottawa, ON, Canada. [Lenker, James] SUNY Buffalo, Dept Rehabil Sci, Buffalo, NY 14260 USA. [De Ruyter, Frank] Duke Univ, Med Ctr, Div Speech Pathol & Audiol, Durham, NC USA. RP Demers, L (reprint author), Inst Univ Geriatr Montreal, Res Ctr, 4565 Queen Mary Rd, Montreal, PQ H3W 1W5, Canada. NR 53 TC 10 Z9 11 U1 5 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD AUG PY 2009 VL 88 IS 8 BP 645 EP 655 DI 10.1097/PHM.0b013e3181ae0e70 PG 11 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 476VW UT WOS:000268475400006 PM 19620830 ER PT J AU Huang, L Stinchcomb, DG Pickle, LW Dill, J Berrigan, D AF Huang, Lan Stinchcomb, David G. Pickle, Linda W. Dill, Jennifer Berrigan, David TI Identifying Clusters of Active Transportation Using Spatial Scan Statistics SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID PHYSICAL-ACTIVITY; BUILT ENVIRONMENT; UNITED-STATES; OBESITY; WALKING; TESTS; INTERVENTIONS; SURVEILLANCE; FRAMEWORK; ADULTS AB Background: There is an intense interest in the possibility that neighborhood characteristics influence active transportation such as walking or biking. The purpose of this paper is to illustrate how a spatial cluster identification method can evaluate the geographic variation of active transportation and identify neighborhoods with unusually high/low levels of active transportation. Methods: Self-reported walking/biking prevalence, demographic characteristics, street connectivity variables, and neighborhood socioeconomic data were collected from respondents to the 2001 California Health Interview Survey (CHIS; N=10,688) in Los Angeles County (LAC) and San Diego County (SDC). Spatial scan statistics were used to identify clusters of high or low prevalence (with and without age-adjustment) and the quantity of time spent walking and biking. The data, a subset from the 2001 CHIS, were analyzed in 2007-2008. Results: Geographic clusters of significantly high or low prevalence of walking and biking were detected in LAC and SDC. Structural variables such as street connectivity and shorter block lengths are consistently associated with higher levels of active transportation, but associations between active transportation and socioeconomic variables at the individual and neighborhood levels are mixed. Only one cluster with less time spent walking and biking among walkers/bikers was detected in LAC, and this was of borderline significance. Age-adjustment affects the clustering pattern of walking/biking prevalence in LAC, but not in SDC. Conclusions: The use of spatial scan statistics to identify significant clustering of health behaviors such as active transportation adds to the more traditional regression analysis that examines associations between behavior and environmental factors by identifying specific geographic areas with unusual levels of the behavior independent of predefined administrative units. (Am J Prev Med 2009;37(2):157-166) Published by Elsevier Inc. on behalf of American journal of Preventive Medicine C1 [Berrigan, David] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Huang, Lan; Stinchcomb, David G.; Pickle, Linda W.] NCI, Stat Res & Applicat Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Dill, Jennifer] Portland State Univ, Coll Urban & Publ Affairs, Portland, OR 97207 USA. RP Berrigan, D (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, Room 4010,6116 Execut Blvd, Bethesda, MD 20892 USA. EM berrigad@mail.nih.gov RI Dill, Jennifer/D-5971-2011 OI Dill, Jennifer/0000-0001-5498-3928 FU Intramural NIH HHS [Z99 CA999999] NR 36 TC 15 Z9 16 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2009 VL 37 IS 2 BP 157 EP 166 DI 10.1016/j.amepre.2009.04.021 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 475FO UT WOS:000268344200011 PM 19589451 ER PT J AU Moore, RS McLellan, DL Tauras, JA Fagan, P AF Moore, Roland S. McLellan, Deborah L. Tauras, John A. Fagan, Pebbles TI Securing the Health of Disadvantaged Women A Critical Investigation of Tobacco-Control Policy Effects on Women Worldwide Introduction SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material ID UNINTENDED CONSEQUENCES; SMOKING; WORKPLACE; RESTRICTIONS; FRAMEWORK; INDONESIA; NICOTINE; EXPOSURE; IMPACT; POOR C1 [Moore, Roland S.] Prevent Res Ctr, Pacific Inst Res & Evaluat, Berkeley, CA 94704 USA. [McLellan, Deborah L.] Brandeis Univ, Heller Sch Social Policy Management, Waltharn, MA USA. [Tauras, John A.] Univ Chicago, Chicago, IL 60637 USA. [Fagan, Pebbles] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Moore, RS (reprint author), Prevent Res Ctr, Pacific Inst Res & Evaluat, 1995 Univ Ave,Suit 450, Berkeley, CA 94704 USA. EM roland@prev.org OI Moore, Roland/0000-0003-1072-2755 FU NCI NIH HHS [R01 CA100772, R01 CA100772-03] NR 37 TC 3 Z9 3 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2009 VL 37 IS 2 BP S117 EP S120 DI 10.1016/j.amepre.2009.05.015 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 475FQ UT WOS:000268344400001 PM 19591749 ER PT J AU Day, SM Pingel, JM Schwandt, ML Lindell, SG Davis, E Barry, CS Suomi, SJ Higley, JD AF Day, S. M. Pingel, J. M. Schwandt, M. L. Lindell, S. G. Davis, E. Barry, C. S. Suomi, S. J. Higley, J. D. TI SELF INJURY AND THE INTRUDER CHALLENGE PARADIGM: A COMPARATIVE STUDY EXAMINING GENOTYPE, HORMONAL, AND BEHAVIORAL INTERACTIONS IN LABORATORY RHESUS MACAQUES SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-Society-of-Primatologists CY SEP 18-21, 2009 CL San Diego, CA SP Amer Soc Primatol, San Diego Zoo, Mira Costa Coll C1 [Day, S. M.; Pingel, J. M.; Higley, J. D.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Schwandt, M. L.; Lindell, S. G.; Barry, C. S.] NIAA, NIH, Anim Ctr, LCTS, Poolesville, MD 20837 USA. [Davis, E.; Suomi, S. J.] NICHD, NIH, Anim Ctr, LCE, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2009 VL 71 MA 39 BP 41 EP 41 PG 1 WC Zoology SC Zoology GA 488SJ UT WOS:000269369800040 ER PT J AU Jones, BB Stringfellow, B Dennis, W Tate, T Schwandt, ML Lindell, SG Barr, CS Suomi, SJ Higley, JD AF Jones, B. B. Stringfellow, B. Dennis, W. Tate, T. Schwandt, M. L. Lindell, S. G. Barr, C. S. Suomi, S. J. Higley, J. D. TI BIOLOGICAL AND ADOPTIVE MOTHER-INFANT RELATIONSHIPS OF LABORATORY-REARED RHESUS MONKEYS (MACACA MULATTA) ACROSS THE FIRST SIX MONTHS OF LIFE: ADOPTIVE MOTHERS AND THEIR EFFECTS ON INFANTS' CORTISOL AND ACTH LEVELS SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-Society-of-Primatologists CY SEP 18-21, 2009 CL San Diego, CA SP Amer Soc Primatol, San Diego Zoo, Mira Costa Coll C1 [Jones, B. B.; Stringfellow, B.; Dennis, W.; Tate, T.; Higley, J. D.] Brigham Young Univ, Dept Neurosci, Provo, UT 84602 USA. [Schwandt, M. L.; Lindell, S. G.; Barr, C. S.] NIAAA, NIH, Anim Ctr, LCTS, Bethesda, MD 20892 USA. [Suomi, S. J.] NICHD, NIH, Anim Ctr, LCE, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2009 VL 71 MA 48 BP 44 EP 44 PG 1 WC Zoology SC Zoology GA 488SJ UT WOS:000269369800049 ER PT J AU Bowling, NA Mallott, EK Novak, MFSX Miller, ML Sackett, GP Suomi, SJ Robbins, KL Ionica, CS AF Bowling, N. A. Mallott, E. K. Novak, M. F. S. X. Miller, M. L. Sackett, G. P. Suomi, S. J. Robbins, K. L. Ionica, C. S. TI DIFFERENTIAL PREGNANCY EXPERIENCES AND POSTNATAL OUTCOMES MAY INDICATE INDIVIDUAL DIFFERENCES IN FETAL RESPONSES TO MATERNAL PSYCHOLOGICAL CHALLENGE IN RHESUS MACAQUES (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-Society-of-Primatologists CY SEP 18-21, 2009 CL San Diego, CA SP Amer Soc Primatol, San Diego Zoo, Mira Costa Coll C1 [Bowling, N. A.; Mallott, E. K.; Novak, M. F. S. X.; Miller, M. L.; Suomi, S. J.; Robbins, K. L.; Ionica, C. S.] NICHD, NIH, LCE, NIH Anim Ctr, Poolesville, MD 20837 USA. [Sackett, G. P.] Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. RI Ionica, Consuel/A-5186-2009 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2009 VL 71 MA 54 BP 46 EP 46 PG 1 WC Zoology SC Zoology GA 488SJ UT WOS:000269369800055 ER PT J AU Bassett, A Schwandt, ML Lindell, SG Barr, CS Suomi, SJ Higley, JD AF Bassett, A. Schwandt, M. L. Lindell, S. G. Barr, C. S. Suomi, S. J. Higley, J. D. TI EFFECTS OF PREMATURE MATERNAL REJECTION ON THE DEVELOPMENT OF LABORATORY-REARED RHESUS MONKEYS (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-Society-of-Primatologists CY SEP 18-21, 2009 CL San Diego, CA SP Amer Soc Primatol, San Diego Zoo, Mira Costa Coll C1 [Bassett, A.; Higley, J. D.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Schwandt, M. L.; Lindell, S. G.; Barr, C. S.] NIAAA, NIH Anim Ctr, LCTS, Poolesville, MD 20837 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2009 VL 71 MA 55 BP 47 EP 47 PG 1 WC Zoology SC Zoology GA 488SJ UT WOS:000269369800056 ER PT J AU Sorenson, AN Maxwell, WF Schwandt, ML Barr, CS Suomi, SJ Higley, J AF Sorenson, A. N. Maxwell, W. F. Schwandt, M. L. Barr, C. S. Suomi, S. J. Higley, J. TI DIFFERENT DEVELOPMENTAL OUTCOMES FOLLOWING LABORATORY REARING BY BIOLOGICAL OR ADOPTIVE MOTHERS: MATERNAL INFLUENCE ON BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO SEPARATION STRESS IN RHESUS MACAQUES (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-Society-of-Primatologists CY SEP 18-21, 2009 CL San Diego, CA SP Amer Soc Primatol, San Diego Zoo, Mira Costa Coll C1 [Sorenson, A. N.; Maxwell, W. F.; Higley, J.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Schwandt, M. L.; Barr, C. S.] NIAAA, NIH Anim Ctr, LCTS, Poolesville, MD 20837 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2009 VL 71 MA 56 BP 47 EP 47 PG 1 WC Zoology SC Zoology GA 488SJ UT WOS:000269369800057 ER PT J AU Bower, S Paukner, A Suomi, SJ AF Bower, S. Paukner, A. Suomi, S. J. TI GAZE FOLLOWING IN BROWN CAPUCHIN MONKEYS: A COMPARISON OF SCORING METHODS SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-Society-of-Primatologists CY SEP 18-21, 2009 CL San Diego, CA SP Amer Soc Primatol, San Diego Zoo, Mira Costa Coll C1 [Bower, S.; Paukner, A.; Suomi, S. J.] NIH Anim Ctr, Comparat Ethol Lab, Poolesville, MD 20837 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2009 VL 71 MA 60 BP 48 EP 48 PG 1 WC Zoology SC Zoology GA 488SJ UT WOS:000269369800061 ER PT J AU Higley, JD Capitanio, JP Champoux, M AF Higley, J. D. Capitanio, J. P. Champoux, M. TI WRITING AND GETTING GRANTS-LESSONS ABOUT SURVIVING AFTER GRADUATE SCHOOL SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-Society-of-Primatologists CY SEP 18-21, 2009 CL San Diego, CA SP Amer Soc Primatol, San Diego Zoo, Mira Costa Coll C1 [Higley, J. D.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Capitanio, J. P.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Champoux, M.] NIH, Ctr Sci Review, 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2009 VL 71 MA 111 BP 65 EP 65 PG 1 WC Zoology SC Zoology GA 488SJ UT WOS:000269369800112 ER PT J AU Crockett, CM Baker, KC Lutz, CK Coleman, K Fahey, MA Bloomsmith, MA McCowan, B Sullivan, J Weed, JL AF Crockett, C. M. Baker, K. C. Lutz, C. K. Coleman, K. Fahey, M. A. Bloomsmith, M. A. McCowan, B. Sullivan, J. Weed, J. L. TI DEVELOPING A RELIABLE LABORATORY PRIMATE ALOPECIA SCORING SYSTEM FOR INTERFACILITY COLLABORATION AND ON-LINE TRAINING SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-Society-of-Primatologists CY SEP 18-21, 2009 CL San Diego, CA SP Amer Soc Primatol, San Diego Zoo, Mira Costa Coll C1 [Crockett, C. M.] Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Weed, J. L.] NIH, Div Vet Resources, Off Res Serv, DHHS, Bethesda, MD USA. NR 0 TC 4 Z9 4 U1 0 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2009 VL 71 MA 133 BP 73 EP 73 PG 1 WC Zoology SC Zoology GA 488SJ UT WOS:000269369800134 ER PT J AU Paukner, A Huntsberry, ME Suomi, SJ AF Paukner, A. Huntsberry, M. E. Suomi, S. J. TI VISUAL DISCRIMINATION OF MALE AND FEMALE FACES BY INFANT RHESUS MACAQUES (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-Society-of-Primatologists CY SEP 18-21, 2009 CL San Diego, CA SP Amer Soc Primatol, San Diego Zoo, Mira Costa Coll C1 [Paukner, A.; Suomi, S. J.] NIH, Comparat Ethol Lab, Anim Ctr, Poolesville, MD 20837 USA. [Huntsberry, M. E.] SoBran Inc, Bethesda, MD USA. [Huntsberry, M. E.] NIH, Div Vet Resources, ORS, DHHS, 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2009 VL 71 MA 156 BP 80 EP 80 PG 1 WC Zoology SC Zoology GA 488SJ UT WOS:000269369800157 ER PT J AU Dettmer, AM Novak, MA Meyer, JS Vallender, EJ Miller, GM Suomi, SJ AF Dettmer, A. M. Novak, M. A. Meyer, J. S. Vallender, E. J. Miller, G. M. Suomi, S. J. TI INFLUENCE OF REARING CONDITION AND 5-HTTLPR GENOTYPE ON THE RELATIONSHIP BETWEEN HAIR CORTISOL AND ANXIETY AFTER A MAJOR SOCIAL CHALLENGE IN RHESUS MACAQUES (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-Society-of-Primatologists CY SEP 18-21, 2009 CL San Diego, CA SP Amer Soc Primatol, San Diego Zoo, Mira Costa Coll C1 [Dettmer, A. M.; Novak, M. A.; Meyer, J. S.] Univ Massachusetts, Neurosci & Behav Program, Amherst, MA 01003 USA. [Dettmer, A. M.; Suomi, S. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, Poolesville, MD 20837 USA. [Novak, M. A.; Meyer, J. S.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. [Vallender, E. J.; Miller, G. M.] Harvard Univ, Sch Med, New England Primate Res Ctr, Div Neurochem, Southborough, MA 01772 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 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2009 VL 71 MA 178 BP 88 EP 88 PG 1 WC Zoology SC Zoology GA 488SJ UT WOS:000269369800179 ER PT J AU Herman, KN Delaney, D Chisolm, K McLaughlin, SM Cummins, A Noble, P Suomi, SJ Winslow, JT Nelson, EE AF Herman, K. N. Delaney, D. Chisolm, K. McLaughlin, S. M. Cummins, A. Noble, P. Suomi, S. J. Winslow, J. T. Nelson, E. E. TI EARLY REARING HISTORY AND THE TEMPORAL DYNAMICS OF SOCIAL BUFFERING IN RHESUS MACAQUES SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the American-Society-of-Primatologists CY SEP 18-21, 2009 CL San Diego, CA SP Amer Soc Primatol, San Diego Zoo, Mira Costa Coll C1 [Herman, K. N.; Suomi, S. J.] NIH Anim Ctr, Comparat Ethol Lab, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Poolesville, MD 20842 USA. [McLaughlin, S. M.; Nelson, E. E.] NIMH, Sect Affect Dev & Neurosci, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD AUG PY 2009 VL 71 MA 194 BP 93 EP 93 PG 1 WC Zoology SC Zoology GA 488SJ UT WOS:000269369800195 ER PT J AU Barnett, JH Heron, J Goldman, D Jones, PB Xu, K AF Barnett, Jennifer H. Heron, Jon Goldman, David Jones, Peter B. Xu, Ke TI Effects of Catechol-O-Methyltransferase on Normal Variation in the Cognitive Function of Children SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT Congress of the Schizophrenia-International-Research-Society CY JUN 21-25, 2008 CL Vienna, AUSTRIA SP Schizophrenia Int Res Soc ID PREFRONTAL CORTEX; GENETIC-VARIATION; MESSENGER-RNA; COMT GENOTYPE; HUMAN BRAIN; PROTEIN EXPRESSION; ENZYME-ACTIVITY; WORKING-MEMORY; SCHIZOPHRENIA; POLYMORPHISM AB Objective: Genetic variants that contribute to the risk of psychiatric disorders may also affect normal variation in psychological function. Indeed, the behavioral effects of many genetic variants may be better understood as process-specific rather than disease-specific. A functional valine-to-methionine (Val(158)Met) polymorphism in the catechol-O-methyltransferase (COMT) gene has been associated with cognitive function and brain metabolic activity accompanying such tasks. Not all studies are consistent, and less is known about the effect of this polymorphism during development. The authors tested the hypothesis that a more informative COMT haplotype predicts normal cognitive development in a large population-based cohort of children enrolled in the Avon Longitudinal Study of Parents and Children. Method: Effects on verbal and performance IQ as well as verbal inhibition were assessed at age 8, and effects on working memory were assessed at age 10. From the five COMT single nucleotide polymorphisms (SNPs) genotyped, the effect of a functional three-SNP haplotype consisting of Val158Met and two synonymous SNPs (rs6269 and rs4818), which together exert a major influence on the level of COMT expression and enzyme activity, was evaluated. Results: This three-SNP haplotype predicted both verbal inhibition and working memory, and there was a genotype-bysex interaction on verbal IQ. The effect of COMT genotype (diplotype) on cognition was curvilinear, which is consistent with the "inverted U" model of dopamine effect on frontal cortical efficiency. In addition, the SNP rs2075507 (previously rs2097603) was independently associated with verbal inhibition, while rs165599 showed no main cognitive effects. However, rs165599 showed a genotype-by-sex interaction with working memory. Conclusions: Genetic variation at several loci in the COMT gene affects normal cognitive function in children. C1 Univ Cambridge, Dept Psychiat, Cambridge, England. Univ Cambridge, Ctr Family Res, Cambridge, England. Cambridge Cognit Ltd, Cambridge, England. Univ Bristol, Dept Social Med, Bristol, Avon, England. NIAAA, Neurogenet Lab, Bethesda, MD USA. Natl Inst Hlth Res Collaborat Leadership Appl Hlt, Bethesda, MD USA. Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. RP Barnett, JH (reprint author), Addenbrookes Hosp, Dept Psychiat, Box 189, Cambridge CB2 2QQ, England. EM jhb32@cam.ac.uk RI Goldman, David/F-9772-2010; Heron, Jon/D-5884-2011; OI Goldman, David/0000-0002-1724-5405; Heron, Jon/0000-0001-6199-5644; Jones, Peter/0000-0002-0387-880X FU Intramural NIH HHS [Z01 AA000306-02, Z01 AA000280-18]; Medical Research Council [, G9815508]; Wellcome Trust NR 43 TC 44 Z9 45 U1 0 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2009 VL 166 IS 8 BP 909 EP 916 DI 10.1176/appi.ajp.2009.08081251 PG 8 WC Psychiatry SC Psychiatry GA 479DC UT WOS:000268638900013 PM 19605537 ER PT J AU Turkbey, B Kobayashi, H Ogawa, M Bernardo, M Choyke, PL AF Turkbey, Baris Kobayashi, Hisataka Ogawa, Mikako Bernardo, Marcelino Choyke, Peter L. TI Imaging of Tumor Angiogenesis: Functional or Targeted? SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE angiogenesis; functional imaging; targeted imaging; tumor angiogenesis ID POSITRON-EMISSION-TOMOGRAPHY; ENDOTHELIAL GROWTH-FACTOR; CONTRAST-ENHANCED MR; INTEGRIN ALPHA(V)BETA(3) EXPRESSION; POWER DOPPLER ULTRASOUND; BREAST-CANCER; IN-VIVO; BLOOD-FLOW; OVARIAN-CANCER; HEPATOCELLULAR-CARCINOMA AB OBJECTIVE. Angiogenesis-the growth of new vessels-is both a normal physiologic response and a critical step in many pathologic processes, particularly cancer. Imaging has long relied on the different enhancement characteristics of cancer compared with normal tissue; the information generated is often primarily morphologic and qualitative. However, more quantitative methods based on functional and targeted imaging have recently emerged. CONCLUSION. In this article, we review both functional and targeted imaging techniques for assessing tumor angiogenesis. C1 [Turkbey, Baris; Kobayashi, Hisataka; Ogawa, Mikako; Bernardo, Marcelino; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NCI, Mol Imaging Program, NIH, 10 Ctr Dr,MSC 1182,Bldg 10,Rm 1B40, Bethesda, MD 20892 USA. EM pchoyke@mail.nih.gov FU Intramural NIH HHS [Z01 BC010714-03] NR 80 TC 55 Z9 57 U1 1 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2009 VL 193 IS 2 BP 304 EP 313 DI 10.2214/AJR.09.2869 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 472RB UT WOS:000268148600006 PM 19620425 ER PT J AU Gierada, DS Garg, K Nath, H Strollo, DC Fagerstrom, RM Ford, MB AF Gierada, David S. Garg, Kavita Nath, Hrudaya Strollo, Diane C. Fagerstrom, Richard M. Ford, Melissa B. TI CT Quality Assurance in the Lung Screening Study Component of the National Lung Screening Trial: Implications for Multicenter Imaging Trials SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE CT; lung cancer screening; multicenter trial; quality assurance ID NETWORK; CANCER AB OBJECTIVE. The purpose of this study was to describe the effect of implementing an imaging quality assurance program on CT image quality in the Lung Screening Study component of the National Lung Screening Trial. MATERIALS AND METHODS. The National Lung Screening Trial is a multicenter study in which 53,457 subjects at increased risk of lung cancer were randomized to undergo three annual chest CT or radiographic screenings for lung cancer to determine the relative effect of use of the two screening tests on lung cancer mortality. Of the 26,724 subjects randomized to the CT screening arm of the National Lung Screening Trial, the Lung Screening Study randomized 17,309 through 10 screening centers. The others were randomized through the American College of Radiology Imaging Network. Quality assurance procedures were implemented that included centralized review of a random sample of 1,504 Lung Screening Study CT examinations. Quality defect rates were tabulated. RESULTS. Quality defect rates ranged from 0% (section reconstruction interval) to 7.1% (reconstructed field of view), and most errors were sporadic. However, a recurrently high effective tube current-time product setting at one center, excessive streak artifact at one center, and excessive section thickness at one center were detected and corrected through the quality assurance process. Field-of-view and scan length errors were less frequent over the second half of the screening period (p < 0.01 for both parameters, two-tailed, paired Student's t test). Error rates varied among the screening centers and reviewers for most parameters evaluated. CONCLUSION. Our experience suggested that centralized monitoring of image quality is helpful for reducing quality defects in multicenter trials. C1 [Gierada, David S.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO 63105 USA. [Garg, Kavita] Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. [Nath, Hrudaya] Univ Alabama, Dept Radiol, Birmingham, AL USA. [Strollo, Diane C.] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. [Fagerstrom, Richard M.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Ford, Melissa B.] Westat Corp, Rockville, MD USA. RP Gierada, DS (reprint author), Washington Univ, Sch Med, Mallinckrodt Inst Radiol, 510 S Kingshighway Blvd,Campus Box 8131, St Louis, MO 63105 USA. EM gieradad@wustl.edu FU NCI NIH HHS [N01 CN25476, N01 CN25511, N01 CN25514, N01 CN25516, N01 CN75022, N01-CN-2547, N01-CN-25476, N01-CN-25511, N01-CN-25514, N01-CN-25516, N01-CN-75022] NR 8 TC 14 Z9 15 U1 2 U2 5 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2009 VL 193 IS 2 BP 419 EP 424 DI 10.2214/AJR.08.1995 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 472RB UT WOS:000268148600019 PM 19620438 ER PT J AU Garantziotis, S Palmer, SM AF Garantziotis, S. Palmer, S. M. TI An Unwelcome Guest: Aspergillus Colonization in Lung Transplantation and Its Association with Bronchiolitis Obliterans Syndrome SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material C1 [Palmer, S. M.] Duke Univ, Med Ctr, Div Pulm & Crit Care Med, Durham, NC 27706 USA. [Garantziotis, S.] NIEHS, Div Lung Biol, Res Triangle Pk, NC USA. RP Palmer, SM (reprint author), Duke Univ, Med Ctr, Div Pulm & Crit Care Med, Durham, NC 27706 USA. EM palme002@mc.duke.edu RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU NHLBI NIH HHS [K24 HL091140, K24 HL091140-01A1] NR 6 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 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD AUG PY 2009 VL 9 IS 8 BP 1705 EP 1706 DI 10.1111/j.1600-6143.2009.02709.x PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 471IO UT WOS:000268050200004 PM 19538485 ER PT J AU Shi, ZD Motabar, O Goldin, E Liu, K Southall, N Sidransky, E Austin, CP Griffiths, GL Zheng, W AF Shi, Zhen-Dan Motabar, Omid Goldin, Ehud Liu, Ke Southall, Noel Sidransky, Ellen Austin, Christopher P. Griffiths, Gary L. Zheng, Wei TI Synthesis and characterization of a new fluorogenic substrate for alpha-galactosidase SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Alpha-galactosidase; Enzyme assay; Assay optimization; Assay miniaturization; Fabry disease ID ENZYME REPLACEMENT THERAPY; FABRY-DISEASE; GLYCOSIDASES AB Alpha-galactosidase A hydrolyzes the terminal alpha-galactosyl moieties from glycolipids and glycoproteins in lysosomes. Mutations in alpha-galactosidase cause lysosomal accumulation of the glycosphingolipid, globotriaosylceramide, which leads to Fabry disease. Small-molecule chaperones that bind to mutant enzyme proteins and correct their misfolding and mistrafficking have emerged as a potential therapy for Fabry disease. We have synthesized a red fluorogenic substrate, resorufinyl alpha-d-galactopyranoside, for a new alpha-galactosidase enzyme assay. This assay can be measured continuously at lower pH values, without the addition of a stop solution, due to the relatively low pK (a) of resorufin (similar to 6). In addition, the assay emits red fluorescence, which can significantly reduce interferences due to compound fluorescence and dust/lint as compared to blue fluorescence. Therefore, this new red fluorogenic substrate and the resulting enzyme assay can be used in high-throughput screening to identify small-molecule chaperones for Fabry disease. C1 [Motabar, Omid; Liu, Ke; Southall, Noel; Austin, Christopher P.; Zheng, Wei] NHGRI, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. [Shi, Zhen-Dan; Griffiths, Gary L.] NHLBI, Imaging Probe Dev Ctr, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Motabar, Omid; Goldin, Ehud; Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Zheng, W (reprint author), NHGRI, Chem Genom Ctr, NIH, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014 OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757 FU NIH; National Human Genome Research Institute FX This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Programs of the National Human Genome Research Institute. NR 18 TC 7 Z9 7 U1 0 U2 7 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD AUG PY 2009 VL 394 IS 7 BP 1903 EP 1909 DI 10.1007/s00216-009-2879-5 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 470SP UT WOS:000268000600021 PM 19521690 ER PT J AU Bhargava, R Perlman, RS Fernandez, DC Levin, IW Bartick, EG AF Bhargava, Rohit Perlman, Rebecca Schwartz Fernandez, Daniel C. Levin, Ira W. Bartick, Edward G. TI Non-invasive detection of superimposed latent fingerprints and inter-ridge trace evidence by infrared spectroscopic imaging SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Latent fingerprints; Trace evidence; Infrared spectroscopy; IR; FT-IR; Spectroscopic imaging; Chemical imaging ID ENHANCEMENT; MICROSCOPY AB Current latent print and trace evidence collecting technologies are usually invasive and can be destructive to the original deposits. We describe a non-invasive vibrational spectroscopic approach that yields latent fingerprints that are overlaid on top of one another or that may contain trace evidence that needs to be distinguished from the print. Because of the variation in the chemical composition distribution within the fingerprint, we demonstrate that linear unmixing applied to the spectral content of the data can be used to provide images that reveal superimposed fingerprints. In addition, we demonstrate that the chemical composition of the trace evidence located in the region of the print can potentially be identified by its infrared spectrum. Thus, trace evidence found at a crime scene that previously could not be directly related to an individual, now has the potential to be directly related by its presence in the individual-identifying fingerprints. C1 [Perlman, Rebecca Schwartz; Bartick, Edward G.] FBI Acad, FBI Lab, Counterterrorism & Forens Sci Res Unit, Quantico, VA 22135 USA. [Bhargava, Rohit; Fernandez, Daniel C.; Levin, Ira W.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bartick, EG (reprint author), Suffolk Univ, Dept Chem & Biochem, 41 Temple St, Boston, MA 02114 USA. EM ebartick@suffolk.edu OI Bhargava, Rohit/0000-0001-7360-994X NR 19 TC 37 Z9 37 U1 1 U2 18 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD AUG PY 2009 VL 394 IS 8 BP 2069 EP 2075 DI 10.1007/s00216-009-2817-6 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 476WT UT WOS:000268478100010 PM 19415243 ER PT J AU Miao, N Levin, SW Baker, EH Caruso, RC Zhang, ZJ Gropman, A Koziol, D Wesley, R Mukherjee, AB Quezado, ZMN AF Miao, Ning Levin, Sondra W. Baker, Eva H. Caruso, Rafael C. Zhang, Zhongjian Gropman, Andrea Koziol, Deloris Wesley, Robert Mukherjee, Anil B. Quezado, Zenaide M. N. TI Children with Infantile Neuronal Ceroid Lipofuscinosis Have an Increased Risk of Hypothermia and Bradycardia During Anesthesia SO ANESTHESIA AND ANALGESIA LA English DT Article ID PALMITOYL-PROTEIN THIOESTERASE; BATTEN-DISEASE; TEMPERATURE; SEVOFLURANE; MANAGEMENT; PATIENT; NCL AB BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurodegenerative diseases characterized by lysosomal accumulation of autofluorescent material in neurons and other cell types. The infantile NCL (INCL) subtype is rare (1 in >100,000 births), the most devastating of childhood subtypes, and is caused by mutations in the gene CLN1, which encodes palmitoyl-protein thioesterase-1. METHODS: To investigate the incidence of hypothermia and bradycardia during general anesthesia in patients with INCL, we conducted a case-control study to examine the perianesthetic course of patients with INCL and of controls receiving anesthesia for diagnostic studies. RESULTS: Eight children with INCL (mean age 25 mo [range, 10-32] at first anesthetic) and 25 controls (mean age 44 mo [range, 18-92]) underwent 62 anesthetics for nonsurgical procedures. Patients with INCL had neurologic deficits including developmental delay, myoclonus, and visual impairment. Patients with INCL had lower baseline temperature (36.4 +/- 0.1 vs 36.8 +/- 0.1, INCL versus controls, P < 0.007), and during anesthesia, despite active warming techniques, had significantly more hypothermia (18 vs 0 episodes, P < 0.001) and sinus bradycardia (10 vs 1, P < 0.001) compared with controls. INCL diagnosis was significantly associated with temperature decreases during anesthesia (P < 0.001), whereas age, sex, and duration of anesthesia were not (P = NS). CONCLUSIONS: We report that patients with LNCL have lower baseline body temperature and during general anesthesia, despite rewarming interventions, are at increased risk for hypothermia and bradycardia. This suggests a previously unknown INCL phenotype, impaired thermoregulation. Therefore, when anesthetizing these children, careful monitoring and routine use of warming interventions are warranted. (Anesth Analg 2009109:372-8) C1 [Miao, Ning; Quezado, Zenaide M. N.] NIH, Dept Anesthesia & Surg Serv, Ctr Clin, Bethesda, MD 20892 USA. [Levin, Sondra W.; Zhang, Zhongjian; Mukherjee, Anil B.] NICHHD, Sect Dev Genet, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Levin, Sondra W.] Walter Reed Army Med Ctr, Dept Pediat, Washington, DC 20307 USA. [Baker, Eva H.] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Caruso, Rafael C.] NEI, Visual Funct Sect, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Gropman, Andrea] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Gropman, Andrea] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Koziol, Deloris; Wesley, Robert] NIH, Biostat & Clin Epidemiol Serv, Off Director, Ctr Clin, Bethesda, MD 20892 USA. RP Quezado, ZMN (reprint author), NIH, Dept Anesthesia & Surg Serv, Ctr Clin, 10 Ctr Dr,MSC-1512,Bldg 10,Room 2C624, Bethesda, MD 20892 USA. EM zquezado@nih.gov RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NTH Clinical Center FX Supported by the Intramural Research Program of the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the NTH Clinical Center. NR 24 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2009 VL 109 IS 2 BP 372 EP 378 DI 10.1213/ane.0b013e3181aa6e95 PG 7 WC Anesthesiology SC Anesthesiology GA 474QH UT WOS:000268298600014 PM 19608805 ER PT J AU Lam, TK Ruczinski, I Helzlsouer, K Shugart, YY Li, KE Clipp, S Strickland, PT Alberg, AJ AF Lam, Tram Kim Ruczinski, Ingo Helzlsouer, Kathy Shugart, Yin Yao Li, Kelly E. Clipp, Sandra Strickland, Paul T. Alberg, Anthony J. TI Copy Number Variants of GSTM1 and GSTT1 in Relation to Lung Cancer Risk in a Prospective Cohort Study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Glutathione S-Transferase; GSTM1; GSTT1; Lung Carcinoma; Hemizygous Deletion; Homozygous Deletion; Copy Number Variants; Metabolic Genes ID S-TRANSFERASE M1; REAL-TIME PCR; GENETIC POLYMORPHISMS; GSTP1 POLYMORPHISMS; AFRICAN-AMERICANS; BREAST-CANCER; GENOTYPES; DNA; SMOKING; POPULATION AB PURPOSE: Previous studies did not discriminate wild-type from hemizygous genotypes of GSTM1 and GSTT1. In this study, we investigated wild-type, hemizygous deletion, and homozygous deletion genotypes of GSTM1 and GSTT1 and lung cancer risk. METHODS: We conducted a nested case-control study of 143 primary incident lung cancer cases matched to 447 cancer-free controls. Genotyping was carried out using a real-time polymerase chain reaction (PCR)-based assay. Conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Compared to GSTM1 wild-type carriers, the relative odds of lung cancer increased from 1.49 (95% CI = 0.66-3.40) to 1.80 (95% Cl = 0.81-4.02) for the hemizygous and homozygous deletion genotypes, respectively (p-trend = 0.13). The strongest associations were seen among those who smoked less than one pack per day and had greater than or equal to one deletion variant of GSTM1 (OR = 3.25; 95% CI = 0.93-11.34; p-trend = 0.07) whereas the reverse was observed for smokers who smoked greater than or equal to one pack per day (OR = 0.80; 95% CI = 0.24-2.67; p-interaction = 0.08). No clear associations were observed for GSTT1 genotypes. CONCLUSIONS: Risk of lung cancer increased as the number of deletion variants increased for GSTM1, although the associations were nonsignificant. Discriminating between the wild-type, hemizygous, and homozygous deletion GSTM1 genotypes permitted a more precise characterization of the associations between GSTM1 deletion variants and lung cancer. Ann Epidemiol 2009;19:546-552. (C) 2009 Elsevier Inc. All rights reserved. C1 [Alberg, Anthony J.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Alberg, Anthony J.] Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, Charleston, SC 29425 USA. [Clipp, Sandra; Alberg, Anthony J.] George W Comstock Ctr Publ Hlth Res & Prevent, Hagerstown, MD USA. [Li, Kelly E.] Appl Biosyst Inc, Foster City, CA 94404 USA. [Helzlsouer, Kathy] St Johns Mercy Med Ctr, Baltimore, MD USA. [Lam, Tram Kim] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, Canc Prevent Div,NIH, Bethesda, MD USA. [Lam, Tram Kim; Helzlsouer, Kathy; Shugart, Yin Yao; Clipp, Sandra; Alberg, Anthony J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Ruczinski, Ingo] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Strickland, Paul T.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. RP Alberg, AJ (reprint author), Med Univ S Carolina, Hollings Canc Ctr, POB 250955, Charleston, SC 29425 USA. EM alberg@musc.edu FU Institutional Research Epidemiology Fellowship [T32CA009314]; National Institute of Aging [5U01AG018033]; National Cancer Institute [CA105069] FX This work was supported by the Institutional Research Epidemiology Fellowship (T32CA009314), National Institute of Aging (5U01AG018033), and National Cancer Institute (CA105069). The authors express their appreciation to the participants of the CLUE 11 cohort and thank the staff at the George W. Comstock Center for Public Health Research and Prevention for their dedication and contributions to the study. NR 41 TC 10 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 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2009 VL 19 IS 8 BP 546 EP 552 DI 10.1016/j.annepidem.2009.03.003 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 474QP UT WOS:000268299400004 PM 19394866 ER PT J AU Pelser, C Dazzi, C Graubard, BI Lauria, C Vitale, F Goedert, JJ AF Pelser, Colleen Dazzi, Carmelo Graubard, Barry I. Lauria, Carmela Vitale, Francesco Goedert, James J. TI Risk of Classic Kaposi Sarcoma with Residential Exposure to Volcanic and Related Soils in Sicily SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Herpesviridae; Kaposi Sarcoma; Italy; Soils ID IRON; COFACTOR AB PURPOSE: Before AIDS, endemic (African) Kaposi sarcoma (KS) was noted to occur in volcanic areas and was postulated to result from dirt chronically embedded in the skin of the lower extremities. The primary cause of all KS types is KS-associated herpesvirus (KSHV) infection, but cofactors contribute to the neoplasia. We investigated whether residential exposure to volcanic or related soils was associated with the risk of classic Kaposi sarcoma (cKS) in Sicily. METHODS: Risk of incident cKS (N = 141) compared with population-based KSHV seropositive controls (N = 123) was estimated for residential exposure to four types of soil, categorized with maps from the European Soil Database and direct surveying. Questionnaire data provided covariates. RESULTS: Residents in communities high in luvisols were approximately 2.7 times more likely to have cKS than those in communities with no luvisols. Risk was not specific for cKS on the limbs, but it was elevated approximately four- to five-fold with frequent bathing or tap water drinking in communities with high luvisols. Risk was unrelated to communities high in andosols, tephra, or clay soils. CONCLUSIONS: Iron and alumino-silicate clay, major components of luvisols, may increase cKS risk, but formal investigation and consideration of other soil types and exposures are needed. Ann Epidemiol 2009;19:597-601. Published by Elsevier, Inc. C1 [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. [Pelser, Colleen] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Dazzi, Carmelo] Univ Palermo, DAAT, Fac Agr, Palermo, Italy. [Vitale, Francesco] Univ Palermo, Dept Sci Hlth Promot G DAlessandro, Sect Hyg, I-90133 Palermo, Italy. [Lauria, Carmela] Lega Italiana Lotta Contro Tumori Sez Ragusa, Ragusa, Italy. RP Goedert, JJ (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 7068, Rockville, MD 20892 USA. EM goedertj@mail.nih.gov OI Dazzi, Carmelo/0000-0001-8165-269X FU National Cancer Institute [N02-CP-91027]; Science Applications International Corporation [N01-CO-12400] FX We are grateful to Dr. Giuseppe Lo Papa and Matt Airola for their assistance with this project. NR 17 TC 11 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2009 VL 19 IS 8 BP 597 EP 601 DI 10.1016/j.annepidem.2009.04.002 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 474QP UT WOS:000268299400012 PM 19576540 ER PT J AU Hallett, M AF Hallett, Mark TI Dystonia: A Sensory and Motor Disorder of Short Latency Inhibition SO ANNALS OF NEUROLOGY LA English DT Editorial Material ID FOCAL HAND DYSTONIA; PRIMARY SOMATOSENSORY CORTEX; WRITERS CRAMP; SURROUND INHIBITION; SPATIAL DISCRIMINATION; ABNORMALITIES C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 25 TC 14 Z9 14 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD AUG PY 2009 VL 66 IS 2 BP 125 EP 127 DI 10.1002/ana.21762 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 494UX UT WOS:000269845400002 PM 19743461 ER PT J AU Compton, CC AF Compton, Carolyn C. TI The Surgical Specimen Is the Personalized Part of Personalized Cancer Medicine SO ANNALS OF SURGICAL ONCOLOGY LA English DT Editorial Material ID RADICAL PROSTATECTOMY; GENE-EXPRESSION; ISCHEMIA TIME C1 NCI, Off Biorepositories & Biospecimen Res, Bethesda, MD 20892 USA. RP Compton, CC (reprint author), NCI, Off Biorepositories & Biospecimen Res, Bethesda, MD 20892 USA. EM comptcar@mail.nih.gov NR 5 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD AUG PY 2009 VL 16 IS 8 BP 2079 EP 2080 DI 10.1245/s10434-009-0526-1 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA 472AQ UT WOS:000268101900001 PM 19472010 ER PT J AU Sharma, M Manoharlal, R Shukla, S Puri, N Prasad, T Ambudkar, SV Prasad, R AF Sharma, Monika Manoharlal, Raman Shukla, Suneet Puri, Nidhi Prasad, Tulika Ambudkar, Suresh V. Prasad, Rajendra TI Curcumin Modulates Efflux Mediated by Yeast ABC Multidrug Transporters and Is Synergistic with Antifungals SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID RESISTANCE PROTEIN-1 ABCC1; HUMAN PATHOGENIC YEAST; P-GLYCOPROTEIN ABCB1; CANDIDA-ALBICANS; SACCHAROMYCES-CEREVISIAE; AZOLE RESISTANCE; DRUG-RESISTANCE; TURMERIC POWDER; UP-REGULATION; CDR1P AB Curcumin (CUR), a natural product of turmeric, from rhizomes of Curcuma longa, is a known agent of reversal of drug resistance phenotypes in cancer cells overexpressing ATP-binding cassette (ABC) transporters, viz., ABCB1, ABCG2, and ABCC1. In the present study, we evaluated whether CUR could also modulate multidrug transporters of yeasts that belong either to the ABC family or to the major facilitator superfamily (MFS). The effect of CUR on multidrug transporter proteins was demonstrated by examining rhodamine 6G (R6G) efflux in Saccharomyces cerevisiae cells overexpressing the Candida albicans ABC transporters Cdr1p and Cdr2p (CaCdr1p and CaCdr2p, respectively) and the MFS transporters CaMdr1p and S. cerevisiae Pdr5p. CUR decreased the extracellular concentration of R6G in ABC transporter-expressing cells but had no effect on methotrexate efflux mediated through the MFS transporter CaMdr1p. CUR competitively inhibited R6G efflux and the photolabeling of CaCdr1p by [(125)I] iodoarylazidoprazosin, a drug analogue of the substrate prazosin (50% inhibitory concentration, 14.2 mu M). Notably, the mutant variants of CaCdr1p that displayed abrogated efflux of R6G also showed reduced modulation by CUR. Drug susceptibility testing of ABC protein-expressing cells by spot assays and checkerboard tests revealed that CUR was selectively synergistic with drug substrates such as R6G, ketoconazole, itraconazole, and miconazole but not with fluconazole, voriconazole, anisomycin, cycloheximide, or FK520. Taken together, our results provide the first evidence that CUR modulates only ABC multidrug transporters and could be exploited in combination with certain conventional antifungal drugs to reverse multidrug resistance in Candida cells. C1 [Sharma, Monika; Manoharlal, Raman; Puri, Nidhi; Prasad, Tulika; Prasad, Rajendra] Jawaharlal Nehru Univ, Sch Life Sci, Membrane Biol Lab, New Delhi 110067, India. [Prasad, Tulika] Jawaharlal Nehru Univ, Facil Adv Instrumentat, Univ Sci Instrumentat Ctr, New Delhi 110067, India. [Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Prasad, R (reprint author), Jawaharlal Nehru Univ, Sch Life Sci, Membrane Biol Lab, New Delhi 110067, India. EM rp47@mail.jnu.ac.in RI shukla, suneet/B-4626-2012 FU Indo-DFG [INT/DFG/P-05/2005]; Department of Science and Technology [SR/SO/BB-12/2004]; Council of Scientific and Industrial Research [38(1122)/06/EMR-II]; Department of Biotechnology [BT/PR9100/Med/29/03/2007, BT/PR9563/ BRB/10/567/2009]; NIH; National Cancer Institute; Center for Cancer Research FX The work presented in this paper has been supported in part by grants to R. P. from Indo-DFG (INT/DFG/P-05/2005), the Department of Science and Technology (SR/SO/BB-12/2004), the Council of Scientific and Industrial Research [38(1122)/06/EMR-II], and the Department of Biotechnology (BT/PR9100/Med/29/03/2007, BT/PR9563/ BRB/10/567/2009). S. Shukla and S. V. Ambudkar were supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. M. S. acknowledges the Department of Biotechnology, India, for the award of junior and senior research fellowships. NR 32 TC 38 Z9 38 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2009 VL 53 IS 8 BP 3256 EP 3265 DI 10.1128/AAC.01497-08 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 471ZW UT WOS:000268098300011 PM 19470507 ER PT J AU Clark, J Yao, L Pavletic, SZ Krumlauf, M Mitchell, S Turner, ML Cowen, EW AF Clark, Jason Yao, Lawrence Pavletic, Steven Z. Krumlauf, Michael Mitchell, Sandra Turner, Maria L. Cowen, Edward W. TI Magnetic Resonance Imaging in Sclerotic-Type Chronic Graft-vs-Host Disease SO ARCHIVES OF DERMATOLOGY LA English DT Article ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; EOSINOPHILIC FASCIITIS; CLINICAL-TRIALS; DIAGNOSIS; MANIFESTATIONS; CRITERIA; SKIN; MRI AB Background: Sclerotic-type chronic graft-vs-host disease (cGVHD) of the skin is an uncommon but potentially debilitating sequela of allogeneic hematopoietic stem cell transplantation. There is no standardized assessment measure for this form of cGVHD. Because a full-thickness incisional biopsy specimen to the level of the fascia may be needed to make a definitive histologic diagnosis of cGVHD-related fasciitis, a noninvasive technique for the assessment and monitoring of sclerotic-type cGVHD, particularly cGVHD-related fasciitis, would be of potential value. Observations: Sixty-two consecutive patients with cGVHD following allogeneic hematopoietic stem cell transplantation were evaluated for sclerotic skin disease. Forty-four patients (71%) had cutaneous cGVHD, and 28 patients (45%) had evidence of sclerotic involvement based on physical examination findings. Fifteen patients agreed to undergo research magnetic resonance imaging to evaluate quantifiable changes in the dermis, subcutaneous tissue, and muscle. Among 15 patients, magnetic resonance imaging identified abnormalities in the skin in 7 (47%), subcutaneous fibrous septa in 13 (87%), deep fascia in 12 (80%), epimysium in 9 (60%), and muscle in 3 (20%). Conclusions: Magnetic resonance imaging should be considered in the evaluation of patients with cGVHD suspected of having subcutaneous or fascial involvement. Additional studies are needed to validate this noninvasive modality for serial monitoring of disease activity and response to therapy. C1 [Clark, Jason; Turner, Maria L.; Cowen, Edward W.] NCI, Ctr Canc Res, Dermatol Branch, Bethesda, MD 20892 USA. [Pavletic, Steven Z.; Krumlauf, Michael] NCI, Ctr Canc Res, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Yao, Lawrence] NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Ctr Canc Res, Dermatol Branch, 10 Ctr Dr,Mail Stop Code 1908,Bldg 10,Room 12N238, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov FU National Institutes of Health; Center for Cancer Research; National Cancer Institute; National Institutes of Health/Pfizer Clinical Research Training Program FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. Dr Clark was jointly supported by the National Institutes of Health/Pfizer Clinical Research Training Program. NR 11 TC 6 Z9 7 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD AUG PY 2009 VL 145 IS 8 BP 918 EP 922 PG 5 WC Dermatology SC Dermatology GA 484CJ UT WOS:000269020600010 PM 19687424 ER PT J AU Kong, HH Fine, HA Stern, JB Turner, MLC AF Kong, Heidi H. Fine, Howard A. Stern, Jere B. Turner, Maria L. Chanco TI Cutaneous Pigmentation After Photosensitivity Induced by Vandetanib Therapy SO ARCHIVES OF DERMATOLOGY LA English DT Article ID CELL LUNG-CANCER; JAPANESE PATIENTS; ZD6474 AB Background: Photosensitivity has been reported in patients who were treated with vandetanib (ZD6474), an inhibitor of epidermal growth factor receptor, vascular endothelial growth factor receptor, and the RET (rearranged during transfection) kinases. Observations: We describe the occurrence of cutaneous hyperpigmentation after photosensitivity in 2 patients who were treated with vandetanib. The pigmentation patterns were variable within and between patients. Biopsy specimens from different sites revealed variability in Perls and Fontana staining patterns. Conclusions: These 2 cases highlight the unusual occurrence of cutaneous hyperpigmentation after vandetanib-associated photosensitivity, a reaction that demonstrates that medications are important causes of acquired photosensitivity and hyperpigmentation. Aggressive photoprotection may facilitate the resolution of diffuse hyperpigmentation. Dermatologists should endeavor to identify and report novel cutaneous adverse effects as new targeted therapies are developed. C1 [Kong, Heidi H.; Turner, Maria L. Chanco] NCI, Ctr Canc Res, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Fine, Howard A.] NCI, Ctr Canc Res, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. [Stern, Jere B.] NCI, Ctr Canc Res, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Kong, HH (reprint author), NCI, Ctr Canc Res, Dermatol Branch, NIH, Bldg 10,Room 12N238,10 Ctr Dr, Bethesda, MD 20892 USA. EM konghe@mail.nih.gov OI Kong, Heidi/0000-0003-4424-064X FU Center for Cancer Research; National Cancer Institute; National Institutes of Health FX This study was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 6 TC 16 Z9 16 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD AUG PY 2009 VL 145 IS 8 BP 923 EP 925 PG 3 WC Dermatology SC Dermatology GA 484CJ UT WOS:000269020600011 PM 19687425 ER PT J AU Shaw, P Lalonde, F Lepage, C Rabin, C Eckstrand, K Sharp, W Greenstein, D Evans, A Giedd, JN Rapoport, J AF Shaw, Philip Lalonde, Francois Lepage, Claude Rabin, Cara Eckstrand, Kristen Sharp, Wendy Greenstein, Deanna Evans, Alan Giedd, J. N. Rapoport, Judith TI Development of Cortical Asymmetry in Typically Developing Children and Its Disruption in Attention-Deficit/Hyperactivity Disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; AUTOMATED 3-D EXTRACTION; FALSE DISCOVERY RATE; HUMAN MOTOR CORTEX; GRAY-MATTER; CEREBRAL ASYMMETRY; BRAIN-DEVELOPMENT; PLANUM TEMPORALE; INTERHEMISPHERIC ASYMMETRY; STRUCTURAL ASYMMETRIES AB Context: Just as typical development of anatomical asymmetries in the human brain has been linked with normal lateralization of motor and cognitive functions, disruption of asymmetry has been implicated in the pathogenesis of neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD). No study has examined the development of cortical asymmetry using longitudinal neuroanatomical data. Objective: To delineate the development of cortical asymmetry in children with and without ADHD. Design: Longitudinal study. Setting: Government Clinical Research Institute. Participants: A total of 218 children with ADHD and 358 typically developing children, from whom 1133 neuroanatomical magnetic resonance images were acquired prospectively. Main Outcome Measures: Cortical thickness was estimated at 40 962 homologous points in the left and right hemispheres, and the trajectory of change in asymmetry was defined using mixed-model regression. Results: In right-handed typically developing individuals, a mean (SE) increase in the relative thickness of the right orbitofrontal and inferior frontal cortex with age of 0.011 (0.0018) mm per year (t(337)=6.2, P < .001) was balanced against a relative left-hemispheric increase in the occipital cortical regions of 0.013 (0.0015) mm per year (t(337)=8.1, P < .001). Age-related change in asymmetry in non-right-handed typically developing individuals was less extensive and was localized to different cortical regions. In ADHD, the posterior component of this evolving asymmetry was intact, but the prefrontal component was lost. Conclusions: These findings explain the way that, in typical development, the increased dimensions of the right frontal and left occipital cortical regions emerge in adulthood from the reversed pattern of childhood cortical asymmetries. Loss of the prefrontal component of this evolving asymmetry in ADHD is compatible with disruption of prefrontal function in the disorder and demonstrates the way that disruption of typical processes of asymmetry can inform our understanding of neurodevelopmental disorders. C1 [Shaw, Philip; Lalonde, Francois; Rabin, Cara; Eckstrand, Kristen; Sharp, Wendy; Greenstein, Deanna; Giedd, J. N.; Rapoport, Judith] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Lepage, Claude; Evans, Alan] McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. RP Shaw, P (reprint author), NIMH, Child Psychiat Branch, Room 3N202,Bldg 10,Ctr Dr, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU Intramural Program of the National Institute of Mental Health FX This study was funded by the Intramural Program of the National Institute of Mental Health. Additional Information: A video and the eFigure, eTables, and eMethods text are available at http://archgenpsychiatry.com. NR 81 TC 97 Z9 101 U1 3 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD AUG PY 2009 VL 66 IS 8 BP 888 EP + PG 11 WC Psychiatry SC Psychiatry GA 479BT UT WOS:000268634500009 PM 19652128 ER PT J AU Schoenbaum, M Butler, B Kataoka, S Norquist, G Springgate, B Sullivan, G Duan, N Kessler, RC Wells, K AF Schoenbaum, Michael Butler, Brittany Kataoka, Sheryl Norquist, Grayson Springgate, Benjamin Sullivan, Greer Duan, Naihua Kessler, Ronald C. Wells, Kenneth TI Promoting Mental Health Recovery After Hurricanes Katrina and Rita What Can Be Done at What Cost SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PRIMARY-CARE; MAJOR DEPRESSION; NATURAL DISASTER; ILLNESS; SUICIDALITY; MANAGEMENT; OUTCOMES; PTSD; LIFE AB Context: Concerns about mental health recovery persist after the 2005 Gulf storms. We propose a recovery model and estimate costs and outcomes. Objective: To estimate the costs and outcomes of enhanced mental health response to large-scale disasters using the 2005 Gulf storms as a case study. Design: Decision analysis using state-transition Markov models for 6-month periods from 7 to 30 months after disasters. Simulated movements between health states were based on probabilities drawn from the clinical literature and expert input. Setting: A total of 117 counties/parishes across Louisiana, Mississippi, Alabama, and Texas that the Federal Emergency Management Agency designated as eligible for individual relief following hurricanes Katrina and Rita. Participants: Hypothetical cohort, based on the size and characteristics of the population affected by the Gulf storms. Intervention: Enhanced mental health care consisting of evidence-based screening, assessment, treatment, and care coordination. Main Outcome Measures: Morbidity in 6-month episodes of mild/moderate or severe mental health problems through 30 months after the disasters; units of service (eg, office visits, prescriptions, hospital nights); intervention costs; and use of human resources. Results: Full implementation would cost $1133 per capita, or more than $12.5 billion for the affected population, and yield 94.8% to 96.1% recovered by 30 months, but exceed available provider capacity. Partial implementation would lower costs and recovery proportionately. Conclusions: Evidence-based mental health response is feasible, but requires targeted resources, increased provider capacity, and advanced planning. C1 [Schoenbaum, Michael] RAND Corp, Arlington, VA USA. [Butler, Brittany; Kataoka, Sheryl; Duan, Naihua; Wells, Kenneth] Univ Calif Los Angeles, Hlth Serv Res Ctr, Semel Inst, Los Angeles, CA USA. [Norquist, Grayson] Univ Mississippi, Dept Psychiat, University, MS 38677 USA. [Springgate, Benjamin] Univ Calif Los Angeles, Robert Wood Johnson Fdn, Clin Scholars Program, Los Angeles, CA 90024 USA. [Springgate, Benjamin] REACH NOLA, New Orleans, LA USA. [Sullivan, Greer] Little Rock Vet Affairs, Little Rock, AR USA. [Sullivan, Greer] Univ Arkansas, Dept Psychiat, Fayetteville, AR 72701 USA. [Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Healthcare Policy, Boston, MA USA. [Butler, Brittany] RAND Corp, New Orleans, LA USA. [Sullivan, Greer] RAND Corp, Santa Monica, CA USA. [Duan, Naihua] Columbia Univ, New York, NY USA. RP Schoenbaum, M (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd,Room 7142,MSC 9629, Bethesda, MD 20892 USA. EM schoenbaumm@mail.nih.gov FU National Institutes of Mental Health [P50MH54623]; RAND Corporation; Robert Wood Johnson Foundation; South Central Veterans Affairs Mental Illness Research and Education Center FX This study was supported by National Institutes of Mental Health grant P50MH54623; the RAND Corporation; the Robert Wood Johnson Foundation; and the South Central Veterans Affairs Mental Illness Research and Education Center. NR 40 TC 16 Z9 17 U1 2 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD AUG PY 2009 VL 66 IS 8 BP 906 EP + PG 11 WC Psychiatry SC Psychiatry GA 479BT UT WOS:000268634500011 PM 19652130 ER PT J AU Cox, JT Moriarty, AT Castle, PE AF Cox, John Thomas Moriarty, Ann T. Castle, Philip E. TI Commentary on Statement on Human Papillomavirus Test Utilization SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Editorial Material ID CANCER-SOCIETY GUIDELINE; CERVICAL-CANCER; SCREENING-TESTS; NEOPLASIA; COHORT; WOMEN; AMERICAN; RISK; METAANALYSIS; MANAGEMENT C1 [Cox, John Thomas] Univ Calif Santa Barbara, Student Hlth Serv, Santa Barbara, CA 93460 USA. [Moriarty, Ann T.] AmeriPath Indiana, Pathol, Indianapolis, IN USA. [Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Cox, JT (reprint author), Univ Calif Santa Barbara, Student Hlth Serv, Bldg 588,El Colegio Rd, Santa Barbara, CA 93460 USA. EM tom.cox@sa.ucsb.edu NR 21 TC 1 Z9 1 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD AUG PY 2009 VL 133 IS 8 BP 1192 EP 1194 PG 3 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 482TA UT WOS:000268910400007 PM 19653706 ER PT J AU Faia, LJ Chan, CC AF Faia, Lisa J. Chan, Chi-Chao TI Primary Intraocular Lymphoma SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID NERVOUS-SYSTEM LYMPHOMA; POLYMERASE-CHAIN-REACTION; CHEMOKINE RECEPTORS; DIAGNOSIS; INVOLVEMENT; EXPRESSION; SPECIMENS; CYTOLOGY; FEATURES; OUTCOMES AB Primary intraocular lymphoma, recently suggested to be renamed primary retinal lymphoma, is a subset of primary central nervous system lymphoma and is usually an aggressive diffuse large B-cell lymphoma. Between 56% and 85% of patients who initially present with primary intraocular lymphoma alone will develop cerebral lesions. Patients typically complain of decreased vision and floaters, most likely secondary to the chronic vitritis and subretinal lesions. The diagnosis of primary intraocular lymphoma can be difficult to make and requires tissue for diagnosis. The atypical lymphoid cells are large and display a high nuclear to cytoplasmic ratio, prominent nucleoli, and basophilic cytoplasm. Flow cytometry, immunohistochemistry, cytokine analysis, and gene rearrangements also aid in the diagnosis. Local and systemic treatments, such as chemotherapy and radiation, are employed, although the relapse rate remains high. (Arch Pathol Lab Med. 2009; 133: 1228-1232) C1 [Chan, Chi-Chao] NEI, Immunopathol Sect, NIH, Immunol Lab, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, NIH, Immunol Lab, Bldg 10,Rm 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov FU Intramural NIH HHS [Z01 EY000222-22] NR 32 TC 19 Z9 20 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD AUG PY 2009 VL 133 IS 8 BP 1228 EP 1232 PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 482TA UT WOS:000268910400016 PM 19653715 ER PT J AU Solomon, D Papillo, JL Davey, DD AF Solomon, Diane Papillo, Jacalyn L. Davey, Diane D. CA Cytopathology Educ Technology Cons TI Statement on Human Papillomavirus DNA Test Utilization SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID CANCER C1 [Solomon, Diane] NCI, NIH, Canc Prevent Div, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Papillo, Jacalyn L.] Fletcher Allen Hlth Care, Dept Anat Pathol, Burlington, VT USA. [Davey, Diane D.] Univ Cent Florida, Coll Med, Orlando, FL 32816 USA. RP Solomon, D (reprint author), NCI, NIH, Canc Prevent Div, Dept Hlth & Human Serv, 6130 Execut Blvd, Rockville, MD 20852 USA. EM ds87v@nih.gov NR 3 TC 6 Z9 6 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD AUG PY 2009 VL 133 IS 8 BP 1276 EP 1277 PG 2 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 482TA UT WOS:000268910400026 PM 19653725 ER PT J AU Flores-Santana, W Switzer, C Ridnour, LA Basudhar, D Mancardi, D Donzelli, S Thomas, DD Miranda, KM Fukuto, JM Wink, DA AF Flores-Santana, Wilmarie Switzer, Christopher Ridnour, Lisa A. Basudhar, Debashree Mancardi, Daniele Donzelli, Sonia Thomas, Douglas D. Miranda, Katrina M. Fukuto, Jon M. Wink, David A. TI Comparing the Chemical Biology of NO and HNO SO ARCHIVES OF PHARMACAL RESEARCH LA English DT Review DE Nitric oxide; Cancer; Nitrosative stress ID PROTEIN-TYROSINE NITRATION; NITRIC-OXIDE SYNTHASE; WOODCHUCK HEPATITIS-VIRUS; CENTER DOT NO; NITROXYL HNO; S-NITROSOTHIOLS; SUPEROXIDE-DISMUTASE; ANGELIS SALT; IN-VIVO; NITROSATING AGENTS AB For the past couple of decades nitric oxide (NO) and nitroxyl (HNO) have been extensively studied due to the important role they play in many physiological and/or pharmacological processes. Many researchers have reported important signaling pathways as well as mechanisms of action of these species, showing direct and indirect effects depending on the environment. Both NO and HNO can react with, among others, metals, proteins, thiols and heme proteins via unique and distinct chemistry leading to improvement of some clinical conditions. Understanding the basic chemistry of NO and HNO and distinguishing their mechanisms of action as well as methods of detection are crucial for understanding the current and potential clinical applications. In this review, we summarize some of the most important findings regarding NO and HNO chemistry, revealing some of the possible mechanisms of their beneficial actions. C1 [Flores-Santana, Wilmarie; Switzer, Christopher; Ridnour, Lisa A.; Basudhar, Debashree; Wink, David A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Basudhar, Debashree; Miranda, Katrina M.] Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. [Mancardi, Daniele] Univ Turin, Dept Clin & Biol Sci, I-10124 Turin, Italy. [Donzelli, Sonia] Univ Hosp Hamburg Eppendorf, Dept Neurol & Expt & Clin Pharmacol & Toxicol, Hamburg, Germany. [Thomas, Douglas D.] Univ Illinois, Sch Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. [Fukuto, Jon M.] Sonoma State Univ, Dept Chem, Sonoma, CA 94928 USA. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B35, Bethesda, MD 20892 USA. EM wink@mail.nih.gov RI Miranda, Katrina/B-7823-2009; Switzer, Christopher/D-9203-2013; OI MANCARDI, Daniele/0000-0003-3809-6047 FU 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. NR 108 TC 25 Z9 26 U1 0 U2 10 PU PHARMACEUTICAL SOC KOREA PI SEOUL PA 1489-3 SUHCHO-DONG, SUHCHO-KU, SEOUL 137-071, SOUTH KOREA SN 0253-6269 J9 ARCH PHARM RES JI Arch. Pharm. Res. PD AUG PY 2009 VL 32 IS 8 BP 1139 EP 1153 DI 10.1007/s12272-009-1805-x PG 15 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 490FF UT WOS:000269483400007 PM 19727606 ER PT J AU Stineman, MG Chan, L AF Stineman, Margaret G. Chan, Leighton TI Commentary on the Comparative Effectiveness of Alternative Settings for Joint Replacement Rehabilitation SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Editorial Material DE Delivery of health care; Hospitalization; Joints; Nursing facilities, skilled; Outcome assessment (health care); Rehabilitation ID SURGICAL VOLUME; STROKE; TRIALS; CARE AB Stineman MG, Chan L. Commentary on the comparative effectiveness of alternative settings for joint replacement rehabilitation. Arch Phys Med Rehabil 2009;90: 1257-9. The comprehensive Joint Replacement Outcomes in Inpatient Rehabilitation Facilities and Nursing Treatment Sites 1 and 2 studies presented in this issue of the Archives by DeJong and colleagues focus on an important issue facing U.S. rehabilitation today: the comparative effectiveness of alternative rehabilitation settings for the management of conditions such as joint replacement. Although there are hints in the data that patients receiving care in inpatient rehabilitation facilities compared with those treated in skilled nursing facilities may have slightly better recoveries of physical function, the evidence is weaker than for a number of other conditions. It is important to look beyond the question of which setting is best, toward gaining a deeper understanding of the elements within these settings that most enhance outcomes. C1 [Stineman, Margaret G.] Univ Penn, Sch Med, Dept Rehabil Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Chan, Leighton] NIH, Dept Rehabil Med, Ctr Clin, CRC, Bethesda, MD 20892 USA. RP Chan, L (reprint author), NIH, Dept Rehabil Med, Ctr Clin, CRC, Bldg 10,Room 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM chanle@cc.nih.gov NR 14 TC 5 Z9 5 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD AUG PY 2009 VL 90 IS 8 BP 1257 EP 1259 DI 10.1016/j.apmr.2009.05.004 PG 3 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 483PY UT WOS:000268981000001 PM 19651259 ER PT J AU Webb, R Merrill, JT Kelly, JA Sestak, A Kaufman, KM Langefeld, CD Ziegler, J Kimberly, RP Edberg, JC Ramsey-Goldman, R Petri, M Reveille, JD Alarcon, GS Vila, LM Alarcon-Riquelme, ME James, JA Gilkeson, GS Jacob, CO Moser, KL Gaffney, PM Vyse, TJ Nath, SK Lipsky, P Harley, JB Sawalha, AH AF Webb, Ryan Merrill, Joan T. Kelly, Jennifer A. Sestak, Andrea Kaufman, Kenneth M. Langefeld, Carl D. Ziegler, Julie Kimberly, Robert P. Edberg, Jeffrey C. Ramsey-Goldman, Rosalind Petri, Michelle Reveille, John D. Alarcon, Graciela S. Vila, Luis M. Alarcon-Riquelme, Marta E. James, Judith A. Gilkeson, Gary S. Jacob, Chaim O. Moser, Kathy L. Gaffney, Patrick M. Vyse, Timothy J. Nath, Swapan K. Lipsky, Peter Harley, John B. Sawalha, Amr H. TI A Polymorphism Within IL21R Confers Risk for Systemic Lupus Erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Article ID PLASMA-CELL GENERATION; FUNCTIONAL VARIANT; REVISED CRITERIA; GENOME SCAN; T-CELLS; IL-21; DISEASE; DIFFERENTIATION; CLASSIFICATION; AUTOIMMUNITY AB Objective. Interleukin-21 (IL-21) is a member of the type I cytokine superfamily that has a variety of effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. The expression of IL-21 receptor (IL-21R) is reduced in the B cells of patients with systemic lupus erythematosus (SLE), while serum IL-21 levels are increased both in lupus patients and in some murine lupus models. We recently reported that polymorphisms within the IL21 gene are associated with increased susceptibility to SLE. The aim of this study was to examine the genetic association between single-nucleotide polymorphisms (SNPs) within IL21R and SLE. Methods. We genotyped 17 SNPs in the IL21R gene in 2 large cohorts of lupus patients (a European-derived cohort and a Hispanic cohort) and in ethnically matched healthy controls. Results. We identified and confirmed the association between rs3093301 within the IL21R gene and SLE in the 2 cohorts (meta-analysis odds ratio 1.16 [95% confidence interval 1.08-1.25], P = 1.0 x 10(-4)). Conclusion. Our findings indicate that IL21R is a novel susceptibility gene for SLE. C1 [Kaufman, Kenneth M.; Harley, John B.; Sawalha, Amr H.] Univ Oklahoma, Oklahoma Med Res Fdn, Hlth Sci Ctr, Oklahoma City, OK USA. [Kaufman, Kenneth M.; Harley, John B.; Sawalha, Amr H.] VAMC, Oklahoma City, OK USA. [Langefeld, Carl D.; Ziegler, Julie] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Kimberly, Robert P.; Edberg, Jeffrey C.; Alarcon, Graciela S.] Univ Alabama, Birmingham, AL USA. [Ramsey-Goldman, Rosalind] Northwestern Univ, Chicago, IL 60611 USA. [Petri, Michelle] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr, Houston, TX USA. [Vila, Luis M.] Univ Puerto Rico, San Juan, PR 00936 USA. [Alarcon-Riquelme, Marta E.] Uppsala Univ, Uppsala, Sweden. [Gilkeson, Gary S.] Univ S Carolina, Charleston, SC USA. [Jacob, Chaim O.] Univ S Carolina, Sch Med, Los Angeles, CA USA. [Vyse, Timothy J.] Univ London Imperial Coll Sci Technol & Med, Healthcare Natl Hlth Serv Trust, London, England. [Lipsky, Peter] NIAMSD, Bethesda, MD 20892 USA. RP Sawalha, AH (reprint author), 825 NE 13th St,MS 24, Oklahoma City, OK 73104 USA. EM amr-sawalha@omrf.ouhsc.edu OI Kimberly, Robert/0000-0002-5330-3086; Alarcon Riquelme, Marta Eugenia/0000-0002-7632-4154 FU NIH [R03-AI-076729, P20-RR-015577, P01-AR-49084, P60-AR-48095, K24-AR-002138, M01-RR-00048, RR-15577, AR-053483, AR-043274-13, AR-052125-04, AI-063274-05, P30-AR-053483, P20-RR-020143, R01-AR-42460, R01-AI-31584, N01-AR-12253, R01-DE015223, R37-AI-24717, NOI-AR-62277, AR-048940, AR-0490084]; Wake Forest University Health Sciences Center for Public Health Genomics; Alliance for Lupus Research; Alliance for Lupus Research [52104]; Lupus Foundation of Minnesota; Arthritis National Research Foundation; Lupus Foundation of America; Department of Veterans Affairs; University of Oklahoma College of Medicine FX Supported by the NIH (grants R03-AI-076729 and P20-RR-015577). Dr. Langefeld and Ms Ziegler's work was supported by the Wake Forest University Health Sciences Center for Public Health Genomics and the Alliance for Lupus Research. Dr. Kimberly's work was supported by the NIH (grants P01-AR-49084 and P60-AR-48095). Dr. Ramsey-Goldman's work was supported by the NIH (grants P01-AR-49084, K24-AR-002138, and M01-RR-00048). Dr. Alarcon's work was supported by the NIH (P01-AR-49084). Dr. James' work was supported by the NIH (grants RR-15577 and AR-053483). Dr Jacob's work was supported by the Alliance for Lupus Research (grant 52104). Dr.. Moser's work was supported by the NIH (grant AR-043274-13) and the Lupus Foundation of Minnesota. Dr. Gaffney's work was supported by the NIH (grants AR-052125-04 and AI-063274-05) and the Lupus Foundation of Minnesota. Dr. Nath's work was supported by the NIH (grants P30-AR-053483 and P20-RR-020143). Dr. Harley is recipient of a Kirkland Scholar award, and his work was supported by the NIH (R01-AR-42460, R01-AI-31584, N01-AR-12253, R01-DE015223, P20-RR-020143, R37-AI-24717, NOI-AR-62277, AR-048940, and AR-0490084) and the Alliance for Lupus Research. Dr. Sawalha's work was supported by the NIH (grants R03-AI-076729 and P20-RR-015577), the Arthritis National Research Foundation, the Lupus Foundation of America, the Department of Veterans Affairs, and the University of Oklahoma College of Medicine. NR 24 TC 64 Z9 65 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2009 VL 60 IS 8 BP 2402 EP 2407 DI 10.1002/art.24658 PG 6 WC Rheumatology SC Rheumatology GA 483NL UT WOS:000268973600022 PM 19644854 ER PT J AU Love, LA Weinberg, CR McConnaughey, DR Oddis, CV Medsger, TA Reveille, JD Arnett, FC Targoff, IN Miller, FW AF Love, Lori A. Weinberg, Clarice R. McConnaughey, D. Robert Oddis, Chester V. Medsger, Thomas A., Jr. Reveille, John D. Arnett, Frank C. Targoff, Ira N. Miller, Frederick W. TI Ultraviolet Radiation Intensity Predicts the Relative Distribution of Dermatomyositis and Anti-Mi-2 Autoantibodies in Women SO ARTHRITIS AND RHEUMATISM LA English DT Article ID UV-RADIATION; IMMUNOSUPPRESSION; MECHANISMS; DISEASE AB Objective. Because studies suggest that ultraviolet (UV) radiation modulates the myositis phenotype and Mi-2 autoantigen expression, we conducted a retrospective investigation to determine whether UV radiation may influence the relative prevalence of dermatomyositis and anti-Mi-2 autoantibodies in the US. Methods. We assessed the relationship between surface UV radiation intensity in the state of residence at the time of onset with the relative prevalence of dermatomyositis and myositis autoantibodies in 380 patients with myositis from referral centers in the US. Myositis autoantibodies were detected by validated immunoprecipitation assays. Surface UV radiation intensity was estimated from UV Index data collected by the US National Weather Service. Results. UV radiation intensity was associated with the relative proportion of patients with dermatomyositis (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 0.9-5.8) and with the proportion of patients expressing anti-Mi-2 autoantibodies (OR 6.0, 95% CI 1.1-34.1). Modeling of these data showed that these associations were confined to women (OR 3.8, 95% CI 1.3-11.0 and OR 1.73, 95% CI 1.8-162.4, respectively) and suggests that sex influences the effects of UV radiation on autoimmune disorders. Significant associations were not observed in men, nor were UV radiation levels related to the presence of antisynthetase or anti-signal recognition particle autoantibodies. Conclusion. This first study of the distribution of myositis phenotypes and UV radiation exposure in the US showed that UV radiation may modulate the clinical and immunologic expression of autoimmune disease in women. Further investigation of the mechanisms by which these effects are produced may provide insights into pathogenesis and suggest therapeutic or preventative strategies. C1 [Love, Lori A.; Weinberg, Clarice R.; Miller, Frederick W.] NIH, Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Love, Lori A.; Weinberg, Clarice R.; Miller, Frederick W.] NIH, Inst Environm Hlth Sci, Bethesda, MD USA. [McConnaughey, D. Robert] WESTAT Corp, Res Triangle Pk, NC USA. [Oddis, Chester V.; Medsger, Thomas A., Jr.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Reveille, John D.; Arnett, Frank C.] Univ Texas Med Sch, Houston, TX USA. [Targoff, Ira N.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City Vet Affairs Med Ctr, Oklahoma City, OK USA. [Targoff, Ira N.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. RP Miller, FW (reprint author), NIEHS, Environm Autoimmun Grp, Off Clin Res, DHHS,NIH, 10,Room 4-2330,MSC 1301, Bethesda, MD 20892 USA. EM millerf@mail.nih.gov OI Miller, Frederick/0000-0003-2831-9593 FU National Institute of Environmental Health Sciences, NIH FX Supported in part by the Intramural Research programs of the National Institute of Environmental Health Sciences, NIH. NR 15 TC 32 Z9 32 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2009 VL 60 IS 8 BP 2499 EP 2504 DI 10.1002/art.24702 PG 6 WC Rheumatology SC Rheumatology GA 483NL UT WOS:000268973600033 PM 19644877 ER PT J AU Ogata, M Tsujita, M Hossain, MA Akita, N Gonzalez, FJ Staels, B Suzuki, S Fukutomi, T Kimura, G Yokoyama, S AF Ogata, Masaki Tsujita, Maki Hossain, Mohammad Anwar Akita, Nobukatsu Gonzalez, Frank J. Staels, Bart Suzuki, Shogo Fukutomi, Tatsuya Kimura, Genjiro Yokoyama, Shinji TI On the mechanism for PPAR agonists to enhance ABCA1 gene expression SO ATHEROSCLEROSIS LA English DT Article DE ABCA1; PPAR; LXR; ABCA1; HDL; Cholesterol ID HIGH-DENSITY-LIPOPROTEIN; RECEPTOR-DELTA AGONIST; FATTY-ACID-METABOLISM; FOAM-CELL-FORMATION; NUTRITIONAL REGULATION; CHOLESTEROL EFFLUX; LIPID-METABOLISM; CROSS-TALK; ALPHA; LXR AB Expression of ATP binding cassette transporter A1 (ABCA1), a major regulator of high density lipoprotein (HDL) biogenesis, is known to be up-regulated by the transcription factor liver X receptor (LXR) alpha, and expression is further enhanced by activation of the peroxisome proliferator activated receptors (PPARs). We investigated this complex regulatory network using specific PPAR agonists: four fibrates (fenofibrate, bezafibrate, gemfibrozil and LY518674), a PPAR delta agonist (GW501516) and a PPAR gamma agonist (pioglitazone). All of these compounds increased the expression of LXRs, PPARs and ABCA1 mRNAs, and associated apoA-I-mediated lipid release in THP-1 macrophage, W138 fibroblast and mouse fibroblast. When mouse fibroblasts lacking expression of PPAR alpha were examined. the effects of fenofibrate and LY518674 were markedly diminished while induction by other ligands were retained. The PPAR alpha promoter was activated by all of these compounds in an LXR alpha-dependent manner, and partially in a PPAR alpha-dependent manner, in mouse fibroblast. The LXR responsive element (LXRE)-luciferase activity was enhanced by all the compounds in an LXR alpha-dependent manner in mouse fibroblast. This activation was exclusively PPAR alpha-dependent by fenofibrate and LY518674, but nonexclusively by the others. We conclude that PPARs and LXRs are involved in the regulation of ABCA1 expression and HDL biogenesis in a cooperative signal transduction pathway. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Ogata, Masaki; Tsujita, Maki; Hossain, Mohammad Anwar; Akita, Nobukatsu; Yokoyama, Shinji] Nagoya City Univ, Grad Sch Med Sci, Mizuho Ku, Nagoya, Aichi, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Staels, Bart] Inst Pasteur, F-59019 Lille, France. [Staels, Bart] INSERM, UMR 545, F-509191 Lille, France. [Staels, Bart] Univ Lille 2, Fac Sci Pharmaceut & Biol, F-59006 Lille, France. [Staels, Bart] Univ Lille 2, Fac Med, F-59006 Lille, France. RP Yokoyama, S (reprint author), Nagoya City Univ, Grad Sch Med Sci, Mizuho Ku, Kawasumi 1,Mizuho Cho, Nagoya, Aichi, Japan. EM syokoyam@med.nagoya-cu.ac.jp OI TSUJITA, MAKI/0000-0003-1108-621X; Staels, Bart/0000-0002-3784-1503 FU Ministry of Education, Science, Culture and Sports and Technology of Japan; Japan Health Science Foundation; Promotion of Fundamental Studies FX This work was supported by Grants-in-Aid from the Ministry of Education, Science, Culture and Sports and Technology of Japan and from Japan Health Science Foundation, and by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation. NR 31 TC 58 Z9 65 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2009 VL 205 IS 2 BP 413 EP 419 DI 10.1016/j.atherosclerosis.2009.01.008 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 487QI UT WOS:000269289500015 PM 19201410 ER PT J AU Dietrich, M Jacques, PF Pencina, MJ Lanier, K Keyes, MJ Kaur, G Wolf, PA D'Agostino, RB Vasan, RS AF Dietrich, M. Jacques, P. F. Pencina, M. J. Lanier, K. Keyes, M. J. Kaur, G. Wolf, P. A. D'Agostino, R. B. Vasan, R. S. TI Vitamin E supplement use and the incidence of cardiovascular disease and all-cause mortality in the Framingham Heart Study: Does the underlying health status play a role? SO ATHEROSCLEROSIS LA English DT Article DE Vitamin E supplements; Health status; Cardiovascular disease; All-cause mortality; Framingham Heart Study ID FOOD FREQUENCY QUESTIONNAIRE; RANDOMIZED-TRIALS; ALPHA-TOCOPHEROL; E CONSUMPTION; RISK; PREVENTION; REPRODUCIBILITY; METAANALYSIS; EXPRESSION; VALIDITY AB Background: Observational studies generally showed beneficial associations between supplemental vitamin E intake and cardiovascular disease (CVD) risk whereas intervention trials reported adverse effects of vitamin E supplements. We hypothesize that these discordant findings result from differing underlying health status of study participants in observational and intervention studies. Objective: Determine if the relation between supplemental vitamin E intake and CVD and all-cause mortality (ACM) depends on pre-existing CVD. Design: Proportional hazards regression to relate supplemental vitamin E intake to the 10-year incidence of CVD and ACM in 4270 Framingham Study participants stratified by baseline CVD status. Results: Eleven percent of participants used vitamin E supplements at baseline. In participants with preexisting CVD, there were 28 (44%) and 20 (32%) incident cases of CVD and ACM in the vitamin E supplement users versus 249 (47%) and 202 (38%) in the non-users, respectively (CVD HR, 0.90; 95% CL 0.60-1.32; ACM HR, 0.74; 95% CL, 0.46-1.17). In participants without pre-existing CVD, there were 51 (13%) and 47 (12%) cases of CVD and ACM in the vitamin E supplement group versus 428 (13%) and 342 (10%) in the non-vitamin E supplement group, respectively (CVD HR, 1.00; 95% CL, 0.75-1.34; ACM HR 1.20; 95% CL, 0.89-1.64). Conclusion: CVD status has no apparent influence on the association of supplemental vitamin E intake and risk for CVD and ACM in this large, community-based study. Further research is needed to clarify the basis for the discrepant results between intervention and observational studies of supplemental vitamin E intake. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Dietrich, M.; Jacques, P. F.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Pencina, M. J.; Lanier, K.; Keyes, M. J.; Kaur, G.; D'Agostino, R. B.] Boston Univ, Dept Math, Sch Med, Boston, MA 02215 USA. [Wolf, P. A.; D'Agostino, R. B.; Vasan, R. S.] NHLBI Framingham Heart Study, Framingham, MA USA. [Vasan, R. S.] Boston Univ, Prevent Med Sect, Dept Med, Sch Med, Boston, MA 02215 USA. [Vasan, R. S.] Boston Univ, Cardiol Sect, Dept Med, Sch Med, Boston, MA 02215 USA. RP Dietrich, M (reprint author), Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. EM mariondietric@msn.com OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI [NO1-HC-25195, 2 K 24 HL 04334]; NIH/NIDDK [DK07651-17, AHA 0735131N]; U.S. Department of Agriculture [58-1950-4-401] FX This work was supported by the following grants: NHLBI Contract NO1-HC-25195: 2 K 24 HL 04334 (for R.S.V.); NIH/NIDDK DK07651-17 and AHA 0735131N (for M.D.); this material is based upon work supported by the U.S. Department of Agriculture, under agreement No. 58-1950-4-401. NR 23 TC 29 Z9 31 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2009 VL 205 IS 2 BP 549 EP 553 DI 10.1016/j.atherosclerosis.2008.12.019 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 487QI UT WOS:000269289500038 PM 19195657 ER PT J AU Preabrazhenskaya, YV Kim, IY Stadtman, TC AF Preabrazhenskaya, Y. V. Kim, I. Y. Stadtman, T. C. TI Binding of ATP and its derivatives to selenophosphate synthetase from Escherichia coli (Retracted Article. See vol 75, pg 1302, 2010) SO BIOCHEMISTRY-MOSCOW LA English DT Article DE selenophosphate synthetase; truncated mutants; ATP-binding; fluorescence enhancement ID SELENOPROTEIN SYNTHESIS; SELENIUM; ENZYME; SELENOCYSTEINE; PURIFICATION; MECHANISM; PROTEINS; AFFINITY; PEPTIDE; GENES AB Mechanistically similar selenophosphate synthetases (SPS) have been isolated from different organisms. SPS from Escherichia coli is an ATP-dependent enzyme with a C-terminal glycine-rich Walker sequence that has been assumed to take part in the first step of ATP binding. Three C-terminally truncated mutants of SPS, containing the N-terminal 238 (SPS(238)), 262 (SPS(262)), and 332 (SPS(332)) amino acids of the 348-amino-acid protein, have been extracted from cell pellets, and two of these (SPS(262) and SPS(332)) have been purified to homogeneity. SPS(238) has been obtained in a highly purified form. Binding of the fluorescent ATP-derivative TNP-ATP and Mn-ATP to the proteins was examined for all truncated mutants of SPS and a catalytically inactive C17S mutant. It has been shown that TNP-ATP can be used as a structural probe for ATP-binding sites of SPS. We observed two TNP-ATP binding sites per molecule of enzyme for wild-type SPS and SPS(332) mutant and one TNP-ATP binding site for SPS(238) mutant. The stoichiometry of Mn-ATP-binding was 2 mol of ATP per mol of protein determined with [(14)C]ATP by HPLC gel-filtration column chromatography under saturating conditions. The binding stoichiometries for SPS(332), SPS(262), and SPS(238) were 2, 1.6, and 1, respectively. The C17S mutant exhibits about one third of wild type SPS TNP-ATP-binding ability and converts 12% of ATP in the ATPase reaction to ADP in the absence of selenide. The C-terminus contributes two thirds to the TNP-ATP binding; SPS(238) likely has one ATP-binding site removed by truncation. C1 [Preabrazhenskaya, Y. V.; Kim, I. Y.; Stadtman, T. C.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. [Preabrazhenskaya, Y. V.] Grodno State Univ, Dept Biol & Ecol, Grodno 230015, Byelarus. RP Preabrazhenskaya, YV (reprint author), NHLBI, Biochem Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM yuliya.preabrazh@gmail.com NR 24 TC 2 Z9 2 U1 3 U2 9 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0006-2979 J9 BIOCHEMISTRY-MOSCOW+ JI Biochem.-Moscow PD AUG PY 2009 VL 74 IS 8 BP 910 EP 916 DI 10.1134/S0006297909080136 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 486QL UT WOS:000269212600013 PM 19817692 ER PT J AU Rosa, AO Rapoport, SI AF Rosa, Angelo O. Rapoport, Stanley I. TI Intracellular- and extracellular-derived Ca2+ influence phospholipase A(2)-mediated fatty acid release from brain phospholipids SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Review DE Phospholipase A(2); Calcium; Arachidonic acid; Docosahexaenoic acid; Endoplasmic reticulum; Signaling ID PLATELET-ACTIVATING-FACTOR; CENTRAL-NERVOUS-SYSTEM; ENDOPLASMIC-RETICULUM DYSFUNCTION; MAJOR DEPRESSIVE DISORDER; AMYLOID-BETA-PEPTIDE; D-ASPARTATE RECEPTOR; RAT CEREBRAL-CORTEX; ARACHIDONIC-ACID; DOCOSAHEXAENOIC ACID; ALZHEIMERS-DISEASE AB Docosahexaenoic acid (DHA) and arachidonic acid (AA) are found in high concentrations in brain cell membranes and are important for brain function and structure. Studies suggest that AA and DHA are hydrolyzed selectively from the sn-2 position of synaptic membrane phospholipids by Ca2+-dependent cytosolic phospholipase A(2) (cPLA(2)) and Ca2+-independent phospholipase A(2) (iPLA(2)), respectively, resulting in increased levels of the unesterified fatty acids and lysophospholipids. Cell studies also suggest that AA and DHA release depend on increased concentrations of Ca2+, even though iPLA(2) has been thought to be Ca2+-independent. The source of Ca2+ for activation of cPLA(2) is largely extracellular, whereas Ca2+ released from the endoplasmic reticulum can activate iPLA(2) by a number of mechanisms. This review focuses on the role of Ca2+ in modulating cPLA(2) and iPLA(2) activities in different conditions. Furthermore, a model is suggested in which neurotransmitters regulate the activity of these enzymes and thus the balanced and localized release of AA and DHA from phospholipid in the brain, depending on the primary source of the Ca2+ signal. (C) 2009 Elsevier B.V. All rights reserved. C1 [Rosa, Angelo O.; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Rosa, AO (reprint author), MUSC Lab, Dept Pharmacol, BSC 327,Off BSC 324,173 Ashley Ave, Charleston, SC 29425 USA. EM darosa@musc.edu OI da Rosa, Angelo/0000-0003-3715-4751 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX We thank J. Bell, Dr. M. Basselin, Dr. J. Rao, Dr. M. Igarashi, Dr. F. Gao, Dr. J.Y. Park and the NIH Fellows Editorial Board for reviewing the manuscript. We also thank Kathy Benjamin for correcting the language of this manuscript. This study was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. The authors have no conflict of interest. NR 199 TC 26 Z9 29 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 EI 0006-3002 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD AUG PY 2009 VL 1791 IS 8 BP 697 EP 705 DI 10.1016/j.bbalip.2009.03.009 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 479HQ UT WOS:000268650700001 PM 19327408 ER PT J AU Jia, YP Alayash, AI AF Jia, Yiping Alayash, Abdu I. TI Effects of cross-linking and zero-link polymerization on oxygen transport and redox chemistry of bovine hemoglobin SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Article DE Hemoglobin; Zero-link; Rapid kinetics; Stopped-flow; Oxygen affinity ID HEME DEGRADATION-PRODUCTS; CHLORIDE-BINDING SITES; BLOOD SUBSTITUTES; FUNCTIONAL CONSEQUENCES; NITRIC-OXIDE; OXIDATION; CARRIERS; GLUTARALDEHYDE; DISSOCIATION; AFFINITY AB Cross-linked hemoglobins (Hbs) were found to have enhanced oxidative reactions which compromise the ability of cell-free Hb to carry oxygen. Zero-link bovine Hb (ZL-HbBv). also known as OxyVita(TM), a large polymer held together by pseudopeptide bonds on the surface of adjacent tetramers, provides a model in which these reactions can be evaluated. The oxygen affinity of ZL-HbBv was greatly increased, whereas the oxygen binding cooperativity (n(50)) as well as the regulatory responses to pH and chloride ions was diminished. Rapid mixing kinetic studies revealed faster carbon monoxide (CO) and nitric oxide (NO) binding to ZL-HbBv. consistent with a more accessible heme pocket conformation. The rate of autoxidation of ferrous ZL-HbBv was 3 folds faster than the unmodified HbBv (control) but only slightly suppressed by the presence of superoxide dismutase and catalase enzymes. The peroxide (H(2)O(2)) reaction rates of ferric ZL-HbBv and its degradation were comparable to that of the control. The rate of heme loss from ZL-HbBv to a mutant apomyoglobin (H64Y/V68F) was also very close to that of the control. Taken together, allosteric and redox reactions of this protein are altered due to heme accessibility to solvent. however, the compact tetramer to tetramer interaction of the ZL-HbBv polymer appears to restrict heme loss even in the presence of excess H(2)O(2). Published by Elsevier B.V. C1 [Jia, Yiping; Alayash, Abdu I.] US FDA, LBVB, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Jia, YP (reprint author), Natl Inst Hlth NIH Campus,8800 Rockville Pike,Bld, Bethesda, MD 20892 USA. EM yiping.jia@fda.hhs.gov NR 47 TC 13 Z9 13 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD AUG PY 2009 VL 1794 IS 8 BP 1234 EP 1242 DI 10.1016/j.bbapap.2009.04.008 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 467VV UT WOS:000267772100017 PM 19409516 ER PT J AU Das, A Zhou, YX Ivanov, AA Carter, RL Harden, TK Jacobson, KA AF Das, Arijit Zhou, Yixing Ivanov, Andrei A. Carter, Rhonda L. Harden, T. Kendall Jacobson, Kenneth A. TI Enhanced Potency of Nucleotide-Dendrimer Conjugates as Agonists of the P2Y(14) Receptor: Multivalent Effect in G Protein-Coupled Receptor Recognition SO BIOCONJUGATE CHEMISTRY LA English DT Article ID DRUG-DELIVERY; POLYAMIDOAMINE DENDRIMERS; UDP-GLUCOSE; MOLECULAR-DYNAMICS; POLY(AMIDOAMINE) DENDRIMERS; FUNCTIONALIZED DENDRIMERS; BIOMEDICAL APPLICATIONS; PAMAM DENDRIMERS; CONTRAST AGENTS; CELLS AB The P2Y(14) receptor is a G protein-coupled receptor activated by uridine-5'-diphosphoglucose and other nucleotide sugars that modulates immune function. Covalent conjugation of P2Y(14) receptor agonists to PAMAM (polyamidoamine) dendrimers enhanced pharmacological activity. Uridine-5'-diphosphoglucuronic acid (UDPGA) and its ethylenediamine adduct were suitable functionalized congeners for coupling to several generations (G2.5-6) of dendrimers (both terminal carboxy and amino). Prosthetic groups, including biotin for avidin complexation, a chelating group for metal complexation (and eventual magnetic resonance imaging), and a fluorescent moiety, also were attached with the eventual goals of molecular detection and characterization of the P2Y(14) receptor. The activities of conjugates were assayed in HEK293 cells stably expressing the human P2Y(14) receptor. A G3 PAMAM conjugate containing 20 bound nucleotide moieties (UDPGA) was 100-fold more potent (EC50 2.4 nM) than the native agonist uridine-5'-diphosphoglucose. A molecular model of this conjugate docked in the human P2Y(14) receptor showed that the nucleotide-substituted branches could extend far beyond the dimensions of the receptor and be available for multivalent docking to receptor aggregates. Larger dendrimer carriers and greater loading favored higher potency. A similar conjugate of G6 with 147 out of 256 amino groups substituted with UDPGA displayed an EC50 value of 0.8 nM. Thus, biological activity was either retained or dramatically enhanced in the multivalent dendrimer conjugates in comparison with monomeric P2Y(14) receptor agonists, depending on size, degree of substitution, terminal functionality, and attached prosthetic groups. C1 [Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Zhou, Yixing; Carter, Rhonda L.; Harden, T. Kendall] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIH [GM38213]; NIDDK FX This research was supported in part by the Intramural Research Program of the NIH, NIDDK, and by NIH grant GM38213 toT.K.H. We thank Dr. Herman Yell and Dr. Athena M. Keene-Klutz of NIDDK for helpful advice oil the NMR experiments and chemical synthesis. We thank Dr. John Lloyd (NIDDK) for mass spectral measurements. NR 56 TC 16 Z9 17 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD AUG PY 2009 VL 20 IS 8 BP 1650 EP 1659 DI 10.1021/bc900206g PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 484KB UT WOS:000269042100028 PM 19572637 ER PT J AU Fong, JH Marchler-Bauer, A AF Fong, Jessica H. Marchler-Bauer, Aron TI CORAL: aligning conserved core regions across domain families SO BIOINFORMATICS LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; PROFILE ALIGNMENT; STATISTICAL SIGNIFICANCE; SCORING FUNCTIONS; PSI-BLAST; DATABASE; PROTEINS; SIMILARITIES; IDENTIFICATION; INFORMATION AB Motivation: Homologous protein families share highly conserved sequence and structure regions that are frequent targets for comparative analysis of related proteins and families. Many protein families, such as the curated domain families in the Conserved Domain Database (CDD), exhibit similar structural cores. To improve accuracy in aligning such protein families, we propose a pro. le pro. le method CORAL that aligns individual core regions as gap-free units. Results: CORAL computes optimal local alignment of two profiles with heuristics to preserve continuity within core regions. We benchmarked its performance on curated domains in CDD, which have pre-defined core regions, against COMPASS, HHalign and PSI-BLAST, using structure superpositions and comprehensive curator-optimized alignments as standards of truth. CORAL improves alignment accuracy on core regions over general pro. le methods, returning a balanced score of 0.57 for over 80% of all domain families in CDD, compared with the highest balanced score of 0.45 from other methods. Further, CORAL provides E-values to aid in detecting homologous protein families and, by respecting block boundaries, produces alignments with improved 'readability' that facilitate manual refinement. C1 [Fong, Jessica H.; Marchler-Bauer, Aron] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Fong, JH (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM fongj@ncbi.nlm.nih.gov RI Marchler-Bauer, Aron/A-9681-2009; OI Marchler-Bauer, Aron/0000-0003-1516-0712 FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX Funding: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 35 TC 4 Z9 4 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD AUG 1 PY 2009 VL 25 IS 15 BP 1862 EP 1868 DI 10.1093/bioinformatics/btp334 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 472CP UT WOS:000268107100003 PM 19470584 ER PT J AU Nicodemus, KK Malley, JD AF Nicodemus, Kristin K. Malley, James D. TI Predictor correlation impacts machine learning algorithms: implications for genomic studies SO BIOINFORMATICS LA English DT Article ID RANDOM FORESTS; HAPLOTYPE RECONSTRUCTION; EXPLOITING INTERACTIONS; VARIABLE IMPORTANCE; GENE-EXPRESSION; CLASSIFICATION; SNPS; REGRESSION; SELECTION; TRAITS AB Motivation: The advent of high-throughput genomics has produced studies with large numbers of predictors (e. g. genome-wide association, microarray studies). Machine learning algorithms (MLAs) are a computationally efficient way to identify phenotype-associated variables in high-dimensional data. There are important results from mathematical theory and numerous practical results documenting their value. One attractive feature of MLAs is that many operate in a fully multivariate environment, allowing for small-importance variables to be included when they act cooperatively. However, certain properties of MLAs under conditions common in genomic-related data have not been well-studied-in particular, correlations among predictors pose a problem. Results: Using extensive simulation, we showed considering correlation within predictors is crucial in making valid inferences using variable importance measures (VIMs) from three MLAs: random forest (RF), conditional inference forest (CIF) and Monte Carlo logic regression (MCLR). Using a case-control illustration, we showed that the RF VIMs-even permutation-based-were less able to detect association than other algorithms at effect sizes encountered in complex disease studies. This reduction occurred when 'causal' predictors were correlated with other predictors, and was sharpest when RF tree building used the Gini index. Indeed, RF Gini VIMs are biased under correlation, dependent on predictor correlation strength/number and over-trained to random fluctuations in data when tree terminal node size was small. Permutation-based VIM distributions were less variable for correlated predictors and are unbiased, thus may be preferred when predictors are correlated. MLAs are a powerful tool for high-dimensional data analysis, but well-considered use of algorithms is necessary to draw valid conclusions. C1 [Nicodemus, Kristin K.] Univ Oxford, Dept Stat Genet, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Nicodemus, Kristin K.] Univ Oxford, Dept Clin Pharmacol, Oxford OX3 7DQ, England. [Nicodemus, Kristin K.] NIMH, Cognit & Psychosis Program, Intramural Res Program, Bethesda, MD 20892 USA. [Malley, James D.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Nicodemus, KK (reprint author), Univ Oxford, Dept Stat Genet, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England. EM kristin.nicodemus@well.ox.ac.uk NR 28 TC 49 Z9 49 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD AUG 1 PY 2009 VL 25 IS 15 BP 1884 EP 1890 DI 10.1093/bioinformatics/btp331 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 472CP UT WOS:000268107100006 PM 19460890 ER PT J AU Zang, CZ Schones, DE Zeng, C Cui, KR Zhao, KJ Peng, WQ AF Zang, Chongzhi Schones, Dustin E. Zeng, Chen Cui, Kairong Zhao, Keji Peng, Weiqun TI A clustering approach for identification of enriched domains from histone modification ChIP-Seq data SO BIOINFORMATICS LA English DT Article ID TRANSCRIPTION FACTOR-BINDING; GENOME-WIDE IDENTIFICATION; EMBRYONIC STEM-CELLS; FALSE DISCOVERY RATE; LYSINE 9; H3; PROTEINS; SITES; METHYLATIONS; RECOGNITION AB Motivation: Chromatin states are the key to gene regulation and cell identity. Chromatin immunoprecipitation (ChIP) coupled with high-throughput sequencing (ChIP-Seq) is increasingly being used to map epigenetic states across genomes of diverse species. Chromatin modi. cation profiles are frequently noisy and diffuse, spanning regions ranging from several nucleosomes to large domains of multiple genes. Much of the early work on the identification of ChIP-enriched regions for ChIP-Seq data has focused on identifying localized regions, such as transcription factor binding sites. Bioinformatic tools to identify diffuse domains of ChIP-enriched regions have been lacking. Results: Based on the biological observation that histone modi. cations tend to cluster to form domains, we present a method that identifies spatial clusters of signals unlikely to appear by chance. This method pools together enrichment information from neighboring nucleosomes to increase sensitivity and specificity. By using genomic-scale analysis, as well as the examination of loci with validated epigenetic states, we demonstrate that this method outperforms existing methods in the identification of ChIP-enriched signals for histone modi. cation profiles. We demonstrate the application of this unbiased method in important issues in ChIP-Seq data analysis, such as data normalization for quantitative comparison of levels of epigenetic modi. cations across cell types and growth conditions. C1 [Zang, Chongzhi; Zeng, Chen; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Schones, Dustin E.; Cui, Kairong; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Peng, WQ (reprint author), George Washington Univ, Dept Phys, Washington, DC 20052 USA. EM wpeng@gwu.edu RI Zang, Chongzhi/D-1445-2011 FU University Facilitating Fund; National Science Foundation [DMR0313129]; Intramural Research Program for the National Heart Lung and blood Institute; National Institute of Health FX University Facilitating Fund (to W. P., in parts); the National Science Foundation (DMR0313129 to Chen Zeng in parts); Intramural Research Program for the National Heart Lung and blood Institute; National Institute of Health (to K. Z., in parts). NR 38 TC 351 Z9 354 U1 2 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD AUG 1 PY 2009 VL 25 IS 15 BP 1952 EP 1958 DI 10.1093/bioinformatics/btp340 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 472CP UT WOS:000268107100015 PM 19505939 ER PT J AU Hasler, G Luckenbaugh, DA Snow, J Meyers, N Waldeck, T Geraci, M Roiser, J Knutson, B Charney, DS Drevets, WC AF Hasler, Gregor Luckenbaugh, David A. Snow, Joseph Meyers, Noah Waldeck, Tracy Geraci, Marilla Roiser, Jonathan Knutson, Brian Charney, Dennis S. Drevets, Wayne C. TI Reward Processing After Catecholamine Depletion in Unmedicated, Remitted Subjects with Major Depressive Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Anhedonia; dopamine; major depressive disorder; monetary incentive delay task; norepinephrine; reward ID NUCLEUS-ACCUMBENS; HYPOTHESIS; REMISSION; DOPAMINE AB Background: We investigated whether performance on a reward processing task differs between fully remitted patients with major depressive disorder (MDD) and healthy control subjects after catecholamine depletion. Methods: Seventeen unmedicated subjects with remitted MDD (RMDD) and 13 healthy control subjects underwent catecholamine depletion with oral alpha-methyl-para-tyrosine (AMPT) in a randomized, placebo-controlled, double-blind crossover study. The main outcome measure was the reaction time on the monetary incentive delay (MID) task. Results: A diagnosis X drug interaction was evident (p = .001), which was attributable to an increase in reaction time across all incentive levels after AMPT in RMDD subjects (p = .001) but no significant AMPT effect on reaction time in control subjects (p = .17). There was no drug X diagnosis interaction on control tasks involving working memory or attention. In the RMDD sample the AMPT-induced depressive symptoms correlated with AMPT-induced changes in reaction time at all incentive levels of the MID task (r values = .58-.82, p < .002). Conclusions: Under catecholamine depletion the RMDD subjects were robustly differentiated from control subjects by development of performance deficits on a reward processing task. These performance deficits correlated directly with the return of depressive symptoms after AMPT administration. The sensitivity of central reward processing systems to reductions in brain catecholamine levels thus seems to represent a trait-like marker in MDD. C1 [Hasler, Gregor] Univ Zurich Hosp, Dept Psychiat, CH-8091 Zurich, Switzerland. [Luckenbaugh, David A.; Snow, Joseph; Meyers, Noah; Waldeck, Tracy; Geraci, Marilla; Roiser, Jonathan; Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, Bethesda, MD USA. [Knutson, Brian] Stanford Univ, Sch Med, Dept Psychiat, Stanford, CA USA. [Charney, Dennis S.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Charney, Dennis S.] Mt Sinai Sch Med, Dept Neurosci & Pharmacol, New York, NY USA. [Charney, Dennis S.] Mt Sinai Sch Med, Dept Biol Chem, New York, NY USA. RP Hasler, G (reprint author), Univ Zurich Hosp, Dept Psychiat, Culmannstr 8, CH-8091 Zurich, Switzerland. EM g.hasler@bluewin.ch RI Roiser, Jonathan/A-1791-2010; Hasler, Gregor/E-4845-2012; OI Hasler, Gregor/0000-0002-8311-0138; Knutson, Brian/0000-0002-7669-426X FU National Institutes of Mental Health. FX This research was supported by the Intramural Research Program of the National Institutes of Mental Health. NR 16 TC 36 Z9 36 U1 0 U2 5 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 AUG 1 PY 2009 VL 66 IS 3 BP 201 EP 205 DI 10.1016/j.biopsych.2009.02.029 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 470FW UT WOS:000267961600002 PM 19393989 ER PT J AU Sportes, C Steinberg, SM Liewehr, DJ Gea-Banacloche, J Danforth, DN Avila, DN Bryant, KE Krumlauf, MC Fowler, DH Pavletic, S Hardy, NM Bishop, MR Gress, RE AF Sportes, Claude Steinberg, Seth M. Liewehr, David J. Gea-Banacloche, Juan Danforth, David N. Avila, Daniele N. Bryant, Kelly E. Krumlauf, Michael C. Fowler, Daniel H. Pavletic, Steven Hardy, Nancy M. Bishop, Michael R. Gress, Ronald E. TI Strategies to Improve Long-Term Outcome in Stage IIIB Inflammatory Breast Cancer: Multimodality Treatment Including Dose-intensive Induction and High-Dose Chemotherapy SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Inflammatory breast cancer; High-dose chemotherapy; Autologous transplantation; Multimodality therapy ID STEM-CELL SUPPORT; CONVENTIONAL ADJUVANT CHEMOTHERAPY; COLONY-STIMULATING FACTOR; RANDOMIZED-TRIAL; SEQUENTIAL CHEMOTHERAPY; LYMPH-NODES; PHASE-III; FOLLOW-UP; CARCINOMA; TRANSPLANTATION AB Inflammatory breast cancer (IBC) is a rare clinicopathologic entity with a poor prognosis, lagging far behind any other form of nonmetastatic breast cancer. Since the advent of systemic chemotherapy over 35 years ago, only minimal progress has been made in long-term outcome. Although multiple randomized trials of high-dose chemotherapy and autologous progenitor cell transplantation (ASCT) for the treatment of breast cancer have yielded disappointing results, these data are not necessarily relevant to IBC, a distinct clinical and pathologic entity. Therefore, the optimal multimodality therapy for IBC is not well established, and remains unsatisfactory. We treated 21 women with nonmetastatic IBC with a multimodality strategy including high-dose melphalan (Mel)/etoposide and ASCT The treatment was overall tolerated with acceptable morbidity, and no post-ASCT 100-day mortality. With a median potential follow-up of approximately 8 years, the estimated progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) at 6 years from on-study date are: 67%, 55%, and 69%, respectively. These results from a small phase 11 study are among the most promising of mature outcome data for IBC. They strongly suggest, along with results of several already published phase II trials, that ASCT could play a significant role in the first line treatment of IBC. Biol Blood Marrrow Transplant 15: 963-970 (2009) (C) 2009 American Society for Blood and Marrow Transplantation C1 [Sportes, Claude; Gea-Banacloche, Juan; Avila, Daniele N.; Bryant, Kelly E.; Krumlauf, Michael C.; Fowler, Daniel H.; Pavletic, Steven; Hardy, Nancy M.; Bishop, Michael R.; Gress, Ronald E.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.; Liewehr, David J.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Danforth, David N.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Sportes, C (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Room 43142, Bethesda, MD 20892 USA. EM csportes@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 41 TC 4 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2009 VL 15 IS 8 BP 963 EP 970 DI 10.1016/j.bbmt.2009.04.018 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 477PH UT WOS:000268530500009 PM 19589486 ER PT J AU Pang, ALY Peacock, S Johnson, W Bear, DH Rennert, OM Chan, WY AF Pang, Alan Lap-Yin Peacock, Stephanie Johnson, Warren Bear, Deborah H. Rennert, Owen M. Chan, Wai-Yee TI Cloning, Characterization, and Expression Analysis of the Novel Acetyltransferase Retrogene Ard1b in the Mouse SO BIOLOGY OF REPRODUCTION LA English DT Article DE gametogenesis; gene regulation; meiosis; spermatogenesis; testis ID N-TERMINAL ACETYLTRANSFERASE; MALE GERM-CELLS; GENE-EXPRESSION; TRANSLATIONAL CONTROL; SPERMATOGENESIS; COMPLEX; TESTIS; TRANSCRIPTOME; ACETYLATION; PROTEINS AB N-alpha-terminal acetylation is a modification process that occurs cotranslationally on most eukaryotic proteins. The major enzyme responsible for this process, N-alpha-terminal acetyltransferase, is composed of the catalytic subunit ARD1A and the auxiliary subunit NAT1. We cloned, characterized, and studied the expression pattern of Ard1b (also known as Ard2), a novel homolog of the mouse Ard1a. Comparison of the genomic structures suggests that the autosomal Ard1b is a retroposed copy of the X-linked Ard1a. Expression analyses demonstrated a testis predominance of Ard1b. A reciprocal expression pattern between Ard1a and Ard1b is also observed during spermatogenesis, suggesting that Ard1b is expressed to compensate for the loss of Ard1a starting from meiosis. Both ARD1A and ARD1B can interact with NAT1 to constitute a functional N-alpha-terminal acetyltransferase in vitro. The expression of ARD1B protein can be detected in mouse testes but is delayed until the first appearance of round spermatids. In a cell culture model, the inclusion of the long 3' untranslated region of Ard1b leads to reduction of luciferase reporter activity, which implicates its role in translational repression of Ard1b during spermatogenesis. Our results suggest that ARD1B may have an important role in the later course of the spermatogenic process. C1 [Pang, Alan Lap-Yin; Peacock, Stephanie; Johnson, Warren; Bear, Deborah H.; Rennert, Owen M.; Chan, Wai-Yee] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Clin Gen, Natl Inst Hlth, Bethesda, MD 20892 USA. [Chan, Wai-Yee] Georgetown Univ, Dept Pediat, Washington, DC 20057 USA. RP Pang, ALY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Clin Gen, Natl Inst Hlth, Bethesda, MD 20892 USA. EM panga@mail.nih.gov FU National Institute of Child Health and Human Development; National Institutes of Health; [EU192141] FX Supported by the Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The nucleotide sequence of Ard1b (Ard2) transcript had been deposited in GenBank under the accession number EU192141. NR 43 TC 11 Z9 11 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD AUG PY 2009 VL 81 IS 2 BP 302 EP 309 DI 10.1095/biolreprod.108.073221 PG 8 WC Reproductive Biology SC Reproductive Biology GA 474IP UT WOS:000268277300008 PM 19246321 ER PT J AU Banerjee, HN Verma, M AF Banerjee, Hirendra Nath Verma, Mukesh TI Epigenetic mechanisms in cancer SO BIOMARKERS IN MEDICINE LA English DT Review DE acetylation; cancer; chromatin; epigenetics; histone; methylation; miRNA; RDA; representational differential analysis; tumor ID CELL LUNG-CANCER; TUMOR-SUPPRESSOR GENE; ACUTE MYELOID-LEUKEMIA; MGMT PROMOTER HYPERMETHYLATION; CPG ISLAND HYPERMETHYLATION; DNA METHYLATION MARKERS; GROWTH-FACTOR-II; COLORECTAL-CANCER; BREAST-CANCER; COLON-CANCER AB After the completion of the human genome, a need was identified by scientists to look for a functional map of the human genome. Epigenomics provided functional characteristics of genes identified in the genome. Epigenetics is the alteration in gene expression (function) without changing the nucleotide sequence. Both activation and inactivation of cancer-associated genes can occur by epigenetic mechanisms. The major players in epigenetic mechanisms of gene regulation are DNA methylation, histone deacetylation, chromatin remodeling, small noncoding RNA expression and gene imprinting. In the last few years, epigenetic mechanisms have been studied in a number of tumor types and epigenetic markers have been identified that are suitable for cancer detection, diagnosis, follow-up of treatment and screening high-risk populations. One interesting aspect of epigenetics is the reactivation of genes by successful reversion of some epigenetic changes using chemicals. The reversibility of epigenetic aberrations has made them attractive targets for cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases, leading to the reactivation of silenced genes. In this article, we have described the current status of this powerful science and discussed the challenges in the clinical fields where epigenetic approaches in cancer are applied. C1 [Banerjee, Hirendra Nath] Elizabeth City State Univ, Dept Biol, Elizabeth City, NC 27909 USA. [Verma, Mukesh] NCI, Methods & Technol Branch, Epidemiol & Genet Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Banerjee, HN (reprint author), Elizabeth City State Univ, Dept Biol, Campus Box 930,1704 Weeksville Rd, Elizabeth City, NC 27909 USA. EM bhirendranath@mail.ecsu.edu NR 215 TC 16 Z9 18 U1 0 U2 18 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 J9 BIOMARK MED JI Biomark. Med. PD AUG PY 2009 VL 3 IS 4 BP 397 EP 410 DI 10.2217/BMM.09.26 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 486EP UT WOS:000269179000017 PM 20477485 ER PT J AU Jones, CN Tuleuova, N Lee, JY Ramanculov, E Reddi, AH Zern, MA Revzin, A AF Jones, Caroline N. Tuleuova, Nazgul Lee, Ji Youn Ramanculov, Erlan Reddi, A. Hari Zern, Mark A. Revzin, Alexander TI Cultivating liver cells on printed arrays of hepatocyte growth factor SO BIOMATERIALS LA English DT Article DE Protein microarrays; Micropatterned co-cultures; Hepatocytes; Growth factor microarrays ID EMBRYONIC STEM-CELLS; GENE-EXPRESSION PATTERNS; LONG-TERM CULTURE; EXTRACELLULAR-MATRIX; RAT HEPATOCYTES; SANDWICH CONFIGURATION; DEFINITIVE ENDODERM; FACTOR-BINDING; DNA-SYNTHESIS; DIFFERENTIATION AB Growth factors are commonly present in soluble form during in vitro cell cultivation experiments in order to provide signals for cellular proliferation or differentiation. In contrast to these traditional experiments, we investigated solid-phase presentation of a hepatocyte growth factor (HGF), a protein important in liver development and regeneration, on microarrays of extracellular matrix (ECM) proteins. In our experiments, HGF was mixed in solution with ECM proteins (collagen (1), (IV) or laminin) and robotically printed onto silane-modified glass slides. Primary rat hepatocytes were seeded onto HGF/ECM protein microarrays and formed cellular clusters that corresponded in size to the dimensions of individual protein spots (500 mu m diameter). Analysis of liver-specific products, albumin and alpha 1-antitrypsin, revealed several fold higher levels of expression of these proteins in hepatocytes cultured on HGF/ECM microarrays compared to cells cultivated on ECM proteins alone. In addition, cultivation of hepatocytes on HGF/ECM protein spots led to spontaneous reorganization of cellular clusters from a monolayer into three-dimensional spheroids. We also investigated the effects of surface-tethered HGF on hepatocytes co-cultivated with stromal cells and observed a significantly higher level of albumin in co-cultures where hepatocytes were stimulated by HGF/ECM spots compared to co-cultures created on ECM protein islands without the growth factor. In summary, our study suggests that incorporation of HGF into ECM protein microarrays has a profound and long-lasting effect on the morphology and phenotype of primary hepatocytes. In the future, the number of growth factors printed on ECM microarrays will be expanded to enable multiplexed and combinatorial screening of inducers of cellular differentiation or proliferation. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Jones, Caroline N.; Tuleuova, Nazgul; Lee, Ji Youn; Revzin, Alexander] Univ Calif Davis, Dept Biomed Chem, Davis, CA 95616 USA. [Reddi, A. Hari] Calif State Univ Sacramento, Ctr Tissue Regenerat & Repair, Dept Orthopaed Surg, Sacramento, CA 95817 USA. [Zern, Mark A.] Calif State Univ Sacramento, Transplant Res Inst, Dept Med, Sacramento, CA 95817 USA. [Tuleuova, Nazgul; Ramanculov, Erlan] Natl Biotechnol Ctr, Astana, Kazakhstan. RP Revzin, A (reprint author), Univ Calif Davis, Dept Biomed Chem, 451 E Hlth Sci Dr 2519, Davis, CA 95616 USA. EM arevzin@ucdavis.edu FU National Center for Biotechnology, Republic of Kazakhstan; NIH [DK073901] FX We thank Mr. Sunny Shah for the assistance with collection of SEM micrographs. NT was supported by a fellowship from the National Center for Biotechnology, Republic of Kazakhstan. Financial support for this work was provided by NIH grant (DK073901) awarded to AR. NR 50 TC 27 Z9 28 U1 3 U2 14 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2009 VL 30 IS 22 BP 3733 EP 3741 DI 10.1016/j.biomaterials.2009.03.039 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 461OM UT WOS:000267277400011 PM 19375794 ER PT J AU Meenakshisundaram, G Eteshola, E Pandian, RP Bratasz, A Selvendiran, K Lee, SC Krishna, MC Swartz, HM Kuppusamy, P AF Meenakshisundaram, Guruguhan Eteshola, Edward Pandian, Ramasamy P. Bratasz, Anna Selvendiran, Karuppaiyah Lee, Stephen C. Krishna, Murali C. Swartz, Harold M. Kuppusamy, Periannan TI Oxygen sensitivity and biocompatibility of an implantable paramagnetic probe for repeated measurements of tissue oxygenation SO BIOMEDICAL MICRODEVICES LA English DT Article DE EPR oximetry; Oxygen sensor; Particulate probe; Encapsulation; Polymer coating; Biocompatible EPR probe ID IN-SITU OXYGENATION; LITHIUM PHTHALOCYANINE; NITRIC-OXIDE; ELECTROCHEMICAL PREPARATION; RESONANCE OXIMETRY; SKELETAL MYOBLASTS; TUMOR OXYGENATION; EPR SPECTROSCOPY; SPIN-PROBE; VIVO AB The use of oxygen-sensing water-insoluble paramagnetic probes, such as lithium octa-n-butoxynaphthalocyanine (LiNc-BuO), enables repeated measurements of pO(2) from the same location in tissue by electron paramagnetic resonance (EPR) spectroscopy. In order to facilitate direct in vivo application, and hence eventual clinical applicability, of LiNc-BuO, we encapsulated LiNc-BuO microcrystals in polydimethylsiloxane (PDMS), an oxygen-permeable and bioinert polymer, and developed an implantable chip. In vitro evaluation of the chip, performed under conditions of sterilization, high-energy irradiation, and exposure to cultured cells, revealed that it is biostable and biocompatible. Implantation of the chip in the gastrocnemius muscle tissue of mice showed that it is capable of repeated and real-time measurements of tissue oxygenation for an extended period. Functional evaluation using a murine tumor model established the suitability and applicability of the chip for monitoring tumor oxygenation. This study establishes PDMS-encapsulated LiNc-BuO as a promising choice of probe for clinical EPR oximetry. C1 [Meenakshisundaram, Guruguhan; Pandian, Ramasamy P.; Bratasz, Anna; Selvendiran, Karuppaiyah; Kuppusamy, Periannan] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Eteshola, Edward; Lee, Stephen C.] Ohio State Univ, Dept Biomed Engn, Columbus, OH 43210 USA. [Meenakshisundaram, Guruguhan; Eteshola, Edward; Pandian, Ramasamy P.; Bratasz, Anna; Selvendiran, Karuppaiyah; Lee, Stephen C.; Kuppusamy, Periannan] Ohio State Univ, Davis Heart & Lung Res Inst, Columbus, OH 43210 USA. [Krishna, Murali C.] NCI, Biophys Spect Sect, Radiat Biol Branch, Bethesda, MD 20892 USA. [Swartz, Harold M.] Dartmouth Med Sch, EPR Ctr Viable Syst, Hanover, NH 03755 USA. RP Kuppusamy, P (reprint author), Ohio State Univ, Dept Internal Med, 420 W 12th Ave,Room 114, Columbus, OH 43210 USA. EM kuppusamy.1@osu.edu RI Lee, Stephen/C-2394-2011 FU NIH [EB004031] FX This study was supported by NIH grant EB004031. We would like to thank Dr. Charles Hitchcock for his assistance with histological analysis. NR 32 TC 17 Z9 17 U1 0 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1387-2176 J9 BIOMED MICRODEVICES JI Biomed. Microdevices PD AUG PY 2009 VL 11 IS 4 BP 817 EP 826 DI 10.1007/s10544-009-9298-4 PG 10 WC Engineering, Biomedical; Nanoscience & Nanotechnology SC Engineering; Science & Technology - Other Topics GA 469HF UT WOS:000267886400013 PM 19319683 ER PT J AU Lu, L Cai, Q Tian, JH Sheng, ZH AF Lu, Li Cai, Qian Tian, Jin-Hua Sheng, Zu-Hang TI Snapin associates with late endocytic compartments and interacts with late endosomal SNAREs SO BIOSCIENCE REPORTS LA English DT Article DE late endocytic organelle; late endosome; lysosome-associated membrane protein-1 (LAMP-1); membrane fusion; membrane trafficking; soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE) ID LYSOSOME-RELATED ORGANELLES; HERMANSKY-PUDIAK-SYNDROME; SYNAPTIC-TRANSMISSION; PROTEIN; COMPLEX; FUSION; IDENTIFICATION; EXOCYTOSIS; BLOC-1; BIOGENESIS AB Late endocytic membrane trafficking delivers target materials and newly synthesized hydrolases into lysosomes and is critical for maintaining an efficient degradation process and cellular homoeostasis. Although some features of late endosome-lysosome trafficking have been described, the mechanisms underlying regulation of this event remain to be elucidated. Our previous studies showed that Snapin, as a SNAP25 (25 kDa synaptosome-associated protein)binding protein, plays a critical role in priming synaptic vesicles for synchronized fusion in neurons. In the present study, we report that Snapin also associates with late endocytic membranous organelles and interacts with the late endosome-targeted SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) complex. Using a genetic mouse model, we further discovered that Snapin is required to maintain a proper balance of the late endocytic protein LAMP-1 (lysosome-associated membrane protein-1) and late endosomal SNARE proteins syntaxin 8 and Vti1b (vesicle transport through interaction with target SNARES homologue 1b). Deleting the snapin gene in mice selectively led to the accumulation of these proteins in late endocytic organelles. Thus our present study suggests that Snapin serves as art important regulator of the late endocytic fusion machinery, in addition to its established role in regulating synaptic vesicle fusion. C1 [Lu, Li; Cai, Qian; Tian, Jin-Hua; Sheng, Zu-Hang] Natl Inst Neurol Disorders & Stroke, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Lu, Li] Shanghai Jiao Tong Univ, Dept Neurobiol, Sch Med, Shanghai 200030, Peoples R China. RP Sheng, ZH (reprint author), Natl Inst Neurol Disorders & Stroke, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bldg 35,Room 38203,35 Convent Dr, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke; National Institutes of Health; National Institutes of Health Intramural Research Program FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (to Z.-H.S.) L.L. is a graduate student of the National Institutes of Health-Shanghai JiaoTong University Joint PhD Program in Neuroscience, supported by the National Institutes of Health Intramural Research Program. NR 42 TC 13 Z9 13 U1 0 U2 2 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0144-8463 J9 BIOSCIENCE REP JI Biosci. Rep. PD AUG PY 2009 VL 29 IS 4 BP 261 EP 269 DI 10.1042/BSR20090043 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 485QA UT WOS:000269137400006 PM 19335339 ER PT J AU Davatzikos, C Xu, F An, Y Fan, Y Resnick, SM AF Davatzikos, Christos Xu, Feng An, Yang Fan, Yong Resnick, Susan M. TI Longitudinal progression of Alzheimers-like patterns of atrophy in normal older adults: the SPARE-AD index SO BRAIN LA English DT Article DE early Alzheimers disease; mild cognitive impairment; neuroimaging; ageing; SPARE-AD ID MILD COGNITIVE IMPAIRMENT; MACHINE LEARNING-METHODS; VOXEL-BASED MORPHOMETRY; GRAY-MATTER LOSS; ELASTIC REGISTRATION; MEMORY IMPAIRMENT; SPATIAL-PATTERNS; BRAIN VOLUMES; MR-IMAGES; DISEASE AB A challenge in developing informative neuroimaging biomarkers for early diagnosis of Alzheimers disease is the need to identify biomarkers that are evident before the onset of clinical symptoms, and which have sufficient sensitivity and specificity on an individual patient basis. Recent literature suggests that spatial patterns of brain atrophy discriminate amongst Alzheimers disease, mild cognitive impairment (MCI) and cognitively normal (CN) older adults with high accuracy on an individual basis, thereby offering promise that subtle brain changes can be detected during prodromal Alzheimers disease stages. Here, we investigate whether these spatial patterns of brain atrophy can be detected in CN and MCI individuals and whether they are associated with cognitive decline. Images from the Alzheimers Disease Neuroimaging Initiative (ADNI) were used to construct a pattern classifier that recognizes spatial patterns of brain atrophy which best distinguish Alzheimers disease patients from CN on an individual person basis. This classifier was subsequently applied to longitudinal magnetic resonance imaging scans of CN and MCI participants in the Baltimore Longitudinal Study of Aging (BLSA) neuroimaging study. The degree to which Alzheimers disease-like patterns were present in CN and MCI subjects was evaluated longitudinally in relation to cognitive performance. The oldest BLSA CN individuals showed progressively increasing Alzheimers disease-like patterns of atrophy, and individuals with these patterns had reduced cognitive performance. MCI was associated with steeper longitudinal increases of Alzheimers disease-like patterns of atrophy, which separated them from CN (receiver operating characteristic area under the curve equal to 0.89). Our results suggest that imaging-based spatial patterns of brain atrophy of Alzheimers disease, evaluated with sophisticated pattern analysis and recognition methods, may be useful in discriminating among CN individuals who are likely to be stable versus those who will show cognitive decline. Future prospective studies will elucidate the temporal dynamics of spatial atrophy patterns and the emergence of clinical symptoms. C1 [Davatzikos, Christos; Xu, Feng; Fan, Yong] Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. [An, Yang; Resnick, Susan M.] NIA, Lab Personal & Cognit, Baltimore, MD 21224 USA. RP Davatzikos, C (reprint author), Univ Penn, Dept Radiol, Sect Biomed Image Anal, 3600 Market St,Suite 380, Philadelphia, PA 19104 USA. EM christos@rad.upenn.edu RI Scharre, Douglas/E-4030-2011; OI Fan, Yong/0000-0001-9869-4685 FU Intramural NIH HHS [Z01 AG000191-11]; NIA NIH HHS [N01-AG-3-2124, R01-AG14971, U19 AG010483] NR 54 TC 108 Z9 110 U1 0 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD AUG PY 2009 VL 132 BP 2026 EP 2035 DI 10.1093/brain/awp091 PN 8 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 475BJ UT WOS:000268330500004 PM 19416949 ER PT J AU Tonelli, LH Katz, M Kovacsics, CE Gould, TD Joppy, B Hoshino, A Hoffman, G Komarow, H Postolache, TT AF Tonelli, Leonardo H. Katz, Morgan Kovacsics, Colleen E. Gould, Todd D. Joppy, Belzora Hoshino, Akina Hoffman, Gloria Komarow, Hirsh Postolache, Teodor T. TI Allergic rhinitis induces anxiety-like behavior and altered social interaction in rodents SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Intranasal; Anxiety; Prefrontal cortex; Allergies; Cytokines; CRH; Inflammation; Neuroimmune ID CORTICOTROPIN-RELEASING HORMONE; QUALITY-OF-LIFE; CRH1 RECEPTOR ANTAGONISTS; ELEVATED PLUS-MAZE; ATOPIC DISORDERS; MOOD DISORDERS; MURINE MODEL; AIRWAY INFLAMMATION; DAYTIME SOMNOLENCE; AVOIDANCE-BEHAVIOR AB Epidemiological and clinical studies report higher incidences of anxiety and increased emotional reactivity in individuals suffering from respiratory allergies. To evaluate if respiratory allergies are capable of promoting anxiety-like behavior in rodents, we used models of allergic rhinitis and behavioral evaluations followed by assessment of mRNA for cytokines in relevant brain regions. Mice and rats were sensitized to ovoalbumin or pollen, respectively, following standard sensitization and challenge protocols. After challenge, the animals were evaluated in the open field, elevated plus-maze and resident-intruder tests. Cytokines and corticotropin-releasing factor expression were assessed in several brain regions by real-time RT-PCR and plasma corticosterone concentrations by radioimmunoassay. Mice and rats sensitized and exposed to allergen showed increased anxiety-like behavior and reduced social interaction without any overt behavioral signs of sickness. T-helper type 2 (T(H)2) cytokines were induced in both rats and mice in the olfactory bulbs and prefrontal cortex and remained unchanged in the temporal cortex and hypothalamus. The same results were found for CRF mRNA expression. No differences were observed in corticosterone concentrations 1 h after the last behavioral test. These results show that sensitization and challenge with allergens induce anxiety across rodent species and that these effects were paralleled by an increased expression of T(H)2 cytokines and CRF in the prefrontal cortex. These studies provide experimental evidence that sensitized rodents experience neuroimmune-mediated anxiety and reduced social interaction associated with allergic rhinitis. (C) 2009 Elsevier Inc. All rights reserved. C1 [Tonelli, Leonardo H.; Katz, Morgan; Joppy, Belzora; Hoshino, Akina] Univ Maryland, Lab Behav Neuroimmunol, Mood & Anxiety Program, Dept Psychiat,Sch Med, Baltimore, MD 21201 USA. [Hoffman, Gloria] Univ Maryland, Dept Anat & Neurobiol, Sch Med, Baltimore, MD 21201 USA. [Komarow, Hirsh] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Tonelli, LH (reprint author), Univ Maryland, Lab Behav Neuroimmunol, Mood & Anxiety Program, Dept Psychiat,Sch Med, 685 W Baltimore St,MSTF Bldg,Room 934 C, Baltimore, MD 21201 USA. EM ltonelli@psych.umaryland.edu FU [R21MH075905]; [R21MH075891]; [R01MH074891] FX Supported by Grants R21MH075905, R21MH075891 and R01MH074891. The authors wish to thanks Dr. James I. Koenig, PhD for his help with the corticosterone determinations. NR 75 TC 26 Z9 29 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD AUG PY 2009 VL 23 IS 6 BP 784 EP 793 DI 10.1016/j.bbi.2009.02.017 PG 10 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 474SR UT WOS:000268304800010 PM 19268702 ER PT J AU Dignam, JJ Dukic, V Anderson, SJ Mamounas, EP Wickerham, DL Wolmark, N AF Dignam, James J. Dukic, Vanja Anderson, Stewart J. Mamounas, Eleftherios P. Wickerham, D. Lawrence Wolmark, Norman TI Hazard of recurrence and adjuvant treatment effects over time in lymph node-negative breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Lymph node-negative; Estrogen receptor; Systemic adjuvant therapy; Hazard; Prognosis ID RECEPTOR-POSITIVE TUMORS; CLINICAL-TRIALS; SEQUENTIAL METHOTREXATE; REGRESSION-MODELS; UPDATED FINDINGS; TAMOXIFEN; CHEMOTHERAPY; THERAPY; WOMEN; FLUOROURACIL AB Background For patients with axillary lymph node-negative breast cancer, benefits from adjuvant therapy are smaller than in node-positive disease and thus more selective use is warranted, prompting development of risk profiling to identify those most likely to benefit. Examination of the magnitude and changes in the hazard of failure over time in node-negative breast cancer may also be informative in this regard. Methods Among 9,444 participants from five randomized trials (accrual 1982-1998) investigating chemotherapy and tamoxifen for node-negative breast cancer, we estimated recurrence hazards over time by tumor estrogen receptor (ER) status and adjuvant treatment. Results In patients treated by surgery only, we observed the previously noted larger hazard peak followed by a rapid decrease in ER-negative patients and smaller but more persistent hazard in ER-positive patients. After approximately 48 months, the ER-positive hazard is greater. For adjuvant treatment, while tamoxifen decreases the early hazard in ER-positive patients to that of the chemotherapy-treated ER-negative group, in later follow-up (beyond 5 years) the hazard for ER-positive patients again exceeds that of ER-negative patients. Adding chemotherapy to tamoxifen in ER-positive patients results in large early hazard reduction, but in later follow-up the hazard converges with those of patients treated by surgery only or tamoxifen. Conclusions Recurrence hazards over time reveal changes in risk that may have biologic and therapeutic strategy relevance. In ER-negative tumors, a large early chemotherapy benefit is followed by a consistently low recurrence hazard over time. In ER-positive patients, the chemotherapy benefit appears concentrated mostly in earlier follow-up, and a greater recurrence risk remains. C1 [Dignam, James J.; Dukic, Vanja] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Dignam, James J.; Anderson, Stewart J.] Ctr Biostat, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Anderson, Stewart J.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Mamounas, Eleftherios P.; Wickerham, D. Lawrence; Wolmark, Norman] NSABP Operat Ctr, Pittsburgh, PA USA. [Mamounas, Eleftherios P.] Altman Canc Ctr, Canton, OH USA. RP Dignam, JJ (reprint author), Univ Chicago, Dept Hlth Studies, 5841 S Maryland Ave,MC 2007, Chicago, IL 60637 USA. EM jdignam@health.bsd.uchicago.edu OI Anderson, Stewart/0000-0001-8948-0650; Dukic, Vanja/0000-0002-0348-0834 FU Cure Foundation; US National Cancer Institute [NCI-U10-CA-12027, NCI-U10-CA-69651, NCI-U10-CA-69974, NCI P30-CA-14599] FX Supported by a grant from the Susan G. Komen for the Cure Foundation (JJD, VMD) and Public Health Service grants NCI-U10-CA-12027, NCI-U10-CA-69651, NCI-U10-CA69974, NCI-U10-CA-12027, and NCI P30-CA-14599 from the US National Cancer Institute. NR 45 TC 50 Z9 52 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD AUG PY 2009 VL 116 IS 3 BP 595 EP 602 DI 10.1007/s10549-008-0200-5 PG 8 WC Oncology SC Oncology GA 471KA UT WOS:000268055100021 PM 18830816 ER PT J AU Mazereeuw-Hautier, J Aufenvenne, K Deraison, C Ahvazi, B Oji, V Traupe, H Hovnanian, A AF Mazereeuw-Hautier, J. Aufenvenne, K. Deraison, C. Ahvazi, B. Oji, V. Traupe, H. Hovnanian, A. TI Acral self-healing collodion baby: report of a new clinical phenotype caused by a novel TGM1 mutation SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article DE ichthyosis; self-healing collodion baby; transglutaminase-1 ID RECESSIVE CONGENITAL ICHTHYOSIS; BATHING SUIT ICHTHYOSIS; LAMELLAR ICHTHYOSIS; KERATINOCYTE TRANSGLUTAMINASE; HARLEQUIN ICHTHYOSIS; PROTEIN MODELS; GENE; ERYTHRODERMA; ALOX12B; ABCA12 AB A minority of collodion babies, called 'self-healing collodion babies', heal spontaneously. We describe a novel clinical phenotype of acral self-healing collodion baby caused by a new TGM1 mutation. The proband, born to healthy parents, presented at birth as a collodion baby strictly localized to the extremities. The skin condition returned to normal at the age of 3 weeks. The older sister was born as a generalized collodion baby; the condition then developed into lamellar ichthyosis. Molecular analysis of TGM1 revealed three novel mutations in the family. The proband was compound heterozygous for the p.Val359Met and p.Arg396His mutations, whereas the older sister was compound heterozygous for p.Arg396His and a deletion mutation c.1922_1926+2delGGCCTGT. Structural modelling of the p.Val359Met mutation suggested a minor disruption of the protein structure, whereas a modification of protein-protein interaction was predicted for p.Arg396His. These predictions corroborated the analysis of recombinant transglutaminase (TGase)-1 proteins carrying the p.Val359Met and p.Arg396His mutations. Both showed decreased levels of protein expression: p.Val359Met displayed residual activity (12 center dot 8%), while p.Arg396His caused a dramatic loss of activity (3 center dot 3%). These observations demonstrate for the first time that TGM1 mutations can be associated with acral self-healing collodion baby, and expand the clinical spectrum of TGase-1 deficiency. C1 [Mazereeuw-Hautier, J.] CHU Purpan, Dept Dermatol, F-31024 Toulouse, France. [Mazereeuw-Hautier, J.; Deraison, C.; Hovnanian, A.] CHU Purpan, Reference Ctr Rare Skin Dis, F-31024 Toulouse, France. [Hovnanian, A.] CHU Purpan, Dept Genet, F-31024 Toulouse, France. [Aufenvenne, K.; Oji, V.; Traupe, H.] Univ Munster, Dept Dermatol, D-48149 Munster, Germany. [Hovnanian, A.] INSERM, U563, F-31300 Toulouse, France. [Ahvazi, B.] NIAMSD, Xray Crystallog Facil, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. RP Mazereeuw-Hautier, J (reprint author), CHU Purpan, Dept Dermatol, F-31024 Toulouse, France. EM mazereeuw-hautier.j@chu-toulouse.fr OI Oji, Vinzenz/0000-0003-1380-4828 FU French Ministry of Health FX We thank Ms Anne-Marie Mazarguil, Ms Tatjana Walker, Laetitia Lacaze-Buzy and Alexandra Millet for their technical assistance in this work. C.D. and Laetitia Lacaze-Buzy are funded by the French Ministry of Health (Reference Centre for Rare Skin Diseases). The work of K.A., V.O. and H.T. is supported by grants from Selbsthilfe Ichthyose e.V. and by the Bundesministerium fur Bildung und Forschung as part of the Network for Rare Diseases NIRK. NR 26 TC 8 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-0963 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD AUG PY 2009 VL 161 IS 2 BP 456 EP 463 DI 10.1111/j.1365-2133.2009.09277.x PG 8 WC Dermatology SC Dermatology GA 473NV UT WOS:000268215100034 PM 19500103 ER PT J AU Liang, XY Caporaso, N McMaster, ML Ng, D Landgren, O Yeager, M Chanock, S Goldin, LR AF Liang, Xueying (Sharon) Caporaso, Neil McMaster, Mary Lou Ng, David Landgren, Ola Yeager, Meredith Chanock, Stephen Goldin, Lynn R. TI Common genetic variants in candidate genes and risk of familial lymphoid malignancies SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE candidate genes; association; familial; lymphoid malignancies; chronic lymphocytic leukaemia ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; FALSE DISCOVERY RATE; WALDENSTROM MACROGLOBULINEMIA; SUSCEPTIBILITY LOCI; MULTIPLE-MYELOMA; LYMPHOPROLIFERATIVE TUMORS; ASSOCIATION; GENOMEWIDE; THERAPY AB P>Familial aggregation, linkage and case-control studies support the role of germline genes in the aetiology of lymphoid malignancies. To further examine the role of genetic variation underlying susceptibility, we analysed 1536 single nucleotide polymorphisms in 152 genes involved in apoptosis, DNA repair, immune response and oxidative stress pathways among a unique sample of 165 unrelated familial cases including patients with chronic lymphocytic leukaemia (CLL), Waldenstrom macroglobulinaemia (WM) and Hodgkin lymphoma (HL), and 107 spouse controls. We confirmed previous studies showing a polymorphism in the IL10 promoter (rs1800890/-3575T > A) to be associated with non-Hodgkin lymphoma, as this allele was found to be associated with both CLL and WM. We also confirmed the role of IL6 variation to be associated with HL. Polymorphisms in TNFSF10 were associated with both CLL and WM. Future replication and functional studies are needed to clarify the role of these genetic variants. Finally, our data further support the close association of WM and CLL. C1 [Liang, Xueying (Sharon); Caporaso, Neil; McMaster, Mary Lou; Ng, David; Goldin, Lynn R.] NCI, NIH, Genet Epidemiol Branch, Div Canc Epidemiol & Genet,DCEG, Bethesda, MD 20892 USA. [Landgren, Ola] NCI, NIH, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. [Yeager, Meredith; Chanock, Stephen] NCI, NIH, DCEG, Core Genotyping Facil, Bethesda, MD 20892 USA. RP Liang, XY (reprint author), NCI, NIH, Genet Epidemiol Branch, Div Canc Epidemiol & Genet,DCEG, 6120 Execut Blvd,EPS-7007, Bethesda, MD 20892 USA. EM liangx2@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The authors have no conflict of interest to declare. NR 42 TC 24 Z9 26 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD AUG PY 2009 VL 146 IS 4 BP 418 EP 423 DI 10.1111/j.1365-2141.2009.07790.x PG 6 WC Hematology SC Hematology GA 476QP UT WOS:000268457900009 PM 19573080 ER PT J AU Ray, GL Baidoo, KE Wong, KJ Williams, M Garmestani, K Brechbiel, MW Milenic, DE AF Ray, G. L. Baidoo, K. E. Wong, K. J. Williams, M. Garmestani, K. Brechbiel, M. W. Milenic, D. E. TI Preclinical evaluation of a monoclonal antibody targeting the epidermal growth factor receptor as a radioimmunodiagnostic and radioimmunotherapeutic agent SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE panitumumab; radioimmunodiagnosis; radioimmunotherapy; EGFR; preclinical evaluation; In-111 ID COLORECTAL-CANCER; CARCINOMA XENOGRAFTS; PANITUMUMAB; CETUXIMAB; CHEMOTHERAPY; THERAPY; BINDING; CELLS; CC49 AB Background and purpose: The studies described here are the first to evaluate the in vitro and in vivo properties of In-111-CHX-A '-panitumumab for radioimmunotherapy (alpha- and beta(-)-emitters) and radioimmunoimaging (single photon emission computed tomography and positron emission tomography). Experimental approach: Twenty-seven human carcinoma cell lines were analysed for expression of epidermal growth factor receptors by flow cytometry. Panitumumab was conjugated with CHX-A '-DTPA (diethylenetriamine-pentaacetic acid) and radiolabelled with In-111. Immunoreactivity of the CHX-A '-DTPA-panitumumab and In-111-CHX-A '-DTPA-panitumumab was evaluated by radioimmunoassays. Tumour targeting was determined in vivo by direct quantitation of tumour and normal tissues and by gamma-scintigraphy. Key results: For 26 of 27 human tumour cell lines, 95% of the cells expressed epidermal growth factor receptors over a range of intensity. Immunoreactivity of panitumumab was retained after modification with CHX-A '-DTPA. Radiolabelling of the immunoconjugate with In-111 was efficient with a specific activity of 19.5 +/- 8.9 mCi center dot mg(-1) obtained. Immunoreactivity and specificity of binding of the In-111-panitumumab was shown with A431 cells. Tumour targeting by In-111-panitumumab was demonstrated in athymic mice bearing A431, HT-29, LS-174T, SHAW or SKOV-3 s.c. xenografts with little uptake observed in normal tissues. The In-111-panitumumab was also evaluated in non-tumour-bearing mice. Pharmacokinetic studies compared the plasma retention time of the In-111-panitumumab in both non-tumour-bearing and A431 tumour-bearing mice. Tumour targeting was also visualized by gamma-scintigraphy. Conclusions and implications: Panitumumab can be efficiently radiolabelled with In-111 with high labelling yields. Based on the efficiency in tumour targeting and low normal tissue uptake, panitumumab may be an effective targeting component for radioimmunodiagnostic and radioimmunotherapeutic applications. C1 [Ray, G. L.; Baidoo, K. E.; Garmestani, K.; Brechbiel, M. W.; Milenic, D. E.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Reseach,NIH, Bethesda, MD 20892 USA. [Wong, K. J.; Williams, M.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Milenic, DE (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Reseach,NIH, 10 Ctr Dr,MSC 1088,Bldg 10,Room 1B40, Bethesda, MD 20892 USA. EM dm71q@nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 34 TC 17 Z9 19 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD AUG PY 2009 VL 157 IS 8 BP 1541 EP 1548 DI 10.1111/j.1476-5381.2009.00327.x PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 477PN UT WOS:000268531100024 PM 19681874 ER PT J AU Craddock, N Kerdler, K Neale, M Nurnberger, J Purcell, S Rietschel, M Perlis, R Santangelo, SL Schulze, T Smoller, JW Thapar, A AF Craddock, Nick Kerdler, Kenneth Neale, Michael Nurnberger, John Purcell, Shaun Rietschel, Marcella Perlis, Roy Santangelo, Susan L. Schulze, Thomas Smoller, Jordan W. Thapar, Anita CA Psychiat GWAS Consortium TI Dissecting the phenotype in genome-wide association studies of psychiatric illness SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID GENETICS; DISEASE; FRAMEWORK; INSIGHTS; LOCI AB Over the past 2 years genome-wide association studies have made major contributions to understanding the genetic architecture of many common human diseases. This editorial outlines the development of such studies in psychiatry and highlights the opportunities for advancing understanding of the biological underpinnings and nosological structure of psychiatric disorders. C1 [Craddock, Nick; Thapar, Anita] Cardiff Univ, Sch Med, Dept Psychol Med, Cardiff CF14 4XN, S Glam, Wales. [Kerdler, Kenneth; Neale, Michael] Virginia Commonwealth Univ, Med Coll Virginia, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23298 USA. [Kerdler, Kenneth; Neale, Michael] Virginia Commonwealth Univ, Med Coll Virginia, Dept Psychiat, Richmond, VA 23298 USA. [Kerdler, Kenneth; Neale, Michael] Virginia Commonwealth Univ, Med Coll Virginia, Dept Human & Mol Genet, Richmond, VA 23298 USA. [Nurnberger, John] Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Purcell, Shaun; Perlis, Roy; Santangelo, Susan L.; Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Purcell, Shaun] Harvard & Massachusetts Inst Technol, Broad Inst, Cambridge, MA USA. [Rietschel, Marcella; Schulze, Thomas] Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-6800 Mannheim, Germany. [Perlis, Roy] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. [Santangelo, Susan L.; Smoller, Jordan W.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Santangelo, Susan L.; Smoller, Jordan W.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Schulze, Thomas] NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, DHHS, Bethesda, MD 20892 USA. RP Craddock, N (reprint author), Cardiff Univ, Sch Med, Dept Psychol Med & Neurol, Heath Pk, Cardiff CF14 4XN, S Glam, Wales. EM craddockn@cardiff.ac.uk OI Nurnberger, John/0000-0002-7674-1767; Thapar, Anita/0000-0002-3689-737X NR 19 TC 37 Z9 37 U1 0 U2 4 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD AUG PY 2009 VL 195 IS 2 BP 97 EP 99 DI 10.1192/bjp.bp.108.063156 PG 3 WC Psychiatry SC Psychiatry GA 479WF UT WOS:000268691700001 ER PT J AU Lencz, T Lipsky, RH DeRosse, P Burdick, KE Goldman, D Hodgkinson, C Kane, JM Malhotra, AK AF Lencz, Todd Lipsky, Robert H. DeRosse, Pamela Burdick, Katherine E. Goldman, David Hodgkinson, Colin Kane, John M. Malhotra, Anil K. TI BDNF Val66met polymorphism and the affective component Reply SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Letter ID SCHIZOPHRENIA; ASSOCIATION C1 [Lencz, Todd] Zucker Hillside Hosp, Glen Oaks, NY 11004 USA. [Lipsky, Robert H.] NIAAA, Neurogenet Lab, Bethesda, MD USA. [DeRosse, Pamela] Zucker Hillside Hosp, Div Psychiat Res, New York, NY USA. [Burdick, Katherine E.; Kane, John M.; Malhotra, Anil K.] Feinstein Inst Med Res, Ctr Translat Psychiat, New York, NY USA. [Burdick, Katherine E.; Malhotra, Anil K.] Zucker Hillside Hosp, Div Psychiat Res, New York, NY USA. [Goldman, David; Hodgkinson, Colin] NIAAA, Sect Human Neurogenet, Rockville, MD 20852 USA. [Kane, John M.] Zucker Hillside Hosp, Dept Psychiat, New York, NY USA. RP Lencz, T (reprint author), Zucker Hillside Hosp, 75-59 263rd St, Glen Oaks, NY 11004 USA. EM lencz@lij.edu RI Hodgkinson, Colin/F-9899-2010; Goldman, David/F-9772-2010; Lencz, Todd/J-3418-2014 OI Goldman, David/0000-0002-1724-5405; Lencz, Todd/0000-0001-8586-338X NR 5 TC 0 Z9 0 U1 0 U2 0 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD AUG PY 2009 VL 195 IS 2 BP 179 EP 180 DI 10.1192/bjp.195.2.179a PG 2 WC Psychiatry SC Psychiatry GA 479WF UT WOS:000268691700017 ER PT J AU John, S Yeh, S Lew, JC Nussenblatt, RA AF John, Sheeja Yeh, Steven Lew, Julie C. Nussenblatt, Robert A. TI Protean manifestations of pediatric neurosarcoidosis SO CANADIAN JOURNAL OF OPHTHALMOLOGY-JOURNAL CANADIEN D OPHTALMOLOGIE LA English DT Letter ID SARCOIDOSIS C1 [John, Sheeja; Yeh, Steven; Lew, Julie C.; Nussenblatt, Robert A.] NEI, NIH, Bethesda, MD 20892 USA. RP Nussenblatt, RA (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM DrBob@nei.nih.gov FU Intramural NIH HHS NR 4 TC 5 Z9 5 U1 0 U2 0 PU CANADIAN OPHTHAL SOC PI OTTAWA PA 1525 CARLING AVE SUITE 610, OTTAWA, ONTARIO K1Z 8R9, CANADA SN 0008-4182 J9 CAN J OPHTHALMOL JI Can. J. Opthalmol.-J. Can. Opthalmol. PD AUG PY 2009 VL 44 IS 4 BP 469 EP 470 DI 10.3129/i09-143 PG 2 WC Ophthalmology SC Ophthalmology GA 488OU UT WOS:000269360100027 PM 19606180 ER PT J AU Higgins, JP Bernstein, MB Hodge, JW AF Higgins, Jack P. Bernstein, Michael B. Hodge, James W. TI Enhancing immune responses to tumor-associated antigens SO CANCER BIOLOGY & THERAPY LA English DT Review DE tumor-associated antigen; immunotherapy; vaccine; costimulation ID REGULATORY T-CELLS; INTENSITY FOCUSED ULTRASOUND; COLONY-STIMULATING FACTOR; RECOMBINANT INTERLEUKIN-2 THERAPY; RADIOFREQUENCY THERMAL ABLATION; REFRACTORY PROSTATE-CANCER; RANDOMIZED PHASE-II; METASTATIC MELANOMA; GM-CSF; DENDRITIC CELLS AB The goal of vaccine-based cancer immunotherapy is to induce a tumor-specific immune response that ultimately reduces tumor burden. However, the immune system is often tolerant to antigens presented by the tumor, as the cancer originates from within a patient and is therefore recognized as self. This article reviews selected clinical strategies for overcoming this immune tolerance, and approaches to enhance generation of immunity to tumor-associated antigens by activating innate immunity, potentiating adaptive immunity, reducing immunosuppression, and enhancing tumor immunogenicity. Success in the field of cancer vaccines has yet to be fully realized, but intelligent choice of immunomodulators, tumor antigens and patient populations will likely lead to clinically relevant uses for cancer vaccines. C1 [Higgins, Jack P.; Bernstein, Michael B.; Hodge, James W.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hodge, JW (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B13,MSC 1750, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 138 TC 20 Z9 21 U1 0 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4047 EI 1555-8576 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG 1 PY 2009 VL 8 IS 15 BP 1440 EP 1449 DI 10.4161/cbt.8.15.9133 PG 10 WC Oncology SC Oncology GA 486TM UT WOS:000269221100002 PM 19556848 ER PT J AU Doubeni, CA Laiyemo, AO Reed, G Field, TS Fletchers, RH AF Doubeni, Chyke A. Laiyemo, Adeyinka O. Reed, George Field, Terry S. Fletchers, Robert H. TI Socioeconomic and Racial Patterns of Colorectal Cancer Screening among Medicare Enrollees in 2000 to 2005 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SERVICES TASK-FORCE; FECAL OCCULT-BLOOD; UNITED-STATES; COST-EFFECTIVENESS; HEALTH-INSURANCE; CARE; POPULATION; COLONOSCOPY; DISPARITIES; VISITS AB Background: Lower rates of screening among minorities and low-income populations contribute to colorectal cancer health disparities. Therefore, we examined patterns of colorectal cancer screening and associations with race-ethnicity, education, and income over time. Methods: Repeated cross-sectional data from the Medicare Current Beneficiary Survey of noninstitutionalized colorectal cancer-free Medicare enrollees ages 65 to 80 years interviewed in 2000 (n = 8,355), 2003 (n = 7,922), and 2005 (n = 7,646). We examined rates of colonoscopy/sigmoidoscopy use within 5 years (recent endoscopy), colonoscopy/sigmoidoscopy use >5 years previously, or fecal occult blood test (FOBT) within 2 years. Results: Among those included in the analyses, there was a steady increase in recent endoscopy rates and decrease in FOBT use over the 6-year period among all racial, educational, and income groups. During each of the survey years, those less educated or in lower-income groups were less likely to undergo colorectal cancer screening in a dose-response fashion. In multinomial regression analyses that adjusted for factors including health insurance, there were no significant differences in recent endoscopy or FOBT rates between Blacks or Hispanics and Whites, but differences by education and income remained. Compared with those in higher-income group, lower-income enrollees had lower rates of screening, and differences by income were larger for enrollees residing in metropolitan areas. Conclusion: Among Medicare beneficiaries, there are persistent colorectal cancer screening disparities due to a complex combination of socioeconomic disadvantages from lower education and income, place of residence, and inadequate insurance. However, insurance alone does not eliminate socioeconomic differences in colorectal cancer screening. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2170-5) C1 [Doubeni, Chyke A.] Univ Massachusetts, Sch Med, Dept Family Med & Community Hlth, Worcester, MA 01655 USA. [Reed, George] Univ Massachusetts, Sch Med, Dept Med, Div Prevent & Behav Med, Worcester, MA 01655 USA. [Doubeni, Chyke A.; Field, Terry S.] Univ Massachusetts, Sch Med, Meyers Primary Care Inst, Worcester, MA USA. [Doubeni, Chyke A.; Field, Terry S.] Fallon Clin Fdn, Worcester, MA USA. [Doubeni, Chyke A.; Field, Terry S.] Fallon Community Hlth Plan, Worcester, MA USA. [Laiyemo, Adeyinka O.] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Laiyemo, Adeyinka O.] NCI, Biometry Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Fletchers, Robert H.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Fletchers, Robert H.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA 02115 USA. RP Doubeni, CA (reprint author), Univ Massachusetts, Sch Med, Dept Family Med & Community Hlth, 55 Lake Ave N, Worcester, MA 01655 USA. EM Chyke.Doubeni@umassmed.edu OI Doubeni, Chyke/0000-0001-7495-0285 FU National Cancer Institute [5K01CA127118-02] FX Grant support: National Cancer Institute career development award 5K01CA127118-02 (C.A. Doubeni). NR 40 TC 61 Z9 61 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2009 VL 18 IS 8 BP 2170 EP 2175 DI 10.1158/1055-9965.EPI-09-0104 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 483IW UT WOS:000268958600003 PM 19622721 ER PT J AU Ma, HY Wang, YP Sullivan-Halley, J Weiss, L Burkman, RT Simon, MS Malone, KE Strom, BL Ursin, G Marchbanks, PA McDonald, JA Spirtas, R Press, MF Bernstein, L AF Ma, Huiyan Wang, Yaping Sullivan-Halley, Jane Weiss, Linda Burkman, Ronald T. Simon, Michael S. Malone, Kathleen E. Strom, Brian L. Ursin, Giske Marchbanks, Polly A. McDonald, Jill A. Spirtas, Robert Press, Michael F. Bernstein, Leslie TI Breast Cancer Receptor Status: Do Results from a Centralized Pathology Laboratory Agree with SEER Registry Reports? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PROGESTERONE-RECEPTOR; ESTROGEN-RECEPTOR; HORMONE-RECEPTOR; RISK-FACTORS; MONOCLONAL-ANTIBODIES; WOMEN; AGE; IMMUNOHISTOCHEMISTRY; LOCALIZATION; ESTROPHILIN AB We investigated the extent to which estrogen receptor (ER) and progesterone receptor (PR) status results from a centralized pathology laboratory agree with ER and PR results from community pathology laboratories reported to two Surveillance, Epidemiology and End Results (SEER) registries (Los Angeles County and Detroit) and whether statistical estimates for the association between reproductive factors and breast cancer receptor subtypes differ by the source of data. The agreement between the centralized laboratory and SEER registry classifications was substantial for ER (kappa = 0.70) and nearly so for PR status (kappa = 0.60). Among the four subtypes defined by joint ER and PR status, the agreement between the two sources was substantial for the two major breast cancer subtypes (ER-/PR-, kappa = 0.69; ER+/PR+, kappa = 0.62) and poor for the two rarer subtypes (ER+/PR-, kappa = 0.30; ER-/PR+, kappa = 0.05). Estimates for the association between reproductive factors (number of full-term pregnancies, age at first full-term pregnancy, and duration of breastfeeding) and the two major subtypes (ER+/PR+ and ER-/PR-) differed minimally between the two sources of data. For example, parous women with at least four full-term pregnancies had 40% lower risk for ER+/PR+ breast cancer than women who had never been pregnant [centralized laboratory, odds ratio, 0.60 (95% confidence interval, 0.39-0.92); SEER, odds ratio, 0.57 (95% confidence interval, 0.38-0.85)]; no association was observed for ER-/PR- breast cancer (both P(trend) > 0.30). Our results suggest that conclusions based on SEER registry data are reasonably reliable for ER+/PR+ and ER-/PR- subtypes. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2214-20) C1 [Ma, Huiyan; Sullivan-Halley, Jane; Bernstein, Leslie] City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, Duarte, CA 91010 USA. [Wang, Yaping; Bernstein, Leslie] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Press, Michael F.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Marchbanks, Polly A.; McDonald, Jill A.] Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. [Burkman, Ronald T.] Baystate Med Ctr, Dept Obstet & Gynecol, Springfield, MA USA. [Simon, Michael S.] Wayne State Univ, Karmanos Canc Inst, Div Hematol Oncol, Detroit, MI USA. [Malone, Kathleen E.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Strom, Brian L.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Ursin, Giske] Univ Oslo, Dept Nutr, Oslo, Norway. [Weiss, Linda] NCI, Canc Ctr Branch, Bethesda, MD 20892 USA. [Spirtas, Robert] NICHD, Contracept & Reprod Hlth Branch, Populat Res Ctr, Bethesda, MD USA. RP Bernstein, L (reprint author), City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM LBernstein@coh.org FU National Institute for Child Health and Human Development [NO1-HD-3-3175]; National Cancer Institute [CA48780]; Emory University [N01-HD-3-3168]; Fred Hutchinson Cancer Research Center [N01-HD-2-3166]; Karmanos Cancer Institute at Wayne State University [N01-HD-3-3174]; University of Pennsylvania [NO1-HD-3-3276]; University of Southern California [N01-HD-3-3175]; Centers for Disease Control and Prevention [Y01-HD-7022]; California Department of Health Services [103885]; [N01-PC-67006]; [N01-CN-65064]; [N01-PC-67010]; [N01-CN-0532] FX Grant support: Contract from the National Institute for Child Health and Human Development (NO1-HD-3-3175) and a grant from the National Cancer Institute (CA48780); data collection for the Women's Contraceptive and Reproductive Experiences study supported by National Institute of Child Health and Human Development and National Cancer Institute, NIH, through contracts with Emory University (N01-HD-3-3168), Fred Hutchinson Cancer Research Center (N01-HD-2-3166), Karmanos Cancer Institute at Wayne State University (N01-HD-3-3174), University of Pennsylvania (NO1-HD-3-3276), and University of Southern California (N01-HD-3-3175), and interagency agreement with Centers for Disease Control and Prevention (Y01-HD-7022); collection of cancer incidence data in Los Angeles County by University of Southern California supported by California Department of Health Services as part of statewide cancer reporting program mandated by California Health and Safety Code, Section 103885; and support for the use of Surveillance, Epidemiology, and End Results cancer registries through contracts N01-PC-67006 (Atlanta), N01-CN-65064 (Detroit), N01-PC-67010 (Los Angeles), and N01-CN-0532 (Seattle). NR 36 TC 31 Z9 31 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2009 VL 18 IS 8 BP 2214 EP 2220 DI 10.1158/1055-9965.EPI-09-0301 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 483IW UT WOS:000268958600011 PM 19661080 ER PT J AU Grimley, PM Matsuno, RK Rosenberg, PS Henson, DE Schwartz, AM Anderson, WF AF Grimley, Philip M. Matsuno, Rayna K. Rosenberg, Philip S. Henson, Donald E. Schwartz, Arnold M. Anderson, William F. TI Qualitative Age Interactions between Low-grade and High-grade Serous Ovarian Carcinomas SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-for-Investigative-Pathology CY APR 07, 2008 CL San Diego, CA SP Amer Soc Investigat Pathol ID BREAST-CANCER INCIDENCE; EARLY-STAGE; NEW-MODEL; PATHOGENESIS; MUTATIONS; P53; CARCINOGENESIS; HETEROGENEITY; EXPRESSION; PATHWAYS AB Purpose: Ovarian epithelial carcinomas, including the predominant serous ovarian carcinoma (SOC) type, are heterogeneous malignancies. Even though invasive SOCs of low and high grade can be distinguished by morphology and molecular or immunohistochemical profiles, age-specific risks relevant to their separate carcinogenic pathways and clinical features have not been fully explored. Methods: In search of further clues to the etiology/pathogenesis of low-grade and high-grade SOCs, we analyzed incidence rate patterns. Case and age-adjusted population data were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for years 1990 through 2005. Descriptive epidemiology for n = 19,899 cases was supplemented with age-period-cohort models fitted by grade. Results: SOC age-adjusted incidence rate ratios (IRR) of high to low grade (IRR(H/L)) were <1.0 before age 40, and >1.0 thereafter. Accordingly, SOC age-specific incidence rates were also greater for low grade before age 40 years, and then greater for high grade. The reversals of IRR(H/L), with crossings of the age-specific incidence rate near age 40 years occurred irrespective of early or late SOC stage. These results were reproducible and reliable in age-period-cohort models that were adjusted for period and cohort effects (P approximate to 0 for age interactions by grade). Conclusions: Robust qualitative age interactions between low-grade and high-grade SOC showed that grade is an age-specific effect modifier in these malignancies. With increasing research interest in identifying the genomic determinants of SOC risk, therapeutic response, and outcome, future analytic studies and clinical trials should be powered to account for age-dependent grade interactions. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2256-61) C1 [Grimley, Philip M.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Pathol, Bethesda, MD 20814 USA. [Grimley, Philip M.] Uniformed Serv Univ Hlth Sci, US Mil Canc Inst, Bethesda, MD 20814 USA. [Matsuno, Rayna K.; Rosenberg, Philip S.; Anderson, William F.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Matsuno, Rayna K.] Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Grad Program, Baltimore, MD USA. [Henson, Donald E.] George Washington Univ, Inst Canc, Off Canc Prevent & Control, Washington, DC USA. [Schwartz, Arnold M.] George Washington Univ, Sch Med, Dept Pathol, Washington, DC USA. RP Grimley, PM (reprint author), Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Pathol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM pgrimley@usuhs.mil FU Intramural NIH HHS NR 44 TC 14 Z9 15 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2009 VL 18 IS 8 BP 2256 EP 2261 DI 10.1158/1055-9965.EPI-09-0240 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 483IW UT WOS:000268958600017 PM 19622723 ER PT J AU Black, A Grubb, RL Andriole, GL AF Black, Amanda Grubb, Robert L., III Andriole, Gerald L., Jr. TI Hemodilution of Prostate-Specific Antigen Levels Among Obese Men Response SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Letter C1 [Black, Amanda] NCI, Early Detect Res Grp, Bethesda, MD 20892 USA. [Grubb, Robert L., III; Andriole, Gerald L., Jr.] Washington Univ, Sch Med, Div Urol, St Louis, MO USA. RP Black, A (reprint author), NCI, Early Detect Res Grp, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2009 VL 18 IS 8 BP 2343 EP 2344 DI 10.1158/1055-9965.EPI-09-0625 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 483IW UT WOS:000268958600033 ER PT J AU Grade, M Gaedcke, J Wangsa, D Varma, S Beckmann, J Liersch, T Hess, C Becker, H Difilippantonio, MJ Ried, T Ghadimi, BM AF Grade, Marian Gaedcke, Jochen Wangsa, Danny Varma, Sudhir Beckmann, Jaje Liersch, Torsten Hess, Clemens Becker, Heinz Difilippantonio, Michael J. Ried, Thomas Ghadimi, B. Michael TI Chromosomal copy number changes of locally advanced rectal cancers treated with preoperative chemoradiotherapy SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; CELL NUCLEAR ANTIGEN; PHASE-II TRIAL; THYMIDYLATE-SYNTHASE; TUMOR-REGRESSION; COLORECTAL-CANCER; DIHYDROPYRIMIDINE-DEHYDROGENASE; NEOADJUVANT CHEMORADIOTHERAPY; CONCURRENT CHEMORADIOTHERAPY; HISTOPATHOLOGIC RESPONSE AB Standard treatment of rectal cancer patients comprises preoperative chemoradiotherapy followed by radical surgery. However, clinicians are faced with the problem that response rates vary from one individual to another. Predictive biomarkers would therefore be helpful. To identify genomic imbalances that might assist in stratifying tumors into responsive or nonresponsive categories, we used metaphase comparative genomic hybridization to prospectively analyze pretherapeutic biopsies from 42 patients with locally advanced rectal cancers. These patients were subsequently treated with 5-fluorouracil-based preoperative chemoradiotherapy. Based on downsizing of the T-category, 21 rectal cancers were later classified as responsive, while the other 21 were nonresponsive. Comparing these two groups, we could show that gains of chromosomal regions 7q32 similar to q36 and 7q11 similar to q31, as well as amplifications of 20q11 similar to q13, were significantly associated with responsiveness to preoperative chemoradiotherapy (P < 0.05). However, the probability of detecting these copy number changes by chance is high (P = 0.21). Our primary results suggest that pretherapeutic evaluation of chromosomal copy number changes may be of value for response prediction of rectal cancers to preoperative chemoradiotherapy. This will require validation in a larger cohort of patients. (C) 2009 Elsevier Inc. All rights reserved. C1 [Grade, Marian; Wangsa, Danny; Difilippantonio, Michael J.; Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Grade, Marian; Gaedcke, Jochen; Beckmann, Jaje; Liersch, Torsten; Becker, Heinz; Ghadimi, B. Michael] Univ Gottingen, Dept Gen & Visceral Surg, Univ Med, D-37075 Gottingen, Germany. [Varma, Sudhir] NCI, Biometr Res Branch, NIH, Rockville, MD 20852 USA. [Hess, Clemens] Univ Gottingen, Dept Radiat Oncol & Radiotherapy, Univ Med, D-37075 Gottingen, Germany. RP Ried, T (reprint author), NCI, Genet Branch, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM riedt@mail.nih.gov; mghadim@uni-goettingen.de RI Varma, Sudhir/N-8763-2014 OI Varma, Sudhir/0000-0002-4096-4782 FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; Deutsche Forschungsgerneinschaft [KFO 179] FX The authors thank Ms. Jessica Eggert for excellent technical assistance, Buddy Chen for help with the illustrations, Joseph Cheng for IT-support, and Drs. Laszlo FUzesi and Hilka Rothe for pathology reports. This manuscript is part of the doctoral thesis of J.B. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the Deutsche Forschungsgerneinschaft (KFO 179). NR 43 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD AUG PY 2009 VL 193 IS 1 BP 19 EP 28 DI 10.1016/j.cancergencyto.2009.03.016 PG 10 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 482XC UT WOS:000268922900003 PM 19602460 ER PT J AU Booth, NL Sayers, TJ Brooks, AD Thomas, CL Jacobsen, K Goncharova, EI McMahon, JB Henrich, CJ AF Booth, Nancy Lynn Sayers, Thomas J. Brooks, Alan D. Thomas, Cheryl L. Jacobsen, Kristen Goncharova, Ekaterina I. McMahon, James B. Henrich, Curtis J. TI A cell-based high-throughput screen to identify synergistic TRAIL sensitizers SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE High-throughput screening; TRAIL sensitizer; Synergistic chemotherapy; Caspase-8 cleavage and activation; Natural products ID APOPTOSIS-INDUCING LIGAND; MALIGNANT GLIOMA-CELLS; PROSTATE-CANCER CELLS; RESISTANT TUMOR-CELLS; NF-KAPPA-B; MEDIATED APOPTOSIS; IN-VIVO; DEATH RECEPTORS; CARCINOMA-CELLS; MONOCLONAL-ANTIBODY AB We have developed a high-throughput screen (HTS) to search for novel molecules that can synergize with TRAIL, thus promoting apoptosis of ACHN renal tumor cells in a combinatorial fashion. The HTS detects synthetic compounds and pure natural products that can pre-sensitize the cancer cells to TRAIL-mediated apoptosis, yet have limited toxicity on their own. We have taken into account the individual effects of the single agents, versus the combination, and have identified hits that are synergistic, synergistic-toxic, or additive when combined with TRAIL in promoting tumor cell death. Preliminary mechanistic studies indicate that a subset of the synergistic TRAIL sensitizers act very rapidly to promote cleavage and activation of caspase-8 following TRAIL binding. Caspase-8 is an apical enzyme that initiates programmed cell death via the extrinsic apoptotic pathway. Thus, these TRAIL sensitizers may potentially reduce resistance of tumor cells to TRAIL-mediated apoptosis. Two representative sensitizers were found to increase levels of p53 but did not inhibit the proteasome, suggesting that early DNA damage-sensing pathways may be involved in their mechanisms of action. C1 [Booth, Nancy Lynn; Thomas, Cheryl L.; Goncharova, Ekaterina I.; McMahon, James B.; Henrich, Curtis J.] NCI, Ctr Canc Res, Mol Targets Dev Program, Frederick, MD 21702 USA. [Sayers, Thomas J.; Brooks, Alan D.; Jacobsen, Kristen] NCI, Ctr Canc Res, Expt Immunol Lab, Frederick, MD 21702 USA. [Sayers, Thomas J.; Brooks, Alan D.; Jacobsen, Kristen] NCI, Ctr Canc Res, Canc Inflammat Program, Frederick, MD 21702 USA. [Sayers, Thomas J.; Brooks, Alan D.; Henrich, Curtis J.] SAIC Frederick Inc, Frederick, MD 21702 USA. [Goncharova, Ekaterina I.] Data Management Serv Inc, Frederick, MD 21702 USA. RP Booth, NL (reprint author), Spherix Inc, 6430 Rockledge Dr 503, Bethesda, MD 20817 USA. EM nancylynnbooth@gmail.com RI Sayers, Thomas/G-4859-2015 FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; U. S. Government FX Jennifer Wilson generously assisted with numerous XTT assays during the development of the TRAIL HTS; Heidi R. Bokesch conducted LC-MS and NMR quality control evaluations on compounds provided by the NCI Natural Products Repository; and Antony M. Wamiru and Nancy B. Shulley were instrumental in the design and trouble-shooting of Beckman 384-FX robot programs for use in the screen. The authors thank Kirk R. Gustafson for his time to read and comment on the manuscript. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 77 TC 20 Z9 20 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD AUG PY 2009 VL 58 IS 8 BP 1229 EP 1244 DI 10.1007/s00262-008-0637-8 PG 16 WC Oncology; Immunology SC Oncology; Immunology GA 450AE UT WOS:000266372400006 PM 19089423 ER PT J AU Fry, TJ Shand, JL Milliron, M Tasian, SK Mackall, CL AF Fry, Terry J. Shand, Jessica L. Milliron, Matthew Tasian, Sarah K. Mackall, Crystal L. TI Antigen loading of DCs with irradiated apoptotic tumor cells induces improved anti-tumor immunity compared to other approaches SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Dendritic cell vaccines; Cancer vaccines; Antitumor immunity ID DENDRITIC CELLS; IN-VIVO; DYING CELLS; T-CELLS; TOLERANCE; IMMUNOGENICITY; IMMUNOTHERAPY; INDUCTION; CANCER; CONSEQUENCES AB Dendritic cells (DCs) serve as central regulators of adaptive immunity by presenting antigens and providing necessary co-signals. Environmental information received by the DCs determines the co-signals delivered to the responding adaptive cells and, ultimately, the outcome of the interaction. DCs loaded with relevant antigens have been used as therapeutic cellular vaccines, but the optimal antigen loading method has not been determined. We compared different methods to load class I and class II epitopes from the male antigenic complex, HY, onto DCs for the potency of the immune response induced in vivo. Co-incubation of female DCs with HY peptides, RNA or cell lysate from HY expressing tumor induced immune responses equivalent to male DCs. In contrast, female DCs incubated with irradiated, apoptotic HY expressing tumor cells (or male B cells) generated a stronger immune response than male DCs or female DCs loaded using any of the other methods. DC loading with apoptotic tumor resulted in complete protection against high dose HY-expressing tumor challenge whereas 100% lethality was observed in groups receiving DCs that were loaded with peptides, RNA, or lysate. We conclude that signals provided to the DCs by apoptotic cells substantially augment the potency of DC vaccines. C1 [Fry, Terry J.; Shand, Jessica L.; Milliron, Matthew; Tasian, Sarah K.; Mackall, Crystal L.] NIH, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Mackall, CL (reprint author), Bldg 10,Room 1-3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM fryt@mail.nih.gov; mackallc@mail.nih.gov OI Tasian, Sarah/0000-0003-1327-1662 FU National Cancer Institute; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Howard Hughes Medical Institute FX This work was funded by the Intramural Research Program of the National Cancer Institute. TF performed experiments, analyzed data and partially wrote the manuscript; JS performed experiments, analyzed data and partially wrote the manuscript; MM and ST performed experiments and analyzed data; CM provided intellectual and financial support for the experiments shown, analyzed data and partially wrote the manuscript. The authors thank Dr. Martin Guimond for his careful review of this manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. ST and JK were supported by the Howard Hughes Medical Institute Research Scholars Program. NR 28 TC 23 Z9 26 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD AUG PY 2009 VL 58 IS 8 BP 1257 EP 1264 DI 10.1007/s00262-008-0638-7 PG 8 WC Oncology; Immunology SC Oncology; Immunology GA 450AE UT WOS:000266372400008 PM 19139888 ER PT J AU Cullen, M Seaman, S Chaudhary, A Yang, MY Hilton, MB Logsdon, D Haines, DC Tessarollo, L St Croix, B AF Cullen, Mike Seaman, Steven Chaudhary, Amit Yang, Mi Young Hilton, Mary Beth Logsdon, Daniel Haines, Diana C. Tessarollo, Lino St Croix, Brad TI Host-Derived Tumor Endothelial Marker 8 Promotes the Growth of Melanoma SO CANCER RESEARCH LA English DT Article ID INFANTILE SYSTEMIC HYALINOSIS; CAPILLARY MORPHOGENESIS; ANTHRAX TOXIN; ANGIOGENESIS; RECEPTOR; GENES; FIBROMATOSIS; EXPRESSION; MUTATIONS; COLLAGEN AB Tumor endothelial marker 8 (TEM8) was initially identified as a gene overexpressed in the vasculature of human tumors and was subsequently identified as an anthrax toxin receptor. To assess the functional role of TEM8, we disrupted the TEM8 gene in mice by targeted homologous recombination. TEM8(-/-) mice were viable and reached adulthood without defects in physiologic angiogenesis. However, histopathologic analysis revealed an excess of extracellular matrix in several tissues, including the ovaries, uterus, skin, and periodontal ligament of the incisors, the latter resulting in dental dysplasia. When challenged with B16 melanoma, tumor growth was delayed in TEM8(-/-) mice, whereas the growth of other tumors, such as Lewis lung carcinoma, was unaltered. These studies show that host-derived TEM8 promotes the growth of certain tumors and suggest that TEM8 antagonists may have utility in the development of new anticancer therapies. [Cancer Res 2009;69(15):6021-6] C1 [Cullen, Mike; Seaman, Steven; Chaudhary, Amit; Yang, Mi Young; Hilton, Mary Beth; St Croix, Brad] NCI, Tumor Angiogenesis Sect, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Hilton, Mary Beth; Logsdon, Daniel] NCI, Basic Res Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. [Haines, Diana C.] NCI, Pathol Histotechnol Lab, Sci Applicat Int Corp, Frederick, MD 21702 USA. [Tessarollo, Lino] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP St Croix, B (reprint author), NCI, Tumor Angiogenesis Sect, Mouse Canc Genet Program, Bldg 560,POB B, Frederick, MD 21702 USA. EM stcroix@nciferf.gov RI Seaman, Steven/A-2755-2013 OI Seaman, Steven/0000-0003-3349-3334 FU National Cancer Institute [HHSN261200800001E]; NIH; Department of Health and Human Services FX Grant support: Intramural Research Program of the National Cancer Institute, NIH, Department of Health and Human Services and federal funds from the National Cancer Institute under Contract No. HHSN261200800001E. NR 18 TC 32 Z9 33 U1 0 U2 3 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 AUG 1 PY 2009 VL 69 IS 15 BP 6021 EP 6026 DI 10.1158/0008-5472.CAN-09-1086 PG 6 WC Oncology SC Oncology GA 480MC UT WOS:000268737900003 PM 19622764 ER PT J AU Zaharoff, DA Hoffman, BS Hooper, HB Benjamin, CJ Khurana, KK Hance, KW Rogers, CJ Pinto, PA Schlom, J Greiner, JW AF Zaharoff, David A. Hoffman, Benjamin S. Hooper, H. Brooks Benjamin, Compton J., Jr. Khurana, Kiranpreet K. Hance, Kenneth W. Rogers, Connie J. Pinto, Peter A. Schlom, Jeffrey Greiner, John W. TI Intravesical Immunotherapy of Superficial Bladder Cancer with Chitosan/Interleukin-12 SO CANCER RESEARCH LA English DT Article ID BACILLUS-CALMETTE-GUERIN; TRANSITIONAL-CELL CARCINOMA; IN-VIVO; BCG IMMUNOTHERAPY; INTERFERON-GAMMA; IFN-GAMMA; ANTITUMOR IMMUNITY; GENE-THERAPY; INTERLEUKIN-12; CHITOSAN AB Intravesical BCG has been used successfully to treat superficial bladder cancer for three decades. However, 20% to 30% of patients will fail initial BCG therapy and 30% to 50% of patients will develop recurrent tumors within 5 years. Alternative or complementary strategies for the management of superficial bladder cancer are needed. Interleukin-12 (IL-12) is a potent T(H)1 cytokine with robust antitumor activity and the ability to potentiate immunologic memory. Unfortunately, intravesical IL-12 did not show antitumor efficacy in a recent clinical study of patients with recurrent superficial bladder cancer. We hypothesized that coformulation of IL-12 with chitosan, a biocompatible, mucoadhesive polysaccharide, could improve intravesical IL-12 delivery and provide an effective and durable alternative for the treatment of superficial bladder cancer. In antitumor studies, 88% to 100% of mice bearing orthotopic bladder tumors were cured after four intravesical treatments with chitosan/IL-12. In contrast, only 38% to 60% of mice treated with IL-12 alone and 0% treated with BCG were cured. Antitumor responses following chitosan/IL-12 treatments were durable and provided complete protection from intravesical tumor rechallenge. Urinary cytokine analysis showed that chitosan/IL-12 induced multiple T(H)1 cytokines at levels significantly higher than either IL-12 alone or BCG. Immunohistochemistry revealed moderate to intense tumor infiltration by T cells and macrophages following chitosan/IL-12 treatments. Bladder submucosa from cured mice contained residual populations of immune cells that returned to baseline levels after several months. Intravesical chitosan/IL-12 is a well-tolerated, effective immunotherapy that deserves further consideration for testing in humans for the management of superficial bladder cancer. [Cancer Res 2009;69(15):6192-9] C1 [Greiner, John W.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hoffman, Benjamin S.; Hooper, H. Brooks; Benjamin, Compton J., Jr.; Khurana, Kiranpreet K.; Pinto, Peter A.] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Greiner, JW (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM jg117s@nih.gov OI Zaharoff, David/0000-0001-6885-6727; Khurana, Kiranpreet/0000-0002-2750-4909 FU Intramural NIH HHS [Z99 CA999999] NR 50 TC 43 Z9 43 U1 0 U2 6 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 AUG 1 PY 2009 VL 69 IS 15 BP 6192 EP 6199 DI 10.1158/0008-5472.CAN-09-1114 PG 8 WC Oncology SC Oncology GA 480MC UT WOS:000268737900025 PM 19638573 ER PT J AU Balansky, R Ganchev, G Iltcheva, M Steele, VE De Flora, S AF Balansky, Roumen Ganchev, Gancho Iltcheva, Marietta Steele, Vernon E. De Flora, Silvio TI Prenatal N-acetylcysteine prevents cigarette smoke-induced lung cancer in neonatal mice SO CARCINOGENESIS LA English DT Article ID MOUSE LUNG; TRANSPLACENTAL CARCINOGENESIS; LIVER; NEWBORN; LIGHT; MODEL; BIRTH; TUMORIGENESIS; EXPOSURE; MOTHERS AB Certain adult diseases may have their origin early in life, and perinatal exposures may contribute to cancers both during childhood and later in life. We recently demonstrated that mainstream cigarette smoke (MCS) induces a potent carcinogenic response in mice when exposure starts soon after birth. We also showed that the antioxidant N-acetylcysteine (NAC) prevents the extensive nucleotide and gene expression alterations that occur 'physiologically' at birth in mouse lung. The present study was designed to evaluate whether administration of NAC during pregnancy may affect the yield of tumors in mice exposed to MCS, starting after birth and continuing for 120 days. The results obtained showed that 210 days after birth, one adenoma only was detectable in sham-exposed mice. In contrast, as much as the 61.1% (33/54) of MCS-exposed mice born from untreated dams had lung tumors, including both benign tumors and bronchoalveolar carcinomas. Treatment with NAC during pregnancy strikingly inhibited the formation of benign lung tumors and totally prevented occurrence of carcinomas. In addition, prenatal NAC inhibited the MCS-induced hyperplasia of the urinary bladder epithelium. These findings demonstrate for the first time that treatment during pregnancy with an antioxidant chemopreventive agent can affect the induction of tumors consequent to exposure to a carcinogen after birth. C1 [Balansky, Roumen; De Flora, Silvio] Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. [Balansky, Roumen; Ganchev, Gancho; Iltcheva, Marietta] Natl Oncol Ctr, Sofia 1756, Bulgaria. [Steele, Vernon E.] NCI, Rockville, MD 20892 USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM sdf@unige.it FU Bulgarian Ministry of Education and Science; US National Cancer Institute [N01-CN53301] FX Bulgarian Ministry of Education and Science; US National Cancer Institute ( contract N01-CN53301). NR 29 TC 30 Z9 30 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2009 VL 30 IS 8 BP 1398 EP 1401 DI 10.1093/carcin/bgp128 PG 4 WC Oncology SC Oncology GA 478KG UT WOS:000268586400018 PM 19458036 ER PT J AU Williams, IA Sleeper, LA Colan, SD Lu, MM Stephenson, EA Newburger, JW Gersony, WM Cohen, MS Cnota, JF Atz, AM Williams, RV Margossian, R Powell, AJ Stylianou, MP Hsu, DT AF Williams, Ismee A. Sleeper, Lynn A. Colan, Steven D. Lu, Minmin Stephenson, Elizabeth A. Newburger, Jane W. Gersony, Welton M. Cohen, Meryl S. Cnota, James F. Atz, Andrew M. Williams, Richard V. Margossian, Renee Powell, Andrew J. Stylianou, Mario P. Hsu, Daphne T. CA Pediat Heart Network Investigators TI Functional state following the Fontan procedure SO CARDIOLOGY IN THE YOUNG LA English DT Article DE Clinical outcomes; single ventricle; univentricular heart ID HEALTH-STATUS; OPERATION; CHILDREN; EXERCISE; HEART; LIFE AB Background: Despite improvements in outcomes after completion of the Fontan circulation, long-term functional state varies. We sought to identify pre- and postoperative characteristics associated with overall function. Methods and Results: We analyzed data from 476 survivors with the Fontan circulation enrolled in the Pediatric Heart Network Fontan Cross-sectional Study. Mean age at creation of the Fontan circulation was 3.4 plus or minus 2.1 years, with a range from 0.7 to 17.5 years, and time since completion was 8.7 plus or minus 3.4 years, the range being from 1.1 to 17.3 years. We calculated a functional score for the survivors by averaging the percentile ranks of ventricular ejection fraction, maximal consumption of oxygen, the physical summary score for the Child Health Questionnaire, and a function of brain natriuretic peptide. The mean calculated score was 49.5 plus or minus 17.3, with a range from 3 to 87. After adjustment for time since completion of the circulation, we found that a lower score, and hence worse functional state, was associated with: right ventricular morphology (p less than 0.001), higher ventricular end-diastolic pressure (p equals 0.003) and lower saturations of oxygen (p equals 0.047) prior to completion of the Fontan circulation, lower income for the caregiver (p equals 0.003), and, in subjects without a prior superior cavopulmonary anastomosis, arrhythmias after completion of the circulation (p equals 0.003). The model explained almost one-fifth (18%) of the variation in the calculated scores. The score was not associated with surgical centre, sex, age, weight, fenestration, or the period of stay in hospital after completion of the Fontan circuit. A validation model, using 71 subjects randomly excluded from initial analysis, weakly correlated (R equals 0.17, p equals 0.16) with the score calculated from the dataset. Conclusions: Right ventricular morphology, higher ventricular end-diastolic pressure and lower saturations of oxygen prior to completion of the Fontan circuit, lower income for the provider of care, and arrhythmias after creation of the circuit, are all associated with a worse functional state. Unmeasured factors also influence outcomes. C1 [Williams, Ismee A.; Gersony, Welton M.; Hsu, Daphne T.] Columbia Univ, Dept Pediat, Div Cardiol, Med Ctr, New York, NY 10027 USA. [Sleeper, Lynn A.; Lu, Minmin] New England Res Inst, Watertown, MA 02172 USA. [Colan, Steven D.; Newburger, Jane W.; Margossian, Renee; Powell, Andrew J.] Childrens Hosp Boston, Dept Cardiol, Boston, MA USA. [Stephenson, Elizabeth A.] Univ Toronto, Hosp Sick Children, Dept Pediat, Div Cardiol, Toronto, ON M5G 1X8, Canada. [Cohen, Meryl S.] Childrens Hosp Philadelphia, Dept Pediat, Div Cardiol, Philadelphia, PA 19104 USA. [Cnota, James F.] Wake Forest Univ, Sch Med, Dept Pediat Cardiol, Winston Salem, NC 27109 USA. [Atz, Andrew M.] Med Univ S Carolina, Dept Pediat, Div Cardiol, Charleston, SC 29425 USA. [Williams, Richard V.] Univ Utah, Dept Pediat, Div Cardiol, Salt Lake City, UT USA. [Stylianou, Mario P.] NHLBI, Bethesda, MD 20892 USA. RP Williams, IA (reprint author), Columbia Univ Coll Phys & Surg, Morgan Stanley Childrens Hosp New York, 2 North,3959 Broadway, New York, NY 10032 USA. EM iib6@columbia.edu OI Hsu, Daphne/0000-0002-2654-0430 FU National Heart, Lung, and Blood Institute [HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288]; National Centre for Research Resources [KL2 RR024157]; National Institutes of Health; National Institutes of Health Roadmap for Medical Research FX Supported by U01 grants from the National Heart, Lung, and Blood Institute (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288). Dr. Williams reports support from Grant Number KL2 RR024157 from the National Centre for Research Resources, a component of the National Institutes of Health, and National Institutes of Health Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of National Centre for Research Resources or National Institutes of Health. Information on National Centre for Research Resources is available at http://wxvw.ncrr.nih.gov/. Information on Re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap. nih.gov/clinicalresearch/overview-translational.asp. NR 13 TC 13 Z9 13 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1047-9511 J9 CARDIOL YOUNG JI Cardiol. Young PD AUG PY 2009 VL 19 IS 4 BP 320 EP 330 DI 10.1017/S1047951109990382 PG 11 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA 482WY UT WOS:000268922400004 PM 19523266 ER PT J AU Callen, E Bunting, S Huang, CY Difilippantonio, MJ Wong, N Khor, B Mahowald, G Kruhlak, MJ Ried, T Sleckman, BP Nussenzweig, A AF Callen, Elsa Bunting, Sam Huang, Ching-Yu Difilippantonio, Michael J. Wong, Nancy Khor, Bernard Mahowald, Grace Kruhlak, Michael J. Ried, Thomas Sleckman, Barry P. Nussenzweig, Andre TI Chimeric IgH-TCR/translocations in T lymphocytes mediated by RAG SO CELL CYCLE LA English DT Article DE translocations; T cell leukemia; V(D)J recombination; ATM ID ATM-DEFICIENT MICE; ATAXIA-TELANGIECTASIA; GENOMIC INSTABILITY; CHROMOSOME BREAKS; CELL-RECEPTOR; REARRANGEMENT; GENES; LOCUS; RECOMBINATION; PREVENTS AB Translocations involving the T cell receptor alpha/delta (TCR alpha/delta) chain locus, which bring oncogenes in the proximity of the TCR alpha enhancer, are one of the hallmark features of human T cell malignancies from ataxia telangiectasia (AT) and non-AT patients. These lesions are frequently generated by the fusion of DNA breaks at the TCR alpha/delta locus to a disperse region centromeric of the immunoglobulin heavy chain (IgH) locus. Aberrant VDJ joining accounts for TCR alpha/delta associated DNA cleavage, but the molecular mechanism that leads to generation of the "oncogene partner" DNA break is unclear. Here we show that in ATM deficient primary mouse T cells, IgH/TCR alpha/delta fusions arise at a remarkably similar frequency as in human AT lymphocytes. Recombinase-activating gene (RAG) is responsible for both TCR alpha/delta as well as IgH associated breaks on chromosome 12 (Chr12), which are subject to varying degrees of chromosomal degradation. We suggest a new model for how oncogenic translocations can arise from two non-concerted physiological DSBs. C1 [Callen, Elsa; Bunting, Sam; Wong, Nancy; Kruhlak, Michael J.; Nussenzweig, Andre] Natl Canc Inst, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. [Huang, Ching-Yu; Khor, Bernard; Mahowald, Grace; Sleckman, Barry P.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Difilippantonio, Michael J.; Ried, Thomas] Natl Canc Inst, Sect Canc Genom, NIH, Genet Branch, Bethesda, MD 20892 USA. [Callen, Elsa] Univ Autonoma Barcelona, Dept Genet & Microbiol, E-08193 Barcelona, Spain. [Callen, Elsa] Univ Autonoma Barcelona, Ctr Biomed Network Res Rare Dis, CIBERER, E-08193 Barcelona, Spain. RP Nussenzweig, A (reprint author), Natl Canc Inst, NIH, Expt Immunol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov RI Huang, Ching-Yu /E-3981-2010 FU NIH [AI074953] FX We thank Joseph Cheng for help with the image analysis system and for comments on the manuscript. This work is supported in part by the Intramural research Program of the NIH, National Cancer Institute, Center for Cancer Research. B. S. is supported by NIH grant AI074953. The authors declare no financial conflict of interest. NR 23 TC 16 Z9 16 U1 0 U2 1 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 AUG 1 PY 2009 VL 8 IS 15 BP 2408 EP 2412 DI 10.4161/cc.8.15.9085 PG 5 WC Cell Biology SC Cell Biology GA 477RH UT WOS:000268535700024 PM 19556863 ER PT J AU Galluzzi, L Aaronson, SA Abrams, J Alnemri, ES Andrews, DW Baehrecke, EH Bazan, NG Blagosklonny, MV Blomgren, K Borner, C Bredesen, DE Brenner, C Castedo, M Cidlowski, JA Ciechanover, A Cohen, GM De Laurenzi, V De Maria, R Deshmukh, M Dynlacht, BD El-Deiry, WS Flavell, RA Fulda, S Garrido, C Golstein, P Gougeon, ML Green, DR Gronemeyer, H Hajnoczky, G Hardwick, JM Hengartner, MO Ichijo, H Jaattela, M Kepp, O Kimchi, A Klionsky, DJ Knight, RA Kornbluth, S Kumar, S Levine, B Lipton, SA Lugli, E Madeo, F Malorni, W Marine, JCW Martin, SJ Medema, JP Mehlen, P Melino, G Moll, UM Morselli, E Nagata, S Nicholson, DW Nicotera, P Nunez, G Oren, M Penninger, J Pervaiz, S Peter, ME Piacentini, M Prehn, JHM Puthalakath, H Rabinovich, GA Rizzuto, R Rodrigues, CMP Rubinsztein, DC Rudel, T Scorrano, L Simon, HU Steller, H Tschopp, J Tsujimoto, Y Vandenabeele, P Vitale, I Vousden, KH Youle, RJ Yuan, J Zhivotovsky, B Kroemer, G AF Galluzzi, L. Aaronson, S. A. Abrams, J. Alnemri, E. S. Andrews, D. W. Baehrecke, E. H. Bazan, N. G. Blagosklonny, M. V. Blomgren, K. Borner, C. Bredesen, D. E. Brenner, C. Castedo, M. Cidlowski, J. A. Ciechanover, A. Cohen, G. M. De Laurenzi, V. De Maria, R. Deshmukh, M. Dynlacht, B. D. El-Deiry, W. S. Flavell, R. A. Fulda, S. Garrido, C. Golstein, P. Gougeon, M-L Green, D. R. Gronemeyer, H. Hajnoczky, G. Hardwick, J. M. Hengartner, M. O. Ichijo, H. Jaattela, M. Kepp, O. Kimchi, A. Klionsky, D. J. Knight, R. A. Kornbluth, S. Kumar, S. Levine, B. Lipton, S. A. Lugli, E. Madeo, F. Malorni, W. Marine, J-C W. Martin, S. J. Medema, J. P. Mehlen, P. Melino, G. Moll, U. M. Morselli, E. Nagata, S. Nicholson, D. W. Nicotera, P. Nunez, G. Oren, M. Penninger, J. Pervaiz, S. Peter, M. E. Piacentini, M. Prehn, J. H. M. Puthalakath, H. Rabinovich, G. A. Rizzuto, R. Rodrigues, C. M. P. Rubinsztein, D. C. Rudel, T. Scorrano, L. Simon, H-U Steller, H. Tschopp, J. Tsujimoto, Y. Vandenabeele, P. Vitale, I. Vousden, K. H. Youle, R. J. Yuan, J. Zhivotovsky, B. Kroemer, G. TI Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes SO CELL DEATH AND DIFFERENTIATION LA English DT Review DE apoptosis; caspases; cytofluorometry; immunofluorescence microscopy; mitotic catastrophe; necrosis ID MITOCHONDRIAL-MEMBRANE PERMEABILIZATION; INDUCED THYMOCYTE APOPTOSIS; CYTOCHROME-C; CANCER-CELLS; OXIDATIVE STRESS; FLOW-CYTOMETRY; NUCLEAR-DNA; AUTOPHAGY; DROSOPHILA; RELEASE AB Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases. Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies. It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios. Thus far, dozens of methods have been proposed to quantify cell death-related parameters. However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate. Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls. These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise. Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells. Cell Death and Differentiation (2009) 16, 1093-1107; doi:10.1038/cdd.2009.44; published online 17 April 2009 C1 [Galluzzi, L.; Castedo, M.; Kepp, O.; Morselli, E.; Vitale, I.; Kroemer, G.] Inst Gustave Roussy, INSERM, U848, F-94805 Villejuif, France. [Galluzzi, L.; Castedo, M.; Kepp, O.; Morselli, E.; Vitale, I.; Kroemer, G.] Univ Paris 11, F-94805 Villejuif, France. [Aaronson, S. A.] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY 10029 USA. [Abrams, J.] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA. [Andrews, D. W.] Thomas Jefferson Univ, Kimmel Canc Inst, Ctr Apoptosis Res, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA. [Andrews, D. W.] McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON L8N 3Z5, Canada. [Baehrecke, E. H.] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. [Bazan, N. G.] Louisiana State Univ, Hlth Sci Ctr, Sch Med, Neurosci Ctr Excellence, New Orleans, LA 70112 USA. [Blagosklonny, M. V.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Blomgren, K.] Univ Gothenburg, Inst Neurosci & Physiol, Ctr Brain Repair & Rehabil, SE-40530 Gothenburg, Sweden. [Blomgren, K.] Queen Silvia Childrens Hosp, Dept Pediat Oncol, SE-41685 Gothenburg, Sweden. [Borner, C.] Univ Freiburg, Inst Mol Med & Cell Res ZBMZ, D-79104 Freiburg, Germany. [Bredesen, D. E.] Buck Inst Age Res, Novato, CA 94945 USA. [Bredesen, D. E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Brenner, C.] Univ Versailles St Quentin, F-78035 Versailles, France. [Brenner, C.] CNRS, UMR8159, F-78035 Versailles, France. [Cidlowski, J. A.] Natl Inst Environm Hlth Sci, NIH, Duhram, NC 27709 USA. [Ciechanover, A.] Technion Israel Inst Technol, Rappaport Fac Med, Vasc & Tumor Biol Res Ctr, IL-31096 Haifa, Israel. [Cohen, G. M.; Melino, G.; Nicotera, P.] Univ Leicester, Toxicol Unit, MRC, Leicester LE1 9HN, Leics, England. [De Laurenzi, V.] Univ G dAnnunzio, Dipartimento Sci Biomed, I-66100 Chieti, Italy. [De Maria, R.] Ist Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, Italy. [De Maria, R.] Mediterranean Inst Oncol, I-95030 Catania, Italy. [Deshmukh, M.] Univ N Carolina, Dept Cell & Dev Biol, Ctr Neurosci, Chapel Hill, NC 27599 USA. [Dynlacht, B. D.] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [El-Deiry, W. S.] Univ Penn, Sch Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Flavell, R. A.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA. [Flavell, R. A.; Levine, B.; Steller, H.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Fulda, S.] Univ Childrens Hosp, D-89075 Ulm, Germany. [Garrido, C.] INSERM, UMR866, F-21049 Dijon, France. [Garrido, C.] Univ Burgundy, Fac Med & Pharm, F-21049 Dijon, France. [Golstein, P.] INSERM, U631, F-13288 Marseille, France. [Golstein, P.] CNRS, UMR6102, F-13288 Marseille, France. [Golstein, P.] Aix Marseille Univ, Ctr Immunol Marseille Luminy, F-13288 Marseille, France. [Gougeon, M-L] Inst Pasteur, Antiviral Immun Biotherapy & Vaccine Unit, F-75015 Paris, France. [Green, D. R.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. [Gronemeyer, H.] Inst Genet & Biol Mol & Cellulaire, Dept Canc Biol, F-67404 Illkirch Graffenstaden, France. [Gronemeyer, H.] CNRS, UMR7104, F-67404 Illkirch Graffenstaden, France. [Gronemeyer, H.] INSERM, U964, F-67404 Illkirch Graffenstaden, France. [Hajnoczky, G.] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Hardwick, J. M.] Johns Hopkins Univ, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Hengartner, M. O.] Univ Zurich, Inst Mol Biol, CH-8057 Zurich, Switzerland. [Ichijo, H.] Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo 1130033, Japan. [Jaattela, M.] Inst Canc Biol, Dept Apoptosis, Danish Canc Soc, DK-2100 Copenhagen, Denmark. [Kimchi, A.] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. [Klionsky, D. J.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Klionsky, D. J.] Univ Michigan, Dept Mol Cellular & Dev Biol & Biol Chem, Ann Arbor, MI 48109 USA. [Knight, R. A.] UCL, Inst Child Hlth, London WC1N 1EH, England. [Kornbluth, S.] Duke Univ, Sch Med, Durham, NC 27710 USA. [Kumar, S.] Ctr Canc Biol, Hanson Inst, Adelaide, SA 5000, Australia. [Levine, B.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Lipton, S. A.] Burnham Inst Med Res, La Jolla, CA 92037 USA. [Lipton, S. A.] Salk Inst Biol Studies, La Jolla, CA 92037 USA. [Lipton, S. A.] Scripps Res Inst, La Jolla, CA 92037 USA. [Lipton, S. A.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Lugli, E.] NIAID, Immunotechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Madeo, F.] Graz Univ, Inst Mol Biosci, A-8010 Graz, Austria. [Malorni, W.] Ist Super Sanita, Sect Cell Aging & Degenerat, Dept Therapeut Res & Med Evaluat, I-00161 Rome, Italy. [Marine, J-C W.] Univ Ghent VIB, Lab Mol Canc Biol, B-9052 Ghent, Belgium. [Marine, J-C W.; Vandenabeele, P.] Univ Ghent, Dept Mol Biol, B-9052 Ghent, Belgium. [Martin, S. J.] Trinity Coll Dublin, Dept Genet, Dublin 2, Ireland. [Medema, J. P.] Acad Med Ctr, Ctr Expt & Mol Med, NL-1105 AZ Amsterdam, Netherlands. [Medema, J. P.] Univ Amsterdam, NL-1012 ZA Amsterdam, Netherlands. [Mehlen, P.] Ctr Leon Berard, Apoptosis Canc & Dev Lab, F-69008 Lyon, France. [Mehlen, P.] CNRS, UMR5238, F-69008 Lyon, France. [Mehlen, P.] Univ Lyon, F-69008 Lyon, France. [Melino, G.] Univ Roma Tor Vergata, Dept Expt Med & Biochem Sci, I-00133 Rome, Italy. [Moll, U. M.] SUNY Stony Brook, Dept Pathol, Stony Brook, NY 11794 USA. [Moll, U. M.] Gottingen Ctr Mol Biosci, Dept Mol Oncol, D-37077 Gottingen, Germany. [Moll, U. M.] Univ Gottingen, Fac Med, D-37077 Gottingen, Germany. Kyoto Univ, Grad Sch Med, Dept Med Chem, Kyoto 6068501, Japan. [Nicholson, D. W.] Merck Res Labs, Rahway, NJ 07065 USA. [Nunez, G.] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Oren, M.] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. [Penninger, J.] Austrian Acad Sci, Inst Mol Biotechnol, A-1030 Vienna, Austria. [Pervaiz, S.] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore. [Pervaiz, S.] Natl Univ Singapore, Singapore MIT Alliance, Singapore 117576, Singapore. [Pervaiz, S.] Duke NUS Grad Med Sch, Singapore 169547, Singapore. [Peter, M. E.] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA. [Piacentini, M.] Natl Inst Infect Dis IRCCS L Spallanzani, Cell Biol Lab, I-00149 Rome, Italy. [Piacentini, M.] Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy. [Prehn, J. H. M.] Royal Coll Surgeons Ireland, Dept Physiol & Med Phys, Dublin 2, Ireland. [Puthalakath, H.] La Trobe Univ, Dept Biochem, Bundoora, Vic 3086, Australia. [Rabinovich, G. A.] IBYME CONICET, Inst Biol & Med Expt, Lab Inmunopatol, Buenos Aires, DF, Argentina. [Rizzuto, R.] Univ Padua, Dept Biomed Sci, I-35121 Padua, Italy. [Rodrigues, C. M. P.] Univ Lisbon, Fac Pharm, iMed UL, P-1649003 Lisbon, Portugal. [Rubinsztein, D. C.] Cambridge Inst Med Res, Cambridge CB2 0XY, England. [Rudel, T.] Univ Wurzburg, Bioctr, D-97074 Wurzburg, Germany. [Scorrano, L.] Univ Geneva, Sch Med, Dept Cell Physiol & Metab, CH-1211 Geneva, Switzerland. [Scorrano, L.] Venetian Inst Mol Med, Dulbecco Telethon Inst, I-35129 Padua, Italy. [Simon, H-U] Univ Bern, Dept Pharmacol, CH-3010 Bern, Switzerland. [Steller, H.] Rockefeller Univ, Lab Apoptosis & Canc Biol, New York, NY 10065 USA. [Tschopp, J.] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Tsujimoto, Y.] Osaka Univ, Sch Med, Dept Med Genet, Suita, Osaka 5650871, Japan. [Vandenabeele, P.] Univ Ghent VIB, Dept Mol Biomed Res, B-9052 Ghent, Belgium. [Vousden, K. H.] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland. [Youle, R. J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Yuan, J.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Zhivotovsky, B.] Karolinska Inst, Div Toxicol, Inst Environm Med, SE-17177 Stockholm, Sweden. RP Kroemer, G (reprint author), Inst Gustave Roussy, INSERM, U848, PR1,39 Rue Camille Desmoulins, F-94805 Villejuif, France. EM kroemer@orange.fr RI iMed.ULisboa, iMed.ULisboa/C-6292-2014; Pervaiz, Shazib/C-4188-2015; Malorni, Walter/G-5874-2016; Marine, Jean-Christophe/K-3292-2016; Piacentini, Mauro/I-2411-2016; iMed.ULisboa, CellFun /A-4244-2014; Gronemeyer, Hinrich/H-7002-2016; Penninger, Josef/I-6860-2013; Rodrigues, Cecilia/M-3572-2013; Scorrano, Luca/A-6652-2008; Vandenabeele, Peter/C-8597-2009; Puthalakath, Hamsa/B-8541-2011; Rubinsztein, David/C-3472-2011; Fulda, Simone/D-5864-2011; Hengartner, Michael/E-6235-2011; Gronemeyer, Hinrich/G-6240-2011; Prehn, Jochen/A-3928-2010; Galluzzi, Lorenzo/K-2709-2012; Kroemer, Guido/B-4263-2013; Golstein, Pierre/A-4954-2014 OI Marine, Jean-Christophe/0000-0003-2433-9837; Piacentini, Mauro/0000-0003-2919-1296; Gronemeyer, Hinrich/0000-0001-9454-2449; VITALE, ILIO/0000-0002-5918-1841; malorni, walter/0000-0002-1223-7000; Hengartner, Michael/0000-0002-7584-596X; Simon, Hans-Uwe/0000-0002-9404-7736; Zhivotovsky, Boris/0000-0002-2238-3482; Andrews, David/0000-0002-9266-7157; Blomgren, Klas/0000-0002-0476-7271; Jaattela, Marja/0000-0001-5950-7111; Kumar, Sharad/0000-0001-7126-9814; Penninger, Josef/0000-0002-8194-3777; Rodrigues, Cecilia/0000-0002-4829-754X; Scorrano, Luca/0000-0002-8515-8928; Gronemeyer, Hinrich/0000-0001-9454-2449; Prehn, Jochen/0000-0003-3479-7794; Galluzzi, Lorenzo/0000-0003-2257-8500; Golstein, Pierre/0000-0003-1750-3483 FU Ligue Nationale contre le Cancer (LNC); Agence Nationale de Recherche (ANR); Agence Nationale de Recherches sur le SIDA (ANRS); Institut National du Cancer (INCa); Canceropole Ile-de-France; Fondation pour la Recherche Medicale (FRM); Sidaction (to GK); European Commission; NIH; National Health and Medical Research Council (NHMRC); EMBO; ApopTrain; Wellcome Trust; Fondazione Telethon FX We declare no conflicting financial interests. This work was supported by a special grant from Ligue Nationale contre le Cancer (LNC), as well as grants by Agence Nationale de Recherche (ANR), Agence Nationale de Recherches sur le SIDA (ANRS), Institut National du Cancer (INCa), Canceropole Ile-de-France, Fondation pour la Recherche Medicale (FRM), Sidaction (to GK) and the European Commission (Active p53, Apo-Sys, ApopTrain, DeathTrain, TransDeath, RIGHT). This work was supported by the NIH intramural program. SAA, JA, EA, EHB, NGB, MVB, DEB, JAC, MD, BDD, WSE, RAF, DRG, GH, JMH, DJK, SK, BL, SAL, EL, UMM, GN, MEP, HS, RJY and JY are supported by the National Institute of Health (NIH). HP is funded by the National Health and Medical Research Council (NHMRC). OK is the recipient of an EMBO Ph. D. fellowship. EM is funded by an ApopTrain Ph. D. student fellowship. DCR is a Wellcome Trust Senior Clinical Fellow. NR 82 TC 328 Z9 333 U1 10 U2 91 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD AUG PY 2009 VL 16 IS 8 BP 1093 EP 1107 DI 10.1038/cdd.2009.44 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 470BY UT WOS:000267948900004 PM 19373242 ER PT J AU Luo, Q Mitchell, D Cheng, X Mondillo, K Mccaffrey, D Holroyd, T Carver, F Coppola, R Blair, J AF Luo, Qian Mitchell, Derek Cheng, Xi Mondillo, Krystal Mccaffrey, Daniel Holroyd, Tom Carver, Frederick Coppola, Richard Blair, James TI Visual Awareness, Emotion, and Gamma Band Synchronization SO CEREBRAL CORTEX LA English DT Article DE consciousness; emotion; gamma; MEG; synchronization; visual awareness ID TASK-RELATED CHANGES; CONSCIOUS PERCEPTION; CORTICAL SYNCHRONIZATION; FACIAL EXPRESSIONS; BOLD RESPONSE; CORTEX; HUMANS; BRAIN; MAGNETOENCEPHALOGRAPHY; OSCILLATIONS AB What makes us become aware? A popular hypothesis is that if cortical neurons fire in synchrony at a certain frequency band (gamma), we become aware of what they are representing. We tested this hypothesis adopting brain-imaging techniques with good spatiotemporal resolution and frequency-specific information. Specifically, we examined the degree to which increases in event-related synchronization (ERS) in the gamma band were associated with awareness of a stimulus (its detectability) and/or the emotional content of the stimulus. We observed increases in gamma band ERS within prefrontal-anterior cingulate, visual, parietal, posterior cingulate, and superior temporal cortices to stimuli available to conscious awareness. However, we also observed increases in gamma band ERS within the amygdala, visual, prefrontal, parietal, and posterior cingulate cortices to emotional relative to neutral stimuli, irrespective of their availability to conscious access. This suggests that increased gamma band ERS is related to, but not sufficient for, consciousness. C1 [Luo, Qian; Mitchell, Derek; Mondillo, Krystal; Mccaffrey, Daniel; Blair, James] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Cheng, Xi] NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Holroyd, Tom; Carver, Frederick; Coppola, Richard] NIMH, MEG Core Facil, Bethesda, MD 20892 USA. RP Luo, Q (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K N Dr,Room 300C,MSC 2670, Bethesda, MD 20892 USA. EM luoj@mail.nih.gov FU NIMH Intramural Research Program FX NIMH Intramural Research Program. Funding to pay the Open Access publication charges of this article was provided by the NIMH Intramural Research Program. NR 55 TC 49 Z9 51 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD AUG PY 2009 VL 19 IS 8 BP 1896 EP 1904 DI 10.1093/cercor/bhn216 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 469HV UT WOS:000267888000017 PM 19047574 ER PT J AU Lloyd-Evans, E Zhang, JZ Haslett, L Wassif, C Porter, FD Platt, F AF Lloyd-Evans, Emyr Zhang, Jinzhi Haslett, Luke Wassif, Christopher Porter, Forbes D. Platt, Fran TI Inhibition of NPC1 function by cholesterol precursors in Smith-Lemli-Opitz syndrome induces an intracellular phenotype identical to Niemann-Pick C disease SO CHEMISTRY AND PHYSICS OF LIPIDS LA English DT Meeting Abstract CT 50th International Conference on Bioscience of Lipids CY SEP 01-05, 2009 CL Regenburg, GERMANY SP Agilent Technol, Appl Biosyst, Avanti Polar Lipids, BBA/Elsevier, BD Biosci, Cayman Chem Co, KSV Instruments, Leica Microsyst, MoBiTec GmbH, QIAGEN, Roche Diagnost, Sanofi-Aventis, Siemens Hlthcare C1 [Lloyd-Evans, Emyr; Zhang, Jinzhi; Haslett, Luke; Platt, Fran] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England. [Wassif, Christopher; Porter, Forbes D.] NICHD, NIH, Bethesda, MD USA. EM emyr.lloyd-evans@pharm.ox.ac.uk NR 0 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-3084 J9 CHEM PHYS LIPIDS JI Chem. Phys. Lipids PD AUG PY 2009 VL 160 BP S4 EP S4 DI 10.1016/j.chemphyslip.2009.06.098 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 489AB UT WOS:000269390600011 ER PT J AU Russ, PL Gonzalez-Moa, MJ Vu, BC Sigano, DM Kelley, JA Lai, CC Deschamps, JR Hughes, SH Marquez, VE AF Russ, Pamela L. Gonzalez-Moa, Maria J. Vu, B. Christie Sigano, Dina M. Kelley, James A. Lai, Christopher C. Deschamps, Jeffrey R. Hughes, Stephen H. Marquez, Victor E. TI North- and South-Bicyclo[3.1.0]Hexene Nucleosides: The Effect of Ring Planarity on Anti-HIV Activity SO CHEMMEDCHEM LA English DT Article DE antiviral agents; carbocycles; conformationally locked; nucleosides; pseudorotational cycles ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 REVERSE-TRANSCRIPTASE; AZT RESISTANCE; DNA-SYNTHESIS; WILD-TYPE; ANALOGS; CONFORMATION; MECHANISM; TRIPHOSPHATE; DISCRIMINATE AB The syntheses of new conformationally locked North- and South-bicyclo[3.1.0]hexene nucleosides is reported. The North analogues were synthesized by a convergent approach from the known (1S,2R,5R)-5-[(tert-butyldiphenylsilyloxy)methyl]bicyclo[3.1.0]hex-3-en-2-ol by Mitsunobu coupling with the nucleobases. The South analogues were synthesized from their bicyclo[3.1.0]hexane nucleoside precursors by the selective protection of the primary hydroxy group, conversion of the secondary alcohol into a good leaving group, and base-catalyzed elimination to generate the olefin. The transformation of a bicyclo[3.1.0]hexane nucleoside into a bicyclo[3.1.0]hexene nucleoside flattens the five-membered ring of the.. bicyclic system and rescues anti-HIV activity for North-D4T, North-D4A, and South D4C. The relationship between planarity and the anti/syn disposition of, the nucleobase that is favored by a particular pseudosugar platform are proposed as key parameters in controlling biological activity. C1 [Russ, Pamela L.; Gonzalez-Moa, Maria J.; Sigano, Dina M.; Kelley, James A.; Lai, Christopher C.; Marquez, Victor E.] NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. [Vu, B. Christie; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. [Deschamps, Jeffrey R.] USN, Res Lab, Washington, DC 20375 USA. RP Russ, PL (reprint author), NCI, Med Chem Lab, NIH, 376 Boyles St, Frederick, MD 21702 USA. EM marquezv@mail.nih.gov RI Sigano, Dina/M-6144-2014; OI Sigano, Dina/0000-0001-7489-9555; Deschamps, Jeffrey/0000-0001-5845-0010 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. NR 22 TC 4 Z9 4 U1 0 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1860-7179 J9 CHEMMEDCHEM JI ChemMedChem PD AUG PY 2009 VL 4 IS 8 BP 1354 EP 1363 DI 10.1002/cmdc.200900153 PG 10 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 481CH UT WOS:000268784100016 PM 19533724 ER PT J AU Chadwick, LH Chadwick, BP Jaye, DL Wade, PA AF Chadwick, Lisa Helbling Chadwick, Brian P. Jaye, David L. Wade, Paul A. TI The Mi-2/NuRD complex associates with pericentromeric heterochromatin during S phase in rapidly proliferating lymphoid cells SO CHROMOSOMA LA English DT Article ID DNA METHYLTRANSFERASE GENE; HISTONE DEACETYLASE; CENTROMERIC HETEROCHROMATIN; IMMUNODEFICIENCY SYNDROME; JUMPING TRANSLOCATIONS; ICF IMMUNODEFICIENCY; REPLICATION SITES; BINDING-PROTEINS; MAMMALIAN-CELLS; CHROMATIN AB Chromosomal replication results in the duplication not only of DNA sequence but also of the patterns of histone modification, DNA methylation, and nucleoprotein structure that constitute epigenetic information. Pericentromeric heterochromatin in human cells is characterized by unique patterns of histone and DNA modification. Here, we describe association of the Mi-2/NuRD complex with specific segments of pericentromeric heterochromatin consisting of Satellite II/III DNA located on human chromosomes 1, 9, and 16 in some but not all cell types. This association is linked in part to DNA replication and chromatin assembly and may suggest a role in these processes. Mi-2/NuRD accumulation is independent of Polycomb association and is characterized by a unique pattern of histone modification. We propose that Mi-2/NuRD constitutes an enzymatic component of a pathway for assembly and maturation of chromatin utilized by rapidly proliferating lymphoid cells for replication of constitutive heterochromatin. C1 [Chadwick, Lisa Helbling; Wade, Paul A.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Chadwick, Brian P.] Duke Univ, Inst Genome Sci & Policy, Durham, NC 27710 USA. [Chadwick, Brian P.] Duke Univ, Dept Cell Biol, Durham, NC 27710 USA. [Jaye, David L.] Emory Univ, Dept Pathol & Lab Med, Sch Med, Atlanta, GA 30322 USA. RP Wade, PA (reprint author), NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM wadep2@niehs.nih.gov FU National Institute of Environmental Health Sciences [Z01ES101965]; NIH [GM073120, DK60647] FX We thank Dr. Huntington Willard (Duke University), Dr. Weidong Wang (National Institute of Aging), Dr. Judd Rice (University of Southern California), Dr. Stephen Smale (UCLA), and Dr. Maureen Powers (Emory University) for the generous gift of antibodies used in this study. We are grateful to Dr. Beth Sullivan for excellent suggestions and to Jeff Reece and the NIEHS Confocal Microscopy Center for assistance with confocal imaging. This manuscript was substantially improved by critical comments from Dr. Karen Adelman, Dr. Melanie Erlich, and Dr. Harriet Kinyamu. We gratefully acknowledge technical assistance from Dr. Anne Lai and Dr. Jennifer Sims in the isolation and analysis of primary B lymphocytes. We thank the various members of the Wade, Adelman, and Archer laboratories for useful discussions during the course of this work. This work was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (Project number Z01ES101965), NIH (PW), and by grants from the National Institutes of Health (GM073120 to BPC, DK60647 to DLJ). NR 52 TC 22 Z9 22 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-5915 J9 CHROMOSOMA JI Chromosoma PD AUG PY 2009 VL 118 IS 4 BP 445 EP 457 DI 10.1007/s00412-009-0207-7 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 462OK UT WOS:000267365300005 ER PT J AU Cluett, C McDermott, MM Guralnik, J Ferrucci, L Bandinelli, S Miljkovic, I Zmuda, JM Li, RL Tranah, G Harris, T Rice, N Henley, W Frayling, TM Murray, A Melzer, D AF Cluett, Christie McDermott, Mary McGrae Guralnik, Jack Ferrucci, Luigi Bandinelli, Stefania Miljkovic, Iva Zmuda, Joseph M. Li, Rongling Tranah, Greg Harris, Tamara Rice, Neil Henley, William Frayling, Timothy M. Murray, Anna Melzer, David TI The 9p21 Myocardial Infarction Risk Allele Increases Risk of Peripheral Artery Disease in Older People SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE genetics; myocardial infarction; peripheral vascular disease; 9p21; CDKN2a/2b ID ANKLE-BRACHIAL INDEX; GENOME-WIDE ASSOCIATION; ENDOTHELIAL PROGENITOR CELLS; SUBCLINICAL ATHEROSCLEROSIS; CARDIOVASCULAR HEALTH; CHROMOSOME 9P21; ARM INDEX; P16(INK4A); SUSCEPTIBILITY; LOCUS AB Background-A common variant at chromosome 9p21 (tagged by the rs1333049 or rs10757278 single-nucleotide polymorphism) is strongly associated with myocardial infarction and major arterial aneurysms. An association with peripheral arterial disease (PAD) was also reported in a sample younger than 75 years, but this disappeared on removal of respondents with a myocardial infarction history, resulting in an odds ratio of 1.09 for PAD (P = 0.075). We aimed at estimating the association of this variant with an Ankle-Brachial Index (ABI) and PAD in 3 older populations. Methods and Results-We used data from the InCHIANTI, Baltimore Longitudinal Study of Aging, and Health, Aging, and Body Composition studies. In 2630 white individuals (mean age, 76.4 years), the C allele at rs1333049 was associated with lower mean ABI measures and with an increased prevalence of PAD. These associations remained after removal of baseline and incident myocardial infarction cases over a 6-year follow-up for both ABI (-0.017 ABI units; 95% CI, -0.03 to -0.01; P = 1.3 x 10(-4)) and PAD (per allele odds ratio, 1.29; 95% CI, 1.06 to 1.56; P = 0.012). These associations also remained after adjustment for known atherosclerosis risk factors, including diabetes mellitus, smoking, hypercholesterolemia, and hypertension. Conclusions-The C allele at rs1333049 is associated with an increased prevalence of PAD and lower mean ABI. This association was independent of the presence of diagnosed myocardial infarction and atherosclerotic risk factors in 3 older white populations. (Circ Cardiovasc Genet. 2009; 2: 347-353.) C1 [Melzer, David] Peninsula Med Sch, Epidemiol & Publ Hlth Grp, Exeter EX2 5DW, Devon, England. [McDermott, Mary McGrae] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [Melzer, David] NIA, NIH, Baltimore, MD 21224 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Florence, Italy. [Miljkovic, Iva; Zmuda, Joseph M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Li, Rongling] Univ Tennessee, Ctr Hlth Sci, Coll Med, Dept Prevent Med, Memphis, TN 38163 USA. [Li, Rongling] Univ Tennessee, Ctr Hlth Sci, Coll Med, Ctr Genom & Bioinformat, Memphis, TN 38163 USA. [Tranah, Greg] Calif Pacific Med Ctr, Res Inst, San Francisco Coordinating Ctr, San Francisco, CA USA. [Guralnik, Jack; Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Melzer, D (reprint author), Peninsula Med Sch, Epidemiol & Publ Hlth Grp, RD&E Wonford Site,Barrack Rd, Exeter EX2 5DW, Devon, England. EM david.melzer@pms.ac.uk OI Murray, Anna/0000-0002-2351-2522; Miljkovic, Iva/0000-0002-3155-9777; Melzer, David/0000-0002-0170-3838 FU National Institutes of Health/National Institute on Aging [R01 AG24233, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health/National Institute on Aging and also in part by National Institutes of Health/National Institute on Aging grant R01 AG24233. The National Institute on Aging contract numbers of the Health ABC participating centers are N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. NR 45 TC 48 Z9 49 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD AUG PY 2009 VL 2 IS 4 BP 347 EP 353 DI 10.1161/CIRCGENETICS.108.825935 PG 7 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 574HG UT WOS:000275979400007 PM 20031606 ER PT J AU Huang, CC Fornage, M Lloyd-Jones, DM Wei, GS Boerwinkle, E Liu, K AF Huang, Chiang-Ching Fornage, Myriam Lloyd-Jones, Donald M. Wei, Gina S. Boerwinkle, Eric Liu, Kiang TI Longitudinal Association of PCSK9 Sequence Variations With Low-Density Lipoprotein Cholesterol Levels The Coronary Artery Risk Development in Young Adults Study SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE PCSK9; LDL-C; genetic variant; longitudinal study ID AUTOSOMAL-DOMINANT HYPERCHOLESTEROLEMIA; SINGLE-NUCLEOTIDE POLYMORPHISM; GENETIC-VARIANTS; HEART-DISEASE; TARGET GENES; ATHEROSCLEROSIS; POPULATION; MUTATIONS; CARDIA; MICE AB Background-Mutations of PCSK9 are associated cross-sectionally with plasma low-density lipoprotein cholesterol (LDL-C) levels, but little is known about their longitudinal association with LDL-C levels from young adulthood to middle age. Methods and Results-We investigated the associations of 6 PCSK9 variants with LDL-C over 20 years in 1750 blacks and 1828 whites from the Coronary Artery Risk Development In Young Adults study. Generalized estimating equations were used to assess longitudinal differences in LDL-C levels between genotype categories. For blacks, LDL-C levels at age 18 were significantly lower (P < 0.001) among those with 3 genetic variants (L253F, C679X, and Y142X; 81.5 mg/dL) and A443T (95.5 mg/dL) compared with noncarriers (109.6 mg/dL). The difference in LDL-C levels from noncarriers tended to widen for those with the 3 variants only, by 0.24 mg/dL per year of age (P = 0.14). For whites with the R46L variant, compared with noncarriers, LDL-C levels at age 18 were significantly lower (84.4 mg/dL versus 100.9 mg/dL; P < 0.001), and the increase in LDL-C with age was similar to noncarriers. The 3 genetic variants and the A443T variant in black men were associated with lower carotid intima-media thickness and lower prevalence of coronary calcification measured at ages 38 to 50. Conclusions-Our results suggest that participants with several genetic variants of PCSK9 have persistently lower serum LDL-C levels than noncarriers from ages 18 to 50. Such long-term reduction in LDL-C levels is associated with reduced subclinical atherosclerosis burden in black men. (Circ Cardiovasc Genet. 2009; 2: 354-361.) C1 [Huang, Chiang-Ching; Lloyd-Jones, Donald M.; Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Brown Fdn Inst Mol Med, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Wei, Gina S.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. RP Liu, K (reprint author), 680 N Lake Shore Dr,Suite 1102, Chicago, IL 60611 USA. EM kiangliu@northwestern.edu RI Lloyd-Jones, Donald/C-5899-2009 FU National Heart, Lung, and Blood Institute, National Institutes of Health [N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050] FX The CARDIA study was supported by contracts N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, and N01-HC-48050 from the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 29 TC 41 Z9 43 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD AUG PY 2009 VL 2 IS 4 BP 354 EP U112 DI 10.1161/CIRCGENETICS.108.828467 PG 12 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 574HG UT WOS:000275979400008 PM 20031607 ER PT J AU Franceschini, N Rose, KM Storti, KL Rutherford, S Voruganti, VS Laston, S Goring, HHH Dyer, TD Umans, JG Lee, ET Best, LG Fabsitz, RR Cole, SA MacCluer, JW North, KE AF Franceschini, Nora Rose, Kathryn M. Storti, Kristi L. Rutherford, Sue Voruganti, V. Saroja Laston, Sandy Goring, Harald H. H. Dyer, Thomas D. Umans, Jason G. Lee, Elisa T. Best, Lyle G. Fabsitz, Richard R. Cole, Shelley A. MacCluer, Jean W. North, Kari E. TI Social- and Behavioral-Specific Genetic Effects on Blood Pressure Traits The Strong Heart Family Study SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE blood pressure; hypertension; epidemiology; genetics ID LIVING PHYSICAL-ACTIVITY; CARDIOVASCULAR-DISEASE; AMERICAN-INDIANS; RISK-FACTORS; ELECTRONIC PEDOMETERS; ALCOHOL-CONSUMPTION; LINKAGE ANALYSIS; MEASURING STEPS; HYPERTENSION; HEALTH AB Background-Population studies have demonstrated an important role of social, behavioral, and environmental factors in blood pressure (BP) levels. Accounting for the genetic interaction of these factors may help to identify common BP susceptibility alleles. Methods and Results-We studied the interaction of additive genetic effects and behavioral (physical activity, smoking, alcohol use) and socioeconomic (education) factors on BP in approximate to 3600 American Indian participants of the Strong Heart Family Study, using variance component models. The mean and SD of resting systolic and diastolic BPs were 123 +/- 17 and 76 +/- 11 mm Hg, respectively. We detected evidence for distinct genetic effects on diastolic BP among ever smokers compared with never smokers (P = 0.01). For alcohol intake, we observed significant genotype-by-environment interactions on diastolic (rho g = 0.10, P = 0.0003) and on systolic BPs (rho g = 0.59, P = 0.0008) among current drinkers compared with former or never drinkers. We also detected genotype-by-physical activity interactions on diastolic BP (rho g = 0.35, P = 0.0004). Finally, there was evidence for distinct genetic effects on diastolic BP among individuals with less than high school education compared with those with 12 or more years of education (rho g = 0.41, P = 0.02). Conclusions-Our findings suggest that behavioral and socioeconomic factors can modify the genetic effects on BP phenotypes. Accounting for context dependent factors may help us to better understand the complexities of the gene effects on BP and other complex phenotypes with high levels of genetic heterogeneity. (Circ Cardiovasc Genet. 2009; 2: 396-401.) C1 [Franceschini, Nora; Rose, Kathryn M.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Storti, Kristi L.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Rutherford, Sue; Voruganti, V. Saroja; Laston, Sandy; Goring, Harald H. H.; Dyer, Thomas D.; Cole, Shelley A.; MacCluer, Jean W.] SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. [Umans, Jason G.] Georgetown Univ, Med Ctr, Div Nephrol & Hypertens, Washington, DC 20007 USA. [Umans, Jason G.] MedStar Res Inst, Washington, DC USA. [Lee, Elisa T.] Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK USA. [Best, Lyle G.] Missouri Breaks Ind Res Inc, Timber Lake, SD USA. [Fabsitz, Richard R.] NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. [North, Kari E.] Univ N Carolina, Ctr Genome Sci, Chapel Hill, NC 27514 USA. RP Franceschini, N (reprint author), Univ N Carolina, Dept Epidemiol, 137 Franklin St,Suite 306,CB 8050, Chapel Hill, NC 27514 USA. EM noraf@unc.edu FU National Heart, Lung, and Blood Institute [U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65521]; National Institutes of Health [MH059490]; American Heart Association [0675001N, 1R01HL089651-01, 1U01HG004803-01] FX This research was funded by a cooperative agreement that includes grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, and U01 HL65521 from the National Heart, Lung, and Blood Institute. Development of SOLAR and the methods implemented in it are supported by US Public Health Service grant MH059490 from the National Institutes of Health. Dr Franceschini is supported by the American Heart Association grant 0675001N, 1R01HL089651-01, and 1U01HG004803-01. NR 37 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD AUG PY 2009 VL 2 IS 4 BP 396 EP U250 DI 10.1161/CIRCGENETICS.109.853630 PG 10 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 574HG UT WOS:000275979400013 PM 20031612 ER PT J AU Marques, A Brown, MR Fleisher, TA AF Marques, Adriana Brown, Margaret R. Fleisher, Thomas A. TI Natural Killer Cell Counts Are Not Different between Patients with Post-Lyme Disease Syndrome and Controls SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID CD57 LYMPHOCYTE SUBSET AB It has been reported that patients with "chronic Lyme disease" have a decreased number of natural killer cells, as defined by the CD57 marker. We performed immunophenotyping in 9 individuals with post-Lyme disease syndrome, 12 who recovered from Lyme disease, and 9 healthy volunteers. The number of natural killer cells was not significantly different between the groups. C1 [Marques, Adriana] NIAID, Clin Studies Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Brown, Margaret R.; Fleisher, Thomas A.] NIH, Serv Immunol, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Marques, A (reprint author), NIAID, Clin Studies Unit, Lab Clin Infect Dis, NIH, Bldg 10,Room 11N234,10 Ctr Dr,MSC 1888, Bethesda, MD 20892 USA. EM amarques@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX This study was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases. NR 11 TC 26 Z9 28 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD AUG PY 2009 VL 16 IS 8 BP 1249 EP 1250 DI 10.1128/CVI.00167-09 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 476PX UT WOS:000268455800021 PM 19515868 ER PT J AU Imrich, R Vernino, S Eldadah, BA Holmes, C Goldstein, DS AF Imrich, Richard Vernino, Steven Eldadah, Basil A. Holmes, Courtney Goldstein, David S. TI Autoimmune autonomic ganglionopathy: treatment by plasma exchanges and rituximab SO CLINICAL AUTONOMIC RESEARCH LA English DT Article DE Autoimmune autonomic ganglionopathy; Pure autonomic failure; Rituximab; Plasma exchange ID AUTOANTIBODIES; RECEPTOR AB This case report describes successful treatment of autoimmune autonomic ganglionopathy (AAG) in a 74-year-old woman by total plasma exchanges (PLEX) and rituximab. Two series of PLEX temporarily, but dramatically improved orthostatic intolerance and hypotension and baroreflex function, in a manner inversely related to ganglionic neuronal nicotinic receptor antibody titer. After rituximab treatment, the antibody titer was decreased modestly but persistently, and the patient had symptomatic and clinical laboratory evidence of continued benefit for at least 10 months, supporting the autoimmune pathogenesis of AAG. C1 [Imrich, Richard] Slovak Acad Sci, Inst Expt Endocrinol, Ctr Mol Med, Bratislava 83101, Slovakia. [Vernino, Steven] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Imrich, Richard; Eldadah, Basil A.; Holmes, Courtney; Goldstein, David S.] Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, Bethesda, MD 20892 USA. RP Imrich, R (reprint author), Slovak Acad Sci, Inst Expt Endocrinol, Ctr Mol Med, Vlarska 3-7, Bratislava 83101, Slovakia. EM richard.imrich@savba.sk FU NINDS FX The authors acknowledge Dr. Kaho Wong, MD who administered rituximab to the patient. The authors thank clinical support personnel of the Clinical Neurocardiology Section, including Sandra Pechnik, RN, LaToya Sewell, CRNP, and Tereza Jenkins. The study was supported by the intramural research program of the NINDS. NR 5 TC 14 Z9 15 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI HEIDELBERG PA TIERGARTENSTRASSE 17, 69121 HEIDELBERG, GERMANY SN 0959-9851 J9 CLIN AUTON RES JI Clin. Auton. Res. PD AUG PY 2009 VL 19 IS 4 BP 259 EP 262 DI 10.1007/s10286-009-0012-7 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 483OR UT WOS:000268977600009 PM 19399547 ER PT J AU Kelly, RJ Barrett, C Swan, N McDermott, R AF Kelly, Ronan J. Barrett, Ciara Swan, Niall McDermott, Ray TI Metastatic Phyllodes Tumor Causing Small-Bowel Obstruction SO CLINICAL BREAST CANCER LA English DT Article DE Adjuvant therapy; Breast conservation therapy; Local recurrence; Mastectomy; Nuclear pleomorphism; Prognostic factors; Stromal overgrowth ID CYSTOSARCOMA-PHYLLODES; BREAST AB Cystosarcoma phyllodes is an important but relatively uncommon fibroepithelial breast neoplasm that accounts for 0.5%-1.0% of female breast carcinomas. Malignant forms comprise nearly 25% of cases. These usually metastasize to the lung, pleura, bone, and liver. Metastases to the small intestine are extremely rare, with only 1 case of metastatic spread to the deodenuim reported in the literature. No previous reports of metastatic spread to the ileum have been published. This report highlights a unique case of a metastatic phyllodes breast tumor leading to small bowel obstruction. Phyllodes tumors are generally classified into histologic subtypes of benign, intermediate, and malignant, using agreed classification systems. The tumor characteristics that can lead to the dedifferentiation of a relatively benign phenotype to an overt malignant process rare discussed. Chemotherapeutic regimens that might be effective treatments are discussed, and the importance e of regular clinical and radiologic follow up in patients with poor prognostic factors is outlined. C1 [Kelly, Ronan J.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Kelly, RJ (reprint author), NCI, Med Oncol Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kellyro@mail.nih.gov OI McDermott, Ray/0000-0002-8952-4315 NR 12 TC 2 Z9 3 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1526-8209 J9 CLIN BREAST CANCER JI Clin. Breast Cancer PD AUG PY 2009 VL 9 IS 3 BP 193 EP 195 DI 10.3816/CBC.2009.n.033 PG 3 WC Oncology SC Oncology GA 478ZV UT WOS:000268628600011 PM 19661046 ER PT J AU Sacks, DB Van den Berghe, G Kirkman, S Kost, G Ng, R Sandberg, S AF Sacks, David B. Van den Berghe, Greet Kirkman, Sue Kost, Gerald Ng, Ron Sandberg, Sverre TI Tight Glucose Control in Critically Ill Patients: Should Glucose Meters Be Used? SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 [Sacks, David B.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Van den Berghe, Greet] Catholic Univ Louvain, Dept Intens Care Med, B-3000 Louvain, Belgium. [Van den Berghe, Greet] Catholic Univ Louvain, Div Acute Med Sci, B-3000 Louvain, Belgium. [Kirkman, Sue] Amer Diabet Assoc, Alexandria, VA USA. [Kost, Gerald] Univ Calif Davis, Pathol & Lab Med, Sch Med, Davis, CA 95616 USA. [Kost, Gerald] Lawrence Livermore Natl Lab, Natl Inst Biomed Imaging & BioEngn, Point Of Care Technol Ctr, NIH, Davis, CA USA. [Ng, Ron] Abbott Diabet Care, Clin Res, Alameda, CA USA. [Sandberg, Sverre] Haukeland Hosp, Lab Clin Biochem, N-5021 Bergen, Norway. [Sandberg, Sverre] Haukeland Hosp, Norwegian Porphyria Ctr, N-5021 Bergen, Norway. [Sandberg, Sverre] Norwegian Qual Improvement Primary Care Labs NOKL, Bergen, Norway. RP Sacks, DB (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. OI Sacks, David/0000-0003-3100-0735 NR 0 TC 6 Z9 6 U1 0 U2 4 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD AUG PY 2009 VL 55 IS 8 BP 1580 EP 1583 DI 10.1373/clinchem.2009.131318 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 477ZM UT WOS:000268557500024 PM 19556440 ER PT J AU Hunter, KW Alsarraj, J AF Hunter, Kent W. Alsarraj, Jude TI Gene expression profiles and breast cancer metastasis: a genetic perspective SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Article DE Metastasis; Breast cancer; Gene expression; Genetic background; Polymorphism ID INDUCED MAMMARY-TUMOR; PROGNOSTIC SIGNATURE; MOLECULAR SIGNATURE; SUPPRESSOR GENE; MOUSE; PROGRESSION; STRAINS; PREDICT; LUNG; POLYMORPHISMS AB The majority of cancer mortality is attributed to metastasis, which is the spread of tumor cells to a secondary site. Several studies have demonstrated that the genetic background on which a tumor arises has a major effect on both metastatic efficiency and on predictive gene expression profiles. These observations suggest that there is variability in metastasis frequency between individuals and that some individuals could be more prone to secondary tumor formation and development than others. Thus, genetic background might have important clinical implications in metastasis detection, management and prevention. C1 [Hunter, Kent W.; Alsarraj, Jude] NCI, Lab Canc Biol & Genet, CCR, NIH, Bethesda, MD 20892 USA. RP Hunter, KW (reprint author), NCI, Lab Canc Biol & Genet, CCR, NIH, Bldg 37 Room 5046,37 Convent Dr, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov NR 55 TC 12 Z9 12 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD AUG PY 2009 VL 26 IS 6 BP 497 EP 503 DI 10.1007/s10585-009-9249-8 PG 7 WC Oncology SC Oncology GA 476YW UT WOS:000268483700001 PM 19347591 ER PT J AU Ning, YM Figg, WD Dahut, WL AF Ning, Yang-min Figg, William D. Dahut, William L. TI Reversal of Docetaxel Resistance With Bevacizumab and Thalidomide SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Antiangiogenesis; Castration-resistant prostate cancer; Reversal of taxane resistance ID REFRACTORY PROSTATE-CANCER; PHASE-2; TUMORS AB Taxane resistance is a common clinical problem in the treatment of many metastatic malignancies. Observational clues or evidence of overcoming such resistance is important for developing treatments that can extend taxane activity. We report a case of the reversal of docetaxel resistance with the addition of antiangiogenic agents bevacizumab and thalidomide to docetaxel and prednisone in a patient with metastatic castration-resistant prostate cancer after PSAWG progression on docetaxel and prednisone. The patient then responded for an additional 7 months. The addition of bevacizumab and thalidomide after progression on docetaxel/prednisone might reverse docetaxel resistance. These or other antiangiogenic agents for overcoming clinical taxane resistance are candidates for further study. C1 [Figg, William D.; Dahut, William L.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Ning, Yang-min] US FDA, DDOP, OODP, CDER, Silver Spring, MD USA. RP Dahut, WL (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. EM dahutw@mail.nih.gov RI Figg Sr, William/M-2411-2016 FU National Cancer Institute, Center for Cancer Research, National Institutes of Health FX This project has been supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. The observations discussed herein do not represent the views of the federal agencies nor does mention of the combined antiangiogenic therapy imply approval by these agencies. NR 9 TC 4 Z9 4 U1 1 U2 2 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD AUG PY 2009 VL 7 IS 2 BP E37 EP E38 DI 10.3816/CGC.2009.n.020 PG 2 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 528PX UT WOS:000272460000008 PM 19692321 ER PT J AU Herold, KC Gitelman, S Greenbaum, C Puck, J Hagopian, W Gottlieb, P Sayre, P Bianchine, P Wong, E Seyfert-Margolis, V Bourcier, K Bluestone, JA AF Herold, Kevan C. Gitelman, Stephen Greenbaum, Carla Puck, Jennifer Hagopian, William Gottlieb, Peter Sayre, Peter Bianchine, Peter Wong, Emelita Seyfert-Margolis, Vicki Bourcier, Kasia Bluestone, Jeffrey A. CA Immune Tolerance Network TI Treatment of patients with new onset Type 1 diabetes with a single course of anti-CD3 mAb teplizumab preserves insulin production for up to 5 years SO CLINICAL IMMUNOLOGY LA English DT Article DE Type 1 diabetes mellitus; Immunotherapy; Anti-CD3 monoclonal antibody; T lymphocyte ID HUMAN T-CELLS; MONOCLONAL-ANTIBODY; THYMIC FUNCTION; IN-VIVO; POPULATION; OKT3; HOKT3-GAMMA-1(ALA-ALA); STIMULATION; ACTIVATION; APOPTOSIS AB Anti-CD3 mAbs may prolong 1 cell function up to 2 years in patients with new onset Type 1 diabetes (T1DM). A randomized open label trial of anti-CD3 mAb, Teplizumab, in T1DM was stopped after 10 subjects because of increased adverse events than in a previous trial related with higher dosing of drug. Teplizumab caused transient reduction in circulating T cells, but the recovered cells were not new thymic emigrants because T cell receptor excision circles were not increased. There was a trend for reduced loss of C-peptide over 2 years with drug treatment (p=0.1), and insulin use was lower (p<0.001). In 4 drug-treated subjects followed up to 60 months, C-peptide responses were maintained. We conclude that increased doses of Teplizumab are associated with greater adverse events without improved efficacy. The drug may marginate rather than deplete T cells. C-peptide levels may remain detectable up to 5 years after treatment. (C) 2009 Elsevier Inc. All rights reserved. C1 [Herold, Kevan C.] Yale Univ, Dept Immunobiol, New Haven, CT 06520 USA. [Herold, Kevan C.] Yale Univ, Dept Med, New Haven, CT 06520 USA. [Gitelman, Stephen; Puck, Jennifer] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Wong, Emelita] Univ Calif San Francisco, Dept Stat, San Francisco, CA 94143 USA. [Wong, Emelita] PPD Inc, Wilmington, NC USA. [Bluestone, Jeffrey A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Greenbaum, Carla] Benaroya Res Inst, Seattle, WA USA. [Hagopian, William] Pacific NW Res Inst, Dept Med, Seattle, WA USA. [Hagopian, William] Univ Washington, Seattle, WA 98195 USA. [Gottlieb, Peter] Univ Colorado, Dept Med, Denver, CO USA. [Bianchine, Peter] Natl Inst Allergy Immunol & Infect Dis, Bethesda, MD USA. [Sayre, Peter; Seyfert-Margolis, Vicki; Bourcier, Kasia; Bluestone, Jeffrey A.] Immune Tolerance Network, Bethesda, MD USA. RP Herold, KC (reprint author), Yale Univ, Dept Immunobiol, 10 Amistad St,131D, New Haven, CT 06520 USA. FU National Center for Research Resources (NCRR) [N01-Al-15416-3700, DK057846, UL1 RR024139, UL1 RR024131, M01-RR-00037, M01-RR00069]; National Institutes of Health (NIH); US Immunodeficiency Network (USIDNET) FX Supported by grants N01-Al-15416-3700, DK057846, and CTSA grants UL1 RR024139 (Yale Univ), UL1 RR024131 (UCSF), and grants M01-RR-00037 (Univ Wash) and M01-RR00069 (UnivColo) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). The authors relied on the expertise of Diana Gonzalez for running the TREC test. JMP received support from the US Immunodeficiency Network (USIDNET). We would like to thank JM McCune, UCSF for the helpful discussions of the manuscript. NR 22 TC 110 Z9 117 U1 2 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD AUG PY 2009 VL 132 IS 2 BP 166 EP 173 DI 10.1016/j.clim.2009.04.007 PG 8 WC Immunology SC Immunology GA 474GB UT WOS:000268269500003 PM 19443276 ER PT J AU Knisz, J Banks, A McKeag, L Metcalfe, DD Rothman, PB Brown, JM AF Knisz, Judit Banks, Alex McKeag, Lisa Metcalfe, Dean D. Rothman, Paul B. Brown, Jared M. TI Loss of SOCS7 in mice results in severe cutaneous disease and increased mast cell activation SO CLINICAL IMMUNOLOGY LA English DT Article DE Allergy; Atopic dermatitis; Suppressor of cytokine signaling; SOCS; TSLP; Mast cell ID THYMIC STROMAL LYMPHOPOIETIN; FC-EPSILON-RI; HUMAN EPITHELIAL-CELLS; ALLERGIC INFLAMMATION; CYTOKINE SIGNALING-1; ATOPIC-DERMATITIS; IN-VITRO; SUPPRESSOR; INHIBITION; EXPRESSION AB The Suppressor of Cytokine Signaling (SOCS) protein family plays a central role in the negative regulation of cytokine action and has been implicated in the development of atopic diseases. Lack of SOCS7 is associated with severe skin disease in mice. We sought to explore the underlying mechanisms resulting in this phenotype. Skin samples were analyzed and serum immunoglobulin production was measured. Cytokine production by bone marrow derived mast cells was determined by ELISA. Mast cell thymic stromal lymphopoietin (TSLP) production was assessed by quantitative real-time PCR. Data obtained revealed that Socs7(-/-) mice have increased serum IgE and IgG(1) production and exhibit an increased mast cell infiltrate, as well as un-provoked mast cell degranulation in the dermis as compared to controls. In vitro, bone marrow derived mast cells from Socs7(-/-) mice are hyperactive to IgE-mediated stimuli, with elevated production of proinflammatory cytokines (IL-13, IL-6, TNF-alpha). Further, activated Socs7(-/-) bone marrow derived mast cells have increased IL-7R alpha transcript, which is part of the heterodimeric receptor for TSLP. Finally, lack of SOCS7 was accompanied by an increase in TSLP mRNA and protein production by mast cells following Fc epsilon RI aggregation. These data implicate SOCS7 in the modulation of allergic inflammation and demonstrate that SOCS7 is involved in the regulation of TSLP signaling in mast cells. (C) 2009 Published by Elsevier Inc. C1 [Knisz, Judit; McKeag, Lisa; Rothman, Paul B.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [Banks, Alex] Columbia Univ, Dept Microbiol, New York, NY 10032 USA. [Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Brown, Jared M.] E Carolina Univ, Dept Pharmacol & Toxicol, Brody Sch Med, Greenville, NC USA. RP Rothman, PB (reprint author), Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Internal Med, SE308 GH,200 Hawkins Dr, Iowa City, IA 52242 USA. EM paul-rothman@uiowa.edu RI Banks, Alexander/B-4832-2012 OI Banks, Alexander/0000-0003-1787-6925 FU NIH [R01 DK-67231, Al-054821]; Division of Intramural Research, MAID, NIH; East Carolina University FX Funded by NIH R01 DK-67231, Al-054821 (P.B.R.), Division of Intramural Research, MAID, NIH (DDM) and in part from East Carolina University (JMB). NR 30 TC 15 Z9 16 U1 2 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD AUG PY 2009 VL 132 IS 2 BP 277 EP 284 DI 10.1016/j.clim.2009.04.003 PG 8 WC Immunology SC Immunology GA 474GB UT WOS:000268269500014 PM 19427817 ER PT J AU Breman, JG AF Breman, Joel G. TI No Man Is an Island: Multiple Pathologies in Patients with Malaria SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID LIFE-THREATENING MALARIA; INFECTIOUS-DISEASES; AFRICAN CHILDREN; COINFECTION C1 US NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Breman, JG (reprint author), US NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. EM jbreman@nih.gov NR 13 TC 0 Z9 0 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 AUG 1 PY 2009 VL 49 IS 3 BP 344 EP 345 DI 10.1086/600300 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 468LK UT WOS:000267819700004 PM 19548832 ER PT J AU Lash, JP Go, AS Appel, LJ He, J Ojo, A Rahman, M Townsend, RR Xie, DW Cifelli, D Cohan, J Fink, JC Fischer, MJ Gadegbeku, C Hamm, LL Kusek, JW Landis, JR Narva, A Robinson, N Teal, V Feldman, HI AF Lash, James P. Go, Alan S. Appel, Lawrence J. He, Jiang Ojo, Akinlolu Rahman, Mahboob Townsend, Raymond R. Xie, Dawei Cifelli, Denise Cohan, Janet Fink, Jeffrey C. Fischer, Michael J. Gadegbeku, Crystal Hamm, L. Lee Kusek, John W. Landis, J. Richard Narva, Andrew Robinson, Nancy Teal, Valerie Feldman, Harold I. CA Chronic Renal Insufficiency Cohort TI Chronic Renal Insufficiency Cohort (CRIC) Study: Baseline Characteristics and Associations with Kidney Function SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID NONTRADITIONAL RISK-FACTORS; GLOMERULAR-FILTRATION-RATE; CORONARY-HEART-DISEASE; BLOOD-PRESSURE; SOCIOECONOMIC-STATUS; SERUM CREATININE; AFRICAN-AMERICAN; CARDIOVASCULAR OUTCOMES; ATHEROSCLEROSIS RISK; UNITED-STATES AB Background and objectives: The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for the progression of chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with CKD. We examined baseline demographic and clinical characteristics. Design, setting, participants, & measurements: Seven clinical centers recruited adults who were aged 21 to 74 yr and had CKD using age-based estimated GFR (eGFR) inclusion criteria. At baseline, blood and urine specimens were collected and information regarding health behaviors, diet, quality of life, and functional status was obtained. GFR was measured using radiolabeled iothalamate in one third of participants. Results: A total of 3612 participants were enrolled with mean age +/- SD of 58.2 +/- 11.0 yr, 46% were women, and 47% had diabetes. Overall, 45% were non-Hispanic white, 46% were non-Hispanic black, and 5% were Hispanic. Eighty-six percent reported hypertension, 22% coronary disease, and 10% heart failure. Mean body mass index was 32.1 +/- 7.9 kg/m(2), and 47% had a BP >130/80 mmHg. Mean eGFR was 43.4 +/- 13.5 ml/min per 1.73 m(2), and median (interquartile range) protein excretion was 0.17 g/24 h (0.07 to 0.81 g/24 h). Lower eGFR was associated with older age, lower socioeconomic and educational level, cigarette smoking, self-reported CVD, peripheral arterial disease, and elevated BP. Conclusions: Lower level of eGFR was associated with a greater burden of CVD as well as lower socioeconomic and educational status. Long-term follow-up of participants will provide critical insights into the epidemiology of CKD and its relationship to adverse outcomes. Clin J Am Soc Nephrol 4: 1302-1311, 2009. doi: 10.2215/CJN.00070109 C1 [Lash, James P.] Univ Illinois, Dept Med, Nephrol Sect MC 793, Chicago, IL 60612 USA. [Go, Alan S.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Appel, Lawrence J.] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [He, Jiang; Hamm, L. Lee] Tulane Univ, Dept Med, New Orleans, LA 70118 USA. [He, Jiang] Tulane Univ, Dept Epidemiol, New Orleans, LA 70118 USA. [Ojo, Akinlolu; Gadegbeku, Crystal] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Rahman, Mahboob] Case Western Univ, Dept Med, Cleveland, OH USA. [Townsend, Raymond R.; Feldman, Harold I.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Xie, Dawei; Cifelli, Denise; Landis, J. Richard; Robinson, Nancy; Teal, Valerie; Feldman, Harold I.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Fink, Jeffrey C.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Fischer, Michael J.] Jesse Brown VAMC, Ctr Management Complex Chron Care, Chicago, IL USA. [Fischer, Michael J.] Edward Hines VA, Maywood, IL USA. [Kusek, John W.; Narva, Andrew] NIDDK, NIH, Bethesda, MD USA. RP Lash, JP (reprint author), Univ Illinois, Dept Med, Nephrol Sect MC 793, 820 S Wood St, Chicago, IL 60612 USA. EM jplash@uic.edu RI Landis, J. Richard/A-9330-2010; OI Fink, Jeffrey/0000-0002-5622-5052 FU National Institute of Diabetes and Digestive and Kidney Diseases [5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, 5U01DK060902]; institutional Clinical Translational Science Awards; National Institutes of Health; Johns Hopkins University [UL1 RR-025005]; University of Maryland GRCR [M01 RR-16500]; Case Western Reserve University Clinical and Translational Science Collaborative [UL1 RR-024989]; University of Michigan GCRC [M01 RR-000042]; CTSA [UL1 RR024986]; University of Illinois at Chicago Clinical Research Center [M01 RR-013987-06]; Tulane/LSU/Charity Hospital General Clinical Research Center [RR-05096]; Kaiser NIH/NCRR UCSF-CTSI ULI [RIZ024131, 5K24DK002651]; National Center for Minority Health and Health Disparities; National Institutes of Health, and Department of Veterans Affairs FX In addition to funding under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, and 5U01DK060902), this work was supported in part by the following institutional Clinical Translational Science Awards and other National Institutes of Health grants: Johns Hopkins University UL1 RR-025005, University of Maryland GRCR M01 RR-16500, Case Western Reserve University Clinical and Translational Science Collaborative (University Hospitals of Cleveland, Cleveland Clinic Foundation, and MetroHealth) UL1 RR-024989, University of Michigan GCRC M01 RR-000042 and CTSA UL1 RR024986, University of Illinois at Chicago Clinical Research Center, M01 RR-013987-06, Tulane/LSU/Charity Hospital General Clinical Research Center RR-05096, and Kaiser NIH/NCRR UCSF-CTSI ULI RIZ024131 and 5K24DK002651. Additional support provided by the National Center for Minority Health and Health Disparities, National Institutes of Health, and Department of Veterans Affairs (Career Development Award to M.J.F.). NR 50 TC 173 Z9 177 U1 0 U2 5 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD AUG PY 2009 VL 4 IS 8 BP 1302 EP 1311 DI 10.2215/CJN.00070109 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 479RJ UT WOS:000268678300004 PM 19541818 ER PT J AU Bartholomew, LK Cushman, WC Cutler, JA Davis, BR Dawson, G Einhorn, PT Graumlich, JF Piller, LB Pressel, S Roccella, EJ Simpson, L Whelton, PK Williard, A AF Bartholomew, L. Kay Cushman, William C. Cutler, Jeffrey A. Davis, Barry R. Dawson, Glenna Einhorn, Paula T. Graumlich, James F. Piller, Linda B. Pressel, Sara Roccella, Edward J. Simpson, Lara Whelton, Paul K. Williard, Angela CA ALLHAT Collaborative Res Grp TI Getting clinical trial results into practice: design, implementation, and process evaluation of the ALLHAT Dissemination Project SO CLINICAL TRIALS LA English DT Article ID LIPID-LOWERING TREATMENT; HEART-ATTACK TRIAL; RANDOMIZED CONTROLLED-TRIAL; CONTINUING MEDICAL-EDUCATION; ACUTE MYOCARDIAL-INFARCTION; JOINT NATIONAL COMMITTEE; ACUTE STROKE THERAPY; HIGH BLOOD-PRESSURE; PRACTICE GUIDELINES; PRESCRIBING PATTERNS AB Background Conventional dissemination of clinical trial results has inconsistent impact on physician practices. A more comprehensive plan to influence determinants of prescribing practices is warranted. Purpose To report the response from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial to the National Heart, Lung, and Blood Institute's requirement for dissemination and evaluation of trials with potential immediate public health applicability. Methods ALLHAT's dissemination plan had two-components: (1) a traditional approach of media coverage, scientific presentation, and publication; and (2) a theory-based approach targeting determinants of clinician behavior. Strategies included: (1) academic detailing, in which physicians approach colleagues regarding blood pressure management, (2) direct patient messages to stimulate communication with physicians regarding blood pressure control, (3) approaches to formulary systems to use educational and economic incentives for evidence-based prescription, and (4) direct professional organization appeals to clinicians. Results One hundred and forty-seven Investigator Educators reported 1698 presentations to 18,524 clinicians in 41 states and the District of Columbia. The pre- and post-test responses of 1709 clinicians in the face-to-face meetings indicated significant changes in expectations for positive patient outcomes and intention to prescribe diuretics. Information was mailed to 55 individuals representing 20 professional organizations and to eight formulary systems. Direct-to-patient messages were provided to 14 sites that host patient newsletters and Web sites such as health plans and insurance companies, 62 print mass media outlets, and 12 broadcast media sites. Limitations It was not within the scope of the project to conduct a randomized trial of the impact of the dissemination. However, impact evaluation using quasi-experimental designs is ongoing. Conclusion A large multi-method dissemination of clinical trial results is feasible. Planning for dissemination efforts, including evaluation research, should be considered as a part of the funding and design of the clinical trial and should begin early in trial planning. Clinical Trials 2009;6:329-343.http://ctj.sagepub.com C1 [Pressel, Sara] Univ Texas Houston, Hlth Sci Ctr, Coordinating Ctr Clin Trials, Sch Publ Hlth, Houston, TX 77030 USA. [Cushman, William C.] Vet Affairs Med Ctr, Memphis, TN USA. [Cutler, Jeffrey A.; Einhorn, Paula T.; Roccella, Edward J.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Graumlich, James F.] Univ Illinois, Coll Med, Peoria, IL 61656 USA. [Whelton, Paul K.] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. [Williard, Angela] Tulane Univ, New Orleans, LA 70118 USA. RP Pressel, S (reprint author), Univ Texas Houston, Hlth Sci Ctr, Coordinating Ctr Clin Trials, Sch Publ Hlth, 1200 Herman Pressler St,Suite E801, Houston, TX 77030 USA. EM Sara.L.Pressel@uth.tmc.edu FU National Heart, Lung, and Blood Institute [N01-HC-35130]; National Institutes of Health; US Department of Health and Human Services, Bethesda, MD FX This research was supported by Health and Human Services contract number N01-HC-35130 from the National Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services, Bethesda, MD. The ALLHAT investigators acknowledge contributions of study medications supplied by Pfizer, Inc. (amlodipine), AstraZeneca (atenolol and lisinopril), and BristolMyers Squibb (pravastatin) and financial support provided by Pfizer, Inc. NR 78 TC 7 Z9 7 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2009 VL 6 IS 4 BP 329 EP 343 DI 10.1177/1740774509338234 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 481UD UT WOS:000268836600004 PM 19587068 ER PT J AU Brubaker, L Moalli, P Richter, HE Albo, M Sirls, L Chai, T Kraus, SR Norton, P Chang, D Tennstedt, SL AF Brubaker, Linda Moalli, Pamela Richter, Holly E. Albo, Michael Sirls, Larry Chai, Toby Kraus, Stephen R. Norton, Peggy Chang, Debuene Tennstedt, Sharon L. TI Challenges in designing a pragmatic clinical trial: the mixed incontinence-medical or surgical approach (MIMOSA) trial experience SO CLINICAL TRIALS LA English DT Article ID UROGENITAL DISTRESS INVENTORY; FEMALE URINARY-INCONTINENCE; PELVIC FLOOR DISORDERS; FREE VAGINAL TAPE; EPIDEMIOLOGIC SURVEY; IMPACT QUESTIONNAIRE; STRESS-INCONTINENCE; URGE INCONTINENCE; SHORT FORMS; WOMEN AB Background Mixed urinary incontinence (MUI)is a common, bothersome condition in women. In MUI, the two subtypes of urinary incontinence that coexist are treated differently; stress urinary incontinence (SUI) is primarily treated surgically while urge urinary incontinence (UUI) is primarily treated medically. There is no evidence to guide the treatment for women with significant bother from both incontinence subtypes. Therefore, investigators of the Urinary Incontinence Treatment Network (UITN) designed and initiated a randomized clinical trial comparing outcomes for two distinct initial treatment approaches for women with mixed urinary incontinence (MUI): therapy initiated with surgery versus therapy initiated with nonsurgical treatment. Purpose The aim of this manuscript is to describe the challenges in planning and implementing this randomized clinical trial. Methods The mixed incontinence: medical or surgical approach (MIMOSA) trial was designed as a practical or pragmatic clinical trial to establish the relative efficacy of two specific treatment approaches. The design presented many challenging decisions including: (1) selection of practical paradigm; (2) refining inclusion/exclusion criteria to offer equipoise; (3) selection of feasibility sample size; (4) recruitment challenges for two divergent treatment approaches (medical vs. surgical), and (5) resolution of ethical and methodological issues. Results MIMOSA recruitment was planned in two phases, starting with a 5-month pilot and feasibility phase followed by a full trial contingent on the outcome of the first phase. The feasibility portion of the MIMOSA trial started in November 2008. 1198 subjects were screened and approached forstudy enrollment, but only 27 consented to randomization. The feasibility study was halted due to lack of enrollment in March 2009. Limitations The challenges of this trial included a lack of information from subjects who did not enroll, increasing the difficulty of interpreting the feasibility phase. Conclusions Successful recruitment to a randomized trial that compares significantly different treatment approaches poses a challenge. Clinical Trials 2009; 6: 355-364.http://ctj.sagepub.com C1 [Brubaker, Linda] Loyola Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Brubaker, Linda] Loyola Univ, Dept Urol, Chicago, IL 60611 USA. [Moalli, Pamela] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Richter, Holly E.] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Albo, Michael] Univ Calif San Diego, Dept Reprod Med, San Diego, CA 92103 USA. [Sirls, Larry] William Beaumont Hosp, Dept Urol, Royal Oak, MI 48072 USA. [Chai, Toby] Univ Maryland, Dept Urol, College Pk, MD 20742 USA. [Kraus, Stephen R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Norton, Peggy] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Chang, Debuene] NIDDK, NIH, Bethesda, MD USA. [Tennstedt, Sharon L.] New England Res Inst, Watertown, MA 02172 USA. RP Brubaker, L (reprint author), Loyola Univ Chicago, 2160 S 1st Ave,Bldg 103,Room 1004D, Maywood, IL 60153 USA. EM Lbrubaker@lumc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK58225, U01 DK58229, U01 DK58234, U01 DK58231, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, U01 DK60401, NCT00064662] FX This trial was supported by cooperative agreements from the National Institute of Diabetes and Digestive and Kidney Diseases, U01 DK58225, U01 DK58229, U01 DK58234, U01 DK58231, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, and U01 DK60401. This trial is registered at Clinicaltrials. gov NCT00064662. The authors wish to acknowledge the guidance of Stuart J. Pocock, BSc, MSc, PhD. For a list of UITN investigators see Appendix A. NR 33 TC 15 Z9 16 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2009 VL 6 IS 4 BP 355 EP 364 DI 10.1177/1740774509339239 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 481UD UT WOS:000268836600006 PM 19625327 ER PT J AU Bridge, H Smolskis, M Bianchine, P Dixon, DO Kelly, G Herpin, B Tavel, J AF Bridge, Heather Smolskis, Mary Bianchine, Peter Dixon, Dennis O. Kelly, Grace Herpin, Betsey Tavel, Jorge CA NIAID Clinical Res Subcomm TI Development and Implementation of Clinical Trial Protocol Templates at the National Institute of Allergy and Infectious Diseases SO CLINICAL TRIALS LA English DT Article AB Background A clinical research protocol document must reflect both sound scientific rationale as well as local, national and, when applicable, international regulatory and human subject protections requirements. These requirements originate from a variety of sources, undergo frequent revision and are subject to interpretation. Tools to assist clinical investigators in the production of clinical protocols could facilitate navigating these requirements and ultimately increase the efficiency of clinical research. Purpose The National Institute of Allergy and Infectious Diseases ( NIAID) developed templates for investigators to serve as the foundation for protocol development. These protocol templates are designed as tools to support investigators in developing clinical protocols. Methods NIAID established a series of working groups to determine how to improve its capacity to conduct clinical research more efficiently and effectively. The Protocol Template Working Group was convened to determine what protocol templates currently existed within NIAID and whether standard NIAID protocol templates should be produced. After review and assessment of existing protocol documents and requirements, the group reached consensus about required and optional content, determined the format and identified methods for distribution as well as education of investigators in the use of these templates. Results The templates were approved by the NIAID Executive Committee in 2006 and posted as part of the NIAID Clinical Research Toolkit [ 1] website for broad access. These documents require scheduled revisions to stay current with regulatory and policy changes. Limitations The structure of any clinical protocol template, whether comprehensive or specific to a particular study phase, setting or design, affects how it is used by investigators. Each structure presents its own set of advantages and disadvantages. While useful, protocol templates are not stand-alone tools for creating an optimal protocol document, but must be complemented by institutional resources and support. Education and guidance of investigators in the appropriate use of templates is necessary to ensure a complete yet concise protocol document. Due to changing regulatory requirements, clinical protocol templates cannot become static, but require frequent revisions. C1 [Bridge, Heather] NIAID, NIH, DCR, Bethesda, MD 20892 USA. RP Bridge, H (reprint author), NIAID, NIH, DCR, 6700 B Rockledge Dr,Room 1221, Bethesda, MD 20892 USA. EM bridgeh@mail.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 9 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2009 VL 6 IS 4 BP 386 EP 391 DI 10.1177/1740774509341482 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 481UD UT WOS:000268836600010 PM 19625326 ER PT J AU Williams, KM Mella, H Lucas, PJ Williams, JA Telford, W Gress, RE AF Williams, Kirsten M. Mella, Heather Lucas, Philip J. Williams, Joy A. Telford, William Gress, Ronald E. TI Single Cell Analysis of Complex Thymus Stromal Cell Populations: Rapid Thymic Epithelia Preparation Characterizes Radiation Injury SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE thymic epithelial cell; separation; radiation ID BONE-MARROW-TRANSPLANTATION; KERATINOCYTE GROWTH-FACTOR; INTENSITY CONDITIONING REGIMEN; RECOVERING RAT THYMUS; IMMUNE RECONSTITUTION; FACTOR KGF; T-CELLS; EXPANSION; THYMOPOIESIS; IRRADIATION AB Thymic epithelial cells (TECs) and dendritic cells are essential for the maintenance of thymopoiesis. Because these stromal elements define the progenitor niche, provide critical survival signals and growth factors, and direct positive and negative selection, detailed study of these populations is necessary to understand important elements for thymic renewal after cytotoxic injury. Study of TEC is currently hindered by lengthy enzymatic separation techniques with decreased viability. We present a new rapid separation technique that yields consistent viable TEC numbers in a quarter of the prior preparation time. Using this new procedure, we identify changes in stromal populations following total body irradiation (TBI). By flow cytometry, we show that TBI significantly depletes UEA+ medullary TEC, while sparing Ly51+ CD45- cells. Further characterization of the Ly51+ subset reveals enrichment of fibroblasts (CD45-Ly51+ MHCII-), while cortical TECs (CD45- Ly51+ MHCII+) were markedly reduced. Dendritic cells (CD11c+ CD45+) were also decreased following TBI. These data suggest that cytotoxic preparative regimens may impair thymic renewal by reducing critical populations of cortical and medullary TEC, and that such thymic damage can be assessed by this new rapid separation technique, thereby providing a means of assessing optimal conditioning pretransplant for enhancing thymic-dependent immune reconstitution posttransplant. C1 [Williams, Kirsten M.; Mella, Heather; Lucas, Philip J.; Telford, William; Gress, Ronald E.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Williams, Joy A.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Williams, KM (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. EM williaki@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX This study was supported by intramural funds provided by the National Cancer Institute, National Institutes of Health. We thank Yu-Waye Chu for his review of this article. The authors have no conflicting financial interests. NR 46 TC 11 Z9 12 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD AUG PY 2009 VL 2 IS 4 BP 279 EP 285 DI 10.1111/j.1752-8062.2009.00128.x PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 533RX UT WOS:000272843400010 PM 19750208 ER PT J AU Unverzagt, FW Smith, DM Rebok, GW Marsiske, M Morris, JN Jones, R Willis, SL Ball, K King, JW Koepke, KM Stoddard, A Tennstedt, SL AF Unverzagt, Frederick W. Smith, David M. Rebok, George W. Marsiske, Michael Morris, John N. Jones, Richard Willis, Sherry L. Ball, Karlene King, Jonathan W. Koepke, Kathy Mann Stoddard, Anne Tennstedt, Sharon L. TI The Indiana Alzheimer Disease Center's Symposium on Mild Cognitive Impairment. Cognitive Training in Older Adults: Lessons from the ACTIVE Study SO CURRENT ALZHEIMER RESEARCH LA English DT Article ID TRIAL; PERFORMANCE; TASKS AB This paper is based on a presentation made during the Indiana Alzheimer Disease Center's Symposium on Mild Cognitive Impairment on April 19, 2008. The results of the ACTIVE study (Advanced Cognitive Training for Independent and Vital Elderly) were presented at the symposium including review of previously published study findings. The ACTIVE study is a multicenter, randomized, controlled clinical trial that has been examining the long-term effectiveness of cognitive training on enhancing mental abilities (memory, reasoning, and attention) and preserving activities of daily living (managing finances, taking medication, using the telephone, and driving) in older adults. Six centers across the eastern United States enrolled nearly 3000 people initially. Participants underwent detailed assessments of mental and functional ability on multiple occasions over several years of follow-up. ACTIVE has shown positive effects of cognitive training at 5 years post-intervention for basic mental abilities, health-related quality of life, and improved ability to perform instrumental activities of daily living (IADL). A subgroup analysis through 2 years of follow-up suggested that subjects with mild cognitive impairment (MCI) did not benefit from memory training; however, they did benefit, to the same degree as cognitively normal participants, from training in reasoning and speed of processing. This finding suggests that MCI may interfere with a person's ability to benefit from some forms of cognitive enhancement. Limitations of ACTIVE and directions for future research are reviewed. C1 [Unverzagt, Frederick W.] Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Smith, David M.] Indiana Univ, Sch Med, Dept Med, Bloomington, IN 47405 USA. [Rebok, George W.] Johns Hopkins Univ, Dept Mental Hlth, Baltimore, MD 21218 USA. [Marsiske, Michael] Univ Florida, Inst Aging, Gainesville, FL 32611 USA. [Marsiske, Michael] Univ Florida, Dept Clin & Hlth Psychol, Gainesville, FL 32611 USA. [Willis, Sherry L.] Penn State Univ, Dept Human Dev & Family Studies, University Pk, PA 16802 USA. [Ball, Karlene] Univ Alabama, Dept Psychol, Birmingham, AL USA. [King, Jonathan W.] NIA, Bethesda, MD 20892 USA. [Koepke, Kathy Mann] NINR, Bethesda, MD USA. RP Unverzagt, FW (reprint author), Indiana Univ, Sch Med, Dept Psychiat, 1111 W 10th St,Suite PB 218A, Indianapolis, IN 46202 USA. EM funverza@iupui.edu OI Marsiske, Michael/0000-0001-5973-2116; Jones, Richard/0000-0002-1049-218X FU National Institutes of Health [R01 NR04508, R01 AG026096, P30 AG10133]; Hebrew Senior Life, Boston [R01 NR04507]; Johns Hopkins University [R01 AG14260]; New England Research Institutes [R01 AG14282]; Pennsylvania State University [R01 AG14263]; University of Alabama at Birmingham [R01 AG14289]; University of Florida [R01 AG014276]; Posit Science FX Supported by grants from the National Institutes of Health to six field sites and the coordinating center, including: Indiana University School of Medicine (R01 NR04508; R01 AG026096; and P30 AG10133), Hebrew Senior Life, Boston (R01 NR04507), Johns Hopkins University (R01 AG14260), New England Research Institutes (R01 AG14282), Pennsylvania State University (R01 AG14263), University of Alabama at Birmingham (R01 AG14289), and University of Florida (R01 AG014276). Dr. Rebok is an investigator with Compact Disc Incorporated for the development of an electronic version of the ACTIVE memory intervention. Dr. Marsiske has received support from Posit Science in the form of site licenses for the Insight program for a different research project. Karlene Ball owns stock in the Visual Awareness Research Group (formerly Visual Awareness, Inc.), and Posit Science, Inc., the companies that market the Useful Field of View Test and speed of processing training software (now called Insight). Posit Science acquired Visual Awareness, and Dr. Ball continues to collaborate on the design and testing of these assessment and training programs as a member of the Posit Science Scientific Advisory Board. NR 23 TC 15 Z9 16 U1 0 U2 8 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD AUG PY 2009 VL 6 IS 4 BP 375 EP 383 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 513SS UT WOS:000271344300010 PM 19689237 ER PT J AU Jia, L Zhao, YQ Liang, XJ AF Jia, Lee Zhao, Yuqing Liang, Xing-Jie TI Current Evaluation of the Millennium Phytomedicine- Ginseng (II): Collected Chemical Entities, Modern Pharmacology, and Clinical Applications Emanated from Traditional Chinese Medicine SO CURRENT MEDICINAL CHEMISTRY LA English DT Review DE Ginseng; ginsenosides; phytomedicine; nitric oxide; diabetics; aphrodisia; neuropharmacology; anti-apoptosis ID KOREAN RED GINSENG; PANAX-QUINQUEFOLIUM-L; PROTEIN-KINASE-C; RADICAL-INDUCED HEMOLYSIS; VITRO ANTICANCER ACTIVITY; NF-KAPPA-B; AMERICAN GINSENG; IN-VITRO; NITRIC-OXIDE; CANCER-CELLS AB This review, a sequel to part 1 in the series, collects about 107 chemical entities separated from the roots, leaves and flower buds of Panax ginseng, quinquefolius and notoginseng, and categorizes these entities into about 18 groups based on their structural similarity. The bioactivities of these chemical entities are described. The 'Yin and Yang' theory and the fundamentals of the 'five elements' applied to the traditional Chinese medicine (TCM) are concisely introduced to help readers understand how ginseng balances the dynamic equilibrium of human physiological processes from the TCM perspectives. This paper concerns the observation and experimental investigation of biological activities of ginseng used in the TCM of past and present cultures. The current biological findings of ginseng and its medical applications are narrated and critically discussed, including 1) its antihyperglycemic effect that may benefit type II diabetics; in vitro and in vivo studies demonstrated protection of ginseng on beta-cells and obese diabetic mouse models. The related clinical trial results are stated. 2) its aphrodisiac effect and cardiovascular effect that partially attribute to ginseng's bioactivity on nitric oxide (NO); 3) its cognitive effect and neuropharmacological effect that are intensively tested in various rat models using purified ginsenosides and show a hope to treat Parkinson's disease (PD); 4) its uses as an adjuvant or immunotherapeutic agent to enhance immune activity, appetite and life quality of cancer patients during their chemotherapy and radiation. Although the apoptotic effect of ginsenosides, especially Rh2, Rg3 and Compound K, on various tumor cells has been shown via different pathways, their clinical effectiveness remains to be tested. This paper also updates the antioxidant, anti-inflammatory, anti-apoptotic and immune-stimulatory activities of ginseng, its ingredients and commercial products, as well as common side effects of ginseng mainly due to its overdose, and its pharmacokinetics. C1 [Jia, Lee] NCI, Dev Therapeut Program, NIH, Rockville, MD 20852 USA. [Zhao, Yuqing] Shenyang Pharmaceut Univ, Shenyang 110006, Peoples R China. [Liang, Xing-Jie] Natl Ctr Nanosci & Technol China, Div Nanomed & Nanobiol, Lab Nanobiomed & Nanosafety, Beijing 100190, Peoples R China. RP Jia, L (reprint author), 6130 Execut Blvd,Room 8042, Rockville, MD 20852 USA. EM jiale@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 174 TC 131 Z9 135 U1 3 U2 43 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD AUG PY 2009 VL 16 IS 22 BP 2924 EP 2942 PG 19 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 474BZ UT WOS:000268258600010 PM 19689273 ER PT J AU Berzofsky, JA Terabe, M AF Berzofsky, Jay A. Terabe, Masaki TI The Contrasting Roles of NKT Cells in Tumor Immunity SO CURRENT MOLECULAR MEDICINE LA English DT Review DE NKT cells; tumor immunity; immunosurveillance; immunoregulation; alpha-galactosylceramide; cancer; IL-13; TGF-beta ID KILLER-T-CELLS; NONOBESE DIABETIC MICE; GROWTH-FACTOR-BETA; HEPATITIS-B-VIRUS; NATURAL-KILLER; ALPHA-GALACTOSYLCERAMIDE; DENDRITIC CELLS; IN-VIVO; ANTITUMOR IMMUNITY; CUTTING EDGE AB NKT cells are true T cells that serve as a bridge between the innate and adaptive immune system, acting as first responders. They recognize lipid antigens rather than peptides, and respond to these when presented by a non-classical class I MHC molecule, CD1d. NKT cells can play a pathogenic role in asthma or a protective role against several autoimmune diseases, in part based on their cytokine profile. In cancer, they can play opposite roles, contributing to anti-tumor immunity or suppressing it. The protective NKT cells were found to be primarily type I NKT cells defined by use of a semi-invariant T cell receptor involving V alpha 14J alpha 18 in mice and V alpha 24J alpha 18 in humans and responding to alpha-galactosylceramide, and the most protective were among the minority that are CD4(-). The suppressive NKT cells were found to be CD4(+) and to be primarily type II NKT cells, that have diverse T-cell receptors and respond to other lipids. Further, the type I and type II NKT cells were found to counter-regulate each other, forming a new immunoregulatory axis. This axis may have broad implications beyond cancer, as NKT cells play a role in steering other adaptive immune responses. The balance along this axis could affect immunity to tumors and infectious diseases and responses to vaccines. C1 [Berzofsky, Jay A.; Terabe, Masaki] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM berzofsk@helix.nih.gov; terabe@mail.nih.gov FU Intramural NIH HHS [Z01 SC004020-30] NR 103 TC 62 Z9 66 U1 0 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD AUG PY 2009 VL 9 IS 6 BP 667 EP 672 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 514FW UT WOS:000271380700002 PM 19689293 ER PT J AU Strober, W Kitani, A Fichtner-Feigl, S Fuss, IJ AF Strober, Warren Kitani, Atsushi Fichtner-Feigl, Stefan Fuss, Ivan J. TI The Signaling Function of the IL-13R alpha 2 Receptor in the Development of Gastrointestinal Fibrosis and Cancer Surveillance SO CURRENT MOLECULAR MEDICINE LA English DT Review ID BRONCHIAL EPITHELIAL-CELLS; GROWTH-FACTOR-BETA; TUMOR IMMUNOSURVEILLANCE; IL-13 RECEPTOR-ALPHA-2; TISSUE FIBROSIS; T-CELLS; ANTITUMOR-ACTIVITY; OXAZOLONE COLITIS; ALPHA-2 CHAIN; GLIOMA-CELLS AB The IL-13R alpha 2 receptor is a high affinity receptor for IL-13 that is used only by IL-13 and is quite distinct from the well known IL-13R alpha 1 receptor that IL-13 shares with IL-4. It was widely considered to be a secreted receptor that is devoid of signaling activity and functional only as a decoy receptor that retarded signaling via IL-13R alpha 1. In recent studies, however, it was shown to be capable of robust signaling that results in production of TGF-beta 1 and through the latter cytokine, the induction of fibrosis occuring in various experimental inflammatory states. Thus, in initial studies, IL-13 signaling via IL-13R alpha 2 was shown to play an important role in the fibrosis developing in both oxazolone colitis and bleomycin-induced pulmonary fibrosis; later, it was also shown to be critical to the development of fibrosis in a model of chronic colitis induced by trinitrobenzene sulphonic acid (TNBS). These studies suggest that blockade of IL-13 or IL-13R alpha 2 signaling might be an excellent target for the prevention of inflammation-associated fibrosis. A second role of IL-13 signaling via IL-13R alpha 2 is in tumor immune surveillance. Thus, in the relevant studies it was shown that NKT cells stimulated by tumor antigens produce IL-13 that then acts on Gr-1 cells to induce TGF-beta 1; the latter then inhibits CD8(+) T cells engaged in tumor immune surveillance; in effect, then, receptor signaling favors tumor growth. In addition to its signaling function and the induction of TGF-beta 1, IL-13R alpha 2 also influences IL-13R alpha 1 signaling in complex ways; thus, IL-13R alpha 2 emerges as a important component of IL-13 signaling, not only in its own right but also in its possible effect on its companion receptor. C1 [Strober, Warren; Kitani, Atsushi; Fuss, Ivan J.] NIAID, Mucosal Immun Sect, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [Fichtner-Feigl, Stefan] Univ Regensburg, Dept Surg, D-93053 Regensburg, Germany. RP Fuss, IJ (reprint author), NIAID, Mucosal Immun Sect, Lab Host Defenses, NIH, CRC Build,Rm 5W-3864, Bethesda, MD 20892 USA. EM IFUSS@niaid.nih.gov NR 35 TC 15 Z9 16 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 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD AUG PY 2009 VL 9 IS 6 BP 740 EP 750 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 514FW UT WOS:000271380700010 PM 19689301 ER PT J AU Li, X Fasano, R Wang, E Yao, KT Marincola, FM AF Li, Xin Fasano, Ross Wang, Ena Yao, Kai-Tai Marincola, Francesco M. TI HLA Associations with Nasopharyngeal Carcinoma SO CURRENT MOLECULAR MEDICINE LA English DT Review DE Nasopharyngeal carcinoma; human leukocyte antigen; epstein - barr virus; disease associations ID EPSTEIN-BARR-VIRUS; IMMUNOGLOBULIN-LIKE RECEPTORS; CLASS-I; SUSCEPTIBILITY LOCUS; HIV-1 INFECTION; LATENT MEMBRANE-PROTEIN-1; GENETIC POLYMORPHISMS; ANTIGEN PRESENTATION; IMMUNE-RESPONSES; CHROMOSOME 3P21 AB Several associations have been described between the frequency of human leukocyte antigen (HLA) class I genes in certain populations and the risk of developing nasopharyngeal carcinoma (NPC). Associations between ethnic background and geographic distribution, and relative disease incidence have been reported. Populations in geographical areas at higher risk of developing NPC display HLA distribution patterns different and sometimes opposite from areas of low incidence, whereas populations in areas with intermediate incidence display a totally independent pattern. Two main reasons may explain this association between HLA phenotype distribution and the risk of developing NPC in various populations. First, given the fact that expression of Epstein-Barr Virus (EBV) proteins by cancer cells is tightly linked with NPC development, HLA may influence the development of NPC by modulating the expression of EBV proteins. This explanation is, however, based primarily on theoretical assumptions given that no clear definition of HLA binding pattern of EBV epitopes has been directly shown to significantly alter the recognition of EBV proteins and the risk of developing the disease. Alternatively, HLA may represent a genetic marker flagging the presence of a NPC predisposition locus in close linkage disequilibrium with the HLA class I region. A critical review of known HLA associations in various geographical areas and their interpretation will be presented in this review. C1 [Li, Xin; Fasano, Ross; Wang, Ena; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Li, Xin; Yao, Kai-Tai] So Med Univ, Canc Res Inst, Guangzhou 510515, Guangdong, Peoples R China. RP Li, X (reprint author), NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM xinli268@gmail.com; FMarincola@mail.cc.nih.gov FU Intramural NIH HHS [ZIA CL002118-04] NR 91 TC 20 Z9 21 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD AUG PY 2009 VL 9 IS 6 BP 751 EP 765 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 514FW UT WOS:000271380700011 PM 19689302 ER PT J AU Samara, RN Khleif, SN AF Samara, Raed N. Khleif, Samir N. TI HPV as a Model for the Development of Prophylactic and Therapeutic Cancer Vaccines SO CURRENT MOLECULAR MEDICINE LA English DT Review ID HUMAN-PAPILLOMAVIRUS TYPE-16; CERVICAL INTRAEPITHELIAL NEOPLASIA; MINOR CAPSID PROTEIN; RANDOMIZED CONTROLLED-TRIAL; PARTICLE VACCINE; NEUTRALIZATION EPITOPE; CROSS-NEUTRALIZATION; QUADRIVALENT VACCINE; CELL CARCINOMA; DOUBLE-BLIND AB HPV has been linked to many human malignancies and, as such, represents a major public health crisis. The understanding of HPV biology, however, has helped tremendously in developing prophylactic vaccines, which should help in decreasing mortality due to HPV infections. Understanding HPV biology has allowed researchers to use the virus as a model for the development of not only prophylactic vaccines, but also therapeutic ones. The advantages of HPV as a model stem from the limited number of proteins encoded by the HPV genome that can be targeted by vaccines, and also from the restricted expression of certain viral proteins during different stages of infection. In this review, we discuss how HPV can be used as a model for the development of both prophylactic and therapeutic vaccines. C1 [Samara, Raed N.; Khleif, Samir N.] NCI NNMC, Canc Vaccine Sect, Bethesda, MD 20889 USA. RP Khleif, SN (reprint author), NCI NNMC, Canc Vaccine Sect, Bldg 10,Rm 5101, Bethesda, MD 20889 USA. EM khleifs@navmed.nci.nih.gov NR 71 TC 1 Z9 1 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD AUG PY 2009 VL 9 IS 6 BP 766 EP 773 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 514FW UT WOS:000271380700012 PM 19689303 ER PT J AU Puligilla, C Kelley, MW AF Puligilla, Chandrakala Kelley, Matthew W. TI Building the world's best hearing aid; regulation of cell fate in the cochlea SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID MAMMALIAN INNER-EAR; OTIC PLACODE INDUCTION; HAIR-CELLS; SENSORY EPITHELIUM; PROSENSORY PATCHES; EXPRESSING CELLS; NOTCH LIGANDS; GENE-TRANSFER; CHICK LIMB; MOUSE AB In mammals, auditory perception is initially mediated through sensory cells located in a rigorously patterned mosaic of unique cell types located within the coiled cochlea. Identification of the factors that direct multipotent progenitor cells to develop as each of these specialized cell types has the potential to enhance our understanding of the development of the auditory system and to identify potential targets for regenerative therapies. Recent results have identified specific signaling molecules and pathways, including Notch, Hedgehog, Sox2 and Fgfs, that guide progenitor cells to develop first as a sensory precursor, referred to as a prosensory cell, and subsequently as one of the specialized cell types within the sensory mosaic. C1 [Puligilla, Chandrakala; Kelley, Matthew W.] Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Puligilla, C (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM PuligillaC@nidcd.nih.gov; Kelleymt@nidcd.nih.gov FU Intramural Program of the National Institute on Deafness and Other Communication Disorders at National Institutes of Health FX The authors' research is supported by the Intramural Program of the National Institute on Deafness and Other Communication Disorders at National Institutes of Health. The authors wish to apologize to any of the colleagues whose work was unavoidably excluded from this review owing to space constrains. NR 45 TC 18 Z9 19 U1 2 U2 5 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD AUG PY 2009 VL 19 IS 4 BP 368 EP 373 DI 10.1016/j.gde.2009.06.004 PG 6 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 494KN UT WOS:000269811800011 PM 19604683 ER PT J AU Bassett, DS Bullmore, ET AF Bassett, Danielle S. Bullmore, Edward T. TI Human brain networks in health and disease SO CURRENT OPINION IN NEUROLOGY LA English DT Article DE graph; modularity; network; small world; wiring cost ID GRAPH-THEORETICAL ANALYSIS; STATE FUNCTIONAL CONNECTIVITY; SMALL-WORLD NETWORKS; ALZHEIMERS-DISEASE; CORTICAL THICKNESS; CEREBRAL-CORTEX; DISCONNEXION SYNDROMES; SCHIZOPHRENIA; ORGANIZATION; MRI AB Purpose of review Recent developments in the statistical physics of complex networks have been translated to neuroimaging data in an effort to enhance our understanding of human brain structural and functional networks. This review focuses on studies using graph theoretical measures applied to structural MRI, diffusion MRI, functional MRI, electroencephalography, and magnetoencephalography data. Recent findings Complex network properties have been identified with some consistency in all modalities of neuroimaging data and over a range of spatial and time scales. Conserved properties include small worldness, high efficiency of information transfer for low wiring cost, modularity, and the existence of network hubs. Structural and functional network metrics have been found to be heritable and to change with normal aging. Clinical studies, principally in Alzheimer's disease and schizophrenia, have identified abnormalities of network configuration in patients. Future work will likely involve efforts to synthesize structural and functional networks in integrated models and to explore the interdependence of network configuration and cognitive performance. Summary Graph theoretical analysis of neuroimaging data is growing rapidly and could potentially provide a relatively simple but powerful quantitative framework to describe and compare whole human brain structural and functional networks under diverse experimental and clinical conditions. C1 [Bassett, Danielle S.; Bullmore, Edward T.] Addenbrookes Hosp, Dept Psychiat, Behav & Clin Neurosci Inst, Cambridge CB2 0SZ, England. [Bassett, Danielle S.] Univ Cambridge, Dept Phys, Biol Soft Syst Sector, Cambridge, England. [Bassett, Danielle S.] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Bullmore, Edward T.] Addenbrookes Hosp, Clin Unit Cambridge, Cambridge CB2 0SZ, England. RP Bullmore, ET (reprint author), Addenbrookes Hosp, Dept Psychiat, Behav & Clin Neurosci Inst, Herchel Smith Bldg Brain & Mind Sci, Cambridge CB2 0SZ, England. EM etb23@cam.ac.uk RI Bullmore, Edward/C-1706-2012 OI Bullmore, Edward/0000-0002-8955-8283 FU National Institute of Biomedical Imaging and Bioengineering; National Institute of Mental Health; Intramural Research Program of the National Institutes of Health, NIMH FX This research was supported by a Human Brain Project grant from the National Institute of Biomedical Imaging and Bioengineering and the National Institute of Mental Health, and by the Intramural Research Program of the National Institutes of Health, NIMH. D.S.B. was supported by the National Institutes of Health Graduate Partnerships Program. NR 52 TC 295 Z9 305 U1 4 U2 43 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD AUG PY 2009 VL 22 IS 4 BP 340 EP 347 DI 10.1097/WCO.0b013e32832d93dd PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 475SC UT WOS:000268380000002 PM 19494774 ER PT J AU Wang, F Arun, P Friedman, J Chen, Z Van Waes, C AF Wang, Frederick Arun, Pattatheyil Friedman, Jay Chen, Zhong Van Waes, Carter TI Current and potential inflammation targeted therapies in head and neck cancer SO CURRENT OPINION IN PHARMACOLOGY LA English DT Review ID SQUAMOUS-CELL CARCINOMA; FACTOR-KAPPA-B; GROWTH-FACTOR RECEPTOR; MAMMALIAN TARGET; MOLECULAR TARGET; TUMOR-GROWTH; PHASE-II; SURVIVAL; INTERLEUKIN-6; RAPAMYCIN AB Inflammation often exists in the tumor microenvironment and is induced by inflammatory mediators (cytokines, chemokines, and growth factors) produced by the tumor, stroma, and infiltrating cells. These factors modulate tissue remodeling and angiogenesis and actively promote tumor cell survival and chemoresistance through autocrine and paracrine mechanisms. Head and neck squamous cell carcinomas (HNSCCs) are highly inflammatory and aggressive in nature, and they express a number of cytokines and growth factors involved in inflammation. These cytokines and growth factors activate important signal transduction pathways, including NF-kappa B, JAK/STAT, and PI3K/Akt/mTOR, which regulate the expression of genes controlling growth, survival, and chemosensitivity. This review provides an update on recent advances in the understanding of the mechanisms driving cancer-related inflammation in HNSCC and on molecular targeted therapies under preclinical and clinical investigation. C1 [Wang, Frederick; Arun, Pattatheyil; Friedman, Jay; Chen, Zhong; Van Waes, Carter] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. [Wang, Frederick] Howard Hughes Med Inst, NIH, Res Scholars Program, Bethesda, MD 20814 USA. RP Van Waes, C (reprint author), Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, 10 Ctr Dr,Rm 5D-55, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov FU NIDCD intramural [Z01-DC-000016, Z01-DC-000073]; Howard Hughes Medical Institute-National Institutes of Health Research Scholars FX The work is supported by NIDCD intramural projects Z01-DC-000016 and Z01-DC-000073 and Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program (FW). NR 50 TC 56 Z9 56 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4892 J9 CURR OPIN PHARMACOL JI Curr. Opin. Pharmacol. PD AUG PY 2009 VL 9 IS 4 BP 389 EP 395 DI 10.1016/j.coph.2009.06.005 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 494KM UT WOS:000269811600006 PM 19570715 ER PT J AU Qian, BF Wahl, SM AF Qian, Bi-Feng Wahl, Sharon M. TI TGF-beta can leave you breathless SO CURRENT OPINION IN PHARMACOLOGY LA English DT Review ID GROWTH-FACTOR-BETA; REGULATORY T-CELLS; ROR-GAMMA-T; NEUTROPHIL RECRUITMENT; ALLERGIC DISEASE; HELPER-CELLS; DIFFERENTIATION; ASTHMA; T(H)17; INFLAMMATION AB Transforming growth factor-beta (TGF-beta), a ubiquitous and multifunctional cytokine, is central to the evolution and modulation of host defense. Early on, TGF-beta was recognized for its chemotactic and pro-inflammatory properties, but then identification of its powerful suppressive activities focused attention on dissecting its mechanisms of immune inhibition. Just as quickly as TGF-beta-mediated regulation of a population of CD4(+)CD25(+)Foxp3(+) regulatory T cells became the rage, a surprising finding that TGF-beta was the impetus behind a subset of pro-inflammatory T helper (Th)17 cells brought back a re-emphasis on its broader ability to dictate inflammatory events. Emerging evidence indicates that much remains to be discovered regarding the complex and intertwined roles of TGF-beta in inflammation, T cell lineage commitment, antibody generation, immune suppression, and tolerance. While it may appear that TGF-beta has multiple, ill-defined, contradictory and overlapping modes of activity that are impossible to unravel, the current excitement for dissecting how TGF-beta controls immunity defines a challenge worthy of pursuit. The lung is particularly vulnerable to the influences of TGF-beta, which is produced by its immune and non-immune cell populations. In its absence, lung pathology becomes lethal, whereas TGF-beta overproduction also has untoward consequences, potentially leaving one breathless, and underscoring the paradoxical, but essential contribution of TGF-beta to tissue and immune homeostasis. C1 [Qian, Bi-Feng; Wahl, Sharon M.] Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Wahl, SM (reprint author), Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. EM smwahl@dir.nidcr.nih.gov FU Intramural Research Program of the NIH; National Institute of Dental; Craniofacial Research FX The authors gratefully acknowledge the editorial assistance of Nis Data Stoney. This research was supported partly by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research. NR 50 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4892 J9 CURR OPIN PHARMACOL JI Curr. Opin. Pharmacol. PD AUG PY 2009 VL 9 IS 4 BP 454 EP 461 DI 10.1016/j.coph.2009.04.001 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 494KM UT WOS:000269811600015 PM 19467929 ER PT J AU Bartesaghi, A Subramaniam, S AF Bartesaghi, Alberto Subramaniam, Sriram TI Membrane protein structure determination using cryo-electron tomography and 3D image averaging SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Review ID ELECTRON CRYOMICROSCOPY; BACTERIAL CHEMORECEPTORS; MOLECULAR ARCHITECTURE; IN-SITU; RESOLUTION; CLASSIFICATION; VIRUS; MACROMOLECULES; RECONSTRUCTION; COMPLEXES AB The vast majority of membrane protein complexes of biological interest cannot be purified to homogeneity, or removed from a physiologically relevant context without loss of function. It is therefore not possible to easily determine the 3D structures of these protein complexes using X-ray crystallography or conventional cryo-electron microscopy. Newly emerging methods that combine cryo-electron tomography with 3D image classification and averaging are, however, beginning to provide unique opportunities for in situ determination of the structures of membrane protein assemblies in intact cells and nonsymmetric viruses. Here we review recent progress in this field and assess the potential of these methods to describe the conformation of membrane proteins in their native environment. C1 [Bartesaghi, Alberto; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM subramas@mail.nih.gov FU Intramural NIH HHS [Z01 BC010825-01] NR 30 TC 43 Z9 44 U1 0 U2 13 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X EI 1879-033X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD AUG PY 2009 VL 19 IS 4 BP 402 EP 407 DI 10.1016/j.sbi.2009.06.005 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 496VS UT WOS:000270008300006 PM 19646859 ER PT J AU Hirai, T Subramaniam, S Lanyi, JK AF Hirai, Teruhisa Subramaniam, Sriram Lanyi, Janos K. TI Structural snapshots of conformational changes in a seven-helix membrane protein: lessons from bacteriorhodopsin SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Review ID ELECTRON-PARAMAGNETIC-RESONANCE; CRYSTAL-STRUCTURE; CRYSTALLOGRAPHIC STRUCTURE; COUPLED RECEPTOR; PROTON TRANSLOCATION; L-INTERMEDIATE; M-STATE; TRANSPORT MECHANISM; ANGSTROM RESOLUTION; L-PHOTOINTERMEDIATE AB Recent advances in crystallizing integral membrane proteins have led to atomic models for the structures of several seven-helix membrane proteins, including those in the G-protein-coupled receptor family. Further steps toward exploring structure-function relationships will undoubtedly involve determination of the structural changes that occur during the various stages of receptor activation and deactivation. We expect that these efforts will bear many parallels to the studies of conformational changes in bacteriorhodopsin, which still remains the best-studied seven-helix membrane protein. Here, we provide a brief review of some of the lessons learned, the challenges faced, and the controversies over the last decade with determining conformational changes in bacteriorhodopsin. Our hope is that this analysis will be instructive for similar structural studies, especially of other seven-helix membrane proteins, in the coming decade. C1 [Hirai, Teruhisa] RIKEN SPring 8, Dimens Microscopy Res Team 3, Sayo, Hyogo 6795148, Japan. [Subramaniam, Sriram] NCI, Cell Biol Lab, NIH, Bethesda, MD 20817 USA. [Lanyi, Janos K.] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92697 USA. RP Hirai, T (reprint author), RIKEN SPring 8, Dimens Microscopy Res Team 3, 1-1-1 Kouto, Sayo, Hyogo 6795148, Japan. EM thirai@spring8.or.jp; ss1@nih.gov; jklanyi@uci.edu RI Lanyi, Janos/C-3808-2011; Hirai, Teruhisa/G-2105-2015 OI Hirai, Teruhisa/0000-0002-2114-8149 FU NIGMS NIH HHS [R37 GM029498, R37 GM029498-29] NR 53 TC 47 Z9 48 U1 5 U2 32 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD AUG PY 2009 VL 19 IS 4 BP 433 EP 439 DI 10.1016/j.sbi.2009.07.009 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 496VS UT WOS:000270008300010 PM 19643594 ER PT J AU Kalish, H Phillips, TM AF Kalish, Heather Phillips, Terry M. TI The Application of Micro-Analytical Techniques to Biomedical Analysis SO CURRENT PHARMACEUTICAL ANALYSIS LA English DT Review DE Microfluidics; Bioanalysis; Chip-based CE; Micro-HPLC; Lab-on-a-chip ID PERFORMANCE LIQUID-CHROMATOGRAPHY; IMMUNOAFFINITY CAPILLARY-ELECTROPHORESIS; TANDEM MASS-SPECTROMETRY; LASER-INDUCED FLUORESCENCE; MONOLITHIC STATIONARY PHASES; HIGH-ABUNDANCE PROTEINS; GEL-ELECTROPHORESIS; MICROCHIP ELECTROPHORESIS; BIOLOGICAL-FLUIDS; ALPHA-1-ACID GLYCOPROTEIN AB The current interest in micro- and nano-scale devices has lead to their development for biomedical analysis. This ranges from static nucleic acid and protein arrays to complex analytical techniques based on chromatographic and electrokinetic techniques utilizing small-bore capillaries and chips. This review will describe the range of technologies available and examine the different platforms used in micro- and nano-device driven design. Additionally, the review will cover specific devices and device-driven technologies, such as standard and chip-based capillary electrophoresis and nano-flow chromatography that either have potential or are currently available for biomedical analysis. With more laboratories turning towards high throughput, cost effective analytical processes there is a special need for biomedical analysis to be performed at the micro- and ultra-micro level because of limited sample availability. Although limited at present, micro- and nano-technologies have been successfully applied to the examination of not only basic research samples, but also to clinical samples. Currently, micro- analytical techniques hold the potential of being able to examine specialized samples such as single cells and their secretions, extremely small samples from newborn and young patients, precious limited material archive specimens, and perform real-time bedside monitoring. C1 [Kalish, Heather; Phillips, Terry M.] Natl Inst Biomed Imaging & Bioengn, Ultramicro Immunodiagnost Sect, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Kalish, H (reprint author), Natl Inst Biomed Imaging & Bioengn, Ultramicro Immunodiagnost Sect, Lab Bioengn & Phys Sci, NIH, Bldg 13,Room 3E42,9000 Rockville Pike, Bethesda, MD 20892 USA. EM KalishH@mail.nih.gov NR 139 TC 6 Z9 6 U1 2 U2 19 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1573-4129 J9 CURR PHARM ANAL JI Curr. Pharm. Anal. PD AUG PY 2009 VL 5 IS 3 BP 208 EP 228 PG 21 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 487BZ UT WOS:000269246800001 ER PT J AU Wang, HW Finzi, L Lewis, DEA Dunlap, D AF Wang, Haowei Finzi, Laura Lewis, Dale E. A. Dunlap, David TI AFM Studies of lambda Repressor Oligomers Securing DNA Loops SO CURRENT PHARMACEUTICAL BIOTECHNOLOGY LA English DT Article CT 5th Biennial Winter Workshop on Single Molecule Biophysics CY JAN 02-09, 2009 CL Aspen, CO DE Lambda repressor; DNA looping; Atomic force microscopy ID ATOMIC-FORCE MICROSCOPY; BACTERIOPHAGE-LAMBDA; GENE-REGULATION; CI-REPRESSOR; TRANSCRIPTION ACTIVATION; PROTEIN-PROTEIN; RIGHT OPERATOR; LAC REPRESSOR; BINDING; CONSTANTS AB Large, cooperative assemblies of proteins that wrap and/or loop genomic DNA may "epigenetically" shift configurational equilibria that determine developmental pathways. Such is the case of the lambda bacteriophage which may exhibit virulent (lytic) or quiescent (lysogenic) growth. The lysogenic state of lambda prophages is maintained by the lambda repressor (CI), which binds to tripartite operator sites in each of the O(L) and O(R) control regions located about 2.3 kbp apart on the phage genome and represses lytic promoters. Dodd and collaborators have suggested that an initial loop formed by interaction between CI bound at O(R) and O(L) provides the proper scaffold for additional CI binding to attenuate the P(RM) promoter and avoid over production of CI. Recently, the looping equilibrium as a function of CI concentration was measured using tethered particle motion analysis, but the oligomerization of CI in looped states could not be determined. Scanning force microscopy has now been used to probe these details directly. An equilibrium distribution of looped and unlooped molecules confined to a plane was found to be commensurate to that for tethered molecules in solution, and the occupancies of specific operator sites for several looped and unlooped conformations were determined. Some loops appeared to be sealed by oligomers of 6-8, most by oligomers of 10-12, and a few by oligomers of 14-16. C1 [Dunlap, David] Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA 30322 USA. [Wang, Haowei; Finzi, Laura] Emory Univ, Dept Phys, Atlanta, GA 30322 USA. [Lewis, Dale E. A.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dunlap, D (reprint author), Emory Univ, Sch Med, Dept Cell Biol, Whitehead Bldg Rm 475, Atlanta, GA 30322 USA. EM ddunlap@emory.edu FU NIGMS NIH HHS [R01 GM084070] NR 27 TC 15 Z9 15 U1 1 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2010 J9 CURR PHARM BIOTECHNO JI Curr. Pharm. Biotechnol. PD AUG PY 2009 VL 10 IS 5 BP 494 EP 501 PG 8 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 482TZ UT WOS:000268913000005 PM 19689317 ER PT J AU Di Giorgio, A Sambataro, F Bertolino, A AF Di Giorgio, A. Sambataro, F. Bertolino, A. TI Functional Imaging as a Tool to Investigate the Relationship between Genetic Variation and Response to Treatment with Antipsychotics SO CURRENT PHARMACEUTICAL DESIGN LA English DT Review ID CATECHOL-O-METHYLTRANSFERASE; DOPAMINE-RECEPTOR GENE; MONOZYGOTIC TWINS CONCORDANT; CLOZAPINE TREATMENT RESPONSE; NEGATIVE SYMPTOM RESPONSE; VAL(108/158) MET GENOTYPE; EXON-III POLYMORPHISM; WORKING-MEMORY; SCHIZOPHRENIC-PATIENTS; PROMOTER REGION AB Recent evidence suggests that genetic variation is associated with individual variability in response to treatment with antipsychotics. Although numerous studies have been performed for identification of potential genetic variants affecting response to treatment, initial enthusiasm has been tempered by inconsistent results. Along with some specific methodological issues, another plausible explanation for such inconsistencies is lack of sensitivity of the phenotype ( clinical measures) used to define response. In this paper, we review use of Imaging Genetics, a relatively new approach that combines genetic assessment with functional neuroimaging, to explore in vivo neurobiological effects of genetic variation. Moreover, we propose to use Imaging Genetics as a tool to evaluate and predict response to treatment with antipsychotics based on the individual genetic makeup. C1 [Sambataro, F.] NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Bertolino, A.] IRCCSS Casa Sollievo della Sofferenza, Dept Neuroradiol, San Giovanni Rotondo, Italy. [Di Giorgio, A.; Sambataro, F.; Bertolino, A.] Univ Bari, Dept Neurol & Psychiat Sci, Sect Mental Disorders, Psychiat Neurosci Grp, I-70124 Bari, Italy. RP Bertolino, A (reprint author), Univ Bari, Dept Neurol & Psychiat Sci, Sect Mental Disorders, Psychiat Neurosci Grp, Piazza Giulio Cesare 9, I-70124 Bari, Italy. EM a.bertolino@psichiat.uniba.it RI Sambataro, Fabio/E-3426-2010; Di Giorgio, Annabella /D-7353-2017 OI Sambataro, Fabio/0000-0003-2102-416X; Di Giorgio, Annabella /0000-0001-7876-3495 NR 166 TC 7 Z9 7 U1 0 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD AUG PY 2009 VL 15 IS 22 BP 2560 EP 2572 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 482UW UT WOS:000268915400004 PM 19689328 ER PT J AU Kreitman, RJ AF Kreitman, Robert J. TI Recombinant Immunotoxins for the Treatment of Chemoresistant Hematologic Malignancies SO CURRENT PHARMACEUTICAL DESIGN LA English DT Review ID HAIRY-CELL LEUKEMIA; ACUTE MYELOID-LEUKEMIA; SINGLE-CHAIN IMMUNOTOXIN; PSEUDOMONAS EXOTOXIN-A; CHRONIC LYMPHOCYTIC-LEUKEMIA; COLONY-STIMULATING FACTOR; DIPHTHERIA-TOXIN RECEPTOR; MINIMAL RESIDUAL DISEASE; PHASE-I TRIAL; INTERLEUKIN-2 FUSION PROTEIN AB Recombinant immunotoxins are proteins composed of fragments of monoclonal antibodies fused to truncated protein toxins. No agents of this class are approved yet for medical use, although a related molecule, denileukin diftitox, composed of interleukin-2 fused to truncated diphtheria toxin, is approved for relapsed/refractory cutaneous T-cell lymphoma. Recombinant immunotoxins which have been tested in patients with chemotherapy-pretreated hematologic malignancies include LMB-2 (anti-CD25), BL22 (CAT-3888, anti-CD22) and HA22 (CAT-8015, anti-CD22), each containing an Fv fragment fused to truncated Pseudomonas exotoxin. Major responses were observed with LMB-2 in adult T-cell leukemia, chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma, Hodgkin's disease, and hairy cell leukemia (HCL). BL22 resulted in a high complete remission rate in patients with HCL, particularly those without excessive tumor burden. HA22, an improved version of BL22 with higher affinity to CD22, is now undergoing phase I testing in HCL, CLL, non-Hodgkin's lymphoma, and pediatric acute lymphoblastic leukemia. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NCI, Mol Biol Lab, NIH, 37-5124B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU NCI; MedImmune, LLC FX The work regarding LMB-2, BL22, HA22 and DT388GM-CSF, was in part supported by the intramural program, NCI. Clinical development regarding BL22 and HA22 was in part funded by MedImmune, LLC. NR 188 TC 31 Z9 32 U1 2 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD AUG PY 2009 VL 15 IS 23 BP 2652 EP 2664 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 482UX UT WOS:000268915500002 PM 19689336 ER PT J AU Marchand, C Maddali, K Metifiot, M Pommier, Y AF Marchand, Christophe Maddali, Kasthuraiah Metifiot, Mathieu Pommier, Yves TI HIV-1 IN Inhibitors: 2010 Update and Perspectives SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Review DE HIV-1 IN; diketo acids; HIV inhibitors; AIDS; IN inhibitors; peptides; oligonucleotides ID HUMAN-IMMUNODEFICIENCY-VIRUS; RETROVIRAL DNA-INTEGRATION; CHAIN VARIABLE FRAGMENT; PHOTO-CROSS-LINKING; L-CHICORIC ACID; METAL-DEPENDENT INHIBITION; STRAND TRANSFER-REACTION; N-TERMINAL DOMAIN; BETA-DIKETO ACIDS; RNASE-H DOMAIN AB Integrase (IN) is the newest validated target against AIDS and retroviral infections. The remarkable activity of raltegravir (Isentress (R)) led to its rapid approval by the FDA in 2007 as the first IN inhibitor. Several other IN strand transfer inhibitors (STIs) are in development with the primary goal to overcome resistance due to the rapid occurrence of IN mutations in raltegravir-treated patients. Thus, many scientists and drug companies are actively pursuing clinically useful IN inhibitors. The objective of this review is to provide an update on the IN inhibitors reported in the last two years, including second generation STI, recently developed hydroxylated aromatics, natural products, peptide, antibody and oligonucleotide inhibitors. Additionally, the targeting of IN cofactors such as LEDGF and Vpr will be discussed as novel strategies for the treatment of AIDS. C1 [Marchand, Christophe; Maddali, Kasthuraiah; Metifiot, Mathieu; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Center for Cancer Research, an Intramural Division of the National Cancer Institute, National Institutes of Health FX This work was supported by the Center for Cancer Research, an Intramural Division of the National Cancer Institute, National Institutes of Health. We wish to thank Dr. Thomas Dexheimer for his careful reading and suggestion for this review. We also wish to thank all the other members of the Laboratory of Molecular Pharmacology for stimulating discussions. NR 179 TC 62 Z9 62 U1 1 U2 10 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PD AUG PY 2009 VL 9 IS 11 BP 1016 EP 1037 PG 22 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 514HD UT WOS:000271384100005 PM 19747122 ER PT J AU Laverty, HG Wakefield, LM Occleston, NL O'Kane, S Ferguson, MWJ AF Laverty, H. G. Wakefield, L. M. Occleston, N. L. O'Kane, S. Ferguson, M. W. J. TI TGF-beta 3 and cancer: A review SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE Transforming growth factor beta; Tumourigenesis; Cytokines; Avotermin ID TRANSFORMING-GROWTH-FACTOR; TGF-BETA-ISOFORMS; GENE-EXPRESSION SIGNATURE; BENIGN PROSTATIC HYPERPLASIA; HUMAN-MELANOMA CELLS; RAT MAMMARY-GLAND; BREAST-CANCER; IN-VITRO; DIFFERENTIAL EXPRESSION; NEUTRALIZING ANTIBODY AB With the development of growth factors and growth factor modulators as therapeutics for a range of disorders, it is prudent to consider whether modulating the growth factor profile in a tissue can influence turnout initiation or progression. As recombinant human TGF-beta 3 (avotermin) is being developed for the improvement of scarring in the skin it is important to understand the role, if any, of this cytokine in turnout progression. Elevated levels of TGF-beta 3 expression detected in late-stage turnours have linked this cytokine with tumourigenesis, although functional data to support a causative role are lacking. While it has proved tempting for researchers to interpret a 'correlation' as a 'cause' of disease, what has often been overlooked is the normal biological role of TGF-beta 3 in processes that are often subverted in tumourigenesis. Clarifying the role of this cytokine is complicated by inappropriate extrapolation of the data relating to TGF-beta 1 in tumourigenesis, despite marked differences in biology between the TGF-beta isoforms. Indeed, published studies have indicated that TGF-beta 3 may actually play a protective role against tumourigenesis in a range of tissues including the skin, breast, oral and gastric mucosa. Based on currently available data it is reasonable to hypothesize that administration of acute low doses of exogenous TGF-beta 3 is unlikely to influence turnout initiation or progression. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Laverty, H. G.; Occleston, N. L.; O'Kane, S.; Ferguson, M. W. J.] Renovo Grp Plc, Core Technol Facil, Manchester M13 9XX, Lancs, England. [Wakefield, L. M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Ferguson, MWJ (reprint author), Renovo Grp Plc, Core Technol Facil, 48 Grafton St, Manchester M13 9XX, Lancs, England. EM mark.ferguson@renovo.com FU Renovo FX Preparation of the manuscript was funded by Renovo. The authors would like to thank Dawn Lobban for editorial assistance. NR 163 TC 36 Z9 40 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD AUG PY 2009 VL 20 IS 4 BP 305 EP 317 DI 10.1016/j.cytogfr.2009.07.002 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 499WB UT WOS:000270256100005 PM 19656717 ER PT J AU Moore, J Roederer, M AF Moore, Jonni Roederer, Mario TI The Flow Cytometry Shared Resource Laboratory: Best Practices to Assure a High-Quality, Cost-Effective Partnership with Biomedical Research Laboratories SO CYTOMETRY PART A LA English DT Article C1 [Moore, Jonni] Univ Penn, Sch Med, Dept Pathol & Lab Med, Flow Cytometry & Cell Sorting Resource Lab, Philadelphia, PA 19104 USA. [Roederer, Mario] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Moore, J (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, Flow Cytometry & Cell Sorting Resource Lab, 220 John Morgan Bldg, Philadelphia, PA 19104 USA. EM moorej@mail.med.upenn.edu NR 2 TC 7 Z9 7 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD AUG PY 2009 VL 75A IS 8 BP 643 EP 649 DI 10.1002/cyto.a.20742 PG 7 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 474MX UT WOS:000268289300001 PM 19582865 ER PT J AU Geetha, S Allen, CE Hunt, RC Plum, E Garfield, S Friedman, SL Soejima, K Sauna, ZE Kimchi-Sarfaty, C AF Geetha, S. Allen, Courtni E. Hunt, Ryan C. Plum, Elizabeth Garfield, Susan Friedman, Scott L. Soejima, Kenji Sauna, Zuben E. Kimchi-Sarfaty, Chava TI Detection of Intracellular ADAMTS13, a Secreted Zinc-Metalloprotease, via Flow Cytometry SO CYTOMETRY PART A LA English DT Article DE ADAMTS13; flow cytometry; intracellular protein expression ID VON-WILLEBRAND-FACTOR; FACTOR-CLEAVING PROTEASE; THROMBOTIC THROMBOCYTOPENIC PURPURA; STELLATE CELLS; WESTERN-BLOT; EXPRESSION; CLEAVAGE AB ADAMTS13 is a secreted metalloprotease that cleaves von Willebrand Factor multimers in order to maintain proper homeostasis. A severe deficiency in ADAMTS13 triggers a disorder known as thrombotic thrombocytopenic purpura. At present, ADAMTS13 expression levels are determined by immunoblotting. We established a flow cytometry methodology to detect intracellular ADAMTS13 in liver and kidney cells using a polyclonal antibody, BL154G, and several monoclonal antibodies previously used to detect ADAMTS13 by immunoblotting. The results were validated using confocal microscopy, immunoblotting, and an activity assay (FRETS-VWF73). We show that labeling ADAMTS13 with specific antibodies and detection by flow cytometry yields results that are comparable with previously established methods for ADAMTS13 detection. Specifically, we compared the endogenous expression levels of ADAMTS13 in various liver cell lines using flow cytometry and obtained results that parallel immunoblot analysis. Knockdown of ADAMTS13 expression via targeted siRNA resulted in significantly reduced median signal, displaying the sensitivity of this detection method. A further analysis of reliability and specificity was achieved through plasmid DNA and transfection reagent dose response studies. The flow cytometry method described here is useful in determining the expression of both endogenous and recombinant forms of intracellular ADAMTS13. Flow cytometry is a convenient, efficient, and cost-effective way to measure the expression levels of ADAMTS13. Published 2009 Wiley-Liss, Inc. C1 [Geetha, S.; Allen, Courtni E.; Hunt, Ryan C.; Plum, Elizabeth; Sauna, Zuben E.; Kimchi-Sarfaty, Chava] US FDA, Div Hematol, Lab Hemostasis, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Garfield, Susan] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Friedman, Scott L.] Mt Sinai Sch Med, Dept Med, Div Liver Dis, New York, NY USA. [Soejima, Kenji] Chemo Sero Therapeut Res Inst, Dept Res 1, Kumamoto, Japan. RP Kimchi-Sarfaty, C (reprint author), US FDA, Div Hematol, Lab Hemostasis, Ctr Biol Evaluat & Res, 29 Lincoin Dr, Bethesda, MD 20892 USA. EM chava.kimchi-sarfaty@fda.hhs.gov FU Intramural NIH HHS [Z01 BC010858-01] NR 20 TC 3 Z9 3 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD AUG PY 2009 VL 75A IS 8 BP 675 EP 681 DI 10.1002/cyto.a.20748 PG 7 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 474MX UT WOS:000268289300005 PM 19526483 ER PT J AU Seifert, AW Yamaguchi, T Cohn, MJ AF Seifert, Ashley W. Yamaguchi, Terry Cohn, Martin J. TI Functional and phylogenetic analysis shows that Fgf8 is a marker of genital induction in mammals but is not required for external genital development SO DEVELOPMENT LA English DT Article DE Evolution; Fgf8; Genitalia; Wnt5a; Cloaca ID FIBROBLAST-GROWTH-FACTOR; NORMAL LIMB DEVELOPMENT; VERTEBRATE LIMB; SONIC-HEDGEHOG; URETHRAL EPITHELIUM; MOLECULAR ANALYSIS; CONCERTED ACTIONS; OUTGROWTH; EMBRYO; FAMILY AB In mammalian embryos, male and female external genitalia develop from the genital tubercle. Outgrowth of the genital tubercle is maintained by the urethral epithelium, and it has been reported that Fgf8 mediates this activity. To test directly whether Fgf8 is required for external genital development, we conditionally removed Fgf8 from the cloacal/urethral epithelium. Surprisingly, Fgf8 is not necessary for initiation, outgrowth or normal patterning of the external genitalia. In early genital tubercles, we found no redundant Fgf expression in the urethral epithelium, which contrasts with the situation in the apical ectodermal ridge (AER) of the limb. Analysis of Fgf8 pathway activity showed that four putative targets are either absent from early genital tubercles or are not regulated by Fgf8. We therefore examined the distribution of Fgf8 protein and report that, although it is present in the AER, Fgf8 is undetectable in the genital tubercle. Thus, Fgf8 is transcribed, but the signaling pathway is not activated during normal genital development. A phylogenetic survey of amniotes revealed Fgf8 expression in genital tubercles of eutherian and metatherian mammals, but not turtles or alligators, indicating that Fgf8 expression is neither a required nor a conserved feature of amniote external genital development. The results indicate that Fgf8 expression is an early readout of the genital initiation signal rather than the signal itself. We propose that induction of external genitalia involves an epithelial-epithelial interaction at the cloacal membrane, and suggest that the cloacal ectoderm may be the source of the genital initiation signal. C1 [Seifert, Ashley W.; Cohn, Martin J.] Univ Florida, Dept Zool, Genet Inst, Gainesville, FL 32611 USA. [Cohn, Martin J.] Univ Florida, Dept Anat & Cell Biol, Genet Inst, Gainesville, FL 32611 USA. [Yamaguchi, Terry] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Cohn, MJ (reprint author), Univ Florida, Dept Zool, Genet Inst, POB 103610, Gainesville, FL 32611 USA. EM mjcohn@ufl.edu FU National Institutes of Health [5R01HD054554]; National Science Foundation [0843590] FX We gratefully acknowledge funding from the National Institutes of Health (5R01HD054554) and the National Science Foundation (0843590). Deposited in PMC for release after 12 months. NR 43 TC 33 Z9 34 U1 0 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD AUG 1 PY 2009 VL 136 IS 15 BP 2643 EP 2651 DI 10.1242/dev.036830 PG 9 WC Developmental Biology SC Developmental Biology GA 469MZ UT WOS:000267905000016 PM 19592577 ER PT J AU Szabo, R Hobson, JP Christoph, K Kosa, P List, K Bugge, TH AF Szabo, Roman Hobson, John P. Christoph, Kristina Kosa, Peter List, Karin Bugge, Thomas H. TI Regulation of cell surface protease matriptase by HAI2 is essential for placental development, neural tube closure and embryonic survival in mice SO DEVELOPMENT LA English DT Article DE Kunitz-type inhibitors; Embryonic development; Neural tube defects; Nonalleic noncomplementation; Placental labyrinth; Tissue morphogenesis; Mouse ID HEPATOCYTE GROWTH-FACTOR; MACROPHAGE-STIMULATING PROTEIN; FACTOR ACTIVATOR INHIBITOR; EPIDERMAL BARRIER FUNCTION; ANCHORED SERINE-PROTEASE; SODIUM-CHANNEL; PROTEOLYTIC CLEAVAGE; KUNITZ DOMAINS; TRANSMEMBRANE; EXPRESSION AB Hypomorphic mutations in the human SPINT2 gene cause a broad spectrum of abnormalities in organogenesis, including organ and digit duplications, atresia, fistulas, hypertelorism, cleft palate and hamartoma. SPINT2 encodes the transmembrane serine protease inhibitor HAI2 (placental bikunin), and the severe developmental effects of decreased HAI2 activity can be hypothesized to be a consequence of excess pericellular proteolytic activity. Indeed, we show here that HAI2 is a potent regulator of protease-guided cellular responses, including motogenic activity and transepithelial resistance of epithelial monolayers. Furthermore, we show that inhibition of the transmembrane serine protease matriptase (encoded by St14) is an essential function of HAI2 during tissue morphogenesis. Genetic inactivation of the mouse Spint2 gene led to defects in neural tube closure, abnormal placental labyrinth development associated with loss of epithelial cell polarity, and embryonic demise. Developmental defects observed in HAI2-deficient mice were caused by unregulated matriptase activity, as both placental development and embryonic survival in HAI2-deficient embryos were completely restored by the simultaneous genetic inactivation of matriptase. However, neural tube defects were detected in HAI2-deficient mice even in the absence of matriptase, although at lower frequency, indicating that the inhibition of additional serine protease(s) by HAI2 is required to complete neural development. Finally, by genetic complementation analysis, we uncovered a unique and complex functional interaction between HAI2 and the related HAI1 in the regulation of matriptase activity during development. This study indicates that unregulated matriptase-dependent cell surface proteolysis can cause a diverse array of abnormalities in mammalian development. C1 [Szabo, Roman; Hobson, John P.; Christoph, Kristina; Kosa, Peter; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [List, Karin] Wayne State Univ, Dept Pharmacol, Barbara Ann Karmanos Canc Inst, Sch Med, Detroit, MI 48201 USA. RP Bugge, TH (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov FU Intramural NIH HHS NR 63 TC 55 Z9 56 U1 0 U2 4 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 AUG 1 PY 2009 VL 136 IS 15 BP 2653 EP 2663 DI 10.1242/dev.038430 PG 11 WC Developmental Biology SC Developmental Biology GA 469MZ UT WOS:000267905000017 PM 19592578 ER PT J AU Saravanamuthu, SS Gao, CY Zelenka, PS AF Saravanamuthu, Senthil S. Gao, Chun Y. Zelenka, Peggy S. TI Notch signaling is required for lateral induction of Jagged1 during FGF-induced lens fiber differentiation SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Notch signaling; Lens differentiation; Lens fiber cells; Jag1; Jagged; Notch2; Lateral induction; FGF-2; NICD; p57Kip2; N-cadherin ID TO-MESENCHYMAL TRANSITION; CDK INHIBITORS P27(KIP1); EPIDERMAL-GROWTH-FACTOR; CELL-DIFFERENTIATION; EPITHELIAL-CELLS; TRANSGENIC MICE; MAMMALIAN LENS; BETA-CATENIN; E-CADHERIN; PHOSPHATIDYLINOSITOL 3-KINASE AB Previous studies of the developing lens have shown that Notch signaling regulates differentiation of lens fiber cells by maintaining a proliferating precursor pool in the anterior epithelium. However, whether Notch signaling is further required after the onset of fiber cell differentiation is not clear. This work investigates the role of Notch2 and Jagged1 (Jag1) in secondary fiber cell differentiation using rat lens epithelial explants undergoing FGF-2 dependent differentiation in vitro. FGF induced Jag1 expression and Notch2 signaling (as judged by the appearance of activated Notch2 Intracellular Domain (N2ICD)) within 12-24 h. These changes were correlated with induction of the Notch effector, Hes5, upregulation of N-cadherin (N-cad), and downregulation of E-cadherin (E-cad), a cadherin switch characteristic of fiber cell differentiation. Induction of Jag1 was efficiently blocked by U0126, a specific inhibitor of MAPK/ERK signaling, indicating a requirement for signaling through this pathway downstream of the FGF receptor. Other growth factors that activate MAPK/ERK signaling (EGF, PDGF, IGF) did not induce Jag1. Inhibition of Notch signaling using gamma secretase inhibitors DAPT and L-685,458 or anti-Jag1 antibody markedly decreased FGF-dependent expression of Jag1 demonstrating Notch-dependent lateral induction. In addition, inhibition of Notch signaling reduced expression of N-cad, and the cyclin dependent kinase inhibitor, p57Kip2, indicating a direct role for Notch signaling in secondary fiber cell differentiation. These results demonstrate that Notch-mediated lateral induction of Jag1 is an essential component of FGF-dependent lens fiber cell differentiation. Published by Elsevier Inc C1 [Saravanamuthu, Senthil S.; Gao, Chun Y.; Zelenka, Peggy S.] NEI, LMDB, NIH, Bethesda, MD 20892 USA. RP Zelenka, PS (reprint author), NEI, LMDB, NIH, 5635 Fishers Lane,Room 1127, Bethesda, MD 20892 USA. EM zelenkap@nei.nih.gov FU National Eye Institute Intramural [Z01-EY000238-20] FX We thank Drs. Nadean Brown, Stanislav Tomarev, Joram Piatigorsky and Pushpa Pandiyan for valuable discussions and critical reading of this manuscript and general support, and the NEI Biological Imaging Core for confocal microscopy. This work was supported by the National Eye Institute Intramural Research Program Z01-EY000238-20. NR 76 TC 39 Z9 42 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 1 PY 2009 VL 332 IS 1 BP 166 EP 176 DI 10.1016/j.ydbio.2009.05.566 PG 11 WC Developmental Biology SC Developmental Biology GA 472GG UT WOS:000268117600014 PM 19481073 ER PT J AU Biehl, JK Yamanaka, S Desai, TA Boheler, KR Russell, B AF Biehl, Jesse K. Yamanaka, Satoshi Desai, Tejal A. Boheler, Kenneth R. Russell, Brenda TI Proliferation of Mouse Embryonic Stem Cell Progeny and the Spontaneous Contractile Activity of Cardiomyocytes Are Affected by Microtopography SO DEVELOPMENTAL DYNAMICS LA English DT Article DE embryonic stem cells; cardiomyocytes; proliferation; microtopography ID CONTACT GUIDANCE; STRESS FIBERS; RHO; ORGANIZATION; MATRIX; ADHESION; SHAPE; LOCALIZATION; FABRICATION; EXPRESSION AB The niche in which stem cells reside and differentiate is a complex physicochemical microenvironment that regulates cell function. The role played by three-dimensional physical contours was studied on cell progeny derived from mouse embryonic stem cells using microtopographies created on PDMS (poly-dimethylsiloxane) membranes. While markers of differentiation were not affected, the proliferation of heterogeneous mouse embryonic stem cell-derived progeny was attenuated by 15 mu m-, but not 5 mu m-high microprojections. This reduction was reversed by Rho kinase and myosin light chain kinase inhibition, which diminishes the tension generating ability of stress fibers. Purified cardiomyocytes derived from embryonic stem cells also showed significant blunting of proliferation and increased beating rates compared with cells grown on flat substrates. Thus, proliferation of stem cell-derived progeny appears to be regulated by microtopography through tension-generation of contractility in the third-dimension. These results emphasize the importance of topographic cues in the modulation of stem cell progeny behavior. Developmental Dynamics 238:1964-1973, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Biehl, Jesse K.; Russell, Brenda] Univ Illinois, Dept Bioengn, Chicago, IL 60612 USA. [Yamanaka, Satoshi; Boheler, Kenneth R.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Desai, Tejal A.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Russell, Brenda] Univ Illinois, Dept Physiol & Biophys, Chicago, IL 60612 USA. RP Russell, B (reprint author), Univ Illinois, Dept Bioengn, MC 901,835 S Wolcott Ave, Chicago, IL 60612 USA. EM russell@uic.edu FU NIH [HL 62426]; State of Illinois funds for Regenerative Medicine; National Institute on Aging; National Science Foundation FX The research was supported by NIH (HL 62426), the State of Illinois funds for Regenerative Medicine, the Intramural Research Program of the NIH, National Institute on Aging, and the National Science Foundation. The nestin (Rat-401) and SSEA-1 (MC-480) antibodies developed by Hockfield, S. and Solter, D./Knowles, BB., respectively, were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa (Department of Biology, Iowa City, IA 52242). NR 42 TC 18 Z9 18 U1 0 U2 22 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD AUG PY 2009 VL 238 IS 8 BP 1964 EP 1973 DI 10.1002/dvdy.22030 PG 10 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 479TZ UT WOS:000268685100009 PM 19618471 ER PT J AU Wu, SH Arevalo, JC Sarti, F Tessarollo, L Gan, WB Chao, MV AF Wu, Synphen H. Carlos Arevalo, Juan Sarti, Federica Tessarollo, Lino Gan, Wen-Biao Chao, Moses V. TI Ankyrin Repeat-Rich Membrane Spanning/Kidins220 Protein Regulates Dendritic Branching and Spine Stability In Vivo SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE spines; dendritic arbors; barrel cortex; dentate gyrus ID LONG-TERM POTENTIATION; NEUROTROPHIC FACTOR; VISUAL EXPERIENCE; BDNF; GROWTH; NEURONS; CORTEX; MODULATION; PLASTICITY; RECEPTORS AB The development of nervous system connectivity depends upon the arborization of dendritic fields and the stabilization of dendritic spine synapses. It is well established that neuronal activity and the neurotrophin BDNF modulate these correlated processes. However, the downstream mechanisms by which these extrinsic signals regulate dendritic development and spine stabilization are less well known. Here we report that a substrate of BDNF signaling, the Ankyrin Repeat-rich Membrane Spanning (ARMS) protein or Kidins220, plays a critical role in the branching of cortical and hippocampal dendrites and in the turnover of cortical spines. In the barrel somatosensory cortex and the dentate gyrus, regions where ARMS/Kidins220 is highly expressed, no difference in the complexity of dendritic arbors was observed in 1-month-old adolescent ARMS/Kidins220(+/-) mice compared to wild-type litter-mates. However, at 3 months of age, young adult ARMS/Kidins220(+/-) mice exhibited decreased dendritic complexity. This suggests that ARMS/Kidins220 does not play a significant role in the initial formation of dendrites but, rather, is involved in the refinement or stabilization of the arbors later in development. In addition, at I month of age, the rate of spine elimination was higher in ARMS/Kidins220(+/-) mice than in wild-type mice, suggesting that ARMS/Kidins220(+/-) levels regulate spine stability. Taken together, these data suggest that ARMS/Kidins220 is important for the growth of dendritic arbors and spine stability during an activity- and BDNF-dependent period of development. (C) 2009 Wiley Periodicals. Inc. Develop Neurobiol 69: 547-557, 2009 C1 [Wu, Synphen H.; Carlos Arevalo, Juan; Sarti, Federica; Gan, Wen-Biao; Chao, Moses V.] NYU, Sch Med, Dept Physiol & Neurosci, Skirball Inst Biomol Med,Mol Neurobiol Program, New York, NY 10016 USA. [Tessarollo, Lino] NCI, Neural Dev Grp, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Chao, Moses V.] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. RP Chao, MV (reprint author), NYU, Sch Med, Dept Physiol & Neurosci, Skirball Inst Biomol Med,Mol Neurobiol Program, New York, NY 10016 USA. EM moses.chao@med.nyu.edu RI 2009, Secribsal/A-1266-2012; ArAvalo, Juan Carlos/J-8154-2014; OI ArAvalo, Juan Carlos/0000-0003-1994-3095; Chao, Moses/0000-0002-6969-3744 FU NIH; Community Research and Development Information Service (CORDIS); European Commission FX Contract grant sponsors: NIH (Medical Scientist Training program to SHW): Community Research and Development Information Service (CORDIS) (European Commission) (Marie Curie International Reintegration Grant Within the Seventh European Community Framework Programme to JCA); Center for Cancer Research of the NIH (NCI Intramural Research Program to LT). NR 47 TC 31 Z9 32 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1932-8451 J9 DEV NEUROBIOL JI Dev. Neurobiol. PD AUG PY 2009 VL 69 IS 9 BP 547 EP 557 DI 10.1002/dneu.20723 PG 11 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 471LA UT WOS:000268058000001 PM 19449316 ER PT J AU Khan, MH Harlan, DM AF Khan, Mahfuzul H. Harlan, David M. TI Counterpoint: Clinical Islet Transplantation: Not Ready for Prime Time SO DIABETES CARE LA English DT Editorial Material ID DEPENDENT DIABETES-MELLITUS; QUALITY-OF-LIFE; PANCREAS TRANSPLANTATION; INSULIN-SECRETION; CARDIOVASCULAR-DISEASE; KIDNEY-TRANSPLANT; EDMONTON PROTOCOL; RENAL-FUNCTION; COMPLICATIONS; RISK C1 [Khan, Mahfuzul H.; Harlan, David M.] NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Harlan, DM (reprint author), NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. EM davidmh@mail.nih.gov NR 41 TC 14 Z9 15 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2009 VL 32 IS 8 BP 1570 EP 1574 DI 10.2337/dc09-0611 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 479UX UT WOS:000268687800043 PM 19638528 ER PT J AU Wu, LT Pan, JJ Blazer, DG Tai, B Brooner, RK Stitzer, ML Patkar, AA Blaine, JD AF Wu, Li-Tzy Pan, Jeng-Jong Blazer, Dan G. Tai, Betty Brooner, Robert K. Stitzer, Maxine L. Patkar, Ashwin A. Blaine, Jack D. TI The construct and measurement equivalence of cocaine and opioid dependences: A National Drug Abuse Treatment Clinical Trials Network (CTN) study SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Clinical trials network; Cocaine dependence; DSM-IV Checklist; Item response theory; Multiple indicators-multiple causes; Opioid dependence ID ITEM RESPONSE THEORY; DIFFERENT PSYCHOACTIVE SUBSTANCES; METHADONE-MAINTENANCE TREATMENT; DSM-IV; EPIDEMIOLOGIC SURVEY; USE DISORDERS; ALCOHOL DEPENDENCE; TREATMENT PROGRAMS; CRITERIA; MARIJUANA AB Introduction: Although DSM-IV criteria are widely used in making diagnoses of substance use disorders, gaps exist regarding diagnosis classification, use of dependence criteria, and effects of measurement bias on diagnosis assessment. We examined the construct and measurement equivalence of diagnostic criteria for cocaine and opioid dependences, including whether each criterion maps onto the dependence construct, how well each Criterion performs, how much information each contributes to a diagnosis, and whether symptom-endorsing is equivalent between demographic groups. Methods: Item response theory (IRT) and multiple indicators-multiple causes (MIMIC) modeling were performed on a sample of stimulant-using methadone maintenance patients enrolled in a multisite study of the National Drug Abuse Treatment Clinical Trials Network (CTN) (N = 383). Participants were recruited from six community-based methadone maintenance treatment programs associated with the CTN and major U.S. Providers. Cocaine and opioid dependences were assessed by DSM-IV Checklist. Results: IRT modeling showed that symptoms of cocaine and opioid dependences, respectively, were arrayed along a continuum of severity. All symptoms had moderate to high discrimination in distinguishing drug users between severity levels. "Withdrawal" identified the most severe symptom of the cocaine dependence continuum. MIMIC modeling revealed some support for measurement equivalence. Conclusions: Study results suggest that self-reported symptoms of cocaine and opioid dependences and their underlying constructs can be measured appropriately among treatment-seeking polysubstance users. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Wu, Li-Tzy] Duke Univ, Med Ctr, Duke Clin Res Inst, Dept Psychiat & Behav Sci,Sch Med, Durham, NC 27710 USA. [Pan, Jeng-Jong] Vet Hlth Adm, Washington, DC USA. [Tai, Betty; Blaine, Jack D.] Natl Inst Drug Abuse, Ctr Clin Trials Network, Bethesda, MD USA. [Brooner, Robert K.; Stitzer, Maxine L.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP Wu, LT (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, Dept Psychiat & Behav Sci,Sch Med, Box 3419, Durham, NC 27710 USA. EM litzy.wu@duke.edu FU U.S. National Institute on Drug Abuse of the National institutes of Health to the Duke University Medical Center [HHSN271200522071C] FX This work was supported by a contract from the U.S. National Institute on Drug Abuse of the National institutes of Health to the Duke University Medical Center (HHSN271200522071C; Principal Investigator: Blazer). The opinions expressed in this paper are solely those of the authors and do not necessarily reflect those of the sponsoring agency. The authors wish to thank the participants, staff, investigators, and others who made the original studies and this work possible. We also thank Jonathan McCall for editorial assistance. This study, which used existing de-identified, public-use data files, was declared exempt from review by the Duke University Institutional Review Board. NR 50 TC 25 Z9 25 U1 5 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD AUG 1 PY 2009 VL 103 IS 3 BP 114 EP 123 DI 10.1016/j.drugalcdep.2009.01.018 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 471LC UT WOS:000268058200004 PM 19423244 ER PT J AU Fletcher, BW Lehman, WEK Wexler, HK Melnick, G Taxman, FS Young, DW AF Fletcher, Bennett W. Lehman, Wayne E. K. Wexler, Harry K. Melnick, Gerald Taxman, Faye S. Young, Douglas W. TI Measuring collaboration and integration activities in criminal justice and substance abuse treatment agencies SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Interorganizational relationships; Systems integration; Criminal justice; Cross-agency collaboration; Substance abuse treatment ID DRUG-INVOLVED OFFENDERS; MENTAL-HEALTH-SERVICES; CASE-MANAGEMENT; ACCESS PROGRAM; PARTNERSHIP SYNERGY; SUPERVISION PROGRAM; COMMUNITY-HEALTH; ILL PERSONS; SYSTEM; IMPLEMENTATION AB Individuals with Substance abuse problems who are involved in the criminal justice system frequently need community-based drug and alcohol abuse treatment and other services. To reduce the risk of relapse to illicit drugs and criminal recidivism, criminal justice agencies may need to establish collaborations with substance abuse treatment and other community-based service providers. Although there are many variations of interorganizational relationships, the nature of these interagency collaborations among justice agencies and treatment providers has received little systematic study. As a first step, we present an instrument to measure interagency collaboration and integration activities using items in the National Criminal justice Treatment Practices Surveys conducted as part of the Criminal justice Drug Abuse Treatment Studies (CJ-DATS). Collaboration and integration activities related to drug-involved offenders were examined between substance abuse treatment providers, Correctional agencies, and the judiciary. The measurement scale reliably identified two levels of collaboration: less structured, informal networking and coordination and more structured and formalized levels of cooperation and collaboration. An illustration of the use of the systems integration tool is presented. Published by Elsevier Ireland Ltd. C1 [Fletcher, Bennett W.; Lehman, Wayne E. K.] Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. [Wexler, Harry K.; Melnick, Gerald] Natl Dev & Res Inst Inc, New York, NY 10010 USA. [Taxman, Faye S.] George Mason Univ, Manassas, VA 20110 USA. [Young, Douglas W.] Univ Maryland, Bur Govt Res, College Pk, MD 20740 USA. RP Fletcher, BW (reprint author), Natl Inst Drug Abuse, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM bfletche@nida.nih.gov FU NIDA NIH HHS [U01 DA16200., U01 DA16213,] NR 73 TC 25 Z9 25 U1 1 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD AUG 1 PY 2009 VL 103 BP S54 EP S64 DI 10.1016/j.drugalcdep.2009.01.001 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 476IL UT WOS:000268432800007 PM 20088023 ER PT J AU Lehman, WEK Fletcher, BW Wexler, HK Melnick, G AF Lehman, Wayne E. K. Fletcher, Bennett W. Wexler, Harry K. Melnick, Gerald TI Organizational factors and collaboration and integration activities in criminal justice and drug abuse treatment agencies SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Interorganizational relationships; Systems integration; Criminal justice; Drug abuse treatment; Organizational characteristics ID TREATMENT PROGRAMS; SERVICE DELIVERY; COMMUNITY-HEALTH; CASE-MANAGEMENT; OFFENDERS; SYSTEM; IMPACT; JAILS; POPULATIONS; FRAMEWORK AB Despite strong interest in improving collaborations between correctional and substance abuse treatment organizations, there is a lack of empirical data describing the existing practices. The Current Study used a national Survey of correctional administrators to examine organizational factors related to cross-agency collaboration and integration activities between corrections and Substance abuse treatment organization. Using a measure of collaboration that scaled cross-agency activities from less Structured, informal networking and coordination to more structured and formalized levels of cooperation and collaboration, we found that different correctional settings (e.g., community Corrections, jails, prisons) differed significantly in terms of their collaborative activities with Substance abuse treatment agencies. We also found that the organizational characteristics that were associated with different levels of collaboration and integration differed across the Correctional settings. Further research is needed to better understand how and why correctional agencies decide to formalize collaborative arrangements with treatment agencies and whether these efforts lead to more favorable outcomes. (C) 2009 Published by Elsevier Ireland Ltd. C1 [Lehman, Wayne E. K.; Fletcher, Bennett W.] Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. [Wexler, Harry K.; Melnick, Gerald] Natl Dev & Res Inst Inc, New York, NY 10010 USA. RP Fletcher, BW (reprint author), 6001 Execut Blvd,Room 5159, Bethesda, MD 20892 USA. EM bfletche@nida.nih.gov FU NIDA NIH HHS [U01 DA16200] NR 36 TC 20 Z9 20 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD AUG 1 PY 2009 VL 103 BP S65 EP S72 DI 10.1016/j.drugalcdep.2009.01.004 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 476IL UT WOS:000268432800008 PM 19307068 ER PT J AU McCarty, D Chandler, RK AF McCarty, Dennis Chandler, Redonna K. TI Understanding the importance of organizational and system variables on addiction treatment services within criminal justice settings SO DRUG AND ALCOHOL DEPENDENCE LA English DT Editorial Material DE Criminal justice; Process improvement; CJ-DATS ID IMPROVEMENT; RETENTION; NETWORK; ACCESS AB NIDA's Criminal Justice Drug Abuse Treatment Studies (CJ-DATS) is the primary vehicle for testing emerging treatment interventions and fostering adoption of evidence-based therapies in criminal justice settings. The papers in this issue of Drug and Alcohol Dependence use data from the CJ-DATS National Criminal Justice Treatment practice Survey to explore the influence of organizational and system variables oil access to addiction treatment and the types of services available within correctional settings. This essay provides context for the papers in this issue of Drug and Alcohol Dependence. Systems and organizational interventions that improve the delivery and quality of drug abuse treatment services are described and the potential to apply systems change thinking to addiction treatment services available in the criminal justice system is discussed. Each paper is described briefly. CJ-DATS is evolving to Support research at the organizational and systems level that facilitates the implementation and sustainability of research-supported treatments and business practices in criminal justice settings. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [McCarty, Dennis] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97329 USA. [Chandler, Redonna K.] Natl Inst Drug Abuse, Serv Res Branch, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. RP McCarty, D (reprint author), Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, CB669,3181 SW Sam Jackson Pk Rd, Portland, OR 97329 USA. EM mccartyd@ohsu.edu FU NIDA NIH HHS [R01 DA018282, R01 DA024024, R01 DA020832, R01 DA016341, U10 DA013036] NR 16 TC 9 Z9 9 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD AUG 1 PY 2009 VL 103 BP S91 EP S93 DI 10.1016/j.drugalcdep.2009.03.001 PG 3 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 476IL UT WOS:000268432800011 PM 19356862 ER PT J AU Cheng, J Ma, XC Krausz, KW Idle, JR Gonzalez, FJ AF Cheng, Jie Ma, Xiaochao Krausz, Kristopher W. Idle, Jeffrey R. Gonzalez, Frank J. TI Rifampicin-Activated Human Pregnane X Receptor and CYP3A4 Induction Enhance Acetaminophen-Induced Toxicity SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID HUMAN CYTOCHROME-P450 3A4; NUCLEAR RECEPTOR; INDUCED HEPATOTOXICITY; NULL MICE; XENOBIOTIC RECEPTOR; HUMAN-LIVER; WILD-TYPE; GLUTATHIONE; METABOLOMICS; TRANSFERASE AB Acetaminophen (APAP) is safe at therapeutic levels but causes hepatotoxicity via N-acetyl-p-benzoquinone imine-induced oxidative stress upon overdose. To determine the effect of human (h) pregnane X receptor (PXR) activation and CYP3A4 induction on APAP-induced hepatotoxicity, mice humanized for PXR and CYP3A4 (TgCYP3A4/hPXR) were treated with APAP and rifampicin. Human PXR activation and CYP3A4 induction enhanced APAP-induced hepatotoxicity as revealed by hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities elevated in serum, and hepatic necrosis after coadministration of rifampicin and APAP, compared with APAP administration alone. In contrast, hPXR mice, wild-type mice, and Pxr-null mice exhibited significantly lower ALT/AST levels compared with TgCYP3A4/hPXR mice after APAP administration. Toxicity was coincident with depletion of hepatic glutathione and increased production of hydrogen peroxide, suggesting increased oxidative stress upon hPXR activation. Moreover, mRNA analysis demonstrated that CYP3A4 and other PXR target genes were significantly induced by rifampicin treatment. Urinary metabolomic analysis indicated that cysteine-APAP and its metabolite S-(5-acetylamino-2-hydroxyphenyl) mercaptopyruvic acid were the major contributors to the toxic phenotype. Quantification of plasma APAP metabolites indicated that the APAP dimer formed coincident with increased oxidative stress. In addition, serum metabolomics revealed reduction of lysophosphatidylcholine in the APAP-treated groups. These findings demonstrated that human PXR is involved in regulation of APAP-induced toxicity through CYP3A4-mediated hepatic metabolism of APAP in the presence of PXR ligands. C1 [Cheng, Jie; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ma, Xiaochao] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA. [Idle, Jeffrey R.] Charles Univ Prague, Inst Pharmacol, Fac Med 1, Prague, Czech Republic. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov OI Idle, Jeff/0000-0002-6143-1520 FU National Cancer Institute; U.S. Smokeless Tobacco Company FX This work was supported in part by the National Cancer Institute Intramural Research Program; and the U.S. Smokeless Tobacco Company. NR 56 TC 61 Z9 66 U1 1 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD AUG PY 2009 VL 37 IS 8 BP 1611 EP 1621 DI 10.1124/dmd.109.027565 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 471ZN UT WOS:000268097300008 PM 19460945 ER PT J AU Gonzalez, FJ Chen, C Patterson, AD Krausz, KW Idle, JR AF Gonzalez, Frank J. Chen, Chi Patterson, Andrew D. Krausz, Kristopher W. Idle, Jeffrey R. TI Discovery of Biomarkers for Gene Expression and Drug Toxicity and Efficacy SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 3rd Asian Pacific Regional Meeting of the International-Society-for-the-Study-of-Xenobiotics CY MAY 10-12, 2009 CL Bangkok, THAILAND SP Int Soc Study Xenobiot C1 [Gonzalez, Frank J.; Chen, Chi; Patterson, Andrew D.; Krausz, Kristopher W.; Idle, Jeffrey R.] NCI, Lab Metab, Bethesda, MD 20892 USA. RI Patterson, Andrew/G-3852-2012 OI Patterson, Andrew/0000-0003-2073-0070 NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2009 VL 41 MA 30 BP 19 EP 20 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 490FE UT WOS:000269483300031 ER PT J AU Sordet, O Redon, CE Guirouilh-Barbat, J Smith, S Solier, S Douarre, C Conti, C Nakamura, AJ Das, BB Nicolas, E Kohn, KW Bonner, WM Pommier, Y AF Sordet, Olivier Redon, Christophe E. Guirouilh-Barbat, Josee Smith, Susan Solier, Stephanie Douarre, Celine Conti, Chiara Nakamura, Asako J. Das, Benu B. Nicolas, Estelle Kohn, Kurt W. Bonner, William M. Pommier, Yves TI Ataxia telangiectasia mutated activation by transcription- and topoisomerase I-induced DNA double-strand breaks SO EMBO REPORTS LA English DT Article DE ATM; DNA double-strand break; R-loop; topoisomerase; transcription ID RNA-POLYMERASE-II; CLEAVAGE COMPLEXES; CELL-DEATH; ATM; DAMAGE; PHOSPHORYLATION; REPAIR; PATHWAY; CAMPTOTHECIN; OPINION AB Ataxia telangiectasia mutated (ATM), the deficiency of which causes a severe neurodegenerative disease, is a crucial mediator for the DNA damage response (DDR). As neurons have high rates of transcription that require topoisomerase I (TOP1), we investigated whether TOP1 cleavage complexes (TOP1cc)-which are potent transcription-blocking lesions-also produce transcription-dependent DNA double-strand breaks (DSBs) with ATM activation. We show the induction of DSBs and DDR activation in post-mitotic primary neurons and lymphocytes treated with camptothecin, with the induction of nuclear DDR foci containing activated ATM, gamma-H2AX (phosphorylated histone H2AX), activated CHK2 (checkpoint kinase 2), MDC1 (mediator of DNA damage checkpoint 1) and 53BP1 (p53 binding protein 1). The DSB-ATM- DDR pathway was suppressed by inhibiting transcription and gamma-H2AX signals were reduced by RNase H1 transfection, which removes transcription-mediated R-loops. Thus, we propose that Top1cc produce transcription arrests with R-loop formation and generate DSBs that activate ATM in post-mitotic cells. C1 [Sordet, Olivier; Redon, Christophe E.; Guirouilh-Barbat, Josee; Solier, Stephanie; Douarre, Celine; Conti, Chiara; Nakamura, Asako J.; Das, Benu B.; Kohn, Kurt W.; Bonner, William M.; Pommier, Yves] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Smith, Susan] NINCDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Nicolas, Estelle] Univ Toulouse 3, CNRS, LBCMCP, UMR5088, F-31062 Toulouse, France. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Sordet, Olivier/M-3271-2014; Nicolas, Estelle/C-4425-2008 OI Nicolas, Estelle/0000-0003-0412-8477 FU National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 29 TC 83 Z9 83 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD AUG PY 2009 VL 10 IS 8 BP 887 EP 893 DI 10.1038/embor.2009.97 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 479EA UT WOS:000268641300020 PM 19557000 ER PT J AU Vinh, DC Shea, YR Jones, PA Freeman, AF Zelazny, A Holland, SM AF Vinh, Donald C. Shea, Yvonne R. Jones, Pamela A. Freeman, Alexandra F. Zelazny, Adrian Holland, Steven M. TI Chronic Invasive Aspergillosis caused by Aspergillus viridinutans SO EMERGING INFECTIOUS DISEASES LA English DT Article ID AMPHOTERICIN-B; IN-VITRO; FUMIGATUS; SUSCEPTIBILITY; IDENTIFICATION; ITRACONAZOLE; VORICONAZOLE AB Aspergillus viridinutans, a mold phenotypically resembling A. fumigatus, was identified by gene sequence analyses from 2 patients. Disease was distinct from typical aspergillosis, being chronic and spreading in a contiguous manner across anatomical planes. We emphasize the recognition of fumigati-mimetic molds as agents of chronic or refractory aspergillosis. C1 [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Freeman, Alexandra F.] NCI, Frederick, MD 21701 USA. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, NIH, Bldg 10CRC,Rm B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov OI VINH, DONALD/0000-0003-1347-7767 FU Canadian Institutes of Health Research; Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health (NIH) [N01-CO-12400]; National Cancer Institute FX Dr Vinh is an infectious disease specialist and medical microbiologist undertaking a visiting fellowship at NIH in primary immunodeficiencies. His research interests include characterizing immunologic defects that pennit specific infections among immunocompromised hosts. NR 15 TC 32 Z9 32 U1 0 U2 2 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD AUG PY 2009 VL 15 IS 8 BP 1292 EP 1294 DI 10.3201/eid1508.090251 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 481NT UT WOS:000268819100022 PM 19751595 ER PT J AU Helena, C Gustafsson, JA Korach, K Pfaff, D Anselmo-Franci, JA Ogawa, S AF Helena, Cleyde Gustafsson, Jan-Ake Korach, Kenneth Pfaff, Donald Anselmo-Franci, Janete A. Ogawa, Sonoko TI Effects of estrogen receptor alpha and beta gene deletion on estrogenic induction of progesterone receptors in the locus coeruleus in female mice SO ENDOCRINE LA English DT Article DE Estradiol; Progesterone and estrogen receptors; Locus coeruleus; Knockout mice; LHRH ID HORMONE-RELEASING HORMONE; CENTRAL-NERVOUS-SYSTEM; MEDIAL PREOPTIC AREA; LUTEINIZING-HORMONE; RAT-BRAIN; TYROSINE-HYDROXYLASE; OVARIECTOMIZED RATS; DISRUPTED MICE; IN-VIVO; NORADRENERGIC NEURONS AB Locus coeruleus (LC) is involved in the LHRH regulation by gonadal steroids. We investigated the expression of progesterone and estrogen receptors (PR; ER) in LC neurons of ER alpha (alpha ERKO) or ER beta (beta ERKO) knockout mice, and their wild-type (alpha WT and beta WT). Immunocytochemical studies showed that LC expresses PR and both ERs, although ER beta was more abundant. Estradiol benzoate (EB) decreased ER alpha-positive cells in WT and beta ERKO mice, and progesterone caused a further reduction, whereas none of the steroids influenced ER beta expression. ER beta deletion increased ER alpha while ER alpha deletion did not alter ER beta expression. In both WT mice, EB increased PR expression, which was diminished by progesterone. These steroid effects were also observed in alpha ERKO animals but to a lesser extent, suggesting that ER alpha is partially responsible for the estrogenic induction of PR in LC. Steroid effects on PR in beta ERKO mice were similar to those in the alpha ERKO but to a lesser extent, probably because PR expression was already high in the oil-treated group. This expression seems to be specific of LC neurons, since it was not observed in other areas studied, the preoptic area and ventromedial nucleus of hypothalamus. These findings show that LC in mice expresses alpha ER, beta ER, and PR, and that a balance between them may be critical for the physiological control of reproductive function. C1 [Anselmo-Franci, Janete A.] Univ Sao Paulo, Lab Neuroendocrinol & Reprod, Sch Dent Ribeirao Preto, BR-14040904 Ribeirao Preto, SP, Brazil. [Anselmo-Franci, Janete A.] Univ Sao Paulo, Dept Physiol, Sch Dent Ribeirao Preto, BR-14040904 Ribeirao Preto, SP, Brazil. [Ogawa, Sonoko] Univ Tsukuba, Lab Behav Neuroendocrinol, Behav & Brain Sci Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058577, Japan. [Helena, Cleyde] Univ Sao Paulo, Dept Physiol, Sch Med Ribeirao Preto, BR-14040904 Ribeirao Preto, SP, Brazil. [Helena, Cleyde; Pfaff, Donald; Ogawa, Sonoko] Rockefeller Univ, Neurobiol & Behav Lab, New York, NY 10021 USA. [Gustafsson, Jan-Ake] Karolinska Inst, Dept Biosci & Nutr, S-14186 Huddinge, Sweden. [Gustafsson, Jan-Ake] Univ Houston, Dept Biol & Biochem, Ctr Nucl Receptors & Cell Signaling, Houston, TX USA. [Korach, Kenneth] NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Anselmo-Franci, JA (reprint author), Univ Sao Paulo, Lab Neuroendocrinol & Reprod, Sch Dent Ribeirao Preto, Av Cafe S-N, BR-14040904 Ribeirao Preto, SP, Brazil. EM jaafranc@usp.br; ogawa@kansei.tsukuba.ac.jp RI Anselmo-Franci, Janete/E-7124-2012; OI Anselmo-Franci, Janete/0000-0002-6480-1187; Helena, Cleyde/0000-0002-5775-4546 FU CAPES; FAPESP; NIMH [62147] FX The authors gratefully acknowledge Dr. Celso R. Franci, for his generous support for the steroid radioimmunoassay and Ms. Sonia M. Zanon Batista for her technical assistance. This study was supported by CAPES and FAPESP (CVH) and NIMH 62147 (SO). NR 51 TC 9 Z9 9 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0969-711X J9 ENDOCRINE JI Endocrine PD AUG PY 2009 VL 36 IS 1 BP 169 EP 177 DI 10.1007/s12020-009-9207-x PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467YY UT WOS:000267781000027 PM 19551522 ER PT J AU Noyes, PD McElwee, MK Miller, HD Clark, BW Van Tiem, LA Walcott, KC Erwin, KN Levin, ED AF Noyes, Pamela D. McElwee, Matthew K. Miller, Hilary D. Clark, Bryan W. Van Tiem, Lindsey A. Walcott, Kia C. Erwin, Kyle N. Levin, Edward D. TI The toxicology of climate change: Environmental contaminants in a warming world SO ENVIRONMENT INTERNATIONAL LA English DT Review DE Air pollution; Climate change; Global warming; Multiple stressors; Ozone; Particulate matter; Persistent organic pollutant; Pesticide; Precipitation; Salinity; Temperature; Toxicokinetics ID PERSISTENT ORGANIC POLLUTANTS; PARTICULATE AIR-POLLUTION; TROUT ONCORHYNCHUS-MYKISS; US NATIONAL ASSESSMENT; LONG-RANGE TRANSPORT; SEALS PHOCA-CASPICA; HUMAN HEALTH; GLOBAL CLIMATE; MULTIPLE STRESSORS; PESTICIDE EXPOSURE AB Climate change induced by anthropogenic warming of the earth's atmosphere is a daunting problem. This review examines one of the consequences of climate change that has only recently attracted attention: namely, the effects of climate change on the environmental distribution and toxicity of chemical pollutants. A review was undertaken of the scientific literature (original research articles, reviews, government and intergovernmental reports) focusing on the interactions of toxicants with the environmental parameters, temperature, precipitation, and salinity, as altered by climate change. Three broad classes of chemical toxicants of global significance were the focus: air pollutants, persistent organic pollutants (POPs), including some organochlorine pesticides, and other classes of pesticides. Generally, increases in temperature will enhance the toxicity of contaminants and increase concentrations of tropospheric ozone regionally, but will also likely increase rates of chemical degradation. While further research is needed, climate change coupled with air pollutant exposures may have potentially serious adverse consequences for human health in urban and polluted regions. Climate change producing alterations in: food webs, lipid dynamics. ice and snow melt, and organic carbon cycling could result in increased POP levels in water, soil, and biota. There is also compelling evidence that increasing temperatures could be deleterious to pollutant-exposed wildlife. For example, elevated water temperatures may alter the biotransformation of contaminants to more bioactive metabolites and impair homeostasis. The complex interactions between climate change and pollutants may be particularly problematic for species living at the edge of their physiological tolerance range where acclimation capacity may be limited. In addition to temperature increases, regional precipitation patterns are projected to be altered with climate change. Regions subject to decreases in precipitation may experience enhanced volatilization of POPs and pesticides to the atmosphere. Reduced precipitation will also increase air pollution in urbanized regions resulting in negative health effects, which may be exacerbated by temperature increases. Regions subject to increased precipitation will have lower levels of air pollution, but will likely experience enhanced surface deposition of airborne POPs and increased run-off of pesticides. Moreover, increases in the intensity and frequency of storm events linked to climate change could lead to more severe episodes of chemical contamination of water bodies and surrounding watersheds. Changes in salinity may affect aquatic organisms as an independent stressor as well as by altering the bioavailability and in some instances increasing the toxicity of chemicals. A paramount issue will be to identify species and populations especially vulnerable to climate-pollutant interactions, in the context of the many other physical, chemical, and biological stressors that will be altered with climate change. Moreover, it will be important to predict tipping points that might trigger or accelerate synergistic interactions between climate change and contaminant exposures, (C) 2009 Published by Elsevier Ltd. C1 [Noyes, Pamela D.; McElwee, Matthew K.; Miller, Hilary D.; Clark, Bryan W.; Van Tiem, Lindsey A.; Walcott, Kia C.; Erwin, Kyle N.; Levin, Edward D.] Duke Univ, Integrated Toxicol & Environm Hlth Program, Durham, NC 27706 USA. [Noyes, Pamela D.; McElwee, Matthew K.; Miller, Hilary D.; Clark, Bryan W.; Van Tiem, Lindsey A.] Duke Univ, Nicholas Sch Environm, Durham, NC 27708 USA. [McElwee, Matthew K.] Natl Inst Environm Hlth Sci, Mol Toxicol Lab, NIH, DHHS, Res Triangle Pk, NC USA. RP Levin, ED (reprint author), Duke Univ, Integrated Toxicol & Environm Hlth Program, Durham, NC 27706 USA. EM edlevin@duke.edu FU NIH; National Institute of Environmental Health Sciences FX This review is supported [in part] by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The authors would also like to give special thanks to Dr. Windy Boyd, Dr. Christopher Portier. and Dr. Heather Stapleton for their assistance. NR 172 TC 255 Z9 264 U1 36 U2 350 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 J9 ENVIRON INT JI Environ. Int. PD AUG PY 2009 VL 35 IS 6 BP 971 EP 986 DI 10.1016/j.envint.2009.02.006 PG 16 WC Environmental Sciences SC Environmental Sciences & Ecology GA 463FM UT WOS:000267415500020 PM 19375165 ER PT J AU Drake, JW AF Drake, J. W. TI Mechanisms of Induction of Multiple Mutations by DNA Polymerases SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Drake, J. W.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 535 EP 535 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400014 ER PT J AU Bishop, JB Wassom, JS AF Bishop, J. B. Wassom, J. S. TI The Next 50 Years in Germ Cell Mutagenesis Research SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Bishop, J. B.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Wassom, J. S.] Oak Ridge Natl Lab, Oak Ridge, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 537 EP 537 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400019 ER PT J AU Zhang, L Lan, Q Li, G Ren, X Shen, M Vermeulen, R Rappaport, SM Ji, Z Yin, S Chanock, S Rothman, N Smith, MT AF Zhang, L. Lan, Q. Li, G. Ren, X. Shen, M. Vermeulen, R. Rappaport, S. M. Ji, Z. Yin, S. Chanock, S. Rothman, N. Smith, M. T. TI Benzene Induced Hematotoxicity: Susceptibility Genes and DNA Repair Mechanisms SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Zhang, L.; Ren, X.; Rappaport, S. M.; Ji, Z.; Smith, M. T.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Lan, Q.; Shen, M.; Vermeulen, R.; Chanock, S.; Rothman, N.] NCI, NIH, DHHS, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Li, G.; Yin, S.] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 539 EP 539 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400024 ER PT J AU Tice, RR Witt, KL Shockley, KR Caspary, WJ Xia, M Huang, R Austin, CP AF Tice, R. R. Witt, K. L. Shockley, K. R. Caspary, W. J. Xia, M. Huang, R. Austin, C. P. TI The Use of Quantitative High Throughput Screens (qHTS) in Genetic Toxicology SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Tice, R. R.; Witt, K. L.; Shockley, K. R.; Caspary, W. J.] NIEHS, NTP, Res Triangle Pk, NC 27709 USA. [Xia, M.; Huang, R.; Austin, C. P.] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 542 EP 542 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400035 ER PT J AU Olivero, OA AF Olivero, O. A. TI Centrosomal Amplification (CA) SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Olivero, O. A.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 545 EP 545 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400046 ER PT J AU Davila, K Yu, M Poirier, MC Olivero, OA AF Davila, K. Yu, M. Poirier, M. C. Olivero, O. A. TI Centrosomal Amplification Induced by Nucleoside Reverse Transcriptase Inhibitors (NRTIs) in Cultured Human Breast Epithelial MCF 10A Cells SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Davila, K.] Univ Texas San Antonio, San Antonio, TX USA. [Davila, K.; Yu, M.; Poirier, M. C.; Olivero, O. A.] NCI, 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 546 EP 546 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400050 ER PT J AU Verma, M AF Verma, M. TI NCI Funding Opportunities for Cancer Epidemiology SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Verma, M.] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 550 EP 550 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400064 ER PT J AU Abraham, J Marietta, C Brooks, PJ AF Abraham, J. Marietta, C. Brooks, P. J. TI Activation of FA-BRCA1 Pathway by Intracellular Alcohol Metabolism: Implications for Alcohol-Related Cancers SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Abraham, J.; Marietta, C.; Brooks, P. J.] NIAAA, Rockville, MD 20852 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 559 EP 559 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400097 ER PT J AU Zhang, L Lan, Q Guo, W Hubbard, A Li, G Rappaport, SM Ji, Z Shen, M Vermeulen, R Yin, S Rothman, N Smith, MT AF Zhang, L. Lan, Q. Guo, W. Hubbard, A. Li, G. Rappaport, S. M. Ji, Z. Shen, M. Vermeulen, R. Yin, S. Rothman, N. Smith, M. T. TI Spectrum of Chromosomal Aneuploidy, Benzene Exposure and Leukemia Risk SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Zhang, L.; Guo, W.; Hubbard, A.; Rappaport, S. M.; Ji, Z.; Smith, M. T.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Lan, Q.; Shen, M.; Vermeulen, R.; Rothman, N.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Li, G.; Yin, S.] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 560 EP 560 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400102 ER PT J AU Marietta, CA Brooks, PJ AF Marietta, C. A. Brooks, P. J. TI Cockayne Syndrome (CS)-A and CS-B Cells are Defective in Host-Cell Reactivation of Plasmids Containing an 8,5 '(S)-Cyclodeoxyadenosine Lesion SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Marietta, C. A.; Brooks, P. J.] NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 566 EP 566 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400122 ER PT J AU Schultz, GE Drake, JW AF Schultz, Jr G. E. Drake, J. W. TI The Effect of UV on Templated Mutagenesis in Bacteriophage T4 Involving Imperfect Direct or Indirect Sequence Repeats SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Schultz, Jr G. E.] Marshall Univ, Huntington, WV USA. [Drake, J. W.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 567 EP 567 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400126 ER PT J AU Swartz, CD Recio, L Green, A Lentz, C Witt, KL AF Swartz, C. D. Recio, L. Green, A. Lentz, C. Witt, K. L. TI Lack of Genotoxicity of Three Different Preparations of Aloe Barbadensis by the Salmonella/E. coli Mutagenicity (Ames) Assay SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Swartz, C. D.; Recio, L.; Green, A.; Lentz, C.] Integrated Syst Lab, Res Triangle Pk, NC USA. [Witt, K. L.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 567 EP 567 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400127 ER PT J AU John, K Pratt, MM McMullen, G Poirier, MC AF John, K. Pratt, M. M. McMullen, G. Poirier, M. C. TI Benzo(a)pyrene (BP)-DNA Adduct Formation in XPA(-/-)p53(+/-) Transgenic Mice SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [John, K.; Pratt, M. M.; McMullen, G.; Poirier, M. C.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 571 EP 571 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400145 ER PT J AU Hobbs, CA Recio, L Shepard, K Baldetti, C Winters, J Green, A Allen, P Streicker, M Caspary, W Witt, KL AF Hobbs, C. A. Recio, L. Shepard, K. Baldetti, C. Winters, J. Green, A. Allen, P. Streicker, M. Caspary, W. Witt, K. L. TI Enhanced Susceptibility to Genotoxic Damage in Wistar Han Rats Compared to Fischer 344/N Rats SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 40th Annual Meeting of the Environment-Mutagen-Society CY OCT 24-28, 2009 CL St Louis, MO SP Environm Mutagen Soc C1 [Hobbs, C. A.; Recio, L.; Shepard, K.; Baldetti, C.; Winters, J.; Green, A.; Allen, P.] Integrated Lab Syst Inc, Div Genet Toxicol, Res Triangle Pk, NC USA. [Streicker, M.] Integrated Lab Syst Inc, Invest Toxicol Div, Res Triangle Pk, NC USA. [Caspary, W.; Witt, K. L.] NIEHS, Biomol Screening Branch, Res Triangle Pk, NC 27709 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2009 VL 50 IS 7 BP 584 EP 584 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 484LM UT WOS:000269046400192 ER PT J AU Resnik, DB AF Resnik, David B. TI Environmental Health Research and the Observer's Dilemma SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE beneficence; environmental health research; ethics; human subjects; observation; regulations; risk; risk communication ID EXPOSURE; CHILDREN; CARE AB BACKGROUND: Environmental health researchers frequently study people in occupational, educational, recreational, or domestic settings who are exposed to hazardous agents. OBJECTIVE/DISCUSSION: Deciding whether-and how-to inform research subjects about risks they face in their environment can be a challenging task for investigators. Because legal rules and professional guidelines do not cover this topic, investigators must carefully consider their ethical obligations in light of the facts and circumstances. CONCLUSION: To navigate through this dilemma, investigators should consider the evidence for the risks, the nature of the risks, the usefulness of risk information to the subjects, and the effects on the study and community of informing subjects about risks. C1 NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Dept Hlth & Human Serv, Mail Drop CU 03,Box 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS); National Institutes of Health (NIH) FX This research was sponsored by the intramural program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). It does not represent the views of the NIEHS, NIH, or U.S. government. NR 34 TC 7 Z9 7 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 2009 VL 117 IS 8 BP 1191 EP 1194 DI 10.1289/ehp.0900861 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 478DD UT WOS:000268567100020 PM 19672396 ER PT J AU Bridbord, K Hanson, D AF Bridbord, Kenneth Hanson, David TI A Personal Perspective on the Initial Federal Health-Based Regulation to Remove Lead from Gasoline SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE gasoline; government; health-based regulation; lead; policy; US EPA ID LESS-THAN-10 MU-G/DL; EXPOSURE; CHILDREN; CHILDHOOD; TOXICITY; VULNERABILITY; ABSORPTION; DEFICITS; INDUSTRY; LEVEL AB OBJECTIVE: This article describes the personal experience and perspective of the authors, who had primary responsibility for drafting the initial health-based regulation limiting lead content of gasoline during the early 1970s while employed by the U.S. Environmental Protection Agency (EPA). DATA SOURCE: Information used by the U.S. EPA in developing the initial health-based regulation limiting lead content of gasoline in December 1973 and studies documenting the impact of that and subsequent actions. DATA EXTRACTION: Among the lessons learned from this experience is the importance of having input from independent scientists to the regulatory decision-making process. This also demonstrates the critical role of independent peer-reviewed research, such as that supported by the National Institutes of Health, as well as research conducted by scientists from the Centers for Disease Control and Prevention, in delineating the consequences of lead exposure in the population. DATA SYNTHESIS: Removal of lead from gasoline in the United States has been described as one of the great public health achievements of the 20th century, but it almost did not happen. The experience of the authors in developing this regulation may be helpful to others involved in developing health-based regulatory policy in the future. CONCLUSION: The initial U.S. EPA health-based regulation to remove lead from gasoline is clearly an example where science successfully affected public policy. The leadership of the U.S. EPA at that time deserves much credit for establishing an atmosphere in which this was possible. C1 [Bridbord, Kenneth] NIH, Div Int Training & Res, Fogarty Int Ctr, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hanson, David] Matanuska Susitna Borough, Econ Dev Dept, Palmer, AK USA. RP Bridbord, K (reprint author), NIH, Div Int Training & Res, Fogarty Int Ctr, Dept Hlth & Human Serv, 31 Ctr Dr,Room B2C39, Bethesda, MD 20892 USA. EM ken_bridbord@nih.gov NR 51 TC 14 Z9 14 U1 0 U2 3 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 2009 VL 117 IS 8 BP 1195 EP 1201 DI 10.1289/ehp.0800534 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 478DD UT WOS:000268567100021 PM 19672397 ER PT J AU Nepomnaschy, PA Baird, DD Weinberg, CR Hoppin, JA Longnecker, MP Wilcox, AJ AF Nepomnaschy, Pablo A. Baird, Donna Day Weinberg, Clarice R. Hoppin, Jane A. Longnecker, Matthew P. Wilcox, Allen J. TI Within-person variability in urinary bisphenol A concentrations: Measurements from specimens after long-term frozen storage SO ENVIRONMENTAL RESEARCH LA English DT Article DE Bisphenol A; Temporal variability; Reproducibility; Menstrual cycle ID HUMAN EXPOSURE; TEMPORAL VARIABILITY; MECHANISMS; PHENOLS AB Background: Bisphenol A (BPA) is an estrogenic contaminant of food and water associated with adverse developmental effects in laboratory animals. BPA has recently been linked to morbidity in adult humans, but studies of developmental effects in humans are methodologically more difficult. The ability to measure BPA in urine samples after long-term storage could aid in such studies. Because the half-life of BPA is < 6 h, a single measurement would be useful only if the environmental exposure is relatively constant over weeks or months. Our aims were to evaluate the stability of BPA in specimens after 22-24 years of storage and to measure within-person temporal variability in urinary BPA. Methods: We measured total BPA concentration by mass spectrometry in first-morning urine samples from 60 premenopausal women. We selected from each woman's stored daily collections three urine samples approximately 2 and 4 weeks apart. Samples were selected from both the follicular and luteal phases of the menstrual cycle to assess cycle effects. Temporal variability was assessed with mixed model regression and correlations. Results: BPA levels had an inter-quartile range from 1.1 to 3.1 ng/mg creatinine, slightly higher than levels in specimens from NHANES collected 3-11 years later. The Spearman correlation was approximately 0.5 for samples 2 weeks apart and 0.3 for samples 4 weeks apart. Menstrual cycle phase did not influence levels. BPA tended to increase during the three-year collection period, but not significantly. Conclusions: The similar distribution to NHANES samples and correlation of BPA levels taken at 2-week intervals provide indirect evidence that BPA is relatively stable during long-term freezer storage. The correlations indicate generally stable exposures over periods of weeks. These findings suggest that developmental effects of BPA exposure could be investigated with measurements from stored urine. (C) 2009 Published by Elsevier Inc. C1 [Nepomnaschy, Pablo A.; Baird, Donna Day; Hoppin, Jane A.; Longnecker, Matthew P.; Wilcox, Allen J.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. [Weinberg, Clarice R.] Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Res Triangle Pk, NC USA. RP Baird, DD (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. EM baird@niehs.nih.gov RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Longnecker, Matthew/0000-0001-6073-5322; Wilcox, Allen/0000-0002-3376-1311 FU Intramural NIH HHS [Z01 ES049003-19] NR 23 TC 44 Z9 46 U1 2 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 J9 ENVIRON RES JI Environ. Res. PD AUG PY 2009 VL 109 IS 6 BP 734 EP 737 DI 10.1016/j.envres.2009.04.004 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 471JR UT WOS:000268054100012 PM 19463991 ER PT J AU Richard, SA Sugaya, N Simonsen, L Miller, MA Viboud, C AF Richard, S. A. Sugaya, N. Simonsen, L. Miller, M. A. Viboud, C. TI A comparative study of the 1918-1920 influenza pandemic in Japan, USA and UK: mortality impact and implications for pandemic planning SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE Age patterns; excess mortality; geography; influenza; pandemic ID EPIDEMIOLOGIC EVIDENCE; SPANISH INFLUENZA; UNITED-STATES; AGE; PATTERNS; ENGLAND; WALES; CITY; WAVE AB Historical studies of influenza pandemics can provide insight into transmission and mortality patterns, and may aid in planning for a future pandemic. Here, we analyse historical vital statistics and quantify the age-specific mortality patterns associated with the 1918-1920 influenza pandemic in Japan, USA, and UK. All three Countries showed highly elevated mortality risk in young adults relative to surrounding non-pandemic years. By contrast, the risk of death was low in the very young and very old. In Japan, the overall mortality impact was not limited to winter 1918-1919, and continued during winter 1919-1920. Mortality impact varied as much as threefold across the 47 Japanese prefectures, and differences in baseline mortality, population demographics, and density explained a small fraction of these variations. Our study highlights important geographical variations in timing and mortality impact of historical pandemics, in particular between the Eastern and Western hemispheres. In a future pandemic, vaccination in one region could save lives even months after the emergence of a pandemic virus in another region. C1 [Richard, S. A.; Miller, M. A.; Viboud, C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Sugaya, N.] Keiyu Hosp, Dept Pediat, Yokohama, Kanagawa, Japan. [Simonsen, L.] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC USA. RP Viboud, C (reprint author), NIH, Fogarty Int Ctr, 16 Ctr Dr,MSC6705,Bldg 16, Bethesda, MD 20892 USA. EM viboudc@mail.nih.gov OI Simonsen, Lone/0000-0003-1535-8526 FU Fogarty International Center; National Institutes of Health FX This work was funded by the Intramural Research Program of the Fogarty International Center, National Institutes of Health. We thank Dr Wladimir Alonso and his staff for assistance in entering historical mortality data for Japan. NR 29 TC 19 Z9 19 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD AUG PY 2009 VL 137 IS 8 BP 1062 EP 1072 DI 10.1017/S0950268809002088 PG 11 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 477MU UT WOS:000268524000002 PM 19215637 ER PT J AU Larsson, SC Mannisto, S Virtanen, MJ Kontto, J Albanes, D Virtamo, J AF Larsson, S. C. Mannisto, S. Virtanen, M. J. Kontto, J. Albanes, D. Virtamo, J. TI Dietary fiber and fiber-rich food intake in relation to risk of stroke in male smokers SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE cereals; dietary fiber; fruits; prospective studies; stroke; vegetables ID CAROTENE-CANCER-PREVENTION; CORONARY-HEART-DISEASE; BLOOD-PRESSURE; ALPHA-TOCOPHEROL; METAANALYSIS; COHORT; CEREAL; WOMEN; MEN; SUPPLEMENTATION AB Background/Objectives: There is convincing evidence that a high dietary fiber intake may lower the risk of coronary heart disease. However, the role of fiber in the prevention of stroke is unclear. We examined the associations of dietary fiber and fiber-rich food intake with risk of stroke within the Alpha-tocopherol, Beta-carotene Cancer Prevention Study. Subjects/Methods: Between 1985 and 1988, 26 556 Finnish male smokers aged 50-69 years, who had no history of stroke, completed a dietary questionnaire. During a mean follow-up of 13.6 years, 2702 cerebral infarctions, 383 intracerebral hemorrhages and 196 subarachnoid hemorrhages were ascertained. Results: After adjustment for cardiovascular risk factors and folate and magnesium intakes, there was no significant association between intake of total fiber, water-soluble fiber, water-insoluble fiber, or fiber derived from fruit or cereal sources and risk of any stroke subtype. Vegetable fiber intake, as well as the consumption of fruit, vegetables and cereals, was inversely associated with the risk of cerebral infarction; the multivariate relative risks for the highest quintile of intake as compared with the lowest were 0.86 (95% confidence interval (CI): 0.76-0.99) for vegetable fiber, 0.82 (95% CI: 0.73-0.93) for fruit, 0.75 (95% CI: 0.66-0.85) for vegetables and 0.87 (95% CI: 0.74-1.03) for cereals. Vegetable consumption was inversely associated with risk of subarachnoid hemorrhage (relative risk for highest versus lowest quintile: 0.62; 95% CI: 0.40-0.98), and cereal consumption was inversely associated with risk of intracerebral hemorrhage (relative risk: 0.64; 95% CI: 0.41-1.01). Conclusions: These findings suggest a beneficial effect of the consumption of fruits, vegetables and cereals on stroke risk. European Journal of Clinical Nutrition (2009) 63, 1016-1024; doi: 10.1038/ejcn.2009.16; published online 25 March 2009 C1 [Larsson, S. C.; Mannisto, S.; Virtanen, M. J.; Kontto, J.; Albanes, D.; Virtamo, J.] Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden. [Mannisto, S.; Virtanen, M. J.; Kontto, J.; Virtamo, J.] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [Albanes, D.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Larsson, SC (reprint author), Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, Box 210, SE-17177 Stockholm, Sweden. EM susanna.larsson@ki.se RI Albanes, Demetrius/B-9749-2015; Larsson, Susanna/F-6065-2015; OI Larsson, Susanna/0000-0003-0118-0341; Mannisto, Satu/0000-0002-8668-3046; Kontto, Jukka/0000-0003-3899-9852 FU US National Cancer Institute [N01-CN-45165, N01-RC-45035, N01-RC-37004]; National Institutes of Health; Department of Health and Human Services, Bethesda; MD. Dr Larsson's postdoctoral research at the National Public Health Institute in Helsinki, Finland; Swedish Council for Working Life and Social Research FX This ATBC Study was supported by Public Health Service contracts N01-CN-45165, N01-RC-45035 and N01-RC-37004 from the US National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. Dr Larsson's postdoctoral research at the National Public Health Institute in Helsinki, Finland, was supported by a grant from the Swedish Council for Working Life and Social Research. NR 32 TC 29 Z9 32 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD AUG PY 2009 VL 63 IS 8 BP 1016 EP 1024 DI 10.1038/ejcn.2009.16 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 479HK UT WOS:000268650100012 PM 19319150 ER PT J AU El-Chemaly, S Taveira-DaSilva, A Stylianou, MP Moss, J AF El-Chemaly, S. Taveira-DaSilva, A. Stylianou, M. P. Moss, J. TI Statins in lymphangioleiomyomatosis: a word of caution SO EUROPEAN RESPIRATORY JOURNAL LA English DT Letter ID ATORVASTATIN; CELLS C1 [El-Chemaly, S.; Taveira-DaSilva, A.; Moss, J.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Stylianou, M. P.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10,Rm 6D03,MSC 1590, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov FU Intramural NIH HHS [Z01 HL002541-13, Z01 HL002541-12, ZIA HL002541-14] NR 7 TC 13 Z9 13 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 J9 EUR RESPIR J JI Eur. Resp. J. PD AUG PY 2009 VL 34 IS 2 BP 513 EP 514 DI 10.1183/09031936.00012709 PG 2 WC Respiratory System SC Respiratory System GA 477NP UT WOS:000268526100028 PM 19648526 ER PT J AU Cai, Q Sheng, ZH AF Cai, Qian Sheng, Zu-Hang TI Mitochondrial transport and docking in axons SO EXPERIMENTAL NEUROLOGY LA English DT Review DE Mitochondria; Axonal transport; Docking; Synaptic plasticity; Kinesin; Motor adaptor; Anterograde transport; Retrograde transport; Stationary mitochondria; Mitochondrial mobility ID MOTOR-NEURON DISEASE; CULTURED HIPPOCAMPAL-NEURONS; KINESIN HEAVY-CHAIN; NERVE GROWTH-FACTOR; BRAIN MYOSIN-V; CYTOPLASMIC DYNEIN; IN-VITRO; MEMBRANOUS ORGANELLES; DYNACTIN COMPLEX; LIGHT-CHAIN AB Proper transport and distribution of mitochondria in axons and at synapses are critical for the normal physiology of neurons. Mitochondria in axons display distinct motility patterns and undergo saltatory and bidirectional movement, where mitochondria frequently stop, start moving again, and change direction. While approximately one-third of axonal mitochondria are mobile in mature neurons, a large proportion remains stationary. Their net movement is significantly influenced by recruitment to stationary or motile states. In response to the diverse physiological states of axons and synapses, the mitochondrial balance between motile and stationary phases is a possible target Of regulation by intracellular signals and synaptic activity. Efficient control of mitochondrial retention (docking) at particular stations, where energy production and calcium homeostasis capacity are highly demanded, is likely essential for neuronal development and function. In this review, we introduce the molecular and cellular mechanisms underlying the complex mobility patterns of axonal mitochondria and discuss how motor adaptor complexes and docking machinery contribute to mitochondrial transport and distribution in axons and at synapses. In addition, we briefly discuss the physiological evidence how axonal mitochondrial mobility impacts synaptic function. Published by Elsevier Inc. C1 [Cai, Qian; Sheng, Zu-Hang] NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Cai, Q (reprint author), NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bldg 35,Room 3B203,35 Convent Dr, Bethesda, MD 20892 USA. EM caiq@ninds.nih.gov; shengz@ninds.nih.gov FU NINDS; NIH FX We thank the members of the Sheng laboratory for helpful discussion and D. Schoenberg for critical reading of the manuscript. The authors are supported by the Intramural Research Program of NINDS, NIH. NR 83 TC 39 Z9 40 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD AUG PY 2009 VL 218 IS 2 BP 257 EP 267 DI 10.1016/j.expneurol.2009.03.024 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 472GE UT WOS:000268117400011 PM 19341731 ER PT J AU Stutzer, C Mans, BJ Gaspar, ARM Neitz, AWH Maritz-Olivier, C AF Stutzer, Christian Mans, Ben J. Gaspar, Anabella R. M. Neitz, Albert W. H. Maritz-Olivier, Christine TI Ornithodoros savignyi: Soft tick apyrase belongs to the 5 '-nucleotidase family SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE Apyrase; 5 '-Nucleotidase; Platelet aggregation inhibitors; Ornithodoros savignyi; Soft tick ID IXODES-SCAPULARIS; BOOPHILUS-MICROPLUS; POLYACRYLAMIDE-GELS; SEQUENCE ALIGNMENT; SECRETED PROTEINS; SALIVARY APYRASE; EXPRESSION; EVOLUTION; MOSQUITO; IDENTIFICATION AB Salivary apyrases are nucleotide-metabolising enzymes that blood-feeding parasites utilise for modulation of extracellular nucleotides to prevent platelet activation and aggregation. In this study a 5'-nucleotidase specific degenerate primer was used to identify homologous transcripts from Ornithodoros savignyi salivary gland cDNA. Two 5'-nucleotidase isoforms that share significant sequence identity to putative apyrases from Rhipicephalus appendiculatus and Ixodes scapularis were identified. Structure prediction showed a tertiary structure similar to periplasmic ecto-5'-nucleotidase from Escherichia coli, with high conservation of functional residues. The O. savignyi 5'-nucleotidase isoform I was recombinantly expressed in Pichia pastoris. Cross-reactivity was demonstrated with polyclonal anti-apyrase antisera produced against O. savignyi apyrase. Subsequent Edman sequencing and MS/MS analysis of purified O. savignyi apyrase identified peptide sequence fragments that shared sequence identity with both newly identified 5'-nucleotidase isoforms. It was concluded that wild-type apyrase is a mixture of the isoforms identified from the salivary glands of O. savignyi. These results represent the first confirmation of a soft (argasid) tick apyrase that belongs to the 5'-nucleotidase family of enzymes. (C) 2009 Elsevier Inc. All rights reserved. C1 [Stutzer, Christian; Gaspar, Anabella R. M.; Neitz, Albert W. H.; Maritz-Olivier, Christine] Univ Pretoria, Dept Biochem, ZA-0002 Pretoria, South Africa. [Mans, Ben J.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Mans, BJ (reprint author), Onderstepoort Vet Inst, Bldg 34, ZA-0110 Onderstepoort, Gauteng, South Africa. EM mansb@arc.agric.za OI Mans, Ben/0000-0002-0177-0029 FU Wellcome Trust [0757990]; International Cooperation Program of the European Union [510561] FX We thank the National Research Foundation of South Africa and the University of Pretoria for financial support. The expression system used in this study was funded by Wellcome Trust under the Animal Health in the Developing World initiative (Project No. 0757990): "Adapting recombinant anti-tick vaccines to livestock in Africa". We also acknowledge the support facilitated through the Integrated Consortium on Ticks and Tick-borne Diseases (ICTTD-3), financed by the International Cooperation Program of the European Union, coordination action project No. 510561. Mark Garfield and Carl Hammer from the Research Technology Branch of the NIAD is thanked for Edman sequencing and MS-MS analysis. NR 50 TC 16 Z9 16 U1 2 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 EI 1090-2449 J9 EXP PARASITOL JI Exp. Parasitol. PD AUG PY 2009 VL 122 IS 4 BP 318 EP 327 DI 10.1016/j.exppara.2009.04.007 PG 10 WC Parasitology SC Parasitology GA 466BU UT WOS:000267636400009 PM 19393241 ER PT J AU Li, XM Su, JW Cui, XZ Li, Y Barochia, A Eichacker, PQ AF Li, Xuemei Su, Junwu Cui, Xizhong Li, Yan Barochia, Amisha Eichacker, Peter Q. TI Can we predict the effects of NF-kappa B inhibition in sepsis? Studies with parthenolide and ethyl pyruvate SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Review DE inflammation; NF-kappa B; sepsis; therapy ID TOLL-LIKE RECEPTOR-4; NITRIC-OXIDE SYNTHASE; ACTIVATED PROTEIN-C; LIPOPOLYSACCHARIDE-INDUCED SHOCK; STAPHYLOCOCCUS-AUREUS PNEUMONIA; HEPATIC STELLATE CELLS; DIRECTLY TARGETING P65; ACUTE LUNG INJURY; IN-VIVO; SESQUITERPENE LACTONE AB Background: Based partially on encouraging findings from preclinical models, interest has grown in therapeutic inhibition of NF-kappa B to limit inflammatory injury during sepsis. However, NF-kappa B also regulates protective responses, and predicting the net survival effects of such inhibition may be difficult. Objectives: To highlight the caution necessary with this therapeutic approach, we review our investigations in a mouse sepsis model with parthenolide and ethyl pyruvate, two NF-kappa B inhibitors proposed for clinical study. Results: Consistent with published studies, parthenolide decreased NF-kappa B binding activity and inflammatory cytokine release from lipopolysaccharide (LPS) stimulated RAW 264.7 cells in vitro. In LPS-challenged mice (C57BL/6J), however, while both agents decreased lung and kidney NF-kappa B binding activity and plasma cytokines early (1 - 3 h), these measures were increased later (6 - 12 h) in patterns differing significantly over time. Furthermore, despite studying several doses of parthenolide (0.25 - 4.0 mg/kg) and ethyl pyruvate (0.1 - 100 mg/kg), each produced small but consistent decreases in survival which overall were significant (p <= 0.04 for each agent). Conclusion: While NF-kappa B inhibitors hold promise for inflammatory conditions such as sepsis, caution is necessary. Clear understanding of the net effects of NF-kappa B inhibitors on outcome will be necessary before such agents are used clinically. C1 [Eichacker, Peter Q.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Li, Xuemei] Beijing Union Med Coll Hosp, Peking Union Med Coll, Dept Nephrol, Beijing 100730, Peoples R China. [Li, Xuemei] Chinese Acad Med Sci, Beijing 100730, Peoples R China. [Su, Junwu] Capital Med Univ, Anzhen Hosp, Surg Dept Pediat Cardiol, Beijing, Peoples R China. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Room 2C145, Bethesda, MD 20892 USA. EM peichacker@mail.cc.nih.gov FU NIH Clinical Center FX This research was supported by the intramural program of the NIH Clinical Center. NR 116 TC 9 Z9 13 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-3784 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD AUG PY 2009 VL 18 IS 8 BP 1047 EP 1060 DI 10.1517/13543780903018880 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 481EJ UT WOS:000268789900001 PM 19555300 ER PT J AU Adamson, CS Salzwedel, K Freed, EO AF Adamson, Catherine S. Salzwedel, Karl Freed, Eric O. TI Virus maturation as a new HIV-1 therapeutic target SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE assembly; Gag; HIV; maturation inhibitors ID HUMAN-IMMUNODEFICIENCY-VIRUS; INHIBITOR BEVIRIMAT PA-457; TYPE-1 GAG POLYPROTEIN; AMINO-TERMINAL DOMAIN; CAPSID PROTEIN; IN-VITRO; BETULINIC ACID; ANTIRETROVIRAL THERAPY; ASSEMBLY INHIBITOR; ELECTRON CRYOTOMOGRAPHY AB Development of novel therapeutic targets against HIV-1 is a high research priority owing to the serious clinical consequences associated with acquisition of resistance to current antiretroviral drugs. The HIV-1 structural protein Gag represents a potential new therapeutic target as it plays a central role in virus particle production yet is not targeted by any of the antiretroviral drugs approved at present. The Gag polyprotein precursor multimerizes to form immature particles that bud from the infected cell. Concomitant with virus release, the Gag precursor undergoes proteolytic processing by the viral protease to generate the mature Gag proteins, which include capsid (CA). Once liberated from the Gag polyprotein precursor, CA molecules interact to reassemble into a condensed conical core, which organizes the viral RNA genome and several viral proteins to facilitate virus replication in the next round of infection. Correct Gag proteolytic processing and core assembly are therefore essential for virus infectivity. In this review, we discuss new strategies to inhibit maturation by targeting proteolytic cleavage sites in Gag or CA-CA interactions required for core formation. The identification and development of lead maturation inhibitors are highlighted. C1 [Adamson, Catherine S.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Salzwedel, Karl] Panacos Pharmaceut, Gaithersburg, MD 20877 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Bldg 535 Room 108,1050 Boyles St, 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 Research in our lab is 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 124 TC 37 Z9 40 U1 1 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8222 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD AUG PY 2009 VL 13 IS 8 BP 895 EP 908 DI 10.1517/14728220903039714 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 481MU UT WOS:000268816500002 PM 19534569 ER PT J AU Tsai, CC Cheng, CY Liu, CY Kao, SC Kau, HC Hsu, WM Wei, YH AF Tsai, C-C Cheng, C-Y Liu, C-Y Kao, S-C Kau, H-C Hsu, W-M Wei, Y-H TI Oxidative stress in patients with Graves' ophthalmopathy: relationship between oxidative DNA damage and clinical evolution SO EYE LA English DT Article DE oxidative stress; Graves' ophthalmopathy; oxidative DNA damage ID THYROID-ASSOCIATED OPHTHALMOPATHY; INFLAMMATORY-BOWEL-DISEASE; FACTOR-I RECEPTOR; PERIPHERAL PARAMETERS; ORBITAL FIBROBLASTS; FREE-RADICALS; CIGARETTE-SMOKING; PATHOGENESIS; METHIMAZOLE; 8-HYDROXYDEOXYGUANOSINE AB Purpose To evaluate the relationship between oxidative stress and clinical evolution in patients with Graves' ophthalmopathy (GO). Methods Thirty-one euthyroid GO patients and 25 healthy subjects participated in this study. Oxidative DNA damage was assessed by determination of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) level in urine by ELISA. The relationship of oxidative DNA damage to the clinical evolutions of GO, especially the smoking status, clinical activity scores (CAS), and ophthalmopathy index was examined. Results The mean 8-OHdG was significantly higher in GO patients than that of normal controls (12.6 +/- 5.7 vs 6.7 +/- 2.5 ng/mg creatinine, P<0.001). Smokers had significant higher 8-OHdG than did never smokers in GO patients (P = 0.029), but not in healthy controls (P = 0.374). Among GO patients, only CAS remained significantly correlated with 8-OHdG (P = 0.001) after adjusting for age, sex, disease duration, the status of antithyroid drug and smoking, and thyroid-stimulating hormone level. Patients with active GO (CAS>3) had higher 8-OHdG than did the patients with CAS <= 3 (16.3 +/- 4.9 vs 8.6 +/- 3.0 ng/mg creatinine). Conclusions Our findings suggest that urinary 8-OHdG is increased in GO patients and is correlated with the disease activity. Smoking had a higher impact on the increased 8-OHdG among GO patients. Eye (2009) 23, 1725-1730; doi: 10.1038/eye.2008.310; published online 10 October 2008 C1 [Wei, Y-H] Natl Yang Ming Univ, Dept Biochem & Mol Biol, Sch Med, Taipei 112, Taiwan. [Tsai, C-C; Cheng, C-Y; Kao, S-C; Kau, H-C] Natl Yang Ming Univ, Taipei Vet Gen Hosp, Dept Ophthalmol, Taipei 112, Taiwan. [Tsai, C-C; Wei, Y-H] Natl Yang Ming Univ, Inst Clin Med, Taipei 112, Taiwan. [Cheng, C-Y] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Cheng, C-Y] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Kau, H-C] Sun Yat Sen Canc Ctr, Dept Ophthalmol, Koo Fdn, Taipei, Taiwan. [Hsu, W-M] Taipei Med Univ, Dept Ophthalmol, Shuang Ho Hosp, Taipei, Taiwan. RP Wei, YH (reprint author), Natl Yang Ming Univ, Dept Biochem & Mol Biol, Sch Med, 155 Li Nong St,Sect 2, Taipei 112, Taiwan. EM joeman@ym.edu.tw RI Cheng, Ching-Yu/K-7017-2013 OI Cheng, Ching-Yu/0000-0003-0655-885X FU National Science Council of Taiwan [NSC96-2314-B-075-023, NSC96-2320-B-010-006]; Taipei Veterans General Hospital, Taipei, Taiwan [V96-B1002] FX This study was partially supported by Grants (NSC96-2314-B-075-023 and NSC96-2320-B-010-006) from the National Science Council of Taiwan and a Grant (V96-B1002) from Taipei Veterans General Hospital, Taipei, Taiwan. NR 39 TC 25 Z9 32 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-222X J9 EYE JI Eye PD AUG PY 2009 VL 23 IS 8 BP 1725 EP 1730 DI 10.1038/eye.2008.310 PG 6 WC Ophthalmology SC Ophthalmology GA 482VB UT WOS:000268915900018 PM 18849914 ER PT J AU Ishizuya-Oka, A Hasebe, T Buchholz, DR Kajita, M Fu, LZ Shi, YB AF Ishizuya-Oka, Atsuko Hasebe, Takashi Buchholz, Daniel R. Kajita, Mitsuko Fu, Liezhen Shi, Yun-Bo TI Origin of the adult intestinal stem cells induced by thyroid hormone in Xenopus laevis SO FASEB JOURNAL LA English DT Article DE transgenic frog; organ culture; tissue recombination; gut remodeling; metamorphosis ID MATRIX-METALLOPROTEINASE STROMELYSIN-3; ACID-BINDING PROTEIN; AMPHIBIAN METAMORPHOSIS; GENE-EXPRESSION; POSTEMBRYONIC DEVELOPMENT; EPITHELIAL DEVELOPMENT; EXTRACELLULAR-MATRIX; CONNECTIVE-TISSUE; TADPOLE INTESTINE; PROGENITOR CELLS AB In the amphibian intestine during metamorphosis, de novo stem cells generate the adult epithelium analogous to the mammalian counterpart. Interestingly, to date the exact origin of these stem cells remains to be determined, making intestinal metamorphosis a unique model to study development of adult organ-specific stem cells. Here, to determine their origin, we made use of transgenic Xenopus tadpoles expressing green fluorescent protein (GFP) for recombinant organ cultures. The larval epithelium separated from the wild-type (Wt) or GFP transgenic (Tg) intestine before metamorphic climax was recombined with homologous and heterologous nonepithelial tissues and was cultivated in the presence of thyroid hormone, the causative agent of metamorphosis. In all kinds of recombinant intestine, adult progenitor cells expressing markers for intestinal stem cells such as sonic hedgehog became detectable and then differentiated into the adult epithelium expressing intestinal fatty acid binding-protein, a marker for absorptive cells. Notably, whenever the epithelium was derived from Tg intestine, both the adult progenitor/stem cells and their differentiated cells expressed GFP, whereas neither of them expressed GFP in the Wt-derived epithelium. Our results provide direct evidence that stem cells that generate the adult intestinal epithelium originate from the larval epithelium, through thyroid hormone-induced dedifferentiation.-Ishizuya-Oka, A., Hasebe, T., Buchholz, D. R., Kajita, M., Fu, L., Shi, Y.-B. The origin of the adult intestinal stem cells induced by thyroid hormone in Xenopus laevis. FASEB J. 23, 2568-2575 (2009) C1 [Ishizuya-Oka, Atsuko] Nippon Med Sch, Dept Biol, Nakahara Ku, Kanagawa 2210063, Japan. [Ishizuya-Oka, Atsuko; Kajita, Mitsuko] Nippon Med Sch, Inst Dev & Aging Sci, Kanagawa 2210063, Japan. [Buchholz, Daniel R.] Univ Cincinnati, Dept Biol Sci, Cincinnati, OH 45221 USA. [Fu, Liezhen; Shi, Yun-Bo] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Ishizuya-Oka, A (reprint author), Nippon Med Sch, Dept Biol, Nakahara Ku, 2-297-2 Kosugi Cho, Kanagawa 2210063, Japan. EM a-oka@nms.ac.jp FU Japan Society for the Promotion of Science [20570060]; National Institute of Child Health and Human Development, U.S. National Institutes of Health FX We thank Dr. Dave Turner (University of Michigan, Ann Arbor, MI, USA) and Dr. Gert Jan C. Veenstra (University of Nijmegen, Nijmegen, The Netherlands) for kind gifts of plasmids. This work was supported in part by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (C) (grant 20570060 to A.I.-O.) and in part by the Intramural Research Program of the National Institute of Child Health and Human Development, U.S. National Institutes of Health (to Y.-B.S.). NR 52 TC 39 Z9 41 U1 0 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD AUG PY 2009 VL 23 IS 8 BP 2568 EP 2575 DI 10.1096/fj.08-128124 PG 8 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 481UE UT WOS:000268836700025 PM 19299481 ER PT J AU Hlouchova, K Barinka, C Konvalinka, J Lubkowski, J AF Hlouchova, Klara Barinka, Cyril Konvalinka, Jan Lubkowski, Jacek TI Structural insight into the evolutionary and pharmacologic homology of glutamate carboxypeptidases II and III SO FEBS JOURNAL LA English DT Article DE GCPIII; M28 family; metallopeptidase; NAALADase II; prostate specific membrane antigen ID LINKED ACIDIC DIPEPTIDASE; MEMBRANE ANTIGEN; PROSTATE-CANCER; N-ACETYLASPARTYLGLUTAMATE; ELECTRON-DENSITY; PEPTIDASE; PROTEIN; EXPRESSION; INHIBITORS; SUBSTRATE AB Glutamate carboxypeptidase III (GCPIII) is a metalloenzyme that belongs to the transferrin receptor/glutamate carboxypeptidase II (GCPII; EC 3.4.17.21) superfamily. GCPIII has been studied mainly because of its evolutionary relationship to GCPII, an enzyme involved in a variety of neuropathologies and malignancies, such as glutamatergic neurotoxicity and prostate cancer. Given the potential functional and pharmacological overlap between GCPIII and GCPII, studies addressing the structural and physiological properties of GCPIII are crucial for obtaining a deeper understanding of the GCPII/GCPIII system. In the present study, we report high-resolution crystal structures of the human GCPIII ectodomain in a 'pseudo-unliganded' state and in a complex with: (a) l-glutamate (a product of hydrolysis); (b) a phosphapeptide transition state mimetic, namely (2S,3'S)-{[(3'-amino-3'-carboxy-propyl)-hydroxyphosphinoyl]methyl}-pentanedioic acid; and (c) quisqualic acid, a glutamate biostere. Our data reveal the overall fold and quaternary arrangement of the GCPIII molecule, define the architecture of the GCPIII substrate-binding cavity, and offer an experimental evidence for the presence of Zn(2+) ions in the bimetallic active site. Furthermore, the structures allow us to detail interactions between the enzyme and its ligands and to characterize the functional flexibility of GCPIII, which is essential for substrate recognition. A comparison of these GCPIII structures with the equivalent GCPII complexes reveals differences in the organization of specificity pockets, in surface charge distribution, and in the occupancy of the co-catalytic zinc sites. The data presented here provide information that should prove to be essential for the structurally-aided design of GCPIII-specific inhibitors and might comprise guidelines for future comparative GCPII/GCPIII studies. C1 [Lubkowski, Jacek] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Hlouchova, Klara; Konvalinka, Jan] Charles Univ Prague, Fac Nat Sci, Dept Biochem, Prague, Czech Republic. [Hlouchova, Klara; Konvalinka, Jan] Acad Sci Czech Republic, Inst Organ Chem & Biochem, Gilead Sci & IOCB Res Ctr, CR-16610 Prague 6, Czech Republic. RP Lubkowski, J (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, 539 Boyles St, Frederick, MD 21702 USA. EM konval@uochb.cas.cz; jacek@ncifcrf.gov RI Konvalinka, Jan/G-7518-2014; OI Konvalinka, Jan/0000-0003-0695-9266; Hlouchova, Klara/0000-0002-5651-4874 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng38]; NIH FX We thank Takashi Tsukamoto and Pavel Majer for the generous gift of EPE, Jana Starkova for excellent technical assistance, Zbyszek Dauter for assistance with the X-ray experiments, and Hillary Hoffman for corrections to the language. Diffraction data were collected at the South-East Regional Collaborative Access Team (SER-CAT) beamline 22-ID at the Advanced Photon Source, Argonne National Laboratory. The use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng38. This project was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (J.L. and C.B.). J.K. and K.H. were supported in part by the Ministry of Education of the Czech Republic (Research Centre for New Antivirals and Antineoplastics, 1M0508). NR 50 TC 15 Z9 17 U1 1 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD AUG PY 2009 VL 276 IS 16 BP 4448 EP 4462 DI 10.1111/j.1742-4658.2009.07152.x PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 476SZ UT WOS:000268466600016 PM 19678840 ER PT J AU Orshan, SA Ventura, JL Covington, SN Vanderhoof, VH Troendle, JF Nelson, LM AF Orshan, Susan A. Ventura, June L. Covington, Sharon N. Vanderhoof, Vien H. Troendle, James F. Nelson, Lawrence M. TI Women with spontaneous 46,XX primary ovarian insufficiency (hypergonadotropic hypogonadism) have lower perceived social support than control women SO FERTILITY AND STERILITY LA English DT Article DE Primary ovarian insufficiency; hypergonadotropic hypogonadism; premature ovarian failure; premature menopause; infertility; coping; perceived social support; self-esteem ID INVOLUNTARY CHILDLESSNESS; YOUNG-WOMEN; FAILURE; HEALTH; GRIEF; INFERTILITY; DISEASE; STIGMA; BEREAVEMENT; INTEGRATION AB Objective: To test the hypothesis that women with spontaneous primary ovarian insufficiency differ from control women with regard to perceived social support and to investigate the relationship between perceived social support and self-esteem. Design: Cross-sectional. Setting: Mark O. Hatfield Clinical Research Center, National Institutes of Health. Patient(s): Women diagnosed with spontaneous primary ovarian insufficiency (n = 154) at a mean age of 27 years and healthy control women (n = 63). Intervention(s): Administration of validated self-reporting instruments. Main Outcome Measure(s): Personal Resource Questionnaire 85 and Rosenberg Self-Esteem Scale. Result(s): Women with primary ovarian insufficiency had significantly lower scores than controls on the perceived social support scale and the self-esteem scale. The findings remained significant after modeling with multivariate regression for differences in age, marital status, and having children. There was a significant positive correlation between self-esteem scores and perceived social support in patients. We found no significant differences in perceived social support or self-esteem related to marital status, whether or not the women had children, or time since diagnosis. Conclusion(s): This evidence supports the need for prospective controlled studies. Strategies to improve social support and self-esteem might provide a therapeutic approach to reduce the emotional suffering that accompanies the life-altering diagnosis of spontaneous primary ovarian insufficiency. (Fertil Steril (R) 2009;92:688-93. (C)2009 by American Society for Reproductive Medicine.) C1 [Orshan, Susan A.; Ventura, June L.; Covington, Sharon N.; Vanderhoof, Vien H.; Nelson, Lawrence M.] NIH, Integrated Reprod Med Unit, Intramural Res Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Troendle, James F.] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biometry & Math Stat Branch, Bethesda, MD 20892 USA. RP Nelson, LM (reprint author), NIH, Integrated Reprod Med Unit, Intramural Res Program Reprod & Adult Endocrinol, CRC 1-3330,10 Ctr Dr,MSC-1103, Bethesda, MD 20892 USA. EM Lawrence_Nelson@nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health; Human Development, National Institutes of Health FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. Vien H. Vanderhoof and Lawrence M. Nelson are Commissioned Officers in the United States Public Health Service. NR 54 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD AUG PY 2009 VL 92 IS 2 BP 688 EP 693 DI 10.1016/j.fertnstert.2008.07.1718 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 482UU UT WOS:000268915200042 PM 18829005 ER PT J AU Payson, M Malik, M Morris, SSN Segars, JH Chason, R Catherino, WH AF Payson, Mark Malik, Minnie Morris, Sarah Siti-Nur Segars, James H. Chason, Rebecca Catherino, William H. TI Activating transcription factor 3 gene expression suggests that tissue stress plays a role in leiomyoma development SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 61st Annual Meeting of the American-Society-for-Reproductive-Medicine/51st Annual Meeting of the Canadian-Fertility-and-Andrology-Society CY OCT 15-19, 2005 CL Montreal, CANADA SP Amer Soc Reprod Med, Canadian Fertil & Androl Soc DE Fibroid; myometrium; jun; fos; ATF3; racial disparity; stress ID UTERINE LEIOMYOMA; INDUCIBLE GENE; RISK-FACTORS; APOPTOSIS; FIBROIDS; ATF3; PROGESTERONE; MYOMETRIUM; PROTEIN; MYOMAS AB Objective: To determine whether expression of the stress response gene ATF3 and related members of activator protein complex-1, cJun and cFos, were altered in leiomyoma compared with myometrium, and whether this difference might correlate with leiomyoma size or race. Design: Laboratory study. Setting: University hospital. Patient(s): Fifteen women undergoing hysterectomy for symptomatic leiomyoma. Intervention(s): Tissue procurement, RNA isolation, reverse-transcriptase polymerase chain reaction, real-time reverse-transcriptase polymerase (RT-PCR) chain reaction, immunohistochemistry, Western blot. Main Outcome Measure(s): Expression of mRNA and protein in leiomyoma and patient-matched myometrium. Result(s): mRNA transcripts of ATF3 were decreased in leiomyoma compared with matched myometrium by both RT-PCR and real-time RT-PCR. The decrease was greater than fivefold in a majority of samples. The reduction seen in ATF3 mRNA expression did not show a correlation with race and leiomyoma size. Surprisingly, immunohistochemistry and Western blot analysis demonstrated an elevation of ATF3 protein expression by a mean of 2.9-fold. Transcripts of related AP-1 genes, cJun and cFos, were significantly decreased by a mean of -29.57 for cJun and -23.78 for cFos, but there was no significant change in protein expression of the two transcription factors. Conclusions: Alterations in ATF3 gene expression resemble the response to mechanical and ischemic stress reported in other tissues. Results suggested that ATF3 protein expression was increased in leiomyoma, and may reflect increased tissue stress. (Fertil Steril (R) 2009;92:748-55. (C)2009 by American Society for Reproductive Medicine.) C1 [Payson, Mark; Malik, Minnie; Morris, Sarah Siti-Nur; Segars, James H.; Chason, Rebecca; Catherino, William H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Payson, Mark; Segars, James H.; Catherino, William H.] NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. RP Catherino, WH (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bldg A,Room 3078,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM catheriw@mail.nih.gov OI Malik, Minnie/0000-0003-1129-6575 FU Intramural NIH HHS [Z01 HD008737-07, Z01 HD008737-08] NR 36 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD AUG PY 2009 VL 92 IS 2 BP 748 EP 755 DI 10.1016/j.fertnstert.2008.06.030 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 482UU UT WOS:000268915200050 PM 18692824 ER PT J AU Miyakawa, H Mason, RP Jiang, JJ Kadiiska, MB AF Miyakawa, Hisako Mason, Ronald P. Jiang, JinJie Kadiiska, Maria B. TI Lipid-derived free radical production in superantigen-induced interstitial pneumonia SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article; Proceedings Paper CT 16th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine CY NOV 18-22, 2009 CL San Francisco, CA SP Soc Free Rad Biol & Med DE Autoimmune disease; Interstitial pneumonia; Superantigen; Lipid-derived carbon-centered free radical; ESR spin trapping; Free radicals ID ACUTE LUNG INJURY; XANTHINE-OXIDASE ACTIVITY; RHEUMATOID-ARTHRITIS; NITRIC-OXIDE; GENE-EXPRESSION; NADPH OXIDASE; MICE; DISEASE; CELLS; MACROPHAGES AB We studied the free radical generation involved in the development of interstitial pneumonia (IP) in an animal model of autoimmune disease. We observed an electron spin resonance (ESR) spectrum of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) radical adducts detected in the lipid extract Of lungs in autoimmune-prone mice after intratracheal instillation of staphylococcal enterotoxin B. The POBN adducts detected by ESR were paralleled by infiltration of macrophages and neutrophils into the bronchoalveolar lavage fluid. To further investigate the mechanism of free radical generation, mice were pretreated with the macrophage toxicant gadolinium chloride, which significantly Suppressed the radical generation. Free radical generation was also decreased by pretreatment with the xanthine oxidise (XO) inhibitor allopurinol, the iron chelator Desferal, and the inducible nitric oxide synthase (iNOS) inhibitor 1400W. Histopathologically, these drugs significantly reduced both the cell infiltration into the alveolar septal walls and the synthesis of pulmonary collagen fibers. Experiments with NADPH oxidase knockout mice showed that NADPH oxidase did not contribute to lipid radical generation. These results suggest that lipid-derived carbon-centered free radical production is important in the manifestation of IP and that a macrophage toxicant, an XO inhibitor, an iron chelator, and an iNOS inhibitor protect against both radical generation and the manifestation of IP. Published by Elsevier Inc. C1 [Miyakawa, Hisako; Mason, Ronald P.; Jiang, JinJie; Kadiiska, Maria B.] NIEHS, Free Radical Metabolite Sect, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Kadiiska, MB (reprint author), NIEHS, Free Radical Metabolite Sect, Pharmacol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM kadiiska@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999, Z01 ES050117-17] NR 48 TC 6 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG 1 PY 2009 VL 47 IS 3 BP 241 EP 249 DI 10.1016/j.freeradbiomed.2009.04.017 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 464UI UT WOS:000267532800005 PM 19376221 ER PT J AU Whitehead, WE Borrud, L Goode, PS Meikle, S Mueller, ER Tuteja, A Weidner, A Weinstein, M Ye, W AF Whitehead, William E. Borrud, Lori Goode, Patricia S. Meikle, Susan Mueller, Elizabeth R. Tuteja, Ashok Weidner, Alison Weinstein, Milena Ye, Wen CA Pelvic Floor Disorders Network TI Fecal Incontinence in US Adults: Epidemiology and Risk Factors SO GASTROENTEROLOGY LA English DT Article ID PELVIC FLOOR DISORDERS; PAD-WEIGHING TESTS; SEVERITY INDEX; STOOL FORM; URINARY-INCONTINENCE; PREVALENCE; WOMEN; COMMUNITY; TRANSIT; SYMPTOMS AB BACKGROUND & AIMS: The study aims were to estimate the prevalence of different types and frequencies of fecal incontinence (FI), describe demographic factors, and identify risk factors. METHODS: The National Health and Nutrition Examination Survey (NHANES) assesses health status in the civilian noninstitutionalized US population. The validated Fecal Incontinence Severity Index was added to NHANES in 2005-2006. Participants were 2229 women and 2079 men aged 20 years or older. FI was defined as accidental leakage of solid, liquid, or mucus at least once in the preceding month. Sampling weights were used to obtain prevalence estimates for the national population. Multivariate logistic regression identified independent risk factors. RESULTS: The estimated prevalence of FI in noninstitutionalized US adults is 8.3% (95% confidence interval, 7.1-9.5) and consists of liquid stool in 6.2%, solid stool in 1.6%, and mucus in 3.1%. It occurs at least weekly in 2.7%. Prevalence is similar in women (8.9%) and men (7.7%) and increases with age from 2.6% in 20 to 29 year olds up to 15.3% in participants aged 70 years and older. FI is not significantly associated with race/ethnicity, education, income, or marital status after adjusting for age. Independent risk factors in women are advancing age, loose or watery stools, more than 21 stools per week, multiple chronic illnesses, and urinary incontinence. Independent risk factors in men are age, loose or watery stools, poor self-rated health, and urinary incontinence. CONCLUSIONS: FI is a prevalent age-related disorder. Chronic diarrhea is a strong modifiable risk factor that may form the basis for prevention and treatment. C1 [Whitehead, William E.] Univ N Carolina, Dept Med, Ctr Funct Gastrointestinal & Motil Disorders, Chapel Hill, NC 27599 USA. [Whitehead, William E.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC 27599 USA. [Borrud, Lori] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Goode, Patricia S.] Vet Affairs Med Ctr, Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. [Goode, Patricia S.] Univ Alabama, Birmingham, AL USA. [Meikle, Susan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pelv Floor Disorders Program, Contracept & Reprod Hlth Branch, Bethesda, MD USA. [Mueller, Elizabeth R.] Loyola Univ, Med Ctr, Dept Urol, Maywood, IL 60153 USA. [Mueller, Elizabeth R.] Loyola Univ, Med Ctr, Dept Obstet & Gynecol, Maywood, IL 60153 USA. [Tuteja, Ashok] George E Wahlen Vet Affairs Med Ctr, Salt Lake City, UT USA. [Tuteja, Ashok] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. [Weidner, Alison] Duke Univ, Sch Med, Dept Obstet & Gynecol, Durham, NC USA. [Weinstein, Milena] Univ Calif San Diego, Dept Obstet & Gynecol, San Diego, CA 92103 USA. [Ye, Wen] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. RP Whitehead, WE (reprint author), Univ N Carolina, Dept Med, Ctr Funct Gastrointestinal & Motil Disorders, Campus Box 7080, Chapel Hill, NC 27599 USA. EM william_whitehead@med.unc.edu OI Mueller, Elizabeth R./0000-0003-3069-4069 FU NICHD NIH HHS [U10 HD041268-01, U01 HD041249, U01 HD041249-01, U01 HD41249, U10 HD041248, U10 HD041248-01, U10 HD041250, U10 HD041250-01, U10 HD041261, U10 HD041261-01, U10 HD041263, U10 HD041263-01, U10 HD041267, U10 HD041267-01, U10 HD041268, U10 HD041269, U10 HD041269-01, U10 HD41248, U10 HD41250, U10 HD41261, U10 HD41263, U10 HD41267, U10 HD41268, U10 HD41269] NR 28 TC 200 Z9 203 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2009 VL 137 IS 2 BP 512 EP 517 DI 10.1053/j.gastro.2009.04.054 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 477WZ UT WOS:000268551000025 PM 19410574 ER PT J AU Everhart, JE Lok, AS Kim, HY Morgan, TR Lindsay, KL Chung, RT Bonkovsky, HL Ghany, MG AF Everhart, James E. Lok, Anna S. Kim, Hae-Young Morgan, Timothy R. Lindsay, Karen L. Chung, Raymond T. Bonkovsky, Herbert L. Ghany, Marc G. CA HALT-C Trial Grp TI Weight-Related Effects on Disease Progression in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial SO GASTROENTEROLOGY LA English DT Article ID NUTRITION EXAMINATION SURVEY; FATTY LIVER-DISEASE; UNTREATED PATIENTS; NATIONAL-HEALTH; UNITED-STATES; STEATOSIS; FIBROSIS; OBESITY; INSULIN; OVERWEIGHT AB BACKGROUND & AIMS: With the limited efficacy of current therapy for chronic hepatitis C, modifiable risk factors for liver disease progression are important to identify. Because obesity is associated with liver disease, we examined the effects of weight-related conditions on disease outcomes in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. METHODS: Of 1050 patients, 985 could be evaluated for predefined progression of liver disease not related to hepatocellular carcinoma. Clinical outcomes were determined over 3.5 years for all patients and progression to cirrhosis on protocol biopsy among patients who had bridging fibrosis (56.5% of cohort) at entry. RESULTS: At study entry, median body mass index was high (29.2 kg/m(2)) and accompanied by other weight-related conditions, including diabetes (24.9%), high median waist circumference, and insulin resistance (by updated homeostasis model assessment of insulin resistance; HOMA2-IR). Among noninvasive measures, HOMA2-IR was most strongly associated with outcomes with hazard ratio (HR) of 1.26 per quartile increase (95% CI, 1.09-1.45). Presence of steatosis on baseline biopsy was associated with an increased outcome rate among patients with bridging fibrosis (P < .0001) and a decreased rate among patients with cirrhosis (P = .006). Presence of Mallory bodies was associated with outcomes (HR, 1.59; 95% CI, 1.10-2.31) as was significant weight change of >= 5% in the first year after randomization (HR, 1.25 per category increase in weight, 95% Cl, 1.01-1.55). CONCLUSIONS: Insulin resistance, histologic features of fatty liver disease, and weight change were associated with outcomes of chronic hepatitis C. Improvement in these weight-related factors might modify disease progression. C1 [Everhart, James E.] NIDDKD, NIH, Div Digest Dis & Nutr, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lok, Anna S.] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. [Kim, Hae-Young] New England Res Inst, Watertown, MA 02172 USA. [Morgan, Timothy R.] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. [Morgan, Timothy R.] VA Long Beach Healthcare Syst, Gastroenterol Serv, Long Beach, CA USA. [Lindsay, Karen L.] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Chung, Raymond T.] Harvard Univ, Sch Med, Boston, MA USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Mol & Struct Biol, Farmington, CT USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Liver Biliary Pancreat Ctr, Farmington, CT USA. [Ghany, Marc G.] NIDDKD, NIH, Liver Dis Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Everhart, JE (reprint author), NIDDKD, NIH, Div Digest Dis & Nutr, Dept Hlth & Human Serv, 2 Democracy Plaza,Room 655,6707 Democracy Blvd,MS, Bethesda, MD 20892 USA. EM JE17g@nih.gov OI Yang, Shuman/0000-0002-9638-0890 FU National Institute of Allergy and Infectious Diseases (NIAID); National Cancer Institute; National Center for Minority Health and Health Disparities; National Center for Research Resources; National Institutes of Health FX This study was supported by the National Institute of Diabetes, Digestive, and Kidney Diseases (contract numbers are listed with the acknowledgments). Additional support was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General Clinical Research Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed below). Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc, through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health. NR 24 TC 60 Z9 62 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2009 VL 137 IS 2 BP 549 EP 557 DI 10.1053/j.gastro.2009.05.007 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 477WZ UT WOS:000268551000030 PM 19445938 ER PT J AU Matsumura, T Hu, ZY Kato, T Dreux, M Zhang, YY Imamura, M Hiraga, N Juteau, JM Cosset, FL Chayama, K Vaillant, A Liang, TJ AF Matsumura, Takuya Hu, Zongyi Kato, Takanobu Dreux, Marlene Zhang, Yong-Yuan Imamura, Michio Hiraga, Nobuhiko Juteau, Jean-Marc Cosset, Francois-Loic Chayama, Kazuaki Vaillant, Andrew Liang, T. Jake TI Amphipathic DNA Polymers Inhibit Hepatitis C Virus Infection by Blocking Viral Entry SO GASTROENTEROLOGY LA English DT Article ID MEMBRANE-FUSION PROTEINS; ENVELOPE GLYCOPROTEIN E2; SCAVENGER RECEPTOR; CELL ENTRY; LIVER-TRANSPLANTATION; PARTICLES; BINDING; PH; RIBAVIRIN; OLIGONUCLEOTIDES AB BACKGROUND & AIMS: Hepatitis C virus (HCV) gains entry into susceptible cells by interacting with cell surface receptor(s). Viral entry is an attractive target for antiviral development because of the highly conserved mechanism. METHODS: HCV culture systems were used to study the effects of phosphorothioate oligonucteotides (PS-ONs), as amphipathic DNA polymers (APs), on HCV infection. The in vivo effects of APs were tested in urokinase plasminogen activator (uPA)/severe combined immunodeficient (SCID) mice engrafted with human hepatocytes. RESULTS: We show the sequence-independent inhibitory effects of APs on HCV infection. APs were shown to potently inhibit HCV infection at submicromolar concentrations. APs exhibited a size-dependent antiviral activity and were equally active against HCV pseudoparticles of various genotypes. Control phosphodiester oligonucleotide (PO-ON) polymer without the amphipathic structure was inactive. APs had no effect on vital replication in the HCV replicon system or binding of HCV to cells but inhibited vital internalization, indicating that the target of inhibition is at the postbinding, cell entry step. In uPA/SCID mice engrafted with human hepatocytes, APs efficiently blocked de novo HCV infection. CONCLUSIONS: Our results demonstrate that APs are a novel class of antiviral compounds that hold promise as a drug to inhibit HCV entry. C1 [Matsumura, Takuya; Hu, Zongyi; Kato, Takanobu; Zhang, Yong-Yuan; Liang, T. Jake] NIDDKD, NIH, Liver Dis Branch, Bethesda, MD 20892 USA. [Dreux, Marlene; Cosset, Francois-Loic] Univ Lyon, INSERM, U758, Lyon, France. [Dreux, Marlene; Cosset, Francois-Loic] Ecole Normale Super Lyon, F-69364 Lyon, France. [Imamura, Michio; Hiraga, Nobuhiko; Chayama, Kazuaki] Hiroshima Univ, Grad Sch Biomed Sci, Dept Med & Mol Sci, Div Frontier Med Sci, Hiroshima, Japan. [Juteau, Jean-Marc; Vaillant, Andrew] REPLICor Inc, Laval, PQ, Canada. RP Liang, TJ (reprint author), NIDDK, NIH, LDB, Bldg 10-9B16,10 Ctr Dr, Bethesda, MD 20892 USA. EM JakeL@bdg10.niddk.nih.gov RI Dreux, Marlene/M-7295-2014 OI Dreux, Marlene/0000-0002-6607-4796 FU National Institute of Diabetes and Digestive and Kidney Diseases; NIH; NIDDK and REPLICor, Inc [DK-06-0367] FX Supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, and a NIH Cooperative Research and Development Agreement (DK-06-0367) between NIDDK and REPLICor, Inc. NR 44 TC 45 Z9 48 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2009 VL 137 IS 2 BP 673 EP 681 DI 10.1053/j.gastro.2009.04.048 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 477WZ UT WOS:000268551000042 PM 19394333 ER PT J AU Gupta, AK Pinsky, P Rall, C Mutch, M Dry, S Seligson, D Schoen, RE AF Gupta, Akshay K. Pinsky, Paul Rall, Christopher Mutch, Matthew Dry, Sarah Seligson, David Schoen, Robert E. TI Reliability and accuracy of the endoscopic appearance in the identification of aberrant crypt foci SO GASTROINTESTINAL ENDOSCOPY LA English DT Article; Proceedings Paper CT Digestive Disease Week Meeting/109th Annual Meeting of the American-Gastroenterological-Association CY MAY 17-22, 2008 CL San Diego, CA SP Amer Gastroenterol Assoc ID HUMAN COLON; CANCER; QUANTIFICATION; COLONOSCOPY AB Background: Aberrant crypt foci (ACF) have emerged as a putative precursor to colorectal adenoma, with potential use as a biomarker of colorectal cancer. However, there are wide differences in ACF prevalence, dysplasia, and histologic confirmation rates across studies. These differences may, in part, be because of variability in identification of endoscopic criteria. Objective: To systematically evaluate the accuracy and reliability of various endoscopic criteria used to identify ACF when using magnification chromoendoscopy (MCE). Design: Images obtained via MCE were shown to participating endoscopists who diagnosed them as ACF or not and who assessed them for the endoscopic characteristics used to identify ACF in the literature. Main Outcome Measurements: The predictive ability of the endoscopic criteria (crypt number, staining, margin, crypt size, epithelial thickness, and lumen shape) for histologic confirmation of ACF, and their reliability across endoscopists. The accuracy of the examiners in identifying ACF that were histologically confirmed was also assessed. Results: The interrater agreement rate for all except one of the endoscopic criteria (crypt number) was low and did not improve with training. None of the criteria could significantly predict histologic confirmation of ACE Despite training exercises, accuracy of endoscopists to correctly identify a histologically proven ACF remained low Limitations: Still images with x40 optical magnification were analyzed rather than real-time endoscopy All ACF samples were hyperplastic; none were dysplastic. Conclusions: No endoscopic criteria evaluated by our study predicted histologic confirmation of ACE MCE had low accuracy and poor reliability (Gastrointest Endosc 2009;70:322-30.) C1 [Gupta, Akshay K.] Univ Michigan, Dept Gastroenterol, Ann Arbor, MI 48109 USA. [Pinsky, Paul] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Rall, Christopher] Marshfield Clin Fdn Med Res & Educ, Dept Gastroenterol, Marshfield, WI USA. [Mutch, Matthew] Washington Univ, Sch Med, Div Gen Surg, Sect Colon & Rectal Surg, St Louis, MO USA. [Dry, Sarah; Seligson, David] Univ Calif Los Angeles, Dept Pathol, Los Angeles, CA 90024 USA. [Schoen, Robert E.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Schoen, Robert E.] Univ Pittsburgh, Div Gastroenterol, Pittsburgh, PA 15261 USA. RP Schoen, RE (reprint author), PUH, Wing C, Mezzanine Level,200 Lothrop St, Pittsburgh, PA 15213 USA. EM rschoen@pitt.edu FU NCRR NIH HHS [M01 RR000056-430770] NR 18 TC 13 Z9 13 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD AUG PY 2009 VL 70 IS 2 BP 322 EP 330 DI 10.1016/j.gie.2008.12.060 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 480OJ UT WOS:000268745200021 PM 19539919 ER PT J AU Shibata, SB Di Pasquale, G Cortez, SR Chiorini, JA Raphael, Y AF Shibata, S. B. Di Pasquale, G. Cortez, S. R. Chiorini, J. A. Raphael, Y. TI Gene transfer using bovine adeno-associated virus in the guinea pig cochlea SO GENE THERAPY LA English DT Article DE scala media; scala tympani; bovine adeno-associated virus ID MAMMALIAN INNER-EAR; IN-VIVO; TRANSGENE EXPRESSION; ADENOVIRUS-RECEPTOR; HAIR-CELLS; TRANSDUCTION; VECTORS; ORGAN; CORTI; INOCULATION AB Gene transfer into the cells of the cochlea is useful for both research and therapy. Bovine adeno-associated virus (BAAV) is a new viral vector with potential for long-term gene expression with little or no side effects. In this study, we assessed transgene expression using BAAV with beta-actin-GFP as a reporter gene, in the cochleae of normal and deafened guinea pigs. We used two different routes to inoculate the cochlea: scala media (SM) or scala tympani (ST). Auditory brainstem response assessments were carried out before inoculation, 7 days after inoculation and immediately before killing, to assess the functional consequences of the treatment. We observed threshold shifts because of the surgical invasion, but no apparent pathology associated with the virus. Fourteen days after the injection, animals were killed and cochleae assessed histologically. Epi-fluorescence showed that BAAV transduced the supporting cells of both normal and deafened animals through SM and ST inoculations. Transgene expression in cells of the membranous labyrinth after ST inoculation is an important outcome because of the greater feasibility of this route for future clinical application. BAAV facilitates efficient transduction of the membranous labyrinth epithelium with minimum pathogenicity and may become clinically applicable for inner ear gene therapy. Gene Therapy (2009) 16, 990-997; doi: 10.1038/gt.2009.57; published online 21 May 2009 C1 [Shibata, S. B.; Cortez, S. R.; Raphael, Y.] Univ Michigan, Kresge Hearing Res Inst, Dept Otolaryngol, Ann Arbor, MI 48109 USA. [Shibata, S. B.] Kansai Med Univ, Dept Otolaryngol, Osaka, Japan. [Di Pasquale, G.; Chiorini, J. A.] Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD USA. RP Raphael, Y (reprint author), Univ Michigan, Kresge Hearing Res Inst, Dept Otolaryngol, Ann Arbor, MI 48109 USA. EM yoash@umich.edu FU A Alfred Taubman Medical Research Institute; Berte and Alan Hirschfield Foundation; R Jamison and Betty Williams Professorship; NIH/NIDCD [R01-DC01634, R01-DC05401, R01-DC03685, T32DC005356, P30-DC05188] FX We thank Donald Swiderski and Agnieszka Rzadzinska for assistance. This work was supported by the A Alfred Taubman Medical Research Institute, the Berte and Alan Hirschfield Foundation, the R Jamison and Betty Williams Professorship, and NIH/NIDCD Grants R01-DC01634, R01-DC05401, R01-DC03685, T32DC005356 and P30-DC05188. NR 31 TC 24 Z9 28 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD AUG PY 2009 VL 16 IS 8 BP 990 EP 997 DI 10.1038/gt.2009.57 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 482VH UT WOS:000268916800007 PM 19458651 ER PT J AU Peng, PD Cohen, CJ Yang, S Hsu, C Jones, S Zhao, Y Zheng, Z Rosenberg, SA Morgan, RA AF Peng, P. D. Cohen, C. J. Yang, S. Hsu, C. Jones, S. Zhao, Y. Zheng, Z. Rosenberg, S. A. Morgan, R. A. TI Efficient nonviral Sleeping Beauty transposon-based TCR gene transfer to peripheral blood lymphocytes confers antigen-specific antitumor reactivity SO GENE THERAPY LA English DT Article DE Sleeping Beauty transposon; TCR gene therapy; adoptive immunotherapy; nonviral vector; T-cell gene transfer ID ADOPTIVE CELL TRANSFER; PRIMARY T-CELLS; HUMAN TUMOR; MUTATIONAL ANALYSIS; RETROVIRAL VECTOR; TRANSFER THERAPY; EXPRESSION; CANCER; INTEGRATION; SYSTEM AB Genetically engineered lymphocytes hold promise for the treatment of genetic disease, viral infections and cancer. However, current methods for genetic transduction of peripheral blood lymphocytes rely on viral vectors, which are hindered by production and safety-related problems. In this study, we demonstrated an efficient novel nonviral platform for gene transfer to lymphocytes. The Sleeping Beauty transposon-mediated approach allowed for long-term stable expression of transgenes at similar to 50% efficiency. Utilizing transposon constructs expressing tumor antigen-specific T-cell receptor genes targeting p53 and MART-1, we demonstrated sustained expression and functional reactivity of transposon-engineered lymphocytes on encountering target antigen presented on tumor cells. We found that transposon- and retroviral-modified lymphocytes had comparable transgene expression and phenotypic function. These results demonstrate the promise of nonviral ex vivo genetic modification of autologous lymphocytes for the treatment of cancer and immunologic disease. Gene Therapy (2009) 16, 1042-1049; doi: 10.1038/gt.2009.54; published online 4 June 2009 C1 [Peng, P. D.; Cohen, C. J.; Yang, S.; Hsu, C.; Jones, S.; Zhao, Y.; Zheng, Z.; Rosenberg, S. A.; Morgan, R. A.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,CRC 3W-3864, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov FU National Institute of Health, National Cancer Institute, Center for Cancer Research FX We thank Dr Steven R Yant and Dr Mark A Kay of the Departments of Pediatrics and Genetics, Stanford University School of Medicine, Stanford, CA, for their generous gift of the Sleeping Beauty transposon plasmids and hyperactive transposase, as well as for their helpful suggestions on this project. We thank FACS lab and TIL lab in Surgery Branch for providing technical support and maintenance of tumor cells from patients. This work is supported by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research. NR 44 TC 42 Z9 45 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD AUG PY 2009 VL 16 IS 8 BP 1042 EP 1049 DI 10.1038/gt.2009.54 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 482VH UT WOS:000268916800012 PM 19494842 ER PT J AU Newman, TK Parker, CC Suomi, SJ Goldman, D Barr, CS Higley, JD AF Newman, T. K. Parker, C. C. Suomi, S. J. Goldman, D. Barr, C. S. Higley, J. Dee TI DRD1 5'UTR variation, sex and early infant stress influence ethanol consumption in rhesus macaques SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Alcohol consumption; animal models; dopamine; genetics; nonhuman primate; vulnerability ID NONHUMAN PRIMATE MODEL; D-1 RECEPTOR GENE; ALCOHOL-CONSUMPTION; DOPAMINE D1; MONKEYS; ASSOCIATION; POLYMORPHISMS; BEHAVIORS; TEMPERAMENT; PERSONALITY AB The mesolimbic dopamine system plays an important role in mediating a variety of behaviors and is involved in mediating the reinforcing effects of ethanol. Genes encoding dopamine receptor subtypes are thus good candidate loci for understanding the genetic etiologies of susceptibility to alcohol dependence and its antecedent behavioral phenotypes. We tested whether variation in DRD1 influences alcohol consumption in rhesus macaques and whether its influence is mediated by sex and early rearing experience. We genotyped a single nucleotide polymorphism (-111 G/T) in the 5'UTR of DRD1 in 96 subjects raised with their mothers until 6 months of age (n = 43) or in peer-only groups (n = 53). As young adults they underwent a 7-week voluntary ethanol consumption experiment. anova revealed a significant main effect of sex (F(1,95) = 6.3, P = 0.014) and an interaction between genotype, sex and rearing on ethanol consumption (F(7,95) = 4.63, P = 0.0002). Maternally deprived males heterozygous for the T allele consumed significantly more ethanol (P > t < 0.0001) than the other subgroups. Maternal deprivation can produce individuals that are anxious and impulsive, both of which are known risk factors for alcohol dependence. Our work demonstrates a potential role for the dopamine D1 receptor gene in modulating alcohol consumption, especially in the context of early environmental stress. C1 [Newman, T. K.; Barr, C. S.; Higley, J. Dee] NIAAA, Lab Clin & Translat Studies, Bethesda, MD USA. [Newman, T. K.; Parker, C. C.; Goldman, D.; Barr, C. S.] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Parker, C. C.; Suomi, S. J.] NICHD, Comparat Ethol Lab, NIH, Poolesville, MD USA. RP Newman, TK (reprint author), Cape Biotech Trust, Genom & Bioinformat Platform, POB 13372, ZA-7705 Cape Town, South Africa. EM tim.newman@capebiotech.co.za RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU NICHD; NIAAA FX This research was funded by the NICHD and NIAAA intramural research programs. None of the authors have conflicts of interest to declare. NR 34 TC 8 Z9 10 U1 1 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD AUG PY 2009 VL 8 IS 6 BP 626 EP 630 DI 10.1111/j.1601-183X.2009.00507.x PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 479JJ UT WOS:000268655200007 PM 19563515 ER PT J AU Kim, HH Kuwano, Y Srikantan, S Lee, EK Martindale, JL Gorospe, M AF Kim, Hyeon Ho Kuwano, Yuki Srikantan, Subramanya Lee, Eun Kyung Martindale, Jennifer L. Gorospe, Myriam TI HuR recruits let-7/RISC to repress c-Myc expression SO GENES & DEVELOPMENT LA English DT Article DE Post-transcriptional gene regulation; RNA-binding protein; microRNAs; ribonucleoprotein complex ID RNA-BINDING-PROTEINS; MESSENGER-RNA; TRANSLATION; CELLS; MICRORNAS; GROWTH; STABILITY; ELEMENT AB RNA-binding proteins (RBPs) and microRNAs (miRNAs) are potent post-transcriptional regulators of gene expression. Here, we show that the RBP HuR reduced c-Myc expression by associating with the c-Myc 3' untranslated region (UTR) next to a miRNA let-7-binding site. Lowering HuR or let-7 levels relieved the translational repression of c-Myc. Unexpectedly, HuR and let-7 repressed c-Myc through an interdependent mechanism, as let-7 required HuR to reduce c-Myc expression and HuR required let-7 to inhibit c-Myc expression. Our findings suggest a regulatory paradigm wherein HuR inhibits c-Myc expression by recruiting let-7-loaded RISC (RNA miRNA-induced silencing complex) to the c-Myc 3'UTR. C1 [Kim, Hyeon Ho; Kuwano, Yuki; Srikantan, Subramanya; Lee, Eun Kyung; Martindale, Jennifer L.; Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, Res Program, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, Cellular & Mol Biol Lab, Res Program, NIH, Baltimore, MD 21224 USA. EM kimhye@grc.nia.nih.gov; myriam-gorospe@nih.gov OI srikantan, subramanya/0000-0003-1810-6519 FU NIA; NIH FX We thank R. H. Singer (Albert Einstein College of Medicine) for providing reagents. This research was supported by the Intramural Research Program of the NIA, NIH. NR 28 TC 270 Z9 278 U1 0 U2 16 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG PY 2009 VL 23 IS 15 BP 1743 EP 1748 DI 10.1101/gad.1812509 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 478OW UT WOS:000268598600006 PM 19574298 ER PT J AU Khoury, MJ McBride, CM Schully, SD Ioannidis, JPA Feero, WG Janssens, ACJW Gwinn, M Simons-Morton, DG Bernhardt, JM Cargill, M Chanock, SJ Church, GM Coates, RJ Collins, FS Croyle, RT Davis, BR Downing, GJ DuRoss, A Friedman, S Gail, MH Ginsburg, GS Green, RC Greene, MH Greenland, P Gulcher, JR Hsu, A Hudson, KL Kardia, SLR Kimmel, PL Lauer, MS Miller, AM Offit, K Ransohoff, DF Roberts, JS Rasooly, RS Stefansson, K Terry, SF Teutsch, SM Trepanier, A Wanke, KL Witte, JS Xu, JF AF Khoury, Muin J. McBride, Colleen M. Schully, Sheri D. Ioannidis, John P. A. Feero, W. Gregory Janssens, A. Cecile J. W. Gwinn, Marta Simons-Morton, Denise G. Bernhardt, Jay M. Cargill, Michele Chanock, Stephen J. Church, George M. Coates, Ralph J. Collins, Francis S. Croyle, Robert T. Davis, Barry R. Downing, Gregory J. DuRoss, Amy Friedman, Susan Gail, Mitchell H. Ginsburg, Geoffrey S. Green, Robert C. Greene, Mark H. Greenland, Philip Gulcher, Jeffrey R. Hsu, Andro Hudson, Kathy L. Kardia, Sharon L. R. Kimmel, Paul L. Lauer, Michael S. Miller, Amy M. Offit, Kenneth Ransohoff, David F. Roberts, J. Scott Rasooly, Rebekah S. Stefansson, Kari Terry, Sharon F. Teutsch, Steven M. Trepanier, Angela Wanke, Kay L. Witte, John S. Xu, Jianfeng TI The Scientific Foundation for Personal Genomics: Recommendations from a National Institutes of Health-Centers for Disease Control and Prevention Multidisciplinary Workshop SO GENETICS IN MEDICINE LA English DT Review DE behavioral sciences; epidemiologic methods; evidence-based medicine; genetics; genetic testing; genomics; medicine; public health ID EGAPP WORKING GROUP; GENETIC RISK FEEDBACK; BREAST-CANCER; WIDE ASSOCIATION; COMMON DISEASE; ALZHEIMERS-DISEASE; PREDICTIVE ABILITY; BEHAVIOR-CHANGE; ROC CURVE; SUSCEPTIBILITY AB The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed. Genet Med 2009:11(8):559-567. C1 [Khoury, Muin J.; Gwinn, Marta; Coates, Ralph J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Khoury, Muin J.; Schully, Sheri D.; Chanock, Stephen J.; Croyle, Robert T.; Gail, Mitchell H.; Greene, Mark H.] NCI, NIH, Bethesda, MD 20892 USA. [McBride, Colleen M.; Feero, W. Gregory; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Ioannidis, John P. A.] Univ Ioannina, Sch Med, Dept Epidemiol, GR-45110 Ioannina, Greece. [Ioannidis, John P. A.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Janssens, A. Cecile J. W.] Erasmus Univ, Dept Epidemiol & Biostat, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Simons-Morton, Denise G.; Lauer, Michael S.] NHLBI, NIH, Bethesda, MD 20892 USA. [Bernhardt, Jay M.] Ctr Dis Control & Prevent, Natl Ctr Hlth Mkt, Atlanta, GA USA. [Cargill, Michele; DuRoss, Amy] Navigenics, Redwood Shores, CA USA. [Church, George M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Davis, Barry R.] Univ Texas Houston, Sch Publ Hlth, Dept Biostat, Houston, TX USA. [Downing, Gregory J.] US Dept HHS, Washington, DC 20201 USA. [Friedman, Susan] FORCE, Tampa, FL USA. [Ginsburg, Geoffrey S.] Duke Univ, Inst Genome Sci & Policy, Ctr Genom Med, Durham, NC USA. [Green, Robert C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Green, Robert C.] Boston Univ, Sch Med, Dept Med Genet, Boston, MA 02118 USA. [Green, Robert C.] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02118 USA. [Green, Robert C.] Boston Univ, Sch Publ Hlth, Dept Neurol, Boston, MA USA. [Green, Robert C.] Boston Univ, Sch Publ Hlth, Dept Med Genet, Boston, MA USA. [Green, Robert C.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Greenland, Philip] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Gulcher, Jeffrey R.; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Hsu, Andro] 23andMe Inc, Mountain View, CA USA. [Hudson, Kathy L.] Johns Hopkins Univ, Genet & Publ Policy Ctr, Washington, DC USA. [Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Kimmel, Paul L.; Rasooly, Rebekah S.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Miller, Amy M.] Personalized Med Coalit, Washington, DC USA. [Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, New York, NY 10021 USA. [Ransohoff, David F.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Ransohoff, David F.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Ransohoff, David F.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Roberts, J. Scott] Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. [Terry, Sharon F.] Genet Alliance, Washington, DC USA. [Teutsch, Steven M.] Los Angeles Cty Dept Publ Hlth, Los Angeles, CA USA. [Trepanier, Angela] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Wanke, Kay L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Witte, John S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Inst Human Genet, San Francisco, CA 94143 USA. [Xu, Jianfeng] Wake Forest Univ, Sch Med, Ctr Canc Genom, Winston Salem, NC 27109 USA. RP Khoury, MJ (reprint author), Ctr Dis Control & Prevent, Off Publ Hlth Genom, 1600 Clifton Rd,MS E61, Atlanta, GA 30333 USA. EM mkhoury@cdc.gov RI Ioannidis, John/G-9836-2011; Lauer, Michael/L-9656-2013; OI Lauer, Michael/0000-0002-9217-8177; Bernhardt, Jay/0000-0002-2045-4005; Rasooly, Rebekah/0000-0002-6357-5528; Janssens, A Cecile/0000-0002-6153-4976 FU NCRR NIH HHS [M01 RR000533, M01 RR000533-360391]; NHGRI NIH HHS [R01 HG002213, R01 HG002213-01, R01 HG005092, R01 HG005092-01A1]; NIA NIH HHS [K24 AG027841, K24 AG027841-01A1, P30 AG013846, P30 AG013846-069001] NR 93 TC 122 Z9 126 U1 4 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD AUG PY 2009 VL 11 IS 8 BP 559 EP 567 DI 10.1097/GIM.0b013e3181b13a6c PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 487KV UT WOS:000269273900001 PM 19617843 ER PT J AU Grosse, SD McBride, CM Evans, JP Khoury, MJ AF Grosse, Scott D. McBride, Colleen M. Evans, James. P. Khoury, Muin J. TI Personal utility and genomic information: Look before you leap SO GENETICS IN MEDICINE LA English DT Editorial Material ID WOMENS PREFERENCES; BREAST-CANCER; CHILDREN; DISEASE C1 [Grosse, Scott D.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [McBride, Colleen M.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Evans, James. P.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. RP Grosse, SD (reprint author), Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, 1600 Clifton Rd,Mail Stop E88, Atlanta, GA 30333 USA. EM sgrosse@cdc.gov FU Intramural NIH HHS [Z01 HG200344-01] NR 20 TC 38 Z9 38 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD AUG PY 2009 VL 11 IS 8 BP 575 EP 576 DI 10.1097/GIM.0b013e3181af0a80 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 487KV UT WOS:000269273900004 PM 19623080 ER PT J AU McBride, CM Alford, SH Reid, RJ Larson, EB Baxevanis, AD Brody, LC AF McBride, Colleen M. Alford, Sharon Hensley Reid, Robert J. Larson, Eric B. Baxevanis, Andreas D. Brody, Lawrence C. TI Characteristics of users of online personalized genomic risk assessments: Implications for physician-patient interactions SO GENETICS IN MEDICINE LA English DT Article DE personalized genomics; risk assessment; internet; psychosocial predictors ID FAMILY-HISTORY; CANCER SUSCEPTIBILITY; BREAST-CANCER; HEALTH; DISEASE; PERCEPTIONS; MEDICINE; PREFERENCES; BEHAVIORS; EDUCATION AB Purpose: To evaluate what psychological and behavioral factors predict who is likely to seek SNP-based genetic tests for multiple common health conditions where feedback can be used to motivate primary prevention. Methods: Adults aged 25-40 years who were enrolled in a large managed care organization were surveyed. Those eligible could log on to a secure study Web site to review information about the risks and benefits of a SNP-based genetic test and request free testing. Two primary outcomes are addressed: accessing the Web (yes or no) and deciding to be tested (completed a blood draw at the clinic) Results: Those considering genetic susceptibility testing did not hold genetically deterministic beliefs (0.42 on scale of 0 [behavior] to 1 [genetic]) but believed genetic information to be valuable and were confident they could understand such information. Individuals who believed it important to learn about genetics (odds ratio = 1.28), were confident they could understand genetics (odds ratio = 1.26), and reported the most health habits to change (odds ratio = 1.39) were most likely to get tested. Conclusions: Individuals who present to health care providers with online genetics information may be among the most motivated to take steps toward healthier lifestyles. These motives might be leveraged by health care providers to promote positive health outcomes. Genet Med 2009:11(8):582-587. C1 [McBride, Colleen M.] Natl Human Genome Res Inst, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Alford, Sharon Hensley] Henry Ford Hlth Syst, Dept Biostatist & Res Epidemiol, Detroit, MI USA. [Reid, Robert J.; Larson, Eric B.] Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. [Baxevanis, Andreas D.; Brody, Lawrence C.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. RP McBride, CM (reprint author), Natl Human Genome Res Inst, Social & Behav Res Branch, NIH, Bldg 31,MSC 2073,31 Ctr Dr,Room B1B54, Bethesda, MD 20892 USA. EM cmcbride@mail.nih.gov FU Intramural NIH HHS [Z01 HG200344-01, ZIA HG200344-03] NR 26 TC 67 Z9 67 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD AUG PY 2009 VL 11 IS 8 BP 582 EP 587 DI 10.1097/GIM.0b013e3181b22c3a PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 487KV UT WOS:000269273900007 PM 19606049 ER PT J AU Ashida, S Palmquist, AEL Basen-Engquist, K Singletary, SE Koehly, LM AF Ashida, Sato Palmquist, Aunchalee E. L. Basen-Engquist, Karen Singletary, S. Eva Koehly, Laura M. TI Changes in Female Support Network Systems and Adaptation After Breast Cancer Diagnosis: Differences Between Older and Younger Patients SO GERONTOLOGIST LA English DT Article DE Social relationships; Social support; Cancer survivor; Social selectivity; Psychological adaptation ID QUALITY-OF-LIFE; SOCIOEMOTIONAL SELECTIVITY; PSYCHOLOGICAL ADJUSTMENT; SOCIAL SUPPORT; WOMEN; AGE; RELIABILITY; PARTNERS; ONSET AB Purpose: This study evaluates the changes in social networks of older and younger breast cancer patients over a 6-month period following their first diagnosis and how such modifications are associated with changes in the patients' mood state. Design and Methods: Newly diagnosed breast cancer patients were interviewed shortly after their diagnosis and again 6 months later. Female support network members enumerated by patients were interviewed once within 3 months of the patients' initial interview. Results: Findings based on information for 149 network members of 26 patients indicate that members in older (>= 51 years) patients' networks were less likely to be dropped at follow-up (odds ratio [OR] = 0.21, p = .04) compared with those in younger patients' networks. Network members who provided more support were less likely to be dropped by younger patients (OR = 0.42, p < .01). Decrease in network size was associated with decrease in mood disturbances among younger patients (Profile of Mood State-Bipolar: beta = 0. 35, p < .01). Implications: Reducing the number of network members after cancer diagnosis may not necessarily lead to psychological distress, providing support for self-regulation of social network resources among cancer patients. Older patients' network members were more embedded in patients' networks, making it more stable over time. Identifying important network members (e.g., frequent support providers for younger patients and family members for older patients) and facilitating positive social interactions between these network members and patients may be beneficial. C1 [Ashida, Sato; Palmquist, Aunchalee E. L.; Koehly, Laura M.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Basen-Engquist, Karen] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. [Singletary, S. Eva] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. RP Ashida, S (reprint author), NHGRI, Social & Behav Res Branch, 31 Ctr Dr,B1B37C, Bethesda, MD 20892 USA. EM ashidas@mail.nih.gov FU Intramural NIH HHS NR 33 TC 16 Z9 16 U1 0 U2 4 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD AUG PY 2009 VL 49 IS 4 BP 549 EP 559 DI 10.1093/geront/gnp048 PG 11 WC Gerontology SC Geriatrics & Gerontology GA 472EC UT WOS:000268111200010 PM 19465702 ER PT J AU Gouras, P Braun, K Ivert, L Neuringer, M Mattison, JA AF Gouras, P. Braun, K. Ivert, L. Neuringer, M. Mattison, J. A. TI Bestrophin detected in the basal membrane of the retinal epithelium and drusen of monkeys with drusenoid maculopathy SO GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Article DE Bestrophin; Drusen; Age related maculopathy; Monkeys; Macula; Retinal pigment epithelium ID MACULAR DYSTROPHY; RHESUS-MONKEYS; BEST-DISEASE; GENE; PATHOGENESIS; VMD2 AB To determine if bestrophin is present in the basal membrane of macular retinal pigment epithelium (RPE) and in drusen of rhesus monkeys with age-related drusenoid maculopathy. The macular region of three rhesus monkeys (Macaca mulatta), 23-24 years of age, with drusenoid maculopathy was dissected from eyes fixed with 4% paraformaldehyde. The macula was sectioned into rectangular pieces. The sclera was removed from each segment and the remainder separated into segments of neural retina with retinal epithelium or choroid with retinal epithelium. These segments were incubated with a goat polyclonal antibody to human bestrophin 1, reacted with gold-labeled rabbit antibody to goat IgG, silver-enhanced, and processed for transmission electron microscopy. Bestrophin-labeled gold particles were found in quasi-linear arrays on the basal surface of the macular RPE and also within drusen where bestrophin was found in segments of membranous-like material. The array density of the bestrophin-linked gold particles on the basal membrane of the epithelium had a maximal value of about 5-100 bestrophin molecules/micron(2). Immuno-detection of bestrophin was most effective when examined in an RPE layer that remained attached to the neural retina, where the basal surface of the epithelium is more directly exposed to the antibodies. Bestrophin is present on the basal membrane of macular RPE of rhesus monkeys with age-related drusenoid maculopathy, and also found in the membranous-like structures of drusen. The latter finding provides insight into the pathogenesis of drusen by indicating that segments of the basal membrane of RPE contribute to the material that accumulates within drusen. C1 [Gouras, P.] Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA. [Braun, K.] Columbia Univ, Dept Pathol, New York, NY 10027 USA. [Ivert, L.] St Eriks Hosp, Stockholm, Sweden. [Neuringer, M.] Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Mattison, J. A.] NIA, Baltimore, MD 21224 USA. RP Gouras, P (reprint author), Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA. EM pg10@columbia.edu FU NEI [R015293, RR00163]; Foundation Fighting Blindness; Research to Prevent Blindness Inc; Intramural Research Program of the NIH; National Institute on Aging FX We thank Hild Kjeldbye for her assistance with the histology. We were supported by NEI grant R015293 and RR00163, the Foundation Fighting Blindness, Research to Prevent Blindness Inc and in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 9 TC 7 Z9 7 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0721-832X J9 GRAEF ARCH CLIN EXP JI Graefes Arch. Clin. Exp. Ophthalmol. PD AUG PY 2009 VL 247 IS 8 BP 1051 EP 1056 DI 10.1007/s00417-009-1091-9 PG 6 WC Ophthalmology SC Ophthalmology GA 469KK UT WOS:000267896700006 PM 19421767 ER PT J AU Yu, KJ Rader, JS Borecki, I Zhang, ZY Hildesheim, A AF Yu, Kelly J. Rader, Janet S. Borecki, Ingrid Zhang, Zhengyan Hildesheim, Allan TI CD83 polymorphisms and cervical cancer risk SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Human papillomaviruses; Cervix; Epidemiology; Genetics ID HUMAN-PAPILLOMAVIRUS INFECTION; SQUAMOUS-CELL CARCINOMAS; WOMEN; ADENOCARCINOMAS; HISTORY; BREAST AB Objectives. Studies have suggested that polymorphisms in genes involved in immune recognition and antigen presentation are associated with cervical cancer risk. We sought to replicate a recent study which reported an association between specific SNPs on CD83 and cervical cancer and to further explore whether effects varied by age, clinical stage (in situ versus invasive), and histology (squamous carcinomas versus adenocarcinomas). Methods. We evaluated the association between SNPs on CD83 and cervical cancer in a multicenter case-control study of cervical cancer conducted in the Eastern United States (263 cases, 307 controls), focusing on the five SNPs (RS9296925, RS853360, RS9230, RS9370729, RS750749) previously found to be associated with cervical cancer. We also pooled data from the Eastern U.S. (263 cases) with those from the original report (377 cases) to assess the effects of CD83 on the age at diagnosis, disease stage, and histology. Risk estimates (ORs) and 95% confidence intervals were estimated using logistic regression; trend tests were performed under an additive model. Results. Consistent with the original report, carriers of the CT or CC genotypes for one of the five CD83 SNPs evaluated (rs750749) demonstrated a 30% and 50% reduction in disease risk, relative to carriers of the more common TT genotype (p-trend=0.02). Two additional SNPs also resulted in consistent findings (rs9296925: p-trend = 0.07 and rs9370729: p-trend = 0.08), although the effects observed did not reach statistical significance at the 0.05 level. Pooled evaluation of cases from the two aforementioned studies suggested differences in the distribution of susceptibility alleles by histology; adenocarcinoma cases were more likely to be carriers of the Susceptibility alleles for SNP rs9370729 (p-trend 0.02) and SNP rs750749 (p-trend = 0.09). No differences were observed in the age or stage of diagnosis of carriers for CD83 susceptibility alleles relative to non-carriers. Conclusions. We confirm an association between CD83 polymorphisms and cervical cancer and suggest the possibility that CD83-disease associations might be heterogenous by tumor histology. Published by Elsevier Inc. C1 [Yu, Kelly J.] NCI, Infect & Immunoepidemiol Branch, DCEG, NIH,DHHS, Bethesda, MD 20852 USA. [Rader, Janet S.; Zhang, Zhengyan] Washington Univ, Sch Med, Dept Obstet & Gynecol, Div Gynecol Oncol, St Louis, MO 63110 USA. [Borecki, Ingrid] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA. RP Yu, KJ (reprint author), NCI, Infect & Immunoepidemiol Branch, DCEG, NIH,DHHS, 6120 Execut Blvd,Room 7057, Bethesda, MD 20852 USA. EM yuke@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU Intramural NIH HHS [Z01 CP010158-07]; NCI NIH HHS [CA95713, R01 CA094141, CA94141, R01 CA095713] NR 22 TC 11 Z9 12 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2009 VL 114 IS 2 BP 319 EP 322 DI 10.1016/j.ygyno.2009.04.033 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 470JQ UT WOS:000267971400032 PM 19446866 ER PT J AU Massad, LS Einstein, M Myers, E Wheeler, CM Wentzensen, N Solomon, D AF Massad, L. Stewart Einstein, Mark Myers, Evan Wheeler, Cosette M. Wentzensen, Nicolas Solomon, Diane TI The impact of human papillomavirus vaccination on cervical cancer prevention efforts SO GYNECOLOGIC ONCOLOGY LA English DT Review DE Human papillomavirus (HPV); HPV vaccine; Cervical cancer prevention; Test accuracy; HPV epidemiology ID INTRAEPITHELIAL NEOPLASIA; PARTICLE VACCINE; UNITED-STATES; SOCIETY GUIDELINE; HPV-VACCINATION; VIRAL LOAD; WOMEN; PREVALENCE; RISK; INFECTION AB Objectives. To review concepts, information, obstacles, and approaches to cervical cancer screening and prevention as vaccination against human papillomavirus (HPV) types 16 and 18 is adopted. Methods. Expert forum, conducted September 12-13, 2008, hosted by the Society of Gynecologic Oncologists, including 56 experts in cervical cancer and titled Future Strategies of Cervical Cancer Prevention: What Do We Need to Do Now to Prepare? Results. The current approach to cervical cancer screening in the U.S. is limited by its opportunistic nature. If given to women before exposure, a vaccine against HPV 16,18 can decrease cervical cancer risk by up to 70%. The impact on abnormal cytology and cervical intraepithelial neoplasia (CIN) will be less but still substantial. As the prevalence of high-grade CIN falls, fewer women with positive screening tests will have truly preinvasive disease. To minimize harm from false positive tests in women who are at low risk for cancer because of early vaccination, later initiation of and longer intervals between screenings are ideal. However, the vaccine is less effective when administered after first intercourse, and delivering and documenting HPV vaccination to girls at optimal ages may Prove difficult. Conclusions. Until population-based data on the performance of cytology, HPV testing, and alternate screening or triage interventions become available, modifying current screening guidelines is premature. Current recommendations to initiate screening as late as age 21 and to screen less often than annually are appropriate for young women known to have been vaccinated before first intercourse. (C) 2009 Elsevier Inc. All rights reserved. C1 [Massad, L. Stewart] Washington Univ, Sch Med, Div Gynecol Oncol, St Louis, MO 63110 USA. [Einstein, Mark] Albert Einstein Coll Med, Div Gynecol Oncol, Bronx, NY 10467 USA. [Einstein, Mark] Montefiore Med Ctr, Bronx, NY 10467 USA. [Myers, Evan] Duke Univ, Sch Med, Dept Obstet & Gynecol, Durham, NC USA. [Wheeler, Cosette M.] Univ New Mexico, Hlth Sci Ctr, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Wheeler, Cosette M.] Univ New Mexico, Hlth Sci Ctr, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. [Solomon, Diane] NCI, Canc Prevent Div, Rockville, MD USA. RP Massad, LS (reprint author), Washington Univ, Sch Med, Div Gynecol Oncol, Box 8064,4911 Barnes Jewish Hosp Plaza, St Louis, MO 63110 USA. EM massadl@wudosis.wustl.edu FU Merck; GlaxoSmithKline; Hologic; Roche; Qiagen; National Cancer Institute FX Dr Wheeler has received funding through the University of New Mexico from GlaxoSmith Kline and Merck to conduct HPV vaccine research and from Roche Molecular Systems to conduct HPV genotyping research. NR 42 TC 17 Z9 19 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2009 VL 114 IS 2 BP 360 EP 364 DI 10.1016/j.ygyno.2009.04.005 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 470JQ UT WOS:000267971400040 PM 19410282 ER PT J AU Castle, PE Fetterman, B Akhtar, I Husain, M Gold, MA Guido, R Glass, AG Kinney, W AF Castle, Philip E. Fetterman, Barbara Akhtar, Israh Husain, Mujtaba Gold, Michael A. Guido, Richard Glass, Andrew G. Kinney, Walter TI Age-appropriate use of human papillomavirus vaccines in the US SO GYNECOLOGIC ONCOLOGY LA English DT Review DE Human papillomavirus (HPV); Cervical intraepithelial neoplasia; Cervical cancer; HPV; Vaccination; Genital warts ID CERVICAL INTRAEPITHELIAL NEOPLASIA; CANCER-SOCIETY GUIDELINE; NONVACCINE HPV TYPES; PARTICLE VACCINE; UNITED-STATES; QUADRIVALENT VACCINE; YOUNG-WOMEN; INFECTION; PERSISTENCE; POPULATION AB Cervical infections by approximately 15 cancer-associated (carcinogenic) human papillomavirus (HPV) genotypes Cause virtually all cervical cancer and its immediate precursor lesions worldwide. Prophylactic vaccines against human papillomavirus (HPV) types HPV16 and HP18, which cause 70% of cervical cancer worldwide, hold great promise for reducing the burden of cervical cancer worldwide. However, current HPV vaccines prevent future infections and related cervical abnormalities and do not treat pre-existing HPV infections. In the U.S., HPV vaccine introduction should be considered in the context of a very Successful cervical cancer screening program that has reduced the rates of cervical cancer by 75% or more. Thus, HPV vaccines will only prevent an incremental number of additional cervical cancers in the U.S. The introduction of HPV vaccines can also prevent other HPV-related sequelae, most importantly cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3), which precede the development of cervical cancer and require clinical follow-up and treatment. Examining data from 7 clinical centers in the U.S., the median age of CIN2/3 is typically between 25 and 30 years of age in 2007; if screen-detected CIN2/3 develops on average 5-10 years after the causal infection is acquired, HPV vaccination will only prevent a significant proportion of CIN2/3 if it is given to women before the age of 26 and more so if given to women IS and younger. It is increasingly evident that prophylactic HPV vaccines will provide the greatest Public health or Population benefit only when delivered to adolescent, mostly HPV-naive women. Published by Elsevier Inc C1 [Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Fetterman, Barbara] Kaiser Permanente No Calif, Reg Lab, Berkeley, CA USA. [Akhtar, Israh] Univ Mississippi, Dept Pathol, Jackson, MS 39216 USA. [Husain, Mujtaba] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Gold, Michael A.] Univ Oklahoma, Dept Obstet & Gynecol, Oklahoma City, OK USA. [Guido, Richard] Magee Womens Hosp, Dept Obstet & Gynecol & Reprod Serv, Pittsburgh, PA USA. [Glass, Andrew G.] Kaiser Permanente Hosp, Ctr Hlth Res, Portland, OR USA. [Kinney, Walter] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Sacramento, CA USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS Room 5004,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU National Cancer Institute; National Institutes of Health; Department of Health and Human Services FX This work was supported [in part] by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. However, the views expressed within this commentary are solely those of the authors and do not represent the views of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, or the U.S. Government. The financial activities of the NCI author (P.E.C.) are monitored by the NCI Ethics Office. We thank Brenda Rush (Kaiser Permanente Northwest, Portland, OR) and the Division of Gynecologic Oncology, University of Alabama Birmingham (Birmingham, AL) for providing data. NR 37 TC 15 Z9 17 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2009 VL 114 IS 2 BP 365 EP 369 DI 10.1016/j.ygyno.2009.04.035 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 470JQ UT WOS:000267971400041 PM 19464729 ER PT J AU Kristinsson, SY Goldin, LR Bjorkholm, M Turesson, I Landgren, O AF Kristinsson, Sigurdur Y. Goldin, Lynn R. Bjorkholm, Magnus Turesson, Ingemar Landgren, Ola TI Risk of solid tumors and myeloid hematological malignancies among first-degree relatives of patients with monoclonal gammopathy of undetermined significance SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Letter DE MGUS; solid tumors; familial aggregation; susceptibility ID MULTIPLE-MYELOMA; FAMILIAL MYELOMA; LONG-TERM; DISORDERS; CANCER C1 [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Landgren, Ola] Karolinska Univ Hosp Solna, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Landgren, Ola] Karolinska Inst, Stockholm, Sweden. [Goldin, Lynn R.; Landgren, Ola] NCI, NIH, Bethesda, MD 20892 USA. [Turesson, Ingemar] Malmo Univ Hosp, Dept Med, Sect Hematol, Malmo, Sweden. RP Kristinsson, SY (reprint author), Karolinska Univ Hosp Solna, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. EM sigur-dur.kristinsson@karolinska.se RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU Intramural NIH HHS NR 12 TC 8 Z9 9 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD AUG PY 2009 VL 94 IS 8 BP 1179 EP 1181 DI 10.3324/haematol.2009.006346 PG 3 WC Hematology SC Hematology GA 479QY UT WOS:000268677200020 PM 19546435 ER PT J AU Vidal, L Tsao, MS Pond, GR Cohen, EEW Cohen, RB Chen, EX Agulnik, M Hotte, S Winquist, E Laurie, S Hayes, DN Ho, J Dancey, J Siu, LL AF Vidal, Laura Tsao, Ming S. Pond, Gregory R. Cohen, Ezra E. W. Cohen, Roger B. Chen, Eric X. Agulnik, Mark Hotte, Sebastien Winquist, Eric Laurie, Scott Hayes, D. Neil Ho, James Dancey, Janet Siu, Lillian L. TI FLUORESCENCE IN SITU HYBRIDIZATION GENE AMPLIFICATION ANALYSIS OF EGFR AND HER2 IN PATIENTS WITH MALIGNANT SALIVARY GLAND TUMORS TREATED WITH LAPATINIB SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article; Proceedings Paper CT 19th European-Organisation-for-Reseach-and-Treatment-of-Cancer/National-Cance r-Institute/American-Association-for-Cancer-Research International Conference on Molecular Targets and Cancer Therapeutics-Discovery, Biology, and Clinical Applications CY OCT 22-26, 2007 CL San Francisco, CA SP European Org Res & Treatment Canc, Natl Canc Inst, Amer Assoc Canc Res DE MSGT; lapatinib; EGFR and HER2 gene amplification; FISH ID GROWTH-FACTOR RECEPTOR; ADENOID CYSTIC CARCINOMA; CELL LUNG-CANCER; PHASE-II; TYROSINE KINASES; DUCT CARCINOMAS; HER-2/NEU GENE; PAROTID-GLAND; COPY NUMBER; EXPRESSION AB Background. Gene amplification status of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2) were analyzed and correlated with clinical outcome in patients with progressive malignant salivary glands tumors (MSGT) treated with the dual EGFR/Her2 tyrosine kinase inhibitor lapatinib. Methods. Fluorescence in situ hybridization (FISH) analysis for both EGFR and HER2 gene amplification was performed successfully in the archival tumor specimens of 20 patients with adenoid cystic carcinomas (ACC) and 17 patients with non-ACC, all treated with lapatinib. Results. For ACC, no EGFR or HER2 amplifications were detected. For non-ACC, no EGFR gene amplifications were detected but 3 patients (18%) were HER2 amplified and all had stained 3+ for both EGFR and HER2 by immunohistochemistry (IHC) in their archival specimens. Two of these patients had time-to-progression (TTP) durations of 8.3 months and 18.4 months, respectively. Interestingly, patients with low and high HER2/chromosome-specific centromeric enumeration probe (CEP) 17 ratio had a prolonged TTP than those with moderate ratios for both ACC and non-AAC subtypes. Conclusions. HER2 to CEP17 FISH ratio may predict which patients with MSGT have an increased likelihood to benefit from lapatinib. The finding of HER2:CEP17 ratio as a predictive marker of efficacy to lapatinib warrants further investigation. (C) 2009 Wiley Periodicals, Inc. Head Neck 31: 1006-1012, 2009 C1 [Vidal, Laura; Tsao, Ming S.; Pond, Gregory R.; Cohen, Roger B.; Chen, Eric X.; Agulnik, Mark; Hotte, Sebastien; Winquist, Eric; Laurie, Scott; Ho, James; Siu, Lillian L.] Princess Margaret Hosp, Phase Consortium 2, Toronto, ON M4X 1K9, Canada. [Cohen, Ezra E. W.] Univ Chicago, Phase Consortium 2, Chicago, IL 60637 USA. [Hayes, D. Neil] Univ N Carolina, Chapel Hill, NC USA. [Dancey, Janet] NCI, Bethesda, MD 20892 USA. RP Siu, LL (reprint author), Princess Margaret Hosp, Phase Consortium 2, Toronto, ON M4X 1K9, Canada. EM lillian.siu@uhn.on.ca OI Hayes, D. Neil/0000-0001-6203-7771 FU NCI NIH HHS [N01 CM062203, N01-CM-57018-16, N01-CM-62203, N01CM62203, U01 CA132123, U01 CA132123-01] NR 30 TC 21 Z9 22 U1 0 U2 7 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1043-3074 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD AUG PY 2009 VL 31 IS 8 BP 1006 EP 1012 DI 10.1002/hed.21052 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 477PB UT WOS:000268529900004 PM 19309723 ER PT J AU Hirayama, T Nakayama, M Isomoto, H Hatakeyama, M Azuma, T Yamaoka, Y Moss, J AF Hirayama, T. Nakayama, M. Isomoto, H. Hatakeyama, M. Azuma, T. Yamaoka, Y. Moss, J. TI H-pylori VacA Induces GSK3 Inhibition Through the PI3K/Akt Signaling Pathway SO HELICOBACTER LA English DT Meeting Abstract CT 22nd International Workshop on Helicobacter and Related Bacteria in Chronic Digestive Inflammation and Gastric Cancer CY SEP 17-19, 2009 CL Oporto, PORTUGAL SP European Helicobacter Study Grp C1 [Isomoto, H.] Nagasaki Univ, Sch Med, Nagasaki 852, Japan. [Hatakeyama, M.] Hokkaido Univ, Sapporo, Hokkaido, Japan. [Azuma, T.] Kobe Univ, Sch Med, Kobe, Hyogo 650, Japan. [Moss, J.] NHLBI, NIH, Bethesda, MD 20892 USA. [Yamaoka, Y.] Oita Univ, Sch Med, Oita 87011, Japan. [Yamaoka, Y.] Baylor Coll Med, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1083-4389 J9 HELICOBACTER JI Helicobacter PD AUG PY 2009 VL 14 IS 4 BP 336 EP 336 PG 1 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA 474FZ UT WOS:000268269300074 ER PT J AU Laurence, A Klennerman, P AF Laurence, Arian Klennerman, Paul TI Interleukin 27 and Viral Hepatitis: Smarter Than the Average Cytokine SO HEPATOLOGY LA English DT Editorial Material ID C VIRUS; DENDRITIC CELLS; T-CELLS; DIFFERENTIATION; INDUCTION; INFECTION; INFLAMMATION; BETA C1 [Laurence, Arian] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Klennerman, Paul] Univ Oxford, Nuffield Dept Med, Oxford, England. RP Laurence, A (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 13C120-9B, Bethesda, MD 20892 USA. EM laurencea@mail.nih.gov RI Laurence, Arian/A-8770-2009 OI Laurence, Arian/0000-0003-0942-8292 FU Intramural NIH HHS [Z99 AR999999] NR 20 TC 1 Z9 1 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 2009 VL 50 IS 2 BP 358 EP 360 DI 10.1002/hep.23063 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 478WN UT WOS:000268619400006 PM 19585619 ER PT J AU Ji, JF Yamashita, T Budhu, A Forgues, M Jia, HL Li, CL Deng, CX Wauthier, E Reid, LM Ye, QH Qin, LX Yang, W Wang, HY Tang, ZY Groce, CM Wang, XW AF Ji, Junfang Yamashita, Taro Budhu, Anuradha Forgues, Marshonna Jia, Hu-Liang Li, Cuiling Deng, Chuxia Wauthier, Elaine Reid, Lola M. Ye, Qing-Hai Qin, Lun-Xiu Yang, Wen Wang, Hong-Yang Tang, Zhao-You Groce, Carlo M. Wang, Xin Wei TI Identification of MicroRNA-181 by Genome-Wide Screening as a Critical Player in EpCAM-Positive Hepatic Cancer Stem Cells SO HEPATOLOGY LA English DT Article ID TUMOR-INITIATING CELLS; HEPATOCELLULAR-CARCINOMA; STEM/PROGENITOR CELLS; LIVER-CANCER; IN-VITRO; EXPRESSION; DIFFERENTIATION; DIVISION; PATHWAY; DISEASE AB MicroRNAs (miRNAs) are endogenous small noncoding RNAs that regulate gene expression with functional links to tumorigenesis. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and it is heterogeneous in clinical outcomes and biological activities. Recently, we have identified a subset of highly invasive epithelial cell adhesion molecule (EpCAM)(+) HCC cells from alpha-fetoprotein (AFP)(+) tumors with cancer stem/progenitor cell features, that is, the abilities to self-renew, differentiate, and initiate aggressive tumors in vivo. Here, using a global microarray-based miRNA profiling approach followed by validation with quantitative reverse transcription polymerase chain reaction, we have demonstrated that conserved miR-181 family members were up-regulated in EpCAM(+)AFP(+) HCCs and in EpCAM(+) HCC cells isolated from AFP(+) tumors. Moreover, miR-181 family members were highly expressed in embryonic livers and in isolated hepatic stem cells. Importantly, inhibition of miR-181 led to a reduction in EpCAM(+) HCC cell quantity and tumor initiating ability, whereas exogenous miR-181 expression in HCC cells resulted in an enrichment of EpCAM(+) HCC cells. We have found that miR-181 could directly target hepatic transcriptional regulators of differentiation (for example, caudal type homeobox transcription factor 2 [CDX2] and GATA binding protein 6 [GATA6]) and an inhibitor of Wnt/beta-catenin signaling (nemo-like kinase [NLK]). Taken together, our results define a novel regulatory link between miR-181s and human EpCAM(+) liver cancer stem/progenitor cells and imply that molecular targeting of miR-181 may eradicate HCC. (HEPATOLOGY 2009;50:472-480.) C1 [Wang, Xin Wei] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, CCR,NIH, Bethesda, MD 20892 USA. [Jia, Hu-Liang; Ye, Qing-Hai; Qin, Lun-Xiu; Tang, Zhao-You] Fudan Univ, Liver Canc Inst, Shanghai 200433, Peoples R China. [Jia, Hu-Liang; Ye, Qing-Hai; Qin, Lun-Xiu; Tang, Zhao-You] Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. [Li, Cuiling; Deng, Chuxia] NIDDK, Mammalian Genet Sect, Bethesda, MD USA. [Wauthier, Elaine; Reid, Lola M.] Univ N Carolina, Sch Med, Dept Cell & Mol Physiol, Chapel Hill, NC USA. [Yang, Wen; Wang, Hong-Yang] Eastern Hepatobiliary Surg Inst, Int Cooperat Lab Signal Transduct, Shanghai, Peoples R China. [Groce, Carlo M.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Wang, XW (reprint author), NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, CCR,NIH, 37 Convent DR,Bldg 37 Room 3044A, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI deng, chuxia/N-6713-2016; Wang, Hongyang/B-1340-2010; Wang, Xin/B-6162-2009 FU Center for Cancer Research; US National Cancer Institute [Z01 BC 0103 13, Z01 BC 010876] FX Supported in part by the Intramural Research Program of the Center for Cancer Research, the US National Cancer Institute (Z01 BC 0103 13 and Z01 BC 010876). NR 40 TC 262 Z9 282 U1 7 U2 49 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 2009 VL 50 IS 2 BP 472 EP 480 DI 10.1002/hep.22989 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 478WN UT WOS:000268619400020 PM 19585654 ER PT J AU Drori-Herishanu, L Horvath, A Nesterova, M Patronas, Y Lodish, M Bimpaki, E Patronas, N Agarwal, S Salvatori, R Martari, M Mericq, V Stratakis, CA AF Drori-Herishanu, L. Horvath, A. Nesterova, M. Patronas, Y. Lodish, M. Bimpaki, E. Patronas, N. Agarwal, S. Salvatori, R. Martari, M. Mericq, V. Stratakis, C. A. TI An Intronic Mutation is Associated with Prolactinoma in a Young Boy, Decreased Penetrance in his Large Family, and Variable Effects on MEN1 mRNA and Protein SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE genotype; menin; pituitary tumors; children; multiple endocrine neoplasia type 1 ID ISOLATED PITUITARY-ADENOMAS; ENDOCRINE NEOPLASIA TYPE-1; GENETIC FEATURES; MEN1 GENE; CHILDHOOD; MACROPROLACTINOMA; MACROADENOMA; DISEASE AB Prolactinomas are rare tumors in prepubertal children. A prolactinoma in a young child may be due to sequence variants in genes that are known to cause these tumors (MEN1, PRKAR1A, AIP). An 11-year-old boy with a macroprolactinoma was treated with cabergoline and the tumor receded. We studied the patient and his family for genetic causes of this tumor. No mutations were present in the coding sequence of PRKAR1A and AIR A novel heterozygous substitution (IVS3-7 c>a) was identified in intron 3 of MEN1. We also found an additional PCR amplicon that incorporated the entire intron 3 of the gene (210bp) in the patient's cDNA. The same amplicon was present with lower intensity in some of the control individuals who were not mutation carriers. Intron 3 harbors an in-frame stop codon and its incorporation is predicted to result in a prematurely terminated protein. We conclude that a novel MEN1 variation was identified in a young boy with prolactinoma and six of his relatives who did not present with prolactinoma or other MEN1 related symptoms. This novel MEN1 variation may be associated with low penetrance of the disease. The IVS3-7 c>a defect is suggested to be pathogenic because it is associated with lower menin levels in the cells of these patients, but its consequences may be mitigated by a variety of factors including changes in transcription and translation of the MEN1 gene. C1 [Stratakis, C. A.] NICHD, Sect Endocrinol & Genet, PDEGEN, NIH, Bethesda, MD 20892 USA. [Lodish, M.; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, PEITP, NIH, Bethesda, MD USA. [Patronas, N.] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Agarwal, S.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD USA. [Salvatori, R.] Johns Hopkins Univ, Dept Med, Div Endocrinol, Bethesda, MD USA. [Mericq, V.] Univ Chile, Santiago, Chile. RP Stratakis, CA (reprint author), NICHD, Sect Endocrinol & Genet, PDEGEN, NIH, Room 1-3330,10 Ctr Dr,MSC-1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Mericq, Veronica/F-3927-2010; Agarwal, Sunita/D-1428-2016; OI Agarwal, Sunita/0000-0002-7557-3191; Mericq, Veronica/0000-0003-2287-0181 FU NICHD, NIH FX This work was Supported by the intramural program of NICHD, NIH. NR 26 TC 8 Z9 8 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD AUG PY 2009 VL 41 IS 8 BP 630 EP 634 DI 10.1055/s-0029-1216358 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 486RS UT WOS:000269216000009 PM 19391077 ER PT J AU Chatzipapas, C Boikos, S Drosos, GI Kazakos, K Tripsianis, G Serbis, A Stergiopoulos, S Tilkeridis, C Verettas, DA Stratakis, CA AF Chatzipapas, C. Boikos, S. Drosos, G. I. Kazakos, K. Tripsianis, G. Serbis, A. Stergiopoulos, S. Tilkeridis, C. Verettas, D. -A. Stratakis, C. A. TI Polymorphisms of the Vitamin D Receptor Gene and Stress Fractures SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE Vit D receptor gene; polymorphism; stress fracture; calcaneal stiffness index ID BONE-MINERAL DENSITY; START CODON POLYMORPHISM; TRANSLATION INITIATION SITE; CIRCULATING OSTEOCALCIN; ADOLESCENT BOYS; RISK-FACTORS; WOMEN; FOKI; MEN; METAANALYSIS AB Our aim was to evaluate the association between VDR polymorphisms and calcaneal Stiffness Index (SI) with stress fractures in a case control study including male military personnel. Thirty-two patients with stress fractures were matched with 32 uninjured healthy volunteers (controls), by gender, age, height, body weight, and level of physical activity. The two groups were genotyped for the FokI, BsmI, ApaI, and TaqI polymorphisms of the VDR gene with PCR-RFLP method. In addition, calcaneal SI was measured by heel quantitative ultrasound in both groups. Data were analyzed by chi-squared test and logistic regression analysis. The IF allele was significantly more frequent in patients than in controls (p=0.013), while the B allele showed Such a tendency with-out reaching statistical significance (p=0.052). Among the entire cohort, a 2.7-fold and a 2.0-fold increase in risk of stress fractures was associated with the f and B alleles (OR, 2.7, 95% CI, 1.2-5.9; p=0.014 and OR, 2.0, 95% CI, 1.0-4.1; p=0.053, respectively). No statistically significant association was found between the incidence of stress fractures and t or a alleles. Decreased T-scores were also associated with the presence of IF and B alleles. Mean values of T-scores of SI were statistically significantly lower in patients than in controls (p=0.018). These results Suggest that the Fold and BsmI polymorphisms of the VDR gene could be associated with increased risk of stress fractures among military personnel. Moreover, a low calcaneal SI Could represent a measurable index of this increased risk. C1 [Stratakis, C. A.] NICHD, SEGEN, PDEGEN, DEB,NIH, Bethesda, MD 20892 USA. [Chatzipapas, C.; Drosos, G. I.; Kazakos, K.; Tilkeridis, C.; Verettas, D. -A.] Democritus Univ Thrace, Univ Gen Hosp Alexandroupolis, Dept Orthopaed Surg, Sch Med, Alexandroupolis, Greece. [Tripsianis, G.] Democritus Univ Thrace, Dept Med Stat, Sch Med, Alexandroupolis, Greece. RP Stratakis, CA (reprint author), NICHD, SEGEN, PDEGEN, DEB,NIH, Room 1-3330,10 Ctr Dr,MSC-1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU NICHID, NIH FX This work was supported in part by the intramural program of NICHID, NIH. NR 39 TC 18 Z9 18 U1 0 U2 4 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 EI 1439-4286 J9 HORM METAB RES JI Horm. Metab. Res. PD AUG PY 2009 VL 41 IS 8 BP 635 EP 640 DI 10.1055/s-0029-1216375 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 486RS UT WOS:000269216000010 PM 19391078 ER PT J AU Cizza, G Eskandari, F Coyle, M Krishnamurthy, P Wright, EC Mistry, S Csako, G AF Cizza, G. Eskandari, F. Coyle, M. Krishnamurthy, P. Wright, E. C. Mistry, S. Csako, G. CA POWER Premenopausal Osteoporosis TI Plasma CRP Levels in Premenopausal Women with Major Depression: A 12-Month Controlled Study SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE obesity; women's health; inflammation; cytokine; cardiovascular morbidity; metabolic syndrome ID C-REACTIVE PROTEIN; CORONARY-HEART-DISEASE; ACUTE-PHASE PROTEINS; CARDIOVASCULAR RISK; SERUM-LEVELS; INFLAMMATORY MARKERS; METABOLIC SYNDROME; ARTERY-DISEASE; DISORDER; ASSOCIATION AB C-reactive protein (CRP), an inflammatory marker of cardiovascular risk, is often elevated in major depressive disorder (MDD). The magnitude and consistency of this elevation have not been previously characterized in premenopausal women with MDD. The aim of the study was to prospectively assess plasma CRP levels, body composition, endocrine and metabolic parameters, and depressive status in premenopausal women with MDD (n=77) and controls (n=41), aged 21 to 45. Women were enrolled ill a 12-month, controlled study of bone turnover, the P.O.W.E.R. (Premenopausal, Osteoporosis, Women, Alendronate, Depression) Study. Blood samples were taken at Baseline, Month 6, and Month 12. Most subjects with MDD were in clinical remission. These women tended to have consistently higher CRP levels than controls over 12 months (p=0.077). BMI was positively related to log[CRP] in women with MDD only. Nine women with MDD had CRP levels greater than 10mg/l, a value associated with a very high cardiovascular risk. This subset was obese and had significantly higher triglycerides, total cholesterol, LDL-cholesterol, fasting insulin, and HOMA-IR than the rest of women with MDD. The variations in CRP levels over time were high (intra- and inter-individual coefficients of variations of similar to 30-50% and similar to 70-140%, respectively). No control had CRP levels greater than 10mg/l. Depression was associated with increased plasma CRP in women with MDD. The clinical significance of abnormal plasma CRP for cardiovascular risk needs to be assessed in large prospective studies of women with depression. C1 [Cizza, G.; Coyle, M.; Krishnamurthy, P.; Mistry, S.] NIDDK, Clin Endocrine Sect, Clin Endocrinol Branch, NIH,DHHS, Bethesda, MD USA. [Eskandari, F.] NIMH, Sect Neuroendocrine Immunol & Behav, Integrat Neural Immune Program, NIH,DHHS, Bethesda, MD 20892 USA. [Csako, G.] NIH, Dept Lab Med, Ctr Clin, DHHS, Bethesda, MD 20892 USA. RP Cizza, G (reprint author), Bldg 10,CRC Rm 6-3940, Bethesda, MD 20892 USA. EM cizzag@intra.niddk.nih.gov FU National Institute of Mental Health; National Institute of Diabetes, Digestive and Kidney Diseases; Clinical Center of the National Institutes of Health; DHHS in Bethesda, MD FX This research was supported in part by the Intramural Research Programs of the National Institute of Mental Health, the National Institute of Diabetes, Digestive and Kidney Diseases, and the Clinical Center of the National Institutes of Health, DHHS in Bethesda, MD. We would like to thank all the Subjects participating in this study and Mr. Rene Costello for performing CRP assays. The following individuals were investigators of the P.O.W.E.R. Protocol (Premenopausal, Osteoporosis, Women, Alendronate, Depression): Giovanni Cizza (Principal Investigator) and, alphabetically, Anne Berger, Marc R. Blackman, Karim A. Calis, Gyorgy Csako, Bart Drinkard, Farideh Eskandari, Philip W. Gold, McDonald Horne, Christine Kotila, Pedro Martinez, Kate Musallarn, Terry M. Phillips, James. C. Reynolds, Nancy G. Sebring, Esther Sternberg, and Sara Torvik (Associate Investigators). NR 51 TC 14 Z9 17 U1 0 U2 7 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD AUG PY 2009 VL 41 IS 8 BP 641 EP 648 DI 10.1055/s-0029-1220717 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 486RS UT WOS:000269216000011 PM 19408214 ER PT J AU Virag, T Cecchini, S Kotin, RM AF Virag, Tamas Cecchini, Sylvain Kotin, Robert M. TI Producing Recombinant Adeno-Associated Virus in Foster Cells: Overcoming Production Limitations Using a Baculovirus-Insect Cell Expression Strategy SO HUMAN GENE THERAPY LA English DT Review ID LARGE-SCALE PRODUCTION; HEPATITIS-E VIRUS; VECTOR PRODUCTION; RAAV VECTORS; HIGH-TITER; MUSCULAR-DYSTROPHY; VIRAL VECTORS; MDX MOUSE; PARTICLES; GENE AB Establishing pharmacological parameters, such as efficacy, routes of administration, and toxicity, for recombinant adeno-associated virus (rAAV) vectors is a prerequisite for gaining acceptance for clinical applications. In fact, even a therapeutic window, that is, the dose range between therapeutic efficacy and toxicity, has yet to be determined for rAAV in vivo. Multiphase clinical trials investigating the safety and efficacy of recombinant AAV-based therapeutics will require unprecedented vector production capacity to meet the needs of preclinical toxicology studies, and the progressive clinical protocol phases of safety/dose escalation (phase I), efficacy (phase II), and high-enrollment, multicenter evaluations (phase III). Methods of rAAV production capable of supporting such trials must be scalable, robust, and efficient. We have taken advantage of the ease of scalability of nonadherent cell culture techniques coupled with the inherent efficiency of viral infection to develop an rAAV production method based on recombinant baculovirus-mediated expression of AAV components in insect-derived suspension cells. C1 [Virag, Tamas; Cecchini, Sylvain; Kotin, Robert M.] NHLBI, Mol Virol & Gene Delivery Sect, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Kotin, RM (reprint author), NHLBI, Mol Virol & Gene Delivery Sect, Lab Biochem Genet, NIH, Bldg 10, Bethesda, MD 20892 USA. EM kotinr@nih.gov RI kotin, robert/B-8954-2008 FU Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH); International Collaborative Effort for Duchenne Muscular Dystrophy FX The authors were supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH) and receive additional support from the International Collaborative Effort for Duchenne Muscular Dystrophy, Duchenne Parent Project France (DPPF), and the Association Monegasque contre les Myopathies (AMM). The authors thank Mathew P. Daniels and the NHLBI Electron Microscopy Core Facility for assisting and advising on the use of the electron microscope. Dr. Masashi Urabe's contributions, including Figure 3, is greatly appreciated. The authors thank Dr. Richard H. Smith for critical reading of the manuscript. NR 50 TC 36 Z9 41 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD AUG PY 2009 VL 20 IS 8 BP 807 EP 817 DI 10.1089/hum.2009.092 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 485LG UT WOS:000269122400006 PM 19604040 ER PT J AU Joe, B Saad, Y Lee, NH Frank, BC Achinike, OH Luu, TV Gopalakrishnan, K Toland, EJ Farms, P Yerga-Woolwine, S Manickavasagam, E Rapp, JP Garrett, MR Coe, D Apte, SS Rankinen, T Perusse, L Ehret, GB Ganesh, SK Cooper, RS O'Connor, A Rice, T Weder, AB Chakravarti, A Rao, DC Bouchard, C AF Joe, Bina Saad, Yasser Lee, Norman H. Frank, Bryan C. Achinike, Ovokeraye H. Luu, Truong V. Gopalakrishnan, Kathirvel Toland, Edward J. Farms, Phyllis Yerga-Woolwine, Shane Manickavasagam, Ezhilarasi Rapp, John P. Garrett, Michael R. Coe, David Apte, Suneel S. Rankinen, Tuomo Perusse, Louis Ehret, Georg B. Ganesh, Santhi K. Cooper, Richard S. O'Connor, Ashley Rice, Treva Weder, Alan B. Chakravarti, Aravinda Rao, Dabeeru C. Bouchard, Claude TI Positional identification of variants of Adamts16 linked to inherited hypertension SO HUMAN MOLECULAR GENETICS LA English DT Article ID BLOOD-PRESSURE QTL; EPITHELIAL SODIUM-CHANNEL; QUANTITATIVE TRAIT LOCUS; WIDE LINKAGE ANALYSIS; RAT CONGENIC STRAINS; EXPRESSION ANALYSIS; GENE; GENOME; MUTATIONS; FAMILY AB A previously reported blood pressure (BP) quantitative trait locus on rat Chromosome 1 was isolated in a short congenic segment spanning 804.6 kb. The 804.6 kb region contained only two genes, LOC306664 and LOC306665. LOC306664 is predicted to translate into A Disintegrin-like and Metalloproteinase with Thrombospondin Motifs-16 (Adamts16). LOC306665 is a novel gene. All predicted exons of both LOC306664 and LOC306665 were sequenced. Non-synonymous variants were identified in only one of these genes, LOC306664. These variants were naturally existing polymorphisms among inbred, outbred and wild rats. The full-length rat transcript of Adamts16 was detected in multiple tissues. Similar to ADAMTS16 in humans, expression of Adamts16 was prominent in the kidney. Renal transcriptome analysis suggested that a network of genes related to BP was differential between congenic and S rats. These genes were also differentially expressed between kidney cell lines with or without knock-down of Adamts16. Adamts16 is conserved between rats and humans. It is a candidate gene within the homologous region on human Chromosome 5, which is linked to systolic and diastolic BP in the Quebec Family Study. Multiple variants, including an Ala to Pro variant in codon 90 (rs2086310) of human ADAMTS16, were associated with human resting systolic BP (SBP). Replication study in GenNet confirmed the association of two variants of ADAMTS16 with SBP, including rs2086310. Overall, our report represents a high resolution positional cloning and translational study for Adamts16 as a candidate gene controlling BP. C1 [Lee, Norman H.; Frank, Bryan C.; Achinike, Ovokeraye H.; Luu, Truong V.] George Washington Univ, Dept Physiol & Pharmacol, Washington, DC USA. [Coe, David; Apte, Suneel S.] Cleveland Clin, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44106 USA. [Rankinen, Tuomo; Bouchard, Claude] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA USA. [Perusse, Louis] Univ Laval, Dept Prevent Med, Quebec City, PQ, Canada. [Ehret, Georg B.; O'Connor, Ashley; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Ehret, Georg B.] Univ Hosp Geneva, Div Cardiol, Geneva, Switzerland. [Ganesh, Santhi K.] NHGRI, Bethesda, MD 20892 USA. [Cooper, Richard S.] Loyola Univ, Stritch Sch Med, Dept Epidemiol & Prevent Med, Chicago, IL 60611 USA. [Joe, Bina; Saad, Yasser; Gopalakrishnan, Kathirvel; Toland, Edward J.; Farms, Phyllis; Yerga-Woolwine, Shane; Manickavasagam, Ezhilarasi; Rapp, John P.; Garrett, Michael R.] Univ Toledo, Dept Physiol & Pharmacol, Physiol Genom Lab, Coll Med, Toledo, OH 43614 USA. [Coe, David; Apte, Suneel S.] Cleveland Clin, Lerner Res Inst, Orthoped Res Ctr, Cleveland, OH 44106 USA. [Rice, Treva; Rao, Dabeeru C.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Weder, Alan B.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. RP Joe, B (reprint author), Univ Toledo, Dept Physiol & Pharmacol, Physiol Genom Lab, Coll Med, 3000 Arlington Ave, Toledo, OH 43614 USA. EM bina.joe@utoledo.edu RI Bouchard, Claude/A-7637-2009; Rice, Treva/D-1385-2009; EHRET, Georg/A-9532-2009; Perusse, Louis/A-3444-2012 OI EHRET, Georg/0000-0002-5730-0675; FU National Institutes of Health [HL076709, HL075414, HL45670, HL054512, AR049930]; Bray Chair in Nutrition; National Institute for Arthritis; Musculoskeletal and Skin Diseases training award [1T32 AR050959]; Department of physiology and pharmacology; University of Toledo College of Medicine FX This work was supported by funding from the National Institutes of Health (HL076709 to B. J., HL075414 to B. J., N. H. L., HL45670 to C. B., HL054512 to A. W., AR049930 to S. A.). C. B. is partially funded by the George A. Bray Chair in Nutrition. C. D. M. is supported by a post- doctoral fellowship from the National Institute for Arthritis, Musculoskeletal and Skin Diseases training award (1T32 AR050959; awarded to P. R. Cavanagh and J. Iannotti). Funding to pay the Open Access charge was provided by the Department of physiology and pharmacology, University of Toledo College of Medicine. NR 47 TC 33 Z9 34 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 1 PY 2009 VL 18 IS 15 BP 2825 EP 2838 DI 10.1093/hmg/ddp218 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 469IB UT WOS:000267888600010 PM 19423552 ER PT J AU Stewart, R Xue, QL Masaki, K Petrovitch, H Ross, GW White, LR Launer, LJ AF Stewart, Robert Xue, Qian-Li Masaki, Kamal Petrovitch, Helen Ross, G. Webster White, Lon R. Launer, Lenore J. TI Change in Blood Pressure and Incident Dementia A 32-Year Prospective Study SO HYPERTENSION LA English DT Article DE blood pressure; hypertension; hypotension; dementia; Alzheimer's disease; vascular dementia ID ALZHEIMERS-DISEASE; KUNGSHOLMEN PROJECT; COGNITIVE FUNCTION; VASCULAR DEMENTIA; APOE GENE; DIAGNOSIS; RISK; HYPOPERFUSION; ASSOCIATION; COMMUNITY AB Studies of the association of high blood pressure (BP) with dementia are not consistent. Understanding long-term trajectories in blood pressure of those who do and do not develop dementia can help clarify the issue. The Honolulu Heart Program/Honolulu-Asia Aging Study followed a cohort of Japanese American men for an average of 32 years, with systolic BP (SBP) and diastolic BP (DBP) measured at 6 examinations and dementia assessed at the final 3. In an analysis of 1890 men who completed all 6 of the exams, 112 diagnosed with incident dementia at examination 6 were compared with the 1778 survivors without dementia. Trajectories in SBP and DBP up to and including the sixth examination were estimated with a repeated-measures analysis using 3 splines. From midlife to late life, men who went on to develop dementia had an additional age-adjusted increase in SBP of 0.26 mm Hg (95% CI: 0.01 to 0.51 mm Hg) per year compared with survivors without dementia. Over the late-life examinations, this group had an additional age-adjusted decline in SBP of 1.36 mm Hg (95% CI: 0.64 to 2.07 mm Hg) per year. These associations were strongest for vascular dementia and were reduced substantially in men who were previously taking antihypertensive medication. Similar changes in diastolic BP were observed, but only for vascular dementia, and the findings were not modified by antihypertensive treatment. Over a 32-year period, compared with men who did not, those who did develop dementia had a greater increase, followed by a greater decrease, in SBP. Both of these trends are modified by antihypertensive therapy. (Hypertension. 2009; 54: 233-240.) C1 [Stewart, Robert] Kings Coll London, Inst Psychiat, Epidemiol Sect, London SE5 8AF, England. [Xue, Qian-Li] Johns Hopkins Ctr Aging & Hlth, Baltimore, MD USA. [Masaki, Kamal; Petrovitch, Helen; Ross, G. Webster; White, Lon R.] Pacific Hlth Res Inst, Honolulu, HI USA. [Masaki, Kamal; Petrovitch, Helen; Ross, G. Webster; White, Lon R.] Honolulu Asia Aging Study, Kuakini Med Ctr, Honolulu, HI USA. [Masaki, Kamal; Petrovitch, Helen; Ross, G. Webster; Launer, Lenore J.] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Stewart, R (reprint author), Kings Coll London, Inst Psychiat, Epidemiol Sect, Box 60,De Crespigny Pk, London SE5 8AF, England. EM r.stewart@iop.kcl.ac.uk OI Stewart, Robert/0000-0002-4435-6397 FU Intramural Research Program of the National Institutes of Health; National Institute on Aging [U01 AG019349, R01 AG0-17155 S1]; National Heart, Lung, and Blood Institute [N01 HC05102]; National Institute for Health Research Biomedical Research Centre for Mental Health; South London and Maudsley National Health Service Foundation Trust; Institute of Psychiatry, King's College London FX The Honolulu-Asia Aging Study is supported by the Intramural Research Program of the National Institutes of Health, the National Institute on Aging (grants U01 AG019349 and R01 AG0-17155 S1), and the National Heart, Lung, and Blood Institute (grant N01 HC05102). R. S. is funded by the UK National Institute for Health Research Biomedical Research Centre for Mental Health, the South London and Maudsley National Health Service Foundation Trust, and the Institute of Psychiatry, King's College London. NR 29 TC 97 Z9 100 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD AUG PY 2009 VL 54 IS 2 BP 233 EP 240 DI 10.1161/HYPERTENSIONAHA.109.128744 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 473YW UT WOS:000268250300014 PM 19564551 ER PT J AU Wang, ZS Maier, A Logothetis, NK Liang, HL AF Wang, Zhisong Maier, Alexander Logothetis, Nikos K. Liang, Hualou TI Extraction of Bistable-Percept-Related Features From Local Field Potential by Integration of Local Regression and Common Spatial Patterns SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Common spatial patterns (CSPs); event-related synchronization and desynchronization; feature extraction; local field potential (LFP); local regression; locally weighted scatterplot smoothing (LOWESS); nonstationary time series; single trial; stimulus-evoked activity; structure-from-motion (SFM); support vector machine (SVM) ID SINGLE-TRIAL EEG; WEIGHTED REGRESSION; MOVEMENT; CORTEX AB Bistable perception arises when an ambiguous stimulus under continuous view is perceived as an alternation of two mutually exclusive states. Such a stimulus provides a unique opportunity for understanding the neural basis of visual perception because it dissociates the perception from the visual input. In this paper, we focus on extracting the percept-related features from the local field potential (LFP) in monkey visual cortex for decoding its bistable structure-from-motion (SFM) perception. Our proposed feature extraction approach consists of two stages. First, we estimate and remove from each LFP trial the nonpercept-related stimulus-evoked activity via a local regression method called the locally weighted scatterplot smoothing because of the dissociation between the perception and the stimulus in our experimental paradigm. Second, we use the common spatial patterns approach to design spatial filters based on the residue signals of multiple channels to extract the percept-related features. We exploit a support vector machine (SVM) classifier on the extracted features to decode the reported perception on a single-trial basis. We apply the proposed approach to the multichannel intracortical LFP data collected from the middle temporal (MT) visual cortex in a macaque monkey performing an SFM task. We demonstrate that our approach is effective in extracting the discriminative features of the percept-related activity from LFP and achieves excellent decoding performance. We also find that the enhanced gamma band synchronization and reduced alpha and beta band desynchronization may be the underpinnings of the percept-related activity. C1 [Liang, Hualou] Drexel Univ, Sch Biomed Engn, Philadelphia, PA 19104 USA. [Wang, Zhisong] Microsoft Corp, Bellevue, WA 98007 USA. [Maier, Alexander] NIH, Bethesda, MD 20892 USA. [Logothetis, Nikos K.] Max Planck Inst Biol Cybernet, Neurophysiol Div, Tubingen, Germany. RP Liang, HL (reprint author), Drexel Univ, Sch Biomed Engn, Philadelphia, PA 19104 USA. EM nikos.logothetis@tuebingen.mpg.de; hualou.liang@drexel.edu RI Maier, Alexander/B-7489-2009 OI Maier, Alexander/0000-0002-7250-502X FU National Institutes of Health [NIH R01 MH072034]; Max Planck Society FX This work was supported by the National Institutes of Health under Grant NIH R01 MH072034 and by the Max Planck Society. Asterisk indicates corresponding author. NR 16 TC 3 Z9 3 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD AUG PY 2009 VL 56 IS 8 BP 2095 EP 2103 DI 10.1109/TBME.2009.2018630 PG 9 WC Engineering, Biomedical SC Engineering GA 472XA UT WOS:000268165000015 PM 19362902 ER PT J AU Yu, P Xiong, SD He, QZ Chu, YW Lu, C Ramlogan, CA Steel, JC AF Yu, Ping Xiong, Sidong He, Qiuzao Chu, Yiwei Lu, Chi Ramlogan, Charmaine A. Steel, Jason C. TI Induction of allogeneic mixed chimerism by immature dendritic cells and bone marrow transplantation leads to prolonged tolerance to major histocompatibility complex disparate allografts SO IMMUNOLOGY LA English DT Article DE allogeneic chimerism; bone marrow transplantaton; immature dendritic cells; immune tolerance; regulatory T cells ID COLONY-STIMULATING FACTOR; REGULATORY T-CELLS; IN-VIVO; LIVER-TRANSPLANTATION; MICE; EXPRESSION; RECIPIENTS; SURVIVAL; RECEPTOR; THERAPY AB P>Mixed chimerism has been shown to lead to prolonged major histocompatibility complex (MHC) disparate allograft survival and immune-specific tolerance; however, traditional conditioning regimes often involve myeloablation, which may pose a significant safety risk. In this study we examined the use of donor C57BL/6 (H-2(b)) immature dendritic cells (imDCs) to tolerize the BALB/c (H-2(d)) recipient to bone marrow transplantation (BMT), allowing the induction of mixed chimerism without immunosuppression or myeloablation. We showed that successful mismatched bone marrow engraftment can be achieved using imDCs given up to 3 days prior to BMT and that mixed chimerism can be established and detected in excess of 100 days post-BMT without evidence of graft-versus-host disease. Furthermore, we showed that imDCs can suppress lymphocyte proliferation in response to mismatched MHC stimulation, leading to increased expression of interleukin (IL)-4 and IL-10 and decreased expression of IL-2 and interferon-gamma (IFN-gamma). The induction of stable chimeras through pre-conditioning of mice with donor imDCs followed by BMT led to tolerance, allowing the long-term survival (> 110 days) of mismatched cardiac allografts and the prolonged survival of mismatched skin allografts without the need for immunosuppression or myeloablation. Transplantation with third-party C3H allografts were rapidly rejected in this model, suggesting that immune-specific tolerance was achieved. The induction of immune-specific tolerance without the need for immunosuppression or myeloablation represents a significant advance in transplant immunology and may provide clinicians with a plausible alternative in combating organ rejection following transplantation. C1 [Yu, Ping; Ramlogan, Charmaine A.; Steel, Jason C.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yu, Ping; Xiong, Sidong; He, Qiuzao; Chu, Yiwei] Fudan Univ, Shanghai Med Coll, Dept Immunol, Ctr Gene Immunizat & Vaccine Res, Shanghai 200433, Peoples R China. [Lu, Chi] Univ Kentucky, Ctr Nanoscale Sci & Engn, Lexington, KY USA. RP Yu, P (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bldg 10,Rm 4N115,10 Ctr Dr, Bethesda, MD 20892 USA. EM yuping2@mail.nih.gov; sdxiong@shmu.edu.cn; heqiuzao@126.com RI Steel, Jason/D-1805-2013 OI Steel, Jason/0000-0003-3608-7542 FU National Natural Science Foundation of China [39830340]; Shanghai Science and Technology Committee Funding [03JC14085]; Major State Basic Research Development Program of People's Republic of China [2001CB510006]; NIH, National Cancer Institute, Center for Cancer Research. FX This work was supported by the National Natural Science Foundation of China (no. 39830340), the Shanghai Science and Technology Committee Funding (no. 03JC14085) and the Major State Basic Research Development Program of People's Republic of China (2001CB510006). This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The authors are thankful to the faculty members of Department of Immunology, Fudan University. NR 32 TC 18 Z9 22 U1 0 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD AUG PY 2009 VL 127 IS 4 BP 500 EP 511 DI 10.1111/j.1365-2567.2009.03057.x PG 12 WC Immunology SC Immunology GA 467PO UT WOS:000267752700007 PM 19604303 ER PT J AU Palmore, TN Stock, F White, M Bordner, M Michelin, A Bennett, JE Murray, PR Henderson, DK AF Palmore, Tara N. Stock, Frida White, Margaret Bordner, MaryAnn Michelin, Angela Bennett, John E. Murray, Patrick R. Henderson, David K. TI A Cluster of Cases of Nosocomial Legionnaires Disease Linked to a Contaminated Hospital Decorative Water Fountain SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article; Proceedings Paper CT 18th Annual Scientific Meeting of the Society-for-Healthcare-Epidemiology-of-America CY APR 05-08, 2008 CL Orlando, FL SP Soc Healthcare Epidemiol Amer ID LEGIONELLA-PNEUMOPHILA; LARGE OUTBREAK; PONTIAC FEVER; PNEUMONIA; INFECTION; WORKERS; OZONE AB BACKGROUND. Nosocomial outbreaks of Legionnaires disease have been linked to contaminated water in hospitals. Immunocompromised patients are particularly vulnerable and, when infected, have a high mortality rate. We report the investigation of a cluster of cases of nosocomial pneumonia attributable to Legionella pneumophila serogroup 1 that occurred among patients on our stem cell transplantation unit. METHODS. We conducted a record review to identify common points of potential exposure, followed by environmental and water sampling for Legionella species from those sources. We used an air sampler to in an attempt to detect aerosolized Legionella and pulsed-field gel electrophoresis to compare clinical and environmental isolates. RESULTS. The most likely sources identified were the water supply in the patients' rooms and a decorative fountain in the radiation oncology suite. Samples from the patients' rooms did not grow Legionella species. Cultures of the fountain, which had been restarted 4 months earlier after being shut off for 5 months, yielded L. pneumophila serogroup 1. The isolates from both patients and the fountain were identical by pulsed-field gel electrophoresis. Both patients developed pneumonia within 10 days of completing radiation therapy, and each reported having observed the fountain at close range. Both patients' infections were identified early and treated promptly, and both recovered. CONCLUSIONS. This cluster was caused by contamination of a decorative fountain despite its being equipped with a filter and ozone generator. Fountains are a potential source of nosocomial Legionnaires disease despite standard maintenance and sanitizing measures. In our opinion, fountains present unacceptable risk in hospitals serving immunocompromised patients. C1 [Palmore, Tara N.; Stock, Frida; White, Margaret; Bordner, MaryAnn; Michelin, Angela; Murray, Patrick R.; Henderson, David K.] NIH, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Palmore, Tara N.; Bennett, John E.] NIAID, NIH, Bethesda, MD 20892 USA. RP Palmore, TN (reprint author), NIH, Warren Grant Magnuson Clin Ctr, 10 Ctr Dr,Room 11N234,MSC 1888, Bethesda, MD 20892 USA. EM tpalmore@mail.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 21 TC 39 Z9 41 U1 0 U2 15 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD AUG PY 2009 VL 30 IS 8 BP 764 EP 768 DI 10.1086/598855 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 469LD UT WOS:000267898800008 PM 19580436 ER PT J AU Lin, J Wilbur, WJ AF Lin, Jimmy Wilbur, W. John TI Modeling actions of PubMed users with n-gram language models SO INFORMATION RETRIEVAL LA English DT Article DE Search behavior; Query log analysis ID WORLD-WIDE-WEB; SEARCH; PAPERCHASE; STRATEGIES; PATTERNS; LOGS; LIFE AB Transaction logs from online search engines are valuable for two reasons: First, they provide insight into human information-seeking behavior. Second, log data can be used to train user models, which can then be applied to improve retrieval systems. This article presents a study of logs from PubMed(A (R)), the public gateway to the MEDLINEA (R) database of bibliographic records from the medical and biomedical primary literature. Unlike most previous studies on general Web search, our work examines user activities with a highly-specialized search engine. We encode user actions as string sequences and model these sequences using n-gram language models. The models are evaluated in terms of perplexity and in a sequence prediction task. They help us better understand how PubMed users search for information and provide an enabler for improving users' search experience. C1 [Lin, Jimmy] Univ Maryland, Coll Informat Studies, iSch, College Pk, MD 20742 USA. [Lin, Jimmy; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Lin, J (reprint author), Univ Maryland, Coll Informat Studies, iSch, College Pk, MD 20742 USA. EM jimmylin@umd.edu; wilbur@ncbi.nlm.nih.gov FU NIH, National Library of Medicine FX We'd like to thank three anonymous reviewers for their helpful comments. This work was supported by the Intramural Research Program of the NIH, National Library of Medicine. The first author would also like to thank Esther and Kiri for their kind support. NR 40 TC 7 Z9 7 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1386-4564 EI 1573-7659 J9 INFORM RETRIEVAL JI Inf. Retr. PD AUG PY 2009 VL 12 IS 4 BP 487 EP 503 DI 10.1007/s10791-008-9067-7 PG 17 WC Computer Science, Information Systems SC Computer Science GA 458AS UT WOS:000266983300003 PM 19684883 ER PT J AU Zhu, JJ Wang, OM Ruan, LF Hou, XW Cui, YH Wang, JM Le, YY AF Zhu, Jingjing Wang, Oumei Ruan, Lingfei Hou, Xinwei Cui, Youhong Wang, Ji Ming Le, Yingying TI The green tea polyphenol (-)-epigallocatechin-3-gallate inhibits leukocyte activation by bacterial formylpeptide through the receptor FPR SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Article DE EGCG; Leukocyte; fMLF; Inflammation; Calcium mobilization; MAP kinase ID CHEMOKINE RECEPTORS; MURINE MODEL; IN-VIVO; INFLAMMATION; CHEMOTAXIS; NEUTROPHIL; CATECHINS; GALLATE; IDENTIFICATION; DEGRANULATION AB Although green tea polyphenol catechin is considered as a potential anti-inflammatory agent, its effect on bacterial component-induced inflammation has been poorly investigated. We examined the capacity of epigallocatechin gallate (EGCG) to regulate leukocyte responses to bacterial chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLF), which is recognized by a human G protein-coupled receptor FPR on phagocytic leukocytes. Pretreatment of human monocytic cells or FPR-transfected rat basophilic leukemia cells (ETFR cells) with EGCG significantly inhibited fMLF-induced chemotaxis. Intraperitoneal administration of EGCG in mice suppressed fMLF-induced leukocyte infiltration into the air pouch created in the skin. Mechanistic studies revealed that EGCG dose-dependently suppressed fMLF-induced calcium flux in monocytic cells and ETFR cells. fMLF-induced ETFR cell migration was significantly inhibited by a specific MEK1/2 inhibitor, PD98059, which was associated with reduction in fMLF-induced ERK1/2 phosphorylation. These results suggest that EGCG inhibits FPR-mediated leukocyte activation thus is a promising anti-inflammatory compound. (C) 2009 Elsevier B.V. All rights reserved. C1 [Zhu, Jingjing; Wang, Oumei; Ruan, Lingfei; Hou, Xinwei; Cui, Youhong; Le, Yingying] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Nutr & Metab, Shanghai 200031, Peoples R China. [Wang, Oumei; Ruan, Lingfei; Hou, Xinwei; Le, Yingying] Chinese Acad Sci, Grad Sch, Shanghai 200031, Peoples R China. [Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Le, YY (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Nutr & Metab, Shanghai 200031, Peoples R China. EM yyle@sibs.ac.cn RI wang, oumei/P-5528-2015 FU Chief Scientist Program of Shanghai Institutes for Biological Sciences [SIBS2008006]; Chinese Academy of Sciences, and by the Science & Technology Commission of Shanghai Municipality [06JC14077, 07DJ14005] FX This work was supported by the Chief Scientist Program of Shanghai Institutes for Biological Sciences (SIBS2008006), Chinese Academy of Sciences, and by the Science & Technology Commission of Shanghai Municipality (06JC14077, 07DJ14005). NR 26 TC 11 Z9 11 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD AUG PY 2009 VL 9 IS 9 BP 1126 EP 1130 DI 10.1016/j.intimp.2009.05.002 PG 5 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 475LN UT WOS:000268360800016 PM 19426837 ER PT J AU Islami, F Boffetta, P Ren, JS Pedoeim, L Khatib, D Kamangar, F AF Islami, Farhad Boffetta, Paolo Ren, Jian-Song Pedoeim, Leah Khatib, Dara Kamangar, Farin TI High-temperature beverages and foods and esophageal cancer risk-A systematic review SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE tea; coffee; mate; temperature; review; case-control; cohort; esophageal cancer; squamous cell carcinoma; adenocarcinoma ID SQUAMOUS-CELL CARCINOMA; GREEN TEA CONSUMPTION; POLYCYCLIC AROMATIC-HYDROCARBONS; UPPER AERODIGESTIVE TRACT; HIGH-INCIDENCE AREA; HIGH-EPIDEMIC AREA; LIFE-STYLE FACTORS; JIANGSU PROVINCE; MATE DRINKING; COFFEE CONSUMPTION AB Coffee, tea and mate may cause esophageal cancer (EC) by causing thermal injury to the esophageal mucosa. If so, the risk of EC attributable to thermal injury could be large in populations in which these beverages are commonly consumed. In addition, these drinks may cause or prevent EC via their chemical constituents. Therefore, a large number of epidemiologic studies have investigated the association of an indicator of amount or temperature of use of these drinks or other hot foods and beverages with risk of EC. We conducted a systematic review or these studies and report the results for amount and temperature of use separately. By searching PubMed and the ISI, we found 59 eligible studies. For coffee and tea, there was little evidence for an association between amount of use and EC risk; however, the majority of studies showed an increased risk of EC associated with higher drinking temperature which was statistically significant in most of them. For mate drinking, the number of studies was limited, but they consistently showed that EC risk increased with both amount consumed and temperature, and these 2 were independent risk factors. For other hot foods and drinks, over half of the studies showed statistically significant increased risks of EC associated with higher temperature of intake. Overall, the available results strongly suggest that high-temperature beverage drinking increases the risk of EC. Future studies will require standardized strategies that allow for combining data and results should be reported by histological subtypes of EC. (C) 2009 UICC C1 [Ren, Jian-Song; Pedoeim, Leah; Khatib, Dara; Kamangar, Farin] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Islami, Farhad] Univ Tehran Med Sci, Digest Dis Res Ctr, Tehran, Iran. [Islami, Farhad; Boffetta, Paolo] Int Agcy Res Canc, Lifestyle Environm & Canc Grp, F-69372 Lyon, France. [Islami, Farhad] Kings Coll London, Thames Canc Registry, London WC2R 2LS, England. RP Kamangar, F (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 3034, Bethesda, MD 20892 USA. EM kamangar@mail.nih.gov FU National Cancer Institute; National Institutes of Health FX Grant sponsors: National Cancer Institute, National Institutes of Health. NR 121 TC 100 Z9 102 U1 7 U2 23 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 AUG 1 PY 2009 VL 125 IS 3 BP 491 EP 524 DI 10.1002/ijc.24445 PG 34 WC Oncology SC Oncology GA 466CG UT WOS:000267637600001 PM 19415743 ER PT J AU McSorley, MA Alberg, AJ Allen, DS Allen, NE Brinton, LA Dorgan, JF Kaaks, R Rinaldi, S Helzlsouer, KJ AF McSorley, Meghan A. Alberg, Anthony J. Allen, Diane S. Allen, Naomi E. Brinton, Louise A. Dorgan, Joanne F. Kaaks, Rudolf Rinaldi, Sabina Helzlsouer, Kathy J. TI Prediagnostic circulating follicle stimulating hormone concentrations and ovarian cancer risk SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE follicle stimulating hormone (FSH); ovarian cancer; gonadotropins; epidemiology; cohort study ID SURFACE EPITHELIAL-CELLS; POSTMENOPAUSAL WOMEN; REPRODUCTIVE HORMONES; LUTEINIZING-HORMONE; PROLIFERATION; EXPRESSION; FSH; LH AB Gonadotropins have been indicted in ovarian carcinogenesis but direct evidence has been limited and inconsistent. The aim of this study was to determine the association between prediagnostic levels of follicle stimulating hormone (FSH) and subsequent development of invasive epithelial ovarian cancer. A nested case-control study was conducted using cases and controls drawn from three cohorts: CLUE I and CLUE II of Washington County, MD, and the Island of Guernsey Study, United Kingdom. In total, 67 Incident invasive epithelial ovarian cancer cases were each matched to 1 to 2 controls on age, menopausal status, time since last menstrual period, current hormone use and other relevant factors. FSH concentrations were classified into ranked thirds of low, medium or high based on the distribution among controls. Conditional logistic regression was used to estimate the odds ratio (OR) across increasing thirds of FSH concentrations. Results of the analysis showed that ovarian cancer risk decreased with higher FSH concentrations (p-trend = 0.005). Compared with the lowest third of FSH concentrations, the OR among those in the middle and highest thirds were 0.45 [95% Confidence Interval (CI): 0.20-1.00] and 0.26 (95% CI: 0.10-0.70), respectively. Associations persisted after excluding cases diagnosed within 5 years of follow-up. In conclusion, a reduction in subsequent risk of invasive epithelial ovarian cancer was observed among women with higher circulating FSH concentrations. These findings contradict the hypothesized role of FSH as a risk factor in ovarian carcinogenesis. (C) 2009 UICC C1 [Helzlsouer, Kathy J.] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD 21202 USA. [McSorley, Meghan A.; Alberg, Anthony J.; Helzlsouer, Kathy J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Alberg, Anthony J.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Alberg, Anthony J.] Med Univ S Carolina, Dept Bioinformat & Epidemiol, Charleston, SC 29425 USA. [Allen, Diane S.] Guys Hosp, Acad Oncol Unit, London SE1 9RT, England. [Allen, Naomi E.] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Dorgan, Joanne F.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Kaaks, Rudolf; Rinaldi, Sabina] German Canc Res Ctr, Div Canc Epidemiol, D-6900 Heidelberg, Germany. RP Helzlsouer, KJ (reprint author), Mercy Med Ctr, Prevent & Res Ctr, 227 St Paul Pl, Baltimore, MD 21202 USA. EM khelzlsouer@mdmercy.com RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU National Cancer Institute [CA-97857, CA-86308]; M. Jean Goutal (donation); Woodrow Wilson Foundation/Johnson and Johnson; Lloyds TSB Charitable Foundation for the Channel Islands FX Grant sponsor: National Cancer Institute: Grant numbers: CA-97857, CA-86308; Grant sponsor: M. Jean Goutal (donation): Grant sponsors: The Woodrow Wilson Foundation/Johnson and Johnson, The Lloyds TSB Charitable Foundation for the Channel Islands. NR 21 TC 6 Z9 9 U1 0 U2 2 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 AUG 1 PY 2009 VL 125 IS 3 BP 674 EP 679 DI 10.1002/ijc.24406 PG 6 WC Oncology SC Oncology GA 466CG UT WOS:000267637600020 PM 19444906 ER PT J AU Koh, KK Quon, MJ AF Koh, Kwang Kon Quon, Michael J. TI The importance of considering alternative or combination strategies for lowering LDL-C SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Editorial Material ID THERAPEUTIC INTERVENTIONS; CHOLESTEROL; SIMVASTATIN; ATORVASTATIN; MORTALITY; STATINS; CANCER; RISK; MEN; HYPERCHOLESTEROLEMIA C1 [Koh, Kwang Kon] Gachon Univ, Gil Med Ctr, Vasc Med & Atherosclerosis Unit, Div Cardiol, Inchon 405760, South Korea. [Quon, Michael J.] NIH, Diabet Unit, NCCAM, Bethesda, MD 20892 USA. RP Koh, KK (reprint author), Gachon Univ, Gil Med Ctr, Vasc Med & Atherosclerosis Unit, Div Cardiol, 1198 Kuwol Dong, Inchon 405760, South Korea. EM kwangk@gilhospital.com OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 FU Intramural NIH HHS [Z01 AT000001-06] NR 24 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD AUG PY 2009 VL 136 IS 2 BP 115 EP 119 DI 10.1016/j.ijcard.2009.03.035 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 474XC UT WOS:000268317100001 PM 19345431 ER PT J AU Brennan, P McKay, J Moore, L Zaridze, D Mukeria, A Szeszenia-Dabrowska, N Lissowska, J Rudnai, P Fabianova, E Mates, D Bencko, V Foretova, L Janout, V Chow, WH Rothman, N Chabrier, A Gaborieau, V Timpson, N Hung, RJ Smith, GD AF Brennan, Paul McKay, James Moore, Lee Zaridze, David Mukeria, Anush Szeszenia-Dabrowska, Neonilia Lissowska, Jolanta Rudnai, Peter Fabianova, Eleonora Mates, Dana Bencko, Vladimir Foretova, Lenka Janout, Vladimir Chow, Wong-Ho Rothman, Nathaniel Chabrier, Amelie Gaborieau, Valerie Timpson, Nic Hung, Rayjean J. Smith, George Davey TI Obesity and cancer: Mendelian randomization approach utilizing the FTO genotype SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Obesity; cancer; Mendelian randomization ID EPIDEMIOLOGY AB Methods To avoid these biases we used a Mendelian randomization approach incorporating an analysis of variants in the FTO gene that are strongly associated with BMI levels among 7000 subjects from a study of lung, kidney and upper-aerodigestive cancer. Results The FTO A allele which is linked with increased BMI was associated with a decreased risk of lung cancer (allelic odds ratio (OR) = 0.92, 95% confidence interval (CI) 0.84-1.00). It was also associated with a weak increased risk of kidney cancer, which was more apparent before the age of 50 (OR = 1.44, CI 1.09-1.90). Conclusion Our results highlight the potential for genetic variation to act as an unconfounded marker of environmentally modifiable factors, and offer the potential to obtain estimates of the causal effect of obesity. However, far larger sample sizes than studied here will be required to undertake this with precision. C1 [Brennan, Paul; McKay, James; Chabrier, Amelie; Gaborieau, Valerie; Hung, Rayjean J.] Int Agcy Res Canc, Genet Epidemiol Grp, F-69008 Lyon, France. [Moore, Lee; Chow, Wong-Ho; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Zaridze, David; Mukeria, Anush] Russian Acad Med Sci, Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Lissowska, Jolanta] Marie Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Fabianova, Eleonora] Specialized Inst Hyg & Epidemiol, Banska Bystrica, Slovakia. [Mates, Dana] Inst Publ Hlth, Bucharest, Romania. [Bencko, Vladimir] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague 2, Czech Republic. [Foretova, Lenka] Mazaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Janout, Vladimir] Palacky Univ, Fac Med, Dept Prevent Med, CR-77147 Olomouc, Czech Republic. [Timpson, Nic; Smith, George Davey] MRC, Ctr Causal Analyses Translat Epidemiol, CAITE, Dept Social Med, Bristol, Avon, England. [Hung, Rayjean J.] Univ Toronto, Canc Care Ontario Res Chair, Samuel Lunenfeld Res Inst, Toronto, ON M5S 1A1, Canada. RP Brennan, P (reprint author), Int Agcy Res Canc, Genet Epidemiol Grp, 150 Cours Albert Thomas, F-69008 Lyon, France. EM brennan@iarc.fr RI Hung, Rayjean/A-7439-2013; Zaridze, David/K-5605-2013; Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; Fox, Laura /C-6249-2016; Davey Smith, George/A-7407-2013; OI Davey Smith, George/0000-0002-1407-8314; Monsalve, Beatriz Elena/0000-0002-5994-866X; mates, dana/0000-0002-6219-9807; Lissowska, Jolanta/0000-0003-2695-5799; Timpson, Nicholas/0000-0002-7141-9189 FU European Commission [IC15-CT96-0313]; National Cancer Institute R01 grant [09203901A2] FX European Commission's INCO-COPERNICUS Programme ( Contract No. IC15-CT96-0313); National Cancer Institute R01 grant ( contract no. CA 09203901A2). NR 6 TC 51 Z9 55 U1 4 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 2009 VL 38 IS 4 BP 971 EP 975 DI 10.1093/ije/dyp162 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 481LK UT WOS:000268812300014 PM 19542184 ER PT J AU Islami, F Kamangar, F Nasrollahzadeh, D Aghcheli, K Sotoudeh, M Abedi-Ardekani, B Merat, S Nasseri-Moghaddam, S Semnani, S Sepehr, A Wakefield, J Moller, H Abnet, CC Dawsey, SM Boffetta, P Malekzadeh, R AF Islami, Farhad Kamangar, Farin Nasrollahzadeh, Dariush Aghcheli, Karim Sotoudeh, Masoud Abedi-Ardekani, Behnoush Merat, Shahin Nasseri-Moghaddam, Siavosh Semnani, Shahryar Sepehr, Alireza Wakefield, Jon Moller, Henrik Abnet, Christian C. Dawsey, Sanford M. Boffetta, Paolo Malekzadeh, Reza TI Socio-economic status and oesophageal cancer: results from a population-based case-control study in a high-risk area SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Oesophageal cancer; socio-economic status; case-control; epidemiology; Iran; factor analysis; correspondence analysis ID NORTHEASTERN IRAN; HEALTH RESEARCH; MORTALITY; OPIUM; DISPARITIES; POSITION AB Methods Data were obtained from a population-based case-control study conducted between 2003 and 2007 with 300 histologically proven OSCC cases and 571 matched neighbourhood controls. We used conditional logistic regression to compare cases and controls for individual SES indicators, for a composite wealth score constructed using multiple correspondence analysis, and for factors obtained from factors analysis. Results We found that various dimensions of SES, such as education, wealth and being married were all inversely related to OSCC. The strongest inverse association was found with education. Compared with no education, the adjusted odds ratios (95% confidence intervals) for primary education and high school or beyond were 0.52 (0.27-0.98) and 0.20 (0.06-0.65), respectively. Conclusions The strong association of SES with OSCC after adjustment for known risk factors implies the presence of yet unidentified risk factors that are correlated with our SES measures; identification of these factors could be the target of future studies. Our results also emphasize the importance of using multiple SES measures in epidemiological studies. C1 [Islami, Farhad; Boffetta, Paolo] Int Agcy Res Canc, F-69008 Lyon, France. [Islami, Farhad; Nasrollahzadeh, Dariush; Aghcheli, Karim; Sotoudeh, Masoud; Abedi-Ardekani, Behnoush; Merat, Shahin; Nasseri-Moghaddam, Siavosh; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. [Islami, Farhad; Moller, Henrik] Kings Coll London, Thames Canc Registry, London WC2R 2LS, England. [Kamangar, Farin; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Nasrollahzadeh, Dariush] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Semnani, Shahryar] Golestan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan, Iran. [Sepehr, Alireza] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Wakefield, Jon] Univ Washington, Dept Stat, Seattle, WA 98195 USA. RP Boffetta, P (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69008 Lyon, France. EM boffetta@iarc.fr; malek@ams.ac.ir RI Semnani, Shahryar/N-2270-2016; Abedi-Ardekani, Behnoush/O-7829-2016; Abnet, Christian/C-4111-2015 OI Semnani, Shahryar/0000-0002-8768-6142; Abedi-Ardekani, Behnoush/0000-0002-0980-0587; Moller, Henrik/0000-0001-8200-5929; Malekzadeh, Reza/0000-0003-1043-3814; Abnet, Christian/0000-0002-3008-7843 FU Intramural NIH HHS NR 44 TC 82 Z9 83 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 2009 VL 38 IS 4 BP 978 EP 988 DI 10.1093/ije/dyp195 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 481LK UT WOS:000268812300016 PM 19416955 ER PT J AU Sinha, R Devesa, S Rastogi, T Mathew, A AF Sinha, Rashmi Devesa, Susan Rastogi, Tanuja Mathew, Aleyamma TI Response to Cancer incidence rates among South Asians in four geographic regions: India, Singapore, UK and US - Authors response SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 [Sinha, Rashmi; Devesa, Susan; Rastogi, Tanuja] NCI, Div Canc Epidemiol & Genet DCEG, NIH, DHHS, Rockville, MD USA. [Mathew, Aleyamma] Reg Canc Ctr, Trivandrum 695011, Kerala, India. RP Sinha, R (reprint author), 6120 Execut Blvd,Rm 3046,EPS, Rockville, MD 20852 USA. EM sinhar@nih.gov RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 NR 6 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 2009 VL 38 IS 4 BP 1158 EP 1159 DI 10.1093/ije/dyn120 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 481LK UT WOS:000268812300042 ER PT J AU Dotson, VM Beason-Held, L Kraut, MA Resnick, SM AF Dotson, Vonetta M. Beason-Held, Lori Kraut, Michael A. Resnick, Susan M. TI Longitudinal study of chronic depressive symptoms and regional cerebral blood flow in older men and women SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE subthreshold depression; late-life depression; sex differences; positron emission tomography; aging; longitudinal studies ID POSITRON-EMISSION-TOMOGRAPHY; LATE-ONSET MINOR; SCALE CES-D; MAJOR DEPRESSION; SEX-DIFFERENCES; ALZHEIMERS-DISEASE; COGNITIVE DECLINE; SUBTHRESHOLD DEPRESSION; GERIATRIC DEPRESSION; CRITERION VALIDITY AB Objectives Late-life depression is associated with alterations in regional cerebral blood flow (rCBF) and metabolism in a neural network that includes frontostriatal and limbic regions and the cerebellum. Prior studies suggest that clinical depression and subthreshold depressive symptoms (SDS) are associated with similar cognitive deficits and structural brain changes, but little is known about the relationship between SDS and patterns of brain activity. Additionally, the neural correlates of depression have not been fully explored in men and women separately. This study investigated cross-sectional and longitudinal relationships between SDS and rCBF in older men and women. Methods Sixty-one dementia-free older adults (35 men, 26 women), 56 years of age and older at baseline, from the neuroimaging substudy of the Baltimore Longitudinal Study of Aging participated. Participants underwent resting-state PET scans at baseline and at year 9 and completed the Center for Epidemiologic Studies Depression Scale annually. Results At 8-year follow-up, both men and women showed cross-sectional associations between mean depressive symptom scores and activity in primarily frontal and temporal regions and the cerebellum. Higher average depressive symptoms were associated with longitudinal rCBF decreases in frontal regions in both men and women, and in temporal regions in men. Conclusion Regions showing associations between activity and SDS were similar to those found in studies of clinical depression, providing support for the hypothesis that depressive syndromes exist on a continuum of severity. Sex differences in associations provide some evidence that the pathophysiology of depressive disorders differs between men and women. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Dotson, Vonetta M.] NIA, Lab Personal & Cognit, Intramural Res Program, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. [Kraut, Michael A.] Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21205 USA. RP Dotson, VM (reprint author), NIA, Lab Personal & Cognit, Intramural Res Program, NIH,Biomed Res Ctr, 251 Bayview Blvd,Suite 100,Room 4B316, Baltimore, MD 21224 USA. EM dotsonv@mail.nih.gov RI Dotson, Vonetta/K-6090-2015; OI Dotson, Vonetta/0000-0002-3043-3320 FU Intramural NIH HHS [Z01 AG000191-11] NR 48 TC 23 Z9 23 U1 3 U2 6 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0885-6230 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD AUG PY 2009 VL 24 IS 8 BP 809 EP 819 DI 10.1002/gps.2298 PG 11 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 477XM UT WOS:000268552300004 PM 19484709 ER PT J AU Koska, J Stefan, N Dubois, S Trinidad, C Considine, RV Funahashi, T Bunt, JC Ravussin, E Permana, PA AF Koska, J. Stefan, N. Dubois, S. Trinidad, C. Considine, R. V. Funahashi, T. Bunt, J. C. Ravussin, E. Permana, P. A. TI mRNA concentrations of MIF in subcutaneous abdominal adipose cells are associated with adipocyte size and insulin action SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE adipocytes; preadipocytes; MIF; insulin action; inflammation; adiponectin ID MIGRATION INHIBITORY FACTOR; INFLAMMATION-RELATED GENES; IMPAIRED GLUCOSE-TOLERANCE; NONOBESE PIMA-INDIANS; NECROSIS-FACTOR-ALPHA; INCREASED EXPRESSION; OBESE SUBJECTS; IN-VITRO; TISSUE; RESISTANCE AB Objective: To determine whether the mRNA concentrations of inflammation response genes in isolated adipocytes and in cultured preadipocytes are related to adipocyte size and in vivo insulin action in obese individuals. Design: Cross-sectional inpatient study. Subjects: Obese Pima Indians with normal glucose tolerance. Measurements: Adipocyte diameter (by microscope technique; n 29), expression of candidate genes (by quantitative real-time PCR) in freshly isolated adipocytes (monocyte chemoattractant protein (MCP) 1 and MCP2, macrophage inflammatory protein (MIP) 1 alpha, MIP1 beta and MIP2, macrophage migration inhibitory factor (MIF), tumor necrosis factor alpha, interleukin (IL) 6 and IL8; n = 22) and cultured preadipocytes (MCP1, MIP1 alpha, MIF, IL6 and matrix metalloproteinase 2; n = 33) from subcutaneous abdominal adipose tissue (by aspiration biopsy, n = 34), body fat by dual-energy X-ray absorptiometry, glucose tolerance by 75 g oral glucose tolerance test and insulin action by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU m(-2) min(-1)) (all n = 34). Results: MIF was the only gene whose expression in both freshly isolated adipocytes and cultured preadipocytes was positively associated with adipocytes diameter and negatively associated with peripheral and hepatic insulin action (all P < 0.05). In multivariate analysis, the association between adipocyte MIF mRNA concentrations and adipocytes diameter was independent of the percentage of body fat (P = 0.03), whereas adipocyte MIF mRNA concentrations, but not adipocyte diameter, independently predicted peripheral insulin action. The mRNA expression concentrations of the MIF gene in adipocytes were not associated with plasma concentrations of MIF, but were negatively associated with plasma adiponectin concentrations (P = 0.004). In multivariate analysis, adipocyte MIF RNA concentrations (P = 0.03) but not plasma adiponectin concentrations (P = 0.4) remained a significant predictor of insulin action. Conclusions: Increased expression of MIF gene in adipose cells may be an important link between obesity characterized by enlarged adipocytes and insulin resistance in normal glucose tolerant people. International Journal of Obesity (2009) 33, 842-850; doi: 10.1038/ijo.2009.106; published online 9 June 2009 C1 [Koska, J.; Permana, P. A.] Phoenix Vet Affairs Hlth Care Syst, Phoenix, AZ 85012 USA. [Koska, J.; Trinidad, C.; Bunt, J. C.; Permana, P. A.] NIDDK, Obes & Diabet Clin Res Sect, NIH, DHHS, Phoenix, AZ USA. [Stefan, N.] Univ Tubingen, Div Endocrinol, Dept Internal Med, Tubingen, Germany. [Dubois, S.; Ravussin, E.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Considine, R. V.] Indiana Univ, Sch Med, Indianapolis, IN 46204 USA. [Funahashi, T.] Osaka Univ, Grad Sch Med, Osaka, Japan. RP Koska, J (reprint author), Phoenix Vet Affairs Hlth Care Syst, 650 E Indian Sch Rd, Phoenix, AZ 85012 USA. EM juraj.koska@va.gov OI Stefan, Norbert/0000-0002-2186-9595 FU NIDDK/NIH/DHHS FX This work was funded by the intramural research program of the NIDDK/NIH/DHHS. We gratefully acknowledge Thomas Brookshire, PA and nursing and dietary staffs of the NIH metabolic unit for the care of the volunteers, and Emma Rousseau and Shannon Parrington for excellent technical assistance. We are grateful to the members and leaders of the Gila River Indian Community for their continuing cooperation in our studies. We thank Dr Susanne Votruba for helpful comments on this article. Clinical trial registration number: NCT00410800. NR 41 TC 20 Z9 22 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD AUG PY 2009 VL 33 IS 8 BP 842 EP 850 DI 10.1038/ijo.2009.106 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 481HU UT WOS:000268799200005 PM 19506561 ER PT J AU Gillis, B Mobley, C Stadler, DD Hartstein, J Virus, A Volpe, SL El Ghormli, L Staten, MA Bridgman, J McCormick, S AF Gillis, B. Mobley, C. Stadler, D. D. Hartstein, J. Virus, A. Volpe, S. L. El Ghormli, L. Staten, M. A. Bridgman, J. McCormick, S. CA HEALTHY Study Grp TI Rationale, design and methods of the HEALTHY study nutrition intervention component SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE childhood obesity; diabetes prevention; food service; middle school intervention; nutrition; school food environment ID METABOLIC SYNDROME; MIDDLE SCHOOLS; DIETARY; PREVENTION; OBESITY; KILOCALORIES; ENVIRONMENTS; ASSOCIATION; CHILDREN; FOODS AB The HEALTHY study was a randomized, controlled, multicenter and middle school-based, multifaceted intervention designed to reduce risk factors for the development of type 2 diabetes. The study randomized 42 middle schools to intervention or control, and followed students from the sixth to the eighth grades. Here we describe the design of the HEALTHY nutrition intervention component that was developed to modify the total school food environment, defined to include the following: federal breakfast, lunch, after school snack and supper programs; a la carte venues, including snack bars and school stores; vending machines; fundraisers; and classroom parties and celebrations. Study staff implemented the intervention using core and toolbox strategies to achieve and maintain the following five intervention goals: (1) lower the average fat content of foods, (2) increase the availability and variety of fruits and vegetables, (3) limit the portion sizes and energy content of dessert and snack foods, (4) eliminate whole and 2% milk and all added sugar beverages, with the exception of low fat or nonfat flavored milk, and limit 100% fruit juice to breakfast in small portions and (5) increase the availability of higher fiber grain-based foods and legumes. Other nutrition intervention component elements were taste tests, cafeteria enhancements, cafeteria line messages and other messages about healthy eating, cafeteria learning laboratory (CLL) activities, twice-yearly training of food service staff, weekly meetings with food service managers, incentives for food service departments, and twice yearly local meetings and three national summits with district food service directors. Strengths of the intervention design were the integration of nutrition with the other HEALTHY intervention components (physical education, behavior change and communications), and the collaboration and rapport between the nutrition intervention study staff members and food service personnel at both school and district levels. International Journal of Obesity (2009) 33, S29-S36; doi:10.1038/ijo.2009.114 C1 [Gillis, B.] Univ Pittsburgh, Western Psychiat Inst & Clin, Med Ctr, Pittsburgh, PA 15213 USA. [Mobley, C.] Univ Nevada, Sch Dent Med, Las Vegas, NV 89154 USA. [Stadler, D. D.; McCormick, S.] Oregon Hlth & Sci Univ, Div Hlth Promot & Sports Med, Portland, OR 97201 USA. [Hartstein, J.] Univ Calif Irvine, Dept Pediat, Irvine, CA 92717 USA. [Virus, A.] Temple Univ, Ctr Obes Res & Educ, Philadelphia, PA 19122 USA. [Volpe, S. L.] Univ Penn, Sch Nursing, Div Biobehav & Hlth Sci, Philadelphia, PA 19104 USA. [El Ghormli, L.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Staten, M. A.] NIDDK, NIH, Bethesda, MD USA. [Bridgman, J.] Univ N Carolina, Sch Nursing, Chapel Hill, NC USA. RP Gillis, B (reprint author), Univ Pittsburgh, Western Psychiat Inst & Clin, Med Ctr, 3811 Ohara St, Pittsburgh, PA 15213 USA. EM gillisbp@upmc.edu FU NIDDK NIH HHS [U01 DK061230-08, U01 DK061230, U01-DK61223, U01-DK61230, U01-DK61231, U01-DK61249] NR 30 TC 26 Z9 26 U1 2 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD AUG PY 2009 VL 33 BP S29 EP S36 DI 10.1038/ijo.2009.114 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 492EV UT WOS:000269638600004 PM 19623185 ER PT J AU Ishii, H Choudhuri, R Mathias, A Sowers, AL Flanders, KC Cook, JA Mitchell, JB AF Ishii, Hisanari Choudhuri, Rajani Mathias, Askale Sowers, Anastasia L. Flanders, Kathleen C. Cook, John A. Mitchell, James B. TI Halofuginone mediated protection against radiation-induced leg contracture SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE fibrosis; TGF-beta; radiation; halofuginone; protection ID GROWTH-FACTOR-BETA; TGF-BETA; FIBROSIS; THERAPY; INJURY; IRRADIATION; CANCER; AMELIORATION; RADIOTHERAPY; ACTIVATION AB Fibrosis of normal tissues often accompanies radiation treatment of cancer. Activation of the transforming growth factor-beta (TGF-beta) signaling pathway is thought to play a major role in radiation-induced fibrosis and has prompted the development and assessment of low molecular weight inhibitors of the pathway. Previous studies with halofuginone have shown it to inhibit TGF-beta signaling in vitro and protect mice from radiation-induced leg contraction (a model for soft tissue fibrosis). The current study confirms these findings for HaCaT cells stimulated with exogenous TGF-beta treatment. Reducing the halifuginone treatment from 7 days/week (used previously) to 5 days/week post-radiation exposure provided significant protection against radiation-induced leg contraction in mice 3 and 4 months post-radiation treatment. Halofuginone treatment was shown to attenuate TGF-beta signaling molecules taken from irradiated skin including TGF-beta RII, pSmad3, Smad7, and TSP1. The latter, TSP1, a co-activator of TGF-beta may serve as a suitable biomarker for monitoring the efficacy of halofuginone should it be evaluated in a clinical setting for protection against radiation-induced fibrosis. C1 [Ishii, Hisanari; Choudhuri, Rajani; Mathias, Askale; Sowers, Anastasia L.; Cook, John A.; Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Flanders, Kathleen C.] NCI, Lab Cell Regulat & Carcinogenesis, Ctr Canc Res, Bethesda, MD 20892 USA. RP Mitchell, JB (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. EM jbm@helix.nih.gov FU Intramural Research Program; Center for Cancer Research; National Cancer Institute; NIH FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH. NR 22 TC 10 Z9 12 U1 0 U2 1 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD AUG PY 2009 VL 35 IS 2 BP 315 EP 319 DI 10.3892/ijo_00000342 PG 5 WC Oncology SC Oncology GA 469CQ UT WOS:000267873400011 PM 19578745 ER PT J AU Duncan, CC Mirsky, AF Lovelace, CT Theodore, WH AF Duncan, Connie C. Mirsky, Allan F. Lovelace, Christopher T. Theodore, William H. TI Assessment of the attention impairment in absence epilepsy: Comparison of visual and auditory P300 SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article; Proceedings Paper CT 14th World Congress of Psychophysiology the Olympics of the Brain CY SEP 08-13, 2008 CL St Petersburg, RUSSIA SP Int Org Psychophysiol DE Event-related potentials; P300; Absence epilepsy; Complex partial epilepsy; Attention; CPT ID EVENT-RELATED POTENTIALS; JUVENILE MYOCLONIC EPILEPSY; CENTRENCEPHALIC EPILEPSY; TEMPORAL-LOBE; PERFORMANCE; INFORMATION; DEFICITS AB We report an investigation of P300 measures of information processing in patients with generalized epilepsy of the absence type and those with complex partial epilepsy. Studies have demonstrated that absence patients perform more poorly than complex partial patients on behavioral tests of sustained attention (the Continuous Performance Test, or CPT). Duncan (Duncan, C.C., 1988. Application of event-related brain potentials to the analysis of interictal attention in absence epilepsy. In: Myslobodsky, M.S., Mirsky A.F. (Eds.), Elements of Petit Mal Epilepsy. Peter Lang, New York, pp. 341-364] reported that P300 was significantly reduced in a group of absence patients as compared with healthy controls. The present investigation was undertaken to compare the attention deficit in absence patients to that in complex partial seizure patients. Thus, ERPs were recorded while participants with absence seizure disorder, complex partial seizure disorder, and healthy controls performed auditory and visual versions of the CPT. A significant reduction in the amplitude of P300 on the visual CPT was observed in both groups of seizure patients as compared to controls. In contrast, P300 on the auditory CPT was reduced only in the group with absence seizures. These ERP data support and amplify previous behavioral findings of the impaired capacity of absence patients to mobilize and sustain attentional resources. Auditory sustained attention seems to be more affected by the pathophysiology of absence epilepsy than visual attention. Two possible factors may be involved: (a) There are separate visual and auditory attention systems in the brain, and the latter is more vulnerable than the former [Duncan, C.C., Kosmidis, M.H., Mirsky, A.F., 2005. Closed head injury-related information processing deficits: An event-related potential analysis. Int. J. Psychophysiol. 58, 133-157]; and (b) Auditory processing depends on intact mechanisms in the brainstem, which are dysfunctional in patients with absence seizures. (C) 2009 Elsevier B.V. All rights reserved. C1 [Duncan, Connie C.] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Clin Psychophysiol & Psychopharmacol Lab, Bethesda, MD 20814 USA. [Mirsky, Allan F.] NIMH, NIH, Bethesda, MD 20892 USA. [Lovelace, Christopher T.] Univ Missouri, Dept Psychol, Kansas City, MO 64110 USA. [Theodore, William H.] NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. RP Duncan, CC (reprint author), USU, Dept Psychiat, CPPL, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM cduncan@usuhs.mil FU Intramural NIH HHS [Z01 NS002858-16] NR 30 TC 9 Z9 10 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD AUG PY 2009 VL 73 IS 2 BP 118 EP 122 DI 10.1016/j.ijpsycho.2009.03.005 PG 5 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 478YW UT WOS:000268625700010 PM 19414047 ER PT J AU Lewis, DR Clegg, LX Johnson, NJ AF Lewis, D. R. Clegg, L. X. Johnson, N. J. TI Lung disease mortality in the United States: the Nationa Longitudinal Mortality Study SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Article DE cancer; mortality; lung diseases; health disparities; income; education ID OBSTRUCTIVE PULMONARY-DISEASE; GLOBAL BURDEN; CANCER; SMOKING; RACE/ETHNICITY; EPIDEMIOLOGY; DEATHS; TRENDS; AREA AB SETTING: The National Longitudinal Mortality Study (NLMS) offers the advantage of assessing mortality in a representative population of the United States. OBJECTIVE: To evaluate health disparities associated with lung cancer and chronic obstructive pulmonary disease (COPD) mortality in the United States and whether these associations are similar between these outcomes. DESIGN: The NLMS is a prospective study. Data from NLMS cohort years 1985, 1992, 1993, 1995 and 1.996 were included, representing nearly 1.5 million person-years. Lung cancer and COPD mortality relative risks (RRs) from Cox regression analysis, including residential characteristics, marital status, education, health insurance and family income, were evaluated. RESULTS: By 1998, 1273 lung cancer deaths and 772 COPD deaths occurred. Lung cancer mortality rates were approximately two times higher than COPD mortality rates among race and ethnic groups. Cox regression analysis revealed that low education (RR = 1.77, significant, P = 0.01) and low family income (RR = 1.50, significant, P = 0.01) are associated with lung cancer and COPD mortality, controlling for age, race/ethnicity, sex and smoking status. CONCLUSIONS: COPD and lung cancer mortality have similar associations with health disparity indicators in the NLMS data, with some differences in the magnitude of the effect. C1 [Lewis, D. R.] NCI, Surveillance Res Program, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Clegg, L. X.] US Dept Vet Affairs, Off Healthcare Inspect, Off Inspector Gen, Washington, DC USA. [Johnson, N. J.] US Bur Census, Suitland, MD USA. RP Lewis, DR (reprint author), NCI, Surveillance Res Program, NIH, US Dept Hlth & Human Serv, 6116 Execut Blvd,Room 504,MSC 8316, Bethesda, MD 20892 USA. EM lewisde@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 35 TC 13 Z9 13 U1 1 U2 5 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 EI 1815-7920 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD AUG PY 2009 VL 13 IS 8 BP 1008 EP 1014 PG 7 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA 477JW UT WOS:000268516300014 PM 19723382 ER PT J AU An, FQ Li, Q Tu, ZD Bu, H Chan, CC Caspi, RR Lin, F AF An, Fengqi Li, Qing Tu, Zhidan Bu, Hong Chan, Chi-Chao Caspi, Rachel R. Lin, Feng TI Role of DAF in Protecting against T-Cell Autoreactivity that Leads to Experimental Autoimmune Uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID DECAY-ACCELERATING FACTOR; COLONY-STIMULATING FACTOR; COMPLEMENT REGULATORY PROTEINS; POSTERIOR UVEITIS; ANTERIOR UVEITIS; IFN-GAMMA; UVEORETINITIS; ACTIVATION; EXPRESSION; INDUCTION AB PURPOSE. To investigate the role of decay-accelerating factor (DAF), a cell surface complement regulator that recently has been linked to T-cell responses and autoimmunity in the pathogenesis of experimental autoimmune uveitis (EAU). METHODS. EAU was induced in wild-type (WT) and Daf1(-/-) mice, and their disease severities, IRBP specific Th1/Th17 responses, and cytokine expression profiles were compared. In a test of the efficacy of treatment with soluble mouse DAF protein, EAU was induced in disease-susceptible B10. RIII mice, and they were treated with 0.5 mg soluble DAF protein or equal volume of PBS IP every other day. Retinal histology and IRBP-specific T-cell responses were compared after 14 days. RESULTS. Both EAU incidence and histopathology scores were significantly greater in Daf1(-/-) mice. There was a >10-fold greater mononuclear cell influx into the retina together with severe vasculitic lesions, retinal folding, and photoreceptor cell layer destruction. There were 5- to 7-fold greater Th1 and 3- to 4-fold greater Th17 responses against IRBP in Daf1(-/-) mice with EAU, and they expressed significantly elevated levels of GM-CSF, IL-2, IL-3, and IFN-gamma. WT B10. RIII mice that received soluble DAF protein treatments exhibited decreased IRBP-specific Th1/Th17 responses and were protected from retinal injury compared with the mice that received PBS treatments. CONCLUSIONS. DAF significantly influences IRBP-specific Th1 and Th17 responses and disease severity in EAU. Systemic upregulation of DAF levels could be used to suppress retinal antigen(s)-specific autoimmunity to treat autoimmune posterior uveitis. (Invest Ophthalmol Vis Sci. 2009; 50: 3778-3782) DOI: 10.1167/iovs.08-3264 C1 [Lin, Feng] Case Western Reserve Univ, Inst Pathol, Sch Med, Cleveland, OH 44106 USA. [Li, Qing; Tu, Zhidan; Bu, Hong] Sichuan Univ, Dept Pathol, Chengdu 610064, Peoples R China. [Chan, Chi-Chao; Caspi, Rachel R.] NEI, Dept Immunol, NIH, Bethesda, MD 20892 USA. RP Lin, F (reprint author), Case Western Reserve Univ, Inst Pathol, Sch Med, 2085 Adelbert Rd,Room 306, Cleveland, OH 44106 USA. EM feng.lin@case.edu RI Li, Qing/E-6328-2012; OI Caspi, Rachel/0000-0002-7140-7671 FU National Institute of Health [NS052471]; Natural Science Foundation of China [30671988] FX Supported by National Institute of Health Grant NS052471 (FL). QL and HB were supported in part by Natural Science Foundation of China Grant 30671988. NR 39 TC 22 Z9 23 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2009 VL 50 IS 8 BP 3778 EP 3782 DI 10.1167/iovs.08-3264 PG 5 WC Ophthalmology SC Ophthalmology GA 475XA UT WOS:000268398000032 PM 19443714 ER PT J AU Raz-Prag, D Zeng, Y Sieving, PA Bush, RA AF Raz-Prag, Dorit Zeng, Yong Sieving, Paul A. Bush, Ronald A. TI Photoreceptor Protection by Adeno-Associated Virus-Mediated LEDGF Expression in the RCS Rat Model of Retinal Degeneration: Probing the Mechanism SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID DOMINANT RETINITIS-PIGMENTOSA; STRESS-RELATED GENES; ROD OUTER SEGMENTS; GROWTH-FACTOR; HEAT-SHOCK; CULTURED NEURONS; CYTOCHROME-C; PHOTOPIC ERG; REAL-TIME; IN-VIVO AB PURPOSE. Lens epithelium-derived growth factor (LEDGF) is upregulated in response to stress and enhances the survival of neurons in the retina and optic nerve, as well as a wide range of other cells, such as fibroblasts and keratinocytes. Photoreceptor protection was investigated in the RCS rat retinal degeneration model after Ledgf delivery with an adeno-associated virus (AAV) and the mechanism of protection explored. METHODS. Thirty-six RCS and nine P23H rats had bilateral sub-retinal injections of AAV-Ledgf in one eye and buffer in the contralateral eye as the control. Retinal function was evaluated 8 weeks later by the electroretinogram and compared with photoreceptor cell layer count. LEDGF mRNA and protein levels and mRNA levels of known stress-related factors were compared in treated and control retinas to explore the mechanism of LEDGF protection. Nine RCS rats were treated with adenovirus-heat shock protein 27 (Ad-HSP27) and examined for protection. RESULTS. Significant photoreceptor protection was evident functionally and morphologically in 65% to 100% of the RCS rats treated at early ages of up to 7 weeks. Cell protection was more prominent in the superior retinal hemisphere which has a slower natural degeneration rate in untreated eyes. Although many of the heat shock proteins and other stress-related genes showed significant elevation in the AAV-Ledgf-treated eyes, all increases were approximately twofold or less. Transduction of retinal cells with Ad-HSP27 also resulted in photoreceptor protection. AAV-Ledgf elicited no photoreceptor functional protection in P23H rhodopsin transgenic rat retina. CONCLUSIONS. Chronic LEDGF treatment via AAV-Ledgf administration gave successful protection of photoreceptors in the RCS rat retina and retarded cell death by about 2 weeks. Induction of heat shock proteins also gave photoreceptor protection. However, compelling evidence was not found that LEDGF protection was associated with upregulation of heat shock proteins. (Invest Ophthalmol Vis Sci. 2009; 50: 3897-3906) DOI: 10.1167/iovs.08-3153 C1 [Bush, Ronald A.] Natl Inst Deafness & Commun Disorders, Sect Translat Res Retinal & Macular Degenerat, NIH, Bethesda, MD 20892 USA. [Sieving, Paul A.] NEI, Off Director, NIH, Bethesda, MD 20892 USA. RP Bush, RA (reprint author), Natl Inst Deafness & Commun Disorders, Sect Translat Res Retinal & Macular Degenerat, NIH, 50 S Dr,Rm 4339,MSC 8021, Bethesda, MD 20892 USA. EM bushr@nidcd.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute on Deafness and Other Communication Disorders; National Eye Institute FX Supported by the Intramural Research Program of the National Institutes of Health, National Institute on Deafness and Other Communication Disorders, and the National Eye Institute. NR 52 TC 16 Z9 17 U1 1 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2009 VL 50 IS 8 BP 3897 EP 3906 DI 10.1167/iovs.08-3153 PG 10 WC Ophthalmology SC Ophthalmology GA 475XA UT WOS:000268398000048 PM 19324854 ER PT J AU Luna, G Kjellstrom, S Verardo, MR Lewis, GP Byun, J Sieving, PA Fisher, SK AF Luna, Gabriel Kjellstrom, Sten Verardo, Mark R. Lewis, Geoffrey P. Byun, Jiyun Sieving, Paul A. Fisher, Steven K. TI The Effects of Transient Retinal Detachment on Cavity Size and Glial and Neural Remodeling in a Mouse Model of X-Linked Retinoschisis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID LEBERS CONGENITAL AMAUROSIS; GENE-THERAPY; JUVENILE RETINOSCHISIS; MICE DEFICIENT; CELLS; PHOTORECEPTOR; DEGENERATION; EXPRESSION; RECOVERY; PROTEIN AB PURPOSE. To determine the cellular consequences of retinal detachment in retinoschisin knockout (Rs1-KO) mice, a model for retinoschisin in humans. METHODS. Experimental retinal detachments (RDs) were induced in the right eyes of both Rs1-KO and wild-type (wt) control mice. Immunocytochemistry was performed on retinal tissue at 1, 7, or 28 days after RD with antibodies to anti-GFAP, -neurofilament, and -rod opsin to examine cellular changes after detachment. Images of the immunostained tissue were captured by laser scanning confocal microscopy. Quantitative analysis was performed to measure the number of Hoechststained photoreceptor nuclei and their density, number, and size of inner retinal cavities, as well as the number of subretinal glial scars. RESULTS. Since detachments were created with balanced salt solution, by examination, all retinas had spontaneously reattached by 1 day. Cellular responses common to many photoreceptor degenerations occurred in the nondetached retinas of Rs1-KO mice, and, of importance, RD did not appear to significantly accentuate these responses. The number of schisis cavities was not changed after detachment, but their size was reduced. CONCLUSIONS. These data indicate that large short-term RD in Rs1-KO mice, followed by a period of reattachment may cause a slight increase in photoreceptor cell death, but detachments do not accentuate the gliosis and neurite sprouting already present and may in fact reduce the size of existing retinal cavities. This finding suggests that performing subretinal injections to deliver therapeutic agents may be a viable option in the treatment of patients with retinoschisis without causing significant cellular damage to the retina. (Invest Ophthalmol Vis Sci. 2009;50:3977-3984) DOI: 10.1167/iovs.08-2910 C1 [Luna, Gabriel; Verardo, Mark R.; Lewis, Geoffrey P.; Fisher, Steven K.] Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA. [Luna, Gabriel; Verardo, Mark R.; Lewis, Geoffrey P.; Byun, Jiyun; Fisher, Steven K.] Univ Calif Santa Barbara, Ctr Bioimage Informat, Santa Barbara, CA 93106 USA. [Fisher, Steven K.] Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA. [Kjellstrom, Sten; Sieving, Paul A.] NIDCD, NEI, NIH, Bethesda, MD USA. [Kjellstrom, Sten] Lund Univ, Dept Ophthalmol, Wallenberg Retina Ctr, Lund, Sweden. RP Fisher, SK (reprint author), Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA. EM fisher@lifesci.ucsb.edu FU National Eye Institute [EY-000888]; National Institutes of Health [ITR-0331697]; National Science Foundation [IIS-0808772]; National Institutes of Health, Intramural Research Program; NCRR Shared Instrumentation [1S10RR017753-01] FX Supported in part by research Grant EY-000888 (SKF) from the National Eye Institute, National Institutes of Health; Grants ITR-0331697 and IIS-0808772 (SKF) from the National Science Foundation; the National Institutes of Health, Intramural Research Program (PAS); and NCRR Shared Instrumentation Grant 1S10RR017753-01. NR 46 TC 7 Z9 8 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2009 VL 50 IS 8 BP 3977 EP 3984 DI 10.1167/iovs.08-2910 PG 8 WC Ophthalmology SC Ophthalmology GA 475XA UT WOS:000268398000058 PM 19387072 ER PT J AU Fuller-Thomson, E Nuru-Jeter, A Minkler, M Guralnik, JM AF Fuller-Thomson, Esme Nuru-Jeter, A. Minkler, Meredith Guralnik, Jack M. TI Black-White Disparities in Disability Among Older Americans Further Untangling the Role of Race and Socioeconomic Status SO JOURNAL OF AGING AND HEALTH LA English DT Article DE African Americans; ethnicity; health inequalities; activities of daily living; functional limitations ID UNITED-STATES; LIFE EXPECTANCY; EDUCATIONAL-DIFFERENCES; PHYSICAL PERFORMANCE; HEALTH INEQUALITIES; FUNCTIONAL DECLINE; ETHNIC-DIFFERENCES; ALLOSTATIC LOAD; SELF-REPORT; AGE AB Objectives: To explore the impact of adjusting for income and education on disparities in functional limitations and limitations in activities of daily living (ADLs) between Black and White older Americans. Method: Data from the 2003 American Community Survey were used to examine the associations of education and income, stratified by race and gender, with functional limitations and ADLs, in a sample of 16,870 non-Hispanic Blacks and 186,086 non-Hispanic Whites aged 55 to 74. Sequential logistic regressions were used to examine the relative contribution of income and education to racial disparities. Results: Ninety percent of the Black-White difference in disability rates for men and 75% of the difference for women aged 55 to 64 were explained by income and education. Discussion: The greatly elevated risk of disability among Blacks aged 55 to 74 is largely explained by differences in socioeconomic status. Reductions in Black-White health disparities require a better understanding of the mechanisms whereby lower income and education are associated with functional outcomes in older persons. C1 [Fuller-Thomson, Esme] Univ Toronto, Fac Social Work, Toronto, ON M5S 1A1, Canada. [Nuru-Jeter, A.; Minkler, Meredith] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Guralnik, Jack M.] NIA, Bethesda, MD 20892 USA. RP Fuller-Thomson, E (reprint author), Univ Toronto, Fac Social Work, 246 Bloor St W, Toronto, ON M5S 1A1, Canada. EM esme.fuller.thomson@utoronto.ca FU Intramural NIH HHS [ZIA AG007460-03] NR 80 TC 30 Z9 30 U1 1 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0898-2643 J9 J AGING HEALTH JI J. Aging Health PD AUG PY 2009 VL 21 IS 5 BP 677 EP 698 DI 10.1177/0898264309338296 PG 22 WC Gerontology; Health Policy & Services SC Geriatrics & Gerontology; Health Care Sciences & Services GA 467AU UT WOS:000267709100002 PM 19584411 ER PT J AU Salo, PM Sever, ML Zeldin, DC AF Salo, Paeivi M. Sever, Michelle L. Zeldin, Darryl C. TI Indoor allergens in school and day care environments SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Allergen; indoor; exposure; asthma; allergy; school; day care ID HOUSE-DUST MITE; URBAN ELEMENTARY-SCHOOLS; F-I ALLERGENS; DER-P-I; FEL D 1; CAT ALLERGEN; RESPIRATORY SYMPTOMS; COCKROACH ALLERGEN; SETTLED DUST; BRONCHIAL REACTIVITY AB Most studies that have examined exposure to indoor allergens have focused on home environments. However, allergen exposures can be encountered in environments other than the home. For example, many children spend a large part of their time in schools and day care facilities. Over the past 2 decades, a large number of studies have been conducted in school and day care environments. However, the role of indoor exposures in allergy and asthma development or morbidity in these settings is not well characterized. The purpose of this review is to evaluate the importance of indoor allergen exposures in school and day care settings. We summarize the key findings from recent scientific literature, describe exposure characteristics, discuss the role of these exposures in relation to asthma and allergy symptoms, and provide information on the effectiveness of published interventions. (J Allergy Clin Immunol 2009;124:185-92.) C1 [Salo, Paeivi M.; Sever, Michelle L.; Zeldin, Darryl C.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), NIEHS, NIH, 111 Alexander Dr,Mail Drop D2-01, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov RI Osborne, Nicholas/N-4915-2015; OI Osborne, Nicholas/0000-0002-6700-2284; Sever, Michelle/0000-0002-2435-1214 FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES025041] FX Supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES025041). NR 86 TC 57 Z9 58 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2009 VL 124 IS 2 BP 185 EP 192 DI 10.1016/j.jaci.2009.05.012 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 482CD UT WOS:000268860400002 PM 19577284 ER PT J AU Gruchalla, RS Sampson, HA Matsui, E David, G Gergen, PJ Calatroni, A Brown, M Liu, AH Bloomberg, GR Chmiel, JF Kumar, R Lamm, C Smartt, E Sorkness, CA Steinbach, SF Stone, KD Szefler, SJ Busse, WW AF Gruchalla, Rebecca S. Sampson, Hugh A. Matsui, Elizabeth David, Gloria Gergen, Peter J. Calatroni, Agustin Brown, Mark Liu, Andrew H. Bloomberg, Gordon R. Chmiel, James F. Kumar, Rajesh Lamm, Carin Smartt, Ernestine Sorkness, Christine A. Steinbach, Suzanne F. Stone, Kelly D. Szefler, Stanley J. Busse, William W. TI Asthma morbidity among inner-city adolescents receiving guidelines-based therapy: Role of predictors in the setting of high adherence SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; exhaled nitric oxide; inner-city; allergic sensitization; airway inflammation; asthma severity ID EXHALED NITRIC-OXIDE; EOSINOPHILIC AIRWAY INFLAMMATION; RANDOMIZED CONTROLLED-TRIAL; DIFFICULT ASTHMA; CHILDREN; SPUTUM; ADULTS; EXACERBATIONS; EXPOSURE; ALLERGEN AB Background: With the expanding effort to provide guidelines-based therapy to adolescents with asthma, attention must be directed to evaluating which factors predict future asthma control when guidelines-based management is applied. Objective: We evaluated the role of fraction of exhaled nitric oxide in parts per billion, markers of allergic sensitization, airway inflammation, and measures of asthma severity in determining future risk of asthma symptoms and exacerbations in adolescents and young adults participating in the Asthma Control Evaluation study. Methods: Five hundred forty-six inner-city residents, ages 12 through 20 years, with persistent asthma were extensively evaluated at study entry for predictors of future symptoms and exacerbations over the subsequent 46 weeks, during which guidelines-based, optimal asthma management was offered. Baseline measurements included fraction of exhaled nitric oxide in parts per billion, total IgE, allergen-specific IgE, allergen skin test reactivity, asthma symptoms, lung function, peripheral blood eosinophils, and, for a subset, airway hyperresponsiveness and sputum eosinophils. Results: The baseline characteristics we examined accounted for only a small portion of the variance for future maximum symptom days and exacerbations-11.4% and 12.6%, respectively. Future exacerbations were somewhat predicted by asthma symptoms, albuterol use, previous exacerbations, and lung function, whereas maximum symptom days were predicted, also to a modest extent, by symptoms, albuterol use, and previous exacerbations, but not lung function. Conclusion: Our findings demonstrate that the usual predictors of future disease activity have little predictive power when applied to a highly adherent population with persistent asthma that is receiving guidelines-based care. Thus, new predictors need to be identified that will be able to measure the continued fluctuation of disease that persists in highly adherent, well-treated populations such as the one studied. (J Allergy Clin Immunol 2009;124:213-21.) C1 [Gruchalla, Rebecca S.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Sampson, Hugh A.] Mt Sinai Sch Med, New York, NY USA. [Matsui, Elizabeth] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [David, Gloria; Calatroni, Agustin] Rho Inc, Chapel Hill, NC USA. [Gergen, Peter J.; Smartt, Ernestine] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD USA. [Brown, Mark] Univ Arizona, Coll Med, Tucson, AZ 85721 USA. [Liu, Andrew H.; Szefler, Stanley J.] Natl Jewish Hlth, Denver, CO USA. [Liu, Andrew H.] Univ Colorado, Hlth Sci Ctr, Boulder, CO 80309 USA. [Bloomberg, Gordon R.] Washington Univ, St Louis, MO USA. [Chmiel, James F.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Kumar, Rajesh] Childrens Mem Hosp, Chicago, IL 60614 USA. [Lamm, Carin] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Steinbach, Suzanne F.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Stone, Kelly D.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Szefler, Stanley J.] Univ Colorado, Denver Sch Med, Boulder, CO 80309 USA. RP Gruchalla, RS (reprint author), Univ Texas SW Med Ctr Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM Rebecca.Gruchalla@utsouthwestern.edu OI Brown, Mark A/0000-0002-4458-6563 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [NO1-Al-25496, NO1-Al-25482]; National Center for Research Resources, National Institutes of Health [RR00052, M01 RR00533, M01RR0071, 5UL1RR024992-02, 5M01RR020359-04] FX Supported in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under contracts NO1-Al-25496 and NO1-Al-25482 and from the National Center for Research Resources, National Institutes of Health, under grants RR00052, M01 RR00533, M01RR0071. 5UL1RR024992-02, and 5M01RR020359-04. NR 42 TC 23 Z9 23 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2009 VL 124 IS 2 BP 213 EP 221 DI 10.1016/j.jaci.2009.05.036 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 482CD UT WOS:000268860400006 PM 19615730 ER PT J AU Clare, BA Conroy, RS Spelman, K AF Clare, Bevin A. Conroy, Richard S. Spelman, Kevin TI The Diuretic Effect in Human Subjects of an Extract of Taraxacum officinale Folium over a Single Day SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Article ID SPONTANEOUSLY HYPERTENSIVE-RATS; NITRIC-OXIDE; CONSEQUENCE; NOCTURIA AB Background: Taraxacum officinale (L.) Weber (Asteraceae) has been extensively employed as a diuretic in traditional folk medicine and in modern phytotherapy in Europe, Asia, and the Americas without prior clinical trial substantiation. Objectives: In this pilot study, a high-quality fresh leaf hydroethanolic extract of the medicinal plant T. officinale (dandelion) was ingested by volunteers to investigate whether an increased urinary frequency and volume would result. Design: Volume of urinary output and fluid intake were recorded by subjects. Baseline values for urinary frequency and excretion ratio (urination volume: fluid intake) were established 2 days prior to dandelion dosing (8 mL TID) and monitored throughout a 1-day dosing period and 24 hours postdosing. Results: For the entire population (n = 17) there was a significant (p < 0.05) increase in the frequency of urination in the 5-hour period after the first dose. There was also a significant (p < 0.001) increase in the excretion ratio in the 5-hour period after the second dose of extract. The third dose failed to change any of the measured parameters. Conclusions: Based on these first human data, T. officinale ethanolic extract shows promise as a diuretic in humans. Further studies are needed to establish the value of this herb for induction of diuresis in human subjects. C1 [Clare, Bevin A.; Spelman, Kevin] Tai Sophia Inst, Dept Herbal Med, Laurel, MD 20723 USA. [Clare, Bevin A.; Spelman, Kevin] Massachusetts Coll Pharm & Hlth Sci, Boston, MA USA. [Conroy, Richard S.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Spelman, Kevin] Univ N Carolina, Dept Chem & Biochem, Greensboro, NC 27412 USA. RP Spelman, K (reprint author), Tai Sophia Inst, Dept Herbal Med, 7750 Montpelier Rd, Laurel, MD 20723 USA. EM phytochemks@gmail.com RI Conroy, Richard/D-1979-2009 OI Conroy, Richard/0000-0002-8896-6090 FU National Research Council Research FX R. C. acknowledges the support of a National Research Council Research Associateship Award, held at National Institute of Neurological Disorders and Stroke. K. S. acknowledges educational support from Tai Sophia Institute. Special thanks to Oregon Wild Harvest for providing the Taraxacum extract and Matthew Creswell for providing the TLC data. In addition, special thanks are owed to Jerry Cott, Kimberly Duncan, Steven Dentali, Simon Mills, Dorena Rode, and James Snow for editorial commentary. NR 33 TC 20 Z9 20 U1 5 U2 12 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1075-5535 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD AUG PY 2009 VL 15 IS 8 BP 929 EP 934 DI 10.1089/acm.2008.0152 PG 6 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 483BK UT WOS:000268936600017 PM 19678785 ER PT J AU Thorpe, JM Van Houtven, CH Sleath, BL AF Thorpe, Joshua M. Van Houtven, Courtney Harold Sleath, Betsy L. TI Barriers to Outpatient Care in Community-Dwelling Elderly With Dementia The Role of Caregiver Life Satisfaction SO JOURNAL OF APPLIED GERONTOLOGY LA English DT Article DE access; outpatient care; caregivers; dementia; mental health ID QUALITY-OF-LIFE; MANAGING ALZHEIMERS-DISEASE; CONTROLLED-TRIAL; OLDER-ADULTS; PHYSICIANS PERSPECTIVES; PSYCHOLOGICAL DISTRESS; FAMILY CAREGIVERS; HUMAN-SERVICES; MEDICAL-CARE; HEALTH-CARE AB The purpose of this study was to examine the relationship between informal care-giver life satisfaction and receipt of outpatient medical care in persons with dementia. We obtained data from the National Longitudinal Caregiver Survey (NLCS), a survey of 1,269 veterans with dementia and their primary informal caregivers. NLCS data were merged with 12 months of Veteran Administration outpatient claims. Outpatient visits were classified as (a) primary, (b) specialty, or (c) mental health care. Greater levels of caregiver-reported life dissatisfaction were associated with decreased likelihood of care-recipient outpatient visits for both primary and mental health care. In addition, we found that care-recipients with African American caregivers were less likely to receive a mental health visit, and those coresiding with their caregiver were more likely to receive a specialty care visit. Our findings suggest that low caregiver life satisfaction may signal an impending breakdown in care-recipients' access to primary and mental health care. C1 [Thorpe, Joshua M.] Univ Wisconsin, Sch Pharm, Div Social & Adm Sci, Madison, WI 53706 USA. [Van Houtven, Courtney Harold] Duke Univ, Med Ctr, Durham, NC USA. [Sleath, Betsy L.] Univ N Carolina, Sch Pharm, Chapel Hill, NC USA. [Thorpe, Joshua M.] NIA, Bethesda, MD 20892 USA. [Van Houtven, Courtney Harold] Durham Vet Adm, Durham, NC USA. [Sleath, Betsy L.] NHLBI, Bethesda, MD 20892 USA. RP Thorpe, JM (reprint author), Univ Wisconsin, Sch Pharm, Div Social & Adm Sci, Madison, WI 53706 USA. EM thorpe2@wisc.edu RI Thorpe, Joshua/C-1188-2013 NR 49 TC 3 Z9 3 U1 2 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0733-4648 J9 J APPL GERONTOL JI J. Appl. Gerontol. PD AUG PY 2009 VL 28 IS 4 BP 436 EP 460 DI 10.1177/0733464808328605 PG 25 WC Gerontology SC Geriatrics & Gerontology GA 470HH UT WOS:000267965300003 ER PT J AU Kaufman, DR Pevzner, J Rodriguez, M Cimino, JJ Ebner, S Fields, L Moreno, V McGuiness, C Weinstock, RS Shea, S Starren, J AF Kaufman, David R. Pevzner, Jenia Rodriguez, Martha Cimino, James J. Ebner, Susana Fields, Lesley Moreno, Vilma McGuiness, Christina Weinstock, Ruth S. Shea, Steven Starren, Justin TI Understanding workflow in telehealth video visits: Observations from the IDEATel project SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Telemedicine; Workflow; Distributed cognition; Nurse case manager; Video analysis; Communication modalities; Diabetes; Interaction design ID COLUMBIA-UNIVERSITY INFORMATICS; DISTRIBUTED COGNITION; DIABETES MANAGEMENT; ETHNICALLY DIVERSE; TELEMEDICINE; CARE; USABILITY; EDUCATION; MELLITUS AB Home telemedicine is an emerging healthcare paradigm that has the potential to transform the treatment of chronic illness. The purpose of this paper is to: (I) develop a theoretical and methodological framework for studying workflow in telemediated clinician-patient encounters drawing on a distributed cognition approach and (2) employ the framework in an in-depth analysis of workflow in the IDEATel project, a telemedicine program for older adults with diabetes. The methods employed in this research included (a) videotaped observations of 27 nurse-patient encounters and (b) semi-structured interviews with participants. The analyses were used to provide a descriptive analysis of video visits, understand the mediating role of different technologies and to characterize the ways in which artifacts and representations are used to understand the state of the patient. The study revealed barriers to productive use of telehealth technology as well as adaptations that circumvented such limitations. This research has design implications for: (a) improving the coordination of communication and (b) developing tools that better integrate and display information. Although home telemedicine programs will differ in important respects. there are invariant properties across such systems. Explicating these properties can serve as a needs requirement analysis to develop more effective systems and implementation plans. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kaufman, David R.; Pevzner, Jenia; Rodriguez, Martha; Cimino, James J.] Columbia Univ, Dept Biomed Informat, New York, NY 10027 USA. [Cimino, James J.] NIH, Ctr Clin, Lab Informat Dev, Bethesda, MD 20892 USA. [Ebner, Susana] Columbia Univ, Naomi Berrie Diabet Ctr, New York, NY USA. [Weinstock, Ruth S.] SUNY Upstate Med Univ, Vet Affairs Med Ctr, Joslin Diabet Ctr, Dept Med, Syracuse, NY USA. [Shea, Steven] Columbia Univ, Joseph Mailman Sch Publ Hlth, Dept Med, New York, NY USA. [Shea, Steven] Columbia Univ, Joseph Mailman Sch Publ Hlth, Dept Publ Hlth, New York, NY USA. [Starren, Justin] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA. RP Kaufman, DR (reprint author), Columbia Univ, Dept Biomed Informat, New York, NY 10027 USA. EM davek@dbmi.columbia.edu OI Cimino, James/0000-0003-4101-1622 FU National Library of Medicine [LM007663-OIA2]; Centers for Medicare and Medicaid Services [95-C-90998] FX The research described in this paper was partially supported by a grant from the National Library of Medicine to Justin Starren (LM007663-OIA2) and a Cooperative Agreement from Centers for Medicare and Medicaid Services to Steven Shea (95-C-90998). In addition, we acknowledge the IDEATel consortium (www.ideatel.org/acknowledgei-nent.html). We thank Jessica Ancker, Connie Chan, Albert Lai, Lisa Matthews, Yalini Senathirajah and anonymous reviewers for constructive comments on earlier versions of the manuscript. NR 29 TC 7 Z9 8 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 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD AUG PY 2009 VL 42 IS 4 BP 581 EP 592 DI 10.1016/j.jbi.2009.03.012 PG 12 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 468UB UT WOS:000267846800001 PM 19358897 ER PT J AU Shen, Y Delaglio, F Cornilescu, G Bax, A AF Shen, Yang Delaglio, Frank Cornilescu, Gabriel Bax, Ad TI TALOS plus : a hybrid method for predicting protein backbone torsion angles from NMR chemical shifts SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Heteronuclear chemical shift; Secondary structure; Order parameter; Dynamics; TALOS ID SECONDARY STRUCTURE; SEQUENCE HOMOLOGY; SOLID-STATE; NEURAL-NETWORKS; 82-KDA ENZYME; C-13 NMR; ASSIGNMENT; SPECTROSCOPY; C-13(ALPHA); DATABASE AB NMR chemical shifts in proteins depend strongly on local structure. The program TALOS establishes an empirical relation between (13)C, (15)N and (1)H chemical shifts and backbone torsion angles I center dot and psi (Cornilescu et al. J Biomol NMR 13 289-302, 1999). Extension of the original 20-protein database to 200 proteins increased the fraction of residues for which backbone angles could be predicted from 65 to 74%, while reducing the error rate from 3 to 2.5%. Addition of a two-layer neural network filter to the database fragment selection process forms the basis for a new program, TALOS+, which further enhances the prediction rate to 88.5%, without increasing the error rate. Excluding the 2.5% of residues for which TALOS+ makes predictions that strongly differ from those observed in the crystalline state, the accuracy of predicted I center dot and psi angles, equals +/- 13A degrees. Large discrepancies between predictions and crystal structures are primarily limited to loop regions, and for the few cases where multiple X-ray structures are available such residues are often found in different states in the different structures. The TALOS+ output includes predictions for individual residues with missing chemical shifts, and the neural network component of the program also predicts secondary structure with good accuracy. C1 [Shen, Yang; Delaglio, Frank; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Cornilescu, Gabriel] Natl Magnet Resonance Facil, Madison, WI 53706 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov RI Shen, Yang/C-3064-2008; Cornilescu, Gabriel/H-3113-2011 OI Shen, Yang/0000-0003-1408-8034; Cornilescu, Gabriel/0000-0002-1204-8904 FU Intramural Research Program of the NIDDK; NIH; NIH [P41RR02301, P41GM66326] FX We thank Alex Grishaev for carrying out the MSG calculation with the new TALOS? backbone angle restraints. This work was funded by the Intramural Research Program of the NIDDK, NIH. G. C. was supported by NIH grants P41RR02301 (BRTP/NCRR) and P41GM66326 (NIGMS) NR 47 TC 1183 Z9 1187 U1 10 U2 107 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD AUG PY 2009 VL 44 IS 4 BP 213 EP 223 DI 10.1007/s10858-009-9333-z PG 11 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 474VG UT WOS:000268311800005 PM 19548092 ER PT J AU Ahmet, I Kapoor, K Lakatta, EG Talan, MI AF Ahmet, Ismayil Kapoor, Kapil Lakatta, Edward G. Talan, Mark I. TI Effect of GLP-1 Receptor Agonist on Acute Myocardial Infarction and Post-MI Chronic Heart Failure in Rats SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 13th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 13-16, 2009 CL Boston, MA SP Heart Failure Soc Amer C1 [Ahmet, Ismayil; Kapoor, Kapil; Lakatta, Edward G.; Talan, Mark I.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2009 VL 15 IS 6 MA 238 BP S72 EP S73 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 482OC UT WOS:000268897500236 ER PT J AU Chang, PP Rosamond, WD Shahar, E Bertoni, AG Russell, SD Samdarshi, T Mosley, TH Ni, HY Wagenknecht, LF Chambless, LE AF Chang, Patricia P. Rosamond, Waync D. Shahar, Eyal Bertoni, Alain G. Russell, Stuart D. Samdarshi, Tandaw Mosley, Thomas H. Ni, Hanyu Wagenknecht, Lynne F. Chambless, Lloyd E. TI Incidence of Hospitalized Acute Decompensated Heart Failure in Four US Communities: The Atherosclerosis Risk in Communities (ARIC) Study SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 13th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 13-16, 2009 CL Boston, MA SP Heart Failure Soc Amer C1 [Chang, Patricia P.; Rosamond, Waync D.; Chambless, Lloyd E.] Univ N Carolina, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Shahar, Eyal] Univ Arizona, Tucson, AZ USA. [Bertoni, Alain G.; Wagenknecht, Lynne F.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Russell, Stuart D.] Johns Hopkins Univ, Baltimore, MD USA. [Samdarshi, Tandaw; Mosley, Thomas H.] Univ Mississippi, Jackson, MS 39216 USA. [Ni, Hanyu] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2009 VL 15 IS 6 MA 268 BP S81 EP S81 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 482OC UT WOS:000268897500266 ER PT J AU Farasat, SM Bolger, DT Shetty, V Menachery, EP Gerstenblith, G Kasper, EK Najjar, SS AF Farasat, S. Morteza Bolger, Dennis T. Shetty, Veena Menachery, Elizabeth P. Gerstenblith, Gary Kasper, Edward K. Najjar, Samer S. TI beta-Blocker Therapy Is Associated with Increased Re-Hospitalization for Heart Failure in Women with Heart Failure and Preserved Ejection Fraction SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 13th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 13-16, 2009 CL Boston, MA SP Heart Failure Soc Amer C1 [Farasat, S. Morteza; Shetty, Veena] NIA ASTRA Harbor Hosp, MedStar Res Inst, Baltimore, MD USA. [Bolger, Dennis T.; Menachery, Elizabeth P.; Gerstenblith, Gary; Kasper, Edward K.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Najjar, Samer S.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2009 VL 15 IS 6 MA 362 BP S108 EP S108 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 482OC UT WOS:000268897500360 ER PT J AU Gottlieb, JD Schwartz, A Najjar, SS Gottlieb, SS AF Gottlieb, Joshua D. Schwartz, Alan Najjar, Samer S. Gottlieb, Stephen S. TI Hypoxia, Not the Frequency of Sleep Apnea, Causes Acute Hemodynamic Stress in Patients with Congestive Heart Failure SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 13th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 13-16, 2009 CL Boston, MA SP Heart Failure Soc Amer C1 [Gottlieb, Joshua D.] Harvard Univ, Cambridge, MA 02138 USA. [Schwartz, Alan] Johns Hopkins Univ, Bayview Med Ctr, Baltimore, MD USA. [Najjar, Samer S.] NIA, Baltimore, MD 21224 USA. [Gottlieb, Stephen S.] Univ Maryland, Baltimore, MD 21201 USA. OI Gottlieb, Joshua/0000-0001-8730-0468 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2009 VL 15 IS 6 MA 030 BP S12 EP S13 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 482OC UT WOS:000268897500031 ER PT J AU Reed, SD Whellan, DJ Li, YH Friedman, JY Pina, IL Settles, SJ Davidson-Ray, L Johnson, J Cooper, LS O'Connor, CM Schulman, KA AF Reed, Shelby D. Whellan, David J. Li, Yanhong Friedman, Joelle Y. Pina, Ileana L. Settles, Sharon J. Davidson-Ray, Linda Johnson, Johanna Cooper, Lawton S. O'Connor, Christopher M. Schulman, Kevin A. TI Cost of Exercise Training and Its Impact on Medical Resource Use and Costs: Results of HF-ACTION SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 13th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 13-16, 2009 CL Boston, MA SP Heart Failure Soc Amer C1 [Reed, Shelby D.; Li, Yanhong; Friedman, Joelle Y.; Settles, Sharon J.; Davidson-Ray, Linda; Johnson, Johanna; O'Connor, Christopher M.; Schulman, Kevin A.] Duke Clin Res Inst, Durham, NC USA. [Whellan, David J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Pina, Ileana L.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Cooper, Lawton S.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2009 VL 15 IS 6 MA 307 BP S93 EP S93 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 482OC UT WOS:000268897500305 ER PT J AU Giallauria, F Cirillo, P Lucci, R Pacileo, M D'Agostino, M Maietta, P Vitelli, A Chiariello, M Vigorito, C AF Giallauria, Francesco Cirillo, Plinio Lucci, Rosa Pacileo, Mario D'Agostino, Mariantonietta Maietta, Paola Vitelli, Alessandra Chiariello, Massimo Vigorito, Carlo TI Effects of exercise-based cardiac rehabilitation on high mobility group box-1 levels after acute myocardial infarction: rationale and design SO JOURNAL OF CARDIOVASCULAR MEDICINE LA English DT Article DE cardiac rehabilitation; cardiac remodeling; exercise training; high-mobility group box-1; myocardial infarction ID LEFT-VENTRICULAR DYSFUNCTION; HEART-RATE RECOVERY; SECONDARY PREVENTION; PROTEIN HMGB1; TRIAL; RECOMMENDATIONS; QUANTIFICATION; DISEASE; CELLS AB Background High-mobility group box-1 (HMGB1) is a ubiquitous nuclear protein recently recognized as a critical mediator of inflammatory processes. HMGB1 is a novel predictor of adverse postinfarction clinical outcomes, playing a crucial role in the appropriate healing process after myocardial infarction (MI). The present trial is designed in order to reveal the postinfarction HMGB1 expression pattern and its relationship with cardiac remodeling. The effects of an exercise-based cardiac rehabilitation program on HMGB1 expression pattern will be addressed as well. Design Single-center, randomized, controlled study carried out at a university hospital. Methods Postinfarction patients are randomized into a training group (enrolled in a 6-month exercise-based cardiac rehabilitation program) and into a control group. HMGB1 levels are evaluated by enzyme-linked immunosorbent assay. Results Postinfarction patients are enrolled from September 2008 through December 2009. Results will be available in mid-2010. Conclusion Despite the importance of the inflammatory response and healing process in postinfarction left ventricular remodeling, the mechanisms that initiate and control these processes remain to be elucidated. The rationale and design of the present study is designed to test the postinfarction HMGB1 expression pattern and its relationship with cardiac remodeling as well as the effects of an exercise-based cardiac rehabilitation program. J Cardiovasc Med 10:659-663 (C) 2009 Italian Federation of Cardiology. C1 [Giallauria, Francesco; Lucci, Rosa; D'Agostino, Mariantonietta; Vitelli, Alessandra] Univ Naples Federico 2, Dept Clin Med Cardiovasc & Immunol Sci, Cardiac Rehabil Unit, Naples, Italy. [Giallauria, Francesco] Harbor Hosp, NIA, NIH, Longitudinal Studies Sect,Clin Res Branch, Baltimore, MD USA. [Cirillo, Plinio; Pacileo, Mario; Maietta, Paola; Chiariello, Massimo; Vigorito, Carlo] Univ Naples Federico 2, Dept Clin Med Cardiovasc & Immunol Sci, Div Cardiol, Naples, Italy. RP Giallauria, F (reprint author), Univ Naples Federico 2, Dept Clin Med Cardiovasc & Immunol Sci, Cardiac Rehabil Unit, Naples, Italy. EM giallauria@libero.it RI Giallauria, Francesco/B-5681-2013; OI Giallauria, Francesco/0000-0003-4119-9397; CIRILLO, Plinio/0000-0001-7818-4952 FU University of Naples; NIH; National Institute on Aging FX This research is supported by University of Naples 'Federico II' and in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 28 TC 6 Z9 6 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1558-2027 J9 J CARDIOVASC MED JI J. Cardiovasc. Med. PD AUG PY 2009 VL 10 IS 8 BP 659 EP 663 DI 10.2459/JCM.0b013e32832d4979 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 475LL UT WOS:000268360500013 PM 19451831 ER PT J AU Reddy, AJ Christie, JD Aplenc, R Fuchs, B Lanken, PN Kleeberger, SR AF Reddy, Anita J. Christie, Jason D. Aplenc, Richard Fuchs, Barry Lanken, Paul N. Kleeberger, Steven R. TI Association of human NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphism with development of acute lung injury SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE gene; susceptibility; ARDS; acute respiratory distress syndrome; hyperoxia; endotoxin; hydrogen peroxide; oxidant stress; SNP; single nucleotide polymorphism; lung disease ID RESPIRATORY-DISTRESS-SYNDROME; SUPEROXIDE SCAVENGER; GENE-EXPRESSION; DT-DIAPHORASE; CELLS; PROTECTION; ARDS; ANTIOXIDANTS; INDUCTION; MECHANISM AB Acute lung injury (ALI) is a syndrome with significant morbidity and mortality, but its genetic susceptibility is not clearly understood. In the present study, we characterized functional promoter single nucleotide polymorphisms (SNPs) in the phase II antioxidant gene NQO1 (NAD(P)H:quinone oxidoreductase1) to evaluate its role in susceptibility to ALI. Three previously uncharacterized SNPs in the NQO1 promoter were selected for investigation. Luciferase assays were performed using constructs of each promoter polymorphism to evaluate function. Functional SNPs were genotyped in a prospective cohort of major trauma patients (N = 264) and assessed for association with development of ALI. The A/C SNP at -1221 decreased in vitro transcription of NQO1 at baseline and after exposure to hyperoxia and other oxidant stressors. Patients heterozygous for the -1221 C allele were at significantly lesser risk of ALI after major trauma compared with patients with wild-type alleles, even after adjustment for APACHE III score, and mechanism of trauma [OR, 0.46 (95% CI 0.23, 0.90); P = 0.024]. This study demonstrated that the AC genotype at position -1221 in the NQO1 gene caused decreased transcription and was associated with a lower incidence of ALI following major trauma. These novel findings may have important implications in diseases with oxidant stress aetiologies. C1 [Reddy, Anita J.; Kleeberger, Steven R.] NIEHS, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Reddy, Anita J.] Duke Univ, Med Ctr, Dept Med, Div Pulm Allergy & Crit Care Med, Durham, NC 27710 USA. [Christie, Jason D.; Fuchs, Barry; Lanken, Paul N.] Univ Penn, Sch Med, Dept Med, Div Pulm & Crit Care Med, Philadelphia, PA 19104 USA. [Aplenc, Richard] Childrens Hosp Philadelphia, Div Hematol & Oncol, Philadelphia, PA 19104 USA. RP Kleeberger, SR (reprint author), NIEHS, Lab Resp Biol, 111 TW Alexander Dr,Bldg 101,Rm D240, Res Triangle Pk, NC 27709 USA. EM kleeber1@niehs.nih.gov FU Doris Duke Charitable Foundation; Intramural Program at the National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services; [P50 HL60290-01]; [K23 HL04243] FX This study was supported by P50 HL60290-01 (JC, PL), K23 HL04243 (JC), the Doris Duke Charitable Foundation (RA), and the Intramural Program at the National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services (AR, SK). We thank Dr. Hye-Youn Cho, Dr. Xuting Wang, Ms Jacqui Marzec and Mr. Wes Gladwell for assistance with the investigation. We also thank Drs. Donald Cook and Michael Fessler for reviewing the manuscript. Conflict of Interest statement. The authors declare that they have no competing financial interests. NR 29 TC 15 Z9 15 U1 0 U2 0 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 AUG PY 2009 VL 13 IS 8B BP 1784 EP 1791 DI 10.1111/j.1582-4934.2008.00581.x PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 525CN UT WOS:000272190800016 PM 19017358 ER PT J AU Provenzano, M Sais, G Bracci, L Egli, A Anselmi, M Viehl, CT Schaub, S Hirsch, HH Stroncek, DF Marincola, FM Spagnoli, GC AF Provenzano, Maurizio Sais, Giovanni Bracci, Laura Egli, Adrian Anselmi, Maurizio Viehl, Carsten T. Schaub, Stefan Hirsch, Hans H. Stroncek, David F. Marincola, Francesco M. Spagnoli, Giulio C. TI A HCMV pp65 polypeptide promotes the expansion of CD4+and CD8+T cells across a wide range of HLA specificities SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE peptide cross-presentation; immunotherapy; vaccine ID CYTOTOXIC T-LYMPHOCYTES; REAL-TIME PCR; MHC CLASS-II; HUMAN CYTOMEGALOVIRUS; DENDRITIC CELLS; CMV INFECTION; COSTIMULATORY MOLECULES; TRANSPLANT RECIPIENTS; MELANOMA PATIENTS; IMMUNE-RESPONSES AB Human cytomegalovirus (HCMV) can cause life-threatening disease in infected hosts. Immunization with human leukocyte antigen (HLA)-restricted immunodominant synthetic peptides and adoptive transfer of epitope-specific T cells have been envisaged to generate or boost HCMV-specific cellular immunity, thereby preventing HCMV infection or reactivation. However, induction or expansion of T cells effective against HCMV are limited by the need of utilizing peptides with defined HLA restrictions. We took advantage of a combination of seven predictive algorithms to identify immunogenic peptides of potential use in the prevention or treatment of HCMV infection or reactivation. Here we describe a pp65-derived peptide (pp65(340-355), RQYDPVAALFFFDIDL: RQY16-mer), characterized by peculiar features. First, RQY-16mer is able to stimulate HCMV pp65 specific responses in both CD4+ and CD8+ T cells, restricted by a wide range of HLA class I and II determinants. Second, RQY-16mer is able to induce an unusually wide range of effector functions in CD4+ T cells, including proliferation, killing of autologous HCMV-infected target cells and cytokine production. Third, and most importantly, the RQY-16mer is able to stimulate CD4+ and CD8+ T-cell responses in pharmacologically immunosuppressed patients. These data suggest that a single reagent might qualify as synthetic immunogen for potentially large populations exposed to HCMV infection or reactivation. C1 [Provenzano, Maurizio; Sais, Giovanni; Bracci, Laura; Anselmi, Maurizio; Viehl, Carsten T.; Spagnoli, Giulio C.] Univ Basel Hosp, Inst Surg Res & Hosp Management, Basel, Switzerland. [Provenzano, Maurizio; Sais, Giovanni; Bracci, Laura; Anselmi, Maurizio; Viehl, Carsten T.; Spagnoli, Giulio C.] Univ Basel Hosp, Dept Biomed, Basel, Switzerland. [Egli, Adrian; Hirsch, Hans H.] Univ Basel, Inst Med Microbiol, CH-4003 Basel, Switzerland. [Schaub, Stefan] Univ Basel Hosp, Dept Transplantat Immunol & Nephrol, Basel, Switzerland. [Stroncek, David F.; Marincola, Francesco M.] NIH, Dept Transfus Med, Infect Dis & Immunogenet Sect, Ctr Clin, Bethesda, MD 20892 USA. RP Provenzano, M (reprint author), Univ Zurich Hosp, Dept Urol, Frauenklin Str 10, CH-8091 Zurich, Switzerland. EM Maurizio.provenzano@usz.ch RI BRACCI, LAURA/J-8777-2016 OI BRACCI, LAURA/0000-0002-2535-4353 FU Swiss National Funds for Scientific Research FX This work was partially supported by a grant from Swiss National Funds for Scientific Research to Giulio C Spagnoli. Cell-free endotheliotrophic (HUVEC) HCMV VR1814 strain and the goat anti-IE72 mAb were provided by G. Gerna (Policlinico San Matteo, Pavia, Italy). Recombinant human IL-4 and IL-6 were a gift of A. Lanzavecchia (Institute for Research in Biomedicine, Bellinzona, Switzerland). Recombinant human GM-CSF was a gift from the Laboratorio Pablo Cassara', Buenos Aires, Argentina. NR 54 TC 5 Z9 5 U1 0 U2 4 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 AUG PY 2009 VL 13 IS 8B BP 2131 EP 2147 DI 10.1111/j.1582-4934.2008.00531.x PG 17 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 525CN UT WOS:000272190800047 PM 19604317 ER PT J AU Rajesh, M Mukhopadhyay, P Batkai, S Mukhopadhyay, B Patel, V Hasko, G Szabo, C Mabley, JG Liaudet, L Pacher, P AF Rajesh, Mohanraj Mukhopadhyay, Partha Batkai, Sandor Mukhopadhyay, Bani Patel, Vivek Hasko, Gyoergy Szabo, Csaba Mabley, Jon G. Liaudet, Lucas Pacher, Pal TI Xanthine oxidase inhibitor allopurinol attenuates the development of diabetic cardiomyopathy SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE oxidative stress; diabetic cardiomyopathy; iNOS; peroxynitrite; fibrosis ID INDUCED HEART-FAILURE; ENDOTHELIAL DYSFUNCTION; POLY(ADP-RIBOSE) POLYMERASE; DILATED CARDIOMYOPATHY; NITROSATIVE STRESS; OXIDATIVE STRESS; NITRIC-OXIDE; PEROXYNITRITE; COMPLICATIONS; DISEASE AB In this study, we investigated the effect of the xanthine oxidase (XO) inhibitor, allopurinol (ALP), on cardiac dysfunction, oxidative-nitrosative stress, apoptosis, poly(ADP-ribose) polymerase (PARP) activity and fibrosis associated with diabetic cardiomyopathy in mice. Diabetes was induced in C57/BL6 mice by injection of streptozotocin. Control and diabetic animals were treated with ALP or placebo. Left ventricular systolic and diastolic functions were measured by pressure-volume system 10 weeks after established diabetes. Myocardial XO, p22phox, p40phox, p47phox, gp91phox, iNOS, eNOS mRNA and/or protein levels, ROS and nitrotyrosine (NT) formation, caspase3/7 and PARP activity, chromatin fragmentation and various markers of fibrosis (collagen-1, TGF-beta, CTGF, fibronectin) were measured using molecular biology and biochemistry methods or immunohistochemistry. Diabetes was characterized by increased myocardial, liver and serum XO activity (but not expression), increased myocardial ROS generation, p22phox, p40phox, p47phox, p91phox mRNA expression, iNOS (but not eNOS) expression, NT generation, caspase 3/7 and PARP activity/expression, chromatin fragmentation and fibrosis (enhanced accumulation of collagen, TGF-beta, CTGF and fibronectin), and declined systolic and diastolic myocardial performance. ALP attenuated the diabetes-induced increased myocardial, liver and serum XO activity, myocardial ROS, NT generation, iNOS expression, apoptosis, PARP activity and fibrosis, which were accompanied by improved systolic (measured by the evaluation of both load-dependent and independent indices of myocardial contractility) and diastolic performance of the hearts of treated diabetic animals. Thus, XO inhibition with ALP improves type 1 diabetes-induced cardiac dysfunction by decreasing oxidative/nitrosative stress and fibrosis, which may have important clinical implications for the treatment and prevention of diabetic cardiomyopathy and vascular dysfunction. C1 [Rajesh, Mohanraj; Mukhopadhyay, Partha; Batkai, Sandor; Mukhopadhyay, Bani; Patel, Vivek; Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, Rockville, MD 20852 USA. [Hasko, Gyoergy] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Szabo, Csaba] Univ Texas Galveston, Dept Anesthesiol, Galveston, TX 77555 USA. [Mabley, Jon G.] Univ Brighton, Sch Pharm & Biomol Sci, Brighton, E Sussex, England. [Liaudet, Lucas] Univ Lausanne Hosp, Dept Intens Care Med, Lausanne, Switzerland. RP Pacher, P (reprint author), NIAAA, Sect Oxidat Stress & Tissue Injury, NIH, 5625 Fishers Lane,MSC 9413,Room 2N-17, Rockville, MD 20852 USA. EM pacher@mail.nih.gov RI MUKHOPADHYAY, PARTHA/G-3890-2010; Mabley, Jon/D-2296-2010; Batkai, Sandor/G-3889-2010; Pacher, Pal/B-6378-2008; Batkai, Sandor/H-7983-2014; Liaudet, Lucas/E-1322-2017 OI MUKHOPADHYAY, PARTHA/0000-0002-1178-1274; Pacher, Pal/0000-0001-7036-8108; Liaudet, Lucas/0000-0003-2670-4930 FU Intramural Research Program of the NIH/NIAAA FX This study was supported by Intramural Research Program of the NIH/NIAAA to P.P. NR 44 TC 33 Z9 33 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD AUG PY 2009 VL 13 IS 8B BP 2330 EP 2341 DI 10.1111/j.1582-4934.2008.00564.x PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 525CN UT WOS:000272190800064 PM 19175688 ER PT J AU Davani, B Ariely, S Ikonomou, L Oron, Y Gershengorn, MC AF Davani, Behrous Ariely, Sahar Ikonomou, Laertis Oron, Yoram Gershengorn, Marvin C. TI Human islet-derived precursor cells can cycle between epithelial clusters and mesenchymal phenotypes SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE mesenchymal progenitor cells; pancreatic islets; cell proliferation; epithelial and mesenchymal markers ID PANCREATIC BETA-CELLS; IN-VITRO DEDIFFERENTIATION; STEM-CELLS; PROGENITOR CELLS; BREAST-CANCER; STROMAL CELLS; TRANSITION; EXPRESSION; EXPANSION; VIMENTIN AB We showed previously that undifferentiated, proliferating human islet-derived precursor cells (hIPCs) are a type of mesenchymal stem/stromal cell (MSC) that can be induced by serum deprivation to form clusters and ultimately differentiate in vitro to endocrine cells. We also demonstrated that partially differentiated hIPC clusters, when implanted under the kidney capsules of mice, continued to differentiate in vivo into hormone-producing cells. However, we noted that not all hIPC preparations yielded insulin-secreting cells in vivo and that in some animals no hormone-expressing cells were found. This suggested that the implanted cells were not always irreversibly committed to further differentiation and may even de-differentiate to a mesenchymal phenotype. In this study, we show that human cells with a mesenchymal phenotype are indeed found in the grafts of mice implanted with hIPCs in epithelial cell clusters (ECCs), which are obtained after 4-day in vitro culture of hIPCs in serum-free medium (SFM); mesenchymal cells were predominant in some grafts. We could mimic the transition of ECCs to de-differentiated mesenchymal cells in vitro by exposure to foetal bovine serum (FBS) or mouse serums, and to a significantly lesser extent to human serum. In a complementary series of experiments, we show that mouse serum and FBS are more effective stimulants of mesenchymal hIPC migration than is human serum. We found that proliferation was not needed for the transition from ECCs to de-differentiated cells because mitomycin-treated hIPCs that could not proliferate underwent a similar transition. Lastly, we show that cells exhibiting a mesenchymal phenotype can be found in grafts of adult human islets in mice. We conclude that epithelial-to-mesenchymal transition (EMT) of cells in hIPC ECCs can occur following implantation in mice. This potential for EMT of human islets or differentiated precursor cells must be considered in strategies for cell replacement therapy for diabetes. C1 [Davani, Behrous; Ariely, Sahar; Ikonomou, Laertis; Gershengorn, Marvin C.] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Ariely, Sahar; Oron, Yoram] Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, Ramat Aviv, Israel. RP Gershengorn, MC (reprint author), NIDDK, Clin Endocrinol Branch, NIH, 9000 Rockville Pike,Bldg 50-4126, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov RI Ikonomou, Laertis/D-4579-2009 OI Ikonomou, Laertis/0000-0003-0993-6713 FU NIDDK; National Institutes of Health; Juvenile Diabetes Research Foundation FX This work was supported by the Intramural Research Program of the NIDDK, National Institutes of Health, and in part by a grant of the Juvenile Diabetes Research Foundation to Y.O. We are grateful to Bruce M. Raaka and Elizabeth Geras-Raaka, NIDDK, for suggestions and critical reading of this manuscript. This work constitutes a partial fulfillment for Ph.D. thesis requirements of S.A. at the Sackler Faculty of Medicine, Tel Aviv University. NR 45 TC 7 Z9 7 U1 0 U2 8 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 AUG PY 2009 VL 13 IS 8B BP 2570 EP 2581 DI 10.1111/j.1582-4934.2008.00570.x PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 525CN UT WOS:000272190800082 PM 19175683 ER PT J AU McCarroll, EM Lindsey, EW MacKinnon-Lewis, C Chambers, JC Frabutt, JM AF McCarroll, Elizabeth M. Lindsey, Eric W. MacKinnon-Lewis, Carol Chambers, Jessica Campbell Frabutt, James M. TI Health Status and Peer Relationships in Early Adolescence: The Role of Peer Contact, Self-esteem, and Social Anxiety SO JOURNAL OF CHILD AND FAMILY STUDIES LA English DT Article DE Health status; Peer relationships; Self-esteem; Social anxiety; Early adolescence ID JUNIOR-HIGH-SCHOOL; CHRONIC ILLNESS; PSYCHOLOGICAL ADJUSTMENT; CHRONICALLY ILL; CHILDREN; AGGRESSION; TRANSITION; CHILDHOOD; SUPPORT; GENDER AB We examined associations between children's health status and the quality of their peer relationships, as well as factors that may account for individual variation in the quality of chronically ill and healthy children's peer relationships. Our sample included 268 children (138 boys; 130 girls) with 149 European-Americans and 119 African-Americans. There were 91 children with a chronic illness; 35 with asthma, 26 with diabetes, and 30 with obesity. Chronically ill children were characterized by teachers as displaying less prosocial behavior, less overt aggression, and less relational aggression with peers than healthy children. Chronically ill children reported lower levels of peer contact and higher levels of social anxiety than healthy children. Among chronically ill children those with high self-esteem were more prosocial and less aggressive than those with low self-esteem. Our findings suggest that chronically ill children are at risk for peer relationship difficulties, but that self-esteem may serve as a protective factor against poor peer relationships for some chronically ill children. C1 [Lindsey, Eric W.] Penn State Berks, Appl Psychol Program, Reading, PA 19610 USA. [McCarroll, Elizabeth M.] Texas Womens Univ, Dept Family Sci, Denton, TX 76204 USA. [MacKinnon-Lewis, Carol] Univ S Florida, Dept Child & Family Studies, Tampa, FL USA. [Chambers, Jessica Campbell] Natl Inst Drug Abuse, Bethesda, MD USA. [Frabutt, James M.] Univ Notre Dame, ACE Leadership Program, Notre Dame, IL USA. RP Lindsey, EW (reprint author), Penn State Berks, Appl Psychol Program, 7009 Tulpehocken Rd, Reading, PA 19610 USA. EM ewl10@psu.edu NR 41 TC 14 Z9 16 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1062-1024 J9 J CHILD FAM STUD JI J. Child Fam. Stud. PD AUG PY 2009 VL 18 IS 4 BP 473 EP 485 DI 10.1007/s10826-008-9251-9 PG 13 WC Family Studies; Psychology, Developmental; Psychiatry SC Family Studies; Psychology; Psychiatry GA 507GU UT WOS:000270840900011 ER PT J AU Batista, DL Oldfield, EH Keil, MF Stratakis, CA AF Batista, Dalia L. Oldfield, Edward H. Keil, Margaret F. Stratakis, Constantine A. TI Postoperative Testing to Predict Recurrent Cushing Disease in Children SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; TRANSSPHENOIDAL SURGERY; PITUITARY-ADENOMAS; CORTISOL-LEVELS; SERUM CORTISOL; ADOLESCENTS; CHILDHOOD; MICROSURGERY; EXPERIENCE; MICROADENOMECTOMY AB Context: Postoperative testing after transsphenoidal surgery (TSS) for Cushing disease (CD) in children and its usefulness in predicting residual disease or recurrence are not well studied. Objective: The objective of the study was to identify which one of three tests that are routinely performed in our institution after TSS performs better in the identification of noncured patients or predict relapse for CD. Design: This was a retrospective review of clinical data of 72 children who received surgery for CD (age range 5.8-18.3 yr). Setting: The study was conducted at a tertiary care center. Methods: After TSS, plasma ACTH and serum cortisol (at 0800 h), urinary free cortisol (UFC) values and an ovine CRH (oCRH) stimulation test were obtained. Patients were followed up for 24-120 months by a formal protocol. Results: Of 72 children with CD, 66 (94%) achieved sustained remission after TSS. Two children had persistent disease after TSS, whereas four children appeared cured at first but relapsed later. All four had low or undetectable UFCs that were not different from cured patients (P > 0.0.1). Children who remained in remission had significantly lower morning ACTH and cortisol levels after TSS compared with thosewhorelapsed (P < 0.001). During an oCRH stimulation test, ACTH and cortisol values were higher in patients who relapsed vs. those in remission (P < 0.001). Lack of histological confirmation of an adenoma, normal serum cortisol or ACTH, a normal response to oCRH, and glucocorticoid replacement for less than 6 months after surgery were associated with relapse. Conclusion: In pediatric patients with CD, low UFCs after TSS are not good predictors of sustained remission; morning ACTH and cortisol values and/ or an oCRH test after TSS predicted patients that recurred. (J Clin Endocrinol Metab 94: 2757-2765, 2009) C1 [Batista, Dalia L.; Stratakis, Constantine A.] NINDS, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Batista, Dalia L.; Keil, Margaret F.; Stratakis, Constantine A.] NINDS, Program Dev Endocrinol & Genet, Eunice Kennedy Shriver NICHHD, Pediat Endocrinol Interinst Training Program,NIH, Bethesda, MD 20892 USA. [Oldfield, Edward H.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,CRC,East Labs, Bldg 10,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural [Z01-HD-000642-04] FX Address all correspondence and requests for reprints to: Constantine A. Stratakis, M. D., D(Med). Sci., Section on Endocrinology and Genetics, Program in Developmental Endocrinology and Genetics, and Pediatric Endocrinology Program, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, CRC (East Laboratories), Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892. E-mail: stratakc@mail.nih.gov.; This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Project Z01-HD-000642-04 (to C. A. S.).; Current address for E. H. O.: Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia 22908-0212. NR 39 TC 24 Z9 25 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2009 VL 94 IS 8 BP 2757 EP 2765 DI 10.1210/jc.2009-0302 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 479UW UT WOS:000268687700013 PM 19470618 ER PT J AU Hsiao, HP Kirschner, LS Bourdeau, I Keil, MF Boikos, SA Verma, S Robinson-White, AJ Nesterova, M Lacroix, A Stratakis, CA AF Hsiao, Hui-Pin Kirschner, Lawrence S. Bourdeau, Isabelle Keil, Margaret F. Boikos, Sosipatros A. Verma, Somya Robinson-White, Audrey J. Nesterova, Maria Lacroix, Andre Stratakis, Constantine A. TI Clinical and Genetic Heterogeneity, Overlap with Other Tumor Syndromes, and Atypical Glucocorticoid Hormone Secretion in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Compared with Other Adrenocortical Tumors SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID DEPENDENT CUSHINGS-SYNDROME; GASTRIC-INHIBITORY POLYPEPTIDE; CORTISOL SECRETION; IN-VITRO; SYNDROME SECONDARY; CARNEY COMPLEX; RECEPTORS; DISEASE; VASOPRESSIN; EXPRESSION AB Objective: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is often associated with subclinical cortisol secretion or atypical Cushing's syndrome (CS). We characterized a large series of patients of AIMAH and compared them with patients with other adrenocortical tumors. Design and Patients: We recruited 82 subjects with: 1) AIMAH (n = 16); 2) adrenocortical cortisol-producing adenoma with CS (n = 15); 3) aldosterone-producing adenoma (n = 19); and 4) single adenomas with clinically nonsignificant cortisol secretion (n = 32). Methods: Urinary free cortisol (UFC) and 17-hydroxycorticosteroid (17OHS) were collected at baseline and during dexamethasone testing; aberrant receptor responses was also sought by clinical testing and confirmed molecularly. Peripheral and/or tumor DNA was sequenced for candidate genes. Results: AIMAH patients had the highest 17OHS excretion, even when UFCs were within or close to the normal range. Aberrant receptor expression was highly prevalent. Histology showed at least two subtypes of AIMAH. For three patients with AIMAH, there was family history of CS; germline mutations were identified in three other patients in the genes for menin (one), fumarate hydratase (one), and adenomatosis polyposis coli (APC) (one); a PDE11A gene variant was found in another. One patient had a GNAS mutation in adrenal nodules only. There were no mutations in any of the tested genes in the patients of the other groups. Conclusions: AIMAH is a clinically and genetically heterogeneous disorder that can be associated with various genetic defects and aberrant hormone receptors. It is frequently associated with atypical CS and increased 17OHS; UFCs and other measures of adrenocortical activity can be misleadingly normal. (J Clin Endocrinol Metab 94: 2930-2937, 2009) C1 [Stratakis, Constantine A.] NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Clin Res Ctr,NIH, Bethesda, MD 20892 USA. [Keil, Margaret F.; Verma, Somya; Stratakis, Constantine A.] NICHHD, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD 20892 USA. [Kirschner, Lawrence S.] Ohio State Univ, Dept Internal Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Bourdeau, Isabelle; Lacroix, Andre] Ctr Hosp Univ Montreal, Dept Med, Div Endocrinol, Montreal, PQ H2W 1T8, Canada. [Hsiao, Hui-Pin] Kaohsiung Med Univ, Kaohsiung Municipal Hsiao Kang Hosp, Dept Pediat, Kaohsiung 807, Taiwan. Kaohsiung Med Univ, Coll Med, Fac Med, Dept Pediat, Kaohsiung 807, Taiwan. RP Stratakis, CA (reprint author), NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Clin Res Ctr,NIH, 10 Ctr Dr,Bldg 10,Room 1-3330,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Hsiao, Hui-Pin/B-3892-2010; Levesque, Isabelle/A-1899-2012 FU National Institute of Child Health and Human Development [Z01-HD-000642-04]; NIH FX This work was supported in part by the National Institute of Child Health and Human Development, intramural NIH project Z01-HD-000642-04 ( to Dr. C. A. S.) and in part by the NIH Clinical Center. H.P. H. was supported for a fellowship at the laboratory of C. A. S. by the Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, and College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. NR 47 TC 56 Z9 58 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2009 VL 94 IS 8 BP 2930 EP 2937 DI 10.1210/jc.2009-0516 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 479UW UT WOS:000268687700037 PM 19509103 ER PT J AU Lai, EW Joshi, BH Martiniova, L Dogra, R Fujisawa, T Leland, P de Krijger, RR Lubensky, IA Elkahloun, AG Morris, JC Puri, RK Pacak, K AF Lai, Edwin W. Joshi, Bharat H. Martiniova, Lucia Dogra, Ritika Fujisawa, Toshio Leland, Pamela de Krijger, Ronald R. Lubensky, Irina A. Elkahloun, Abdel G. Morris, John C. Puri, Raj K. Pacak, Karel TI Overexpression of Interleukin-13 Receptor-alpha 2 in Neuroendocrine Malignant Pheochromocytoma: A Novel Target for Receptor Directed Anti-Cancer Therapy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CHIMERIC FUSION PROTEINS; IL-13 RECEPTOR; ANTITUMOR-ACTIVITY; PSEUDOMONAS EXOTOXIN; GLIOMA THERAPY; ALPHA-2 CHAIN; CYTOTOXIN; CANCER; EXPRESSION; MODEL AB Context: Pheochromocytomas and paragangliomas are rare catecholamine-secreting neuroendocrine tumors arising from the adrenal medulla and sympathetic tissues. When complete surgical resection is not an option, the treatment of pheochromocytoma is limited. Objective: The objective of the study was to identify and characterize overexpression of IL-13 receptor-alpha 2 (IL-13R alpha 2) gene expression in human and murine tumors and verify xenograft mouse pheochromocytoma cell (MPC)-derived tumor's response to a selective cytotoxin. Design/Setting/Patients: Expression of IL-13R alpha 2 was evaluated in a panel of 25 human pheochromocytoma clinical samples by RT-PCR and eight MPC tumors by indirect immunofluorescence assay and RT-PCR. Intervention: The function of IL-13R alpha 2 in these tumor cells was examined by evaluating tumor sensitivity to a recombinant IL-13-Pseudomonas exotoxin (IL-13PE). Subcutaneous small and large MPC tumors in athymic nude mice (n = 10) were treated intratumorally with IL-13PE (100 mu g/kg). Main Outcome Measures: IC(50) and tumor size were measured. Results: IL-13PE immunotoxin was highly cytotoxic to IL-13R alpha 2-overexpressing MPC cells (IC(50) < 2.5 ng/ml) in vitro. Furthermore, IL-13PE was highly cytotoxic to sc tumors. Our results showed a statistically significant decrease in tumor size as early as 3 d after initial treatment and further suppressed growth of MPC tumors. All tumors displayed a histological evidence of necrosis in response to IL-13 immunotoxin without any adverse effects in host at this dose. Conclusions: Human and murine neuroendocrine pheochromocytoma overexpress the IL-13R alpha 2 chain, and an IL-13PE-based receptor-directed anticancer approach may prove useful in treatment for metastatic pheochromocytoma patients. (J Clin Endocrinol Metab 94: 2952-2957, 2009) C1 [Lai, Edwin W.; Martiniova, Lucia; Pacak, Karel] NCI, Sect Med Neuroendocrinol, Ctr Canc Res, Bethesda, MD 20892 USA. [Joshi, Bharat H.; Dogra, Ritika; Fujisawa, Toshio; Leland, Pamela; Puri, Raj K.] NCI, Eunice Kennedy Shriver Natl Inst Child & Human De, NIH, Tumor Vaccines & Biotechnol Branch,Ctr Canc Res, Bethesda, MD 20892 USA. [Lubensky, Irina A.] NCI, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, US FDA,Canc Diag Program,Ctr Canc Res, Bethesda, MD 20892 USA. [Elkahloun, Abdel G.] NCI, NHGRI, Ctr Canc Res, Bethesda, MD 20892 USA. [Morris, John C.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [de Krijger, Ronald R.] Univ Med Ctr, Erasmus Med Ctr, Josephine Nefkens Inst, Dept Pathol, NL-3000 DR Rotterdam, Netherlands. RP Pacak, K (reprint author), NICHHD, Sect Med Neuroendocrinol, Reprod & Adult Endocrinol Program, CRC,NIH, Bldg 10,Room 1-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM raj.puri@fda.hhs.gov; karel@mail.nih.gov FU Intramural NIH HHS NR 26 TC 6 Z9 7 U1 0 U2 1 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 AUG PY 2009 VL 94 IS 8 BP 2952 EP 2957 DI 10.1210/jc.2009-0309 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 479UW UT WOS:000268687700040 PM 19491224 ER PT J AU Zemskova, MS Nylen, ES Patronas, NJ Oldfield, EH Becker, KL Nieman, LK AF Zemskova, Marina S. Nylen, Eric S. Patronas, Nicholas J. Oldfield, Edward H. Becker, Kenneth L. Nieman, Lynnette K. TI Diagnostic Accuracy of Chromogranin A and Calcitonin Precursors Measurements for the Discrimination of Ectopic ACTH Secretion from Cushing's Disease SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MEDULLARY-THYROID CARCINOMA; DIFFERENTIAL-DIAGNOSIS; GLYCOPROTEIN HORMONES; ALPHA-SUBUNIT; FOLLOW-UP; MARKER; PHEOCHROMOCYTOMA; PROCALCITONIN; INFLAMMATION; PEPTIDES AB Context: Inferior petrosal sinus sampling (IPSS) best discriminates between the two causes of ACTH-dependent Cushing's syndrome, Cushing's disease (CD) and ectopic ACTH secretion (EAS). However, when sampling is not available, adjunctive diagnostic tests might be helpful. Neuroendocrine tumors may secrete chromogranin A (CgA), calcitonin (CT), procalcitonin (ProCT), a fragment of the amino terminus of procalcitonin (NProCT), and/or ACTH. Objective: The aim of the study was to evaluate the ability of serum CgA, CT, ProCT, or NProCT values to distinguish CD from EAS. Design and Setting: We conducted a prospective pilot study at a clinical research center. Subjects and Methods: Serum ProCT, NProCT, and CgA were measured in six patients with occult EAS diagnosed by IPSS, 25 CD patients, and 11 patients with histologically proven EAS. Results: Nine EAS patients (53%) had at least one value above the reference range, including CgA alone (n = 4), ProCT alone (n = 3), CgA and ProCT (n = 1), and NProCT and ProCT (n = 1). Of nine (36%) CD patients with one or two abnormal values, seven had increased ProCT only, one had increased NProCT only, and one had increased CgA and ProCT. CgA had a positive predictive value of 83% and a negative predictive value of 70% for the diagnosis of EAS; other markers showed less discrimination. On pituitary magnetic resonance imaging, no EAS patient had an abnormality, whereas 21 of 25 patients with CD had a mass. Conclusion: These preliminary results suggest that an abnormal CgA and normal pituitary magnetic resonance imaging favor the diagnosis of EAS, but normal tumor markers do not exclude the diagnosis. (J Clin Endocrinol Metab 94: 2962-2965, 2009) C1 [Zemskova, Marina S.; Nieman, Lynnette K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Nylen, Eric S.; Becker, Kenneth L.] Vet Affairs Med Ctr, Washington, DC 20422 USA. [Nylen, Eric S.; Becker, Kenneth L.] George Washington Univ, Washington, DC 20422 USA. [Patronas, Nicholas J.] NIH, Dept Diagnost Radiol, Warren O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Oldfield, Edward H.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), CRC, Bldg 10,1 East,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM NiemanL@nih.gov FU National Institutes of Health FX This work was supported, in part, by the Intramural Research Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health. NR 20 TC 4 Z9 4 U1 0 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2009 VL 94 IS 8 BP 2962 EP 2965 DI 10.1210/jc.2009-0604 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 479UW UT WOS:000268687700042 PM 19470624 ER PT J AU Mishra, PJ Merlino, G AF Mishra, Prasun J. Merlino, Glenn TI MicroRNA reexpression as differentiation therapy in cancer SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID MYOGENIC DIFFERENTIATION; RHABDOMYOSARCOMA; CELLS; PROLIFERATION; POLYMORPHISMS; THERAPEUTICS; EXPRESSION; ONCOGENES; MEDICINE; GROWTH AB Since their discovery in the early 2000s, microRNAs (miRNAs) and their penchant for RNA interference have taken the scientific community by storm, working their way into virtually every corner of biological inquiry. The very nature of heir action, the ability to simultaneously extinguish the expression of a multitude of genes and negate their functions, immediately suggested therapeutic promise. In this issue of the JCI, a step toward the realization of this promise is described. Taulli et al. demonstrate that the miRNAs miR-1/miR-206, which are routinely lost in advanced, poorly differentiated rhabdomyosarcoma (RMS) but characteristically expressed in the mature skeletal muscle from which these tumors arise, restore the myogenic differentiation program and block the tumorigenic phenotype (see the related article beginning on page 2366). Their data support the notion that these small RNAs, effectively functioning as "micro-sheriffs" by restoring myogenic law and order, hold substantial clinical potential as differentiation therapy for RMS and perhaps other solid tumors. miRNA reexpression therapy constitutes a novel approach to handcuff oncogenes and arrest tumor development. C1 [Mishra, Prasun J.; Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Merlino, G (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bldg 37,Room 5002,37 Convent Dr, Bethesda, MD 20892 USA. EM gmerlino@helix.nih.gov NR 34 TC 56 Z9 61 U1 0 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2009 VL 119 IS 8 BP 2119 EP 2123 DI 10.1172/JCI40107 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 478NW UT WOS:000268596000002 PM 19620782 ER PT J AU Kato, GJ AF Kato, Gregory J. TI Haptoglobin halts hemoglobin's havoc SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID SICKLE-CELL-DISEASE; ACUTE CHEST SYNDROME; SCAVENGER RECEPTOR; HEMOLYSIS; CHILDREN; CD163; DYSFUNCTION; ANEMIA; SYSTEM AB Hemoglobin (Hb) is crucial to the function of the red blood cell. However, when it is released during intravascular hemolysis from the cell into blood plasma, it produces a state of NO depletion, oxidant stress, and vascular dysfunction, including hypertension. In their study reported in this issue of the JCI, Boretti and colleagues used canine and guinea pig models to demonstrate that pharmacological doses of glucocorticoid can increase the plasma levels of haptoglobin (Hp), the principal phasma-binding protein for free Hb (see the related article beginning on page 2271). Hp prevented Hb-induced hypertension and the generation of oxidant damage to the kidney. Neutralization of free Hb appears to be part of the downstream and inflammatory properties of glucocorticoid. C1 [Kato, Gregory J.] NHLBI, Sickle Cell Vasc Dis Sect, Pulm & Vasc Med Branch, Bethesda, MD 20892 USA. [Kato, Gregory J.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Kato, GJ (reprint author), 10 Ctr Dr,MSC 1476,Bldg 10CRC,Room 5-5140, Bethesda, MD 20892 USA. EM gkato@nhlbi.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [ZIA HL006012-02, ZIA HL006014-01, ZIA HL006014-02, ZIA HL006012-01] NR 21 TC 27 Z9 27 U1 0 U2 1 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 AUG PY 2009 VL 119 IS 8 BP 2140 EP 2142 DI 10.1172/JCI40258 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 478NW UT WOS:000268596000008 PM 19620777 ER PT J AU Hedrick, MN Lonsdorf, AS Shirakawa, AK Lee, CCR Liao, F Singh, SP Zhang, HWH Grinberg, A Love, PE Hwang, ST Farber, JM AF Hedrick, Michael N. Lonsdorf, Anke S. Shirakawa, Aiko-Konno Lee, Chyi-Chia Richard Liao, Fang Singh, Satya P. Zhang, Hongwei H. Grinberg, Alexander Love, Paul E. Hwang, Sam T. Farber, Joshua M. TI CCR6 is required for IL-23-induced psoriasis-like inflammation in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY; ROR-GAMMA-T; CHEMOKINE RECEPTOR 6; VERSUS-HOST-DISEASE; GROWTH-FACTOR-BETA; AUTOIMMUNE INFLAMMATION; CONTROLLED-TRIAL; DOUBLE-BLIND; TH17 CELLS; IN-VIVO AB Psoriasis is a common immune-mediated chronic inflammatory skin disorder, but the mechanisms of pathogenesis are still poorly understood. IL-23 is expressed in psoriatic skin, and IL-23 injection produces IL-22-dependent psoriasiform changes in mouse skin. Th17 cells produce IL-22 and display CCR6, the CCL20 receptor; CCR6(+) T cells and CCL20 are abundant in psoriatic skin. We investigated a possible role for CCR6 in recruiting Th17 cells and producing psoriasiform pathology by injecting IL-23 into the skin of WT and Ccr6(-/-) mice. Unlike for WT mice, IL-23-injected ears of Ccr6(-/-) mice showed neither substantial epidermal/dermal changes nor increased 1122 mRNA expression. However, injection of IL-22 yielded equivalent psoriasiform changes in WT and Ccr6(-/-) mice. Surprisingly, IL-23-injected ears of WT and Ccr6(-/-) mice contained similar numbers of Th cells able to make IL-17A and/or IL-22. Furthermore, in ears of Ragl(-/-) mice, IL-23 initially induced skin changes and levels of Il22 mRNA that were indistinguishable from WT mice, revealing at least one non-T cell source for IL-22. We conclude that CCR6 is essential in a model of IL-23-induced, IL-22-mediated dermatitis, which develops in sequential T cell-independent and T cell-dependent phases. These findings reveal an expanded role for CCR6 in IL-23-related responses and identify CCR6 as a potential therapeutic target in psoriasis. C1 [Hedrick, Michael N.; Shirakawa, Aiko-Konno; Liao, Fang; Singh, Satya P.; Zhang, Hongwei H.; Farber, Joshua M.] NIAID, Inflammat Biol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Lonsdorf, Anke S.; Hwang, Sam T.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lonsdorf, Anke S.] Univ Heidelberg Hosp, Dept Dermatol, Heidelberg, Germany. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Grinberg, Alexander; Love, Paul E.] NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Farber, JM (reprint author), NIAID, Inflammat Biol Sect, Lab Mol Immunol, NIH, Bldg 10,Room 11N-112, Bethesda, MD 20892 USA. EM jfarber@niaid.nih.gov RI Lee, Chyi-Chia/I-1938-2013 OI Lee, Chyi-Chia/0000-0002-5306-7781 FU NIH/Deutsche Forschungsgemeinschaft Research Career Transition Award; NIAID; NCI; NICHD; NIH FX We are grateful to Se-Jin Lee for providing materials, Hua Gu for consultations, Eileen O'Hara and Hong Duc V. Dang for expert technical assistance in preparing the pPNT-muccr6 targeting vector, and Saeko Nomura for blastocyst injections. A.S. Lonsdorf was Supported by a NIH/Deutsche Forschungsgemeinschaft Research Career Transition Award. This research was supported by the intramural Research Program, NIAID, NCI, and NICHD, NIH. NR 85 TC 94 Z9 97 U1 0 U2 6 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 AUG PY 2009 VL 119 IS 8 BP 2317 EP 2329 DI 10.1172/JCI37378 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 478NW UT WOS:000268596000022 PM 19662682 ER PT J AU Berglund, ED Lee-Young, RS Lustig, DG Lynes, SE Donahue, EP Camacho, RC Meredith, ME Magnuson, MA Charron, MJ Wasserman, DH AF Berglund, Eric D. Lee-Young, Robert S. Lustig, Daniel G. Lynes, Sara E. Donahue, E. Patrick Camacho, Raul C. Meredith, M. Elizabeth Magnuson, Mark A. Charron, Maureen J. Wasserman, David H. TI Hepatic energy state is regulated by glucagon receptor signaling in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ACTIVATED PROTEIN-KINASE; ACETYL-COA CARBOXYLASE; CYTOSOLIC PHOSPHOENOLPYRUVATE CARBOXYKINASE; RAT-LIVER; SKELETAL-MUSCLE; METABOLIC-RESPONSE; SHORT-TERM; IN-VIVO; GLUCOSE-METABOLISM; ACUTE EXERCISE AB The hepatic energy state, defined by adenine nucleotide levels, couples metabolic pathways with energy requirements. This coupling is fundamental in the adaptive response to many conditions and is impaired in metabolic disease. We have found that the hepatic energy state is substantially reduced following exercise, fasting, and exposure to other metabolic stressors in C57BL/6 mice. Glucagon receptor signaling was hypothesized to mediate this reduction because increased plasma levels of glucagon are characteristic of metabolic stress and because this hormone stimulates energy consumption linked to increased gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and associated pathways. We developed what we believe to be a novel hyperglucagonemic-euglycemic clamp to isolate an increment in glucagon levels while maintaining fasting glucose and insulin. Metabolic stress and a physiological rise in glucagon lowered the hepatic energy state and amplified AMP-activated protein kinase signaling in control mice, but these changes were abolished in glucagon receptor-mill mice and mice with fiver-specific PEPCK-C deletion. 129X1/Sv mice, which do not mount a glucagon response to hypoglycemia, displayed an increased hepatic energy state compared with CS7BL/6 mice in which glucagon was elevated. Taken together, these data demonstrate in vivo that the hepatic energy state is sensitive to glucagon receptor activation and requires PEPCK-C, thus providing new insights into liver metabolism. C1 [Berglund, Eric D.] Vanderbilt Univ, Med Ctr, Sch Med, Dept Physiol & Mol Biophys, Nashville, TN 37232 USA. [Charron, Maureen J.] Albert Einstein Coll Med, Dept Biochem, New York, NY USA. [Wasserman, David H.] Vanderbilt Univ, Vanderbilt NIH Mouse Metab Phenotyping Ctr, Sch Med, Nashville, TN 37232 USA. RP Berglund, ED (reprint author), Vanderbilt Univ, Med Ctr, Sch Med, Dept Physiol & Mol Biophys, 2200 Pierce Ave,823 Light Hall, Nashville, TN 37232 USA. EM berglunde@gmail.com RI Magnuson, Mark/B-1335-2009 OI Magnuson, Mark/0000-0002-8824-6499 FU NIH [DKS0277, DK59637] FX We would like to thank Wanda Snead, Bakula Trivedi, and Eric Allen in the Vanderbilt University Mouse Metabolic Phenoryping Center Hormone and Analytical Core for measuring glucagon, insulin, and catecholamines. We would also like to thank Julio Ayala for technical advice and review of the manuscript. This work was supported by NIH grants DKS0277 and DK59637 (to D.H. Wasserman) and by an NIH grant to the Vanderbilt University Molecular Endocrinology Training Program. NR 77 TC 39 Z9 40 U1 1 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 AUG PY 2009 VL 119 IS 8 BP 2412 EP 2422 DI 10.1172/JCI38650 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 478NW UT WOS:000268596000030 PM 19662685 ER PT J AU Wang, RX Sheng, ZM Taubenberger, JK AF Wang, Ruixue Sheng, Zong-Mei Taubenberger, Jeffery K. TI Detection of Novel (Swine Origin) H1N1 Influenza A Virus by Quantitative Real-Time Reverse Transcription-PCR SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Letter C1 [Wang, Ruixue; Sheng, Zong-Mei; Taubenberger, Jeffery K.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wang, RX (reprint author), NIAID, Infect Dis Lab, NIH, 33 North Dr,Rm 3E19A-2,MSC 3203, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov NR 8 TC 45 Z9 45 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2009 VL 47 IS 8 BP 2675 EP 2677 DI 10.1128/JCM.01087-09 PG 3 WC Microbiology SC Microbiology GA 477DV UT WOS:000268499600059 PM 19553589 ER PT J AU Grant, CS Ingle, JN Suman, VJ Dumesic, DA Wickerham, DL Gelber, RD Flynn, PJ Weir, LM Intra, M Jones, WO Perez, EA Hartmann, LC AF Grant, Clive S. Ingle, James N. Suman, Vera J. Dumesic, Daniel A. Wickerham, D. Lawrence Gelber, Richard D. Flynn, Patrick J. Weir, Lorna M. Intra, Mattia Jones, Wayne O. Perez, Edith A. Hartmann, Lynn C. TI Menstrual Cycle and Surgical Treatment of Breast Cancer: Findings From the NCCTG N9431 Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DISEASE-FREE SURVIVAL; PREMENOPAUSAL WOMEN; SERUM PROGESTERONE; 5-YEAR ANALYSIS; RECEPTOR STATUS; SURGERY; PHASE; PROGNOSIS; CARCINOMA; CURE AB Purpose For nearly two decades, multiple retrospective reports, small prospective studies, and meta-analyses have arrived at conflicting results regarding the value of timing surgical intervention for breast cancer on the basis of menstrual cycle phase. We present the results of a multicooperative group, prospective, observational trial of menstrual cycle phase and outcome after breast cancer surgery, led by the North Central Cancer Treatment Group (NCCTG) in collaboration with the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the International Breast Cancer Study Group (IBCSG). Patients and Methods Premenopausal women age 18 to 55 years, who were interviewed for menstrual history and who were surgically treated for stages I to II breast cancer, had serum drawn within 1 day of surgery for estradiol, progesterone, and luteinizing hormone levels. Menstrual history and hormone levels were used to determine menstrual phase: luteal, follicular, and other. Disease-free survival (DFS) and overall survival (OS) rates were determined by Kaplan-Meier method and were compared by using the log-rank test and Cox proportional hazard modeling. Results Of 1,118 women initially enrolled, 834 women comprised the study cohort: 230 (28%) in luteal phase; 363 (44%) in follicular phase; and 241 grouped as other. During a median follow-up of 6.6 years, and in analysis that accounted for nodal disease, estrogen receptor status, adjuvant radiation therapy or chemotherapy, neither DFS nor OS differed with respect to menstrual phase. The 5-year DFS rates were 82.7%, 82.1%, and 79.2% for follicular, luteal, or other phases, respectively. Corresponding OS survival rates were 91.9%, 92.2%, and 91.8%, respectively. Conclusion When menstrual cycle phases were strictly defined, neither DFS nor OS differed between women who underwent surgery during the follicular phase versus the luteal phase. Nearly 30% of the patients did not meet criteria for either follicular-or luteal-phase categories. J Clin Oncol 27: 3620-3626. (C) 2009 by American Society of Clinical Oncology C1 [Grant, Clive S.] Mayo Clin, Div Gen Surg, N Cent Canc Treatment Grp, Dept Surg,Div Med Oncol,Canc Ctr Stat, Rochester, MN 55905 USA. Reprod Med & Infertil Associates, N Cent Canc Treatment Grp, Woodbury, MN USA. Allegheny Canc Ctr, N Cent Canc Treatment Grp, Pittsburgh, PA USA. Dana Farber Canc Inst, Natl Surg Adjuvant Breast & Bowel Project, Boston, MA 02115 USA. Community Clin Oncol Program Metrominnesota, Int Breast Canc Study Grp, Natl Surg Adjuvant Breast & Bowel Project, St Louis Pk, MN USA. British Columbia Canc Agcy, Vancouver Canc Ctr, Natl Surg Adjuvant Breast & Bowel Project, Vancouver, BC V5Z 4E6, Canada. European Inst Oncol, Div Breast Surg, Milan, Italy. Auckland City Hosp, Dept Surg, Int Breast Canc Study Grp, Auckland, New Zealand. Mayo Clin, Int Breast Canc Study Grp, N Cent Canc Treatment Grp, Jacksonville, FL 32224 USA. Mayo Clin, Div Hematol Oncol, Australian New Zealand Breast Canc Trials Grp, Jacksonville, FL 32224 USA. RP Grant, CS (reprint author), Mayo Clin, Div Gen Surg, N Cent Canc Treatment Grp, Dept Surg,Div Med Oncol,Canc Ctr Stat, 200 1st St SW, Rochester, MN 55905 USA. EM cgrant@mayo.edu FU NCI NIH HHS [U10 CA025224-26, U10 CA025224, U10 CA012027, U10 CA069974, U10-CA-69651, CA25224, CA075364, U10 CA069651, U10-CA-12027, U10 CA037377, U10-CA-69974, U10-CA-37377] NR 34 TC 13 Z9 13 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2009 VL 27 IS 22 BP 3620 EP 3626 DI 10.1200/JCO.2008.21.3603 PG 7 WC Oncology SC Oncology GA 477EX UT WOS:000268502500010 PM 19487378 ER PT J AU Tamayo, JM Sutton, VK Mattei, MA Diaz, B Jamal, HH Vieta, E Zarate, CA Fumero, I Tohen, M AF Tamayo, Jorge M. Sutton, Virginia K. Mattei, Manuel A. Diaz, Barbara Jamal, Hassan H. Vieta, Eduard Zarate, Carlos A., Jr. Fumero, Ileana Tohen, Mauricio TI Effectiveness and Safety of the Combination of Fluoxetine and Olanzapine in Outpatients With Bipolar Depression An Open-Label, Randomized, Flexible-Dose Study in Puerto Rico SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE bipolar depression; continuation treatment; fluoxetine; OFC; olanzapine ID DOUBLE-BLIND TRIAL; OLANZAPINE/FLUOXETINE COMBINATION; DISORDER; ANTIDEPRESSANTS; LAMOTRIGINE AB We studied the effectiveness of olanzapine/fluoxetine combination (OFC) treatment of bipolar depressive episode (7 weeks, Study period 1 [SP1]). Study period 1 responders (mean modal daily OFC dosage, 10.8/27.8 mg) were randomized to OFC continuation treatment or olanzapine (OLZ) monotherapy starting at 10 mg (12 weeks, SP2). Seventy-three percent of the 114 patients who entered into SP2 completed the trial. The Montgomery-Asberg Depression Rating Scale total score changes from baseline in SP1 (primary outcome) were significant (-20 +/- 10, P < 0.001) and, during SP2, worsened for patients in the OLZ group (OFC vs OLZ, -0.4 +/- 7.55 vs +8.2 +/- 14, 1, respectively; P<0.001). During SP1, 69% responded and 59% remitted. During SP2, significantly more patients in the OFC group maintained response (31.3% vs 12.5%) and remission (71.4% vs 39.6%) than patients in the OLZ group. Treatment-emergent adverse events with OFC (SP1 and SP2) included increased appetite, increased weight, somnolence, anxiety, insomnia, and depressed mood. Since visit 1, the mean weight increases (in pounds) were 4.8 +/- 6.8 for SP1 (P<0.001)and 6.3 +/- 10.3 (OFC) or 10.7 +/- 11.3 (OLZ) for SP2; 50% (OLZ) and 33% (OFC) of the patients had a 7% or higher weight increase. For cholesterol, triglycerides, and low-density lipoprotein levels and some hepatic enzymes, there were statistically and clinically significant changes in both study periods but no differences between the SP2 groups. Study limitations included the open-label design and exclusion of the SP1 nonresponders from SP2. These study results suggest that improvements resulting from 7 weeks of acute OFC treatment of a bipolar depressive episode are maintained in responders for an additional 12 weeks with OFC, but switching to OLZ alone may result in symptom worsening. C1 [Tamayo, Jorge M.] CES Univ, Medellin, Colombia. [Sutton, Virginia K.; Jamal, Hassan H.] i3 Res, Cary, NC USA. [Mattei, Manuel A.] Lilly USA LLC, Indianapolis, IN USA. [Diaz, Barbara; Fumero, Ileana] Ashford Med Ctr, San Juan, PR USA. [Vieta, Eduard] Univ Barcelona, Hosp Clin, CIBERSAM, IDIBAPS, Barcelona, Spain. [Zarate, Carlos A., Jr.] NIMH, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Tohen, Mauricio] Harvard Univ, McLean Hosp, Sch Med, Belmont, MA 02178 USA. [Tohen, Mauricio] Univ Texas Hlth Sci Ctr San Antonio, Div Mood & Anxiety Disorders, San Antonio, TX 78229 USA. RP Tamayo, JM (reprint author), CES Univ, CII 7 39-197, Medellin, Colombia. EM tamayojm@gmail.com RI Vieta, Eduard/I-6330-2013 OI Vieta, Eduard/0000-0002-0548-0053 FU Lilly USA, LLC FX Financial support was provided by Lilly USA, LLC. NR 19 TC 16 Z9 16 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD AUG PY 2009 VL 29 IS 4 BP 358 EP 361 DI 10.1097/JCP.0b013e3181ad223f PG 4 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 470QX UT WOS:000267995200007 PM 19593175 ER PT J AU Zhang, Y Song, G Vinar, T Green, ED Siepel, A Miller, W AF Zhang, Yu Song, Giltae Vinar, Tomas Green, Eric D. Siepel, Adam Miller, Webb TI Evolutionary History Reconstruction for Mammalian Complex Gene Clusters SO JOURNAL OF COMPUTATIONAL BIOLOGY LA English DT Article; Proceedings Paper CT 12th Annual International Conference on Research Computational Molecular Biology CY MAR 30-APR 02, 2008 CL Singapore, SINGAPORE SP Natl Univ Singapore, NUS Bioinformat Programme, Lilly, IBM, ISCB, World Sci, Taylor & Francis DE alignment; computational molecular biology; genetic mapping; haplotypes; Markov chains ID TANDEMLY REPEATED GENES; COPY NUMBER VARIATION; HUMAN GENOME; IDENTIFICATION; DUPLICATION; ALIGNMENTS; DIVERGENCE; SEQUENCES; DATABASE; MOUSE AB Clusters of genes that evolved from single progenitors via repeated segmental duplications present significant challenges to the generation of a truly complete human genome sequence. Such clusters can confound both accurate sequence assembly and downstream computational analysis, yet they represent a hotbed of functional innovation, making them of extreme interest. We have developed an algorithm for reconstructing the evolutionary history of gene clusters using only human genomic sequence data, which allows the tempo of large-scale evolutionary events in human gene clusters to be estimated. We further propose an extension of the method to simultaneously reconstructing the evolutionary histories of orthologous gene clusters in multiple primates, which will facilitate primate comparative sequencing studies that aim to reconstruct their evolutionary history more fully. C1 [Zhang, Yu] Penn State Univ, Dept Stat, University Pk, PA 16802 USA. [Zhang, Yu; Song, Giltae; Miller, Webb] Penn State Univ, Ctr Comparat Genom & Bioinformat, University Pk, PA 16802 USA. [Vinar, Tomas; Siepel, Adam] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY USA. [Green, Eric D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Green, Eric D.] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Zhang, Y (reprint author), Penn State Univ, Dept Stat, 325 Thomas Bldg, University Pk, PA 16802 USA. EM yuzhang@stat.psu.edu RI Vinar, Tomas/I-3695-2014; OI Vinar, Tomas/0000-0003-3898-3447; Song, Giltae/0000-0001-8796-4678; Siepel, Adam/0000-0002-3557-7219 FU NHGRI NIH HHS [HG002238, R01 HG002238, R01 HG002238-21] NR 26 TC 4 Z9 4 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1066-5277 J9 J COMPUT BIOL JI J. Comput. Biol. PD AUG PY 2009 VL 16 IS 8 BP 1051 EP 1070 DI 10.1089/cmb.2009.0040 PG 20 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 492FA UT WOS:000269639100007 PM 19645598 ER PT J AU Rosta, E Woodcock, HL Brooks, BR Hummer, G AF Rosta, Edina Woodcock, H. Lee Brooks, Bernard R. Hummer, Gerhard TI Artificial Reaction Coordinate "Tunneling" in Free-Energy Calculations: The Catalytic Reaction of RNase H SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE QM/MM; free energy; enzyme; catalysis; umbrella sampling; RNase H; proton transfer; reaction coordinate ID ELASTIC BAND METHOD; TRANSITION-STATE; STATISTICAL-MECHANICS; SUBSTRATE-SPECIFICITY; ENZYMATIC-REACTIONS; RNA/DNA HYBRID; SADDLE-POINTS; HYDROLYSIS; DYNAMICS; PATHS AB We describe a method for the systematic improvement of reaction coordinates in quantum mechanical/molecular mechanical (QM/MM) calculations of reaction free-energy profiles. In umbrella-sampling free-energy calculations, a biasing potential acting on a chosen reaction coordinate is used to sample the system in reactant, product, and transition states. Sharp, nearly discontinuous changes along the resulting reaction path are used to identify coordinates that are relevant for the reaction but not properly sampled. These degrees of freedom are then included in an extended reaction coordinate. The general formalism is illustrated for the catalytic cleavage of the RNA backbone of an RNA/DNA hybrid duplex by the RNase H enzyme of Bacillus halodurans. We find that in the initial attack of the phosphate diester by water, the oxygen-phosphor-us distances alone are not sufficient as reaction coordinates, resulting in substantial hysteresis in the proton degrees of freedom and a barrier that is too low (similar to 10 kcaV mol). If the proton degrees of freedom are included in an extended reaction coordinate, we obtain a barrier of 21.6 kcal/mol consistent with the experimental rates. As the barrier is approached, the attacking water molecule transfers one of its protons to the O1P oxygen of the phosphate group. At the barrier top, the resulting hydroxide ion forms a penta-coordinated phosphate intermediate. The method used to identify important degrees of freedom, and the procedure to optimize the reaction coordinate are general and should be useful both in classical and in QM/MM free-energy calculations. (C) 2009 Wiley Periodicals, Inc. J Comput Chem 30: 1634-1641, 2009 C1 [Rosta, Edina; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Woodcock, H. Lee; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM gerhard.hummer@nih.gov RI Woodc, Henry/D-9275-2011; Hummer, Gerhard/A-2546-2013; OI Hummer, Gerhard/0000-0001-7768-746X; Woodcock, Henry/0000-0003-3539-273X; Rosta, Edina/0000-0002-9823-4766 FU NIH FX ER. and G.H. thank Dr. Wei Yang (NIH), Dr. Marcin Nowotny (Warsaw), and Dr. Attila Szabo (NIH) for their helpful discussions. E.R. thanks Dr. Yihan Shao, Dr. Sergio Hassan, and Dr. Peter Steinbach for their valuable help and comments and the NCI, CCR Fellows Editorial Board for help in editing the manuscript. This research used the Biowulf Linux cluster at the NIH. NR 44 TC 48 Z9 48 U1 2 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 EI 1096-987X J9 J COMPUT CHEM JI J. Comput. Chem. PD AUG PY 2009 VL 30 IS 11 SI SI BP 1634 EP 1641 DI 10.1002/jcc.21312 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 464KS UT WOS:000267504400003 PM 19462398 ER PT J AU Jiao, D Zhang, JJ Duke, RE Li, GH Schnieders, MJ Ren, PY AF Jiao, Dian Zhang, Jiajing Duke, Robert E. Li, Guohui Schnieders, Michael J. Ren, Pengyu TI Trypsin-Ligand Binding Free Energies from Explicit and Implicit Solvent Simulations with Polarizable Potential SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE trypsin; binding; free energy; simulation; force field; polarizable ID MOLECULAR-DYNAMICS SIMULATIONS; INITIO QUANTUM-CHEMISTRY; CHARGE FORCE-FIELD; CONTINUUM SOLVENT; FLUCTUATING CHARGE; AB-INITIO; BENZAMIDINIUM CHLORIDE; MECHANICS; MODEL; SOLVATION AB We have calculated the binding free energies of a series of benzamidine-like inhibitors to trypsin with a polarizable force field using both explicit and implicit solvent approaches. Free energy perturbation has been performed for the ligands in bulk water and in protein complex with molecular dynamics simulations. The binding free energies calculated from explicit solvent simulations are well within the accuracy of experimental measurement and the direction of change is predicted correctly in all cases. We analyzed the molecular dipole moments of the ligands in gas, water and protein environments. Neither binding affinity nor ligand solvation free energy in bulk water shows much dependence on the molecular dipole moments of the ligands. Substitution of the aromatic or the charged group in the ligand results in considerable change in the solvation energy in bulk water and protein whereas the binding affinity varies insignificantly due to cancellation. The effect of chemical modification on ligand charge distribution is mostly local. Replacing benzene with diazine has minimal impact on the atomic multipoles at the amidinium group. We have also utilized an implicit solvent based end-state approach to evaluate the binding free energies of these inhibitors. In this approach, the polarizable multipole model combined with Poisson-Boltzmann/surface area (PMPB/SA) provides the electrostatic interaction energy and the polar solvation free energy. Overall the relative binding free energies obtained from the MM-PMPB/SA model are in good agreement with the experimental data. (C) 2009 Wiley Periodicals, Inc. J Comput Chem 30: 1701-1711, 2009 C1 [Jiao, Dian; Zhang, Jiajing; Ren, Pengyu] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Duke, Robert E.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. [Duke, Robert E.] Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Li, Guohui] Chinese Acad Sci, Dalian Inst Chem Phys, Dalian 116023, Liaoning, Peoples R China. [Li, Guohui] Biogen Idec Inc, Cambridge, MA 02140 USA. [Schnieders, Michael J.] Stanford Univ, Sch Med, Dept Chem, Stanford, CA 94305 USA. RP Ren, PY (reprint author), Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. EM pren@mail.utexas.edu RI Jiao, Dian/E-5814-2011; Jiao, Dian/F-4337-2011; Li, Guohui/C-2271-2012 FU NHLBI NIH HHS [HL-06350, P01 HL006350]; NIGMS NIH HHS [R01 GM079686, R01 GM079686-02, R01GM079686] NR 64 TC 61 Z9 62 U1 3 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD AUG PY 2009 VL 30 IS 11 SI SI BP 1701 EP 1711 DI 10.1002/jcc.21268 PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 464KS UT WOS:000267504400010 PM 19399779 ER PT J AU Hien, DA Wells, EA Jiang, HP Suarez-Morales, L Campbell, ANC Cohen, LR Miele, GM Killeen, T Brigham, GS Zhang, YL Hansen, C Hodgkins, C Hatch-Maillette, M Brown, C Kulaga, A Kristman-Valente, A Chu, M Sage, R Robinson, JA Liu, D Nunes, EV AF Hien, Denise A. Wells, Elizabeth A. Jiang, Huiping Suarez-Morales, Lourdes Campbell, Aimee N. C. Cohen, Lisa R. Miele, Gloria M. Killeen, Therese Brigham, Gregory S. Zhang, Yulei Hansen, Cheri Hodgkins, Candace Hatch-Maillette, Mary Brown, Chanda Kulaga, Agatha Kristman-Valente, Allison Chu, Melissa Sage, Robert Robinson, James A. Liu, David Nunes, Edward V. TI Multisite Randomized Trial of Behavioral Interventions for Women With Co-Occurring PTSD and Substance Use Disorders SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE PTSD; substance abuse; comorbidity; cognitive-behavioral treatment; randomized control trial ID POSTTRAUMATIC-STRESS-DISORDER; ABUSE TREATMENT; SEEKING-SAFETY; PSYCHIATRIC-DISORDERS; TRAUMA; CLINICIAN; OUTCOMES; THERAPY; PREVALENCE; INSTRUMENT AB The authors compared the effectiveness of the Seeking Safety group, cognitive-behavioral treatment for substance use disorder and posttraumatic stress disorder (PTSD), to an active comparison health education group (Women's Health Education [WHE]) within the National Institute on Drug Abuse's Clinical Trials Network. The authors randomized 353 women to receive 12 sessions of Seeking Safety (M = 6.2 sessions) or WHE (M = 6.0 sessions) with follow-up assessment I week and 3, 6, and 12 months posttreatment. Primary outcomes were the Clinician Administered PTSD Scale (CAPS), the PTSD Symptom Scale-Self Report (PSS-SR), and a substance use inventory (self-reported abstinence and percentage of days of use over 7 days). Intention-to-treat analysis showed large, clinically significant reductions in CAPS and PSS-SR symptoms (d = 1.94 and 1.12, respectively) but no reliable difference between conditions. Substance use outcomes were not significantly different over time between the two treatments and at follow-up showed no significant change from baseline. Study results do not favor Seeking Safety over WHE as an adjunct to substance use disorder treatment for women with PTSD and reflect considerable opportunity to improve clinical outcomes in community-based treatments for these co-occurring conditions. C1 [Hien, Denise A.] CUNY, Dept Psychol, New York, NY 10021 USA. [Hien, Denise A.; Nunes, Edward V.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Wells, Elizabeth A.] Univ Washington, Sch Social Work, Seattle, WA USA. [Jiang, Huiping] New York State Psychiat Inst & Hosp, Div Biostat, New York, NY 10032 USA. [Suarez-Morales, Lourdes] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Ctr Studies Family, Miami, FL USA. [Campbell, Aimee N. C.] Columbia Univ, Sch Social Work, Social Intervent Grp, New York, NY 10027 USA. [Cohen, Lisa R.; Miele, Gloria M.; Nunes, Edward V.] New York State Psychiat Inst & Hosp, Subst Abuse Div, New York, NY 10032 USA. [Cohen, Lisa R.] CUNY City Coll, Res Ctr Trauma & Addict, Dept Psychol, New York, NY USA. [Killeen, Therese] Med Univ S Carolina, Inst Psychiat, Charleston, SC USA. [Brigham, Gregory S.] Maryhaven Inc, Columbus, OH USA. [Hansen, Cheri] VillageSouth Inc, Miami, FL USA. [Hodgkins, Candace] Gateway Community Serv, Jacksonville, FL USA. [Hatch-Maillette, Mary] Univ Washington, Inst Alcohol & Drug Abuse, Seattle, WA USA. [Brown, Chanda] Charleston Ctr, Charleston, SC USA. [Kulaga, Agatha] NYU, Dept Psychiat, Sch Med, Brooklyn, NY USA. [Chu, Melissa; Sage, Robert] Addict Res & Treatment Corp, Brooklyn, NY USA. [Robinson, James A.] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. [Liu, David] Ctr Clin Trials Network, Natl Inst Drug Abuse, Bethesda, MD USA. RP Hien, DA (reprint author), CUNY City Coll, N Acad Campus,Room 8-131,138th St & Convent Ave, New York, NY 10030 USA. EM dah26@columbia.edu OI Brigham, Gregory/0000-0003-1150-4493 FU NIDA NIH HHS [U10 DA013035-05S1, U10 DA013035-04, U10 DA013035-07, U10 DA013035-08S1, U10 DA013046, U10 DA013035-02S1, U10 DA013727, U10 DA13714, U10 DA13732, U10 DA013035-05S4, U10 DA013035, U10 DA013035-02, U10 DA013035-03S1, U10 DA013035-05, U10 DA013035-05S2, U10 DA013035-06S1, U10 DA013035-08, U10 DA013035-08S2, U10 DA013038, U10 DA13727, K24 DA022412, U10 DA13038, U10 DA013035-03, U10 DA013035-04S1, U10 DA013035-05S3, U10 DA013035-06, U10 DA013035-07S1, U10 DA013714, U10 DA013720, U10 DA013732, U10 DA13035] NR 45 TC 110 Z9 111 U1 2 U2 11 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 AUG PY 2009 VL 77 IS 4 BP 607 EP 619 DI 10.1037/a0016227 PG 13 WC Psychology, Clinical SC Psychology GA 477SK UT WOS:000268538800002 PM 19634955 ER PT J AU Erausquin, JT Duan, NH Grusky, O Swanson, AN Kerrone, D Rudy, ET AF Erausquin, Jennifer Toller Duan, Naihua Grusky, Oscar Swanson, Aimee-Noelle Kerrone, Dustin Rudy, Ellen T. TI Increasing the Reach of HIV Testing to Young Latino MSM: Results of a Pilot Study Integrating Outreach and Services SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE HIV/AIDS; men who have sex with men (MSM); Latino; community-based organization ID SEXUAL RISK BEHAVIOR; UNITED-STATES; SAN-FRANCISCO; HETEROSEXUAL TRANSMISSION; PERSONS AWARE; MEN; AIDS; GAY; PERCEPTIONS; POPULATION AB Background. In the U.S., HIV infections are increasing among men who have sex with men (MSM), particularly young, racial/ethnic minority MSM. Objective. To examine the feasibility of increasing HIV testing among young Latino MSM by integrating tailored outreach strategies with testing, counseling, and HIV medical services. Design. Descriptive study comparing demographic characteristics, behaviors, and HIV test results of clients from the intervention period with clients who tested during other time periods. Results. Clients in the intervention period were younger and more likely to be Latino than those in other time periods. In addition, clients who received outreach were more likely than those who did not receive outreach to report methamphetamine use, sex with an HIV-positive person, and sex with a sex worker. Conclusion. Venue-based and selective media outreach, in combination with linking rapid testing to HIV care, may help overcome some of the barriers to testing among high-risk young Latino MSM. C1 [Erausquin, Jennifer Toller] Univ Calif Los Angeles, Sch Publ Hlth, Dept Community Hlth Sci, Los Angeles, CA 90095 USA. [Duan, Naihua] Columbia Univ, Dept Psychiat, Div Biostat, Med Ctr, New York, NY 10027 USA. [Grusky, Oscar] Univ Calif Los Angeles, AIDS Res Training Program, Los Angeles, CA 90095 USA. [Swanson, Aimee-Noelle] Univ Calif Los Angeles, Dept Family Med, Ctr Excellence P50, NIDA, Los Angeles, CA 90095 USA. [Kerrone, Dustin] Los Angeles Gay & Lesbian Ctr, SPOT, HIV Testing Satellite Clin, Los Angeles, CA USA. [Rudy, Ellen T.] Los Angeles Cty Dept Publ Hlth, Sexually Transmitted Dis Program, Los Angeles, CA USA. RP Erausquin, JT (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, Dept Community Hlth Sci, Box 951772 36-071 CHS, Los Angeles, CA 90095 USA. EM jtoller@ucla.edu FU NIMH NIH HHS [T32 MH019127, T32-MH19127]; NINR NIH HHS [P30 NR00504]; PHS HHS [P30 58107] NR 38 TC 9 Z9 10 U1 2 U2 5 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD AUG PY 2009 VL 20 IS 3 BP 756 EP 765 PG 10 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 473JT UT WOS:000268203000014 PM 19648703 ER PT J AU Osipovich, OA Subrahmanyam, R Pierce, S Sen, R Oltz, EM AF Osipovich, Oleg A. Subrahmanyam, Ramesh Pierce, Steven Sen, Ranjan Oltz, Eugene M. TI Cutting Edge: SWI/SNF Mediates Antisense Igh Transcription and Locus-Wide Accessibility in B Cell Precursors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID V(D)J RECOMBINATION; INTERGENIC TRANSCRIPTION; INTRONIC ENHANCER; REMODELING COMPLEXES; MU; LYSINE-4 AB The stepwise process of Ag receptor gene assembly, termed V(D)J recombination, is coordinated during lymphocyte development by sweeping changes in chromatin that permit or deny access to a single recombinase enzyme. We now show that switching/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes are recruited to the Igh locus by an enhancer-dependent process and that these complexes are essential for generating recombinase accessibility throughout the locus. Depletion of SWI/SNF in pro-B cells also inhibits antisense transcription through all clusters of Igh gene segments, a pioneering process that has been implicated in the initial opening of chromatin. We conclude that SWI/SNF complexes play multiple roles in Igh gene assembly, ranging from initial locus activation to the spreading and maintenance of chromatin accessibility over large V(H), D(H), and J(H) domains. The Journal of Immunology, 2009, 183: 1509-1513. C1 [Osipovich, Oleg A.; Pierce, Steven; Oltz, Eugene M.] Vanderbilt Univ, Dept Microbiol & Immunol, Nashville, TN 37232 USA. [Subrahmanyam, Ramesh; Sen, Ranjan] NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP Oltz, EM (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, 660 Euclid Ave,Campus Box 8118, St Louis, MO 63110 USA. EM eoltz@pathology.wusd.edu RI Subrahmanyam, Ramesh/K-5503-2012 FU National Institutes of Health [Al 079732, P30 CA68485] FX This work is supported by National Institutes of Health Grants Al 079732 and P30 CA68485 and by the Intramural Research Program of the National Institute of Aging (Baltimore, MD). NR 16 TC 18 Z9 18 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2009 VL 183 IS 3 BP 1509 EP 1513 DI 10.4049/jimmunol.0900896 PG 5 WC Immunology SC Immunology GA 477LB UT WOS:000268519500003 PM 19596997 ER PT J AU Myers, L Messer, RJ Carmody, AB Hasenkrug, KJ AF Myers, Lara Messer, Ronald J. Carmody, Aaron B. Hasenkrug, Kim J. TI Tissue-Specific Abundance of Regulatory T Cells Correlates with CD8(+) T Cell Dysfunction and Chronic Retrovirus Loads SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LIVER-TRANSPLANT TOLERANCE; MURINE-LEUKEMIA-VIRUS; IMMUNOLOGICAL-TOLERANCE; ENVELOPE PROTEIN; GAMMA-INTERFERON; INFECTED MICE; FRIEND; SUPPRESSION; IMMUNITY; RECEPTOR AB Infection of mice with Friend virus induces the activation of CD4(+) regulatory T cells (Tregs) that suppress virus-specific CD8(+) T cells. This suppression leads to incomplete virus clearance and the establishment of virus persistence. We now show that Treg-mediated suppression of CD8(+) T cells is tissue specific, occurring in the spleen but not the liver. Regardless of infection status, there was a 5-fold lower proportion of Tregs in the liver than in the spleen, much lower absolute cell numbers, and the relatively few Tregs present expressed less CD25. Results indicated that reduced expression of CD25 on liver Tregs was due to microenvironmental factors including low levels of IL-2 production by CD4(+) Th cells in that tissue. Low CD25 expression on liver Tregs did not impair their ability to suppress CD8(+) T cells in vitro. Correlating with the decreased proportion of Tregs in the liver was a significantly increased proportion of virus-specific CD8(+) T cells compared with the spleen. The virus-specific CD8(+) T cells from the liver did not appear suppressed given that they produced both IFN-gamma and granzyme B, and they also showed evidence of recent cytolytic activity (CD107a(+)). The functional phenotype of the virus-specific CD8(+) T cells correlated with a 10-fold reduction of chronic Friend virus levels in the liver compared with the spleen. Thus, suppression of CD8(+) T cells by virus-induced Tregs occurs in a tissue-specific manner and correlates with profound effects on localized levels of chronic infection. The Journal of Immunology, 2009, 183: 1636-1643. C1 [Myers, Lara; Messer, Ronald J.; Carmody, Aaron B.; Hasenkrug, Kim J.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Hasenkrug, KJ (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM khasenkrug@nih.gov FU Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 44 TC 21 Z9 21 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2009 VL 183 IS 3 BP 1636 EP 1643 DI 10.4049/jimmunol.0900350 PG 8 WC Immunology SC Immunology GA 477LB UT WOS:000268519500019 PM 19587016 ER PT J AU Sikder, H Zhao, Y Balato, A Chapoval, A Fishelevich, R Gade, P Singh, IS Kalvakolanu, DV Johnson, PF Gaspari, AA AF Sikder, Hashmat Zhao, Yuming Balato, Anna Chapoval, Andre Fishelevich, Rita Gade, Padmaja Singh, Ishwar S. Kalvakolanu, Dhananjaya V. Johnson, Peter F. Gaspari, Anthony A. TI A Central Role for Transcription Factor C/EBP-beta in Regulating CD1d Gene Expression in Human Keratinocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRIGLYCERIDE TRANSFER PROTEIN; ANTIGEN-PRESENTING CELLS; I-LIKE MOLECULE; NKT CELLS; T-CELLS; CONTACT-DERMATITIS; DENDRITIC CELLS; B-1B CELLS; INKT-CELLS; ACTIVATION AB CD1d is a nonclassical Ag-presenting molecule that presents glycolipid Ags to NKT cells that are involved in immune defense and tumor rejection. It also plays a role in immunoregulatory functions in the epidermis. The mechanisms controlling the expression of CD1d are not well understood. Therefore, we cloned the CD1d gene promoter and characterized its activities in primary human keratinocytes and other cell lines of epithelial origin. We found that a CCAAT box in the CD1d promoter is required for its expression in keratinocytes. We show here that transcription factor C/FBP-beta binds to the CCAAT box in the CD1d promoter in vitro and in vivo. Consistent with these observations, deletion of the gene encoding for C/EBP-beta caused a loss of CD1d expression. The in vivo regulation of CD1d has significant implications for the pathologic mechanisms of certain immunologic skin diseases in which NKT cells play a role, such as allergic contact dermatitis and psoriasis. Together, these data show a central role for C/EBP-beta in regulating CD1d transcription. The Journal of Immunology, 2009, 183: 1657-1666. C1 [Sikder, Hashmat; Zhao, Yuming; Balato, Anna; Fishelevich, Rita; Johnson, Peter F.; Gaspari, Anthony A.] Univ Maryland, Sch Med, Dept Dermatol, Baltimore, MD 21201 USA. [Chapoval, Andre] Univ Maryland, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21201 USA. [Gade, Padmaja; Gaspari, Anthony A.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Singh, Ishwar S.] Univ Maryland, Sch Med, Dept Internal Med, Baltimore, MD 21201 USA. [Kalvakolanu, Dhananjaya V.] NCI, Ft Detrick, MD 21702 USA. RP Johnson, PF (reprint author), Univ Maryland Baltimore, Sch Med, Dept Dermatol, 405 W Redwood St,6th Floor, Baltimore, MD 21201 USA. EM agasp001@umaryland.edu RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute [R0-1-AR46108-05, CA78282, CA 105005] FX This work was supported by Grant R0-1-AR46108-05 (to A.A.G.), CA78282 and CA 105005 (to D.V.K.), and the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (to P.F.J.). NR 45 TC 9 Z9 9 U1 1 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2009 VL 183 IS 3 BP 1657 EP 1666 DI 10.4049/jimmunol.0900057 PG 10 WC Immunology SC Immunology GA 477LB UT WOS:000268519500021 PM 19592659 ER PT J AU Selvapandiyan, A Dey, R Nylen, S Duncan, R Sacks, D Nakhasi, HL AF Selvapandiyan, Angamuthu Dey, Ranadhir Nylen, Susanne Duncan, Robert Sacks, David Nakhasi, Hira L. TI Intracellular Replication-Deficient Leishmania donovani Induces Long Lasting Protective Immunity against Visceral Leishmaniasis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELLS; TH1 RESPONSE; NITRIC-OXIDE; BALB/C MICE; INFECTION; VACCINATION; DISEASE; MODEL; PARASITES; MEXICANA AB No vaccine is currently available for visceral leishmaniasis (VL) caused by Leishmania donovani. This study addresses whether a live attenuated centrin gene-deleted L. donovani (LdCen1(-/-)) parasite can persist and be both safe and protective in animals. LdCen1(-/-) has a defect in amastigote replication both in vitro and ex vivo in human macrophages. Safety was shown by the lack of parasites in spleen and liver in susceptible BALB/c mice, immune compromised SCID mice, and human VL, model hamsters 10 wk after infection. Mice immunized with LdCen1(-/-) showed early clearance of virulent parasite challenge not seen in mice immunized with heat killed parasites. Upon virulent challenge, the immunized mice displayed in the CD4(+) T cell population a significant increase of single and multiple cytokine (IFN-gamma, IL-2, and TNF) producing cells and IFN-gamma/IL10 ratio. Immunized mice also showed increased IgG2a immunoglobulins and NO production in macrophages. These features indicated a protective Th1-type immune response. The Th1 response correlated with a significantly reduced parasite burden in the spleen and no parasites in the liver compared with naive mice 10 wk post challenge. Protection was observed, when challenged even after 16 wk post immunization, signifying a sustained immunity. Protection by immunization with attenuated parasites was also seen in hamsters. Immunization with LdCen1(-/-) also cross-protected mice against infection with L. braziliensis that causes mucocutaneous leishmaniasis. Results indicate that LdCen1(-/-) can be a safe and effective vaccine candidate against VL as well as mucocutaneous leishmaniasis causing parasites. The Journal of Immunology, 2009, 183: 1813-1820. C1 [Selvapandiyan, Angamuthu; Dey, Ranadhir; Duncan, Robert; Nakhasi, Hira L.] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Nylen, Susanne; Sacks, David] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Nakhasi, HL (reprint author), US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM hira.nakhasi@fda.hhs.gov RI Duncan, Robert/I-8168-2015; OI Duncan, Robert/0000-0001-8409-2501; Nylen, Susanne/0000-0002-3875-3353 NR 42 TC 57 Z9 57 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2009 VL 183 IS 3 BP 1813 EP 1820 DI 10.4049/jimmunol.0900276 PG 8 WC Immunology SC Immunology GA 477LB UT WOS:000268519500038 PM 19592661 ER PT J AU Morimoto, M Zhao, AP Sun, R Stiltz, J Madden, KB Mentink-Kane, M Ramalingam, T Wynn, TA Urban, JF Shea-Donohue, T AF Morimoto, Motoko Zhao, Aiping Sun, Rex Stiltz, Jennifer Madden, Kathleen B. Mentink-Kane, Margaret Ramalingam, Thirumalai Wynn, Thomas A. Urban, Joseph F., Jr. Shea-Donohue, Terez TI IL-13 Receptor alpha 2 Regulates the Immune and Functional Response to Nippostrongylus brasiliensis Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EPITHELIAL-CELL FUNCTION; NEMATODE PARASITE; TISSUE FIBROSIS; TH2 CYTOKINE; MURINE; INTERLEUKIN-13; EXPRESSION; STAT6; INDUCTION; COLITIS AB IL-13 has a prominent role in host defense against the gastrointestinal nematode Nippostrongylus brasiliensis; however, the role of IL-13R alpha 2 in the immune and functional response to enteric infection is not known. In the current study, we investigated changes in smooth muscle and epithelial cell function as well as alterations in gene expression of IL-13 and IL-4 and their receptors using laser-capture microdissection of specific cell types in the small intestine of N. brasiliensis-infected mice. An infection-induced up-regulation of IL-13R alpha 2 gene expression was confined to smooth muscle and was dependent on STAT6 and IL-13, but not on IL-4. In contrast, expression of IL-13R alpha 1 was reduced, indicating that changes in IL-13 alpha 2 expression serve to limit the biological effects of IL-13. The increased availability of IL-13 in IL-13R alpha 2(-/-) mice resulted in marked changes in constitutive epithelial and smooth muscle function. In addition, maximal changes in smooth muscle hypercontractility and epithelial cell resistance peaked earlier after infection in IL-13R alpha 2(-/-) compared with wild-type mice. This did not coincide with an earlier Th2 immune response as expression of IL-4 and IL-13 was attenuated in IL-13R alpha 2(-/-) mice and worm expulsion was similar to that of wild-type mice. These data show that IL-13R alpha 2 plays an important role in nematode infection by limiting the availability of IL-13 during infection, thereby regulating both the immune and biological effects of IL-13. The Journal of Immunology, 2009, 183: 1934-1939. C1 [Morimoto, Motoko; Zhao, Aiping; Sun, Rex; Stiltz, Jennifer; Shea-Donohue, Terez] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Morimoto, Motoko; Zhao, Aiping; Sun, Rex; Stiltz, Jennifer; Shea-Donohue, Terez] Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA. [Madden, Kathleen B.; Wynn, Thomas A.] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. [Mentink-Kane, Margaret; Ramalingam, Thirumalai] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Urban, Joseph F., Jr.] ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. RP Shea-Donohue, T (reprint author), Univ Sch Med, Dept Med, Baltimore, MD 21201 USA. EM tdonohue@mbrc.umaryland.edu RI Wynn, Thomas/C-2797-2011 FU National Institutes of Health [R01-Al/DK49316]; U.S. Department of Agriculture [1235-52000-053]; Miyagi University; National Institute of Allergy and Infectious Diseases/National Institutes of Health FX This work was supported by National Institutes of Health Grants R01-Al/DK49316 (to T.S.-D), by U.S. Department of Agriculture CRIS Project 1235-52000-053 (to J.F.U.), by Miyagi University Overseas Research Fund (to M.M.), and by the intramural research program of National Institute of Allergy and Infectious Diseases/National Institutes of Health. NR 24 TC 25 Z9 25 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2009 VL 183 IS 3 BP 1934 EP 1939 DI 10.4049/jimmunol.0804299 PG 6 WC Immunology SC Immunology GA 477LB UT WOS:000268519500051 PM 19587021 ER PT J AU Saha, RN Ghosh, A Palencia, CA Fung, YK Dudek, SM Pahan, K AF Saha, Ramendra N. Ghosh, Anamitra Palencia, Carlos A. Fung, Yin K. Dudek, Serena M. Pahan, Kalipada TI TNF-alpha Preconditioning Protects Neurons via Neuron-Specific Up-Regulation of CREB-Binding Protein SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; HIV-ASSOCIATED DEMENTIA; NITRIC-OXIDE SYNTHASE; ISCHEMIC TOLERANCE; SUPEROXIDE-DISMUTASE; NEURODEGENERATIVE DISORDERS; MEDIATED ACTIVATION; PRIMARY ASTROCYTES; BRAIN TOLERANCE AB Despite being a proinflammatory cytokine, TNF-alpha preconditions neurons against various toxic insults. However, underlying molecular mechanisms are poorly understood. The present study identifies the importance of CREB-binding protein (CBP) in facilitating TNF-alpha-mediated preconditioning in neurons. Treatment of rat primary neurons with fibrillar amyloid beta 1-42 (A beta) resulted in the loss of CBP protein. However, this loss was compensated by TNF-alpha preconditioning as the expression of neuronal CBP was up-regulated in response to TNF-alpha treatment. The induction of CBP by TNF-alpha was observed only in neurons, but not in astroglia and microglia, and it was contingent on the activation of transcription factor NF-kappa B. Interestingly, antisense knockdown of CBP abrogated the TNF-alpha-mediated preconditioning of neurons against A beta and glutamate toxicity. Similarly in vivo, preadministration of TNF-alpha in mouse neocortex prevented A beta-induced apoptosis and loss of choline acetyltransferase-positive cholinergic neurons. However, coadministration of cbp antisense, but not scrambled oligonucleotides, negated the protective effect of TNF-alpha against A beta neurotoxicity. This study illustrates a novel biological role of TNF-alpha in increasing neuron-specific expression of CBP for preconditioning that may have therapeutic potential against neurodegenerative disorders. The Journal of Immunology, 2009, 183: 2068-2078. C1 [Saha, Ramendra N.; Ghosh, Anamitra; Palencia, Carlos A.; Pahan, Kalipada] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Saha, Ramendra N.; Fung, Yin K.; Pahan, Kalipada] Univ Nebraska, Dept Oral Biol, Sect Neurosci, Med Ctr, Lincoln, NE 68583 USA. [Saha, Ramendra N.; Dudek, Serena M.] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Pahan, K (reprint author), Rush Univ, Med Ctr, Dept Neurol Sci, Cohn Res Bldg,Suite 320,1735 W Harrison St, Chicago, IL 60612 USA. EM Kalipada_Pahan@rush.edu RI Saha, Ramendra/C-7000-2014; Ghosh, Anamitra/C-5118-2015 OI Saha, Ramendra/0000-0002-5494-2584; FU National Institutes of Health [NS39940, NS48923]; Alzheimer's Association [IIRG-07-58684]; Intramural Research Program of the National Institutes of Health; National Institute on Environmental Health Sciences; University of Nebraska Medical Center FX This study was supported by grants from the National Institutes of Health (Grants NS39940 and NS48923) and the Alzheimer's Association (Grant IIRG-07-58684) to K.P., the Intramural Research Program of the National Institutes of Health and the National Institute on Environmental Health Sciences (to S.M.D.) and a University of Nebraska Medical Center graduate research assistantship (to R.N.S.). NR 57 TC 41 Z9 42 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2009 VL 183 IS 3 BP 2068 EP 2078 DI 10.4049/jimmunol.0801892 PG 11 WC Immunology SC Immunology GA 477LB UT WOS:000268519500066 PM 19596989 ER PT J AU Weiss, GE Crompton, PD Li, SP Walsh, LA Moir, S Traore, B Kayentao, K Ongoiba, A Doumbo, OK Pierce, SK AF Weiss, Greta E. Crompton, Peter D. Li, Shanping Walsh, Laura A. Moir, Susan Traore, Boubacar Kayentao, Kassoum Ongoiba, Aissata Doumbo, Ogobara K. Pierce, Susan K. TI Atypical Memory B Cells Are Greatly Expanded in Individuals Living in a Malaria-Endemic Area SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PLASMODIUM-FALCIPARUM; EXHAUSTION; EXPRESSION; CHILDREN; INFECTION; IMMUNITY; GENE AB Epidemiological observations in malaria endemic areas have long suggested a deficiency in the generation and maintenance of B cell memory to Plasmodium falciparum (Pf) in individuals chronically reinfected with the parasite. Recently, a functionally and phenotypically distinct population of FCRL4(+) hyporesponsive memory B cells (MBCs) was reported to be expanded in HIV-infected individuals with high viral loads. In this study, we provide evidence that a phenotypically similar atypical MBC population is significantly expanded in Pf-exposed Malian adults and children as young as 2 years of age as compared with healthy U.S. adult controls. The number of these atypical MBCs was higher in children with chronic asymptomatic Pf infections compared with uninfected children, suggesting that the chronic presence of the parasite may drive expansion of these distinct MBCs. This is the first description of an atypical MBC phenotype associated with malaria. Understanding the origin and function of these MBCs could be important in informing the design of malaria vaccines. The Journal of Immunology, 2009, 183: 2176-2182. C1 [Weiss, Greta E.; Crompton, Peter D.; Li, Shanping; Walsh, Laura A.; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Moir, Susan] NIAID, Immunoregulat Lab, NIH, Rockville, MD 20852 USA. [Traore, Boubacar; Kayentao, Kassoum; Ongoiba, Aissata; Doumbo, Ogobara K.] Univ Bamako, Fac Med Pharm & Odontostomatol, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Twinbrook 2,12441 Parklawn Dr,Room 200B,MSC 8180, Rockville, MD 20852 USA. EM spierce@nih.gov RI Crompton, Peter/N-1130-2016 FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 24 TC 125 Z9 127 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2009 VL 183 IS 3 BP 2176 EP 2182 DI 10.4049/jimmunol.0901297 PG 7 WC Immunology SC Immunology GA 477LB UT WOS:000268519500078 PM 19592645 ER PT J AU Ben-Ami, R Luna, M Lewis, RE Walsh, TJ Kontoyiannis, DP AF Ben-Ami, Ronen Luna, Mario Lewis, Russell E. Walsh, Thomas J. Kontoyiannis, Dimitrios P. TI A clinicopathological study of pulmonary mucormycosis in cancer patients: Extensive angioinvasion but limited inflammatory response SO JOURNAL OF INFECTION LA English DT Article DE Mucormycosis; Cancer; Histopathology ID STEM-CELL TRANSPLANT; ZYGOMYCOSIS; ASPERGILLOSIS; TISSUE; HOST; IDENTIFICATION; PATHOGENESIS; INFECTIONS; PATTERNS; BIOPSY AB Objectives: Pulmonary mucormycosis (PMM) is an emerging, frequently lethal fungal infection in immunosuppressed cancer patients. We sought to characterize the histopathologic features of PMM in this population. Methods: We identified patients with PMM who underwent autopsy or lung biopsy between 1990 and 2007. Histopathology slides were blindly reviewed by a pathologist and findings were scored on standardized forms. Pathologic findings were correlated with demographic and clinical data abstracted from patient's medical records. Results: Twenty patients with PMM were included in this study. Nineteen patients (95%) had hematologic malignancies. High frequencies of angioinvasion (100%), hemorrhagic infarction (90%), coagulative necrosis (85%), and intra-alveolar hemorrhage (85%) were observed, whereas inflammatory infiltrates were uncommon (30%). Neutropenic patients had more extensive angioinvasion compared with non-neutropenic patients (77% versus 29%, P = 0.06). Allogeneic hematopoietic stem cell transplantation (HSCT) recipients, all of whom had graft-versus-host disease, had more inflammatory cell infiltration but less intra-alveolar hemorrhage than non-HSCT patients (67% versus 14%, P = 0.04; 50% versus 100%, P = 0.02, respectively). Conclusions: PMM in immunocompromised cancer patients is characterized by extensive angioinvasion and coagulative necrosis. The different histopathologic features of PMM in neutropenic, non-neutropnic, and HSCT patients may reflect differences in the pathobiology of PMM in these populations. (C) 2009 The British Infection Society. Published by Elsevier Ltd. All rights reserved. C1 [Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Dept Infect Dis Infect Control & Employee Hlth, Unit 1460, Houston, TX 77030 USA. [Luna, Mario] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Lewis, Russell E.; Kontoyiannis, Dimitrios P.] Univ Houston, Coll Pharm, Houston, TX 77030 USA. [Walsh, Thomas J.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Kontoyiannis, DP (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Infect Dis Infect Control & Employee Hlth, Unit 1460, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM dkontoyi@mdanderson.org OI Lewis, Russell/0000-0002-2002-4339 NR 18 TC 23 Z9 25 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0163-4453 J9 J INFECTION JI J. Infect. PD AUG PY 2009 VL 59 IS 2 BP 134 EP 138 DI 10.1016/j.jinf.2009.06.002 PG 5 WC Infectious Diseases SC Infectious Diseases GA 489OI UT WOS:000269429500009 PM 19576639 ER PT J AU Breman, JG Plowe, CV AF Breman, Joel G. Plowe, Christopher V. TI A Malaria Vaccine for Control: More Progress SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; PLASMODIUM-FALCIPARUM; GLOBAL DISTRIBUTION; CHILDREN; COMMITMENT; INFECTION; EFFICACY; DISEASE C1 [Breman, Joel G.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Plowe, Christopher V.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Malaria Sect, Baltimore, MD 21201 USA. [Plowe, Christopher V.] Univ Maryland, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21201 USA. RP Breman, JG (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, 16 Ctr Dr, Bethesda, MD 20892 USA. EM jbreman@nih.gov NR 22 TC 8 Z9 8 U1 0 U2 1 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 AUG 1 PY 2009 VL 200 IS 3 BP 317 EP 320 DI 10.1086/600121 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 465RH UT WOS:000267604000001 PM 19569963 ER PT J AU Butler, LM Dorsey, G Hladik, W Rosenthal, PJ Brander, C Neilands, TB Mbisa, G Whitby, D Kiepiela, P Mosam, A Mzolo, S Dollard, SC Martin, JN AF Butler, Lisa M. Dorsey, Grant Hladik, Wolfgang Rosenthal, Philip J. Brander, Christian Neilands, Torsten B. Mbisa, Georgina Whitby, Denise Kiepiela, Photini Mosam, Anisa Mzolo, Similo Dollard, Sheila C. Martin, Jeffrey N. TI Kaposi Sarcoma-Associated Herpesvirus (KSHV) Seroprevalence in Population-Based Samples of African Children: Evidence for At Least 2 Patterns of KSHV Transmission SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 14th Conference on Retroviruses and Opportunistic Infections CY FEB 25-28, 2007 CL Los Angeles, CA ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIGHLY ENDEMIC AREA; HUMAN-HERPESVIRUS-8 INFECTION; BLOOD-TRANSFUSION; UGANDAN CHILDREN; RISK-FACTORS; VERTICAL TRANSMISSION; SEXUAL TRANSMISSION; SEROLOGIC EVIDENCE; HHV-8 INFECTION AB Background. Kaposi sarcoma-associated herpesvirus ( KSHV) infection is endemic among adult populations in Africa. A prevailing view is that childhood transmission is primarily responsible for the high seroprevalence of KSHV among adults that is observed throughout the continent. However, few studies have directly examined children, particularly in locations where KS is not commonly endemic. Methods. Participants were children aged 1.5-8.9 years, including 427 children from a population-based sample in South Africa, 422 from a population-based sample in Uganda, and 567 from a clinic-based sample in Uganda. All serum specimens were tested by the same laboratory for KSHV antibodies with use of 2 enzyme immunoassays (against K8.1 and ORF65) and 1 immunofluorescence assay. Results. KSHV seroprevalence was 7.5%-9.0% among South African children and was not associated with age. In contrast, in the Ugandan population-based sample, KSHV seroprevalence increased from 10% among 2-year-old children to 30.6% among 8-year-old children (P(trend) <.001). In the Ugandan clinic-based sample, sero-prevalence increased from 9.3% among 2-year-old children to 36.4% among 8-year-old children (P(trend) <.001). trend Conclusion. Two distinct relationships between age and KSHV infection among children imply that KSHV transmission among children is not uniform throughout Africa and is therefore not always responsible for the high seroprevalence observed in adults. There are at least 2 patterns of KSHV transmission in Africa. C1 [Butler, Lisa M.; Dorsey, Grant; Rosenthal, Philip J.; Neilands, Torsten B.; Martin, Jeffrey N.] Univ Calif San Francisco, San Francisco, CA 94105 USA. [Hladik, Wolfgang; Dollard, Sheila C.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Brander, Christian] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Cambridge, MA 02138 USA. [Brander, Christian] Inst Catalana Recerca & Estudis Avancats, Barcalona, Spain. [Brander, Christian] Hosp Univ Germans Trias & Pujol, Inst Recerca Sida, Badalona, Catalonia, Spain. [Mbisa, Georgina; Whitby, Denise] Natl Canc Inst Frederick, Frederick, MD USA. [Kiepiela, Photini] MRC, HIV Prevent & Res Unit, Durban, South Africa. [Mosam, Anisa; Mzolo, Similo] Univ KwaZulu Natal, Durban, South Africa. RP Butler, LM (reprint author), Univ Calif San Francisco, 50 Beale St,Suite 120, San Francisco, CA 94105 USA. EM lbutler@psg.ucsf.edu OI Brander, Christian/0000-0002-0548-5778 FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E, R01 CA119903]; NIAID NIH HHS [P30 AI027763, U01 AI052142]; NICHD NIH HHS [K01 HD052020, K01 HD052020-03]; NIMH NIH HHS [T32 MH019105] NR 51 TC 33 Z9 33 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 AUG 1 PY 2009 VL 200 IS 3 BP 430 EP 438 DI 10.1086/600103 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 465RH UT WOS:000267604000015 PM 19534596 ER PT J AU Capitini, CM Chisti, AA Mackall, CL AF Capitini, C. M. Chisti, A. A. Mackall, C. L. TI Modulating T-cell homeostasis with IL-7: preclinical and clinical studies SO JOURNAL OF INTERNAL MEDICINE LA English DT Review DE cytokines; immunotherapy; lymphopenia; T cell ID BONE-MARROW-TRANSPLANTATION; INTERLEUKIN-7 RECEPTOR-ALPHA; VERSUS-HOST-DISEASE; IMMUNODEFICIENCY-VIRUS TYPE-1; RECENT THYMIC EMIGRANTS; TUMOR-NECROSIS-FACTOR; TRANSGENIC MICE; IN-VIVO; INTENSIVE CHEMOTHERAPY; CHRONIC COLITIS AB Interleukin-7 (IL-7) is required for the development and survival of T cells and plays a critical role in modulating T-cell homeostasis. This review will address current understanding of IL-7 biology, review recent clinical experiences and discuss potential future clinical applications of IL-7, or IL-7 blockade, in the setting of disease. C1 [Capitini, C. M.; Chisti, A. A.; Mackall, C. L.] NCI, Immunol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Capitini, CM (reprint author), NCI, Immunol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, 10 Ctr Dr,Room 1W-5832, Bethesda, MD 20892 USA. EM capitinic@mail.nih.gov OI Capitini, Christian/0000-0002-2276-6731 FU NCI FX This work was supported by intramural research funds at the NCI. NR 114 TC 56 Z9 60 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD AUG PY 2009 VL 266 IS 2 BP 141 EP 153 DI 10.1111/j.1365-2796.2009.02085.x PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 469GE UT WOS:000267883100001 PM 19623690 ER PT J AU Coelho, SG Choi, W Brenner, M Miyamura, Y Yamaguchi, Y Wolber, R Smuda, C Batzer, J Kolbe, L Ito, S Wakamatsu, K Zmudzka, BZ Beer, JZ Miller, SA Hearing, VJ AF Coelho, Sergio G. Choi, Wonseon Brenner, Michaela Miyamura, Yoshinori Yamaguchi, Yuji Wolber, Rainer Smuda, Christoph Batzer, Jan Kolbe, Ludger Ito, Shosuke Wakamatsu, Kazumasa Zmudzka, Barbara Z. Beer, Janusz Z. Miller, Sharon A. Hearing, Vincent J. TI Short- and Long-Term Effects of UV Radiation on the Pigmentation of Human Skin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY SYMPOSIUM PROCEEDINGS LA English DT Article CT 9th Annual Meeting of the Society-of-Japanese-Photo-Aging-Research CY MAY 13, 2008 CL Kyoto, JAPAN SP Soc Japanese Photo Aging Res ID ULTRAVIOLET-RADIATION; MELANIN PIGMENTATION; DNA-DAMAGE; MECHANISMS; IRRADIATION; APOPTOSIS; RESPONSES; EPIDERMIS; CANCER AB The incidence of skin cancer, including cutaneous melanoma, has risen substantially in recent years, and epidemiological and laboratory studies show that UV radiation is a major causative factor of this increase. UV damage also underlies photoaging of the skin, and these deleterious effects of UV can be, in part, prevented in skin with higher levels of constitutive pigmentation. We review the clinical studies we have made in recent years regarding the rapid and the long-term responses of the pigmentary system in human skin to UV exposure. C1 [Coelho, Sergio G.; Choi, Wonseon; Brenner, Michaela; Miyamura, Yoshinori; Yamaguchi, Yuji; Hearing, Vincent J.] NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Wolber, Rainer; Smuda, Christoph; Batzer, Jan; Kolbe, Ludger] Beiersdorf AG, R&D Skin Res, Hamburg, Germany. [Ito, Shosuke; Wakamatsu, Kazumasa] Fujita Hlth Univ, Sch Hlth Sci, Dept Chem, Aichi, Japan. [Zmudzka, Barbara Z.; Beer, Janusz Z.; Miller, Sharon A.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Hearing, VJ (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bldg 37,Room 2132,MSC 4256, Bethesda, MD 20892 USA. EM hearingv@nih.gov OI Ito, Shosuke/0000-0001-9182-5144; Wakamatsu, Kazumasa/0000-0003-1748-9001 FU Intramural NIH HHS [ZIA BC010784-03] NR 29 TC 8 Z9 10 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0024 J9 J INVEST DERM SYMP P JI J. Invest. Dermatol. Symp. Proc. PD AUG PY 2009 VL 14 IS 1 BP 32 EP 35 DI 10.1038/jidsymp.2009.10 PG 4 WC Dermatology SC Dermatology GA 483LD UT WOS:000268967100007 PM 19675550 ER PT J AU Yamaguchi, Y Morita, A Maeda, A Hearing, VJ AF Yamaguchi, Yuji Morita, Akimichi Maeda, Akira Hearing, Vincent J. TI Regulation of Skin Pigmentation and Thickness by Dickkopf 1 (DKK1) SO JOURNAL OF INVESTIGATIVE DERMATOLOGY SYMPOSIUM PROCEEDINGS LA English DT Article CT 9th Annual Meeting of the Society-of-Japanese-Photo-Aging-Research CY MAY 13, 2008 CL Kyoto, JAPAN SP Soc Japanese Photo Aging Res ID EPITHELIAL-MESENCHYMAL INTERACTIONS; EXPOSING BONE-MARROW; PALMOPLANTAR FIBROBLASTS; DIFFERENTIATION; CELLS; KERATINOCYTES; EXPRESSION; THERAPY; PROGRAM AB Dickkopf 1 (DKK1), an inhibitor of Wnt signaling, not only functions as a head inducer during development, but also regulates joint remodeling and bone formation, which suggests roles for DKK1 in the pathogenesis of rheumatoid arthritis and multiple myeloma. We recently demonstrated that levels of DKK1 in palmoplantar dermal fibroblasts are physiologically higher than those observed in non-palmoplantar dermal fibroblasts. Thus, the DKK1-rich mesenchyme in palmoplantar dermis affects the overlying epithelium and induces a palmoplantar phenotype in the epidermis. More specifically, DKK1 suppresses melanocyte function and growth through the regulation of microphthalmia-associated transcription factor (MITF) and P-catenin. Furthermore, DKK1 induces the expression of keratin 9 and a-Kelch-like ECT2-interacting protein (alpha KLEIP) but downregulates the expression of beta-catenin, glycogen synthase kinase 3 beta, protein kinase C, and proteinase-activated receptor-2 (PAR-2) in keratinocytes. Treatment of reconstructed skin with DKK1 reproduces the hypopigmentation and thickening of skin through Wnt/beta-catenin signaling. These studies elucidate why human palmoplantar skin is thicker and paler than non-palmoplantar skin through the secretion of DKK1 by fibroblasts that affect the overlying epidermis. Thus, DKK1 may be useful for reducing skin pigmentation and for thickening photo-aged skin and palmoplantar wounds caused by diabetes mellitus and rheumatic skin diseases. C1 [Yamaguchi, Yuji; Morita, Akimichi; Maeda, Akira] Nagoya City Univ, Grad Sch Med Sci, Dept Geriatr & Environm Dermatol, Mizuho Ku, Nagoya, Aichi 4678601, Japan. [Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yamaguchi, Y (reprint author), Nagoya City Univ, Grad Sch Med Sci, Dept Geriatr & Environm Dermatol, Mizuho Ku, 1 Kawasumi,Mizuho Cho, Nagoya, Aichi 4678601, Japan. EM yujin@med.nagoya-cu.ac.jp FU Intramural NIH HHS [ZIA BC010786-03] NR 24 TC 21 Z9 23 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0024 J9 J INVEST DERM SYMP P JI J. Invest. Dermatol. Symp. Proc. PD AUG PY 2009 VL 14 IS 1 BP 73 EP 75 DI 10.1038/jidsymp.2009.4 PG 3 WC Dermatology SC Dermatology GA 483LD UT WOS:000268967100016 PM 19675559 ER PT J AU An, L Zhang, Y Thomasson, DM Latour, LL Baker, EH Shen, J Warach, S AF An, Li Zhang, Yan Thomasson, David M. Latour, Lawrence L. Baker, Eva H. Shen, Jun Warach, Steven TI Measurement of Glutathione in Normal Volunteers and Stroke Patients at 3T Using J-Difference Spectroscopy with Minimized Subtraction Errors SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE spectral registration; J-difference; subtraction errors; stroke; glutathione ID MAGNETIC-RESONANCE-SPECTROSCOPY; BRAIN IN-VIVO; GABA; METABOLITE; GLUTAMATE; SPECTRA; TESLA AB Purpose: To develop and optimize a (1)H magnetic resonance spectroscopy (MRS) method for measuring brain glutathione (GSH) levels. Materials and Methods: Phantom experiments and density operator simulations were performed to determine the optimal TE for measuring GSH at 3T using J-difference spectral editing. In vivo data collected from 11 normal volunteers (43 measurements) and five stroke patients (10 measurements) were processed using a new spectral alignment method (adaptive spectral registration). Results: In phantom experiments and density operator simulations where relaxation effects were ignored, close to maximum GSH signal (2.95 ppm) was obtained at TE approximate to 131 msec with minimum N-acetyl-aspartate (NAA) signal interference. Using adaptive spectral, registration, GSH levels in healthy volunteers were found to be 1.20 +/- 0.14 mM (mean +/- standard deviation [SDI). GSH levels in stroke patients were found to be 1.19 +/- 0.24 mM in lesion and 1.25 +/- 0.19 mM in contralateral normal tissue. In comparison, the SDs were significantly larger when only the NAA singlet (2.01 ppm) was used as a navigator for spectral alignment. Conclusion: Spectral editing using J-differences is a reliable method for measuring GSH levels in volunteers and stroke patients. C1 [An, Li] Suburban Hosp, NINDS, NIH, Stroke Program Off, Bethesda, MD 20814 USA. [Zhang, Yan; Shen, Jun] NIMH, NIH, Bethesda, MD 20892 USA. [Thomasson, David M.; Baker, Eva H.] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP An, L (reprint author), Suburban Hosp, NINDS, NIH, Stroke Program Off, 4th Floor,8600 Old Georgetown Rd, Bethesda, MD 20814 USA. EM anl@ninds.nih.gov FU National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS); National Institute of Mental Health (NIMH); NIH Clinical Center FX Contract grant sponsors: National Institutes of Health (NIH): National Institute of Neurological Disorders and Stroke (NINDS): National Institute of Mental Health (NIMH): NIH Clinical Center. NR 22 TC 11 Z9 11 U1 0 U2 9 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD AUG PY 2009 VL 30 IS 2 BP 263 EP 270 DI 10.1002/jmri.21832 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 478SZ UT WOS:000268609900003 PM 19629994 ER PT J AU El Khouli, RH Macura, KJ Barker, PB Elkady, LM Jacobs, MA Vogel-Claussen, J Bluemke, DA AF El Khouli, Riham H. Macura, Katarzyna J. Barker, Peter B. Elkady, Laila M. Jacobs, Michael A. Vogel-Claussen, Jens Bluemke, David A. TI MRI-Guided Vacuum-Assisted Breast Biopsy: A Phantom and Patient Evaluation of Targeting Accuracy SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE breast cancer; MRI; biopsy; phantom study; gadolinium ID CLINICAL-EXPERIENCE; INITIAL-EXPERIENCE; DIFFERENTIATION; BENIGN AB Purpose: To determine the spatial localization errors of magnetic resonance imaging (MRI)-guided core biopsy for breast lesions using the handheld vacuum-assisted core biopsy device in phantoms and patients. Materials and Methods: Biopsies were done using a 10-gauge handheld vacuum-assisted core biopsy system (Vacora, Bard, AZ, USA) on a 1.5T MRI scanner (Philips Achiever, Best, The Netherlands). A standardized biopsy localization protocol was followed by trained operators for multiplanar planning of the biopsy on a separate workstation. Biopsy localization errors were determined as the distance from needle tip to center of the target in three dimensions. Results: Twenty MRI-guided biopsies of phantoms were performed by three different operators. The biopsy target mean size was 6.8 +/- 0.6 mm. The overall mean three-dimensional (3D) biopsy targeting error was 4.4 +/- 2.9 mm. Thirty-two MRI breast biopsies performed in 22 patients were reviewed. The lesion mean size was 10.5 +/- 9.4 mm. The overall mean 3D localization error was 5.7 +/- 3.0 mm. No significant differences between phantom and patients biopsy errors were found (P > 0.5). Conclusion: MRI-guided handheld vacuum-assisted core biopsy device shows good targeting accuracy and should allow localization of lesions to within similar to 5 to 6 mm. C1 [El Khouli, Riham H.; Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [El Khouli, Riham H.; Elkady, Laila M.] Suez Canal Univ, Dept Diagnost Radiol, Sch Med, Ismailia, Egypt. [Macura, Katarzyna J.; Barker, Peter B.; Jacobs, Michael A.; Vogel-Claussen, Jens] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD USA. [Jacobs, Michael A.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Bluemke, DA (reprint author), NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. EM bluemked@nih.gov RI Jacobs, Michael/G-2901-2010; OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health (NIH)/Clinical Center Intramural Research Program [R01CA125258, P50CA103175, R01-100184]; Egyptian government FX Contract grant sponsor: National Institutes of Health (NIH)/Clinical Center Intramural Research Program: Contract grant sponsor: Egyptian government; Contract grant sponsor: NIH; Contract grant numbers: R01CA125258, P50CA103175, R01-100184. NR 13 TC 6 Z9 6 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD AUG PY 2009 VL 30 IS 2 BP 424 EP 429 DI 10.1002/jmri.21831 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 478SZ UT WOS:000268609900025 PM 19629977 ER PT J AU Kocaturk, O Kim, AH Saikus, CE Guttman, MA Faranesh, AZ Ozturk, C Lederman, RJ AF Kocaturk, Ozgur Kim, Ann H. Saikus, Christina E. Guttman, Michael A. Faranesh, Anthony Z. Ozturk, Cengizhan Lederman, Robert J. TI Active Two-Channel 0.035 '' Guidewire for Interventional Cardiovascular MRI SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE interventional magnetic resonance imaging methods; active instrument; equipment design; catheterization methods ID VISUALIZATION; CATHETERS; TRACKING AB Purpose: To develop an "active" (receiver-coil) clinical-grade guidewire with enhanced visibility for magnetic resonance imaging (MRI) and favorable mechanical characteristics for interventional MRI procedures that require conspicuous intravascular instruments distinguishable from, surrounding tissues. Materials and Methods: We designed a 0.035-inch guidewire combining two antenna designs on separate channels. A loop antenna visualizes the tip and a dipole antenna visualizes the whole shaft. We compared mechanical characteristic g of guidewire with x-ray alternatives and tested MRI performance at 1.5T in vitro and in vivo in swine. Results: Images reflected tip position within 0.97 +/- 0.42 mm and afforded whole-shaft visibility under expected conditions without sacrificing device size or handling., We re port tip stiffness, torquability, and pushability comparable to commercial interventional guidewires. Conclusions: Our clinical-grade 0.035-inch active guide-wire is conspicuous under MRI and has mechanical performance comparable to x-ray interventional guidewires. This may enable a range of interventional procedures using real-time MRI. C1 [Kocaturk, Ozgur; Kim, Ann H.; Saikus, Christina E.; Guttman, Michael A.; Faranesh, Anthony Z.; Lederman, Robert J.] NHLBI, Translat Med Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Kocaturk, Ozgur; Ozturk, Cengizhan] Bogazici Univ, Inst Biomed Engn, Istanbul, Turkey. RP Kocaturk, O (reprint author), NHLBI, Translat Med Branch, Div Intramural Res, NIH, Bldg 10,Rm B1D416, Bethesda, MD 20892 USA. EM kocaturko@nhlbi.nih.gov RI Kocaturk, Ozgur/A-1419-2016; Ozturk, Cengizhan/A-6177-2016; OI Ozturk, Cengizhan/0000-0002-6966-0774; lederman, robert/0000-0003-1202-6673 FU National Heart Lung and Blood Institute [Z01-HL005062-04] FX Contract grant sponsor: National Heart Lung and Blood Institute: Contract grant number: Z01-HL005062-04. NR 12 TC 10 Z9 10 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD AUG PY 2009 VL 30 IS 2 BP 461 EP 465 DI 10.1002/jmri.21844 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 478SZ UT WOS:000268609900031 PM 19629968 ER PT J AU Lakatta, EG DiFrancesco, D AF Lakatta, Edward G. DiFrancesco, Dario TI What keeps us ticking: a funny current, a calcium clock, or both? SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Editorial Material DE funny channels; pacemaker; I-f current; HCN channels; heart rate; diastolic depolarization; ivabradine; biological pacemaker; HCN4 channelopathies; sinus bradycardia; cardiac pacemaker cells; Ca2+ cycling; ion channels; I-f, I-CaL, I-NCX; SERCA-2 Ryanodine receptors; phospholamban; cAMP; protein kinase A-depdendent phosphorylation; beta-adrenergic receptor stimulation ID RABBIT SINOATRIAL NODE; HYPERPOLARIZATION-ACTIVATED CURRENT; PACE-MAKER CURRENT; MOUSE EMBRYONIC CARDIOMYOCYTE; CARDIAC RYANODINE RECEPTOR; INTRACELLULAR CA2+ RELEASE; NA+-CA2+ EXCHANGE CURRENT; MESSENGER-RNA EXPRESSION; SPONTANEOUS BEATING RATE; CALF PURKINJE-FIBERS C1 [Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [DiFrancesco, Dario] Lab Mol Physiol & Neurobiol, Dept Biomol Sci & Biotechnol, I-20133 Milan, Italy. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@grc.nia.nih.gov; dario.difrancesco@unimi.it FU Intramural NIH HHS [ZIA AG000258-02] NR 142 TC 118 Z9 118 U1 3 U2 55 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 AUG PY 2009 VL 47 IS 2 BP 157 EP 170 DI 10.1016/j.yjmcc.2009.03.022 PG 14 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 471FQ UT WOS:000268041800001 PM 19361514 ER PT J AU Chandrasekaran, V Lee, CJ Lin, P Duke, RE Pedersen, LG AF Chandrasekaran, Vasudevan Lee, Chang Jun Lin, Ping Duke, Robert E. Pedersen, Lee G. TI A computational modeling and molecular dynamics study of the Michaelis complex of human protein Z-dependent protease inhibitor (ZPI) and factor Xa (FXa) SO JOURNAL OF MOLECULAR MODELING LA English DT Article DE Antithrombin III; Factor Xa; Homology modeling; Molecular dynamics simulation; Protein-protein docking; Protein Z-dependent protease inhibitor; Reactive center loop; Serpins ID HEPARIN-COFACTOR-II; VENOUS THROMBOEMBOLIC DISEASE; PARTICLE MESH EWALD; ALLOSTERIC MECHANISM; ANGSTROM STRUCTURE; ISCHEMIC STROKE; TERMINAL DOMAIN; ANTITHROMBIN; THROMBIN; REVEALS AB Protein Z-dependent protease inhibitor (ZPI) and antithrombin III (AT3) are members of the serpin superfamily of protease inhibitors that inhibit factor Xa (FXa) and other proteases in the coagulation pathway. While experimental structural information is available for the interaction of AT3 with FXa, at present there is no structural data regarding the interaction of ZPI with FXa, and the precise role of this interaction in the blood coagulation pathway is poorly understood. In an effort to gain a structural understanding of this system, we have built a solvent equilibrated three-dimensional structural model of the Michaelis complex of human ZPI/FXa using homology modeling, protein-protein docking and molecular dynamics simulation methods. Preliminary analysis of interactions at the complex interface from our simulations suggests that the interactions of the reactive center loop (RCL) and the exosite surface of ZPI with FXa are similar to those observed from X-ray crystal structure-based simulations of AT3/FXa. However, detailed comparison of our modeled structure of ZPI/FXa with that of AT3/FXa points to differences in interaction specificity at the reactive center and in the stability of the inhibitory complex, due to the presence of a tyrosine residue at the P1 position in ZPI, instead of the P1 arginine residue in AT3. The modeled structure also shows specific structural differences between AT3 and ZPI in the heparin-binding and flexible N-terminal tail regions. Our structural model of ZPI/FXa is also compatible with available experimental information regarding the importance for the inhibitory action of certain basic residues in FXa. C1 [Chandrasekaran, Vasudevan; Lee, Chang Jun; Duke, Robert E.; Pedersen, Lee G.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27515 USA. [Lin, Ping] Penn State Univ, Mat Res Inst, University Pk, PA 16802 USA. [Duke, Robert E.; Pedersen, Lee G.] Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC USA. RP Pedersen, LG (reprint author), Univ N Carolina, Dept Chem, Chapel Hill, NC 27515 USA. EM lee_pedersen@unc.edu RI pedersen, lee/A-8567-2009; Pedersen, Lee/E-3405-2013; Lin, Ping/C-7115-2008 OI Pedersen, Lee/0000-0003-1262-9861; Lin, Ping/0000-0003-1200-4423 FU National Institute of Health [HL-06350]; NIEHS [Z01-ES043010-23]; National Science Foundation (FRG DMR) [084549] FX This work was supported by the National Institute of Health (HL-06350), The intramural Program of NIEHS (Z01-ES043010-23), and National Science Foundation (FRG DMR 084549). We acknowledge the use of the computational resources provided by ITS at UNC-CH and the Biomedical Unit of the Pittsburgh Supercomputing Center. We thank our colleagues at UNC-CH for helpful conversations. NR 52 TC 10 Z9 11 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1610-2940 J9 J MOL MODEL JI J. Mol. Model. PD AUG PY 2009 VL 15 IS 8 BP 897 EP 911 DI 10.1007/s00894-008-0444-3 PG 15 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Multidisciplinary; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Chemistry; Computer Science GA 459ZY UT WOS:000267154200002 PM 19172319 ER PT J AU Klausmeyer, P Howard, OMZ Shipley, SM McCoud, TG AF Klausmeyer, Paul Howard, O. M. Zack Shipley, Suzanne M. McCoud, Thomas G. TI An Inhibitor of CCL2-Induced Chemotaxis from the Fungus Leptoxyphium sp. SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID DIKETOPIPERAZINES; CHEMOKINE; ANALOGS; SYSTEM AB A biological screen used to identify inhibitors of monocyte chemotactic protein-1 (CCL2)-induced chemotaxis was applied in the activity-guided fractionation of an extract from a fungus of the genus Leptoxyphium sp. Inhibition of CCL2-induced chemotaxis was traced to a new dichlorinated diketopiperazine, cyclo(13,15-dichloro-L-Pro-L-Tyr). A structure-activity relationship (SAR) study evaluating relative activities of cyclo(13,15-dichloro-L-Pro-L-Tyr) and a nonchlorinated homologue cyclo(L-Pro-L-Tyr) showed that the dichlorinated molecule was 10- to 20-fold more active than the nonchlorinated form, while no activity was observed for cyclo(D-N-methylLeu-L-Trp). C1 [Klausmeyer, Paul; Shipley, Suzanne M.; McCoud, Thomas G.] SAIC Frederick Inc, Nat Prod Support Grp, Frederick, MD 21702 USA. [Howard, O. M. Zack] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP McCoud, TG (reprint author), SAIC Frederick Inc, Nat Prod Support Grp, Frederick, MD 21702 USA. EM mccloud@dtpax2.ncifcrf.gov RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 FU National Cancer Institute; National Institutes of Health [NO1-CO-12400] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract 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 of the National Cancer Institute. We gratefully acknowledge R. Collins for obtaining the Leptoxyphium spores, J. Klose for NMR experiments, T. Meragelman for informative NNW discussions, R. Akee for assistance with amino acid derivatization, J. Britt for robotics support, J. J. Oppenheim for critical evaluation, and E. Hudson for technical support. NR 18 TC 9 Z9 9 U1 0 U2 4 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 AUG PY 2009 VL 72 IS 8 BP 1369 EP 1372 DI 10.1021/np800745r PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 490FS UT WOS:000269485100001 PM 19637889 ER PT J AU Huang, DD Lin, P Fei, DY Chen, XD Bai, O AF Huang, Dandan Lin, Peter Fei, Ding-Yu Chen, Xuedong Bai, Ou TI Decoding human motor activity from EEG single trials for a discrete two-dimensional cursor control SO JOURNAL OF NEURAL ENGINEERING LA English DT Article ID BRAIN-COMPUTER-INTERFACE; EVENT-RELATED DESYNCHRONIZATION; SUPPORT VECTOR MACHINES; FINGER MOVEMENTS; CORTICAL CONTROL; CLASSIFICATION; COMMUNICATION; SIGNAL; CLASSIFIERS; TECHNOLOGY AB This study aims to explore whether human intentions to move or cease to move right and left hands can be decoded from spatiotemporal features in non-invasive EEG in order to control a discrete two-dimensional cursor movement for a potential multidimensional brain-computer interface (BCI). Five naive subjects performed either sustaining or stopping a motor task with time locking to a predefined time window by using motor execution with physical movement or motor imagery. Spatial filtering, temporal filtering, feature selection and classification methods were explored. The performance of the proposed BCI was evaluated by both offline classification and online two-dimensional cursor control. Event-related desynchronization (ERD) and post-movement event-related synchronization (ERS) were observed on the contralateral hemisphere to the hand moved for both motor execution and motor imagery. Feature analysis showed that EEG beta band activity in the contralateral hemisphere over the motor cortex provided the best detection of either sustained or ceased movement of the right or left hand. The offline classification of four motor tasks (sustain or cease to move right or left hand) provided 10-fold cross-validation accuracy as high as 88% for motor execution and 73% for motor imagery. The subjects participating in experiments with physical movement were able to complete the online game with motor execution at an average accuracy of 85.5 +/- 4.65%; the subjects participating in motor imagery study also completed the game successfully. The proposed BCI provides a new practical multidimensional method by noninvasive EEG signal associated with human natural behavior, which does not need long-term training. C1 [Huang, Dandan; Fei, Ding-Yu; Bai, Ou] Virginia Commonwealth Univ, Dept Biomed Engn, Richmond, VA 23284 USA. [Lin, Peter] Natl Inst Neurol Disorders, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Chen, Xuedong] Huazhong Univ Sci & Technol, Sch Mech Sci & Engn, Wuhan 430074, Hubei, Peoples R China. RP Bai, O (reprint author), Virginia Commonwealth Univ, Dept Biomed Engn, Richmond, VA 23284 USA. EM obai@vcu.edu RI Huang, Dandan/I-3108-2013 NR 39 TC 22 Z9 23 U1 1 U2 14 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 EI 1741-2552 J9 J NEURAL ENG JI J. Neural Eng. PD AUG PY 2009 VL 6 IS 4 AR 046005 DI 10.1088/1741-2560/6/4/046005 PG 12 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA 490EH UT WOS:000269480300006 PM 19556679 ER PT J AU Fuxe, K Marcellino, D Woods, AS Giuseppina, L Antonelli, T Ferraro, L Tanganelli, S Agnati, LF AF Fuxe, Kjell Marcellino, Daniel Woods, Amina S. Giuseppina, Leo Antonelli, Tiziana Ferraro, Luca Tanganelli, Sergio Agnati, Luigi F. TI Integrated signaling in heterodimers and receptor mosaics of different types of GPCRs of the forebrain: relevance for schizophrenia SO JOURNAL OF NEURAL TRANSMISSION LA English DT Article; Proceedings Paper CT International Conference on Brain Plasticity, Aging and Neuropsychiatric Disorders CY MAY 13-14, 2008 CL Madrid, SPAIN SP Ramon Areces Fdn DE D(2); Heterodimers receptor mosaics; A(2A); mGluR5; CB(1); NTS(1) D(3); 5HT(2A); Ventral striatum; Cerebral cortex; Prefrontal cortex; Schizophrenia; Hallucinogenic drugs ID ADENOSINE A(2A) RECEPTORS; DOPAMINE D2 RECEPTORS; MEDIODORSAL THALAMIC NUCLEUS; MEDIUM SPINY NEURONS; METABOTROPIC GLUTAMATE RECEPTORS; VENTRAL STRIATOPALLIDAL SYSTEM; POSITIVE ALLOSTERIC MODULATOR; LYSERGIC ACID DIETHYLAMIDE; PROTEIN-COUPLED RECEPTORS; CENTRAL MONOAMINE NEURONS AB Receptor-receptor interactions within receptor heterodimers and receptor mosaics formed by different types of GPCRs represent an important integrative mechanism for signaling in brain networks at the level of the plasma membrane. The malfunction of special heterodimers and receptor mosaics in the ventral striatum containing D(2) receptors and 5-HT(2A) receptors in cortical networks may contribute to disturbances of key pathways involving ventral striato-pallidal GABA neurons and mediodorsal thalamic prefrontal glutamate neurons that may lead to the development of schizophrenia. The ventral striatum transmits emotional information to the cerebral cortex through a D(2) regulated accumbal-ventral pallidal-mediodorsal-prefrontal circuit which is of special interest to schizophrenia in view of the reduced number of glutamate mediodorsal-prefrontal projections associated with this disease. This circuit is especially vulnerable to D(2) receptor activity in the nucleus accumbens, since it produces a reduction in the prefrontal glutamate drive from the mediodorsal nucleus. The following D(2) receptor containing heterodimers/receptor mosaics are of special interest to schizophrenia: A(2A)-D(2), mGluR5-D(2), CB(1)-D(2), NTS(1)-D(2) and D(2)-D(3) and are discussed in this review. They may have a differential distribution pattern in the local circuits of the ventral striato-pallidal GABA pathway, predominantly located extrasynaptically. Specifically, trimeric receptor mosaics consisting of A(2A)-D(2)-mGluR5 and CB(1)-D(2)-A(2A) may also exist in these local circuits and are discussed. The integration of receptor signaling within assembled heterodimers/receptor mosaics is brought about by agonists and allosteric modulators. These cause the intramembrane receptor-receptor interactions, via allosteric mechanisms, to produce conformational changes that pass over the receptor interfaces. Exogenous and endogenous cooperativity is discussed as well as the role of the cortical mGluR2-5-HT(2A) heterodimer/receptor mosaic in schizophrenia (Gonzalez-Maeso et al. 2008). Receptor-receptor interactions within receptor heterodimer/receptor mosaics of different receptors in the ventral striatum and cerebral cortex give novel strategies for treatment of schizophrenia involving, e.g., monotherapy with either A(2A), mGluR5, CB(1) or NTS(1) agonists or combined therapies with some of these agonists combined with D(2)-like antagonists that specifically target the ventral striatum. In addition, a combined targeting of receptor mosaics in the ventral striatum and in the cerebral cortex should also be considered. C1 [Fuxe, Kjell; Marcellino, Daniel] Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. [Woods, Amina S.] NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD USA. [Giuseppina, Leo; Agnati, Luigi F.] Univ Modena, Dept Biomed Sci, I-41100 Modena, Italy. [Giuseppina, Leo; Agnati, Luigi F.] IRCCS Lido, Venice, Italy. [Antonelli, Tiziana; Ferraro, Luca; Tanganelli, Sergio] Univ Ferrara, Dept Clin & Expt Med, Pharmacol Sect, I-44100 Ferrara, Italy. RP Fuxe, K (reprint author), Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden. EM Kjell.Fuxe@ki.se RI Ferraro, Luca/F-9915-2015; Antonelli, Tiziana/I-7677-2015; Tanganelli, Sergio/I-7704-2015; OI Ferraro, Luca/0000-0003-2390-6414; Antonelli, Tiziana/0000-0001-5895-7807; Tanganelli, Sergio/0000-0001-7576-3510; Marcellino, Daniel/0000-0002-4618-7267; Fuxe, Kjell/0000-0001-8491-4288 FU Intramural NIH HHS [Z99 DA999999] NR 167 TC 27 Z9 29 U1 3 U2 7 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0300-9564 J9 J NEURAL TRANSM JI J. Neural Transm. PD AUG PY 2009 VL 116 IS 8 BP 923 EP 939 DI 10.1007/s00702-008-0174-9 PG 17 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 470ZD UT WOS:000268020100002 PM 19156349 ER PT J AU Meethal, SV Liu, TB Chan, HW Ginsburg, E Wilson, AC Gray, DN Bowen, RL Vonderhaar, BK Atwood, CS AF Meethal, Sivan Vadakkadath Liu, Tianbing Chan, Hsien W. Ginsburg, Erika Wilson, Andrea C. Gray, Danielle N. Bowen, Richard L. Vonderhaar, Barbara K. Atwood, Craig S. TI Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors SO JOURNAL OF NEUROCHEMISTRY LA English DT Review DE Alzheimer's disease; estrogen receptor; feedback loop; gonadotropin-releasing hormone receptor I; neurosteroid; steroidogenic acute regulatory protein ID GONADOTROPIN-RELEASING-HORMONE; LEYDIG TUMOR-CELLS; MESSENGER-RIBONUCLEIC-ACID; BLOOD-BRAIN-BARRIER; HIPPOCAMPAL ESTROGEN SYNTHESIS; PORCINE GRANULOSA-CELLS; CENTRAL-NERVOUS-SYSTEM; CHAIN CLEAVAGE ENZYME; RAT GLIAL-CELLS; GROWTH-FACTOR-I AB Brain sex steroids are derived from both peripheral (primarily gonadal) and local (neurosteroids) sources and are crucial for neurogenesis, neural differentiation and neural function. The mechanism(s) regulating the production of neurosteroids is not understood. To determine whether hypothalamic-pituitary-gonadal axis components previously detected in the extra-hypothalamic brain comprise a feedback loop to regulate neuro-sex steroid (NSS) production, we assessed dynamic changes in expression patterns of steroidogenic acute regulatory (StAR) protein, a key regulator of steroidogenesis, and key hypothalamic-pituitary-gonadal endocrine receptors, by modulating peripheral sex hormone levels in female mice. Ovariectomy (OVX; high serum gonadotropins, low serum sex steroids) had a differential effect on StAR protein levels in the extrahypothalamic brain; increasing the 30- and 32-kDa variants but decreasing the 37-kDa variant and is indicative of cholesterol transport into mitochondria for steroidogenesis. Treatment of OVX animals with E(2), P(4), or E(2) + P(4) for 3 days, which decreases OVX-induced increases in GnRH/gonadotropin production, reversed this pattern. Suppression of gonadotropin levels in OVX mice using the GnRH agonist leuprolide acetate inhibited the processing of the 37-kDa StAR protein into the 30-kDa StAR protein, confirming that the differential processing of brain StAR protein is regulated by gonadotropins. OVX dramatically suppressed extra-hypothalamic brain gonadotropin-releasing hormone 1 receptor expression, and was further suppressed in E(2)- or P(4)-treated OVX mice. Together, these data indicate the existence of endocrine and autocrine/paracrine feedback loops that regulate NSS synthesis. Further delineation of these feedback loops that regulate NSS production will aid in developing therapies to maintain brain sex steroid levels and cognition. C1 [Meethal, Sivan Vadakkadath; Liu, Tianbing; Chan, Hsien W.; Wilson, Andrea C.; Atwood, Craig S.] Univ Wisconsin & Geriatr Res, Dept Med, Vet Adm Hosp, Educ & Clin Ctr, Madison, WI USA. [Ginsburg, Erika; Vonderhaar, Barbara K.] NCI, Mammary Biol & Tumorigenesis Lab, Bethesda, MD 20892 USA. [Gray, Danielle N.] Tuskegee Univ, Dept Biol, Tuskegee, AL 36088 USA. [Bowen, Richard L.] OTB Res, Raleigh, NC USA. [Atwood, Craig S.] Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA. [Atwood, Craig S.] Edith Cowan Univ, Sch Exercise Biomed & Hlth Sci, Joondalup, WA, Australia. RP Atwood, CS (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Wm S Middleton Mem VA GRECC 11G, 2500 Overlook Terrace, Madison, WI 53705 USA. EM csa@medicine.wisc.edu FU Alzheimer's Association FX This work was supported by funds from the Alzheimer's Association. This is VA GRECC manuscript 2009-06. NR 140 TC 18 Z9 18 U1 3 U2 10 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 AUG PY 2009 VL 110 IS 3 BP 1014 EP 1027 DI 10.1111/j.1471-4159.2009.06192.x PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 470IP UT WOS:000267968700023 PM 19493163 ER PT J AU Kim, HJ Leeds, P Chuang, DM AF Kim, Hyeon Ju Leeds, Peter Chuang, De-Maw TI The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE brain-derived neurotrophic factor; bromo-2'-deoxyuridine; cerebral ischemia; histone deacetylase inhibitors; K252a; neurogenesis ID ELEMENT-BINDING PROTEIN; FOCAL CEREBRAL-ISCHEMIA; HISTONE DEACETYLASE INHIBITION; TRANSIENT GLOBAL-ISCHEMIA; ROSTRAL MIGRATORY STREAM; ADULT DENTATE GYRUS; SUBVENTRICULAR ZONE; NEUROTROPHIC FACTOR; NEURONAL DIFFERENTIATION; PROGENITOR CELLS AB In the healthy adult brain, neurogenesis normally occurs in the subventricular zone (SVZ) and hippocampal dentate gyrus (DG). Cerebral ischemia enhances neurogenesis in neurogenic and non-neurogenic regions of the ischemic brain of adult rodents. This study demonstrated that post-insult treatment with a histone deacetylase inhibitor, sodium butyrate (SB), stimulated the incorporation of bromo-2'-deoxyuridine (BrdU) in the SVZ, DG, striatum, and frontal cortex in the ischemic brain of rats subjected to permanent cerebral ischemia. SB treatment also increased the number of cells expressing polysialic acid-neural cell adhesion molecule, nestin, glial fibrillary acidic protein, phospho-cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF) in various brain regions after cerebral ischemia. Furthermore, extensive co-localization of BrdU and polysialic acid-neural cell adhesion molecule was observed in multiple regions after ischemia, and SB treatment up-regulated protein levels of BDNF, phospho-CREB, and glial fibrillary acidic protein. Intraventricular injection of K252a, a tyrosine kinase B receptor antagonist, markedly reduced SB-induced cell proliferation detected by BrdU and Ki67 in the ipsilateral SVZ, DG, and other brain regions, blocked SB-induced nestin expression and CREB activation, and attenuated the long-lasting behavioral benefits of SB. Together, these results suggest that histone deacetylase inhibitor-induced cell proliferation, migration and differentiation require BDNF-tyrosine kinase B signaling and may contribute to long-term beneficial effects of SB after ischemic injury. C1 [Kim, Hyeon Ju; Leeds, Peter; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, Mood & Anxiety Disorders Program, NIH, Bldg 10,Room 3D38,10 Ctr Dr MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov FU Intramural Research Program, NIMH, NIH; NIMH and the NIH Fellows Editorial Board FX This study was supported by the Intramural Research Program, NIMH, NIH. We thank Dr Carolyn Smith of NINDS, NIH for technical assistance with the confocal microscope study. We are grateful for the assistance of Ioline Henter of NIMH and the NIH Fellows Editorial Board for their review of this manuscript. NR 49 TC 113 Z9 128 U1 1 U2 7 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 AUG PY 2009 VL 110 IS 4 BP 1226 EP 1240 DI 10.1111/j.1471-4159.2009.06212.x PG 15 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 473QB UT WOS:000268221500009 PM 19549282 ER PT J AU Chen, J Liu, Y Soh, JW Aguilera, G AF Chen, Jun Liu, Ying Soh, Jae-Won Aguilera, Greti TI Antiapoptotic effects of vasopressin in the neuronal cell line H32 involve protein kinase C alpha and beta SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE apoptosis; Bad; extracellular signal-regulated kinases; protein kinase C; V1a receptor; vasopressin ID NERVE GROWTH-FACTOR; SYMPATHETIC NEURONS; RECEPTOR ANTAGONIST; PHORBOL ESTERS; PKC-DELTA; APOPTOSIS; SURVIVAL; ACTIVATION; RELEASE; RAT AB Activation of V1 vasopressin (VP) receptors prevents serum deprivation-induced apoptosis in neuronal H32 cells, partially through mitogen-activated protein kinase (MAPK) mediated Bad phosphorylation. In this study, we investigated the role of protein kinases C (PKC) and B (PKB) mediating VP-induced antiapoptosis in H32 cells. Serum deprivation increased PKC delta but not PKC alpha or PKC beta activity, while VP increased PKC alpha and PKC beta without affecting PKC delta activity. Inhibition of PKC delta prevented caspase 3 activation, indicating that PKC delta mediates the pro-apoptotic actions of serum deprivation. Simultaneous inhibition of PKC alpha and beta and MAPK abolished VP-induced Bad phosphorylation, but it only partially prevented caspase 3 inhibition. Complete abolition of the protective effect of VP on serum deprivation-induced caspase 3 activity required additional blockade of phosphoinositide 3 kinase (PI3K)/protein kinase B. The data demonstrate that VP exerts antiapoptosis through multiple pathways; while PKC alpha and beta together with extracellular signal-regulated kinases/MAPK activation mediates Bad phosphorylation (inactivation), the full protective action of VP requires additional activation of PKB (PI3K/protein kinase B) pathway. C1 [Aguilera, Greti] NICHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH,CRC, Bethesda, MD 20892 USA. [Soh, Jae-Won] Inha Univ, Dept Chem, Inchon, South Korea. RP Aguilera, G (reprint author), NICHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH,CRC, Room 1E-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM Greti_Aguilera@nih.gov FU Intramural Research Program of National Institute of Child Health and Human Development, NIH FX This work was supported by the Intramural Research Program of National Institute of Child Health and Human Development, NIH. NR 40 TC 12 Z9 12 U1 0 U2 0 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 AUG PY 2009 VL 110 IS 4 BP 1310 EP 1320 DI 10.1111/j.1471-4159.2009.06219.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 473QB UT WOS:000268221500016 PM 19519660 ER PT J AU Cooper, O Astradsson, A Hallett, P Robertson, H Mendez, I Isacson, O AF Cooper, Oliver Astradsson, Arnar Hallett, Penny Robertson, Harold Mendez, Ivar Isacson, Ole TI Lack of functional relevance of isolated cell damage in transplants of Parkinson's disease patients SO JOURNAL OF NEUROLOGY LA English DT Article; Proceedings Paper CT 17th Symposium on the Treatment of Parkinsons Disease CY NOV 27, 2008 CL Tokyo, JAPAN DE Cell transplantation; Lewy body; Therapy; Dopaminergic ID MIDBRAIN DOPAMINE NEURONS; FETAL NIGRAL TRANSPLANTATION; DEEP BRAIN-STIMULATION; SUBTHALAMIC NUCLEUS; NEURODEGENERATIVE DISEASES; MESENCEPHALIC TISSUE; ANIMAL-MODEL; FOLLOW-UP; GRAFTS; SURVIVE AB Postmortem analyses from clinical neural transplantation trials of several subjects with Parkinson's disease revealed surviving grafted dopaminergic neurons after more than a decade. A subset of these subjects displayed isolated dopaminergic neurons within the grafts that contained Lewy body-like structures. In this review, we discuss why this isolated cell damage is unlikely to affect the overall graft function and how we can use these observations to help us to understand age-related neurodegeneration and refine our future cell replacement therapies. C1 [Cooper, Oliver; Astradsson, Arnar; Hallett, Penny; Isacson, Ole] Harvard Univ, McLean Hosp, Sch Med,Ctr Neuroregenerat Res, NINDS Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. [Robertson, Harold] Dalhousie Univ, Dept Pharmacol, Halifax, NS B3H 4H7, Canada. [Mendez, Ivar] Dalhousie Univ, Queen Elizabeth II Hlth Sci Ctr, Div Neurosurg & Neurosci, Halifax, NS B3H 4H7, Canada. RP Isacson, O (reprint author), Harvard Univ, McLean Hosp, Sch Med,Ctr Neuroregenerat Res, NINDS Udall Parkinsons Dis Res Ctr Excellence, MRC 130,115 Mill St, Belmont, MA 02478 USA. EM isacson@hms.harvard.edu OI Cooper, Oliver/0000-0001-6567-7491; Hallett, Penelope/0000-0002-8858-9096 NR 49 TC 18 Z9 18 U1 0 U2 1 PU DR DIETRICH STEINKOPFF VERLAG PI HEIDELBERG PA TIERGARTENSTRASSE 17, 69121 HEIDELBERG, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD AUG PY 2009 VL 256 BP S310 EP S316 DI 10.1007/s00415-009-5242-z PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 494FQ UT WOS:000269797500008 PM 19711122 ER PT J AU Ragert, P Camus, M Vandermeeren, Y Dimyan, MA Cohen, LG AF Ragert, Patrick Camus, Mickael Vandermeeren, Yves Dimyan, Michael A. Cohen, Leonardo G. TI Modulation of Effects of Intermittent Theta Burst Stimulation Applied Over Primary Motor Cortex (M1) by Conditioning Stimulation of the Opposite M1 SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; NONINVASIVE BRAIN-STIMULATION; HOMEOSTATIC PLASTICITY; ASSOCIATIVE PLASTICITY; CORTICAL PLASTICITY; QUANTAL AMPLITUDE; STROKE PATIENTS; PINCH STRENGTH; EXCITABILITY; INHIBITION AB Ragert P, Camus M, Vandermeeren Y, Dimyan MA, Cohen LG. Modulation of effects of intermittent theta burst stimulation applied over primary motor cortex (M1) by conditioning stimulation of the opposite M1. J Neurophysiol 102: 766-773, 2009. First published May 27, 2009; doi:10.1152/jn.00274.2009. The excitability of the human primary motor cortex (M1) as tested with transcranial magnetic stimulation (TMS) depends on its previous history of neural activity. Homeostatic plasticity might be one important physiological mechanism for the regulation of corticospinal excitability and synaptic plasticity. Although homeostatic plasticity has been demonstrated locally within M1, it is not known whether priming M1 could result in similar homeostatic effects in the homologous M1 of the opposite hemisphere. Here, we sought to determine whether down-regulating excitability (priming) in the right (R) M1 with 1-Hz repetitive transcranial magnetic stimulation (rTMS) changes the excitability-enhancing effect of intermittent theta burst stimulation (iTBS) applied over the homologous left (L) M1. Subjects were randomly allocated to one of four experimental groups in a sham-controlled parallel design with real or sham R M1 1-Hz TMS stimulation always preceding L M1 iTBS or sham by about 10 min. The primary outcome measure was corticospinal excitability in the L M1, as measured by recruitment curves (RCs). Secondary outcome measures included pinch force, simple reaction time, and tapping speed assessed in the right hand. The main finding of this study was that preconditioning R M1 with 1-Hz rTMS significantly decreased the excitability-enhancing effects of subsequent L M1 iTBS on RCs. Application of 1-Hz rTMS over R M1 alone and iTBS over L M1 alone resulted in increased RC in L M1 relative to sham interventions. The present findings are consistent with the hypothesis that homeostatic mechanisms operating across hemispheric boundaries contribute to regulate motor cortical function in the primary motor cortex. C1 [Ragert, Patrick; Camus, Mickael; Vandermeeren, Yves; Dimyan, Michael A.; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20817 USA. [Ragert, Patrick] Max Planck Inst Human Cognit & Brain Sci, Dept Cognit Neurol, Leipzig, Germany. [Vandermeeren, Yves] Univ Catholique Louvain Mt Godinne, Dept Neurobiol, Clin Univ, Yvoir, Belgium. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20817 USA. EM cohen1@ninds.nih.gov RI Dimyan, Michael/B-1715-2012; OI Dimyan, Michael/0000-0002-9715-9741 FU Deutsche Forschungsgemeinschaft [Ra 13911-1]; National Institute of Neurological Disorders and Stroke (NINDS); Research Council of the University of Louvain (Belgium) FX This research was supported by Deutsche Forschungsgemeinschaft Grant Ra 13911-1 to P. Ragert and by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS). Y. Vandermeeren and M. A. Dimyan were supported by a NINDS Competitive Fellowship Grant. Y. Vandermeeren was supported by a postdoctoral grant from the Research Council of the University of Louvain (Belgium). NR 45 TC 20 Z9 20 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2009 VL 102 IS 2 BP 766 EP 773 DI 10.1152/jn.00274.2009 PG 8 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 490KS UT WOS:000269500400012 PM 19474173 ER PT J AU Feng, X Henriquez, VM Walters, JR Ludlow, CL AF Feng, Xin Henriquez, Victor M. Walters, Judith R. Ludlow, Christy L. TI Effects of Dopamine D-1 and D-2 Receptor Antagonists on Laryngeal Neurophysiology in the Rat SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID SUBTHALAMIC NUCLEUS STIMULATION; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; MUSCLE TONE; BLINK REFLEX; SQUIRREL-MONKEY; SPEECH; D1; BRAIN; VOCALIZATION AB Feng X, Henriquez VM, Walters JR, Ludlow CL. Effects of dopamine D-1 and D-2 receptor antagonists on laryngeal neurophysiology in the rat. J Neurophysiol 102: 1193-1205, 2009. First published June 17, 2009; doi: 10.1152/jn.00121.2009. Hypophonia is an early symptom in Parkinson's disease (PD) that involves an increase in laryngeal muscle activity, interfering with voice production. Our aim was to use an animal model to better understand the role of different dopamine receptor subtypes in the control of laryngeal neurophysiology. First, we evaluated the combined effects of SCH23390-a D-1 receptor antagonist with a D-2 receptor antagonist (eticlopride) on laryngeal neurophysiology, and then tested the separate effects of selective receptor antagonists. Thyroarytenoid (TA) and gastrocnemius (GN) muscle activity was measured at rest and while stimulating the internal branch of superior laryngeal nerve to elicit the laryngeal adductor response (LAR) in alpha-chloralose-anesthetized rats. Paired stimuli at different interstimulus intervals between 250 and 5,000 ms measured central conditioning of the LAR. Changes in resting muscle activity, response latency, amplitude, and LAR conditioning after each drug were compared with the saline control. SCH23390 alone increased the resting TA muscle activity (P < 0.05). With the combined SCH23390 + eticlopride or SCH23390 alone, response latency decreased (P < 0.01), amplitude increased (P < 0.01), and the test LAR was reduced at 2,000-ms ISI (P < 0.01). No LAR changes occurred when eticlopride was administered alone at a low dose and only a tendency to suppress responses was found at a high dose. No changes in GN muscle activity occurred in any of the groups. The results suggest that a loss of stimulation of D-1 receptors plays a significant role in laryngeal pathophysiology in PD. C1 [Feng, Xin; Henriquez, Victor M.; Ludlow, Christy L.] NINDS, Laryngeal & Speech Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Walters, Judith R.] NINDS, Neurophysiol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Ludlow, CL (reprint author), NINDS, Laryngeal & Speech Sect, Med Neurol Branch, NIH, Bldg 10,Room5D38, Bethesda, MD 20892 USA. EM ludlowcx@jmu.edu OI Ludlow, Christy/0000-0002-2015-6171 FU Intramural Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This work was supported by the Intramural Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 53 TC 8 Z9 8 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2009 VL 102 IS 2 BP 1193 EP 1205 DI 10.1152/jn.00121.2009 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 490KS UT WOS:000269500400050 PM 19535485 ER PT J AU Israelsson, C Wang, Y Kylberg, A Pick, CG Hoffer, BJ Ebendal, T AF Israelsson, Charlotte Wang, Yun Kylberg, Annika Pick, Chaim G. Hoffer, Barry J. Ebendal, Ted TI Closed Head Injury in a Mouse Model Results in Molecular Changes Indicating Inflammatory Responses SO JOURNAL OF NEUROTRAUMA LA English DT Article DE closed head injury; GeneChip array; inflammation; mild trauma; quantitative RT-PCR; weight drop impact ID TRAUMATIC BRAIN-INJURY; RAT CEREBRAL-CORTEX; GENE-EXPRESSION; COGNITIVE DEFICITS; HYPOXIA-ISCHEMIA; MICE; MECHANISMS; CHEMOKINES; PATTERNS; SEQUELAE AB Cerebral gene expression changes in response to traumatic brain injury will provide useful information in the search for future trauma treatment. In order to characterize the outcome of mild brain injury, we studied C57BL/6J mice in a weight-drop, closed head injury model. At various times post-injury, mRNA was isolated from neocortex and hippocampus and transcriptional alterations were studied using quantitative reverse transcriptase PCR and gene array analysis. At three days post-injury, the results showed unilateral injury responses, both in neocortex and hippocampus, with the main effect seen on the side of the skull hit by the dropping weight. Upregulated transcripts encoded products characterizing reactive astrocytes, phagocytes, microglia, and immune-reactive cells. Markers for oligodendrocytes and T-cells were not altered. Notably, strong differences in the responses among individual mice were seen (e. g., for the Gfap transcript expressed by reactive astrocytes and the chemokine Ccl3 transcript expressed by activated microglial cells). In conclusion, mild TBI chiefly activates transcripts leading to tissue signaling, inflammatory processes, and chemokine signaling, as in focal brain injury, suggesting putative targets for drug development. C1 [Israelsson, Charlotte; Kylberg, Annika; Ebendal, Ted] Uppsala Univ, Biomed Ctr, Dept Neurosci, SE-75124 Uppsala, Sweden. [Wang, Yun; Hoffer, Barry J.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. [Pick, Chaim G.] Tel Aviv Univ, Sackler Fac Med, Dept Anat & Anthropol, IL-69978 Tel Aviv, Israel. RP Ebendal, T (reprint author), Uppsala Univ, Biomed Ctr, Dept Neurosci, POB 593, SE-75124 Uppsala, Sweden. EM Ted.Ebendal@neuro.uu.se RI Pick, Chaim/D-4789-2009 FU Swedish Research Council [2006-3014]; Swedish Brain Research Foundation; Sparbanksstiftelsen Upland; NIH; NIDA FX This work was supported by the Swedish Research Council (grant no. 2006-3014 [T. E.]), the Swedish Brain Research Foundation/Sparbanksstiftelsen Upland (T. E. and C. I.), and intramural grants from NIH/NIDA (B. J. H.). Hanna Goransson and Maria Rydaker carried out the GeneChip procedures. NR 23 TC 32 Z9 32 U1 0 U2 3 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 AUG PY 2009 VL 26 IS 8 BP 1307 EP 1314 DI 10.1089/neu.2008.0676 PG 8 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 479AF UT WOS:000268629900013 PM 19317611 ER PT J AU Endres, CJ Pomper, MG James, M Uzuner, O Hammoud, DA Watkins, CC Reynolds, A Hilton, J Dannals, RF Kassiou, M AF Endres, Christopher J. Pomper, Martin G. James, Michelle Uzuner, Ovsev Hammoud, Dima A. Watkins, Crystal C. Reynolds, Aaron Hilton, John Dannals, Robert F. Kassiou, Michael TI Initial Evaluation of C-11-DPA-713, a Novel TSPO PET Ligand, in Humans SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE compartmental analysis; microglia; positron emission tomography; translocator protein ID PERIPHERAL BENZODIAZEPINE-RECEPTOR; POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; HUMAN BRAIN; TRANSLOCATOR PROTEIN; ACTIVATED MICROGLIA; BINDING-SITES; 18 KDA; RADIOLIGAND; NEUROINFLAMMATION AB Translocator protein (TSPO) is upregulated in activated microglia and thus can serve as a marker of neuroinflammation. Recently, a novel radioligand, C-11-N, N-diethyl-2-[2-(4-methoxyphenyl)-5,7dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-acetamide (C-11-DPA-713), has been described that binds to TSPO with high affinity. Here, we report the first examination of C-11-DPA-713 in human subjects using PET. Methods: Five healthy controls were studied with PET for 90 min after a bolus injection of high-specific-activity C-11-DPA-713. For comparison, 2 additional healthy controls were studied with C-11-R-PK11195. Arterial blood sampling and metabolite analysis were performed to allow the accurate quantification of tracer kinetics. Tracer uptake was evaluated for several brain regions. Tissue time-activity curves were fitted using 1- and 2-tissue-compartment-models, with goodness-of-fit tests showing a preference for the 2-tissue model. Results: In the healthy brain, the average plasma-to-tissue clearance and the total volume of distribution were an order of magnitude larger than measured for C-11-R-PK11195. Accordingly, dose-normalized time -activity curves showed that C-11-DPA-713 gives a larger brain signal. Conclusion: Studies in patient populations will help determine whether C-11-DPA-713 provides better sensitivity for evaluating increased TSPO expression. This initial study in humans shows that C-11-DPA-713 is a promising ligand for evaluating TSPO binding with PET. C1 [Endres, Christopher J.; Pomper, Martin G.; Uzuner, Ovsev; Watkins, Crystal C.; Hilton, John; Dannals, Robert F.] Johns Hopkins Univ, Div Neuroradiol, Baltimore, MD 21231 USA. [James, Michelle; Kassiou, Michael] Univ Sydney, Brain & Mind Res Inst, Sydney, NSW 2006, Australia. [Hammoud, Dima A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Reynolds, Aaron; Kassiou, Michael] Univ Sydney, Sch Chem, Sydney, NSW 2006, Australia. [Kassiou, Michael] Univ Sydney, Discipline Med Radiat Sci, Sydney, NSW 2006, Australia. RP Endres, CJ (reprint author), Johns Hopkins Univ, Div Neuroradiol, 1550 Orleans St,CRB 2,Room 491, Baltimore, MD 21231 USA. EM endres@jhmi.edu RI Hammoud, Dima/C-2286-2015 FU Dana Foundation; NIMH FX We appreciate the contribution of our research coordinators Rena Geckle and Priscilla Matthews for recruiting subjects, screening, and organizing subject records. This study is supported by a grant from The Dana Foundation (to M. G. P.) and the NIMH Toxicological Evaluation of Novel Ligands Program. NR 32 TC 58 Z9 58 U1 0 U2 4 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD AUG PY 2009 VL 50 IS 8 BP 1276 EP 1282 DI 10.2967/jnumed.109.062265 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 529VX UT WOS:000272548100018 PM 19617321 ER PT J AU Harris-Love, MO Shrader, JA AF Harris-Love, Michael O. Shrader, Joseph A. TI Patellofemoral Knee Pain in an Adult With Radiographic Osteoarthritis and Human Immunodeficiency Virus Infection SO JOURNAL OF ORTHOPAEDIC & SPORTS PHYSICAL THERAPY LA English DT Article DE human immunodeficiency virus (HIV); Kaposi's sarcoma; knee pain; physical therapy ID ANTERIOR CRUCIATE LIGAMENT; LACHMAN TEST; PHYSICAL-EXAMINATION; CLINICAL-DIAGNOSIS; HIP STRENGTH; DRAWER SIGN; RELIABILITY; AIDS; INDIVIDUALS; MANAGEMENT AB STUDY DESIGN: Resident's case problem. BACKGROUND: Kaposi's sarcoma (KS) is the most common form of cancer in patients with human immunodeficiency virus (HIV) infection. Although KS is often initially asymptomatic, this neoplasm may progress to affect multiple organ systems, including structures of the musculoskeletal system, which can produce symptoms similar to those associated with common orthopaedic conditions. This resident's case problem describes the evaluation and differential diagnosis of a 45-year-old male with HIV and KS, referred to physical therapy with an initial diagnosis of radiographic osteoarthritis (OA) and patellofemoral pain syndrome (PFPS) of the left knee. His primary complaint was knee pain during end range knee flexion. DIAGNOSIS: The history systems review, and examination suggested a source of pain of a nonorthopaedic origin. Differential examination ruled out clinical CA, PFPS, ligament/cartilage derangement, and tendonitis. Avascular necrosis of the medial femoral condyle was also considered as a possible source of pain. Recent blood tests indicated a high viral load and low CD4 count, which might have increased susceptibility to opportunistic infections or KS tumor progression. The patient was referred back to his physician for additional follow-up. Magnetic resonance imaging (MRI) of the knees were consistent with a systemic inflammatory process such as KS. A true-cut biopsy was subsequently scheduled, which confirmed KS lesions at the left knee. DISCUSSION: Physical therapists who manage orthopaedic conditions should be aware of the disablement that may result from acquired immunodeficiency syndrome-related KS. A thorough joint-specific examination, with a broad differential diagnosis, should be employed for patients having known systemic diseases. C1 [Harris-Love, Michael O.] Washington DC VAMC, Res Serv, Geriatr & Extended Care Serv, Washington, DC 20422 USA. [Harris-Love, Michael O.] George Washington Univ, Sch Med & Hlth Sci, Doctor Phys Therapy Program, Washington, DC 20052 USA. [Harris-Love, Michael O.; Shrader, Joseph A.] NIH, Dept Rehabil Med, Phys Therapy Sect, Ctr Clin,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Harris-Love, MO (reprint author), Washington DC VAMC, Res Serv, Geriatr & Extended Care Serv, G11,50 Irving St,NW, Washington, DC 20422 USA. EM michael.harris-love@va.gov RI Harris-Love, Michael/J-1359-2014 OI Harris-Love, Michael/0000-0002-1842-3269 NR 51 TC 1 Z9 1 U1 0 U2 4 PU J O S P T, PI ALEXANDRIA PA 1111 NORTH FAIRFAX ST, STE 100, ALEXANDRIA, VA 22314-1436 USA SN 0190-6011 J9 J ORTHOP SPORT PHYS JI J. Orthop. Sports Phys. Ther. PD AUG PY 2009 VL 39 IS 8 BP 612 EP 617 DI 10.2519/jospt.2009.2961 PG 6 WC Orthopedics; Rehabilitation; Sport Sciences SC Orthopedics; Rehabilitation; Sport Sciences GA 482BZ UT WOS:000268859900005 PM 19648722 ER PT J AU Kassis, JN Virador, VM Guancial, EA Kimm, D Ho, AS Mishra, M Chuang, EY Cook, J Gius, D Kohn, EC AF Kassis, Jareer N. Virador, Victoria M. Guancial, Elizabeth A. Kimm, Daniel Ho, Allen S. Mishra, Mark Chuang, Eric Y. Cook, John Gius, David Kohn, Elise C. TI Genomic and phenotypic analysis reveals a key role for CCN1 (CYR61) in BAG3-modulated adhesion and invasion SO JOURNAL OF PATHOLOGY LA English DT Article DE adhesion; BAG3; genomic analysis; CCN1; Cyr61; integrin engagement ID EPITHELIAL-MESENCHYMAL TRANSITION; PRO-ANGIOGENIC ACTIVITIES; IMMEDIATE-EARLY GENE; SMOOTH-MUSCLE-CELLS; ENDOTHELIAL-CELLS; BINDING-SITE; CANCER-CELLS; IN-VIVO; EXPRESSION; PROTEINS AB Chaperone protein quantity may regulate the balance of proteins involved in invasion and malignancy. BAG3 is a co-chaperone and pro-survival protein that has been implicated in adhesion, migration, and metastasis. We reported that BAG3 overexpression in MDA435 human breast cancer cells results in a significant decrease in migration and adhesion to matrix molecules that is reversed upon deletion of the BAG3 proline-rich domain (dPXXP). We now hypothesize that transcriptional analysis would identify proteins involved in matrix-related processes that are regulated by BAG3 and/or its PXXP domain mutant. Expression array analysis of MDA435 cells overexpressing either wild-type BAG3 (FL) or dPXXP identified CCN1 as a BAG3 target protein. CCN1 is a known AP-1 target. Increased AP-1 transcriptional activity and AP-1 DNA-binding was found in MDA435 dPXXP cells. Consistent with these findings, CCN1 quantity and secretion were increased in dPXXP mutants but suppressed in FL cells; both BAG3 forms resulted in up-regulated CCN1 in HeLa cells. CCN1 silencing in the BAG3 FL overexpressors reduced the already low phospho-integrin beta 1 in response to attachment on collagen IV. Matrigel invasion of HeLa cells engineered with the BAG3 constructs was enhanced in FL cells and minimal in dPXXP cells. CCN1 silencing blocked a greater percentage of the serum-induced invasion in FL cells than in dPXXP cells. This implies a context-dependent function of BAG3 oil CCN1 and thus mesenchymal behaviour. CCN1 may be necessary for adhesion and matrix-related signalling in FL cells, abrogating a negative signal of the PXXP domain when BAG3 is intact. We propose that BAG3 regulates CCN1 expression to regulate tumour cell adhesion Published in 2009 by John Wiley & Sons, Ltd. C1 [Kassis, Jareer N.; Virador, Victoria M.; Guancial, Elizabeth A.; Kimm, Daniel; Kohn, Elise C.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Ho, Allen S.; Mishra, Mark; Chuang, Eric Y.; Gius, David] NCI, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Cook, John] NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kohn, EC (reprint author), 10 Ctr Dr,MSC 1906, Bethesda, MD 20892 USA. EM kohne@mail.nih.gov FU Howard Hughes Medical Institute/National Institutes of Health Research Scholar; Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX EAG was it Howard Hughes Medical Institute/National Institutes of Health Research Scholar. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 40 TC 14 Z9 14 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3417 EI 1096-9896 J9 J PATHOL JI J. Pathol. PD AUG PY 2009 VL 218 IS 4 BP 495 EP 504 DI 10.1002/path.2557 PG 10 WC Oncology; Pathology SC Oncology; Pathology GA 477IA UT WOS:000268511400010 PM 19402132 ER PT J AU Gulmann, C Sheehan, KM Conroy, RM Wulfkuhie, JD Espina, V Mullarkey, MJ Kay, EW Liotta, LA Petricoin, EF AF Gulmann, Christian Sheehan, Katherine M. Conroy, Ronan M. Wulfkuhie, Julia D. Espina, Virginia Mullarkey, Michelle J. Kay, Elaine W. Liotta, Lance A. Petricoin, Emanuel F., III TI Quantitative cell signalling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer SO JOURNAL OF PATHOLOGY LA English DT Article DE colorectal cancer; MAPK; Erk; p38; phosphorylation; proteomics ID PHASE PROTEIN MICROARRAYS; DIFFERENTIAL REGULATION; KINASE; CARCINOMA; EXPRESSION AB Mitogen-activated protein kinases (MAPK) are considered to play significant roles in colonic carcinogenesis and kinase inhibitor therapy has been proposed as a potential tool in the treatment of this disease. Reverse-phase microarray assays using phospho-specific antibodies can directly measure levels of phosphorylated protein isoforms. In the current study, samples from 35 cases of untreated colorectal cancer colectomies were laser capture-microdissected to isolate epithelium and stroma from cancer as well as normal (i.e. uninvolved) mucosa. Lysates generated from these four tissue types were spotted onto reverse-phase protein microarrays and probed with a panel of antibodies to ERK, p-ERK, p38, p-p38, p-JNK, MEK and p-MEK. Whereas total protein levels were unchanged, or slightly elevated (p38, p = 0.0025) in cancers, activated isoforms, including p-ERK, p-p38 and p-JNK, were decreased two- to four-fold in cancers compared with uninvolved mucosa (p < 0.0023 in all cases except for p-JNK in epithelium, where decrement was non-significant). This was backed up by western blotting. Dukes' stage B and C cancers displayed lower p-ERK and p-p38 expression than Dukes' stage A cancers, although this was not statistically significant. It is concluded that MAPK activity may be down-regulated in colorectal cancer and that further exploration of inhibitory therapy in this system should be carefully evaluated if this finding is confirmed in larger series. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Gulmann, Christian; Sheehan, Katherine M.; Kay, Elaine W.] Beaumont Hosp, Dept Pathol, Dublin 9, Ireland. [Sheehan, Katherine M.; Mullarkey, Michelle J.; Kay, Elaine W.] Royal Coll Surgeons Ireland, Dept Pathol, Dublin 2, Ireland. [Gulmann, Christian; Sheehan, Katherine M.; Espina, Virginia; Liotta, Lance A.] NCI, FDA Clin Prote Program, Pathol Lab, Bethesda, MD USA. [Conroy, Ronan M.] Royal Coll Surgeons Ireland, Dept Epidemiol, Dublin 2, Ireland. [Wulfkuhie, Julia D.; Espina, Virginia; Liotta, Lance A.; Petricoin, Emanuel F., III] George Mason Univ, Ctr Appl Prote & Mol Med, Manassas, VA USA. [Wulfkuhie, Julia D.; Petricoin, Emanuel F., III] NCI, FDA Clin Prote Program, US FDA, Bethesda, MD 20892 USA. RP Gulmann, C (reprint author), Beaumont Hosp, Dept Pathol, Beaumont Rd, Dublin 9, Ireland. EM christiangulmann@beaumont.ie OI Espina, Virginia/0000-0001-5080-5972; Conroy, Ronan/0000-0001-5983-8682 FU Pathological Society of Great Britain and Ireland; Laboratory of Molecular Pharmacology, Center for Cancer Research, NIH Bethesda, MD, USA FX The Pathological Society of Great Britain and Ireland is gratefully acknowledged for financial support (to CG and KS). Gabriel S. Eichler, Laboratory of Molecular Pharmacology, Center for Cancer Research, NIH Bethesda, MD, USA, is gratefully acknowledged for his help with standardization of data. NR 20 TC 34 Z9 36 U1 1 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0022-3417 J9 J PATHOL JI J. Pathol. PD AUG PY 2009 VL 218 IS 4 BP 514 EP 519 DI 10.1002/path.2561 PG 6 WC Oncology; Pathology SC Oncology; Pathology GA 477IA UT WOS:000268511400012 PM 19396842 ER PT J AU Winter, HS Oleske, JM Hughes, MD McKinney, RE Elgie, C Powell, C Purdue, L Puga, AM Jimenez, E Scott, GB Cruz, MLS Moye, J AF Winter, Harland S. Oleske, James M. Hughes, Michael D. McKinney, Ross E., Jr. Elgie, Carol Powell, Christine Purdue, Lynette Puga, Ana M. Jimenez, Eleanor Scott, Gwendolyn B. Santos Cruz, Maria Leticia Moye, Jack, Jr. CA Pediat AIDS Clinical Trials Grp P TI Randomized Controlled Trial of Feeding a Concentrated Formula to Infants Born to Women Infected by Human Immunodeficiency Virus SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE AIDS; HIV; Nutrition ID WORKING GROUP-REPORT; SUB-SAHARAN AFRICA; PEDIATRIC GASTROENTEROLOGY; ADULT HYPERTENSION; GLUCOSE-TOLERANCE; WORLD CONGRESS; HIV-INFECTION; BIRTH-WEIGHT; GROWTH; NUTRITION AB Objective: We tested the hypothesis that concentrated formula (CF) begun within the first 2 weeks of life increases growth in infants born to human immunodeficiency virus (HIV)-infected mothers. Materials and Methods: HIV-exposed infants from the United States, the Bahamas, and Brazil were randomized in a double-blind, controlled trial to receive either a CF[87 kcal/100 mL 126 kcal/oz]) or a standard formula [SF; 67 kcal/100 mL 120 kcal/oz]) for 8 weeks. This article presents results for infants who were not determined to be HIV infected based oil testing at 4 weeks. Primary outcomes were safety, tolerability, and growth in weight and length. Results: Two thousand ninety-seven infants were enrolled, of whom 1998 were uninfected and had study formula dispensed. At weeks 4 and 8, uninfected infants receiving CF showed higher energy intake than those who were receiving SF (P < 0.001). By week S. uninfected infants assigned to CF weighed more than infants receiving SF. There were no consistent differences in measures of tolerability, and rates of discontinuation or perceived formula intolerance were similar between treatment groups. Conclusions: A CF is well tolerated and results in increased weight gain compared with SF. Until the HIV status of ail infant is reliably determined, early introduction of a CF in HIV-exposed children may have beneficial effects on growth. The role of early nutritional intervention remains to be determined for individuals living in countries with endemic malnutrition for whom formula feeding is a viable option. JPGN 49:222-232, 2009. C1 [Winter, Harland S.] MassGen Hosp Children, Pediat Gastroenterol & Nutr Unit, Boston, MA 02114 USA. [Oleske, James M.] Univ Med & Dent New Jersey, Div Allergy & Immunol, Newark, NJ 07103 USA. [Hughes, Michael D.] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. [McKinney, Ross E., Jr.] Duke Univ, Med Ctr, Pediat Clin Trials Unit, Durham, NC USA. [Elgie, Carol] Frontier Sci Technol & Res Fdn, Amherst, NY USA. [Powell, Christine] Harvard Univ, Sch Publ Hlth, Ctr Biostat Res, Boston, MA 02115 USA. [Purdue, Lynette] NIAID, NIH, Div Aids, Pharmaceut Affairs Branch,US Dept HHS, Bethesda, MD 20892 USA. [Puga, Ana M.] Childrens Diagnost & Treatment Ctr Inc, Comprehens Family AIDS Program, Ft Lauderdale, FL USA. [Jimenez, Eleanor] San Juan City Hosp, Dept Pediat, San Juan, PR USA. [Scott, Gwendolyn B.] Univ Miami, Dept Pediat, Miami, FL 33152 USA. [Santos Cruz, Maria Leticia] Hosp Servidores Estado, Serv Doencas Infecciosas & Parasitarias, Rio De Janeiro, Brazil. [Moye, Jack, Jr.] NICHHD, NIH,Ctr Res Mothers & Children, Pediat Adolescent & Maternal AIDS Branch, US Dept HHS, Bethesda, MD 20892 USA. RP Winter, HS (reprint author), MassGen Hosp Children, Pediat Gastroenterol & Nutr Unit, 175 Cambridge St,CPZS 5-560, Boston, MA 02114 USA. EM hwinter@partners.org RI Oleske, James/C-1951-2016; OI Oleske, James/0000-0003-2305-5605; moye, john/0000-0001-9976-8586 FU Protocol 247 team; Pediatric AIDS Clinical Trials Group (PACTG) of the National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health; Pediatric/Perinatal HIV Clinical Trials Network of the National Institute of Child Health and Human Development (NICHD) [N01-HD-3-3162, N01-HD-3-3345]; Statistical and Data Management Center of the PACTG [AI-41110]; Ross Products Division of Abbott Laboratories FX The authors would like to express their gratitude to all of the children and their families who participated in this Study. and acknowledge the contributions and support of the entire Protocol 247 team.; This work was Supported by the Pediatric AIDS Clinical Trials Group (PACTG) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, the Pediatric/Perinatal HIV Clinical Trials Network of the National Institute of Child Health and Human Development (NICHD), National Institutes of Health, the Statistical and Data Management Center of the PACTG (NIAID cooperative agreement AI-41110), Ross Products Division of Abbott Laboratories, and NICHD contract numbers N01-HD-3-3162 and N01-HD-3-3345. NR 37 TC 3 Z9 3 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 EI 1536-4801 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD AUG PY 2009 VL 49 IS 2 BP 222 EP 232 PG 11 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 477LD UT WOS:000268519700012 PM 19543114 ER PT J AU Vistica, DT Hollingshead, M Borgel, SD Kenney, S Stockwin, LH Raffeld, M Schrump, DS Burkett, S Stone, G Butcher, DO Shoemaker, RH AF Vistica, David T. Hollingshead, Melinda Borgel, Suzanne D. Kenney, Susan Stockwin, Luke H. Raffeld, Mark Schrump, David S. Burkett, Sandra Stone, Gary Butcher, Donna O. Shoemaker, Robert H. TI Therapeutic Vulnerability of an In Vivo Model of Alveolar Soft Part Sarcoma (ASPS) to Antiangiogenic Therapy SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE Alveolar Soft Part Sarcoma (ASPS); in vivo growth model; antiangiogenic Therapy of ASPS ID HYPOXIA-INDUCIBLE FACTOR-1; TUMOR ANGIOGENESIS; HUMAN-CHROMOSOMES; GENE; TOPOTECAN; CANCER; TRANSCRIPTION; CAMPTOTHECIN; CHEMOTHERAPY; BEVACIZUMAB AB In vivo growth of alveolar soft part sarcoma (ASPS) was achieved using subcutaneous xenografts in sex-matched nonobese diabetic severe combined immunodeficiency mice. One tumor, currently at passage 6, has been maintained in vivo for 32 months and has maintained characteristics consistent with those of the original ASPS tumor including (1) tumor histology and staining with periodic acid Schiff/diastase, (2) the presence of the ASPL-TFE3 type I fusion transcript, (3) nuclear staining with antibodies to the ASPL-TFE3 type I fusion protein, (4) maintenance of the t(X;17)(p11;q25) translocation characteristic of ASPS, (5) stable expression of signature ASPS gene transcripts and finally, the development and maintenance of a functional vascular network, a hallmark of ASPS. The ASPS xenograft tumor vasculature encompassing nests of ASPS cells is highly reactive to antibodies against the endothelial antigen CD34 and is readily accessible to intravenously administered fluorescein isothiocyanate-dextran. The therapeutic vulnerability of this tumor model to antiangiogenic therapy, targeting vascular endothelial growth factor and hypoxia-inducible factor-1 alpha, was examined using bevacizumab and topotecan alone and in combination. Together, the 2 drugs produced a 70% growth delay accompanied by a 0.7 net log cell kill that was superior to the antitumor effect produced by either drug alone. In summary, this Study describes a preclinical in vivo model for ASPS which will facilitate investigation into the biology of this slow growing soft tissue sarcoma and demonstrates the feasibility of using an antiangiogenic approach in the treatment of ASPS. C1 [Vistica, David T.] NCI, Screening Technol Branch, Dev Therapeut Program, Frederick, MD 21702 USA. [Hollingshead, Melinda] NCI, Biol Testing Branch, Frederick, MD 21702 USA. [Borgel, Suzanne D.; Stockwin, Luke H.] NCI, Dev Therapeut Program, SAIC Frederick, Frederick, MD 21702 USA. [Burkett, Sandra; Stone, Gary] NCI, Comparat Mol Cytogenet Core Facil, Ctr Canc Res, Frederick, MD 21702 USA. [Butcher, Donna O.] NCI, Pathol Histotechnol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Raffeld, Mark] NCI, Pathol Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Schrump, David S.] NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Frederick, MD 21702 USA. RP Vistica, DT (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Bldg 322,Room 104, Frederick, MD 21702 USA. EM visticad@mail.nih.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the United States Government. This research was supported by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 28 TC 22 Z9 25 U1 0 U2 0 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 AUG PY 2009 VL 31 IS 8 BP 561 EP 570 PG 10 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 481MH UT WOS:000268815000007 PM 19636271 ER PT J AU Berger, A AF Berger, Ann TI Healing Cancer Pain SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Meeting Abstract C1 [Berger, Ann] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD AUG PY 2009 VL 31 IS 8 BP 605 EP 605 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 481MH UT WOS:000268815000018 ER PT J AU Kitazawa, T Asakawa, K Nakamura, T Teraoka, H Unno, T Komori, S Yamada, M Wess, J AF Kitazawa, Takio Asakawa, Koichi Nakamura, Tatsuro Teraoka, Hiroki Unno, Toshihiro Komori, Sei-ichi Yamada, Masahisa Wess, Juergen TI M-3 Muscarinic Receptors Mediate Positive Inotropic Responses in Mouse Atria: A Study with Muscarinic Receptor Knockout Mice SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID FUNCTIONAL M-3-MUSCARINIC RECEPTORS; ACETYLCHOLINE-RECEPTORS; HUMAN HEART; GUINEA-PIG; VENTRICULAR MYOCYTES; RAT-HEART; SUBTYPES; EXPRESSION; ADULT AB The potential functional roles of M-3 muscarinic receptors in mouse atria were examined by pharmacological and molecular biological techniques, using wild-type mice, muscarinic M-2 or M-3 receptor single knockout (M2KO, M3KO), and M-2 and M-3 muscarinic receptor double knockout mice (M-2/M3KO). Realtime quantitative reverse transcriptase-polymerase chain reaction analysis showed that the M-2 receptor mRNA was expressed predominantly in mouse atria but that the M-1, M-3, M-4, and M-5 receptor subtypes were also expressed at low levels. Carbachol (10 nM-30 mu M) decreased the spontaneous beating frequency of right atria isolated from wild-type mice. Studies with subtype-preferring antagonists and atria from M2KO mice confirmed that this activity is mediated by the M-2 receptor subtype. In left atria from wild-type mice, carbachol decreased the amplitude of electrical field stimulation-evoked contractions (negative inotropic action), but this inhibition was transient and was followed by a gradual increase in contraction amplitude (positive inotropic response). In atria from M-3 KO mice, the transient negative inotropic action of carbachol changed to a sustained negative inotropic action. In contrast, in atria from M2KO mice, carbachol showed only positive inotropic activity. In atria from M-2/M-3 double KO mice, carbachol was devoid of any inotropic activity. These observations, complemented by functional studies with subtype-preferring antagonists, convincingly demonstrate that atrial M-3 muscarinic receptors mediate positive inotropic effects in mouse atria. Physiologically, this activity may serve to dampen the inhibitory effects of M-2 receptor activation on atrial contractility. C1 [Kitazawa, Takio; Asakawa, Koichi; Nakamura, Tatsuro] Rakuno Gakuen Univ, Sch Vet Med, Dept Pharmacol, Ebetsu, Hokkaido 0698501, Japan. [Teraoka, Hiroki] Rakuno Gakuen Univ, Sch Vet Med, Dept Toxicol, Ebetsu, Hokkaido 0698501, Japan. [Unno, Toshihiro; Komori, Sei-ichi] Gifu Univ, Fac Appl Biol Sci, Pharmacol Lab, Gifu, Japan. [Yamada, Masahisa] RIKEN, Brain Sci Inst, Yamada Res Unit, Saitama, Japan. [Wess, Juergen] NIDDK, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Kitazawa, T (reprint author), Rakuno Gakuen Univ, Sch Vet Med, Dept Pharmacol, Ebetsu, Hokkaido 0698501, Japan. EM tko-kita@rakuno.ac.jp FU National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health [National Institute of Diabetes and Digestive and Kidney Diseases]. NR 28 TC 16 Z9 17 U1 0 U2 1 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 AUG PY 2009 VL 330 IS 2 BP 487 EP 493 DI 10.1124/jpet.109.153304 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 472RY UT WOS:000268150900013 PM 19429792 ER PT J AU Zeller, S Marx, SJ Lungu, AO Cowen, EW Turner, ML AF Zeller, Sarah Marx, Stephen J. Lungu, Andreea O. Cowen, Edward W. Turner, Maria L. TI Multiple angiofibromas and collagenomas in a 45-year-old man with recurrent nephrolithiasis, fatigue, and vision loss SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID ENDOCRINE NEOPLASIA TYPE-1; FACIAL ANGIOFIBROMAS; CUTANEOUS TUMORS; MEN TYPE-1; GENE; FREQUENCY; MUTATIONS C1 [Cowen, Edward W.; Turner, Maria L.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zeller, Sarah] Univ Oklahoma, Dept Dermatol, Hlth Sci Ctr, Norman, OK 73019 USA. [Lungu, Andreea O.] NIDDK, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov FU Intramural Program of the NIH; Center for Cancer Research; National Cancer Institute; National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Program of the NIH, Center for Cancer Research, National Cancer Institute, and National Institute of Diabetes and Digestive and Kidney Diseases. NR 13 TC 2 Z9 2 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 AUG PY 2009 VL 61 IS 2 BP 319 EP 322 DI 10.1016/j.jaad.2009.01.026 PG 4 WC Dermatology SC Dermatology GA 480ZH UT WOS:000268775500016 PM 19615541 ER PT J AU Kong, HH Turner, ML AF Kong, Heidi H. Turner, Maria L. TI Array of cutaneous adverse effects associated with sorafenib SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Kong, Heidi H.; Turner, Maria L.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kong, HH (reprint author), Bldg 10,Rm 12N238,10 Ctr Dr, Bethesda, MD 20892 USA. EM konghe@mail.nib.gov OI Kong, Heidi/0000-0003-4424-064X FU Intramural NIH HHS [Z99 CA999999] NR 5 TC 21 Z9 21 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 AUG PY 2009 VL 61 IS 2 BP 360 EP 361 DI 10.1016/j.jaad.2009.02.004 PG 2 WC Dermatology SC Dermatology GA 480ZH UT WOS:000268775500026 PM 19615549 ER PT J AU Thompson, FE McNeel, TS Dowling, EC Midthune, D Morrissette, M Zeruto, CA AF Thompson, Frances E. McNeel, Timothy S. Dowling, Emily C. Midthune, Douglas Morrissette, Meredith Zeruto, Christopher A. TI Interrelationships of Added Sugars Intake, Socioeconomic Status, and Race/Ethnicity in Adults in the United States: National Health Interview Survey, 2005 SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID PHYSICAL-ACTIVITY; ENERGY DENSITY; DIETARY; OBESITY; NUTRIENTS; WOMEN; CONSUMPTION; AMERICANS; NUTRITION; CARIES AB Background The consumption of added sugars (eg, white sugar, brown sugar, and high-fructose corn syrup) displaces nutrient-dense foods in the diet. The intake of added sugars in the United States is, excessive. Little is known about the predictors of added sugar intake. Objective To examine the independent relationships of socioeconomic status and race/ethnicity with added sugar intake, and to evaluate the consistency of relationships using a short instrument to those from a different survey using more precise dietary assessment. Design Cross-sectional, nationally representative, interviewer-administered survey. Subjects/setting Adults (aged >= 18 years) participating in the 2005 US National Health Interview Survey Cancer Control Supplement responding to four added sugars questions (n=28,948). Statistical analyses performed The intake of added sugars was estimated using validated scoring algorithms. Multivariate analysis incorporating sample weights and design effects was conducted. Least squares means and confidence intervals, and significance tests using Wald F statistics are presented. Analyses were stratified by sex and controlled for potential confounders. Results The intake of added sugars was higher among men than women and inversely related to age, educational status, and family income. Asian Americans had the lowest intake and Hispanics the next lowest intake. Among men, African Americans had the highest intake, although whites and American Indians/Alaskan Natives also had high intakes. Among women, African Americans and American Indians/Alaskan Natives had the highest intakes. Intake of added sugars was inversely related to educational attainment in whites, African Americans, Hispanic men, and American Indians/Alaskan Native men, but was unrelated in Asian Americans. These findings were generally consistent with relationships in National Health and Nutrition Examination Survey 20032004 (using one or two 24-hour dietary recalls). Conclusions Race/ethnicity, family income, and educational status are independently associated with intake of added sugars. Groups with low income and education are particularly vulnerable to diets with high added sugars. Differences among race/ethnicity groups suggest that interventions to reduce intake of added sugars should be tailored. The National Health Interview Survey added sugars questions with accompanying scoring algorithms appear to provide an affordable and useful means of assessing relationships between various factors and added sugars intake. J Am Diet Assoc. 2009;109:1376-1383. C1 [Thompson, Frances E.; Dowling, Emily C.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. [McNeel, Timothy S.; Zeruto, Christopher A.] Informat Management Serv Inc, Silver Spring, MD USA. [Midthune, Douglas] NCI, Canc Prevent Div, Biometry Res Grp, Bethesda, MD 20892 USA. [Morrissette, Meredith] NHLBI, Bethesda, MD 20892 USA. RP Thompson, FE (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, 6130 Execut Blvd,EPN 4095A, Bethesda, MD 20892 USA. EM thompson@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 35 TC 50 Z9 50 U1 0 U2 17 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 2009 VL 109 IS 8 BP 1376 EP 1383 DI 10.1016/j.jada.2009.05.002 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 480AD UT WOS:000268702800010 PM 19631043 ER PT J AU Cawthon, PM Fox, KM Gandra, SR Delmonico, MJ Chiou, CF Anthony, MS Sewall, A Goodpaster, B Satterfield, S Cummings, SR Harris, TB AF Cawthon, Peggy Mannen Fox, Kathleen M. Gandra, Shravanthi R. Delmonico, Matthew J. Chiou, Chiun-Fang Anthony, Mary S. Sewall, Ase Goodpaster, Bret Satterfield, Suzanne Cummings, Steven R. Harris, Tamara B. CA Hlth Aging & Body Composition Study TI Do Muscle Mass, Muscle Density, Strength, and Physical Function Similarly Influence Risk of Hospitalization in Older Adults? SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Geriatrics-Society CY APR 30-MAY 04, 2008 CL Washington, DC SP Amer Geriatr Soc DE hospitalization; lean mass; physical function; muscle fat infiltration; walking speed ID LOWER-EXTREMITY PERFORMANCE; BODY-COMPOSITION; SKELETAL-MUSCLE; HEALTH; MEN; WOMEN; FALLS; LIMITATIONS; ATTENUATION; PREDICTORS AB OBJECTIVES To examine the association between strength, function, lean mass, muscle density, and risk of hospitalization. DESIGN Prospective cohort study. SETTING Two U.S. clinical centers. PARTICIPANTS Adults aged 70 to 80 (N=3,011) from the Health, Aging and Body Composition Study. MEASUREMENTS Measurements were of grip strength, knee extension strength, lean mass, walking speed, and chair stand pace. Thigh computed tomography scans assessed muscle area and density (a proxy for muscle fat infiltration). Hospitalizations were confirmed by local review of medical records. Negative binomial regression models estimated incident rate ratios (IRRs) of hospitalization for race- and sex-specific quartiles of each muscle and function parameter separately. Multivariate models adjusted for age, body mass index, health status, and coexisting medical conditions. RESULTS During an average 4.7 years of follow-up, 1,678 (55.7%) participants experienced one or more hospitalizations. Participants in the lowest quartile of muscle density were more likely to be subsequently hospitalized (multivariate IRR=1.47, 95% confidence interval (CI)=1.24-1.73) than those in the highest quartile. Similarly, participants with the weakest grip strength were at greater risk of hospitalization (multivariate IRR=1.52, 95% CI=1.30-1.78, Q1 vs. Q4). Comparable results were seen for knee strength, walking pace, and chair stands pace. Lean mass and muscle area were not associated with risk of hospitalization. CONCLUSION Weak strength, poor function, and low muscle density, but not muscle size or lean mass, were associated with greater risk of hospitalization. Interventions to reduce the disease burden associated with sarcopenia should focus on increasing muscle strength and improving physical function rather than simply increasing lean mass. C1 [Cawthon, Peggy Mannen; Cummings, Steven R.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA. [Fox, Kathleen M.] Strateg Healthcare Solut LLC, Monkton, MD USA. [Gandra, Shravanthi R.; Chiou, Chiun-Fang; Anthony, Mary S.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Delmonico, Matthew J.] Univ Rhode Isl, Kingston, RI 02881 USA. [Sewall, Ase] Sewall Inc, Bethesda, MD USA. [Goodpaster, Bret] Univ Pittsburgh, Sch Med, Div Endocrinol & Metab, Pittsburgh, PA USA. [Satterfield, Suzanne] Univ Tennessee, Dept Preventat Med, Memphis, TN USA. [Harris, Tamara B.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. RP Cawthon, PM (reprint author), Calif Pacific Med Ctr, Res Inst, 185 Berry St,Lobby 4,Suite 5700, San Francisco, CA 94107 USA. EM pcawthon@sfcc-cpmc.net FU Intramural NIH HHS; NIA NIH HHS [N01 AG062101, N01 AG062103, N01 AG062106, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 28 TC 110 Z9 113 U1 3 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2009 VL 57 IS 8 BP 1411 EP 1419 DI 10.1111/j.1532-5415.2009.02366.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 477QH UT WOS:000268533100010 PM 19682143 ER PT J AU Huang, BX Kim, HY AF Huang, Bill X. Kim, Hee-Yong TI Probing Akt-Inhibitor Interaction by Chemical Cross-Linking and Mass Spectrometry SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID PROTEIN-KINASE-B; PLECKSTRIN-HOMOLOGY-DOMAIN; CONFORMATIONAL-CHANGES; SERUM-ALBUMIN; ACTIVATION; SURVIVAL; PHOSPHORYLATION; IDENTIFICATION; PATHWAY; B/AKT AB The serine/threonine kinase Akt is a critical enzyme that regulates cell survival. As high Akt activity has been shown to contribute to the pathogenesis of various human malignancies, inhibition of Akt activation is a promising therapeutic strategy for cancers. We have previously demonstrated that changes in Akt interdomain arrangements from a closed to open conformation occur upon Akt-membrane interaction, which in turn allows Akt phosphorylation/activation. In the present Study, we demonstrate a novel strategy to discern mechanisms for Akt inhibition based on Akt conformational changes using chemical cross-linking and 180 labeling mass spectrometry. By quantitative comparison of two interdomain cross-linked peptides, which represent the proximity of the domains involved, we found that the binding of Akt to an inhibitor (PI analog) caused the open interdomain conformation where the PH and regulatory domains moved away from the kinase domain, even before interacting with membranes, subsequently preventing translocation of Akt to the plasma membrane. In contrast, the interdomain conformation remained unchanged after incubating with another type of inhibitor (peptide TCL1). Subsequent interaction with unilamellar vesicles suggested that TCL1 impaired particularly the opening of the PH domain for exposing T308 for phosphorylation at the plasma membrane. This novel approach based on the conformation-based molecular interaction mechanism should be potentially useful for drug discovery efforts for specific Akt inhibitors or anti-tumor agents. (J Am Soc Mass Spectrom 2009, 20,1504-1513) (C) 2009 American Society for Mass Spectrometry C1 [Kim, Hee-Yong] NIAAA, Mol Signalling Lab, Sect Mass Spectrometry, NIH, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Mol Signalling Lab, Sect Mass Spectrometry, NIH, 5625 Fishers Lane,Room 3N-07, Bethesda, MD 20892 USA. EM hykim@nih.gov FU Intramural NIH HHS [Z01 AA000284-18] NR 39 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD AUG PY 2009 VL 20 IS 8 BP 1504 EP 1513 DI 10.1016/j.jasms.2009.04.004 PG 10 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 480MV UT WOS:000268739900014 PM 19446470 ER PT J AU Laiyemo, AO Jack, M Dawkins, FW Smoot, DT AF Laiyemo, Adeyinka O. Jack, Momodu Dawkins, Fitzroy W. Smoot, Duane T. TI Upper Gastrointestinal Bleeding From Metastatic Testicular Cancer SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE men's health; cancer; intestines; metastasis; chemotherapy ID INVOLVEMENT; TESTIS; TRACT AB We report a 22-year-old man who presented with a 2-week history of intermittent melena and worsening scrotal and leg swelling. His medical history was significant for testicular cancer for which he had undergone orchiectomy, lymphadenectomy, and platinum-based chemotherapy. Esophagogastroduodenoscopy (EGD) performed revealed polypoid mass lesions in the second and third portions of the duodenum. Biopsy revealed mixed germ cell tumor with immature teratoma, the same histology as his testicular cancer. His chemotherapy was changed to an ifosphamide-based regimen and a repeat upper endoscopic examination 5 months later revealed complete resolution of previously noted polypoid duodenal mass lesions. This also demonstrates the effectiveness of ifosphamide as second-line therapy in the setting of resistance to platinum-based therapy. C1 [Laiyemo, Adeyinka O.] NCI, Canc Prevent Div, Biometry Res Grp,NIH, Canc Prevent Fellowship Program,Off Prevent Oncol, Bethesda, MD 20892 USA. [Jack, Momodu; Smoot, Duane T.] Howard Univ Hosp, Dept Med, Div Gastroenterol, Washington, DC USA. [Dawkins, Fitzroy W.] Howard Univ Hosp, Dept Med, Div Hematol Oncol, Washington, DC USA. RP Laiyemo, AO (reprint author), NCI, Canc Prevent Div, Biometry Res Grp,NIH, Canc Prevent Fellowship Program,Off Prevent Oncol, 6130 Execut Blvd,Rm 3121, Bethesda, MD 20892 USA. EM laiyemoa@mail.nih.gov NR 9 TC 1 Z9 1 U1 0 U2 0 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 AUG PY 2009 VL 101 IS 8 BP 808 EP 809 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 482PJ UT WOS:000268900900011 PM 19715045 ER PT J AU FitzGerald, MP Anderson, RU Potts, J Payne, CK Peters, KM Clemens, JQ Kotarinos, R Fraser, L Cosby, A Fortman, C Neville, C Badillo, S Odabachian, L Sanfield, A O'Dougherty, B Halle-Podell, R Cen, LY Chuai, S Landis, JR Mickelberg, K Barrell, T Kusek, JW Nyberg, LM AF FitzGerald, Mary P. Anderson, Rodney U. Potts, Jeannette Payne, Christopher K. Peters, Kenneth M. Clemens, J. Quentin Kotarinos, Rhonda Fraser, Laura Cosby, Annemarie Fortman, Carole Neville, Cynthia Badillo, Suzanne Odabachian, Lisa Sanfield, Andrea O'Dougherty, Betsy Halle-Podell, Rick Cen, Liyi Chuai, Shannon Landis, J. Richard Mickelberg, Keith Barrell, Ted Kusek, John W. Nyberg, Leroy M. CA Urological Pelvic Pain TI Randomized Multicenter Feasibility Trial of Myofascial Physical Therapy for the Treatment of Urological Chronic Pelvic Pain Syndromes SO JOURNAL OF UROLOGY LA English DT Article DE prostatitis; cystitis; interstitial; physical therapy modalities ID PROSTATITIS SYMPTOM INDEX; INTERSTITIAL-CYSTITIS; FLOOR DYSFUNCTION; PREVALENCE; WOMEN; MEN; POPULATION; BIOFEEDBACK AB Purpose: We determined the feasibility of conducting a randomized clinical trial designed to compare 2 methods of manual therapy (myofascial physical therapy and global therapeutic massage) in patients with urological chronic pelvic pain syndromes. Materials and Methods: We recniited 48 subjects with chronic prostatitis/chronic pelvic pain syndrome or interstitial cystitis/painful bladder syndrome at 6 clinical centers. Eligible patients were randomized to myofascial physical therapy or global therapeutic massage and were scheduled to receive up to 10 weekly treatments of I hour each. Criteria to assess feasibility included adherence of therapists to prescribed therapeutic protocol as determined by records of treatment, adverse events during study treatment and rate of response to therapy as assessed by the patient global response assessment. Primary outcome analysis compared response rates between treatment arms using Mantel-Haenszel methods. Results: There were 23 (49%) men and 24 (51%) women randomized during a 6-month period. Of the patients 24 (51%) were randomized to global therapeutic massage, 23 (49%) to myofascial physical therapy and 44 (94%) completed the study. Therapist adherence to the treatment protocols was excellent. The global response assessment response rate of 57% in the myofascial physical therapy group was significantly higher than the rate of 21% in the global therapeutic massage treatment group (p = 0.03). Conclusions: We judged the feasibility of conducting a full-scale trial of physical therapy methods and the preliminary findings of a beneficial effect of myofascial physical therapy warrants further study. C1 [FitzGerald, Mary P.; Kotarinos, Rhonda; Fortman, Carole] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. [Neville, Cynthia; Badillo, Suzanne] Rehabil Inst Chicago, Chicago, IL 60611 USA. [Anderson, Rodney U.; Payne, Christopher K.; Fraser, Laura; Cosby, Annemarie] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Potts, Jeannette; O'Dougherty, Betsy] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Peters, Kenneth M.; Odabachian, Lisa; Sanfield, Andrea] William Beaumont Hosp, Royal Oak, MI 48072 USA. [Clemens, J. Quentin] Univ Michigan, Med Ctr, Ann Arbor, MI USA. [Cen, Liyi; Chuai, Shannon; Landis, J. Richard; Mickelberg, Keith; Barrell, Ted] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Kusek, John W.; Nyberg, Leroy M.] NIH, Bethesda, MD 20892 USA. RP FitzGerald, MP (reprint author), Loyola Univ, Med Ctr, Bldg 103,Room 1004, Maywood, IL 60153 USA. EM mfitzg8@lumc.edu RI Landis, J. Richard/A-9330-2010 FU NIDDK NIH HHS [U01 DK065209, U01 DK065209-06] NR 28 TC 64 Z9 64 U1 0 U2 14 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 AUG PY 2009 VL 182 IS 2 BP 570 EP 580 DI 10.1016/j.juro.2009.04.022 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 468UW UT WOS:000267850300056 PM 19535099 ER PT J AU Schmitz, A Knobloch, M Levionnois, O Portier, C Theurillat, R Lassahn, PG Thormann, W Mevissen, M AF Schmitz, A. Knobloch, M. Levionnois, O. Portier, C. Theurillat, R. Lassahn, P. -G. Thormann, W. Mevissen, M. TI Metabolism of ketamine in horses - what's new? SO JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS LA English DT Meeting Abstract C1 [Schmitz, A.; Knobloch, M.; Mevissen, M.] Univ Bern, Div Vet Pharmacol & Toxicol, Bern, Switzerland. [Levionnois, O.] Univ Bern, Div Vet Anesthesiol, Bern, Switzerland. [Portier, C.] NIEHS, Res Triangle Pk, NC 27709 USA. [Theurillat, R.; Thormann, W.] Univ Bern, Dept Clin Pharmacol & Visceral Res, Bern, Switzerland. [Lassahn, P. -G.] Thermo Fisher Sci, Birsfelden, Switzerland. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 3 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0140-7783 J9 J VET PHARMACOL THER JI J. Vet. Pharmacol. Ther. PD AUG PY 2009 VL 32 BP 87 EP 88 PG 2 WC Pharmacology & Pharmacy; Veterinary Sciences SC Pharmacology & Pharmacy; Veterinary Sciences GA 472AI UT WOS:000268100600075 ER PT J AU Rotman, Y Liang, TJ AF Rotman, Yaron Liang, T. Jake TI Coinfection with Hepatitis C Virus and Human Immunodeficiency Virus: Virological, Immunological, and Clinical Outcomes SO JOURNAL OF VIROLOGY LA English DT Review ID ACTIVE ANTIRETROVIRAL THERAPY; HIV-INFECTED PATIENTS; INTERFERON PLUS RIBAVIRIN; CHRONIC HCV INFECTION; LIVER FIBROSIS PROGRESSION; T-CELL RESPONSES; RISK-FACTORS; HIV/HCV COINFECTION; MITOCHONDRIAL TOXICITY; IMMUNE RECOVERY C1 [Rotman, Yaron; Liang, T. Jake] NIDDK, NIH, LDB, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIDDK, NIH, LDB, 10 Ctr Dr,Bldg 10,Room 9B16, Bethesda, MD 20892 USA. EM JakeL@bdg10.niddk.nih.gov OI Rotman, Yaron/0000-0002-7549-8216 NR 136 TC 57 Z9 59 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG 1 PY 2009 VL 83 IS 15 BP 7366 EP 7374 DI 10.1128/JVI.00191-09 PG 9 WC Virology SC Virology GA 467OE UT WOS:000267747400001 PM 19420073 ER PT J AU Streeck, H Jolin, JS Qi, Y Yassine-Diab, B Johnson, RC Kwon, DS Addo, MM Brumme, C Routy, JP Little, S Jessen, HK Kelleher, AD Hecht, FM Sekaly, RP Rosenberg, ES Walker, BD Carrington, M Altfeld, M AF Streeck, Hendrik Jolin, Jonathan S. Qi, Ying Yassine-Diab, Bader Johnson, Randall C. Kwon, Douglas S. Addo, Marylyn M. Brumme, Chanson Routy, Jean-Pierre Little, Susan Jessen, Heiko K. Kelleher, Anthony D. Hecht, Frederick M. Sekaly, Rafick-Pierre Rosenberg, Eric S. Walker, Bruce D. Carrington, Mary Altfeld, Marcus TI Human Immunodeficiency Virus Type 1-Specific CD8(+) T-Cell Responses during Primary Infection Are Major Determinants of the Viral Set Point and Loss of CD4(+) T Cells SO JOURNAL OF VIROLOGY LA English DT Article ID PRIMARY HIV-1 INFECTION; GASTROINTESTINAL-TRACT; LYMPHOCYTES; DEPLETION; VIREMIA; EPITOPE; LOAD; AIDS; GAG; SEROCONVERSION AB Primary HIV-1 infection (PHI) is marked by a flu-like syndrome and high levels of viremia that decrease to a viral set point with the first emergence of virus-specific CD8(+) T-cell responses. Here, we investigated in a large cohort of 527 subjects the immunodominance pattern of the first virus-specific cytotoxic T-lymphocyte (CTL) responses developed during PHI in comparison to CTL responses in chronic infection and demonstrated a distinct relationship between the early virus-specific CTL responses and the viral set point, as well as the slope of CD4(+) T-cell decline. CTL responses during PHI followed clear hierarchical immunodominance patterns that were lost during the transition to chronic infection. Importantly, the immunodominance patterns of human immunodeficiency virus type 1 (HIV-1)-specific CTL responses detected in primary, but not in chronic, HIV-1 infection were significantly associated with the subsequent set point of viral replication. Moreover, the preservation of the initial CD8(+) T-cell immunodominance patterns from the acute into the chronic phase of infection was significantly associated with slower CD4(+) T-cell decline. Taken together, these data show that the specificity of the initial CTL response to HIV is critical for the subsequent control of viremia and have important implications for the rational selection of antigens for future HIV-1 vaccines. C1 [Streeck, Hendrik; Jolin, Jonathan S.; Kwon, Douglas S.; Addo, Marylyn M.; Brumme, Chanson; Rosenberg, Eric S.; Walker, Bruce D.; Altfeld, Marcus] MIT, Ragon Inst MGH, Boston, MA 02129 USA. [Streeck, Hendrik; Jolin, Jonathan S.; Kwon, Douglas S.; Addo, Marylyn M.; Brumme, Chanson; Rosenberg, Eric S.; Walker, Bruce D.; Altfeld, Marcus] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Streeck, Hendrik; Jolin, Jonathan S.; Kwon, Douglas S.; Addo, Marylyn M.; Brumme, Chanson; Rosenberg, Eric S.; Walker, Bruce D.; Altfeld, Marcus] Harvard Univ, Sch Med, Boston, MA USA. [Yassine-Diab, Bader; Sekaly, Rafick-Pierre] CHUM, Immunol Lab, Ctr Rech, Montreal, PQ, Canada. [Qi, Ying; Johnson, Randall C.; Carrington, Mary] NCI, SAIC Frederick Inc, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21701 USA. [Routy, Jean-Pierre] McGill Univ, Royal Victoria Hosp, Div Hematol & Immunodeficiency Serv, Montreal, PQ H3A 1A1, Canada. [Little, Susan] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Jessen, Heiko K.] HIV Clin Praxis Jessen, Berlin, Germany. [Kelleher, Anthony D.] Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Darlinghurst, NSW, Australia. [Hecht, Frederick M.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Cahse, MD USA. RP Altfeld, M (reprint author), MIT, Ragon Inst MGH, 149 13th St, Boston, MA 02129 USA. EM maltfeld@partners.org RI Johnson, Randall/B-1517-2014; OI Johnson, Randall/0000-0001-7754-0847; Brumme, Chanson/0000-0003-2722-5288 FU CCR NIH HHS [HHSN261200800001C]; Howard Hughes Medical Institute; Intramural NIH HHS; NCI NIH HHS [HHSN261200800001E, N01-CO-12400, N01CO12400]; NIAID NIH HHS [P01 AI074415, AI43638, R01 AI050429, R01 AI50429, U01 AI043638, U01 AI052403]; PHS HHS [HHSN261200800001E] NR 32 TC 113 Z9 116 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG 1 PY 2009 VL 83 IS 15 BP 7641 EP 7648 DI 10.1128/JVI.00182-09 PG 8 WC Virology SC Virology GA 467OE UT WOS:000267747400029 PM 19458000 ER PT J AU Ott, DE Coren, LV Shatzer, T AF Ott, David E. Coren, Lori V. Shatzer, Teresa TI The Nucleocapsid Region of Human Immunodeficiency Virus Type 1 Gag Assists in the Coordination of Assembly and Gag Processing: Role for RNA-Gag Binding in the Early Stages of Assembly SO JOURNAL OF VIROLOGY LA English DT Article ID ROUS-SARCOMA-VIRUS; HIV-1 MATRIX PROTEIN; IN-VITRO; PARTICLE-PRODUCTION; BASIC RESIDUES; LIVE CELLS; DOMAIN; POLYPROTEIN; INFECTIVITY; DIMER AB Human immunodeficiency virus type 1 (HIV-1) Gag-RNA interactions are required for virus assembly. However, our prior study found that a defect in particle production exhibited by an HIV-1 proviral mutant with a severe deletion in the RNA-binding nucleocapsid (NC) region of Gag, NX, could be reversed by eliminating its protease activity. While our follow-up study indicated that a secondary RNA-binding site in Gag can also provide the required RNA-binding function, how protease activity inhibits NX virion production is still unclear. Therefore, we tested three possible mechanisms: NX virions are unstable and fall apart after budding; NX Gag assembly is slowed, allowing protease processing to start before particle formation; or the protease region within NX Gag-Pol becomes activated prematurely and processes the assembling Gag. We found that NX particles were as stable as wild-type virions. Furthermore, even a modest slowing of protease activity could rescue NX. Pulse-chase analysis revealed that the initial particle production by NC-deleted Gag was delayed compared to that of wild type Gag, but once started, the rate of production was similar, revealing a defect in the initiation of assembly. Wild-type Gag particle production was not eliminated or decreased in the presence of excess NX Gag-Pol, inconsistent with a premature activation of protease. Overall, these results indicate that the particle formation defect of NX is due to delayed initiation of assembly caused by the absence of NC in Gag, making it vulnerable to protease processing before budding can occur. Therefore, NC plays an important initiating role in Gag assembly. C1 [Ott, David E.; Coren, Lori V.; Shatzer, Teresa] Natl Canc Inst, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Ott, DE (reprint author), Natl Canc Inst, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM ott@ncifcrf.gov FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [N01-CO-12400, N01CO12400, HHSN261200800001E]; PHS HHS [HHSN261200800001E] NR 61 TC 19 Z9 19 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 AUG 1 PY 2009 VL 83 IS 15 BP 7718 EP 7727 DI 10.1128/JVI.00099-09 PG 10 WC Virology SC Virology GA 467OE UT WOS:000267747400036 PM 19457986 ER PT J AU Khattar, SK Yan, YQ Panda, A Collins, PL Samal, SK AF Khattar, Sunil K. Yan, Yongqi Panda, Aruna Collins, Peter L. Samal, Siba K. TI A Y526Q Mutation in the Newcastle Disease Virus HN Protein Reduces Its Functional Activities and Attenuates Virus Replication and Pathogenicity SO JOURNAL OF VIROLOGY LA English DT Article ID HEMAGGLUTININ-NEURAMINIDASE PROTEIN; SITE; MUTAGENESIS AB The hemagglutinin-neuraminidase (HN) protein of Newcastle disease virus (NDV) is a multifunctional protein that plays a crucial role in virus infectivity. In this study, using the mesogenic strain Beaudette C (BC), we mutated three conserved amino acids thought to be part of the binding/catalytic active site in the HN protein. We also mutated five additional residues near the proposed active site that are nonconserved between BC and the avirulent strain LaSota. The eight recovered NDV HN mutants were assessed for effects on biological activities. While most of the mutations had surprisingly little effect, mutation at conserved residue Y526 reduced the neuraminidase, receptor binding, and fusion activities and attenuated viral virulence in eggs and young birds. C1 [Khattar, Sunil K.; Yan, Yongqi; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Panda, Aruna] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, 8075 Greenmead Dr, College Pk, MD 20742 USA. EM ssamal@umd.edu FU NIAID [N01A060009]; NIH FX This research was supported by NIAID contract N01A060009 (85% support) and the NIAID NIH Intramural Research Program (15% support). NR 16 TC 19 Z9 22 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG 1 PY 2009 VL 83 IS 15 BP 7779 EP 7782 DI 10.1128/JVI.00536-09 PG 4 WC Virology SC Virology GA 467OE UT WOS:000267747400042 PM 19474107 ER PT J AU Huang, LQ Sayer, JM Swinford, M Louis, JM Chen, C AF Huang, Liangqun Sayer, Jane M. Swinford, Marie Louis, John M. Chen, Chaoping TI Modulation of Human Immunodeficiency Virus Type 1 Protease Autoprocessing by Charge Properties of Surface Residue 69 SO JOURNAL OF VIROLOGY LA English DT Article ID INFECTIOUS-ANEMIA VIRUS; MATURE HIV-1 PROTEASE; VIRAL INFECTIVITY; STABILITY; PROTEINS; CLEAVAGE AB Mature, fully active human immunodeficiency virus protease (PR) is liberated from the Gag-Pol precursor via regulated autoprocessing. A chimeric protease precursor, glutathione S-transferase-transframe region (TFR)-PR-FLAG, also undergoes N-terminal autocatalytic maturation when it is expressed in Escherichia coli. Mutation of the surface residue H69 to glutamic acid, but not to several neutral or basic amino acids, impedes protease autoprocessing in bacteria and mammalian cells. Only a fraction of mature PR with an H69E mutation (PRH69E) folds into active enzymes, and it does so with an apparent K-d (dissociation constant) significantly higher than that of the wild-type protease, corroborating the marked retardation of the in vitro N-terminal autocatalytic processing of TFR-PRH69E and suggesting a folding defect in the precursor. C1 [Huang, Liangqun; Swinford, Marie; Chen, Chaoping] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. [Sayer, Jane M.; Louis, John M.] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Chen, C (reprint author), Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. EM johnl@niddk.nih.gov; chaoping@colostate.edu FU NIDDK, NIH FX This work was supported in part by the Intramural Research Program of the NIDDK, NIH. We acknowledge the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH, for providing human anti-HIV antibodies (catalog no. 3957), rabbit HIV-1 protease antiserum (catalog no. 4105), and DRV (reagent 11447 from Tibotec Pharmaceuticals). NR 21 TC 8 Z9 8 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG 1 PY 2009 VL 83 IS 15 BP 7789 EP 7793 DI 10.1128/JVI.00473-09 PG 5 WC Virology SC Virology GA 467OE UT WOS:000267747400044 PM 19457992 ER PT J AU Wilbur, J Zenk, S Wang, E Oh, A McDevitt, J Block, D McNeil, S Ju, SK AF Wilbur, JoEllen Zenk, Shannon Wang, Edward Oh, April McDevitt, Judith Block, Dick McNeil, Sue Ju, SuKyung TI Neighborhood Characteristics, Adherence to Walking, and Depressive Symptoms in Midlife African American Women SO JOURNAL OF WOMENS HEALTH LA English DT Article ID MIDDLE-AGED WOMEN; PHYSICAL-ACTIVITY; AEROBIC EXERCISE; MENTAL-HEALTH; OLDER-ADULTS; LIFE-STYLE; PSYCHOLOGICAL OUTCOMES; RANDOMIZED-TRIAL; OBESE WOMEN; ENVIRONMENT AB Background: African American women have more symptoms of depressed mood than white women. Adverse neighborhood conditions may contribute to these symptoms. Although reductions in depressive symptoms with physical activity have been demonstrated in white adults, little research has examined the mental health benefits of physical activity in African American women. Further, it is unknown whether physical activity can offset the effects of living in disadvantaged neighborhoods on depressive symptoms. The purpose of this study was to examine the relationships among neighborhood characteristics, adherence to a physical activity intervention, and change over time in depressive symptoms in midlife African American women. Methods: Two hundred seventy-eight women participated in a home-based, 24-week moderate-intensity walking intervention. Either a minimal treatment (MT) or enhanced treatment (ET) version of the intervention was randomly assigned to one of the two community health centers. Walking adherence was measured as the percentage of prescribed walks completed. Objective and perceived measures of neighborhood deterioration and crime were included. Results: Adjusting for demographics, body mass index (BMI), and depressive symptoms at baseline, walking adherence and objective neighborhood deterioration were associated with significantly lower depressive symptoms, whereas perceived neighborhood deterioration was associated with significantly higher depressive symptoms at 24 weeks. Conclusions: Adherence to walking as well as aspects of the environment may influence depressive symptoms in African American women. In addition to supporting active lifestyles, improving neighborhood conditions may also promote mental health among African American women. C1 [Wilbur, JoEllen] Rush Univ, Coll Nursing, Chicago, IL 60612 USA. [Zenk, Shannon; Wang, Edward; McDevitt, Judith; Ju, SuKyung] Univ Illinois, Coll Nursing, Chicago, IL USA. [Oh, April] DCCPS Natl Canc Inst, Hlth Promot Res Branch, Behav Res Program, Washington, DC USA. [Block, Dick] Loyola Univ, Dept Sociol, Chicago, IL 60611 USA. [McNeil, Sue] Univ Delaware, Dept Civil & Environm Engn, Newark, DE USA. RP Wilbur, J (reprint author), Rush Univ, Coll Nursing, 600 S Paulina, Chicago, IL 60612 USA. EM JoEllen_Wilbur@Rush.edu RI Weaver, Marissa/C-4027-2012 FU National Institute of Nursing Research, National Institutes of Health [RO1 NRO4234, P30 NR09014]; Robert Wood Johnson Foundation Active Living Research FX This work was supported by the National Institute of Nursing Research, National Institutes of Health (RO1 NRO4234), and Robert Wood Johnson Foundation Active Living Research. We thank the Multiethnic Advisory Board of Center for Reducing Risks in Vulnerable Populations NIH/NINR P30 NR09014. We also thank Dr. Louis Fogg, Rush University, for assistance in the statistical analyses. NR 76 TC 16 Z9 17 U1 3 U2 11 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD AUG PY 2009 VL 18 IS 8 BP 1201 EP 1210 DI 10.1089/jwh.2008.1168 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 482CC UT WOS:000268860300015 PM 19630546 ER PT J AU Njajou, OT Hsueh, WC Blackburn, EH Newman, AB Wu, SH Li, RL Simonsick, EM Harris, TM Cummings, SR Cawthon, RM AF Njajou, Omer T. Hsueh, Wen-Chi Blackburn, Elizabeth H. Newman, Anne B. Wu, Shih-Hsuan Li, Rongling Simonsick, Eleanor M. Harris, Tamara M. Cummings, Steve R. Cawthon, Richard M. CA Hlth ABC Study TI Association Between Telomere Length, Specific Causes of Death, and Years of Healthy Life in Health, Aging, and Body Composition, a Population-Based Cohort Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Telomere; Survival; Life span; Health status; Years of healthy life ID REPLICATIVE SENESCENCE; CELLULAR SENESCENCE; STEM-CELLS; OLDEST-OLD; MORTALITY; SURVIVAL; LEUKOCYTES; PEOPLE; BLOOD; SPAN AB Although telomere length (TL) is known to play a critical role in cellular senescence, the relationship of TL to aging and longevity in humans is not well understood. In a large biracial population-based cohort, we tested the hypotheses that elderly persons with shorter TL in peripheral white blood cells have poorer survival, shorter life span, and fewer years of healthy life (YHL). Associations were evaluated using Cox proportional hazard models and linear regression analyses where appropriate. TL (in kilo base pairs) was not associated with overall survival (hazard ratio 1.0; 95% confidence interval 0.9-1.1) or death from any specific underlying cause including infectious diseases, cancer, or cardiac and cerebrovascular diseases. TL, however, was positively associated with more YHL (beta = 0.08 +/- 0.04, p = .03). Findings suggest that TL may not be a strong biomarker of survival in older individuals, but it may be an informative biomarker of healthy aging. C1 [Njajou, Omer T.; Hsueh, Wen-Chi; Wu, Shih-Hsuan] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Blackburn, Elizabeth H.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Li, Rongling] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Harris, Tamara M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Cummings, Steve R.] Calif Pacific Med Ctr, Res Inst, San Francisco Coordinating Ctr, San Francisco, CA USA. [Cawthon, Richard M.] Univ Utah, Dept Human Genet, Salt Lake City, UT USA. RP Hsueh, WC (reprint author), Univ Calif San Francisco, Dept Med, 513 Parnassus St,HSE 672, San Francisco, CA 94143 USA. EM wen-chi.hsueh@ucsf.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institutes of Health (NIH), National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, K01 AG22782, R01 AG023692, U19 AG023122] FX This study was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging, and NIH contracts (N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106) and grants (K01 AG22782 and R01 AG023692 to W. C. H. and U19 AG023122 to R. M. C.). NR 30 TC 99 Z9 107 U1 2 U2 22 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 AUG PY 2009 VL 64 IS 8 BP 860 EP 864 DI 10.1093/gerona/glp061 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 472EB UT WOS:000268111000005 PM 19435951 ER PT J AU Pilotto, A Addante, F Ferrucci, L Leandro, G D'Onofrio, G Corritore, M Niro, V Scarcelli, C Dallapiccola, B Franceschi, M AF Pilotto, Alberto Addante, Filomena Ferrucci, Luigi Leandro, Gioacchino D'Onofrio, Grazia Corritore, Michele Niro, Valeria Scarcelli, Carlo Dallapiccola, Bruno Franceschi, Marilisa TI The Multidimensional Prognostic Index Predicts Short- and Long-Term Mortality in Hospitalized Geriatric Patients With Pneumonia SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Multidimensional prognostic index; Comprehensive geriatric assessment; Pneumonia; Mortality; Elderly people ID COMMUNITY-ACQUIRED PNEUMONIA; ELDERLY-PATIENTS; OLDER PATIENTS; SEVERITY; VALIDATION; PEOPLE; POPULATION; CRITERIA; ADULTS AB Multidimensional impairment of older patients may influence the clinical outcome of acute or chronic diseases. Our purpose is to evaluate the usefulness of a multidimensional prognostic index (MPI) based on a comprehensive geriatric assessment (CGA) for predicting mortality risk in older patients with community-acquired pneumonia (CAP). This prospective study included 134 hospitalized patients aged 65 and older with a diagnosis of CAP. A standardized CGA that included information on clinical, cognitive, functional, and nutritional status as well as comorbidities, medications, and social support network was used to calculate MPI. The pneumonia severity index (PSI) was also calculated. The predictive value of the MPI for all cause mortality over a 1-year follow-up was evaluated and was compared with that of PSI. Higher MPI values were significantly associated with higher mortality at 30 days (Grade 1 = 3%, Grade 2 = 12%, Grade 3 = 44%, p < .001), 6 months (Grade 1 = 7%, Grade 2 = 21%, Grade 3 = 50%, p < .001), and 1 year (Grade 1 = 10%, Grade 2 = 33%, Grade 3 = 53%, p < .001). A close agreement was found between the estimated mortality by MPI and the observed mortality. MPI had a significant greater discriminatory power than PSI both at 30 days (area under the receiver operating characteristic [ROC] curve = 0.83 vs 0.71, p = .019) and 6 months (0.79 vs 0.69, p = .035), but not after 1 year of follow-up (0.80 vs 0.75, p = .185). This MPI, calculated from information collected in a standardized CGA, accurately stratifies hospitalized elderly patients with CAP into groups at varying risk of short- and long-term mortality. The predictive accuracy of the MPI was higher than the predictive value of the PSI. C1 [Pilotto, Alberto; Addante, Filomena; D'Onofrio, Grazia; Corritore, Michele; Niro, Valeria; Scarcelli, Carlo; Franceschi, Marilisa] IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Geriatr Unit, San Giovanni Rotondo, Italy. [Pilotto, Alberto; Addante, Filomena; D'Onofrio, Grazia; Corritore, Michele; Niro, Valeria; Scarcelli, Carlo; Franceschi, Marilisa] IRCCS Casa Sollievo Sofferenza, Gerontol Geriatr Res Lab, San Giovanni Rotondo, Italy. [Ferrucci, Luigi] Harbor Hosp Ctr, NIA, Longitudinal Studies Sect, Baltimore, MD USA. [Leandro, Gioacchino] IRCCS Saverio De Bellis, Biostat & Gastroenterol Unit, Castellana Grotte, Italy. [Dallapiccola, Bruno] IRCCS Casa Sollievo Sofferenza Mendel Inst, Rome, Italy. [Dallapiccola, Bruno] Univ Roma La Sapienza, Dept Expt Med & Pathol, Rome, Italy. [Franceschi, Marilisa] Univ Parma, Dept Gastroenterol, I-43100 Parma, Italy. RP Pilotto, A (reprint author), IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Geriatr Unit, Viale Cappuccini 1, I-71013 Foggia, Italy. EM alberto.pilotto@operapadrepio.it RI D'Onofrio, Grazia/K-9740-2016; Dallapiccola, Bruno/K-8692-2016 OI D'Onofrio, Grazia/0000-0002-5905-6063; Leandro, Gioacchino/0000-0001-6624-4532; Dallapiccola, Bruno/0000-0002-5031-1013 FU Ministero della Salute; National Institutes of Health, National Institute on Aging FX This work was fully supported by grants from Ministero della Salute, IRCCS Research Program 2006-2008, Line 2: "Malattie di rilevanza sociale." This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 29 TC 44 Z9 44 U1 0 U2 1 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 AUG PY 2009 VL 64 IS 8 BP 880 EP 887 DI 10.1093/gerona/glp031 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 472EB UT WOS:000268111000008 PM 19349589 ER PT J AU Rosansky, SJ Clark, WF Eggers, P Glassock, RJ AF Rosansky, Steven Jay Clark, William F. Eggers, Paul Glassock, Richard J. TI Initiation of dialysis at higher GFRs: is the apparent rising tide of early dialysis harmful or helpful? SO KIDNEY INTERNATIONAL LA English DT Review DE chronic dialysis; chronic renal failure; ESRD; hemodialysis adequacy; hemodialysis hazards ID CHRONIC KIDNEY-DISEASE; HEMODIALYSIS-PATIENTS; PERITONEAL-DIALYSIS; SURVIVAL; MORTALITY; ADEQUACY; OUTCOMES AB Over the past decade a trend of increasing estimated glomerular filtration rate (eGFR) at the initiation of dialysis for treatment of end-stage renal disease (ESRD) has been noted in the United States. In 1996, only 19% of patients began dialysis therapy with an eGFR of greater than 10 ml/min/1.73m(2) (denoted as 'early start'), but by 2005 the fraction of early start dialysis patients had risen to 45%. This review examines US dialysis data, national guidelines, and publications relevant to the early start phenomenon. It is not known whether early start of dialysis is beneficial, harmful or neutral with respect to the outcome of dialysis treatment for ESRD. Available data indicate that mortality while on dialysis therapy may be higher in those subjects with early start. Comorbidities present at the time of dialysis initiation do not appear to be a major driving force for early start patients. As well, residual kidney function in these patients is a major contributor to total urea or creatinine clearance. This can be a positive factor for patient outcomes and might be compromised by early start. Finally, we estimate the dollar cost of early start to the US Medicare-supported ESRD program. Properly designed, prospective and randomized studies may help to clarify the benefit or harm of early start of dialysis for ESRD. Kidney International (2009) 76, 257-261; doi:10.1038/ki.2009.161; published online 20 May 2009 C1 [Rosansky, Steven Jay] William Jennings Bryan Dorn VA Hosp, Renal Sect, Dept Primary Care & Subspecialty Med, Columbia, SC 29209 USA. [Glassock, Richard J.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Eggers, Paul] NIDDKD, Dept Kidney & Urol Epidemiol, Bethesda, MD 20892 USA. [Clark, William F.] London Hlth Sci Ctr, London, ON, Canada. [Clark, William F.] Lawson Hlth Res Inst, London, ON, Canada. RP Rosansky, SJ (reprint author), William Jennings Bryan Dorn VA Hosp, Renal Sect, Dept Primary Care & Subspecialty Med, 6439 Garners Ferry Rd, Columbia, SC 29209 USA. EM sjrcra@yahoo.com NR 21 TC 99 Z9 104 U1 0 U2 5 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 AUG PY 2009 VL 76 IS 3 BP 257 EP 261 DI 10.1038/ki.2009.161 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 470KE UT WOS:000267972800006 PM 19455195 ER PT J AU Kim, MJ Romero, R Gervasi, MT Kim, JS Yoo, W Lee, DC Mittal, P Erez, O Kusanovic, JP Hassan, SS Kim, CJ AF Kim, Mi Jeong Romero, Roberto Gervasi, Maria Teresa Kim, Jung-Sun Yoo, Wonsuk Lee, Deug-Chan Mittal, Pooja Erez, Offer Kusanovic, Juan Pedro Hassan, Sonia S. Kim, Chong Jai TI Widespread microbial invasion of the chorioamniotic membranes is a consequence and not a cause of intra-amniotic infection SO LABORATORY INVESTIGATION LA English DT Article DE 16S rRNA; amniotic fluid; chorioamnionitis; fluorescent in situ hybridization; intra-amniotic infection; polymerase chain reaction ID PLACEBO-CONTROLLED TRIAL; REAL-TIME-PCR; POLYMERASE-CHAIN-REACTION; IN-SITU HYBRIDIZATION; 7-YEAR FOLLOW-UP; PRETERM LABOR; UREAPLASMA-UREALYTICUM; AMNIOTIC CAVITY; FETAL MEMBRANES; CLINICAL MICROBIOLOGY AB Acute chorioamnionitis is a response to amniotic fluid (AF) infection. However, it remains unclear whether substantial bacterial propagation in the chorioamniotic membranes (CAMs) precedes microbial invasion of the amniotic cavity (MIAC), which is inconsistent with characteristic 'amniotropic neutrophil migration' in acute chorioamnionitis. This study was performed to determine whether CAMs have widespread bacterial infection during MIAC and whether bacteria normally colonize CAMs. AF pellets and CAMs from the following groups were studied: group 1, patients with positive (n=18) or negative (n=22) AF cultures; group 2, patients with or without acute chorioamnionitis in which the amnion and chorion were studied separately (n=60); and group 3, patients at term who underwent a cesarean delivery (n=30). SYTO 9/propidium iodide fluorescent staining and fluorescent in situ hybridization for 16S rRNA were performed. Real-time quantitative PCR for 16S rDNA and PCR for genital mycoplasmas were also conducted. Bacteria were more frequently detected in AF than in CAMs of patients with positive AF culture (100 vs. 33%; P<0.0001). Bacteria were detected more frequently in CAMs as the severity of chorioamnionitis increased (P<0.01). The median 16S rRNA gene copy number in the amnion was significantly greater than in the chorion (group 2; P<0.0001). Bacteria were not detected in CAMs or AF in women at term before labor (group 3). A fraction of patients with chorioamnionitis or MIAC did not have bacteria in CAMs. Collectively, the findings herein indicate that MIAC does not follow widespread infection of CAMs, but precedes it. We propose a model of MIAC: the initial stage is intra-amniotic bacterial invasion through a discrete region of the CAMs, followed by intra-amniotic proliferation, and bacterial invasion of CAMs primarily extends from the amniotic fluid. This study emphasizes the importance of assessing the intra-amniotic compartment for diagnosis and treatment of preterm birth. Laboratory Investigation (2009) 89, 924-936; doi:10.1038/labinvest.2009.49; published online 8 June 2009 C1 [Kim, Mi Jeong; Romero, Roberto; Kim, Jung-Sun; Lee, Deug-Chan; Mittal, Pooja; Erez, Offer; Kusanovic, Juan Pedro; Hassan, Sonia S.; Kim, Chong Jai] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Kim, Mi Jeong; Romero, Roberto; Kim, Jung-Sun; Lee, Deug-Chan; Mittal, Pooja; Erez, Offer; Kusanovic, Juan Pedro; Hassan, Sonia S.; Kim, Chong Jai] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Romero, Roberto; Mittal, Pooja; Erez, Offer; Kusanovic, Juan Pedro; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Gervasi, Maria Teresa] Azienda Osped Univ, UO Ostetr & Ginecol, Padua, Italy. [Kim, Jung-Sun; Kim, Chong Jai] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Yoo, Wonsuk] Wayne State Univ, Sch Med, Dept Internal Med, Detroit, MI 48201 USA. RP Kim, CJ (reprint author), Wayne State Univ, Sch Med, Dept Pathol, Hutzel Womens Hosp, 4 Brush N,Room 4620,3990 John R, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu; cjkim@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported (in part) by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 62 TC 66 Z9 67 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD AUG PY 2009 VL 89 IS 8 BP 924 EP 936 DI 10.1038/labinvest.2009.49 PG 13 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 476JI UT WOS:000268435900008 PM 19506551 ER PT J AU van Nederveen, FH Gaal, J Favier, J Korpershoek, E Oldenburg, RA de Bruyn, EMCA Sleddens, HFBM Derkx, P Riviere, J Dannenberg, H Petri, BJ Komminoth, P Pacak, K Hop, WCJ Pollard, PJ Mannelli, M Bayley, JP Perren, A Niemann, S Verhofstadt, AA de Bruine, AP Maher, ER Tissier, F Meatchi, T Badoual, C Bertherat, J Amar, L Alataki, D Van Marck, E Ferrau, F Francois, J de Herder, WW Peeters, MPFMV van Linge, A Lenders, JWM Gimenez-Roqueplo, AP de Krijgert, RR Dinjens, WNM AF van Nederveen, Francien H. Gaal, Jose Favier, Judith Korpershoek, Esther Oldenburg, Rogier A. de Bruyn, Elly M. C. A. Sleddens, Hein F. B. M. Derkx, Pieter Riviere, Julie Dannenberg, Hilde Petri, Bart-Jeroen Komminoth, Paul Pacak, Karel Hop, Wim C. J. Pollard, Patrick J. Mannelli, Massimo Bayley, Jean-Pierre Perren, Aurel Niemann, Stephan Verhofstadt, Albert A. de Bruine, Adriaan P. Maher, Eamonn R. Tissier, Frederique Meatchi, Tchao Badoual, Cecile Bertherat, Jerome Amar, Laurence Alataki, Despoina Van Marck, Eric Ferrau, Francesco Francois, Jerney de Herder, Wouter W. Peeters, Mark-Paul F. M. Vrancken van Linge, Anne Lenders, Jacques W. M. Gimenez-Roqueplo, Anne-Paule de Krijgert, Ronald R. Dinjens, Winand N. M. TI An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis SO LANCET ONCOLOGY LA English DT Article ID MITOCHONDRIAL RESPIRATORY-CHAIN; COMPLEX-II; MALIGNANT PHEOCHROMOCYTOMAS; ENZYMATIC-ACTIVITY; LINE MUTATIONS; SUCCINATE; FEATURES; HYPOXIA; DISEASE; UPDATE AB Background Phaeochromocytomas and paragangliomas are neuro-endocrine tumours that occur sporadically and in several hereditary tumour syndromes, including the phaeochromocytoma-paraganglioma syndrome. This syndrome is caused by germline mutations in succinate dehydrogenase B (SDHB), C (SDHC), or D (SDHD) genes. Clinically, the phaeochromocytoma-paraganglioma syndrome is often unrecognised, although 10-30% of apparently sporadic phaeochromocytomas and paragangliomas harbour germline SDH-gene mutations. Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma-paraganglioma syndrome is rarely done because of time and financial constraints. We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series. Methods Immunohistochemistry for SDHB was done on 220 tumours. Two retrospective series of 175 phaeochromocytomas and paragangliomas with known germline mutation status for phaeochromocytoma-susceptibility or paraganglioma-susceptibility genes were investigated. Additionally, a prospective series of 45 phaeochromocytomas and paragangliomas was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing. Findings SDHB protein expression was absent in all 102 phaeochromocytomas and paragangliomas with an SDHB, SDHC, or SDHD mutation, but was present in all 65 paraganglionic tumours related to multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and neurofibromatosis type 1. 47 (89%) of the 53 phaeochromocytomas and paragangliomas with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDH mutation in the prospective series were 100% (95% CI 87-100) and 84% (60-97), respectively. Interpretation Phaeochromocytoma-paraganglioma syndrome can be diagnosed reliably by an immunohistochemical procedure. SDHB, SDHC, and SDHD germline mutation testing is indicated only in patients with SDHB-negative tumours. SDHB immunohistochemistry on phaeochromocytomas and paragangliomas could improve the diagnosis of phaeochromocytoma-paraganglioma syndrome. Funding The Netherlands Organisation for Scientific Research, Dutch Cancer Society Vanderes Foundation, Association pour la Recherche contre le Cancer, Institut National de la Sante et de la Recherche Medicale, and a PHRC grant COMETE 3 for the COMETE network. C1 [van Nederveen, Francien H.; Gaal, Jose; Korpershoek, Esther; de Bruyn, Elly M. C. A.; Sleddens, Hein F. B. M.; Derkx, Pieter; Dannenberg, Hilde; Petri, Bart-Jeroen; Ferrau, Francesco; Francois, Jerney; de Krijgert, Ronald R.; Dinjens, Winand N. M.] Erasmus MC, Univ Med Ctr, Josephine Nefkens Inst, Dept Pathol, Rotterdam, Netherlands. [Oldenburg, Rogier A.] Erasmus MC, Univ Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. [Hop, Wim C. J.] Erasmus MC, Univ Med Ctr, Dept Biostat, Rotterdam, Netherlands. [de Herder, Wouter W.] Erasmus MC, Univ Med Ctr, Dept Internal Med, Endocrinol Sect, Rotterdam, Netherlands. [Peeters, Mark-Paul F. M. Vrancken] Erasmus MC, Univ Med Ctr, Dept Surg, Rotterdam, Netherlands. [van Linge, Anne] Erasmus MC, Univ Med Ctr, Dept Otolaryngol, Rotterdam, Netherlands. [Komminoth, Paul] Inst Pathol, Stadtspital Triemli, Zurich, Switzerland. [Favier, Judith; Riviere, Julie; Gimenez-Roqueplo, Anne-Paule] Coll France, F-75231 Paris, France. [Favier, Judith; Riviere, Julie; Gimenez-Roqueplo, Anne-Paule] INSERM, U970, Paris, France. [Favier, Judith; Riviere, Julie; Gimenez-Roqueplo, Anne-Paule] Univ Paris 05, Fac Med, Paris, France. [Pacak, Karel] NIH, Reprod & Adult Endocrinol Program, Bethesda, MD 20892 USA. [Pollard, Patrick J.] Univ Oxford, Oxford, England. [Mannelli, Massimo] Univ Florence, Dept Clin Physiopathol, Florence, Italy. [Bayley, Jean-Pierre] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Perren, Aurel] Klinikum Rechts Der Isar, Dept Pathol, Munich, Germany. [Niemann, Stephan] Univ Giessen, Inst Humangenet, Giessen, Germany. [Lenders, Jacques W. M.] Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6525 ED Nijmegen, Netherlands. [Verhofstadt, Albert A.] Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6525 ED Nijmegen, Netherlands. [de Bruine, Adriaan P.] Maastricht Univ, Dept Pathol, GROW Sch Oncol & Dev Biol, Maastricht, Netherlands. [Maher, Eamonn R.] Univ Birmingham, Dept Med & Mol Genet, Inst Biomed Res, Birmingham, W Midlands, England. [Maher, Eamonn R.] Birmingham Womens Hosp, W Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Tissier, Frederique] Hop Cochin, AP HP, Serv Anat Pathol, F-75674 Paris, France. [Meatchi, Tchao; Badoual, Cecile] Hop Europeen Georges Pompidou, AP HP, Serv Anat Pathol, Paris, France. [Amar, Laurence] Serv Hypertens Arterielle, Paris, France. [Gimenez-Roqueplo, Anne-Paule] Serv Genet, Paris, France. [Tissier, Frederique] Univ Paris Decartes, Fac Med Paris Descartes, INSERM, Inst Cochin,U567, Paris, France. [Bertherat, Jerome] Hop Cochin, Ctr Reference Malad Rares Surrenale, F-75674 Paris, France. [Alataki, Despoina] Hippokrateion Hosp, Dept Pathol, Thessaloniki, Greece. [Van Marck, Eric] Univ Antwerp, Pathol Lab, Univ Antwerp Hosp, Edegem, Belgium. [Lenders, Jacques W. M.] Univ Hosp Carl Gustav Carus, Dept Internal Med 3, Dresden, Germany. RP Dinjens, WNM (reprint author), Erasmus MC, Univ Med Ctr, Josephine Nefkens Inst, Dept Pathol, Room Be320A, Rotterdam, Netherlands. EM w.dinjens@erasmusmc.nl RI MAHER, EAMONN/A-9507-2008; Pollard, Patrick/F-7516-2012; Lenders, J.W.M./L-4487-2015; Ferrao, Francesco/P-8852-2015; OI MAHER, EAMONN/0000-0002-6226-6918; Pollard, Patrick/0000-0002-4459-4993; Ferrao, Francesco/0000-0002-7472-6598; Mannelli, Massimo/0000-0002-8001-9857; Perren, Aurel/0000-0002-6819-6092 FU The Netherlands Organisation for Scientific Research; Dutch Cancer Society Vanderes Foundation; Association pour la Recherche contre le Cancer; Institut National de la Sante et de la Recherche Medicale; PHRC FX The Netherlands Organisation for Scientific Research, Dutch Cancer Society Vanderes Foundation, Association pour la Recherche contre le Cancer, Institut National de la Sante et de la Recherche Medicale, and a PHRC grant COMETE 3 for the COMETE network. NR 33 TC 190 Z9 190 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD AUG PY 2009 VL 10 IS 8 BP 764 EP 771 DI 10.1016/S1470-2045(09)70164-0 PG 8 WC Oncology SC Oncology GA 479YH UT WOS:000268697700015 PM 19576851 ER PT J AU Klug, SJ Ressing, M Koenig, J Abba, MC Agorastos, T Brenna, SMF Ciotti, M Das, BR Del Mistro, A Dybikowska, A Giuliano, AR Gudleviciene, Z Gyllensten, U Haws, ALF Helland, A Herrington, CS Hildesheim, A Humbey, O Jee, SH Kim, JW Madeleine, MM Menczer, J Ngan, HYS Nishikawa, A Niwa, Y Pegoraro, R Pillai, MR Ranzani, G Rezza, G Rosenthal, AN Roychoudhury, S Saranath, D Schmitt, VM Sengupta, S Settheetham-Ishida, W Shirasawa, H Snijders, PJF Stoler, MH Suarez-Rincon, AE Szarka, K Tachezy, R Ueda, M van der Zee, AGJ Doeberitz, MV Wu, MT Yamashita, T Zehbe, I Blettner, M AF Klug, Stefanie J. Ressing, Meike Koenig, Jochem Abba, Martin C. Agorastos, Theodoros Brenna, Sylvia M. F. Ciotti, Marco Das, B. R. Del Mistro, Annarosa Dybikowska, Aleksandra Giuliano, Anna R. Gudleviciene, Zivile Gyllensten, Ulf Haws, Andrea L. F. Helland, Aslaug Herrington, C. Simon Hildesheim, Alan Humbey, Olivier Jee, Sun H. Kim, Jae Weon Madeleine, Margaret M. Menczer, Joseph Ngan, Hextan Y. S. Nishikawa, Akira Niwa, Yoshimitsu Pegoraro, Rosemary Pillai, M. R. Ranzani, Gulielmina Rezza, Giovanni Rosenthal, Adam N. Roychoudhury, Susanta Saranath, Dhananjaya Schmitt, Virginia M. Sengupta, Sharmila Settheetham-Ishida, Wannapa Shirasawa, Hiroshi Snijders, Peter J. F. Stoler, Mark H. Suarez-Rincon, Angel E. Szarka, Krisztina Tachezy, Ruth Ueda, Masatsugu van der Zee, Ate G. J. Doeberitz, Magnus von Knebel Wu, Ming-Tsang Yamashita, Tsuyoshi Zehbe, Ingeborg Blettner, Maria TI TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies SO LANCET ONCOLOGY LA English DT Article ID SQUAMOUS INTRAEPITHELIAL LESIONS; HUMAN-PAPILLOMAVIRUS TYPE-16; HARDY-WEINBERG EQUILIBRIUM; P53 ARG72PRO POLYMORPHISM; WILD-TYPE P53; HEALTHY WOMEN; HPV INFECTION; INDIAN WOMEN; RISK-FACTORS; GENOTYPES AB Background Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer. Methods Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy-Weinberg equilibrium, study quality, and the material used to determine TP53 genotype. Findings The pooled estimates (OR) for invasive cervical cancer were 1.22 (95% CI 1.08-1-39) for arginine homozygotes compared with heterozygotes, and 1.13 (0.94-1.35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy-Weinberg equilibrium (1.71 [1.21-2.42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1.35 [1.15-1.58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1.39 [1.13-1.73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes). Interpretation Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies. Funding German Research Foundation (DFG). C1 [Klug, Stefanie J.; Ressing, Meike; Koenig, Jochem; Blettner, Maria] Johannes Gutenberg Univ Mainz, IMBEI, Univ Med Ctr, D-55101 Mainz, Germany. [Abba, Martin C.] Natl Univ La Plata, Fac Med Sci, CINIBA, La Plata, Buenos Aires, Argentina. [Agorastos, Theodoros] Aristotle Univ Thessaloniki, Dept Obstet & Gynecol 1, Papageorgiou Hosp, GR-54006 Thessaloniki, Greece. [Brenna, Sylvia M. F.] City Sao Paolo Univ UNICID, Sch Med, Sao Paulo, Brazil. [Brenna, Sylvia M. F.] Leonor Mendes de Barros Matern Hosp, Sao Paulo, Brazil. [Ciotti, Marco] Univ Hosp Tor Vergata, Mol Virol Lab, Rome, Italy. [Das, B. R.] Super Religare Labs Ltd, Bombay, Maharashtra, India. [Del Mistro, Annarosa] IRCCS, Ist Oncol Veneto, Padua, Italy. [Dybikowska, Aleksandra] Med Univ Gdansk, Dept Hematol & Transplantal, Gdansk, Poland. [Giuliano, Anna R.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol & Genet, Tampa, FL 33612 USA. [Gudleviciene, Zivile] Vilnius State Univ, Inst Oncol, Dept Cancerogenesis & Tumor Pathophysiol, Vilnius, Lithuania. [Gyllensten, Ulf] Uppsala Univ, Dept Genet & Pathol, Rudbeck Lab, Uppsala, Sweden. [Haws, Andrea L. F.] Baylor Coll Med, Houston, TX 77030 USA. [Helland, Aslaug] Norwegian Radium Hosp, Dept Genet Oncol, Oslo, Norway. [Herrington, C. Simon] Univ St Andrews, Bute Med Sch, St Andrews, Fife, Scotland. [Hildesheim, Alan] NCI, Div Cancer Epidemiol & Genet, Rockville, MD USA. [Humbey, Olivier] Univ Franche Comte, IBCT, IFR 133, EA 3181, F-25030 Besancon, France. [Jee, Sun H.] Yonsei Univ, Inst Hlth Promot, Grad Sch Publ Hlth, Seoul 120749, South Korea. [Kim, Jae Weon] Seoul Natl Univ, Dept Obstet & Gynecol, Canc Res Inst, Seoul, South Korea. [Madeleine, Margaret M.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Menczer, Joseph] Med Ctr, Dept Obstet & Gynecol, Gynecol Oncol Unit, Holon, Israel. [Ngan, Hextan Y. S.] Queen Marys Hosp, Dept Obstet & Gynecol, Hong Kong, Hong Kong, Peoples R China. [Nishikawa, Akira] NTT E Sapporo Hosp, Dept Obstet & Gynecol, Sapporo, Hokkaido, Japan. [Niwa, Yoshimitsu] Niwa Clin, Nisshin 4580815, Japan. [Pegoraro, Rosemary] Univ KwaZulu Natal, Dept Clin Med, Nelson R Mandela Sch Med, Congella, South Africa. [Pillai, M. R.] Rajiv Gandhi Ctr Biotechnol, Thycaud, Kerala, India. [Ranzani, Gulielmina] Univ Pavia, Dept Genet & Microbiol, I-27100 Pavia, Italy. [Rezza, Giovanni] Ist Super Sanita, Dept Infect Parasit & Immune Mediated Dis, I-00161 Rome, Italy. [Rosenthal, Adam N.] UCL, EGA Inst Womens Hlth, London, England. [Roychoudhury, Susanta] CSIR, Inst Biol Chem, Mol & Human Genet Div, Kolkata, India. [Saranath, Dhananjaya] Reliance Life Sci, Mol Med, Navi Mumbai, India. [Schmitt, Virginia M.] Pontificia Univ Catolica Rio Grande do Sul, Fac Pharm, Porto Alegre, RS, Brazil. [Sengupta, Sharmila] Indian Stat Inst, Human Genet Unit, Kolkata, India. [Settheetham-Ishida, Wannapa] Khon Kaen Univ, Fac Med, Dept Physiol, Khon Kaen, Thailand. [Shirasawa, Hiroshi] Chiba Univ, Grad Sch Med, Dept Mol Virol E2, Chiba, Japan. [Snijders, Peter J. F.] Vrije Univ Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Stoler, Mark H.] Univ Virginia Hlth Syst, Dept Pathol, Charlottesville, VA USA. [Suarez-Rincon, Angel E.] Inst Mexicano Seguro Social, Dept Med Educ & Res, Hosp Gen Reg 45, Guadalajara, Jalisco, Mexico. [Szarka, Krisztina] Univ Debrecen, Dept Med Microbiol, Med & Hlth Sci Ctr, H-4012 Debrecen, Hungary. [Tachezy, Ruth] Inst Hematol & Blood Transfus, Natl Reference Lab Papillomaviruses, Dept Expt Virol, CR-12820 Prague, Czech Republic. [Ueda, Masatsugu] Osaka Canc Prevent & Detect Ctr, Osaka, Japan. [van der Zee, Ate G. J.] Univ Groningen, Univ Med Ctr Groningen, Dept Obstet & Gynecol, NL-9713 AV Groningen, Netherlands. [Doeberitz, Magnus von Knebel] Univ Hosp, Inst Pathol, Heidelberg, Germany. [Wu, Ming-Tsang] Kaohsiung Med Univ Hosp, Dept Family Med, Kaohsiung, Taiwan. [Wu, Ming-Tsang] Kaohsiung Med Univ Hosp, Grad Inst Occupat Safety & Hlth, Kaohsiung, Taiwan. [Wu, Ming-Tsang] Kaohsiung Med Univ, Kaohsiung, Taiwan. [Yamashita, Tsuyoshi] Hakodate Municipal Hosp, Dept Obstet & Gynecol, Hakodate, Hokkaido, Japan. [Zehbe, Ingeborg] Thunder Bay Reg Res Inst, Thunder Bay, ON, Canada. RP Klug, SJ (reprint author), Johannes Gutenberg Univ Mainz, IMBEI, Univ Med Ctr, D-55101 Mainz, Germany. EM klug@imbei.uni-mainz.de RI Khon Kaen University, Faculty of Medicine/A-3133-2009; Wu, Ming-Tsang/D-2385-2009; Kim , Jae Weon/C-5549-2012; del mistro, annarosa/E-9352-2014; Hildesheim, Allan/B-9760-2015; Helland, Aslaug/H-3910-2015; von Knebel Doeberitz, Magnus/D-2372-2016; REZZA, GIOVANNI/D-4393-2016; OI Herrington, C Simon/0000-0001-9177-8165; Kim, Jae-Weon/0000-0003-1835-9436; del mistro, annarosa/0000-0001-7201-9374; Hildesheim, Allan/0000-0003-0257-2363; Helland, Aslaug/0000-0002-5520-0275; von Knebel Doeberitz, Magnus/0000-0002-0498-6781; REZZA, GIOVANNI/0000-0003-0268-6790; Rosenthal, Adam/0000-0001-6924-0721; Abba, Martin/0000-0002-9206-2369 FU German Research Foundation (DFG) FX The analysis of the pooled data was supported by a grant from the German Research Foundation (DFG). Susanne Glodny helped with the internet search for published and unpublished studies, and Thomas Ziegler helped to generate the common database. Heiko Gotte discussed the possibilities of different statistical analyses. NR 86 TC 89 Z9 90 U1 0 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD AUG PY 2009 VL 10 IS 8 BP 772 EP 784 DI 10.1016/S1470-2045(09)70187-1 PG 13 WC Oncology SC Oncology GA 479YH UT WOS:000268697700016 PM 19625214 ER PT J AU Carson, KR Focosi, D Major, EO Petrini, M Richey, EA West, DP Bennett, CL AF Carson, Kenneth R. Focosi, Daniele Major, Eugene O. Petrini, Mario Richey, Elizabeth A. West, Dennis P. Bennett, Charles L. TI Monoclonal anti body-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project SO LANCET ONCOLOGY LA English DT Review ID B-CELL DEPLETION; JC VIRUS-DNA; MULTIPLE-SCLEROSIS PATIENTS; IDIOPATHIC THROMBOCYTOPENIC PURPURA; HEMATOPOIETIC PROGENITOR CELLS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; HIV-NEGATIVE PATIENTS; HUMAN BRAIN; T-CELLS; DEMYELINATING DISEASE AB Progressive multifocal leucoencephalopathy (PML) is a serious and usually fatal CNS infection caused by JC polyoma virus. CD4+ and CD8+ T lymphopenia, resulting from HIV infection, chemotherapy, or immunosuppressive therapy, are the primary risk factors. The immune modulatory monoclonal antibodies rituximab, natalizumab, and efalizumab have received regulatory approval in the USA and Europe for treatment of non-Hodgkin lymphoma, rheumatoid arthritis, and chronic lymphocytic leukaemia (Europe only); multiple sclerosis and Crohn's disease; and psoriasis, respectively. Efalizumab and natalizumab administration is associated with CD4+ T lymphopenia and altered trafficking of T lymphocytes into the CNS, and rituximab leads to prolonged B-lymphocyte depletion. Unexpected cases of PML developing in people who receive these drugs have been reported, with many of the affected individuals dying from this disease. Herein, we review clinical findings, pathology, epidemiology, basic science, and risk-management issues associated with PML infection developing after treatment with these monoclonal antibodies. C1 [Richey, Elizabeth A.; Bennett, Charles L.] Northwestern Univ, Feinberg Sch Med, Div Hematol Oncol, Chicago, IL 60611 USA. [Carson, Kenneth R.] Washington Univ, Sch Med, Dept Internal Med, Div Med Oncol,Siteman Canc Ctr, St Louis, MO 63110 USA. [Focosi, Daniele; Petrini, Mario] Univ Pisa, Div Haematol, Pisa, Italy. [Major, Eugene O.] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. [West, Dennis P.] Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA. [Bennett, Charles L.] Robert H Lurie Comprehens Canc Ctr, Chicago, IL USA. [Bennett, Charles L.] VA Ctr Management Complex Chron Condit, Jesse Brown VAMC, Chicago, IL USA. RP Bennett, CL (reprint author), Northwestern Univ, Feinberg Sch Med, Div Hematol Oncol, 710 N Fairbanks Ct,Olson Pavil,Suite 8-250, Chicago, IL 60611 USA. EM cbenne@northwestern.edu OI Focosi, Daniele/0000-0001-8811-195X; West, Dennis/0000-0002-9107-6697 FU National Cancer Institute [1R01 CA125077-01A1] FX This review was supported in part by a National Cancer Institute grant (1R01 CA125077-01A1 to CLB). NR 74 TC 242 Z9 247 U1 1 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD AUG PY 2009 VL 10 IS 8 BP 816 EP 824 PG 9 WC Oncology SC Oncology GA 479YH UT WOS:000268697700021 PM 19647202 ER PT J AU Stetler-Stevenson, M AF Stetler-Stevenson, Maryalice TI Flow cytometric immunophenotyping: Emerging as an important diagnostic tool in the evaluation of cytopenic patients SO LEUKEMIA RESEARCH LA English DT Editorial Material ID MYELODYSPLASTIC SYNDROMES; ABNORMALITIES C1 NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, Bldg 10,Room 2A-33,Mail Stop 1500, Bethesda, MD 20892 USA. EM stetler@mail.nih.gov FU Intramural NIH HHS [Z01 SC009372-15, Z99 CA999999] NR 10 TC 3 Z9 3 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD AUG PY 2009 VL 33 IS 8 BP 1020 EP 1021 DI 10.1016/j.leukres.2009.02.029 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 455KS UT WOS:000266759000004 PM 19327830 ER PT J AU Hussein, N Fedorova, I Moriguchi, T Hamazaki, K Kim, HY Hoshiba, J Salem, N AF Hussein, Nahed Fedorova, Irina Moriguchi, Toru Hamazaki, Kei Kim, Hee-Yong Hoshiba, Junji Salem, Norman, Jr. TI Artificial Rearing of Infant Mice Leads to n-3 Fatty Acid Deficiency in Cardiac, Neural and Peripheral Tissues SO LIPIDS LA English DT Article DE Artificial rearing; Artificial mouse milk; Docosahexaenoic acid; Docosapentaenoic acid; Brain; Heart; Retina; Liver; Plasma; Phospholipid class ID PERFORMANCE LIQUID-CHROMATOGRAPHY; FISH-OIL SUPPLEMENTATION; SPATIAL TASK-PERFORMANCE; DOCOSAHEXAENOIC ACID; SUDDEN-DEATH; MOUSE PUPS; MYOCARDIAL-INFARCTION; DOCOSAPENTAENOIC ACID; MASS-SPECTROMETRY; ACYL COMPOSITION AB The ability to control the fatty acid content of the diet during early development is a crucial requirement for a one-generation model of docosahexaenoic acid (DHA; 22:6n3) deficiency. A hand feeding method using artificial rearing (AR) together with sterile, artificial milk was employed for feeding mice from postnatal day 2-15. The pups were fed an n-3 fatty acid adequate (3% alpha-linolenic acid (LNA; 18:3n3) + 1% 22:6n3) or a deficient diet (0.06% 18:3n3) with linoleic acid (LA; 18:2n6) as the only dietary source of essential fatty acids by AR along with a dam-reared control group (3.1% 18:3n3). The results indicate that restriction of n-3 fatty acid intake during postnatal development leads to markedly lower levels of brain, retinal, liver, plasma and heart 22:6n3 at 20 weeks of age with replacement by docosapentaenoic acid (DPAn6; 22:5n6), arachidonic acid (ARA; 20:4n6) and docosatetraenoic acid (DTA; 22:4n6). A detailed analysis of phospholipid classes of heart tissue indicated that phosphatidylethanolamine, phosphatidylcholine and cardiolipin were the major repositories of 22:6n3, reaching 40, 29 and 15%, respectively. A novel heart cardiolipin species containing four 22:6n3 moieties is described. This is the first report of the application of artificially rearing to mouse pup nutrition; this technique will facilitate dietary studies of knockout animals as well as the study of essential fatty acid (EFA) functions in the cardiovascular, neural and other organ systems. C1 [Salem, Norman, Jr.] Martek Biosci Corp, Columbia, MD 21045 USA. [Hussein, Nahed] Ain Shams Univ, Fac Specif Educ, Cairo, Egypt. [Fedorova, Irina; Moriguchi, Toru; Salem, Norman, Jr.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Hamazaki, Kei; Kim, Hee-Yong] NIAAA, Lab Mol Signaling, NIH, Bethesda, MD 20892 USA. [Hoshiba, Junji] Okayama Univ, Dept Anim Resources, Adv Sci Res Ctr, Okayama, Japan. RP Salem, N (reprint author), Martek Biosci Corp, 6480 Dobbin Rd, Columbia, MD 21045 USA. EM nsalem@martek.com FU Intramural NIH HHS [Z01 AA000284-18] NR 56 TC 13 Z9 13 U1 0 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0024-4201 J9 LIPIDS JI Lipids PD AUG PY 2009 VL 44 IS 8 BP 685 EP 702 DI 10.1007/s11745-009-3318-2 PG 18 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 474RO UT WOS:000268301900002 PM 19588181 ER PT J AU Latella, G Vetuschi, A Sferra, R Catitti, V D'Angelo, A Zanninelli, G Flanders, KC Gaudio, E AF Latella, Giovanni Vetuschi, Antonella Sferra, Roberta Catitti, Valentina D'Angelo, Angela Zanninelli, Giuliana Flanders, Kathleen C. Gaudio, Eugenio TI Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in mice SO LIVER INTERNATIONAL LA English DT Article DE chronic hepatitis; DMN-induced hepatitis; ECM; fibrosis; liver fibrosis; Smad proteins; TGF-beta ID TISSUE GROWTH-FACTOR; LIVER FIBROSIS; TGF-BETA; STELLATE CELLS; NUCLEAR-LOCALIZATION; RENAL FIBROSIS; RATS; EXPRESSION; COLLAGEN; FIBROGENESIS AB Background Hepatic fibrosis is characterized by a progressive accumulation of fibrillar extracellular matrix (ECM) proteins including collagen, which occurs in most types of chronic liver diseases. Transforming growth factor-beta (TGF-beta)/Smad3 signalling plays a central role in tissue fibrogenesis, acting as a potent stimulus of ECM accumulation. Aim To evaluate the potential protective role of Smad3 deficiency in the pathogenesis of liver fibrosis induced by dimethylnitrosamine (DMN) in Smad3 null mice. Methods Chronic hepatitis-associated fibrosis was induced in 13 Smad3 null and 13 wild-type (WT) mice by intraperitoneal DMN administration (10 mu g/g body weight/day) for three consecutive days per week for 6 weeks. The liver was excised for macroscopic examination and histological, morphometric and immunohistochemical (IHC) analyses. For IHC, alpha-smooth muscle actin (alpha-SMA), collagen types I-III, TGF-beta 1, connective tissue growth factor (CTGF), Smad3, Smad7 and CD3 antibodies were used. Results At macroscopic examination, the liver of DMN-treated Smad3 WT appeared harder with a dark brown colouring and necrotic areas compared with that from null mice. Histological and morphometric evaluation revealed a significantly higher degree of hepatic fibrosis and accumulation of connective tissue in the Smad3 WT compared with null mice. IHC evaluation showed a marked increase in alpha-SMA, CTGF, collagen I-III, TGF-beta and Smad3 staining in the liver of Smad3 WT compared with that in null mice, whereas Smad7 was increased only in null mice. Conclusions The results indicate that Smad3 loss confers resistance to the development of DMN-induced hepatic fibrosis. The reduced fibrotic response appears to be due to a reduction of fibrogenic myofibroblast activation and ECM production and accumulation. Smad3 could be a novel target for potential treatment of fibrosis complicating chronic hepatitis. C1 [Latella, Giovanni; Catitti, Valentina; D'Angelo, Angela; Zanninelli, Giuliana] Univ Aquila, Dept Internal Med, GI Unit, I-67100 Laquila, Italy. [Vetuschi, Antonella; Sferra, Roberta] Univ Aquila, Dept Expt Med, I-67100 Laquila, Italy. [Flanders, Kathleen C.] NCI, NIH, Bethesda, MD 20892 USA. [Gaudio, Eugenio] Univ Roma La Sapienza, Dept Human Anat, Rome, Italy. RP Latella, G (reprint author), Univ Aquila, Dipartimento Med Interna & Sanita Publ, Div Gastroenterol Epatol & Nutr, Piazza Salvatore Tommasi 1, I-67100 Laquila, Italy. EM giolatel@tin.it NR 64 TC 54 Z9 63 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1478-3223 J9 LIVER INT JI Liver Int. PD AUG PY 2009 VL 29 IS 7 BP 997 EP 1009 DI 10.1111/j.1478-3231.2009.02011.x PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 467AW UT WOS:000267709300005 PM 19422482 ER PT J AU Herzka, DA Kotys, MS Sinkus, R Pettigrew, RI Gharib, AM AF Herzka, D. A. Kotys, M. S. Sinkus, R. Pettigrew, R. I. Gharib, A. M. TI Magnetic Resonance Elastography in the Liver at 3 Tesla Using a Second Harmonic Approach SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE liver fibrosis; magnetic resonance elastography; elastography; liver stiffness ID MR ELASTOGRAPHY; NONINVASIVE ASSESSMENT; BREAST-LESIONS; FIBROSIS; RATIO AB Magnetic resonance elastography (MIRE) using mechanical stimulation has demonstrated diagnostic value and clinical promise in breast, liver, and kidney at 1.5 Tesla (T). However, MRE at 1.5T suffers from long imaging times and would benefit from greater signal-to-noise for more robust postprocessing. We present an MRE sequence modified for liver imaging at 3.0T. To avoid artifacts in the phase images, the sequence maintains a short TE by using a second harmonic approach, including stronger motion encoding gradients, shorter radio frequency pulses and an echo-planar readout. Scan time was decreased by a factor of similar to 2 relative to 1.5T by using an EPI readout and a higher density sampling of the phase waveform was used to calculate shear stiffness and viscosity. Localized (small region of interest) and global (whole-liver region of interest) measurements in normal healthy subjects compared very favorably with previously published results at 1.5T. There was no significant difference between global and localized measures. Magn Reson Med 62:284-291, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Herzka, D. A.; Kotys, M. S.] NHLBI, NIH, DHHS, Bethesda, MD USA. [Herzka, D. A.] Philips Res N Amer, Clin Sites Res Program, Bethesda, MD USA. [Kotys, M. S.] Philips Healthcare, MR Clin Sci, Cleveland, OH USA. [Sinkus, R.] ESPCI, Lab Ondes & Acoust, F-75005 Paris, France. [Pettigrew, R. I.; Gharib, A. M.] NIDDK, Bethesda, MD USA. RP Herzka, DA (reprint author), Johns Hopkins Univ, Sch Med, Dept Biomed Engn, 720 Rutland Ave,726 Ross Bldg, Baltimore, MD 21205 USA. EM daniel.herzka@gmail.com RI Gharib, Ahmed/O-2629-2016; OI Gharib, Ahmed/0000-0002-2476-481X; Herzka, Daniel/0000-0002-9400-7814 NR 14 TC 16 Z9 16 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD AUG PY 2009 VL 62 IS 2 BP 284 EP 291 DI 10.1002/mrm.21956 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 476IH UT WOS:000268432400002 PM 19449374 ER PT J AU Kotys, MS Herzka, DA Vonken, EJ Ohayon, J Heroux, J Gharib, AM Stuber, M Pettigrew, RI AF Kotys, Melanie S. Herzka, Daniel A. Vonken, Evert-Jan Ohayon, Jacques Heroux, Julie Gharib, Ahmed M. Stuber, Matthias Pettigrew, Roderic I. TI Profile Order and Time-Dependent Artifacts in Contrast-Enhanced Coronary MR Angiography at 3T: Origin and Prevention SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE magnetic resonance angiography artifact; coronary artery; contrast agent enhancement; profile order; simulation ID SPINAL-CORD; ACQUISITION AB To enhance the clinical value of coronary magnetic resonance angiography (MRA), high-relaxivity contrast agents have recently been used at 3T. Here we examine a uniform bilateral shadowing artifact observed along the coronary arteries in MRA images collected using such a contrast agent. Simulations were performed to characterize this artifact, including its origin, to determine how best to mitigate this effect, and to optimize a data acquisition/injection scheme. An intraluminal contrast agent concentration model was used to simulate various acquisition strategies with two profile orders for a slow-infusion of a high-relaxivity contrast agent. Filtering effects from temporally variable weighting in k-space are prominent when a centric, radial (CR) profile order is applied during contrast infusion, resulting in decreased signal enhancement and underestimation of vessel width, while both pre- and postinfusion steady-state acquisitions result in overestimation of the vessel width. Acquisition during the brief postinfusion steady-state produces the greatest signal enhancement and minimizes k-space filtering artifacts. Magn Reson Med 62:292-299, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Ohayon, Jacques; Heroux, Julie; Gharib, Ahmed M.; Pettigrew, Roderic I.] NIDDK, NIH, Bethesda, MD 20892 USA. [Kotys, Melanie S.] Philips Healthcare N Amer, MR Clin Sci, Cleveland, OH USA. [Herzka, Daniel A.] Philips Healthcare N Amer, Clin Sites Res Program, Cleveland, OH USA. [Vonken, Evert-Jan; Stuber, Matthias] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA. [Kotys, Melanie S.; Herzka, Daniel A.] NHLBI, NIH, Bethesda, MD 20892 USA. [Ohayon, Jacques] IN3S, UMR 5525, CNRS, Lab Tech Ingn Med & Complexite Informat Math & Ap, Grenoble, France. RP Pettigrew, RI (reprint author), NIDDK, NIH, Bldg 31,Rm 1C14,31 Ctr Dr,MSC 2281, Bethesda, MD 20892 USA. EM rpettig@mail.nih.gov RI Stuber, Matthias/B-2949-2010; Gharib, Ahmed/O-2629-2016; OI Stuber, Matthias/0000-0001-9843-2028; Gharib, Ahmed/0000-0002-2476-481X; Herzka, Daniel/0000-0002-9400-7814 NR 21 TC 7 Z9 7 U1 0 U2 0 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 AUG PY 2009 VL 62 IS 2 BP 292 EP 299 DI 10.1002/mrm.21997 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 476IH UT WOS:000268432400003 PM 19526488 ER PT J AU Shin, WY Gu, H Yang, YH AF Shin, Wanyong Gu, Hong Yang, Yihong TI Incidental Magnetization Transfer Contrast by Fat Saturation Preparation Pulses in Multislice Look-Locker Echo Planar Imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE magnetic resonance imaging; magnetization transfer contrast; fat saturation pulse; Look-Locker EPI; T(1) measurement ID WATER; TISSUE; INHOMOGENEITIES; EXCITATION; SEQUENCES AB In this study, it is demonstrated that fat saturation (FS) preparation (prep) pulses generate incidental magnetization transfer contrast (MTC) in multislice Look-Locker (LL) imaging. It is shown that frequency-selective FS prep pulses can invoke MTC through the exchange between free and motion-restricted protons. Simulation reveals that the fractional signal loss by these MTC effects is more severe for smaller flip angles (FAs), shorter repetition times (TRs), and greater number of slices (SN). These incidental MTC effects result in a signal attenuation at a steady state (up to 30%) and a T(1) measurement bias (up to 20%) when using inversion recovery (IR) LL echo-planar imaging (EPI) sequences. Furthermore, it is shown that water-selective MRI using binomial pulses has the potential to minimize the signal attenuation and provide unbiased T(1) measurement without fat artifacts in MR images. Magn Reson Med 62:520-526, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Shin, Wanyong; Gu, Hong; Yang, Yihong] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. RP Shin, WY (reprint author), NIDA, Neuroimaging Res Branch, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM shinwa@nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse (NIDA); National Institutes of Health (NIH) FX Intramural Research Program of the National Institute on Drug Abuse (NIDA); National Institutes of Health (NIH). NR 21 TC 6 Z9 6 U1 0 U2 0 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 AUG PY 2009 VL 62 IS 2 BP 520 EP 526 DI 10.1002/mrm.22034 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 476IH UT WOS:000268432400027 PM 19526506 ER PT J AU Koay, CG AF Koay, Cheng Guan TI On the six-dimensional orthogonal tensor representation of the rotation in three dimensions: A simplified approach SO MECHANICS OF MATERIALS LA English DT Article ID DIFFUSION; FRAMEWORK AB The six-dimensional orthogonal tensor representation of the rotation about an axis in three dimensions was first proposed by Mehrabadi et at. [Mehrabadi, M.M., Cowin, S.C., Jaric, J., 1995. Six-dimensional orthogonal tensor representation of the rotation about an axis in three dimensions. International journal of Solids and Structures 32 (3-4), 439-449]. In this brief note, a simple and coherent approach is presented to construct the six-dimensional orthogonal tensor representation of the rotation of any parametrization in three dimensions and to prove its orthogonality. Published by Elsevier Ltd. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. RP Koay, CG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, NIH, Bldg 13,Rm 3W16,13 South Dr,MSC 5772, Bethesda, MD 20892 USA. EM guankoac@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The author thanks Drs. Peter J. Basser and Maher Moakher for bringing the work of Prof. Mehrabadi and coworkers to his attention, and to Dr. Maher Moakher for helpful discussion on the significance of the MCR convention in elasticity. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 12 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-6636 J9 MECH MATER JI Mech. Mater. PD AUG PY 2009 VL 41 IS 8 BP 951 EP 953 DI 10.1016/j.mechmat.2008.12.006 PG 3 WC Materials Science, Multidisciplinary; Mechanics SC Materials Science; Mechanics GA 464NY UT WOS:000267513200005 PM 20161108 ER PT J AU Soerensen, M Gredilla, R Muller-Ohldach, M Werner, A Bohr, VA Osiewacz, HD Stevnsner, T AF Soerensen, Mette Gredilla, Ricardo Mueller-Ohldach, Mathis Werner, Alexandra Bohr, Vilhelm A. Osiewacz, Heinz D. Stevnsner, Tinna TI A potential impact of DNA repair on ageing and lifespan in the ageing model organism Podospora anserina: Decrease in mitochondrial DNA repair activity during ageing SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE DNA repair; Mitochondria; Ageing; Base excision repair; DNA glycosylases; Podospora anserina ID BASE EXCISION-REPAIR; AGE-ASSOCIATED DAMAGE; PLASMID-LIKE DNA; OXIDATIVE DAMAGE; FILAMENTOUS FUNGUS; MAMMALIAN-CELLS; CAENORHABDITIS-ELEGANS; DEGENERATIVE DISEASES; SENESCENT CULTURES; ENDO-EXONUCLEASE AB The free radical theory of ageing states that ROS play a key role in age-related decrease in mitochondrial function via the damage of mitochondrial DNA (mtDNA), proteins and lipids. In the sexually reproducing ascomycete Podospora anserina ageing is, as in other eukaryotes, associated with mtDNA instability and mitochondrial dysfunction. Part of the mtDNA instabilities may arise due to accumulation of ROS induced mtDNA lesions, which, as previously suggested for mammals, may be caused by an age-related decrease in base excision repair (BER). Alignments of known BER protein sequences with the A anserina genome revealed high homology. We report for the first time the presence of BER activities in P. anserina mitochondrial extracts. DNA glycosylase activities decrease with age, suggesting that the increased mtDNA instability with age may be caused by decreased ability to repair mtDNA damage and hence contribute to ageing and lifespan control in this ageing model. Additionally, we find low DNA glycosylase activities in the long-lived mutants grisea and Delta PaCox17::ble, which are characterized by low mitochondrial ROS generation. Overall, our data identify a potential role of mtDNA repair in controlling ageing and life span in P. anserina, a mechanism possibly regulated in response to ROS levels. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Soerensen, Mette; Gredilla, Ricardo; Stevnsner, Tinna] Univ Aarhus, Danish Ctr Mol Gerontol, DK-8000 Aarhus C, Denmark. [Soerensen, Mette; Gredilla, Ricardo; Stevnsner, Tinna] Univ Aarhus, Dept Mol Biol, Aarhus Univ, Danish Aging Res Ctr, DK-8000 Aarhus C, Denmark. [Mueller-Ohldach, Mathis; Werner, Alexandra; Osiewacz, Heinz D.] Goethe Univ Frankfurt, Inst Mol Biosci, Fac Biosci & Cluster Excellence Macromol Complexe, D-60438 Frankfurt, Germany. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Stevnsner, T (reprint author), Univ Aarhus, Danish Ctr Mol Gerontol, CF Moellers Alle 1130, DK-8000 Aarhus C, Denmark. EM tvs@mb.au.dk RI Osiewacz, Heinz/D-3454-2011; Soerensen, Mette/O-1817-2015; OI Soerensen, Mette/0000-0001-5268-3366 FU European Commission [LSHM-CT-2004-512020]; HDO; Danish Aging Research Center [VELUX 95-103-11419]; German Research Foundation (DFG) [OS75/12] FX This research was supported by a grant from the European Commission (LSHM-CT-2004-512020) to TS and HDO, by the Danish Aging Research Center (VELUX 95-103-11419) to TS. and the German Research Foundation (DFG, OS75/12) to HDO. Professor R. Lill (Philipps-Universitat, Marburg, Germany) is thanked for the supply of cytochrome c antibody and Ulla Birk Henriksen is thanked for excellent technical assistance. NR 81 TC 12 Z9 12 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD AUG PY 2009 VL 130 IS 8 BP 487 EP 496 DI 10.1016/j.mad.2009.05.003 PG 10 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 487RH UT WOS:000269292000003 PM 19486911 ER PT J AU Csiszar, A Labinskyy, N Jimenez, R Pinto, JT Ballabh, P Losonczy, G Pearson, KJ de Cabo, R Ungvari, Z AF Csiszar, Anna Labinskyy, Nazar Jimenez, Rosario Pinto, John T. Ballabh, Praveen Losonczy, Gyorgy Pearson, Kevin J. de Cabo, Rafael Ungvari, Zoltan TI Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: Role of circulating factors and SIRT1 SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE Aging; Oxidative stress; Inflammation; Calorie restriction; Resveratrol ID NF-KAPPA-B; OXIDATIVE STRESS RESISTANCE; NECROSIS-FACTOR-ALPHA; DISEASE RISK-FACTORS; DIETARY RESTRICTION; CORONARY-ARTERIES; ENDOTHELIAL-CELLS; WEIGHT-LOSS; LIFE-SPAN; RESVERATROL AB Endothelial dysfunction, oxidative stress and inflammation are associated with vascular aging and promote the development of cardiovascular disease. Caloric restriction (CR) mitigates conditions associated with aging, but its effects on vascular dysfunction during aging remain poorly defined. To determine whether CR exerts vasoprotective effects in aging, aortas of ad libitum (AL) fed young and aged and CR-aged F344 rats were compared. Aging in AL-rats was associated with impaired acetylcholine-induced relaxation, vascular oxidative stress and increased NF-kappa B activity. Lifelong CR significantly improved endothelial function, attenuated vascular ROS production, inhibited NF-kappa B activity and down-regulated inflammatory genes. To elucidate the role of circulating factors in mediation of the vasoprotective effects of CR, we determined whether sera obtained from CR animals can confer anti-oxidant and anti-inflammatory effects in cultured coronary arterial endothelial cells (CAECs), mimicking the effects of CK In CAECs cultured in the presence of AL serum TNF alpha elicited oxidative stress, NF-kappa B activation and inflammatory gene expression. By contrast, treatment of CAECs with CR serum attenuated TNF alpha-induced ROS generation and prevented NF-kappa B activation and induction of inflammatory genes. siRNA knockdown of SIRT1 mitigated the anti-oxidant and anti-inflammatory effects of CR serum. CR exerts anti-oxidant and anti-inflammatory vascular effects, which are likely mediated by circulating factors, in part, via a SIRT1-dependent pathway. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Csiszar, Anna; Ungvari, Zoltan] Univ Oklahoma, Hlth Sci Ctr, Dept Geriatr Med, Reynolds Oklahoma Ctr Aging, Oklahoma City, OK 73104 USA. [Csiszar, Anna; Labinskyy, Nazar; Jimenez, Rosario; Ungvari, Zoltan] New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. [Pinto, John T.] New York Med Coll, Dept Biochem, Valhalla, NY 10595 USA. [Ballabh, Praveen] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. [Losonczy, Gyorgy; Ungvari, Zoltan] Semmelweis Univ, Dept Pulmonol, H-1085 Budapest, Hungary. [Pearson, Kevin J.; de Cabo, Rafael] NIA, Lab Expt Gerontol, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Ungvari, Z (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Geriatr Med, Reynolds Oklahoma Ctr Aging, Oklahoma City, OK 73104 USA. EM ungzol@yahoo.com RI JIMENEZ, ROSARIO/K-9701-2014; de Cabo, Rafael/J-5230-2016; OI JIMENEZ, ROSARIO/0000-0003-3872-2669; de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU American Diabetes Association; American Federation for Aging Research; NIH [HL077256, HL43023, CA111842]; Hungarian Science Fund [OTKA 68758]; Proyecto de Excelencia [P06-CTS-01555]; Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III [RD06/0009]; Intramural Research Program of the National Institute on Aging, NIH FX This work was supported by grants from the American Diabetes Association (to ZU), the American Federation for Aging Research (to AC), the NIH (HL077256 and HL43023, to ZU, CA111842 to JP), the Hungarian Science Fund (OTKA 68758 to GL) and Proyecto de Excelencia (P06-CTS-01555, to RJ) and by the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (Red HERACLES RD06/0009,Spain; to RJ) and the Intramural Research Program of the National Institute on Aging, NIH (to RDC). NR 45 TC 121 Z9 128 U1 0 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD AUG PY 2009 VL 130 IS 8 BP 518 EP 527 DI 10.1016/j.mad.2009.06.004 PG 10 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 487RH UT WOS:000269292000007 PM 19549533 ER PT J AU Bubenshchikova, E Morrical, S Kasnic, G Verlander, J Sedor, J Chtinis, A Obara, T AF Bubenshchikova, Ekaterina Morrical, Stephen Kasnic, George Verlander, Jill Sedor, John Chtinis, Ajay Obara, Tomoko TI Wtip regulates the formation of multiple ciliated cells in the zebrafish pronephros SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-of-Development-Biologists CY SEP 06-10, 2009 CL Edinburgh, SCOTLAND SP Int Soc Dev Biol C1 [Bubenshchikova, Ekaterina; Morrical, Stephen; Sedor, John; Obara, Tomoko] MHMC CWRU, Cleveland, OH USA. [Kasnic, George; Verlander, Jill] UFCM, Gainesville, FL USA. [Chtinis, Ajay] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD AUG PY 2009 VL 126 BP S264 EP S264 DI 10.1016/j.mod.2009.06.700 PG 1 WC Developmental Biology SC Developmental Biology GA 497DM UT WOS:000270034900775 ER PT J AU Canham, M Sharov, A Ko, M Brickman, J AF Canham, Maurice Sharov, Alexei Ko, Minoru Brickman, Joshua TI Functional heterogeneity of murine embryonic stem cells revealed through translational amplification in an early endoderm marker SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-of-Development-Biologists CY SEP 06-10, 2009 CL Edinburgh, SCOTLAND SP Int Soc Dev Biol C1 [Canham, Maurice; Brickman, Joshua] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Sharov, Alexei; Ko, Minoru] NIA, Baltimore, MD 21224 USA. RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD AUG PY 2009 VL 126 BP S280 EP S281 DI 10.1016/j.mod.2009.06.756 PG 2 WC Developmental Biology SC Developmental Biology GA 497DM UT WOS:000270034900826 ER PT J AU Livigni, A Jones, L Pernagallo, S Hammachi, F Sharov, A Morrison, G Ko, M Bradley, M Brickman, J AF Livigni, Alessandra Jones, Lucy Pernagallo, Salvatore Hammachi, Fella Sharov, Alexei Morrison, Gillian Ko, Minoru Bradley, Mark Brickman, Joshua TI Identification of evolutionarily conserved targets of the Oct4 transcription factor SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-of-Development-Biologists CY SEP 06-10, 2009 CL Edinburgh, SCOTLAND SP Int Soc Dev Biol C1 [Livigni, Alessandra; Jones, Lucy; Hammachi, Fella; Morrison, Gillian; Brickman, Joshua] Univ Edinburgh, MRC Ctr Regenerat Med, Inst Stem Cell Res, Edinburgh, Midlothian, Scotland. [Pernagallo, Salvatore; Bradley, Mark] Univ Edinburgh, Chem Biol Sect, Sch Chem, Edinburgh, Midlothian, Scotland. [Sharov, Alexei; Ko, Minoru] NIA, NIH, Baltimore, MD 21224 USA. RI Pernagallo, Salvatore/B-4739-2009; Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD AUG PY 2009 VL 126 BP S286 EP S287 DI 10.1016/j.mod.2009.06.775 PG 2 WC Developmental Biology SC Developmental Biology GA 497DM UT WOS:000270034900844 ER PT J AU Matsuda, M Nogare, DD Heredia, D Chitnis, A AF Matsuda, Miho Nogare, Damian Dalle Heredia, David Chitnis, Ajay TI Pre-enteric migration of sacral neural crest cells is affected in Dominant megacolon embryos SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-of-Development-Biologists CY SEP 06-10, 2009 CL Edinburgh, SCOTLAND SP Int Soc Dev Biol C1 [Matsuda, Miho; Nogare, Damian Dalle; Chitnis, Ajay] NICHD, NIH, Bethesda, MD USA. [Heredia, David] Univ Louisville, Louisville, KY 40292 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD AUG PY 2009 VL 126 SU S BP S305 EP S305 DI 10.1016/j.mod.2009.06.835 PG 1 WC Developmental Biology SC Developmental Biology GA 497DM UT WOS:000270034900901 ER PT J AU Matsuda, M Nogare, DD Heredia, D Chitnis, A AF Matsuda, Miho Nogare, Damian Dalle Heredia, David Chitnis, Ajay TI Modeling the dynamic interactions that lead to the self-organization of the lateral line system SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-of-Development-Biologists CY SEP 06-10, 2009 CL Edinburgh, SCOTLAND SP Int Soc Dev Biol C1 [Matsuda, Miho; Nogare, Damian Dalle; Chitnis, Ajay] NICHD, NIH, Bethesda, MD USA. [Heredia, David] Univ Louisville, Louisville, KY 40292 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD AUG PY 2009 VL 126 SU S BP S305 EP S305 DI 10.1016/j.mod.2009.06.834 PG 1 WC Developmental Biology SC Developmental Biology GA 497DM UT WOS:000270034900900 ER PT J AU Monti, M Ko, MSH Redi, CA AF Monti, Manuela Ko, Minoru S. H. Redi, Carlo Alberto TI Analysis of gene expression in mouse antral SN and NSN oocytes SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-of-Development-Biologists CY SEP 06-10, 2009 CL Edinburgh, SCOTLAND SP Int Soc Dev Biol C1 [Monti, Manuela; Ko, Minoru S. H.] NIA, NIH, Baltimore, MD 21224 USA. [Redi, Carlo Alberto] Osped San Matteo, Pavia, Italy. RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD AUG PY 2009 VL 126 BP S331 EP S331 DI 10.1016/j.mod.2009.06.1220 PG 1 WC Developmental Biology SC Developmental Biology GA 497DM UT WOS:000270034900985 ER PT J AU Ostrander, EA AF Ostrander, Elaine A. TI Finding genes controlling complex traits in the domestic dog SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-of-Development-Biologists CY SEP 06-10, 2009 CL Edinburgh, SCOTLAND SP Int Soc Dev Biol C1 [Ostrander, Elaine A.] NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD AUG PY 2009 VL 126 BP S14 EP S14 DI 10.1016/j.mod.2009.06.978 PG 1 WC Developmental Biology SC Developmental Biology GA 497DM UT WOS:000270034900036 ER PT J AU Tzanavari, T Sharov, AA Hall, EA Piao, YL Drummond, N Smith, A Ko, MSH Kunath, T AF Tzanavari, Theodora Sharov, Alexei A. Hall, Emma A. Piao, Yulan Drummond, Nicola Smith, Austin Ko, Minoru S. H. Kunath, Tilo TI Transcriptome analysis of FGF signalling in embryonic stem cells SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-of-Development-Biologists CY SEP 06-10, 2009 CL Edinburgh, SCOTLAND SP Int Soc Dev Biol C1 [Tzanavari, Theodora; Hall, Emma A.; Drummond, Nicola; Kunath, Tilo] Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh, Midlothian, Scotland. [Sharov, Alexei A.; Piao, Yulan; Ko, Minoru S. H.] NIA, NIH, Baltimore, MD 21224 USA. [Smith, Austin] Wellcome Trust Ctr Stem Cell Res, Cambridge, England. RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD AUG PY 2009 VL 126 BP S282 EP S283 DI 10.1016/j.mod.2009.06.762 PG 2 WC Developmental Biology SC Developmental Biology GA 497DM UT WOS:000270034900832 ER PT J AU DiMartino, LD Hammill, BG Curtis, LH Gottdiener, JS Manolio, TA Powe, NR Schulman, KA AF DiMartino, Lisa D. Hammill, Bradley G. Curtis, Lesley H. Gottdiener, John S. Manolio, Teri A. Powe, Neil R. Schulman, Kevin A. TI External Validity of the Cardiovascular Health Study A Comparison With the Medicare Population SO MEDICAL CARE LA English DT Article DE cardiovascular diseases; cohort studies; epidemiologic methods; health services research; Medicare; United states ID OLDER-ADULTS; RISK-FACTORS; ADMINISTRATIVE DATA; MARITAL-STATUS; MORTALITY; DISEASE; ICD-9-CM; QUALITY; EVENTS; STROKE AB Background: The Cardiovascular Health Study (CHS), a population-based prospective cohort study, has been used to identify major risk factors associated with cardiovascular disease and stroke in the elderly. Objective: To assess the external validity of the CHS. Research Design: Comparison of the CHS cohort to a national cohort of Medicare beneficiaries and to Medicare beneficiaries residing in the CHS geographic regions. Subjects: CHS participants and a 5% sample of Medicare beneficiaries. Measures: Demographic and administrative characteristics, comorbid conditions, resource use, and mortality. Results: Compared with both Medicare cohorts, the CHS cohort was older and included more men and African American participants. CHS participants were more likely to be enrolled in Medicare managed care than beneficiaries in the national Medicare cohort. Compared with the Medicare cohorts, mortality in the CHS was more than 40% lower at 1 year, approximately 25% lower at 5 years, and approximately 15% lower at 10 years. There were minimal differences in comorbid conditions and health care resource use. Conclusion: The CHS cohort is comparable with the Medicare population, particularly with regard to comorbid conditions and resource use, but had lower mortality. The difference in mortality may reflect the CHS recruitment strategy or volunteer bias. These findings suggest it may not be appropriate to project absolute rates of disease and outcomes based on CHS data to the entire Medicare population. However, there is no reason to expect that the relative risks associated with physiologic processes identified by CHS data would differ for nonparticipants. C1 [DiMartino, Lisa D.; Hammill, Bradley G.; Curtis, Lesley H.; Schulman, Kevin A.] Duke Univ, Sch Med, Duke Clin Res Inst, Ctr Clin & Genet Econ, Durham, NC 27715 USA. [Curtis, Lesley H.; Powe, Neil R.; Schulman, Kevin A.] Duke Univ, Sch Med, Dept Med, Durham, NC 27715 USA. [Gottdiener, John S.] Univ Maryland, Sch Med, Div Cardiol, Bethesda, MD USA. [Manolio, Teri A.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Powe, Neil R.] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Powe, Neil R.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. RP Curtis, LH (reprint author), Duke Univ, Sch Med, Duke Clin Res Inst, Ctr Clin & Genet Econ, POB 17969, Durham, NC 27715 USA. EM lesley.curtis@duke.edu FU National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke [N01HC85079, N01HC85086, N01HC35129, N01HC15103, N01HC55222, N01HC75150, N01HC45133, U01HL080295] FX Supported by contracts N01HC85079 through N01HC85086, N01HC35129, N01HC15103, N01HC55222, N01HC75150, and N01HC45133 and grant U01HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. NR 29 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD AUG PY 2009 VL 47 IS 8 BP 916 EP 923 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 477PY UT WOS:000268532200014 PM 19597373 ER PT J AU Colbert, LH Westerlind, KC Perkins, SN Haines, DC Berrigan, D Donehower, LA Fuchs-Young, R Hursting, SD AF Colbert, Lisa H. Westerlind, Kim C. Perkins, Susan N. Haines, Diana C. Berrigan, David Donehower, Lawrence A. Fuchs-Young, Robin Hursting, Stephen D. TI Exercise Effects on Tumorigenesis in a p53-Deficient Mouse Model of Breast Cancer SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE PHYSICAL ACTIVITY; MAMMARY; IGF-1; BODY COMPOSITION ID INDUCED MAMMARY TUMORIGENESIS; WNT-1 TRANSGENIC MICE; REDUCED ENERGY-INTAKE; CALORIE RESTRICTION; PHYSICAL-ACTIVITY; APC(MIN) MICE; TREADMILL EXERCISE; POLYP DEVELOPMENT; DIETARY-FAT; CARCINOGENESIS AB COLBERT, L. H., K. C. WESTERLIND, S. N. PERKINS, D. C. HAINES, D. BERRIGAN, L. A. DONEHOWER, R. FUCHS-YOUNG, and S. D. HURSTING. Exercise Effects on Tumorigenesis in a p53-Deficient Mouse Model of Breast Cancer. Med. Sci. Sports Exerc., Vol. 41, No. 8, pp 1597-1605, 2009. Purpose: Physically active women have a reduced risk of breast cancer, but the dose of activity necessary and the role of energy balance and other potential mechanisms have not been fully explored in animal models. We examined treadmill and wheel running effects on mammary tumorigenesis and biomarkers in p53-deficient (p53(+/-)):MMTV-Wnt-1 transgenic mice. Methods: Female mice (9 wk old) were randomly assigned to the following groups in experiment 1: treadmill exercise 5 d.wk(-1), 45 min.d(-1), 5% grade at 20 m.min(-1), similar to 0.90 km.d(-1) (TREX1, n = 20) or at 24 m.min(-1), similar to 1.08 km.d(-1) (TREX2, n = 21) or a nonexercise control (CON-TREX, n = 22). In experiment 2, mice were randomly assigned to voluntary wheel running (WHL, n = 21, 2.46 +/- 1.11 km.d(-1) (mean +/- SD)) or to a nonexercise control (CON-WHL, n = 22). Bodycomposition was measured at similar to 9 wk and serum insulin-like growth factor 1 (IGF-1) at two to three monthly time points beginning at similar to 9 wk on study. Mice were sacrificed when tumors reached 1.5 cut, mice became moribund, or there was only one mouse per treatment group remaining. Results: TREX1 (24 wk) and TREX2 (21 wk) had shorter median survival times than CON-TREX (34 wk; P < 0.01), whereas those of WHL and CON-WHL were similar (23 vs 24 wk: P = 0.32). TREX2 had increased multiplicity of mammary gland carcinoma compared with CON-TREX; WHL had a higher turner incidence than CON-WHL. All exercising animals were lighter than their respective controls. and WHL had lower body fat than CON-WHL (P < 0.01). There was no difference in IGF-1 between groups (P > 0.05). Conclusions: Despite beneficial or no effects on body weight, body fat, or IGF-1, exercise had detrimental effects Oil tumorigenesis in this p53-deficient mouse model of spontaneous mammary cancer. C1 [Colbert, Lisa H.] Univ Wisconsin, Dept Kinesiol, Madison, WI 53706 USA. [Westerlind, Kim C.] Univ Colorado, Denver Hlth Sci Ctr, Denver, CO 80202 USA. [Perkins, Susan N.; Hursting, Stephen D.] Univ Texas Austin, Austin, TX 78712 USA. [Haines, Diana C.] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Berrigan, David] NCI, Bethesda, MD 20892 USA. [Donehower, Lawrence A.] Baylor Coll Med, Houston, TX 77030 USA. [Fuchs-Young, Robin; Hursting, Stephen D.] Univ Texas MD Anderson Canc Ctr, Smithville, TX USA. RP Colbert, LH (reprint author), Univ Wisconsin, Dept Kinesiol, 2000 Observ Dr, Madison, WI 53706 USA. EM lhcolbert@education.wisc.edu FU The U.S. Army Medical Research Material Command [DAMD 17-01-1-0338]; National Cancer Institute, National Institutes of Health [N01-CO-12400]; Breast Cancer Research Foundation; DOD Concept Award [06-10636] FX The U.S. Army Medical Research Material Command under DAMD 17-01-1-0338 supported this work (to L.H.C.). This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. S.D.H. was supported in part by the Breast Cancer Research Foundation and a DOD Concept Award (06-10636). The content of this publication does not necessarily reflect the views of 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 results of this study do not constitute endorsement by ACSM. NR 41 TC 19 Z9 20 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD AUG PY 2009 VL 41 IS 8 BP 1597 EP 1605 DI 10.1249/MSS.0b013e31819f1f05 PG 9 WC Sport Sciences SC Sport Sciences GA 472IL UT WOS:000268123700009 PM 19568200 ER PT J AU Kireeva, M Nedialkov, YA Gong, XQ Zhang, CF Xiong, YL Moon, W Burton, ZF Kashlev, M AF Kireeva, Maria Nedialkov, Yuri A. Gong, Xue Qian Zhang, Chunfen Xiong, Yalin Moon, Woo Burton, Zachary F. Kashlev, Mikhail TI Millisecond phase kinetic analysis of elongation catalyzed by human, yeast, and Escherichia coli RNA polymerase SO METHODS LA English DT Article DE Rapid chemical quench flow; Pre-steady state kinetic analysis; Elongation; RNA polymerase II; RNA polymerase; Elongation factors; Ternary elongation complex; Transient state inhibition; alpha-Amanitin ID HEPATITIS-DELTA ANTIGEN; NTP-DRIVEN TRANSLOCATION; II ELONGATION; TRANSCRIPTION ELONGATION; ALPHA-AMANITIN; NUCLEOSIDE TRIPHOSPHATES; STRUCTURAL BASIS; DEPENDENT RNA-POLYMERASE-(3D(POL)); RIBONUCLEOTIDE INCORPORATION; TERNARY COMPLEXES AB Strategies for assembly and analysis of human, yeast, and bacterial RNA polymerase elongation complexes are described, and methods are shown for millisecond phase kinetic analyses of elongation using rapid chemical quench flow. Human, yeast, and bacterial RNA polymerases function very similarly in NTP-Mg(2+) commitment and phosphodiester bond formation. A "running start, two-bond, double-quench" protocol is described and its advantages discussed. These studies provide information about stable NTP-Mg(2+) loading, phosphodiester bond synthesis, the processive transition between bonds, and sequence-specific effects on transcription elongation dynamics. (C) 2009 Elsevier Inc. All rights reserved. C1 [Nedialkov, Yuri A.; Gong, Xue Qian; Zhang, Chunfen; Xiong, Yalin; Moon, Woo; Burton, Zachary F.] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. [Kireeva, Maria; Nedialkov, Yuri A.; Kashlev, Mikhail] NCI, Gene Regulat & Chromosome Biol, Frederick, MD 21702 USA. RP Burton, ZF (reprint author), Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. EM burton@msu.edu FU National Institutes of Health [GM57461]; Michigan State University; Michigan State University Agricultural Experiment Station; Michigan State University College of Osteopathic Medicine FX This work was in part supported by the National Institutes of Health Grant GM57461 (to Z.F.B.). Z.F.B. receives support from Michigan State University, the Michigan State University Agricultural Experiment Station, and the Michigan State University College of Osteopathic Medicine. The contents of this publication do 345 not necessarily reveal 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 43 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 1046-2023 J9 METHODS JI Methods PD AUG PY 2009 VL 48 IS 4 BP 333 EP 345 DI 10.1016/j.ymeth.2009.04.008 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 486DF UT WOS:000269175000003 PM 19398005 ER PT J AU Gilchrist, DA Fargo, DC Adelman, K AF Gilchrist, Daniel A. Fargo, David C. Adelman, Karen TI Using ChIP-chip and ChIP-seq to study the regulation of gene expression: Genome-wide localization studies reveal widespread regulation of transcription elongation SO METHODS LA English DT Review DE Transcription elongation; Gene expression; ChIP-chip; ChIP-seq ID RNA-POLYMERASE-II; DROSOPHILA-MELANOGASTER; P-TEFB; PRODUCTIVE ELONGATION; TERMINAL DOMAIN; HSP70 GENE; IN-VIVO; PROMOTER; CELLS; COMPLEX AB Transcription is a sophisticated multi-step process in which RNA polymerase II (Pol II) transcribes a DNA template into RNA in concert with a broad array of transcription initiation, elongation, capping, termination, and histone modifying factors. Recent global analyses of Pol II distribution have indicated that many genes are regulated during the elongation phase, shedding light on a previously underappreciated mechanism for controlling gene expression. Understanding how various factors regulate transcription elongation in living cells has been greatly aided by chromatin immunoprecipitation (ChIP) studies, which can provide spatial and temporal resolution of protein-DNA binding events. The coupling of ChIP with DNA microarray and high-throughput sequencing technologies (ChIP-chip and ChIP-seq) has significantly increased the scope of ChIP studies and genome-wide maps of Pol If or elongation factor binding sites can now be readily produced. However, while ChIP-chip/ChIP-seq data allow for high-resolution localization of protein-DNA binding sites, they are not sufficient to dissect protein function. Here we describe techniques for coupling ChIP-chip/ChIP-seq with genetic, chemical, and experimental manipulation to obtain mechanistic insight from genome-wide protein-DNA binding studies. We have employed these techniques to discern immature promoter-proximal Pol II from productively elongating Pol II, and infer a critical role for the transition between initiation and full elongation competence in regulating development and gene induction in response to environmental signals. (C) 2009 Published by Elsevier Inc. C1 [Gilchrist, Daniel A.; Adelman, Karen] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Fargo, David C.] NIEHS, Lib & Informat Serv, NIH, Res Triangle Pk, NC 27709 USA. RP Adelman, K (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. EM adelmank@niehs.nih.gov OI Gilchrist, Daniel/0000-0003-1668-2790 FU NIH; National Institute of Environmental Health Sciences [Z01 ES101987] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences to K.A. (Z01 ES101987). NR 45 TC 38 Z9 41 U1 2 U2 20 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD AUG PY 2009 VL 48 IS 4 BP 398 EP 408 DI 10.1016/j.ymeth.2009.02.024 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 486DF UT WOS:000269175000011 PM 19275938 ER PT J AU Lopez, JE Porcella, SF Schrumpf, ME Raffel, SJ Hammer, CH Zhao, M Robinson, MA Schwan, TG AF Lopez, Job E. Porcella, Stephen F. Schrumpf, Merry E. Raffel, Sandra J. Hammer, Carl H. Zhao, Ming Robinson, Mary Ann Schwan, Tom G. TI Identification of conserved antigens for early serodiagnosis of relapsing fever Borrelia SO MICROBIOLOGY-SGM LA English DT Article ID GLYCEROPHOSPHODIESTER PHOSPHODIESTERASE GLPQ; MEMBRANE PROTEIN P66; WHITE-FOOTED MICE; LYME-DISEASE; B1B LYMPHOCYTES; CELL-SURFACE; STREPTOCOCCUS-PNEUMONIAE; OUTER-MEMBRANE; FACTOR-H; HAEMOPHILUS-DUCREYI AB Borrelia hermsii is a blood-borne pathogen transmitted by the argasid tick Ornithodoros hermsi. Since spirochaete clearance in mice is associated with an IgM-mediated response, an immunoproteomic analysis was used to identify proteins reactive with IgM. We report that IgM from both mice and human patients infected with B. hermsii not only reacted with the previously identified variable membrane proteins but also identified candidate antigens including heat-shock proteins, an adhesin protein, ABC transporter proteins, flagellar proteins, housekeeping proteins, an immune evasion protein, and proteins with unknown function. Furthermore, IgM reactivity to recombinant glycerophosphodiester phosphodiesterase was detected during early spirochaete infection and prior to a detectable IgG response. Lastly, a conserved hypothetical protein was produced in Escherichia coli and tested with immune serum against B. hermsii and Borrelia recurrentis. These results identify a much larger set of immunoreactive proteins, and could help in the early serodiagnosis of this tick-borne infection. C1 [Lopez, Job E.; Schrumpf, Merry E.; Raffel, Sandra J.; Schwan, Tom G.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Porcella, Stephen F.] NIAID, Res Technol Sect, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Hammer, Carl H.; Zhao, Ming; Robinson, Mary Ann] NIAID, Res Technol Sect, Res Technol Branch, NIH, Rockville, MD 20852 USA. RP Lopez, JE (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM lopezjob@niaid.nih.gov FU Division of Intramural Research; NIAID; NIH FX We thank B. Joseph Hinnebusch and Philip E. Stewart for reviewing this manuscript, Anita Mora and Gary Hettrick for photographic assistance, Robert A. Heinzen for use of his 2D electrophoresis equipment, Glen A. Nardone for his technical expertise, and Robert J. Hohman for his logistic support. This work was supported by the Division of Intramural Research, NIAID, NIH. NR 71 TC 11 Z9 12 U1 2 U2 3 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-SGM JI Microbiology-(UK) PD AUG PY 2009 VL 155 BP 2641 EP 2651 DI 10.1099/mic.0.029918-0 PG 11 WC Microbiology SC Microbiology GA 484FI UT WOS:000269028900018 PM 19443544 ER PT J AU Nace, MC Dunlow, S Armstrong, AY AF Nace, M. Catherine Dunlow, Susan Armstrong, Alicia Y. TI Professionalism in Medicine: We Should Set the Standard SO MILITARY MEDICINE LA English DT Article ID DEANS LETTERS; DISCIPLINARY ACTION; SCHOOLS; PHYSICIAN; RESIDENTS; AWARENESS; BEHAVIOR AB As military physicians we have a unique set of professional values that may differ from our civilian counterparts because we have both our professional responsibilities to our patients as well as our professional values as military officers. Our core military values provide a solid foundation to set the standard for professionalism in medicine. As educators for medical students, residents, and fellows we have an obligation to not only teach them the art of medicine but to mentor them as professional military officers. The objectives of this article are threefold: first to define professionalism, second to identify measurement tools, and finally to offer suggestions for documentation and remediation when problems of professionalism are identified among residents and fellows. C1 [Nace, M. Catherine; Dunlow, Susan] Walter Reed Army Med Ctr, Dept Obstet & Gynecol, Washington, DC 20307 USA. [Armstrong, Alicia Y.] Natl Inst Child Hlth & Human Dev, Program Reprod & Adult Endocrinol, Bethesda, MD USA. RP Nace, MC (reprint author), Walter Reed Army Med Ctr, Dept Obstet & Gynecol, Washington, DC 20307 USA. NR 17 TC 2 Z9 2 U1 0 U2 0 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD AUG PY 2009 VL 174 IS 8 BP 807 EP 810 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 601LG UT WOS:000278060300009 PM 19743734 ER PT J AU Rusiecki, J Thomas, CD Blair, A AF Rusiecki, Jennifer Thomas, Dana Blair, Aaron TI Mortality Among United States Coast Guard Marine Inspectors: A Follow Up SO MILITARY MEDICINE LA English DT Article ID NON-HODGKINS-LYMPHOMA; OCCUPATIONAL EXPOSURES; VINYL-CHLORIDE; WORKERS; CIRRHOSIS; CANCER; LIVER; TRICHLOROETHYLENE; EPIDEMIOLOGY; RATIO AB We previously assessed mortality among U.S. Coast Guard (USCG) marine inspectors (inspectors) and Coast Guard officers who were not marine inspectors (noninspectors). Here, we extended follow-up of the cohort by 14 years, ascertaining vital status 1980-1994, calculating standardized mortality ratios (SMRs) for inspectors and noninspectors, and comparing mortality rates via directly adjusted rate ratios (RRs). Both inspectors and noninspectors had deficits for all causes of death (SMR = 75 and 61, respectively) and all malignant neoplasms (SMR = 86 and 69, respectively). Compared with noninspectors, inspectors had nonstatistically significant excesses of liver cirrhosis (SMR = 124; RR = 2.2) and chronic rheumatic heart disease (SMR = 129; RR = 2.6) and deficits of cancer of the respiratory system (SMR = 59; RR = 0.8). SMRs and RRs rose with increasing probability of exposure to chemicals for cirrhosis of the liver, all accidents and motor vehicle accidents, although they fell for all causes of death, diseases of the nervous system, diseases of the circulatory system, and cancers of the respiratory system. These results suggest that contact with chemicals during inspection of merchant vessels may be involved in the development of these diseases, although other aspects of the job, such as physical activity may account for deficits in respiratory cancers. C1 [Rusiecki, Jennifer] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Thomas, Dana] US Coast Guard, Off Safety & Environm Hlth, Washington, DC 20593 USA. [Blair, Aaron] NCI, Occupat & Environm Epidemiol Branch, Bethesda, MD 20854 USA. RP Rusiecki, J (reprint author), Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. FU National Institutes of Health (Division of Cancer Epidemiology and Genetics of the National Cancer Institute) FX We thank the U.S. Coast Guard for assistance in this study, which is, in turn, supported by the Intramural Research Program of the National Institutes of Health (Division of Cancer Epidemiology and Genetics of the National Cancer Institute). NR 35 TC 1 Z9 1 U1 0 U2 0 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD AUG PY 2009 VL 174 IS 8 BP 843 EP 851 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 601LG UT WOS:000278060300016 PM 19743741 ER PT J AU Oleaga, A Perez-Sanchez, R Pages, E Marcos-Atxutegi, C Simon, F AF Oleaga, Ana Perez-Sanchez, Ricardo Pages, Elaine Marcos-Atxutegi, Cristina Simon, Fernando TI Identification of immunoreactive proteins from the dog heartworm (Dirofilaria immitis) differentially recognized by the sera from dogs with patent or occult infections SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Antigens; Dirofilaria immitis; Dogs; Mass spectrometry; Soluble proteome ID EXCRETORY-SECRETORY PRODUCTS; HUMORAL IMMUNE-RESPONSE; HAEMONCHUS-CONTORTUS; ECHINOSTOMA-CAPRONI; SCHISTOSOMA-MANSONI; MOLECULAR-CLONING; PARASITE; WOLBACHIA; NEMATODE; SUPPRESSES AB Heartworm disease caused by Dirofilaria immitis affects canine and feline hosts. Moreover, the parasite can infect humans, causing pulmonary dirofilariosis. Most affected dogs have patent infections with circulating microfilariae in peripheral blood. although infected dogs sometimes develop occult infections characterized by the absence of microfilariae. Microfilaremic infections (mf+) are associated with a predominant Th2-type immune response, whereas a Th1-type response predominates in amicrofilaremic infections (mf-), suggesting a role for this response in the suppression of circulating microfilariae. However, nothing is known about the molecules involved in the immune regulation of these infections. The objective of the present work was to identify the parasite proteins recognized differentially by the immune response of dogs with patent or occult infections, using two-dimensional electrophoresis and mass spectrometry. Nineteen proteins of D. immitis were identified, of which 6 were immunoreactive against serum samples from both mf+ and mf- dogs, while another two groups of 6 and 7 different proteins were differentially recognized by sera from mf+ or mf- dogs, respectively. The results point to the existence of differential antigen recognition in patent and occult infections due to D. immitis. Several proteins that could be involved in the immune regulation of these infections are identified. Additionally, the findings seem to suggest that some antigens of D. immitis, together with Wolbachia antigens, could contribute to the stimulation of the Th1-type response. (C) 2009 Elsevier B.V. All rights reserved. C1 [Oleaga, Ana; Perez-Sanchez, Ricardo] CSIC, Inst Recursos Nat & Agrobiol Salamanca, Parasitol Lab, Salamanca 37008, Spain. [Pages, Elaine; Marcos-Atxutegi, Cristina; Simon, Fernando] Univ Salamanca, Parasitol Lab, Salamanca 37007, Spain. [Pages, Elaine] Univ Puerto Rico, Sch Med, NIH MIRT Fogarty Int Ctr Program T37 TW 00046 05, San Juan, PR 00936 USA. RP Oleaga, A (reprint author), CSIC, Inst Recursos Nat & Agrobiol Salamanca, Parasitol Lab, Cordel Merinas 40-52, Salamanca 37008, Spain. EM ana.oleaga@irnasa.csic.es RI 2009, Secribsal/A-1266-2012; OLEAGA, ANA/E-9564-2011; Perez-Sanchez, Ricardo/B-7656-2008 OI OLEAGA, ANA/0000-0002-8019-7354; FU Agency of Economic Development of Castilla y Leon (FEDER funds) FX We would like to thank Dr. L. Venco, Clinica Veterinaria Citts di Pavia (Italy), who kindly provided us the D. immitis adult worms: Dr. Emilio Camafeita Fernandez from the Proteomic Unit of the Centro Nacional cle Investigaciones Card iovascu la res of Madrid (Spain) for his assistance in MS analyses. This research was supported by the research contract entitled "Design of a therapy for the treatment of pulmonary dirofilariosis" with the company Chemical Wrica Productos Veterinarios S.L., funded by the Agency of Economic Development of Castilla y Leon (FEDER funds). NR 48 TC 17 Z9 17 U1 0 U2 5 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 AUG PY 2009 VL 166 IS 2 BP 134 EP 141 DI 10.1016/j.molbiopara.2009.03.005 PG 8 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 458EJ UT WOS:000266997300006 PM 19450730 ER PT J AU Li, J Zhang, YH Liu, SF Hong, LX Sullivan, M McCutchan, TF Carlton, JM Su, XZA AF Li, Jian Zhang, Yanhui Liu, Shengfa Hong, Lingxian Sullivan, Margery McCutchan, Thomas F. Carlton, Jane M. Su, Xin-zhuan TI Hundreds of microsatellites for genotyping Plasmodium yoelii parasites SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Rodent malaria parasite; Simple sequence repeat (SSR); Genetic markers; Genotyping; MS ID FRAGMENT LENGTH POLYMORPHISM; RODENT MALARIA PARASITE; LINKAGE GROUP SELECTION; FALCIPARUM; GENOME; MAP; CHABAUDI; IDENTIFICATION; DIVERSITY; SEQUENCE AB Genetic crosses have been employed to study various traits of rodent malaria parasites and to locate loci that contribute to drug resistance, immune protection, and disease virulence. Compared with human malaria parasites, genetic crossing of rodent malaria parasites is more easily performed; however, genotyping methods using microsatellites (MSs) or large-scale single nucleotide polymorphisms (SNPs) that have been widely used in typing Plasmodium falciparum are not available for rodent malaria species. Here we report a genome-wide search of the Plasmodium yoelii yoelii (P. yoelii) genome for simple sequence repeats (SSRs) and the identification of nearly 600 polymorphic MS markers for typing the genomes of P, yoelii and Plasmodium berghei. The MS markers are randomly distributed across the 14 physical chromosomes assembled from genome sequences of three rodent malaria species, although some variations in the numbers of MS expected according to chromosome size exist. The majority of the MS markers are AT-rich repeats, similar to those found in the P. falciparum genome. The MS markers provide an important resource for genotyping, lay a foundation for developing linkage maps, and will greatly facilitate genetic studies of P. yoelii. Published by Elsevier B.V. C1 [Sullivan, Margery; McCutchan, Thomas F.; Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Li, Jian; Zhang, Yanhui; Liu, Shengfa; Hong, Lingxian; Su, Xin-zhuan] Xiamen Univ, Sch Life Sci, Minist Educ Cell Biol & Tumor Cell Engn, Key Lab, Xiamen 361005, Fujian, Peoples R China. [Carlton, Jane M.] NYU, Langone Med Ctr, Dept Med Parasitol, New York, NY 10010 USA. RP Su, XZA (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 National Basic Research Program of China [2007CB513103]; Xiamen University, China; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Professors Weiqing Pan and Fusheng Huang for making the parasite lines available to us, Dr. S. Pattaradilokrat for constructive comments, and NIAID intramural editor Brenda Rae Marshall for assistance. This study was supported by the National Basic Research Program of China, 973 Program 2007CB513103; by a graduate student fund from Xiamen University, China; and by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.; Because T.F.M. and X.-z.S. are US government employees and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMed Central for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U.S. subject to a government use license. NR 26 TC 8 Z9 8 U1 0 U2 0 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 AUG PY 2009 VL 166 IS 2 BP 153 EP 158 DI 10.1016/j.molbiopara.2009.03.011 PG 6 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 458EJ UT WOS:000266997300008 PM 19450732 ER PT J AU Sudarshan, S Sourbier, C Kong, HS Block, K Romero, VAV Yang, YF Galindo, C Mollapour, M Scroggins, B Goode, N Lee, MJ Gourlay, CW Trepel, J Linehan, WM Neckers, L AF Sudarshan, Sunil Sourbier, Carole Kong, Hye-Sik Block, Karen Romero, Vladimir A. Valera Yang, Youfeng Galindo, Cynthia Mollapour, Mehdi Scroggins, Bradley Goode, Norman Lee, Min-Jung Gourlay, Campbell W. Trepel, Jane Linehan, W. Marston Neckers, Len TI Fumarate Hydratase Deficiency in Renal Cancer Induces Glycolytic Addiction and Hypoxia-Inducible Transcription Factor 1 alpha Stabilization by Glucose-Dependent Generation of Reactive Oxygen Species SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SMOOTH-MUSCLE-CELLS; HEREDITARY LEIOMYOMATOSIS; HIF-ALPHA; OXIDATIVE STRESS; NAD(P)H OXIDASE; TUMOR; ACTIVATION; EXPRESSION; MUTATIONS; PROTEIN AB Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited cancer syndrome linked to biallelic inactivation of the gene encoding the tricarboxylic acid cycle enzyme fumarate hydratase (FH). Individuals with HLRCC are at risk to develop cutaneous and uterine leiomyomas and an aggressive form of kidney cancer. Pseudohypoxic drive-the aberrant activation of cellular hypoxia response pathways despite normal oxygen tension-is considered to be a likely mechanism underlying the etiology of this tumor. Pseudohypoxia requires the oxygen-independent stabilization of the alpha subunit of the hypoxia-inducible transcription factor (HIF-1 alpha). Under normoxic conditions, proline hydroxylation of HIF-1 alpha permits VHL recognition and subsequent targeting for proteasomal degradation. Here, we demonstrate that inactivating mutations of FH in an HLRCC-derived cell line result in glucose-mediated generation of cellular reactive oxygen species (ROS) and ROS-dependent HIF-1 alpha stabilization. Additionally, we demonstrate that stable knockdown of FH in immortalized renal epithelial cells results in ROS-dependent HIF-1 alpha stabilization. These data reveal that the obligate glycolytic switch present in HLRCC is critical to HIF stabilization via ROS generation. C1 [Neckers, Len] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Sudarshan, Sunil; Galindo, Cynthia] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78212 USA. [Block, Karen] Univ Texas Hlth Sci Ctr San Antonio, Dept Nephrol, San Antonio, TX 78212 USA. [Lee, Min-Jung; Trepel, Jane] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Gourlay, Campbell W.] Univ Kent, Dept Biosci, Canterbury CT2 7NJ, Kent, England. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. EM neckersl@mail.nih.gov RI Bell, Tiffany/F-4403-2010 FU Intramural NIH HHS [Z01 BC010683-03, Z01 SC006659-25]; NCI NIH HHS [R01 CA131272, R01 CA 131272] NR 43 TC 102 Z9 103 U1 1 U2 2 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 AUG PY 2009 VL 29 IS 15 BP 4080 EP 4090 DI 10.1128/MCB.00483-09 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 469ZB UT WOS:000267939400006 PM 19470762 ER PT J AU Figueroa, A Kotani, H Toda, Y Mazan-Mamczarz, K Mueller, EC Otto, A Disch, L Norman, M Ramdasi, RM Keshtgar, M Gorospe, M Fujita, Y AF Figueroa, Angelica Kotani, Hirokazu Toda, Yoshinobu Mazan-Mamczarz, Krystyna Mueller, Eva-Christina Otto, Albrecht Disch, Lena Norman, Mark Ramdasi, Rasika Mohan Keshtgar, Mohammed Gorospe, Myriam Fujita, Yasuyuki TI Novel Roles of Hakai in Cell Proliferation and Oncogenesis SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID TRCP UBIQUITIN LIGASE; NF-KAPPA-B; E-CADHERIN; MESSENGER-RNA; SPLICING FACTOR; C-CBL; RECEPTOR; PROTEIN; PSF; PHOSPHORYLATION AB During tumor development, cells acquire multiple phenotypic changes upon misregulation of oncoproteins and tumor suppressor proteins. Hakai was originally identified as an E3 ubiquitin-ligase for the E-cadherin complex that regulates cell-cell contacts. Here, we present evidence that Hakai plays a crucial role in various cellular processes and tumorigenesis. Overexpression of Hakai affects not only cell-cell contacts but also proliferation in both epithelial and fibroblast cells. Furthermore, the knockdown of Hakai significantly suppresses proliferation of transformed epithelial cells. Expression of Hakai is correlated to the proliferation rate in human tissues and is highly up-regulated in human colon and gastric adenocarcinomas. Moreover, we identify PTB-associated splicing factor (PSF), an RNA-binding protein, as a novel Hakai-interacting protein. By using cDNA arrays, we have determined various specific PSF-associated mRNAs encoding proteins that are involved in several cancer-related processes. Hakai affects the ability of PSF to bind these mRNAs, and expression of PSF short hairpin RNA or a dominant-negative PSF mutant significantly suppresses proliferation of Hakai-overexpressing cells. Collectively, these results suggest that Hakai is an important regulator of cell proliferation and that Hakai may be an oncoprotein and a potential molecular target for cancer treatment. C1 [Figueroa, Angelica; Disch, Lena; Norman, Mark; Ramdasi, Rasika Mohan; Fujita, Yasuyuki] UCL, MRC, Mol Cell Biol Lab, London WC1E 6BT, England. [Figueroa, Angelica; Disch, Lena; Norman, Mark; Ramdasi, Rasika Mohan; Fujita, Yasuyuki] UCL, MRC, Cell Biol Unit, London WC1E 6BT, England. [Fujita, Yasuyuki] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England. [Kotani, Hirokazu; Toda, Yoshinobu] Kyoto Univ, Grad Sch Med, Ctr Anat Studies, Sakyo Ku, Kyoto 6068501, Japan. [Mazan-Mamczarz, Krystyna; Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. [Mueller, Eva-Christina; Otto, Albrecht] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. [Keshtgar, Mohammed] Royal Free Hosp, Dept Surg, London NW3 2QG, England. RP Fujita, Y (reprint author), UCL, MRC, Mol Cell Biol Lab, Mortimer St, London WC1E 6BT, England. EM y.fujita@ucl.ac.uk RI Fujita, Yasuyuki/A-4324-2012 FU Ministerio de Educacion, Cultura y Deporte of Spain; Medical Research Council FX We thank Mark Marsh for critical reading of the manuscript. We thank Cristina Azevedo for helpful discussions. We also thank Fiona Watt and Hector Garcia-Palmer for technical advice for immunohistochemistry, Alison Lloyd for providing antibodies against various cell cycle regulators, James G. Patton for providing PSF constructs, and Walter Birchmeier for providing Hakai constructs. A. F. was supported by a postdoctoral fellowship from Ministerio de Educacion, Cultura y Deporte of Spain. This work is supported by Medical Research Council funding to the Cell Biology Unit. NR 31 TC 24 Z9 26 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG 1 PY 2009 VL 20 IS 15 BP 3533 EP 3542 DI 10.1091/mbc.E08-08-0845 PG 10 WC Cell Biology SC Cell Biology GA 477UV UT WOS:000268545300009 PM 19535458 ER PT J AU Vasudevan, SA Shang, XY Chang, SR Ge, NL Diaz-Miron, JL Russell, HV Hicks, MJ Ludwig, AD Wesson, CL Burlingame, SM Kim, ES Khan, J Yang, JH Nuchtern, JG AF Vasudevan, Sanjeev A. Shang, Xiaoyi Chang, Shirong Ge, Ningling Diaz-Miron, Jose L. Russell, Heidi V. Hicks, M. John Ludwig, Andrew D. Wesson, Catherine L. Burlingame, Susan M. Kim, Eugene S. Khan, Javed Yang, Jianhua Nuchtern, Jed G. TI Neuroblastoma-derived secretory protein is a novel secreted factor overexpressed in neuroblastoma SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID NEUROTROPHIC RECEPTOR TRKB; HIGH-RISK NEUROBLASTOMA; GENE-EXPRESSION; PROSTATE-CANCER; N-MYC; GROWTH; CELLS; ANOIKIS; DIFFERENTIATION; METASTASIS AB Secreted proteins such as growth factors, cytokines, and chemokines play important roles in tumor development. Through expression microarray and bioinformatic analysis, we discovered a novel secreted protein, neuroblastoma-derived secretory protein (NDSP). The NDSP gene is found on chromosome 1q25.2 and encodes a 167 amino acid protein with a putative signal peptide. Using real-time PCR and immunoblotting, we find that NDSP is specifically overexpressed in neuroblastoma at much higher levels than other adult and pediatric malignancies and normal tissues. NDSP is an 18-kDa protein that can be secreted by NDSP-transfected HEK-293T cells, as well as, neuroblastoma cell lines endogenously expressing NDSP. Inhibiting NDSP expression in neuroblastoma cell lines with retrovirally transduced NDSP small hairpin interfering RNA, sh-NDSP, results in decreased cellular proliferation and colony formation. We also find inhibited extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in the sh-NDSP cell line. Treating the parental cell line with MAP/ERK kinase 1/2 inhibitors, which diminish ERK 1/2 phosphorylation, results in decreased cell proliferation. Culturing these transduced cells with recombinant NDSP, reintroducing NDSP overexpression in the knockdown cell line, or inducing Ras oncogene overexpression for constitutive ERK 1/2 activation results in a reversal of the growth-inhibited phenotype and proliferation rates similar to the control cells. In addition, reintroduction of NDSP overexpression in the sh-NDSP cell line results in ERK 1/2 phosphorylation similar to control. We conclude that NDSP is specifically overexpressed in neuroblastoma and actively secreted from tumor cells. Furthermore, NDSP serves as a growth factor for neuroblastoma tumor cells through activation of the ERK-mediated proliferation pathway. [Mol Cancer Ther 2009;8(8):2478-89] C1 [Shang, Xiaoyi; Ge, Ningling; Russell, Heidi V.; Kim, Eugene S.; Yang, Jianhua; Nuchtern, Jed G.] Baylor Coll Med, Dept Pediat, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Vasudevan, Sanjeev A.; Chang, Shirong; Diaz-Miron, Jose L.; Ludwig, Andrew D.; Wesson, Catherine L.; Burlingame, Susan M.; Kim, Eugene S.; Nuchtern, Jed G.] Baylor Coll Med, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Hicks, M. John] Baylor Coll Med, Dan L Duncan Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Ge, Ningling] Fudan Univ, Zhongshan Hosp, Liver Canc Inst, Shanghai 200433, Peoples R China. [Khan, Javed] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Yang, JH (reprint author), Baylor Coll Med, Dept Pediat, Texas Childrens Canc Ctr, Room C-1030-17,MC3-3320,1102 Bates, Houston, TX 77030 USA. EM jianhuay@bcm.edu; nuchtern@bcm.edu RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU Children's Oncology Group Translational Research Award; National Cancer Institute [1R21CA106513-01A2]; Baylor College of Medicine Cancer Center Pilot; American Cancer Society [RSG-06-070-01-TBE]; Hope Street Kids Foundation; Bear Necessities Pediatric Cancer Foundation; Society of University Surgeons Ethicon Resident Scholarship; NIH Mational Cancer Institute-NRSA [1F32CAl13059-01A1] FX Children's Oncology Group Translational Research Award (J.G. Nuchtern), National Cancer Institute grant 1R21CA106513-01A2 (J. Yang), Baylor College of Medicine Cancer Center Pilot Project grant (J. Yang), American Cancer Society grant RSG-06-070-01-TBE (J. Yang), Hope Street Kids Foundation (J. Yang), Bear Necessities Pediatric Cancer Foundation (J. Yang), Society of University Surgeons Ethicon Resident Scholarship (S.A.Vasudevan), and the NIH Mational Cancer Institute-NRSA training grant 1F32CAl13059-01A1 (S.A.Vasudevan). NR 35 TC 4 Z9 4 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD AUG PY 2009 VL 8 IS 8 BP 2478 EP 2489 DI 10.1158/1535-7163.MCT-08-1132 PG 12 WC Oncology SC Oncology GA 484FM UT WOS:000269029300043 PM 19671756 ER PT J AU Hursting, SD Perkins, SN Lavigne, JA Beltran, L Haines, DC Hill, HL Alvord, WG Barrett, JC DiGiovanni, J AF Hursting, Stephen D. Perkins, Susan N. Lavigne, Jackie A. Beltran, Linda Haines, Diana C. Hill, Heather L. Alvord, W. Gregory Barrett, J. Carl DiGiovanni, John TI Urothelial Overexpression of Insulin-Like Growth Factor-1 Increases Susceptibility to p-Cresidine-Induced Bladder Carcinogenesis in Transgenic Mice SO MOLECULAR CARCINOGENESIS LA English DT Article DE indomethacin; growth hormone; transitional cell carcinoma ID MOUSE URINARY-BLADDER; CELL-PROLIFERATION; CYCLOOXYGENASE-2 INHIBITORS; CALORIE RESTRICTION; P53-DEFICIENT MICE; HORMONE LEVELS; CANCER; EXPRESSION; INDOMETHACIN; PREVENTION AB To establish a role for insulin-like growth factor-1 (IGF-1) in bladder cancer susceptibility, we tested the effect of p-cresidine, a potent bladder carcinogen, in transgenic (TG) mice with human IGF-1 expression in the bladder driven by the bovine keratin 5 promoter (referred to as BK5.IGF-1 TG mice). Indomethacin was also tested to determine if the cyclooxygenase (COX) pathway is a target for bladder cancer prevention in this model. Thirty-three female BK5.IGF-1 TG mice and 29 female nontransgenic littermates were randomized to the following treatments: (1) AIN-76A diet; (2) AIN-76A diet with 0.5% p-cresidine; or (3) AIN-76A diet with 0.5% p-cresidine+0.00075% indomethacin. BK5.IGF-1 TG mice, with twofold greater total serum IGF-1 than nontransgenic mice, exhibited greatly increased susceptibility to p-cresidine-induced bladder tumors compared to nontransgenic mice. The most common type of bladder tumor in the BK5.IGF-1 TG mice was transitional cell carcinoma, which is the predominant type of bladder cancer observed in developed countries. indomethacin inhibition of bladder tumor development in BK5.IGF-1 TG mice was not statistically significant. These results present further evidence for the role of IGF-1 in bladder cancer progression. In addition, these transgenic mice provide a useful model for studying the role of the IGF-1 pathway in bladder carcinogenesis and its prevention. (C) 2009 Wiley-Liss, Inc. C1 [Hursting, Stephen D.; Perkins, Susan N.] Univ Texas Austin, Dept Nutr Sci, Austin, TX 78712 USA. [Hursting, Stephen D.; Beltran, Linda; DiGiovanni, John] Univ Texas MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX USA. [Lavigne, Jackie A.] NCI, Off Educ, Rockville, MD USA. [Haines, Diana C.; Hill, Heather L.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Alvord, W. Gregory] Data Management Serv Inc, Frederick, MD USA. [Barrett, J. Carl] Novartis Inst BioMed Res Inc, Cambridge, MA USA. RP Hursting, SD (reprint author), Univ Texas Austin, Dept Nutr Sci, 1 Univ Stn A2703, Austin, TX 78712 USA. FU National Cancer Institute [N01-CO-12400]; [CA37111] FX This work was supported in part by Grant CA37111 and with federal funds from the National Cancer Institute under contract N01-CO-12400 to SAIC-Frederick. Animal care was provided in accordance with the procedures outlined in the "Guide for the Care and Use of Laboratory Animals" (National Academies Press, 1996). NR 37 TC 6 Z9 6 U1 0 U2 0 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 AUG PY 2009 VL 48 IS 8 BP 671 EP 677 DI 10.1002/mc.20548 PG 7 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 474MV UT WOS:000268289100001 PM 19415693 ER PT J AU Kraus, JP Hasek, J Kozich, V Collard, R Venezia, S Janosikova, B Wang, J Stabler, SP Allen, RH Jakobs, C Finn, CT Chien, YH Hwu, WL Hegele, RA Mudd, SH AF Kraus, Jan P. Hasek, Jindrich Kozich, Viktor Collard, Renata Venezia, Sarah Janosikova, Bohumila Wang, Jian Stabler, Sally P. Allen, Robert H. Jakobs, Cornelis Finn, Christine T. Chien, Yin-Hsiu Hwu, Wuh-Liang Hegele, Robert A. Mudd, S. Harvey TI Cystathionine gamma-lyase: Clinical, metabolic, genetic, and structural studies SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Cystathionine gamma-lyase; Cystathioninuria; Hypercystathioninemia; Mutations; Deletion ID CHROMATOGRAPHY MASS-SPECTROMETRY; TOTAL HOMOCYSTEINE; FOLATE-DEFICIENCY; HYDROGEN-SULFIDE; TRANSSULFURATION; CYSTEINE; SERUM; POLYMORPHISM; ELEVATION; COBALAMIN AB We report studies of six individuals with marked elevations of cystathionine in plasma and/or urine. Studies of CTH, the gene that encodes cystathionine gamma-lyase, revealed the presence among these individuals of either homozygous or compound heterozygous forms of a novel large deletion, p.Gly57_Gln196-del, two novel missense mutations, c.589C>T (p.Arg197Cys) and c.932C>T (p.Thr311Ile), and one previously reported alteration, c.200C>T (p.Thr67Ile). Another novel missense mutation, c.185G>T (p.Arg62His), was found in heterozygous form in three mildly hypercystathioninemic members of a Taiwanese family. In one severely hypercystathioninemic individual no CTH mutation was found. Brief clinical histories of the cystathioninemic/cystathioninuric patients are presented. Most of the novel mutations were expressed and the CTH activities of the mutant proteins determined. The crystal structure of the human enzyme, hCTH, and the evidence available as to the effects of the mutations in question, as well as those of the previously reported p.Gln240Glu, on protein structure, enzymatic activity, and responsiveness to vitamin B-6 administration are discussed. Among healthy Czech controls, 9.3% were homozygous for CTH c.1208G>T (p.Ser403Ile), previously found homozygously in 7.5% of Canadians for whom plasma total homocysteine (tHcy) had been measured. Compared to wild-type homozygotes, among the 55 Czech c.1208G>T (p.Ser403Ile) homozygotes a greater level of plasma cystathionine was found only after methionine loading. Three of the four individuals homozygous or compound heterozygous for inactivating CTH mutations had mild plasma tHcy elevations, perhaps indicating a cause-and-effect relationship. The experience with the present patients provides no evidence that severe loss of CTH activity is accompanied by adverse clinical effects. Published by Elsevier Inc. C1 [Mudd, S. Harvey] NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. [Kraus, Jan P.; Collard, Renata; Venezia, Sarah] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO USA. [Hasek, Jindrich] Acad Sci Czech Republic, Inst Macromol Chem, Dept Struct Anal, Prague, Czech Republic. [Kozich, Viktor; Janosikova, Bohumila] Charles Univ Prague, Fac Med 1, Inst Inherited Metab Dis, Prague, Czech Republic. [Wang, Jian; Hegele, Robert A.] Robarts Res Inst, London, ON N6A 5C1, Canada. [Stabler, Sally P.; Allen, Robert H.] Univ Colorado, Hlth Sci Ctr, Div Hematol, Aurora, CO USA. [Jakobs, Cornelis] Vrije Univ Amsterdam, Med Ctr, Dept Clin Chem, Amsterdam, Netherlands. [Finn, Christine T.] Massachusetts Gen Hosp, Dept Psychiat, Harvard Partners Ctr Genet & Genom, Boston, MA 02114 USA. [Chien, Yin-Hsiu; Hwu, Wuh-Liang] Natl Taiwan Univ Hosp, Dept Med Genet, Taipei, Taiwan. [Chien, Yin-Hsiu; Hwu, Wuh-Liang] Natl Taiwan Univ Hosp, Dept Pediat, Taipei 10016, Taiwan. RP Mudd, SH (reprint author), NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. EM muddh@mail.nih.gov RI Hasek, Jindrich/G-3267-2014; Hegele, Robert/G-3301-2011; Janosikova, Bohumila/D-2940-2017; Kozich, Viktor/A-7672-2008 OI Hasek, Jindrich/0000-0001-7973-1815; Janosikova, Bohumila/0000-0002-0081-4018; HWU, WUH-LIANG/0000-0001-6690-4879; Kozich, Viktor/0000-0001-5820-5277 FU American Heart Association [AHA 2-5-80663]; NIH [HL065217-06A2, AG09834]; Jerome Lejeune foundation [305/07/1073]; Wellcome Trust [070255/Z/03/Z]; Ministry of Education of the Czech Republic [MSM0021620806] FX The authors thank Dr. William M. Sugden, Wisconsin Alumni Research Foundation for establishing the immortalized line of lymphocytes from patient #3051. The plasmid pET22b+hCTH was a generous gift from Dr. Markus Wahl. We are grateful to Dr. Harvey Levy for help in gathering patient information. This work was supported by grants from the American Heart Association (AHA 2-5-80663), from the NIH (HL065217-06A2 and AG09834) and Jerome Lejeune foundation to J.PX, by grants from the Grant Agency of the Czech Republic 305/07/1073, GAAV CR lAA500500701, and MSMT T400500402 to J.H., and from the Wellcome Trust (Reg. No. 070255/Z/03/Z) and the Ministry of Education of the Czech Republic (MSM0021620806) to VX A generous gift from Ms. Margie McGlynn is also acknowledged. NR 31 TC 17 Z9 18 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 2009 VL 97 IS 4 BP 250 EP 259 DI 10.1016/j.ymgme.2009.04.001 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 472TW UT WOS:000268156100004 PM 19428278 ER PT J AU Pospisil, R Kabat, J Mage, RG AF Pospisil, Richard Kabat, Juraj Mage, Rose G. TI Characterization of rabbit CD5 isoforms SO MOLECULAR IMMUNOLOGY LA English DT Article DE Rabbit; T lymphocytes; CD5; Monoclonal antibody; Glycan array ID CELL SURFACE-IMMUNOGLOBULIN; POTENTIAL SELECTING LIGAND; MONOCLONAL-ANTIBODIES; B-LYMPHOCYTES; SUPERANTIGENS; RECOMBINANT; APPENDIX; TISSUES; PROTEIN AB Previously described polyclonal or monoclonal antibodies (mAb) to rabbit CD5, raised against expressed recombinant protein or peptides, recognize CD5 on most rabbit B cells. The mAb KEN-5 was originally reported to recognize rabbit CD5. However, KEN-5 binds almost exclusively to T cells and only to a minor population of B cells. We show here that by Enzyme-linked Immunosorbent Assay (ELISA), KEN-5 binds to recombinant rabbit CD5. This interaction is partially inhibited by polyclonal goat anti-CD5 antibody. In addition, immunoprecipitations from lysates of surface biotinylated rabbit lymphocytes with KEN-5 or our anti-CD5 mAb isolate molecules that migrate identically on gels with the same approximate relative molecular mass of 67,000 M, By flow cytometric analyses of individual cells from spleen. thymus and appendix, KEN-5 recognizes CD5-like molecules mainly on T cells and on 3-6% of IgM(+) B cells. Immunohistochemical staining of splenic and appendix tissues and confocal immunofluorescent imaging confirm and extend results from flow cytometric analyses. Quantitation of fluorescent colocalization indicates that staining by KEN-5 colocalizes with staining by anti-CD5 on small percentage lymphocytes in splenic tissue sections. As CD5 has both N- and O-linked glycosylation, we hypothesised that differential binding of KEN-5 to T cells and B-cells may be explained by different glycan structures on the CD5 present on T compared to B cells. This hypothesis is supported by ELISA data that show that deglycosylation diminishes the binding of KEN-5 to recombinant rabbit CD5. Screening KEN-5 on an array with 406 glycans was inconclusive. Although we did not identify a strongly binding glycan structure, the data are suggestive that the epitope recognized by KEN-5 may be influenced by glycan structures. The epitope this mAb recognizes may either be the glycan itself, or more likely, is influenced by neighboring glycan structure. Our findings suggest that development, selection and function of different B- and T-cell subsets or their preferential survival may be directly or indirectly dependent on different glycan structures associated with CD5 or CD5-like molecules expressed on T cells compared to B cells. (C) 2009 Published by Elsevier Ltd. C1 [Pospisil, Richard; Mage, Rose G.] NIAID, LI, NIH, Bethesda, MD 20892 USA. [Kabat, Juraj] NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Mage, RG (reprint author), NIAID, LI, NIH, Bldg 10,Rm IIN3II,10 Ctr Dr, Bethesda, MD 20892 USA. EM rmage@niaid.nih.gov RI Pospisil, Richard/B-7467-2012 FU NIH; NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. We thank members of the of the Laboratory of Immunology including Cornelius Alexander, Satyajit Ray, Folake Soetan and Rami Zahr of the Laboratory of Immunology, NIAID for technical support. We are very grateful to Drs. Chander Raman and Katherine Knight for sharing and discussion of unpublished results concerning attempts to detect expressed recombinant fulllength rabbit CD5 with KEN-5 transfected into A20 cells. Confocal imaging and analyses were conducted in the Biological Imaging Section of the NIAID Research Technologies Branch (RTB). We thank Drs. Owen M. Schwartz, and Lily Koo of the RTB for their contributions to this part of our study. We thank Drs. David Smith and Jamie Heimburg-Molinaro of the Consortium for Functional Glycomics Protein-Glycan Interaction Core (H) for advice, conducting the glycan array analysis, and depositing the data in the functional analysis database. We thank Dr. Denong Wang for earlier carbohydrate microarray analysis of KEN-5 and Dr. Yang Yang for Hi-D FACS analysis of murine lymphocytes for KEN-5 binding. We also acknowledge Drs. Michael Mage, Denong Wang, and Ethan Shevach for helpful advice and comments about the manuscript and Ms. Shirley Starnes for expert editorial assistance. NR 24 TC 7 Z9 7 U1 2 U2 4 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 AUG PY 2009 VL 46 IS 13 BP 2456 EP 2464 DI 10.1016/j.molimm.2009.05.026 PG 9 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 484SY UT WOS:000269069000003 PM 19520434 ER PT J AU Grodzki, ACG Moon, KD Berenstein, EH Siraganian, RP AF Grodzki, Ana Cristina G. Moon, Kyungduk D. Berenstein, Elsa H. Siraganian, Reuben P. TI Fc epsilon RI-induced activation by low antigen concentrations results in nuclear signals in the absence of degranulation SO MOLECULAR IMMUNOLOGY LA English DT Article DE Mast cells; Fc epsilon RI; Signal transduction; NFAT signaling; Degranulation ID TRANSCRIPTION FACTOR NFAT1; AFFINITY IGE RECEPTOR; MAST-CELL ACTIVATION; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; TYROSINE PHOSPHORYLATION; MEDIATOR RELEASE; GENE-EXPRESSION; HUMAN BASOPHILS; RBL-2H3 CELLS AB High affinity IgE receptor (Fc epsilon RI)-induced activation of mast cells results in degranulation and generation of leukotrienes and cytokines. Fc epsilon RI-induced mast cell activation was analyzed at a single cell basis using a rat basophilic leukemia (RBL-2H3) cell line transfected with a reporter plasmid containing three tandem NFAT (nuclear factor of activated T cells) binding sites fused to enhanced green fluorescent protein (GFP). Surprisingly, with this sensitive detection system, there is activation of IgE sensitized cells at concentrations of antigen as low as 10 pg/ml, which was 10-fold lower than was detected by degranulation. There were differences in signaling pathways leading to degranulation compared to NFAT-mediated gene activation. Both signaling to NFAT activation and degranulation required Syk and calcineurin. However inhibitors of the phosphatidylinositol 3-kinase pathway blocked degranulation but did not NFAT activation. The results also indicate that NFAT was activated at lower intracellular signals compared to degranulation. Therefore, FceRI activation can result in nuclear signals in the absence of the release of mediators. Published by Elsevier Ltd. C1 [Grodzki, Ana Cristina G.; Moon, Kyungduk D.; Berenstein, Elsa H.; Siraganian, Reuben P.] NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Siraganian, RP (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 49-1A16, Bethesda, MD 20892 USA. EM rsiraganian@mail.nih.gov FU National Institutes of Health; NIDCR FX The authors thank Dr. Takashi Saito, Riken Research Center for Allergy and Immunology, Yokohama, Japan, for providing the plasmid containing NFAT binding sites fused to eGFP; Lynda Weedon for technical assistance for the calcium experiments; Santosh Mishra for technical assistance for the microarray experiments and Andrea Marques for assistance in statistical analysis. We thank Dr. Juan Lisa Zhang for discussions and reviewing the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, NIDCR. NR 47 TC 16 Z9 16 U1 0 U2 5 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 AUG PY 2009 VL 46 IS 13 BP 2539 EP 2547 DI 10.1016/j.molimm.2009.05.013 PG 9 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 484SY UT WOS:000269069000012 PM 19540596 ER PT J AU Kitao, Y Kono, T Korenaga, H Lizasa, T Nakamura, K Savan, R Sakai, M AF Kitao, Yoichi Kono, Tomoya Korenaga, Hiroki Lizasa, Toshiyuki Nakamura, Keisuke Savan, Ram Sakai, Masahiro TI Characterization and expression analysis of type I interferon in common carp Cyprinus carpio L. SO MOLECULAR IMMUNOLOGY LA English DT Article DE Common carp; Type I interferon; Cloning; Structural analysis; mRNA expression ID ART. NO. 29; IDENTIFICATION; FISH; VERTEBRATES; EVOLUTION; PROTEIN; SYSTEM; CELLS; GENE; DNA AB The type I interferon (I-IFN) gene has recently been cloned and sequenced in the common carp species Cyprinus carpio L Carp I-IFN cDNA is composed of 675 base pairs and is translated into a protein of 186 amino acid residues. The carp I-IFN encodes a predicted signal peptide of 23 amino acid residues and contains the I-IFN family signature His(140)-Trp(158). Analysis of the homology between carp I-IFN and other known I-IFN and type II interferon (II-IFN) family members has revealed significant similarities to grass carp I-IFN. Phylogenetic analysis demonstrated that carp I-IFN clusters with I-IFN in teleosts, away from the other II-IFN family members. In addition, the gene structure for carp I-IFN is composed of 5 exons and 4 introns, a composition that is similar to that of the teleost I-IFN gene. RT-PCR analysis did not reveal gene expression in un-stimulated tissues including intestine, liver, gill, head kidney, muscle, spleen, mid-kidney and skin. However, I-IFN expression levels increased following stimulation with imiquimod in the head kidney cells. Furthermore, recombinant carp I-IFN protein (mature form) produced via the cell-free protein synthesis system stimulated the expression of the interferon-inducible Mx gene in the head kidney cells. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Kitao, Yoichi; Kono, Tomoya; Korenaga, Hiroki; Lizasa, Toshiyuki; Nakamura, Keisuke; Sakai, Masahiro] Miyazaki Univ, Fac Agr, Miyazaki 8892192, Japan. [Savan, Ram] NCI, Ctr Canc Res, Expt Immunol Lab, Frederick, MD 21702 USA. RP Sakai, M (reprint author), Miyazaki Univ, Fac Agr, 1-1 Gakuen Kibanadai Nishi, Miyazaki 8892192, Japan. EM m.sakai@cc.miyazaki-u.ac.jp FU Japan Society for the Promotion of Science (JSPS) [20580206, 21780180] FX This study was partially supported by Grant-in-Aid for Scientific Research (20580206) and Young Scientists (21780180) of the Japan Society for the Promotion of Science (JSPS). NR 29 TC 28 Z9 29 U1 0 U2 5 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 AUG PY 2009 VL 46 IS 13 BP 2548 EP 2556 DI 10.1016/j.molimm.2009.05.012 PG 9 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 484SY UT WOS:000269069000013 PM 19520432 ER PT J AU Tross, D Petrenko, L Klaschik, S Zhu, Q Klinman, DM AF Tross, Debra Petrenko, Lev Klaschik, Sven Zhu, Qing Klinman, Dennis M. TI Global changes in gene expression and synergistic interactions induced by TLR9 and TLR3 SO MOLECULAR IMMUNOLOGY LA English DT Article DE Gene regulation; CpG oligodeoxynucleotides; Poly (I:C); TLR; Synergy; Molecular biology ID DOUBLE-STRANDED-RNA; TOLL-LIKE RECEPTOR-3; INNATE IMMUNE DEFENSE; DENDRITIC CELLS; BACTERIAL-DNA; CPG MOTIFS; ACTIVATION; RESPONSES; PATHWAYS; SIGNALS AB The innate immune system is triggered when pathogen-associated molecular patterns (PAMPs) expressed by infectious microorganisms interact with toll-like receptors (TLR) present on immune cells. Individual TLRs signal through distinct molecular pathways. For example, TLR9 interacts with unmethylated CpG motifs expressed by bacterial DNA and triggers via a MyD88 dependent pathway whereas TLR3 recognizes viral RNA through a MyD88-independent pathway. Bioinformatic analysis of microarray data was used to identify the regulatory patterns underlying changes in gene expression induced when RAW 264.7 macrophages were stimulated via TLR9 by CpG oligonucleotides (ODN) and/or via TLR3 by poly (I:C). While the genes activated by each ligand mediated similar functions, poly (I:C) elicited a larger and more diverse change in gene expression. Co-stimulation with both ligands accelerated gene expression and synergistically activated genes primarily associated with immune function. This is the first work to compare global changes in gene regulation triggered by distinct TLR pathways and clarify their impact on gene expression. Published by Elsevier Ltd. C1 [Tross, Debra; Petrenko, Lev; Klaschik, Sven; Klinman, Dennis M.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Zhu, Qing] NCI, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. RP Klinman, DM (reprint author), NCI, Canc & Inflammat Program, Bldg 567,Room 205, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU Intramural NIH HHS [Z01 BC010852-01] NR 31 TC 22 Z9 24 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 AUG PY 2009 VL 46 IS 13 BP 2557 EP 2564 DI 10.1016/j.molimm.2009.05.011 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 484SY UT WOS:000269069000014 PM 19535142 ER PT J AU Barchi, J Kaczmarek, P AF Barchi, Joe Kaczmarek, Piotr TI Untitled SO MOLECULAR INTERVENTIONS LA English DT Letter ID INTERSTITIAL CYSTITIS C1 [Barchi, Joe; Kaczmarek, Piotr] NCI, Frederick, MD 21702 USA. RP Barchi, J (reprint author), NCI, 376 Boyles St,POB B, Frederick, MD 21702 USA. EM barchi@helix.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD AUG 1 PY 2009 VL 9 IS 4 BP 156 EP 156 DI 10.1124/mi.9.4.1 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 497TF UT WOS:000270084600001 PM 19720746 ER PT J AU Shears, SB AF Shears, Stephen B. TI Diphosphoinositol Polyphosphates: Metabolic Messengers? SO MOLECULAR PHARMACOLOGY LA English DT Review ID ACTIVATED PROTEIN-KINASE; INOSITOL HEXAKISPHOSPHATE KINASE-2; CYCLIC ADENINE RIBONUCLEOTIDE; OVARIAN-CARCINOMA CELLS; SACCHAROMYCES-CEREVISIAE; CELLULAR SENESCENCE; TELOMERE LENGTH; IN-VIVO; MYOINOSITOL HEXAKISPHOSPHATE; RAT-LIVER AB The diphosphoinositol polyphosphates ("inositol pyrophosphates") are a specialized subgroup of the inositol phosphate signaling family. This review proposes that many of the current data concerning the metabolic turnover and biological effects of the diphosphoinositol polyphosphates are linked by a common theme: these polyphosphates act as metabolic messengers. This review will also discuss the latest proposals concerning possible molecular mechanisms of action of this intriguing class of molecules. C1 Natl Inst Environm Hlth Sci, Inositide Signaling Grp, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Shears, SB (reprint author), Natl Inst Environm Hlth Sci, Inositide Signaling Grp, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences. NR 172 TC 75 Z9 78 U1 0 U2 9 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 2009 VL 76 IS 2 BP 236 EP 252 DI 10.1124/mol.109.055897 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 472SV UT WOS:000268153400003 PM 19439500 ER PT J AU Nicodemus, KK Law, AJ Luna, A Vakkalanka, R Straub, RE Kleinman, JE Weinberger, DR AF Nicodemus, K. K. Law, A. J. Luna, A. Vakkalanka, R. Straub, R. E. Kleinman, J. E. Weinberger, D. R. TI A 5 ' promoter region SNP in NRG1 is associated with schizophrenia risk and type III isoform expression SO MOLECULAR PSYCHIATRY LA English DT Letter ID NEUREGULIN-1; SUSCEPTIBILITY; BRAIN C1 [Nicodemus, K. K.; Law, A. J.; Luna, A.; Vakkalanka, R.; Straub, R. E.; Kleinman, J. E.; Weinberger, D. R.] NIMH, Genes Cognit & Psychosis Program, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Nicodemus, K. K.] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Stat Genet, Oxford, England. [Nicodemus, K. K.] Univ Oxford, Dept Clin Pharmacol, Oxford, England. [Law, A. J.] Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford, England. RP Nicodemus, KK (reprint author), NIMH, Genes Cognit & Psychosis Program, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM weinberd@mail.nih.gov RI Luna, Alain/F-4888-2012; Law, Amanda/G-6372-2012; OI Law, Amanda/0000-0002-2574-1564 FU Intramural NIH HHS [Z01 MH002903-02]; Medical Research Council [G120/997] NR 11 TC 24 Z9 24 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 AUG PY 2009 VL 14 IS 8 BP 741 EP 743 DI 10.1038/mp.2008.150 PG 4 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 473VR UT WOS:000268239200002 PM 19626024 ER PT J AU Smith, EN Bloss, CS Badner, JA Barrett, T Belmonte, PL Berrettini, W Byerley, W Coryell, W Craig, D Edenberg, HJ Eskin, E Foroud, T Gershon, E Greenwood, TA Hipolito, M Koller, DL Lawson, WB Liu, C Lohoff, F McInnis, MG McMahon, FJ Mirel, DB Murray, SS Nievergelt, C Nurnberger, J Nwulia, EA Paschall, J Potash, JB Rice, J Schulze, TG Scheftner, W Panganiban, C Zaitlen, N Zandi, PP Zollner, S Schork, NJ Kelsoe, JR AF Smith, E. N. Bloss, C. S. Badner, J. A. Barrett, T. Belmonte, P. L. Berrettini, W. Byerley, W. Coryell, W. Craig, D. Edenberg, H. J. Eskin, E. Foroud, T. Gershon, E. Greenwood, T. A. Hipolito, M. Koller, D. L. Lawson, W. B. Liu, C. Lohoff, F. McInnis, M. G. McMahon, F. J. Mirel, D. B. Murray, S. S. Nievergelt, C. Nurnberger, J. Nwulia, E. A. Paschall, J. Potash, J. B. Rice, J. Schulze, T. G. Scheftner, W. Panganiban, C. Zaitlen, N. Zandi, P. P. Zoellner, S. Schork, N. J. Kelsoe, J. R. TI Genome-wide association study of bipolar disorder in European American and African American individuals SO MOLECULAR PSYCHIATRY LA English DT Article DE ANK3; Bipolar Genome Study; genetic background; allelic heterogeneity; GAIN ID FAMILY-BASED ASSOCIATION; NEUROTROPHIC FACTOR GENE; BRAIN; TRANSMISSION; LINKAGE; SUSCEPTIBILITY; SCHIZOPHRENIA; METAANALYSIS; DISEASE; MODELS AB To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 x 10(-6)) and rs10193871 in NAP5 at 2q21.2 (P=9.8 x 10(-6)). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 x 10(-6)) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 x 10(-5)). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 x 10(-6)), rs4657247 in RGS5 at 1q23.3 (P=4.1 x 10(-6)), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 x 10(-6)). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry. Molecular Psychiatry (2009) 14, 755-763; doi:10.1038/mp.2009.43; published online 2 June 2009 C1 [Smith, E. N.; Murray, S. S.; Schork, N. J.] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Smith, E. N.; Bloss, C. S.; Murray, S. S.; Schork, N. J.] Scripps Translat Sci Inst, La Jolla, CA USA. [Bloss, C. S.; Murray, S. S.; Schork, N. J.] Scripps Hlth, La Jolla, CA USA. [Badner, J. A.; Gershon, E.; Liu, C.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Barrett, T.] Portland VA Med Ctr, Dept Psychiat, Portland, OR USA. [Belmonte, P. L.; Potash, J. B.; Zandi, P. P.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. [Berrettini, W.; Lohoff, F.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Byerley, W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Coryell, W.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Craig, D.; Panganiban, C.] Translat Genom Res Inst, Neurogenom Div, Phoenix, AZ USA. [Edenberg, H. J.] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN USA. [Edenberg, H. J.; Foroud, T.] Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Eskin, E.; Zaitlen, N.] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90024 USA. [Greenwood, T. A.; Nievergelt, C.; Kelsoe, J. R.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Hipolito, M.; Lawson, W. B.; Nwulia, E. A.] Howard Univ, Dept Psychiat, Washington, DC 20059 USA. [Koller, D. L.; Nurnberger, J.] Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [McInnis, M. G.; Zoellner, S.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [McMahon, F. J.; Schulze, T. G.] NIMH, Genet Basis Mood & Anxiety Disorders Unit, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Mirel, D. B.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Mirel, D. B.] MIT, Cambridge, MA 02139 USA. [Paschall, J.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Rice, J.] Washington Univ, Div Biostat, St Louis, MO USA. [Scheftner, W.] Rush Univ, Dept Psychiat, Chicago, IL 60612 USA. [Kelsoe, J. R.] VA San Diego Healthcare Syst, Dept Psychiat, La Jolla, CA USA. RP Schork, NJ (reprint author), Scripps Res Inst, Dept Mol & Expt Med, 10550 N Torrey Pines Ave,MEM 275, La Jolla, CA 92037 USA. EM nschork@scripps.edu RI Greenwood, Tiffany/F-6356-2012; Schulze, Thomas/H-2157-2013; Lohoff, Falk/M-7951-2016; Smith, Erin/E-5933-2011; Liu, Chunyu/G-7561-2012; McInnis, Melvin/F-6963-2012; Eskin, Eleazar/J-9187-2012; OI Greenwood, Tiffany/0000-0002-6080-6503; Lawson, William/0000-0002-9324-7090; Liu, Chunyu/0000-0002-5986-4415; McInnis, Melvin/0000-0002-0375-6247; Eskin, Eleazar/0000-0003-1149-4758; Nurnberger, John/0000-0002-7674-1767; Nievergelt, Caroline/0000-0001-5766-8923; McMahon, Francis/0000-0002-9469-305X; Edenberg, Howard/0000-0003-0344-9690 FU NIMH [R01 MH59553, U01 MH46282, R01 MH59545, U01 MH46280, R01 MH059534, U01 MH46274, R01 MH59533, R01 MH60068, R01 MH059548, R01 MH59535, R01 MH59567, R01 MH059556]; NHGRI [MH078151, MH081804, MH059567]; Genetic Association Information Network ( GAIN; NIH [R01 MH59553, K08 MH080372, 1U54RR025204-01]; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD; NIMH Intramural Research Program, Bethesda, MD [1Z01MH00281001] FX We thank the participants in the study, as without them this work would not have been possible. For best estimate diagnostic work, we thank Vegas Coleman, Robert Schweitzer, N Leela Rau and Kelly Rhoadarmer. For data management, we thank Mariano Erpe and for study coordination Carre Fisher RN. This work was supported by grants from the NIMH and NHGRI to JRK (MH078151, MH081804, MH059567 supplement), and by the Genetic Association Information Network ( GAIN). This work was additionally supported by the NIMH Intramural Research Program (FJM and TGS). WHB was supported by a grant from the Tzedakah Foundation, a grant from NIH (R01 MH59553) and a grant from Philip and Marcia Cohen. Falk Lohoff was supported by the Daland Fellowship Award from the American Philosophical Society and by NIH grant K08 MH080372. David Craig and Corrie Panganiban acknowledge the Stardust foundation. Follow-up genotyping was performed in the laboratory of HE at Indiana University School of Medicine. This research was also supported, in part, by the Intramural Research Program of the NIH, National Library of Medicine. Dr Smith, Dr Bloss, Dr Murray and Dr Schork are supported in part by National Institutes of Health grant NIH 1U54RR025204-01. Data and biomaterials were collected in four projects that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 1991 to 1998, the principal investigators and coinvestigators were: Indiana University, Indianapolis, IN, U01 MH46282, John Nurnberger, Marvin Miller and Elizabeth Bowman; Washington University, St Louis, MO, U01 MH46280, Theodore Reich, Allison Goate and John Rice; Johns Hopkins University, Baltimore, MD U01 MH46274, J Raymond DePaulo, Jr, Sylvia Simpson and Colin Stine; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD, Elliot Gershon, Diane Kazuba and Elizabeth Maxwell. Data and biomaterials were collected as part of 10 projects that participated in the National Institute of Mental Health ( NIMH) Bipolar Disorder Genetics Initiative. From 1999 to 2007, the principal investigators and coinvestigators were: Indiana University, Indianapolis, IN, R01 MH59545, John Nurnberger, Marvin J Miller, Elizabeth S Bowman, N Leela Rau, P Ryan Moe, Nalini Samavedy, Rif El-Mallakh ( at University of Louisville), Husseini Manji ( at Wayne State University), Debra A Glitz ( at Wayne State University), Eric T Meyer, Carrie Smiley, Tatiana Foroud, Leah Flury, Danielle M Dick, Howard Edenberg; Washington University, St Louis, MO, R01 MH059534, John Rice, Theodore Reich, Allison Goate, Laura Bierut; Johns Hopkins University, Baltimore, MD, R01 MH59533, Melvin McInnis, J Raymond DePaulo, Jr, Dean F MacKinnon, Francis M Mondimore, James B Potash, Peter P Zandi, Dimitrios Avramopoulos and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553, Wade Berrettini; University of California at Irvine, CA, R01 MH60068, William Byerley and Mark Vawter; University of Iowa, IA, R01 MH059548, William Coryell and Raymond Crowe; University of Chicago, IL, R01 MH59535, Elliot Gershon, Judith Badner, Francis McMahon, Chunyu Liu, Alan Sanders, Maria Caserta, Steven Dinwiddie, Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567, John Kelsoe, Rebecca McKinney; Rush University, IL, R01 MH059556, William Scheftner, Howard M Kravitz, Diana Marta, Annette VaughnBrown and Laurie Bederow; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH00281001, Francis J McMahon, Layla Kassem, Sevilla DeteraWadleigh, Lisa Austin, Dennis L Murphy. NR 32 TC 198 Z9 201 U1 2 U2 15 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 AUG PY 2009 VL 14 IS 8 BP 755 EP 763 DI 10.1038/mp.2009.43 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 473VR UT WOS:000268239200005 PM 19488044 ER PT J AU Deroo, BJ Hewitt, SC Collins, JB Grissom, SF Hamilton, KJ Korach, KS AF Deroo, Bonnie J. Hewitt, Sylvia C. Collins, Jennifer B. Grissom, Sherry F. Hamilton, Katherine J. Korach, Kenneth S. TI Profile of Estrogen-Responsive Genes in an Estrogen-Specific Mammary Gland Outgrowth Model SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Article ID BREAST-CANCER CELLS; GROWTH-FACTOR RECEPTOR; BROWN ADIPOSE-TISSUE; EXPRESSION PATTERNS; EPITHELIAL-CELLS; IMMUNOCYTOCHEMICAL IDENTIFICATION; BRANCHING MORPHOGENESIS; TARGETED DISRUPTION; DOWN-REGULATION; INDUCIBLE GENE AB Both ovarian and pituitary hormones are required for the pubertal development of the mouse mammary gland. Estradiol directs ductal elongation and branching, while progesterone leads to tertiary branching and alveolar development. The purpose of this investigation was to identify estrogen-responsive genes associated with pubertal ductal growth in the mouse mammary gland in the absence of other ovarian hormones and at different stages of development. We hypothesized that the estrogen-induced genes and their associated functions at early stages of ductal elongation would be distinct from those induced after significant ductal elongation had occurred. Therefore, ovariectomized prepubertal mice were exposed to 17 beta-estradiol from two to 28 days, and mammary gland global gene expression analyzed by microarray analysis at various times during this period. We found that: (a) gene expression changes in our estrogen-only model mimic those changes that occur in normal pubertal development in intact mice, (b) both distinct and overlapping gene profiles were observed at varying extents of ductal elongation, and (c) cell proliferation, the immune response, and metabolism/catabolism were the most common functional categories associated with mammary ductal growth. Particularly striking was the novel observation that genes active during carbohydrate metabolism were rapidly and robustly decreased in response to estradiol. Lastly, we identified mammary estradiol-responsive genes that are also co-expressed with estrogen receptor a in human breast cancer. In conclusion, our genomic data support the physiological observation that estradiol is one of the primary hormonal signals driving ductal elongation during pubertal mammary development. C1 [Korach, Kenneth S.] NIEHS, Environ Dis Med Program, Reprod & Dev Toxicol Lab, Receptor Biol Sect,NIH, Res Triangle Pk, NC 27709 USA. [Deroo, Bonnie J.] Univ Western Ontario, Dept Biochem, Schulich Sch Med & Dent, London, ON, Canada. [Deroo, Bonnie J.] Lawson Hlth Res Inst, Childrens Hlth Res Inst, Canc Res Lab Program, London, ON, Canada. [Collins, Jennifer B.; Grissom, Sherry F.] NIEHS, Microarray Grp, NIH, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, Environ Dis Med Program, Reprod & Dev Toxicol Lab, Receptor Biol Sect,NIH, Alexander Dr, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU Intramural NIH HHS [Z01 ES070065-31] NR 93 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 1040-452X J9 MOL REPROD DEV JI Mol. Reprod. Dev. PD AUG PY 2009 VL 76 IS 8 BP 733 EP 750 DI 10.1002/mrd.21041 PG 18 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA 470UM UT WOS:000268006400005 PM 19484750 ER PT J AU Jothi, R Balaji, S Wuster, A Grochow, JA Gsponer, J Przytycka, TM Aravind, L Babu, MM AF Jothi, Raja Balaji, S. Wuster, Arthur Grochow, Joshua A. Gsponer, Joerg Przytycka, Teresa M. Aravind, L. Babu, M. Madan TI Genomic analysis reveals a tight link between transcription factor dynamics and regulatory network architecture SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE dynamics; hierarchy; noise; systems biology; transcription network ID STOCHASTIC GENE-EXPRESSION; SACCHAROMYCES-CEREVISIAE; ESCHERICHIA-COLI; HIERARCHICAL STRUCTURE; FLUCTUATING ENVIRONMENTS; LINEAGE-COMMITMENT; METABOLIC NETWORKS; EUKARYOTIC GENOME; PROGENITOR CELLS; SINGLE-CELL AB Although several studies have provided important insights into the general principles of biological networks, the link between network organization and the genome-scale dynamics of the underlying entities (genes, mRNAs, and proteins) and its role in systems behavior remain unclear. Here we show that transcription factor (TF) dynamics and regulatory network organization are tightly linked. By classifying TFs in the yeast regulatory network into three hierarchical layers (top, core, and bottom) and integrating diverse genome-scale datasets, we find that the TFs have static and dynamic properties that are similar within a layer and different across layers. At the protein level, the top-layer TFs are relatively abundant, long-lived, and noisy compared with the core- and bottom-layer TFs. Although variability in expression of top-layer TFs might confer a selective advantage, as this permits at least some members in a clonal cell population to initiate a response to changing conditions, tight regulation of the core- and bottom-layer TFs may minimize noise propagation and ensure fidelity in regulation. We propose that the interplay between network organization and TF dynamics could permit differential utilization of the same underlying network by distinct members of a clonal cell population. Molecular Systems Biology 5: 294; published online 18 August 2009; doi: 10.1038/msb.2009.52 C1 [Jothi, Raja] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Balaji, S.; Przytycka, Teresa M.; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Grochow, Joshua A.] Univ Chicago, Dept Comp Sci, Chicago, IL 60637 USA. [Wuster, Arthur; Gsponer, Joerg; Babu, M. Madan] MRC, Mol Biol Lab, Cambridge CB2 2QH, England. RP Jothi, R (reprint author), NIEHS, Biostat Branch, NIH, 111 TW Alexander Dr,MD A3-03, Res Triangle Pk, NC 27709 USA. EM jothi@mail.nih.gov; madanm@mrc-lmb.cam.ac.uk RI Jothi, Raja/G-3780-2015 FU National Institutes of Health, NIEHS; National Institutes of Health, NLM; MRC FX We thank several colleagues from National Institutes of Health (NIH) and Medical Research Council (MRC) for providing helpful comments on the paper. We also thank the anonymous referees for helpful suggestions on a previous version of this paper. RJ was supported by the intramural research program of the National Institutes of Health, NIEHS. SB, TMP, and LA were supported by the intramural research program of National Institutes of Health, NLM. MMB acknowledges Darwin College and Schlumberger Ltd. MMB, AW, and JG acknowledge the MRC for funding their research. JG was supported by the MRC special training award in computational biology. NR 84 TC 87 Z9 87 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD AUG PY 2009 VL 5 AR 294 DI 10.1038/msb.2009.52 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 566RG UT WOS:000275390100002 PM 19690563 ER PT J AU Le Novere, N Hucka, M Mi, HY Moodie, S Schreiber, F Sorokin, A Demir, E Wegner, K Aladjem, MI Wimalaratne, SM Bergman, FT Gauges, R Ghazal, P Kawaji, H Li, L Matsuoka, Y Villeger, A Boyd, SE Calzone, L Courtot, M Dogrusoz, U Freeman, TC Funahashi, A Ghosh, S Jouraku, A Kim, S Kolpakov, F Luna, A Sahle, S Schmidt, E Watterson, S Wu, GM Goryanin, I Kell, DB Sander, C Sauro, H Snoep, JL Kohn, K Kitano, H AF Le Novere, Nicolas Hucka, Michael Mi, Huaiyu Moodie, Stuart Schreiber, Falk Sorokin, Anatoly Demir, Emek Wegner, Katja Aladjem, Mirit I. Wimalaratne, Sarala M. Bergman, Frank T. Gauges, Ralph Ghazal, Peter Kawaji, Hideya Li, Lu Matsuoka, Yukiko Villeger, Alice Boyd, Sarah E. Calzone, Laurence Courtot, Melanie Dogrusoz, Ugur Freeman, Tom C. Funahashi, Akira Ghosh, Samik Jouraku, Akiya Kim, Sohyoung Kolpakov, Fedor Luna, Augustin Sahle, Sven Schmidt, Esther Watterson, Steven Wu, Guanming Goryanin, Igor Kell, Douglas B. Sander, Chris Sauro, Herbert Snoep, Jacky L. Kohn, Kurt Kitano, Hiroaki TI The Systems Biology Graphical Notation SO NATURE BIOTECHNOLOGY LA English DT Article ID COLLABORATIVE CONSTRUCTION; CELLULAR PATHWAYS; NETWORKS; REPRESENTATION; DIAGRAM AB Circuit diagrams and Unified Modeling Language diagrams are just two examples of standard visual languages that help accelerate work by promoting regularity, removing ambiguity and enabling software tool support for communication of complex information. Ironically, despite having one of the highest ratios of graphical to textual information, biology still lacks standard graphical notations. The recent deluge of biological knowledge makes addressing this deficit a pressing concern. Toward this goal, we present the Systems Biology Graphical Notation (SBGN), a visual language developed by a community of biochemists, modelers and computer scientists. SBGN consists of three complementary languages: process diagram, entity relationship diagram and activity flow diagram. Together they enable scientists to represent networks of biochemical interactions in a standard, unambiguous way. We believe that SBGN will foster efficient and accurate representation, visualization, storage, exchange and reuse of information on all kinds of biological knowledge, from gene regulation, to metabolism, to cellular signaling. C1 [Le Novere, Nicolas; Li, Lu; Schmidt, Esther] EMBL European Bioinformat Inst, Hinxton, England. [Hucka, Michael] CALTECH, Pasadena, CA 91125 USA. [Mi, Huaiyu] SRI Int, Menlo Pk, CA 94025 USA. [Moodie, Stuart; Ghazal, Peter; Watterson, Steven; Goryanin, Igor] Univ Edinburgh, Ctr Syst Biol Edinburgh, Edinburgh, Midlothian, Scotland. [Schreiber, Falk] Leibniz Inst Plant Genet & Crop Plant Res, Gatersleben, Germany. [Schreiber, Falk] Univ Halle Wittenberg, Inst Comp Sci, Halle, Germany. [Sorokin, Anatoly] Univ Edinburgh, Sch Informat, Edinburgh, Midlothian, Scotland. [Demir, Emek; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10021 USA. [Wegner, Katja] Univ Hertfordshire, Sci & Technol Res Inst, Hatfield AL10 9AB, Herts, England. [Aladjem, Mirit I.; Kim, Sohyoung; Luna, Augustin; Kohn, Kurt] NCI, Bethesda, MD 20892 USA. [Wimalaratne, Sarala M.] Univ Auckland, Auckland Bioengn Inst, Auckland 1, New Zealand. [Bergman, Frank T.; Sauro, Herbert] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. [Gauges, Ralph; Sahle, Sven] Univ Heidelberg, BIOQUANT, Heidelberg, Germany. [Ghazal, Peter; Freeman, Tom C.] Univ Edinburgh, Sch Med, Div Pathway Med, Edinburgh, Midlothian, Scotland. [Kawaji, Hideya] RIKEN, OMICS Sci Ctr, Yokohama, Kanagawa, Japan. [Matsuoka, Yukiko; Ghosh, Samik; Kitano, Hiroaki] Syst Biol Inst, Tokyo, Japan. [Villeger, Alice] Univ Manchester, Sch Comp Sci, Manchester, Lancs, England. [Villeger, Alice; Kell, Douglas B.] Manchester Interdisciplinary Bioctr, Manchester, Lancs, England. [Boyd, Sarah E.] Monash Univ, Fac Informat Technol, Clayton Sch Informat Technol, Melbourne, Vic 3004, Australia. [Calzone, Laurence] Inst Curie, INSERM, U900, Paris, France. [Courtot, Melanie] British Columbia Canc Res Ctr, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. [Dogrusoz, Ugur; Watterson, Steven] Bilkent Univ, Bilkent Ctr Bioinformat, Ankara, Turkey. [Freeman, Tom C.] Univ Edinburgh, Roslin Inst, Edinburgh, Midlothian, Scotland. [Funahashi, Akira; Jouraku, Akiya] Keio Univ, Dept Biosci & Informat, Kouhoku Ku, Yokohama, Kanagawa 223, Japan. [Kolpakov, Fedor] Inst Syst Biol, Novosibirsk, Russia. [Kolpakov, Fedor] Design Technol Inst Digital Tech SB RAS, Novosibirsk, Russia. [Wu, Guanming] Ontario Inst Canc Res, Toronto, ON, Canada. [Kell, Douglas B.] Univ Manchester, Sch Chem, Manchester, Lancs, England. [Snoep, Jacky L.] Univ Stellenbosch, Dept Biochem, Matieland, South Africa. [Kitano, Hiroaki] Sony Comp Sci Labs, Tokyo, Japan. [Kitano, Hiroaki] Okinawa Inst Sci & Technol, Okinawa, Japan. RP Le Novere, N (reprint author), EMBL European Bioinformat Inst, Hinxton, England. EM lenov@ebi.ac.uk RI Sorokin, Anatoly/A-9090-2008; Aladjem, Mirit/G-2169-2010; Boyd, Sarah/I-9047-2012; Kawaji, Hideya/N-5116-2015; Kell, Douglas/E-8318-2011; Le Novere, Nicolas/F-9973-2010; sander, chris/H-1452-2011; Hucka, Michael/B-1896-2012; Funahashi, Akira/C-4923-2014; OI Sorokin, Anatoly/0000-0002-0047-0606; Aladjem, Mirit/0000-0002-1875-3110; Kawaji, Hideya/0000-0002-0575-0308; Calzone, Laurence/0000-0002-7835-1148; Sauro, Herbert/0000-0002-3659-6817; Kell, Douglas/0000-0001-5838-7963; Le Novere, Nicolas/0000-0002-6309-7327; Watterson, Steven/0000-0002-2750-6410; Li, Lu/0000-0002-6199-522X; Kolpakov, Fedor/0000-0002-0396-0256; Snoep, Jacky/0000-0002-0405-8854; Demir, Emek/0000-0002-3663-7113; Kim, Sohyoung/0000-0002-6140-7918; Courtot, Melanie/0000-0002-9551-6370; Boyd, Sarah/0000-0002-7264-8602; Wimalaratne, Sarala/0000-0002-5355-2576; Funahashi, Akira/0000-0003-0605-239X FU Biotechnology and Biological Sciences Research Council [BB/F010516/1, ]; Chief Scientist Office [ETM/202]; Intramural NIH HHS; NIGMS NIH HHS [1R01GM081070-01] NR 34 TC 277 Z9 282 U1 3 U2 31 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 AUG PY 2009 VL 27 IS 8 BP 735 EP 741 DI 10.1038/nbt.1558 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 480YY UT WOS:000268774500023 PM 19668183 ER PT J AU Benjamin, EJ Rice, KM Arking, DE Pfeufer, A van Noord, C Smith, AV Schnabel, RB Bis, JC Boerwinkle, E Sinner, MF Dehghan, A Lubitz, SA D'Agostino, RB Lumley, T Ehret, GB Heeringa, J Aspelund, T Newton-Cheh, C Larson, MG Marciante, KD Soliman, EZ Rivadeneira, F Wang, TJ Eiriksdottir, G Levy, D Psaty, BM Li, M Chamberlain, AM Hofman, A Vasan, RS Harris, TB Rotter, JI Kao, WHL Agarwal, SK Stricker, BHC Wang, K Launer, LJ Smith, NL Chakravarti, A Uitterlinden, AG Wolf, PA Sotoodehnia, N Kottgen, A van Duijn, CM Meitinger, T Mueller, M Perz, S Steinbeck, G Wichmann, HE Lunetta, KL Heckbert, SR Gudnason, V Alonso, A Kaab, S Ellinor, PT Witteman, JCM AF Benjamin, Emelia J. Rice, Kenneth M. Arking, Dan E. Pfeufer, Arne van Noord, Charlotte Smith, Albert V. Schnabel, Renate B. Bis, Joshua C. Boerwinkle, Eric Sinner, Moritz F. Dehghan, Abbas Lubitz, Steven A. D'Agostino, Ralph B., Sr. Lumley, Thomas Ehret, Georg B. Heeringa, Jan Aspelund, Thor Newton-Cheh, Christopher Larson, Martin G. Marciante, Kristin D. Soliman, Elsayed Z. Rivadeneira, Fernando Wang, Thomas J. Eiriksdottir, Gudny Levy, Daniel Psaty, Bruce M. Li, Man Chamberlain, Alanna M. Hofman, Albert Vasan, Ramachandran S. Harris, Tamara B. Rotter, Jerome I. Kao, W. H. Linda Agarwal, Sunil K. Stricker, Bruno H. Ch Wang, Ke Launer, Lenore J. Smith, Nicholas L. Chakravarti, Aravinda Uitterlinden, Andre G. Wolf, Philip A. Sotoodehnia, Nona Koettgen, Anna van Duijn, Cornelia M. Meitinger, Thomas Mueller, Martina Perz, Siegfried Steinbeck, Gerhard Wichmann, H-Erich Lunetta, Kathryn L. Heckbert, Susan R. Gudnason, Vilmundur Alonso, Alvaro Kaeaeb, Stefan Ellinor, Patrick T. Witteman, Jacqueline C. M. TI Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry SO NATURE GENETICS LA English DT Article ID TRANSCRIPTION FACTOR ATBF1; LIFETIME RISK; DIFFERENTIATION; PREVALENCE AB We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)). C1 [Benjamin, Emelia J.; Schnabel, Renate B.; D'Agostino, Ralph B., Sr.; Newton-Cheh, Christopher; Larson, Martin G.; Wang, Thomas J.; Levy, Daniel; Vasan, Ramachandran S.; Wolf, Philip A.; Lunetta, Kathryn L.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Benjamin, Emelia J.; Levy, Daniel; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.; Levy, Daniel; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Rice, Kenneth M.; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Arking, Dan E.; Ehret, Georg B.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Pfeufer, Arne; Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Dept Human Genet, D-8000 Munich, Germany. [Pfeufer, Arne] German Natl Res Ctr Environm Hlth, Helmholtz Ctr Munich, Dept Human Genet, Munich, Germany. [van Noord, Charlotte; Dehghan, Abbas; Heeringa, Jan; Rivadeneira, Fernando; Hofman, Albert; Stricker, Bruno H. Ch; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [van Noord, Charlotte] Dutch Med Evaluat Board, The Hague, Netherlands. [van Noord, Charlotte; Witteman, Jacqueline C. M.] Netherlands Consortium Healthy Aging, Leiden, Netherlands. [Smith, Albert V.; Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Schnabel, Renate B.] Johannes Gutenberg Univ Mainz, Gutenberg Heart Study, Med Clin Cardiol 2, Mainz, Germany. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA 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. [Sinner, Moritz F.; Mueller, Martina; Steinbeck, Gerhard; Kaeaeb, Stefan] Univ Munich, Klinikum Grosshadern, Dept Med 1, D-8000 Munich, Germany. [Lubitz, Steven A.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Lubitz, Steven A.; Newton-Cheh, Christopher; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [D'Agostino, Ralph B., Sr.; Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Marciante, Kristin D.; Psaty, Bruce M.; Sotoodehnia, Nona] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Marciante, Kristin D.] Univ Washington, Dept Gen Internal Med, Seattle, WA 98195 USA. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. [Rivadeneira, Fernando; Stricker, Bruno H. Ch; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Psaty, Bruce M.; Smith, Nicholas L.; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Ctr Hlth Studies, Grp Hlth, Washington, DC USA. [Li, Man; Kao, W. H. Linda; Koettgen, Anna] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Chamberlain, Alanna M.; Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Harris, Tamara B.; Launer, Lenore J.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Agarwal, Sunil K.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Stricker, Bruno H. Ch] Inspectorate Hlth Care, The Hague, Netherlands. [Wang, Ke; Lunetta, Kathryn L.] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs, Off Res & Dev, Seattle, WA USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Clin Chem, Rotterdam, Netherlands. [Wolf, Philip A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [Mueller, Martina; Wichmann, H-Erich] Deutsch Forschungszentrum Gesundheit & Umwelt, Inst Epidemiol, Helmholtz Zentrum Munchen, Munich, Germany. [Perz, Siegfried] Deutsch Forschungszentrum Gesundheit & Umwelt Gmb, Inst Med Informat, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Ellinor, Patrick T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv, Boston, MA USA. RP Benjamin, EJ (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM emelia@bu.edu; j.witteman@erasmusmc.nl RI Smith, Albert/K-5150-2015; Rivadeneira, Fernando/O-5385-2015; Alonso, Alvaro/A-4917-2010; Soliman, Elsayed/D-8124-2011; Aspelund, Thor/F-4826-2011; EHRET, Georg/A-9532-2009; Kottgen, Anna/D-2920-2012; Kaab, Stefan/H-3915-2012; Rice, Kenneth/A-4150-2013; Pfeufer, Arne/B-6634-2013; Aspelund, Thor/C-5983-2008; Schnabel, Renate/F-6527-2014; Gudnason, Vilmundur/K-6885-2015; Meitinger, Thomas/O-1318-2015 OI Smith, Albert/0000-0003-1942-5845; Lunetta, Kathryn/0000-0002-9268-810X; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Dehghan, Abbas/0000-0001-6403-016X; Rivadeneira, Fernando/0000-0001-9435-9441; Alonso, Alvaro/0000-0002-2225-8323; Soliman, Elsayed/0000-0001-5632-8150; EHRET, Georg/0000-0002-5730-0675; Rice, Kenneth/0000-0001-5779-4495; Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; FU NCRR NIH HHS [M01 RR000069, M01 RR000425-30S1, UL1 RR025005]; NHGRI NIH HHS [U01 HG004402, U01 HG004402-01]; NHLBI NIH HHS [N01HC85086, 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 HC085079, N01 HC085080, N01 HC085081, N01 HC085082, N01 HC085083, N01 HC085084, N01 HC085085, N01 HC085086, N01HC25195, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC55222, N01HC75150, N01HC85079, N02 HL64278, R01 HL059367, R01 HL059367-02, R01 HL076784, R01 HL076784-01, R01 HL080124, R01 HL080124-01, R01 HL086694, R01 HL086694-01A1, R01 HL086694-02, R01 HL087641, R01 HL087641-01, R01 HL087652, R01 HL087652-01, R01 HL088456, R01 HL088456-01, R01 HL092577, R01 HL092577-01A1, R01 HL093328, R01 HL093328-01, R01 HL104156, T32 HL007575, T32 HL007575-23, U01 HL080295, U01 HL080295-01]; NIA NIH HHS [N01 AG012100, N01AG12100, R01 AG028321, R01 AG028321-01]; NIDDK NIH HHS [P30 DK063491, P30 DK063491-019004, P30 DK063491-029004, P30 DK063491-039004, P30 DK063491-049004, P30 DK063491-05, P30 DK063491-06, R01 DK033651]; NINDS NIH HHS [R01 NS017950, R01 NS017950-23] NR 14 TC 196 Z9 198 U1 0 U2 10 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 AUG PY 2009 VL 41 IS 8 BP 879 EP 881 DI 10.1038/ng.416 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 476IM UT WOS:000268432900008 PM 19597492 ER PT J AU Murga, M Bunting, S Montana, MF Soria, R Mulero, F Canamero, M Lee, Y McKinnon, PJ Nussenzweig, A Fernandez-Capetillo, O AF Murga, Matilde Bunting, Samuel Montana, Maria F. Soria, Rebeca Mulero, Francisca Canamero, Marta Lee, Youngsoo McKinnon, Peter J. Nussenzweig, Andre Fernandez-Capetillo, Oscar TI A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging SO NATURE GENETICS LA English DT Article ID HEMATOPOIETIC STEM-CELLS; DNA-DAMAGE RESPONSE; ATAXIA-TELANGIECTASIA; CHROMOSOME INSTABILITY; DEFICIENT MICE; GENE ATR; CHECKPOINT; AGE; LEADS; P53 AB Although DNA damage is considered a driving force for aging, the nature of the damage that arises endogenously remains unclear. Replicative stress, a source of endogenous DNA damage, is prevented primarily by the ATR kinase. We have developed a mouse model of Seckel syndrome characterized by a severe deficiency in ATR. Seckel mice show high levels of replicative stress during embryogenesis, when proliferation is widespread, but this is reduced to marginal amounts in postnatal life. In spite of this decrease, adult Seckel mice show accelerated aging, which is further aggravated in the absence of p53. Together, these results support a model whereby replicative stress, particularly in utero, contributes to the onset of aging in postnatal life, and this is balanced by the replicative stress-limiting role of the checkpoint proteins ATR and p53. C1 [Murga, Matilde; Montana, Maria F.; Soria, Rebeca; Fernandez-Capetillo, Oscar] Spanish Natl Canc Res Ctr CNIO, Genom Instabil Grp, Madrid, Spain. [Bunting, Samuel; Nussenzweig, Andre] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Mulero, Francisca] CNIO, Mol Imaging Unit, Madrid, Spain. [Canamero, Marta] CNIO, Comparat Pathol Unit, Madrid, Spain. [Lee, Youngsoo; McKinnon, Peter J.] St Jude Childrens Hosp, Dept Genet & Tumor Cell Biol, Memphis, TN 38105 USA. RP Murga, M (reprint author), Spanish Natl Canc Res Ctr CNIO, Genom Instabil Grp, Madrid, Spain. EM mmurga@cnio.es; ofernandez@cnio.es RI Mulero, Francisca/M-3289-2014; Fernandez-Capetillo, Oscar/H-3508-2015 OI Mulero, Francisca/0000-0001-9584-4211; Fernandez-Capetillo, Oscar/0000-0002-2690-6885 FU Spanish Ministry of Science [RYC-2003-002731, CSD200700017, SAF2008-01596]; Fondo de Investigaciones Sanitarias [PI080220]; European Molecular Biology Organization Young Investigator Programme; European Research Council [ERC-210520]; Epigenome Network of Excellence FX We thank M. Serrano and A. Ramiro for critical comments on the manuscript. We also thank S. P. Jackson for his help with the PIKK inhibitors and A. Garcia for cytometry. M. M. is supported by a Ramon y Cajal contract from the Spanish Ministry of Science (RYC-2003-002731) and from a grant from Fondo de Investigaciones Sanitarias (PI080220). Work in O. F.-C.' s laboratory is supported by grants from the Spanish Ministry of Science (RYC-2003-002731, CSD200700017 and SAF2008-01596), European Molecular Biology Organization Young Investigator Programme, European Research Council (ERC-210520) and Epigenome Network of Excellence. NR 50 TC 150 Z9 152 U1 3 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 AUG PY 2009 VL 41 IS 8 BP 891 EP U46 DI 10.1038/ng.420 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 476IM UT WOS:000268432900012 PM 19620979 ER PT J AU Bishop, DT Demenais, F Iles, MM Harland, M Taylor, JC Corda, E Randerson-Moor, J Aitken, JF Avril, MF Azizi, E Bakker, B Bianchi-Scarra, G Bressac-de Paillerets, B Calista, D Cannon-Albright, LA Chin-A-Woeng, T Debniak, T Galore-Haskel, G Ghiorzo, P Gut, I Hansson, J Hocevar, M Hoiom, V Hopper, JL Ingvar, C Kanetsky, PA Kefford, RF Landi, MT Lang, J Lubinski, J Mackie, R Malvehy, J Mann, GJ Martin, NG Montgomery, GW van Nieuwpoort, FA Novakovic, S Olsson, H Puig, S Weiss, M van Workum, W Zelenika, D Brown, KM Goldstein, AM Gillanders, EM Boland, A Galan, P Elder, DE Gruis, NA Hayward, NK Lathrop, GM Barrett, JH Bishop, JAN AF Bishop, D. Timothy Demenais, Florence Iles, Mark M. Harland, Mark Taylor, John C. Corda, Eve Randerson-Moor, Juliette Aitken, Joanne F. Avril, Marie-Francoise Azizi, Esther Bakker, Bert Bianchi-Scarra, Giovanna Bressac-de Paillerets, Brigitte Calista, Donato Cannon-Albright, Lisa A. Chin-A-Woeng, Thomas Debniak, Tadeusz Galore-Haskel, Gilli Ghiorzo, Paola Gut, Ivo Hansson, Johan Hocevar, Marko Hoiom, Veronica Hopper, John L. Ingvar, Christian Kanetsky, Peter A. Kefford, Richard F. Landi, Maria Teresa Lang, Julie Lubinski, Jan Mackie, Rona Malvehy, Josep Mann, Graham J. Martin, Nicholas G. Montgomery, Grant W. van Nieuwpoort, Frans A. Novakovic, Srdjan Olsson, Hakan Puig, Susana Weiss, Marjan van Workum, Wilbert Zelenika, Diana Brown, Kevin M. Goldstein, Alisa M. Gillanders, Elizabeth M. Boland, Anne Galan, Pilar Elder, David E. Gruis, Nelleke A. Hayward, Nicholas K. Lathrop, G. Mark Barrett, Jennifer H. Bishop, Julia A. Newton TI Genome-wide association study identifies three loci associated with melanoma risk SO NATURE GENETICS LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; MULTIPLE PRIMARY MELANOMAS; SUN EXPOSURE; PHENOTYPIC CHARACTERISTICS; CDKN2A MUTATIONS; FAMILY-HISTORY; MC1R VARIANTS; GENES; SUSCEPTIBILITY; WOMEN AB We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317K tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional two cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genome-wide screen identified five loci with genotyped or imputed SNPs reaching P < 5 x 10(-7). Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 x 10(-27) for rs258322), 11q14-q21 encompassing TYR (P = 2.41 x 10(-14) for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 x 10(-7) for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognized melanoma risk factors. Common variants within the 9p21 locus have not previously been associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk. C1 [Bishop, D. Timothy; Iles, Mark M.; Harland, Mark; Taylor, John C.; Randerson-Moor, Juliette; Barrett, Jennifer H.; Bishop, Julia A. Newton] St James Univ Hosp, Epidemiol & Biostat Sect, Leeds Inst Mol Med, Canc Res UK Clin Ctr Leeds, Leeds LS9 7TF, W Yorkshire, England. [Demenais, Florence; Corda, Eve] Fdn Jean Dausset CEPH, INSERM, U946, F-75010 Paris, France. [Aitken, Joanne F.] Canc Council, Viertel Ctr Res Canc Control, Brisbane, Qld, Australia. [Avril, Marie-Francoise] Hop Cochin, AP HP, Fac Paris 5, Serv Dermatol, F-75674 Paris, France. [Azizi, Esther; Galore-Haskel, Gilli] Tel Aviv Univ, Sackler Fac Med, Sheba Med Ctr, Dept Dermatol, IL-52621 Tel Hashomer, Israel. [Bakker, Bert; Weiss, Marjan] Leiden Univ, Dept Clin Genet, Ctr Human & Clin Genet, Med Ctr, Leiden, Netherlands. [Bianchi-Scarra, Giovanna; Ghiorzo, Paola] Univ Genoa, Dept Oncol Biol & Genet, Genoa, Italy. [Bressac-de Paillerets, Brigitte] CNRS, Inst Canc Gustave Roussy, Serv Genet, FRE 2939, Villejuif, France. [Calista, Donato] Maurizio Bufalini Hosp, Dermatol Unit, Cesena, Italy. [Cannon-Albright, Lisa A.] Univ Utah, Salt Lake City, UT USA. [Chin-A-Woeng, Thomas; van Workum, Wilbert] ServiceXS, NL-2333 BZ Leiden, Netherlands. [Debniak, Tadeusz; Lubinski, Jan] Pomeranian Med Univ, Int Hereditary Canc Ctr, Szczecin, Poland. [Gut, Ivo; Zelenika, Diana; Boland, Anne; Lathrop, G. Mark] Ctr Natl Genotypage, Inst Genom, Commissariat Energie Atorn, Evry, France. [Hansson, Johan; Hoiom, Veronica] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Hocevar, Marko; Novakovic, Srdjan] Inst Oncol Ljubljana, Ljubljana, Slovenia. [Hopper, John L.] Univ Melbourne, Sch Populat Hlth, Ctr Mol Environm Genet & Analyt MEGA Epidemiol, Melbourne, Vic 3010, Australia. [Ingvar, Christian; Olsson, Hakan] Univ Lund Hosp, Dept Oncol, S-22185 Lund, Sweden. [Kanetsky, Peter A.] Univ Penn, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kefford, Richard F.; Mann, Graham J.] Univ Sydney, Westmead Inst Canc Res, Westmead Millennium Inst, Westmead, NSW 2145, Australia. [Kefford, Richard F.; Mann, Graham J.] Melanoma Inst Australia, Westmead, NSW, Australia. [Landi, Maria Teresa; Goldstein, Alisa M.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lang, Julie; Mackie, Rona] Univ Glasgow, Dept Med Genet, Glasgow G12 8QQ, Lanark, Scotland. [Mackie, Rona] Univ Glasgow, Dept Publ Hlth & Hlth Policy, Glasgow G12 8QQ, Lanark, Scotland. [Malvehy, Josep; Puig, Susana] Hosp Clin Barcelona, Melanoma Unit, Dept Dermatol, IDIBAPS, E-08036 Barcelona, Spain. [Malvehy, Josep; Puig, Susana] CIBER Enfermedades Raras, Barcelona, Spain. [Martin, Nicholas G.; Montgomery, Grant W.; Hayward, Nicholas K.] Queensland Inst Med Res, Herston, Qld 4006, Australia. [van Nieuwpoort, Frans A.; Gruis, Nelleke A.] Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. [Brown, Kevin M.] Translat Genom Res Inst, Melanoma Genom Lab, Phoenix, AZ USA. [Gillanders, Elizabeth M.] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Galan, Pilar] CRNH Idf, INSERM, INRA, CNAM,UMR U557,U1125, Bobigny, France. [Elder, David E.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Bishop, DT (reprint author), St James Univ Hosp, Epidemiol & Biostat Sect, Leeds Inst Mol Med, Canc Res UK Clin Ctr Leeds, Leeds LS9 7TF, W Yorkshire, England. EM d.t.bishop@leeds.ac.uk RI Aitken, Joanne/C-5289-2009; Bakker, Egbert/D-3525-2009; Mann, Graham/G-4758-2014; Bianchi Scarra, Giovanna/G-8933-2014; Demenais, Florence/G-3298-2013; hayward, nicholas/C-1367-2015; Montgomery, Grant/B-7148-2008; Hoiom, Veronica/F-4153-2012; OI Bishop, Tim/0000-0002-8752-8785; Bakker, Egbert/0000-0002-2843-7357; Mann, Graham/0000-0003-1301-405X; Bianchi Scarra, Giovanna/0000-0002-6127-1192; Demenais, Florence/0000-0001-8361-0936; hayward, nicholas/0000-0003-4760-1033; Montgomery, Grant/0000-0002-4140-8139; Gruis, Nelleke/0000-0002-5210-9150; Barrett, Jenny/0000-0002-1720-7724; albright, lisa/0000-0003-2602-3668; Newton Bishop, Julia/0000-0001-9147-6802; Puig, Susana/0000-0003-1337-9745; , Srdjan/0000-0002-8888-4810; Martin, Nicholas/0000-0003-4069-8020 FU Cancer Research UK [A4994, C588/A4994]; Intramural NIH HHS; NCI NIH HHS [CA88363, R0-1 CA 83115, R01 CA083115, R01 CA083115-08, R01 CA102422, R01 CA5558, R01 ROI CA83115] NR 42 TC 229 Z9 231 U1 3 U2 26 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 AUG PY 2009 VL 41 IS 8 BP 920 EP U85 DI 10.1038/ng.411 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 476IM UT WOS:000268432900018 PM 19578364 ER PT J AU Jin, CY Zang, CZ Wei, G Cui, KR Peng, WQ Zhao, KJ Felsenfeld, G AF Jin, Chunyuan Zang, Chongzhi Wei, Gang Cui, Kairong Peng, Weiqun Zhao, Keji Felsenfeld, Gary TI H3.3/H2A.Z double variant-containing nucleosomes mark 'nucleosome-free regions' of active promoters and other regulatory regions SO NATURE GENETICS LA English DT Article ID GENOME-WIDE; SACCHAROMYCES-CEREVISIAE; HISTONE MODIFICATIONS; GENE-EXPRESSION; HUMAN-CELLS; CHROMATIN; H2A.Z; H3.3; IDENTIFICATION; OCCUPANCY AB To understand how chromatin structure is organized by different histone variants, we have measured the genome-wide distribution of nucleosome core particles (NCPs) containing the histone variants H3.3 and H2A.Z in human cells. We find that a special class of NCPs containing both variants is enriched at 'nucleosome-free regions' of active promoters, enhancers and insulator regions. We show that preparative methods used previously in studying nucleosome structure result in the loss of these unstable double-variant NCPs. It seems likely that this instability facilitates the access of transcription factors to promoters and other regulatory sites in vivo. Other combinations of variants have different distributions, consistent with distinct roles for histone variants in the modulation of gene expression. C1 [Wei, Gang; Cui, Kairong; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Jin, Chunyuan; Felsenfeld, Gary] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Zang, Chongzhi; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. RP Zhao, KJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov; gary.felsenfeld@nih.gov RI Wei, Gang/A-3291-2011; Zang, Chongzhi/D-1445-2011 FU Intramural Research Programs of the National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases FX We thank H. Tagami, Y. Nakatani and G. Almouzni for H3.3- Flag cells, T. Roh, D. E. Schones and P. Khil for Solexa pipeline analysis and S. Sharmeen and G. Poy for Solexa sequencing. We also acknowledge members of the Felsenfeld laboratory for criticism of the manuscript. This research was supported by the Intramural Research Programs of the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases. NR 38 TC 378 Z9 384 U1 4 U2 16 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 AUG PY 2009 VL 41 IS 8 BP 941 EP U112 DI 10.1038/ng.409 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 476IM UT WOS:000268432900022 PM 19633671 ER PT J AU Johnson, AL Aravind, L Shulzhenko, N Morgun, A Choi, SY Crockford, TL Lambe, T Domaschenz, H Kucharska, EM Zheng, LX Vinuesa, CG Lenardo, MJ Goodnow, CC Cornall, RJ Schwartz, RH AF Johnson, Andy L. Aravind, L. Shulzhenko, Natalia Morgun, Andre Choi, See-Young Crockford, Tanya L. Lambe, Teresa Domaschenz, Heather Kucharska, Edyta M. Zheng, Lixin Vinuesa, Carola G. Lenardo, Michael J. Goodnow, Christopher C. Cornall, Richard J. Schwartz, Ronald H. TI Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection SO NATURE IMMUNOLOGY LA English DT Article ID T-CELL DEVELOPMENT; RECEPTOR TRANSGENIC MICE; NF-KAPPA-B; LINEAGE COMMITMENT; TARGET GENE; PROTEIN; AUTOIMMUNE; EXPRESSION; TOLERANCE; DELETION AB T cell antigen receptor (TCR) signaling in CD4(+)CD8(+) double-positive thymocytes determines cell survival and lineage commitment, but the genetic and molecular basis of this process is poorly defined. To address this issue, we used ethylnitrosourea mutagenesis to identify a previously unknown T lineage-specific gene, Themis, which is critical for the completion of positive selection. Themis contains a tandem repeat of a unique globular domain (called 'CABIT' here) that includes a cysteine motif that defines a family of five uncharacterized vertebrate proteins with orthologs in most animal species. Themis-deficient thymocytes showed no substantial impairment in early TCR signaling but did show altered expression of genes involved in the cell cycle and survival before and during positive selection. Our data suggest a unique function for Themis in sustaining positive selection. C1 [Johnson, Andy L.; Crockford, Tanya L.; Lambe, Teresa; Cornall, Richard J.] Univ Oxford, Nuffield Dept Clin Med, Oxford, England. [Johnson, Andy L.; Shulzhenko, Natalia; Morgun, Andre; Choi, See-Young; Schwartz, Ronald H.] NIAID, Cellular & Mol Immunol Lab, Bethesda, MD 20892 USA. [Aravind, L.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Domaschenz, Heather; Kucharska, Edyta M.; Vinuesa, Carola G.; Goodnow, Christopher C.] Australian Natl Univ, John Curtin Sch Med Res, Genet Lab, Australian Canc Res Fdn, Canberra, ACT 2601, Australia. [Domaschenz, Heather; Kucharska, Edyta M.; Vinuesa, Carola G.; Goodnow, Christopher C.] Australian Phen Facil, Canberra, ACT, Australia. [Zheng, Lixin; Lenardo, Michael J.] NIH, Immunol Lab, Bethesda, MD 20892 USA. RP Cornall, RJ (reprint author), Univ Oxford, Nuffield Dept Clin Med, Oxford, England. EM richard.cornall@ndm.ox.ac.uk; rschwartz@niaid.nih.gov RI Vinuesa, Carola/B-1108-2010; Lambe, Teresa/E-5733-2016 OI Vinuesa, Carola/0000-0001-9799-0298; Lambe, Teresa/0000-0001-7711-897X FU Intramural NIH HHS [Z01 AI000485-21]; Medical Research Council [, G0700830]; Wellcome Trust NR 49 TC 55 Z9 60 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2009 VL 10 IS 8 BP 831 EP U52 DI 10.1038/ni.1769 PG 11 WC Immunology SC Immunology GA 472OM UT WOS:000268141400011 PM 19597497 ER PT J AU Lesourne, R Uehara, S Lee, J Song, KD Li, LQ Pinkhasov, J Zhang, YQ Weng, NP Wildt, KF Wang, L Bosselut, R Love, PE AF Lesourne, Renaud Uehara, Shoji Lee, Jan Song, Ki-Duk Li, LiQi Pinkhasov, Julia Zhang, Yongqing Weng, Nan-Ping Wildt, Kathryn F. Wang, Lie Bosselut, Remy Love, Paul E. TI Themis, a T cell-specific protein important for late thymocyte development SO NATURE IMMUNOLOGY LA English DT Article ID CD4-CD8 LINEAGE COMMITMENT; POSITIVE SELECTION SIGNALS; IN-VIVO; CORECEPTOR EXPRESSION; TRANSCRIPTION FACTORS; DIFFERENTIATION; CD4; TCR; RECEPTOR; THYMUS AB During positive selection, thymocytes transition through a stage during which T cell antigen receptor (TCR) signaling controls CD4-versus-CD8 lineage 'choice' and subsequent maturation. Here we describe a previously unknown T cell-specific protein, Themis, that serves a distinct function during this stage. In Themis(-/-) mice, thymocyte selection was impaired and the number of transitional CD4(+)CD8(int) thymocytes as well as CD4(+) or CD8(+) single-positive thymocytes was lower. Notably, although we detected no overt TCR-proximal signaling deficiencies, Themis(-/-) CD4(+)CD8(int) thymocytes showed developmental defects consistent with attenuated signaling that were reversible by TCR stimulation. Our results identify Themis as a critical component of the T cell developmental program and suggest that Themis functions to sustain and/or integrate signals required for proper lineage commitment and maturation. C1 [Lesourne, Renaud; Uehara, Shoji; Lee, Jan; Song, Ki-Duk; Li, LiQi; Pinkhasov, Julia; Love, Paul E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mammalian Genes & Dev, Bethesda, MD USA. [Zhang, Yongqing] NIMH, Intramural Res Program, DNA Array Unit, Bethesda, MD 20892 USA. [Weng, Nan-Ping] NIA, Immunol Lab, Bethesda, MD 20892 USA. [Wildt, Kathryn F.; Wang, Lie; Bosselut, Remy] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Love, PE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mammalian Genes & Dev, Bethesda, MD USA. EM lovep@mail.nih.gov RI Lesourne, Renaud/M-1855-2014 FU Intramural NIH HHS [Z01 AG000757-10] NR 37 TC 60 Z9 62 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2009 VL 10 IS 8 BP 840 EP U53 DI 10.1038/ni.1768 PG 9 WC Immunology SC Immunology GA 472OM UT WOS:000268141400012 PM 19597498 ER PT J AU Haigwood, NL Hirsch, VM AF Haigwood, Nancy L. Hirsch, Vanessa M. TI Blocking and tackling HIV SO NATURE MEDICINE LA English DT Editorial Material ID NEUTRALIZING ANTIBODIES; VIRUS; PLASMA AB Two studies suggest that low levels of antibodies, when present continuously, effectively limit or prevent HIV infection (pages 951-954 and 901-906). The findings provide hope for the development of a vaccine. C1 [Haigwood, Nancy L.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Hirsch, Vanessa M.] NIAID, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Haigwood, NL (reprint author), Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR USA. EM haigwood@ohsu.edu NR 12 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2009 VL 15 IS 8 BP 841 EP 842 DI 10.1038/nm0809-841 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 480XK UT WOS:000268770400019 PM 19661984 ER PT J AU Sodora, DL Allan, JS Apetrei, C Brenchley, JM Douek, DC Else, JG Estes, JD Hahn, BH Hirsch, VM Kaur, A Kirchhoff, F Muller-Trutwin, M Pandrea, I Schmitz, JE Silvestri, G AF Sodora, Donald L. Allan, Jonathan S. Apetrei, Cristian Brenchley, Jason M. Douek, Daniel C. Else, James G. Estes, Jacob D. Hahn, Beatrice H. Hirsch, Vanessa M. Kaur, Amitinder Kirchhoff, Frank Muller-Trutwin, Michaela Pandrea, Ivona Schmitz, Joern E. Silvestri, Guido TI Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts SO NATURE MEDICINE LA English DT Article ID T-CELL DEPLETION; SOOTY MANGABEY MONKEYS; GREEN MONKEYS; SIV INFECTION; IMMUNE ACTIVATION; VIRAL REPLICATION; MANDRILLUS-SPHINX; HIV; RESPONSES; DISEASE AB The design of an effective AIDS vaccine has eluded the efforts of the scientific community to the point that alternative approaches to classic vaccine formulations have to be considered. We propose here that HIV vaccine research could greatly benefit from the study of natural simian immunodeficiency virus (SIV) infections of African nonhuman primates. Natural SIV hosts (for example, sooty mangabeys, African green monkeys and mandrills) share many features of HIV infection of humans; however, they usually do not develop immunodeficiency. These natural, nonprogressive SIV infections represent an evolutionary adaptation that allows a peaceful coexistence of primate lentiviruses and the host immune system. This adaptation does not result in reduced viral replication but, rather, involves phenotypic changes to CD4(+) T cell subsets, limited immune activation and preserved mucosal immunity, all of which contribute to the avoidance of disease progression and, possibly, to the reduction of vertical SIV transmission. Here we summarize the current understanding of SIV infection of African nonhuman primates and discuss how unraveling these evolutionary adaptations may provide clues for new vaccine designs that might induce effective immune responses without the harmful consequences of excessive immune activation. (C) 2009 Nature America, Inc. All rights reserved. C1 [Else, James G.; Silvestri, Guido] Yerkes Natl Primate Res Ctr, Atlanta, GA USA. [Sodora, Donald L.] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Allan, Jonathan S.] SW Natl Primate Res Ctr, San Antonio, TX USA. [Apetrei, Cristian; Pandrea, Ivona] Tulane Univ, Tulane Natl Primate Res Ctr, Covington, LA USA. [Apetrei, Cristian; Pandrea, Ivona] Univ Pittsburgh, Ctr Vaccine Res, Pittsburgh, PA USA. [Brenchley, Jason M.; Hirsch, Vanessa M.] NIAID, Mol Microbiol Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Douek, Daniel C.] Vaccine Res Ctr, Atlanta, GA USA. [Estes, Jacob D.] US Natl Canc Inst, Frederick, MD USA. [Hahn, Beatrice H.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Hahn, Beatrice H.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Kaur, Amitinder] Harvard Univ, Sch Med, New England Primate Res Ctr, Southborough, MA 01772 USA. [Kirchhoff, Frank] Univ Ulm, Inst Mol Virol, Ulm, Germany. [Muller-Trutwin, Michaela] Inst Pasteur, Unite Regulat Infect Retrovirales, Paris, France. [Schmitz, Joern E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Viral Pathogenesis, Boston, MA 02215 USA. [Silvestri, Guido] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Silvestri, G (reprint author), Yerkes Natl Primate Res Ctr, Atlanta, GA USA. EM gsilvest@mail.med.upenn.edu FU Intramural NIH HHS [Z99 AI999999]; NIAID NIH HHS [R01 AI065335] NR 51 TC 139 Z9 141 U1 1 U2 10 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 AUG PY 2009 VL 15 IS 8 BP 861 EP 865 DI 10.1038/nm.2013 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 480XK UT WOS:000268770400026 PM 19661993 ER PT J AU Stamatatos, L Morris, L Burton, DR Mascola, JR AF Stamatatos, Leonidas Morris, Lynn Burton, Dennis R. Mascola, John R. TI Neutralizing antibodies generated during natural HIV-1 infection: good news for an HIV-1 vaccine? SO NATURE MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CORECEPTOR BINDING-SITE; MONOCLONAL-ANTIBODIES; SERUM NEUTRALIZATION; CHIMERIC VIRUS; ENV CLONES; IN-VITRO; GLYCOPROTEIN; PROTECTION; MACAQUES AB Most existing viral vaccines generate antibodies that either block initial infection or help eradicate the virus before it can cause disease. For HIV-1, obstacles to eliciting protective neutralizing antibodies (NAbs) have often seemed insurmountable. The target of HIV-specific NAbs, the viral envelope glycoprotein (Env), is highly variable in amino acid sequence and glycosylation pattern. Conserved elements of HIV-1 Env seem to be poorly immunogenic, and previous attempts to generate broadly reactive NAbs by vaccination have proven ineffective. However, recent studies show that in the sera of some HIV-1-infected individuals can neutralize diverse HIV-1 isolates. Detailed analyses of these sera provide new insights into the viral epitopes targeted by broadly reactive NAbs. The findings discussed here suggest that the natural NAb response to HIV-1 can inform future vaccine design. A concerted effort of structure-based vaccine design will help guide the development of improved antibody-based vaccines for HIV-1. C1 [Stamatatos, Leonidas] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Stamatatos, Leonidas] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Morris, Lynn] Natl Inst Communicable Dis, AIDS Virus Res Unit, Johannesburg, South Africa. [Morris, Lynn] Ctr AIDS Programme Res S Africa, Johannesburg, South Africa. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Mascola, John R.] NIAID, Vaccine Res Ctr, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Stamatatos, L (reprint author), Seattle Biomed Res Inst, 4 Nickerson St, Seattle, WA 98109 USA. EM leo.stamatatos@sbri.org OI , Lynn/0000-0003-3961-7828 NR 46 TC 272 Z9 279 U1 1 U2 18 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 AUG PY 2009 VL 15 IS 8 BP 866 EP 870 DI 10.1038/nm.1949 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 480XK UT WOS:000268770400027 PM 19525964 ER PT J AU Beaumier, CM Harris, LD Goldstein, S Klatt, NR Whitted, S McGinty, J Apetrei, C Pandrea, I Hirsch, VM Brenchley, JM AF Beaumier, Coreen M. Harris, Levelle D. Goldstein, Simoy Klatt, Nichole R. Whitted, Sonya McGinty, John Apetrei, Cristian Pandrea, Ivona Hirsch, Vanessa M. Brenchley, Jason M. TI CD4 downregulation by memory CD4(+) T cells in vivo renders African green monkeys resistant to progressive SIVagm infection SO NATURE MEDICINE LA English DT Article ID SIMIAN-IMMUNODEFICIENCY-VIRUS; NONHUMAN PRIMATE HOSTS; SOOTY MANGABEYS; MICROBIAL TRANSLOCATION; NATURAL HOSTS; PLASMA LIPOPOLYSACCHARIDE; AIDS PATHOGENESIS; IMMUNE ACTIVATION; CORECEPTOR USAGE; HIV-INFECTION AB African green monkeys (genus Chlorocebus) can be infected with species-specific simian immunodeficiency virus (SIVagm) but do not develop AIDS. These natural hosts of SIV, like sooty mangabeys, maintain high levels of SIV replication but have evolved to avoid immunodeficiency. Elucidating the mechanisms that allow natural hosts to coexist with SIV without overt disease may provide crucial information for understanding AIDS pathogenesis. Here we show that many CD4(+) T cells from African green monkeys downregulate CD4 in vivo as they enter the memory pool; that downregulation of CD4 by memory T cells is independent of SIV infection; that the CD4(-) memory T cells maintain functions that are normally attributed to CD4(+) T cells, including production of interleukin-2 (IL-2), production of IL-17, expression of forkhead box P3 and expression of CD40 ligand; that loss of CD4 expression protects these T cells from infection by SIVagm in vivo; and that these CD4(-) T cells can maintain major histocompatibility complex class II restriction. These data show that the absence of SIV-induced disease progression in natural host species may be partially explained by preservation of a subset of T cells that maintain CD4(+) T cell function while being resistant to SIV infection in vivo. (C) 2009 Nature America, Inc. All rights reserved. C1 [Beaumier, Coreen M.; Harris, Levelle D.; Goldstein, Simoy; Klatt, Nichole R.; Whitted, Sonya; McGinty, John; Hirsch, Vanessa M.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Apetrei, Cristian; Pandrea, Ivona] Tulane Natl Primate Ctr, Div Comparat Pathol, New Orleans, LA USA. [Apetrei, Cristian; Pandrea, Ivona] Tulane Natl Primate Ctr, Div Microbiol, New Orleans, LA USA. RP Brenchley, JM (reprint author), NIAID, Mol Microbiol Lab, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbrenchl@mail.nih.gov FU intramural National Institute of Allergy and Infectious Diseases; US National Institutes of Health program; Tulane National Primate Center [R01 AI064066, R01 AI065325, RR-00168] FX These studies were supported by the intramural National Institute of Allergy and Infectious Diseases, US National Institutes of Health program and by R01 AI064066 (I. P.), R01 AI065325 (C. A.) and RR-00168 (Tulane National Primate Center). We would like to thank the Bad Boys of Cleveland, D. Douek (Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health) and D. Price (Cardiff University) for helpful discussions. We are grateful to J. E. Schmitz and R. Zahn (Harvard University) for the kind donation of microbeads coated with antibody to CD3 and CD28 for stimulation of T cells from nonhuman primates. We also appreciate the technical advice of B. Lafont and G. Mettler. NR 55 TC 81 Z9 81 U1 0 U2 2 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 AUG PY 2009 VL 15 IS 8 BP 879 EP U75 DI 10.1038/nm.1970 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 480XK UT WOS:000268770400031 PM 19525963 ER PT J AU Chomont, N El-Far, M Ancuta, P Trautmann, L Procopio, FA Yassine-Diab, B Boucher, G Boulassel, MR Ghattas, G Brenchley, JM Schacker, TW Hill, BJ Douek, DC Routy, JP Haddad, EK Sekaly, RP AF Chomont, Nicolas El-Far, Mohamed Ancuta, Petronela Trautmann, Lydie Procopio, Francesco A. Yassine-Diab, Bader Boucher, Genevieve Boulassel, Mohamed-Rachid Ghattas, Georges Brenchley, Jason M. Schacker, Timothy W. Hill, Brenna J. Douek, Daniel C. Routy, Jean-Pierre Haddad, Elias K. Sekaly, Rafick-Pierre TI HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation SO NATURE MEDICINE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS TYPE-1; EFFECTOR MEMORY CD4(+); LATENT RESERVOIR; INFECTED INDIVIDUALS; PROGRAMMED DEATH-1; IMMUNE ACTIVATION; GENE-EXPRESSION; VIRAL LOAD; IN-VIVO AB HIV persists in a reservoir of latently infected CD4(+) T cells in individuals treated with highly active antiretroviral therapy (HAART). Here we identify central memory (T(CM)) and transitional memory (T(TM)) CD4(+) T cells as the major cellular reservoirs for HIV and find that viral persistence is ensured by two different mechanisms. HIV primarily persists in T(CM) cells in subjects showing reconstitution of the CD4(+) compartment upon HAART. This reservoir is maintained through T cell survival and low-level antigen-driven proliferation and is slowly depleted with time. In contrast, proviral DNA is preferentially detected in T(TM) cells from aviremic individuals with low CD4(+) counts and higher amounts of interleukin-7-mediated homeostatic proliferation, a mechanism that ensures the persistence of these cells. Our results suggest that viral eradication might be achieved through the combined use of strategic interventions targeting viral replication and, as in cancer, drugs that interfere with the self renewal and persistence of proliferating memory T cells. (C) 2009 Nature America, Inc. All rights reserved. C1 [Chomont, Nicolas; El-Far, Mohamed; Trautmann, Lydie; Procopio, Francesco A.; Yassine-Diab, Bader; Boucher, Genevieve; Haddad, Elias K.; Sekaly, Rafick-Pierre] CR CHUM St Luc, Immunol Lab, Montreal, PQ, Canada. [Chomont, Nicolas; El-Far, Mohamed; Trautmann, Lydie; Procopio, Francesco A.; Yassine-Diab, Bader; Haddad, Elias K.; Sekaly, Rafick-Pierre] Univ Montreal, Dept Microbiol & Immunol, Immunol Lab, Quebec City, PQ, Canada. [Chomont, Nicolas; El-Far, Mohamed; Ancuta, Petronela; Trautmann, Lydie; Procopio, Francesco A.; Yassine-Diab, Bader; Haddad, Elias K.; Sekaly, Rafick-Pierre] Univ Montreal, CR CHUM, U743, Inst Natl Sante & Rech Med, Montreal, PQ, Canada. [Boulassel, Mohamed-Rachid; Routy, Jean-Pierre] McGill Univ, MUHC, Immunodeficiency Serv, Montreal, PQ, Canada. [Boulassel, Mohamed-Rachid; Routy, Jean-Pierre] McGill Univ, MUHC, Div Hematol, Montreal, PQ, Canada. [Ghattas, Georges] MUHC, Dept Gastroenterol, Montreal, PQ, Canada. [Brenchley, Jason M.] NIAID, Mol Microbiol Lab, US Natl Inst Hlth, Bethesda, MD USA. [Schacker, Timothy W.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Hill, Brenna J.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Routy, Jean-Pierre; Haddad, Elias K.; Sekaly, Rafick-Pierre] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. [Sekaly, Rafick-Pierre] Oregon Hlth & Sci Univ, Dept Microbiol & Immunol, Portland, OR 97201 USA. RP Sekaly, RP (reprint author), CR CHUM St Luc, Immunol Lab, Montreal, PQ, Canada. EM rafick-pierre.sekaly@umontreal.ca OI Boucher, Genevieve/0000-0001-6389-9007 FU Intramural NIH HHS [Z99 AI999999] NR 56 TC 545 Z9 551 U1 8 U2 51 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 AUG PY 2009 VL 15 IS 8 BP 893 EP U92 DI 10.1038/nm.1972 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 480XK UT WOS:000268770400033 PM 19543283 ER PT J AU Meier, A Chang, JJ Chan, ES Pollard, RB Sidhu, HK Kulkarni, S Wen, TF Lindsay, RJ Orellana, L Mildvan, D Bazner, S Streeck, H Alter, G Lifson, JD Carrington, M Bosch, RJ Robbins, GK Altfeld, M AF Meier, Angela Chang, J. Judy Chan, Ellen S. Pollard, Richard B. Sidhu, Harlyn K. Kulkarni, Smita Wen, Tom Fang Lindsay, Robert J. Orellana, Liliana Mildvan, Donna Bazner, Suzane Streeck, Hendrik Alter, Galit Lifson, Jeffrey D. Carrington, Mary Bosch, Ronald J. Robbins, Gregory K. Altfeld, Marcus TI Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1 SO NATURE MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; IFN-ALPHA PRODUCTION; IMMUNE ACTIVATION; VIRAL LOAD; PROGNOSTIC VALUE; SIV INFECTION; RNA LEVELS; T-CELLS; I INTERFERON; SERUM-LEVELS AB Manifestations of viral infections can differ between women and men(1), and marked sex differences have been described in the course of HIV-1 disease. HIV-1-infected women tend to have lower viral loads early in HIV-1 infection but progress faster to AIDS for a given viral load than men(2-7). Here we show substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce markedly more interferon-alpha (IFN-alpha) in response to HIV-1-encoded Toll-like receptor 7 (TLR7) ligands than pDCs derived from men, resulting in stronger secondary activation of CD8(+) T cells. In line with these in vitro studies, treatment-naive women chronically infected with HIV-1 had considerably higher levels of CD8(+) T cell activation than men after adjusting for viral load. These data show that sex differences in TLR-mediated activation of pDCs may account for higher immune activation in women compared to men at a given HIV-1 viral load and provide a mechanism by which the same level of viral replication might result in faster HIV-1 disease progression in women compared to men. Modulation of the TLR7 pathway in pDCs may therefore represent a new approach to reduce HIV-1-associated pathology. C1 [Meier, Angela; Chang, J. Judy; Sidhu, Harlyn K.; Wen, Tom Fang; Lindsay, Robert J.; Bazner, Suzane; Streeck, Hendrik; Alter, Galit; Altfeld, Marcus] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Chan, Ellen S.; Orellana, Liliana; Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Pollard, Richard B.] Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. [Kulkarni, Smita; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD 21701 USA. [Lifson, Jeffrey D.] NCI, Sci Applicat Int Corp Frederick, AIDS & Canc Virus Program, Frederick, MD 21701 USA. [Mildvan, Donna] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Bazner, Suzane; Robbins, Gregory K.; Altfeld, Marcus] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA USA. RP Altfeld, M (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. EM maltfeld@partners.org RI Robbins, Gregory/F-7988-2011; Orellana, Liliana/S-3302-2016 OI Orellana, Liliana/0000-0003-3736-4337 FU US National Institutes of Health (NIH)-National Institute of Allergy Infectious Diseases [R21 AI071806, PO1 AI074415, K01AI062435]; Harvard University Center for AIDS Research; Bill & Melinda Gates Foundation; Doris Duke Charitable Foundation; German Research Society (Deutsche Forschungsgemeinschaft); National Health and Medical Research Council of Australia [519578]; National Institute of Allergy and Infectious Diseases [AI38855, AI27659, AI38858, AI25879, AI27666]; Agouron/Pfizer, Bristol Myers Squibb and GlaxoSmithKline; US National Cancer Institute (NCI), NIH [HHSN261200800001E] FX We thank S. Deeks, P. Hunt, B. Walker and J. Spritzler for valuable intellectual input and discussions and the ACTG 384 main study and immunology A5007 substudy teams. These studies were supported by US National Institutes of Health (NIH)-National Institute of Allergy and Infectious Diseases grants to M. A. (R21 AI071806, PO1 AI074415) and G. K. R. (K01AI062435), the Harvard University Center for AIDS Research, the Bill & Melinda Gates Foundation and the Doris Duke Charitable Foundation. A. M. was supported by a fellowship from the German Research Society (Deutsche Forschungsgemeinschaft), and J. J. C. was supported by a Fellowship awarded from the National Health and Medical Research Council of Australia (519578). ACTG 384 was supported in part by National Institute of Allergy and Infectious Diseases grants AI38855, AI27659, AI38858, AI25879 and AI27666 and by Agouron/Pfizer, Bristol Myers Squibb and GlaxoSmithKline. This project has been funded in whole or in part with federal funds from the US National Cancer Institute (NCI), NIH, under Contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Support Program of the NIH, NCI, Center for Cancer Research. M. A. is a Distinguished Clinical Scientist of the Doris Duke Charitable Foundation. We thank the Mark and Lisa Schwartz Foundation and the Phillip T. and Susan M. Ragon Foundation for their support. NR 39 TC 198 Z9 202 U1 0 U2 2 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 AUG PY 2009 VL 15 IS 8 BP 955 EP U161 DI 10.1038/nm.2004 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 480XK UT WOS:000268770400042 PM 19597505 ER PT J AU Wu, XS McNeil, BD Xu, JH Fan, JM Xue, L Melicoff, E Adachi, R Bai, L Wu, LG AF Wu, Xin-Sheng McNeil, Benjamin D. Xu, Jianhua Fan, Junmei Xue, Lei Melicoff, Ernestina Adachi, Roberto Bai, Li Wu, Ling-Gang TI Ca2+ and calmodulin initiate all forms of endocytosis during depolarization at a nerve terminal SO NATURE NEUROSCIENCE LA English DT Article ID ADRENAL CHROMAFFIN CELLS; RETINAL BIPOLAR CELLS; CLATHRIN-MEDIATED ENDOCYTOSIS; FROG NEUROMUSCULAR-JUNCTION; SYNAPTIC VESICLE EXOCYTOSIS; READILY RELEASABLE POOL; FAST CNS SYNAPSE; HIPPOCAMPAL SYNAPSES; RAPID ENDOCYTOSIS; PHYSIOLOGICAL TEMPERATURES AB Although endocytosis maintains synaptic transmission, how endocytosis is initiated is unclear. We found that calcium influx initiated all forms of endocytosis at a single nerve terminal in rodents, including clathrin-dependent slow endocytosis, bulk endocytosis, rapid endocytosis and endocytosis overshoot (excess endocytosis), with each being evoked with a correspondingly higher calcium threshold. As calcium influx increased, endocytosis gradually switched from very slow endocytosis to slow endocytosis to bulk endocytosis to rapid endocytosis and to endocytosis overshoot. The calcium-induced endocytosis rate increase was a result of the speeding up of membrane invagination and fission. Pharmacological experiments suggested that the calcium sensor mediating these forms of endocytosis is calmodulin. In addition to its role in recycling vesicles, calcium/calmodulin-initiated endocytosis facilitated vesicle mobilization to the readily releasable pool, probably by clearing fused vesicle membrane at release sites. Our findings provide a unifying mechanism for the initiation of various forms of endocytosis that are critical in maintaining exocytosis. C1 [Wu, Xin-Sheng; McNeil, Benjamin D.; Xu, Jianhua; Fan, Junmei; Xue, Lei; Bai, Li; Wu, Ling-Gang] Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20824 USA. [Melicoff, Ernestina; Adachi, Roberto] Univ Texas MD Anderson Canc Ctr, Dept Pulm Med, Houston, TX 77030 USA. RP Wu, LG (reprint author), Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20824 USA. EM wul@ninds.nih.gov RI fan, junmei/D-6147-2011; OI Xu, Jianhua/0000-0003-0084-8856; McNeil, Benjamin/0000-0001-7545-3598 FU National Institute of Neurological Disorders; US National Institutes of Health FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program of the US National Institutes of Health. NR 50 TC 117 Z9 118 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 2009 VL 12 IS 8 BP 1003 EP U70 DI 10.1038/nn.2355 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 475WS UT WOS:000268396300014 PM 19633667 ER PT J AU Koya, E Golden, SA Harvey, BK Guez-Barber, DH Berkow, A Simmons, DE Bossert, JM Nair, SG Uejima, JL Marin, MT Mitchell, TB Farquhar, D Ghosh, SC Mattson, BJ Hope, BT AF Koya, Eisuke Golden, Sam A. Harvey, Brandon K. Guez-Barber, Danielle H. Berkow, Alexander Simmons, Danielle E. Bossert, Jennifer M. Nair, Sunila G. Uejima, Jamie L. Marin, Marcelo T. Mitchell, Timothy B. Farquhar, David Ghosh, Sukhen C. Mattson, Brandi J. Hope, Bruce T. TI Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization SO NATURE NEUROSCIENCE LA English DT Article ID INDUCED LOCOMOTOR-ACTIVITY; FOS EXPRESSION; DRUG-ADDICTION; SEEKING; GENE; DOPAMINE; BEHAVIOR; RATS; CUES; AMPHETAMINE AB Learned associations between effects of abused drugs and the drug administration environment are important in drug addiction. Histochemical and electrophysiological studies suggest that these associations are encoded in sparsely distributed nucleus accumbens neurons that are selectively activated by drugs and drug-associated cues. Although correlations have been observed between nucleus accumbens neuronal activity and responsivity to drugs and drug cues, no technique exists for selectively manipulating these activated neurons and establishing their causal role in behavioral effects of drugs and drug cues. Here we describe a new approach, which we term the 'Daun02 inactivation method', that selectively inactivates a minority of neurons previously activated by cocaine in an environment repeatedly paired with cocaine to demonstrate a causal role for these activated neurons in context-specific cocaine-induced psychomotor sensitization in rats. This method provides a new tool for studying the causal roles of selectively activated neurons in behavioral effects of drugs and drug cues and in other learned behaviors. C1 [Koya, Eisuke; Golden, Sam A.; Harvey, Brandon K.; Guez-Barber, Danielle H.; Berkow, Alexander; Simmons, Danielle E.; Bossert, Jennifer M.; Nair, Sunila G.; Uejima, Jamie L.; Marin, Marcelo T.; Mitchell, Timothy B.; Mattson, Brandi J.; Hope, Bruce T.] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. [Farquhar, David; Ghosh, Sukhen C.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. RP Hope, BT (reprint author), Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. EM bhope@intra.nida.nih.gov RI Harvey, Brandon/A-5559-2010; Hope, Bruce/A-9223-2010; Marin, Marcelo/J-3026-2012; OI Hope, Bruce/0000-0001-5804-7061; Golden, Sam/0000-0002-2104-2272 FU Intramural Research Program of the National Institute on Drug Abuse FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse. We thank E. Wentzell for her excellent editorial assistance, K. Knestaut for breeding the cfos-lacZ rats and T. Adams-Deutsch, C. Pickens and K. Wihbey for technical assistance. We are especially thankful to Y. Shaham for his comments over the years and for his help in writing this manuscript, and to R. Wise for providing the inspiration for this study. NR 40 TC 101 Z9 104 U1 2 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 2009 VL 12 IS 8 BP 1069 EP U152 DI 10.1038/nn.2364 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 475WS UT WOS:000268396300023 PM 19620976 ER PT J AU Chen, HX Cleck, JN AF Chen, Helen X. Cleck, Jessica N. TI Adverse effects of anticancer agents that target the VEGF pathway SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; RENAL-CELL CARCINOMA; POSTERIOR LEUKOENCEPHALOPATHY SYNDROME; METASTATIC COLORECTAL-CANCER; TYROSINE KINASE INHIBITOR; GASTROINTESTINAL STROMAL TUMORS; PACLITAXEL PLUS BEVACIZUMAB; COOPERATIVE-ONCOLOGY-GROUP; ADVANCED BREAST-CANCER; RANDOMIZED PHASE-III AB Antiangiogenesis agents that target the VEGF/VEGF receptor pathway have become an important part of standard therapy in multiple cancer indications. with expanded clinical experience with this class of agents has come the increasing recognition of the diverse adverse effects related to disturbance of VEGF-dependent physiological functions and homeostasis in the cardiovascular and renal systems, as well as wound healing and tissue repair. Although most adverse effects of VEGF inhibitors are modest and manageable, some are associated with serious and life-threatening consequences, particularly in high-risk patients and in certain clinical settings. This review examines the toxicity profiles of anti-VEGF antibodies and small-molecule inhibitors. The potential mechanisms of the adverse effects, risk factors, and the implications for selection of patients and management are discussed. C1 [Chen, Helen X.] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MD 20851 USA. [Cleck, Jessica N.] Tech Res Int, Bethesda, MD USA. RP Chen, HX (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, 6130 Execut Blvd,Suite 7131, Bethesda, MD 20851 USA. EM helen.chen@nih.gov NR 99 TC 221 Z9 230 U1 8 U2 47 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD AUG PY 2009 VL 6 IS 8 BP 465 EP 477 DI 10.1038/nrclinonc.2009.94 PG 13 WC Oncology SC Oncology GA 477LG UT WOS:000268520000007 PM 19581909 ER EF