FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Han, PK Arnold, RM AF Han, Paul K. Arnold, Robert M. TI Physician responsibility: The authors' response SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Letter C1 NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Pittsburgh, Montefiore Hosp, UPMC, Pittsburgh, PA 15213 USA. RP Han, PK (reprint author), NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, 6130 Execut Plaza,EPN 4095A,MSC 7344, Bethesda, MD 20892 USA. EM hanp@mail.nih.gov; rabob@pitt.edu OI Han, Paul/0000-0003-0165-1940 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 J9 J PALLIAT MED JI J. Palliat. Med. PD AUG PY 2006 VL 9 IS 4 BP 840 EP 840 DI 10.1089/jpm.2006.9.840 PG 1 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 078AT UT WOS:000240074000004 ER PT J AU Gunay-Aygun, M Avner, ED Bacallao, RL Choyke, PL Flynn, JT Germino, GG Guay-Woodford, L Harris, P Heller, T Ingelfinger, J Kaskel, F Kleta, R LaRusso, NF Mohan, P Pazour, GJ Shneider, BL Torres, VE Wilson, P Zak, C Zhou, J Gahl, WA AF Gunay-Aygun, Meral Avner, Ellis D. Bacallao, Robert L. Choyke, Peter L. Flynn, Joseph T. Germino, Gregory G. Guay-Woodford, Lisa Harris, Peter Heller, Theo Ingelfinger, Julie Kaskel, Frederick Kleta, Robert LaRusso, Nicholas F. Mohan, Parvathi Pazour, Gregory J. Shneider, Benjamin L. Torres, Vicente E. Wilson, Patricia Zak, Colleen Zhou, Jing Gahl, William A. TI Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: Summary statement of a first National Institutes of Health/Office of Rare Diseases Conference SO JOURNAL OF PEDIATRICS LA English DT Article ID PKHD1 MUTATIONS; PRIMARY CILIA; PROTEIN; ARPKD; GENE; PATHOGENESIS; FIBROCYSTIN; MECHANISMS; EXPRESSION; DIAGNOSIS C1 NHGRI, NIH, Mol Imaging Program, NIDDK, Bethesda, MD 20892 USA. Med Coll Wisconsin, Childrens Hosp Wisconsin, Milwaukee, WI 53226 USA. Indiana Univ, Sch Med, Bloomington, IN 47405 USA. Albert Einstein Coll Med, Childrens Hosp Montefiore, New York, NY USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. Univ Alabama, Tuscaloosa, AL 35487 USA. Mayo Clin, Rochester, MN USA. Harvard Univ, Massachusetts Gen Hosp, Massachusetts Gen Hosp Children, Sch Med, Cambridge, MA 02138 USA. Harvard Univ, Inst Med, Autosomal Recess Polycyst Kidney Dis Congenital H, Boston, MA 02115 USA. Harvard Univ, Inst Med, Dept Internal Med, Boston, MA 02115 USA. George Washington Univ, Childrens Natl Med Ctr, Washington, DC USA. Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. RP Gunay-Aygun, M (reprint author), NHGRI, NIH, Mol Imaging Program, NIDDK, 10 Ctr Dr Bldg 10,Room 10C103A, Bethesda, MD 20892 USA. EM mgaygun@mail.nih.gov OI Bacallao, Robert/0000-0002-5703-5701; Germino, Gregory/0000-0002-3609-5588; Pazour, Gregory/0000-0002-6285-8796 FU Intramural NIH HHS [Z99 HG999999] NR 35 TC 40 Z9 44 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD AUG PY 2006 VL 149 IS 2 BP 159 EP 164 DI 10.1016/j.jpeds.2006.03.014 PG 6 WC Pediatrics SC Pediatrics GA 073JG UT WOS:000239738300006 PM 16887426 ER PT J AU Horn, IB Brenner, R Rao, M Cheng, TL AF Horn, Ivor B. Brenner, Ruth Rao, Malla Cheng, Tina L. TI Beliefs about the appropriate age for initiating toilet training: Are there racial and socioeconomic differences? SO JOURNAL OF PEDIATRICS LA English DT Article ID CHILDREN; RECOMMENDATIONS AB Objective To examine racial and socioeconomic differences in parental beliefs about the appropriate age at which to initiate toilet training. Study design A cross-sectional survey of 779 parents visiting child health providers in 3 clinical sites in Washington, DC and the surrounding metropolitan area completed a self-report survey. The main outcome variable was parental beliefs about the appropriate age at which to initiate toilet training. Using multiple linear regression, differences in beliefs were assessed in relation to race, family income, parental education, parental age, and age of the oldest and youngest children. Results Among respondents, parents felt that the average age at which toilet training should be initiated was 20.6 months (+/- 7.6 months), with a range of 6 to 48 months. Caucasian parents believed that toilet training should be initiated at a significantly later age (25.4 months) compared with both African-American parents (18.2 months) and parents of other races (19.4 months). In the multiple regression model, factors predicting belief in when to initiate toilet training were Caucasian race and higher income. Conclusions Race and income were independent predictors of belief in age at which to initiate toilet training. More research is needed to determine what factors contribute to toilet training practices in diverse populations. C1 Childrens Natl Med Ctr, Childrens Hlth Ctr Good Hope Rd, Dept Gen Pediat & Adolescent Med, Washington, DC 20010 USA. Childrens Res Inst, Ctr Hlth Serv & Community Res, Washington, DC USA. George Washington Univ, Sch Med, Dept Pediat, Washington, DC 20052 USA. NICHHD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Johns Hopkins Univ, Div Gen Pediat & Adolescent Med, Baltimore, MD 21218 USA. RP Horn, IB (reprint author), Childrens Natl Med Ctr, Childrens Hlth Ctr Good Hope Rd, Dept Gen Pediat & Adolescent Med, Good Hope Rd,2501 Good Hope Rd SE, Washington, DC 20010 USA. EM ihorn@cnmc.org NR 21 TC 13 Z9 17 U1 4 U2 12 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD AUG PY 2006 VL 149 IS 2 BP 165 EP 168 DI 10.1016/j.jpeds.2006.03.004 PG 4 WC Pediatrics SC Pediatrics GA 073JG UT WOS:000239738300007 PM 16887427 ER PT J AU Jeha, GS Lowenthal, ED Chan, WY Wu, SM Karaviti, LP AF Jeha, George S. Lowenthal, Elizabeth D. Chan, Wai-Yee Wu, Shao-Ming Karaviti, Lefkothea P. TI Variable presentation of precocious puberty associated with the D564G mutation of the LHCGR gene in children with testotoxicosis SO JOURNAL OF PEDIATRICS LA English DT Article ID LUTEINIZING-HORMONE RECEPTOR; FAMILIAL SEXUAL PRECOCITY; LEYDIG; HEIGHT AB We report on a family with familial male-limited precocious puberty (FMPP) due to a D564G mutation of the LHCGR gene. Family members show a varied phenotypic expression from severe precocity unresponsive to therapy with compromise of the predicted final height in some members, to attainment of tall final stature in other members who never received medical treatment. DNA amplification and sequencing of exon 11 of the LHCGR gene was done for the three affected male members and their mother. DNA analysis revealed a D564G mutation in the third cytoplasmic loop of the LHCGR receptor. All three males had precocious puberty with elevated testosterone levels. The index case developed central precocious puberty and evidence of compromised final height while on therapy. In contrast, the untreated older siblings attained a tall final height. This report underscores the possibility that the effects of the mutant luteinizing hormone/choriogonadotropin receptor on phenotypic expression of FMPP, such as adult final height, are modified by other factors. C1 Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. NICHD, Lab Clin Genom, NIH, Bethesda, MD USA. Georgetown Univ, Sch Med, Washington, DC USA. RP Jeha, GS (reprint author), Texas Childrens Hosp, Baylor Coll Med, Clin Care Ctr, 6621 Fannin,Suite 102005, Houston, TX 77030 USA. EM gsjeha@texaschildrenshospital.org OI Jeha, George/0000-0002-3531-5059 NR 14 TC 7 Z9 12 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD AUG PY 2006 VL 149 IS 2 BP 271 EP 274 DI 10.1016/j.jpeds.2006.03.017 PG 4 WC Pediatrics SC Pediatrics GA 073JG UT WOS:000239738300031 PM 16887451 ER PT J AU Zolkowska, D Rothman, RB Baumann, MH AF Zolkowska, Dorota Rothman, Richard B. Baumann, Michael H. TI Amphetamine analogs increase plasma serotonin: Implications for cardiac and pulmonary disease SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID SMOOTH-MUSCLE-CELLS; PLATELET SEROTONIN; PARA-CHLOROAMPHETAMINE; CLINICAL IMPROVEMENT; INTERSTITIAL-CELLS; HEART-DISEASE; FENFLURAMINE; TRANSPORTER; HYPERTENSION; PHENTERMINE AB Elevations in plasma serotonin (5-HT) have been implicated in the pathogenesis of cardiac and pulmonary disease. Normally, plasma 5-HT concentrations are kept low by transporter-mediated uptake of 5-HT into platelets and by metabolism to 5-hydroxyindoleacetic acid (5-HIAA). Many abused drugs ( e. g., substituted amphetamines) and prescribed medications ( e. g., fluoxetine) target 5-HT transporters and could thereby influence circulating 5-HT. We evaluated the effects of amphetamines analogs [(+/-)-fenfluramine, (+/-)-3,4-methylenedioxymethamphetamine, (+)-methamphetamine, (+)-amphetamine, phentermine] on extracellular levels (i.e., plasma levels) of 5-HT and 5-HIAA in blood from catheterized rats. Effects of the 5-HT uptake blocker fluoxetine were examined for comparison. Drugs were tested in vivo and in vitro; plasma indoles were measured using a novel microdialysis method in whole blood. We found that baseline dialysate levels of 5-HT are similar to 0.22 nM, and amphetamine analogs evoke large dose-dependent increases in plasma 5-HT ranging from 4 to 20 nM. The ability of drugs to elevate plasma 5-HT is positively correlated with their potency as 5-HT transporter substrates. Fluoxetine produced small, but significant, increases in plasma 5-HT. Although the drug-evoked 5-HT concentrations are below the micromolar levels required for contraction of pulmonary arteries, they approach concentrations reported to stimulate mitogenesis in pulmonary artery smooth muscle cells. Additional studies are needed to determine the effects of chronic administration of amphetamines on circulating 5-HT. C1 NIDA, Clin Psychopharmacol Sect, IRP, Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. RP Baumann, MH (reprint author), NIDA, Clin Psychopharmacol Sect, IRP, Dept Hlth & Human Serv,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mbaumann@intra.nida.nih.gov FU Intramural NIH HHS NR 41 TC 41 Z9 42 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2006 VL 318 IS 2 BP 604 EP 610 DI 10.1124/jpet.106.101618 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 063MS UT WOS:000239023100018 PM 16644904 ER PT J AU Ansonoff, MA Zhang, JW Czyzyk, T Rothman, RB Stewart, J Xu, H Zjwiony, J Siebert, DJ Yang, F Roth, BL Pintar, JE AF Ansonoff, Michael A. Zhang, Jiwen Czyzyk, Traci Rothman, Richard B. Stewart, Jeremy Xu, Heng Zjwiony, Jordan Siebert, Daniel J. Yang, Feng Roth, Bryan L. Pintar, John E. TI Antinociceptive and hypothermic effects of salvinorin A are abolished in a novel strain of kappa-opioid receptor-1 knockout mice SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PLANT-DERIVED HALLUCINOGEN; GUINEA-PIG BRAIN; SALVIA-DIVINORUM; BODY-TEMPERATURE; IN-VITRO; AGONIST; MORPHINE; DRUGS; RAT; ANTAGONISTS AB Salvia divinorum is a natural occurring hallucinogen that is traditionally used by the Mazatec Indians of central Mexico. The diterpene salvinorin A was identified as an active component of S. divinorum over 20 years ago, but only recently has biochemical screening indicated that a molecular target of salvinorin A in vitro is the kappa-opioid receptor. We have examined whether salvinorin A, the C2-substituted derivative salvinorinyl-2-propionate, and salvinorin B can act as kappa-opioid receptor agonists in vivo. We found that following intracerebroventricular injection over a dose range of 1 to 30 mu g of both salvinorin A and salvinorinyl-2-propionate produces antinociception in wild-type mice but not in a novel strain of kappa-opioid receptor knockout mice. Moreover, both salvinorin A and salvinorinyl-2-propionate reduce rectal body temperature, similar to conventional kappa-opioid receptor agonists, in a genotype-dependent manner. In addition, we determined that salvinorin A has high affinity for kappa 1- but not kappa(2)-opioid receptors, demonstrating selectivity for this receptor subclass. Finally, treatment over the same dose range with salvinorin B, which is inactive in vitro, produced neither antinociceptive nor hypothermic effects in wild-type mice. These data demonstrate that salvinorin A is the active component of S. divinorum, selective for kappa(1)-opioid receptors, and that salvinorin A and specific structurally related analogs produce behavioral effects that require the kappa(1)-opioid receptor. C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA. Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. NIDA, Intramural Res Program, Dept Hlth & Human Serv, NIH, Baltimore, MD 21224 USA. NIDA, Intramural Res Program, Dept Hlth & Human Serv, NIH, Malibu, CA USA. RP Pintar, JE (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, 675 Hoes Lane, Piscataway, NJ 08854 USA. EM pintar@cabm.rutgers.edu RI Roth, Bryan/F-3928-2010 FU NIA NIH HHS [MH/AG 19957]; NIDA NIH HHS [DA-017204, DA-009040, DA-015237, F32 DA-14755] NR 38 TC 46 Z9 48 U1 0 U2 4 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 2006 VL 318 IS 2 BP 641 EP 648 DI 10.1124/jpet.106.101998 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 063MS UT WOS:000239023100022 PM 16672569 ER PT J AU Merrick, BA Bruno, ME Madenspacher, JH Wetmore, BA Foley, J Pieper, R Zhao, M Makusky, AJ McGrath, AM Zhou, JX Taylor, J Tomer, KB AF Merrick, B. Alex Bruno, Maribel E. Madenspacher, Jennifer H. Wetmore, Barbara A. Foley, Julie Pieper, Rembert Zhao, Ming Makusky, Anthony J. McGrath, Andrew M. Zhou, Jeff X. Taylor, John Tomer, Kenneth B. TI Alterations in the rat serum proteome during liver injury from acetaminophen exposure SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MITOCHONDRIAL PERMEABILITY TRANSITION; NECROSIS-FACTOR RECEPTOR-1; INDUCED HEPATOTOXICITY; HYDROGEN-PEROXIDE; METABOLIC-ACTIVATION; MOUSE-LIVER; TOXICITY; REGENERATION; IDENTIFICATION; EXPRESSION AB Changes in the serum proteome were identified during early, fulminant, and recovery phases of liver injury from acetaminophen in the rat. Male F344 rats received a single, noninjury dose or a high, injury-producing dose of acetaminophen for evaluation at 6 to 120 h. Two-dimensional gel electrophoresis of immunodepleted serum separated approximately 800 stained proteins per sample from which differentially expressed proteins were identified by mass spectrometry. Serum alanine aminotransferase/aspartate aminotransferase levels and histopathology revealed the greatest liver damage at 24 and 48 h after high-dose acetaminophen corresponding to the time of greatest serum protein alterations. After 24 h, 68 serum proteins were significantly altered of which 23 proteins were increased by > 5-fold and 20 proteins were newly present compared with controls. Only minimal changes in serum proteins were noted at the low dose without any histopathology. Of the 54 total protein isoforms identified by mass spectrometry, gene ontology processes for 38 unique serum proteins revealed involvement of acute phase response, coagulation, protein degradation, intermediary metabolism, and various carrier proteins. Elevated serum tumor necrosis factor-alpha from 24 to 48 h suggested a mild inflammatory response accompanied by increased antioxidant capability demonstrated by increased serum catalase activity. Antibody array and enzyme-linked immunosorbent assay analyses also showed elevation in the chemokine monocyte chemoattractant protein-1 and the metalloprotease inhibitor tissue inhibitor of metalloproteinases-1 during this same period of liver injury. This study demonstrates that serum proteome alterations probably reflect both liver damage and a concerted, complex response of the body for organ repair and recovery during acute hepatic injury. C1 NIEHS, Proteom Grp, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Mass Spectrometry Grp, Res Triangle Pk, NC 27709 USA. Large Scale Biol Corp, Germantown, MD USA. RP Merrick, BA (reprint author), NIEHS, Proteom Grp, D2-04,POB 12233, Res Triangle Pk, NC 27709 USA. EM merrick@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013 FU Intramural NIH HHS [Z01 ES010017-08]; NIEHS NIH HHS [N01ES25495] NR 39 TC 28 Z9 34 U1 1 U2 3 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 2006 VL 318 IS 2 BP 792 EP 802 DI 10.1124/jpet.106.102681 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 063MS UT WOS:000239023100038 PM 16687475 ER PT J AU Utsuki, T Yu, QS Davidson, D Chen, D Holloway, HW Brossi, A Sambamurti, K Lahiri, DK Greig, NH Giordano, T AF Utsuki, Tada Yu, Qian-sheng Davidson, Diane Chen, Demao Holloway, Harold W. Brossi, Arnold Sambamurti, Kumar Lahiri, Debomoy K. Greig, Nigel H. Giordano, Tony TI Identification of novel small molecule inhibitors of amyloid precursor protein synthesis as a route to lower Alzheimer's disease amyloid-beta peptide SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID TERM SYNAPTIC PLASTICITY; MESSENGER-RNA; A-BETA; 5'-UNTRANSLATED REGION; RESPONSIVE ELEMENT; NERVOUS-SYSTEM; TRANSLATION; INTERLEUKIN-1; IMMUNIZATION; HIPPOCAMPUS AB A wealth of independent research with transgenic mice, antibodies, and vaccines has pointed to a causative role of the amyloid-beta peptide (A beta) in Alzheimer's disease ( AD). Based on these and earlier associative studies, A beta represents a promising target for development of therapeutics focused on AD disease progression. Interestingly, a cholinesterase inhibitor currently in clinical trials, phenserine, has been shown to inhibit production of both amyloid precursor protein (APP) and A beta. We have shown that this inhibition occurs at the post-transcriptional level with a specific blocking of the synthesis of APP relative to total protein synthesis (Shaw et al., 2001). However, the dose of phenserine necessary to block APP production is far higher than that needed to elicit its anticholinesterase activity, and it is these latter actions that are dose limiting in vivo. The focus of this study was to screen 144 analogs of phenserine to identify additional small molecules that inhibit APP protein synthesis, and thereby A beta production, without possessing potent acetylcholinesterase (AChE) inhibitory activity. An enzyme-linked immunosorbent assay was used to identify analogs capable of suppressing APP production following treatment of human neuroblastoma cells with 20 mu M of compound. Eight analogs were capable of dose dependently reducing APP and A beta production without causing cell toxicity in further studies. Several of these analogs had little to no AChE activities. Translation of APP and A beta actions to mice was demonstrated with one agent. They thus represent interesting lead molecules for assessment in animal models, to define their tolerance and utility as potential AD therapeutics. C1 Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Feist Weiller Canc Ctr, Shreveport, LA 71115 USA. NIA, Neurosci Lab, Sect Drug Design & Dev, NIH, Baltimore, MD USA. Message Pharmaceut Inc, Lead Discovery, Malvern, PA USA. Indiana Univ, Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC 27515 USA. Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA. RP Giordano, T (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Feist Weiller Canc Ctr, Shreveport, LA 71115 USA. EM agiord@lsuhsc.edu FU Intramural NIH HHS; NIA NIH HHS [AG014936] NR 40 TC 23 Z9 24 U1 0 U2 4 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 2006 VL 318 IS 2 BP 855 EP 862 DI 10.1124/jpet.106.103309 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 063MS UT WOS:000239023100046 PM 16690718 ER PT J AU Martinez, JM Sali, T Okazaki, R Anna, C Hollingshead, M Hose, C Monks, A Walker, NJ Baek, SJ Eling, TE AF Martinez, Jeanelle M. Sali, Tina Okazaki, Ryuji Anna, Colleen Hollingshead, Melinda Hose, Curtis Monks, Anne Walker, Nigel J. Baek, Seung Joon Eling, Thomas E. TI Drug-induced expression of nonsteroidal anti-inflammatory drug-activated gene/macrophage inhibitory cytokine-1/prostate-derived factor, a putative tumor suppressor, inhibits tumor growth SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID BETA SUPERFAMILY MEMBER; GENE NAG-1; CANCER CELLS; CYCLOOXYGENASE; P53; INDUCTION; PROTEIN; EGR-1 AB A common in vitro response for many chemopreventive and antitumor agents, including some cyclooxygenase inhibitors, is the increased expression of nonsteroidal anti-inflammatory drug-activated gene (NAG)-1/macrophage inhibitory cytokine (MIC)-1/prostate- derived factor (PDF). The experimental anticancer drug 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F203) was a potent inducer of NAG-1 expression, and in MCF-7 cells, it inhibited cell growth and induced apoptosis. NAG-1 small interfering RNA blocked NAG-1 expression and 5F203-induced apoptosis in MCF-7 cells, indicating that NAG-1 may mediate the apoptosis and anticancer activity. One mechanism by which 5F203 increases NAG-1 expression is by increasing the stability of NAG-1 mRNA, dependent of de novo protein synthesis. Extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was increased by 5F203, and inhibition of ERK1/2 phosphorylation abolished the induction of NAG-1 protein expression and increased the stability of NAG-1 mRNA. Thus, 5F203 regulates NAG-1 expression by a unique mechanism compared with other drugs. A mouse orthotopic mammary tumor model was used to determine whether 5F203 increased NAG-1 expression in vivo and suppressed tumor growth. Treatment of the mice with Phortress, the prodrug of 5F203, increased the in vivo expression of NAG-1 as measured by real-time reverse transcription-polymerase chain reaction from RNA obtained by needle biopsy, and the expression correlated with a reduction of tumor volume. These results confirm that NAG-1 suppresses tumor growth, and its in vivo expression can be controlled by treating mice with anticancer drugs, such as Phortress. Drugs that target NAG-1 could lead to a unique strategy for the development of chemotherapeutic and chemopreventive agents. C1 Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Mol Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Toxicol Operat Branch, NIH, Res Triangle Pk, NC 27709 USA. SAIC Frederick Inc, Screening Technol Branch, Lab Funct Genom, Natl Canc Inst, Frederick, MD 21701 USA. US EPA, Off Solid Waste & Emergency Response, Natl Decontaminat Team, Cincinnati, OH 45268 USA. Univ Tennessee, Coll Vet Med, Dept Pathobiol, Knoxville, TN 37996 USA. Univ Occupat & Environm Hlth, Sch Med, Dept Radiat Biol & Hlth, Kitakyushu, Fukuoka, Japan. RP Eling, TE (reprint author), Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, NIH, 111 TW Alexander Dr,POB 12233,MD E4-09, Res Triangle Pk, NC 27709 USA. EM eling@niehs.nih.gov RI Walker, Nigel/D-6583-2012; OI Walker, Nigel/0000-0002-9111-6855; Baek, Seung/0000-0001-7866-7778 NR 20 TC 32 Z9 33 U1 0 U2 0 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 2006 VL 318 IS 2 BP 899 EP 906 DI 10.1124/jpet.105.100081 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 063MS UT WOS:000239023100051 PM 16714403 ER PT J AU Weinrich, M AF Weinrich, Michael TI National Institutes of Health support of rehabilitation robotics research SO JOURNAL OF REHABILITATION RESEARCH AND DEVELOPMENT LA English DT Editorial Material C1 NICHD, Natl Ctr Med Rehabil Res, NIH, Rockville, MD USA. RP Weinrich, M (reprint author), NICHD, Natl Ctr Med Rehabil Res, NIH, Rockville, MD USA. EM mw287k@nih.gov NR 3 TC 1 Z9 1 U1 0 U2 1 PU JOURNAL REHAB RES & DEV PI BALTIMORE PA DEPT OF VETERANS AFFAIRS REHABIL RES & DEVELOP CTR 103 SOUTH GAY STREET, BALTIMORE, MD 21202-4051 USA SN 0748-7711 J9 J REHABIL RES DEV JI J. Rehabil. Res. Dev. PD AUG-SEP PY 2006 VL 43 IS 5 BP XXI EP XXII DI 10.1682/JRRD.2006.06.0073 PG 2 WC Rehabilitation SC Rehabilitation GA 117OQ UT WOS:000242883000004 PM 17123199 ER PT J AU Ward, MM Odutola, JJ AF Ward, Michael M. Odutola, Jennifer J. TI Inter-hospital transfers of patients with systemic lupus erythematosus: Characteristics, predictors, and outcomes SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE systemic lupus erythematosus; patient transfer; hospital mortality ID ACADEMIC-MEDICAL-CENTER; IN-HOSPITAL MORTALITY; PROPENSITY SCORE; TERTIARY CARE; BIAS AB Objective. To describe the reasons for inter-hospital transfers of patients with systemic lupus erythematosus (SLE), to identify predictors of transfers, and to compare the risk of in-hospital mortality between patients who were transferred and those not transferred. Methods. Data on acute care hospitalizations of patients with SLE in New York and Pennsylvania in 2000-2002 were obtained from state health planning agencies. We identified inter-hospital transfers from discharge and admission codes, and categorized the major reason for transfer (rehabilitation, procedure, or continued medical care). Patient and hospital characteristics were examined as predictors of transfers. We used a matched cohort design with propensity adjustment to compare in-hospital mortality between patients transferred for continued medical care and those who were not transferred. Results. We identified 533 inter-hospital transfers in 490 patients, 524 of which involved one transfer per hospitalization episode. Of these 524 transfers, 122 (23.3%) were for rehabilitation, 158 (30.1%) were for procedures, and 244 (46.6%) were for continued medical care. Patient characteristics and transfer destinations varied among these groups. Transfers for continued medical care were more common among younger patients, those who were more severely ill, had an emergency or urgent admission, or were hospitalized in a smaller, rural or non-teaching hospital, or in Pennsylvania, and were less common among those at proprietary hospitals. In the matched cohort analysis, the risk of in-hospital mortality was 2.25 times higher (95% confidence interval 1.31, 3.85; p = 0.004) among those transferred compared with those who were not transferred. This risk differed with the experience of the attending physician at the receiving hospital: among patients of physicians who treated 3 or fewer patients with SLE per year, this risk was 2.5 times higher (95% CI 1.42, 4.36; p = 0.002), while among patients of physicians who treated more than 3 patients with SLE per year, this risk was 0.56 times (95% CI 0.06, 5.12; p = 0.62) that of matched controls. Conclusion. Patient and transfer-ring hospital characteristics vary with the reason for transfer. Transfers for continued medical care are associated with higher risks of in-hospital mortality, but these risks may differ with the SLE-related experience of the attending physician at the receiving hospital. C1 IRP NIAMS NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), IRP NIAMS NIH, Bldg 10 CRC,Room 4-1339,MSC 1468,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS NR 23 TC 3 Z9 3 U1 0 U2 1 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD AUG PY 2006 VL 33 IS 8 BP 1578 EP 1585 PG 8 WC Rheumatology SC Rheumatology GA 069SR UT WOS:000239469000021 PM 16881114 ER PT J AU Berger, VW AF Berger, Vance W. TI Is the Jadad score the proper evaluation of trials? SO JOURNAL OF RHEUMATOLOGY LA English DT Letter ID OSTEOARTHRITIS; KNEE C1 Univ Maryland Baltimore Cty, NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), Univ Maryland Baltimore Cty, NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 8 TC 26 Z9 26 U1 0 U2 4 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD AUG PY 2006 VL 33 IS 8 BP 1710 EP 1711 PG 2 WC Rheumatology SC Rheumatology GA 069SR UT WOS:000239469000048 PM 16881132 ER PT J AU Kiley, JP Collins, JL Frumkin, H Price, DA AF Kiley, James P. Collins, Janet L. Frumkin, Howard Price, Deborah A. TI Managing asthma in schools - What have we learned? A special issue supported by the Centers for Disease Control and Prevention and The National Heart, Lung, and Blood Institute - Foreword SO JOURNAL OF SCHOOL HEALTH LA English DT Editorial Material C1 NHLBI, Div Lung Dis, NIH, Bethesda, MD 20892 USA. US Dept HHS, Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Agcy Tox Substances & Dis Registry, Bethesda, MD 20814 USA. RP Kiley, JP (reprint author), NHLBI, Div Lung Dis, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-4391 J9 J SCHOOL HEALTH JI J. Sch. Health PD AUG PY 2006 VL 76 IS 6 BP 201 EP 201 PG 1 WC Education & Educational Research; Education, Scientific Disciplines; Health Care Sciences & Services; Public, Environmental & Occupational Health SC Education & Educational Research; Health Care Sciences & Services; Public, Environmental & Occupational Health GA 081NW UT WOS:000240325300001 ER PT J AU Merkle, SL Wheeler, LS Gerald, LB Taggart, VS AF Merkle, Sarah L. Wheeler, Lani S. Gerald, Lynn B. Taggart, Virginia S. TI Introduction: Learning from each other about managing asthma in schools SO JOURNAL OF SCHOOL HEALTH LA English DT Editorial Material ID HEALTH-EDUCATION; CHILDREN; PROGRAM; COST C1 Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Res Applicat Branch, Div Adolescent & Sch Hlth, Atlanta, GA 30341 USA. Univ Alabama, Lung Hlth Ctr, Birmingham, AL 35429 USA. NHLBI, Div Lung Dis, NIH, Bethesda, MD 20892 USA. RP Merkle, SL (reprint author), Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Res Applicat Branch, Div Adolescent & Sch Hlth, 4770 Buford Highway NE,MS K12, Atlanta, GA 30341 USA. EM smerkle@cdc.gov; lwheeler@cdc.gov; geraldl@uab.edu; taggartv@nhlbi.nih.gov NR 28 TC 6 Z9 6 U1 1 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-4391 J9 J SCHOOL HEALTH JI J. Sch. Health PD AUG PY 2006 VL 76 IS 6 BP 202 EP 204 DI 10.1111/j.1746-1561.2006.00096.x PG 3 WC Education & Educational Research; Education, Scientific Disciplines; Health Care Sciences & Services; Public, Environmental & Occupational Health SC Education & Educational Research; Health Care Sciences & Services; Public, Environmental & Occupational Health GA 081NW UT WOS:000240325300002 PM 16918838 ER PT J AU Wheeler, LS Merkle, SL Gerald, LB Taggart, VS AF Wheeler, Lani S. Merkle, Sarah L. Gerald, Lynn B. Taggart, Virginia S. TI Managing asthma in schools: Lessons learned and recommendations SO JOURNAL OF SCHOOL HEALTH LA English DT Article ID PROGRAM; CHILDREN; INTERVENTION; EDUCATION; STUDENTS; TRIAL C1 Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Adolescent & Sch Hlth, Atlanta, GA 30341 USA. Univ Alabama, Lung Hlth Ctr, Birmingham, AL 35294 USA. NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. RP Wheeler, LS (reprint author), Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Adolescent & Sch Hlth, 4770 Buford Highway,NE,MS K12, Atlanta, GA 30341 USA. EM lwheeler@cdc.gov; smerkle@cdc.gov; geraldl@uab.edu; taggartv@nhlbi.nih.gov NR 58 TC 16 Z9 18 U1 2 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-4391 J9 J SCHOOL HEALTH JI J. Sch. Health PD AUG PY 2006 VL 76 IS 6 BP 340 EP 344 DI 10.1111/j.1746-1561.2006.00125.x PG 5 WC Education & Educational Research; Education, Scientific Disciplines; Health Care Sciences & Services; Public, Environmental & Occupational Health SC Education & Educational Research; Health Care Sciences & Services; Public, Environmental & Occupational Health GA 081NW UT WOS:000240325300033 PM 16918868 ER PT J AU Acharya, A Rishi, V Moll, J Vinson, C AF Acharya, Asha Rishi, Vikas Moll, Jonathan Vinson, Charles TI Experimental identification of homodimerizing B-ZIP families in Homo sapiens SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article; Proceedings Paper CT 4th Workshop on Coiled Coils, Collagen and Co-Proteins CY SEP 11-17, 2005 CL Alpbach, AUSTRIA DE B-ZIP; dimerization specificity; ATF6; XBP; NFIL3; oasis; leucine zipper ID LEUCINE-ZIPPER; DNA-BINDING; COILED-COIL; DIMERIZATION SPECIFICITY; C-FOS; PROTEINS; TRANSCRIPTION; DESIGN; STABILITY; REGION AB B-ZIP transcription factors dimerization is mediated by a parallel coiled-coil termed the leucine zipper. We have evaluated the dimerization specificity of the seven coiled-coil B-ZIP proteins (ATF6, XBP, LZIP, NFIL3, TEF, CREB, and C/EBP alpha) with themselves and each other. To do this, we designed dominant negative proteins, termed A-ZIPs, that contain the leucine zipper dimerization domain of a B-ZIP protein and an acidic amphipathic N-terminal extension. The A-ZIPs heterodimerize with B-ZIP proteins in a leucine zipper-dependent manner. The acidic N-terminal extension is hypothesized to form an heterodimeric coiled-coil structure with the basic region, essentially zippering the leucine zipper into the basic region. We now present a new acidic extension design that stabilizes heterodimerization with B-ZIP proteins up to 11 kcal mol(-1). We have used these A-ZIP proteins in a competition EMSA to evaluate which A-ZIP can prevent DNA binding of which B-ZIP domain. Inhibition of DNA binding is interpreted to indicate that the A-ZIP is forming a heterodimer with the B-ZIP domain and thus prevents the B-ZIP from binding to DNA. All leucine zippers examined can homodimerize and two pairs (CREB & NFIL3 and ATF6 & XBP) can heterodimerize. We discuss these results with reference to the amino acid sequence of the leucine zipper region. These A-ZIP reagents may be of value in biological systems to inhibit the DNA binding and transcriptional potential of specific B-ZIP families. Published by Elsevier Inc. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NIH, Bldg 37,Rm 3128, Bethesda, MD 20892 USA. EM Vinsonc@dc37a.nci.nih.gov NR 33 TC 14 Z9 14 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 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD AUG PY 2006 VL 155 IS 2 BP 130 EP 139 DI 10.1016/j.jsb.2006.02.018 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 082OG UT WOS:000240395600003 PM 16725346 ER PT J AU Kajava, AV Steven, AC AF Kajava, Andrey V. Steven, Alasdair C. TI The turn of the screw: Variations of the abundant beta-solenoid motif in passenger domains of Type V secretory proteins SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article; Proceedings Paper CT 4th Workshop on Coiled Coils, Collagen and Co-Proteins CY SEP 11-17, 2005 CL Alpbach, AUSTRIA DE tandem sequence repeats; beta-helix; protein structure prediction; virulence factor; fibrous protein structure; TibA protein ID ENTEROTOXIGENIC ESCHERICHIA-COLI; FILAMENTOUS HEMAGGLUTININ; AUTOTRANSPORTER PROTEINS; BORDETELLA-PERTUSSIS; 2-PARTNER SECRETION; CRYSTAL-STRUCTURE; BACTERIAL; ADHESIN; PATHWAY; RECOGNITION AB Many virulence factors of gram-negative bacteria are secreted by the Type V secretion system via the autotransporter (AT) and two-partner secretion (TPS) pathways. AT proteins effect their own secretion. They comprise three domains: the amino-terminal leader sequence; the secreted passenger domain; and the translocator domain that forms the secretory channel. In the TPS pathway, the passenger and translocator domains are translated as separate proteins. In a previous publication, we proposed a beta-helical structure for the TPS passenger domain of the filamentous hemagglutinin (FHA) of Bordetella pertussis which contains two tracts, R1 and R2, of 19-residue sequence repeats and built molecular models for the R1 and R2 beta-helices. Here, we compare the structure predicted for R1 with the recently determined crystal structure of a fragment containing three R1 repeats and find close agreement, with an RMSD of 1.1 angstrom. In the interim, the number of known AT and TPS protein sequences has increased to > 1000. To investigate the incidence of beta-helical structures among them, we carried out a sequence-based analysis and conclude that, despite wide diversity in the sizes and sequences of passenger domains, most of them contain beta-solenoids that we classify into thirteen types based on distinctive properties of their beta-coils (repeat length, numbers and lengths of beta-strands and turns, cross-sectional shape, presence of specific residues in certain positions) summarized in a 2D coil template. Some coil types are typical for conventional AT proteins, others, for TPS or trimeric AT proteins. Some beta-solenoids consist of stacked subdomains with coils of different types. To illustrate model-building from a coil template, we modeled a type-T4 beta-solenoid for TibA of Escherichia coli which is predicted to have two conserved polar residues, Thr and Gln, in interior positions. (c) 2006 Published by Elsevier Inc. C1 CNRS, FRE 2593, Ctr Rech Biochim Macromol, F-34293 Montpellier 5, France. NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kajava, AV (reprint author), CNRS, FRE 2593, Ctr Rech Biochim Macromol, 1919 Route Mende, F-34293 Montpellier 5, France. EM Andrey.Kajava@crbm.cnrs.fr RI Kajava, Andrey/E-1107-2014 OI Kajava, Andrey/0000-0002-2342-6886 FU Intramural NIH HHS NR 41 TC 59 Z9 60 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 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD AUG PY 2006 VL 155 IS 2 BP 306 EP 315 DI 10.1016/j.jsb.2006.01.015 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 082OG UT WOS:000240395600019 PM 16765057 ER PT J AU Danforth, DN AF Danforth, David N. TI RE: Safety and feasibility of breast conserving therapy in Indian women: Two decades of experience at Tata Memorial Hospital, by Dinshaw KA, Sarin R, Budrikkar AN, et al. SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Editorial Material ID PRIMARY RADIATION-THERAPY; BLACK-AND-WHITE; CONSERVATION SURGERY; RACIAL-DIFFERENCES; CANCER; CARCINOMA; PATIENT; RADIOTHERAPY; KNOWLEDGE C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Danforth, DN (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM david_danforth@nih.gov NR 23 TC 2 Z9 2 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0022-4790 J9 J SURG ONCOL JI J. Surg. Oncol. PD AUG 1 PY 2006 VL 94 IS 2 BP 89 EP 90 DI 10.1002/jso.20412 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA 069TI UT WOS:000239470700001 PM 16847915 ER PT J AU Kovacs, M Sherrill, J George, CJ Pollock, M Tumuluru, RV Ho, V AF Kovacs, Maria Sherrill, Joel George, Charles J. Pollock, Myrna Tumuluru, Rameshwari V. Ho, Vincent TI Contextual emotion-regulation therapy for childhood depression: Description and pilot testing of a new intervention SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE childhood depression; dysthymia; emotion regulation; treatment ID ADOLESCENT DEPRESSION; INTERPERSONAL PSYCHOTHERAPY; DYSTHYMIC DISORDER; CHILDREN; EFFICACY; SCHEDULE; RECOVERY; ANXIETY; FAMILY; BRAIN AB Objective: To pilot test the acceptability and efficacy of contextual emotion-regulation therapy (CERT), anew, developmentally appropriate intervention for childhood depression, which focuses on the self-regulation of dysphoria. Method: Two samples of convenience (n = 29, n = 2) served to verify some CERT constructs; it was then operationalized in a treatment manual. To pilot test CERT, 20 children (ages 7-12; 35% girls) with DSM dysthymic disorder (mean duration 24.4 months) entered an open, 30-session, 10-month, 4-phase trial, with 6- and 12-month follow-up. Assessments included independent clinical evaluations and self-rated questionnaires. Results: Fifteen children completed therapy, four were administratively terminated, and one dropped out. Completers did not clinically differ from the rest, but they were more likely to have better educated and less depressed mothers and intact families. At the end of treatment, 53% of the completers had full and 13% partial remission of dysthymia (remission from superimposed major depression was 80%). By 6- and 12-month follow-up, 79% and 92% had full remission of dysthymia (p < .0001). Self-reported depressive and anxiety symptoms significantly declined by the end of treatment (p < .001) and remained so throughout follow-up. Conclusions: CERT enables clinicians to "match" the intervention to children's emotion regulatory needs and symptoms and was readily accepted by families. The promising results suggest the need for a randomized trial. C1 Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. NIMH, Bethesda, MD 20892 USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15213 USA. CYKE Inc, Atlanta, GA USA. Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. RP Kovacs, M (reprint author), Western Psychiat Inst & Clin, 3811 O'Hara St, Pittsburgh, PA 15213 USA. EM kovacs@pitt.edu FU NIMH NIH HHS [5R21 MH55244, 5P01 MH56193] NR 40 TC 57 Z9 57 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2006 VL 45 IS 8 BP 892 EP 903 DI 10.1097/01.chi.0000222878.742162.5a PG 12 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 067GS UT WOS:000239290500002 PM 16865031 ER PT J AU Hemila, H Virtamo, J Albanes, D Kaprio, J AF Hemila, Harri Virtamo, Jarmo Albanes, Demetrius Kaprio, Jaakko TI The effect of vitamin E on common cold incidence is modified by age, smoking and residential neighborhood SO JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION LA English DT Article DE aging; alpha-tocopherol; cities; randomized controlled trial; respiratory infections ID RANDOMIZED CONTROLLED-TRIAL; RESPIRATORY-TRACT INFECTIONS; PLACEBO-CONTROLLED TRIAL; MALE SMOKERS; BETA-CAROTENE; E SUPPLEMENTATION; FREE-RADICALS; DOUBLE-BLIND; ANTIOXIDANTS; MULTIVITAMIN AB Background: We have previously found a 28% reduction in common cold incidence with 50 mg/day vitamin E supplementation in a subgroup of the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study cohort: older city-dwelling men (>= 65 years) who smoked only 5-14 cigarettes/day. Objective: To carry out more detailed analyses to explore the modification of vitamin E effect by age, smoking, and residential neighborhood. Methods: We examined the effect of vitamin E on common cold risk in subjects consisting of the placebo and vitamin E arms (n = 14,573) of the ATBC Study, which recruited males aged 50-69 years who smoked >= 5 cigarettes/day at the baseline. The ATBC Study was conducted in southwestern Finland in 1985-1993; the active follow-up lasted for 4.7 years (mean). We modeled common cold risk as a function of age-at-follow-up in the vitamin E arm compared with the placebo arm using linear splines in Poisson regression. Results: In participants of 72 years or older at follow-up, the effect of vitamin E diverged. Among those smoking 5-14 cigarettes per day at baseline and living in cities, vitamin E reduced common cold risk (RR = 0.54; 95% CI 0.37-0.80), whereas among those smoking more and living away from cities, vitamin E increased common cold risk (RR = 1.58; 1.23-2.01). Conclusions: Vitamin E may cause beneficial or harmful effects on health depending on various modifying factors. Accordingly, caution should be maintained in public health recommendations on vitamin E supplementation until its effects are better understood. C1 Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland. Natl Inst Publ Hlth, Dept Epidemiol & Hlth Promot, Helsinki, Finland. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Hemila, H (reprint author), Univ Helsinki, Dept Publ Hlth, POB 41, FIN-00014 Helsinki, Finland. EM harri.hemila@helsinki.fi RI Kaprio, Jaakko/A-1820-2008; Albanes, Demetrius/B-9749-2015; OI Hemila, Harri/0000-0002-4710-307X; Kaprio, Jaakko/0000-0002-3716-2455 FU NCI NIH HHS [CN-45035, N01-CN-45165] NR 37 TC 21 Z9 21 U1 0 U2 3 PU AMER COLLEGE NUTRITION PI CLEARWATER PA 300 SOUTH DUNCAN AVENUE, STE 225, CLEARWATER, FL 33755 USA SN 0731-5724 J9 J AM COLL NUTR JI J. Am. Coll. Nutr. PD AUG PY 2006 VL 25 IS 4 BP 332 EP 339 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 084YJ UT WOS:000240570000007 PM 16943455 ER PT J AU Carroll, SL Lee, RE Kaur, H Harris, KJ Strother, ML Huang, TTK AF Carroll, Shawna L. Lee, Rebecca E. Kaur, Harsohena Harris, Kari J. Strother, Myra L. Huang, Terry T. -K. TI Smoking, weight loss intention and obesity-promoting behaviors in college students SO JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION LA English DT Article DE smoking; diet; weight loss; physical activity; college health ID RISK-FACTORS; ASSOCIATION; GIRLS; DEPRESSION; PREVALENCE; INITIATION; ATTITUDES; CESSATION; TOBACCO; WOMEN AB Objective: To examine whether college smoking was associated with trying to lose weight and other weight-related behaviors. Methods: We surveyed 300 students at the University of Kansas about smoking (ever, current, and amount), weight loss intention (y/n), weight-related attitudes, and eating and exercise behavior. Weight, height, and body fat were measured. Results: About half the students (49%) self-identified as having ever smoked while 53 (17.6%) self-identified as current smokers. After controlling for sex, age, and ethnicity, ever smoking was not related to weight loss intention but was associated with greater pressure to maintain a healthy weight (p = 0.05), and having engaged in mild exercise on more days in the previous year (p = 0.05). Compared to nonsmokers, current smokers ate more at restaurants serving high calorie foods.(p < 0.05) and ate more frequently in front of the TV (p < 0.01). Amount smoked was related to diminished use of exercise facilities (p = 0.03) and more frequent eating at restaurants serving high calorie foods (p < 0.05) and in front of the TV (p = 0.01). Conclusions: Current smoking among college students was related to weight loss intention. Despite wanting to lose weight, current smoking was concomitant with obesity-promoting behaviors such as eating higher calorie foods and eating in front of the TV. College-based interventions to prevent smoking initiation or promote smoking cessation should include a focus on healthy eating, exercise and healthful ways to lose or maintain weight. C1 Univ Kansas, Watkins Mem Hlth Ctr, Lawrence, KS 66045 USA. Univ Houston, Dept Hlth & Human Performance, Houston, TX USA. Dept Univ Minnesota Sch Med, Minneapolis, MN USA. Univ Montana, Dept Psychol, Missoula, MT 59812 USA. Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. RP Huang, TTK (reprint author), NICHHD, Pediat Obes & Metab Syndrome Endocrinol Nutr & Gr, 6100 Execut Blvd,4B11,MSC 7510, Rockville, MD 20852 USA. EM huangter@mail.nih.gov NR 30 TC 18 Z9 21 U1 1 U2 5 PU AMER COLLEGE NUTRITION PI CLEARWATER PA 300 SOUTH DUNCAN AVENUE, STE 225, CLEARWATER, FL 33755 USA SN 0731-5724 J9 J AM COLL NUTR JI J. Am. Coll. Nutr. PD AUG PY 2006 VL 25 IS 4 BP 348 EP 353 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 084YJ UT WOS:000240570000009 PM 16943457 ER PT J AU Olson, MT Epstein, JA Yergey, AL AF Olson, Matthew T. Epstein, Jonathan A. Yergey, Alfred L. TI De novo peptide sequencing using exhaustive enumeration of peptide composition SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID TANDEM MASS-SPECTROMETRY; PROTEIN IDENTIFICATION; OF-FLIGHT; CHARGE DERIVATIZATION; FRAGMENTATION; ALGORITHM; DATABASE AB We introduce the use of a peptide composition lookup table indexed by residual mass and number of amino acids for de novo sequencing of polypeptides; Polypeptides of 1600 Daltons (Da) or more can be sequenced effectively through exhaustive compositional analysis of MS/MS spectra obtained by unintolecular decomposition (without CID) in a MALDI TOF/TOF despite a fragment mass accuracy of 50 mDa. Peaks are referenced against the lookup table to obtain a complete profile of amino acid combinations, and combinations are assembled into series of increasing length. Concatenating the differences between successive entries in compositional series yields peptide sequences that can be scored and ranked according to signal intensity. While the current work involves measurements acquired on MALDI TOF-TOF, such general treatment of the data anticipates extension to other types of mass analyzers. C1 NICHD, Lab Cellular & Mol Biophys, Bethesda, MD USA. NICHD, Unit Biol Computat, OSD, NIH, Bethesda, MD USA. RP Yergey, AL (reprint author), NICHD, Lab Cellular & Mol Biophys, Bethesda, MD USA. EM aly@helix.nih.gov FU Intramural NIH HHS NR 26 TC 17 Z9 17 U1 1 U2 3 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 2006 VL 17 IS 8 BP 1041 EP 1049 DI 10.1016/j.jasms.2006.03.007 PG 9 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 071YI UT WOS:000239639400001 PM 16735127 ER PT J AU Oppermann, M Mizel, D Huang, G Li, CL Deng, CX Theilig, F Bachmann, S Briggs, J Schnermann, J Castrop, H AF Oppermann, Mona Mizel, Diane Huang, George Li, Cuiling Deng, Chuxia Theilig, Franziska Bachmann, Sebastian Briggs, Josie Schnermann, Jurgen Castrop, Hayo TI Macula densa control of renin secretion and preglomerular resistance in mice with selective deletion of the B isoform of the Na,K,2Cl co-transporter SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID K-CL COTRANSPORTER; NA-K-2CL COTRANSPORTER; CELLS; NA; FUROSEMIDE; TRANSPORT; MOUSE; GENE; VARIANTS; KNOCKOUT AB Na,K,2Cl co-transporter (NKCC2), the primary NaCl uptake pathway in the thick ascending limb of Henle, is expressed in three different full-length splice variants, called NKCC2F, NKCC2A, and NKCC2B. These variants, derived by differential splicing of the variable exon 4, show a distinct distribution pattern along the loop of Henle, but the functional significance of this organization is unclear. By introduction of premature stop codons into exon 4B, specific for the B isoform, mice with an exclusive NKCC2B deficiency were generated. Relative expression levels and distribution patterns of NKCC2A and NKCC2F were not altered in the NKCC2B-deficient mice. NKCC2B-deficient mice did not display a salt-losing phenotype; basal plasma renin and aldosterone levels were not different from those of wild-type mice. Ambient urine osmolarities, however, were slightly but significantly reduced. Distal Cl concentration was significantly elevated and loop of Henle Cl absorption was reduced in microperfused superficial loops of Henle of NKCC2B-deficient mice. Because of the presence of NKCC2A in the macula densa, maximum tubuloglomerular feedback responses were normal, but tubuloglomerular feedback function curves were right-shifted, indicating reduced sensitivity in the subnormal flow range. Plasma renin concentration in NKCC2B-deficient mice was reduced under conditions of salt loading compared with that in wild-type mice. This study shows the feasibility of generating mice with specific deletions of single splice variants. The mild phenotype of mice that are deficient in the B isoform of NKCC2 indicates a limited role for NKCC2B for overall salt retrieval. Nevertheless, the high-affinity NKCC2B contributes to salt absorption and macula densa function in the low NaCl concentration range. C1 NIDDK, NIH, Bethesda, MD 20892 USA. Humboldt Univ, Charite, Berlin, Germany. Univ Regensburg, Inst Physiol, D-8400 Regensburg, Germany. RP Castrop, H (reprint author), NIDDK, NIH, Bldg 10,Room 4 D51,10 Ctr Dr MSC-1370, Bethesda, MD 20892 USA. EM hayo@castrop.com RI Briggs, Josephine/B-9394-2009; deng, chuxia/N-6713-2016 OI Briggs, Josephine/0000-0003-0798-1190; FU Intramural NIH HHS NR 37 TC 42 Z9 42 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2006 VL 17 IS 8 BP 2143 EP 2152 DI 10.1681/ASN.2006040384 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 069LV UT WOS:000239449000015 PM 16807402 ER PT J AU Zhang, L Kao, WHL Berthier-Schaad, Y Liu, Y Plantinga, L Jaar, BG Fink, N Powe, N Klag, MJ Smith, MW Coresh, J AF Zhang, Lin Kao, W. H. Linda Berthier-Schaad, Yvette Liu, Yongmei Plantinga, Laura Jaar, Bernard G. Fink, Nancy Powe, Neil Klag, Michael J. Smith, Michael W. Coresh, Josef TI Haplotype of signal transducer and activator of transcription 3 gene predicts cardiovascular disease in dialysis patients SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ELEMENT-BINDING PROTEIN; JAK-STAT PATHWAY; HUMAN MACROPHAGES; LINKAGE PHASE; INFLAMMATION; PROTECTION; IL-6; RECONSTRUCTION; EXPRESSION; GROWTH AB Signal transducer and activator of transcription 3 (STAT3) protein has been linked to cardiovascular disease (CVD) through multiple pathways in experimental and animal studies. STAT3 gene variation was examined as a predictor of incident CVD in a subcohort of 529 incident white dialysis patients. Fifteen single-nucleotide polymorphisms of the STAT3 gene were genotyped. Haplotypes were estimated using software PHASE 2.1, and associations with first CVD event were tested using Cox proportional hazards analysis. Adjusted global tests of haplotype association with incident CVD and inflammation markers were performed using permutated P value in R-package Haplo.score. An a priori specified additive genetic model was assumed for haplotype analysis. Both genotypes (four single nucleotide polymorphisms with P < 0.001) and haplotypes (P = 0.002 overall) were associated with incident CVD. Two major haplotype blocks, blocks A and C, were identified. Compared with common haplotype A-1, A-3 was associated with a hazard ratio (HR) of 0.70 (95% confidence interval [CI] 0.51 to 0.94) for CVD events after adjustment for covariates including C-reactive protein (CRP) and interleukin 6. Compared with common haplotype C-1, C-3 was associated with an adjusted HR of 2.12 (95% CI 1.25 to 3.57) for CVD events. Associations were independent of inflammation markers, but IL-6 levels were 14% lower (geometric mean ratio 0.86; 95% CI 6.77 to 0.96) per copy of haplotype A-3 compared with haplotype A-1 in block A after adjustment for CRP and other risk factors (P = 0.008). Variation in the STAT3 gene is associated with the risk for CVD among white dialysis patients independent of serum IL-6 and CRP levels. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. NCI, SAIC Frederick, Lab Genom Divers, Frederick, MD 21701 USA. NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21701 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. RP Coresh, J (reprint author), Johns Hopkins Univ, Dept Epidemiol Biostat & Med, 2024 E Monument St,Suite 2-600, Baltimore, MD 21205 USA. EM coresh@jhu.edu RI Jaar, Bernard/B-1917-2009; Jaar, Bernard/B-5026-2011; Smith, Michael/B-5341-2012 FU AHRQ HHS [R01-HS-08365]; NCI NIH HHS [N01-CO-12400]; NHLBI NIH HHS [R01-HL-62985]; NIDDK NIH HHS [R01-DK-59616] NR 29 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2006 VL 17 IS 8 BP 2285 EP 2292 DI 10.1681/ASN.2005090985 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 069LV UT WOS:000239449000030 PM 16807407 ER PT J AU Espinoza, J Kusanovic, JP Goncalves, LF Nien, JK Hassan, S Lee, W Romero, R AF Espinoza, Jimmy Kusanovic, Juan Pedro Goncalves, Luis F. Nien, Jyh Kae Hassan, Sonia Lee, Wesley Romero, Roberto TI A novel algorithm for comprehensive fetal echocardiography using 4-dimensional ultrasonography and tomographic imaging SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE algorithm; congenital heart disease; fetal echocardiography; 4-dimensional; prenatal diagnosis; spatiotemporal; spatiotemporal image correlation; 3-dimensional ID CONGENITAL HEART-DISEASE; COLOR DOPPLER ULTRASOUND; PRENATAL-DIAGNOSIS; 4-CHAMBER VIEW; 3-DIMENSIONAL ULTRASOUND; GREAT-ARTERIES; LOW-RISK; DEFECTS; DISPLAY; VOLUME AB Objective. Tomographic ultrasound imaging (TUI) is a new display modality that allows simultaneous visualization of up to 8 parallel anatomic planes. This study was designed to determine the role of a novel algorithm combining spatiotemporal image correlation and TUI to visualize standard fetal echocardiographic planes. Methods. Volume data sets from fetuses with and without congenital heart defects (CHDs) were examined with a novel algorithm that allows simultaneous visualization of the 3-vessel and trachea view, the 4-chamber view, and outflow tracts. Visualization rates for these planes as well as the ductal arch and 5-chamber view were calculated. Results. (1) Two hundred twenty-seven volume data sets from fetuses without (n = 138) and with (n = 14) CHDs were reviewed; (2) among fetuses without CHDs, the 4-chamber view, 5-chamber view, ductal arch, 3-vessel and trachea view, left outflow tract, and short axis of the aorta were visualized in 99% (193/195), 96.9% (189/195), 98.5% (192/195), 88.2% (172/195), 93.3% (182/195), and 87.2% (170/195) of the volume data sets, respectively; (3) these views were visualized in 85% (17/20), 80% (16/20), 65% (13/20), 55% (11/20), 55% (11120), and 70% (14/20) of the volume data sets, respectively, from fetuses with CHDs; and (4) simultaneous visualization of the short axis of the aorta, 3-vessel and trachea view, left outflow tract, and 4-chamber view was obtained in 78% (152/195) of the volume data sets from fetuses without CHDs and in 40% (8/20) of those with CHDs. Conclusions. The 3-vessel and trachea view, the 4-chamber view, and both outflow tracts can be simultaneously visualized using a novel algorithm combining spatiotemporal image correlation and TUI. C1 NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48072 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, DHHS, NIH,NICHD,Perinatol Res Branch, 3990 John R,Box 4, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [Z01 HD002401-13] NR 92 TC 41 Z9 48 U1 0 U2 0 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD AUG PY 2006 VL 25 IS 8 BP 947 EP 956 PG 10 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 069KM UT WOS:000239445000001 PM 16870887 ER PT J AU Messing, E Kim, K Sharkey, F Schultz, M Parnes, H Kim, D Saltzstein, D Wilding, G AF Messing, Edward Kim, KyungMann Sharkey, Francis Schultz, Melissa Parnes, Howard Kim, Daniel Saltzstein, Daniel Wilding, George TI Randomized prospective phase III trial of difluoromethylornithine vs placebo in preventing recurrence of completely resected low risk superficial bladder cancer SO JOURNAL OF UROLOGY LA English DT Article DE bladder neoplasms; primary prevention; polyamines; eflornithine ID TRANSITIONAL CELL-CARCINOMA; TRANSURETHRAL RESECTION; SURVIVAL; TUMORS AB Purpose: Ornithine decarboxylase catalyzes the rate limiting step in polyamine synthesis and its activity can be inhibited by difluoromethylornithine, which has been shown in preclinical studies, to prevent bladder cancer. Materials and Methods: To assess the ability of difluoromethylornithine to prevent recurrence of low risk superficial bladder cancer, 454 patients with newly diagnosed (283) or occasionally recurrent (171), stage Ta (425) or T1 (29), grade 1 (263) or grade 2 (191), completely resected urothelial cancer were randomized to receive 1 gm difluoromethylornithine daily or placebo for 1 year. Patients were followed with cystoscopy every 3 months for 2 years and then semiannually for 2 years or until first recurrence. Index and recurrent tumors underwent central pathology review. Results: No serious drug related toxicities were seen in either arm. Two patients died of bladder cancer at 2 and 4 years after randomization, both in the difluoromethylornithine arm. At 42 months followup, 103 patients in the difluoromethylornithine arm (46%) and 97 in the placebo arm (43%) (p = 0.30) experienced at least 1 tumor recurrence. Over 73% of recurrences occurred within 1 year in each arm. Each arm had similar responses for each stratification factor. During the 42 months of followup, 10 (4.4%) difluoromethylornithine and 9 (3.9%) placebo treated patients had progression to TIS or grade 3 disease, and 2 (0.9%) in the difluoromethylornithine arm and none in the placebo arm developed stage T2+ cancers. Conclusions: A year of difluoromethylornithine did not prevent recurrence of completely resected low risk superficial bladder cancer, when started shortly after surgery. C1 Univ Rochester, Dept Urol, Rochester, NY 14642 USA. Univ Wisconsin, Madison, WI USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Urol San Antonio Res, San Antonio, TX USA. NCI, Washington, DC USA. RP Messing, E (reprint author), Univ Rochester, Dept Urol, 601 Elmwood Ave,Box 656, Rochester, NY 14642 USA. EM edward_messing@urmc.rochester.edu FU NCI NIH HHS [N01-CN25434] NR 20 TC 23 Z9 23 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2006 VL 176 IS 2 BP 500 EP 504 DI 10.1016/j.juro.2006.03.061 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 063KZ UT WOS:000239018400021 PM 16813878 ER PT J AU Lee, SJ Locklin, JK Wood, BJ AF Lee, S. Justin Locklin, Julia K. Wood, Bradford J. TI Sodium alterations after irrigation fluid for adjacent organ protection in radiofrequency ablation SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter ID ENDOSCOPIC SURGERY C1 Natl Inst Hlth, Diagnost Radiol Dept, Ctr Clin, Natl Canc Inst, Bethesda, MD USA. Natl Inst Hlth, Urol Oncol Branch, Natl Canc Inst, Bethesda, MD USA. RP Lee, SJ (reprint author), Natl Inst Hlth, Diagnost Radiol Dept, Ctr Clin, Natl Canc Inst, Bethesda, MD USA. FU Intramural NIH HHS [NIH0010126778]; PHS HHS [NIH0010126778] NR 4 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD AUG PY 2006 VL 17 IS 8 BP 1366 EP 1367 DI 10.1097/01.RVI.0000240995.15920.81 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 075MM UT WOS:000239889100018 PM 16923988 ER PT J AU Sudheendra, D Wood, BJ AF Sudheendra, Deepak Wood, Bradford J. TI Appropriate premedication risk reduction during adrenal ablation SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter ID RADIOFREQUENCY ABLATION; PHEOCHROMOCYTOMA; METYROSINE C1 Natl Inst Hlth, Bethesda, MD USA. RP Sudheendra, D (reprint author), Natl Inst Hlth, Bethesda, MD USA. FU Intramural NIH HHS [Z99 CL999999] NR 7 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD AUG PY 2006 VL 17 IS 8 BP 1367 EP 1368 DI 10.1097/01.RVI.0000234616.35625.6A PG 2 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 075MM UT WOS:000239889100019 PM 16923989 ER PT J AU Su, HP Lin, DYW Garboczi, DN AF Su, Hua-Poo Lin, David Yin-Wei Garboczi, David N. TI The structure of G4, the poxvirus disulfide oxidoreductase essential for virus maturation and infectivity SO JOURNAL OF VIROLOGY LA English DT Article ID CELL-CELL FUSION; VACCINIA-VIRUS; BOND FORMATION; MEMBRANE-PROTEIN; CRYSTAL-STRUCTURE; HUMAN THIOREDOXIN; ENTRY; ISOMERASE; TARGET; REFINEMENT AB The possibility of the release of smallpox virus into a predominantly nonimmunized population highlights the importance of understanding poxvirus biology. Poxviruses encode a conserved pathway that is required to oxidize disulfide bonds in nascent viral proteins that fold in the reducing environment of the eukaryotic host cytoplasm. We present the structure of the last enzyme of the vaccinia virus pathway, G4, which is almost identical in smallpox virus. G4 catalyzes the formation of disulfide bonds in proteins that are critical for virus maturation and host cell infection. G4 contains a thioredoxin fold and a Cys-X-X-Cys active site. In solution, G4 monomers and dimers are observed. In the crystal, G4 is found as a dimer that buries 4,500 A(2) in the interface and occludes the active site, which could protect the reactive disulfide from reduction in the cytoplasm. The structure serves as a model for drug design targeting viral disulfide bond formation. C1 NIAID, Struct Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Garboczi, DN (reprint author), 12441 Parklawn Dr, Rockville, MD 20852 USA. EM dgarboczi@niaid.nih.gov FU Intramural NIH HHS NR 50 TC 12 Z9 13 U1 0 U2 1 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 PY 2006 VL 80 IS 15 BP 7706 EP 7713 DI 10.1128/JVI.00521-06 PG 8 WC Virology SC Virology GA 065VX UT WOS:000239189100041 PM 16840349 ER PT J AU Montgomery, SA Berglund, P Beard, CW Johnston, RE AF Montgomery, Stephanie A. Berglund, Peter Beard, Clayton W. Johnston, Robert E. TI Ribosomal protein S6 associates with alphavirus nonstructural protein 2 and mediates expression from alphavirus messages SO JOURNAL OF VIROLOGY LA English DT Article ID SEMLIKI-FOREST-VIRUS; VENEZUELAN EQUINE ENCEPHALITIS; STRAND RNA-SYNTHESIS; TOP MESSENGER-RNAS; SINDBIS VIRUS; REPLICATION COMPLEXES; MINUS-STRAND; BHK CELLS; TRANSLATIONAL CONTROL; RPS6 PHOSPHORYLATION AB Although alphaviruses dramatically alter cellular function within hours of infection, interactions between alphaviruses and specific host cellular proteins are poorly understood. Although the alphavirus nonstructural protein 2 (nsP2) is an essential component of the viral replication complex, it also has critical auxiliary functions that determine the outcome of infection in the host. To gain a better understanding of nsP2 function, we sought to identify cellular proteins with which Venezuelan equine encephalitis virus nsP2 interacted. We demonstrate here that nsP2 associates with ribosomal protein S6 (RpS6) and that nsP2 is present in the ribosome-containing fractions of a polysome gradient, suggesting that nsP2 associates with RpS6 in the context of the whole ribosome. This result was noteworthy, since viral replicase proteins have seldom been described in direct association with components of the ribosome. The association of RpS6 with nsP2 was detected throughout the course of infection, and neither the synthesis of the viral structural proteins nor the presence of the other nonstructural proteins was required for RpS6 interaction with nsP2. nsP1 also was associated with RpS6, but other nonstructural proteins were not. RpS6 phosphorylation was dramatically diminished within hours after infection with alphaviruses. Furthermore, a reduction in the level of RpS6 protein expression led to diminished expression from alphavirus subgenomic messages, whereas no dramatic diminution in cellular translation was observed. Taken together, these data suggest that alphaviruses alter the ribosome during infection and that this alteration may contribute to differential translation of host and viral messages. C1 Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. Univ N Carolina, Carolina Vaccine Inst, Chapel Hill, NC 27599 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Montgomery, SA (reprint author), Univ N Carolina, Dept Microbiol & Immunol, CB 7292,Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. EM smontgo@med.unc.edu FU NIAID NIH HHS [AI 51990, R01 AI051990] NR 67 TC 25 Z9 26 U1 1 U2 1 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 PY 2006 VL 80 IS 15 BP 7729 EP 7739 DI 10.1128/JVI.00425-06 PG 11 WC Virology SC Virology GA 065VX UT WOS:000239189100043 PM 16840351 ER PT J AU Sosnovtsev, SV Belliot, G Chang, KO Prikhodko, VG Thackray, LB Wobus, CE Karst, SM Virgin, HW Green, KY AF Sosnovtsev, Stanislav V. Belliot, Gael Chang, Kyeong-OK Prikhodko, Victor G. Thackray, Larissa B. Wobus, Christiane E. Karst, Stephanie M. Virgin, Herbert W. Green, Kim Y. TI Cleavage map and proteolytic processing of the murine norovirus nonstructural polyprotein in infected cells SO JOURNAL OF VIROLOGY LA English DT Article ID HEMORRHAGIC-DISEASE VIRUS; NORWALK-LIKE VIRUS; PROTEINASE-POLYMERASE PRECURSOR; DEPENDENT RNA-POLYMERASE; FELINE CALICIVIRUS; 3C-LIKE PROTEASE; GENOME ORGANIZATION; ORF1 POLYPROTEIN; CAPSID PROTEIN; IDENTIFICATION AB Murine norovirus (MNV) is presently the only member of the genus Norovirus in the Caliciviridae that can be propagated in cell culture. The goal of this study was to elucidate the proteolytic processing strategy of MNV during an authentic replication cycle in cells. A proteolytic cleavage map of the ORF1 polyprotein was generated, and the virus-encoded 3C-like (3CL) proteinase (Pro) mediated cleavage at five dipeptide cleavage sites, E-341/G(342), Q(705)/N-706, E-870/G(871), E-994/A(995), and (1177)Q/G(1178), that defined the borders of six proteins with the gene order p38.3 (Nterm)-p39.6 (NTPase)-p18.6-p14.3 (VPg)-p19.2 (Pro)-p57.5 (Pol). Bacterially expressed MNV 3CL Pro was sufficient to mediate trans cleavage of the ORF1 polyprotein containing the mutagenized Pro sequence into products identical to those observed during cotranslational processing of the authentic ORF1 polyprotein in vitro and to those observed in MNV-infected cells. Immunoprecipitation and Western blot analysis of proteins produced in virus-infected cells demonstrated efficient cleavage of the proteinase-polymerase precursor. Evidence for additional processing of the Nterm protein in MNV-infected cells by caspase 3 was obtained, and Nterm sequences (DRPD121)-D-118 and (128)DAMD(131) were mapped as caspase 3 cleavage sites by site-directed mutagenesis. The availability of the MNV nonstructural polyprotein cleavage map in concert with a permissive cell culture system should facilitate studies of norovirus replication. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. RP Sosnovtsev, SV (reprint author), 50 S Dr MSC 8007,Bldg 50,Room 6316, Bethesda, MD 20892 USA. EM ss216m@nih.gov FU NIAID NIH HHS [R01 AI054483] NR 52 TC 115 Z9 116 U1 0 U2 11 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 PY 2006 VL 80 IS 16 BP 7816 EP 7831 DI 10.1128/JVI.00532-06 PG 16 WC Virology SC Virology GA 070WV UT WOS:000239557700004 PM 16873239 ER PT J AU Atarashi, R Sim, VL Nishida, N Caughey, B Katamine, S AF Atarashi, Ryuichiro Sim, Valerie L. Nishida, Noriyuki Caughey, Byron Katamine, Shigeru TI Prion strain-dependent differences in conversion of mutant prion proteins in cell culture SO JOURNAL OF VIROLOGY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; SPONGIFORM ENCEPHALOPATHIES; AMYLOID PLAQUES; NATURAL SCRAPIE; TRANSGENIC MICE; MOUSE SCRAPIE; YEAST PRION; PROPAGATION; PRP; TRANSMISSION AB Although the protein-only hypothesis proposes that it is the conformation of abnormal prion protein (PrPSc) that determines strain diversity, the molecular basis of strains remains to be elucidated. In the present study, we generated a series of mutations in the normal prion protein (PrPC) in which a single glutamine residue was replaced with a basic amino acid and compared their abilities to convert to PrPSc in cultured neuronal N2a58 cells infected with either the Chandler or 22L mouse-adapted scrapie strain. In mice, these strains generate PrPSc of the same sequence but different conformations, as judged by infrared spectroscopy. Substitutions at codons 97, 167, 171, and 216 generated PrPC that resisted conversion and inhibited the conversion of coexpressed wild-type PrP in both Chandler-infected and 22L-infected cells. Interestingly, substitutions at codons 185 and 218 gave strain-dependent effects. The Q185R and Q185K PrP were efficiently converted to PrPSc in Chandler-infected but not 22L-infected cells. Conversely, Q218R and Q218H PrP were converted only in 22L-infected cells. Moreover, the Q218K PrP exerted a potent inhibitory effect on the conversion of coexpressed wild-type PrP in Chandler-infected cells but had little effect on 22L-infected cells. These results show that two strains with the same PrP sequence but different conformations have differing abilities to convert the same mutated PrPC. C1 NIAID, Rocky Mt Labs, Lab Persistent Viral Dis, NIH, Hamilton, MT 59840 USA. Nagasaki Univ, Grad Sch Biomed Sci, Dept Mol Microbiol & Immunol, Nagasaki 8538523, Japan. RP Atarashi, R (reprint author), NIAID, Rocky Mt Labs, Lab Persistent Viral Dis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM atarashir@niaid.nih.gov RI Sim, Valerie/C-4137-2013 OI Sim, Valerie/0000-0002-0088-8666 NR 59 TC 34 Z9 34 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 PY 2006 VL 80 IS 16 BP 7854 EP 7862 DI 10.1128/JVI.00424-06 PG 9 WC Virology SC Virology GA 070WV UT WOS:000239557700007 PM 16873242 ER PT J AU Joshi, A Nagashima, K Freed, EO AF Joshi, Anjali Nagashima, Kunio Freed, Eric O. TI Mutation of dileucine-like motifs in the human immunodeficiency virus type 1 capsid disrupts virus assembly, Gag-Gag interactions, Gag-membrane binding, and virion maturation SO JOURNAL OF VIROLOGY LA English DT Article ID ROUS-SARCOMA-VIRUS; IN-VITRO; PLASMA-MEMBRANE; MATRIX PROTEIN; DIMERIZATION DOMAIN; PARTICLE-PRODUCTION; PRIMARY MACROPHAGES; TERMINAL DOMAIN; AMINO-TERMINUS; HIV-1 GAG AB The human immunodeficiency virus type 1 (HIV-1) Gag precursor protein Pr55(Gag) drives the assembly and release of virus-like particles in the infected cell. The capsid (CA) domain of Gag plays an important role in these processes by promoting Gag-Gag interactions during assembly. The C-terminal domain (CTD) of CA contains two dileucine-like motifs (L-189/L-190 and I-201/L-202) implicated in regulating the localization of Gag to multivesicular bodies (MVBs). These dileucine-like motifs are located in the vicinity of the CTD dimer interface, a region of CA critical for Gag-Gag interactions during virus assembly and CA-CA interactions during core formation. To study the importance of the CA dileucine-like motifs in various aspects of HIV-1 replication, we introduced a series of mutations into these motifs in the context of a full-length, infectious HIV-1 molecular clone. CA mutants LL189,190AA and IL201,202AA were both severely impaired in virus particle production because of a variety of defects in the binding of Gag to membrane, Gag multimerization, and CA folding. In contrast to the model suggesting that the CA dileucine-like motifs regulate MVB targeting, the IL201,202AA mutation did not alter Gag localization to the MVB in either HeLa cells or macrophages. Revertants of single-amino-acid substitution mutants were obtained that no longer contained dileucine-like motifs but were nevertheless fully replication competent. The varied phenotypes of the mutants reported here provide novel insights into the interplay among Gag multimerization, membrane binding, virus assembly, CA dimerization, particle maturation, and virion infectivity. C1 NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI, Image Anal Lab, Res Technol Program, SAIC, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Bldg 535,Rm 108,Sultan St, Frederick, MD 21702 USA. EM efreed@mail.nih.gov FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 52 TC 44 Z9 45 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 PY 2006 VL 80 IS 16 BP 7939 EP 7951 DI 10.1128/JVI.00355-06 PG 13 WC Virology SC Virology GA 070WV UT WOS:000239557700016 PM 16873251 ER PT J AU Taraporewala, ZF Jiang, XF Vasquez-Del Capio, R Jayaram, H Prasad, BVV Patton, JT AF Taraporewala, Zenobia F. Jiang, Xiaofang Vasquez-Del Capio, Rodrigo Jayaram, Hariharan Prasad, B. V. Venkataram Patton, John T. TI Structure-function analysis of rotavirus NSP2 octamer by using a novel complementation system SO JOURNAL OF VIROLOGY LA English DT Article ID NONSTRUCTURAL PROTEIN NSP2; DNA-BINDING-PROTEIN; HELIX-DESTABILIZING PROPERTIES; TEMPERATURE-SENSITIVE MUTANTS; GROUP-C ROTAVIRUS; SIMIAN ROTAVIRUS-SA11; GENOME REPLICATION; EXPRESSION SYSTEM; VACCINIA VIRUS; RNA-SYNTHESIS AB Viral inclusion bodies, or viroplasms, that form in rotavirus-infected cells direct replication and packaging of the segmented double-stranded RNA (dsRNA) genome. NSP2, one of two rotavirus proteins needed for viroplasm assembly, possesses NTPase, RNA-binding, and helix-unwinding activities. NSP2 of the rotavirus group causing endemic infantile diarrhea (group A) was shown to self-assemble into large doughnut-shaped octamers with circumferential grooves and deep clefts containing nucleotide-binding histidine triad (HIT)-like motifs. Here, we demonstrate that NSP2 of group C rotavirus, a group that fails to reassort with group A viruses, retains the unique architecture of the group A octamer but differs in surface charge distribution. By using an NSP2-dependent complementation system, we show that the HIT-dependent NTPase activity of NSP2 is necessary for dsRNA synthesis, but not for viroplasm formation. The complementation system also showed that despite the retention of the octamer structure and the HIT-like fold, group C NSP2 failed to rescue replication and viroplasm formation in NSP2-deficient cells infected with group A rotavirus. The distinct differences in the surface charges on the Bristol and SA11 NSP2 octamers suggest that charge complementarity of the viroplasm-forming proteins guides the specificity of viroplasm formation and, possibly, reassortment restriction between rotavirus groups. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. RP Prasad, BVV (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM vprasad@bcm.tmc.edu; jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 FU NCRR NIH HHS [P41 RR002250]; NIAID NIH HHS [R01 AI036040, P01 AI057788, AI36040, R37 AI036040] NR 36 TC 34 Z9 38 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2006 VL 80 IS 16 BP 7984 EP 7994 DI 10.1128/JVI.00172-06 PG 11 WC Virology SC Virology GA 070WV UT WOS:000239557700020 PM 16873255 ER PT J AU Atwood-Moore, A Yan, K Judson, RL Levin, HL AF Atwood-Moore, Angela Yan, Kenneth Judson, Robert L. Levin, Henry L. TI The self primer of the long terminal repeat retrotransposon Tf1 is not removed during reverse transcription SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RNASE-H CLEAVAGE; TY3 INTEGRASE; MECHANISM; PROTEINS; MUTATIONS; GENERATE; COMPLEX; DNA AB The long terminal repeat retrotransposon Tf1 of Schizosaccharomyces pombe uses a unique mechanism of self priming to initiate reverse transcription. Instead of using a tRNA, Tf1 primes minus-strand synthesis with an 11-nucleotide RNA removed from the 5' end of its own transcript. We tested whether the self primer of Tf1 was similar to tRNA primers in being removed from the cDNA by RNase H. Our analysis of Tf1 cDNA extracted from virus-like particles revealed the surprising observation that the dominant species of cDNA retained the self primer. This suggests that integration of the cDNA relies on mechanisms other than reverse transcription to remove the primer. C1 NICHHD, Sect Eukaryot Transposable Elements, Lab Gene Regualt & Dev, NIH, Bethesda, MD 20892 USA. RP Levin, HL (reprint author), NICHHD, Sect Eukaryot Transposable Elements, Lab Gene Regualt & Dev, NIH, Bethesda, MD 20892 USA. EM henry_levin@nih.gov FU Intramural NIH HHS NR 26 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2006 VL 80 IS 16 BP 8267 EP 8270 DI 10.1128/JVI.01915-05 PG 4 WC Virology SC Virology GA 070WV UT WOS:000239557700048 PM 16873283 ER PT J AU Nadon, NL AF Nadon, Nancy L. TI Of mice and monkeys: National Institute on Aging resources supporting the use of animal models in biogerontology research SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID GENE-EXPRESSION PROFILE; MACAQUES MACACA-MULATTA; RHESUS-MONKEYS; CALORIC RESTRICTION; HEMATOLOGY VARIABLES; DIETARY RESTRICTION; BLOOD-CHEMISTRY; RELEVANCE; BRAIN AB The preponderance of our understanding of the biological changes that occur with aging has come from studies using rodents. Rodents are a valuable model for biogerontology research because of similarities to humans in the physiology and cell biology of aging. There are, however, many differences between rodents and humans, so application of findings in rodents to human aging requires the use of a model that is closer to humans at the genetic and physiological level. In aging research, the macaque has filled this need. There are many challenges associated with using nonhuman primates in aging research, not the least of which are the limited availability of aged monkeys and the cost of using them. To facilitate this research, the National Institute on Aging has developed several resources to assist investigators and promote the use of the nonhuman primate model in aging research. C1 NIA, Biol Aging Program, Bethesda, MD 20892 USA. RP Nadon, NL (reprint author), NIA, Biol Aging Program, 7201 Wisconsin Ave,GW 2C231, Bethesda, MD 20892 USA. EM nadonn@nia.nih.gov NR 21 TC 10 Z9 11 U1 1 U2 3 PU GERONTOLOGICAL SOCIETY 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 2006 VL 61 IS 8 BP 813 EP 815 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 075TU UT WOS:000239908900006 PM 16912097 ER PT J AU Holly, MK Dear, JW Hu, X Schechter, AN Gladwin, MT Hewitt, SM Yuen, PST Star, RA AF Holly, M. K. Dear, J. W. Hu, X. Schechter, A. N. Gladwin, M. T. Hewitt, S. M. Yuen, P. S. T. Star, R. A. TI Biomarker and drug-target discovery using proteomics in a new rat model of sepsis-induced acute renal failure SO KIDNEY INTERNATIONAL LA English DT Article DE sepsis; acute renal failure; rat model; proteomics; DIGE ID DIFFERENCE GEL-ELECTROPHORESIS; NITRIC-OXIDE; PROGNOSTIC FACTORS; AGED MICE; MORTALITY; INJURY; IDENTIFICATION; PLASMA; MULTICENTER; MECHANISMS AB Sepsis is one of the common causes of acute renal failure (ARF). The objective of this study was to identify new biomarkers and therapeutic targets. We present a new rat model of sepsis-induced ARF based on cecal ligation and puncture (CLIP). We used this model to find urinary proteins which may be potential biomarkers and/or drug targets. Aged rats were treated with fluids and antibiotics after CLIP. Urinary proteins from septic rats without ARF and urinary proteins from septic rats with ARF were compared by difference in-gel electrophoresis (DIGE). CLIP surgery elevated interleukin (IL)-6 and IL-10 serum cytokines and blood nitrite compared with sham-operated rats. However, there was a range of serum creatinine values at 24 h (0.4-2.3 mg/dl) and only 24% developed ARE Histology confirmed renal injury in these rats. Forty-nine percent of rats did not develop ARF. Rats without ARF also had less liver injury. The mortality rate at 24h was 27% but was increased by housing the post-surgery rats in metabolic cages. Creatinine clearance and urine output 2-8 h after CLIP was significantly reduced in rats which died within 24 h. Using DIGE we identified changes in a number of urinary proteins including albumin, brush-border enzymes (e.g., meprin-l-alpha) and serine protease inhibitors. The meprin-1-alpha inhibitor actinonin prevented ARF in aged mice. In summary, we describe a new rat model of sepsis-induced ARF which has a heterogeneous response similar to humans. This model allowed us to use DIGE to find changes in urinary proteins and this approach identified a potential biomarker and drug target-meprin-1-alpha. C1 NIDDK, Renal Diagnost & Therapeut Unit, Bethesda, MD 20892 USA. NIDDK, Mol Biol & Genet Sect, Bethesda, MD USA. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Star, RA (reprint author), NIDDK, Renal Diagnost & Therapeut Unit, 10 Ctr Dr,Bldg 10,Room 3N108, Bethesda, MD 20892 USA. EM Robert_Star@nih.gov RI Yuen, Peter/B-1954-2008; OI Yuen, Peter/0000-0001-9557-3909; Hewitt, Stephen/0000-0001-8283-1788; Schechter, Alan N/0000-0002-5235-9408 FU Intramural NIH HHS [Z01 DK043400-08, Z01 DK043403-08] NR 46 TC 71 Z9 76 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD AUG PY 2006 VL 70 IS 3 BP 496 EP 506 DI 10.1038/sj.ki.5001575 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 068QT UT WOS:000239390200014 PM 16760904 ER PT J AU Turban, S T Beutler, K Morris, RG Masilamani, S Fenton, RA Knepper, MA Packer, RK AF Turban, S. T Beutler, K. Morris, R. G. Masilamani, S. Fenton, R. A. Knepper, M. A. Packer, R. K. TI Long-term regulation of proximal tubule acid-base transporter abundance by angiotensin II SO KIDNEY INTERNATIONAL LA English DT Article DE candesartan; acid-base; AT1; NBC1; NHE3; NaPi-2 ID THICK ASCENDING LIMB; RENAL BRUSH-BORDER; NA+-H+ EXCHANGE; RAT-KIDNEY; METABOLIC-ACIDOSIS; ANTIPORTER ACTIVITY; STRAIGHT TUBULES; ENAC; COTRANSPORTERS; EXPRESSION AB In the proximal tubule, angiotensin II (Ang-II) regulates HCO3-reabsorption and H+ secretion by binding the type 1 Ang-II (AT1) receptor, stimulating Na+/HCO3-cotransport and Na+/H+ exchange. Studies were carried out to determine if longterm changes in Ang-II receptor occupation alter the abundance of the basolateral Na+/HCO3-cotransporter (NBC1) or the apical membrane type 3 Na+/H+ exchanger (NHE3). In the first set of experiments, rats eating a lowsodium diet were infused with the AT1 blocker, candesartan, or vehicle. In the second, lisinopril-infused rats were infused with either Ang II or vehicle. Transporter abundances were determined in whole kidney homogenates (WKH) and in brush border membrane (BBM) preparations by semiquantitative immunoblotting. Tissue distribution of transporters was assessed by immunocytochemistry. Blockade of the AT1 receptor by candesartan caused decreased abundance of NBC1 in WKH (59 +/- 9% of control; P < 0.05) and Ang-II infusion increased abundance (130 +/- 7% of control; P < 0.05). Changes in NBC1 in response to candesartan were confirmed immunohistochemically. Neither candesartan nor Ang II infusion affected the abundance of NHE3 in WKH or cortical homogenates. Candesartan decreased type 2 sodium-phosphate cotransporter abundance in both WKH (52 +/- 7% of control; P < 0.05) and BBM (32 +/- 7% of control; P < 0.05). Serum bicarbonate was decreased by candesartan and increased by Ang-II. Candesartan also decreased urinary ammonium excretion (P < 0.05). The long-term effects of Ang-II in the proximal tubule may be mediated in part by regulation of NBC1 abundance, modifying bicarbonate reabsorption. C1 George Washington Univ, Dept Biol Sci, Washington, DC 20052 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Packer, RK (reprint author), George Washington Univ, Dept Biol Sci, 320 Lisner Hall, Washington, DC 20052 USA. EM rkp@gwu.edu FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [Z01-HL-01285-KE] NR 44 TC 18 Z9 20 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD AUG PY 2006 VL 70 IS 4 BP 660 EP 668 DI 10.1038/sj.ki.5001571 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 077FW UT WOS:000240015100015 PM 16807546 ER PT J AU Hummel, FC Cohen, LG AF Hummel, Friedhelm C. Cohen, Leonardo G. TI Non-invasive brain stimulation: a new strategy to improve neurorehabilitation after stroke? SO LANCET NEUROLOGY LA English DT Review ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; UNAFFECTED HEMISPHERE; CORTICAL STIMULATION; INTERHEMISPHERIC INTERACTIONS; PREMOTOR CORTEX; ISCHEMIC-STROKE; HAND MOVEMENTS; RECOVERY; EXCITABILITY AB Background Motor impairment resulting from chronic stroke can have extensive physical, psychological, financial, and social implications despite available neurorehabilitative treatments. Recent studies in animals showed that direct epidural stimulation of the primary motor cortex surrounding a small infarct in the lesioned hemisphere (M1(lesioned hemisphere)) elicits improvements in motor function. Recent developments In human beings, proof of principle studies from different laboratories showed that non-invasive transcranial magnetic stimulation and direct current stimulation that upregulate excitability within M1(lesioned hemisphere) or downregulate excitability in the intact hemisphere (M1(intact hemisphere)) results in improvement in motor function in patients with stroke. Possible mechanisms mediating these effects can include the correction of abnormally persistent interhemispheric inhibitory drive from M1(intact hemisphere) to M1(lesioned hemisphere) in the process of generation of voluntary movements by the paretic hand, a disorder correlated with the magnitude of impairment. In this paper we review these mechanistically oriented interventional approaches. What next? These findings suggest that transcranial magnetic stimulation and transcranial direct current stimulation could develop into useful adjuvant strategies in neurorehabilitation but have to be further assessed in multicentre clinical trials. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20817 USA. NINDS, Stroke Neurorehabil Clin, NIH, Bethesda, MD 20817 USA. Univ Hamburg, Med Ctr, Dept Neurol, Cort Physiol Res Grp, Hamburg, Germany. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20817 USA. EM cohenl@ninds.nih.gov FU Intramural NIH HHS NR 54 TC 358 Z9 372 U1 4 U2 37 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD AUG PY 2006 VL 5 IS 8 BP 708 EP 712 DI 10.1016/S1474-4422(06)70525-7 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 068ZV UT WOS:000239415100023 PM 16857577 ER PT J AU Yadavalli, VK Forbes, JG Wang, K AF Yadavalli, Vamsi K. Forbes, Jeffrey G. Wang, Kuan TI Functionalized self-assembled monolayers on ultraflat gold as platforms for single molecule force spectroscopy and imaging SO LANGMUIR LA English DT Article ID SCANNING PROBE MICROSCOPY; IMMOBILIZATION STRATEGY; PROTEIN ADSORPTION; COILED-COIL; SURFACES; AFM; IMMUNOGLOBULIN; ALKANETHIOLS; BIOMOLECULES; FABRICATION AB Single molecule force spectroscopy is a valuable tool for studying unfolding and nanomechanical properties of proteins. The common practice is to stretch proteins from a surface that was dosed to give a reasonable hit rate and to analyze the curves that exhibit the expected characteristics of a single polymer. Whether the surface-bound proteins are indeed single and isolated remains unclear, and the undesirable protein/surface interactions that obscure informative features of the force curves are implicitly assumed to be absent. In this study, mixed self-assembled monolayers ( SAMs) consisting of N-hydroxysuccinimide ( NHS) and oligoethylene glycol ( OEG) terminated thiols on an ultraflat gold surface were used to covalently immobilize proteins via lysine residues. By the optimization of attachment sites via lysine-NHS linkages amidst a protein-resistant layer of the OEG SAM, it was possible to isolate single proteins for study in a controlled fashion. The single protein distribution on the surface is clearly demonstrated by atomic force microscopy ( AFM) imaging. The OEG also significantly reduces nonspecific tip-surface interactions between the cantilever and surface. Stretching covalently attached single proteins produces high-quality and reproducible force-extension curves. This experimental strategy is an attractive platform with which to study protein structure, interactions, and nanomechanical properties of single proteins. C1 NIAMSD, Muscle Proteom & Nanotechnol Sect, Muscle Biol Lab, DHHS,NIH, Bethesda, MD 20892 USA. RP Wang, K (reprint author), NIAMSD, Muscle Proteom & Nanotechnol Sect, Muscle Biol Lab, DHHS,NIH, Bethesda, MD 20892 USA. EM wangk@exchange.nih.gov OI Yadavalli, Vamsi/0000-0002-8879-1948 FU Intramural NIH HHS NR 54 TC 25 Z9 25 U1 1 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD AUG 1 PY 2006 VL 22 IS 16 BP 6969 EP 6976 DI 10.1021/la060320h PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 066OB UT WOS:000239238100040 PM 16863247 ER PT J AU Griffith, AJ Yang, Y Pryor, SP Park, HJ Jabs, EW Nadol, JB Russell, LJ Wasserman, DI Richard, G Adams, JC Merchant, SN AF Griffith, Andrew J. Yang, Yandan Pryor, Shannon P. Park, Hong-Joon Jabs, Ethylin Wang Nadol, Joseph B., Jr. Russell, Laura J. Wasserman, Daniel I. Richard, Gabriele Adams, Joe C. Merchant, Saumil N. TI Cochleosaccular dysplasia associated with a connexin 26 mutation in keratitis-ichthyosis-deafness syndrome SO LARYNGOSCOPE LA English DT Article DE Scheibe dysplasia; cochleosaccular dysplasia; connexin 26; GJB2; hearing; KID syndrome ID HEARING IMPAIRMENT; KID SYNDROME; HISTOPATHOLOGY; EXPRESSION AB Objective: The objective of this study was to characterize the temporal bone phenotype associated with a mutation of GJB2 (encoding connexin 26). Study Design: The authors conducted correlative clinical, molecular genetic, and postmortem histopathologic analysis. Methods: The study subject was a male infant with keratitis-ichthyosis-deafness (KID) syndrome. We performed a nucleotide sequence analysis of GJB2 and a histopathologic analysis of the temporal bones. Results: The subject was heterozygous for G45E, a previously reported KID syndrome mutation of GJB2. The primary inner ear abnormality was dysplasia of the cochlear and saccular neuroepithelium. Conclusions: GJB2 mutations can cause deafness in KID syndrome, and possibly in other GJB2 mutant phenotypes, by disrupting cochlear differentiation. C1 NIDCD, Sect Gene Struct & Funct, NIH, Bethesda, MD USA. NIDCD, Hearing Sect, NIH, Bethesda, MD USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Inst Med Genet, Baltimore, MD 21205 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. McGill Univ, Montreal Childrens Hosp, Dept Pediat, Montreal, PQ H3H 1P3, Canada. Thomas Jefferson Univ, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA. RP Griffith, AJ (reprint author), 5 Res Court,Room 2A-01, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov OI Jabs, Ethylin/0000-0001-8983-5466 FU NIDCD NIH HHS [1Z01 DC 000064-02, Z01 DC000064, 1Z01 DC 000060-02, Z01 DC000060, R01 DC003929]; PHS HHS [NIH 13849] NR 15 TC 32 Z9 33 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD AUG PY 2006 VL 116 IS 8 BP 1404 EP 1408 DI 10.1097/01.mlg.0000224549.75161.ca PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 071RN UT WOS:000239619500016 PM 16885744 ER PT J AU Kobrin, C Cha, SC Qin, H Raffeld, M Fend, F Quintanilla-Martinez, L Grove, S Jaffe, ES Kwak, LW AF Kobrin, Carol Cha, Soung-Chul Qin, Hong Raffeld, Mark Fend, Falko Quintanilla-Martinez, Leticia Grove, Sheldon Jaffe, Elaine S. Kwak, Larry W. TI Molecular analysis of light-chain switch and acute lymphoblastic leukemia transformation in two follicular lymphomas: Implications for lymphomagenesis SO LEUKEMIA & LYMPHOMA LA English DT Article DE immunoglobulin (Ig) receptor revision; idiotype vaccine; immune selection ID B-CELL LYMPHOMA; LASER-CAPTURE-MICRODISSECTION; NON-HODGKINS-LYMPHOMAS; VARIABLE REGION GENES; GERMINAL CENTER; SOMATIC HYPERMUTATION; IMMUNOGLOBULIN GENES; CHROMOSOMAL TRANSLOCATION; V(D)J RECOMBINATION; CLUSTER REGION AB We observed novel transformations of follicular lymphoma ( FL), first, a switch in immunoglobulin ( Ig) light chain, and second, transformation of FL to acute lymphoblastic leukemia ( ALL). Each set of tumors shared a common clonal origin, as demonstrated by expression of identical, unique CDR IIIH sequences, shared somatic mutations in JH, and identical bcl- 2 translocation breakpoints of microdissected ALL cells. Molecular analysis of lambda V- gene expression demonstrated lambda- bearing cells in the original kappa tumor, while expansion of the lambda subclone at relapse occurred after active immunotherapy targeting the Ig receptor. These exceptional cases are compatible with a more contemporary model of lymphomagenesis in which critical events originate from genetic mechanisms which normally occur in germinal center ( GC) B cells and challenge the current paradigm of parallel generation of subclones from an early, pre- GC precursor. It is also possible that the outgrowth of these variants was a consequence of immunoselection. C1 NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Bethesda, MD 20892 USA. NCI, Pathol Lab, Div Clin Sci, Bethesda, MD 20892 USA. Tech Univ Munich, Dept Pathol, D-8000 Munich, Germany. GSF, Res Ctr, Munich, Germany. NCI, Lab Expt Transplantat & Immunol, Canc Res Ctr, Bethesda, MD USA. RP Kwak, LW (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, 1515 Holcombe Blvd,Unit 429, Houston, TX 77030 USA. EM lkwak@mdanderson.org FU NCI NIH HHS [N01-CO-56000] NR 56 TC 15 Z9 15 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD AUG PY 2006 VL 47 IS 8 BP 1523 EP 1534 DI 10.1080/10428190600612909 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA 083DH UT WOS:000240435600017 PM 16966263 ER PT J AU Robyn, J AF Robyn, Jamie TI Imatinib-responsive hypereosinophilic syndrome SO LEUKEMIA RESEARCH LA English DT Editorial Material ID MYELOPROLIFERATIVE VARIANT; EOSINOPHILIC DISORDERS; MESYLATE; MASTOCYTOSIS; THERAPY; FUSION C1 NIH, Lab Allerg Dis, Bethesda, MD 20892 USA. RP Robyn, J (reprint author), NIH, Lab Allerg Dis, 10 Ctr Dr,Room 11C205 MSC 1881, Bethesda, MD 20892 USA. EM jrobyn@niaid.nih.gov FU Intramural NIH HHS NR 14 TC 0 Z9 0 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 2006 VL 30 IS 8 BP 915 EP 916 DI 10.1016/j.leukres.2006.02.007 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 062IA UT WOS:000238936600002 PM 16530830 ER PT J AU Bennett, KM Hyde, JS Schmainda, KM AF Bennett, Kevin M. Hyde, James S. Schmainda, Kathleen M. TI Water diffusion heterogeneity index in the human brain is insensitive to the orientation of applied magnetic field gradients SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE diffusion-weighted; MRI; stretched-exponential; human; brain ID SPIN-LATTICE-RELAXATION; RESTRICTED DIFFUSION; RAT-BRAIN; RESONANCE; SPECTROSCOPY; COEFFICIENT; STROKE; GLIOMA; TENSOR; TUMORS AB The a diffusion-weighted imaging (DWI) method was developed to study heterogeneous water diffusion in the human brain using magnetic resonance imaging (MRI). An advantage of this model is that it does not require an assumption about the shape of the intravoxel distribution of apparent diffusion rates, and it has a calculable relationship to this distribution. The alpha-DWI technique is useful for detecting microstructural tissue changes associated with brain tumor invasion, and may be useful for directing therapy to invading tumor cells. In previous work, a-DWI was performed with magnetic field gradients applied along a single direction in order to avoid artificially introducing a source of heterogeneity to the decay. However, it is known that restricted diffusion is anisotropic in the brain, and the a-DWI method must take this into account to be complete. In this work the relationship between the applied magnetic field gradients and the fitted stretched-exponential model parameters was studied in the human brain. It was found the distributed diffusion coefficient (DDC) varies with the direction of applied gradients, while the heterogeneity index a is relatively direction-insensitive. It is proposed that in clinical use, maps of a can be created using diffusion-weighting gradients applied in a single direction that reflect the tissue heterogeneity. C1 Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Dept Radiol, Milwaukee, WI 53226 USA. NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Schmainda, KM (reprint author), Med Coll Wisconsin, Dept Biophys, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM bennettkev@ninds.nih.gov NR 27 TC 36 Z9 39 U1 0 U2 6 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 2006 VL 56 IS 2 BP 235 EP 239 DI 10.1002/mrm.20960 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 069RI UT WOS:000239465500001 PM 16929466 ER PT J AU Matsumoto, K Bernardo, M Subramanian, S Choyke, P Mitchell, JB Krishna, MC Lizak, MJ AF Matsumoto, Ken-ichiro Bernardo, Marcelino Subramanian, Sankaran Choyke, Peter Mitchell, James B. Krishna, Murali C. Lizak, Martin J. TI MR assessment of changes of tumor in response to hyperbaric oxygen treatment SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE relaxation time; hyperbaric oxygenation; tumor hypoxia; MRI; T-1 ID MAGNETIC-RESONANCE; IN-VIVO; CONTRAST; INHALATION; THERAPY; PO(2); FLOW; T-1 AB Enhancement of image intensity, using the T-1-weighted spoiled gradient-echo (SPGR) sequence, was measured in SCC tumor implanted in the flank of C3H mice while they were subjected to several types of oxygenation challenges inside a hyperbaric chamber designed and constructed to fit in an MRI resonator. The central portions of the tumor gave a positive enhancement, while the periphery showed signal reduction during both normobaric (NBO) and hyperbaric (HBO) oxygen challenges. In the contralateral normal leg, nearly 70% of the region showed a decrease in intensity, and the rest showed a positive enhancement. The positive signal enhancement was markedly greater under HBO compared to NBO. Calculated R-1, R-2, and M-0 maps from multivariate fitting of images acquired by a multislice multiecho (MSME) sequence with variable TR before, during, and after HBO treatment confirm that the source of SPGR signal enhancement in the tumor is associated with shortening of T-1. C1 NCI, Radiat Biol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Canc Res Ctr, Bethesda, MD 20892 USA. SAIC Frederick, Res Technol Program, Frederick, MD USA. NINDS, MRI Res Facil, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Canc Res Ctr, NIH, Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM murali@helix.nih.gov FU Intramural NIH HHS NR 26 TC 46 Z9 46 U1 0 U2 15 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 2006 VL 56 IS 2 BP 240 EP 246 DI 10.1002/mrm.20961 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 069RI UT WOS:000239465500002 PM 16795082 ER PT J AU Okajo, A Matsumoto, KI Mitchell, JB Krishna, MC Endo, K AF Okajo, Aya Matsumoto, Ken-ichiro Mitchell, James B. Krishna, Murali C. Endo, Kazutoyo TI Competition of nitroxyl contrast agents as an in vivo tissue redox probe: Comparison of pharmacokinetics by the bile flow monitoring (BFM) and blood circulating monitoring (BCM) methods using X-band EPR and simulation of decay profiles SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE paramagnetic contrast agent; nitroxyl radical; redox probe; electron paramagnetic resonance imaging; MRI; pharmacokinetics ID SPIN-RESONANCE SPECTROSCOPY; RAT-LIVER; ESR; MICE; ENHANCEMENT; RADICALS; MOIETY; TUMOR AB Nitroxyl radicals used as tissue redox-sensitive contrast agents in electron paramagnetic resonance (EPR) and/or NMR imaging should satisfy the following two conditions: 1) the molecules disperse into tissues rapidly, and 2) paramagnetic loss occurs by simple reduction of the radical. The pharmacokinetic trends of several nitroxyl contrast agents were compared with the results obtained by bile flow monitoring (BFM) and blood circulation monitoring (BCM) methods using X-band EPR. The nitroxyl radicals (TEMPO, TEMPONE (oxo-TEMPO), and amino-TEMPO) showed additional EPR signals in the bile that were attributed to metabolites formed during transport from blood to bile through the liver. However, the highly hydrophilic CAT-1 (trimethylammonium-TEMPO), which has low membrane permeability, showed minimal concentration in the bile. Probes that have carboxyl moiety, such as carboxy-TEMPO and carboxy-PROXYL, can be transported via anion transporter into hepatic cells. The EPR signal decay profiles of the nitroxyl radicals were simulated based on the experimental data. The simulation, which we previously applied to mouse blood, was modified to simultaneously fit the experimental results of BFM and BCM obtained with rats. The simulation data showed the simplicity/complexity of the pharmacokinetic mechanisms and that carbamoyl-PROXYL and TEMPOL (hydroxy-TEMPO) are suitable contrast agents for assessing tissue redox status. C1 NCI, Ctr Canc Res, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Matsumoto, K (reprint author), Matsumoto,4-9-1 Anagawa,Inage Ku, Chiba 2638555, Japan. EM matsumok@nirs.go.jp NR 27 TC 10 Z9 10 U1 1 U2 3 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 2006 VL 56 IS 2 BP 422 EP 431 DI 10.1002/mrm.20958 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 069RI UT WOS:000239465500022 PM 16810697 ER PT J AU Zhao, YG Morales, DC Hermesz, E Lee, WK Pfaff, SL Westphal, H AF Zhao, Yangu Morales, Donna Chelle Hermesz, Edit Lee, Woon-Kyu Pfaff, Samuel L. Westphal, Heiner TI Reduced expression of the LIM-homeobox gene Lhx3 impairs growth and differentiation of Rathke's pouch and increases cell apoptosis during mouse pituitary development SO MECHANISMS OF DEVELOPMENT LA English DT Article DE pituitary development; Rathke's pouch; differentiation; apoptosis; LIM-homeodomain proteins; Lhx3; Pitx1; Pitx2; mouse ID ANTERIOR-PITUITARY; ORGANOGENESIS; PIT-1; SPECIFICATION; REQUIREMENT; LINEAGE; PITX2; PROP1 AB The formation of the anterior and intermediate lobes of the pituitary gland is a multi-step process regulated by cell-cell interactions involving a number of signaling pathways and by cascades of cell-intrinsic transcription factors. The LIM-homeodoamin protein Lhx3 has previously been shown to play an essential role in the growth of Rathke's pouch, a primordium of the anterior and intermediate lobes of the pituitary. However, the mechanisms underlying the function and regulation of Lhx3 remain to be elucidated. Here we report that a targeted insertion of a DNA fragment in the 3'-untranslated region of the Lhx3 gene reduces the expression of both Lhx3 mRNA and protein in Ratlike's pouch. Mutant mice homozygous for this Lhx3 allele show severe hypoplasia of the pouch, a defect identical to that observed in Lhx3-null mutants. To gain insights into the mechanism of Lhx3 function in pituitary development, we further analyzed the Lhx3 deficient mutants by examination of early pituitary marker expression, cell proliferation, and cell apoptosis. Our results revealed an increase in cell apoptosis and a loss of Islet1 and Calbindin marker expression in Rathke's pouch of these mutants. Recently, increased cell apoptosis in Ratlike's pouch has been described in mutant mice impaired in the function of the bicoid-like homeodomain proteins Pitx1 and Pitx2. In those mutants, the expression of Lhx3 is absent. Our results thus underscore the view that Lhx3 functions downstream of the Pitx factors in the same transcriptional cascade that controls growth and early cell differentiation of the developing pituitary gland. Published by Elsevier Ireland Ltd. C1 NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. Salk Inst Biol Studies, GEL Pfaff, La Jolla, CA 92037 USA. RP Westphal, H (reprint author), NICHHD, Lab Mammalian Genes & Dev, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hw@mail.nih.gov FU Intramural NIH HHS NR 24 TC 26 Z9 26 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 2006 VL 123 IS 8 BP 605 EP 613 DI 10.1016/j.mod.2006.06.005 PG 9 WC Developmental Biology SC Developmental Biology GA 088OM UT WOS:000240821000002 PM 16859901 ER PT J AU Baldwin, LM Klabunde, CN Green, P Barlow, W Wright, G AF Baldwin, Laura-Mae Klabunde, Carrie N. Green, Pam Barlow, William Wright, George TI In search of the perfect comorbidity measure for use with administrative claims data - Does it exist? SO MEDICAL CARE LA English DT Article; Proceedings Paper CT AcademyHealth Annual Meeting CY JUN, 2004 CL San Diego, CA DE comorbidity; claims data; Medicare; risk adjustment ID PROSTATE-CANCER; ELDERLY-PATIENTS; BREAST-CANCER; COLON-CANCER; INDEX; CHEMOTHERAPY; VALIDATION; MORTALITY; MEDICARE; AGE AB Background: Numerous measures of comorbidity have been developed for health services research with administrative claims. Objective: We sought to compare the performance of 4 claims-based comorbidity measures. Objective: We sought to compare the performance of 4 claims-based comorbidity measures. Research Design and Subjects: We undertook a retrospective cohort study of 5777 Medicare beneficiaries ages 66 and older with stage III colon cancer reported to the Surveillance, Epidemiology, and End Results Program between January 1, 1992 and December 31, 1996. Results: For all measures, greater comorbidity significantly predicted lower receipt of chemotherapy and higher noncancer death. Nested logistic regression modeling suggests that using more claims sources to measure comorbidity generally improves the prediction of chemotherapy receipt and noncancer death, but depends on the measure type and outcome studied. All 4 comorbidity measures significantly improved the fit of baseline regression models for both chemotherapy receipt (baseline c-statistic 0.776; ranging from 0.779 after adding ACGs and Klabunde to 0.789 after Elixhauser) and noncancer death (baseline c-statistic 0.687; ranging from 0.717 after adding ACGs to 0.744 after Elixhauser). Conclusions: Although some comorbidity measures demonstrate minor advantages over others, each is fairly robust in predicting both chemotherapy receipt and noncancer death. Investigators should choose among these measures based on their availability, comfort with the methodology, and outcomes of interest. C1 Univ Washington, Dept Family Med, Seattle, WA 98195 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Natl Canc Inst, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD USA. RP Baldwin, LM (reprint author), Univ Washington, Dept Family Med, Box 354982, Seattle, WA 98195 USA. EM lmb@fammed.washington.edu FU NCI NIH HHS [R01 CA089544, R01 CA089544-01, R01CA089544] NR 27 TC 105 Z9 106 U1 2 U2 5 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 2006 VL 44 IS 8 BP 745 EP 753 DI 10.1097/01.mlr.0000223475.70440.07 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 068FE UT WOS:000239357200007 PM 16862036 ER PT J AU Conigliaro, J Justice, AC Gordon, AJ Bryant, K AF Conigliaro, Joseph Justice, Amy C. Gordon, Adam J. Bryant, Kendall CA VACS Alcohol Behavior Change Res G TI Role of alcohol in determining human immunodeficiency virus (HIV)-relevant outcomes - A conceptual model to guide the implementation of evidence-based interventions into practice SO MEDICAL CARE LA English DT Editorial Material ID HIV-INFECTION; SUBSTANCE USE; ANTIRETROVIRAL MEDICATIONS; REPORTED ADHERENCE; SEXUAL-BEHAVIOR; RISK BEHAVIOR; USE DISORDERS; CONSUMPTION; PREDICTORS; DRINKING C1 Univ Kentucky, Program Qual Safety & Patient Rights, Dept Med, Lexington, KY 40536 USA. Yale Univ, VA Connecticut Healthcare Syst, New Haven, CT USA. Univ Pittsburgh, Ctr Hlth Equ Res & Promot, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NIAAA, Rockville, MD 20852 USA. RP Conigliaro, J (reprint author), Univ Kentucky, Program Qual Safety & Patient Rights, Dept Med, 800 Rose St,N118, Lexington, KY 40536 USA. EM jconigliaro@uky.edu FU NIAAA NIH HHS [U01-AA13566] NR 45 TC 32 Z9 33 U1 2 U2 5 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 2006 VL 44 IS 8 SU 2 BP S1 EP S6 DI 10.1097/01.mlr.0000223659.36369.cf PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 069IB UT WOS:000239438500001 PM 16849963 ER PT J AU Cook, RL McGinnis, KA Kraemer, KL Gordon, AJ Conigliaro, J Maisto, SA Samet, JH Crystal, S Rimland, D Bryant, KJ Braithwaite, RS Justice, AC AF Cook, Robert L. McGinnis, Kathleen A. Kraemer, Kevin L. Gordon, Adam J. Conigliaro, Joseph Maisto, Stephen A. Samet, Jeffrey H. Crystal, Stephen Rimland, David Bryant, Kendall J. Braithwaite, R. Scott Justice, Amy C. TI Intoxication before intercourse and risky sexual behavior in male veterans with and without human immunodeficiency virus infection SO MEDICAL CARE LA English DT Article DE HIV infection; HIV-positive status; prevention; risk behaviors; substance abuse ID HIV TRANSMISSION RISK; POSITIVE MEN; ALCOHOL-USE; TRANSMITTED-DISEASES; SUBSTANCE USE; DRUG-USE; PREVENTION; AIDS; PREVALENCE; PREDICTORS AB Background: Male veterans represent a large population at risk for acquiring or transmitting human immunodeficiency virus (HIV) infection. We sought to determine the prevalence of risky sexual behavior among veterans with and without HIV infection and to assess the relationship of intoxication before intercourse and other measures of drug and alcohol use to risky sexual behavior in this population. Methods: We analyzed baseline data on 1009 HIV-positive (mean age 49 years) and 710 HIV-negative male veterans (mean age 55 years) who were participating in the Veterans Aging Cohort 5-Site Study (VACS 5). Participants completed a written questionnaire that included measures of alcohol and drug use and risky sexual behavior. Results: Compared with HIV-negative veterans, HIV-positive veterans were more likely to report 5 or more sexual partners in the past year (14% vs. 4%, P < 0.01), less likely to report not using a condom at last intercourse (25% vs. 75%, P < 0.01), and similarly likely to report having 2 or more partners and inconsistent condom use (10% vs. 10%). Among sexually active HIV-positive veterans, intoxication before intercourse was significantly associated with having 5 or more sexual partners in the past year (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.1-2.8), inconsistent condom use (OR 1.8, 95% CI 1.2-2.7), and the combined measure of 2 or more partners and inconsistent condom use (OR 1.8, 95% CI 1.1-3.0). Intoxication before intercourse was not significantly associated with these behaviors in HIV-negative veterans, although similar trends were noted. Conclusion: Risky sexual behavior was common among male veterans attending outpatient clinics and is more common among HIV-positive veterans who use alcohol and drugs in sexual situations. Asking HIV-positive men a single question about intoxication before intercourse could help to identify men at increased risk of engaging in risky sexual behavior, and specific advice to avoid intoxication in sexual situations could help to reduce risky sexual behavior. C1 Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Ctr Urban & Social Res, Pittsburgh, PA 15213 USA. VA Med Ctr, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. Univ Kentucky, Dept Med, Lexington, KY 40506 USA. Syracuse Univ, Dept Psychol, Syracuse, NY USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Rutgers State Univ, Inst Hlth Hlth Care Policy & Aging Res, New Brunswick, NJ 08903 USA. Emory Univ, Sch Med, Dept Med, Atlanta, GA USA. VA Med Ctr, Atlanta, GA USA. NIAAA, Bethesda, MD USA. Yale Univ, Dept Med, New Haven, CT 06520 USA. W Haven Vet Affairs Med Ctr, New Haven, CT USA. RP Cook, RL (reprint author), Univ Pittsburgh, Dept Med, 230 McKee Pl,Suite 600, Pittsburgh, PA 15213 USA. EM cookrl@upmc.edu FU NIA NIH HHS [K23 AG00826]; NIAAA NIH HHS [3U01 AA 13566] NR 33 TC 22 Z9 22 U1 5 U2 9 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 2006 VL 44 IS 8 SU 2 BP S31 EP S36 DI 10.1097/01.mlr.0000223710.35008.d9 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 069IB UT WOS:000239438500005 PM 16849966 ER PT J AU Fultz, SL Skanderson, M Mole, LA Gandhi, N Bryant, K Crystal, S Justice, AC AF Fultz, Shawn L. Skanderson, Melissa Mole, Larry A. Gandhi, Neel Bryant, Kendall Crystal, Stephen Justice, Amy C. TI Development and verification of a "virtual" cohort using the national VA health information system SO MEDICAL CARE LA English DT Article DE cohort studies; databases; HIV; information systems; validation studies; veterans ID HUMAN-IMMUNODEFICIENCY-VIRUS; ADMINISTRATIVE DATA; MEDICAID CLAIMS; DRUG-USERS; VETERANS; AIDS; SCHIZOPHRENIA; MORTALITY; HOSPITALIZATION; BENEFICIARIES AB Background: The VA's integrated electronic medical record makes it possible to create a "virtual" cohort of veterans with and without HIV infection to monitor trends in utilization, toxicity, and outcomes. Objectives: We sought to develop a virtual cohort of HIV-infected veterans by adapting an existing algorithm, verifying this algorithm against independent clinical data, and finally identifying demographically-similar HIV-uninfected comparators. Research Design: Subjects were identified from VA administrative data in fiscal years 1998-2003 using a modified existing algorithm, then linked with Immunology Case Registry (ICR, the VA's HIV registry) and Pharmacy Benefits Management (centralized database of outpatient prescriptions) to verify accuracy of identification. The algorithm was modified to maximize positive predictive value (PPV) against ICR. Finally, 2 HIV-uninfected comparators were matched to each HIV-infected subject. Results: Using a single HIV code, 30,564 subjects were identified (positive predictive value 69%). Modification to require > 1 outpatient or I inpatient code improved the positive predictive value to 88%. The lack of confirmatory laboratory and pharmacy data for the majority of subjects with a single outpatient code also supported this change. Of subjects identified with the modified algorithm, 89% had confirmatory evidence. When the modified algorithm was applied to fiscal years 1997-2004, 33,420 HIV-infected subjects were identified. Two HIV-uninfected comparators were matched to each subject for an overall cohort sample of 100,260. Conclusions: In the HAART era, HIV-related codes are sufficient for identifying HIV-infected subjects from administrative data when patients with a single outpatient code are excluded. A large cohort of HIV-infected subjects and matched comparators can be identified from existing VA administrative datasets. C1 VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. Yale Univ, Sch Med, New Haven, CT USA. VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Ctr Qual Management Publ Hlth, VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. Emory Univ, Sch Med, Atlanta, GA USA. NIAAA, NIH, Bethesda, MD USA. Rutgers State Univ, New Brunswick, NJ 08903 USA. RP Justice, AC (reprint author), VA Connecticut Healthcare Syst, Bldg 35A,Room 2-212 11 ACSLG,950 Campbell Ave, West Haven, CT 06516 USA. EM amy.justice2@va.gov FU NIA NIH HHS [K08 AG00826]; PHS HHS [U01-13566] NR 27 TC 101 Z9 102 U1 1 U2 5 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 2006 VL 44 IS 8 SU 2 BP S25 EP S30 DI 10.1097/01.mlr.0000223670.00890.74 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 069IB UT WOS:000239438500004 PM 16849965 ER PT J AU Justice, AC Dombrowski, E Conigliaro, J Fultz, SL Gibson, D Madenwald, T Goulet, J Simberkoff, M Butt, AA Rimland, D Rodriguez-Barradas, MC Gibert, CL Oursler, KAK Brown, S Leaf, DA Goetz, MB Bryant, K AF Justice, Amy C. Dombrowski, Elizabeth Conigliaro, Joseph Fultz, Shawn L. Gibson, Deborah Madenwald, Tamra Goulet, Joseph Simberkoff, Michael Butt, Adeel A. Rimland, David Rodriguez-Barradas, Maria C. Gibert, Cynthia L. Oursler, Kris Ann K. Brown, Sheldon Leaf, David A. Goetz, Matthew B. Bryant, Kendall TI Veterans Aging Cohort Study (VACS) - Overview and description SO MEDICAL CARE LA English DT Article DE HIV/AIDS; alcohol; aging veterans; data management/research design ID MITOCHONDRIAL ASPARTATE-AMINOTRANSFERASE; PRIMARY-CARE; PSYCHOMETRIC PROPERTIES; ALCOHOL-CONSUMPTION; REPORTED ADHERENCE; CLINICAL-TRIALS; DISORDERS; AFFAIRS; RELIABILITY; VALIDATION AB Background: The Veterans Aging Cohort Study (VACS) is a study of human immunodeficiency virus (HIV) infected and uninfected patients seen in infectious disease and general medical clinics. VACS includes the earlier 3 and 5 site studies (VACS 3 and VACS 5) as well as the ongoing 8 site study. Objectives: We sought to provide background and context for analyses based upon VACS data, including study design and rationale as well as its basic protocol and the baseline characteristics of the enrolled sample. Research Design: We undertook a prospectively consented multisite observational study of veterans in care with and without HIV infection. Measures: Data were derived from patient and provider self report, telephone interviews, blood and DNA samples, focus groups, and full access to the national VA "paperless" electronic medical record system. Results: More than 7200 veterans have been enrolled in at least one of the studies. The 8 site study (VACS) has enrolled 2979 HIV-infected and 3019 HIV-uninfected age-race-site matched comparators and has achieved stratified enrollment targets for race/ethnicity and age and 99% of its total target enrollment as of October 30, 2005. Participants in VACS are similar to other veterans receiving care within the VA. VACS participants are older and more predominantly black than those reported by the Centers for Disease Control. Conclusions: VACS has assembled a rich, in-depth, and representative sample of veterans in care with and without HIV infection to conduct longitudinal analyses of questions concerning the association between alcohol use and related comorbid and AIDS-defining conditions. C1 VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. Yale Univ, Sch Med, Sect Gen Med, New Haven, CT USA. Yale Univ, Sch Med, Dept Internal Med, Program Aging, New Haven, CT 06510 USA. Univ Kentucky, Med Ctr, Lexington, KY USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. NYU, Sch Med, New York, NY USA. VA New York Harbor Healthcare Syst, New York, NY USA. VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. Emory Univ, Sch Med, Atlanta, GA USA. VA Med Ctr, Atlanta, GA USA. Baylor Coll Med, Houston, TX 77030 USA. Michael E DeBakey VAMC, Houston, TX USA. George Washington Univ, Med Ctr, Washington, DC 20037 USA. VA Med Ctr, Washington, DC USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Baltimore VA Med Ctr, Baltimore, MD USA. Bronx Vet Adm Med Ctr, New York, NY USA. Mt Sinai Sch Med, New York, NY USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NIAAA, HIV AIDS Res, Rockville, MD 20852 USA. RP Justice, AC (reprint author), VA Connecticut Healthcare Syst, Bldg 35A,Room 212,950 Campbell Ave 11-ACLSG, West Haven, CT 06516 USA. EM amy.justice2@va.gov FU NIA NIH HHS [K23 AG024896, K23 AG024896-01A2]; NIAAA NIH HHS [U01 AA 13566, U01 AA013566] NR 43 TC 121 Z9 121 U1 2 U2 6 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 2006 VL 44 IS 8 SU 2 BP S13 EP S24 DI 10.1097/01.mlr.0000223741.02074.66 PG 12 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 069IB UT WOS:000239438500003 PM 16849964 ER PT J AU Justice, AC Lasky, E McGinnis, KA Skanderson, M Conigliaro, J Fultz, SL Crothers, K Rabeneck, L Rodriguez-Barradas, M Weissman, SB Bryant, K AF Justice, Amy C. Lasky, Elaine McGinnis, Kathleen A. Skanderson, Melissa Conigliaro, Joseph Fultz, Shawn L. Crothers, Kristina Rabeneck, Linda Rodriguez-Barradas, Maria Weissman, Sharon B. Bryant, Kendall CA VACS 3 Project Team TI Medical disease and alcohol use among veterans with human immunodeficiency infection - A comparison of disease measurement strategies SO MEDICAL CARE LA English DT Article DE alcohol; HIV; comorbid disease; ICD-9 codes; chart review ID CANCER THERAPY; HIV-INFECTION; ADMINISTRATIVE DATA; USE DISORDERS; AGING COHORT; PRIMARY-CARE; EPIDEMIOLOGY; CONSUMPTION; OUTCOMES; TIME AB Background: Many people with human immunodeficiency (HIV) infection drink alcohol. We asked whether level of exposure to alcohol is associated with medical disease in a linear,or nonlinear manner, whether the association depends upon the proximity of alcohol use, and whether it varies by source used to measure disease (chart review vs. ICD-9 Diagnostic Codes). Methods: The Veterans Aging 3 Site Cohort Study (VACS 3) enrolled 881 veterans, 86% of all HIV-positive patients seen, at 3 VA sites from June 23, 1999, to July 28, 2000. To maximize the sensitivity for alcohol exposure, alcohol use was measured combining data from patient self-report, chart review, and ICD-9 codes. We assigned the greatest exposure level reported from any source. Alcohol use within the past 12 months was considered current. Data on comorbid and AIDS-defining medical diseases were collected via chart review and ICD-9 diagnostic codes. The association of alcohol use (level and timing) and disease was modeled only for diseases demonstrating >= 10% prevalence. Linearity was compared with nonlinearity of association using nested multivariate models and the likelihood ratio test. All multivariate models were adjusted for age, CD4 cell count, viral load, intravenous drug use, exercise, and smoking. Results: Of 881 subjects enrolled, 866 (98%) had sufficient data for multivariate analyses, and 876 (99%) had sufficient data for comparison of chart review with ICD-9 Diagnostic Codes. Of the 866, 42 (5%) were lifetime abstainers; 247 (29%) were past drinkers; and 577 (671/6) were current users. Among the 824 reporting past or current alcohol use, 341 (41%) drank in moderation, 192 (23%) drank hazardously, and 291 (35%) carried a diagnosis of abuse or dependence. ICD-9 codes showed limited sensitivity, but overall agreement with chart review was good for 15 of 20 diseases (kappa > 0.4). The following diseases demonstrated a >= 10% prevalence with both measures (hepatitis C, hypertension, diabetes, obstructive lung disease, candidiasis, and bacterial pneumonia). All of these were associated with alcohol use (P < 0.05). Hepatitis C, hypertension, obstructive lung disease, candidiasis, and bacterial pneumonia demonstrated linear associations with level of alcohol use (P < 0.03). Past alcohol use increased the risk of hepatitis C and diabetes after adjustment for level of exposure (P < 0.01). With the exception of candidiasis, the associations between level and timing of alcohol use were similar when measured by ICD-9 codes or by chart review. Conclusions: Past and current use of alcohol is common among those with HIV infection. Estimates of disease risk associated with alcohol use based upon ICD-9 Diagnostic Codes appear similar to those based upon chart review. After adjustment for level of alcohol exposure, past use is associated with similar (or higher) prevalence of disease as among current drinkers. Finally, level of alcohol use is linearly associated with medical disease. We find no evidence of a "safe" level of consumption among those with HIV infection. C1 VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. Yale Univ, Sch Med, Sect Gen Med, New Haven, CT USA. Univ Pittsburgh, Pittsburgh, PA USA. VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Kentucky, Med Ctr, Lexington, KY USA. Univ Toronto, Toronto Sunnybrook Reg Canc Ctr, Toronto, ON, Canada. Baylor Coll Med, Houston, TX 77030 USA. Michael E DeBakey VAMC, Houston, TX USA. Hosp St Raphael, Haelen Ctr, New Haven, CT USA. NIAAA, HIV AIDS Res, Bethesda, MD USA. RP Justice, AC (reprint author), VA Connecticut Healthcare Syst, Bldg 35A,Room 212,950 Campbell Ave 11-ACLSG, West Haven, CT 06516 USA. EM amy.justice2@va.gov NR 45 TC 92 Z9 95 U1 2 U2 4 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 2006 VL 44 IS 8 SU 2 BP S52 EP S60 DI 10.1097/01.mlr.0000228003.08925.8c PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 069IB UT WOS:000239438500008 PM 16849969 ER PT J AU Justice, AC Erdos, J Brandt, C Conigliaro, J Tierney, W Bryant, K AF Justice, Amy C. Erdos, Joseph Brandt, Cynthia Conigliaro, Joseph Tierney, William Bryant, Kendall TI The veterans affairs healthcare system - A unique laboratory for observational and interventional research SO MEDICAL CARE LA English DT Editorial Material ID RANDOMIZED CLINICAL-TRIALS; QUALITY-OF-CARE; PHYSICIAN ORDER ENTRY; HIV-INFECTED PATIENTS; DECISION-MAKING; PATIENT PREFERENCES; SOCIOECONOMIC-STATUS; RACIAL-DIFFERENCES; AGING COHORT; ALCOHOL-USE C1 Yale Univ, Sch Med, VACT Healthcare Syst, West Haven, CT 06516 USA. Yale Univ, Sch Med, Vet Aging Cohort Study Ctr, West Haven, CT 06516 USA. Yale Univ, Sch Med, Ctr Med Informat, West Haven, CT 06516 USA. Univ Kentucky, Lexington, KY USA. Regenstrief Inst Inc, Indianapolis, IN USA. NIAAA, NIH, Bethesda, MD USA. RP Justice, AC (reprint author), Yale Univ, Sch Med, VACT Healthcare Syst, 950 Campbell Ave,11 ACSLG, West Haven, CT 06516 USA. EM amy.justice2@va.gov NR 89 TC 34 Z9 34 U1 4 U2 4 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 2006 VL 44 IS 8 SU 2 BP S7 EP S12 DI 10.1097/01.mlr.0000228027.80012.c5 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 069IB UT WOS:000239438500002 PM 16849970 ER PT J AU Antachopoulos, C Meletiadis, J Roilides, E Sein, T Sutton, DA Wickes, BL Rinaldi, MG Merz, WG Shea, YR Walsh, TJ AF Antachopoulos, Charalampos Meletiadis, Joseph Roilides, Emmanuel Sein, Tin Sutton, Deanna A. Wickes, Brian L. Rinaldi, Michael G. Merz, William G. Shea, Yvonne R. Walsh, Thomas J. TI Relationship between metabolism and biomass of medically important zygomycetes SO MEDICAL MYCOLOGY LA English DT Article DE zygomycetes; XTT; fungal growth; metabolic activity; Boltzmann model ID FILAMENTOUS FUNGI; IN-VITRO; ANTIFUNGAL SUSCEPTIBILITY; COLORIMETRIC METHOD; HYDROXIDE XTT; ASPERGILLUS; GROWTH; IDENTIFICATION; ZYGOMYCOSIS; FUSARIUM AB Little is known about the relationships between metabolic activity and fungal biomass or time of incubation for medically important fungal pathogens. Understanding these relationships may be especially relevant for rapidly growing organisms, such as zygomycetes. A range of inocula of five clinical isolates of zygomycetes (one each of Rhizopus oryzae, Rhizopus microsporus, Cunninghamella bertholletiae, Mucor circinelloides and Absidia corymbifera) were incubated for 6, 8, 12, 24 and 48 h, after which hyphal mass was assessed spectrophotometrically and metabolic activity was measured using various concentrations of XTT and menadione. Both linear regression and the Boltzmann sigmoid model were used and compared for description of relationships between metabolic activity, biomass and time of incubation. Modeling was further applied to eleven additional zygomycete isolates. The relationships of biomass or metabolic activity as a function of time of incubation were well described with the Boltzmann sigmoid model. The latter was superior to linear regression in describing the relationship between metabolic activity and fungal biomass. For all isolates of zygomycetes, increases in metabolic activity preceded increases in biomass. Inter-species differences in growth patterns were observed, with Rhizopus microsporus and Mucor spp. reaching the plateau of growth earlier compared to other species. These findings on the temporal relationship and inter-species differences of hyphal growth and metabolic activity for zygomycetes may be useful in the design and interpretation of in vitro studies of these emerging pathogens. C1 NCI, Pediat Oncol Branch, CRC, Immuncompromised Host Sect, Bethesda, MD 20892 USA. Aristotle Univ Thessaloniki, Dept Pediat, Hippokration Hosp, GR-54006 Thessaloniki, Greece. Univ Texas, Hlth Sci Ctr San Antonio, Fungus Testing Lab, San Antonio, TX 78285 USA. Univ Texas, Hlth Sci Ctr San Antonio, Dept Microbiol, Adv DNA Technol Core Facil, San Antonio, TX 78285 USA. Johns Hopkins Univ Hosp, Dept Pathol, Microbiol Lab, Baltimore, MD 21287 USA. NIH, Microbiol Serv, Dept Lab Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Pediat Oncol Branch, CRC, Immuncompromised Host Sect, Rm 1-5750,MSC 1100,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov FU Intramural NIH HHS NR 26 TC 6 Z9 6 U1 2 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD AUG PY 2006 VL 44 IS 5 BP 429 EP 438 DI 10.1080/13693780600644878 PG 10 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 083YF UT WOS:000240494500005 PM 16882609 ER PT J AU Badano, A Kyprianou, IS Sempau, J AF Badano, Aldo Kyprianou, Iacovos S. Sempau, Josep TI Anisotropic imaging performance in indirect x-ray imaging detectors SO MEDICAL PHYSICS LA English DT Article DE Monte Carlo simulation; digital imaging; phosphor screen; cesium iodide; point response function; Swank factor ID MONTE-CARLO-SIMULATION; CESIUM IODIDE SCINTILLATORS; POINT-SPREAD FUNCTION; CODE PENELOPE; FLUORESCENT SCREENS; COLUMNAR PHOSPHORS; ELECTRON; EFFICIENCY; LEKSELL-GAMMA-KNIFE(R); COLLECTION AB We report on the variability in imaging system performance due to oblique x-ray incidence, and the associated transport of quanta (both x rays and optical photons) through the phosphor, in columnar indirect digital detectors. The analysis uses MANTIS, a combined x-ray, electron, and optical Monte Carlo transport code freely available. We describe the main features of the simulation method and provide some validation of the phosphor screen models considered in this work. We report x-ray and electron three-dimensional energy deposition distributions and point-response functions (PRFs), including optical spread in, columnar phosphor screens of thickness 100 and 500 mu m, for 19, 39, 59, and 79 keV monoenergetic x-ray beams incident at 0 degrees, 10 degrees, and 15 degrees. In addition, we present pulse-height spectra for the same phosphor thickness, x-ray energies, and angles of incidence. Our results suggest that the PRF due to the phosphor blur is highly nonsymmetrical, and that the resolution properties of a columnar screen in a tomographic, or tomosynthetic imaging system varies significantly with the angle of x-ray incidence. Moreover, we find that the noise due to the variability in the number of light photons detected per primary x-ray interaction, summarized in the information or Swank factor, is somewhat independent of thickness and incidence angle of the x-ray beam. Our results also suggest that the anisotropy in the PRF is not less in screens with absorptive backings, while. the noise introduced by variations in the gain and optical transport is larger. Predictions from MANTIS, after additional validation, can provide the needed understanding of the extent of such variations, and eventually, lead to the incorporation of the changes in imaging performance with incidence angle into the reconstruction algorithms for volumetric x-ray imaging systems. (C) 2006 American Association of Physicists in Medicine. C1 US FDA, Ctr Devices & Radiol Hlth, NIBIB CDRH Lab Assessment Med Imaging Syst, Div Imaging & Appl Math,Off Sci & Engn Labs, Rockville, MD 20857 USA. Univ Politecn Catalunya, Inst Tecn Energet, E-08028 Barcelona, Spain. RP Badano, A (reprint author), US FDA, Ctr Devices & Radiol Hlth, NIBIB CDRH Lab Assessment Med Imaging Syst, Div Imaging & Appl Math,Off Sci & Engn Labs, 12720 Twinbrook Pkwy, Rockville, MD 20857 USA. EM aldo.badano@fda.hhs.gov RI Sempau, Josep/J-7834-2013; OI Sempau, Josep/0000-0002-2754-7685; badano, aldo/0000-0003-3712-6670 NR 42 TC 35 Z9 35 U1 0 U2 3 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD AUG PY 2006 VL 33 IS 8 BP 2698 EP 2713 DI 10.1118/1.2208925 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 074ZZ UT WOS:000239852800004 PM 16967568 ER PT J AU Vgontzas, AN Trakada, G Bixler, EO Lin, HM Pejovic, S Zoumakis, E Chrousos, GP Legro, RS AF Vgontzas, Alexandros N. Trakada, Georgia Bixler, Edward O. Lin, Hung-Mo Pejovic, Slobodanka Zoumakis, Emmanuel Chrousos, George P. Legro, Richard S. TI Plasma interleukin 6 levels are elevated in polycystic ovary syndrome independently of obesity or sleep apnea SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID NECROSIS-FACTOR-ALPHA; NORMAL-WEIGHT WOMEN; C-REACTIVE PROTEIN; INSULIN-RESISTANCE; DAYTIME SLEEPINESS; VISCERAL OBESITY; CYTOKINES; SERUM; RISK; PATHOGENESIS AB Premenopausal women with polycystic ovary syndrome (PCOS) are at a much higher risk for excessive daytime sleepiness, fatigue, and insulin resistance than control women. Elevated levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) are presumably part of the pathogenesis of these clinical manifestations. Forty-two obese women with PCOS, 17 body mass index--comparable obese controls, and 15 normal-weight controls free from apnea participated in the study that included one 8-hour nighttime polysomnography, single morning cytokine plasma concentrations, and insulin resistance indices. Women with PCOS exhibited higher plasma concentrations of IL-6 than obese controls, who had intermediate values, or normal-weight controls, who had the lowest values (4.75 +/- 0.5 vs 3.65 +/- 0.4 vs 1.84 +/- 0.3 mu g/mL, P < .01). Tumor necrosis factor a values were higher in PCOS and obese controls compared with normal-weight controls, but the difference was not statistically significant (4.05 +/- 0.3 vs 3.79 +/- 0.2 vs 3.14 +/- 0.2 pg/mL, P = .103). Based on backward regression analysis, IL-6 levels had a stronger association with the PCOS group than with the obese group, and the sleep or hypoxia variables did not make a significant contribution to either IL-6 or TNF-alpha. Both IL-6 and TNF-alpha correlated positively with body mass index (P < .01) in obese controls but not in women with PCOS. Furthermore, within the PCOS group, IL-6 and TNF-alpha correlated more strongly with indices of insulin resistance than obesity. We conclude that IL-6 levels are elevated in obese women with PCOS independently of obesity or sleep apnea and may represent a pathophysiologic link to insulin resistance. (c) 2006 Elsevier Inc. All rights reserved. C1 Penn State Univ, Coll Med, Dept Psychiat H073, Sleep Res & Treatment Ctr, Hershey, PA 17033 USA. Penn State Univ, Coll Med, Hlth Evaluat Sci A210, Hershey, PA 17033 USA. NIH, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. Penn State Univ, Coll Med, Dept Obstet & Gynecol Reprod Endocrinol, Hershey, PA 17033 USA. RP Vgontzas, AN (reprint author), Penn State Univ, Coll Med, Dept Psychiat H073, Sleep Res & Treatment Ctr, Hershey, PA 17033 USA. EM axv3@psu.edu FU NHLBI NIH HHS [HL64415] NR 33 TC 56 Z9 62 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD AUG PY 2006 VL 55 IS 8 BP 1076 EP 1082 DI 10.1016/j.metabol.2006.04.002 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 067GG UT WOS:000239289300014 PM 16839844 ER PT J AU Peng, H Yang, LT Li, J Lu, ZQ Wang, LY Koup, RA Bailer, RT Wu, CY AF Peng, Hui Yang, Li-tao Li, Jian Lu, Zhi-qiang Wang, Ling-yun Koup, Richard A. Bailer, Robert T. Wu, Chang-you TI Human memory T cell responses to SARS-CoV E protein SO MICROBES AND INFECTION LA English DT Article DE SARS coronavirus; E protein; memory T cells; epitope; human ID ACUTE RESPIRATORY SYNDROME; CORONAVIRUS-E-PROTEIN; NUCLEOCAPSID PROTEIN; PROTECTIVE IMMUNITY; SPIKE PROTEIN; IDENTIFICATION; EXPRESSION; ANTIBODIES; VACCINE; MICE AB E protein is a membrane component of severe acute respiratory syndrome coronavirus (SARS-CoV). Disruption of E protein may reduce viral infectivity. Thus, the SARS-CoV E protein is considered a potential target for the development of antiviral drugs. However, the cellular immune responses to E protein remain unclear in humans. In this study, we found that peripheral blood mononuclear cells (PBMCs) from fully recovered SARS individuals rapidly produced IFN-gamma and IL-2 following stimulation with a pool of 9 peptides overlapping the entire E protein sequence. Analysis of the immune responses by flow cytometry showed that both CD4(+) and CD8(+)T cells were involved in the SARS-CoV E-specific immune responses after stimulation with SARS-CoV E peptides. Moreover, the majority of IFN-gamma(+)CD4(+)T cells were central memory cells expressing CD45RO(+)CCR7(+)CD62L(-); whereas IFN-gamma(+)CD8(+) memory T cells were mostly effector memory cells expressing CD45RO(-)CCR7(-)CD62L(-). The results of T-cell responses to 9 individual peptides indicated that the E protein contained at least two major T cell epitopes (E2 amino acid [aa] 9-26 and E5-6: aa 33-57) which were important in eliciting cellular immune response to SARS-CoV E protein in humans. (c) 2006 Elsevier SAS. All rights reserved. C1 Sun Yat Sen Univ, Zhongshan Med Sch, Dept Immunol, Guangzhou 510089, Peoples R China. Guangzhou Provincial Hosp Tradit Chinese Med, Dept Cardiol, Guangzhou 510020, Peoples R China. Sun Yat Sen Univ, Affiliated Hosp 2, Dept Resp Dis, Guangzhou 510020, Peoples R China. Sun Yat Sen Univ, Affiliated Hosp 2, Dept Digest Dis, Guangzhou 510020, Peoples R China. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Wu, CY (reprint author), Sun Yat Sen Univ, Zhongshan Med Sch, Dept Immunol, 74 Zhongshan Rd 2, Guangzhou 510089, Peoples R China. EM changyou_wu@yahoo.com RI Peng, Hui/I-8579-2015 OI Peng, Hui/0000-0002-2646-129X NR 35 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD AUG PY 2006 VL 8 IS 9-10 BP 2424 EP 2431 DI 10.1016/j.micinf.2006.05.008 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 104XB UT WOS:000241992800012 PM 16844400 ER PT J AU Trimnell, AR Kraemer, SM Mukherjee, S Phippard, DJ Janes, JH Flamoe, E Su, XZ Awadalla, P Smith, JD AF Trimnell, Adama R. Kraemer, Susan M. Mukherjee, Susan Phippard, David J. Janes, Joel H. Flamoe, Eric Su, Xin-zhuan Awadalla, Philip Smith, Joseph D. TI Global genetic diversity and evolution of var genes associated with placental and severe childhood malaria SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE malaria; Plasmodium falciparum; antigenic variation; var genes ID FALCIPARUM-INFECTED ERYTHROCYTES; CHONDROITIN SULFATE-A; PREGNANCY-ASSOCIATED MALARIA; MEMBRANE PROTEIN-1 FAMILY; PLASMODIUM-FALCIPARUM; ANTIGENIC VARIATION; FUNCTIONAL SPECIALIZATION; SURFACE-ANTIGENS; ANTIBODIES; PARASITE AB In Plasmodium falciparum, var genes encode adhesive proteins that are transported to the surface of infected erythrocytes and act as major virulence determinants for infected erythrocyte binding and immune evasion. Var genes are highly diverse and can be classified into five major groups (UpsA, B, C, D, and E). Previous serological studies have suggested that the UpsA var group may contain common antigenic types that have important roles in severe childhood malaria. Here, our analysis found that UpsA vars are highly diverse between 22 world-wide parasite isolates, although they could be grouped into two broad clusters that may be separately recombining. By comparison, orthologs of the UpsA-linked Type 3 var and UpsE-linked var2csa were detected in nearly all parasite isolates, and a var2csa ortholog was also present in a chimpanzee malaria R reichenowi that diverged from P. falciparum similar to 5-7 million years ago. Although the specific function of Type 3 var genes is unknown, var2csa is a leading candidate for a pregnancy associated malaria vaccine. Compared to typical var genes, var2csa is unusually conserved but still had only 54-94% amino acid identity in extracellular binding regions. However, var2csa alleles have extensive gene mosaicism within polymorphic blocks that are shared between world-wide parasite isolates and recognizable in P rechenowi suggesting a high rate of self-self recombination and an ancient and globally-related pool of var2csa polymorphism. These studies aid our understanding of the evolutionary mechanisms that shape var diversity and will be important to the development of vaccines against pregnancy associated malaria and severe malaria. (c) 2006 Elsevier B.V. All rights reserved. C1 N Carolina State Univ, Dept Genet, Raleigh, NC 27695 USA. Seattle Biomed Res Inst, Seattle, WA 98109 USA. Univ Washington, Dept Pathobiol, Seattle, WA 98195 USA. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Awadalla, P (reprint author), N Carolina State Univ, Dept Genet, Raleigh, NC 27695 USA. EM pawadalla@ncsu.edu; joe.smith@sbri.org OI Su, Xinzhuan/0000-0003-3246-3248 FU NIAID NIH HHS [R01 AI47953-01A1] NR 56 TC 111 Z9 113 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD AUG PY 2006 VL 148 IS 2 BP 169 EP 180 DI 10.1016/j.molbiopara.2006.03.012 PG 12 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 068UI UT WOS:000239399600007 PM 16697476 ER PT J AU Raum, JC Gerrish, K Artner, I Henderson, E Guo, M Sussel, L Schisler, JC Newgard, CB Stein, R AF Raum, Jeffrey C. Gerrish, Kevin Artner, Isabella Henderson, Eva Guo, Min Sussel, Lori Schisler, Jonathan C. Newgard, Christopher B. Stein, Roland TI FoxA2, Nkx2.2, and PDX-1 regulate islet beta-cell-specific mafA expression through conserved sequences located between base pairs-8118 and-7750 upstream from the transcription start site SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID INSULIN GENE-TRANSCRIPTION; NUCLEAR FACTOR 3-BETA; PANCREATIC DEVELOPMENT; HOMEODOMAIN PROTEIN; DIABETES-MELLITUS; ALPHA-CELLS; EARLY-ONSET; GLUCOSE; PAX6; DIFFERENTIATION AB The MafA transcription factor is both critical to islet beta-cell function and has a unique pancreatic cell-type-specific expression pattern. To localize the potential transcriptional regulatory region(s) involved in directing expression to the [3 cell, areas of identity within the 5' flanking region of the mouse, human, and rat mafA genes were found between nucleotides -9389 and -9194, -8426 and -8293, -8118 and -7750, -6622 and -6441, -6217 and -6031, and -250 and +56 relative to the transcription start site. The identity between species was greater than 75%, with the highest found between by -8118 and -7750 (similar to 94%, termed region 3). Region 3 was the only upstream mammalian conserved region found in chicken mafA (88% identity). In addition, region 3 uniquely displayed beta-cell-specific activity in cell-line-based reporter assays. Important regulators of beta-cell formation and function, PDX-1, FoxA2, and Nkx2.2, were shown to specifically bind to region 3 in vivo using the chromatin immunoprecipitation assay. Mutational and functional analyses demonstrated that FoxA2 (bp -7943 to -7910), Nkx2.2 (bp -7771 to -7746), and PDX-1 (bp -8087 to -8063) mediated region 3 activation. Consistent with a role in transcription, small interfering RNA-mediated knockdown of PDX-1 led to decreased mafA mRNA production in INS-1-derived beta-cell lines (832/13 and 832/3), while MafA expression was undetected in the pancreatic epithelium of Nkx2.2 null animals. These results suggest that beta-cell-type-specific mafA transcription is principally controlled by region 3-acting transcription factors that are essential in the formation of functional beta-cells. C1 Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. NIEHS, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. Univ Colorado, Hlth Sci Ctr, Dept Biochem & Mol Genet, Denver, CO 80045 USA. Duke Univ, Ctr Med, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27704 USA. Duke Univ, Ctr Med, Dept Pharmacol, Durham, NC 27704 USA. Duke Univ, Ctr Med, Dept Canc Biol, Durham, NC 27704 USA. Duke Univ, Ctr Med, Dept Med, Durham, NC 27704 USA. Duke Univ, Ctr Med, Dept Biochem, Durham, NC 27704 USA. RP Stein, R (reprint author), Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, 723 Light Hall, Nashville, TN 37232 USA. EM roland.stein@vanderbilt.edu FU NIDDK NIH HHS [P60 DK020593, 5T32 DK07563, DK50203, P60 DK20593, R01 DK050203, R56 DK050203, T32 DK007563, U01-DK-56047, U19 DK061248] NR 51 TC 71 Z9 73 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2006 VL 26 IS 15 BP 5735 EP 5743 DI 10.1128/MCB.00249-06 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 067FG UT WOS:000239286600017 PM 16847327 ER PT J AU Sun, Y Boyd, K Xu, W Ma, J Jackson, CW Fu, A Shillingford, JM Robinson, GW Hennighausen, L Hitzler, JK Ma, ZG Morris, SW AF Sun, Yi Boyd, Kelli Xu, Wu Ma, Jing Jackson, Carl W. Fu, Amina Shillingford, Jonathan M. Robinson, Gertraud W. Hennighausen, Lothar Hitzler, Johann K. Ma, Zhigui Morris, Stephan W. TI Acute myeloid leukemia-associated Mkl1 (Mrtf-a) is a key regulator of mammary gland function SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SERUM-RESPONSE FACTOR; MITOCHONDRIAL PERMEABILITY TRANSITION; SMOOTH-MUSCLE DIFFERENTIATION; TRANSCRIPTION FACTOR-B; ATP-CITRATE LYASE; MYOEPITHELIAL CELLS; GENE-EXPRESSION; MEGAKARYOBLASTIC LEUKEMIA; MOLECULAR SWITCH; EPITHELIAL-CELLS AB Transcription of immediate-early genes-as well as multiple genes affecting muscle function, cytoskeletal integrity, apoptosis control, and wound healing/angiogenesis-is regulated by serum response factor (Srf). Extracellular signals regulate Srf in part via a pathway involving megakaryoblastic leukemia 1 (Mkl1, also known as myocardin-related transcription factor A [Mrtf-a]), which coactivates Srf-responsive genes downstream of Rho GTPases. Here we investigate Mkl1 function using gene targeting and show the protein to be essential for the physiologic preparation of the mammary gland during pregnancy and the maintenance of lactation. Lack of Mkl1 causes premature involution and impairs expression of Srf-dependent genes in the mammary myoepithelial cells, which control milk ejection following oxytocin-induced contraction. Despite the importance of Srf in multiple transcriptional pathways and widespread Mkl1 expression, the spectrum of abnormalities associated with Mkl1 absence appears surprisingly restricted. C1 St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA. St Jude Childrens Hosp, Anim Resource Ctr, Memphis, TN 38105 USA. St Jude Childrens Hosp, Dept Biochem, Memphis, TN 38105 USA. St Jude Childrens Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA. St Jude Childrens Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Hosp Sick Children, Dept Paediat, Div Haematol Oncol, Program Dev Biol, Toronto, ON M5G 1X8, Canada. RP Morris, SW (reprint author), Dept Pathol, Thomas Tower,Room 4026,Mail Stop 343,332 N Lauder, Memphis, TN 38105 USA. EM steve.morris@stjude.org RI Robinson, Gertraud/I-2136-2012 FU Intramural NIH HHS; NCI NIH HHS [R01 CA087064, CA 87064]; PHS HHS [21765] NR 84 TC 82 Z9 82 U1 0 U2 1 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 2006 VL 26 IS 15 BP 5809 EP 5826 DI 10.1128/MCB.00024-06 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 067FG UT WOS:000239286600023 PM 16847333 ER PT J AU Kishida, KT Hoeffer, CA Hu, DY Pao, ML Holland, SM Klann, E AF Kishida, Kenneth T. Hoeffer, Charles A. Hu, Daoying Pao, Maryland Holland, Steven M. Klann, Eric TI Synaptic plasticity deficits and mild memory impairments in mouse models of chronic granulomatous disease SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID LONG-TERM POTENTIATION; EXTRACELLULAR-SUPEROXIDE DISMUTASE; NITRIC-OXIDE SYNTHASE; NMDA RECEPTOR ACTIVATION; HIPPOCAMPAL AREA CA1; NADPH OXIDASE; HYDROGEN-PEROXIDE; RESPIRATORY BURST; ARACHIDONIC-ACID; MUTANT MICE AB Reactive oxygen species (ROS) are required in a number of critical cellular signaling events, including those underlying hippocampal synaptic plasticity and hippocampus-dependent memory; however, the source of ROS is unknown. We previously have shown that NADPH oxidase is required for N-methyl-D-aspartate (NMDA) receptor-dependent signal transduction in the hippocampus, suggesting that NADPH oxidase may be required for NMDA receptor-dependent long-term potentiation (LTP) and hippocampus-dependent memory. Herein we present the first evidence that NADPH oxidase is involved in hippocampal synaptic plasticity and memory. We have found that pharmacological inhibitors of NADPH oxidase block LTP. Moreover, mice that lack the NADPH oxidase proteins gp91(phox) and p47(phox), both of which are mouse models of human chronic granulomatous disease (CGD), also lack LTP. We also found that the gp91(phox) and p47(phox) mutant mice have mild impairments in hippocampus-dependent memory. The gp91(phox) mutant mice exhibited a spatial memory deficit in the Morris water maze, and the p47(phox) mutant mice exhibited impaired context-dependent fear memory. Taken together, our results are consistent with NADPH oxidase being required for hippocampal synaptic plasticity and memory and are consistent with reports of cognitive dysfunction in patients with CGD. C1 Baylor Coll Med, Dept Physiol & Mol Biophys, Houston, TX 77030 USA. Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. NIMH, Off Clin Director, NIH, Bethesda, MD 20892 USA. NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Klann, E (reprint author), Baylor Coll Med, Dept Physiol & Mol Biophys, 1 Baylor Plaza BCM 335, Houston, TX 77030 USA. EM eklann@bcm.tmc.edu FU Intramural NIH HHS; NINDS NIH HHS [NS034007, R01 NS047384, R29 NS034007, NS047852, F31 NS047852, NS047384, R01 NS034007, R37 NS034007] NR 58 TC 70 Z9 72 U1 1 U2 4 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 2006 VL 26 IS 15 BP 5908 EP 5920 DI 10.1128/MCB.00269-06 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 067FG UT WOS:000239286600031 PM 16847341 ER PT J AU Whiteley, GR AF Whiteley, Gordon R. TI Proteomic patterns for cancer diagnosis - promise and challenges SO MOLECULAR BIOSYSTEMS LA English DT Article ID PROSTATE-SPECIFIC ANTIGEN; OVARIAN-CANCER; MASS-SPECTROMETRY; PROTEIN MICROARRAYS; SERUM; BIOMARKERS; IDENTIFICATION; FEATURES; MARKERS; ARRAYS AB Proteomic patterns have been discovered for a variety of cancers and cancer related diseases. The platforms used have been both mass spectrometry and microarrays and the incorporation of computer informatics has resulted in innovative possibilities for novel diagnostics. C1 NCI, SAIC Frederick Inc, Gaithersburg, MD 20878 USA. RP Whiteley, GR (reprint author), NCI, SAIC Frederick Inc, 22 Firstfield Rd,Suite 180, Gaithersburg, MD 20878 USA. EM whiteleyg@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 39 TC 7 Z9 7 U1 0 U2 0 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1742-206X J9 MOL BIOSYST JI Mol. Biosyst. PD AUG PY 2006 VL 2 IS 8 BP 358 EP 363 DI 10.1039/b6072600g PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 073OI UT WOS:000239752100007 PM 16880955 ER PT J AU Efferth, T Gillet, JP Sauerbrey, A Zintl, F Bertholet, V de Longueville, F Remacle, J Steinbach, D AF Efferth, Thomas Gillet, Jean-Pierre Sauerbrey, Axel Zintl, Felix Bertholet, Vincent de Longueville, Francoise Remacle, Jose Steinbach, Daniel TI Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID P-GLYCOPROTEIN EXPRESSION; RESISTANCE-ASSOCIATED PROTEIN; ACUTE MYELOID-LEUKEMIA; HUMAN TUMOR-CELLS; MULTIDRUG-RESISTANCE; DRUG-RESISTANCE; TETRAZOLIUM ASSAY; PROGNOSTIC-FACTOR; DE-NOVO; GENE AB A major issue in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters. The majority of these proteins have not yet been examined in T-ALL. Using a newly developed microarray for the simultaneous quantification of 38 ABC transporter genes, we observed a consistent overexpression of ABCA2/ABCA3 in clinical samples of ALL. Therefore, we analyzed the association of these two genes with drug resistance. Treatment of CCRF-CEM and Jurkat cells with methotrexate, vinblastine, or doxorubicin led to an induction of ABCA3 expression, whereas a significant increase of ABCA2 expression was only observed in Jurkat cells. To study the causal relationship of ABCA2/A3 overexpression with drug resistance, we applied RNA interference (RNAi) technology. RINAi specific for ABCA2 or ABCA3 led to a partial decrease of expression in these two ABC transporters. Upon cotreatment of RNAi for ABCA2 with methotrexate and vinblastine, a partial decrease of ABCA2 expression as well as a simultaneous increase of ABCA3 expression was observed. Vice versa, ABCA3 RNAi plus drugs decreased ABCA3 and increased ABCA2 expression. This indicates that down-regulation of one ABC transporter was compensated by the up-regulation of the other. Application of RNAi for both ABCA2 and ABCA3 resulted in a more efficient reduction of the expression sensitization of cells to cytostatic drugs was achieved. In conclusion, ABCA2 and ABCA3 are expressed in many T-ALL and contribute to drug resistance. C1 German Canc Res Ctr, D-69120 Heidelberg, Germany. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Helios Childrens Hosp, Erfurt, Germany. Univ Jena, Childrens Hosp, D-6900 Jena, Germany. Univ Namur, Dept Biol, Namur, Belgium. Eppendorf Array Technol, Namur, Belgium. RP Efferth, T (reprint author), German Canc Res Ctr, M070,Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM t.efferth@dkfz.de RI gillet, jean-pierre/A-3714-2012 NR 46 TC 37 Z9 38 U1 0 U2 6 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 2006 VL 5 IS 8 BP 1986 EP 1994 DI 10.1158/1535-7163.MCT-06-0086 PG 9 WC Oncology SC Oncology GA 077KY UT WOS:000240029400011 PM 16928819 ER PT J AU Chearwae, W Shukla, S Limtrakul, P Ambudkar, SV AF Chearwae, Wanida Shukla, Suneet Limtrakul, Pornngarm Ambudkar, Suresh V. TI Modulation of the function of the multidrug resistance-linked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID HUMAN P-GLYCOPROTEIN; INHIBITOR FUMITREMORGIN-C; I CLINICAL-TRIAL; SUBSTRATE-SPECIFICITY; TURMERIC POWDER; MRP1 ABCC1; PROTEIN; CELLS; GENE; OVEREXPRESSION AB Curcumin (curcumin I), demethoxycurcumin (curcumin II), and bisdemethoxycurcumin (curcumin III) are the major forms of curcuminoids found in the turmeric powder, which exhibit anticancer, antioxidant, and anti-inflammatory activities. In this study, we evaluated the ability of purified curcuminoids to modulate the function of either the wild-type 482R or the mutant 482T ABCG2 transporter stably expressed in HEK293 cells and drug-selected MCF-7 FLV1000 and MCF-7 AdVp3000 cells. Curcuminoids inhibited the transport of mitoxantrone and pheophorbide a from ABCG2-expressing cells. However, both cytotoxicity and [(3)H]curcumin I accumulation assays showed that curcuminoids are not transported by ABCG2. Nontoxic concentration of curcumin I, II, and III sensitized the ABCG2-expressing cells to mitoxantrone, topotecan, SN-38, and doxorubicin. This reversal was not due to reduced expression because ABCG2 protein levels were unaltered by treatment with 10 mu mol/L curcuminoids for 72 hours. Curcumin I, II, and III stimulated (2.4- to 3.3-fold) ABCG2-mediated ATP hydrolysis and the IC(50)s were in the range of 7.5 to 18 nmol/L, suggesting a high affinity of curcuminoids for ABCG2. Curcuminoids also inhibited the photolabeling of ABCG2 with [125 I]iodoarylazidoprazosin and [(3)H]azidopine as well as the transport of these two substrates in ABCG2-expressing cells. Curcuminoids did not inhibit the binding of [alpha-(32)P]8-azidoATP to ABCG2, suggesting that they do not interact with the ATP-binding site of the transporter. Collectively, these data show that, among curcuminoids, curcumin I is the most potent modulator of ABCG2 and thus should be considered as a treatment to increase the efficacy of conventional chemotherapeutic drugs. C1 Natl Canc Inst, Cell Biol Lab, Canc Res Ctr, NIH,Dept Hlth & Human Sci, Bethesda, MD 20892 USA. Chiang Mai Univ, Fac Med, Dept Biochem, Chiang Mai 50000, Thailand. RP Ambudkar, SV (reprint author), Natl Canc Inst, Cell Biol Lab, Canc Res Ctr, NIH,Dept Hlth & Human Sci, Bethesda, MD 20892 USA. EM plimtrak@mail.med.cmu.ac.th; ambudkar@helix.nih.gov RI shukla, suneet/B-4626-2012 FU Intramural NIH HHS NR 59 TC 72 Z9 78 U1 0 U2 9 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 2006 VL 5 IS 8 BP 1995 EP 2006 DI 10.1158/1535-7163.MCT-06-0089 PG 12 WC Oncology SC Oncology GA 077KY UT WOS:000240029400012 PM 16928820 ER PT J AU Qu, W Fuquay, R Sakurai, T Waalkes, MP AF Qu, Wei Fuquay, Richard Sakurai, Teruaki Waalkes, Michael P. TI Acquisition of apoptotic resistance in cadmium-induced malignant transformation: Specific perturbation of JNK signal transiduction pathway and associated metallothionein overexpression SO MOLECULAR CARCINOGENESIS LA English DT Article DE cadmium; malignant transformation; apoptosis; JNK; metallothionein ID N-TERMINAL KINASE; PROSTATE EPITHELIAL-CELLS; RAT-LIVER CELLS; GENE-EXPRESSION; NULL MICE; WILD-TYPE; PROTEIN; JUN; CANCER; EXPOSURE AB Prior work has shown that chronic cadmium exposed rat liver epithelial cells (CCE-LE) become malignantly transformed after protracted low level cadmium exposure. Acquisition of apoptotic resistance is common in oncogenesis and the present work explores this possibility in CCE-LE cells. CCE-LE cells were resistant to apoptosis induced by etoposide or an acute high concentration of cadmium as assessed by flow cytometry with annexin/FITC. Three key mitogen-activated protein kinases (MAPKs), namely ERK1/2, JNK1/2, and p38, were phosphorylated in CCE-LE cells after acute cadmium exposure. However, the levels of phosphorylated JNK1/2 were markedly decreased in CCE-LE cells compared to control. JNK kinase activity was also suppressed in CCE-LE cells exposed to cadmium. Epidermal growth factor (EGF), used as a positive control for stimulating JNK phosphorylation, was much less effective in CCE-LE cells than control cells, Ro318220 (Ro), a strong activator of JNK, increased phosphorylated JNK1/2 to levels similar to the cadmium-treated control cells and also enhanced apoptosis in response to cadmium in CCE-LE cells. Metallothionein (MT), which is thought to potentially inhibit apoptosis, was strongly overexpressed in CCE-LE cells. Further, in MT knockout (MT-/-) fibroblasts, JNK1/2 phosphorylation was markedly increased after cadmium exposure compared with similarly treated wild-type (MT+/+) cells. These results indicate cadmium-transformed cells acquired apoptotic resistance, which may be linked to the specific suppression of the JNK pathway and is associated with MT overexpression, which, in turn, may impact this signal transduction pathway. The acquisition of apoptotic resistance may play an important role in cadmium carcinogenesis by contributing to both tumor initiation and malignant progression. Published 2006 Wiley-Liss, Inc.(dagger) C1 NIEHS, NCI, Lab Comparat Carcinogenesis, Inorgan Carcinogenesis Sect, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, NCI, Lab Comparat Carcinogenesis, Inorgan Carcinogenesis Sect, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. FU Intramural NIH HHS NR 33 TC 32 Z9 34 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 2006 VL 45 IS 8 BP 561 EP 571 DI 10.1002/mc.20185 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 068CE UT WOS:000239348600002 PM 16568437 ER PT J AU Tsyusko, OV Smith, MH Oleksyk, TK Goryanaya, J Glenn, TC AF Tsyusko, Olga V. Smith, Michael H. Oleksyk, Taras K. Goryanaya, Julia Glenn, Travis C. TI Genetics of cattails in radioactively contaminated areas around Chornobyl SO MOLECULAR ECOLOGY LA English DT Article DE Chornobyl; genetic diversity; microsatellites; radiation; sexual and asexual reproduction; Typha ID TYPHA-LATIFOLIA; MICROSATELLITE MUTATIONS; POPULATION SUBDIVISION; CLONAL DIVERSITY; CLEANUP WORKERS; UNITED-STATES; GERMLINE; LOCI; DNA; ANGUSTIFOLIA AB Research on populations from radioactively contaminated areas around Chornobyl has produced ambiguous results for the presence of radiation effects. More studies are needed to provide information on whether radiation exposure at Chornobyl significantly affected genetic diversity in natural populations of various taxa. Eleven and nine variable microsatellite loci were used to test for differences in genetic diversity between reference and Chornobyl populations of two cattail species (Typha angustifolia and Typha latifolia, respectively) from Ukraine. Our purpose was to determine whether radiation had a significant impact on genetic diversities of the Chornobyl Typha populations, or if their genetic composition might be better explained by species demography and/or changes in population dynamics, mainly in sexual and asexual reproduction. Populations closest to the reactor had increased genetic diversities and high number of genets, which likely were due to factors other than radiation including increased gene flow among Chornobyl populations, enhanced sexual reproduction within populations, and/or origin of the genets from seed bank. Both Typha species also demonstrated small but significant effects associated with latitude, geographical regions, and watersheds. Typha's demography in Ukraine possibly varies with these three factors, and the small difference between Chornobyl and reference populations of T. latifolia detected after partitioning the total genetic variance between them is probably due primarily to these factors. However, the positive correlations of several genetic characteristics with radionuclide concentrations suggest that radiation may have also affected genetics of Chornobyl Typha populations but much less than was expected considering massive contamination of the Chornobyl area. C1 Univ Georgia, Savannah River Ecol Lab, Aiken, SC 29802 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Int Radioecol Lab, Slavutich, Ukraine. RP Tsyusko, OV (reprint author), Univ Georgia, Savannah River Ecol Lab, PO E, Aiken, SC 29802 USA. EM tsyusko@srel.edu RI Glenn, Travis/A-2390-2008; Taras, Oleksyk/J-8805-2013; OI Taras, Oleksyk/0000-0002-8148-3918; Tsyusko, Olga/0000-0001-8196-1062 NR 70 TC 5 Z9 5 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1083 EI 1365-294X J9 MOL ECOL JI Mol. Ecol. PD AUG PY 2006 VL 15 IS 9 BP 2611 EP 2625 DI 10.1111/j.1365-294X.2006.02939.x PG 15 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 063HT UT WOS:000239010000025 PM 16842431 ER PT J AU Srinivas, M Ng, L Liu, H Jia, L Forrest, D AF Srinivas, Maya Ng, Lily Liu, Hong Jia, Li Forrest, Douglas TI Activation of the blue opsin gene in cone photoreceptor development by retinoid-related orphan receptor beta SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID THYROID-HORMONE RECEPTOR; HOMEODOMAIN PROTEIN FTZ; MOUSE RETINA; ROR-BETA; HOMEOBOX GENE; CELL FATE; TRANSGENE EXPRESSION; TRANSCRIPTION FACTOR; NUCLEAR RECEPTORS; BIPOLAR CELLS AB Color vision requires the expression of opsin photopigments with different wavelength sensitivities in retinal cone photoreceptors. The basic color visual system of mammals is dichromatic, involving differential expression in the cone population of two opsins with sensitivity to short ( S, blue) or medium ( M, green) wavelengths. However, little is known of the factors that directly activate these opsin genes and thereby contribute to the S or M opsin identity of the cone. We report that the orphan nuclear receptor ROR beta (retinoid-related orphan receptor beta) activates the S opsin gene (Opn1sw) through binding sites upstream of the gene. ROR beta lacks a known physiological ligand and activates the Opn1sw promoter modestly alone but strongly in synergy with the retinal conerod homeobox factor (CRX), suggesting a cooperative means of enhancing ROR beta activity. Comparison of wild-type and mutant lacZ reporter transgenes showed that the ROR beta-binding sites in Opn1sw are required for expression in mouse retina. ROR beta-deficient mice fail to induce S opsin appropriately during postnatal cone development. Photoreceptors in these mice also lack outer segments, indicating additional functions for ROR beta in photoreceptor morphological maturation. The results identify Opn1sw as a target gene for ROR beta and suggest a key role for ROR beta in regulating opsin expression in the color visual system. C1 NIDDK, NIH, Clin Endocrinol Branch, Bethesda, MD 20892 USA. Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA. RP Forrest, D (reprint author), NIDDK, NIH, Clin Endocrinol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM forrestd@niddk.nih.gov FU Intramural NIH HHS; NCI NIH HHS [R24 CA88302] NR 50 TC 62 Z9 66 U1 0 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD AUG PY 2006 VL 20 IS 8 BP 1728 EP 1741 DI 10.1210/me.2005-0505 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 067CC UT WOS:000239277700003 PM 16574740 ER PT J AU Kusakabe, T Kawaguchi, A Hoshi, N Kawaguchi, R Hoshi, S Kimura, S AF Kusakabe, Takashi Kawaguchi, Akio Hoshi, Nobuo Kawaguchi, Rumi Hoshi, Sayuri Kimura, Shioko TI Thyroid-specific enhancer-binding protein/NKX2.1 is required for the maintenance of ordered architecture and function of the differentiated thyroid SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID TRANSCRIPTION FACTOR-I; THYROTROPIN RECEPTOR GENE; PROGRAMMED CELL-DEATH; EPITHELIAL MORPHOGENESIS; FOLLICULAR CELLS; EXPRESSION; PROMOTER; FACTOR-1; T/EBP; TTF-1 AB Thyroid-specific enhancer-binding protein (T/ebp)/Nkx2.1-null mouse thyroids degenerate by embryonic day (E) 12-13 through apoptosis whereas T/ebp/Nkx2.1-heterogyzgous mice exhibit hypothyroidism with elevated TSH levels. To understand the role of T/ebp/Nkx2.1 in the adult thyroid, a thyroid follicular cell-specific conditional knockout (KO) mouse line, T/ebp(fl/fl); TPO-Cre, was established that expresses Cre recombinase under the human thyroid peroxidase (TPO) gene promoter. These mice appeared to be healthy and exhibited loss of T/ebp/Nkx2.1 expression in many, but not all, thyroid follicular cells as determined by immunohistochemistry and real-time PCR, thus presenting a T/ebp-thyroid-conditional hypomorphic mice. Detailed analysis of the thyroids from T/ebp(fl/fl), T/ebp(fl/fl); TPO-Cre, and T/ebp(fl/ko) mice, where the latter mouse line is derived from crosses with the original T/ebp/Nkx2.1-heterozygous mice, revealed that T/ebp(fl/fl); TPO-Cre mice can be classified into two groups with different phenotypes: one having atrophic/degenerative thyroid follicles with frequent presence of adenomas and extremely high serum TSH levels, and the other having an altered thyroid structure with reduced numbers of extraordinary dilated follicles consisting of excessive numbers of follicular cells as compared with those usually found in the normal thyroid. The latter phenotype was also observed in aged T/ebp(fl/ko) mouse thyroids. In vitro three-dimensional thyroid primary cultures using thyroids from T/ebp(fl/fl); TPO-Cre, T/ebp(fl/ko), and T/ebp(fl/fl) mice, and the latter treated with recombinant adenovirus with and without Cre expression, demonstrated that only cells from T/ebp(fl/fl) mice without adeno-Cre treatment formed follicular structures. Taken together, these results suggest that T/ebp/Nkx2.1 is required for maintenance of the normal architecture and function of differentiated thyroids. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Kimura, S (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 3112B, Bethesda, MD 20892 USA. EM shioko@helix.nih.gov FU Intramural NIH HHS [Z99 CA999999, Z01 BC005522-20] NR 45 TC 38 Z9 44 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD AUG PY 2006 VL 20 IS 8 BP 1796 EP 1809 DI 10.1210/me.2005-0327 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 067CC UT WOS:000239277700008 PM 16601074 ER PT J AU Qazi, AM Tsai-Morris, CH Dufau, ML AF Qazi, Aamer M. Tsai-Morris, Chon-Hwa Dufau, Maria L. TI Ligand-independent homo- and heterodimerization of human prolactin receptor variants: Inhibitory action of the short forms by heterodimerization SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID GROWTH-HORMONE RECEPTOR; ERYTHROPOIETIN RECEPTOR; PROMOTER UTILIZATION; SIGNAL-TRANSDUCTION; JAK2 ASSOCIATION; BREAST-CANCER; LONG-FORM; DIMERIZATION; ACTIVATION; TYROSINE AB Prolactin (PRL) acts through the long form (LF) of the human PRL receptor (hPRLR) to cause differentiation of mammary epithelial cells through activation of the Janus kinase-2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) pathway and subsequent transcriptional events. To determine whether the inhibitory action of hPRLR short forms (SFs; S1a and S1b) on PRL-induced signal transduction through the LF results from heterodimerization, we studied complex formation among variant forms of the hPRLR. 3'-Tagged fusion constructs, with activities comparable to the wild-type species, were used to investigate homodimer and heterodimer formation. The LF and both SFs of the hPRLR formed homodimers under nonreducing conditions, independently of PRL, but formed only monomers under reducing conditions. Coimmunoprecipitation of the cotransfected LF with the SFs (S1a or S1b) in transfected cells showed ligand-independent heterodimerization of individual SFs with the LF. Bioluminescence resonance energy transfer analysis demonstrated homo- and heterodimeric associations of hPRLR variants in human embryonic kidney 293 cells. Biotin-avidin immunoprecipitation analysis revealed that hPRLR forms are cell surface receptors and that SFs do not influence the steady state or half-life of the LF. Significant homo- and heterodimerization of biotinylated membrane hPRLR forms was observed. These findings indicate that homo- and heterodimers of hPRLR are constitutively present, and that the bivalent hormone acts on the preformed LF homodimer to induce the active signal transduction configuration. Although SF homodimers and their heterodimers with LF mediate JAK2 activation, the SF heterodimer partner lacks cytoplasmic sequences essential for activation of the JAK2/signal transducer and activator of transcription 5 pathway. This prevents the heterodimeric LF from mediating activation of PRL-induced genes. C1 NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36,49 Convent Dr,MSC 4510, Bethesda, MD 20892 USA. EM dufaum@mail.nih.gov FU Intramural NIH HHS NR 31 TC 60 Z9 63 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD AUG PY 2006 VL 20 IS 8 BP 1912 EP 1923 DI 10.1210/me.2005-0291 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 067CC UT WOS:000239277700016 PM 16556730 ER PT J AU Savelkoul, PJM Manoli, I Sparks, SE Ciccone, C Gahl, WA Krasnewich, DM Huizing, M AF Savelkoul, Paul J. M. Manoli, Irini Sparks, Susan E. Ciccone, Carla Gahl, William A. Krasnewich, Donna M. Huizing, Marjan TI Normal sialylation of serum N-linked and O-GalNAc-linked glycans 'in hereditary inclusion-body myopathy SO MOLECULAR GENETICS AND METABOLISM LA English DT Letter ID ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; DISTAL MYOPATHY; RIMMED VACUOLES; GLYCOPROTEINS; BIOSYNTHESIS; DYSTROGLYCAN; 2-EPIMERASE; MUTATIONS; GENE C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Huizing, M (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1851,Bld 10,Rm 10C103, Bethesda, MD 20892 USA. EM mhuizing@mail.nih.gov OI Manoli, Irini/0000-0003-1543-2941 NR 10 TC 9 Z9 9 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 2006 VL 88 IS 4 BP 389 EP 390 DI 10.1016/j.ymgme.2006.04.011 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 077LB UT WOS:000240029700014 PM 16762577 ER PT J AU Abernethy, DR AF Abernethy, Darrell R. TI Genotyping for drug responsiveness: Learning from warfarin SO MOLECULAR INTERVENTIONS LA English DT Editorial Material C1 NIA, Clin Invest Lab, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. RP Abernethy, DR (reprint author), NIA, Clin Invest Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD AUG PY 2006 VL 6 IS 4 BP 185 EP 185 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 087KK UT WOS:000240741100002 ER PT J AU Windels, F AF Windels, Francois TI Neuronal activity - From in vitro preparation to behaving animals SO MOLECULAR NEUROBIOLOGY LA English DT Review DE in vitro; slice preparation; in vivo; anesthesia; freely moving; experimental models ID AGE-RELATED-CHANGES; METHYL-D-ASPARTATE; SLICES MAINTAINED INVITRO; RAT HIPPOCAMPAL SLICES; SLEEP-WAKE CYCLE; NICOTINIC ACETYLCHOLINE-RECEPTORS; EXCITATORY SYNAPTIC-TRANSMISSION; VOLATILE GENERAL-ANESTHETICS; GATED ION CHANNELS; PRIMARY SOMATOSENSORY CORTEX AB The knowledge of the mechanisms regulating electric neuronal activity is fragmented by the wide variety of techniques and experimental models currently used in neurophysiological research. The interest and importance of the results obtained in any research is improved when interpreted in the perspective of the organism functioning as a whole in physiological conditions. Such interpretation, freed of the constraints imposed by the different techniques and experimental conditions used, is especially important when discussing together results obtained at the behavioral, cellular, and molecular level. This article outlines some of the key factors to consider when experiments from different models are interpreted together. C1 Natl Inst Drug Abuse, Intramural Res Program, Cellular Neurobiol Branch, US Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. RP Windels, F (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Cellular Neurobiol Branch, US Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. EM fwindels@thewindels.org RI Windels, Francois/G-5432-2010 FU Intramural NIH HHS NR 240 TC 6 Z9 6 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD AUG PY 2006 VL 34 IS 1 BP 1 EP 25 DI 10.1385/MN:34:1:1 PG 25 WC Neurosciences SC Neurosciences & Neurology GA 079YZ UT WOS:000240215100001 PM 17003519 ER PT J AU Capelli, C MacPhee, RDE Roca, AL Brisighelli, F Georgiadis, N O'Brien, SJ Greenwood, AD AF Capelli, Cristian MacPhee, Ross D. E. Roca, Alfred L. Brisighelli, Francesca Georgiadis, Nicholas O'Brien, Stephen J. Greenwood, Alex D. TI A nuclear DNA phylogeny of the woolly mammoth (Mammuthus primigenius) SO MOLECULAR PHYLOGENETICS AND EVOLUTION LA English DT Article ID MITOCHONDRIAL CYTOCHROME-B; SEQUENCES; EVOLUTION; ELEPHANT; GENES; AFRICA; GENOME C1 Amer Museum Nat Hist, Div Vertebrate Zool, New York, NY 10024 USA. Univ Cattolica Sacro Cuore, Ist Med Legale, Rome, Italy. SAIC Frederick, Lab Genom Divers, Basic Res Program, Frederick, MD 21702 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Mpala Res Ctr, Nanyuki, Kenya. GSF, Natl Res Ctr Environm & Hlth, Inst Mol Virol, Neuherberg, Germany. Tech Univ Munich, Inst Virol, D-8000 Munich, Germany. RP Greenwood, AD (reprint author), Amer Museum Nat Hist, Div Vertebrate Zool, New York, NY 10024 USA. EM greenwood@gsf.de FU NCI NIH HHS [N01 CO 12400] NR 30 TC 12 Z9 13 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1055-7903 J9 MOL PHYLOGENET EVOL JI Mol. Phylogenet. Evol. PD AUG PY 2006 VL 40 IS 2 BP 620 EP 627 DI 10.1016/j.ympev.2006.03.015 PG 8 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 075AJ UT WOS:000239853900024 PM 16631387 ER PT J AU Shugart, YY Samuels, J Willour, VL Grados, MA D Greenberg, B Knowles, JA T McCracken, J Rauch, SL Murphy, DL Wang, Y Pinto, A Fyer, AJ Piacentini, J Pauls, DL Cullen, B Page, J Rasmussen, SA Bienvenu, OJ Hoehn-Saric, R Valle, D Liang, KY Riddle, MA Nestadt, G AF Shugart, Y. Y. Samuels, J. Willour, V. L. Grados, M. A. D Greenberg, B. Knowles, J. A. T McCracken, J. Rauch, S. L. Murphy, D. L. Wang, Y. Pinto, A. Fyer, A. J. Piacentini, J. Pauls, D. L. Cullen, B. Page, J. Rasmussen, S. A. Bienvenu, O. J. Hoehn-Saric, R. Valle, D. Liang, K. -Y Riddle, M. A. Nestadt, G. TI Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q SO MOLECULAR PSYCHIATRY LA English DT Article DE obsessive-compulsive disorder; genome-wide scan; covariate based linkage analysis; simulation; age of onset ID COMPLEX SEGREGATION ANALYSIS; GENOTYPING ERRORS; FAMILY; ADOLESCENTS; STATISTICS; RATIONALE; GENETICS; CHILDREN; PROBANDS; HISTORY AB Obsessive-compulsive disorder (OCD) is the tenth most disabling medical condition worldwide. Twin and family studies implicate a genetic etiology for this disorder, although specific genes have yet to be identified. Here, we present the first large-scale model-free linkage analysis of both extended and nuclear families using both 'broad' (definite and probable diagnoses) and 'narrow' (definite only) definitions of OCD. We conducted a genome-scan analysis of 219 families collected as part of the OCD Collaborative Genetics Study. Suggestive linkage signals were revealed by multipoint analysis on chromosomes 3q27-28 (P = 0.0003), 6q (P = 0.003), 7p (P = 0.001), 1q (P = 0.003), and 15q (P = 0.006). Using the 'broad' OCD definition, we observed the strongest evidence for linkage on chromosome 3q27-28. The maximum overall Kong and Cox LODall score (2.67) occurred at D3S1262 and D3S2398, and simulation based P-values for these two signals were 0.0003 and 0.0004, respectively, although for both signals, the simulation-based genome-wide significance levels were 0.055. Covariate-linkage analyses implicated a possible role of gene(s) on chromosome 1 in increasing the risk for an earlier onset form of OCD. We are currently pursuing fine mapping in the five regions giving suggestive signals, with a particular focus on 3q27-28. Given probable etiologic heterogeneity in OCD, mapping gene(s) involved in the disorder may be enhanced by replication studies, large-scale family-based linkage studies, and the application of novel statistical methods. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21287 USA. Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21287 USA. Univ Bristol, Dept Social Med, Bristol, Avon, England. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21287 USA. Johns Hopkins Univ, Dept Psychiat, Baltimore, MD 21287 USA. Kennedy Krieger Inst, Baltimore, MD USA. Brown Univ, Sch Med, Butler Hosp, Dept Psychiat & Human Behav, Providence, RI 02912 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. Johns Hopkins Univ, Sch Med, Dept Behav Sci & Pediat, Baltimore, MD USA. RP Shugart, YY (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21287 USA. EM yyao@jhsph.edu RI Piacentini, John/C-4645-2011; Liang, Kung-Yee/F-8299-2011; Pinto, Anthony/D-2718-2017; OI Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 FU NCRR NIH HHS [RR 00052]; NIMH NIH HHS [7K23MH066284, K23-MH64543, R01 MH50214] NR 36 TC 84 Z9 87 U1 2 U2 6 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 2006 VL 11 IS 8 BP 763 EP 770 DI 10.1038/sj.mp.4001847 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 067NL UT WOS:000239309800009 PM 16755275 ER PT J AU Brenner, S Ryser, MF Choi, U Whiting-Theobald, N Kuhlisch, E Linton, G Kang, E Lehmann, R Rosen-Wolff, A Rudikoff, AG Farese, AM MacVittie, TJ Roesler, J Horwitz, ME Malech, HL AF Brenner, Sebastian Ryser, Martin F. Choi, Uimook Whiting-Theobald, Narda Kuhlisch, Eberhard Linton, Gilda Kang, Elizabeth Lehmann, Romy Rosen-Wolff, Angela Rudikoff, Andrew G. Farese, Ann M. MacVittie, Thomas J. Roesler, Joachim Horwitz, Mitchell E. Malech, Harry L. TI Polyclonal long-term MFGS-gp91phox marking in rhesus macaques after nonmyeloablative transplantation with transduced autologous peripheral blood progenitor cells SO MOLECULAR THERAPY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; HEMATOPOIETIC STEM-CELLS; RETROVIRAL VECTOR INTEGRATION; TRANSCRIPTION START REGIONS; MARROW-REPOPULATING CELLS; EFFICIENT GENE-TRANSFER; LARGE-ANIMAL MODEL; NONHUMAN-PRIMATES; ONCORETROVIRAL VECTORS; OXIDASE DEFECT AB We have recently reported that the RD114-pseudotyped MFGS-gp91phox vector achieves unprecedented levels of correction of the NADPH-oxidase gp91phox (approved gene symbol CYBB) defect in CD34(+) cells from patients with X-linked chronic granulomatous disease in the NOD/SCID mouse model. Considering clinical use of this vector, we transplanted autologous mobilized peripheral blood CD34(+) progenitor cells, transduced with the RD114-MFGS-gp91phox vector, into two healthy rhesus macaques following nonmyeloablative conditioning. The moderately high levels of in vivo marking seen in the first months following transduction decreased and stabilized at about 8 months posttransplant. Marking for both healthy animals after 15 months was 0.3 to 1.3 vector copies per 100 cells in lymphocytes, neutrophils, and monocytes. Vector insertion analyses performed by linear amplification-mediated PCR and sequencing identified 32 and 45 separate insertion sites in the animals. Identical insertion sites were found in myeloid cells and lymphocytes, demonstrating the successful transduction of lymphomyeloid progenitors. Some inserts landed in the vicinity of genes controlling cell cycle and proliferation. Statistical analyses of insertion sites 1 year posttransplant suggest a high diversity of insertion sites despite low marking. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Univ Clin Carl Gustav Carus, Dept Pediat, D-01307 Dresden, Germany. Univ Clin Carl Gustav Carus, Dept Med Informat & Biometry, D-01307 Dresden, Germany. Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Duke Univ, Adult Bone Marrow & Stem Cell Transplantat Progra, Durham, NC 27710 USA. RP Brenner, S (reprint author), NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sebastian.brenner@uniklinikum-dresden.de RI Brenner, Sebastian/D-7456-2013; OI Malech, Harry/0000-0001-5874-5775 NR 40 TC 9 Z9 9 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 1525-0016 J9 MOL THER JI Mol. Ther. PD AUG PY 2006 VL 14 IS 2 BP 202 EP 211 DI 10.1016/j.ymthe.2006.01.015 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 066SH UT WOS:000239249900009 PM 16600688 ER PT J AU Avni, I Sharabi, Y Sadeh, M Buchman, AS AF Avni, Irit Sharabi, Yehonatan Sadeh, Menachem Buchman, Aron S. TI Eosinophilia, myositis, and myasthenia gravis associated with a thymoma SO MUSCLE & NERVE LA English DT Article DE eosinophilia; myasthenia gravis; myositis; thymoma ID POLYMYOSITIS; TITIN; PATHOGENESIS; MYOPATHY; CELLS; AUTOANTIBODIES; PERIMYOSITIS; SPECTRUM; PATIENT; MUSCLE AB Hypereosinophilia has been associated with a wide variety of systemic disorders, including myositis. Myositis develops in a minority of patients with myasthenia gravis associated with a thymoma. We present a patient who developed a life-threatening myopathy in which testing demonstrated the concurrence of hypereosinophilia, myositis, and myasthenia gravis associated with thymoma. Thymoma-associated T-cell abnormalities may well have contributed to this rare association. This case underscores the need to reevaluate constantly the presumed cause of clinical complaints, as more than one cause may be present. C1 Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. E Wolfson Med Ctr, Dept Neurol, Holon, Israel. NINDS, Sect Clin Neurocardiol, NIH, Bethesda, MD 20892 USA. Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. RP Buchman, AS (reprint author), Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. EM Aron_S_Buchman@rush.edu NR 25 TC 5 Z9 5 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD AUG PY 2006 VL 34 IS 2 BP 242 EP 245 DI 10.1002/mus.20526 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 068TR UT WOS:000239397800016 PM 16506154 ER PT J AU Barton, JH AF Barton, John H. TI Emerging patent issues in genomic diagnostics SO NATURE BIOTECHNOLOGY LA English DT Editorial Material ID DRUG DEVELOPMENT; PHARMACOGENETICS; CANCER C1 Stanford Law Sch, Stanford, CA 94305 USA. NIH, Dept Clin Bioeth, Bethesda, MD USA. RP Barton, JH (reprint author), Stanford Law Sch, Crown Quadrangle,559 Nathan Abbott Way, Stanford, CA 94305 USA. EM jbarton@stanford.edu FU NHGRI NIH HHS [1R01 HG 02034] NR 26 TC 16 Z9 17 U1 1 U2 1 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 2006 VL 24 IS 8 BP 939 EP 941 DI 10.1038/nbt0806-939 PG 3 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 072VY UT WOS:000239702300029 PM 16900135 ER PT J AU Rouault, TA AF Rouault, Tracey A. TI The role of iron regulatory proteins in mammalian iron homeostasis and disease SO NATURE CHEMICAL BIOLOGY LA English DT Review ID ELEMENT-BINDING-PROTEIN; FERRITIN MESSENGER-RNA; FE-S CLUSTER; HYPERFERRITINEMIA-CATARACT SYNDROME; METAL-ION TRANSPORTER; RESPONSIVE ELEMENT; SULFUR CLUSTER; CYTOSOLIC ACONITASE; TRANSLATIONAL REGULATION; MITOCHONDRIAL ACONITASE AB Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are mammalian proteins that register cytosolic iron concentrations and post-transcriptionally regulate expression of iron metabolism genes to optimize cellular iron availability. In iron-deficient cells, IRPs bind to iron-responsive elements (IREs) found in the mRNAs of ferritin, the transferrin receptor and other iron metabolism transcripts, thereby enhancing iron uptake and decreasing iron sequestration. IRP1 registers cytosolic iron status mainly through an iron-sulfur switch mechanism, alternating between an active cytosolic aconitase form with an iron-sulfur cluster ligated to its active site and an apoprotein form that binds IREs. Although IRP2 is homologous to IRP1, IRP2 activity is regulated primarily by iron-dependent degradation through the ubiquitin-proteasomal system in iron-replete cells. Targeted deletions of IRP1 and IRP2 in animals have demonstrated that IRP2 is the chief physiologic iron sensor. The physiological role of the IRP-IRE system is illustrated by (i) hereditary hyperferritinemia cataract syndrome, a human disease in which ferritin L-chain IRE mutations interfere with IRP binding and appropriate translational repression, and (ii) a syndrome of progressive neurodegenerative disease and anemia that develops in adult mice lacking IRP2. The early death of mouse embryos that lack both IRP1 and IRP2 suggests a central role for IRP-mediated regulation in cellular viability. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Room 101, Bethesda, MD 20892 USA. EM trou@helix.nih.gov FU Intramural NIH HHS NR 106 TC 472 Z9 486 U1 9 U2 77 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD AUG PY 2006 VL 2 IS 8 BP 406 EP 414 DI 10.1038/nchembio807 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 065GD UT WOS:000239146800008 PM 16850017 ER PT J AU Dalakas, MC AF Dalakas, Marinos C. TI Sporadic inclusion body myositis - diagnosis, pathogenesis and therapeutic strategies SO NATURE CLINICAL PRACTICE NEUROLOGY LA English DT Review DE autoimmune; degeneration; immunotherapies; inflammatory myopathies; sporadic inclusion body myositis ID MHC-CLASS-I; ENDOPLASMIC-RETICULUM STRESS; CELL-ADHESION MOLECULES; INFILTRATING T-CELLS; INFLAMMATORY MYOPATHIES; MUSCLE-FIBERS; DIFFERENTIAL EXPRESSION; COSTIMULATORY MOLECULE; MYOFIBRILLAR MYOPATHY; AUTOIMMUNE MYOSITIS AB Sporadic inclusion body myositis (sIBM) presents with a characteristic clinical phenotype of slow-onset weakness and atrophy, affecting proximal and distal. limb muscles and facial and pharyngeal muscles. Histologically, sIBM is characterized by chronic myopathic features, lymphocytic infiltrates invading non-vacuolated fibers, vacuolar degeneration, and accumulation of amyloid-related proteins. The cause of sIBM is unclear, but two processes-one autoimmune and the other degenerative-appear to occur in parallel. In contrast to dystrophies, in sIBM the autoinvasive CD8(+) T cells are cytotoxic and antigen-driven, invading muscle fibers expressing major histocompatibility complex class I antigen and costimulatory molecules. The concurrent degenerative features include vacuolization, filamentous inclusions and intracellular accumulations of amyloid-p-related molecules. Although viruses have not been amplified from the muscle fibers, at least 12 cases of sIBM have been seen in association with retroviral infections, indicating that a chronic persistent viral infection might be a potential triggering factor. Emerging data imply that continuous upregulation of cytokines and major histocompatibility complex class I on the muscle fibers causes an endoplasmic reticulum stress response, resulting in intracellular accumulation of misfolded glycoproteins and activation of the transcription factor NF kappa B, leading to further cytokine activation. In spite of the brisk, antigen-driven T-cell infiltrates, sIBM does not respond to immunotherapies. New therapies using monoclonal antibodies against lymphocyte signaling pathways might prove helpful in arresting disease progression. C1 Natl Inst Neurol Disorders & Stroke, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. George Washington Univ, Washington, DC USA. RP Dalakas, MC (reprint author), Natl Inst Neurol Disorders & Stroke, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. EM dalakasm@ninds.nih.gov FU Intramural NIH HHS NR 63 TC 120 Z9 124 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-834X J9 NAT CLIN PRACT NEURO JI Nat. Clin. Pract. Neurol. PD AUG PY 2006 VL 2 IS 8 BP 437 EP 447 DI 10.1038/ncpneuro0261 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 065IF UT WOS:000239152700012 PM 16932602 ER PT J AU Simon, R Norton, L AF Simon, Richard Norton, Larry TI The Norton-Simon hypothesis: designing more effective and less toxic chemotherapeutic regimens SO NATURE CLINICAL PRACTICE ONCOLOGY LA English DT Editorial Material ID BREAST-CANCER; RANDOMIZED-TRIAL; DOSE-DENSE; SENSITIVITY; DOXORUBICIN; THERAPY; GROWTH C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Evelyn H Lauder Breast Ctr, New York, NY 10021 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, 9000 Rockville Pike,EPN 739, Bethesda, MD 20892 USA. EM rsimon@mail.nih.gov OI Norton, Larry/0000-0003-3701-9250 NR 12 TC 65 Z9 68 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1743-4254 J9 NAT CLIN PRACT ONCOL JI Nat. Clin. Pract. Oncol. PD AUG PY 2006 VL 3 IS 8 BP 406 EP 407 DI 10.1038/ncponc0560 PG 2 WC Oncology SC Oncology GA 067ZK UT WOS:000239341100002 PM 16894366 ER PT J AU Hunter, KW AF Hunter, Kent W. TI Context-dependent cancer risk SO NATURE GENETICS LA English DT Editorial Material ID LUNG CARCINOGENESIS; LOCUS; MICE; TUMORS AB A new study in mice shows that genetic variants underlying a previously mapped lung cancer susceptibility locus can have opposing effects on cancer risk depending on whether an oncogenic somatic mutation at the same locus subsequently arises in cis or in trans. These findings illustrate the complex interplay between genetic background and somatic events in contributing to cancer risk. C1 NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. RP Hunter, KW (reprint author), NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov NR 11 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD AUG PY 2006 VL 38 IS 8 BP 864 EP 865 DI 10.1038/ng0806-864 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 067TO UT WOS:000239325700011 PM 16874325 ER PT J AU Steeg, PS AF Steeg, Patricia S. TI Tumor metastasis: mechanistic insights and clinical challenges SO NATURE MEDICINE LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; BREAST-CANCER CELLS; HUMAN PANCREATIC-CANCER; MATRIX-METALLOPROTEINASE INHIBITORS; MAMMARY-CARCINOMA CELLS; FOCAL-ADHESION KINASE; IN-VIVO; COLORECTAL-CANCER; NUDE-MICE; LIVER METASTASIS AB Metastatic disease is the primary cause of death for most cancer patients. Complex and redundant pathways involving the tumor cell and the microenvironment mediate tumor invasion at the primary site, survival and arrest in the bloodstream, and progressive outgrowth at a distant site. Understanding these pathways and their dynamic interactions will help identify promising molecular targets for cancer therapy and key obstacles to their clinical development. C1 NCI, Ctr Canc Res, Lab Mol Pharmacol, Womens Canc Sect,NIH, Bethesda, MD 20892 USA. RP Steeg, PS (reprint author), NCI, Ctr Canc Res, Lab Mol Pharmacol, Womens Canc Sect,NIH, Bldg 37,Room 1122, Bethesda, MD 20892 USA. EM steegp@mail.nih.gov FU Intramural NIH HHS NR 163 TC 977 Z9 1033 U1 36 U2 199 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2006 VL 12 IS 8 BP 895 EP 904 DI 10.1038/nm1469 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 071TS UT WOS:000239626200019 PM 16892035 ER PT J AU Chattopadhyay, PK Price, DA Harper, TF Betts, MR Yu, J Gostick, E Perfetto, SP Goepfert, P Koup, RA De Rosa, SC Bruchez, MP Roederer, M AF Chattopadhyay, Pratip K. Price, David A. Harper, Theresa F. Betts, Michael R. Yu, Joanne Gostick, Emma Perfetto, Stephen P. Goepfert, Paul Koup, Richard A. De Rosa, Stephen C. Bruchez, Marcel P. Roederer, Mario TI Quantum dot semiconductor nanocrystals for immunophenotyping by polychromatic flow cytometry SO NATURE MEDICINE LA English DT Article ID CD8(+) T-CELLS; EPSTEIN-BARR-VIRUS; LIVE CELLS; INFECTION; MEMORY; LYMPHOCYTES; COMPENSATION; ACTIVATION; EXPRESSION; PHENOTYPE AB Immune responses arise from a wide variety of cells expressing unique combinations of multiple cell-surface proteins. Detailed characterization is hampered, however, by limitations in available probes and instrumentation. Here, we use the unique spectral properties of semiconductor nanocrystals (quantum dots) to extend the capabilities of polychromatic flow cytometry to resolve 17 fluorescence emissions. We show the need for this power by analyzing, in detail, the phenotype of multiple antigen-specific T-cell populations, revealing variations within complex phenotypic patterns that would otherwise remain obscure. For example, T cells specific for distinct epitopes from one pathogen, and even those specific for the same epitope, can have markedly different phenotypes. The technology we describe, encompassing the detection of eight quantum dots in conjunction with conventional fluorophores, should expand the horizons of flow cytometry, as well as our ability to characterize the intricacies of both adaptive and innate cellular immune responses. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Solus Biosyst, Palo Alto, CA 94303 USA. Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. John Radcliffe Hosp, Nuffield Dept Clin Med, Oxford OX3 9DU, England. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. Carnegie Mellon Univ, Dept Chem & Technol, Ctr Networks & Pathways, Pittsburgh, PA 15213 USA. RP Roederer, M (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM Roederer@nih.gov RI Bruchez, Marcel/C-2271-2009; Chattopadhyay, Pratip/B-9227-2008; Roederer, Mario/G-1887-2011; Delehanty, James/F-7454-2012; Price, David/C-7876-2013; OI Bruchez, Marcel/0000-0002-7370-4848; Price, David/0000-0001-9416-2737; Chattopadhyay, Pratip/0000-0002-5457-9666 FU Intramural NIH HHS [Z99 AI999999]; Medical Research Council [G108/441]; NIBIB NIH HHS [R01 EB 000364] NR 29 TC 224 Z9 233 U1 5 U2 30 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2006 VL 12 IS 8 BP 972 EP 977 DI 10.1038/nm1371 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 071TS UT WOS:000239626200031 PM 16862156 ER PT J AU Gil-Da-Costa, R Martin, A Lopes, MA Munoz, M Fritz, JB Braun, AR AF Gil-da-Costa, Ricardo Martin, Alex Lopes, Marco A. Munoz, Monica Fritz, Jonathan B. Braun, Allen R. TI Species-specific calls activate homologs of Broca's and Wernicke's areas in the macaque SO NATURE NEUROSCIENCE LA English DT Article ID VENTROLATERAL PREFRONTAL CORTEX; AUDITORY-CORTEX; RHESUS-MONKEY; FUNCTIONAL NEUROANATOMY; ASSOCIATION CORTEX; COMPLEX SOUNDS; MOTOR SYSTEM; LANGUAGE; REPRESENTATION; PARIETAL AB The origin of brain mechanisms that support human language - whether these originated de novo in humans or evolved from a neural substrate that existed in a common ancestor -remains a controversial issue. Although the answer is not provided by the fossil record, it is possible to make inferences by studying living species of nonhuman primates. Here we identified neural systems associated with perceiving species-specific vocalizations in rhesus macaques using H(2)(15)O positron emission tomography (PET). These vocalizations evoke distinct patterns of brain activity in homologs of the human perisylvian language areas. Rather than resulting from differences in elementary acoustic properties, this activity seems to reflect higher order auditory processing. Although parallel evolution within independent primate species is feasible, this finding suggests the possibility that the last common ancestor of macaques and humans, which lived 25-30 million years ago, possessed key neural mechanisms that were plausible candidates for exaptation during the evolution of language. C1 Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Gulbenkian Inst Sci, Program Biol & Med, P-2781 Oeiras, Portugal. UCL, Inst Child Hlth, London WC1N 3JH, England. Univ Maryland, Syst Res Inst, Ctr Auditory & Acoust Res, College Pk, MD 20742 USA. RP Braun, AR (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. EM brauna@nidcd.nih.gov RI Munoz, Monica/C-9189-2009; martin, alex/B-6176-2009; OI Munoz Lopez, Monica/0000-0002-5530-2394 FU Intramural NIH HHS NR 49 TC 70 Z9 72 U1 1 U2 17 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 2006 VL 9 IS 8 BP 1064 EP 1070 DI 10.1038/nn1741 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 078CZ UT WOS:000240080300020 PM 16862150 ER PT J AU Dancey, JE Chen, HX AF Dancey, Janet E. Chen, Helen X. TI Strategies for optimizing combinations of molecularly targeted anticancer agents SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID CELL LUNG-CANCER; PHASE-III TRIAL; METASTATIC BREAST-CANCER; COOPERATIVE-ONCOLOGY-GROUP; TYROSINE KINASE INHIBITOR; CLINICAL-TRIALS; IN-VITRO; 1ST-LINE CHEMOTHERAPY; TRASTUZUMAB HERCEPTIN; MONOCLONAL-ANTIBODY AB The rapid emergence of hundreds of new agents that modulate an ever-growing list of cancer-specific molecular targets offers tremendous hope for cancer patients. However, evaluating targeted agents individually, in combination with standard treatments, and in combination with other targeted agents presents significant development challenges. Because the number of possible drug combinations is essentially limitless, a strategy for determining the most promising combinations and prioritizing their evaluation is crucial. Here, we consider the crucial elements of a development strategy for targeted-agent combinations. Issues that pose challenges to the rational preclinical and clinical evaluation of such combinations will be described, and possible approaches to overcoming these challenges will be discussed. C1 NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD 20852 USA. RP Dancey, JE (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, 6130 Execut Blvd,EPN 7131, Rockville, MD 20852 USA. EM danceyj@ctep.nci.nih.gov NR 63 TC 215 Z9 222 U1 1 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD AUG PY 2006 VL 5 IS 8 BP 649 EP 659 DI 10.1038/nrd2089 PG 11 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 069VN UT WOS:000239476900021 PM 16883303 ER PT J AU Waldmann, TA AF Waldmann, Thomas A. TI The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID T-CELL LEUKEMIA; ACTIVATED KILLER-CELLS; RECEPTOR-BETA-CHAIN; HUMANIZED ANTI-TAC; RHEUMATOID-ARTHRITIS; MONOCLONAL-ANTIBODY; IL-2 RECEPTOR; ALPHA-CHAIN; IN-VIVO; RENAL-TRANSPLANTATION AB Interleukin-2 and interleukin-15 have pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor subunits in common, these two cytokines have contrasting roles in adaptive immune responses. The unique role of interleukin-2 is in the elimination of self-reactive T cells to prevent autoimmunity. By contrast, interleukin-15 is dedicated to the prolonged maintenance of memory T-cell responses to invading pathogens. As discussed in this Review, the biology of these cytokines will affect the development of novel therapies for malignancy and autoimmune diseases, as well as the design of vaccines against infectious diseases. C1 NCI, Metab Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU Intramural NIH HHS NR 68 TC 503 Z9 521 U1 7 U2 60 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD AUG PY 2006 VL 6 IS 8 BP 595 EP 601 DI 10.1038/nri1901 PG 7 WC Immunology SC Immunology GA 067CE UT WOS:000239277900014 PM 16868550 ER PT J AU Shevach, EM Stephens, GL AF Shevach, Ethan M. Stephens, Geoffrey L. TI The GITR-GITRL interaction: co-stimulation or contrasuppression of regulatory activity? SO NATURE REVIEWS IMMUNOLOGY LA English DT Article ID INDUCED TNF RECEPTOR; COLLAGEN-INDUCED ARTHRITIS; T-CELL-ACTIVATION; IN-VIVO; CUTTING EDGE; COSTIMULATORY RECEPTOR; LIGAND EXPRESSION; FAMILY; CD4(+); SUPPRESSION AB Stimulation of T cells through GITR (glucocorticoid-induced tumour-necrosis-factor- receptor-related protein) has been shown to enhance immunity to tumours and viral pathogens, and to exacerbate autoimmune disease. The effects of stimulation through GITR are generally thought to be caused by attenuation of the effector activity of immunosuppressive CD4(+) CD25(+) regulatory T (T-Reg) cells. Here we propose a model in which GITR-GITR-ligand interactions co-stimulate both responder T-cell functions and the suppressive functions of T-Reg cells. C1 NIAID, Cellular Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Cellular Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov NR 34 TC 164 Z9 168 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD AUG PY 2006 VL 6 IS 8 BP 613 EP 618 DI 10.1038/nri1867 PG 6 WC Immunology SC Immunology GA 067CE UT WOS:000239277900016 PM 16868552 ER PT J AU Bonifacino, JS Rojas, R AF Bonifacino, Juan S. Rojas, Raul TI Retrograde transport from endosomes to the trans-Golgi network SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID MANNOSE 6-PHOSPHATE RECEPTOR; TO-TGN TRANSPORT; YEAST LATE GOLGI; SACCHAROMYCES-CEREVISIAE; MEMBRANE-PROTEINS; SHIGA-TOXIN; MAMMALIAN RETROMER; EARLY/RECYCLING ENDOSOMES; TETHERING FACTORS; CRYSTAL-STRUCTURE AB A subset of intracellular transmembrane proteins such as acid-hydrolase receptors, processing peptidases and SNAREs, as well as extracellular protein toxins such as Shiga toxin and ricin, undergoes 'retrograde' transport from endosomes to the trans-Golgi network. Here, we discuss recent studies that have begun to unravel the molecular machinery that is involved in this process. We also propose a central role for a 'tubular endosomal network' in sorting to recycling pathways that lead not only to the trans-Golgi network but also to different plasma-membrane domains and to specialized storage vesicles. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM juan@helix.nih.gov; rojasr@mail.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 NR 99 TC 340 Z9 345 U1 10 U2 48 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD AUG PY 2006 VL 7 IS 8 BP 568 EP 579 DI 10.1038/nrm1985 PG 12 WC Cell Biology SC Cell Biology GA 066OT UT WOS:000239240000014 PM 16936697 ER PT J AU Imam, SZ Karahalil, B Hogue, BA Souza-Pinto, NC Bohr, VA AF Imam, SZ Karahalil, B Hogue, BA Souza-Pinto, NC Bohr, VA TI Mitochondrial and nuclear DNA-repair capacity of various brain regions in mouse is altered in an age-dependent manner SO NEUROBIOLOGY OF AGING LA English DT Article DE DNA repair; glycosylases; mitochondria; aging; neurodegeneration ID OXIDATIVE DAMAGE; ALZHEIMERS-DISEASE; AGING BRAIN; LYASE ACTIVITY; STRESS; GLYCOSYLASES; RESTRICTION; INCREASES; CHEMISTRY; DELETIONS AB Aging is associated with increased susceptibility to neuronal loss and disruption of cerebral function either as a component of senescence, or as a consequence of neurodegenerative disease or stroke. Here we report differential changes in the repair of oxidative DNA damage in various brain regions during aging. We evaluated mitochondrial and nuclear incision activities of oxoguanine DNA glycosylase (OGG1), uracil DNA glycosylase (UDG) and the endonuclease Ill homologue (NTH1) in the caudate nucleus (CN), frontal cortex (FC), hippocampus (Hip), cerebellum (CE) and brain stem (BS) of 6- and 18-month-old male C5781/6 mice. We observed a significant age-dependent decrease in incision activities of all three glycosylases in the mitochondria of all brain regions, whereas variable patterns of changes were seen in nuclei. No age- or region-specific changes were observed in the mitochondrial repair synthesis incorporation of uracil-initiated base-excision repair (BER). We did not observe any age or region dependent differences in levels of BER proteins among the five brain regions. In summary, our data suggest that a decreased efficiency of mitochondrial BER-glycosylases and increased oxidative damage to mitochondrial DNA might contribute to the normal aging process. These data provide a novel characterization of oxidative DNA damage processing in different brain regions implicated in various neurodegenerative disorders, and suggest that this process is regulated in an age-dependent manner. Manipulation of DNA repair mechanisms may provide a strategy to prevent neuronal loss during age-dependent neurodegenerative disorders. (c) 2005 Elsevier Inc. All rights reserved. C1 NIA, Gerontol Res Ctr, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Gazi Univ, Fac Pharm, Dept Toxicol, TR-06330 Ankara, Turkey. Univ Texas, Hlth Sci Ctr, S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA. RP Bohr, VA (reprint author), NIA, Gerontol Res Ctr, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov RI Souza-Pinto, Nadja/C-3462-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X NR 34 TC 110 Z9 113 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD AUG PY 2006 VL 27 IS 8 BP 1129 EP 1136 DI 10.1016/j.neurobiolaging.2005.06.002 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 057YV UT WOS:000238632000011 PM 16005114 ER PT J AU Irie, F Strozyk, D Peila, R Korf, ES Remaley, AT Masaki, K White, LR Launer, LJ AF Irie, F Strozyk, D Peila, R Korf, ES Remaley, AT Masaki, K White, LR Launer, LJ TI Brain lesions on MRI and endogenous sex hormones in elderly men SO NEUROBIOLOGY OF AGING LA English DT Article DE epidemiology; endogenous sex hormones; bioavailable testosterone; bioavailable estradiol; SHBG; cerebral atrophy; lacunes; hippocampal atrophy; white matter lesions; large infarcts; MRI ID ESTROGEN REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; ALZHEIMERS-DISEASE; COGNITIVE FUNCTION; OLDER MEN; CARDIOVASCULAR-DISEASE; TESTOSTERONE INCREASES; POSTMENOPAUSAL WOMEN; SERUM TESTOSTERONE; BINDING GLOBULIN AB We investigated the association between MRI detected brain lesions and levels of endogenous sex hormones in Japanese-American men aged 74-95 years. Logistic regression was used to estimate the association (OR (95% CI)) of MRI outcome with tertiles of bioavailable testosterone, 17 beta estradiol and sex hormone binding globulin (SHBG). There was a significantly increased risk for cerebral atrophy in the highest tertile of testosterone (3.1 (1.2-7.8)) compared to the lowest. We also found that men with the highest estradiol had a higher risk of lacunes (1.92 (1.1-3.2)). These relationships did not change with adjustment for the other sex hormones, cardiovascular risk factors, or other brain lesions. In contrast, men with the highest SHBG had a lower risk both of cerebral atrophy and lacunes, after adjusting for sex hormones and cardiovascular risk factors. There were no associations between sex hormones and hippocampal atrophy, white matter lesions, and large infarcts. Because the levels of hormone were measured close in time to the acquisition of the MRI, these associations may reflect neurodegeneration in brain regions regulating hormone levels. Published by Elsevier Inc. C1 NIA, Lab Epidemiol, Bethesda, MD 20892 USA. Pacific Hlth Res Inst, Honolulu, HI USA. Vrije Univ Amsterdam, Amsterdam, Netherlands. NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Launer, LJ (reprint author), NIA, Lab Epidemiol, Gateway Bldg,Room 3C-309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. EM launer1@nia.nih.gov RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X FU NHLBI NIH HHS [N01-HC-O5102]; NIA NIH HHS [N01-AG-4-2149, U01 AG019349] NR 57 TC 7 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD AUG PY 2006 VL 27 IS 8 BP 1137 EP 1144 DI 10.1016/j.neurobiolaging.2005.05.015 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 057YV UT WOS:000238632000012 PM 16009466 ER PT J AU Lauretani, F Bandinelli, S Bartali, B Di Iorio, A Giacomini, V Corsi, AM Guralnik, JM Ferrucci, L AF Lauretani, F Bandinelli, S Bartali, B Di Iorio, A Giacomini, V Corsi, AM Guralnik, JM Ferrucci, L TI Axonal degeneration affects muscle density in older men and women SO NEUROBIOLOGY OF AGING LA English DT Article DE axonal degeneration; surface ENG; peroneal CMAP; muscle density; sarcopenia ID MOTOR-NERVE CONDUCTION; AGE-ASSOCIATED CHANGES; SKELETAL-MUSCLE; FIBER TYPES; STRENGTH; MOBILITY; MASS; ATTENUATION; LIMITATIONS; SARCOPENIA AB Using data from InCHIANTI, a prospective population-based survey of older persons, we examined the relationship of peroneal nerve conduction velocity (NCV a measure of nerve myelination) and compound muscle action potential (CMAP, a measure of axonal degeneration) with calf muscle mass and density, two complementary measures of sarcopenia. NCV and CMAP were assessed by surface electroneurography of the right peroneal nerve conducted in 1162 participants, 515 men and 647 women, age 21-96 years, free of major neurological diseases. Cross-sectional muscle area and calf muscle density were measured using peripheral quantitative computerized tomography (pQCT). Both nerve and muscle parameters declined with age although in most cases the decline was not linear. In both sexes, CMAP, but not NCV, was independently and significantly associated with calf muscle density. These findings suggest that intrinsic changes in the muscle tissue are partially caused by a reduction in the number of motor axons. (c) 2005 Published by Elsevier Inc. C1 NIA, Longitudinal Studies Sect, Clin Res Branch, ASTRA Unit, Baltimore, MD 21225 USA. INRCA, Lab Clin Epidemiol, Dept Geriatr, Florence, Italy. Tuscany Reg Hlth Agcy, Florence, Italy. ASL 10, ASF Dept Geriatr Rehabil, Florence, Italy. Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. Univ G DAnnunzio, Lab Clin Epidemiol, Dept Med & Sci Aging, Chieti, Italy. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, ASTRA Unit, 3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 FU Intramural NIH HHS [Z99 AG999999]; PHS HHS [821336, 916413] NR 34 TC 49 Z9 49 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD AUG PY 2006 VL 27 IS 8 BP 1145 EP 1154 DI 10.1016/j.neurobiolaging.2005.06.009 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 057YV UT WOS:000238632000013 PM 16085338 ER PT J AU Greggio, E Jain, S Kingsbury, A Bandopadhyay, R Lewis, P Kaganovich, A van der Brug, MP Beilina, A Blackinton, J Thomas, KJ Ahmad, R Miller, DW Kesavapany, S Singleton, A Lees, A Harvey, RJ Harvey, K Cookson, MR AF Greggio, Elisa Jain, Shushant Kingsbury, Ann Bandopadhyay, Rina Lewis, Patrick Kaganovich, Alice van der Brug, Marcel P. Beilina, Alexandra Blackinton, Jeff Thomas, Kelly Jean Ahmad, Rill Miller, David W. Kesavapany, Sashi Singleton, Andrew Lees, Andrew Harvey, Robert J. Harvey, Kirsten Cookson, Mark R. TI Kinase activity is required for the toxic effects of mutant LRRK2/dardarin SO NEUROBIOLOGY OF DISEASE LA English DT Article DE LRRK2; kinase; Parkinson's disease; alpha-synuclein; substantia nigra ID PARKINSONS-DISEASE; PROTEIN-KINASES; LRRK2 MUTATION; DOMAIN; ROC AB Mutations in the LRRK2 gene, coding for dardarin, cause dominantly inherited Parkinson's disease (PD). Dardarin is a large protein, and mutations are found throughout the gene including the kinase domain. However, it is not clear if kinase activity is important for the damaging effects of pathogenic mutations. In this study, we noted two cellular phenotypes associated with mutant dardarin. First, pathogenic mutations increase the tendency of dardarin to form inclusion bodies. Secondly, neurons and neuronal cell lines undergo cell death after expression of mutant protein. Manipulating activity by replacing the kinase domain with a 'kinase-dead' version blocks inclusion body formation and strongly delays cell death. This predicts that kinase inhibitors will be useful therapeutic agents in patients with LRRK2 mutations and, perhaps, in sporadic PD. We also show that dardarin protein is expressed within human midbrain neurons and that C-terminal epitopes are also found in some Lewy bodies. Published by Elsevier Inc. C1 NIA, Cell Biol & Gene Express Unit, Lab Neurogenet, Bethesda, MD 20892 USA. NIA, Mol Genet Unit, Neurogenet Lab, Bethesda, MD 20892 USA. Inst Neurol, Reta Lila Weston Inst Neurol, London WC1N 1PJ, England. NINDS, Neurochem Lab, Bethesda, MD 20892 USA. Univ London Sch Pharm, Dept Pharmacol, London WC1N 1AX, England. RP Harvey, K (reprint author), NIA, Cell Biol & Gene Express Unit, Lab Neurogenet, 35 Convent Dr, Bethesda, MD 20892 USA. EM kirsten.harvcy@pharmacy.ac.uk; cookson@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Lewis , Patrick/C-3674-2009; Lees, Andrew/A-6605-2009; Bandopadhyay, Rina /C-7926-2009; Greggio, Elisa/H-6119-2013; OI Greggio, Elisa/0000-0002-8172-3598; Lewis, Patrick/0000-0003-4537-0489 FU Parkinson's UK [G-4056] NR 28 TC 376 Z9 380 U1 3 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD AUG PY 2006 VL 23 IS 2 BP 329 EP 341 DI 10.1016/j.nbd.2006.04.001 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 071OO UT WOS:000239611700009 PM 16750377 ER PT J AU Stefanovic, B Bosetti, F Silva, AC AF Stefanovic, Bojana Bosetti, Francesca Silva, Afonso C. TI Modulatory role of cyclooxygenase-2 in cerebrovascular coupling SO NEUROIMAGE LA English DT Article DE brain; functional activation; cerebral blood flow; cyclooxygenase-2; PGE(2); fMRI ID CEREBRAL-BLOOD-FLOW; RAT SOMATOSENSORY CORTEX; NITRIC-OXIDE SYNTHASE; PROSTANOID RECEPTORS; SIGNAL-TRANSDUCTION; PHOSPHOLIPASE A(2); SYNAPTIC ACTIVITY; BARREL CORTEX; TRANSIT-TIME; KAINIC ACID AB To investigate the role of cyclooxygenase-2 (COX-2) in the cerebrovascular coupling, hemodynamic and neuronal responses to forepaw stimulation were measured in alpha-chloralose-anesthetized rats (N = 18) before and after intravenous administration of Meloxicam (MEL), a preferential COX-2 inhibitor, and following a bolus of prostaglandin E-2 (PGE(2)), a prominent vasodilatatory product of COX-2 catalyzed metabolism of arachidonic acid. The cerebral blood flow (CBF) and blood-oxygenation-level-dependent (BOLD) response was quantified using continuous arterial spin labeling magnetic resonance imaging. Neuronal activity was measured by recording somatosensory-evoked potentials (SEPs) via intracranial electrodes. Both MEL and PGE(2) had a significant effect on the activation-elicited CBF (P < 10(-6)) and BOLD (P < 10(-6)) responses, without affecting the baseline perfusion. Meloxicam decreased brain COX enzymatic activity by 57 +/- 14% and decreased the stimulation-induced CBF response to 32 +/- 2% and BOLD to 46 +/- 1% of their respective pre-drug amplitudes. In turn, PGE(2) bolus resulted in a partial recovery of functional hyperemia, with the CBF response recovering to 52 +/- 3% and the BOLD response to 56 +/- 2% of their values prior to MEL administration. There was no concomitant decrease in either amplitudes or latencies of SEP components. These findings suggest a modulatory role of COX-2 products in the cerebrovascular coupling and provide evidence for existence of a functional metabolic buffer. (c) 2006 Elsevier Inc. All rights reserved. C1 NINDS, Lab Funct & Mol Imaging, Cerebral Microcirculat Unit, Bethesda, MD 20892 USA. NIA, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. RP Stefanovic, B (reprint author), NINDS, Lab Funct & Mol Imaging, Cerebral Microcirculat Unit, 10 Ctr Dr,Bldg 10,Room B1D109, Bethesda, MD 20892 USA. EM stefanovicb@ninds.nih.gov RI Silva, Afonso/A-7129-2009 FU Intramural NIH HHS NR 51 TC 35 Z9 37 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2006 VL 32 IS 1 BP 23 EP 32 DI 10.1016/j.neuroimage.2006.03.014 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 070NY UT WOS:000239530700004 PM 16626973 ER PT J AU Arias, M Pardo, J Blanco-Arias, P Sobrido, MJ Arias, S Dapena, D Carracedo, A Goldfarb, LG Navarro, C AF Arias, Manuel Pardo, Julio Blanco-Arias, Patricia Sobrido, Maria-Jesus Arias, Susana Dapena, Dolores Carracedo, Angel Goldfarb, Lev G. Navarro, Carmen TI Distinct phenotypic features and gender-specific disease manifestations in a Spanish family with desmin L370P mutation SO NEUROMUSCULAR DISORDERS LA English DT Article DE desmin; desminopathy; myofibrillar myopathy; cardiomyopathy; sudden death; phenotypic variability ID MYOFIBRILLAR MYOPATHY; SKELETAL MYOPATHY; INTERMEDIATE-FILAMENTS; MISSENSE MUTATION; GENE CAUSES; MUSCLE; POSITIVITY; HUMANS; DOMAIN AB Desminopathies represent a subtype of myofibrillar myopathy caused by mutations in the DES gene, which cause myofibril disruption and intracellular inclusions containing desmin and other protein components. Desminopathy mainly involves skeletal and cardiac muscle, separately or together. Both autosomal dominant and autosomal recessive inheritance have been reported. Here, we describe the second family identified to date with an L370P desmin mutation. The disease in this family shows autosomal dominant inheritance with a particular phenotype, where mates suffer from sudden death of cardiac origin while females exhibit a more benign myopathy of distal onset and slower progression. Because the only family previously identified with this mutation was limited to one studied patient, the present kindred represents the largest clinical investigation of the phenotype associated with the L370P mutation. (C) 2006 Elsevier B.V. All rights reserved. C1 Univ Santiago de Compostela, Hosp Clin, Dept Neurol, Santiago De Compostela 15706, Spain. Univ Santiago de Compostela, Grp Med Xenom, Santiago De Compostela, Spain. Fdn Publ Galega Med Xenom, Santiago De Compostela, Spain. Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. Hosp Clin Univ Vigo Meixoeiro, Dept Pathol & Neuropathol, Vigo, Spain. RP Arias, M (reprint author), Univ Santiago de Compostela, Hosp Clin, Dept Neurol, Travesia Choupana S-N, Santiago De Compostela 15706, Spain. EM mariasg@meditex.es RI Navarro, Carmen/A-9210-2012; Pardo, Julio/K-4420-2016; OI Pardo, Julio/0000-0001-8807-1310; Blanco-Arias, Patricia/0000-0002-6597-2308 NR 26 TC 15 Z9 17 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD AUG PY 2006 VL 16 IS 8 BP 498 EP 503 DI 10.1016/j.nmd.2006.05.011 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 101RV UT WOS:000241759100005 PM 16806931 ER PT J AU Basselin, M Chang, L Bell, JM Rapoport, SI AF Basselin, Mireille Chang, Lisa Bell, Jane M. Rapoport, Stanley I. TI Chronic lithium chloride administration attenuates brain NMDA receptor-initiated signaling via arachidonic acid in unanesthetized rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE arachidonic acid; lithium; bipolar disorder; phospholipase A(2); MK-801; NMDA ID METHYL-D-ASPARTATE; SECRETORY PHOSPHOLIPASE A(2); LONG-TERM POTENTIATION; PROTEIN-KINASE-II; CEREBRAL CORTICAL-NEURONS; CEREBELLAR GRANULE CELLS; DRUG-INDUCED MANIA; BIPOLAR DISORDER; DOCOSAHEXAENOIC ACID; IN-VITRO AB It has been proposed that lithium is effective in bipolar disorder (BID) by inhibiting glutamatergic neurotransmission, particularly via N-methyl-D-aspartate receptors (NMDARs). To test this hypothesis and to see if the neurotransmission could involve the NMDAR-mediated activation of phospholipase A(2) (PLA(2)), to release arachidonic acid (AA) from membrane phospholipid, we administered subconvulsant doses of NMIDA to unanesthetized rats fed a chronic control or LiCl diet. We used quantitative autoradiography following the intravenous injection of radiolabeled AA to measure regional brain incorporation coefficients k* for AA, which reflect receptor-mediated activation of PLA2. In control diet rats, NMDA (25 and 50 mg/kg i.p.) compared with i.p. saline increased k* significantly in 49 and 67 regions, respectively, of the 83 brain regions examined. The regions affected were those with reported NMDARs, including the neocortex, hippocampus, caudate-putamen, thalamus, substantia nigra, and nucleus accumbens. The increases could be blocked by pretreatment with the specific noncompetitive NMDA antagonist MK-801 ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine hydrogen maleate) (0.3 mg/kg i.p.), as well by a 6-week LiCl diet sufficient to produce plasma and brain lithium concentrations known to be effective in BID, MK-801 alone reduced baseline values for k* in many brain regions. The results show that it is possible to image NMDA signaling via PLA(2) activation and AA release in vivo, and that chronic lithium blocks this signaling, consistent with its suggested mechanism of action in BID. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Basselin, M (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room IS126-MSC 0947, Bethesda, MD 20892 USA. EM mirvasln@mail.nih.gov NR 149 TC 74 Z9 76 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2006 VL 31 IS 8 BP 1659 EP 1674 DI 10.1038/sj.npp.1300920 PG 16 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 067ZL UT WOS:000239341200010 PM 16292331 ER PT J AU Neumeister, A Drevets, WC Belfer, I Luckenbaugh, DA Henry, S Bonne, O Herscovitchs, P Goldman, D Charney, DS AF Neumeister, Alexander Drevets, Wayne C. Belfer, Inna Luckenbaugh, David A. Henry, Shannan Bonne, Omer Herscovitchs, Peter Goldman, David Charney, Dennis S. TI Effects of alpha(2C)-adrenoreceptor gene polymorphism on neural responses to facial expressions in depression SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE major depression; noradrenaline; alpha(2) adrenoreceptor subtypes; polymorphism; emotion processing; positron emission tomography ID PITUITARY-ADRENAL AXIS; CORTICOTROPIN-RELEASING HORMONE; CONGESTIVE-HEART-FAILURE; MAJOR DEPRESSION; PLASMA NOREPINEPHRINE; CATECHOLAMINE-HYPOTHESIS; ANTIDEPRESSANT TREATMENT; UNIPOLAR DEPRESSION; AFFECTIVE-DISORDERS; AMYGDALA RESPONSE AB Alterations in processing of emotionally salient information have been reported in individuals with major depressive disorder (MDD). Evidence suggests a role for noradrenaline in the regulation of a cortico-limbic-striatal circuit that has also been implicated in the pathophysiology of MDD. Herein, we studied the physiological consequences of a common coding polymorphism of the gene for the alpha(2C)-adrenoreceptor (AR) subtype-the deletion of four consecutive amino acids at codons 322-325 of the alpha 2C-AR (alpha 2CDel322-325-AR) in medication-free, remitted individuals with MDD (rMDD). and healthy control subjects. After injection of 10 mCi of (H2O)-O-15, positron emission tomography (PET) measures of neural activity were acquired while subjects were viewing unmasked sad, happy, and fearful faces. The neural responses to sad facial expressions were increased in the amygdala and decreased in the left ventral striatum in rMDD patients relative to healthy control subjects. Furthermore, we report that rMDD carriers of one or two copies of the alpha 2CDel322-325-AR exhibit greater amygdala as well as pregenual and subgenual anterior cingulate gyrus neuronal activity in response to sad faces than healthy alpha 2CDel322-325-AR carriers and rMDD noncarriers. These results suggest that the alpha 2CDel322-325-AR confers a change in brain function implicating this alpha 2-AR subtype into the pathophysiology of MDD. C1 Yale Univ, Sch Med, Mol Imaging Program, Clin Neurosci Div,Dept Psychiat, West Haven, CT 06516 USA. NIMH, Sect Neuroimaging Mood & Anxiety Disorders, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. Natl Inst Dent & Craniofacial Res, NICDR, Bethesda, MD USA. Natl Inst Hlth, PET Dept, Ctr Clin, Bethesda, MD USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. RP Neumeister, A (reprint author), Yale Univ, Sch Med, Mol Imaging Program, Clin Neurosci Div,Dept Psychiat, 950 Campbell Ave,Bldg 1,Room 9-174,MSC 151E, West Haven, CT 06516 USA. EM alexander.neumeister@yale.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 41 TC 60 Z9 60 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2006 VL 31 IS 8 BP 1750 EP 1756 DI 10.1038/sj.npp.1301010 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 067ZL UT WOS:000239341200019 PM 16407897 ER PT J AU Li, TK Porjesz, B AF Li, Ting-Kai Porjesz, Bernice TI Henri Begleiter, 1935-2006 - Obituary SO NEUROPSYCHOPHARMACOLOGY LA English DT Biographical-Item C1 NIAAA, Bethesda, MD USA. Med Ctr, Brooklyn, NY USA. RP Li, TK (reprint author), NIAAA, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2006 VL 31 IS 8 BP 1840 EP 1840 DI 10.1038/sj.npp.1301112 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 067ZL UT WOS:000239341200031 PM 16847452 ER PT J AU Rennard, SI Glover, ED Leischow, S Daughton, DM Glover, PN Muramoto, M Franzon, M Danielsson, T Landfeldt, B Westin, A AF Rennard, Stephen I. Glover, Elbert D. Leischow, Scott Daughton, David M. Glover, Penny N. Muramoto, Myra Franzon, Mikael Danielsson, Tobias Landfeldt, Bjorn Westin, Ake TI Efficacy of the nicotine inhaler in smoking reduction: A double-blind, randomized trial SO NICOTINE & TOBACCO RESEARCH LA English DT Article; Proceedings Paper CT 8th Annual Meeting of the Society-for-Research-on-Nicotine-and-Tobacco CY FEB 20-23, 2002 CL SAVANNAH, GA SP Soc Res Nicotine & Tobacco ID LOW-YIELD CIGARETTES; TOBACCO-SMOKE; CESSATION; COMPENSATION; REPLACEMENT; ASSOCIATION; WITHDRAWAL; DEPENDENCE; SYMPTOMS; DILUTION AB Many smokers are not ready to quit but are interested in changing their smoking behavior, particularly if such a change is associated with a reduction in health risk. The present study evaluated the efficacy of the nicotine inhaler in reducing smoking. Exploratory studies assessed whether reduction in smoking was associated with reduction in markers of disease risk. A total of 429 healthy smokers ( smoking at least 20 cigarettes/day) were randomly assigned to either nicotine-containing or placebo inhalers, which subjects were allowed to use ad libitum for up to 1 year. The nicotine inhaler was significantly superior to placebo in achieving reduction in daily cigarette consumption by at least 50% after 4 months, compared with baseline (18% vs. 8%, p=.004). Active treatment promoted smoking cessation: 8% of subjects in the nicotine group and 1% in the placebo group were abstinent at month 15. Throughout the study, smoking reduction, per se, independent of treatment group, was associated with a statistically significant decrease in exhaled carbon monoxide and serum cotinine and thiocyanate. Smoking reduction also improved established risk markers for cardiovascular disease over 4 months. The incidence of adverse events did not differ significantly between the active and placebo groups. The most common treatmen-trelated adverse events were throat irritation and cough. In conclusion, the nicotine inhaler can help smokers who are unable or unwilling to quit to reduce daily cigarette consumption, which may be a health benefit on its own and may further promote quitting. C1 W Virginia Univ, Sch Med, Morgantown, WV 26506 USA. Univ Nebraska, Med Ctr, Dept Pulm & Crit Care Med, Omaha, NE 68198 USA. Univ Arizona, Tucson, AZ USA. Natl Canc Inst, Bethesda, MD USA. Pfizer Consumer Healthcare, Helsingborg, Sweden. RP Rennard, SI (reprint author), Univ Nebraska, Med Ctr, Dept Pulm & Crit Care Med, 985125 Nebraska Med Ctr, Omaha, NE 68198 USA. EM srennard@mail.unmc.edu NR 46 TC 46 Z9 46 U1 4 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD AUG PY 2006 VL 8 IS 4 BP 555 EP 564 DI 10.1080/14622200600789916 PG 10 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 078RJ UT WOS:000240120700009 PM 16920653 ER PT J AU Nagababu, E Ramasamy, S Rifkind, JM AF Nagababu, Enika Ramasamy, Somasundaram Rifkind, Joseph M. TI S-nitrosohemoglobin: A mechanism for its formation in conjunction with nitrite reduction by deoxyhemoglobin SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE nitric oxide; nitrite; hemoglobin; S-nitrosohemoglobin; iron nitrosyl hemoglobin; hypoxia ID RED-BLOOD-CELLS; ELECTRON-TRANSFER; OXYGEN DELIVERY; HEME-PROTEINS; OXIDE; HEMOGLOBIN; NITROSOTHIOLS; NITROSYLATION; OXYHEMOGLOBIN; VASODILATION AB The formation of S-nitrosohemoglobin (SNOHb) in red cells has been a major point of contention among researchers in this field. We have delineated a new mechanism for the formation of SNOHb coupled to nitrite reduction by deoxygenated hemoglobin chains at low oxygen pressures. The establishment of this mechanism required the development of a chemiluminescence assay utilizing Cu(II) and ascorbic acid to directly measure nitrosothiols without any interference from nitrite or heme-NO. The formation of SNOHb was shown to involve a dominant nitrite-reduction intermediate with electron delocalized between the heme iron and the bound NO. The possible mechanisms for the formation of SNOHb from this intermediate in the absence of oxygen are discussed including the role for an expansion of the electron delocalized intermediate to include the beta-93 cysteine residue. This extended delocalization was supported by a direct reaction with unbound NO, simultaneously producing SNOHb and Hb(II)NO, when NO reacts with metHb. The SNOHb found in red cells in vivo can, thus, be explained as originating from nitrite reduction that takes place at reduced oxygen pressures. Published by Elsevier Inc. C1 NIA, Mol Dynam Sect, NIH, Baltimore, MD 21224 USA. RP Rifkind, JM (reprint author), NIA, Mol Dynam Sect, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rifkindj@grc.nia.nih.gov FU Intramural NIH HHS NR 60 TC 61 Z9 61 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 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD AUG PY 2006 VL 15 IS 1 BP 20 EP 29 DI 10.1016/j.niox.2006.01.012 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 065AA UT WOS:000239130600004 PM 16545588 ER PT J AU Pawelczyk, E Arbab, AS Pandit, S Hu, E Frank, JA AF Pawelczyk, Edyta Arbab, Ali S. Pandit, Sunil Hu, Elbert Frank, Joseph A. TI Expression of transferrin receptor and ferritin following ferumoxides-protamine sulfate labeling of cells: implications for cellular magnetic resonance imaging SO NMR IN BIOMEDICINE LA English DT Article DE transferrin receptor (TtR-1); ferritin; mesenchymal stem cells; primary macrophages; cell labeling; SPIO; ferumoxides; protamine sulfate ID SUPERPARAMAGNETIC IRON-OXIDE; MESENCHYMAL STEM-CELLS; IN-VIVO TRACKING; HEMATOPOIETIC PROGENITOR CELLS; TRANSFECTION AGENTS; GENE-EXPRESSION; CONTRAST AGENTS; MOUSE MODEL; T-CELLS; NANOPARTICLES AB Ferumoxides-protamine sulfate (FE-Pro) complexes are used for intracellular magnetic labeling of cells to non-invasively monitor cell trafficking by in vivo MRI. FE-Pro labeling is non-toxic to cells; however, the effects of FE-Pro labeling on cellular expression of transferrin receptor (TfR-1) and ferritin, proteins involved in iron transport and Storage, has not been reported. FE-Pro-labeled human mesenchymal stem cells (MSCs), HeLa cells and primary macrophages were cultured from I week to 2 months and evaluated for TfR-1 and ferritin gene expression by RT-PCR and protein levels were determined using Western blots. MTT (proliferation assay) and reactive oxygen species (ROS) analysis were performed. FE-Pro labeling of HeLa and MSCs resulted in a transient decrease in TfR-1 mRNA and protein levels. In contrast, Fe-Pro labeling of primary macrophages resulted in an increase in TfR-1 mRNA but not in TfR-1 protein levels. Ferritin mRNA and protein levels increased transiently in labeled HeLa and macrophages but were sustained in MSCs. No changes in MTT and ROS analysis were noted. In conclusion, FE-Pro labeling elicited physiological changes of iron metabolism or storage, validating the safety of this procedure for cellular tracking by MRI. Published in 2006 by John Wiley & Sons, Ltd. C1 NIH, Ctr Clin, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. Henry Ford Hlth Syst, Dept Radiol, Detroit, MI 48202 USA. NIH, Ctr Clin, Mol Imaging Lab, Bethesda, MD 20892 USA. RP Pawelczyk, E (reprint author), NIH, Ctr Clin, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. EM pawelczyke@cc.nih.gov FU Intramural NIH HHS NR 37 TC 92 Z9 98 U1 0 U2 9 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD AUG PY 2006 VL 19 IS 5 BP 581 EP 592 DI 10.1002/nbm.1038 PG 12 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 076DI UT WOS:000239936800009 PM 16673357 ER PT J AU Herbert, A Liu, CY Karamohamed, S Liu, J Manning, A Fox, CS Meigs, JB Cupples, LA AF Herbert, Alan Liu, Chunyu Karamohamed, Samer Liu, Jun Manning, Alisa Fox, Caroline S. Meigs, James B. Cupples, L. Adrienne TI BMI modifies associations of IL-6 genotypes with insulin resistance: The Framingham Study SO OBESITY LA English DT Article DE interleukin-6; insulin resistance; type 2 diabetes; genetics; epidemiology ID HOMEOSTASIS MODEL ASSESSMENT; TYPE-2 DIABETES-MELLITUS; PROMOTER POLYMORPHISM; GLUCOSE-TOLERANCE; INFLAMMATORY MARKERS; INTERLEUKIN-6; SENSITIVITY; C-174G; RISK; POPULATION AB Objective: The - 174 interleukin (IL)-6 gene polymorphism has been proposed as a risk factor for type 2 diabetes, but data are conflicting. Because white fat is a major source of IL-6 in resting individuals, we tested the hypothesis that BMI modifies the association among the IL-6 genotype, insulin resistance (IR) (measured using the homeostasis model), and risk of diabetes. Research Methods and Procedures: Outcomes were assessed in a community-based cohort study of 1525 adults (mean age, 55.6 years; 753 men), who participated in the Framingham Offspring Study during the 1991 to 1995 examinations. Results: We found a significant interaction between IL-6 genotype and BMI on levels of IR in men (p < 0.0001), with obese homozygotes for the minor C allele being most resistant. The IL-6-BMI interaction was not significant (p = 0.46) in women. Among men with the CC genotype, increasing BMI was associated with increased prevalence of diabetes [odds ratio (OR) per unit increase in BMI, 1.30; 95% confidence interval (CI), 1.11 to 1.50] but not among those with the GG (OR, 1.10; 95% Cl, 0.98 to 1.22) or GC genotype (OR, 1.05; 95% Cl, 0.97 to 1.14). Discussion: The - 174 IL-6 promoter polymorphism modifies the association of obesity with IR and diabetes risk in men. Weight loss regimens targeted at reducing the risk of diabetes may be of particular benefit for men with a - 174 IL-6 CC genotype. C1 Boston Univ, Sch Med, Dept Genet & Genom, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Framingham Heart Study Genet Lab, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, NHLBI,Framingham Heart Study, Boston, MA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA USA. Massachusetts Gen Hosp, Dept Med, Gen Div, Boston, MA 02114 USA. RP Cupples, LA (reprint author), Boston Univ, Sch Med, Dept Biostat, 715 Albany St, Boston, MA 02118 USA. EM adrienne@bu.edu FU NHLBI NIH HHS [HL64753, HL076784, N01-HC-25195] NR 28 TC 24 Z9 24 U1 0 U2 2 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBESITY JI Obesity PD AUG PY 2006 VL 14 IS 8 BP 1454 EP 1461 DI 10.1038/oby.2006.165 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 087OR UT WOS:000240752200020 PM 16988089 ER PT J AU Gage, JC Hanson, VW Abbey, K Dippery, S Gardner, S Kubota, J Schiffman, M Solomon, D Jeronimo, J AF Gage, Julia C. Hanson, Vivien W. Abbey, Kim Dippery, Susan Gardner, Susi Kubota, Janet Schiffman, Mark Solomon, Diane Jeronimo, Jose CA ASCUS LSIL Triage Study Grp TI Number of cervical biopsies and sensitivity of colposcopy SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID ATYPICAL SQUAMOUS-CELLS; DIRECTED PUNCH BIOPSY; PROSPECTIVE FOLLOW-UP; INTRAEPITHELIAL NEOPLASIA; LOOP EXCISION; UNDETERMINED SIGNIFICANCE; CYTOLOGY INTERPRETATIONS; RANDOMIZED-TRIAL; LESIONS; RISK AB OBJECTIVE: To examine the influence that type of medical training and number of biopsies have on sensitivity of colposcopically guided biopsies. METHODS: Among 408 women with an adequate enrollment colposcopy and a diagnosis of cervical intraepithelial neoplasia (CIN) 3 or cancer (CIN 3+) over 2 years in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions (ASCUS-LSIL) Triage Study, we evaluated factors influencing the sensitivity of the enrollment colposcopic procedure. We used contingency table analysis to examine confounding variables and chi(2) tests to ascertain statistical significance. RESULTS: Overall, 69.9% of women with a cumulative diagnosis of CIN 3+ had a "true-positive" enrollment colposcopically guided biopsy result of CIN 2 or worse (CIN 2+), the threshold that would trigger excisional therapy. The sensitivity of the procedure did not vary significantly by type of colposcopist. However, the sensitivity was significantly greater when the colposcopists took two or more biopsies instead of one (P <.01), a pattern observed across all types of colposcopists. Independent of the severity of the colposcopic impression, the frequency with which colposcopists took two or more biopsies instead of one varied (in descending order) from nurse practitioners to general gynecologists to gynecologic oncology fellows to gynecologic oncologists (P <.01). CONCLUSION: Colposcopy with guided biopsy or biopsies detects approximately two thirds of CIN 3+. Although the sensitivity of the procedure does not differ significantly by type of medical training, it is greater when two or more biopsies are taken. C1 Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98199 USA. NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Univ Washington, Dept Pathol, Seattle, WA 98199 USA. Publ Hlth Seattle King Cty, Seattle, WA USA. NCI, Div Canc Prevent, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Hanson, VW (reprint author), Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, 4032 Burton Pl W, Seattle, WA 98199 USA. EM vhanson@scn.org FU Intramural NIH HHS; NCI NIH HHS [CN-15505, CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159] NR 35 TC 178 Z9 186 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2006 VL 108 IS 2 BP 264 EP 272 DI 10.1097/01.AOG.0000220505.18525.85 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 171XO UT WOS:000246768900005 PM 16880294 ER PT J AU Signore, C Mills, JL Qian, C Yu, K Lam, C Epstein, FH Karumanchi, SA Levine, RJ AF Signore, Caroline Mills, James L. Qian, Cong Yu, Kai Lam, Chun Epstein, Franklin H. Karumanchi, S. Ananth Levine, Richard J. TI Circulating angiogenic factors and placental abruption SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TYROSINE KINASE-1; UNITED-STATES; HUMAN TROPHOBLAST; PREECLAMPSIA; PREGNANCIES; RISK; HYPERTENSION; PATHOGENESIS; PROTEINURIA AB OBJECTIVE: Abnormalities in circulating angiogenic factors have been reported in diseases of abnormal placentation, such as preeclampsia and intrauterine growth restriction. Our objective was to determine whether circulating angiogenic factors are altered in another placental vascular disease, abruptio placentae. METHODS: In a nested case-control study of nulliparous pregnancies, we examined levels of placental growth factor (PIGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in serum collected prospectively from 31 women who later developed placental abruption and from 31 normal control subjects. All serum specimens were collected before the onset of hypertension or abruption and before labor or delivery. Serum angiogenic factors were compared within 3 gestational age windows: early (20 weeks or less), middle (21-32 weeks), and late (33 weeks or more) pregnancy. RESULTS: During early pregnancy women who developed placental abruption had lower PlGF and higher sFlt-1 concentrations and higher sFlt-1/PIGF ratios than women with normal pregnancies. In mid-pregnancy these differences became greater, reaching statistical significance for PIGF concentration (431 versus 654 pg/mL, P <.01) and the sFlt-1/PIGF ratio (25.3 versus 2.5, P <.01). When the women with placental abruption were subdivided into those who did (n=10) and those who did not (n=21) develop preeclampsia or gestational hypertension, significant alterations in angiogenic factors were noted only in women who later developed hypertension in pregnancy. Among these women, PIGF concentrations were decreased in mid-pregnancy (160 versus 723 pg/mL, P <.001), and the mid-pregnancy sFlt-1/PIGF ratio was increased (70.1 versus 2.3, P=.001). CONCLUSION: Serum levels of the proangiogenic factor PIGF were decreased, and those of the antiangiogenic ratio sFlt-1/PIGF were increased in nulliparous women who subsequently developed hypertension and placental abruption. C1 NICHD, Epidemiol Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. NICHD, Biometry & Math Stat Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. NICHD, Div Epidemiol Stat & Prevent Res, NIH, US Dept HHS, Bethesda, MD 20892 USA. Allied Technol Grp, Rockville, MD USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Div Mol & Vasc Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Boston, MA 02115 USA. RP Levine, RJ (reprint author), NICHD, Epidemiol Branch, NIH, US Dept HHS, Bldg 6100,Room 7B03, Bethesda, MD 20892 USA. EM LevineRJ@mail.nih.gov FU Intramural NIH HHS NR 28 TC 53 Z9 54 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2006 VL 108 IS 2 BP 338 EP 344 DI 10.1097/01.AOG.0000216014.72503.09 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 171XO UT WOS:000246768900015 PM 16880304 ER PT J AU Bauer, DC Hunter, DJ Abramson, SB Attur, M Corr, M Felson, D Heinegard, D Jordan, JM Kepler, TB Lane, NE Saxne, T Tyree, B Kraus, VB AF Bauer, D. C. Hunter, D. J. Abramson, S. B. Attur, M. Corr, M. Felson, D. Heinegard, D. Jordan, J. M. Kepler, T. B. Lane, N. E. Saxne, T. Tyree, B. Kraus, V. B. TI Classification of osteoarthritis biomarkers: a proposed approach SO OSTEOARTHRITIS AND CARTILAGE LA English DT Review DE osteoarthritis; biomarkers; study design ID II COLLAGEN DEGRADATION; KNEE OSTEOARTHRITIS; RADIOGRAPHIC PROGRESSION; END-POINTS; ARTHRITIS; PROJECT; MARKERS; PAIN AB Objective: Osteoarthritis (OA) biomarkers are needed by researchers and clinicians to assist in disease diagnosis and assessment of disease severity, risk of onset, and progression. As effective agents for CA are developed and tested in clinical studies, biomarkers; that reliably mirror or predict the progression or amelioration of CA will also be needed. Methods: The NIH-funded CA Biomarkers Network is a multidisciplinary group interested in the development and validation of CA biomarkers. This review summarizes our efforts to characterize and classify CA biomarkers. Results: We propose the "BIPED" biomarker classification (which stands for Burden of Disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic), and offer suggestions on optimal study design and analytic methods for use in CA investigations. Conclusion. The BIPED classification provides specific biomarker definitions with the goal of improving our ability to develop and analyze OA biomarkers, and to communicate these advances within a common framework. (C) 2006 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 Univ Calif San Francisco, Dept Med, San Francisco, CA 94107 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94107 USA. Boston Univ, Sch Med, Clin Epidemiol Res & Training Unit, Boston, MA 02118 USA. NYU, Sch Med, Dept Med, New York, NY USA. NYU, Hosp Joint Dis, New York, NY USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Lund Univ, Dept Expt Med Sci, Lund, Sweden. Univ N Carolina, Dept Med, Chapel Hill, NC USA. Univ N Carolina, Dept Orthoped, Chapel Hill, NC USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Univ Calif Davis, Dept Med, Sacramento, CA 95817 USA. Lund Univ, Dept Clin Sci, Lund, Sweden. NIAMSD, Extramural Program, Bethesda, MD 20892 USA. RP Bauer, DC (reprint author), Univ Calif San Francisco, Dept Med, 185 Berry St,5700, San Francisco, CA 94107 USA. EM dbauer@psg.ucsf.edu RI Hunter, David/A-4622-2010; OI Hunter, David/0000-0003-3197-752X; Felson, David/0000-0002-2668-2447; ATTUR, MUKUNDAN/0000-0001-7080-8118; Abramson, Steven/0000-0002-0668-6344; Kepler, Thomas/0000-0002-1383-6865 NR 21 TC 170 Z9 173 U1 1 U2 7 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD AUG PY 2006 VL 14 IS 8 BP 723 EP 727 DI 10.1016/j.joca.2006.04.001 PG 5 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 068PM UT WOS:000239386900001 PM 16733093 ER PT J AU Dominguez, G AF Dominguez, Geraldina TI The CART gene: Structure and regulation SO PEPTIDES LA English DT Review DE CART gene; promoter; CREB; CRE; PKA; cocaine ID TRANSCRIPT CART; C-FOS; CREB PHOSPHORYLATION; MESOLIMBIC DOPAMINE; MESSENGER-RNA; COCAINE; AMPHETAMINE; PEPTIDE; EXPRESSION; RAT AB CART peptides are important neuropeptides that are involved in a variety of physiologic processes. The regulation of the CART gene is critical since peptides are regulated and secreted in response to specific stimuli. CART mRNA must also be controlled in order to respond to specific stimuli such as psychostimulant drugs and leptin. The regulation of the CART gene is central to maintaining homeostasis of peptide production. The 5' upstream region of the CART gene contains powerful regulatory elements that must be involved in transcriptional regulation via different signaling pathways. This review touches on several aspects related to CART gene regulation such as: (i) CART genomic structure, (ii) stimuli that alter CART mRNA levels, (iii) promoter characterization, (iv) role of the cAMP/PKA/CREB signal transduction pathway, and (v) role of the CART 5' and 3' ends in CART mRNA regulation. The goal of this review is to present current data so as to encourage further work in the field of CART gene regulation. (c) 2006 Elsevier Inc. All rights reserved. C1 Emory Univ, Yerkes Natl Primate Ctr, Div Neurosci, Atlanta, GA 30329 USA. RP Dominguez, G (reprint author), NCI, Off AIDS Malignancy Program, Bethesda, MD 20892 USA. EM gdomin2@yahoo.com NR 47 TC 20 Z9 21 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD AUG PY 2006 VL 27 IS 8 BP 1913 EP 1918 DI 10.1016/j.peptides.2006.01.025 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 072KU UT WOS:000239673100002 PM 16716454 ER PT J AU Terracciano, A Costa, PT McCrae, RR AF Terracciano, Antonio Costa, Paul T., Jr. McCrae, Robert R. TI Personality plasticity after age 30 SO PERSONALITY AND SOCIAL PSYCHOLOGY BULLETIN LA English DT Article DE Five-Factor Model; personality development; long-term stability; individual differences; life span; older adults ID ADULT Q-SET; SELF-REPORTS; INDIVIDUAL-DIFFERENCES; LIFE-COURSE; STABILITY; RATINGS; CONSISTENCY; TRAITS; MODEL; CONTINUITY AB Rank-order consistency of personality traits increases from childhood to age 30. After that, different summaries of the literature predict a plateau at age 30, or at age 50, or a curvilinear peak in consistency at age 50. These predictions were evaluated at group and individual levels using longitudinal data from the Guilford-Zimmerman Temperament Survey and the Revised NEO Personality Inventory for periods of up to 42 years. Consistency declined toward a nonzero asymptote with increasing time interval. Although some scales showed increasing stability after age 30, the rank-order consistencies of the major dimensions and most facets of the Five-Factor Model were unrelated to age. Ipsative stability, assessed with the California Adult Q-Set, also was unrelated to age. These data strengthen claims of predominant personality stability after age 30. C1 NIA, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Terracciano, A (reprint author), Gerontol Res Ctr, Box 03,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM terraccianoa@grc.nia.nih.gov RI terracciano, antonio/B-1884-2008; OI Costa, Paul/0000-0003-4375-1712 FU Intramural NIH HHS [Z99 AG999999, ZIA AG000183-22, ZIA AG000183-23, ZIA AG000197-03, ZIA AG000197-04] NR 45 TC 156 Z9 157 U1 2 U2 32 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0146-1672 J9 PERS SOC PSYCHOL B JI Pers. Soc. Psychol. Bull. PD AUG PY 2006 VL 32 IS 8 BP 999 EP 1009 DI 10.1177/0146167206288599 PG 11 WC Psychology, Social SC Psychology GA 066CI UT WOS:000239206900001 PM 16861305 ER PT J AU Tilson, H Watts, H Covington, D AF Tilson, Hugh Watts, Heather Covington, Deborah TI Effective use of supplemental data in a pregnancy exposure registry SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. NIH, Peidat Adolescent Maternal AIDS Branch, Rockville, MD USA. Charles River Labs, Wilmington, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2006 VL 15 SU 1 MA 179 BP S84 EP S85 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 080XG UT WOS:000240281200180 ER PT J AU Valluri, SC Kouzis, A Zito, JM Gardner, JF Korelitz, J Bethel, J Lasky, T Gerber, RA Safer, DJ AF Valluri, Satish C. Kouzis, Anthony Zito, Julie M. Gardner, James F. Korelitz, James Bethel, James Lasky, Tamar Gerber, Russell A. Safer, Daniel J. TI Psychotropic medication use among publicly insured US youth SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 Univ Maryland, Phamraceut Hlth Serv Res, Baltimore, MD 21201 USA. WESTAT Corp, Rockville, MD 20850 USA. NICHD, Bethesda, MD USA. Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2006 VL 15 SU 1 MA 029 BP S14 EP S14 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 080XG UT WOS:000240281200030 ER PT J AU Morton, LM Schenk, M Hein, DW Davis, S Zahm, SH Cozen, W Cerhan, JR Hartge, P Welch, R Chanock, SJ Rothman, N Wang, SS AF Morton, Lindsay M. Schenk, Maryjean Hein, David W. Davis, Scott Zahm, Shelia Hoar Cozen, Wendy Cerhan, James R. Hartge, Patricia Welch, Robert Chanock, Stephen J. Rothman, Nathaniel Wang, Sophia S. TI Genetic variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2) and risk of non-Hodgkin lymphoma SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE genetic variation; N-acetyltransferase 1; N-acetyltransferase 2; non-Hodgkin lymphoma; single nucleoticle polymorphism ID E-MU-PIM-1 TRANSGENIC MICE; RECOMBINANT HUMAN NAT1; BLADDER-CANCER; METABOLIC-ACTIVATION; MOLECULAR-GENETICS; CIGARETTE-SMOKING; IN-VIVO; POLYMORPHISM; ACETYLATION; ASSOCIATION AB Animal studies suggest that lymphomagenesis can be induced by exposure to carcinogenic aromatic and heterocyclic amines found in diet, cigarette smoke and the environment, but human epidemiologic investigations of these exogenous exposures have yielded conflicting results. As part of our evaluation of the role of aromatic and heterocyclic amines, which are metabolized by N-acetyltransferase (NAT) enzymes, in the etiology of non-Hodgkin lymphoma (NHL), we examined NHL risk in relation to genetic variation in NAT1 and NAT2 and exposure to cigarette smoke and dietary heterocyclic amines and mutagens. We genotyped 10 common single nucleotide polymorphisms (SNPs) in NAT1 and NAT2 among 1136 cases and 922 controls from a population-based case-control study in four geographical areas of the USA. Relative risk of NHL for NAT1 and NAT2 genotypes, NAT2 acetylation phenotype, and exposure to cigarette smoke and dietary heterocyclic amines and mutagens was estimated using odds ratios (ORs) and 95% confidence intervals (Cls) derived from unconditional logistic regression models. We observed increased risk of NHL among individuals with the NAT1*10/*10 genotype compared with individuals with other NAT1 genotypes (OR = 1.60, 95% CI = 1.04-2.46, P = 0.03). We also observed increased NHL risk in a dose-dependent model among NAT2 intermediate- and rapid-acetylators; compared with slow-acetylators, although only the trend was statistically significant (intermediate: OR = 1.18, 95% CI = 0.97-1.44, P = 0.1; rapid: OR = 1.43, 95% CI = 0.97-2.14, P = 0.07; P for linear trend = 0.03). Compared with non-smokers, NHL risk estimates for current cigarette smoking were increased only among NAT2 intermediate/rapid-acetylators (OR = 2.44, 95% CI = 1.15-5.20, P = 0.02). Our data provide evidence that NAT1 and NAT2 genotypes are associated with NHL risk and support a contributory role for carcinogenic aromatic and/or heterocyclic amines in the multi-factorial etiology of NHL. C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48202 USA. Wayne State Univ, Dept Family Med, Detroit, MI 48202 USA. Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. Univ Louisville, Sch Med, James Graham Brown Canc Ctr, Louisville, KY 40292 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Washington, Seattle, WA 98195 USA. Univ So Calif, Los Angeles, CA 90089 USA. Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. Univ Iowa, Iowa City, IA 52242 USA. Natl Canc Inst, Core Genotyping Facil, Ctr Adv Technol, Gaithersburg, MD USA. RP Morton, LM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS-7073,MSC 7234, Rockville, MD 20852 USA. EM mortonli@mail.nih.gov RI Hein, David/A-9707-2008; Zahm, Shelia/B-5025-2015; Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [N01 PC065064, N01 PC067008, N01 PC067009, N01 PC067010, N01-PC-67009, N02-PC-71105] NR 38 TC 36 Z9 38 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD AUG PY 2006 VL 16 IS 8 BP 537 EP 545 DI 10.1097/01.fpc.0000215071.59836.29 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 076PR UT WOS:000239970700001 PM 16847422 ER PT J AU Gaudet, MM Chanock, S Lissowska, J Berndt, SI Yang, XH Peplonska, B Brinton, LA Welch, R Yeager, M Bardin-Mikolajczak, A Sherman, ME Sutter, TR Garcia-Closas, M AF Gaudet, Mia M. Chanock, Stephen Lissowska, Jolanta Berndt, Sonja I. Yang, Xiaohong (Rose) Peplonska, Beata Brinton, Louise A. Welch, Robert Yeager, Meredith Bardin-Mikolajczak, Alicja Sherman, Mark E. Sutter, Thomas R. Garcia-Closas, Montserrat TI Genetic variation of Cytochrome P4501B1 (CYP1B1) and risk of breast cancer among Polish women SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE breast cancer; CYP1B1; family history; haplotypes; P450s ID CATECHOL-O-METHYLTRANSFERASE; ASSOCIATION; POLYMORPHISMS; P4501B1; 1B1; VARIANTS; RECEPTOR; LINKAGE; SUSCEPTIBILITY; EXPRESSION AB Four single nucleotide polymorphisms (SNPs) in CYP1B1 (Ex2+143 C > G, Ex2+356 G > T, Ex3+251 G > C, Ex3+315 A > G) cause amino acid changes (R48G, A119S, L432V and N453S, respectively) and are associated with increased formation of catechol estrogens; however, epidemiologic evidence only weakly supports an association between these variants and breast cancer risk. Because genetic variability conferring increased susceptibility could exist beyond these putative functional variants, we comprehensively examined the common genetic variability within CYP1B1. A total of eight haplotype-tagging (ht)SNPs (including Ex3+315 A > G), in addition to two putatively functional SNPs (Ex2+143 C > G and Ex3 + 251 G > C), were selected and genotyped in a large case-control study of Polish women (1995 cases and 2296 controls). Haplotypes were estimated using the expectation-maximization algorithm, and overall differences in the haplotype distribution between cases and controls were assessed using a global score test. We also evaluated levels of tumor CYP1B1 protein expression in a subset of 841 cases by immunohistochemistry, and their association with genetic variants. In the Polish population, we observed two linkage disequilibrium (LD)-defined blocks. Neither haplotypes (global P-value of 0.99 and 0.67 for each block of LD, respectively), nor individual SNPs (including three putatively functional SNPs) were associated with breast cancer risk. CYP1B1 was expressed in most tumor tissues (98%), and the level of expression was not related to the studied genetic variants. We found little evidence for modification of the estimated effect of haplotypes or individual SNPs by age, family history of breast cancer, or tumor hormone receptor status. The present study provides strong evidence against the existence of a substantial overall association between common genetic variation in CYP1B1 and breast cancer risk. C1 NCI, Core Genotype Facil, Dept Hlth & Human Serv, Rockville, MD 20852 USA. NCI, Ctr Adv Technol, Dept Hlth & Human Serv, Rockville, MD 20852 USA. Natl Canc Inst, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD USA. Ctr Canc, Dept Canc Epidemiol & Prevent, Warsaw, Poland. M Sklodowska Curie Inst Oncol, Warsaw, Poland. Nofer Inst Occupat Med, Dept Occupat & Environm Epidemiol, Lodz, Poland. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. Univ Memphis, W Harry Feinstone Ctr Genom Res, Memphis, TN 38152 USA. RP Gaudet, MM (reprint author), NCI, Core Genotype Facil, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS-7055, Rockville, MD 20852 USA. EM gaudetm@mail.nih.gov RI Peplonska, Beata/F-6004-2010; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Lissowska, Jolanta/0000-0003-2695-5799 FU Intramural NIH HHS NR 32 TC 16 Z9 16 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD AUG PY 2006 VL 16 IS 8 BP 547 EP 553 DI 10.1097/01.fpc.0000215067.29342.6f PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 076PR UT WOS:000239970700002 PM 16847423 ER PT J AU Naito, H Yamanoshita, O Kamijima, M Katoh, T Matsunaga, T Lee, CH Kim, H Aoyama, T Gonzalez, FJ Nakajima, T AF Naito, Hisao Yamanoshita, Osamu Kamijima, Michihiro Katoh, Takahiko Matsunaga, Tadashi Lee, Chul-Ho Kim, Heon Aoyama, Toshifumi Gonzalez, Frank J. Nakajima, Tamie TI Association of V227A PPAR alpha polymorphism with altered serum biochemistry and alcohol drinking in Japanese men SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE alcoholic liver disease; peroxisome proliferator-activated receptor alpha; ALDH2; polymorphism; molecular epidemiology; cholesterol; SNP ID PROLIFERATOR-ACTIVATED RECEPTOR; HUMAN ALDEHYDE DEHYDROGENASES; PEROXISOME PROLIFERATORS; LIPOPROTEIN METABOLISM; HYPOLIPIDEMIC DRUGS; TISSUE DISTRIBUTION; LIPID-METABOLISM; LIVER-DISEASE; FATTY LIVER; IN-VITRO AB Objectives Peroxisome proliferator-activated receptor (PPAR) a plays a major role in alcoholic liver disease in rodents. The two-fold objective of our study was to determine the presence of PPAR alpha polymorphisms and their frequencies in Japanese populations and then to evaluate the effects of any alleles on metabolic parameters and alcohol drinking. Methods Analysis of coding SNP in PPAR alpha was performed in 706 Japanese men; from these subjects 655 men were further studied after exclusion criteria were applied. Results PPAR alpha-V227A, which has not been reported in Europe and North America as a major polymorphism, was discovered with the frequency of 0.05. PPAR alpha-L162V was found in European and North American populations, but not in Japanese, thus confirming the ethnic differences in PPAR alpha allele frequencies. The A227 allele was associated with increased serum concentrations of gamma glutamyltranspeptidase. In non-drinkers, the total cholesterol (TC) levels were significantly lower in those having the PPAR alpha-11227A polymorphism. In drinkers, however, it was comparable among V227A polymorphisms, and conversely higher in those having both A227 and aldehyde dehydrogrenase 2 (ALDH2) variants when further divided according to the ALDH2 polymorphism. Significant interactions between PPAR alpha-V227A polymorphism and drinking were also found for TC, triglyceride levels and AST/ALT ratios. These results suggest that the activity of the A227 allele without drinking may be higher than in wild-type allele, but its activity may become lower during drinking habits. Conclusion PPAR alpha-V227A is a major polymorphism in the Japanese population, and its activity may be greater compared to wild-type, but decreased by alcohol drinking. C1 Nagoya Univ, Grad Sch Med, Dept Environm & Occupat Hlth, Showa Ku, Nagoya, Aichi 4668550, Japan. Miyazaki Univ, Coll Med, Dept Publ Hlth, Miyazaki 88921, Japan. Tokyo Univ Agr & Technol, Dept Biotechnol & Life Sci, Tokyo, Japan. Chungbuk Natl Univ, Coll Med, Dept Prevent Med, Cheongju, Chungbuk, South Korea. Shinshu Univ, Grad Sch Med, Inst Aging & Adaptat, Dept Metab Regulat, Matsumoto, Nagano 390, Japan. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Nakajima, T (reprint author), Nagoya Univ, Grad Sch Med, Dept Environm & Occupat Hlth, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan. EM tnasu23@med.nagoya-u.ac.jp NR 46 TC 13 Z9 15 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD AUG PY 2006 VL 16 IS 8 BP 569 EP 577 DI 10.1097/01.fpc.0000220565.90466.79 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 076PR UT WOS:000239970700005 PM 16847426 ER PT J AU Robertson, SM Formentini, E Alfaro, RM Falloon, J Penzak, SR AF Robertson, Sarah M. Formentini, Elizabeth Alfaro, Raul M. Falloon, Judith Penzak, Scott R. TI Lack of in vivo correlation between indinavir and saquinavir exposure and cytochrome P450 3A phenotype as assessed with oral midazolam as a phenotype probe SO PHARMACOTHERAPY LA English DT Article DE midazolam; saquinavir; indinavir; protease inhibitors; pharmacokinetics; cytochrome P450 3A phenotype; CYP3A phenotype ID ERYTHROMYCIN BREATH TEST; P-GLYCOPROTEIN; HEALTHY-VOLUNTEERS; CYP3A5 POLYMORPHISM; PHARMACOKINETICS; CYCLOSPORINE; DISPOSITION; METABOLISM; VITRO; HIV AB Study Objective. To investigate a potential correlation between exposure to oral midazolam, a commonly used cytochrome P450 (CYP) 3A probe, and saquinavir and indinavir exposure. Design. Open-label, prospective, pharmacokinetic study Setting. Outpatient research center. Subjects. Thirty-six healthy volunteers aged 22-50 years. Intervention. Subjects received a single oral dose of midazolam 8 mg; 4 hours later, blood was drawn to determine their serum midazolam concentrations. Midazolam phenotyping was followed by successive administration of the protease inhibitors indinavir and saquinavir, with blood sampling and pharmacokinetic analyses performed at steady state. Measurements and Main Results. Pharmacokinetic parameters of each protease inhibitor were evaluated to assess for a potential relationship with 4-hour concentrations of midazolam. No correlations between phenotype results for midazolam and any pharmacokinetic parameter for indinavir or saquinavir were identified (r(2)=0.00002-0.073). When the results were analyzed based on race, significant correlations were identified in five African-American subjects, including correlations between 4-hour midazolam levels and apparent oral clearance of saquinavir (r(2)=0.734, p=0.064), area under the plasma concentration-time curve from 0-8 hours (r(2)=0.914, p=0.011), minimum concentration (r(2)=0.857, p=0.024), and maximum concentration (r(2)=0.969, p=0.002). These findings for African-American subjects were not seen with indinavir. No correlation was found between indinavir and saquinavir pharmacokinetic parameters (r(2)=0.0 17-0.261). Conclusion. Oral midazolam was not a useful probe for predicting saquinavir or indinavir exposure at steady state. Reasons for the lack of correlation likely included differences between midazolam and protease inhibitor P-glycoprotein specificity, differences in the relative contribution of CYP3A5-mediated metabolism, and/or variation in intestinal and hepatic CYP3A specificity. The strong correlation between midazolam phenotype and pharmacokinetic parameters for saquinavir in African-American subjects indicated a racial difference in one or more of these confounding variables. C1 Clin Res Ctr, Dept Pharm, NIH, Bethesda, MD 20892 USA. Clin Res Ctr, Dept Crit Care Med, Bethesda, MD USA. NIAID, NIH, Bethesda, MD USA. RP Robertson, SM (reprint author), Clin Res Ctr, Dept Pharm, NIH, Bldg 10,Room 1 N 257, Bethesda, MD 20892 USA. EM robertsonsa@cc.nih.gov NR 44 TC 2 Z9 2 U1 1 U2 1 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD AUG PY 2006 VL 26 IS 8 BP 1051 EP 1059 DI 10.1592/phco.26.8.1051 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 070PA UT WOS:000239533900001 PM 16863481 ER PT J AU Pilia, G Chen, WM Scuteri, A Orru, M Albai, G Dei, M Lai, S Usala, G Lai, M Loi, P Mameli, C Vacca, L Deiana, M Olla, N Masala, M Cao, A Najjar, SS Terracciano, A Nedorezov, T Sharov, A Zonderman, AB Abecasis, GR Costa, P Lakatta, E Schlessinger, D AF Pilia, Giuseppe Chen, Wei-Min Scuteri, Angelo Orru, Marco Albai, Giuseppe Dei, Mariano Lai, Sandra Usala, Gianluca Lai, Monica Loi, Paola Mameli, Cinzia Vacca, Loredana Deiana, Manila Olla, Nazario Masala, Marco Cao, Antonio Najjar, Samer S. Terracciano, Antonio Nedorezov, Timur Sharov, Alexei Zonderman, Alan B. Abecasis, Goncalo R. Costa, Paul Lakatta, Edward Schlessinger, David TI Heritability of cardiovascular and personality traits in 6,148 sardinians SO PLOS GENETICS LA English DT Article ID ARTERIAL STIFFNESS; METABOLIC SYNDROME; HUMAN-POPULATIONS; PEDIGREE ANALYSIS; COMPLEX DISEASES; MEDIA THICKNESS; OLDER-ADULTS; GENE; HEART; RISK AB In family studies, phenotypic similarities between relatives yield information on the overall contribution of genes to trait variation. Large samples are important for these family studies, especially when comparing heritability between subgroups such as young and old, or males and females. We recruited a cohort of 6,148 participants, aged 14-102 y, from four clustered towns in Sardinia. The cohort includes 34,469 relative pairs. To extract genetic information, we implemented software for variance components heritability analysis, designed to handle large pedigrees, analyze multiple traits simultaneously, and model heterogeneity. Here, we report heritability analyses for 98 quantitative traits, focusing on facets of personality and cardiovascular function. We also summarize results of bivariate analyses for all pairs of traits and of heterogeneity analyses for each trait. We found a significant genetic component for every trait. On average, genetic effects explained 40% of the variance for 38 blood tests, 51% for five anthropometric measures, 25% for 20 measures of cardiovascular function, and 19% for 35 personality traits. Four traits showed significant evidence for an X-linked component. Bivariate analyses suggested overlapping genetic determinants for many traits, including multiple personality facets and several traits related to the metabolic syndrome; but we found no evidence for shared genetic determinants that might underlie the reported association of some personality traits and cardiovascular risk factors. Models allowing for heterogeneity suggested that, in this cohort, the genetic variance was typically larger in females and in younger individuals, but interesting exceptions were observed. For example, narrow heritability of blood pressure was approximately 26% in individuals more than 42 y old, but only approximately 8% in younger individuals. Despite the heterogeneity in effect sizes, the same loci appear to contribute to variance in young and old, and in males and females. In summary, we find significant evidence for heritability of many medically important traits, including cardiovascular function and personality. Evidence for heterogeneity by age and sex suggests that models allowing for these differences will be important in mapping quantitative traits. C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Osped Microcitem, Ist Neurogenet & Neurofarmacol, Consiglio Nazl Ric, Cagliari, Italy. Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. Ist Nazl Riposa & Cura Anziani, Unita Operat, Rome, Italy. Presidio Osped Santa Barbara, Unit Operat Semplice Cardiol, Div Med, Iglesias, Italy. RP Schlessinger, D (reprint author), NIA, Gerontol Res Ctr, 4940 Eastern Ave, Baltimore, MD 21224 USA. EM schlessingerd@grc.nia.nih.gov RI terracciano, antonio/B-1884-2008; Chen, Wei-Min/A-8469-2009; Abecasis, Goncalo/B-7840-2010; OI Costa, Paul/0000-0003-4375-1712; Abecasis, Goncalo/0000-0003-1509-1825; Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS [ZIA AG000180-26, Z99 AG999999, ZIA AG000180-25, ZIA AG000183-22, ZIA AG000183-23, ZIA AG000196-03, ZIA AG000196-04, ZIA AG000197-03, ZIA AG000197-04]; NEI NIH HHS [EY12562, R01 EY012562]; NHGRI NIH HHS [HG02651, R01 HG002651]; NIA NIH HHS [N01-AG-1-2109] NR 70 TC 250 Z9 255 U1 2 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2006 VL 2 IS 8 BP 1207 EP 1223 AR e132 DI 10.1371/journal.pgen.0020132 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 077DC UT WOS:000240006900010 PM 16934002 ER PT J AU Subramaniam, S AF Subramaniam, Sriram TI The SIV surface spike imaged by electron tomography: One leg or three? SO PLOS PATHOGENS LA English DT Editorial Material ID 3-DIMENSIONAL STRUCTURE; ENVELOPE GLYCOPROTEINS; RESOLUTION; ORGANIZATION; CORE C1 NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ss1@nih.gov NR 18 TC 18 Z9 18 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2006 VL 2 IS 8 BP 727 EP 730 AR e91 DI 10.1371/journal.ppat.0020091 PG 4 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA V42VK UT WOS:000202894800001 PM 16933994 ER PT J AU Qi, Y Martin, MP Gao, X Jacobson, L Goedert, JJ Buchbinder, S Kirk, GD O'Brien, SJ Trowsdale, J Carrington, M AF Qi, Ying Martin, Maureen P. Gao, Xiaojiang Jacobson, Lisa Goedert, James J. Buchbinder, Susan Kirk, Gregory D. O'Brien, Stephen J. Trowsdale, John Carrington, Mary TI KIR/HLA pleiotropism: Protection against both HIV and opportunistic infections SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; IMMUNOGLOBULIN-LIKE RECEPTOR; HLA-B; AIDS; PROGRESSION; PATHOGENESIS; COHORT AB The compound genotype KIR3DS1/HLA-B Bw4-80I, which presumably favors natural killer cell activation, has been implicated in protection against HIV disease. We show that this genotype confers dual protection over the course of HIV disease; early direct containment of HIV viral load, and late specific defense against opportunistic infections, but not AIDS-related malignancies. The double protection of KIR3DS1/Bw4-80I in an etiologically complex disease such as AIDS, along with the disease specificity of its effects is conceptually novel and underscores the intricacy of host immunogenetics against HIV/AIDS. C1 NCI, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21701 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. San Francisco Dept Publ Hlth, San Francisco, CA USA. Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. RP Carrington, M (reprint author), NCI, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21701 USA. EM carringt@ncifcrf.gov RI Kirk, Gregory/A-8484-2009 FU Intramural NIH HHS; Medical Research Council [G0401569, G9800943]; NCI NIH HHS [N01-CO-12400, N01CO12400]; NIDA NIH HHS [R37 DA004334, DA04334, R01 DA004334, R56 DA004334] NR 20 TC 90 Z9 94 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2006 VL 2 IS 8 BP 741 EP 745 AR e79 DI 10.1371/journal.ppat.0020079 PG 5 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA V42VK UT WOS:000202894800003 PM 16933987 ER PT J AU Bagic, A Lupu, V Kessler, CM Tornatore, C AF Bagic, A. Lupu, V. Kessler, C. M. Tornatore, C. TI Iatrogenic arsenic induced Mees' lines SO POSTGRADUATE MEDICAL JOURNAL LA English DT Editorial Material C1 NINDS, EMG Sect, NIH, CRC, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Dept Neurol & Neurosurg, Pittsburgh, PA USA. Georgetown Univ Hosp, Dept Internal Med, Washington, DC 20007 USA. Georgetown Univ Hosp, Dept Neurol, Washington, DC 20007 USA. RP Lupu, V (reprint author), NINDS, EMG Sect, NIH, CRC, Bldg 10,Room 7-5680,10 Ctr Dr,MSC-1404, Bethesda, MD 20892 USA. EM lupuv@ninds.nih.gov NR 3 TC 1 Z9 1 U1 1 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0032-5473 J9 POSTGRAD MED J JI Postgrad. Med. J. PD AUG PY 2006 VL 82 IS 970 BP 515 EP 515 DI 10.1136/pgmj.2006.045229 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 070WO UT WOS:000239556900008 PM 16891441 ER PT J AU Kasianowicz, JJ Nguyen, TL Stanford, VM AF Kasianowicz, John J. Nguyen, Tam L. Stanford, Vincent M. TI Enhancing molecular flux through nanopores by means of attractive interactions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID ANTHRAX TOXIN; PROTEIN TRANSLOCATION; PROTECTIVE ANTIGEN; BACILLUS-ANTHRACIS; MEMBRANE CHANNEL; SINGLE-CHANNEL; PORE; TRANSPORT; CONDUCTANCE; SELECTIVITY C1 Natl Inst Stand & Technol, Div Semicond Elect, Elect & Elect Engn Lab, Gaithersburg, MD 20899 USA. NCI, Target Struct Based Drug Discovery Grp, SAIC Frederick, Frederick, MD 21702 USA. NIST, Informat Technol Lab, Informat Access Div, Gaithersburg, MD 20899 USA. RP Kasianowicz, JJ (reprint author), Natl Inst Stand & Technol, Div Semicond Elect, Elect & Elect Engn Lab, Gaithersburg, MD 20899 USA. EM john.kasianowicz@nist.gov NR 35 TC 12 Z9 12 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 1 PY 2006 VL 103 IS 31 BP 11431 EP 11432 DI 10.1073/pnas.0603951103 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 071QJ UT WOS:000239616400001 PM 16868083 ER PT J AU Inglese, J Auld, DS Jadhav, A Johnson, RL Simeonov, A Yasgar, A Zheng, W Austin, CP AF Inglese, James Auld, Douglas S. Jadhav, Ajit Johnson, Ronald L. Simeonov, Anton Yasgar, Adam Zheng, Wei Austin, Christopher P. TI Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE 1,536-well; chemical genomics; enzyme assay; PubChem; pyruvate kinase ID STATISTICAL PARAMETER; PYRUVATE-KINASE; ASSAYS; VALIDATION; INHIBITORS AB High-throughput screening (HITS) of chemical compounds to identify modulators of molecular targets is a mainstay of pharmaceutical development. Increasingly, HITS is being used to identify chemical probes of gene, pathway, and cell functions, with the ultimate goal of comprehensively delineating relationships between chemical structures and biological activities. Achieving this goal will require methodologies that efficiently generate pharmacological data from the primary screen and reliably profile the range of biological activities associated with large chemical libraries. Traditional HTS, which tests compounds at a single concentration, is not suited to this task, because HTS is burdened by frequent false positives and false negatives and requires extensive follow-up testing. We have developed a paradigm, quantitative HITS (qHTS), tested with the enzyme pyruvate kinase, to generate concentration-response curves for > 60,000 compounds in a single experiment. We show that this method is precise, refractory to variations in sample preparation, and identifies compounds with a wide range of activities. Concentration-response curves were classified to rapidly identify pyruvate kinase activators and inhibitors with a variety of potencies and efficacies and elucidate structure-activity relationships directly from the primary screen. Comparison of qHTS with traditional sing le-concentration HTS revealed a high prevalence of false negatives in the single-point screen. This study demonstrates the feasibility of qHTS for accurately profiling every compound in large chemical libraries (> 10(5) compounds). qHTS produces rich data sets that can be immediately mined for reliable biological activities, thereby providing a platform for chemical genomics and accelerating the identification of leads for drug discovery. C1 NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. RP Inglese, J (reprint author), NHGRI, NIH Chem Genom Ctr, NIH, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM jinglese@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Intramural NIH HHS NR 21 TC 378 Z9 387 U1 2 U2 42 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 1 PY 2006 VL 103 IS 31 BP 11473 EP 11478 DI 10.1073/pnas.0604348103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 071QJ UT WOS:000239616400011 PM 16864780 ER PT J AU Artzy-Randrup, Y Kondrashov, AS AF Artzy-Randrup, Yael Kondrashov, Alexey S. TI Sympatric speciation under incompatibility selection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE evolution; tradeoff; resource; hypergeometric model ID HABITAT SPECIALIZATION; TRADE-OFFS; GENETIC CORRELATIONS; EVOLUTION; MODEL; POPULATIONS; COMPETITION; ADAPTATION AB The existing theory of sympatric speciation assumes that a local population splits into two species under one-dimensional disruptive selection, which favors both of the opposite extreme values of a quantitative trait. Here we model sympatric speciation under selection that favors high values of either of the two independently inherited traits, each required to efficiently consume one of the two available resources, but acts, because of a tradeoff, against those possessing high values of both traits. Such two-dimensional incompatibility selection is similar to that involved in allopatric speciation. Using a hypergeometric phenotypic model, we show that incompatibility selection readily leads to sympatric speciation. In contrast to disruptive selection, two distinct modes of sympatric speciation exist under incompatibility selection: under strong tradeoffs both of the new species are specialists, each consuming its own resource, but under moderate tradeoffs speciation may be asymmetric and involve the origin of a specialist and a generalist species. Also, incompatibility selection may lead to irreversible specialization: under strong tradeoffs, the population speciates if it consists mostly of unspecialized individuals, but remains undivided if most of the individuals are specialized to consume one of the resources. Incompatibility selection appears to be more realistic than disruptive selection, implying that incompatibility between individually adaptive alleles or trait states drives both allopatric and sympatric speciation. C1 Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Tel Aviv Univ, Dept Zool, Biomath Unit, IL-69978 Tel Aviv, Israel. RP Kondrashov, AS (reprint author), Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM kondrashov@ncbi.nlm.nih.gov NR 33 TC 6 Z9 6 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 1 PY 2006 VL 103 IS 31 BP 11619 EP 11624 DI 10.1073/pnas.0602339103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 071QJ UT WOS:000239616400036 PM 16864787 ER PT J AU Sebbane, F Lemaitre, N Sturdevant, DE Rebeil, R Virtaneva, K Porcella, SF Hinnebusch, BJ AF Sebbane, Florent Lemaitre, Nadine Sturdevant, Daniel E. Rebeil, Roberto Virtaneva, Kimmo Porcella, Stephen F. Hinnebusch, B. Joseph TI Adaptive response of Yersinia pestis to extracellular effectors of innate immunity during bubonic plague SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE inducible nitric oxide synthase; reactive nitrogen species ID NITRIC-OXIDE; ESCHERICHIA-COLI; NITROSATIVE STRESS; GENOME SEQUENCE; VIRULENCE; INFECTION; BACTERIA; AGENT; HOST; MACROPHAGES AB Yersinia, pestis causes bubonic plague, characterized by an enlarged, painful lymph node, termed a bubo, that develops after bacterial dissemination from a fleabite site. In susceptible animals, the bacteria rapidly escape containment in the lymph node, spread systemically through the blood, and produce fatal sepsis. The fulminant progression of disease has been largely ascribed to the ability of Y. pestis to avoid phagocytosis and exposure to antimicrobial effectors of innate immunity. In vivo microarray analysis of Y. pestis gene expression, however, revealed an adaptive response to nitric oxide (NO)-derived reactive nitrogen species and to iron limitation in the extracellular environment of the bubo. Polymorphonuclear neutrophils recruited to the infected lymph node expressed abundant inducible NO synthase, and several Y. pestis homologs of genes involved in the protective response to reactive nitrogen species were up-regulated in the bubo. Mutation of one of these genes, which encodes the Hmp flavohemoglobin that detoxifies NO, attenuated virulence. Thus, the ability of Y. pestis to destroy immune cells and remain extracellular in the bubo appears to limit exposure to some but not all innate immune effectors. High NO levels induced during plague may also influence the developing adaptive immune response and contribute to septic shock. C1 NIAID, Rocky Mt Labs, Lab Zoonot Pathogens, NIH, Hamilton, MT 59840 USA. NIAID, Rocky Mt Labs, Gen Core Facil, NIH, Hamilton, MT 59840 USA. Univ Lille 2, Inst Natl Sante & Rech Med, Unite 801, F-59045 Lille, France. Univ Lille 2, Fac Med Henri Warembourg, F-59045 Lille, France. Inst Pasteur, F-59021 Lille, France. RP Hinnebusch, BJ (reprint author), NIAID, Rocky Mt Labs, Lab Zoonot Pathogens, NIH, Hamilton, MT 59840 USA. EM jhinnebusch@niaid.nih.gov RI Sebbane, Florent/D-4213-2009 FU Intramural NIH HHS NR 39 TC 109 Z9 111 U1 0 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 1 PY 2006 VL 103 IS 31 BP 11766 EP 11771 DI 10.1073/pnas.0601182103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 071QJ UT WOS:000239616400061 PM 16864791 ER PT J AU Rotanova, TV Botos, I Melnikov, EE Rasulova, F Gustchina, A Maurizi, MR Wlodawer, A AF Rotanova, Tatyana V. Botos, Istvan Melnikov, Edward E. Rasulova, Fatima Gustchina, Alla Maurizi, Michael R. Wlodawer, Alexander TI Slicing a protease: Structural features of the ATP-dependent Lon proteases gleaned from investigations of isolated domains SO PROTEIN SCIENCE LA English DT Review DE AAA(+) protein; Lon protease; ATP-dependent protease; Ser-Lys dyad; LonA and LonB subfamilies; domains; crystal structure ID ESCHERICHIA-COLI LON; N-TERMINAL DOMAIN; SER-LYS DYAD; CRYSTAL-STRUCTURE; MYCOBACTERIUM-SMEGMATIS; ANGSTROM RESOLUTION; DEGRADATION MACHINE; PROTEOLYTIC DOMAIN; CATALYTIC DYAD; SACCHAROMYCES-CEREVISIAE AB ATP-dependent Lon proteases are multi-domain enzymes found in all living organisms. All Lon proteases contain an ATPase domain belonging to the AAA(+) superfamily of molecular machines and a proteolytic domain with a serine-lysine catalytic dyad. Lon proteases can be divided into two subfamilies, LonA and LonB, exemplified by the Escherichia coli and Archaeoglobus fulgidus paralogs, respectively. The LonA subfamily is defined by the presence of a large N-terminal domain, whereas the LonB subfamily has no such domain, but has a membrane-spanning domain that anchors the protein to the cytoplasmic side of the membrane. The two subfamilies also differ in their consensus sequences. Recent crystal structures for several individual domains and sub-fragments of Lon proteases have begun to illuminate similarities and differences in structure-function relationships between the two subfamilies. Differences in orientation of the active site residues in several isolated Lon protease domains point to possible roles for the AAA+ domains and/or substrates in positioning the catalytic residues within the active site. Structures of the proteolytic domains have also indicated a possible hexameric arrangement of subunits in the native state of bacterial Lon proteases. The structure of a large segment of the N-terminal domain has revealed a folding motif present in other protein families of unknown function and should lead to new insights regarding ways in which Lon interacts with substrates or other cellular factors. These first glimpses of the structure of Lon are heralding an exciting new era of research on this ancient family of proteases. C1 NCI, Macromol Crystalog Lab, Frederick, MD 21702 USA. NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. Natl Canc Inst, Cell Biol Lab, Bethesda, MD 20892 USA. USN, Med Res Ctr, Enter Dis Dept, Infect Dis Directorate, Silver Spring, MD 20910 USA. Russian Acad Sci, Semyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia. RP Wlodawer, A (reprint author), NCI, Macromol Crystalog Lab, POB B, Frederick, MD 21702 USA. EM rotanova@enzyme.siobc.ras.ru; mmaurizi@helix.nih.gov; wlodawer@ncifcrf.gov FU Intramural NIH HHS NR 97 TC 46 Z9 46 U1 1 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2006 VL 15 IS 8 BP 1815 EP 1828 DI 10.1110/ps.052069306 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 068OD UT WOS:000239383400002 PM 16877706 ER PT J AU Krumpe, LRH Atkinson, AJ Smythers, GW Kandel, A Schumacher, KM McMahon, JB Makowski, L Mori, T AF Krumpe, Lauren R. H. Atkinson, Andrew J. Smythers, Gary W. Kandel, Andrea Schumacher, Kathryn M. McMahon, James B. Makowski, Lee Mori, Toshiyuki TI T7 lytic phage-displayed peptide libraries exhibit less sequence bias than M13 filamentous phage-displayed peptide libraries SO PROTEOMICS LA English DT Article DE bioinformatics; diversity; peptide; phage display; T7 phage ID PROTEIN-BINDING PEPTIDES; STREP-TAG; AFFINITY; STREPTAVIDIN; LIGAND; DIVERSITY; RECEPTOR AB We investigated whether the T7 system of phage display could produce peptide libraries of greater diversity than the M13 system of phage display due to the differing processes of lytic and filamentous phage morphogenesis. Using a bioinformatics-assisted computational approach, collections of random peptide sequences obtained from a T7 12-mer library (X-12) and a T7 7-mer disulfide-constrained library (CX7C) were analyzed and compared with peptide populations obtained from New England BioLabs' M13 Ph.D.-12 (TM) and Ph.D.-C7C (TM) libraries. Based on this analysis, peptide libraries constructed with the T7 system have fewer amino acid biases, increased peptide diversity, and more normal distributions of peptide net charge and hydropathy than the M13 libraries. The greater diversity of T7-displayed libraries provides a potential resource of novel binding peptides for new as well as previously studied molecular targets. To demonstrate their utility, several of the T7-displayed peptide libraries were screened for streptavidin- and neutravidin-binding phage. Novel binding motifs were identified for each protein. C1 Takeda Pharmaceut Co Ltd, Biomed Res Labs, Div Pharmaceut Res, Osaka 5328686, Japan. SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. SAIC Frederick Inc, Adv Biomed Comp Ctr, Frederick, MD USA. NCI, Werner H Kirsten Student Internship Program, Ctr Canc Res, Frederick, MD 21701 USA. NCI, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21701 USA. Argonne Natl Lab, Argonne, IL 60439 USA. RP Mori, T (reprint author), Takeda Pharmaceut Co Ltd, Biomed Res Labs, Div Pharmaceut Res, 2-17-85 Yodogawa Ku, Osaka 5328686, Japan. EM Mori_Toshiyuki2@takeda.co.jp FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 26 TC 67 Z9 71 U1 1 U2 11 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD AUG PY 2006 VL 6 IS 15 BP 4210 EP 4222 DI 10.1002/pmic.200500606 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 075EX UT WOS:000239867600001 PM 16819727 ER PT J AU Rutten, LJF Squiers, L Treiman, K AF Rutten, Lila J. Finney Squiers, Linda Treiman, Katherine TI Requests for information by family and friends of cancer patients calling the National Cancer Institute's Cancer Information Service SO PSYCHO-ONCOLOGY LA English DT Article DE information seeking; cancer care continuum; information needs of family and friends; Cancer Information Service; cancer; oncology ID SIGNIFICANT OTHERS; BREAST-CANCER; NEEDS; WOMEN; PROSTATE; SUPPORT; IMPACT AB Purpose: To characterize their information needs, we examined the main topics of inquiry and discussion (subjects of interaction, SOI) of calls made by family and friends of cancer patients to the National Cancer Institute's Cancer Information Service's (CIS) 1-800-4-CANCER telephone information service and summarized differences by sociodemographic characteristics. Design and analysis: Data from 26 789 family or friends of cancer patients calling the CIS between September 2002 and August 2003 were analyzed. Frequencies, chi(2)'s, and logistic regressions were conducted to ascertain sample characteristics and sociodemographic correlates of each SOI. Results and conclusions: The greatest proportion of calls concerned specific treatment information (54.9%) and general cancer site information (36.9%). Calls about specific treatment information were more likely among Asians, Hawaiian Natives, and Pacific Islanders (OR= 1.23, 1.04-1.45), and those with higher education (OR= 1.21, 1.18-1.25). As age increased, the odds of calls about specific treatment information also increased (OR = 1.05, 1.03-1.07). Females (OR = 0.78, 0.72-0.84), Hispanics (OR = 0.77, 0.67-0.89), African-Americans (OR = 0.68, 0.61-0.76), and American-Indians and Alaskan Natives (OR = 0.74, 0.58-0.93) were less likely to inquire about specific treatment information. Inquiries about general cancer site information were more likely among females (OR = 1.14, 1.06-1.23) and less likely among younger callers (OR = 0.95, 0.93-0.97) and African-Americans (OR = 0.87, 0.78-0.98). Differences in inquiries made by sociodemographic subgroups can inform the CIS' and other cancer-related organizations' efforts to develop and disseminate cancer information for family and friends of cancer patients. Copyright (c) 2005 John Wiley & Sons, Ltd. C1 SAIF Frederick Inc, NCI, Div Canc Control & Populat Sci, Behav Res Program,Hlth Commun & Informat Res Bran, Bethesda, MD 20892 USA. NCI, Off Canc Informat Serv, Off Commun, Bethesda, MD 20892 USA. NCI, Canc Informat Serv, Bethesda, MD 20892 USA. RP Rutten, LJF (reprint author), SAIF Frederick Inc, NCI, Div Canc Control & Populat Sci, Behav Res Program,Hlth Commun & Informat Res Bran, 6130 Execut Blvd,MSC 7365, Bethesda, MD 20892 USA. EM finneyl@mail.nih.gov NR 21 TC 12 Z9 12 U1 1 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD AUG PY 2006 VL 15 IS 8 BP 664 EP 672 DI 10.1002/pon.995 PG 9 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 077MF UT WOS:000240032800002 PM 16302290 ER PT J AU Basselin, M Chang, L Rapoport, SI AF Basselin, Mireille Chang, Lisa Rapoport, Stanley I. TI Chronic lithium chloride administration to rats elevates glucose metabolism in wide areas of brain, while potentiating negative effects on metabolism of dopamine D-2-like receptor stimulation SO PSYCHOPHARMACOLOGY LA English DT Article DE lithium; dopamine D-2 receptor; quinpirole; bipolar disorder; glucose metabolism; brain ID HUMAN CEREBRAL METABOLISM; H-3 QUINPIROLE BINDING; ARACHIDONIC-ACID; REGIONAL-DISTRIBUTION; UNANESTHETIZED RATS; NUCLEUS-ACCUMBENS; FISCHER-344 RATS; BIPOLAR DISORDER; HEALTHY-SUBJECTS; MOOD DISORDERS AB Rationale and objectives The regional cerebral metabolic rate for glucose (rCMR(glc)) can be imaged in vivo as a marker of brain functional activity. The effects of chronic lithium administration on baseline values of rCMR(glc) and values in response to administration of dopamine D-2-like receptor agonists have not been examined in humans or rats. Knowing these effects may elucidate and localize the therapeutic action of lithium in bipolar disorder. Methods In unanesthetized rats, we used the 2-deoxy-D-glucose (2-DG) technique to image the effects of a 6-week control diet or LiCl diet sufficient to produce a plasma lithium concentration therapeutically relevant to bipolar disorder, on rCMR(glc) at baseline and in response to the dopaminergic D-2-like receptor agonist, quinpirole (1 mg/kg i.v.), or to i.v. saline. Results Baseline rCMR(glc) was significantly elevated in 30 of 81 brain regions examined, in LiCl diet compared with control diet rats. Affected were visual and auditory structures, frontal cortex, amygdala, hippocampus, nucleus accumbens, caudate-putamen, interpeduncular nucleus, and substantia nigra. Acute quinpirole significantly decreased rCMR(glc) in four areas of the caudate-putamen in control diet rats, and in these and 19 additional brain areas in LiCl-fed rats. Conclusions In unanesthetized rats, chronic lithium administration widely upregulates baseline rCMR(glc) and potentiates the negative effects on rCMR(glc) of D-2-like receptor OF OF stimulation. The baseline elevation may relate to lithium's reported ability to increase auditory and visual evoked responses in humans, whereas lithium's potentiation of quinpirole's negative effects on rCMR(glc) may be related to its therapeutic efficacy in bipolar disorder. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Basselin, M (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room 1S126 9 Mem Dr, Bethesda, MD 20892 USA. EM mirvasln@mail.nih.gov FU Intramural NIH HHS NR 57 TC 13 Z9 13 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2006 VL 187 IS 3 BP 303 EP 311 DI 10.1007/s00213-006-0425-0 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 082VQ UT WOS:000240415700008 PM 16786332 ER PT J AU Likhtarov, I Kovgan, L Vavilov, S Chepurny, M Ron, E Lubin, J Bouville, A Tronko, N Bogdanova, T Gulak, L Zablotska, L Howe, G AF Likhtarov, I. Kovgan, L. Vavilov, S. Chepurny, M. Ron, E. Lubin, J. Bouville, A. Tronko, N. Bogdanova, T. Gulak, L. Zablotska, L. Howe, G. TI Post-Chornobyl thyroid cancers in Ukraine. Report 2: Risk analysis SO RADIATION RESEARCH LA English DT Article ID POWER-STATION ACCIDENT; NUCLEAR ACCIDENT; TIME TRENDS; BYELARUS; RADIATION; CHILDREN; EXPOSURE; ADOLESCENTS; CHILDHOOD; RUSSIA AB On April 26, 1986, the worst nuclear reactor accident to date occurred at the Chornobyl (Chernobyl) power plant in Ukraine. Millions of people in Ukraine, Belarus and Russia were exposed to radioactive nuclides, especially I-131. Since then, research has been conducted on various subgroups of the exposed population, and it has been demonstrated that the large increase in thyroid cancer is related to the I-131 exposure. However, because of study limitations, quantified risk estimates are limited, and there remains a need for additional information. We conducted an ecological study to investigate the relationship between I-131 thyroid dose and the diagnosis of thyroid cancer in three highly contaminated oblasts in Northern Ukraine. The study population is comprised of 301,907 persons who were between the ages of 1 and 18 at the time of the Chornobyl accident and were living in 1,293 rural settlements in the three study oblasts. Twenty-four percent of the study population had individual thyroid dose estimates and the other 76% had "individualized" estimates of thyroid dose based on direct thyroid measurements taken from a person of the same age and gender living in the same or nearby settlement. Cases include 232 thyroid cancers diagnosed from January 1990 through December 2001, and all were confirmed histologically. Dose-response analyses took into account differences in the rate of ultrasound examinations conducted in the three study oblasts. The estimated excess relative risk per gray was 8.0 (95% CI = 4.6-15) and the excess absolute risk per 10,000 person-year gray was estimated to be 1.5 (95% CI = 1.2-1.9). In broad terms, these estimates are compatible with results of other studies from the contaminated areas, as well as studies of external radiation exposure. (c) 2006 by Radiation Research Society C1 NCI, Div Canc Epidemiol & Genet, DHHS, NIH, Bethesda, MD 20892 USA. Sci Ctr Radiat Med AMS Ukraine, Radiat Protect Inst ATS Ukraine, UA-04050 Kiev, Ukraine. Inst Endocrinol & Metab AMS Ukraine, UA-04114 Kiev, Ukraine. Natl Canc Registry Ukraine, Ukraine Inst Oncol & Radiol AMS Ukraine, Kiev, Ukraine. Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10032 USA. RP Ron, E (reprint author), NCI, Div Canc Epidemiol & Genet, DHHS, NIH, 6120 Execut Blvd,EPS 7054, Bethesda, MD 20892 USA. EM eron@mail.nih.gov FU Intramural NIH HHS NR 47 TC 29 Z9 30 U1 1 U2 2 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD AUG PY 2006 VL 166 IS 2 BP 375 EP 386 DI 10.1667/RR3593.1 PG 12 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 067IB UT WOS:000239294000008 PM 16881739 ER PT J AU Yokley, K Tran, HT Pekari, K Rappaport, S Riihimaki, V Rothman, N Waidyanatha, S Schlosser, PM AF Yokley, Karen Tran, Hien T. Pekari, Kaija Rappaport, Stephen Riihimaki, Vesa Rothman, Nat Waidyanatha, Suramya Schlosser, Paul M. TI Physiologically-based pharmacokinetic modeling of benzene in humans: A Bayesian approach SO RISK ANALYSIS LA English DT Article DE Bayesian; benzene; dosimetry; human; metabolism; PBPK; variability ID IN-VITRO; ALBUMIN ADDUCTS; RISK ASSESSMENT; HEALTH RISK; HUMAN LIVER; EXPOSURE; METABOLISM; OXIDE; HYDROQUINONE; TOXICITY AB Benzene is myelotoxic and leukemogenic in humans exposed at high doses (> 1 ppm, more definitely above 10 ppm) for extended periods. However, leukemia risks at lower exposures are uncertain. Benzene occurs widely in the work environment and also indoor air, but mostly below 1 ppm, so assessing the leukemia risks at these low concentrations is important. Here, we describe a human physiologically-based pharmacokinetic (PBPK) model that quantifies tissue doses of benzene and its key metabolites, benzene oxide, phenol, and hydroquinone after inhalation and oral exposures. The model was integrated into a statistical framework that acknowledges sources of variation due to inherent intra- and interindividual variation, measurement error, and other data collection issues. A primary contribution of this work is the estimation of population distributions of key PBPK model parameters. We hypothesized that observed interindividual variability in the dosimetry of benzene and its metabolites resulted primarily from known or estimated variability in key metabolic parameters and that a statistical PBPK model that explicitly included variability in only those metabolic parameters would sufficiently describe the observed variability. We then identified parameter distributions for the PBPK model to characterize observed variability through the use of Markov chain Monte Carlo analysis applied to two data sets. The identified parameter distributions described most of the observed variability, but variability in physiological parameters such as organ weights may also be helpful to faithfully predict the observed human-population variability in benzene dosimetry. C1 N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. N Carolina State Univ, Ctr Res Sci Computat, Raleigh, NC 27695 USA. Finnish Inst Occupat Hlth, Biomonitoring Lab, Helsinki, Finland. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. Finnish Inst Occupat Hlth, Dept Occupat Hyg & Toxicol, Helsinki, Finland. NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD USA. CIIT Ctr Hlth Res, Res Triangle Pk, NC USA. RP Schlosser, PM (reprint author), US EPA, NCEA, MD B243-01, Res Triangle Pk, NC 27711 USA. EM schlosser.paul@epa.gov OI Schlosser, Paul/0000-0002-9699-9108 FU NIEHS NIH HHS [P30ES10126, P42ES05948]; NIGMS NIH HHS [1R01GM67299-01] NR 42 TC 18 Z9 19 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0272-4332 J9 RISK ANAL JI Risk Anal. PD AUG PY 2006 VL 26 IS 4 BP 925 EP 943 DI 10.1111/j.1539-6924.2006.00789.x PG 19 WC Public, Environmental & Occupational Health; Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods SC Public, Environmental & Occupational Health; Mathematics; Mathematical Methods In Social Sciences GA 075PJ UT WOS:000239897400007 PM 16948686 ER PT J AU Sukhodolets, MV Garges, S Adhya, S AF Sukhodolets, Maxim V. Garges, Susan Adhya, Sankar TI Ribosomal protein S1 promotes transcriptional cycling SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE S1; RNA polymerase; transcription; translation ID COLI RNA-POLYMERASE; RHO-INDEPENDENT TERMINATORS; ESCHERICHIA-COLI; MESSENGER-RNA; TRIPLE HELICES; DNA; ELONGATION; MECHANISM; RELEASE; BINDING AB Prokaryotic RNA polymerases are capable of efficient, continuous synthesis of RNA in vivo, yet purified polymerase-DNA model systems for RNA synthesis typically produce only a limited number of catalytic turnovers. Here, we report that the ribosomal protein S1-which plays critical roles in translation initiation and elongation in Escherichia coli and is believed to stabilize mRNA on the ribosome-is a potent activator of transcriptional cycling in vitro. Deletion of the two C-terminal RNA-binding modules-out of a total of six loosely homologous RNA-binding modules present in S1-resulted in a near-loss of the ability of S1 to enhance transcription, whereas disruption of the very last C-terminal RNA-binding module had only a mild effect. We propose that, in vivo, cooperative interaction of multiple RNA-binding modules in S1 may enhance the transcript release from RNA polymerase, alleviating its inhibitory effect and enabling the core enzyme for continuous reinitiation of transcription. C1 Lamar Univ, Dept Chem & Phys, Beaumont, TX 77710 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Sukhodolets, MV (reprint author), Lamar Univ, Dept Chem & Phys, Beaumont, TX 77710 USA. EM soukhodomv@hal.lamar.edu NR 51 TC 25 Z9 25 U1 3 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD AUG PY 2006 VL 12 IS 8 BP 1505 EP 1513 DI 10.1261/rna.2321606 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 068PA UT WOS:000239385700009 PM 16775305 ER PT J AU Linnstaedt, SD Kasprzak, WK Shapiro, BA Casey, JL AF Linnstaedt, Sarah D. Kasprzak, Wojciech K. Shapiro, Bruce A. Casey, John L. TI The role of a metastable RNA secondary structure in hepatitis delta virus genotype III RNA editing SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE hepatitis delta virus; RNA editing; ADAR1; RNA secondary structure ID PARALLEL GENETIC ALGORITHM; ADENOSINE DEAMINASES; STRUCTURE PREDICTION; WEB SERVER; LARGE FORM; ANTIGEN; ADAR1; REPLICATION; SEQUENCE; EXPRESSION AB RNA editing plays a critical role in the life cycle of hepatitis delta virus (HDV). The host editing enzyme ADAR1 recognizes specific RNA secondary structure features around the amber/W site in the HDV antigenome and deaminates the amber/W adenosine. A previous report suggested that a branched secondary structure is necessary for editing in HDV genotype III. This branched structure, which is distinct from the characteristic unbranched rod structure required for HDV replication, was only partially characterized, and knowledge concerning its formation and stability was limited. Here, we examine the secondary structures, conformational dynamics, and amber/W site editing of HDV genotype III RNA using a miniaturized HDV genotype III RNA in vitro. Computational analysis of this RNA using the MPGAfold algorithm indicated that the RNA has a tendency to form both metastable and stable unbranched secondary structures. Moreover, native polyacrylamide gel electrophoresis demonstrated that this RNA forms both branched and unbranched rod structures when transcribed in vitro. As predicted, the branched structure is a metastable structure that converts readily to the unbranched rod structure. Only branched RNA was edited at the amber/W site by ADAR1 in vitro. The structural heterogeneity of HDV genotype III RNA is significant because not only are both conformations of the RNA functionally important for viral replication, but the ratio of the two forms could modulate editing by determining the amount of substrate RNA available for modification. C1 Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20057 USA. NCI, Basic Res Program, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. NCI, Ctr Canc, Res Nanobiol Program, Ft Detrick, MD 21702 USA. RP Casey, JL (reprint author), Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, 3900 Reservoir Rd NW, Washington, DC 20057 USA. EM caseyj@georgetown.edu FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [R01 AI042324] NR 51 TC 13 Z9 14 U1 1 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD AUG PY 2006 VL 12 IS 8 BP 1521 EP 1533 DI 10.1261/rna.89306 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 068PA UT WOS:000239385700011 PM 16790843 ER PT J AU Schultz, TW Carlson, RE Cronin, MTD Hermens, JLM Johnson, R O'Brien, PJ Roberts, DW Siraki, A Wallace, KB Veith, GD AF Schultz, T. W. Carlson, R. E. Cronin, M. T. D. Hermens, J. L. M. Johnson, R. O'Brien, P. J. Roberts, D. W. Siraki, A. Wallace, K. B. Veith, G. D. TI A conceptual framework for predicting the toxicity of reactive chemicals: modeling soft electrophilicity SO SAR AND QSAR IN ENVIRONMENTAL RESEARCH LA English DT Article DE reactivity toxicity; thiol reactivity; molecular initiating events; QSAR ID VOLATILE ORGANIC-CHEMICALS; SKIN SENSITIZATION; SENSORY IRRITANTS; GLUTATHIONE; APPLICABILITY; METABOLISM; TOXICOLOGY; DISCOVERY AB Although the literature is replete with QSAR models developed for many toxic effects caused by reversible chemical interactions, the development of QSARs for the toxic effects of reactive chemicals lacks a consistent approach. While limitations exit, an appropriate starting-point for modeling reactive toxicity is the applicability of the general rules of organic chemical reactions and the association of these reactions to cellular targets of importance in toxicology. The identification of plausible "molecular initiating events'' based on covalent reactions with nucleophiles in proteins and DNA provides the unifying concept for a framework for reactive toxicity. This paper outlines the proposed framework for reactive toxicity. Empirical measures of the chemical reactivity of xenobiotics with a model nucleophile (thiol) are used to simulate the relative rates at which a reactive chemical is likely to bind irreversibly to cellular targets. These measures of intrinsic reactivity serve as correlates to a variety of toxic effects; what's more they appear to be more appropriate endpoints for QSAR modeling than the toxicity endpoints themselves. C1 Int QSAR Fdn, Two Harbors, MN 55616 USA. Univ Tennessee, Coll Vet Med, Dept Comparat Med, Knoxville, TN 37996 USA. ECOCHEM Res Inc, Chaska, MN 55318 USA. Liverpool John Moores Univ, Sch Pharm & Chem, Liverpool L3 3AF, Merseyside, England. Univ Utrecht, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands. US EPA, Duluth, MN 55804 USA. Univ Toronto, Fac Pharm, Toronto, ON M5S 2S2, Canada. NIEHS, Res Triangle Pk, NC USA. Univ Minnesota, Sch Med, Dept Biochem & Mol Biol, Duluth, MN 55812 USA. RP Veith, GD (reprint author), Int QSAR Fdn, 1501 W Knife River Rd, Two Harbors, MN 55616 USA. EM gdveith@earthlink.net NR 34 TC 73 Z9 75 U1 0 U2 20 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1062-936X J9 SAR QSAR ENVIRON RES JI SAR QSAR Environ. Res. PD AUG PY 2006 VL 17 IS 4 BP 413 EP 428 DI 10.1080/10629360600884371 PG 16 WC Chemistry, Multidisciplinary; Computer Science, Interdisciplinary Applications; Environmental Sciences; Mathematical & Computational Biology; Toxicology SC Chemistry; Computer Science; Environmental Sciences & Ecology; Mathematical & Computational Biology; Toxicology GA 090LV UT WOS:000240953700004 PM 16920662 ER PT J AU Abdi, K Singh, N Matzinger, P AF Abdi, K. Singh, N. Matzinger, P. TI T-cell control of IL-12p75 production SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Article ID DENDRITIC CELLS; INTERFERON-GAMMA; BIOACTIVE IL-12; IN-VIVO; MYCOBACTERIAL INFECTION; BONE-MARROW; MURINE MACROPHAGES; TOXOPLASMA-GONDII; ADAPTIVE IMMUNITY; HUMAN MONOCYTES AB It is currently thought that IL-12, produced by dendritic cells (DC) early after stimulation by bacterial pathogens or lipopolysaccharide (LPS), acts as a pro-inflammatory cytokine bridging the innate and adaptive immune responses. We found, however, that it is only the p40 subunit and not the IL-12p75 heterodimer that is secreted early in copious amounts in response to LPS. Neither naive T cells, nor a variety of microbial products, were able to induce IL-12p75 production unless the DC were conditioned by the presence of interferon-gamma (IFN-gamma) or by encounter with previously activated T cells. The inability of naive T cells or of bacterial products to induce IL-12 argues against its early role as the initiator of innate and adaptive immune responses. C1 NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Abdi, K (reprint author), NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, 9000 Rockville Pike,Bldg 4,Room 111 Msc 0420, Bethesda, MD 20892 USA. EM kabdi@niaid.nih.gov FU Intramural NIH HHS NR 58 TC 32 Z9 33 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD AUG PY 2006 VL 64 IS 2 BP 83 EP 92 DI 10.1111/j.1365-3083.2006.01767.x PG 10 WC Immunology SC Immunology GA 061SR UT WOS:000238893400001 PM 16867152 ER PT J AU Pallesen, S Nordhus, IH Carlstedt, B Thayer, JF Johnsen, TB AF Pallesen, Stale Nordhus, Inger Hilde Carlstedt, Berit Thayer, Julian F. Johnsen, Tom Backer TI A norwegian adaptation of the Penn State Worry Questionnaire: Factor structure, reliability, validity and norms SO SCANDINAVIAN JOURNAL OF PSYCHOLOGY LA English DT Article DE Penn State Worry Questionnaire; factor structure; validity; reliability; norms ID GENERALIZED ANXIETY DISORDER; CONFIRMATORY FACTOR-ANALYSIS; PSYCHOMETRIC PROPERTIES; SELF-ESTEEM; DEPRESSION; INVENTORY; VALIDATION; VERSION AB A Norwegian version of the Penn State Worry Questionnaire (PSWQ) was administered to 304 undergraduate students together with the Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI) and the Maudsley Obsessive Compulsive Inventory (MOCI). The PSWQ was also administered to a community sample comprising 879 subjects, together with the Beck Anxiety Inventory (BAI), the Beck Depression Inventory II (BDI II) and the White Bear Suppression Inventory (WBSI). Structural equation modeling showed that a three-factor solution of the PSWQ gave the best goodness of fit. The Norwegian version of the PSWQ demonstrated adequate psychometric properties in terms of reliability and validity in both samples. Females scored higher than males on PSWQ. C1 Univ Bergen, Dept Psychosocial Sci, N-5015 Bergen, Norway. Swedish Natl Dev Coll, Karlstad, Sweden. NIA, Baltimore, MD 21224 USA. RP Pallesen, S (reprint author), Univ Bergen, Dept Psychosocial Sci, Christiesgt 12, N-5015 Bergen, Norway. EM staale.pallesen@psysp.uib.no NR 50 TC 21 Z9 21 U1 3 U2 7 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0036-5564 J9 SCAND J PSYCHOL JI Scand. J. Psychol. PD AUG PY 2006 VL 47 IS 4 BP 281 EP 291 DI 10.1111/j.1467-9450.2006.00518.x PG 11 WC Psychology, Multidisciplinary SC Psychology GA 061SU UT WOS:000238893700006 PM 16869861 ER PT J AU Purdue, MP Jarvholm, B Bergdahl, I Hayes, RB Baris, D AF Purdue, Mark P. Jarvholm, Bengt Bergdahl, Ingvar Hayes, Richard B. Baris, Dalsu TI Occupational exposures and head and neck cancers among Swedish construction workers SO SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH LA English DT Article DE asbestos; cement dust; cohort study; laryngeal cancer; oral cancer; pharyngeal cancer ID LARYNGEAL-CANCER; RISK-FACTORS; HYPOPHARYNX CANCER; PHARYNGEAL CANCER; RUBBER INDUSTRY; CEMENT DUST; ORAL-CAVITY; ASBESTOS; MORTALITY; CARCINOMA AB Objectives Occupational exposures in the construction industry may increase the risk of head and neck cancers, although the epidemiologic evidence is limited by problems of low study power and inadequate adjustment for tobacco use. In an attempt to address this issue, the relationship between selected occupational exposures and head and neck cancer risk was investigated using data from a large cohort of Swedish construction workers. Methods Altogether 510 squamous cell carcinomas of the head and neck (171 in the oral cavity, 112 in the pharynx, 227 in the larynx) were identified during 1971-2001 among 307 799 male workers in the Swedish construction industry. Exposure to diesel exhaust, asbestos, organic solvents, metal dust, asphalt, wood dust, stone dust, mineral wool, and cement dust was assessed using a semi-quantitative job-exposure matrix. Rate ratios (RR) and 95% confidence intervals (95% CI) were calculated for head and neck cancers in relation to occupational exposure, using Poisson regression with adjustment for age and smoking status. Results Asbestos exposure was related to an increased laryngeal cancer incidence (RR 1.9, 95% CI 1.2-3.1). Excesses of pharyngeal cancer were observed among workers exposed to cement dust (RR 1.9, 95% CI 1.2-3.1). No occupational exposures were associated with oral cavity cancer. These findings did not materially change upon additional adjustment for cigarette pack-years. Conclusions These findings offer further evidence that asbestos increases the risk of laryngeal cancer. The observation of a positive association between cement dust exposure and pharyngeal cancer warrants further investigation. C1 NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. RP Purdue, MP (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 8111, Rockville, MD 20852 USA. EM purduem@mail.nih.gov RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU Intramural NIH HHS NR 48 TC 38 Z9 42 U1 0 U2 3 PU SCANDINAVIAN JOURNAL WORK ENVIRONMENT & HEALTH PI HELSINKI PA TOPELIUKSENKATU 41A, SF-00250 HELSINKI, FINLAND SN 0355-3140 EI 1795-990X J9 SCAND J WORK ENV HEA JI Scand. J. Work Environ. Health PD AUG PY 2006 VL 32 IS 4 BP 270 EP 275 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 078HO UT WOS:000240093500003 PM 16932824 ER PT J AU Lope, V Perez-Gomez, B Aragones, N Lopez-Abentes, G Gustavsson, P Floderus, B Dosemeci, M Silva, A Pollan, M AF Lope, Virginia Perez-Gomez, Beatriz Aragones, Nuria Lopez-Abentes, Gonzalo Gustavsson, Per Floderus, Birgitta Dosemeci, Mustafa Silva, Agustin Pollan, Marina TI Occupational exposure to ionizing radiation and electromagnetic fields in relation to the risk of thyroid cancer in Sweden SO SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH LA English DT Article DE cohort; occupation; risk; thyroid neoplasm ID X-RAY WORKERS; MAGNETIC-FIELD; RADIOLOGIC TECHNOLOGISTS; POOLED ANALYSIS; SWEDISH; HEALTH; WOMEN; EPIDEMIOLOGY; ENDOCRINE; CANADA AB Objectives This study sought to ascertain the risk of thyroid cancer in relation to occupational exposure to ionizing radiation and extremely low-frequency magnetic fields (ELFMF) in a cohort representative of Sweden's gainfully employed population. Methods A historical cohort of 2 992 166 gainfully employed Swedish male and female workers was followed up from 1971 through 1989. Exposure to ELFMF and ionizing radiation was assessed using three job exposure matrices based on industrial branch or occupational codes. Relative risks (RR) for male and female workers, adjusted for age and geographic area, were computed using log-linear Poisson models. Results Occupational ELFMF exposure showed no effect on the risk of thyroid cancer in the study. However, female workers exposed to high intensities of ionizing radiation registered a marked excess risk (RR 1.85, 95% confidence interval (95% CI) 1.02-3.35]. This trend was not in evidence among the men. Conclusions While the study confirms the etiologic role of ionizing radiation, with a higher incidence of thyroid cancer being recorded for the most-exposed female workers, our results do not support the possibility of occupational exposure to ELFMF being a risk factor for the development of thyroid cancer. C1 Carlos III Inst Hlth, Natl Ctr Epidemiol, Canc & Environm Epidemiol Sect, ES-28029 Madrid, Spain. Stockholm Cty Council, Dept Environm & Occupat Hlth, Stockholm, Sweden. Karolinska Inst, Dept Publ Hlth Sci, Div Occupat Hlth, Stockholm, Sweden. Natl Inst Working Life, Stockholm, Sweden. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Alcala de Henares, Fac Med, Dept Hlth & Med Social Sci, Madrid, Spain. RP Lope, V (reprint author), Carlos III Inst Hlth, Natl Ctr Epidemiol, Canc & Environm Epidemiol Sect, C Sinesio Delgado,6, ES-28029 Madrid, Spain. EM vicarvajal@isciii.es RI Pollan, Marina/M-3259-2014; Aragones, Nuria/O-5962-2015; Perez-Gomez, Beatriz/C-4715-2012; LOPE, VIRGINIA/S-4774-2016; Lopez-Abente, Gonzalo/E-5221-2010 OI Aragones, Nuria/0000-0003-0983-2156; Perez-Gomez, Beatriz/0000-0002-4299-8214; LOPE, VIRGINIA/0000-0002-6986-4021; Pollan, Marina/0000-0002-4328-1565; Lopez-Abente, Gonzalo/0000-0003-2423-8075 NR 45 TC 13 Z9 18 U1 0 U2 7 PU SCANDINAVIAN JOURNAL WORK ENVIRONMENT & HEALTH PI HELSINKI PA TOPELIUKSENKATU 41A, SF-00250 HELSINKI, FINLAND SN 0355-3140 EI 1795-990X J9 SCAND J WORK ENV HEA JI Scand. J. Work Environ. Health PD AUG PY 2006 VL 32 IS 4 BP 276 EP 284 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 078HO UT WOS:000240093500004 PM 16932825 ER PT J AU Kay, LM Stopfer, M AF Kay, Leslie M. Stopfer, Mark TI Information processing in the olfactory systems of insects and vertebrates SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE odor; synchrony; antennal lobe; olfactory bulb; coding ID LOCUST ANTENNAL LOBE; OSCILLATING NEURAL ASSEMBLIES; EXTERNAL TUFTED CELLS; PRESYNAPTIC INHIBITION; ODOR REPRESENTATIONS; MITRAL CELLS; IN-VIVO; MITRAL/TUFTED CELLS; RESPONSE PROPERTIES; DROSOPHILA-ANTENNA AB Insects and vertebrates separately evolved remarkably similar mechanisms to process olfactory information. Odors are sampled by huge numbers of receptor neurons, which converge type-wise upon a much smaller number of principal neurons within glomeruli. There, odor information is transformed by inhibitory interneuron-mediated, cross-glomerular circuit interactions that impose slow temporal structures and fast oscillations onto the firing patterns of principal neurons. The transformations appear to improve signal-to-noise characteristics, define odor categories, achieve precise odor identification, extract invariant features, and begin the process of sparsening the neural representations of odors for efficient discrimination, memorization, and recognition. (c) 2006 Elsevier Ltd. All rights reserved. C1 NICHD, NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Psychol, Chicago, IL 60637 USA. RP Stopfer, M (reprint author), NICHD, NIH, Bldg 35,35 Lincoln Dr,Room 3A-102,MSC 3715, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov OI Kay, Leslie/0000-0003-3049-477X FU Intramural NIH HHS; NIDCD NIH HHS [R01 DC007995, R01DC00795-01] NR 83 TC 66 Z9 68 U1 3 U2 26 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD AUG PY 2006 VL 17 IS 4 BP 433 EP 442 DI 10.1016/j.semcdb.2006.04.012 PG 10 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 091WJ UT WOS:000241058700005 PM 16766212 ER PT J AU Kleiner, DE AF Kleiner, David E. TI Granulomas in the liver SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Review DE granuloma; liver; infection; drug injury; sarcoidosis; immunodeficiency ID FIBRIN-RING GRANULOMAS; PRIMARY BILIARY-CIRRHOSIS; CHRONIC HEPATITIS-C; BARR VIRUS-INFECTION; GIANT-CELL ARTERITIS; EPITHELIOID GRANULOMAS; FOLLOW-UP; CLINICOPATHOLOGICAL FEATURES; BCG IMMUNOTHERAPY; DISEASE AB Granulomatous diseases of the liver span a huge range of infectious, drug-related, and immunologic disorders. Familiarity with the different types of granulomas as well as how they present in different diseases can be helpful in narrowing the pathologic differential diagnosis. This review surveys both common and unusual granulomatous diseases with emphasis on practical diagnosis. (c) 2006 Elsevier Inc. All rights reserved. C1 NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Kleiner, DE (reprint author), NCI, Pathol Lab, Bldg 10,Room 2N212,10 Ctr Dr,MSC 1516, Bethesda, MD 20892 USA. EM kleinerd@mail.nih.gov OI Kleiner, David/0000-0003-3442-4453 FU Intramural NIH HHS NR 148 TC 18 Z9 18 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD AUG-NOV PY 2006 VL 23 IS 3-4 BP 161 EP 169 DI 10.1053/j.semdp.2006.11.003 PG 9 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 136PZ UT WOS:000244237900004 PM 17355089 ER PT J AU Berman, HM Burley, SK Chiu, W Sali, A Adzhubei, A Bourne, PE Bryant, SH Dunbrack, RL Fidelis, K Frank, J Godzik, A Henrick, K Joachimiak, A Heymann, B Jones, D Markley, JL Moult, J Montelione, GT Orengo, C Rossmann, MG Rost, B Saibil, H Schwede, T Standley, DM Westbrook, JD AF Berman, Helen M. Burley, Stephen K. Chiu, Wah Sali, Andrej Adzhubei, Alexel Bourne, Philip E. Bryant, Stephen H. Dunbrack, Roland L., Jr. Fidelis, Krzysztof Frank, Joachim Godzik, Adam Henrick, Kim Joachimiak, Andrzej Heymann, Bernard Jones, David Markley, John L. Moult, John Montelione, Gaetano T. Orengo, Christine Rossmann, Michael G. Rost, Burkhard Saibil, Helen Schwede, Torsten Standley, Daron M. Westbrook, John D. TI Outcome of a workshop on archiving structural models of biological macromolecules SO STRUCTURE LA English DT Editorial Material ID PROTEIN-STRUCTURE PREDICTION; DATA-BANK; CRYOELECTRON MICROSCOPY; ELECTRON CRYOMICROSCOPY; FOLD RECOGNITION; E-SCIENCE; MATURATION; DATABASE; VIRUS; REFINEMENT C1 Rutgers State Univ, Res Collaboratory Struct Bioinformat Prot Data Ba, Piscataway, NJ 08854 USA. SGX Pharmaceut Inc, San Diego, CA 92121 USA. Baylor Coll Med, Dept Biochem & Mol Biol, Natl Ctr Macromol Imaging, Houston, TX 77030 USA. Univ Calif San Francisco, Dept Biopharmaceut Sci, San Francisco, CA 94143 USA. Univ Oslo, Biotechnol Ctr Oslo, N-0317 Oslo, Norway. Univ Calif San Diego, Res Collaboratory Struct Bioinformat Prot Data Ba, San Diego Supercomp Ctr, La Jolla, CA 92093 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Fox Chase Canc Ctr, Inst Canc Res, Philadelphia, PA 19111 USA. Univ Calif Davis, Genome & Biomed Sci Facil, Davis, CA 95616 USA. New York State Dept Hlth, Wadsworth Ctr, Dept Biomed Sci, Howard Hughes Med Inst, Albany, NY 12201 USA. Burnham Inst Med Res, Bioinformat & Syst Biol Program, La Jolla, CA 92037 USA. EMBL Outstn Hinxton, European Bioinformat Inst, Cambridge CB10 1SD, England. Argonne Natl Lab, Dept Struct Biol Ctr, Argonne, IL 60439 USA. NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. UCL, Dept Comp Sci, Bioinformat Unit, London WC1E 6BT, England. Univ Wisconsin, Dept Biochem, BioMagResBank, Madison, WI 53706 USA. Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. Rutgers State Univ, Dept Mol Biol & Biochem, Ctr Adv Res Biotechnol, Piscataway, NJ 08854 USA. UCL, Dept Biochem & Mol Biol, Biomol Struct & Modeling Unit, London WC1E 6BT, England. Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. Univ London Birkbeck Coll, Dept Crystallog, Bloomsbury Ctr Struct Biol, London WC1E 7HX, England. Univ Basel, Biozentrum, Div Bioinformat, CH-4056 Basel, Switzerland. Osaka Univ, Inst Prot Res, Prot Data Bank Japan, Osaka 5650871, Japan. RP Berman, HM (reprint author), Rutgers State Univ, Res Collaboratory Struct Bioinformat Prot Data Ba, Piscataway, NJ 08854 USA. EM berman@rcsb.rutgers.edu RI Schwede, Torsten/A-4650-2008; Bourne, Philip/C-2073-2008; Standley, Daron/D-2343-2009; Godzik, Adam/A-7279-2009; OI Schwede, Torsten/0000-0003-2715-335X; Godzik, Adam/0000-0002-2425-852X; Westbrook, John/0000-0002-6686-5475; Moult, John/0000-0002-3012-2282; Heymann, Bernard/0000-0002-8872-5326; Dunbrack, Roland/0000-0001-7674-6667 NR 53 TC 26 Z9 29 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD AUG PY 2006 VL 14 IS 8 BP 1211 EP 1217 DI 10.1016/j.str.2006.06.005 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 076HD UT WOS:000239946700003 PM 16955948 ER PT J AU Malin, JL Ko, C Ayanian, JZ Harrington, D Nerenz, DR Kahn, KL Ganther-Urmie, J Catalano, PJ Zaslavsky, AM Wallace, RB Guadagnoli, E Arora, NK Roudier, MD Ganz, PA AF Malin, Jennifer L. Ko, Clifford Ayanian, John Z. Harrington, David Nerenz, David R. Kahn, Katherine L. Ganther-Urmie, Julie Catalano, Paul J. Zaslavsky, Alan M. Wallace, Robert B. Guadagnoli, Edward Arora, Neeraj K. Roudier, Maryse D. Ganz, Patricia A. TI Understanding cancer patients' experience and outcomes: development and pilot study of the Cancer Care Outcomes Research and Surveillance patient survey SO SUPPORTIVE CARE IN CANCER LA English DT Article DE quality of health care; patterns of care; outcome assessment; process assessment; patient satisfaction; decision making; health disparities ID QUALITY-OF-LIFE; METASTATIC LUNG-CANCER; FUNCTIONAL LIVING INDEX; FORM HEALTH SURVEY; COLORECTAL-CANCER; CLINICAL-TRIALS; ADJUVANT CHEMOTHERAPY; RACIAL-DIFFERENCES; PROSTATE-CANCER; AGE AB Goals of work: The National Cancer Institute's Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium is conducting a population-based study of newly diagnosed patients with lung and colorectal cancer to describe the experience of persons living with cancer and to understand which barriers present the most significant obstacles to their receipt of appropriate care. The keystone to this effort is the baseline patient survey administered approximately 4 months after diagnosis. Patients and methods: We developed a survey to obtain information from patients newly diagnosed with lung and colorectal cancer about their personal characteristics, decision making, experience of care, and outcomes. We conducted a pilot study to evaluate the feasibility of a lengthy and clinically detailed interview in a convenience sample of patients within 8 months of diagnosis (n=71). Main results: The median length of the interviews was 75 min for patients with lung cancer (range 43-130) and 82 min for patients with colorectal cancer (range 46-119). Most patients had received some form of treatment for their cancer: 66.1% had undergone surgery, 28.2% had received radiation therapy, and 54.9% were treated with chemotherapy. In addition, 26.7% reported their overall health was less than 70 on a 0-100 scale, demonstrating that patients with substantial health impairment were able to complete the survey. Conclusions: A clinically detailed survey of newly diagnosed lung and colorectal cancer patients is feasible. A modified version of this survey is being fielded by the CanCORS Consortium and should provide much needed population-based data regarding patients' experiences across the continuum of cancer care and their outcomes. C1 Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Gen Internal Med Hlth Serv Res, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol Oncol, Los Angeles, CA USA. RAND Corp, Santa Monica, CA USA. Amgen Corp, Thousand Oaks, CA 91320 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA USA. Brigham & Womens Hosp, Dept Med, Div Gen Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA USA. Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Henry Ford Hlth Syst, Ctr Hlth Serv Res, Detroit, MI USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. Natl Canc Inst, Outcomes Res Branch, ARP, DCCPS, Bethesda, MD USA. Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90024 USA. RP Malin, JL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Gen Internal Med Hlth Serv Res, Los Angeles, CA 90024 USA. EM jmalin@amgen.com FU NCI NIH HHS [U01 CA93348, U01 CA93329, U01 CA93332, U01 CA93326, U01 CA93344, U01 CA93324, U01 CA93339] NR 62 TC 61 Z9 61 U1 3 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD AUG PY 2006 VL 14 IS 8 BP 837 EP 848 DI 10.1007/s00520-005-0902-8 PG 12 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 063MV UT WOS:000239023400008 PM 16482448 ER PT J AU Nalcioglu, O Clarke, L AF Nalcioglu, Orhan Clarke, Laurence TI Multi-modality imaging in oncology SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT LA English DT Editorial Material C1 Univ Calif Irvine, Irvine, CA USA. NCI, Bethesda, MD 20892 USA. RP Nalcioglu, O (reprint author), Univ Calif Irvine, Irvine, CA USA. EM nalci@uci.edu RI Nalcioglu, Orhan/G-2095-2010 NR 0 TC 1 Z9 1 U1 0 U2 1 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 1533-0346 J9 TECHNOL CANCER RES T JI Technol. Cancer Res. Treat. PD AUG PY 2006 VL 5 IS 4 BP 299 EP 300 PG 2 WC Oncology SC Oncology GA 078GG UT WOS:000240089900001 ER PT J AU Webb, SP AF Webb, Simon P. TI Ab initio electronic structure theory as an aid to understanding excited state hydrogen transfer in moderate to large systems SO THEORETICAL CHEMISTRY ACCOUNTS LA English DT Review DE hypocrellin; hypericin; perylene quinones; excited states; hydrogen transfer; parallel processor CIS; CASSCF; MRMP2 ID DENSITY-FUNCTIONAL THEORY; SELF-CONSISTENT-FIELD; FRAGMENT POTENTIAL METHOD; COUPLED-CLUSTER THEORY; CONFIGURATION-INTERACTION METHOD; MOLECULAR-ORBITAL METHODS; MULTICONFIGURATIONAL PERTURBATION-THEORY; INTRAMOLECULAR PROTON-TRANSFER; SYMMETRICAL PERYLENE QUINONES; LIVER ALCOHOL-DEHYDROGENASE AB Hypocrellin and hypericin are naturally occurring polycyclic perylene quinones, and they have both been found to exhibit photoactivated antiviral and anticancer activity. One mode of action proposed involves excited-state hydrogen transfer. Consequently these compounds have been widely studied using spectroscopic methods, and are found to both absorb and emit in the visible region. Recently an analog dihydroxy perylene quinone was synthesized in order to examine its antiviral activity in relation to the naturally occurring compounds. Its UV-visible absorption and emission spectra are quite different to those of hypocrellin and hypericin, with very weak absorption and no visibility of emission at all. The ab inito excited-state methods, configuration interaction singles (CIS), state-averaged complete active space self-consistent field (SA-CASSCF), and SA-multireference perturbation theory (SA-MRMP2) are used to examine the origin of this different absorption and emission behavior. Owing to the size of these systems (between 24 and 40 heavy atoms) extensive use of parallel processor algorithms was made, especially a parallel atomic orbital-based CIS energy and gradient code developed at the ABCC. The performance of these methods, and possible ,as well as future directions and prospects are discussed. C1 NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Webb, SP (reprint author), NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, POB B, Frederick, MD 21701 USA. NR 138 TC 5 Z9 5 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1432-881X EI 1432-2234 J9 THEOR CHEM ACC JI Theor. Chem. Acc. PD AUG PY 2006 VL 116 IS 1-3 BP 355 EP 372 DI 10.1007/s00214-005-0011-2 PG 18 WC Chemistry, Physical SC Chemistry GA 076LF UT WOS:000239958600032 ER PT J AU Huestis, MA ElSohly, M Nebro, W Barnes, A Gustafson, RA Smith, ML AF Huestis, Marilyn A. ElSohly, Mahmoud Nebro, Wesenyalsh Barnes, Allan Gustafson, Riehard A. Smith, Michael L. TI Estimating time of last oral ingestion of cannabis from plasma THC and THCCOOH concentrations SO THERAPEUTIC DRUG MONITORING LA English DT Article DE tetrahydrocannabinol; oral; prediction models; plasma cannabinoids ID DELTA-9-TETRAHYDROCANNABINOL THC; DELTA(9)-TETRAHYDROCANNABINOL; MARIJUANA; PERFORMANCE; BLOOD; PHARMACOLOGY; METABOLISM; HUMANS AB Estimating the time of last cannabis use is important in assessing possible impairment of drivers involved in accidents, in verifying accuracy of court testimony and in the future, helpful in therapeutic monitoring of cannabis agonists. In 1992, Huestis et al developed model 1, based on plasma Delta(9)-tetrahydrocannabinol (THC) concentrations, and model 2, on plasma 11-nor-9-carboxy-Delta(9)-tetrahydrocannbinol/THC ratios, that predicted 95% confidence intervals for time of last cannabis use. These models seemed to be valuable when applied to the small amount of data from published studies of oral ingestion, a route of administration more popular with the advent of cannabis therapies. A study was designed to further validate the models after oral ingestion of THC, and to determine whether they could predict last usage after multiple oral doses. Eighteen subjects in IRB-approved studies participated after providing informed consent. Each of 12 subjects in one group received a single 10 mg oral dose of dronabinol (synthetic THC). In another protocol, 6 subjects received 4 different oral daily doses, divided into thirds and administered with meals for 5 consecutive days. There was a 10-day washout period between each dosing regimen. Daily doses were 0.39, 0.47, and 14.8 mg THC in hemp oil and 7.5 mg dronabinol. Blood specimens were collected throughout the study and analyzed for plasma THC and 11-nor-9-carboxy-Delta(9)-tetrahydrocannbinol by gas chromatography/mass spectrometry with limits of quantification (LOQs) of 0.5 and 1.0 ng/mL, respectively. Actual times between ingestion of THC and blood collection spanned 0.5 to 16 hours. All plasma specimens with analyte concentrations > LOQ (n = 90) were evaluated. Models I and 2 correctly predicted time of last THC ingestion for 74.4% and 90.0% of plasma specimens, respectively. 96.7% of predicted times were correct with one overestimate and 2 underestimates using the time interval defined by the lowest and highest 95% confidence limit of both models. These results provide further evidence of the usefulness of the predictive models in estimating the time of last oral THC ingestion after single or multiple doses. C1 NIDA, Intramural Res Program, NIH, Baltimore, MD USA. USN, Drug Screening Lab, Jacksonville, FL USA. ElSohly Labs, Oxford, MS USA. Off AF Med Examiner, Div Forens Toxicol, Rockville, MD USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, Baltimore, MD USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS NR 21 TC 24 Z9 25 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD AUG PY 2006 VL 28 IS 4 BP 540 EP 544 DI 10.1097/00007691-200608000-00009 PG 5 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 071HD UT WOS:000239589300009 PM 16885722 ER PT J AU Goodivin, RS Gustafson, RA Barnes, A Nebro, W Moolchan, ET Huestis, MA AF Goodivin, Robert S. Gustafson, Richard A. Barnes, Allan Nebro, Wesenyalsh Moolchan, Eric T. Huestis, Marilyn A. TI Delta(9)-Tetrahydrocannabinol, 11-hydroxy-Delta(9)-tetrahydrocannabinol and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol in human plasma after controlled oral administration of cannabinoids SO THERAPEUTIC DRUG MONITORING LA English DT Article DE oral administration; tetrahydrocannabinol; cannabinoids; plasma; GC/MS; hemp oil ID RANDOMIZED CONTROLLED-TRIAL; EXCRETION HALF-LIFE; MEDICINAL EXTRACTS; NEUROPATHIC PAIN; MARIJUANA USERS; FOOD-PRODUCTS; GC-MS; DELTA-9-TETRAHYDROCANNABINOL; URINE; CONSUMPTION AB A clinical study to investigate the pharmacokinetics and pharmacodynamics of oral tetrahydrocannabinol was performed. This randomized, double-blind, placebo-con trolled, within-subject, inpatient study compared the effects of THC-containing hemp oils in liquid and capsule form to dronabinol (synthetic THC) in doses used for appetite stimulation. The National Institute on Drug Abuse Institutional Review Board approved the protocol and each participant provided informed consent. Detection times and concentrations of THC, 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC), and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THCCOOH) in plasma were determined by gas chromatography-mass spectrometry [limits of quantification (LOQ)=0.5, 0.5, and 1.0 ng/mL, respectively] after oral THC administration. Six volunteers ingested liquid hemp oil (0.39 and 14.8 mg THC/d), hemp oil in capsules (0.47 mg THC/d), dronabinol capsules (7.5 mg THC/d), and placebo. Plasma specimens were collected during and after each dosing condition. THC and 11-OH-THC concentrations were low and never exceeded 6.1 ng/mL. Analytes were detectable 1.5 hour after initiating dosing with the 7.5 mg THC/d regimen and 4.5 hour after starting the 14.8 mg THC/d sessions. THCCOOH was detected 1.5 hour after the first dose, except for the 0.47 mg THC/d session, which required 4.5 hour for concentrations to reach the LOQ. THCCOOH concentrations peaked at 3.1 ng/mL during dosing with the low-dose hemp oils. Plasma THC and 11-OH-THC concentrations were negative for all participants at all doses within 15.5 hours after the last THC dose. Plasma THCCOOH persisted for at least 39.5 hours after the end of dosing and at much higher concentrations (up to 43.0 ng/mL). This study demonstrated that subjects who used high THC content hemp oil (347 mu g/mL) as a dietary supplement had THC and metabolites in plasma in quantities comparable to those of patients using dronabinol for appetite stimulation. There was a significant correlation between body mass index and C-max and body mass index and number of specimens positive for THC and 11-OH-THC. C1 NIDA, Chem & Drug Metab Sect, IRP, NIH, Baltimore, MD 21224 USA. Def Threat Reduct Agcy, Kirtland AFB, NM 87117 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS NR 38 TC 22 Z9 23 U1 3 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD AUG PY 2006 VL 28 IS 4 BP 545 EP 551 DI 10.1097/00007691-200608000-00010 PG 7 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 071HD UT WOS:000239589300010 PM 16885723 ER PT J AU Cunningham, ML AF Cunningham, Michael L. TI Putting the fun into functional toxicogenomics SO TOXICOLOGICAL SCIENCES LA English DT Editorial Material ID TOXICOLOGY C1 Natl Inst Environm Sci, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Cunningham, ML (reprint author), Natl Inst Environm Sci, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. EM cunning1@niehs.nih.gov NR 9 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD AUG PY 2006 VL 92 IS 2 BP 347 EP 348 DI 10.1093/toxsci/kfl027 PG 2 WC Toxicology SC Toxicology GA 061XN UT WOS:000238907300001 PM 16883652 ER PT J AU Grieshaber, SS Grieshaber, NA Miller, N Hackstadt, T AF Grieshaber, Scott S. Grieshaber, Nicole A. Miller, Natalie Hackstadt, Ted TI Chlamydia trachomatis causes centrosomal defects resulting in chromosomal segregation abnormalities SO TRAFFIC LA English DT Article DE centrosome; Chlamydia; cytoskeleton; micro-tubules ID INVASIVE CERVICAL-CANCER; OUTER-MEMBRANE PROTEIN; INCLUSION MEMBRANE; COXIELLA-BURNETII; MICRONUCLEUS TEST; INFECTED-CELLS; RISK-FACTOR; INSTABILITY; MITOSIS; IDENTIFICATION AB Chlamydiae traffic along microtubules to the microtubule organizing center (MTOC) to establish an intracellular niche within the host cell. Trafficking to the MTOC is dynein dependent although the activating and cargo-linking function of the dynactin complex is supplanted by unknown chlamydial protein(s). We demonstrate that once localized to the MTOC, the chlamydial inclusion maintains a tight association with cellular centrosomes. This association is sustained through mitosis and leads to a significant increase in supernumerary centrosomes, abnormal spindle poles, and chromosomal segregation defects. Chlamydial infection thus can lead to chromosome instability in cells that recover from infection. C1 NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. EM ted_hackstadt@nih.gov FU Intramural NIH HHS NR 47 TC 39 Z9 39 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-9219 J9 TRAFFIC JI Traffic PD AUG PY 2006 VL 7 IS 8 BP 940 EP 949 DI 10.1111/j.1600-0854.2006.00439.x PG 10 WC Cell Biology SC Cell Biology GA 061SZ UT WOS:000238894200002 PM 16882039 ER PT J AU Snyder, MD Pierce, SK AF Snyder, Michelle D. Pierce, Susan K. TI A mutation in Epstein-Barr virus LMP2A reveals a role for phospholipase D in B-cell antigen receptor trafficking SO TRAFFIC LA English DT Article DE antigen processing; antigen receptors; endocytosis; Epstein-Barr virus; latent membrane protein 2A; phosphatidic acid; phospholipase D; signal transduction ID MHC CLASS-II; MEDIATED SIGNAL-TRANSDUCTION; LYMPHOCYTE ADAPTER MOLECULE; RESONANCE ENERGY-TRANSFER; EPIDERMAL GROWTH-FACTOR; FC-GAMMA-RI; PHOSPHATIDIC-ACID; LIPID RAFTS; IG-ALPHA; ACTIN CYTOSKELETON AB Epstein-Barr virus (EBV) latent infection of B cells blocks the interrelated signaling and antigen-trafficking functions of the BCR through the activity of its latent membrane protein 2A (LMP2A). At present, the molecular mechanisms by which LMP2A exerts its control of BCR functions are only poorly understood. Earlier studies showed that in B cells expressing LMP2A containing a tyrosine mutation at position 112 in its cytoplasmic domain (Y112-LMP2A), the BCR could initiate signaling but could not properly traffic antigen for processing. Here, we show that BCR signaling in Y112-LMP2A-expressing cells is attenuated with a reduction in both the degree and duration of phosphorylation of key components of the BCR signaling cascade including Syk, BLNK, PI3K, and Btk. Notably, Y112-LMP2A expression completely blocked the BCR-induced activation of phospholipase D (PLD), a lipase implicated in the intracellular trafficking of a variety of surface receptors. We show that blocking PLD activity, by expressing Y112-LMP2A, treating cells with the PLD inhibitor 1-butanol or reducing PLD expression by siRNA, blocked BCR trafficking to class II-containing compartments. Moreover, Y112-LMP2A expression blocked the recruitment of phosphorylated forms of the downstream BCR signaling components, Erk and JNK, through both PLD-dependent and PLD-independent mechanisms. Thus, the investigation of the mechanism by which Y112-LMP2A blocks BCR function revealed an essential role for PLD in BCR trafficking for antigen processing. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM spierce@nih.gov FU Intramural NIH HHS NR 88 TC 8 Z9 8 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-9219 J9 TRAFFIC JI Traffic PD AUG PY 2006 VL 7 IS 8 BP 993 EP 1006 DI 10.1111/j.1600-0854.2006.00450.x PG 14 WC Cell Biology SC Cell Biology GA 061SZ UT WOS:000238894200006 PM 16882041 ER PT J AU Polishchuk, RS San Pietro, E Di Pentima, A Tete, S Bonifacino, JS AF Polishchuk, Roman S. San Pietro, Enrica Di Pentima, Alessio Tete, Stefano Bonifacino, Juan S. TI Ultrastructure of long-range transport carriers moving from the trans-Golgi network to peripheral endosomes SO TRAFFIC LA English DT Article DE clathrin; endosomes; GGAs; long-range transport carriers; TGN ID MANNOSE 6-PHOSPHATE RECEPTORS; IMMATURE SECRETORY GRANULES; COATED VESICLES; PLASMA-MEMBRANE; ENDOPLASMIC-RETICULUM; ELECTRON-MICROSCOPY; AP-1 COMPLEX; LIVING CELLS; CLATHRIN; PROTEIN AB The delivery of mannose 6-phosphate receptors carrying lysosomal hydrolases from the trans-Golgi network (TGN) to the endosomal system is mediated by selective incorporation of the receptor-hydrolase complexes into vesicular transport carriers (TCs) that are coated with clathrin and the adaptor proteins, GGA and AP-1. Previous electron microscopy (EM) and biochemical studies have shown that these TCs consist of spherical coated vesicles with a diameter of 60-100 nm. The use of fluorescent live cell imaging, however, has revealed that at least some of this transport relies on a subset of apparently larger and highly pleiomorphic carriers that detach from the TGN and translocate toward the peripheral cytoplasm until they meet with distally located endosomes. The ultrastructure of such long-range TCs has remained obscure because of the inability to examine by conventional EM the morphological details of rapidly moving organelles. The recent development of correlative light-EM has now allowed us to obtain ultrastructural 'snapshots' of these TCs immediately after their formation from the TGN in live cells. This approach has revealed that such carriers range from typical 60- to 100-nm clathrin-coated vesicles to larger, convoluted tubular-vesicular structures displaying several coated buds. We propose that this subset of TCs serve as vehicles for long-range distribution of biosynthetic or recycling cargo from the TGN to the peripheral endosomes. C1 Consorzio Mario Negri Sud, Dept Cell Biol & Oncol, I-66030 Santa Maria Imbaro, Chieti, Italy. Univ G DAnnunzio, Dept Oral Sci, I-66013 Chieti, Italy. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Polishchuk, RS (reprint author), Consorzio Mario Negri Sud, Dept Cell Biol & Oncol, I-66030 Santa Maria Imbaro, Chieti, Italy. EM polish@dcbo.negrisud.it OI Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural NIH HHS; Telethon [GGP05044] NR 29 TC 36 Z9 38 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-9219 J9 TRAFFIC JI Traffic PD AUG PY 2006 VL 7 IS 8 BP 1092 EP 1103 DI 10.1111/j.1600-0854.2006.00453.x PG 12 WC Cell Biology SC Cell Biology GA 061SZ UT WOS:000238894200013 PM 16787435 ER PT J AU Haddad, SA Lichtiger, B Klein, HG AF Haddad, Salim A. Lichtiger, Benjamin Klein, Harvey G. TI In vivo efficacy of shipped HLA-matched platelets SO TRANSFUSION LA English DT Article ID ALLOIMMUNIZED THROMBOCYTOPENIC PATIENTS; REFRACTORY PATIENTS; STORAGE; TRANSFUSION; TEMPERATURE; AGITATION; TRANSPORTATION; SELECTION; VIABILITY; QUALITY AB Background: Platelet (PLT) concentrates are currently stored in an incubator at 20 to 24 degrees C with continuous gentle agitation. PLTs are routinely shipped for transfusion to thrombocytopenic patients, however. There is a concern that PLT concentrates may be adversely affected during the shipping process. Case Report: A 40-year-old woman with severe aplastic anemia and immune refractory to unselected PLT transfusions was transferred to a distant medical center for a hematopoietic peripheral blood progenitor cell transplant where she continued to receive HLA-matched PLTs from her dedicated donors. Sixteen such components were collected and air-shipped in insulated boxes to the transplant center. Thirty-seven platelet-pheresis components from the same dedicated donors had been transfused to the patient before transfer. Corrected count increments (CCIs) at the two sites were compared, with assessment of the role of HLA-match grades. The mean interruption time of controlled agitation during shipment was approximately 10.5 hours. The mean CCI of all distant transfusions was 14,450 +/- 9700 PLTs per mu L(.)m(2) per 10(11) and that of local transfusions was 10730 +/- 4870. The mean donor-paired difference between CCIs at the two sites was 1140 +/- 9940. At the remote location no clinically significant bleeding occurred and one posttransfusion febrile reaction was noted. Conclusion: Despite the study limitations, the effectiveness, in a single patient, of leukoreduced, irradiated apheresis PLTs shipped by lengthy combined surface and airline transport is reported, as measured by posttransfusion CCIs. C1 Warren G Magnuson Clin Ctr, Dept Transfus Med, NIH, Bethesda, MD USA. Univ Texas, MD Anderson Canc Ctr, Dept Lab Med, Houston, TX USA. RP Haddad, SA (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Blood Res & Review, Div Hematol,Lab Cellular Hematol, 1401 Rockville Pike,HFM 335, Rockville, MD 20852 USA. EM salim.haddad@fda.hhs.gov NR 24 TC 4 Z9 6 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD AUG PY 2006 VL 46 IS 8 BP 1306 EP 1310 DI 10.1111/j.1537-2995.2006.00896.x PG 5 WC Hematology SC Hematology GA 066VZ UT WOS:000239259800009 PM 16934064 ER PT J AU Yewdell, JW Nicchitta, CV AF Yewdell, Jonathan W. Nicchitta, Christopher V. TI The DRiP hypothesis decennial: support, controversy, refinement and extension SO TRENDS IN IMMUNOLOGY LA English DT Review ID MHC CLASS-I; MAJOR HISTOCOMPATIBILITY COMPLEX; DEFECTIVE RIBOSOMAL PRODUCTS; ANTIGEN-PROCESSING PATHWAY; MESSENGER-RNA SURVEILLANCE; NEWLY SYNTHESIZED PROTEINS; CYTOTOXIC LYMPHOCYTES-T; EXON-JUNCTION COMPLEX; ENDOPLASMIC-RETICULUM; MAMMALIAN-CELLS AB In 1996, to explain the rapid presentation of viral proteins to CD8(+) T cells, it was proposed that peptides presented by MHC class I molecules derive from defective ribosomal products (DRiPs), presumed to be polypeptides arising from in-frame translation that fail to achieve native structure owing to inevitable imperfections in transcription, translation, post-translational modifications or protein folding. Here, we consider findings that address the DRiP hypothesis, and extend the hypothesis by proposing that cells possess specialized machinery, possibly in the form of 'immunoribosomes', to couple protein synthesis to antigen presentation. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM JYEWDELL@niaid.nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 FU Intramural NIH HHS; NIDDK NIH HHS [DK 053058, DK 47897] NR 46 TC 127 Z9 128 U1 2 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD AUG PY 2006 VL 27 IS 8 BP 368 EP 373 DI 10.1016/j.it.2006.06.008 PG 6 WC Immunology SC Immunology GA 076TS UT WOS:000239981300005 PM 16815756 ER PT J AU Longo, NS Lipsky, PE AF Longo, Nancy S. Lipsky, Peter E. TI Why do B cells mutate their immunoglobulin receptors? SO TRENDS IN IMMUNOLOGY LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODIES; AMINO-ACID SUBSTITUTIONS; HEAVY-CHAIN GENES; IMMUNE-RESPONSE; SOMATIC MUTATION; GERMINAL-CENTERS; HYPERVARIABLE REGIONS; AFFINITY MATURATION; ANTIGEN AB B cells have the unique ability to acquire large numbers of point mutations in the variable segment of rearranged immunoglobulin (Ig) genes during a germinal center reaction. It is broadly accepted that somatic hypermutation (SHM) and affinity maturation are required to generate memory B cells and to produce antibodies capable of accomplishing the host defense functions of the humoral component of the adaptive immune system. However, several studies illustrate that low-avidity interactions between antigen and the B-cell receptor can induce deletion, receptor editing and a T-dependent immune response, suggesting that the high-avidity binding of antigen is not essential. If enhanced antigen binding is not essential for immune responses, what is the purpose of SHM? An alternative benefit of SHM might be to enhance the ability of B cells to track antigens expressed by rapidly mutating microorganisms. C1 NIAMS, Repertoire Anal Grp, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Lipsky, PE (reprint author), NIAMS, Repertoire Anal Grp, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. EM lipskyp@mail.nih.gov FU Intramural NIH HHS NR 58 TC 18 Z9 18 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD AUG PY 2006 VL 27 IS 8 BP 374 EP 380 DI 10.1016/j.it.2006.06.007 PG 7 WC Immunology SC Immunology GA 076TS UT WOS:000239981300006 PM 16809065 ER PT J AU Walker, LC LeVine, H Mattson, MP Jucker, M AF Walker, Lary C. LeVine, Harry, III Mattson, Mark P. Jucker, Mathias TI Inducible proteoplathies SO TRENDS IN NEUROSCIENCES LA English DT Review ID SOLUBLE AMYLOID OLIGOMERS; MOUSE SENILE AMYLOIDOSIS; ALZHEIMERS-DISEASE BRAIN; PROTEIN-TRANSGENIC MICE; OXIDATIVE STRESS; PRION PROTEIN; NEURODEGENERATIVE DISEASES; ALPHA-SYNUCLEIN; BETA OLIGOMERS; FIBRILS AB Numerous degenerative diseases are characterized by the aberrant polymerization and accumulation of specific proteins. These proteopathies include neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and the prion diseases, in addition to diverse systemic disorders, particularly the amyloidoses. The prion diseases have been shown to be transmissible by an alternative conformation of the normal cellular prion protein. Other proteopathies have been thought to be non-transmissible, but there is growing evidence that some systemic and cerebral amyloidoses can be induced by exposure of susceptible hosts to cognate molecular templates. As we review here, the mechanistic similarities among these diseases provide unprecedented opportunities for elucidating the induction of protein misfolding and assembly in vivo, and for developing an integrated therapeutic approach to degenerative proteopathies. C1 Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. Univ Kentucky, Sanders Brown Ctr Aging, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA. NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. Univ Tubingen, Dept Cellular Neurol, Hertie Inst Clin Brain Res, D-72076 Tubingen, Germany. RP Walker, LC (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. EM lary.walker@emory.edu RI Mattson, Mark/F-6038-2012; Walker, L/J-6541-2015 OI Walker, L/0000-0001-9166-3261 FU NCRR NIH HHS [RR 00165] NR 86 TC 61 Z9 63 U1 0 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD AUG PY 2006 VL 29 IS 8 BP 438 EP 443 DI 10.1016/j.tins.2006.06.010 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 079NU UT WOS:000240184400002 PM 16806508 ER PT J AU Pinsky, PF Kramer, BS Crawford, ED Grubb, RL Urban, DA Andriole, GL Chia, D Levin, DL Gohagan, JK AF Pinsky, Paul F. Kramer, Barnett S. Crawford, E. David Grubb, Robert L. Urban, Donald A. Andriole, Gerald L. Chia, David Levin, David L. Gohagan, John K. TI Prostate volume and prostate-specific antigen levels in men enrolled in a large screening trial SO UROLOGY LA English DT Article ID DIGITAL RECTAL EXAMINATION; TRANSRECTAL ULTRASOUND; CANCER; AGE; HYPERPLASIA; VALIDITY; KRIMPEN; BIOPSY AB Objectives. Prostate volume correlates both with prostate-specific antigen (PSA) values and with the presence of benign prostatic hyperplasia (BPH). Here we examine the relationship between prostate volume and PSA level in a large, geographically diverse sample of men undergoing prostate cancer screening. Methods. We followed 35,323 men enrolled in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Each man was screened with digital rectal examination (DRE) and PSA levels for up to 4 years. Prostate volume was estimated by DRE performed by trained examiners at the PLCO sites. Linear and logistic regression was used to assess the effect of prostate volume and age on PSA levels. Regression coefficients were adjusted for the effect of prostate volume measurement error. Results. Prostate volume estimated by DRE showed considerable measurement error. Averaging volume over screening visits and accounting for examiner bias greatly reduced this error. Linear regression analysis showed a slope of 0.030/cm(3) of log PSA on prostate volume when correcting for measurement error (95% confidence interval [CI], 0.029 to 0.031). Age was independently associated with (log) PSA, with a slope of 0.022 per year. Logistic regression analysis of the risk of having an elevated PSA value (exceeding 4 ng/mL) showed an odds ratio of 1.9 (95% CI, 1.8 to 2.0) associated with a 10 cm(3) increase in prostate volume. The correlation of log PSA and prostate volume was 0.37. Prostate volume was not correlated with body mass index and showed weak correlation (r = 0.14) with age. Conclusions. Prostate volume and age are independently associated with increased PSA levels in a population of men undergoing screening. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NIH, Off Dis Prevent, Bethesda, MD 20892 USA. Univ Colorado Hlth Sci, Denver, CO USA. Washington Univ, Sch Med, St Louis, MO USA. Univ Alabama, Birmingham, AL USA. Univ Calif Los Angeles, Dept Pathol, Los Angeles, CA 90024 USA. RP Pinsky, PF (reprint author), 6130 Execut Blvd,EPN 3064, Bethesda, MD 20892 USA. EM pp4f@nih.gov NR 16 TC 20 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD AUG PY 2006 VL 68 IS 2 BP 352 EP 356 DI 10.1016/j.urology.2006.02.026 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 084WT UT WOS:000240565800027 PM 16904451 ER PT J AU Shia, JR Chen, W Tang, LH Carlson, DL Qin, J Guillem, JG Nobrega, J Wong, WD Klimstra, DS AF Shia, Jinru Chen, Wen Tang, Laura H. Carlson, Diane L. Qin, Jin Guillem, Jose G. Nobrega, Jennifer Wong, W. Douglas Klimstra, David S. TI Extranodal follicular dendritic cell sarcoma: clinical, pathologic, and histogenetic characteristics of an underrecognized disease entity SO VIRCHOWS ARCHIV LA English DT Article DE sarcomas; literature review; reticulum cell; extranodal; dendritic cell ID EPSTEIN-BARR-VIRUS; HYALINE-VASCULAR TYPE; OF-THE-LITERATURE; INFLAMMATORY PSEUDOTUMOR; CASTLEMANS-DISEASE; RETICULUM CELLS; TUMOR; EXPRESSION; PROLIFERATION; LIVER AB It has been more than 10 years since follicular dendritic cell (FDC) sarcoma was first reported to occur in extranodal sites, yet extranodal FDC sarcoma still appears underrecognized, and its clinical and pathological characteristics remain to be defined. This study analyzed the clinical and pathological findings of three such cases that the authors encountered recently and 43 previously reported cases identified in the literature. Assessment of all 46 cases showed a slight female predominance (1.2:1) with a median age of 41.5 years. One-third of the cases were misdiagnosed at initial evaluation mainly because the possibility of FDC sarcoma was not considered. When considered, this disease had distinct pathological characteristics that allowed an accurate diagnosis. Staining for FDC markers, CD21, CD35, and clusterin was particularly helpful. The pathogenesis of the disease appeared heterogeneous, and associated factors included Epstein-Barr virus infection (in hepatic cases) and inflammatory pseudotumor-like conditions. Treatment modality varied widely although surgical resection was often included. With a median follow-up of 18 months, 43% of the cases recurred and 7% died of disease. The 5-year recurrence-free survival was 27.4%. From data available at the current time, we were not able to identify prognostically significant pathologic factors. C1 Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. RP Klimstra, DS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. EM Klimstrd@mskcc.org OI Shia, Jinru/0000-0002-4351-2511 NR 45 TC 48 Z9 61 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD AUG PY 2006 VL 449 IS 2 BP 148 EP 158 DI 10.1007/s00428-006-0231-4 PG 11 WC Pathology SC Pathology GA 078LI UT WOS:000240103900002 PM 16758173 ER PT J AU Peng, H Yang, LT Wang, LY Li, J Huang, J Lu, ZQ Koup, RA Bailer, RT Wu, CY AF Peng, Hui Yang, Li-Tao Wang, Ling-yun Li, Jian Huang, Jun Lu, Zhi-qiang Koup, Richard A. Bailer, Robert T. Wu, Chang-you TI Long-lived memory T lymphocyte responses against SARS coronavirus nucleocapsid protein in SARS-recovered patients SO VIROLOGY LA English DT Article DE severe acute respiratory syndrome (SARS); N protein; memory T cells; epitope ID ACUTE RESPIRATORY SYNDROME; INFECTIOUS-BRONCHITIS VIRUS; IMMUNE-RESPONSES; LETHAL INFECTION; CELL RESPONSES; DNA VACCINE; IDENTIFICATION; INDUCTION; EFFECTOR; ANTIGEN AB The nucleocapsid (N) protein is a structural component of severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and can induce antibody responses in SARS patients during infection. However, it is not known whether SARS-CoV N protein can induce a long persistence of memory T-cell response in human. In this study, we found that peripheral blood mononuclear cells (PBMCs) from fully recovered SARS individuals rapidly produced IFN-gamma and IL-2 following stimulation with a pool of overlapping peptides that cover the entire N protein sequence. The N-specific IFN-gamma(+)CD4(+) T cells were mainly composed of CD45RA(-)CCR7(+)CD62L(-) cells, whereas IFN-gamma(+)CD8(+) memory T cells were mostly contained within CD45RA(+)CCR7(-)CD62L(-) cell population. Epitope mapping study indicated that a cluster of overlapping peptides located in the C-terminal region (amino acids [aa] 331 to 362) of N protein contained at least two different T-cell epitopes. The results indicated that human memory T-cell responses specific for SARS-CoV N protein could persist for 2 years in the absence of antigen, which would be a valuable for the design of effective vaccines against SARS-CoV and for basic studies of human T-cell memory. (c) 2006 Elsevier Inc. All rights reserved. C1 Sun Yat Sen Univ, Dept Immunol, Zhongshan Med Sch, Guangzhou 510089, Peoples R China. Sun Yat Sen Univ, Dept Digest Dis, Affiliated Hosp 2, Guangzhou 510020, Peoples R China. Guangdong Prov Hosp Tradit Chinese Med, Dept Cardiol, Guangzhou 510020, Peoples R China. Sun Yat Sen Univ, Affiliated Hosp 2, Dept Resp Dis, Guangzhou 510020, Peoples R China. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Wu, CY (reprint author), Sun Yat Sen Univ, Dept Immunol, Zhongshan Med Sch, 74 Zhongshan Rd 2, Guangzhou 510089, Peoples R China. EM changyou_wu@yahoo.com NR 41 TC 35 Z9 35 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD AUG 1 PY 2006 VL 351 IS 2 BP 466 EP 475 DI 10.1016/j.virol.2006.03.036 PG 10 WC Virology SC Virology GA 072CF UT WOS:000239649500020 PM 16690096 ER PT J AU Beecken, WD Engl, T Engels, K Blumenberg, C Oppermann, E Camphausen, K Shing, Y Reinecke, G Jonas, D Blaheta, R AF Beecken, Wolf-D. Engl, Tobias Engels, Knut Blumenberg, Christa Oppermann, Elsie Camphausen, Kevin Shing, Yuen Reinecke, Gerd Jonas, Dietger Blaheta, Roman TI Clinical relevance of maspin expression in bladder cancer SO WORLD JOURNAL OF UROLOGY LA English DT Article DE maspin; angiogenesis; bladder cancer; tumor progression ID TUMOR; ANGIOGENESIS; CARCINOMA; GROWTH; LINES; CELLS AB Transitional cell carcinoma (TCC) of the bladder is a solid tumor that induces angiogenesis to maintain nutrition and oxygenation of tumor cells. Maspin, a serpin with tumor suppressing activity, has recently been identified as an inhibitor of angiogenesis. This study examined the impact of maspin expression in the growth pattern of TCC of the bladder. Maspin was identified in a panel of normal tissues, in several bladder carcinoma cell lines, and 51 patient samples of TCC of the bladder. Expression was detected by RT-PCR and immunohistochemistry. Furthermore, the level of maspin was correlated to the growth rate of bladder tumor cell lines in vitro and in vivo. Maspin expression was found in high quantities in normal urothelium. Maspin expression was preserved in superficial bladder cancers but was significantly diminished in invasive carcinomas. Within the group of invasive TCCs, maspin expression was inversely correlated to the patient prognosis. Furthermore, low maspin expression level was coupled to an increased tumor cell growth in vivo. Down-regulation of maspin expression seems to be a specific event in the progression of invasive bladder carcinoma. Maspin might be a useful marker to determine the prognosis of invasive TCC. Furthermore, maspin re-expression might become a therapeutic option in the treatment of invasive, metastatic TCC. C1 JW Goethe Univ, Klin Urol & Kinderurol, D-60590 Frankfurt, Germany. Univ Frankfurt, Senckenbergisches Inst Pathol, D-60590 Frankfurt, Germany. NCI, Radiat Oncol Branch, Bethesda, MD USA. Harvard Univ, Sch Med, Childrens Hosp, Vasc Biol Program, Boston, MA USA. RP Beecken, WD (reprint author), JW Goethe Univ, Klin Urol & Kinderurol, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. EM beecken@em.uni-frankfurt.de NR 15 TC 19 Z9 22 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0724-4983 J9 WORLD J UROL JI World J. Urol. PD AUG PY 2006 VL 24 IS 3 BP 338 EP 344 DI 10.1007/s00345-006-0085-z PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 067RA UT WOS:000239319100017 PM 16832651 ER PT J AU Edskes, HK Naglieri, BM Wickner, RB AF Edskes, Herman K. Naglieri, Benedetta M. Wickner, Reed B. TI Nitrogen source and the retrograde signalling pathway affect detection, not generation, of the [URE3] prion SO YEAST LA English DT Article DE prion; glutamate; MKS1; [URE3]; Ure2p; Dal5p; RTG3 ID SACCHAROMYCES-CEREVISIAE; TOR PROTEINS; GUANIDINE-HYDROCHLORIDE; NUCLEAR-LOCALIZATION; GENE-EXPRESSION; IN-VITRO; YEAST; HSP104; MUTATION; MKS1P AB [URE3] is an infectious (prion) inactive amyloid form of Ure2p, a regulator of nitrogen catabolism. [URE3] clones are selected on NH4+, using their derepressed expression of DAL5 to allow uptake of ureidosuccinate (USA). We previously reported that mks1 Delta prevents generation of [URE3] and others reported that glutamate in the medium or the elevated glutarnate in mks1 Delta strains blocks [URE3] generation. We show here that elevated glutamate does not block [URE3] generation, but that neither does mks1 Delta. Rather, a post-transcriptional effect on DAL5 of mks] A through the retrograde regulation pathway prevents detection of [URE3] prion-containing colonies. Moreover, the presence of both ammonia and glutamate blocks USA uptake. a known [URE3] strain, so that detection of the prion is prevented, rather than its generation. Copyright (c) 2006 John Mliley & Sons, Ltd. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU Intramural NIH HHS NR 32 TC 3 Z9 3 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD AUG PY 2006 VL 23 IS 11 BP 833 EP 840 DI 10.1002/yea.1398 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 088WQ UT WOS:000240842200006 PM 16921555 ER PT J AU Tomihara, K Kaitsuka, T Soga, T Korach, KS Pfaff, DW Takahama, K Ogawa, S AF Tomihara, Kazuya Kaitsuka, Taku Soga, Tomoko Korach, Kenneth S. Pfaff, Donald W. Takahama, Kazuo Ogawa, Sonoko TI Abolition of sex-dependent effects of prenatal exposure to diethylstilbestrol on emotional behavior in estrogen receptor-alpha knockout mice SO NEUROREPORT LA English DT Article DE emotion; estrogenic endocrine disrupters; knockout mouse; light-dark transition test; open-field test ID IN-UTERO EXPOSURE; BISPHENOL-A; REPRODUCTIVE FUNCTION; RATS; CHEMICALS; MOUSE; DIFFERENTIATION; FETAL; FIELD; BETA AB To investigate the contribution of estrogen receptor-alpha in the effects of prenatal exposure to diethylstilnbestreol on emotionality, estrogen receptor-alpha knockout heterozygous pregnant mice were orally 0.1 mu g/animal of diethylstilbestrol from gestational day 11 to 17. Emotional behavior of the offspring was assesses at 5 weeks in light-dark transition tests. Time spent in the light area was significantly decreased (i.e. decrease of emotionality) by diethylstilbestrol exposure in wild-type female mice, whereas in wild-type male mice this measurement tended to be increased (i.e. increase of emotionality) by diethylstilbestrol treatment. These sex-dependent effects of diethylstilbestrol were completely abolished in estrogen receptor-alpha knockout mice. These results suggest that the sex-dependent effects of diethylstilbestrol on emotionality are mainly produced by its action on estrogen receptor-alpha. C1 Univ Tsukuba, Kansei & Cognit Brain Sci, Grad Sch Comprehens Human Sci, Lab Behav Neuroendocrinol, Tsukuba, Ibaraki 3058577, Japan. Kagoshima Univ, Dept Psychol, Fac Law Econ & Humanities, Kagoshima 890, Japan. Kumamoto Univ, Grad Sch Pharmacol Sci, Dept Environm & Mol Hlth Sci, Kumamoto, Japan. Rockefeller Univ, Neurobiol & Behav Lab, New York, NY 10021 USA. Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC USA. RP Ogawa, S (reprint author), Univ Tsukuba, Kansei & Cognit Brain Sci, Grad Sch Comprehens Human Sci, Lab Behav Neuroendocrinol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058577, Japan. EM ogawa@mail.rockefeller.edu OI Korach, Kenneth/0000-0002-7765-418X FU NIMH NIH HHS [MH-62147] NR 18 TC 3 Z9 3 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 31 PY 2006 VL 17 IS 11 BP 1169 EP 1173 DI 10.1097/01.wnr.0000224771.82151.77 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 072JB UT WOS:000239668600018 PM 16837848 ER PT J AU Schaefer, M Heinze, HJ Rotte, M AF Schaefer, Michael Heinze, Hans-Jochen Rotte, Michael TI Verbal memory encoding in patients with left-sided hippocampal sclerosis SO NEUROREPORT LA English DT Article DE epilepsy; functional magnetic resonance imaging; hippocampus; subsequent memory effect; temporal lobe; verbal memory ID TEMPORAL-LOBE EPILEPSY; FUNCTIONAL MRI; LATERALIZATION; ACTIVATION; CORTEX AB Patients with medial temporal lobe epilepsy based on left hippocampal sclerosis often show severe verbal memory deficits. Recent studies suggest that memory formation in these patients may be reallocated to the right hemisphere owing to left hippocampal pathology. To test this hypothesis, we used functional magnetic resonance imaging to examine encoding-related activity of verbal items in temporal lobe epilepsy patients with left hippocampal sclerosis and patients with idiopathic epilepsy as a control group. Results demonstrated that patients with idiopathic epilepsy showed more activation in both left and right hippocampi. The temporal lobe epilepsy group showed enhanced activation in left fusiform gyrus. We discuss these results in terms of different strategy use by the groups. C1 NINDS, Human Cortical Physiol Sect, NIH, Bethesda, MD 20892 USA. Otto Von Guericke Univ, Dept Neurol 2, Magdeburg, Germany. RP Schaefer, M (reprint author), NINDS, Human Cortical Physiol Sect, NIH, Bldg 10,Room 5N-234, Bethesda, MD 20892 USA. EM mischa@neuro2.med.uni-magdeburg.de NR 20 TC 3 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 31 PY 2006 VL 17 IS 11 BP 1219 EP 1223 DI 10.1097/01.wnr.0000223389.28834.19 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 072JB UT WOS:000239668600028 PM 16837858 ER PT J AU Nair, SG Gray, SM Ghitza, UE AF Nair, S. G. Gray, S. M. Ghitza, U. E. TI Role of food type in yohimbine- and pellet-priming-induced reinstatement of food seeking SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE carbohydrate; fiber; palatable food; stress; sucrose; relapse; reinstatement; yohimbine ID STRESS-INDUCED REINSTATEMENT; COCAINE-SEEKING; NORADRENERGIC MECHANISMS; ALCOHOL SEEKING; INDUCED RELAPSE; ANIMAL-MODEL; DRUG; NEUROBIOLOGY; ANXIETY; RATS AB We have recently adapted a reinstatement model, commonly used to study relapse to drugs of abuse, to study the role of stress and anxiety in relapse to palatable food seeking [Ghitza LJE, Gray SM, Epstein DH, Rice KC, Shaham Y. The anxiogenic drug yohimbine reinstates palatable food seeking in a rat relapse model: a role of CRF(1) receptors. Neuropsychopharmacology [in press]]. We found that the anxiogenic drug yohimbine, as well as pellet-priming, reinstate food seeking in food restricted rats previously trained to lever press for palatable food pellets (25% fat, 48% carbohydrate). Here, we studied the generality of the effect of yohimbine and pellet priming on reinstatement of food seeking by using three distinct pellet types: non-sucrose carbohydrate (NSC) (5.5% fat, 60% carbohydrate, 4.5% fiber), fiber (0% fat, 0% carbohydrate, 91% fiber) and sucrose (0% fat, 91% carbohydrate, 4% fiber). Rats were placed on a restricted diet (75-80% of daily standard food) and for 9-12 intermittent training days (9 h/day, every other day) lever-pressed for the food pellets under a fixed ratio-1 (20-s timeout) reinforcement schedule. Subsequently, the rats were given 9-10 daily extinction sessions during which lever-presses were not reinforced, and were then injected with yohimbine (0, 0.5, 1.0, 2.0 mg/kg, i.p.) or given a single food pellet to induce reinstatement of food seeking. Yohimbine reinstated food seeking previously reinforced by NSC and sucrose pellets, but had a minimal effect on food seeking in rats previously trained to lever press for fiber pellets. Pellet priming produced a greater degree of reinstatement of lever pressing in rats previously trained on NSC pellets than in rats trained on fiber or sucrose pellets. Results suggest that the magnitude of the effect of yohimbine and pellet priming on reinstatement of food seeking depends in part on the composition of the food pellets used during training. Published by Elsevier Inc. C1 NIH, Behav Neurosci Branch, IRP, NIDA,DHHS, Baltimore, MD 21224 USA. RP Ghitza, UE (reprint author), NIH, Behav Neurosci Branch, IRP, NIDA,DHHS, Baltimore, MD 21224 USA. EM ghitzau@intra.nida.nih.gov FU Intramural NIH HHS; NIDA NIH HHS [Z01 DA000434-06] NR 40 TC 31 Z9 31 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD JUL 30 PY 2006 VL 88 IS 4-5 BP 559 EP 566 DI 10.1016/j.physbeh.2006.05.014 PG 8 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 075BL UT WOS:000239857100035 PM 16806322 ER PT J AU Chattopadhyay, MK Tabor, CW Tabor, H AF Chattopadhyay, Manas K. Tabor, Celia White Tabor, Herbert TI Polyamine deficiency leads to accumulation of reactive oxygen species in a spe2 Delta mutant of Saccharomyces cerevisiae SO YEAST LA English DT Article DE apoptosis; polyamines; reactive oxygen species; spermidine; spermine; yeast ID OXIDATIVE STRESS; CELL-DEATH; ESCHERICHIA-COLI; SUPEROXIDE DISMUTASE; MEDIATED APOPTOSIS; DNA-REPLICATION; SINGLET OXYGEN; YEAST; SPERMINE; PATHWAY AB We have previously shown that polyamine-deficient Saccharomyces cerevisiae are very sensitive to incubation in oxygen. The current studies show that, even under more physiological conditions (i.e. growth in air), polyamine-deficient cells accumulate reactive oxygen species (ROS). These cells develop an apoptotic phenotype and, after incubation in polyamine-deficient medium, die. To show a specific effect of polyamines on ROS accumulation, uncomplicated by any effects on growth, spermine was added to spermidine-deficient spe2 Delta fms1 Delta cells, since spermine does not affect the growth of this strain. In this strain, spermine addition caused a marked, but not complete, decrease in the accumulation of ROS and a moderate protection against cell death. In other experiments with polyamine-deficient cells containing plasmids that overexpress superoxide dismutases (SOD1, SOD2), ROS decreased but with only a partial protection against cell death. Polyamine-deficient cells incubated anaerobically show markedly less cell death. These data show that part of the function of polyamines is protection of the cells from accumulation of ROS. Copyright (c) 2006 John Wiley & Sons, Ltd. C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Tabor, H (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Room 223, Bethesda, MD 20892 USA. EM tabor@helix.nih.gov FU Intramural NIH HHS NR 47 TC 34 Z9 36 U1 0 U2 8 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD JUL 30 PY 2006 VL 23 IS 10 BP 751 EP 761 DI 10.1002/yea.1393 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 076UH UT WOS:000239982900004 PM 16862607 ER PT J AU Wise, RA AF Wise, Roy A. TI Role of brain dopamine in food reward and reinforcement SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE food; reward; reinforcement; dopamine ID NUCLEUS-ACCUMBENS DOPAMINE; VENTRAL TEGMENTAL AREA; PIMOZIDE-INDUCED EXTINCTION; VITAMIN-DEFICIENT RATS; TASTE REACTIVITY; COCAINE REINFORCEMENT; SELF-STIMULATION; HEDONIC IMPACT; EXTRACELLULAR DOPAMINE; ANHEDONIA HYPOTHESIS AB The ability of food to establish and maintain response habits and conditioned preferences depends largely on the function of brain dopamine systems. While dopaminergic transmission in the nucleus accumbens appears sufficient for some forms of reward, the role of dopamine in food reward does not appear to be restricted to this region. Dopamine plays an important role in both the ability to energize feeding and to reinforce food-seeking behaviour; the role in energizing feeding is secondary to the prerequisite role in reinforcement. Dopaminergic activation is triggered by the auditory and visual as well as the tactile, olfactory, and gustatory stimuli of foods. While dopamine plays a central role in the feeding and food-seeking of normal animals, some food rewarded learning can be seen in genetically engineered dopamine-deficient mice. C1 NIDA, Intramural Res Program, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Wise, RA (reprint author), NIDA, Intramural Res Program, Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rwise@intra.nida.nih.gov RI Wise, Roy/A-6465-2012 FU Intramural NIH HHS NR 137 TC 179 Z9 185 U1 7 U2 30 PU ROYAL SOCIETY PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD JUL 29 PY 2006 VL 361 IS 1471 BP 1149 EP 1158 DI 10.1098/rstb.2006.1854 PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 066OX UT WOS:000239240400007 PM 16874930 ER PT J AU Michishita, E Garces, G Barrett, JC Horikawa, I AF Michishita, Eriko Garces, Giannina Barrett, J. Carl Horikawa, Izumi TI Upregulation of the KIAA 1199 gene is associated with cellular mortality SO CANCER LETTERS LA English DT Article DE cellular senescence; cDNA subtraction; cancer; immortalization ID SENESCENCE; TELOMERASE; CELLS; IMMORTALIZATION; HYBRIDIZATION; ACTIVATION; MECHANISMS; CANCER; HTERT; LOCUS AB The microcell-mediated transfer of a normal human chromosome 3 induces replicative senescence in otherwise immortal renal cell carcinoma cells. To identify the genes involved in the chromosome 3-induced cellular mortality, we previously performed a cDNA subtraction experiment using the immortal renal cell carcinoma cells (RCC23) and the mortal counterpart with the transferred chromosome 3 (RCC23 + 3). We here report the cDNA cloning and characterization of one of the differentially expressed genes, which encodes KIAA1199 protein of unknown function. Northern blot and RT-PCR analyses revealed striking upregulation of KIAA1199 mRNA in mortal RCC23+3 compared with immortal RCC23. However, no significant change in KIAA1199 mRNA expression was observed during replicative aging in vitro (from early passage culture to senescent culture) of mortal human cells including RCC23 + 3, normal fibroblasts and prostate epithelial cells. Interestingly, an immortal fibroblast cell line and two breast cancer cell lines expressed much lower amounts of KIAA1199 mRNA than their normal counterparts. KIAA1199 mRNA is expressed in a wide range of normal human tissues, with the highest level of expression in brain. The gene is located on chromosome band 15q25, where a brain tumor suppressor gene has been mapped. These findings suggest that KIAA1199 gene may play a role in cellular mortality of normal human cells, which counters cell immortalization and carcinogenesis. Published by Elsevier Ireland Ltd. C1 NCI, Lab Biosyst & Canc, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Horikawa, I (reprint author), NCI, Lab Biosyst & Canc, NIH, 9000 Rockville Pike,Bldg 37,Rm 5046,MSC-4264, Bethesda, MD 20892 USA. EM horikawi@mail.nih.gov FU Intramural NIH HHS NR 16 TC 25 Z9 28 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JUL 28 PY 2006 VL 239 IS 1 BP 71 EP 77 DI 10.1016/j.canlet.2005.07.028 PG 7 WC Oncology SC Oncology GA 070VM UT WOS:000239553500009 PM 16157444 ER PT J AU Abramova, MV Pospelova, TV Nikulenkov, FP Hollander, CM Fornace, AJ Pospelov, VA AF Abramova, Maria V. Pospelova, Tatiana V. Nikulenkov, Fedor P. Hollander, Christine M. Fornace, Albert J., Jr. Pospelov, Valery A. TI G(1)/S arrest induced by histone deacetylase inhibitor sodium butyrate in E1A+Ras-transformed cells is mediated through down-regulation of E2F activity and stabilization of beta-catenin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COLORECTAL-CANCER; CARCINOMA-CELLS; ACETYLTRANSFERASE ACTIVITY; TRANSCRIPTIONAL REPRESSOR; DEPENDENT TRANSCRIPTION; TRANSFORMED-CELLS; COLON-CANCER; PATHWAY; APOPTOSIS; ACTIVATION AB Tumor cells are often characterized by a high and growth factor-independent proliferation rate. We have previously shown that REF cells transformed with oncogenes E1A and c-Ha-Ras do not undergo G(1)/S arrest of the cell cycle after treatment with genotoxic factors. In this work, we used sodium butyrate, a histone deacetylase inhibitor, to show that E1A + Ras transformants were able to stop proliferation and undergo G(1)/S arrest. Apart from inducing G1/S arrest, sodium butyrate was shown to change expression of a number of cell cycle regulatory genes. It down-regulated cyclins D1, E, andAas well as c-myc and cdc25A and up-regulated the cyclin-kinase inhibitor p21(waf1). Accordingly, activities of cyclin E-Cdk2 and cyclin A-Cdk2 complexes in sodium butyrate-treated cells were decreased substantially. Strikingly, E2F1 expression was also down-modulated at the levels of gene transcription, the protein content, and the E2F transactivating capability. To further study the role of p21waf1 in the sodium butyrate-induced G(1)/S arrest and the E2F1 down-modulation, we established E1A + Ras transformants from mouse embryo fibroblast cells with deletion of the cdkn1a ( p21waf1) gene. Despite the absence of p21(waf1), sodium butyrate-treated mERas transformants reveal a slightly delayed G(1)/S arrest as well as down-modulation of E2F1 activity, implying that the observed effects are mediated through an alternative p21(waf1)-independent signaling pathway. Subsequent analysis showed that sodium butyrate induced accumulation of beta-catenin, a downstream component of the Wnt signaling. The results obtained indicate that the antiproliferative effect of histone deacetylase inhibitors on E1A + Ras-transformed cells can be mediated, alongside other mechanisms, through down-regulation of E2F activity and stabilization of beta-catenin. C1 Russian Acad Sci, Inst Cytol, St Petersburg 194064, Russia. NCI, Gene Response Unit, NIH, Bethesda, MD 20892 USA. RP Pospelov, VA (reprint author), Russian Acad Sci, Inst Cytol, St Petersburg 194064, Russia. EM Pospelov_v@mail.ru RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X FU PHS HHS [G-3-00-336] NR 55 TC 35 Z9 38 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 28 PY 2006 VL 281 IS 30 BP 21040 EP 21051 DI 10.1074/jbc.M511059200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 065VF UT WOS:000239187300041 PM 16717102 ER PT J AU Liu, HG Tang, JR Choi, YH Napolitano, M Hockman, S Taira, M Degerman, E Manganiello, VC AF Liu, Hanguan Tang, Jing Rong Choi, Young Hun Napolitano, Maria Hockman, Steven Taira, Masato Degerman, Eva Manganiello, Vincent C. TI Importance of cAMP-response element-binding protein in regulation of expression of the murine cyclic nucleotide phosphodiesterase 3B (Pde3b) gene in differentiating 3T3-L1 preadipocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADIPOCYTE DIFFERENTIATION; TRANSCRIPTIONAL ACTIVATION; CARDIOMYOCYTE APOPTOSIS; INSULIN-SECRETION; ADIPOSE-TISSUE; FACTOR CREB; PROMOTER; CELL; AMP; ADIPOGENESIS AB Incubation of 3T3-L1 preadipocytes with isobutylmethylxanthine (IBMX), dexamethasone, and insulin, alone or in combination, demonstrated that IBMX, which increased cAMP-response element-binding protein (CREB) phosphorylation, was the predominant regulator of Pde3b expression. Real time PCR and immunoblotting indicated that in 3T3-L1 preadipocytes, IBMX-stimulated induction of Pde3b mRNA and protein was markedly inhibited by dominant-negative CREB proteins. By transfecting preadipocytes, differentiating preadipocytes, and HEK293A cells with luciferase reporter vectors containing different fragments of the 5'- flanking region of the Pde3b gene, we identified a distal promoter that contained canonical cis-acting cAMP-response elements (CRE) and a proximal, GC-rich promoter region, which contained atypical CRE. Mutation of the CRE sequences dramatically reduced distal promoter activity; H89 inhibited IBMX-stimulated CREB phosphorylation and proximal and distal promoter activities. Distal promoter activity was stimulated by IBMX and phorbol ester (PMA) in Raw264.7 monocytes, but only by IBMX in 3T3-L1 preadipocytes. Chromatin immunoprecipitation analyses with specific antibodies against CREB, phospho-CREB, and CBP/p300 (CREB-binding protein) showed that these proteins associated with both distal and proximal promoters and that interaction of phospho-CREB, the active form of CREB, with both Pde3b promoter regions was increased in IBMX-treated preadipocytes. These results indicate that CRE in distal and proximal promoter regions and activation of CREB proteins play a crucial role in transcriptional regulation of Pde3b expression during preadipocyte differentiation. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. Lund Univ, Dept Cell & Mol Biol, Sect Mol Signaling, S-22100 Lund, Sweden. RP Manganiello, VC (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Rm 5N307,10 Ctr Dr, Bethesda, MD 20892 USA. EM manganiv@nhlbi.nih.gov NR 63 TC 5 Z9 7 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 JUL 28 PY 2006 VL 281 IS 30 BP 21096 EP 21113 DI 10.1074/jbc.M601307200 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 065VF UT WOS:000239187300046 PM 16702214 ER PT J AU Hoashi, T Muller, J Vieira, WD Rouzaud, F Kikuchi, K Tamaki, K Hearing, VJ AF Hoashi, Toshihiko Muller, Jacqueline Vieira, Wilfred D. Rouzaud, Francois Kikuchi, Kanako Tamaki, Kunihiko Hearing, Vincent J. TI The repeat domain of the melanosomal matrix protein PMEL17/GP100 is required for the formation of organellar fibers SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HERMANSKY-PUDLAK-SYNDROME; MONOCLONAL-ANTIBODY; PLASMINOGEN-ACTIVATOR; MELANOCYTE LINEAGE; SILVER LOCUS; CELLS; IDENTIFICATION; GLYCOPROTEIN; TYROSINASE; GP100 AB Over 125 pigmentation-related genes have been identified to date. Of those, PMEL17/GP100 has been widely studied as a melanoma-specific antigen as well as a protein required for the formation of fibrils in melanosomes. PMEL17 is synthesized, glycosylated, processed, and delivered to melanosomes, allowing them to mature from amorphous round vesicles to elongated fibrillar structures. In contrast to other melanosomal proteins such as TYR and TYRP1, the processing and sorting of PMEL17 is highly complex. Monoclonal antibody HMB45 is commonly used for melanoma detection, but has the added advantage that it specifically reacts with sialylated PMEL17 in the fibrillar matrix in melanosomes. In this study, we generated mutant forms of PMEL17 to clarify the subdomain of PMEL17 required for formation of the fibrillar matrix, a process critical to pigmentation. The internal proline/serine/threonine-rich repeat domain (called the RPT domain) of PMEL17 undergoes variable proteolytic cleavage. Deletion of the RPT domain abolished its recognition by HMB45 and its capacity to form fibrils. Truncation of the C-terminal domain did not significantly affect the processing or trafficking of PMEL17, but, in contrast, deletion of the N-terminal domain abrogated both. We conclude that the RPT domain is essential for its function in generating the fibrillar matrix of melanosomes and that the luminal domain is necessary for its correct processing and trafficking to those organelles. C1 Tokai Univ, Fac Med, Dept Dermatol, Tokyo 1138655, Japan. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. US FDA, Div Viral Prod, Rockville, MD 20852 USA. RP Hoashi, T (reprint author), Tokai Univ, Fac Med, Dept Dermatol, Tokyo 1138655, Japan. EM thoashi-tky@umin.ac.jp; hearingv@nih.gov FU Intramural NIH HHS NR 52 TC 64 Z9 67 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 28 PY 2006 VL 281 IS 30 BP 21198 EP 21208 DI 10.1074/jbc.M601643200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 065VF UT WOS:000239187300055 PM 16682408 ER PT J AU Kim, BJ Ryu, SW Song, BJ AF Kim, Bong-Jo Ryu, Seung-Wook Song, Byoung-Joon TI JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYTOCHROME-C RELEASE; BCL-2 PROTEIN FAMILY; SELECTIVE ACTIVATION; NEURONAL APOPTOSIS; CANCER CELLS; KINASE-C; DEATH; PATHWAY; ALPHA; LOCALIZATION AB Mitochondrial translocation of pro-apoptotic Bax prior to apoptosis is well established after treatment with many cell death stimulants or under apoptosis-inducing conditions. The mechanism of mitochondrial translocation of Bax is, however, still unknown. The aim of this work was to investigate the mechanism of Bax activation and mitochondrial translocation to initiate apoptosis of human hepatoma HepG2 and porcine kidney LLC-PK1 cells exposed to various cell death agonists. Phosphorylation of Bax by JNK and p38 kinase activated after treatment with staurosporine, H2O2, etoposide, and UV light was demonstrated by the shift in the pI value of Bax on two-dimensional gels and confirmed by metabolic labeling with inorganic [P-32] phosphate in HepG2 cells. Specific inhibitors of JNK and p38 kinase significantly inhibited Bax phosphorylation and mitochondrial translocation and apoptosis of HepG2 cells. A specific small interfering RNA to MAPKK4 (the upstream protein kinase of JNK and p38 kinase) markedly decreased the levels of MAPKK4 and MAPKK3/6, blocked the activation of JNK or p38 kinase, and inhibited Bax phosphorylation. However, the negative control small interfering RNA did not cause these changes. Confocal microscopy of various Bax mutants showed differential rates of mitochondrial translocation of Bax before and after staurosporine treatment. Among the Bax mutants, T167D did not translocate to mitochondria after staurosporine exposure, suggesting that Thr(167) is a potential phosphorylation site. In conclusion, our results demonstrate, for the first time, that Bax is phosphorylated by stress-activated JNK and/or p38 kinase and that phosphorylation of Bax leads to mitochondrial translocation prior to apoptosis. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, Biochem Sect, NIH, Bethesda, MD 20892 USA. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bjs@mail.nih.gov FU Intramural NIH HHS NR 59 TC 249 Z9 260 U1 0 U2 20 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 JUL 28 PY 2006 VL 281 IS 30 BP 21256 EP 21265 DI 10.1074/jbc.M510644200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 065VF UT WOS:000239187300061 PM 16709574 ER PT J AU De Chiara, G Marcocci, ME Torcia, M Lucibello, M Rosini, P Bonini, P Higashimoto, Y Damonte, G Armirotti, A Amodei, S Palamara, AT Russo, T Garaci, E Cozzolino, F AF De Chiara, Giovanna Marcocci, Maria Elena Torcia, Maria Lucibello, Maria Rosini, Paolo Bonini, Paolo Higashimoto, Yukiro Damonte, Gianluca Armirotti, Andrea Amodei, Sarah Palamara, Anna Teresa Russo, Tommaso Garaci, Enrico Cozzolino, Federico TI Bcl-2 phosphorylation by p38 MAPK - Identification of target sites and biologic consequences SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; B-CELL LINE; INDUCED APOPTOSIS; CARDIAC MYOCYTES; C-JUN; POLYACRYLAMIDE-GELS; FAMILY PROTEINS; DNA-DAMAGE; DEATH; BCL-X(L) AB The antiapoptotic role of Bcl-2 can be regulated by its phosphorylation in serine and threonine residues located in a nonstructured loop that links BH3 and BH4 domains. p38 MAPK has been identified as one of the kinases able to mediate such phosphorylation, through direct interaction with Bcl-2 protein in the mitochondrial compartment. In this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, Ser(87) and Thr(56) as the Bcl-2 residues phosphorylated by p38 MAPK and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of Bcl-2 protein. Furthermore, we obtained evidence that p38 MAPK-induced Bcl-2 phosphorylation plays a key role in the early events following serum deprivation in embryonic fibroblasts. Both cytochrome c release and caspase activation triggered by p38 MAPK activation and Bcl-2 phosphorylation are absent in embryonic fibroblasts from p38 alpha knock-out mice (p38 alpha(-/-) MEF), whereas they occur within 12 h of serum withdrawal in p38 alpha(-/-) MEF; moreover, they can be prevented by p38 MAPK inhibitors and are not associated with the synthesis of the proapoptotic proteins Bax and Fas. Thus, Bcl-2 phosphorylation by activated p38 MAPK is a key event in the early induction of apoptosis under conditions of cellular stress. C1 Ist Super Sanita, Dept Cell Biol & Neurosci, I-00161 Rome, Italy. Univ Roma Tor Vergata, Dipartimento Matemat, Dept Expt Med & Biochem Sci, I-00133 Rome, Italy. Univ Florence, Dept Clin Physiopathol, I-50139 Florence, Italy. CNR, Inst Neurobiol & Mol Med, I-00133 Rome, Italy. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Genoa, Ctr Excellence Biomed Res, Mass Spectrometry Facil, DIMES Biochem Sect, I-16132 Genoa, Italy. Univ Roma La Sapienza, Dept Publ Hlth Sci G Sanarelli, I-00185 Rome, Italy. Univ Naples Federico II, CEINGE Biotecnol Avanzate, Dept Biochem & Med Biotechnol, I-80131 Naples, Italy. RP De Chiara, G (reprint author), Ist Super Sanita, Dept Cell Biol & Neurosci, Viale Regina Elena 299, I-00161 Rome, Italy. EM dechiara@uniroma2.it; f.cozzolino@dfc.unifi.it RI Torcia, Maria/F-8408-2010; Russo, Tommaso/K-1331-2016; OI Russo, Tommaso/0000-0003-4426-0106; DE CHIARA, GIOVANNA/0000-0002-2219-6097; Marcocci, Maria Elena/0000-0003-4751-4263; Torcia, Maria/0000-0003-4740-4646 NR 44 TC 102 Z9 104 U1 0 U2 7 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 JUL 28 PY 2006 VL 281 IS 30 BP 21353 EP 21361 DI 10.1074/jbc.M511052200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 065VF UT WOS:000239187300071 PM 16714293 ER PT J AU Bobay, BG Mueller, GA Thompson, RJ Murzin, AG Venters, RA Strauch, MA Cavanagh, J AF Bobay, Benjamin G. Mueller, Geoffrey A. Thompson, Richele J. Murzin, Alexey G. Venters, Ronald A. Strauch, Mark A. Cavanagh, John TI NMR structure of AbhN and comparison with AbrBN - First insights into the DNA binding promiscuity and specificity of AbrB-like transition state regulator proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRIPLE RESONANCE EXPERIMENTS; BACILLUS-SUBTILIS; GENE-EXPRESSION; CLOSTRIDIUM-ACETOBUTYLICUM; TRANSCRIPTIONAL ANALYSIS; SEQUENTIAL ASSIGNMENT; SPORULATION; RECOGNITION; ANTHRACIS; DOMAIN AB Understanding the molecular mechanisms of transition state regulator proteins is critical, since they play a pivotal role in the ability of bacteria to cope with changing environments. Although much effort has focused on their genetic characterization, little is known about their structural and functional conservation. Here we present the high resolution NMR solution structure of the N-terminal domain of the Bacillus subtilis transition state regulator Abh (AbhN), only the second such structure to date. We then compare AbhN to the N-terminal DNA-binding domain of B. subtilis AbrB (AbrBN). This is the first such comparison between two AbrB-like transition state regulators. AbhN and AbrBN are very similar, suggesting a common structural basis for their DNA binding. However, we also note subtle variances between the AbhN and AbrBN structures, which may play important roles in DNA target specificity. The results of accompanying in vitro DNA-binding studies serve to highlight binding differences between the two proteins. C1 N Carolina State Univ, Dept Mol & Struct Biochem, Raleigh, NC 27695 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. MRC, Ctr Prot Engn, Cambridge CB2 2QH, England. Duke Univ, NMR Ctr, Durham, NC 27710 USA. Univ Maryland, Sch Dent, Dept Biomed Sci, Baltimore, MD 21201 USA. RP Cavanagh, J (reprint author), N Carolina State Univ, Dept Mol & Struct Biochem, Raleigh, NC 27695 USA. EM john_cavanagh@ncsu.edu OI Bobay, Benjamin/0000-0003-4775-3686 FU Intramural NIH HHS [Z99 ES999999]; Medical Research Council [MC_U105192716]; NIGMS NIH HHS [R01 GM055769, GM46700, GM55769, R01 GM046700] NR 62 TC 18 Z9 18 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 JUL 28 PY 2006 VL 281 IS 30 BP 21399 EP 21409 DI 10.1074/jbc.M601963200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 065VF UT WOS:000239187300076 PM 16702211 ER PT J AU Honda, H Pazin, MJ Ji, H Wernyj, RP Morin, PJ AF Honda, Hiroshi Pazin, Michael J. Ji, Hongxiu Wernyj, Roman P. Morin, Patrice J. TI Crucial roles of Sp1 and epigenetic modifications in the regulation of the CLDN4 promoter in ovarian cancer cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CLOSTRIDIUM-PERFRINGENS ENTEROTOXIN; TIGHT JUNCTION PROTEINS; GENE-EXPRESSION; TRANSCRIPTIONAL ACTIVATION; POTENTIAL MARKERS; EPITHELIAL-CELLS; BARRIER FUNCTION; CLAUDIN-4; METHYLATION; CHROMATIN AB Claudins form a large family of tight junction proteins that have essential roles in the control of paracellular ion flux and the maintenance of cell polarity. Many studies have shown that several claudin family members are abnormally expressed in various cancers. In particular, CLDN4 ( encoding claudin-4) is overexpressed in ovarian cancer. However, although CLDN4 overexpression is well established, the mechanisms responsible for this abnormal regulation remain unknown. In the present study, we delineate a small region of the CLDN4 promoter critical for its expression. This region contains two Sp1 sites, both of which are required for promoter activity. However, because of the ubiquitous expression of Sp1, these sites, although necessary, are not sufficient to explain the patterns of gene expression of CLDN4 in various ovarian tissues. We show that the CLDN4 promoter is further controlled by epigenetic modifications of the Sp1-containing critical promoter region. Cells that overexpress CLDN4 exhibit low DNA methylation and high histone H3 acetylation of the critical CLDN4 promoter region, and the reverse is observed in cells that do not express CLDN4. Moreover, the CLDN4-negative cells can be induced to express CLDN4 through treatment with demethylating and/or acetylating agents. Because CLDN4 is elevated in a large fraction of ovarian cancer, the mechanism leading to deregulation may represent a general pathway in ovarian tumorigenesis and may lead to novel strategies for therapy and an overall better understanding of the biology of this disease. C1 NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. RP Morin, PJ (reprint author), NIA, Cellular & Mol Biol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM morinp@grc.nia.nih.gov OI Pazin, Michael/0000-0002-7561-3640 FU Intramural NIH HHS [ZIA AG000377-02] NR 36 TC 82 Z9 85 U1 0 U2 5 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 JUL 28 PY 2006 VL 281 IS 30 BP 21433 EP 21444 DI 10.1074/jbc.M603767200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 065VF UT WOS:000239187300079 PM 16714763 ER PT J AU Protchenko, O Rodriguez-Suarez, R Androphy, R Bussey, H Philpott, CC AF Protchenko, Olga Rodriguez-Suarez, Roberto Androphy, Rachel Bussey, Howard Philpott, Caroline C. TI A screen for genes of heme uptake identifies the FLC family required for import of FAD into the endoplasmic reticulum SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN DISULFIDE-ISOMERASE; GPI-ANCHORED PROTEINS; SACCHAROMYCES-CEREVISIAE; CANDIDA-ALBICANS; GOLGI-APPARATUS; STAPHYLOCOCCUS-AUREUS; SHIGELLA-DYSENTERIAE; BOND FORMATION; IRON-SOURCE; YEAST AB Although Candida albicans and Saccharomyces cerevisiae express very similar systems of iron uptake, these species differ in their capacity to use heme as a nutritional iron source. Whereas C. albicans efficiently takes up heme, S. cerevisiae grows poorly on media containing heme as the sole source of iron. We identified a gene from C. albicans that would enhance heme uptake when expressed in S. cerevisiae. Overexpression of CaFLC1 ( for flavin carrier 1) stimulated the growth of S. cerevisiae on media containing heme iron. In C. albicans, deletion of both alleles of CaFLC1 resulted in a decrease in heme uptake activity, whereas overexpression of CaFLC1 resulted in an increase in heme uptake. The S. cerevisiae genome contains three genes with homology to CaFLC1, and two of these, termed FLC1 and FLC2, also stimulated growth on heme when overexpressed in S. cerevisiae. The S. cerevisiae Flc proteins were detected in the endoplasmic reticulum and the FLC genes encoded an essential function, as strains deleted for either FLC1 or FLC2 were viable, but deletion of both FLC1 and FLC2 was synthetically lethal. FLC gene deletion resulted in pleiotropic phenotypes related to defects in cell wall integrity. High copy suppressors of this synthetic lethality included three mannosyl-transferases, VAN1, KTR4, and HOC1. FLC deletion strains exhibited loss of cell wall mannose phosphates, defects in cell wall assembly, and delayed maturation of carboxypeptidase Y. Permeabilized cells lacking FLC proteins exhibited dramatic loss of FAD import activity. We propose that the FLC genes are required for import of FAD into the lumen of the endoplasmic reticulum, where it is required for disulfide bond formation. C1 NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. McGill Univ, Dept Biol, Montreal, PQ H3A 1B1, Canada. RP Philpott, CC (reprint author), Bldg 10,Rm 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM carolinep@intra.niddk.nih.gov FU Intramural NIH HHS NR 73 TC 33 Z9 40 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 JUL 28 PY 2006 VL 281 IS 30 BP 21445 EP 21457 DI 10.1074/jbc.M512812200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 065VF UT WOS:000239187300080 PM 16717099 ER PT J AU Hu, JX Jiang, JK Costanzi, S Thomas, C Yang, W Feyen, JHM Jacobson, KA Spiegel, AM AF Hu, Jianxin Jiang, Jiankang Costanzi, Stefano Thomas, Craig Yang, Wu Feyen, Jean H. M. Jacobson, Kenneth A. Spiegel, Allen M. TI A missense mutation in the seven-transmembrane domain of the human Ca2+ receptor converts a negative allosteric modulator into a positive allosteric modulator SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; CA2+-SENSING RECEPTOR; ANTAGONIST; ACTIVATION; RHODOPSIN; AGONIST AB G protein-coupled receptors (GPCRs) are the most common targets of drug action. Allosteric modulators bind to the seven-transmembrane domain of family 3 GPCRs and offer enhanced selectivity over orthosteric ligands that bind to the large extracellular N terminus. We characterize a novel negative allosteric modulator of the human Ca2+ receptor, Compound 1, that retains activity against the E837A mutant that lacks a response to previously described positive and negative modulators. A related compound, JKJ05, acts as a negative allosteric modulator on the wild type receptor but as a positive modulator on the E837A mutant receptor. This positive modulation critically depends on the primary amine in JKJ05, which appears to interact with acidic residue Glu(767) in our model of the seven-transmembrane domain of the receptor. Our results suggest the need for identification of possible genetic variation in the allosteric site of therapeutically targeted GPCRs. C1 NIDCD, Mol Pathophysiol Sect, NIH, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Computat Quantum Core Lab, NIH, Bethesda, MD 20892 USA. Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ 08543 USA. RP Hu, JX (reprint author), NIDCD, Mol Pathophysiol Sect, NIH, Bldg 10,Rm 8C-101,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jianxinh@intra.niddk.nih.gov RI Jacobson, Kenneth/A-1530-2009; Costanzi, Stefano/G-8990-2013; OI Jacobson, Kenneth/0000-0001-8104-1493; Costanzi, Stefano/0000-0003-3183-7332 FU Intramural NIH HHS NR 20 TC 30 Z9 31 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 28 PY 2006 VL 281 IS 30 BP 21558 EP 21565 DI 10.1074/jbc.M603682200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 065VF UT WOS:000239187300090 PM 16735501 ER PT J AU Ju, JH Maeng, JS Zemedkun, M Ahronovitz, N Mack, JW Ferretti, JA Gelmann, EP Gruschus, JM AF Ju, Jeong Ho Maeng, Jin-Soo Zemedkun, Micheas Ahronovitz, Natalie Mack, James W. Ferretti, James A. Gelmann, Edward P. Gruschus, James M. TI Physical and functional interactions between the prostate suppressor homeoprotein NKX3.1 and serum response factor SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE NKX3.1; serum response factor; homeodomain; prostate cancer; transcription ID VND/NK-2 HOMEODOMAIN; DNA-BINDING; GENE-EXPRESSION; BACKBONE ASSIGNMENT; SECONDARY STRUCTURE; CRYSTAL-STRUCTURE; NK-2 HOMEODOMAIN; HOMEOBOX GENES; PROTEIN; CANCER AB The NKX3.1 transcription factor is an NK family homeodomain protein and a tumor suppressor gene that is haploinsufficient and down-regulated in the early phases of prostate cancer. Like its cardiac homolog, NKX2.5, NKX3.1 acts synergistically with serum response factor (SRF) to activate expression from the smooth muscle gamma-actin (SMGA) gene promoter. Using NMR spectroscopy, three conserved motifs in a construct containing the N-terminal region and homeodomain of NKX3.1 were observed to interact with the MADS box domain of SRF. These motifs interacted both in the absence of DNA and when both proteins were bound to a SMGA promoter DNA sequence. No significant interaction was seen between the homeodomain and SRF MADS box. One of the SRF-interacting regions was the tinman (TN) or engrailed homology-1 motif (EH-1), residues 29-35 (FLIQDIL), which for other NK proteins is the site of interaction with the repressor protein Groucho. A second hydrophobic interacting region was designated the SRF-interacting (SI) motif and included residues 99-105 (LGSYLLD). A third interacting motif was the acidic region adjacent to the SI motif including residues 88-96 (ETLAETEPE). The acidic domain (AD) motif signals also showed strengthening upon the NKX3.1 homeodomain binding to DNA in the absence of SRF, consistent with the acidic region weakly interacting with the homeodomain in the unbound state. The importance of these linear motifs in the transcriptional interaction of NKX3.1 and SRF was demonstrated by targeted mutagenesis of an NKX3.1 expression vector in a SMGA reporter assay. The results implicate the NKX3.1 N-terminal region in regulation of transcriptional activity of this tumor suppressor. (c) 2006 Elsevier Ltd. All rights reserved. C1 Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC 20059 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gelmann, EP (reprint author), Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, 3800 Reservoir Rd,NW, Washington, DC 20007 USA. EM gelmanne@georgetown.edu FU NCRR NIH HHS [G12RR00348]; NIEHS NIH HHS [ES09888] NR 47 TC 13 Z9 13 U1 0 U2 0 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 JUL 28 PY 2006 VL 360 IS 5 BP 989 EP 999 DI 10.1016/j.jmb.2006.05.064 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 072JR UT WOS:000239670200007 PM 16814806 ER PT J AU Magg, C Kubelka, J Holtermann, G Haas, E Schmid, FX AF Magg, Christine Kubelka, Jan Holtermann, Georg Haas, Elisha Schmid, Franz X. TI Specificity of the initial collapse in the folding of the cold shock protein SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein folding; fluorescence energy transfer; folding intermediates; folding kinetics; intra-molecular distances ID X-RAY-SCATTERING; RESONANCE ENERGY-TRANSFER; SINGLE-MOLECULE; UNFOLDED PROTEINS; INTRAMOLECULAR DISTANCES; PREFERENTIAL HYDRATION; CRYSTAL-STRUCTURE; TRANSITION-STATE; POLYPROLINE-II; EARLY EVENTS AB The two-state folding reaction of the cold shock protein from Bacillus caldolyticus (Bc-Csp) is preceded by a rapid chain collapse. A fast shortening of intra-protein distances was revealed by Forster resonance energy transfer (FRET) measurements with protein variants that carried individual pairs of donor and acceptor chromophores at various positions along the polypeptide chain. Here we investigated the specificity of this rapid compaction. Energy transfer experiments that probed the stretching of strand 2 and the close approach between the strands beta 1 and beta 2 revealed that the beta 1-beta 2 hairpin is barely formed in the collapsed form, although it is native-like in the folding transition state of Bc-Csp. The time course of the collapse could not be resolved by pressure or temperature jump experiments, indicating that the collapsed and extended forms are not separated by an energy barrier. The co-solute (NH4)(2)SO4 stabilizes both native Bc-Csp and the collapsed form, which suggests that the large hydrated SO42- ions are excluded from the surface of the collapsed form in a similar fashion as they are excluded from folded Bc-Csp. Ethylene glycol increases the stability of proteins because it is excluded preferentially from the backbone, which is accessible in the unfolded state. The collapsed form of Bc-Csp resembles the unfolded form in its interaction with ethylene glycol, suggesting that in the collapsed form the backbone is still accessible to water and small molecules. Our results thus rule out that the collapsed form is a folding intermediate with native-like chain topology. It is better described as a mixture of compact conformations that belong to the unfolded state ensemble. However, some of its structural elements are reminiscent of the native protein. (c) 2006 Elsevier Ltd. All rights reserved. C1 Univ Bayreuth, Biochem Lab, D-95440 Bayreuth, Germany. Univ Bayreuth, Bayreuther Zentrum Mol Biowissensch, D-95440 Bayreuth, Germany. NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. Max Planck Inst Mol Physiol, Phys Chem Abt, D-44227 Dortmund, Germany. Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. RP Schmid, FX (reprint author), Univ Bayreuth, Biochem Lab, POB 101251, D-95440 Bayreuth, Germany. EM fx.schmid@uni-bayreuth.de NR 65 TC 41 Z9 41 U1 0 U2 5 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 JUL 28 PY 2006 VL 360 IS 5 BP 1067 EP 1080 DI 10.1016/j.jmb.2006.05.073 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 072JR UT WOS:000239670200013 PM 16815441 ER PT J AU Fauci, AS AF Fauci, Anthony S. TI Twenty-five years of HIV/AIDS SO SCIENCE LA English DT Editorial Material C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 22 Z9 24 U1 0 U2 1 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 JUL 28 PY 2006 VL 313 IS 5786 BP 409 EP 409 DI 10.1126/science.1131993 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 067MZ UT WOS:000239308600001 PM 16873613 ER PT J AU Landi, MT Bauer, J Pfeiffer, RM Elder, DE Hulley, B Minghetti, P Calista, D Kanetsky, PA Pinkel, D Bastian, BC AF Landi, Maria Teresa Bauer, Juergen Pfeiffer, Ruth M. Elder, David E. Hulley, Benjamin Minghetti, Paola Calista, Donato Kanetsky, Peter A. Pinkel, Daniel Bastian, Boris C. TI MC1R germline variants confer risk for BRAF-mutant melanoma SO SCIENCE LA English DT Article ID MELANOCORTIN-1 RECEPTOR MC1R; CUTANEOUS MELANOMA; PIGMENTATION; MELANOCYTES; POPULATION; RADIATION; COLOR AB Germline variants in MC1R, the gene encoding the melanocortin-1 receptor, and sun exposure increase risk for melanoma in Caucasians. The majority of melanomas that occur on skin with little evidence of chronic sun-induced damage (non-CSD melanoma) have mutations in the BRAF oncogene, whereas in melanomas on skin with marked CSD ( CSD melanoma) these mutations are less frequent. In two independent Caucasian populations, we show that MC1R variants are strongly associated with BRAF mutations in non-CSD melanomas. In this tumor subtype, the risk for melanoma associated with MC1R is due to an increase in risk of developing melanomas with BRAF mutations. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. Univ Tubingen, Dept Dermatol, D-72076 Tubingen, Germany. Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Osped Gen Provinciale M Bufalini, Dept Dermatol, I-47023 Cesena, Italy. Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Landi, MT (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; Bauer, Jurgen/B-4656-2008 OI Bauer, Jurgen/0000-0001-8789-1536 FU NCI NIH HHS [P01 CA025874-25-A1, R01 CA5558, K07 CA80700, R01 CA94963, R33 CA95300] NR 16 TC 185 Z9 187 U1 0 U2 4 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 JUL 28 PY 2006 VL 313 IS 5786 BP 521 EP 522 DI 10.1126/science.1127515 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 067MZ UT WOS:000239308600062 PM 16809487 ER PT J AU Kamei, M Saunders, WB Bayless, KJ Dye, L Davis, GE Weinstein, BM AF Kamei, Makoto Saunders, W. Brian Bayless, Kayla J. Dye, Louis Davis, George E. Weinstein, Brant M. TI Endothelial tubes assemble from intracellular vacuoles in vivo SO NATURE LA English DT Article ID 3-DIMENSIONAL EXTRACELLULAR MATRICES; CAPILLARY LUMEN FORMATION; CELL MORPHOGENESIS; FIBRIN MATRICES; ZEBRAFISH; ANGIOGENESIS; MECHANISM; COLLAGEN; INTEGRIN; CAVEOLAE AB The formation of epithelial tubes is crucial for the proper development of many different tissues and organs, and occurs by means of a variety of different mechanisms(1). Morphogenesis of seamless, properly patterned endothelial tubes is essential for the development of a functional vertebrate circulatory system, but the mechanism of vascular lumenization in vivo remains unclear. Evidence dating back more than 100 years has hinted at an important function for endothelial vacuoles in lumen formation(2). More than 25 years ago, in some of the first endothelial cell culture experiments in vitro, Folkman and Haudenschild described "longitudinal vacuoles" that "appeared to be extruded and connected from one cell to the next"(3,4), observations confirmed and extended by later studies in vitro showing that intracellular vacuoles arise from integrin-dependent and cdc42/Rac1-dependent pinocytic events downstream of integrin - extracellular-matrix signalling interactions(5-10). Despite compelling data supporting a model for the assembly of endothelial tubes in vitro through the formation and fusion of vacuoles, conclusive evidence in vivo has been lacking, primarily because of difficulties associated with imaging the dynamics of subcellular endothelial vacuoles deep within living animals. Here we use high-resolution time-lapse two-photon imaging of transgenic zebrafish to examine how endothelial tubes assemble in vivo, comparing our results with time-lapse imaging of human endothelial-cell tube formation in three-dimensional collagen matrices in vitro. Our results provide strong support for a model in which the formation and intracellular and intercellular fusion of endothelial vacuoles drives vascular lumen formation. C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Microscopy & Imaging Core, NIH, Bethesda, MD 20892 USA. Texas A&M Univ Syst, Hlth Sci Ctr, Dept Pathol, College Stn, TX 77843 USA. RP Weinstein, BM (reprint author), NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM bw96w@nih.gov OI Kamei, Makoto/0000-0002-1438-0783 FU Intramural NIH HHS NR 30 TC 270 Z9 279 U1 2 U2 42 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 27 PY 2006 VL 442 IS 7101 BP 453 EP 456 DI 10.1038/nature04923 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 067CI UT WOS:000239278900043 PM 16799567 ER PT J AU Suzuki, T Minehata, K Akagi, K Jenkins, NA Copeland, NG AF Suzuki, Takeshi Minehata, Ken-ichi Akagi, Keiko Jenkins, Nancy A. Copeland, Neal G. TI Tumor suppressor gene identification using retroviral insertional mutagenesis in Blm-deficient mice SO EMBO JOURNAL LA English DT Article DE Bloom syndrome; insertional mutagenesis; lymphoma; retrovirus; tumor suppressor genes ID BLOOMS-SYNDROME GENE; MITOTIC RECOMBINATION; TARGETED DISRUPTION; MISMATCH REPAIR; LEUKEMIA; CELLS; MUTATIONS; GENOME; CANCER; FAMILY AB Retroviral insertional mutagenesis preferentially identifies oncogenes rather than tumor suppressor (TS) genes, presumably because a single retroviral-induced mutation is sufficient to activate an oncogene and initiate a tumor, whereas two mutations are needed to inactivate a TS gene. Here we show that TS genes can be identified by insertional mutagenesis when the screens are performed in Blm-deficient backgrounds. Blm-deficient mice, like Bloom syndrome patients, have increased frequencies of mitotic recombination owing to a mutation in the RecQ protein-like-3 helicase gene. This increased mitotic recombination increases the likelihood that an insertional mutation in one allele of a TS gene will become homozygoused by non-sister chromatid exchange and the homozygosity of the insertion provides a marker for identifying the TS gene. We also show that known as well as novel TS genes can be identified by insertional mutagenesis in Blm-deficient mice and identify two JmjC family proteins that contribute to genome stability in species as evolutionarily diverse as mammals and Caenorhabditis elegans. C1 NCI, Canc Res Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA. Kyoto Univ, Grad Sch Med, Canc Genet Unit, Horizontal Med Res Org, Kyoto, Japan. RP Copeland, NG (reprint author), NCI, Canc Res Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA. EM suzukit@hmro.med.kyoto-u.ac.jp; copeland@ncifcrf.gov NR 38 TC 103 Z9 104 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JUL 26 PY 2006 VL 25 IS 14 BP 3422 EP 3431 DI 10.1038/sj.emboj.7601215 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 071TQ UT WOS:000239625900017 PM 16858412 ER PT J AU Pavkov, ME Bennett, PH Knowler, WC Krakoff, J Sievers, ML Nelson, RG AF Pavkov, Meda E. Bennett, Peter H. Knowler, William C. Krakoff, Jonathan Sievers, Maurice L. Nelson, Robert G. TI Effect of youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID VASCULAR-DISEASE; HEART-DISEASE; CHILDREN; COMPLICATIONS; PREVALENCE; ANTIBODIES; RISK AB Context The long-term outcome of persons with youth-onset type 2 diabetes mellitus has not been well described. Objective To compare incidence of diabetic end-stage renal disease ( ESRD) and mortality in Pima Indians with youth- and older-onset type 2 diabetes mellitus. Design, Setting, and Participants Longitudinal population-based study conducted between 1965 and 2002 in Pima Indians from the state of Arizona. Participants were divided into 2 groups: ( 1) youth- onset type 2 diabetes mellitus ( onset < 20 years of age) and ( 2) older-onset type 2 diabetes mellitus ( onset >= 20 - < 55 years of age). Events and person-years of follow-up were stratified in a time-dependent fashion by decades of age. End-stage renal disease was defined as dialysis attributed to diabetic nephropathy or death from diabetic nephropathy. Main Outcome Measures Incidence rate of diabetic ESRD and mortality between 25 and 55 years of age, according to age at onset of type 2 diabetes mellitus. Results Among the 1856 diabetic participants, 96 had youth- onset type 2 diabetes mellitus. The age-sex - adjusted incidence of diabetic ESRD was 25.0 cases per 1000 person-years (95% confidence interval [CI], 6.7-43.1) in youth- onset diabetes mellitus and 5.4 cases per 1000 person-years ( 95% CI, 4.4-6.4) in older-onset diabetes mellitus ( incidence rate ratio, 4.6; 95% CI, 2.2-9.8). Age-specific incidence rates were higher in participants with youth- onset diabetes mellitus at all ages. Between 25 and 55 years of age, the age-sex - adjusted death rate from natural causes was 15.4 deaths per 1000 person-years ( 95% CI, 0.2-30.5) in participants with youth- onset diabetes mellitus and 7.3 deaths per 1000 person-years ( 95% CI, 5.9-8.7) in individuals with older-onset diabetes mellitus ( death rate ratio, 2.1; 95% CI, 0.8-5.7). Compared with nondiabetic participants, the death rate was 3.0 times as high in individuals with youth- onset diabetes mellitus ( 95% CI, 1.1-8.0) and 1.4 times as high in individuals with older-onset diabetes mellitus ( 95% CI, 1.1-1.8). In a subset of 1386 participants with complete data for all covariates who were observed from the onset of diabetes mellitus, the age at onset of diabetes mellitus was not associated with the incidence of ESRD ( hazard ratio, 1.0; 95% CI, 0.9-1.2) after adjusting for sex, mean arterial pressure, body mass index ( calculated as weight in kilograms divided by height in meters squared), plasma glucose concentration, smoking, hypoglycemic medicines, and blood pressure medicines in a Cox proportional-hazards model. Conclusions Early-onset type 2 diabetes mellitus is associated with substantially increased incidence of ESRD and mortality in middle age. The longer duration of diabetes mellitus by middle age in individuals diagnosed younger than age 20 years largely accounts for these outcomes. C1 NIH, Phoenix Epidemiol & Clin Res Branch, NIDDKD, Phoenix, AZ 85014 USA. RP Pavkov, ME (reprint author), NIH, Phoenix Epidemiol & Clin Res Branch, NIDDKD, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM mpavkov@phx.niddk.nih.gov RI Nelson, Robert/B-1470-2012 FU Intramural NIH HHS NR 26 TC 120 Z9 125 U1 2 U2 6 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 JUL 26 PY 2006 VL 296 IS 4 BP 421 EP 426 DI 10.1001/jama.296.4.421 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 066PN UT WOS:000239242500028 PM 16868300 ER PT J AU Herrmann, JE Wang, SX Zhang, CY Panchal, RG Bavari, S Lyons, CR Lovchik, JA Golding, B Shiloach, J Lu, S AF Herrmann, John E. Wang, Shixia Zhang, Chuanyou Panchal, Rekha G. Bavari, Sina Lyons, C. Rick Lovchik, Julie A. Golding, Basil Shiloach, Joseph Lu, Shan TI Passive immunotherapy of Bacillus anthracis pulmonary infection in mice with antisera produced by DNA immunization SO VACCINE LA English DT Article DE DNA vaccine; protective antibodies; passive immunity; immunotherapy ID PROTECTIVE ANTIGEN; GENETIC IMMUNIZATION; ANTIBODY FRAGMENTS; BIOLOGICAL WEAPONS; EBOLA-VIRUS; GUINEA-PIGS; IMMUNITY; TOXIN; BIOTERRORISM; COMBINATION AB Because of the high failure rate of antibiotic treatment in patients with anthrax there is a need for additional therapies such as passive immunization with therapeutic antibodies. In this study, we used codon-optimized plasmid DNAs (DNA vaccines) encoding Bacillus anthracis protective antigen (PA) to immunize rabbits for producing anti-anthrax antibodies for use in passive immunotherapy. The antisera generated with these DNA vaccines were of high titer as measured by ELISA. The antisera were also able to protect J774 macrophage cells by neutralizing the cytotoxic effect of exogenously added anthrax lethal toxin, and of the toxin released by B. anthracis (Sterne strain) spores following infection. In addition, the antisera passively protected mice against pulmonary challenge with an approximate 50 LD50 dose of B. anthracis (Sterne strain) spores. The protection in mice was obtained when the antiserum was given 1 h before or 1 h after challenge. We further demonstrated that IgG and F(ab')(2) components purified from anti-PA rabbit hyperimmune sera retained similar levels of neutralizing activities against both exogenously added B. anthracis lethal toxin and toxin produced by B. anthracis (Sterne strain) spores. The high titer antisera we produced will enable an immunization strategy to supplement antibiotic therapy for improving the survival of patients with anthrax. (c) 2006 Elsevier Ltd. All rights reserved. C1 Antibody Sci Inc, Worcester, MA 01603 USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. NCI, SAIC Frederick Inc, Target Struct Based Drug Discovery Grp, Frederick, MD 21702 USA. USA, Med Res Inst Infect Dis, Ft Detrick, MD 21705 USA. Univ New Mexico, Hlth Sci Ctr, Dept Internal Med, Albuquerque, NM 87131 USA. US FDA, Div Hematol, Off Blood Res & Review, Rockville, MD 20852 USA. NIDDK, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. RP Herrmann, JE (reprint author), Antibody Sci Inc, 80 Webster St, Worcester, MA 01603 USA. EM ASI@AbScience.com OI Lu, Shan/0000-0002-8417-7588 FU NCI NIH HHS [N01-CO-12400]; NIAID NIH HHS [U54 AI 057156-01, R43 AI056761] NR 34 TC 15 Z9 15 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 26 PY 2006 VL 24 IS 31-32 BP 5872 EP 5880 DI 10.1016/j.vaccine.2006.04.065 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 069TB UT WOS:000239470000014 PM 16790303 ER PT J AU Shukla, S Robey, RW Bates, SE Ambudkar, SV AF Shukla, Suneet Robey, Robert W. Bates, Susan E. Ambudkar, Suresh V. TI The calcium channel blockers, 1,4-dihydropyridines, are substrates of the multidrug resistance-linked ABC drug transporter, ABCG2 SO BIOCHEMISTRY LA English DT Article ID P-GLYCOPROTEIN; FUMITREMORGIN-C; ACQUIRED MUTATIONS; IMATINIB MESYLATE; CARCINOMA CELLS; IN-VITRO; CANCER; PROTEIN; BCRP; TOPOTECAN AB The human ATP-binding cassette transporter, ABCG2, confers resistance to multiple chemotherapeutic agents and also affects the bioavailability of different drugs. [I-125]Iodoarylazidoprazosin (IAAP) and [H-3] azidopine were used for photoaffinity labeling of ABCG2 in this study. We show here for the first time that both of these photoaffinity analogues are transport substrates for ABCG2 and that [H-3] azidopine can also be used to photolabel both wild-type R482-ABCG2 and mutant T482-ABCG2. We further used these assays to screen for potential substrates or modulators of ABCG2 and observed that 1,4-dihydropyridines such as nicardipine and nifedipine, which are clinically used as antihypertensive agents, inhibited the photolabeling of ABCG2 with [I-125] IAAP and [H-3] azidopine as well as the transport of these photoaffinity analogues by ABCG2. Furthermore, [H-3] nitrendipine and bodipy-F1-dihydropyridine accumulation assays showed that these compounds are transported by ABCG2. These dihydropyridines also inhibited the efflux of the known ABCG2 substrates, mitoxantrone and pheophorbide-a, from ABCG2-overexpressing cells, and nicardipine was more potent in inhibiting this transport. Both nicardipine and nifedipine stimulated the ATPase activity of ABCG2, and the nifedipine-stimulated activity was inhibited by fumitremorgin C, suggesting that these agents might interact at the same site on the transporter. In addition, nontoxic concentrations of dihydropyridines increased the sensitivity of ABCG2-expressing cells to mitoxantrone by 3-5-fold. In aggregate, results from the photoaffinity labeling and efflux assays using [I-125] IAAP and [H-3] azidopine demonstrate that 1,4-dihydropyridines are substrates of ABCG2 and that these photolabels can be used to screen new substrates and/or inhibitors of this transporter. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Canc Therapeut Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov RI shukla, suneet/B-4626-2012 FU Intramural NIH HHS NR 38 TC 65 Z9 69 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 25 PY 2006 VL 45 IS 29 BP 8940 EP 8951 DI 10.1021/bi060552f PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 064JU UT WOS:000239086000025 PM 16846237 ER PT J AU Wilbur, WJ Rzhetsky, A Shatkay, H AF Wilbur, W. John Rzhetsky, Andrey Shatkay, Hagit TI New directions in biomedical text annotation: definitions, guidelines and corpus construction SO BMC BIOINFORMATICS LA English DT Article ID INFORMATION-RETRIEVAL; DISCOVERY; GENE; KNOWLEDGE AB Background: While biomedical text mining is emerging as an important research area, practical results have proven difficult to achieve. We believe that an important first step towards more accurate text-mining lies in the ability to identify and characterize text that satisfies various types of information needs. We report here the results of our inquiry into properties of scientific text that have sufficient generality to transcend the confines of a narrow subject area, while supporting practical mining of text for factual information. Our ultimate goal is to annotate a significant corpus of biomedical text and train machine learning methods to automatically categorize such text along certain dimensions that we have defined. Results: We have identified five qualitative dimensions that we believe characterize a broad range of scientific sentences, and are therefore useful for supporting a general approach to text-mining: focus, polarity, certainty, evidence, and directionality. We define these dimensions and describe the guidelines we have developed for annotating text with regard to them. To examine the effectiveness of the guidelines, twelve annotators independently annotated the same set of 101 sentences that were randomly selected from current biomedical periodicals. Analysis of these annotations shows 70-80% inter-annotator agreement, suggesting that our guidelines indeed present a well-defined, executable and reproducible task. Conclusion: We present our guidelines defining a text annotation task, along with annotation results from multiple independently produced annotations, demonstrating the feasibility of the task. The annotation of a very large corpus of documents along these guidelines is currently ongoing. These annotations form the basis for the categorization of text along multiple dimensions, to support viable text mining for experimental results, methodology statements, and other forms of information. We are currently developing machine learning methods, to be trained and tested on the annotated corpus, that would allow for the automatic categorization of biomedical text along the general dimensions that we have presented. The guidelines in full detail, along with annotated examples, are publicly available. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. Columbia Univ, Judith P Sulzberger MD Columbia Genome Ctr, Ctr Computat Biol & Bioinformat, Dept Biomed Informat, New York, NY 10027 USA. Columbia Univ, Dept Biol, New York, NY 10027 USA. Queens Univ, Sch Comp, Kingston, ON K7L 3N6, Canada. RP Wilbur, WJ (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM wilbur@ncbi.nlm.nih.gov; ar345@columbia.edu; shatkay@cs.queensu.ca RI rzhetsky, andrey/B-6118-2012 FU Intramural NIH HHS NR 46 TC 48 Z9 48 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUL 25 PY 2006 VL 7 AR 356 DI 10.1186/1471-2105-7-356 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 080GR UT WOS:000240236400001 PM 16867190 ER PT J AU Giedd, JN Clasen, LS Lenroot, R Greenstein, D Wallace, GL Ordaz, S Molloy, EA Blumenthal, JD Tossell, JW Stayer, C Samango-Sprouse, CA Shen, DG Davatzikos, C Merke, D Chrousos, GP AF Giedd, Jay N. Clasen, Liv S. Lenroot, Rhoshel Greenstein, Dede Wallace, Gregory L. Ordaz, Sarah Molloy, Elizabeth A. Blumenthal, Jonathan D. Tossell, Julia W. Stayer, Catherine Samango-Sprouse, Carole A. Shen, Dinggang Davatzikos, Christos Merke, Deborah Chrousos, George P. TI Puberty-related influences on brain development SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE puberty; magnetic resonance imaging; brain; congenital adrenal hyperplasia; sex chromosome aneuploidy; children and adolescents ID HUMAN CORPUS-CALLOSUM; SEX-CHROMOSOME ABNORMALITIES; CONGENITAL ADRENAL-HYPERPLASIA; EXTRA X-CHROMOSOME; KLINEFELTER-SYNDROME; ELASTIC REGISTRATION; AGES 4-18; DIMORPHISM; ADOLESCENTS; CHILDHOOD AB Puberty is a time of striking changes in cognition and behavior. To indirectly assess the effects of puberty-related influences on the underlying neuroanatomy of these behavioral changes we will review and synthesize neuroimaging data from typically developing children and adolescents and from those with anomalous hormone or sex chromosome profiles. The trajectories (size by age) of brain morphometry differ between boys and girls, with girls generally reaching peak gray matter thickness 1-2 years earlier than boys. Both boys and girls with congenital adrenal hyperplasia (characterized by high levels of intrauterine testosterone), have smaller amygdala volume but the brain morphometry of girls with CAH did not otherwise significantly differ from controls. Subjects with XXY have gray matter reductions in the insula, temporal gyri, amygdala, hippocampus, and cingulate - areas consistent with the language-based learning difficulties common in this group. Published by Elsevier Ireland Ltd. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. George Washington Univ, Neurodev Diagnost Ctr, Washington, DC 20052 USA. Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. NICHHD, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. RP Giedd, JN (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Room 4C110,10 Ctr Dr,MSC 1367, Bethesda, MD 20892 USA. EM jg@nih.gov RI Giedd, Jay/A-3080-2008; Wallace, Gregory/A-4789-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Wallace, Gregory/0000-0003-0329-5054 NR 51 TC 137 Z9 138 U1 0 U2 15 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUL 25 PY 2006 VL 254 BP 154 EP 162 DI 10.1016/j.mce.2006.04.016 PG 9 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 071QO UT WOS:000239616900022 PM 16765510 ER PT J AU Flor-Cisneros, A Roemmich, JN Rogol, AD Baron, J AF Flor-Cisneros, Armando Roemmich, James N. Rogol, Alan D. Baron, Jeffrey TI Bone age and onset of puberty in normal boys SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE puberty; bone age; skeletal maturation ID CONGENITAL ADRENAL-HYPERPLASIA; PRECOCIOUS PUBERTY; GROWTH; MATURATION; TESTOLACTONE; MALNUTRITION; ANDROGEN AB Many conditions that delay skeletal maturation also delay the onset of puberty, whereas conditions that accelerate skeletal maturation often hasten the onset puberty, raising the possibility that skeletal maturation influences pubertal onset. To determine whether this concordance is also present in normal children, we analyzed data from 30 normal boys participating in a longitudinal study. Height, weight, and serum testosterone concentrations were assessed every 6 months and bone age (Fels method) every year. Pubertal onset was defined by serum testosterone >= 30 ng/dL. The variability in bone age at onset of puberty was not less than the variability in chronological age. In addition, there was no significant correlation between skeletal advancement and pubertal advancement (r=0.01, P=0.9). Similarly, there was not a significant correlation between pubertal advancement and height age advancement, weight age advancement, or BMI age advancement. Our findings do not support the hypothesis that skeletal maturation directly influences the age of pubertal onset in normal boys. (c) 2006 Published by Elsevier Ireland Ltd. C1 NIH, CRC 1330, Bone & Extracellular Matrix Branch, NICHHD, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Virginia, Ctr Hlth Sci, Dept Pediat, Charlottesville, VA 22903 USA. RP Baron, J (reprint author), NIH, CRC 1330, Bone & Extracellular Matrix Branch, NICHHD, 10 Ctr Dr MSC 1103, Bethesda, MD 20892 USA. FU Intramural NIH HHS; NICHD NIH HHS [Z01 HD000640-10] NR 19 TC 12 Z9 14 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUL 25 PY 2006 VL 254 BP 202 EP 206 DI 10.1016/j.mce.2006.04.008 PG 5 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 071QO UT WOS:000239616900027 PM 16837127 ER PT J AU Zheng, WM Khrapko, K Coller, HA Thilly, WG Copeland, WC AF Zheng, Weiming Khrapko, Konstantin Coller, Hilary A. Thilly, William G. Copeland, William C. TI Origins of human mitochondrial point mutations as DNA polymerase gamma-mediated errors SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE mitochondrial DNA; mutagenesis; DNA polymerase gamma ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; HUMAN-CELLS; POLG MUTATIONS; STEM-CELLS; HUMAN MTDNA; REPLICATION; SELECTION; FIDELITY; SPECTRUM; GENE AB Mitochondrial mutational spectra in human cells, tissues and derived tumors for bp 10,030-10,130 are essentially identical, suggesting a predominant mutagenic role for endogenous processes. We hypothesized that errors mediated by mitochondrial DNA polymerase gamma were the primary sources of mutations. Point mutations created in this sequence by human DNA pol gamma in vitro were thus compared to the eighteen mutational hotspots, all single base substitutions, previously found in human tissues. The set of concordant hotspots accounted for 83% of these in vivo mutational events. About half of these mutations are insensitive to prolonged heating of DNA during PCR and half increase proportionally with heating time at 98 degrees C. Primary misincorporation errors and miscopying errors past thermal denaturing products such as dearninated cytosines (uracils) thus appear to be of approximately equal importance. For the sequence studied, these data support the conclusion that, endogenous error mediated by DNA pol gamma constitutes the primary source of mitochondrial point mutations in human tissues. Published by Elsevier B.V. C1 Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. MIT, Biol Engn Div, Cambridge, MA 02139 USA. Beth Israel Deaconess Med Ctr, Gerontol Div, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98119 USA. RP Copeland, WC (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, 111 TW Alexander Dr,Bldg 101,Rm E316, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov RI Khrapko, Konstantin/A-3244-2009 FU Intramural NIH HHS; NIEHS NIH HHS [5P30ES02109, P01-ES07168] NR 50 TC 46 Z9 47 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUL 25 PY 2006 VL 599 IS 1-2 BP 11 EP 20 DI 10.1016/j.mrfmmm.2005.12.012 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 071BH UT WOS:000239571400002 PM 16490220 ER PT J AU Kim, YH You, SH Kwon, YH Hallett, M Kim, JH Jang, SH AF Kim, Y. H. You, S. H. Kwon, Y. H. Hallett, M. Kim, J. H. Jang, S. H. TI Longitudinal fMRI study for locomotor recovery in patients with stroke SO NEUROLOGY LA English DT Article ID MOTOR RECOVERY; CORTICAL ACTIVATION; HEMIPARETIC STROKE AB The authors investigated bihemispheric motor network reorganization supporting locomotor recovery after stroke over time. They determined longitudinal changes in locomotor function and fMRI in 10 stroke patients at the subacute stage and the chronic stage. The results suggest that the bihemispheric reorganization mechanism underlying locomotor recovery evolved from the ipsilateral (contralesional) primary sensorimotor cortex (SM1) activation at the subacute stage to the contralateral (ipsilesional) SM1 activation at the chronic stage. C1 Yeungnam Univ, Sch Med, Coll Med, Dept Phys Med & Rehabil, Taegu 705717, South Korea. Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Phys Med & Rehabil, Seoul, South Korea. Hampton Univ, Phys Therapy Program, Hampton, VA 23668 USA. Daegu Univ, Dept Rehabil Sci, Taegu, South Korea. NINCDS, Med Neurol Branch, Human Motor Control Sect, Bethesda, MD 20892 USA. RP Jang, SH (reprint author), Yeungnam Univ, Sch Med, Coll Med, Dept Phys Med & Rehabil, 317-1 Daemyungdong, Taegu 705717, South Korea. EM strokerehab@hanmail.net RI Kim, Yun Hee/F-4600-2014 NR 10 TC 36 Z9 53 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 25 PY 2006 VL 67 IS 2 BP 330 EP 333 DI 10.1212/01.wnl.0000225178.85833.0d PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 066NW UT WOS:000239237600033 PM 16864832 ER PT J AU Freed, EO AF Freed, Eric O. TI HIV-1 Gag: Flipped out for PI(4,5)P-2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID VIRUS TYPE-1 MATRIX; MEMBRANE-BINDING; PLASMA-MEMBRANE; PRIMARY MACROPHAGES; TERMINAL REGION; LIPID RAFTS; LIFE-CYCLE; PROTEIN; MUTATIONS; TRANSPORT C1 NCI, HIV Drug Resistance Program, Virus Cell Interact Sect, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI, HIV Drug Resistance Program, Virus Cell Interact Sect, Frederick, MD 21702 USA. EM efreed@nih.gov NR 27 TC 25 Z9 27 U1 0 U2 0 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 JUL 25 PY 2006 VL 103 IS 30 BP 11101 EP 11102 DI 10.1073/pnas.0604715103 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 068DZ UT WOS:000239353900001 PM 16847255 ER PT J AU Liggett, SB Mialet-Perez, J Thaneemit-Chen, S Weber, SA Greene, SM Hodne, D Nelson, B Morrison, J Domanski, MJ Wagoner, LE Abraham, WT Anderson, JL Carlquist, JF Krause-Steinrauf, HJ Lazzeroni, LC Port, JD Lavori, PW Bristow, MR AF Liggett, Stephen B. Mialet-Perez, Jeanne Thaneemit-Chen, Surai Weber, Stewart A. Greene, Scott M. Hodne, Danielle Nelson, Bradley Morrison, Jennifer Domanski, Michael J. Wagoner, Lynne E. Abraham, William T. Anderson, Jeffrey L. Carlquist, John F. Krause-Steinrauf, Heidi J. Lazzeroni, Laura C. Port, J. David Lavori, Philip W. Bristow, Michael R. TI A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE adenylyl cyclase; G protein-coupled receptor; genetics; myocardium; signaling ID HUMAN VENTRICULAR MYOCARDIUM; DOWN-REGULATION; PARTIAL AGONIST; SURVIVAL TRIAL; MERIT-HF; BUCINDOLOL; METOPROLOL; THERAPY; CARVEDILOL AB Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the beta(1)-adrenergic receptor (beta(1)AR), a beta-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a clinical trial were used to ascertain phenotype and mechanism. In nonfailing and failing isolated ventricles, beta(1)-Arg-389 had respective 2.8 +/- 0.3- and 4.3 +/- 2.1-fold greater agonist-promoted contractility vs. beta(1)-Gly-389, defining enhanced physiologic coupling under relevant conditions of endogenous expression and HF. The beta-blocker bucindolol was an inverse agonist in failing Arg, but not Gly, ventricles, without partial agonist activity at either receptor; carvedilol was a genotype-independent neutral antagonist. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease observed for Arg-389 (435 +/- 80 vs. 115 +/- 23 fmol per well). Potential pathophysiologic correlates were assessed in a placebo-controlled trial of bucindolol in 1,040 HF patients. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of HF. However, the Arg-389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality (P = 0.03) and 34% reduction in mortality or hospitalization (P = 0.004) vs. placebo. In contrast, Gly-389 carriers had no clinical response to bucindolol compared with placebo. Those with Arg-389 and high baseline norepinephrine levels trended toward improved survival, but no advantage with this allele and exaggerated sympatholysis was identified. We conclude that beta(1)AR-389 variation alters signaling in multiple models and affects the beta-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome. C1 Univ Maryland, Dept Med, Baltimore, MD 21201 USA. Univ Maryland, Dept Physiol, Baltimore, MD 21201 USA. Univ Cincinnati, Dept Med, Cincinnati, OH 45267 USA. Dept Vet Affairs, Palo Alto, CA 94025 USA. NHLBI, Bethesda, MD 20892 USA. Ohio State Univ, Div Cardiovasc, Columbus, OH 43210 USA. Univ Utah, Dept Internal Med, Salt Lake City, UT 84109 USA. Univ Colorado, Hlth Sci Ctr, Cardiovasc Inst, Denver, CO 80262 USA. RP Liggett, SB (reprint author), Univ Maryland, Dept Med, 20 Penn St,HSF 2,Room S-112, Baltimore, MD 21201 USA. EM sligg001@umaryland.edu RI Lazzeroni, Laura/F-2903-2010; bristow, michael/G-7850-2011; liggett, stephen/E-7453-2012 FU NHLBI NIH HHS [HL052318, HL071609, HL077101, HL48013, P50 HL052318, P50 HL077101, R01 HL048013, R01 HL071609] NR 36 TC 264 Z9 271 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 JUL 25 PY 2006 VL 103 IS 30 BP 11288 EP 11293 DI 10.1073/pnas.0509937103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 068DZ UT WOS:000239353900034 PM 16844790 ER PT J AU Koga, F Xu, WP Karpova, TS McNally, JG Baron, R Neckers, L AF Koga, Fumitaka Xu, Wanping Karpova, Tatiana S. McNally, James G. Baron, Roland Neckers, Len TI Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer; chaperone; geldanamycin ID FOCAL ADHESION KINASE; C-SRC; PHOSPHATIDYLINOSITOL 3-KINASE; CHAPERONE COMPLEX; TYROSINE KINASES; CANCER CELLS; ATP BINDING; GROWTH; RECEPTOR; CBL AB Hsp90 plays an essential role in maintaining stability and activity of its clients, including oncogenic signaling proteins that regulate key signal transduction nodes. Hsp90 inhibitors interfere with diverse signaling pathways by destabilizing and attenuating activity of such proteins, and thus they exhibit antitumor activity. However, Hsp90 inhibition has recently been reported to activate Akt and Erk and potentiate Akt activation induced by insulin-like growth factor 1 and insulin, raising the concern that clinical use of Hsp90 inhibitors might promote tumor progression under certain circumstances. Here, we show that the prototypical Hsp90 inhibitor geldanamycin induces Akt and Erk activation that is independent of PTEN status and is mediated by transient activation of Src kinase. Activated Src phosphorylates Cbl, which recruits the p85 subunit of phosphatidylinositol 3-kinase, resulting in phosphatidylinositol 3-kinase activation and eventually the activation of Akt and Erk. We show that geldanamycin rapidly disrupts Src association with Hsp90, suggesting that Src activation results directly from dissociation of the chaperone. These data suggest that, under certain circumstances, dual inhibition of Hsp90 and Src may be warranted. C1 NCI, Urol Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Orthoped, New Haven, CT 06510 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Canc Res Ctr, Bldg 10,Room 1-5940, Bethesda, MD 20892 USA. EM neckersl@mail.nih.gov NR 38 TC 75 Z9 76 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 25 PY 2006 VL 103 IS 30 BP 11318 EP 11322 DI 10.1073/pnas.0604705103 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 068DZ UT WOS:000239353900039 PM 16844778 ER PT J AU Lehmann, T Marcet, PL Graham, DH Dahl, ER Dubey, JP AF Lehmann, Tovi Marcet, Paula L. Graham, Doug H. Dahl, Erica R. Dubey, J. P. TI Globalization and the population structure of Toxoplasma gondii SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE evolutionary history; migration; pandemic genotype; protozoan parasite; trade ID MULTILOCUS GENOTYPE DATA; RECOMBINATION; INFERENCE; NETWORKS; LINEAGES; SURVIVAL; STRAINS; LOCI AB Toxoplasma gondii is a protozoan parasite that infects nearly all mammal and bird species worldwide. Usually asymptomatic, toxoplasmosis can be severe and even fatal to many hosts, including people. Elucidating the contribution of genetic variation among parasites to patterns of disease transmission and manifestations has been the goal of many studies. Focusing on the geographic component of this variation, we show that most genotypes are locale-specific, but some are found across continents and are closely related to each other, indicating a recent radiation of a pandemic genotype. Furthermore, we show that the geographic structure of T. gondii is extraordinary in having one population that is found in all continents except South America, whereas other populations are generally confined to South America, and yet another population is found worldwide. Our evidence suggests that South American and Eurasian populations have evolved separately until recently, when ships populated by rats, mice, and cats provided T. gondii with unprecedented migration opportunities, probably during the transatlantic slave trade. Our results explain several enigmatic features of the population structure of T. gondii and demonstrate how pervasive, prompt, and elusive the impact of human globalization is on nature. C1 NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. Ctr Dis Control & Prevent, Div Parasit Dis, Atlanta, GA 30341 USA. USDA, ARS, Anim Parasit Dis Lab, Anim & Nat Resources Inst, Beltsville, MD 20705 USA. RP Lehmann, T (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Room 2W13A, Rockville, MD 20852 USA. EM tlehmann@niaid.nih.gov RI marcet, Paula/B-1758-2012; OI Marcet, Paula/0000-0002-0676-3020 FU Intramural NIH HHS NR 32 TC 204 Z9 212 U1 5 U2 29 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 25 PY 2006 VL 103 IS 30 BP 11423 EP 11428 DI 10.1073/pnas.0601438103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 068DZ UT WOS:000239353900057 PM 16849431 ER PT J AU Wendler, D AF Wendler, David TI One-time general consent for research on biological samples - Is it compatible with the Health Insurance Portability and Accountability Act? SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID GENETIC RESEARCH; INFORMED-CONSENT; TISSUE SAMPLES; STORED TISSUE; BIOBANKS AB The collection and storage of human biological samples has become integral to clinical research.(1) These samples, estimated to be in the hundreds of millions in the United States alone, have enormous potential.(2) However, requiring individuals' informed consent each time collected samples are used for new research could thwart this potential, increasing costs, decreasing response rates, burdening individuals, and precluding some studies altogether. C1 NIH, Ctr Clin, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Ctr Clin, Dept Clin Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 16 TC 15 Z9 16 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 24 PY 2006 VL 166 IS 14 BP 1449 EP 1452 DI 10.1001/archinte.166.14.1449 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 066DZ UT WOS:000239211200004 PM 16864754 ER PT J AU Maraldi, C Volpato, S Kritchevsky, SB Cesari, M Andresen, E Leeuwenburgh, C Harris, TB Newman, AB Kanaya, A Johnson, KC Rodondi, N Pahor, M AF Maraldi, Cinzia Volpato, Stefano Kritchevsky, Stephen B. Cesari, Matteo Andresen, Elena Leeuwenburgh, Christiaan Harris, Tamara B. Newman, Anne B. Kanaya, Alka Johnson, Karen C. Rodondi, Nicolas Pahor, Marco TI Impact of inflammation on the relationship among alcohol consumption, mortality, and cardiac events - The health, aging, and body composition study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CORONARY-HEART-DISEASE; MALE BRITISH DOCTORS; CARDIOVASCULAR HEALTH; OLDER-ADULTS; US ADULTS; RISK; MARKERS; WOMEN; MEN; COHORT AB Background: Uncertainty remains about the overall survival benefit of alcohol consumption and the mechanisms underlying the cardioprotective effect of light to moderate alcohol intake. Recent evidence suggests an anti-inflammatory effect of light to moderate alcohol consumption. We investigated the relationship of alcohol intake with all-cause mortality and cardiac events and evaluated whether this relationship is mediated or modified by inflammatory markers. Methods: The analysis included 2487 subjects, aged 70 to 79 years, without baseline coronary heart disease (CHD) or heart failure (HF), participating in the Health, Aging, and Body Composition study. All-cause mortality and incident cardiac events ( CHD and HF) were detected during a mean follow-up of 5.6 years. Alcohol consumption and serum levels of interleukin-6 (IL-6) and C-reactive protein (CRP) were assessed at baseline. Results: A total of 397 participants died, and 383 experienced an incident cardiac event. Compared with never or occasional drinkers, subjects drinking 1 to 7 drinks per week had lower age-, sex-, and race- adjusted incidences of death (27.4 vs 20.1 per 1000 person-years, respectively) and cardiac events (28.9 vs 20.8 per 1000 person-years). After adjustment for confounders, compared with never or occasional drinkers, light to moderate drinkers (1-7 drinks per week) showed a decreased risk of death (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.56-1.00) andcardiac events (HR, 0.72; CI, 0.54- 0.97). Adjustment for potential mediators, and particularly inflammatory marker levels, did not affect the strength of this association. Conclusion: Light to moderate alcohol consumption was associated with significantly lower rates of cardiac events and longer survival, independent of its antiinflammatory effect. C1 Univ Florida, Coll Med, Inst Aging, Dept Aging & Geriatr Res, Gainesville, FL 32608 USA. Univ Florida, Coll Publ Hlth & Hlth Profess, Div Epidemiol, Gainesville, FL 32608 USA. Univ Ferrara, Dept Clin & Expt Med, I-44100 Ferrara, Italy. Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Calif San Francisco, Dept Med & Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. Univ Lausanne, Dept Community Med & Publ Hlth, Lausanne, Switzerland. N Florida S Georgia Vet Hlth Syst, Malcolm Randall Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Gainesville, FL USA. RP Maraldi, C (reprint author), Univ Florida, Coll Med, Inst Aging, Dept Aging & Geriatr Res, 1329 SW 16th St, Gainesville, FL 32608 USA. EM Cmaraldi@aging.ufl.edu RI Cesari, Matteo/A-4649-2008; Newman, Anne/C-6408-2013; VOLPATO, STEFANO/H-2977-2014 OI Cesari, Matteo/0000-0002-0348-3664; Newman, Anne/0000-0002-0106-1150; VOLPATO, STEFANO/0000-0003-4335-6034 FU NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 29 TC 31 Z9 32 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 24 PY 2006 VL 166 IS 14 BP 1490 EP 1497 DI 10.1001/archinte.166.14.1490 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 066DZ UT WOS:000239211200009 PM 16864759 ER PT J AU Pozsgay, V Ekborg, G Sampathkumar, SG AF Pozsgay, Vince Ekborg, Goran Sampathkumar, Srinivasa-Gopalan TI Synthesis of hexa- to tridecasaccharides related to Shigella dysenteriae type 1 for incorporation in experimental vaccines SO CARBOHYDRATE RESEARCH LA English DT Article DE benzophenone ketal; oligosaccharide; protecting groups; synthesis; conjugation; antibacterial; vaccine ID O-SPECIFIC POLYSACCHARIDE; OLIGOSACCHARIDE SYNTHESIS; PROMOTED REACTIONS; PROTECTING GROUPS; LIPOPOLYSACCHARIDE; ANTIBODIES; GLYCOSIDES; ANTIGEN; DONORS; CHAIN AB Hexa- to tridecasaccharides corresponding to the O-specific polysaccharide (O-SP) of the Gram-negative bacterium Shigella dysenteriae type 1 were synthesized in solution phase. The syntheses utilized tetra-, octa-, and dodecasaccharide intermediates that represent one to three contiguous tetrasaccharide repeating units of the O-SP [Synlett 2003, 743]. These compounds were glycosylated with mono-, di-, and trisaccharide trichloroacetamidates, which were synthesized in this study. The excellent stereodirecting effect of 4,6-O-benzophenone ketals in glycosylation reactions of 2-azido-2-deoxy-glucopyranosyl donors was demonstrated. The free oligosaccharides were characterized by H-1 and C-13 NMR spectroscopy and by high-resolution mass spectrometry. The oligosaccharides described herein contain the 5-(methoxycarbonyl)pentyl aglycon for eventual attachment to immunogenic carriers using a recently published protocol [J. Org. Chem. 2005, 70, 6987]. (c) 2006 Elsevier Ltd. All rights reserved. C1 NICHHD, Dev & Mol Immun Lab, NIH, Bethesda, MD 20892 USA. RP Pozsgay, V (reprint author), NICHHD, Dev & Mol Immun Lab, NIH, 31 Ctr Dr,Rm 2A29,MSC 2423, Bethesda, MD 20892 USA. EM pozsgayv@mail.nih.gov RI Sampathkumar, Srinivasa-Gopalan/C-9951-2017 OI Sampathkumar, Srinivasa-Gopalan/0000-0002-0616-8977 FU Intramural NIH HHS NR 26 TC 5 Z9 5 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD JUL 24 PY 2006 VL 341 IS 10 BP 1408 EP 1427 DI 10.1016/j.carres.2006.04.006 PG 20 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 056ZH UT WOS:000238563300017 PM 16650395 ER PT J AU Koivunen, ME Dettmer, K Vermeulen, R Bakke, B Gee, SJ Hammock, BD AF Koivunen, Marja E. Dettmer, Katja Vermeulen, Roel Bakke, Berit Gee, Shirley J. Hammock, Bruce D. TI Improved methods for urinary atrazine mercapturate analysis - Assessment of an enzyme-linked immunosorbent assay (ELISA) and a novel liquid chromatography-mass spectrometry (LC-MS) method utilizing online solid phase extraction (SPE) SO ANALYTICA CHIMICA ACTA LA English DT Article DE atrazine mercapturate; enzyme-linked immunosorbent assay (ELISA); solid phase extraction (SPE); online solid phase extraction; liquid chromatography-mass spectrometry (LC-MS); human biomonitoring ID EXPOSURE BIOMARKERS TRANS; S-PHENYLMERCAPTURIC ACID; LOOP CLEANUP DEVICE; PESTICIDE METABOLITES; MUCONIC ACID; QUANTIFICATION; APPLICATORS; HERBICIDES; SYSTEM AB Elimination of interfering substances in urine by solid phase extraction (SPE) prior to analysis resulted in 10-fold improvement in the sensitivity of atrazine mercapturate (AM) enzyme-linked immunosorbent assay (ELISA) compared to previous reports. Of the two tested SPE systems, Oasis (R) HLB and MCX, the mixed-mode MCX gave good recoveries (82%) of AM in spiked samples measured by ELISA, whereas the reverse-phase HLB phase was not compatible with the immunochemical method. At relatively high concentrations of urinary AM (> 20 ng mL(-1)), sample dilution was effective enough for the elimination of interfering substances. The new liquid chromatography-mass spectrometry (LC-MS) method developed for AM utilizes online-SPE with Oasis (R) HLB, column switching and a stable-isotope internal standard. The limit of quantification (0.05 ng mL(-1)) indicates improved sensitivity compared with most previously published LC-MS methods for AM. Validation of all three methods, LC-MS, ELISA + SPE and ELISA + dilution with spiked urine samples showed good correlation between the known and measured concentrations with R-2 values of 0.996, 0.957 and 0.961, respectively. When a set (n = 70 plus 12 blind duplicates) of urine samples from farmers exposed to atrazine was analyzed, there was a good agreement (R-2 = 0. 917) between the log normalized data obtained by ELISA + SPE and LC-MS. High correlation among the data obtained by the two tested methods and the LC-MS method by the Center of Disease Control and Prevention (CDC), together with low variability among the blind duplicates, suggests that both methods reported here would be suitable for the analysis of urinary AM as a biomarker for human exposure of atrazine. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. Univ Calif Davis, Ctr Canc, Davis, CA 95616 USA. NCI, Div Canc Epidemiol & Genet, DHHS, NIH, Rockville, MD USA. Natl Inst Occupat Hlth, Oslo, Norway. RP Hammock, BD (reprint author), Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. EM bdhammock@ucdavis.edu RI Vermeulen, Roel/F-8037-2011; Dettmer, Katja/N-4562-2016 OI Vermeulen, Roel/0000-0003-4082-8163; Dettmer, Katja/0000-0001-7337-2380 NR 27 TC 16 Z9 18 U1 0 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0003-2670 EI 1873-4324 J9 ANAL CHIM ACTA JI Anal. Chim. Acta PD JUL 21 PY 2006 VL 572 IS 2 BP 180 EP 189 DI 10.1016/j.aca.2006.05.037 PG 10 WC Chemistry, Analytical SC Chemistry GA 066MX UT WOS:000239234900003 PM 17723476 ER PT J AU Oh, YS Turner, RJ AF Oh, YS Turner, RJ TI Protease digestion indicates that endogenous presenilin 1 is present in at least two physical forms SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE presenilin; Alzheimer's disease; gamma-secretase; beta-amyloid; intramembranous protease; proteinase K ID GAMMA-SECRETASE COMPLEX; SIGNAL PEPTIDE PEPTIDASE; AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; NICASTRIN; PEN-2; EXPRESSION; MEMBRANE; APH-1; IDENTIFICATION AB The membrane-bound protein complex gamma-secretase is an intramembranous protease whose substrates are a number of type I transmembrane proteins including the beta-amyloid precursor protein (APP). A presenilin molecule is thought to be the catalytic unit of gamma-secretase and either of two presenilin homologues, PS1 or PS2, can play this role. Mutations in the presenilins, apparently leading to aberrant processing of APP, have been genetically linked to early-onset familial Alzheimer's disease. To look for possible molecular heterogeneity in presenilin/gamma-secretase we examined the ability of proteinase K (PK) to digest endogenously expressed presenilins in intact endoplasmic reticulum vesicles. We demonstrate the existence of two physically different forms of gamma-secretase-associated PS1, one that is relatively PK-sensitive and one that is significantly more PK-resistant. A similarly PK-resistant form of PS2 was not observed. We speculate that the structural heterogeneity we observe may underlie, at least in part, previous observations indicating the physical and functional heterogeneity of gamma-secretase. In particular, our results suggest that there are significant differences between gamma-secretase complexes incorporating PS1 and PS2. This difference may underlie the more dominant role of PS1 in the generation of beta-amyloid peptides and in familial Alzheimer's disease. Published by Elsevier Inc. C1 Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, Gene Therapy & Therapeut Branch, DHHS,NIH, Bethesda, MD 20892 USA. RP Turner, RJ (reprint author), Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, Gene Therapy & Therapeut Branch, DHHS,NIH, Bethesda, MD 20892 USA. EM rjturner@mail.nih.gov NR 32 TC 3 Z9 4 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 21 PY 2006 VL 346 IS 1 BP 330 EP 334 DI 10.1016/j.bbrc.2006.05.127 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 056TX UT WOS:000238549100046 PM 16756946 ER PT J AU Stern, MD AF Stern, Michael D. TI How to give a cell a heart attack SO CIRCULATION RESEARCH LA English DT Editorial Material DE ischemia; myocyte; hypoxia; reperfusion; mitochondria ID MYOCYTES; RELEASE C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Stern, MD (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Blvd, Baltimore, MD 21224 USA. EM Sternm@grc.nia.nih.gov FU Intramural NIH HHS NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 21 PY 2006 VL 99 IS 2 BP 111 EP 112 DI 10.1161/01.RES.0000234908.21102.f9 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 067MF UT WOS:000239306200002 PM 16857969 ER PT J AU Armoni, M Harel, C Karni, S Chen, H Bar-Yoseph, F Ver, MR Quon, MJ Karnieli, E AF Armoni, Michal Harel, Chava Karni, Shiri Chen, Hui Bar-Yoseph, Fabiana Ver, Marel R. Quon, Michael J. Karnieli, Eddy TI FOXO1 represses peroxisome proliferator-activated receptor-gamma 1 and -gamma 2 gene promoters in primary adipocytes - A novel paradigm to increase insulin sensitivity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; TRANSCRIPTION FACTOR FOXO1; SIGNALING PATHWAYS; EXPRESSION; FKHR; PHOSPHORYLATION; PROTEIN; TRANSACTIVATION; DIFFERENTIATION; INHIBITION AB FOXO1 and peroxisome proliferator-activated receptor-gamma (PPAR gamma) are crucial transcription factors that regulate glucose metabolism and insulin responsiveness in insulin target tissues. We have shown that, in primary rat adipocytes, both factors regulate transcription of the insulin-responsive GLUT4 gene and that PPAR gamma 2 detachment from the GLUT4 promoter upon thiazolidinedione binding up-regulates GLUT4 gene expression, thus increasing insulin sensitivity (Armoni, M., Kritz, N., Harel, C., Bar-Yoseph, F., Chen, H., Quon, M. J., and Karnieli, E. (2003) J. Biol. Chem. 278, 30614-30623). However, the mechanisms regulating PPAR gamma gene transcription are largely unknown. We studied the effects of FOXO1 on human PPAR gamma gene expression in primary rat adipocytes and found that both genes are endogenously expressed. FOXO1 coexpression dose-dependently repressed transcription from either the PPAR gamma 1 or PPAR gamma 2 promoter reporter by 65%, whereas insulin (100 nM, 20-24 h) either partially or completely reversed this effect. Phosphorylation-defective FOXO1 mutants T24A, S256A, S319A, and T24A/S256A/S319A still repressed the PPAR gamma 1 promoter and partially lost their effects on the PPAR gamma 2 promoter in either basal or insulin-stimulated cells. Use of DNA binding-defective FOXO1(H215R) indicated that this domain is crucial for FOXO1 repression of the PPAR gamma 2 (but not PPAR gamma 1) promoter. Progressive 5'-deletion and gel retardation analyses revealed that this repression involves direct and specific binding of FOXO1 to the PPAR gamma 2 promoter; chromatin immunoprecipitation analysis confirmed that this binding occurs in cellulo. We suggest a novel paradigm to increase insulin sensitivity in adipocytes in which FOXO1 repression of PPAR gamma, the latter being a repressor of the GLUT4 promoter, consequently leads to GLUT4 derepression/up-regulation, thus enhancing cellular insulin sensitivity. The newly identified FOXO1-binding site on the PPAR gamma 2 promoter may serve as a therapeutic target for type 2 diabetes. C1 Rambam Med Ctr, Inst Endocrinol Diabet & Metab, Unite Endocrinol Mol, IL-31096 Haifa, Israel. Technion Israel Inst Technol, Rappaport Fac Med, IL-31096 Haifa, Israel. NCCAM, NIH, Bethesda, MD 20892 USA. RP Armoni, M (reprint author), Rambam Med Ctr, Inst Endocrinol Diabet & Metab, Unite Endocrinol Mol, POB 9602, IL-31096 Haifa, Israel. EM amichal@tx.technion.ac.il RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915 NR 25 TC 105 Z9 114 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 21 PY 2006 VL 281 IS 29 BP 19881 EP 19891 DI 10.1074/jbc.M600320200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 063RV UT WOS:000239038200011 PM 16670091 ER PT J AU Park, HJ Ward, SM Desgrosellier, JS Georgescu, SP Papageorge, AG Zhuang, XL Barnett, JV Galper, JB AF Park, Ho-Jin Ward, Simone M. Desgrosellier, Jay S. Georgescu, Serban P. Papageorge, Alexander G. Zhuang, Xiaoli Barnett, Joey V. Galper, Jonas B. TI Transforming growth factor beta regulates the expression of the M-2 muscarinic receptor in atrial myocytes via an effect on RhoA and p190RhoGAP SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEALED MYOCARDIAL-INFARCTION; LOW-DENSITY LIPOPROTEINS; CHICK HEART-CELLS; TGF-BETA; PARASYMPATHETIC RESPONSIVENESS; AUTONOMIC NEUROPATHY; DEPENDENT MECHANISM; SIGNALING PATHWAYS; SUDDEN-DEATH; K+ CHANNEL AB Transforming growth factor beta(TGF beta) signaling is involved in the development and regulation of multiple organ systems and cellular signaling pathways. We recently demonstrated that TGF beta regulates the response of atrial myocytes to parasympathetic stimulation. Here, TGF beta(1) is shown to inhibit expression of the M-2 muscarinic receptor (M2), which plays a critical role in the parasympathetic response of the heart. This effect is mimicked by overexpression of a dominant negative mutant of RhoA and by the RhoA kinase inhibitor Y27632, whereas adenoviral expression of a dominant activating-RhoA reverses TGF beta inhibition of M2 expression. TGF beta(1) also mediates a decrease in GTP-bound RhoA and a reciprocal increase in the expression of the RhoA GTPase-activating protein, p190RhoGAP, whereas total RhoA is unchanged. Inhibition of M2 promoter activity by TGF beta 1 is mimicked by overexpression of p190RhoGAP, whereas a dominant negative mutant of p190RhoGAP reverses this effect of TGF beta 1. In contrast to atrial myocytes, in mink lung epithelial cells, in which TGF beta signaling through activation of RhoA has been previously identified, TGF beta 1 stimulated an increase in GTP-bound RhoA in association with a reciprocal decrease in the expression of p190RhoGAP. Both effects demonstrated a similar dose dependence on TGF beta 1. Thus TGF beta regulation of M2 muscarinic receptor expression is dependent on RhoA, and TGF beta regulation of p190RhoGAP expression may be a cell type-specific mechanism for TGF beta signaling through RhoA. C1 Tufts Univ, New England Med Ctr, Mol Cardiol Res Inst, Dept Med, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37232 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Galper, JB (reprint author), Tufts Univ, New England Med Ctr, Mol Cardiol Res Inst, Dept Med, Boston, MA 02111 USA. EM hpark@tufts-nemc.org; jgalper@tufts-nemc.org FU NHLBI NIH HHS [R01 HL052922-10, HL54225, HL52922, R01 HL052922, HL66467] NR 51 TC 5 Z9 5 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 JUL 21 PY 2006 VL 281 IS 29 BP 19995 EP 20002 DI 10.1074/jbc.M513095200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 063RV UT WOS:000239038200023 PM 16707504 ER PT J AU Kotova, O Al-Khalili, L Talia, S Hooke, C Fedorova, OV Bagrov, AY Chibalin, AV AF Kotova, Olga Al-Khalili, Lubna Talia, Sara Hooke, Catherine Fedorova, Olga V. Bagrov, Alexei Y. Chibalin, Alexander V. TI Cardiotonic steroids stimulate glycogen synthesis in human skeletal muscle cells via a Src- and ERK1/2-dependent mechanism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NA+,K+-ATPASE ALPHA-SUBUNIT; OUABAIN-LIKE COMPOUND; PROTEIN-KINASE-C; NA+/K+-ATPASE; NA/K-ATPASE; ENDOGENOUS OUABAIN; ESSENTIAL-HYPERTENSION; CALCIUM OSCILLATIONS; SIGNAL-TRANSDUCTION; CARDIAC MYOCYTES AB The cardiotonic steroid, ouabain, a specific inhibitor of Na+, K+-ATPase, initiates protein-protein interactions that lead to an increase in growth and proliferation in different cell types. We explored the effects of ouabain on glucose metabolism in human skeletal muscle cells (HSMC) and clarified the mechanisms of ouabain signal transduction. In HSMC, ouabain increased glycogen synthesis in a concentration-dependent manner reaching the maximum at 100 nM. The effect of ouabain was additive to the effect of insulin and was independent of phosphatidylinositol 3-kinase inhibitor LY294002 but was abolished in the presence of a MEK1/2 inhibitor (PD98059) or a Src inhibitor (PP2). Ouabain increased Src-dependent tyrosine phosphorylation of alpha(1)- and alpha(2)-subunits of Na+, K+-ATPase and promoted interaction of alpha(1)- and alpha(2)-subunits with Src, as assessed by co-immunoprecipitation with Src. Phosphorylation of ERK1/2 and GSK3 alpha/beta, as well as p90rsk activity, was increased in response to ouabain in HSMC, and these responses were prevented in the presence of PD98059 and PP2. Incubation of HSMC with 100 nM ouabain increased phosphorylation of the alpha-subunits of the Na-pump at a MAPK-specific Thr-Pro motif. Ouabain treatment decreased the surface abundance of alpha(2)-subunit, whereas abundance of the alpha(1)-subunit was unchanged. Marinobufagenin, an endogenous vertebrate bufadienolide cardiotonic steroid, increased glycogen synthesis in HSMC at 10 nM concentration, similarly to 100 nM ouabain. In conclusion, ouabain and marinobufagenin stimulate glycogen synthesis in skeletal muscle. This effect is mediated by activation of a Src-, ERK1/2-, p90rsk-, and GSK3-dependent signaling pathway. C1 Karolinska Inst, Dept Mol Med & Surg, Sect Integrat Physiol, SE-17177 Stockholm, Sweden. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Chibalin, AV (reprint author), Karolinska Inst, Dept Mol Med & Surg, Sect Integrat Physiol, von Eulers Vag 4,4 Tr, SE-17177 Stockholm, Sweden. EM Alexander.Chibalin@ki.se OI Chibalin, Alexander/0000-0002-6339-6271 FU Intramural NIH HHS NR 59 TC 34 Z9 35 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 JUL 21 PY 2006 VL 281 IS 29 BP 20085 EP 20094 DI 10.1074/jbc.M601577200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 063RV UT WOS:000239038200033 PM 16714287 ER PT J AU Boyko, V Leavitt, M Gorelick, R Fu, W Nikolaitchik, O Pathak, VK Nagashima, K Hu, WS AF Boyko, Vitaly Leavitt, Maria Gorelick, Robert Fu, William Nikolaitchik, Olga Pathak, Vinay K. Nagashima, Kunio Hu, Wei-Shau TI Coassembly and complementation of Gag proteins from HIV-1 and HIV-2, two distinct human pathogens SO MOLECULAR CELL LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MURINE LEUKEMIA-VIRUS; ZINC-FINGER; INFECTION; RNA; RECOMBINATION; DOMAIN; AIDS; RESISTANCE; PARTICLES AB Approximately one million people in the world are dually infected with both HIV-1 and HIV-2. To identity potential interactions between these two human pathogens, we examined whether HIV-1 and HIV-2 Gag proteins can coassemble and functionally complement each other. We generated HIV-1 - and HIV-2-based vectors with mutations in Gag; compared with wild-type vectors, these mutants had drastically decreased viral titers. Coexpression of the mutant HIV-1 and HIV-2 Gag could generate infectious viruses; furthermore, heterologous complementation in certain combinations showed efficiency similar to homologous complementation. Additionally, we used bimolecularfluorescence complementation analysis to directly demonstrate that HIV-1 and HIV-2 Gag can interact and coassemble. Taken together, our results indicate that HIV-1 and HIV-2 Gag polyproteins can coassemble and functionally complement each other during virus replication; to our knowledge, this is the first demonstration of its kind. These studies have important implications for AIDS treatment and the evolution of primate lentiviruses. C1 SAIC Frederick Inc, HIV Drug Resistance Program, NCI, Frederick, MD 21702 USA. SAIC Frederick Inc, AIDS Vaccine Program, Basic Res Program, NCI, Frederick, MD 21702 USA. SAIC Frederick Inc, Image Anal Lab, NCI, Frederick, MD 21702 USA. RP Hu, WS (reprint author), SAIC Frederick Inc, HIV Drug Resistance Program, NCI, Frederick, MD 21702 USA. EM whu@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 26 TC 21 Z9 23 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL 21 PY 2006 VL 23 IS 2 BP 281 EP 287 DI 10.1016/j.molcel.2006.05.028 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 072BN UT WOS:000239647700016 PM 16857594 ER PT J AU Straus, SE Chesney, MA AF Straus, Stephen E. Chesney, Margaret A. TI In defense of NCCAM SO SCIENCE LA English DT Editorial Material ID OSTEOARTHRITIS; KNEE C1 NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Chesney, MA (reprint author), NIH, Natl Ctr Complementary & Alternat Med, Bldg 10, Bethesda, MD 20892 USA. EM chesneym@mail.nih.gov NR 10 TC 9 Z9 9 U1 0 U2 0 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 JUL 21 PY 2006 VL 313 IS 5785 BP 303 EP 304 DI 10.1126/science.1131608 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 065IV UT WOS:000239154300026 PM 16857924 ER PT J AU Marino-Ramirez, L Jordan, IK AF Marino-Ramirez, Leonardo Jordan, I. King TI Transposable element derived DNaseI-hypersensitive sites in the human genome SO BIOLOGY DIRECT LA English DT Article ID SIGNATURE SEQUENCING MPSS; REGULATORY SEQUENCES; MOUSE; GENES; TRANSCRIPTOMES; EVOLUTION; DATABASE; GLOBIN AB Background: Transposable elements (TEs) are abundant genomic sequences that have been found to contribute to genome evolution in unexpected ways. Here, we characterize the evolutionary and functional characteristics of TE-derived human genome regulatory sequences uncovered by the high throughput mapping of DNasel-hypersensitive (HS) sites. Conclusion: The results reported here support the notion that TEs provide a specific genome-wide mechanism for generating functionally relevant gene regulatory divergence between evolutionary lineages. C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Jordan, IK (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM marino@ncbi.nlm.nih.gov; jordan@ncbi.nlm.nih.gov RI Marino-Ramirez, Leonardo/I-5759-2013 OI Marino-Ramirez, Leonardo/0000-0002-5716-8512 FU Intramural NIH HHS [Z99 LM999999] NR 37 TC 20 Z9 20 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 JUL 20 PY 2006 VL 1 AR 20 DI 10.1186/1745-6150-1-20 PG 14 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 133SU UT WOS:000244034400001 PM 16857058 ER PT J AU Dimitrov, DS AF Dimitrov, Dimiter S. TI Interactions of antibody-conjugated nanoparticles with biological surfaces SO COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS LA English DT Article ID VIRUS ENTRY C1 Natl Canc Inst, Prot Interact Grp, CCR Nanobiol Program, Canc Res Ctr, Frederick, MD 21702 USA. RP Dimitrov, DS (reprint author), Natl Canc Inst, Prot Interact Grp, CCR Nanobiol Program, Canc Res Ctr, Frederick, MD 21702 USA. EM dimitrov@ncifcrf.gov NR 4 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0927-7757 J9 COLLOID SURFACE A JI Colloid Surf. A-Physicochem. Eng. Asp. PD JUL 20 PY 2006 VL 282 BP 8 EP 10 DI 10.1016/j.colsurfa.2005.11.001 PG 3 WC Chemistry, Physical SC Chemistry GA 059JX UT WOS:000238730200002 ER PT J AU Chen, HX Mooney, M Boron, M Vena, D Mosby, K Grochow, L Jaffe, C Rubinstein, L Zwiebel, J Kaplan, RS AF Chen, Helen X. Mooney, Margaret Boron, Matthew Vena, Don Mosby, Kimberly Grochow, Louise Jaffe, Carl Rubinstein, Lawrence Zwiebel, James Kaplan, Richard S. TI Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: An NCI Treatment Referral Center trial TRC-0301 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED-TRIAL; SOLID TUMORS; IRINOTECAN; OXALIPLATIN; CETUXIMAB; THERAPY AB Purpose To provide bevacizumab (BV) -based therapy to patients with advanced colorectal cancers (CRC) who had exhausted standard chemotherapy options, and to evaluate the response to BV combined with fluorouracil (FU) and leucovorin (LV) in this patient population. Patients and Methods This was a multicenter, single-arm treatment trial conducted under the National Cancer Institute Treatment Referral Center network nationwide. Patients were treated with BV 5 mg/kg every 2 weeks combined with FU/LV; FU was administered by bolus or continuous infusion. Eligibility criteria included advanced CRC that had progressed after irinotecan- and oxaliplatin-based chemotherapy, Eastern Cooperative Oncology Group performance status 0 to 2, and absence of thromboembolism. The primary end point was objective response rate (RR) in the first 100 assessable patients. All patients received follow-up for toxicity and survival. Results Due to rapid accrual, a total of 350 patients were enrolled at 32 participating sites nationwide by October 2003. In the initially planned cohort of 100 assessable patients, the objective BR was 4% (95% Cl, 1.1% to 9.9%) by investigators' assessment and 1% (95% Cl, 0% to 5.5%) based on independent review; median progression-free survival was 3.5 months and median overall survival was 9.0 months. The safety profile was similar to prior BV trials in CRC. Grade 3 to 4 hemorrhage occurred in 5% of patients, including 3.8% with bleeding in the GI tract. Other adverse events such as hypertension, thrombosis, and bowel perforation were also observed at rates consistent with other studies. Conclusion For patients with advanced CRC that had progressed after both irinotecan-based and oxaliplatin-based chemotherapy regimens, the combination of BV and FU/LV was associated with rare objective responses. C1 NCI, Canc Treatment Evaluat Program, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD USA. RP Chen, HX (reprint author), NCI, Canc Treatment Evaluat Program, 6130 Execut Blvd,EPN 7131, Bethesda, MD 20892 USA. EM Helen_Chen@nih.gov NR 14 TC 137 Z9 145 U1 0 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2006 VL 24 IS 21 BP 3354 EP 3360 DI 10.1200/JCO.2005.05.1573 PG 7 WC Oncology SC Oncology GA 069BC UT WOS:000239418600010 PM 16849749 ER PT J AU Cisneros, GA Piquemal, JP Darden, TA AF Cisneros, G. Andres Piquemal, Jean-Philip Darden, Thomas A. TI Quantum mechanics/molecular mechanics electrostatic embedding with continuous and discrete functions SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID INTERMOLECULAR INTERACTION ENERGY AB A quantum mechanics/molecular mechanics (QM/MM) implementation that uses the Gaussian electrostatic model (GEM) as the MM force field is presented. GEM relies on the reproduction of electronic density by using auxiliary basis sets to calculate each component of the intermolecular interaction. This hybrid method has been used, along with a conventional QM/MM (point charges) method, to determine the polarization on the QM subsystem by the MM environment in QM/MM calculations on 10 individual H2O dimers and a Mg2+-H2O dimer. We observe that GEM gives the correct polarization response in cases when the MM fragment has a small charge, while the point charges produce significant over-polarization of the QM subsystem and in several cases present an opposite sign for the polarization contribution. In the case when a large charge is located in the MM subsystem, for example, the Mg2+ ion, the opposite is observed at small distances. However, this is overcome by the use of a damped Hermite charge, which provides the correct polarization response. C1 Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Cisneros, GA (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, Box 12233,MD F0-08, Res Triangle Pk, NC 27709 USA. EM cisnero1@niehs.nih.gov; darden@niehs.nih.gov RI Piquemal, Jean-Philip/B-9901-2009; Cisneros, Gerardo/B-3128-2010 OI Piquemal, Jean-Philip/0000-0001-6615-9426; FU Intramural NIH HHS [NIH0011757912, ]; PHS HHS [NIH0011757912] NR 18 TC 28 Z9 28 U1 0 U2 5 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 JUL 20 PY 2006 VL 110 IS 28 BP 13682 EP 13684 DI 10.1021/jp062768x PG 3 WC Chemistry, Physical SC Chemistry GA 063EY UT WOS:000239001700002 PM 16836309 ER PT J AU Bhatia, RS Tu, JV Lee, DS Austin, PC Fang, JM Haouzi, A Gong, YY Liu, PP AF Bhatia, R. Sacha Tu, Jack V. Lee, Douglas S. Austin, Peter C. Fang, Jiming Haouzi, Annick Gong, Yanyan Liu, Peter P. TI Outcome of heart failure with preserved ejection fraction in a population-based study SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VENTRICULAR SYSTOLIC FUNCTION; CONVERTING-ENZYME-INHIBITORS; CLINICAL-FEATURES; PROGNOSIS; MORTALITY; DIAGNOSIS; COMMUNITY; TRIAL; AGE; DETERMINANTS AB Background: The importance of heart failure with preserved ejection fraction is increasingly recognized. We conducted a study to evaluate the epidemiologic features and outcomes of patients with heart failure with preserved ejection fraction and to compare the findings with those from patients who had heart failure with reduced ejection fraction. Methods: From April 1, 1999, through March 31, 2001, we studied 2802 patients admitted to 103 hospitals in the province of Ontario, Canada, with a discharge diagnosis of heart failure whose ejection fraction had also been assessed. The patients were categorized in three groups: those with an ejection fraction of less than 40 percent (heart failure with reduced ejection fraction), those with an ejection fraction of 40 to 50 percent (heart failure with borderline ejection fraction), and those with an ejection fraction of more than 50 percent (heart failure with preserved ejection fraction). Two groups were studied in detail: those with an ejection fraction of less than 40 percent and those with an ejection fraction of more than 50 percent. The main outcome measures were death within one year and readmission to the hospital for heart failure. Results: Thirty-one percent of the patients had an ejection fraction of more than 50 percent. Patients with heart failure with preserved ejection fraction were more likely to be older and female and to have a history of hypertension and atrial fibrillation. The presenting history and clinical examination findings were similar for the two groups. The unadjusted mortality rates for patients with an ejection fraction of more than 50 percent were not significantly different from those for patients with an ejection fraction of less than 40 percent at 30 days (5 percent vs. 7 percent, P=0.08) and at 1 year (22 percent vs. 26 percent, P=0.07); the adjusted one-year mortality rates were also not significantly different in the two groups (hazard ratio, 1.13; 95 percent confidence interval, 0.94 to 1.36; P=0.18). The rates of readmission for heart failure and of in-hospital complications did not differ between the two groups. Conclusions: Among patients presenting with new-onset heart failure, a substantial proportion had an ejection fraction of more than 50 percent. The survival of patients with heart failure with preserved ejection fraction was similar to that of patients with reduced ejection fraction. C1 Univ Toronto, Heart & Stroke Richard Lewar Ctr Excellence, Toronto, ON, Canada. Univ Hlth Network, Toronto Gen Hosp, Div Cardiol, Toronto, ON, Canada. Univ Toronto, Sunnybrook & Womens Coll Hlth Sci Ctr, Div Gen Internal Med, Toronto, ON, Canada. NHLBI, Framingham Heart Study, Framingham, MA USA. Inst Clin Evaluat Sci, Toronto, ON, Canada. RP Liu, PP (reprint author), Toronto Gen Hosp, Heart & Stroke Richard Lewar Ctr Excellence, NCSB 11-1266,200 Elizabeth St, Toronto, ON M5G 2C4, Canada. EM peter.liu@utoronto.ca RI Lee, Douglas/J-4315-2014; OI Tu, Jack/0000-0003-0111-722X; Austin, Peter/0000-0003-3337-233X NR 33 TC 868 Z9 923 U1 4 U2 24 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 JUL 20 PY 2006 VL 355 IS 3 BP 260 EP 269 DI 10.1056/NEJMoa051530 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 064NY UT WOS:000239097600007 PM 16855266 ER PT J AU Ishimura, A Lee, HS Bong, YS Saucier, C Mood, K Park, E Daar, IO AF Ishimura, A. Lee, H-S Bong, Y-S Saucier, C. Mood, K. Park, E. K. Daar, I. O. TI Oncogenic Met receptor induces ectopic structures in Xenopus embryos SO ONCOGENE LA English DT Article DE Met receptor; Xenopus; tyrosine kinase signaling ID HEPATOCYTE GROWTH-FACTOR; FACTOR SCATTER FACTOR; EPITHELIAL-MESENCHYMAL TRANSITIONS; TYROSINE KINASE RECEPTOR; NEURAL CREST DEVELOPMENT; GRB2 BINDING-SITE; MESODERM INDUCTION; C-MET; MAP KINASE; CELL-TRANSFORMATION AB When aberrantly expressed or activated, the Met receptor tyrosine kinase is involved in tumor invasiveness and metastasis. In this study, we have used the Xenopus embryonic system to de. ne the role of various Met proximal-binding partners and downstream signaling pathways in regulating an induced morphogenetic event. We show that expression of an oncogenic derivative of the Met receptor (Tpr-Met) induces ectopic morphogenetic structures during Xenopus embryogenesis. Using variant forms of Tpr-Met that are engineered to recruit a specific signaling molecule of choice, we demonstrate that the sole recruitment of either the Grb2 or the Shc adaptor protein is sufficient to induce ectopic structures and anterior reduction, while the recruitment of PI-3Kinase (PI-3K) is necessary but not sufficient for this effect. In contrast, the recruitment of PLC gamma can initiate the induction, but fails to maintain or elongate supernumerary structures. Finally, evidence indicates that the Ras/Raf/MAPK pathway is necessary, but not sufficient to induce these structures. This study also emphasizes the importance of examining signaling molecules in the regulatory context that is provided by receptor/effector interactions when assessing a role in cell growth and differentiation. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. McGill Univ, Ctr Hlth, Mol Oncol Grp, Montreal, PQ, Canada. RP Daar, IO (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Prot Dynam & Signaling, Bldg 560,Room 22-3, Frederick, MD 21702 USA. EM daar@ncifcrf.gov RI Lee, Hyun-Shik/G-3555-2011; OI Daar, Ira/0000-0003-2657-526X FU Intramural NIH HHS NR 93 TC 4 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 20 PY 2006 VL 25 IS 31 BP 4286 EP 4299 DI 10.1038/sj.onc.1209463 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 066OU UT WOS:000239240100004 PM 16518409 ER PT J AU Soeda, E Ferran, MC Baker, CC McBride, AA AF Soeda, Emiko Ferran, Maureen C. Baker, Carl C. McBride, Alison A. TI Repression of HPV16 early region transcription by the E2 protein SO VIROLOGY LA English DT Article DE HPV; papillomavirus; replication; transcription; E1; E2; repression ID HUMAN-PAPILLOMAVIRUS TYPE-16; CARCINOMA CELL-LINES; DNA-REPLICATION; E6 PROMOTER; E1 PROTEIN; E7 GENE; E2-MEDIATED REPRESSION; TRANSIENT REPLICATION; ONCOGENE EXPRESSION; GROWTH-INHIBITION AB HPV16 DNA is often integrated in cancers, disrupting the E1 or E2 genes. E2 can repress the E6/E7 promoter, but other models have been proposed to explain why integration promotes malignant progression. E1 and E2 are required for viral replication, and so genetic analysis of their role in transcriptional regulation is complex. Therefore, we developed an extrachromosomal vector containing HPV16 to under-take a genetic analysis of the E1 and E2 genes. We demonstrate that the E2 protein is primarily a transcriptional repressor when expressed from the virus. Furthermore, repression requires both the transactivation function of E2 and specific binding of E2 to the LCR. We find no evidence that the El protein directly modulates HPV16 gene expression. However, certain Et mutations modulated transcription indirectly by altering splicing of E2 mRNA species. These data provide important insight into which E1 and E2 functions are optimal targets for anti-viral therapies. Published by Elsevier Inc. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. EM amcbride@nih.gov OI McBride, Alison/0000-0001-5607-5157 FU Intramural NIH HHS NR 55 TC 34 Z9 38 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 JUL 20 PY 2006 VL 351 IS 1 BP 29 EP 41 DI 10.1016/j.virol.2006.03.016 PG 13 WC Virology SC Virology GA 067RI UT WOS:000239319900004 PM 16624362 ER PT J AU Machado, RF Anthi, A Steinberg, MH Bonds, D Sachdev, V Kato, GJ Taveira-DaSilva, AM Ballas, SK Blackwelder, W Xu, XL Hunter, L Barton, B Waclawiw, M Castro, O Gladwin, MT AF Machado, Roberto F. Anthi, Anastasia Steinberg, Martin H. Bonds, Duane Sachdev, Vandana Kato, Gregory J. Taveira-DaSilva, Angelo M. Ballas, Samir K. Blackwelder, William Xu, Xiuli Hunter, Lori Barton, Bruce Waclawiw, Myron Castro, Oswaldo Gladwin, Mark T. CA MSH Investigators TI N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY-ARTERY-DISEASE; PRIMARY PULMONARY-HYPERTENSION; NITRIC-OXIDE BIOAVAILABILITY; VENTRICULAR DYSFUNCTION; MYOCARDIAL-INFARCTION; VASCULAR ENDOTHELIUM; ARGININE METABOLISM; PRACTICE GUIDELINES; PLATELET-ADHESION; PROGNOSTIC VALUE AB Context Thirty percent of patients with sickle cell disease (SCD) develop pulmonary hypertension, a major risk factor for death in this population. A validated blood biomarker of pulmonary hypertension in SCD could provide important prognostic and diagnostic information and allow the exploration of the prevalence of pulmonary hypertension in participants in the 1996 Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) Patients' Follow-up Study. Levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) provide such information in patients with idiopathic pulmonary arterial hypertension. Objective To determine the relationship between NT-proBNP levels and severity of pulmonary hypertension and prospective mortality in patients with SCD. Design, Setting, and Participants NT-proBNP levels were measured in 230 participants in the National Institutes of Health (NIH) Sickle Cell Disease-Pulmonary Hypertension Screening Study (enrollment between February 2001 and March 2005) and in 121 samples from patients enrolled starting in 1996 in the MSH Patients' Follow-up Study. A threshold level predictive of high pulmonary artery pressure and mortality was identified in the NIH Sickle Cell Disease-Pulmonary Hypertension Screening Study and used to define an a priori analytical plan to determine the prevalence and associated mortality of pulmonary hypertension in the MSH follow-up study. Main Outcome Measures Severity of pulmonary hypertension and risk of all-cause mortality. Results NT-proBNP levels were higher in patients with sickle cell pulmonary hypertension and correlated directly with tricuspid regurgitant jet velocity in the NIH cohort (R = 0.50, P<.001). An NT-proBNP level of 160 pg/mL or greater had a 78% positive predictive value for the diagnosis of pulmonary hypertension and was an independent predictor of mortality (21 deaths at 31 months' median follow-up; risk ratio, 5.1; 95% confidence interval, 2.1-12.5; P<.001; 19.5% absolute increase in risk of death). In the MSH cohort, 30% of patients had an NT-proBNP level of 160 pg/mL or greater. An NT-proBNP level of 160 pg/mL or greater in the MSH cohort was independently associated with mortality by Cox proportional hazards regression analysis (24 deaths at 47 months' median follow-up; risk ratio, 2.87; 95% confidence interval, 1.2-6.6; P=.02; 11.9% absolute increase in risk of death). Conclusions Pulmonary hypertension, as indicated by an NT-proBNP level of 160 pg/mL or greater, was very common in patients in the NIH study and in the MSH cohort. The MSH analysis suggests that rates of vaso-occlusive pain episodes in these patients were unrelated to risk of death; this risk was largely determined by occult hemolytic anemia-associated pulmonary hypertension. C1 NHLBI, Vasc Med Branch, Ctr Clin, NIH, Bethesda, MD 20892 USA. NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. NHLBI, Cardiovasc Branch, Bethesda, MD 20892 USA. NHLBI, Pulm & Crit Care Med Branch, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Med, Cardeza Fdn, Philadelphia, PA 19107 USA. Maryland Med Res Inst, Baltimore, MD USA. Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. RP Machado, RF (reprint author), NHLBI, Vasc Med Branch, Ctr Clin, NIH, 10 Ctr Dr,Bldg 10-CRC,Room 5-5130, Bethesda, MD 20892 USA. EM robertom@nhlbi.nih.gov RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Barton, Bruce/0000-0001-7878-8895 FU Intramural NIH HHS [Z99 HL999999, ZIA HL006012-01] NR 60 TC 98 Z9 102 U1 0 U2 3 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 JUL 19 PY 2006 VL 296 IS 3 BP 310 EP 318 DI 10.1001/jama.296.3.310 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 064LA UT WOS:000239089900023 PM 16849664 ER PT J AU Kim, BC Choi, JW Hong, HY Lee, SA Hong, S Park, EH Kim, SJ Lim, CJ AF Kim, Byung-Chul Choi, Joung-Woo Hong, Hye-Young Lee, Sin-Ae Hong, Suntaek Park, Eun-Hee Kim, Seong-Jin Lim, Chang-Jin TI Heme oxygenase-1 mediates the anti-inflammatory effect of mushroom Phellinus linteus in LPS-stimulated RAW264.7 macrophages SO JOURNAL OF ETHNOPHARMACOLOGY LA English DT Article DE Phellinus linteus; anti-inflammatory; heme oxygenase-1; reactive oxygen species; c-jun NH2-terminal kinase; nitric oxide ID NITRIC-OXIDE SYNTHASE; NECROSIS-FACTOR-ALPHA; JURKAT T-CELLS; CARBON-MONOXIDE; OXIDATIVE STRESS; UP-REGULATION; EXPRESSION; APOPTOSIS; ANTIOXIDANT; INDUCTION AB This work aimed to elucidate the anti-inflammatory mechanism of the n-BuOH subfraction (PL) prepared from fruiting bodies of Phellinus linteus. PL induced heme oxygenase-1 (HO-1) of the RAW264.7 macrophages in concentration- and time-dependent manner. It suppressed induction of inducible nitric oxide synthase (iNOS) and subsequent production of nitric oxide (NO) through down-regulation of iNOS promoter activity in lipopolysaccharide (LPS)-stimulated macrophages. Zn(II) protoporphyrin IX (ZnPP), a specific inhibitor of HO-1, partly blocked suppression by PL on iNOS promoter activity and NO production, which were elevated in LPS-stimulated macrophages. LPS was able to enhance NO production via reactive oxygen species (ROS) generation, c-Jun NH2-terminal kinase (INK) and c-Jun induction. ZnPP prevented PL from down-regulating ROS generation and JNK activation in LPS-stimulated macrophages. Taken together, PL shows its anti-inflammatory activity via mediation of HO-1 in an in vitro inflammation model. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Kangweon Natl Univ, Coll Nat Sci, Chunchon 200701, South Korea. Kangweon Natl Univ, Div Life Sci, Chunchon 200701, South Korea. Sookmyung Womens Univ, Coll Pharm, Seoul 140742, South Korea. Lab Cell Regulat & Carcinogenesis, NCI, Bethesda, MD 20892 USA. RP Kim, BC (reprint author), Kangweon Natl Univ, Coll Nat Sci, 192-1 Huoja 2 Dong, Chunchon 200701, South Korea. EM bckim@kangwon.ac.kr NR 31 TC 35 Z9 40 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-8741 J9 J ETHNOPHARMACOL JI J. Ethnopharmacol. PD JUL 19 PY 2006 VL 106 IS 3 BP 364 EP 371 DI 10.1016/j.jep.2006.01.009 PG 8 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 062SX UT WOS:000238965900013 PM 16488096 ER PT J AU Bredfeldt, CE Cumming, BG AF Bredfeldt, Christine E. Cumming, Bruce G. TI A simple account of cyclopean edge responses in macaque V2 SO JOURNAL OF NEUROSCIENCE LA English DT Article DE vision; binocular; macaque; V2; contour; disparity ID MONKEY VISUAL-CORTEX; RECEPTIVE-FIELDS; ORIENTATION SELECTIVITY; TEMPORAL-FREQUENCY; ENERGY MODELS; AREA V2; DISPARITY; V1; REPRESENTATION; PERCEPTION AB It has been shown recently that neurons in V2 respond selectively to the edges of figures defined only by disparity (cyclopean edges). These responses are orientation selective, often preferring similar orientations for cyclopean and luminance contours, suggesting that they may support a cue-invariant representation of contours. Here, we investigate the extent to which processing of purely local visual information (in the vicinity of the receptive field) might explain such results, using the most impoverished stimulus possible containing a cyclopean edge (a circular patch of random dots divided into two regions by a single edge). Many V2 cells responded better to the cyclopean edge than to uniform disparities, and most of these were at least broadly selective for the orientation of the cyclopean edge. Two characteristics argue against a cue-invariant contour representation: (1) the cyclopean edge response was frequently abolished by small changes to the component disparities; and (2) although V2 cells frequently responded to both signs of a cyclopean edge (defined by which side of the edge is in front), they did so at different edge locations. These characteristics are consistent with a simple feedforward scheme in which V2 neurons receive inputs from several V1 subunits with different disparity selectivity. We also found a correlation between the preferred orientations for cyclopean edges and contrast stimuli, suggesting that this feedforward wiring is not random. These characteristics suggest that V2 responses to cyclopean edges may be useful in supporting a cue-invariant contour representation higher in the visual pathway. C1 NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Bredfeldt, CE (reprint author), NEI, Sensorimotor Res Lab, 49 Convent Dr,2A50, Bethesda, MD 20892 USA. EM cb@nei.nih.gov FU Intramural NIH HHS NR 25 TC 29 Z9 29 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 19 PY 2006 VL 26 IS 29 BP 7581 EP 7596 DI 10.1523/JNEUROSCI.5308-05.2006 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 068GE UT WOS:000239359900007 PM 16855086 ER PT J AU Weston, MC Gertler, C Mayer, ML Rosenmund, C AF Weston, Matthew C. Gertler, Christoph Mayer, Mark L. Rosenmund, Christian TI Interdomain interactions in AMPA and kainate receptors regulate affinity for glutamate SO JOURNAL OF NEUROSCIENCE LA English DT Article DE glutamate receptor; gating; desensitization; crystal structure; kainate; AMPA ID RAT HIPPOCAMPAL SLICES; LIGAND-BINDING CORE; CRYSTAL-STRUCTURES; FALSE TRANSMITTER; ION CHANNELS; DESENSITIZATION; ACTIVATION; NEURONS; GLUR5; DERIVATIVES AB Ionotropic glutamate receptors perform diverse functions in the nervous system. As a result, multiple receptor subtypes have evolved with different kinetics, ion permeability, expression patterns, and regulation by second messengers. Kainate receptors show slower recovery from desensitization and have different affinities for agonists than AMPA receptors. Based on analysis of ligand binding domain crystal structures, we identified interdomain interactions in the agonist-bound state that are conserved in kainate receptors and absent in AMPA receptors. Mutations in GluR6 designed to disrupt these contacts reduced agonist apparent affinity, speeded up receptor deactivation and increased the rate of recovery from desensitization. Conversely, introduction of mutations in GluR2 that enabled additional interdomain interactions in the agonist-bound state increased agonist apparent affinity 15-fold, and slowed both deactivation and recovery from desensitization. We conclude that interdomain interactions have evolved as a distinct mechanism that contributes to the unique kinetic properties of AMPA and kainate receptors. C1 Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Rosenmund, C (reprint author), Baylor Coll Med, Dept Neurosci, 1 Baylor Plaza,Room 833E, Houston, TX 77030 USA. EM rosenmun@bcm.tmc.edu RI Mayer, Mark/H-5500-2013; OI Rosenmund, Christian/0000-0002-3905-2444 FU Intramural NIH HHS NR 31 TC 56 Z9 60 U1 1 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 19 PY 2006 VL 26 IS 29 BP 7650 EP 7658 DI 10.1523/JNEUROSCI.1519-06.2006 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 068GE UT WOS:000239359900013 PM 16855092 ER PT J AU Anderson, WF Matsuno, R AF Anderson, William F. Matsuno, Rayna TI Breast cancer heterogeneity: A mixture of at least two main types? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID GENE-EXPRESSION PROFILES; BRCA2 MUTATION CARRIERS; ESTROGEN-RECEPTOR; FEMALE BREAST; AGE DISTRIBUTION; UNITED-STATES; STEM-CELLS; BIOLOGIC CHARACTERISTICS; SALPINGO-OOPHORECTOMY; CARCINOMA C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Anderson, WF (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Room 8036,6120 Execut Blvd, Bethesda, MD 20892 USA. EM wanderso@mail.nih.gov FU Intramural NIH HHS NR 67 TC 65 Z9 71 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 19 PY 2006 VL 98 IS 14 BP 948 EP 951 DI 10.1093/jnci/djj295 PG 4 WC Oncology SC Oncology GA 067CJ UT WOS:000239279000003 PM 16849671 ER PT J AU You, WC Brown, LM Zhang, L Li, JY Jin, ML Chang, YS Ma, JL Pan, KF Liu, WD Hu, YR Crystal-Mansour, S Pee, D Blot, WJ Fraumeni, JF Xu, GW Gail, MH AF You, Wei-cheng Brown, Linda M. Zhang, Lian Li, Ji-you Jin, Mao-lin Chang, Yun-Shen Ma, Jun-ling Pan, Kai-feng Liu, Wei-dong Hu, Yuanreng Crystal-Mansour, Susan Pee, David Blot, William J. Fraumeni, Joseph F., Jr. Xu, Guang-wei Gail, Mitchell H. TI Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HELICOBACTER-PYLORI ERADICATION; INTESTINAL METAPLASIA; ATROPHIC GASTRITIS; HIGH-RISK; STOMACH-CANCER; ANTIOXIDANT SUPPLEMENTS; SERUM MICRONUTRIENTS; BETA-CAROTENE; LUNG-CANCER; INFECTION AB Background: Randomized trials have yielded mixed results on the effects of treatment for Helicobacter pylori and little information on the effects of vitamins or garlic supplements on precancerous gastric lesions. We conducted a randomized trial to test the effects of one-time H. pylori treatment and long-term vitamin or garlic supplements in reducing the prevalence of advanced precancerous gastric lesions. Methods: Most of the adults aged 35-64 years in 13 randomly selected villages in Linqu County, Shandong Province, China, were identified and given baseline endoscopies in 1994. In 1995, 3365 eligible subjects were randomly assigned in a factorial design to three interventions or placebos: amoxicillin and omeprazole for 2 weeks in 1995 (H. pylori treatment); vitamin C, vitamin E, and selenium for 7.3 years (vitamin supplement); and aged garlic extract and steam-distilled garlic oil for 7.3 years (garlic supplement). Subjects underwent endoscopies with biopsies in 1999 and 2003, and the prevalence of precancerous gastric lesions was determined by histopathologic examination of seven standard biopsy sites. The 3365 eligible randomized subjects represented 93.5% of those with baseline endoscopy and included all baseline histologic categories except gastric cancer. Only 0.18% had normal gastric mucosa. Logistic regression was used to estimate the intervention effects on the odds of advanced precancerous gastric lesions, and t-tests were used to assess effects on histologic severity. All statistical tests were two-sided. Results: H. pylori treatment resulted in statistically significant decreases in the combined prevalence of severe chronic atrophic gastritis, intestinal metaplasia, dysplasia, or gastric cancer in 1999 (odds ratio [OR] = 0.77; 95% confidence interval [CI] = 0.62 to 0.95) and in 2003 (OR = 0.60; 95% Cl = 0.47 to 0.75), and had favorable effects on the average histopathologic severity and on progression and regression of precancerous gastric lesions in 2003. H. pylori treatment did not reduce the combined prevalence of dysplasia or gastric cancer. However, fewer subjects receiving H. pylori treatment (19/1130; 1.7%) than receiving placebo (27/1128; 2.4%) developed gastric cancer (adjusted P=.14). No statistically significant favorable effects were seen for garlic or vitamin supplements. Conclusion: H. pylori treatment reduces the prevalence of precancerous gastric lesions and may reduce gastric cancer incidence, but further data are needed to prove the latter point. Long-term vitamin or garlic supplementation had no beneficial effects on the prevalence of precancerous gastric lesions or on gastric cancer incidence. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Peking Univ, Beijing Canc Hosp, Sch Oncol, Beijing, Peoples R China. Linqu Cty Publ Hlth Bur, Shandong, Peoples R China. Westat Corp, Rockville, MD USA. Informat Management Serv Inc, Rockville, MD USA. Int Epidemiol Inst Ltd, Rockville, MD USA. Vanderbilt Univ, Nashville, TN USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8032, Bethesda, MD 20892 USA. EM gailm@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N02-CP-21169, N02-CP-71103] NR 34 TC 237 Z9 268 U1 0 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 19 PY 2006 VL 98 IS 14 BP 974 EP 983 DI 10.1093/jnci/djj264 PG 10 WC Oncology SC Oncology GA 067CJ UT WOS:000239279000011 PM 16849680 ER PT J AU McGlynn, KA Abnet, CC Zhang, MD Sun, XD Fan, JH O'Brien, TR Wei, WQ Ortiz-Conde, BA Dawsey, SM Weber, JP Taylor, PR Katki, H Mark, SD Qiao, YL AF McGlynn, Katherine A. Abnet, Christian C. Zhang, Mingdong Sun, Xiu-Di Fan, Jin-Hu O'Brien, Thomas R. Wei, Wen-Qiang Ortiz-Conde, Betty A. Dawsey, Sanfbrd M. Weber, Jean-Philippe Taylor, Philip R. Katki, Hormuzd Mark, Steven D. Qiao, You-Lin TI Serum concentrations of 1,1,1-Trichloro-2,2-bis (p-chlorophenyl)ethane (DDT) and 1,1-Dichloro-2,2-bis (p-chlorophenyl)ethylene (DDE) and risk of primary liver cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ESOPHAGEAL CANCER; GASTRIC CANCERS; CHINA; MORTALITY; PESTICIDES; EXPOSURE; DICHLORODIPHENYLTRICHLOROETHANE; HEPTACHLOR; COHORT; RAT AB Background: 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) exposure has been demonstrated to cause liver tumors in laboratory rodents. DDT's persistent metabolite and environmental degradation product, 1,1-dichloro-2,2bis(p-chlorophenyl)ethylene (DDE), has also been associated with liver tumors in laboratory animals. Whether DDT and DDE are associated with hepatocarcinogenesis in humans is not clear. Methods: We carried out a nested case-control study among the participants of the Nutritional Intervention Trials in Linxian, China. The case group included 168 individuals who developed liver cancer during the trials, and the control group included 385 individuals frequency-matched on age and sex who were alive and well at the end of the study. Serum concentrations of DDT and DDE were measured by gas chromatography-mass spectrometry. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable analysis. Results: In multivariable-adjusted models, the risk of developing liver cancer increased with increased serum DDT concentration (OR for quintile 1 versus quintile 5 = 3.8, 95% CI = 1.7 to 8.6, P-trend =.0024). In contrast, there was no statistically significant association between liver cancer and serum DDE concentration. The association between high serum DDT concentration and liver cancer was stronger among individuals with DDE concentrations below the median value (odds ratio for tertile 3 versus tertile 1 = 3.55, 95% CI =1.45 to 8.74) than those with concentrations above the median (OR = 1.70, 95% CI = 0.97 to 2.98). A calculation of crude liver cancer risk found that there would be 26 liver cancers per 100000 persons per year in the lowest quintile of DDT exposure versus 46 liver cancers per 100000 persons per year in the highest quintile of DDT exposure. Conclusions: DDT may be a risk factor for liver cancer, particularly among persons with lower DDE concentrations. Risk may be particularly increased among persons exposed directly to DDT (resulting in a higher ratio of DDT to DDE) or, alternatively, risk may be associated with individual ability to metabolize DDT to DDE. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. Chinese Univ Hong Kong, Ctr Emerging Infect Dis, Sha Tin 100083, Hong Kong, Peoples R China. Chinese Acad Med Sci, Inst Canc, Beijing 100021, Peoples R China. Natl Canc Inst, Viral Epidemiol Sect, AIDS Vaccine Program, SAIC Frederick, Frederick, MD USA. Natl Publ Hlth Inst, Toxicol Ctr, Ste Foy, PQ, Canada. Univ Colorado, Hlth Sci Ctr, Denver, CO 80202 USA. RP McGlynn, KA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, EPS-7060,6120 Execut Blvd, Rockville, MD 20852 USA. EM mcglynnk@mail.nih.gov RI Qiao, You-Lin/B-4139-2012; Katki, Hormuzd/B-4003-2015; Abnet, Christian/C-4111-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 36 TC 51 Z9 55 U1 3 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 19 PY 2006 VL 98 IS 14 BP 1005 EP 1010 DI 10.1093/jnci/djj266 PG 6 WC Oncology SC Oncology GA 067CJ UT WOS:000239279000014 PM 16849683 ER PT J AU Gan, JH Gu, YJ Li, Y Yan, HG Ji, XH AF Gan, Jianhua Gu, Yijun Li, Yue Yan, Honggao Ji, Xinhua TI Crystal structure of Mycobacterium tuberculosis shikimate kinase in complex with shikimic acid and an ATP analogue SO BIOCHEMISTRY LA English DT Article ID NUCLEOSIDE MONOPHOSPHATE KINASES; BINDING; SPECIFICITY; MOLSCRIPT; REVEALS; PATHWAY AB Shikimate kinase (SK) and other enzymes in the shikimate pathway are potential targets for developing nontoxic antimicrobial agents, herbicides, and antiparasite drugs, because the pathway is essential in microorganisms, plants, and parasites but absent from mammals. SK catalyzes the reaction of phosphoryl transfer from ATP to shikimic acid ( SA). Since 2002, a total of 11 SK structures have been reported, but none contains either the two substrate ( SA and ATP) or the two product (SA- phosphate and ADP) molecules. Here, we present three crystal structures of SK from Mycobacterium tuberculosis (MtSK), including apo-MtSK, a binary complex MtSK, SA, and the ternary complex of MtSK with SA and an ATP analogue, AMPPCP. The structures of apo-MtSK and MtSK, AMPPCP, SA make it possible to elucidate the conformational changes of MtSK upon the binding of both substrates; the structure of MtSK, AMPPCP, SA reveals interactions between the protein and gamma-phosphate which indicate dynamic roles of catalytic residues Lys15 and Arg117. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. RP Ji, XH (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM jix@ncifcrf.gov RI Gu, Yijun/B-6017-2012; Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU Intramural NIH HHS; NIGMS NIH HHS [GM51901] NR 30 TC 26 Z9 28 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 JUL 18 PY 2006 VL 45 IS 28 BP 8539 EP 8545 DI 10.1021/bi0606290 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 062DK UT WOS:000238924600009 PM 16834327 ER PT J AU Garg, PK Tian, L Criqui, MH Liu, K Ferrucci, L Guralnik, JM Tan, J McDermott, MM AF Garg, Parveen K. Tian, Lu Criqui, Michael H. Liu, Kiang Ferrucci, Luigi Guralnik, Jack M. Tan, Jin McDermott, Mary M. TI Physical activity during daily life and mortality in patients with peripheral arterial disease SO CIRCULATION LA English DT Article DE claudication; mortality; peripheral vascular disease; physical activity ID ALL-CAUSE MORTALITY; ANKLE BRACHIAL INDEX; LEISURE-TIME; CARDIOVASCULAR-DISEASE; CALTRAC ACCELEROMETER; 6-MINUTE WALK; LEG SYMPTOMS; PREVALENCE; EXERCISE; QUESTIONNAIRES AB Background - We determined whether patients with lower-extremity peripheral arterial disease ( PAD) who are more physically active during daily life have lower mortality rates than PAD patients who are less active. Methods and Results - Participants were 460 men and women with PAD (mean age 71.9 +/- 8.4 years) followed up for 57 months (interquartile range 36.6 to 61.9 months). At baseline, participants were interviewed about their physical activity. Vertical accelerometers measured physical activity continuously over 7 days in 225 participants. Analyses were adjusted for age, sex, race, body mass index, hypertension, smoking, comorbidities, total cholesterol, HDL cholesterol, leg symptoms, and ankle-brachial index. At 57-month follow-up, 134 participants (29%) had died, including 75 participants (33%) who wore accelerometers. Higher baseline physical activity levels measured by vertical accelerometer were associated with lower all-cause mortality (P-trend = 0.003). Relative to PAD participants in the highest quartile of accelerometer-measured physical activity, those in the lowest quartile had higher total mortality (hazard ratio 3.48, 95% confidence interval 1.23 to 9.87, P=0.019). Similar results were observed for the combined outcome of cardiovascular events or cardiovascular mortality (P-trend = 0.005). Higher numbers of stair flights climbed during 1 week were associated with lower total mortality (P-trend = 0.035). Conclusions - PAD patients with higher physical activity during daily life have reduced mortality and cardiovascular events compared with PAD patients with the lowest physical activity, independent of confounders. Further study is needed to determine whether interventions that increase physical activity during daily life are associated with improved survival in patients with PAD. C1 NYU, Sch Med, New York, NY USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL USA. Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. NIA, Bethesda, MD 20892 USA. RP McDermott, MM (reprint author), 676 N St Clair,Suite 200, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU Intramural NIH HHS [Z99 AG999999]; NCRR NIH HHS [M01 RR000048, RR-00048]; NHLBI NIH HHS [R01 HL073912, R01 HL064739, R01 HL071223, R01 HL073351, R01-HL073351, R01-HL073912, R01-HL58099, R01-HL64739, R01-HL71223] NR 37 TC 106 Z9 113 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 18 PY 2006 VL 114 IS 3 BP 242 EP 248 DI 10.1161/CIRCUALTIONAHA.105.605246 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 064FB UT WOS:000239073500011 PM 16818814 ER PT J AU Kim, H Lee, H Rowan, J Brahim, J Dionne, RA AF Kim, Hyungsuk Lee, Hyewon Rowan, Janet Brahim, Jaime Dionne, Raymond A. TI Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans SO MOLECULAR PAIN LA English DT Article ID O-METHYLTRANSFERASE COMT; DOPAMINE D2 RECEPTOR; VAL158MET POLYMORPHISM; POPULATION-STRUCTURE; AGGRESSIVE-BEHAVIOR; SEX-DIFFERENCES; EXPRESSION; HERITABILITY; GENDER; PHARMACOGENETICS AB Background: Candidate gene studies on the basis of biological hypotheses have been a practical approach to identify relevant genetic variation in complex traits. Based on previous reports and the roles in pain pathways, we have examined the effects of variations of loci in the genes of monoamine neurotransmitter systems including metabolizing enzymes, receptors and transporters on acute clinical pain responses in humans. Results: Variations in the catecholamine metabolizing enzyme genes (MAOA and COMT) showed significant associations with the maximum post- operative pain rating while the serotonin transporter gene ( SLC6A4) showed association with the onset time of post-operative pain. Analgesic onset time after medication was significantly associated with the norepinephrine transporter gene (SLC6A2). However, the association between COMT genetic variation and pain sensitivity in our study differ from previous studies with small sample sizes, population stratification and pain phenotype derived from combining different types of pain stimuli. Correcting for multiple comparisons did not sustain these genetic associations between monoamine neurotransmitter systems and pain sensitivity even in this large and homogeneous sample. Conclusion: These results suggest that the previously reported associations between genetic polymorphisms in the monoamine neurotransmitter systems and the interindividual variability in pain responses cannot be replicated in a clinically relevant pain phenotype. C1 NINR, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD USA. NIH, Dept Nursing, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Clin Res Core, NIH, Bethesda, MD USA. RP Dionne, RA (reprint author), NINR, NIH, Bethesda, MD 20892 USA. EM kimhy@mail.nih.gov; leehye@mail.nih.gov; JRowan@cc.nih.gov; jbrahim@dir.nidcr.nih.gov; dionner@mail.nih.gov FU Intramural NIH HHS NR 45 TC 70 Z9 74 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD JUL 18 PY 2006 VL 2 AR 24 DI 10.1186/1744-8069-2-24 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 165BI UT WOS:000246278400001 PM 16848906 ER PT J AU Best, RB Lindorff-Larsen, K DePristo, MA Vendruscolo, M AF Best, Robert B. Lindorff-Larsen, Kresten DePristo, Mark A. Vendruscolo, Michele TI Relation between native ensembles and experimental structures of proteins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE NMR order parameters; protein dynamics; residual dipolar couplings ID RESIDUAL DIPOLAR COUPLINGS; SIDE-CHAIN DYNAMICS; SMALL ALPHA/BETA PROTEIN; MODEL-FREE APPROACH; MOLECULAR-DYNAMICS; ORDER PARAMETERS; GLOBULAR-PROTEINS; NMR-SPECTROSCOPY; X-RAY; RELAXATION AB Different experimental structures of the same protein or of proteins with high sequence similarity contain many small variations. Here we construct ensembles of "high-sequence similarity Protein Data Bank" (HSP) structures and consider the extent to which such ensembles represent the structural heterogeneity of the native state in solution. We find that different NMR measurements probing structure and dynamics of given proteins in solution, including order parameters, scalar couplings, and residual dipolar couplings, are remarkably well reproduced by their respective high-sequence similarity Protein Data Bank ensembles; moreover, we show that the effects of uncertainties in structure determination are insufficient to explain the results. These results highlight the importance of accounting for native-state protein dynamics in making comparisons with ensemble-averaged experimental data and suggest that even a modest number of structures of a protein determined under different conditions, or with small variations in sequence, capture a representative subset of the true native-state ensemble. C1 Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. Univ Copenhagen, Dept Biochem, Inst Mol Biol & Physiol, DK-2100 Copenhagen O, Denmark. Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. RP Best, RB (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM best@helix.nih.gov RI Vendruscolo, Michele/F-5901-2012; Lindorff-Larsen, Kresten/K-6469-2014; Best, Robert/H-7588-2016 OI Lindorff-Larsen, Kresten/0000-0002-4750-6039; Best, Robert/0000-0002-7893-3543 NR 52 TC 90 Z9 91 U1 0 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 JUL 18 PY 2006 VL 103 IS 29 BP 10901 EP 10906 DI 10.1073/pna.0511156103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 067UD UT WOS:000239327200016 PM 16829580 ER PT J AU Alexander, GE Chen, KW Merkley, TL Reiman, EM Caselli, RJ Aschenbrenner, M Santerre-Lemmon, L Lewis, DJ Pietrini, P Teipel, SJ Hampel, H Rapoport, SI Moeller, JR AF Alexander, Gene E. Chen, Kewei Merkley, Tricia L. Reiman, Eric M. Caselli, Richard J. Aschenbrenner, Melaney Santerre-Lemmon, Laura Lewis, Diana J. Pietrini, Pietro Teipel, Stefan J. Hampel, Harald Rapoport, Stanley I. Moeller, James R. TI Regional network of magnetic resonance imaging gray matter volume in healthy aging SO NEUROREPORT LA English DT Article DE aging; gray matter; magnetic resonance imaging; multivariate analysis; principal component analysis; Scaled Subprofile Model; voxel-based morphometry ID VOXEL-BASED MORPHOMETRY; ALZHEIMERS-DISEASE; METABOLIC TOPOGRAPHY; COGNITIVE RESERVE; BRAIN; AGE; DECLINE; ADULTS; MRI AB Healthy aging has been associated with brain volume reductions preferentially affecting the frontal cortex, but also involving other regions. We used a network model of regional covariance, the Scaled Subprofile Model, with magnetic resonance imaging voxel-based morphometry to identify the regional distribution of gray matter associated with aging in 26 healthy adults, 22-77 years old. Scaled Subprofile Model analysis identified a pattern that was highly correlated with age (R-2 = 0.66, P <= 0.0001). Older age was associated with less gray matter in the bilateral frontal, temporal, thalamic, and right cerebellar regions. Gender differences suggested more advanced brain aging in the men. In this healthy adult sample, aging was associated with a regional pattern of gray matter atrophy most prominently involving the frontal and temporal cortices. Scaled Subprofile Model network analysis may aid in the detection and tracking of brain aging and in the evaluation of putative antiaging therapies. C1 Arizona State Univ, Dept Psychol, Neuroimage Anal Lab, Tempe, AZ 85287 USA. Banner Good Samaritan Med Ctr, Banner Alzheimers Inst, Phoenix, AZ USA. Banner Good Samaritan Med Ctr, Banner Samaritan PET Ctr, Phoenix, AZ USA. Univ Arizona, Hlth Sci Ctr, Dept Psychiat, Tucson, AZ USA. Mayo Clin Scottsdale, Dept Neurol, Scottsdale, AZ USA. NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. Univ Pisa, Sch Med, Dept Clin Biochem & Mol Biol, I-56100 Pisa, Italy. Univ Munich, Dementia & Neuroimaging Res Sect, Alzheimers Mem Ctr, Munich, Germany. Univ Munich, Dept Psychiat, Geriatr Psychiat Branch, D-8000 Munich, Germany. RP Alexander, GE (reprint author), Arizona State Univ, Dept Psychol, Neuroimage Anal Lab, Tempe, AZ 85287 USA. EM gene.alexander@asu.edu RI Chen, kewei/P-6304-2015 OI Chen, kewei/0000-0001-8497-3069 FU NIA NIH HHS [P30AG19610]; NIMH NIH HHS [R01 MH57899] NR 25 TC 39 Z9 40 U1 4 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 17 PY 2006 VL 17 IS 10 BP 951 EP 956 DI 10.1097/01.wnr.0000220135.16844.b6 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 066ER UT WOS:000239213000002 PM 16791083 ER PT J AU Brandt, KR Gardiner, JM Vargha-Khadem, F Baddeley, AD Mishkin, M AF Brandt, Karen R. Gardiner, John M. Vargha-Khadem, Faraneh Baddeley, Alan D. Mishkin, Mortimer TI Using semantic memory to boost 'episodic' recall in a case of developmental amnesia SO NEUROREPORT LA English DT Article DE developmental amnesia; episodic memory; recall; semantic memory ID ACTION EVENTS; FAMILIARITY; RECOGNITION AB We report two experiments that investigated factors that might boost 'episodic' recall for Jon, a developmental amnesic whose episodic memory is gravely impaired but whose semantic memory seems relatively normal. Experiment 1 showed that Jon's recall improved following a semantic study task compared with a non-semantic study task, as well as following four repeated study trials compared with only one. Experiment 2 additionally revealed that Jon's recall improved after acting compared with reading action phrases at study, but only if the phrases were well integrated semantically. The results provide some support for the hypothesis that Jon's 'episodic' recall depends on the extent to which he is able to retrieve events using semantic memory. C1 Univ Keele, Sch Psychol, Keele ST5 5BG, Staffs, England. Univ Sussex, Brighton BN1 9RH, E Sussex, England. UCL, London, England. Great Ormond St Hosp Sick Children, London WC1N 3JH, England. Univ York, York YO10 5DD, N Yorkshire, England. NIMH, NIH, DHHS, Bethesda, MD 20892 USA. RP Brandt, KR (reprint author), Univ Keele, Sch Psychol, Dorothy Hodgkin Bldg, Keele ST5 5BG, Staffs, England. EM k.r.brandt@psy.keele.ac.uk RI Vargha-Khadem, Faraneh/C-2558-2008 FU Intramural NIH HHS; Medical Research Council [G0300117] NR 16 TC 8 Z9 8 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 17 PY 2006 VL 17 IS 10 BP 1057 EP 1060 DI 10.1097/01.wnr.0000220134.09221.04 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 066ER UT WOS:000239213000022 PM 16791103 ER PT J AU Windels, F Kiyatkin, EA AF Windels, Francois Kiyatkin, Eugene A. TI Stability of substantia nigra pars reticulata neuronal discharge rates during dopamine receptor blockade and its possible mechanisms SO NEUROREPORT LA English DT Article DE dopamine deficit; eticlopride; 7-amino-n-butyric acid; rats; receptor hyposensitivity; SCH23390 ID FREELY MOVING RATS; GLUTAMATE; NUCLEUS AB It is hypothesized that substantia nigra pars reticulata neurons become overactive during a deficit of dopamine transmission. In this study, we examined how acute dopamine receptor blockade (SCH23390 and eticlopricle) affects impulse activity of substantia nigra pars reticulata neurons and their response to iontophoretic gamma-amino-n-butyric acid in awake, unrestrained rats. No changes in discharge rate were found during complete dopamine receptor blockade, but these neurons showed a diminished response to gamma-amino-n-butyric acid, suggesting gamma-amino-n-butyric acid receptor hyposensitivity. This may result from tonic increase in gamma-amino-n-butyric acid input from the striatum and globus palliclus, which are activated during dopamine receptor blockade. As substantia nigra pars reticulata neurons are autoactive and resistant to tonic increases in gamma-amino-n-butyric acid input, changes in their responsiveness to phasic gamma-amino-n-butyric acid inputs, not tonic increase discharge rate, may underlie movement disturbance following dopamine deficit. C1 NIDA, Cellular Neurobiol Sect, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, Cellular Neurobiol Sect, Intramural Res Program, NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov RI Windels, Francois/G-5432-2010 FU Intramural NIH HHS NR 20 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 17 PY 2006 VL 17 IS 10 BP 1071 EP 1075 DI 10.1097/01.wnr.0000221845.43126.7d PG 5 WC Neurosciences SC Neurosciences & Neurology GA 066ER UT WOS:000239213000025 PM 16791106 ER PT J AU Koshiol, J Schroeder, J Jamieson, DJ Marshall, SW Duerr, A Heilig, CM Shah, KV Klein, RS Cu-Uvin, S Schuman, P Celentano, D Smith, JS AF Koshiol, J Schroeder, J Jamieson, DJ Marshall, SW Duerr, A Heilig, CM Shah, KV Klein, RS Cu-Uvin, S Schuman, P Celentano, D Smith, JS TI Smoking and time to clearance of human papillomavirus infection in HIV-seropositive and HIV-seronegative women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE HIV; papillomavirus; human; smoking; women ID HUMAN-IMMUNODEFICIENCY-VIRUS; ONCOGENIC HUMAN-PAPILLOMAVIRUS; CERVICAL-CANCER; CIGARETTE-SMOKING; NATURAL-HISTORY; YOUNG-WOMEN; PERSISTENCE; NEOPLASIA; RISK; CYTOLOGY AB Persistent human papillomavirus (HPV) infection seems central to cervical carcinogenesis. Smoking is associated with cervical cancer in HPV DNA-positive women, but its association with HPV persistence is unclear, particularly with respect to human immunodeficiency virus (HIV) serostatus. The authors evaluated smoking and HPV clearance by HIV serostatus among 801 women from the HIV Epidemiology Research Study (United States, 1993-2000). Type-specific HPV duration was defined as the interval between initial MY09/11 polymerase chain reaction positivity and the first of two consecutive HPV-negative study visits. Hazard ratios adjusted for study site and risk behaviors (sexual activity or injection drug use) were estimated using Cox regression. This analysis included 522 HIV-seropositive and 279 HIV-seronegative women (median follow-up, 4.4 years). Ever smoking was associated with reduced clearance of high-risk HPV in HIV-seronegative women (hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.30, 0.88) but not in HIV-seropositive women (HR = 0.96, 95% CI: 0.65, 1.42); similar results were found for current smoking. Current smoking was not associated with clearance of any type-specific HPV in HIV-seropositive (HR = 0.99, 95% CI: 0.82, 1.20) or HIV-seronegative (HR = 0.93, 95% CI: 0.68, 1.26) women. HPV clearance did not appear to vary by amount or duration of smoking. Smoking did not modify overall clearance but was associated with lower high-risk HPV clearance in HIV-seronegative women. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Natl Ctr Chron Dis Prevent & Hlth Promot, Womens Hlth & Fertil Branch, Div Reprod Hlth, Atlanta, GA USA. HIV Vaccine Trials Network, Seattle, WA USA. Ctr Dis Control & Prevent, Off Chief Sci Officer, Atlanta, GA USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Bethesda, MD USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Brown Univ, Brown Med Sch, Dept Obstet & Gynecol, Providence, RI 02912 USA. Virginia Commonwealth Univ, Dept Infect Dis & Qual Hlth Care, Sch Med, Richmond, VA 23298 USA. Wayne State Univ, Sch Med, Div Infect Dis, Dept Med, Detroit, MI USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. RP Koshiol, J (reprint author), NCI, 6120 Execut Blvd,MSC 7236, Bethesda, MD 20892 USA. EM koshiolj@mail.nih.gov RI Heilig, Charles/C-2753-2008; OI Heilig, Charles/0000-0003-1075-1310; Marshall, Stephen/0000-0002-2664-9233 FU NCI NIH HHS [CA09330-22]; NIAID NIH HHS [5 P30 AI050410-07]; PHS HHS [U64/CCU306802, U64/CCU506831, U64/CCU106795, U64/CCU206798] NR 30 TC 27 Z9 27 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 JUL 15 PY 2006 VL 164 IS 2 BP 176 EP 183 DI 10.1093/aje/kwj165 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 059UY UT WOS:000238758900011 PM 16775041 ER PT J AU Sharp, JS Tomer, KB AF Sharp, Joshua S. Tomer, Kenneth B. TI Effects of anion proximity in peptide primary sequence on the rate and mechanism of leucine oxidation SO ANALYTICAL CHEMISTRY LA English DT Article ID AMINO-ACID-RESIDUES; PROTEIN-PROTEIN INTERACTIONS; X-RAY RADIOLYSIS; MASS-SPECTROMETRY; BINDING SITES; STRUCTURAL REORGANIZATION; COPPER; HYDROPEROXIDES; RADICALS; SURFACE AB Hydroxyl radical surface mapping is a useful tool for investigating protein structure and folding. The rate of protein side-chain oxidation by the hydroxyl radical is known to be affected primarily by the chemical reactivity of the side chain and the accessibility of the reactive site to the radical. Efforts have been made to determine the inherent rate of stable product formation of each amino acid side chain, so that the rate of oxidation of an amino acid can be used to accurately estimate the average solvent accessibility of the amino acid side chain in the folded protein. However, the effects of nearby primary sequence on peptide oxidation have not been studied. Here, we examine the amounts of various oxidation products of a small peptide consisting of one leucine and one aspartic acid separated by zero to five glycine residues, as well as with modification of the N- and C-terminus. We find that the relative amounts of certain oxidation products can be heavily influenced by the primary structure of the surrounding peptide. The formation of many products, including hydroxylation, is inhibited by proximity to negative charges, while the formation of other products showed more complicated responses to changing primary sequence. C1 NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Sharp, JS (reprint author), NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM sharp1@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013 FU Intramural NIH HHS NR 38 TC 16 Z9 16 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD JUL 15 PY 2006 VL 78 IS 14 BP 4885 EP 4893 DI 10.1021/ac060329o PG 9 WC Chemistry, Analytical SC Chemistry GA 063KS UT WOS:000239017700017 PM 16841907 ER PT J AU Castillo, CG Mendoza, S Freed, WJ Giordano, M AF Castillo, CG Mendoza, S Freed, WJ Giordano, M TI Intranigral transplants of immortalized GABAergic cells decrease the expression of kainic acid-induced seizures in the rat SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE neural transplantation; glutamate decarboxylase; temporal lobe epilepsy; animal models; substantia nigra; Epstein barr ID LARGE T-ANTIGEN; TEMPORAL-LOBE EPILEPSY; WET DOG SHAKES; SUBSTANTIA-NIGRA; GRANULE CELLS; TSA58 ALLELE; GABA; LINES; NEURONS; GLUTAMATE AB Repeated systemic administration of low doses of kainic acid (KA) induces spontaneous convulsive seizures [Hellier JL, Patrylo PR, Buckmaster PS, DudekFE. Recurrent spontaneous motor seizures after repeated low-dose systemic treatment with kainate: assessment of a rat model of temporal lobe epilepsy. Epilepsy Res 1998;31:73-84]. In this study, mate Sprague-Dawley animals received intranigral transplants of a control cell line M213-20, or a cell line transfected with human GAD67 cDNA (M213-20 CL4) [Conejero-Goldberg C, Tomatore C, Abi-Saab W, Monaco MC, Dillon-Carter O, Vawter M, et al. Transduction of human GAD67 cDNA into immortalized striatal cell lines using an Epstein-Barr virus-based plasmid vector increases GABA content. Exp Neurol 2000;161:453-61], or no transplant. Eight weeks after transplantation surgery, KA was administered (5 mg/kg/h) until animals reached stage V seizures as described by Racine [Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972;32:281-94]. The group transplanted with CL4 required a larger dose of KA and a longer latency to reach a stage V seizure. In addition, this group exhibited significantly fewer stage III and IV seizures. These results indicate that intranigral transplants of a GABA-producing cell line can decrease the number of kainic acid-induced seizures. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ Nacl Autonoma Mexico, Dept Cognit & Behav Neurobiol, Inst Neurobiol, Queretaro 76230, Qro, Mexico. NIDA, NIH, DHHS, Baltimore, MD 21224 USA. RP Giordano, M (reprint author), Univ Nacl Autonoma Mexico, Dept Cognit & Behav Neurobiol, Inst Neurobiol, Campus Juriquilla, Queretaro 76230, Qro, Mexico. EM castilom@inb.unam.mx; solecito75@yahoo.com; WFREED@intra.nida.nih.gov; giordano@servidor.unam.mx OI Giordano, Magda/0000-0002-4335-7953 NR 37 TC 32 Z9 35 U1 0 U2 5 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 JUL 15 PY 2006 VL 171 IS 1 BP 109 EP 115 DI 10.1016/j.bbr.2006.03.025 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 053LI UT WOS:000238306200012 PM 16677720 ER PT J AU Straub, RE Weinberger, DR AF Straub, Ricbard E. Weinberger, Daniel R. TI Schizophrenia genes - Famine to feast SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID SUSCEPTIBILITY; POLYMORPHISM; EPISTASIS C1 NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. RP Straub, RE (reprint author), NIMH, Genes Cognit & Psychosis Program, 6001 Execut Blvd,Rm 8184,MSC 9663, Bethesda, MD 20892 USA. NR 15 TC 56 Z9 60 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 JUL 15 PY 2006 VL 60 IS 2 BP 81 EP 83 DI 10.1016/j.biopsych.2006.002 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 064PJ UT WOS:000239101300001 PM 16843093 ER PT J AU Hasler, G Drevets, WC Gould, TD Gottesman, II Manji, HK AF Hasler, Gregor Drevets, Wayne C. Gould, Todd D. Gottesman, Irving I. Manji, Husseini K. TI Toward constructing an endophenotype strategy for bipolar disorders SO BIOLOGICAL PSYCHIATRY LA English DT Review DE intermediate phenotype; biological marker; bipolar disorder; genetics; twins; families; endophenotypic ID SINGLE NUCLEOTIDE POLYMORPHISM; WHITE-MATTER HYPERINTENSITIES; SUBGENUAL PREFRONTAL CORTEX; SUSTAINED ATTENTION-DEFICIT; ACUTE TRYPTOPHAN DEPLETION; CHOLINERGIC REM-INDUCTION; INDUCED DOPAMINE RELEASE; EARLY-ONSET DEPRESSION; OPEN-FIELD BEHAVIOR; 1ST-DEGREE RELATIVES AB Research aimed at elucidating the underlying neurobiology and genetics of bipolar disorder and factors associated with treatment response,. have been limited by a heterogeneous clinical phenotype and lack of knowledge about its underlying diathesis. We used a survey of clinical.. epidemiological, neurobiological, and genetic studies to select and evaluate candidate endophenotypes for bipolar disorder. Numerous findings regarding brain function, brain structure, and response to pharmacological challenge in bipolar patients and their relatives deserve further investigation. Candidate brain function endophenotypes include attention deficits, deficits in verbal learning and memory, cognitive deficits after tryptophan depletion. circadian rhythm instability, and dysmodulation of motivation and reward. We selected reduced anterior cingulate volume and early-onset white matter abnormalities as candidate brain structure endophenotypes. Symptom provocation endophenotypes might be based on bipolar patients' sensitivity to sleep deprivation. psychostimulants, and cholinergic drugs. Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and genetics of bipolar disorder. We present a strategy constructed to improve the phenotypic definition of bipolar disorder by elucidating candidate endophenotypes. Studies to evaluate candidate endophenotypes with respect to specificity, heritability temporal stability, and prevalence in unaffected relatives are encouraged. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Minnesota, Sch Med, Dept Psychiat & Psychol, Minneapolis, MN USA. RP Hasler, G (reprint author), Univ Zurich Hosp, Dept Psychiat, Culmannstr 8, CH-8091 Zurich, Switzerland. EM g.hasler@bluewin.ch RI G, I/D-8042-2011; Gottesman, Irving/B-9303-2011; Hasler, Gregor/E-4845-2012 OI Hasler, Gregor/0000-0002-8311-0138 NR 208 TC 246 Z9 251 U1 4 U2 23 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 2006 VL 60 IS 2 BP 93 EP 105 DI 10.1016/j.biopsych.2005.11.006 PG 13 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 064PJ UT WOS:000239101300003 PM 16406007 ER PT J AU Detera-Wadleigh, SD McMahon, FJ AF Detera-Wadleigh, Sevilla D. McMahon, Francis J. TI G72/G30 in schizophrenia and bipolar disorder: Review and meta-analysis SO BIOLOGICAL PSYCHIATRY LA English DT Review DE DAAO; DAO; G72; G30; gene ID GENOME-WIDE SCAN; POSSIBLE SUSCEPTIBILITY LOCUS; D-ASPARTATE RECEPTOR; AMINO-ACID OXIDASE; D-SERINE; CHINESE POPULATION; CHROMOSOME 13Q32; LINKAGE ANALYSIS; PEDIGREE SERIES; DARIERS-DISEASE AB Association of the G72/G30 locus with schizophrenia and bipolar disorder has now been reported in several studies. The G72/G30 locus may be one of several that account for the evidence of linkage that spans a broad region of chromosome 13q. However, the story of G72/G30 is complex. Our meta-analysis of published association studies shows highly significant evidence of association between nucleotide variations in the G72/G30 region and schizophrenia, along with compelling evidence of association with bipolar disorder. But the associated alleles and haplotypes are not identical across studies, and some strongly associated variants are located similar to 50 kb telomeric of G72. Interestingly, G72 and G30 are transcribed in opposite directions; hence, their transcripts could cross-regulate translation. A functional native protein and functional motifs for G72 or G30 remain to be demonstrated. The interaction of G72 with D-amino acid oxidase, itself of interest as a modulator of N-methyl-D-aspartate receptors through regulation of D-serine levels, has been reported in one study and could be a key functional link that deserves further investigation. The association findings in the G72/G30 region, among the most compelling in psychiatry, may expose an important molecular pathway involved in susceptibility to schizophrenia and bipolar disorder. C1 NIMH, NIH, Intramural Res Program, Mood & Anxiety Program,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Detera-Wadleigh, SD (reprint author), NIMH, NIH, Intramural Res Program, Mood & Anxiety Program,US Dept Hlth & Human Serv, 35 Convent Dr,Bldg 35,Room 1A-203, Bethesda, MD 20892 USA. EM deteras@intra.nimh.nih.gov RI McMahon, Francis/A-7290-2009; OI McMahon, Francis/0000-0002-9469-305X FU Intramural NIH HHS NR 69 TC 172 Z9 181 U1 0 U2 7 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 JUL 15 PY 2006 VL 60 IS 2 BP 106 EP 114 DI 10.1016/j.biopsych.2006.01.019 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 064PJ UT WOS:000239101300004 PM 16581030 ER PT J AU Tunbridge, EM Harrison, PJ Weinberger, DR AF Tunbridge, Elizabeth M. Harrison, Paul J. Weinberger, Daniel R. TI Catechol-o-methyltransferase, cognition, and psychosis: Val(158)Met and beyond SO BIOLOGICAL PSYCHIATRY LA English DT Review DE catecholamine; dopamine; prefrontal cortex; schizophrenia ID 22Q11 DELETION SYNDROME; RAT PREFRONTAL CORTEX; VAL(108/158) MET GENOTYPE; MESSENGER-RNA EXPRESSION; CARDIO-FACIAL SYNDROME; PARKINSONS-DISEASE; WORKING-MEMORY; FUNCTIONAL POLYMORPHISM; GENE POLYMORPHISM; BIPOLAR DISORDER AB This review summarizes our current understanding of catechol-o-methyltransferase (COMT) and bow it relates to brain function and schizophrenia. We begin by considering the COMT gene, its transcripts and proteins, and its relevance for central catecholamine function. We then describe bow variation in COMT activity affects the function of the prefrontal cortex (PFC) and associated areas, reviewing evidence that COMT modulates executive function and working memory and highlighting recent data that also implicate it in emotional processing. Finally, we discuss briefly the genetic association between COMT and schizophrenia, focusing in particular on the complex interaction of functional loci within the gene that may underlie the mixed results of studies to date. We conclude by outlining preliminary data indicating that COMT is a promising therapeutic target for ameliorating the cognitive deficits associated with schizophrenia. C1 NIMH, Genes Cognit & Psychosis Program, IRP, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Oxford, Dept Psychiat, Oxford, England. RP Weinberger, DR (reprint author), NIMH, Genes Cognit & Psychosis Program, IRP, NIH,US Dept Hlth & Human Serv, Room 4S-235,10 Ctr Dr, Bethesda, MD 20892 USA. EM daniel.weinberger@mail.nih.gov OI Tunbridge, Elizabeth/0000-0002-2966-2281 FU Intramural NIH HHS NR 112 TC 417 Z9 435 U1 5 U2 29 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 JUL 15 PY 2006 VL 60 IS 2 BP 141 EP 151 DI 10.1016/j.biopsych.2005.10.024 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 064PJ UT WOS:000239101300008 PM 16476412 ER PT J AU Talkowski, ME Seltman, H Bassett, AS Brzustowicz, LM Chen, XN Chowdari, KV Collier, DA Cordeiro, Q Corvin, AP Deshpande, SN Egan, MF Gill, M Kendler, KS Kirov, G Heston, LL Levitt, P Lewis, DA Li, T Mimics, K Morris, DW Norton, N O'Donovan, MC Owen, MJ Richard, C Semwal, P Sobell, JL St Clair, D Straub, RE Thelma, BK Vallada, H Weinberger, DR Williams, NM Wood, J Zhang, F Devlin, B Nimgaonkar, VL AF Talkowski, Michael E. Seltman, Howard Bassett, Anne S. Brzustowicz, Linda M. Chen, Xiangning Chowdari, Kodavali V. Collier, David A. Cordeiro, Quirino Corvin, Aiden P. Deshpande, Smita N. Egan, Michael F. Gill, Michael Kendler, Kenneth S. Kirov, George Heston, Leonard L. Levitt, Pat Lewis, David A. Li, Tao Mimics, Karoly Morris, Derek W. Norton, Nadine O'Donovan, Michael C. Owen, Michael J. Richard, Christian Semwal, Prachi Sobell, Janet L. St Clair, David Straub, Richard E. Thelma, B. K. Vallada, Homero Weinberger, Daniel R. Williams, Nigel M. Wood, Joel Zhang, Feng Devlin, Bernie Nimgaonkar, Vishwajit L. TI Evaluation of a susceptibility gene for schizophrenia: Genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples SO BIOLOGICAL PSYCHIATRY LA English DT Article DE rGS4; schizophrenia; meta-analysis; association; polymorphism; linkage ID FAMILY-BASED ASSOCIATION; AT-RISK HAPLOTYPE; TRANSMISSION/DISEQUILIBRIUM TEST; LINKAGE ANALYSIS; DYSBINDIN GENE; RECEPTOR GENE; NEUREGULIN-1 GENE; SER9GLY VARIANT; NO ASSOCIATION; 6P22.3 GENE AB Background. Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotidepolymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. Methods: In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). Results: The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. Conclusions. Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted. C1 Univ Pittsburgh, WPIC, Dept Psychiat, Pittsburgh, PA 15213 USA. Univ Pittsburgh, WPIC, Dept Human Genet, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA 15213 USA. Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA. Univ Wales Coll Cardiff, Coll Med, Dept Psychol Med, Cardiff, Wales. Trinity Coll Dublin, Dept Psychiat, Inst Mol Med, Dublin, Ireland. Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA 23298 USA. Univ Sao Paulo, Dept Psychiat, Sao Paulo, Brazil. Dr Ram Manoher Lohia Hosp, Dept Psychiat, New Delhi, India. Univ Delhi, Dept Human Genet, New Delhi 110021, India. Rutgers State Univ, Dept Genet, Piscataway, NJ USA. Univ Toronto, Dept Psychiat, Toronto, ON, Canada. Ctr Addict & Mental Hlth, Toronto, ON, Canada. Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. Univ So Calif, Dept Prevent Med, Zilkha Neurogenet Inst, Los Angeles, CA 90089 USA. Inst Psychiat, Dept Psychiat, London SE5 8AF, England. NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. Vanderbilt Univ, Vanderbilt Kennedy Ctr Res Human Dev, Nashville, TN USA. Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. Sichuan Univ, Dept Psychiat, W China Hosp, Chengdu, Peoples R China. Univ Aberdeen, Dept Mental Hlth, Aberdeen, Scotland. Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. RP Nimgaonkar, VL (reprint author), Univ Pittsburgh, WPIC, Dept Psychiat, 3811 O'Hara St,Room 441, Pittsburgh, PA 15213 USA. EM nimga@pitt.edu RI turton, miranda/F-4682-2011; Lewis, David/G-4053-2014; Vallada, Homero/D-1333-2014; OI Lewis, David/0000-0002-3225-6778; Vallada, Homero/0000-0001-5123-8295; Morris, Derek/0000-0002-3413-570X; Corvin, Aiden/0000-0001-6717-4089; Seltman, Howard/0000-0002-7543-3578; O'Donovan, Michael/0000-0001-7073-2379; Gill, Michael/0000-0003-0206-5337; Mirnics, Karoly/0000-0002-5521-0254 FU Canadian Institutes of Health Research [53216]; Intramural NIH HHS; Medical Research Council [G9309834, G9810900]; NIMH NIH HHS [MH051456, K02 MH070786, K02 MH07086, MH53459, MH56242, MH62440, R01 MH056242, R01 MH057881, R01 MH062440, R10 MH056242]; Wellcome Trust NR 59 TC 64 Z9 69 U1 0 U2 2 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 JUL 15 PY 2006 VL 60 IS 2 BP 152 EP 162 DI 10.1016/j.biopsych.2006.02:015 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 064PJ UT WOS:000239101300009 PM 16631129 ER PT J AU Yamada, K Hattori, E Iwayama, Y Ohnishi, T Ohba, H Toyota, T Takao, H Minabe, Y Nakatani, N Higuchi, T Detera-Wadleigh, SD Yoshikawa, T AF Yamada, Kazuo Hattori, Eiji Iwayama, Yoshimi Ohnishi, Tetsuo Ohba, Hisako Toyota, Tomoko Takao, Hitomi Minabe, Yoshio Nakatani, Noriaki Higuchi, Teruhiko Detera-Wadleigh, Sevilla D. Yoshikawa, Takeo TI Distinguishable haplotype blocks in the HTR3A and HTR3B region in the Japanese reveal evidence of association of HTR3B with female major depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE schizophrenia; mood disorder; linkage disequilibrium; C178T variant of HTR3A; Tyr129Ser variant of HTR3B; phylogenetic analysis ID DISORDER SUSCEPTIBILITY LOCUS; BIPOLAR-DISORDER; 5-HT3 RECEPTORS; MOOD DISORDERS; GENOME SCAN; LINKAGE; SCHIZOPHRENIA; SUBUNIT; GENE; EXPRESSION AB Background: Genetic variations in the serotonin receptor 3A (HTR3A) and 3B(HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders in samples of European ancestry, But the polymorphisms highlighted in these reports map to different locations in the two genes, therefore it is unclear which gene exerts a stronger effect on susceptibility. Methods: To determine the haplotype block structure in the genomic regions of HTR3A and HTR3B, and to examine whether genetic variations in the region show evidence of association with schizophrenia and affective disorder in the Japanese, we performed haplotype-based case-control analysis using 29 polymorphisms. Results: Two haplotype blocks each were revealed for HTR3A and HTR3B in Japanese samples, In HTR3B, haplotype block 2 that included a nonsynonymous single nucleotide polymorphism (SNP), yielded evidence of association with major depression in females (global p = .0023). Analysis employing genome-wide SNPs using the STRUCTURE program did not detect population stratification in the samples. Conclusions: Our results suggest an important role for HTR3B in major depression in women and also raise the possibility that previously proposed disease-associated SNPs in the HTR3A/B region in Caucasians are in linkage disequilibrium with haplotype block 2 of HTR3B in the Japanese. C1 RIKEN Brain Sci Inst, Lab Mol Psychiat, Wako, Saitama 3510198, Japan. Japan Sci & Technol Agcy, Kawaguchi, Saitama, Japan. Hamamatsu Univ Sch Med, Dept Psychiat & Neurol, Hamamatsu, Shizuoka 43131, Japan. Musashi Hosp, Natl Ctr Neurol & Psychiat, Kodaira, Tokyo, Japan. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Yoshikawa, T (reprint author), RIKEN Brain Sci Inst, Lab Mol Psychiat, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. EM takeo@brain.riken.jp NR 37 TC 57 Z9 59 U1 0 U2 2 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 JUL 15 PY 2006 VL 60 IS 2 BP 192 EP 201 DI 10.1016/j.biopsych.2005.11.008 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 064PJ UT WOS:000239101300013 PM 16487942 ER PT J AU Jeong, LS Lee, HW Kim, HO Jung, JY Gao, ZG Duong, HT Rao, S Jacobson, KA Shin, DH Lee, JA Gunaga, P Lee, SK Jin, DZ Chun, MW Moon, HR AF Jeong, LS Lee, HW Kim, HO Jung, JY Gao, ZG Duong, HT Rao, S Jacobson, KA Shin, DH Lee, JA Gunaga, P Lee, SK Jin, DZ Chun, MW Moon, HR TI Design, synthesis, and biological activity of N-6-substituted-4 '-thioadenosines at the human A(3) adenosine receptor SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE G protein-coupled receptor; nucleoside; radioligand binding; purines; partial agonist; antagonist ID STRUCTURAL DETERMINANTS; CELLS; LIGANDS; SELECTIVITY; BINDING; PHARMACOLOGY; DERIVATIVES; INHIBITION; ACTIVATION; APOPTOSIS AB A large series of N-6-substituted-4'-thioadenosines were synthesized starting from D-gulonic-gamma-Iactone, and structure-activity relationships were studied at the human A(3) and other subtypes of adenosine receptors (ARs). 2-Chloro-substituted and 2-H analogues were compared. 2-Chloro-N-6-methyl-4'-thioadeno sine 19b was a highly potent and selective agonist (K-i = 0.8 +/- 0.1 nM in binding) at the A(3)AR, and displayed the same relative efficacy in receptor activation as a known full agonist, Cl-IB-MECA. Most of N6-substituted-4'-thioadenosines were less potent in binding than the corresponding N-6-substituted-adenosines or N-6-substituted-4'thioadenosine-5'-uronamides. N-6-(3-lodobenzyl) derivative 19g was demonstrated to be an A(3)AR-selective partial agonist displaying a Ki value of 3.2 nM. (c) 2006 Elsevier Ltd. All rights reserved. C1 Ewha Womans Univ, Coll Pharm, Med Chem Lab, Seoul 120750, South Korea. Seoul Natl Univ, Coll Pharm, Seoul 151742, South Korea. NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Pusan Natl Univ, Pusan 609753, South Korea. RP Jeong, LS (reprint author), Ewha Womans Univ, Coll Pharm, Med Chem Lab, Seoul 120750, South Korea. EM lakjeong@ewha.ac.kr RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 23 TC 16 Z9 16 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUL 15 PY 2006 VL 14 IS 14 BP 4718 EP 4730 DI 10.1016/j.bmc.2006.03.030 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 058XV UT WOS:000238698800004 PM 16603368 ER PT J AU Kol, N Gladnikoff, M Barlam, D Shneck, RZ Rein, A Rousso, I AF Kol, Nitzan Gladnikoff, Micha Barlam, David Shneck, Roni Z. Rein, Alan Rousso, Itay TI Mechanical properties of murine leukemia virus particles: Effect of maturation SO BIOPHYSICAL JOURNAL LA English DT Article ID ATOMIC-FORCE MICROSCOPY; ELASTIC PROPERTIES; ORGANIZATION; PROTEASE; GAG; INDENTATION; INFECTIVITY; STIFFNESS; PROTEINS; IMMATURE AB After budding from the host cell, retroviruses undergo a process of internal reorganization called maturation, which is prerequisite to infectivity. Viral maturation is accompanied by dramatic morphological changes, which are poorly understood in physical/mechanistic terms. Here, we study the mechanical properties of live mature and immature murine leukemia virus particles by indentation-type experiments conducted with an atomic force microscope tip. We find that both mature and immature particles have an elastic shell. Strikingly, the virus shell is twofold stiffer in the immature (0.68 N/m) than the mature (0.31 N/m) form. However, finite-element simulation shows that the average Young's modulus of the immature form is more than fourfold lower than that of the mature form. This finding suggests that per length unit, the protein-protein interactions in the mature shell are stronger than those in the immature shell. We also show that the mature virus shell is brittle, since it can be broken by application of large loading forces, by firm attachment to a substrate, or by repeated application of force. Our results are the first analysis of the mechanical properties of an animal virus, and demonstrate a linkage between virus morphology and mechanical properties. C1 Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel. Ben Gurion Univ Negev, Dept Mech Engn, IL-84105 Beer Sheva, Israel. Ben Gurion Univ Negev, Dept Mat Engn, IL-84105 Beer Sheva, Israel. NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Rousso, I (reprint author), Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel. EM itay.rousso@weizmann.ac.il RI Rousso, Itay/A-7662-2013 FU Intramural NIH HHS NR 30 TC 78 Z9 80 U1 1 U2 10 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUL 15 PY 2006 VL 91 IS 2 BP 767 EP 774 DI 10.1529/biophysj.105.079657 PG 8 WC Biophysics SC Biophysics GA 057RA UT WOS:000238611700039 PM 16632508 ER PT J AU Tagaya, Y AF Tagaya, Yutaka TI Time to restore individual rights for IL-2 and IL-15? SO BLOOD LA English DT Editorial Material AB IL-2 and IL-15 transduce distinct signals in the same cell despite their sharing of all signaling receptor components. C1 NCI, Bethesda, MD 20892 USA. RP Tagaya, Y (reprint author), NCI, Bethesda, MD 20892 USA. NR 5 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2006 VL 108 IS 2 BP 409 EP 410 DI 10.1182/blood-2006-05-019463 PG 2 WC Hematology SC Hematology GA 064ZP UT WOS:000239129500003 ER PT J AU Pavletic, S AF Pavletic, Steven TI aGVHDAI: escape from the silo SO BLOOD LA English DT Editorial Material ID HOST DISEASE; GRAFT; MARROW; INDEX AB A new dynamic tool for acute GVHD assessments opens a number of possibilities for use in observational and interventional clinical trials and in clinical care. C1 NCI, Bethesda, MD 20892 USA. RP Pavletic, S (reprint author), NCI, Bethesda, MD 20892 USA. NR 5 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 JUL 15 PY 2006 VL 108 IS 2 BP 412 EP 413 DI 10.1182/blood-2006-05-019547 PG 2 WC Hematology SC Hematology GA 064ZP UT WOS:000239129500006 ER PT J AU Caporaso, N AF Caporaso, Neil TI Chips, candidate genes, and CLL SO BLOOD LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; SCAN AB Rudd and colleagues have conducted a large-scale association study using nonsynonymous SNPs on a population sample of patients with CLL and healthy controls and identified a group of plausible candidate SNPs, including ATM, CHEK2, and BRCA2. C1 NCI, Bethesda, MD 20892 USA. RP Caporaso, N (reprint author), NCI, Bethesda, MD 20892 USA. NR 3 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2006 VL 108 IS 2 BP 415 EP 416 DI 10.1182/blood-2006-05-019489 PG 2 WC Hematology SC Hematology GA 064ZP UT WOS:000239129500010 ER PT J AU Mattei, F Schiavoni, G Borghi, P Venditti, M Canini, I Sestili, P Pietraforte, I Morse, HC Ramoni, C Belardeili, F Gabriele, L AF Mattei, Fabrizio Schiavoni, Giovanna Borghi, Paola Venditti, Massimo Canini, Irene Sestili, Paola Pietraforte, Immacolata Morse, Herbert C., III Ramoni, Carlo Belardeili, Filippo Gabriele, Lucia TI ICSBP/IRF-8 differentially regulates antigen uptake during dendritic-cell development and affects antigen presentation to CD4(+) T cells SO BLOOD LA English DT Article ID IN-VIVO; MANNOSE RECEPTOR; FLUORESCEIN ISOTHIOCYANATE; CONTACT HYPERSENSITIVITY; CROSS-PRESENTATION; IMMUNE-RESPONSES; LANGERHANS CELLS; DOWN-REGULATION; CUTTING EDGE; RHO-GTPASES AB Interferon consensus sequence-binding protein (ICSBP)/interferon regulatory factor 8 (IRF-8) is a transcription factor that plays critical roles in the differentiation of defined dendritic-cell (DC) populations and in the immune response to many pathogens. In this study, we show that splenic DCs (s-DCs) from ICSBP-/- mice are markedly defective in their ability to capture and to present exogenous antigens (Ags) to naive CD4(+) T lymphocytes. We found that CD8 alpha(+) DCs and, to a lesser extent, CD8 alpha(-) DCs from ICSBP-/- mice are impaired at internalizing Ags, either through a receptor-mediated pathway or by macropinocytosis, in spite of having a more immature phenotype than their wildtype (WT) counterparts. These features reflected a greatly impaired ability of ICSBP-/- s-DCs to present injected soluble ovalbumin (OVA) to OVA-specific CD4+ T cells in vivo. Conversely, bone marrow (BM)-derived DCs from ICSBP-/- mice, in keeping with their immature phenotype, exhibited higher endocytic activity than WT cells. However, Ag-loaded ICSBP-/- BM-DCs were defective in priming Ag-specific CD4+ T lymphocytes and failed to induce a contact hypersensitivity (CHS) response when injected into competent WT hosts. Together, these results indicate that, throughout the developmental program of DCs, ICSBP differentially controls Ag uptake and MHC class 11 (MHC-II) presentation affecting both functions only in differentiated peripheral DCs. C1 Ist Super Sanita, Dept Cell Biol & Neurosci, I-00161 Rome, Italy. NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. RP Gabriele, L (reprint author), Ist Super Sanita, Dept Cell Biol & Neurosci, Viale Regina Elena 299, I-00161 Rome, Italy. EM gabrilci@iss.it RI Mattei, Fabrizio/J-6585-2016; OI Mattei, Fabrizio/0000-0002-5357-7773; Schiavoni, Giovanna/0000-0001-9135-0556; Morse, Herbert/0000-0002-9331-3705; Gabriele, Lucia/0000-0002-1483-866X NR 53 TC 18 Z9 19 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2006 VL 108 IS 2 BP 609 EP 617 DI 10.1182/blood-2005-11-4490 PG 9 WC Hematology SC Hematology GA 064ZP UT WOS:000239129500037 PM 16569763 ER PT J AU Zhang, ML Yao, ZS Zhang, Z Garmestani, K Goldman, CK Ravetch, JV Janik, J Brechbiel, MW Waldmann, TA AF Zhang, Meili Yao, Zhengsheng Zhang, Zhuo Garmestani, Kayhan Goldman, Carolyn K. Ravetch, Jeffrey V. Janik, John Brechbiel, Martin W. Waldmann, Thomas A. TI Effective therapy for a murine model of human anaplastic large-cell lymphoma with the anti-CD30 monoclonal antibody, HeFi-1, does not require activating Fc receptors SO BLOOD LA English DT Article ID HUMAN T-CELLS; SIGNAL-TRANSDUCTION; ANTITUMOR-ACTIVITY; CD30 EXPRESSION; IN-VITRO; LEUKEMIA; DISEASE; ANTIGEN; MICE; TAC AB CD30 is a member of the tumor necrosis factor receptor family. Overexpression of CD30 on some neoplasms versus its limited expression on normal tissues makes this receptor a promising target for antibody-based therapy. Anaplastic large-cell lymphoma (ALCL) represents a heterogeneous group of aggressive non-Hodgkin lymphomas characterized by the strong expression of CD30. We investigated the therapeutic efficacy of HeFi-1, a mouse IgG1 monoclonal antibody, which recognizes the ligand-binding site on CD30, and humanized anti-Tac antibody (daclizumab), which recognizes CD25, in a murine model of human ALCL. The ALCL model was established by intravenous injection of karpas299 cells into nonobese diabetic/severe combined immunodeficient (SCID/NOD) wild-type or SCID/NOD Fc receptor common gamma chain-deficient (FcR gamma(-/-)) mice. HeFi-1, given at a dose of 100 mu g weekly for 4 weeks, significantly prolonged survival of the ALCL-bearing SCID/NOD wild-type and SCID/NOD FcR gamma(-/-) mice (P < .01) as compared with the control groups. In vitro studies showed that HeFi-1 inhibited the proliferation of karpas299 cells, whereas daclizumab did not inhibit cell proliferation. We demonstrated that the expression of FcR gamma on polymorphonuclear leukocytes and monocytes was not required for HeFi-1-mediated tumor growth inhibition in vivo, although it was required for daclizumab. C1 NCI, Metab Branch, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10021 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, Radiat Oncol Branch, Ctr Canc Res,NIH, Bldg 10,Rm 4N115,10 Ctr Dr, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU Intramural NIH HHS NR 36 TC 24 Z9 27 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2006 VL 108 IS 2 BP 705 EP 710 DI 10.1182/blood-2005-11-4607 PG 6 WC Hematology SC Hematology GA 064ZP UT WOS:000239129500049 PM 16551968 ER PT J AU Jang, W Yonescu, R Knutsen, T Brown, T Reppert, T Sirotkin, K Schuler, GD Ried, T Kirsch, IR AF Jang, Wonhee Yonescu, Raluca Knutsen, Turid Brown, Theresa Reppert, Tricia Sirotkin, Karl Schuler, Gregory D. Ried, Thomas Kirsch, Ilan R. TI Linking the human cytogenetic map with nucleotide sequence: the CCAP clone set SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID HUMAN GENOME; CLINICOPATHOLOGICAL FEATURES; KARYOTYPIC PATTERN; BURKITT-LYMPHOMA; CANCER; INTEGRATION; GENE; ADENOCARCINOMAS; ABERRATIONS; LINKAGE AB We present the completed dataset and clone repository of the Cancer Chromosome Aberration Project (CCAP), an initiative developed and funded through the intramural program of the U.S. National Cancer Institute, to provide seamless linkage of human cytogenetic markers with the primary nucleotide sequence of the human genome. Spaced at 1-2 Mb intervals across the human aenome, 1,339 bacterial artificial chromosome (BAC) clones have been localized to chromosomal bands through high-resolution fluorescence in situ hybridization (FISH) mapping. Of these clones, 99.8% can be positioned on the primary human genome sequence and 95% are placed at or close to their precise nucleotide starts and stops. This dataset can be studied and manipulated within generally available public Web sites. The clones are available from a commercial repository. The CCAP BAC clone set provides anchors for the interrogation of gene and sequence involvement in oncogenic and developmental disorders when the starting point is the recognition of a structural, numerical, or interstitial chromosomal aberration. This dataset also provides a current view of the quality and coherence of the available genome sequence and insight into the nucleotide and three-dimensional structures that manifest as Giemsa light and dark chromosomal banding patterns. (c) 2006 Elsevier Inc. All rights reserved. C1 NCI, Ctr Canc Res, Genet Branch, NIH, Bethesda, MD 20892 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD USA. RP Ried, T (reprint author), NCI, Ctr Canc Res, Genet Branch, NIH, 9000 Rockville Pike,Bldg 31,Rm 10A03, Bethesda, MD 20892 USA. EM RiedT@mail.nih.gov FU Intramural NIH HHS NR 27 TC 6 Z9 6 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 JUL 15 PY 2006 VL 168 IS 2 BP 89 EP 97 DI 10.1016/j.cancergencyto.2006.01.001 PG 9 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 067JB UT WOS:000239296800001 PM 16843097 ER PT J AU Du, QA Park, KS Guo, Z He, PJ Nagashima, M Shao, LF Sahai, R Geller, DA Hussain, SP AF Du, Qiang Park, Kyung Soo Guo, Zhong He, Peijun Nagashima, Makoto Shao, Lifang Sahai, Rohit Geller, David A. Hussain, S. Perwez TI Regulation of human nitric oxide synthase 2 expression by Wnt beta-catenin signaling SO CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; TRANSCRIPTIONAL ACTIVATION; IN-VIVO; ULCERATIVE-COLITIS; GENE-TRANSCRIPTION; OXIDATIVE STRESS; INTERFERON-GAMMA; UP-REGULATION; COLON-CANCER; PROMOTER AB Nitric oxide (NO center dot) an important mediator of inflammation, and beta-catenin, a component of the Wnt-adenomatous polyposis coli signaling pathway, contribute to the development of cancer. We have identified two T-cell factor 4 (Tcf-4)-binding elements (TBE1 and TBE2) in the promoter of human inducible NO synthase 2 (NOS2). We tested the hypothesis that beta-catenin regulates human NOS2 gene. Mutation in either of the two TBE sites decreased the basal and cytokine-induced NOS2 promoter activity in different cell lines. The promoter activity was significantly reduced when both TBE1 and TBE2 sites were mutated (P < 0.01). Nuclear extract from HCT116, HepG2, or DLD1 cells bound to NOS2 TBE1 or TBE2 oligonucleotides in electrophoretic mobility shift assays and the specific protein-DNA complexes were supershifted with anti-beta-catenin or anti-Tcf-4 antibody. Overexpression of beta-catenin and Tcf-4 significantly increased both basal and cytokine-induced NOS2 promoter activity (P < 0.01), and the induction was dependent on intact TBE sites. Overexpression of beta-catenin or Tcf-4 increased NOS2 mRNA and protein expression in HCT116 cells. Lithium chloride (LiCl), an inhibitor of glycogen synthase kinase-3 beta, increased cytosolic and nuclear 0-catenin level, NOS2 expression, and NO center dot production in primary human and rat hepatocytes and cancer cell lines. Treatment with Wnt-3A-conditioned medium increased beta-catenin and NOS2 expression in fetal human hepatocytes. When administered in vivo, LiCl increased hepatic beta-catenin level in a dose-dependent manner with simultaneous increase in NOS2 expression. These data are consistent with the hypothesis that beta-catenin up-regulates NOS2 and suggest a novel mechanism by which the Wnt/beta-catenin signaling pathway may contribute to cancer by increasing NO center dot production. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15213 USA. RP Hussain, SP (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37,Room 3060D, Bethesda, MD 20892 USA. EM gellerda@upmc.edu; hussainp@mad.nih.gov FU Intramural NIH HHS; NIGMS NIH HHS [R01-GM52051] NR 49 TC 66 Z9 67 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 JUL 15 PY 2006 VL 66 IS 14 BP 7024 EP 7031 DI 10.1158/0008-5472.CAN-05-4110 PG 8 WC Oncology SC Oncology GA 064QE UT WOS:000239103400018 PM 16849547 ER PT J AU Shukla, V Coumoul, X Cao, L Wang, RH Xiao, CY Xu, XL Ando, S Yakar, S LeRoith, D Deng, CX AF Shukla, Vivek Coumoul, Xavier Cao, Liu Wang, Rui-Hong Xiao, Cuiying Xu, Xiaoling Ando, Sebastiano Yakar, Shoshana LeRoith, Derek Deng, Chuxia TI Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members SO CANCER RESEARCH LA English DT Article ID FACTOR BINDING PROTEIN-1; MULTIPLE-MYELOMA CELLS; I IGF-I; TRANSGENIC MICE; POSTNATAL-GROWTH; RECEPTOR GENE; LIFE-SPAN; BRCA1; P53; MIGRATION AB The breast cancer-associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. Mice homozygous for a targeted deletion of full-length BRCA1 (Brca1(Delta 11/Delta 11)) display both increased tumorigenesis and premature aging, yet molecular mechanisms underlying these defects remain elusive. Here, we show that Brca1 deficiency leads to increased expression of several insulin-like growth factor (IGF) signaling axis members in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. Those observations provide a molecular insight in understanding both fundamental and therapeutic BRCA1-associated tumorigenesis and aging. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Diabet Branch, NIH, Bethesda, MD USA. Univ Calabria, Dept Cell Biol, Cosenza, Italy. RP Shukla, V (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, Bldg 10-9N105,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shuklav@mail.nih.gov RI deng, chuxia/N-6713-2016 FU Intramural NIH HHS NR 50 TC 35 Z9 39 U1 1 U2 1 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 JUL 15 PY 2006 VL 66 IS 14 BP 7151 EP 7157 DI 10.1158/0008-5472-CAN-05-4570 PG 7 WC Oncology SC Oncology GA 064QE UT WOS:000239103400033 PM 16849561 ER PT J AU Nam, JS Kang, MJ Suchar, AM Shimamura, T Kohn, EA Michalowska, AM Jordan, VC Hirohashi, S Wakefield, LM AF Nam, Jeong-Seok Kang, Mi-Jin Suchar, Adam M. Shimamura, Takeshi Kohn, Ethan A. Michalowska, Aleksandra M. Jordan, V. Craig Hirohashi, Setsuo Wakefield, Lalage M. TI Chemokine (C-C motif) ligand 2 mediates the prometastatic effect of dysadherin in human breast cancer cells SO CANCER RESEARCH LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; NF-KAPPA-B; LINK NA+/K+-ATPASE; PROGNOSTIC-SIGNIFICANCE; CLINICAL-SIGNIFICANCE; ESTROGEN-RECEPTOR; ADHESION SYSTEM; E-CADHERIN; EXPRESSION; GENE AB Dysadherin, a cancer-associated membrane glycoprotein, down-regulates E-cadherin and promotes cancer metastasis, This study examined the role of dysadherin in breast cancer progression. Expression of dysadherin was found to be highest in breast cancer cell lines and tumors that lacked the estrogen receptor (ER). Knockdown of dysadherin caused increased association of E-cadherin with the actin cytoskeleton in breast cancer cell lines that expressed E-cadherin. However, knockdown of dysadherin could still suppress cell invasiveness in cells that had no functional E-cadherin, suggesting the existence of a novel mechanism of action. Global gene expression analysis identified chemokine (C-C motif) ligand 2 (CCL2) as the transcript most affected by dysadherin knockdown in MDA-MB-231 cells, and dysadherin was shown to regulate CCL2 expression in part through activation of the nuclear factor-kappa B pathway. The ability of dysadherin to promote tumor cell invasion in vitro was dependent on the establishment of a CCL2 autocrine loop, and CCL2 secreted by dysadherin-positive tumor cells also promoted endothelial cell migration in a paracrine fashion. Finally, experimental suppression of CCL2 in MDA-MB-231 cells reduced their ability to metastasize in vivo. This study shows that dysadherin has prometastatic effects that are independent of E-cadherin expression and that CCL2 could play an important role in mediating the prometastatic effect of dysadherin in ER-negative breast cancer. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Natl Canc Ctr, Res Inst, Div Pathol, Tokyo 104, Japan. RP Wakefield, LM (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Room C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. EM wakefiel@dce41.nci.nih.gov RI Jordan, V. Craig/H-4491-2011 FU Intramural NIH HHS; NCI NIH HHS [Z01 BC005785-11] NR 53 TC 55 Z9 60 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 JUL 15 PY 2006 VL 66 IS 14 BP 7176 EP 7184 DI 10.1158/0008-5472.CAN-06-0825 PG 9 WC Oncology SC Oncology GA 064QE UT WOS:000239103400036 PM 16849564 ER PT J AU Riss, J Khanna, C Koo, S Chandramouli, GVR Yang, HH Hu, Y Kleiner, DE Rosenwald, A Schaefer, CF Ben-Sasson, SA Yang, LM Powell, J Kane, DW Star, RA Aprelikova, O Bauer, K Vasselli, JR Maranchie, JK Kohn, KW Buetow, KH Linehan, WM Weinstein, JN Lee, MP Klausner, RD Barrett, JC AF Riss, Joseph Khanna, Chand Koo, Seongjoon Chandramouli, Gadisetti V. R. Yang, Howard H. Hu, Ying Kleiner, David E. Rosenwald, Andreas Schaefer, Carl F. Ben-Sasson, Shmuel A. Yang, Liming Powell, John Kane, David W. Star, Robert A. Aprelikova, Olga Bauer, Kristin Vasselli, James R. Maranchie, Jodi K. Kohn, Kurt W. Buetow, Ken H. Linehan, W. Marston Weinstein, John N. Lee, Maxwell P. Klausner, Richard D. Barrett, J. Carl TI Cancers as wounds that do not heal: Differences and similarities between renal regeneration/repair and renal cell carcinoma SO CANCER RESEARCH LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR; BREAST-CANCER; KIDNEY CANCER; CDNA ARRAY; EXPRESSION; GENES; SURVIVAL; GROWTH; TUMOR; HYBRIDIZATION AB Cancers have been described as wounds that do not heal, suggesting that the two share common features. By comparing microarray data from a model of renal regeneration and repair (RRR) with reported gene expression in renal cell carcinoma (RCC), we asked whether those two processes do, in fact, share molecular features and regulatory mechanisms. The majority (77%) of the genes expressed in RRR and RCC were concordantly regulated, whereas only 23% were discordant (i.e., changed in opposite directions). The orchestrated processes of regeneration, involving cell proliferation and immune response, were reflected in the concordant genes. The discordant gene signature revealed processes (e.g., morphogenesis and glycolysis) and pathways (e.g., hypoxia-inducible factor and insulin-like growth factor-I) that reflect the intrinsic pathologic nature of RCC. This is the first study that compares gene expression patterns in RCC and RRR. It does so, in particular, with relation to the hypothesis that RCC resembles the wound healing processes seen in RRR. However, careful attention to the genes that are regulated in the discordant direction provides new insights into the critical differences between renal carcinogenesis and wound healing. The observations reported here provide a conceptual framework for further efforts to understand the biology and to develop more effective diagnostic biomarkers and therapeutic strategies for renal tumors and renal ischemia. C1 NCI, Lab Biosyst & Canc, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Comparat Oncol Program, Bethesda, MD USA. NCI, Lab Populat Genet, Bethesda, MD USA. NCI, Pathol Lab, Bethesda, MD USA. NCI, Metab Branch, Bethesda, MD USA. NCI, Genet & Bioinformat Grp, Mol Pharmacol Lab, Bethesda, MD USA. NCI, Urol Oncol Branch, Canc Res Ctr, Bethesda, MD USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD USA. NIDDK, Bioinformat & Mol Anal Sect, Computat Biosci & Engn Lab, Ctr Informat Technol,NIH, Bethesda, MD USA. NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD USA. Hebrew Univ Jerusalem, Hadassah Med Sch, IL-91010 Jerusalem, Israel. RP Riss, J (reprint author), NCI, Lab Biosyst & Canc, Canc Res Ctr, NIH, Bldg 37,Room 5032,37 Convent MSC 4264, Bethesda, MD 20892 USA. EM rissjo@mail.nih.gov OI Maranchie, Jodi/0000-0002-8534-9468; Kleiner, David/0000-0003-3442-4453 FU Intramural NIH HHS NR 49 TC 62 Z9 64 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2006 VL 66 IS 14 BP 7216 EP 7224 DI 10.1158/0008-5472.CAN-06-0040 PG 9 WC Oncology SC Oncology GA 064QE UT WOS:000239103400041 PM 16849569 ER PT J AU Choi, SH Hyman, T Blumberg, PM AF Choi, Sung Hee Hyman, Tehila Blumberg, Peter M. TI Differential effect of bryostatin 1 and phorbol 12-myristate 13-acetate on HOP-92 cell proliferation is mediated by down-regulation of protein kinase C delta SO CANCER RESEARCH LA English DT Article ID ESTER-INDUCED DIFFERENTIATION; CAPILLARY ENDOTHELIAL-CELLS; GREEN FLUORESCENT PROTEIN; SMOOTH-MUSCLE-CELLS; PHASE-II TRIAL; PKC-DELTA; TYROSINE PHOSPHORYLATION; ACTIVATION MECHANISMS; CYCLE PROGRESSION; INDUCED APOPTOSIS AB Bryostatin 1 is currently in clinical trials as a cancer chemotherapeutic agent. Although bryostatin 1, like phorbol 12-myristate 13-acetate (PMA), is a potent activator of protein kinase C (PKC), it induces only a subset of those responses induced by PMA and antagonizes others. We report that, in the HOP-92 non-small cell lung cancer line, bryostatin I induced a biphasic proliferative response, with maximal proliferation at I to 10 nmol/L. This biphasic response mirrored a biphasic suppression of the level of PKC delta protein, with maximal suppression likewise at I to 10 mmol/L bryostatin 1. The typical phorbol ester PMA, in contrast to bryostatin 1, had no effect on the level of PKC delta and modest suppression of cell proliferation, particularly evident at later treatment times. Flow cytometric analysis revealed changes in the fraction of cells in the GO-G, and S phases corresponding to the effects on proliferation. Cells overexpressing PKC delta exhibited a lower rate of cell proliferation compared with control untreated cells and showed neither a proliferative response nor a loss of PKC delta in response to bryostatin 1. Conversely, treatment with PKC delta small interfering PNA significantly increased the cellular growth compared with controls. We conclude that the differential effect on cellular proliferation induced by bryostatin I compared with PMA reflects the differential suppression of PKC delta. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Blumberg, PM (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, Bldg 37,Room 4048B,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov FU Intramural NIH HHS NR 56 TC 23 Z9 24 U1 0 U2 5 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 JUL 15 PY 2006 VL 66 IS 14 BP 7261 EP 7269 DI 10.1158/0008-5472.CAN-05-4177 PG 9 WC Oncology SC Oncology GA 064QE UT WOS:000239103400047 PM 16849575 ER PT J AU Lundqvist, A Abrams, SI Schrump, DS Alvarez, G Suffredini, D Berg, M Childs, R AF Lundqvist, Andreas Abrams, Scott I. Schrump, David S. Alvarez, Gauri Suffredini, Dante Berg, Maria Childs, Richard TI Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: A novel method to potentiate natural killer cell tumor cytotoxicity SO CANCER RESEARCH LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; TRAIL-MEDIATED APOPTOSIS; PHASE-II TRIAL; NK CELLS; TUMORICIDAL ACTIVITY; CARCINOMA-CELLS; DOWN-REGULATION; CANCER-CELLS; DEATH DOMAIN; IN-VIVO AB The proteasome inhibitor, bortezomib, and the histone deacetylase inhibitor, depsipeptide (FK228), up-regulate tumor death receptors. Therefore, we investigated whether pretreatment of malignant cells with these agents would potentiate natural killer (NK)-mediated tumor killing. INK cells isolated from healthy donors and patients with cancer were expanded in vitro and then tested for cytotoxicity against tumor cell lines before and after exposure to bortezomib or depsipeptide. In 11 of 13 (85%) renal cell carcinoma cell lines and in 16 of 37 (43%) other cancer cell lines, exposure to these drugs significantly increased NK cell-mediated tumor lysis compared with untreated tumor controls (P < 0.001). Furthermore, NK cells expanded from patients with metastatic renal cell carcinoma were significantly more cytotoxic against autologous tumor cells v.,hen pretreated with either bortezomib or depsipeptide compared with untreated tumors. Tumors sensitized to NK cell cytotoxicity showed a significant increase in surface expression of DR5 [tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-R2; P < 0.05]; in contrast, surface expression of MHC class I, MIC-A/B, DR4 (TRAIL-R1), and Fas (CD95) did not change. The enhanced susceptibility to INK cell killing was completely abolished by blocking TRAIL on NK cells, and partially abolished by blocking DR5 on tumor cells. These findings show that drug-induced sensitization to TRAIL could be used as a novel strategy to potentiate the anticancer effects of adoptively infused NK cells in patients with cancer. C1 NCI, Lab Tumor Immunol & Biol, Canc Res Ctr, NIH, Bethesda, MD USA. NCI, Thorac Oncol Sect, Canc Res Ctr, Surg Branch,NIH, Bethesda, MD USA. RP Childs, R (reprint author), NHLBI, Hematol Branch, NIH, Room 3-5140,Bldg 10-CRC,10 Ctr Dr MSC 1202, Bethesda, MD 20892 USA. EM childsr@nih.nhlbi.gov OI Lundqvist, Andreas/0000-0002-9709-2970 FU Intramural NIH HHS NR 35 TC 107 Z9 110 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 JUL 15 PY 2006 VL 66 IS 14 BP 7317 EP 7325 DI 10.1158/0008-5472.CAN-06-0680 PG 9 WC Oncology SC Oncology GA 064QE UT WOS:000239103400054 PM 16849582 ER PT J AU Swamy, MV Patlolla, JMR Steele, VE Kopelovich, L Reddy, BS Rao, CV AF Swamy, Malisetty V. Patlolla, Jagan M. R. Steele, Vernon E. Kopelovich, Levy Reddy, Bandaru S. Rao, Chinthalapally V. TI Chemoprevention of familial adenomatous polyposis by low doses of atorvastatin and celecoxib given individually and in combination to APC(min) mice SO CANCER RESEARCH LA English DT Article; Proceedings Paper CT 95th Annual Meeting of the American-Association-for-Cancer-Research CY MAR 27-31, 2004 CL Orlando, FL SP Amer Assoc Canc Res ID MULTIPLE INTESTINAL NEOPLASIA; COA REDUCTASE INHIBITOR; ABERRANT CRYPT FOCI; COLON CARCINOGENESIS; CYCLOOXYGENASE-2 INHIBITOR; COLORECTAL-CANCER; GASTROINTESTINAL-TRACT; INDUCED APOPTOSIS; MOUSE MODEL; CELLS AB Preclinical and clinical studies have established evidence that cyclooxygenase-2 (COX-2) inhibitors and statins [hydroxy-3-methylglutaryl CoA reductase (HMGR) inhibitors] inhibit colon carcinogenesis. Chronic use of high doses of COX-2 inhibitors may induce side effects, and combining the low doses of agents may be an effective way to increase their efficacy and minimize the side effects. We assessed the chemopreventive efficacy of atorvastatin (Lipitor) and celecoxib individually or in combination in an animal model of familial adenomatous polyposis. Six-week-old male C57BL/6J-APC(min/+) mice were either fed diets containing 0 or 100 ppm atorvastatin or 300 ppm celecoxib, or a combination of both for similar to 80 days. Mice were sacrificed, and their intestines were scored for tumors. Normal-seeming mucosa and intestinal tumors were harvested and assayed for apoptosis (terminal deoxynucleotidyl transferase-mediated nick-end labeling) and HMGR and COX-2 protein expression and activity. We observed that 100 ppm atorvastatin significantly (P < 0.002) suppressed intestinal polyp formation. As anticipated, 300 ppm celecoxib decreased the rate of formation of intestinal polyps by similar to 70% (P < 0.0001). Importantly, the combination of 100 ppm atorvastatin and 300 ppm celecoxib in the diet suppressed the colon polyps completely and small intestinal polyps by > 86% (P < 0.0001) compared with the control group. The inhibition of tumor formation by the atorvastatin and celecoxib combination was significant (P < 0.005) when compared with tumor inhibition by celecoxib alone. In addition, increased rates of apoptosis in intestinal tumors (P < 0.01-0.0001) were observed in animals fed with atorvastatin and celecoxib and more so with the combinations. Tumors of animals fed atorvastatin showed a significant decrease in HMGR-R activity. Similarly, tumors of mice exposed to celecoxib showed significantly lower levels of COX-2 activity. These observations show that atorvastatin inhibits intestinal tumorigenesis and that, importantly, when given together with low doses of celecoxib, it significantly increases the chemopreventive efficacy in an APC(min) mice. C1 Univ Oklahoma, Hlth Sci Ctr, Inst Canc, Dept Med,Hem Onc Sect, Oklahoma City, OK 73104 USA. NCI, Chemoprevent Agent Dev Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. Rutgers State Univ, Earnest Mario Sch Pharm, Dept Biol Chem, Piscataway, NJ USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, Inst Canc, Dept Med,Hem Onc Sect, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu RI Chinthalapally, Rao/B-3633-2010 FU NCI NIH HHS [CA-94962, N01-CN-25114] NR 55 TC 82 Z9 83 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 JUL 15 PY 2006 VL 66 IS 14 BP 7370 EP 6777 DI 10.1158/0008-5472.CAN-05-4619 PG 8 WC Oncology SC Oncology GA 064QE UT WOS:000239103400061 PM 16849589 ER PT J AU McBride, AA Oliveira, JG McPhillips, MG AF McBride, Alison A. Oliveira, Jaquelline G. McPhillips, Maria G. TI Partitioning viral genomes in mitosis - Same idea, different targets SO CELL CYCLE LA English DT Article DE papillomavirus; HPV; mitosis; virus; replication; episome; partitioning; Brd4; E2; chromosome ID EPSTEIN-BARR-VIRUS; PAPILLOMAVIRUS E2 PROTEIN; SARCOMA-ASSOCIATED HERPESVIRUS; NUCLEAR ANTIGEN-1; MITOTIC CHROMOSOMES; BROMODOMAIN PROTEIN; EPISOMAL MAINTENANCE; HOST CHROMOSOMES; BINDING-SITES; DNA AB Papillomavirus infections are long-lived and persistent. The circular DNA of the viral genome is maintained in dividing epithelial cells as an extrachromosomal element. The E2 protein of the virus binds to the viral genome and tethers it to mitotic chromosomes to ensure that the genome is retained and faithfully partitioned in dividing cells. This mechanism has been best studied for bovine papillomavirus type 1. Recent evidence indicates that while this is a common strategy among papillomaviruses, different viruses have selected different chromosomal targets. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 4,Room 137,4 Ctr Dr MSC 0455, Bethesda, MD 20892 USA. EM amcbride@nih.gov OI McBride, Alison/0000-0001-5607-5157 FU Intramural NIH HHS NR 38 TC 31 Z9 32 U1 0 U2 3 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUL 15 PY 2006 VL 5 IS 14 BP 1499 EP 1502 DI 10.4161/cc.5.14.3094 PG 4 WC Cell Biology SC Cell Biology GA 086UF UT WOS:000240697800006 PM 16861919 ER PT J AU Gallin, JI AF Gallin, John I. TI Taming clinical research's paper tigers SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Ctr Clin, Bethesda, MD 20892 USA. RP Gallin, JI (reprint author), NCI, Ctr Clin, 10 Ctr Dr,Room 6-2551,MSC 1504, Bethesda, MD 20892 USA. EM jgallin@cc.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2006 VL 12 IS 14 BP 4131 EP 4131 DI 10.1158/1078-0432.CCR-06-1095 PN 1 PG 1 WC Oncology SC Oncology GA 068KR UT WOS:000239373200001 PM 16857781 ER PT J AU Athauda, G Giubellino, A Coleman, JA Horak, C Steeg, PS Lee, MJ Trepel, J Wimberly, J Sun, J Coxon, A Burgess, TL Bottaro, DP AF Athauda, Gagani Giubellino, Alessio Coleman, Jonathan A. Horak, Christine Steeg, Patricia S. Lee, Ming-Jung Trepel, Jane Wimberly, Jennifer Sun, Jan Coxon, Angela Burgess, Teresa L. Bottaro, Donald P. TI c-Met ectodomain shedding rate correlates with malignant potential SO CLINICAL CANCER RESEARCH LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; TRANSITIONAL-CELL CARCINOMA; RECEPTOR TYROSINE KINASE; SCATTER FACTOR; LIVER-REGENERATION; INVASIVE GROWTH; METASTASIS; METALLOPROTEINASE; OVEREXPRESSION; MECHANISMS AB Purpose: Many proteins are proteolytically released from the cell surface by a process known as ectodomain shedding. Shedding occurs under normal physiologic conditions and can be increased in certain pathologies. Among the many receptors for which ectodomain shedding has been shown is c-Met, the hepatocyte growth factor (HGF) receptor tyrosine kinase. HGF stimulates mitogenesis, motogenesis, and morphogenesis in a variety of cellular targets during development, homeostasis, and tissue regeneration. Inappropriate HGF signaling resulting in unregulated cell proliferation, motility, and invasion occurs in several human malignancies. This can occur through paracrine signaling, autocrine loop formation, receptor mutation, gene amplification, or gene rearrangement, accompanied frequently with overexpression of ligand and/or receptor proteins. We hypothesized that c-Met overexpression in cancer might result in increased ectodomain shedding, and that its measure could be a useful biomarker of tumor progression. Experimental Design: We developed a sensitive electrochemiluminescent immunoassay to quantitate c-Met protein in cell lysates, culture supernatants, and biological samples. Results: A survey of cultured cell models of oncogenic transformation revealed significant direct correlations (P < 0.001, t test or ANOVA) between malignant potential and the rate of c-Met ectodomain shedding that was independent of steady-state receptor expression level, Moreover, weekly plasma and urine samples from mice harboring s.c. human tumor xenografts (n = 4 per group) displayed soluble human c-Met levels that were measurable before tumors became palpable and that correlated directly with tumor volume (R-2 > 0.92, linear regression). Conclusions: For a variety of human cancers, c-Met ectodomain shedding may provide a reliable and practical indicator of malignant potential and overall tumor burden. C1 NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Sch Med, Dept Urol, Washington, DC USA. Amgen Inc, Dept Canc Biol, Thousand Oaks, CA 91320 USA. RP Bottaro, DP (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bldg 10,CRC 1 West Room 3961,10 Ctr Dr,MSC 1107, Bethesda, MD 20892 USA. EM dbottaro@helix.nih.gov RI Bottaro, Donald/F-8550-2010; OI Bottaro, Donald/0000-0002-5057-5334; Coleman, Jonathan/0000-0002-6428-7835; Giubellino, Alessio/0000-0002-5352-0662 FU Intramural NIH HHS NR 38 TC 52 Z9 52 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2006 VL 12 IS 14 BP 4154 EP 4162 DI 10.1158/1078-0432.CCR-06-0250 PN 1 PG 9 WC Oncology SC Oncology GA 068KR UT WOS:000239373200006 PM 16857786 ER PT J AU Onda, M Nagata, S Ho, M Bera, TK Hassan, R Alexander, RH Pastan, I AF Onda, Masanori Nagata, Satoshi Ho, Mitchell Bera, Tapan K. Hassan, Raffit Alexander, Richard H. Pastan, Ira TI Megakaryocyte potentiation factor cleaved from mesothelin precursor is a useful tumor marker in the serum of patients with mesothelioma SO CLINICAL CANCER RESEARCH LA English DT Article ID OVARIAN-CANCER; MONOCLONAL-ANTIBODIES; MALIGNANT MESOTHELIOMA; ANTITUMOR-ACTIVITY; MOLECULAR-CLONING; DIAGNOSIS; PROTEINS; ADENOCARCINOMAS; EXPRESSION; PANCREAS AB Purpose: To establish monoclonal antibodies (mAb) against megakaryocyte potentiation factor (MPF) and detect MPF in the blood of patients with mesothelioma. Experimental Design: Mice were immunized with a purified recombinant human MPF-rabbit-Fc fusion protein and with MPF. Several hybridomas producing mAbs to MPF were established. A double-determinant (sandwich) ELISA was constructed using mAbs to two different epitopes and used to determine if MPF is present in the serum of patients with mesothelioma. Results: We established seven anti-MPF mAbs whose topographical epitopes were classified into three nonoverlapping groups. All the mAbs reacted with recombinant MPF protein by ELISA. One of the mAbs detected MPF and the mesothelin precursor protein containing MPF in cell lysates on Western blotting. A sandwich ELISA using mAbs to two different epitopes was constructed and used to measure the presence of MPF in the media of various mesothelin-expressing cancer cell lines and in human serum. The ELISA showed that MPF levels were elevated in 91% (51 of 56) of patients with mesothelioma compared with healthy controls. Furthermore, serum MPF fell to normal levels in two patients after surgery for their peritoneal mesothelioma. Conclusions: Using new mAbs to MPF, we showed that MPF is secreted by several mesothelioma cell lines and is frequently elevated in the blood of patients with mesothelioma. Measurement of MPF may be useful in following the response of mesothelioma to treatment. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Room 5106,37 Convent Dr, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov RI Ho, Mitchell/F-5059-2015 FU Intramural NIH HHS NR 30 TC 59 Z9 61 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2006 VL 12 IS 14 BP 4225 EP 4231 DI 10.1158/1078-0432.CCR-06-0472 PN 1 PG 7 WC Oncology SC Oncology GA 068KR UT WOS:000239373200015 PM 16857795 ER PT J AU Liby, K Voong, N Williams, CR Risingsong, R Royce, DB Honda, T Gribble, GW Sporn, MB Letterio, JJ AF Liby, Karen Voong, Nga Williams, Charlotte R. Risingsong, Renee Royce, Darlene B. Honda, Tadashi Gribble, Gordon W. Sporn, Michael B. Letterio, John J. TI The synthetic triterpenoid CDDO-imidazolide suppresses STAT phosphorylation and induces apoptosis in myeloma and lung cancer cells SO CLINICAL CANCER RESEARCH LA English DT Article ID NITRIC-OXIDE PRODUCTION; GROWTH-FACTOR-BETA; TGF-BETA; 12-DIOXOOLEAN-1,9-DIEN-28-OIC ACID; CONFERS RESISTANCE; PANCREATIC-CANCER; MOLECULAR TARGETS; PHASE-2 RESPONSE; TUMOR-GROWTH; T-CELLS AB Purpose: Excessive activity of the transcription factors known as signal transducers and activators of transcription (STAT) contributes to the development and progression of malignancy in many organs. It is, therefore, important to develop new drugs to control the STATs, particularly their phosphorylation state, which is required for their transcriptional activity. Experimental Design: Myeloma and lung cancer cells were treated with the new synthetic triterpenoid CDDO-Imidazolide, and STAT phosphorylation and apoptosis were evaluated by immunoblotting and fluorescence-activated cell sorting analysis. Results: We now report that CDDO-Imidazolide, previously shown to be a potent agent for control of inflammation, cell proliferation, and apoptosis, rapidly (within 30-60 minutes) and potently (at nanomolar levels) suppresses either constitutive or interleukin-6-induced STAT3 and STAT5 phosphorylation in human myeloma and lung cancer cells. Furthermore, in these cells, CDDO-Imidazolide also up-regulates critical inhibitors of STATs, such as suppressor of cytokine signaling-1 and SH2-containing phosphatase-1 (a tyrosine phosphatase). Moreover, gene array studies reported here show that CDDO-imidazolide potently regulates the transcription of important genes that are targets of the STATs. Conclusions: Our new data thus show that CDDO-Imidazolide is a potent suppressor of STAT signaling and provide a further mechanistic basis for future clinical use of this agent to control inflammation or cell proliferation. C1 Dartmouth Coll Sch Med, Hanover, NH USA. Dartmouth Coll, Hanover, NH 03755 USA. NCI, Bethesda, MD 20892 USA. Case Western Reserve Univ, Sch Med, Cleveland, OH USA. RP Letterio, JJ (reprint author), Rainbow Babies & Childrens Hosp, Div Pediat Hematol Oncol, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM John.Letterio@uhhs.com FU NCI NIH HHS [R01 CA78814] NR 40 TC 84 Z9 88 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2006 VL 12 IS 14 BP 4288 EP 4293 DI 10.1158/1078-0432.CCR-06-0215 PN 1 PG 6 WC Oncology SC Oncology GA 068KR UT WOS:000239373200024 PM 16857804 ER PT J AU Ng, SSW Sparreboom, A Shaked, Y Lee, C Man, S Desai, N Soon-Shiong, P Figg, WD Kerbel, RS AF Ng, Sylvia S. W. Sparreboom, Alex Shaked, Yuval Lee, Christina Man, Shan Desai, Neil Soon-Shiong, Patrick Figg, William D. Kerbel, Robert S. TI Influence of formulation vehicle on metronomic taxane chemotherapy: Albumin-bound versus cremophor EL-based paclitaxel SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC BREAST-CANCER; SQUAMOUS-CELL CARCINOMA; NITRIC-OXIDE SYNTHASE; PHASE-I; INTRAARTERIAL CHEMOTHERAPY; NANOPARTICLE FORMULATION; ANTIANGIOGENIC ACTIVITY; INHIBITS ANGIOGENESIS; ANTITUMOR-ACTIVITY; ABI-007 AB Purpose: Low-dose metronomic chemotherapy treatments, especially when combined with 'dedicated' antiangiogenic agents, can induce significant antitumor activity without serious toxicity in various preclinical models. It remains unclear, however, whether some cytotoxic drugs are better suited for metronomic regimens than others. Paclitaxel appears to be a strong candidate for metronomic chemotherapy given its ability to inhibit endothelial cell functions relevant to angiogenesis in vitro at extraordinarily low concentrations and broad-spectrum antitumor activity. Clinically relevant concentrations of the formulation vehicle cremophor EL in Taxol, however, were previously reported to nullify the antiangiogenic effect of paclitaxel, the result of which would hamper its usefulness in metronomic regimens. We hypothesized that ABI-007, a cremophor EL - free, albumin-bound, 130-nm form of paclitaxel, could potentially alleviate this problem. Experimental Design: The antiangiogenic activity of ABI-007 was assessed by multiple in vitro assays. The in vivo optimal dose of ABI-007 for metronomic chemotherapy was determined by measuring circulating endothelial progenitors in peripheral blood. The antitumor effects of metronomic and maximum tolerated dose ABI-007 and Taxol were then evaluated and compared in severe combined immunodeficient mice bearing human MDA-MD-231 breast cancer and PC3 prostate cancer xenografts. Results: ABI-007 significantly inhibited rat aortic microvessel outgrowth, human endothelial cell proliferation, and tube formation. The optimal metronomic dose of ABI-007 was determined to be between 3 and 10 mg/kg. Metronomic ABI-007 but not Taxol, significantly suppressed tumor growth in both xenograft models. Furthermore, the antitumor effect of minimally toxic metronomic ABI-007 approximated that of the maximum tolerated dose of Taxol. Conclusions: Our results underscore the influence of formulation vehicles on the selection of cytotoxic drugs for metronomic chemotherapy. C1 Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. NCI, Clin Pharmacol Res Core, Med Oncol Clin Res Unit, NIH, Bethesda, MD 20892 USA. Abraxis BioSci, Santa Monica, CA USA. RP Kerbel, RS (reprint author), Sunnybrook Hlth Sci Ctr, Room S-217,2075 Bayview Ave, Toronto, ON M4N 3M5, Canada. EM Robert.Kerbel@sri.utoronto.ca RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 37 TC 49 Z9 51 U1 0 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2006 VL 12 IS 14 BP 4331 EP 4338 DI 10.1158/1078-0432.CCR-05-2762 PN 1 PG 8 WC Oncology SC Oncology GA 068KR UT WOS:000239373200028 PM 16857808 ER PT J AU Marti, G Orfao, A Goolsby, C AF Marti, Gerald Orfao, Alberto Goolsby, Chuck TI ZAP-70 in CLL: Towards standardization of a biomarker for patient management: History of clinical cytometry special issue SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Editorial Material DE CLL; ZAP-70; flow cytometry ID CHRONIC LYMPHOCYTIC-LEUKEMIA; EXPRESSION C1 US FDA, Bethesda, MD 20014 USA. Univ Salamanca, Gen Cytometry Serv, Canc Res Ctr, E-37008 Salamanca, Spain. Univ Salamanca, Dept Med, E-37008 Salamanca, Spain. Northwestern Univ, Sch Med, Dept Pathol, Chicago, IL 60611 USA. RP Marti, G (reprint author), NIH, Bldg 29B,room 2NN08,9000 Rockville Pike, Bethesda, MD 20892 USA. EM gemarti@helix.nih.gov NR 24 TC 24 Z9 26 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD JUL 15 PY 2006 VL 70B IS 4 BP 197 EP 200 DI 10.1002/cyto.b.20137 PG 4 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 079ZA UT WOS:000240215200001 PM 16906575 ER PT J AU Wiestner, A AF Wiestner, Adrian TI Flow cytometry for ZAP-70: New colors for chronic lymphocytic leukemia SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Editorial Material DE ZAP-70; chronic lymphocytic leukemia; prognostic marker; flow cytometry ID GENE MUTATION STATUS; CD38 EXPRESSION; GENOMIC ABERRATIONS; DISEASE PROGRESSION; PHENOTYPE; SURVIVAL; PREDICTOR; CLL AB ZAP-70 has become one of the most studied prognostic markers in Chronic Lymphocytic Leukemia (CLL). ZAP-70 is remarkable in many ways: ZAP-70 has been identified as the best discriminating gene between prognostically distinct CLL subtypes using large scale gene expression profiling; ZAP-70 has been shown to enhance signal transduction in CLL B-cells and therefore could contribute to disease progression; and ZAP-70 is one of the rare examples of an intracellular target considered for clinical flow cytometry. This issue attests to the enormous effort and the steady progress made in overcoming technical challenges of testing for ZAP-70 expression and sets the foundation for a successful translation of this important marker into clinical practice. Despite the best effort, one will likely have to accept that not all cases can be clearly assigned to one or the other group, given that ZAP-70 expression between CLL patients falls along a continuum from absent to high. Nevertheless, ZAP-70 expression could become a key parameter to guide patients towards risk adapted treatment strategies in prospective clinical trials. (c) 2006 International Society for Analytical Cytology. C1 NHLBI, NIH, Hematol Branch, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, NIH, Hematol Branch, Bldg 10,CRC 4-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov NR 19 TC 7 Z9 7 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD JUL 15 PY 2006 VL 70B IS 4 BP 201 EP 203 DI 10.1002/cyto.b.20126 PG 3 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 079ZA UT WOS:000240215200002 PM 16906579 ER PT J AU Shen, Q Zhang, Y Uray, IP Hill, JL Kim, HT Lu, CH Young, MR Gunther, EJ Hilsenbeck, SG Chodosh, LA Colburn, NH Brown, PH AF Shen, Qiang Zhang, Yun Uray, Ivan P. Hill, Jamal L. Kim, Hee-Tae Lu, Chunhua Young, Matthew R. Gunther, Edward J. Hilsenbeck, Susan G. Chodosh, Lewis A. Colburn, Nancy H. Brown, Powel H. TI The AP-1 transcription factor regulates postnatal mammary gland development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE AP-1 transcription factor; transcription factor blockade; mammary epithelium; mammary gland development ID ESTROGEN-RECEPTOR-ALPHA; HORMONE-RELATED PROTEIN; BREAST-CANCER CELLS; DOMINANT-NEGATIVE MUTANT; HUMAN PROLACTIN PROMOTER; C-JUN; GENE-EXPRESSION; MATRIX-METALLOPROTEINASE; CELLULAR PROLIFERATION; DUCTAL MORPHOGENESIS AB The AP-1 transcription factor is activated by multiple growth factors that are critical regulators of breast cell proliferation. We previously demonstrated that AP-1 blockade inhibits breast cancer cell growth in vitro. Yet a specific role of AP-1 in normal mammary gland development has not been studied. Using a bi-transgenic mouse expressing an inducible AP-1 inhibitor (Tam67), we found that the AP-1 factor regulates postnatal proliferation of mammary epithelial cells. Mammary epithelial proliferation was significantly reduced after AP-1 blockade in adult, prepubertal, pubertal, and hormone-stimulated mammary glands. In pubertal mice, mammary cell proliferation was greatly reduced, and the cells that did proliferate failed to express Tam67. We also observed structural changes such as suppressed branching and budding, reduced gland tree size, and less fat pad occupancy in developing mammary glands after AP-1 blockade. We further demonstrated that Tam67 suppressed the expression of AP-1-dependent genes (TIMP-1, vinientin, Fra-1, and fibronectin) and the AP-1-dependent growth regulatory genes (cyclin D1 and c-myc) in AP-1-blocked mammary glands. We therefore conclude that AP-1 factor is a pivotal regulator of postnatal mammary gland growth and development. (c) 2006 Elsevier Inc. All rights reserved. C1 Baylor Coll Med, Breast Ctr, Houston, TX 77030 USA. NCI, Gene Regulat Sect, LCP, Ft Detrick, MD 21702 USA. Univ Penn, Dept Canc Biol, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. RP Brown, PH (reprint author), Baylor Coll Med, Breast Ctr, MS600,1 Baylor Pl, Houston, TX 77030 USA. EM pbrown@breastcenter.tmc.edu OI Shen, Qiang/0000-0002-1491-5434 FU Intramural NIH HHS; NCI NIH HHS [CA101211-01] NR 64 TC 23 Z9 26 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2006 VL 295 IS 2 BP 589 EP 603 DI 10.1016/j.ydbio.2006.03.042 PG 15 WC Developmental Biology SC Developmental Biology GA 064YX UT WOS:000239127700011 PM 16678816 ER PT J AU Chignell, CF Kukielczak, BM Sik, RH Bilski, PJ He, YY AF Chignell, Colin F. Kukielczak, Barbara M. Sik, Robert H. Bilski, Piotr J. He, Yu-Ying TI Ultraviolet A sensitivity in Smith-Lemli-Opitz syndrome: Possible involvement of cholesta-5,7,9(11)-trien-3 beta-ol SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article ID SINGLET OXYGEN; HUMAN KERATINOCYTES; VITAMIN-E; PHOTOSENSITIVITY; HYDROPEROXIDE; STEROLS; 2',7'-DICHLOROFLUORESCIN; CARCINOGENESIS; PHOTOTOXICITY; ICHTHYOSIS AB Smith-Lemli-Opitz syndrome (SLOS) is a severe developmental disorder caused by mutations in the DHCR7 gene coding for 7-dehydrocholesterol (7-DHC) reductase, the enzyme involved in the last step of cholesterol biosynthesis. SLOS homozygotes exhibit marked deficiency of cholesterol in plasma and tissues with concomitant increase in 7-DHC. Ultraviolet A (UVA) photosensitivity has been recognized as part of SLOS with maximal response occurring at 350 nm. 7-DHC itself has no UVA absorption and so cannot be the direct cause of SLOS photosensitivity. However, cholesta-5,7,9(11)-trien-3 beta-ol (9-DDHC), a metabolite of 7-DHC, has been detected in plasma from SLOS patients. Because 9-DDHC has strong absorption in the UVA range (epsilon similar to 15,000 @ 324 nm), we have examined its photobiology to determine whether it could be involved in SLOS photosensitivity. High levels of 7-DHC (0.65 mg/100 g wet weight) and measurable amounts of 9-DDHC (0.042 mg/100 g wet weight) were found in skin lipids extracted from CD-1 mice treated with AY9944 (trans-1,4-bis(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride), an inhibitor of 7-DHC reductase. Human HaCaT keratinocytes treated with 9-DDHC (10 mu M) and then immediately exposed to UVA (15 Rem 2) exhibited an 88% decrease in viability (compared to dark controls). No damage was observed in cells exposed to 7-DHC/UVA or UVA alone. However, HaCaT keratinocytes treated with 7-DHC (5 mu M) for 15 h and then exposed to UVA (30 J/cm(2)) were damaged. 9-DDHC was detected in keratinocytes incubated with 7-DHC. Reactive oxygen species were detected in 9-DDHC/UVA-exposed cells using the fluorescent probe 5-(and 6-)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester. Singlet oxygen was generated when 9-DDHC was UVA irradiated in CCl4. UVA irradiation of 9-DDHC in acetonitrile generated superoxide and carbon-centered and alkoxyl radicals which were trapped by 5,5-dimethyl-1-pyrroline N-oxide. These findings suggest that reactive oxygen species generated by 9-DDHC may play a role in the UVA skin photosensitivity of SLOS patients. Furthermore, several statin drugs inhibit 7-DHC reductase, in addition to hydroxymetbylglutaryl-CoenzymeA reductase, so that 9-DDHC may also be responsible for statin-derived photosensitivity, dermatoses, and cataract formation. Finally, we have previously detected 9-DDHC in skin lipids from normal subjects, so this sterol may also be the skin chromophore responsible for skin photoaging and UV-induced skin cancer. (c) Published by Elsevier Inc. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Chignell, CF (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. EM chignell@niehs.nih.gov FU Intramural NIH HHS NR 34 TC 18 Z9 18 U1 1 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 JUL 15 PY 2006 VL 41 IS 2 BP 339 EP 346 DI 10.1016/j.freeradbiomed.2006.04.021 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 063SM UT WOS:000239039900021 PM 16814115 ER PT J AU Calton, BA Lacey, JV Schatzkin, A Schairer, C Colbert, LH Albanes, D Leitzmann, MF AF Calton, BA Lacey, JV Schatzkin, A Schairer, C Colbert, LH Albanes, D Leitzmann, MF TI Physical activity and the risk of colon cancer among women: A prospective cohort study (United States) SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE colon cancer; physical activity; exercise; intensity; cohort; prospective ID COLORECTAL-CANCER; LEISURE-TIME; ACTIVITY QUESTIONNAIRE; REDUCED RISK; FOLLOW-UP; PREVENTION; POPULATION; EXERCISE; MEN; ALCOHOL AB Physical activity has frequently been reported to decrease the risk of colon cancer in men, but data on the relation of physical activity to colon cancer risk in women have generally been less consistent. To further investigate the relationship of physical activity with colon cancer risk in women, we studied a cohort of 31,783 US women participating in the Breast Cancer Detection Demonstration Project Follow-up Study. Information on daily physical activity over the past year was ascertained using a self-administered questionnaire at study baseline. The Cox proportional hazards model was used to estimate relative risks (RRs) relating physical activity to the risk of incident colon cancer. During 270,325 person-years of follow-up, 243 colon cancer cases were identified. No association was observed between physical activity and the subsequent risk of colon cancer. The multivariable RRs of colon cancer across increasing quintiles of total physical activity were 1.0, 1.45, 1.16, 1.27 and 1.15 (95% CI: 0.76, 1.75; p(trend) = 0.77). The multivariable RRs comparing women at the extremes of moderate and vigorous physical activity, respectively, were 1.07 (95% CI: 0.70, 1.62) and 1.10 (95% CI: 0.78, 1.55). The relationship between physical activity and colon cancer risk did not vary by anatomic subsite or across subgroups defined by age, body mass, dietary fiber intake, menopausal status, menopausal hormone use or aspirin use. The results of this large prospective cohort study among women do not support the hypothesis that physical activity is related to a lower incidence of colon cancer. (c) 2006 Wiley-Liss, Inc. C1 NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Kinesiol, Madison, WI USA. RP Calton, BA (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Executive Blvd,EPS 3028, Rockville, MD 20852 USA. EM brook.calton@ucsf.edu RI Albanes, Demetrius/B-9749-2015 NR 53 TC 23 Z9 26 U1 4 U2 10 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 JUL 15 PY 2006 VL 119 IS 2 BP 385 EP 391 DI 10.1002/ijc.21840 PG 7 WC Oncology SC Oncology GA 052XM UT WOS:000238267300019 PM 16489545 ER PT J AU Singh, AK Menard, C Guion, P Simone, NL Smith, S Crouse, NS Godette, DJ Cooley-Zgela, T Sciuto, LC Coleman, J Pinto, P Albert, PS Camphausen, K Coleman, CN AF Singh, Anurag K. Menard, Cynthia Guion, Peter Simone, Nicole L. Smith, Sharon Crouse, Nancy Sears Godette, Denise J. Cooley-Zgela, Theresa Sciuto, Linda C. Coleman, Jonathan Pinto, Peter Albert, Paul S. Camphausen, Kevin Coleman, C. Norman TI Intrarectal amifostine suspension may protect against acute proctitis during radiation therapy for prostate cancer: A pilot study SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE amifostine; proctitis; intrarectal; prostate; radiation ID PHASE-II; RANDOMIZED TRIAL; RECTAL TOXICITY; NECK TUMORS; WR-2721; RADIOPROTECTION; RADIOTHERAPY; PREVENTION; INJURY; DAMAGE AB Purpose: Our goal was to test the ability of intrarectal amifostine to limit symptoms of radiation proctitis. Methods and Materials: The first 18 patients received 1 g of intrarectal amifostine suspension placed 30-45 min before each radiation treatment. The following 12 patients received 2 g of amifostine. Total dose prescribed ranged from 66 to 76 Gy. All patients were treated with three-dimensional conformal radiation therapy. The suspension remained intrarectal during treatment and was expelled after treatment. For gastrointestinal symptoms, during treatment and follow-up, all patients had a Radiation Therapy Oncology Group (RTOG) grade recorded. Results: Median follow-up was 18 months (range, 6-24 months). With 2 g vs. 1 g amifostine, there was a nearly significant decrease in RTOG Grade 2 acute rectal toxicity. Seven weeks after the start of radiation therapy, the incidence of Grade 2 toxicity was 33% in the 1-g group (6/18) compared with 0% (0/12) in the 2-g group (p 0.06). No Grade 3 toxicity or greater occurred in this study. Conclusion: This trial suggests greater rectal radioprotection from acute effects with 2 g vs. 1 g amifostine suspension. Further studies should be conducted in populations at higher risk for developing symptomatic acute and late proctitis. (c) 2006 Elsevier Inc. C1 NCI, Radiat Oncol Branch, NIH, DHHS, Bethesda, MD 20892 USA. Univ Toronto, Princess Margaret Hosp, Hlth Network, Radiat Med Program, Toronto, ON, Canada. NCI, Urol Oncol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. RP Guion, P (reprint author), NCI, Radiat Oncol Branch, NIH, DHHS, Bldg 10,CRC Rm B2-3561,9000 Rockville Pike, Bethesda, MD 20892 USA. EM guionp@mail.nih.gov OI Coleman, Jonathan/0000-0002-6428-7835 FU Intramural NIH HHS NR 23 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2006 VL 65 IS 4 BP 1008 EP 1013 DI 10.1016/j.ijrobp.2006.02.030 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 061NH UT WOS:000238878800007 PM 16730138 ER PT J AU Minton, AP AF Minton, Allen P. TI How can biochemical reactions within cells differ from those in test tubes? SO JOURNAL OF CELL SCIENCE LA English DT Article DE protein associations; protein stability; protein folding; macromolecular crowding; macromolecular confinement; macromolecular adsorption ID EXCLUDED SURFACE-AREA; PROTEIN FIBER FORMATION; ESCHERICHIA-COLI; SELF-ASSOCIATION; MACROMOLECULAR STRUCTURE; GLOBULAR-PROTEINS; ALPHA-SYNUCLEIN; MOLECULAR CONFINEMENT; POLY(ETHYLENE GLYCOL); INERT MACROMOLECULES AB Nonspecific interactions between individual macromolecules and their immediate surroundings ('background interactions') within a medium as heterogeneous and highly volume occupied as the interior of a living cell can greatly influence the equilibria and rates of reactions in which they participate. Background interactions may be either repulsive, leading to preferential size-and-shape-dependent exclusion from highly volume-occupied elements of volume, or attractive, leading to nonspecific associations or adsorption. Nonspecific interactions with different constituents of the cellular interior lead to three classes of phenomena: macromolecular crowding, confinement and adsorption. Theory and experiment have established that predominantly repulsive background interactions tend to enhance the rate and extent of macromolecular associations in solution, whereas predominately attractive background interactions tend to enhance the tendency of macromolecules to associate on adsorbing surfaces. Greater than order-of-magnitude increases in association rate and equilibrium constants attributable to background interactions have been observed in simulated and actual intracellular environments. C1 NIDDK, Sect Phys Biochem, Lab Biochem Pharmacol, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDK, Sect Phys Biochem, Lab Biochem Pharmacol, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM minton@helix.nih.gov OI Minton, Allen/0000-0001-8459-1247 FU Intramural NIH HHS NR 75 TC 226 Z9 236 U1 4 U2 55 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JUL 15 PY 2006 VL 119 IS 14 BP 2863 EP 2869 DI 10.1242/jcs.03063 PG 7 WC Cell Biology SC Cell Biology GA 060ZF UT WOS:000238840300004 PM 16825427 ER PT J AU Grati, M Aggarwal, N Strehler, EE Wenthold, RJ AF Grati, M'hamed Aggarwal, Nisha Strehler, Emanuel E. Wenthold, Robert J. TI Molecular determinants for differential membrane trafficking of PMCA1 and PMCA2 in mammalian hair cells SO JOURNAL OF CELL SCIENCE LA English DT Article DE alternative splicing; inner ear explant; intracellular loop; leucine-isoleucine signal; stereocilia ID POLARIZED EPITHELIAL-CELLS; RETINAL-PIGMENT EPITHELIUM; APICAL TARGETING SIGNAL; DARBY CANINE KIDNEY; SORTING SIGNALS; MDCK CELLS; BASOLATERAL MEMBRANE; TRANSMEMBRANE DOMAIN; CYTOPLASMIC TAIL; DILEUCINE MOTIF AB The plasma membrane Ca2+-ATPase-2 (PMCA2) is expressed in stereocilia of hair cells of the inner ear, whereas PMCA1 is expressed in the basolateral plasma membrane of hair cells. Both extrude excess Ca2+ from the cytosol. They are predicted to contain ten membrane-spanning segments, two large cytoplasmic loops as well as cytosolic N- and C-termini. Several isoform variants are generated for both PMCA1 and PMCA2 by alternative splicing, affecting their first cytosolic loop (A-site) and their C-terminal tail. To understand how these isoforms are differentially targeted in hair cells, we investigated their targeting regions and expression in hair cells. Our results show that a Leu-Ile motif in 'b'-tail splice variants promotes PMCA1b and PMCA2b basolateral sorting in hair cells. Moreover, apical targeting of PMCA2 depends on the size of the A-site-spliced insert, suggesting that the conformation of the cytoplasmic loop plays a role in apical targeting. C1 Natl Inst Deafness & Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Dept Biochem & Mol Biol, Coll Med, Rochester, MN 55905 USA. RP Wenthold, RJ (reprint author), Natl Inst Deafness & Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. EM wenthold@nidcd.nih.gov RI Grati, M'hamed/C-9563-2011 FU Intramural NIH HHS; NIGMS NIH HHS [GM 28835] NR 54 TC 40 Z9 43 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JUL 15 PY 2006 VL 119 IS 14 BP 2995 EP 3007 DI 10.1242/jcs.03030 PG 13 WC Cell Biology SC Cell Biology GA 060ZF UT WOS:000238840300018 PM 16803870 ER PT J AU Calvo, E Ribeiro, JMC AF Calvo, Eric Ribeiro, Jose M. C. TI A novel secreted endonuclease from Culex quinquefasciatus salivary glands SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Article DE mosquito; salivary gland; endonuclease; Culex quinquefasciatus; arthropod ID ADULT FEMALE MOSQUITO; ACTIVE-SITE; NUCLEASE; HEPATOPANCREAS; IDENTIFICATION; PREDICTION; CLEAVAGE; SIALOME; CLONING AB Previous analysis of the salivary gland transcriptome of Culex quinquefasciatus showed the potential presence of an endonuclease with sequence similarities to shrimp, crab and two tsetse salivary proteins. Indeed, not only was the cloned cDNA shown to encode an active double-stranded endonuclease, but also the same activity was demonstrated to be secreted by salivary glands of Cx. quinquefasciatus. Preliminary studies with salivary gland extracts confirmed the presence of a highly active nuclease. This enzyme was shown to be present in the saliva of female mosquitoes by allowing starved mosquitoes to probe DNA-containing agarose gel. The recombinant Cx. quinquefasciatus endonuclease (CuquEndo) produced in mammalian cells showed no sequence specificity for DNA substrate except that it only cleaves double-stranded DNA. Recombinant Cx. quinquefasciatus endonuclease was active in the presence of Mg2+ ions at pH 7.0 - 8.0, but no endonuclease activity was detected in the presence of calcium ions. The final hydrolysis products of this enzyme, detected by ion exchange chromatography, yielded DNA fragments ranging form 8 - 12 base pairs. Although endonucleases have been associated with a variety of cellular functions, their role in mosquito saliva is not clear. This female-specific secreted endonuclease may assist blood meal intake by lowering the local viscosity created by the release of host DNA in the bite site and/or acting as an indirect anticoagulant factor by producing a defibrotide-like mixture of DNA haptamers. C1 Natl Inst Allergy & Infect Dis, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Ribeiro, JMC (reprint author), Natl Inst Allergy & Infect Dis, Lab Malaria & Vector Res, NIH, Twinbrook 3 12735 Twinbrook Pkwy,Room 2E-32D, Rockville, MD 20852 USA. EM jribeiro@niaid.nih.gov OI Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS NR 21 TC 30 Z9 31 U1 1 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 J9 J EXP BIOL JI J. Exp. Biol. PD JUL 15 PY 2006 VL 209 IS 14 BP 2651 EP 2659 DI 10.1242/jeb.02267 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 071YW UT WOS:000239640800010 PM 16809456 ER PT J AU Hamano, S Asgharpour, A Stroup, SE Wynn, TA Leiter, EH Houpt, E AF Hamano, Shinjiro Asgharpour, Amon Stroup, Suzanne E. Wynn, Thomas A. Leiter, Edward H. Houpt, Eric TI Resistance of C57BL/6 mice to amoebiasis is mediated by nonhemopoietic cells but requires hemopoietic IL-10 production SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; CD4(+) T-CELLS; PARASITE ENTAMOEBA-HISTOLYTICA; INTERLEUKIN 10-DEFICIENT MICE; INTERLEUKIN-10-DEFICIENT MICE; IL-10-DEFICIENT MICE; HUMAN INTESTINE; FACTOR-ALPHA; IFN-GAMMA; COLITIS AB Resistance to intestinal amoebiasis is mouse strain dependent. C57BL/6 (136) mice clear Entamoeba histolytica within hours of challenge, whereas C3H and CBA strains are susceptible to infection and disease. In this study, we show using bone marrow (BM) chimeric mice that mouse strain-dependent resistance is mediated by nonhemopoietic cells; specifically, B6 BM -> CBA recipients remained susceptible as measured by amoeba score and culture, whereas CBA BM -> B6 recipients remained resistant. Interestingly, hemopoietic IL-10 was required for maintaining the resistance of B6 mice, in that B6 IL-10-deficient mice and IL-10(-/-) -> wild-type recipients, but not IL-10(+/+) BM -> IL-10(-/-) recipients, exhibited higher amoeba scores than their wild-type controls. Additionally, C57BL/10 IL-10(-/-)Rag2(-/-) mice exhibited diminished amoeba scores and culture rates vs IL-10(-/-) mice, indicating that lymphocytes potentiated the susceptibility of IL-10-deficient mice. We conclude that nonhemopoietic cells mediate the natural resistance to intestinal amoebiasis of B6 mice, yet this resistance depends on hemopoietic IL-10 activity. C1 Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA 22908 USA. Kyushu Univ, Fac Med Sci, Dept Parasitol, Higashi Ku, Fukuoka 812, Japan. NIH, Bethesda, MD 20892 USA. Jackson Lab, Bar Harbor, ME 04609 USA. RP Houpt, E (reprint author), Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA 22908 USA. EM erh6k@virginia.edu RI Wynn, Thomas/C-2797-2011 FU NIAID NIH HHS [AI 052444-01] NR 36 TC 28 Z9 28 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 JUL 15 PY 2006 VL 177 IS 2 BP 1208 EP 1213 PG 6 WC Immunology SC Immunology GA 062ED UT WOS:000238926500051 PM 16818779 ER PT J AU Seydel, KB Milner, DA Kamiza, SB Molyneux, ME Taylor, TE AF Seydel, KB Milner, DA Kamiza, SB Molyneux, ME Taylor, TE TI The distribution and intensity of parasite sequestration in comatose malawian children SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 53rd Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY NOV 07-11, 2004 CL Miami Beach, FL SP Amer Soc Trop Med & Hyg ID FATAL FALCIPARUM-MALARIA; PLASMODIUM-FALCIPARUM; LACTATE-DEHYDROGENASE; MICROVASCULAR SEQUESTRATION; AFRICAN CHILDREN; CEREBRAL MALARIA; ERYTHROCYTES; SEPSIS; HOST AB Background. The sequestration of Plasmodium falciparum-infected erythrocytes in capillary beds is a characteristic feature of severe malaria and is believed to be central to disease pathogenesis. Sequestration occurs in all P. falciparum infections, including those in asymptomatic individuals. Therefore, sequestration cannot be the sole determinant of severe disease; the intensity or distribution of infected erythrocytes may also contribute. Discerning the relationship between sequestration and well-defined clinical syndromes may enhance understanding of disease mechanisms. Methods. We measured the concentration of parasite-derived lactate dehydrogenase (pLDH) in tissue samples obtained at autopsy from patients with clinically defined cerebral malaria. On the basis of the autopsy findings, patients were divided into 2 groups: those with an identifiable, nonmalarial cause of death and those without, who were presumed to have died of cerebral malaria. The concentration of pLDH, as determined by enzyme-linked immunosorbent assay, was used to estimate parasite load in different organs. Results. When pLDH could be detected, the parasite load was higher in patients with presumed cerebral malaria than in parasitemic patients with assumed cerebral malaria with a nonmalaria cause of death identified at autopsy (P < .05 for brain, intestine, and skin). Conclusions. These findings suggest that sequestration in patients with fatal cerebral vasculature. C1 Michigan State Univ, Coll Osteopath Med, Dept Internal Med, E Lansing, MI 48824 USA. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Malawi, Coll Med, Dept Histopathol, Blantyre, Malawi. Univ Malawi, Coll Med, Malawi Liverpool Wellcome Trust Clin Res Programm, Blantyre, Malawi. Univ Malawi, Coll Med, Blantyre Malaria Project, Blantyre, Malawi. Univ Liverpool, Sch Trop Med, Liverpool L69 3BX, Merseyside, England. RP Taylor, TE (reprint author), Michigan State Univ, Coll Osteopath Med, Dept Internal Med, B309-B W Fee Hall, E Lansing, MI 48824 USA. EM taylort@msu.edu FU Intramural NIH HHS; NIAID NIH HHS [R01 AI034969, R01 AI34969]; Wellcome Trust [042390/Z/94] NR 26 TC 67 Z9 69 U1 0 U2 2 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 JUL 15 PY 2006 VL 194 IS 2 BP 208 EP 215 DI 10.1086/505078 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 053WU UT WOS:000238337600011 PM 16779727 ER PT J AU Lipner, EM Dembele, N Souleymane, S Alley, WS Prevots, DR Toe, L Boatin, B Weil, GJ Nutman, TB AF Lipner, EM Dembele, N Souleymane, S Alley, WS Prevots, DR Toe, L Boatin, B Weil, GJ Nutman, TB TI Field applicability of a rapid-format anti-Ov-16 antibody test for the assessment of onchocerciasis control measures in regions of endemicity SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID VECTOR CONTROL; MASS TREATMENT; WEST-AFRICA; IVERMECTIN; VOLVULUS; TRANSMISSION; INFECTION; DIAGNOSIS; DIETHYLCARBAMAZINE; CHALLENGES AB Background. A previously developed, specific, rapid-format immunochromatographic card test that detects immunoglobulin G4 to the recombinant Onchocerca volvulus antigen Ov-16 was modified to detect antibodies in whole blood. Methods. Ov-16 card test results were assessed in 1511 subjects >= 2 years of age in 7 West African villages with varying histories of onchocerciasis control measures. Results. In villages in which control measures had been implemented, anti-Ov-16 antibody prevalence rates ranged from 5.2% to 65.1%. Antibody prevalence rates were close to zero among subjects born after effective control measures had been implemented. In 2 villages without a history of control measures where onchocerciasis was endemic, microfilariae ( MF) prevalence rates were 82.8% and 65.1%, and antibody prevalence rates were 73.1% and 62.1%. In these 2 villages, the sensitivity of the Ov-16 card test was 81.1% and 76.5%, the specificity was 100%, and the positive predictive value was 91.8% and 80.5%. MF and antibody prevalence rates were correlated ( Spearman's r = 0.815; P < .038 Conclusions. The Ov-16 card test is field applicable, exhibits high sensitivity and specificity for O. volvulus infection, and has great potential as a tool for surveillance and for evaluating the success of onchocerciasis control measures. C1 NIAID, Off Global Res, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Div Infect Dis, St Louis, MO 63110 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. WHO, UNICEF, United Nat Dev Programme, World Bank,Special Programme Res & Training Trop, CH-1211 Geneva, Switzerland. WHO, Onchocerciasis Control Programme W Africa, Ouagadougou, Burkina Faso. Minist Sante, Ouagadougou, Burkina Faso. RP Nutman, TB (reprint author), NIAID, Off Global Res, NIH, Bldg 4,Room B1-03,4 Ctr Dr, Bethesda, MD 20892 USA. EM GWEIL@im.wustl.edu; tnutman@niaid.nih.gov FU Intramural NIH HHS NR 22 TC 39 Z9 39 U1 0 U2 2 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 JUL 15 PY 2006 VL 194 IS 2 BP 216 EP 221 DI 10.1086/505081 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 053WU UT WOS:000238337600012 PM 16779728 ER PT J AU Song, EY VanDunk, C Kuddo, T Nelson, PG AF Song, Eun Young VanDunk, Cassandra Kuddo, Thea Nelson, Phillip G. TI Measurement of CGRP in dried blood spots using a modified sandwich enzyme immunoassay SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE EIA; CGRP; dried blood spot ID GENE-RELATED PEPTIDE; MEDULLARY-THYROID CARCINOMA; HUMAN CALCITONIN; ASSAY; EXPRESSION; AUTISM AB Calcitonin gene-related peptide (CGRP) has roles as a neurotransmitter, neuromodulator and trophic factor. CGRP has been reported to be elevated in neonatal blood of children with autism or mental retardation as compared with normal subjects by recycling immuno-affinity chromatography (RIC). While CGRP detection in neonatal blood is thus important, it is not easy to detect CGRP in dried blood spots because of the limitations of sample volume and the specificity and the sensitivity of available assay systems. In the present study, we modified a "Sandwich Enzyme Immunoassay" for the purpose of detecting CGRP in blood spot eluate. We have prepared blood spots from blood collected from normal human subjects and measured CGRP level in eluates from these blood spots. Instead of a purification step, we have introduced a pre-incubation step and used washed erythrocytes as a dilution solution. The modified assay has good recovery and specificity and appropriate dilution curves. We have compared the eluate levels with levels in serum and plasma from the same individuals and find that CGRP levels in blood spot eluate were similar to those of serum and plasma. Thus, the newly modified EIA may be a useful method for the detection of CGRP in blood spot eluate. (c) 2006 Elsevier B.V. All rights reserved. C1 NICHHD, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. Korea Res Inst Biosci & Biotechnol, Cell Biol Lab, Taejon 305600, South Korea. RP Nelson, PG (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. EM nelsonp@mail.nih.gov NR 17 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD JUL 15 PY 2006 VL 155 IS 1 BP 92 EP 97 DI 10.1016/j.jneumeth.2005.12.020 PG 6 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 062IT UT WOS:000238938500011 PM 16466803 ER PT J AU Pannacciulli, N Del Parigi, A Chen, KW Le, DSNT Reiman, EM Tataranni, PA AF Pannacciulli, N Del Parigi, A Chen, KW Le, DSNT Reiman, EM Tataranni, PA TI Brain abnormalities in human obesity: A voxel-based morphometric study SO NEUROIMAGE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; ALZHEIMER-DISEASE; FOLLOW-UP; SATIATION; FOOD; ACTIVATION; INSULIN; MECHANISMS; DOPAMINE; LEPTIN AB Obesity is accompanied by damage to several tissues. Overweight is a risk factor for Alzheimer's disease and other neurodegenerative disorders. Whether structural abnormalities associated with excess body fat may also occur in the brain is unknown. We sought to determine to what extent excess body fat is associated with regional alterations in brain structure using voxel-based morphometry (VBM), a whole-brain unbiased technique based upon high-definition 3D magnetic resonance imaging (MRI) scans normalized into a common standard space and allowing for an objective assessment of neuroanatomical differences throughout the brain. We studied 24 obese (11 male, 13 female; age: 32 +/- 8 years; body mass index [BMI]: 39.4 +/- 4.7 kg/m(2)) and 36 lean (25 male, 11 female; mean age: 33 9 years; BMI: 22.7 +/- 2.2 kg/m(2)) non-diabetic Caucasians. In comparison with the group of lean subjects, the group of obese individuals had significantly lower gray matter density in the post-central gyrus, frontal operculum, putamen, and middle frontal gyrus (P < 0.01 after adjustment for sex, age, handedness, global tissue density, and multiple comparisons). BMI was negatively associated with GM density of the left post-central gyrus in obese but not lean subjects. This study identified structural brain differences in human obesity in several brain areas previously involved In the regulation of taste, reward, and behavioral control. These alterations may either precede obesity, representing a neural marker of increased propensity to gaining weight, or occur as a consequence of obesity, indicating that also the brain is affected by increased adiposity. (c) 2006 Elsevier Inc. All rights reserved. C1 NIDDKD, Obes & Diabet Clin Res Sect, Phoenix Epidemiol, NIH,Dept Hlth & Human Serv, Phoenix, AZ 85016 USA. NIDDKD, Clin Res Branch, NIH, Dept Hlth & Human Serv, Phoenix, AZ 85016 USA. Good Samaritan Hosp, PET Res Ctr, Phoenix, AZ 85031 USA. RP Pannacciulli, N (reprint author), NIDDKD, Obes & Diabet Clin Res Sect, Phoenix Epidemiol, NIH,Dept Hlth & Human Serv, 4212 N 16Th St,Rm 5-28, Phoenix, AZ 85016 USA. EM nicolap@mail.nih.gov RI Chen, kewei/P-6304-2015 OI Chen, kewei/0000-0001-8497-3069 FU Intramural NIH HHS NR 44 TC 230 Z9 231 U1 4 U2 23 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 JUL 15 PY 2006 VL 31 IS 4 BP 1419 EP 1425 DI 10.1016/j.neuroimage.2006.01.047 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 059AC UT WOS:000238704700003 PM 16545583 ER PT J AU Birn, RM Diamond, JB Smith, MA Bandettini, PA AF Birn, RM Diamond, JB Smith, MA Bandettini, PA TI Separating respiratory-variation-related neuronal-activity-related fluctuations in fluctuations from fMRI SO NEUROIMAGE LA English DT Article ID FUNCTIONAL MRI; HUMAN BRAIN; DEFAULT-MODE; OXIDATIVE-METABOLISM; BOLD SIGNAL; CONNECTIVITY; HYPERCAPNIA; LOCALIZATION; VARIABILITY; REGIONS AB Subtle changes in a subject's breathing rate or depth, which occur naturally during rest at low frequencies (< 0.1 Hz), have been shown to be significantly correlated with fMRI signal changes throughout gray matter and near large vessels. The goal of this study was to investigate the impact of these low-frequency respiration variations on both task activation fMRI studies and resting-state functional connectivity analysis. Unlike fMRI signal changes correlated with the breathing motion (similar to 0.3 Hz), BOLD signal changes correlated with across-breath variations in respiratory volume (similar to 0.03 Hz) appear localized to blood vessels and regions with high blood volume, such as gray matter, similar to changes seen in response to a breath-hold challenge. In addition, the respiration-variation-induced signal changes were found to coincide with many of the areas identified as part of the 'default mode' network, a set of brain regions hypothesized to be more active at rest. Regions could therefore be classified as being part of a resting network based on their similar respiration-induced changes rather than their synchronized neuronal activity. Monitoring and removing these respiration variations led to a significant improvement in the identification of task-related activation and deactivation and only slight differences in regions correlated with the posterior cingulate at rest. Regressing out global signal changes or cueing the subject to breathe at a constant rate and depth resulted in an improved spatial overlap between deactivations and resting-state-correlations among areas that showed deactivation. Published by Elsevier Inc. C1 NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Birn, RM (reprint author), NIMH, Lab Brain & Cognit, NIH, 10 Ctr Dr,Bldg 10 Rm 1D80, Bethesda, MD 20892 USA. EM rbirn@nih.gov FU Intramural NIH HHS NR 35 TC 562 Z9 565 U1 2 U2 31 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 JUL 15 PY 2006 VL 31 IS 4 BP 1536 EP 1548 DI 10.1016/j.neuroimage.2006.02.048 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 059AC UT WOS:000238704700013 PM 16632379 ER PT J AU Nakic, M Smith, BW Busis, S Vythilingam, M Blair, RJR AF Nakic, M Smith, BW Busis, S Vythilingam, M Blair, RJR TI The impact of affect and frequency on lexical decision: The role of the amygdala and inferior frontal cortex SO NEUROIMAGE LA English DT Article DE lexical decision task; temporal cortex; anterior cingulate cortex ID EVENT-RELATED FMRI; VISUAL WORD RECOGNITION; ANTERIOR CINGULATE; EMOTIONAL WORDS; SEMANTIC MEMORY; FUNCTIONAL NEUROANATOMY; PREFRONTAL CORTEX; TASK; POTENTIALS; ACTIVATION AB The current study used event-related fMRI to examine BOLD responses associated with two factors that behaviorally determine speed of lexical decision: frequency and emotion. Thirteen healthy adults performed a visual lexical decision task, discriminating between words and orthographically and phonologically legal nonwords. The study involved a 2 (Frequency: high and low) x 3 (Emotional arousal: highly negative, mildly negative, and neutral words) design with word categories matched for number of letters and concreteness. There were significant main effects for both frequency and emotion in lexical decision reaction times but no significant interaction. Negative word lexical decisions were associated with increased activation in bilateral amygdala and middle temporal cortex as well as rostral anterior and posterior cingulate cortex. Low-frequency word lexical decisions, relative to high-frequency word lexical decisions, were associated with increased bilateral activity in inferior frontal cortex. Inferior frontal cortex activation was particularly low during lexical decision for high-frequency emotional words but significant for high-frequency neutral emotional words. We suggest that this is because the semantic representation of high-frequency emotional words may receive sufficient additional augmentation via the reciprocal activation from the amygdala such that selective augmentation by inferior frontal cortex to achieve lexical decision is unnecessary. (c) 2006 Elsevier Inc. All rights reserved. C1 NIMH, Unit Affect Cognit Neurosci, Mood & Anxiety Disorders Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. RP Nakic, M (reprint author), NIMH, Unit Affect Cognit Neurosci, Mood & Anxiety Disorders Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM nakicm@mail.nih.gov RI Frank, David/E-8213-2012 FU Intramural NIH HHS NR 58 TC 65 Z9 69 U1 5 U2 15 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 JUL 15 PY 2006 VL 31 IS 4 BP 1752 EP 1761 DI 10.1016/j.neuroimage.2006.02.022 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 059AC UT WOS:000238704700032 PM 16647271 ER PT J AU Alden, KJ Marosy, B Nzegwu, N Justice, CM Wilson, AF Miller, NH AF Alden, Kris J. Marosy, Beth Nzegwu, Nneka Justice, Cristina M. Wilson, Alexander F. Miller, Nancy H. TI Idiopathic scoliosis: identification of candidate regions on chromosome 19p13 SO SPINE LA English DT Article DE idiopathic scoliosis; genomic screen; chromosome 19; linkage analysis ID PLATELET CALMODULIN LEVELS; CURVE PROGRESSION; LINKAGE ANALYSIS; FIBRILLIN GENES; MARFAN-SYNDROME; SEVERITY; LOCUS; SUSCEPTIBILITY; ABNORMALITIES; PREVALENCE AB Study Design. We performed genomic screening, statistical linkage analysis, and fine mapping of 202 families with at least 2 individuals with idiopathic scoliosis. Objective. To identify regions on chromosome 19p13 statistically linked to the phenotypic expression of idiopathic scoliosis. Summary of Background Data. Idiopathic scoliosis is a common structural curvature of the spine affecting otherwise healthy children. Presently, no clear consensus exists regarding the underlying abnormality or genetic determinants of this disease. Methods. Model-independent linkage analysis of qualitative and quantitative traits related to scoliosis was used to screen genotyping data from 391 markers in 202 families (1198 individuals). Subsets of families with probands having a curve >= 30 degrees were dichotomized based on the most likely mode of inheritance for each family (autosomal dominant or X-linked dominant). Fine mapping was performed to show linkage to candidate regions on chromosome 19. Results. When the threshold of disease was set at a curvature of >= 30 degrees, qualitative linkage analysis revealed significant results at 2 successive markers on chromosome 19. Conclusion. The data confirm a previously reported genetic locus on chromosome 19 as potentially significant in the etiology of idiopathic scoliosis. C1 Johns Hopkins Univ, Dept Orthopaed Surg, Johns Hopkins Bayview Med Ctr, Baltimore, MD 21224 USA. NIH, Genometr Sect, Div Intramural Res, Baltimore, MD USA. RP Miller, NH (reprint author), Johns Hopkins Univ, Dept Orthopaed Surg, Johns Hopkins Bayview Med Ctr, A672,4940 Eastern Ave, Baltimore, MD 21224 USA. EM ehenze1@jhmi.edu RI Wilson, Alexander/C-2320-2009 NR 44 TC 49 Z9 63 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD JUL 15 PY 2006 VL 31 IS 16 BP 1815 EP 1819 DI 10.1097/01.brs.0000227264.23603.dc PG 5 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 065YV UT WOS:000239197200011 PM 16845357 ER PT J AU Troendle, JF Yu, KF AF Troendle, JF Yu, KF TI Likelihood approaches to the non-parametric two-sample problem for right-censored data SO STATISTICS IN MEDICINE LA English DT Article DE empirical likelihood; imputation; non-parametric maximum likelihood; permutation ID BEHRENS-FISHER PROBLEM AB The classical two-sample problem with random right-censoring is considered. We show that non-parametric likelihood techniques can be used to obtain tests for either the identity hypothesis or the non-parametric Behrens-Fisher hypothesis (NBFH). In the case of the identity hypothesis, a special imputed permutation distribution is used to estimate the distribution under the null hypothesis. In the case of the NBFH, simulation from the constrained non-parametric maximum likelihood estimate is used. Simulation shows that the tests using either approximation have excellent control of the type I error rate, even with quite small sample sizes. Further, for Lehmann-type alternatives the likelihood-based methods have similar power to the logrank test, while for the non-Lehmann-type alternatives tried here the likelihood-based methods have superior power. Published in 2005 by John Wiley & Sons, Ltd. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Biometry & Math Stat Branch, NIH, Bethesda, MD 20892 USA. RP Troendle, JF (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Biometry & Math Stat Branch, NIH, DHHS,Bldg 6100,Room 7B05, Bethesda, MD 20892 USA. EM jt3t@nih.gov NR 8 TC 2 Z9 2 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JUL 15 PY 2006 VL 25 IS 13 BP 2284 EP 2298 DI 10.1002/sim.2340 PG 15 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 059KI UT WOS:000238731300008 PM 16217854 ER PT J AU Kim, Y Ton, TV DeAngelo, AB Morgan, K Devereux, TR Anna, C Collins, JB Paules, RS Crosby, LM Sills, RC AF Kim, Yongbaek Ton, Thai-Vu DeAngelo, Anthony B. Morgan, Kevin Devereux, Theodora R. Anna, Colleen Collins, Jennifer B. Paules, Richard S. Crosby, Lynn M. Sills, Robert C. TI Major carcinogenic pathways identified by gene expression analysis of peritoneal mesotheliomas following chemical treatment in F344 rats SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE rat; mesotheliomas; bromochloroacetic acid (BCA); o-nitrotolulene; carcinogenesis; microarray ID MALIGNANT MESOTHELIOMA; HUMAN BREAST; CANCER CELLS; BETA-CATENIN; OVEREXPRESSION; GROWTH; TUMORIGENESIS; ASSOCIATION; ACTIVATION; MICROARRAY AB This study was performed to characterize the gene expression profile and to identify the major carcinogenic pathways involved in rat peritoneal ruesothelioma (RPM) formation following treatment of Fischer 344 rats with o-nitrotoluene (o-NT) or bromochloracetic acid (BCA). Oligo arrays, with over 20,000 target genes, were used to evaluate o-NT- and BCA-induced RPMs, when compared to a non-transformed mesothelial cell line (Fred-PE). Analysis using Ingenuity Pathway Analysis software revealed 169 cancer-related genes that were categorized into binding activity, growth and proliferation, cell cycle progression, apoptosis, and invasion and metastasis. The microarray data were validated by positive correlation with quantitative real-time RT-PCR on 16 selected genes including igf1, tgfb3 and nov. Important carcinogenic pathways involved in RPM formation included insulin-like growth factor I (IGF-1), p38 MAPkinase, Wnt/beta-catenin and integrin signaling pathways. This study demonstrated that mesotheliomas in rats exposed to o-NT- and BCA were similar to mesotheliomas in humans, at least at the cellular and molecular level. Published by Elsevier Inc. C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. NIEHS, Environm Carcinogenesis Program, Res Triangle Pk, NC 27709 USA. NIEHS, Microarray Grp, Res Triangle Pk, NC 27709 USA. US EPA, Res Triangle Pk, NC 27709 USA. Aventis, Bridgewater, NJ 08807 USA. Wyeth Ayerst Res, Chazy, NY 12921 USA. RP Sills, RC (reprint author), NIEHS, Environm Toxicol Program, MD B3-08,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM sills@niehs.nih.gov FU Intramural NIH HHS NR 40 TC 28 Z9 29 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUL 15 PY 2006 VL 214 IS 2 BP 144 EP 151 DI 10.1016/j.taap.2005.12.009 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 066FU UT WOS:000239215900006 PM 16460773 ER PT J AU Goulielmos, GN Fragouli, E Aksentijevich, I Sidiropoulos, P Boumpas, DT Eliopoulos, E AF Goulielmos, GN Fragouli, E Aksentijevich, I Sidiropoulos, P Boumpas, DT Eliopoulos, E TI Mutational analysis of the PRYSPRY domain of pyrin and implications for familial mediterranean fever (FMF) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE familial Mediterranean fever (FMF); pyrin; MEFV; mutational analysis; three-dimensional model (3-D model) ID MULTIPLE SEQUENCE ALIGNMENT; AUTOINFLAMMATORY DISEASES; MEFV MUTATIONS; GENE; PROTEIN; DIAGNOSIS; POPULATION; FREQUENCY; APOPTOSIS; SPECTRUM AB Familial Mediterranean fever (FMF) is an autosomal, recessively inherited disease, characterized by recurrent fever and serositis that affects mainly patients of the Mediterranean basin. The gene responsible for FMF, named MEFV, was cloned and several missense mutations were found to be responsible for the disease. Based on a recent molecular analysis of MEFV gene mutations in 43 patients from Crete aiming to correlate specific genotypes and clinical manifestations of FMF, we were prompted to construct a three-dimensional model (3-D model) of the PRYSPRY domain of pyrin. The majority of the known MEFV mutations located on this domain have been classified, according to disease severity, and localized on this 3-D model. The functional consequences of these mutations and their implications on disease severity are discussed. Moreover, we report a putative novel missense mutation, S702C, which we identified in exon 10 of the MEFV gene and localized on the constructed 3-D model. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ Crete, Dept Internal Med, Iraklion, Crete, Greece. NIAMSD, Genet Sect, Arthritis & Rheumatism Branch, Bethesda, MD 20892 USA. Univ Hosp Heraklion, Dept Rheumatol Clin Immunol & Allergy, Iraklion, Crete, Greece. Agr Univ Athens, Dept Agr Biotechnol, Genet Lab, Athens, Greece. RP Goulielmos, GN (reprint author), Univ Crete, Dept Internal Med, Iraklion, Crete, Greece. EM goulielmos@med.uoc.gr NR 49 TC 11 Z9 12 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 14 PY 2006 VL 345 IS 4 BP 1326 EP 1332 DI 10.1016/j.bbrc.2006.04.185 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 054VH UT WOS:000238406200007 PM 16730661 ER PT J AU Kutty, RK Chen, SY Samuel, W Vijayasarathy, C Duncan, T Tsai, JY Fariss, RN Carper, D Jaworski, C Wiggert, B AF Kutty, RK Chen, SY Samuel, W Vijayasarathy, C Duncan, T Tsai, JY Fariss, RN Carper, D Jaworski, C Wiggert, B TI Cell density-dependent nuclear/cytoplasmic localization of NORPEG (RAI14) protein SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE nuclear/cytoplasmic localization; nuclear localization signal; NORPEG; RAI14; retinal pigment epithelium; immunofluorescence; retinoic acid; nucleolin; ankyrin repeats ID NF-KAPPA-B; NUCLEAR-LOCALIZATION; SUBCELLULAR-LOCALIZATION; EPITHELIAL-CELLS; RETINOIC ACID; EXPRESSION; SIGNALS; NUCLEOLIN; TRANSPORT; RECEPTOR AB NORPEG (RAIN), a developmentally regulated gene induced by retinoic acid, encodes a 980 amino acid (aa) residue protein containing six ankyrin repeats and a long coiled-coil domain [Kutty et al.. J. Biol. Chem. 276 (2001)7 pp. 2831-2840]. We have expressed aa residues 1-287 of NORPEG and used the recombinant protein to produce an anti-NORPEG polyclonal antibody. Confocal immunofluorescence analysis showed that the subcellular localization of NORPEG in retinal pigment epithelial (ARPE-19) cells varies with cell density, with predominantly nuclear localization in nonconfluent cells. but a Cytoplasmic localization. reminiscent of cytoskeleton, in confluent cultures. Interestingly, an evolutionarily conserved putative monopartite nuclear localization signal (p(270)KKRKAP(276)) Was identified by analyzing the sequences of NORPEG and its orthologs. GFP-NORPEG (2-287 aa), a fusion protein containing this signal, was indeed localized to nuclei when expressed in ARPE-19 or COS-7 cells. Deletion and mutation analysis indicated that the identified nuclear localization sequence is indispensable for nuclear targeting. Published by Elsevier Inc. C1 NEI, Biochem Sect, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. NEI, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. NEI, Sect Mol Therapeut, NIH, Bethesda, MD 20892 USA. RP Kutty, RK (reprint author), NEI, Biochem Sect, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM kuttyk@nei.nih.gov FU Intramural NIH HHS NR 28 TC 5 Z9 6 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 14 PY 2006 VL 345 IS 4 BP 1333 EP 1341 DI 10.1016/j.bbrc.2006.04.184 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 054VH UT WOS:000238406200008 PM 16729964 ER PT J AU Xie, T Plagge, A Gavrilova, O Pack, S Jou, W Lai, EW Frontera, M Kelsey, G Weinstein, LS AF Xie, Tao Plagge, Antonius Gavrilova, Oksana Pack, Stephanie Jou, William Lai, Edwin W. Frontera, Marga Kelsey, Gavin Weinstein, Lee S. TI The alternative stimulatory G protein alpha-subunit XL alpha s is a critical regulator of energy and glucose metabolism and sympathetic nerve activity in adult mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID WHITE ADIPOSE-TISSUE; INCREASED INSULIN SENSITIVITY; G(S)ALPHA KNOCKOUT MICE; II GENE-EXPRESSION; MELANOCORTIN-4 RECEPTOR; ADRENERGIC AGONIST; SYSTEM; GNAS; RESISTANCE; OBESITY AB The complex imprinted Gnas locus encodes several gene products including G(s)alpha, the ubiquitously expressed G protein alpha-subunit required for receptor-stimulated cAMP generation, and the neuroendocrine-specific G(s)alpha isoform XL alpha s. XL alpha s is only expressed from the paternal allele, whereas G(s)alpha is biallelically expressed in most tissues. XL alpha s knock-out mice (Gnasxl (m+/p-)) have poor suckling and perinatal lethality, implicating XL alpha s as critical for postnatal feeding. We have now examined the metabolic phenotype of adult Gnasxl(m+/p-) mice. Gnasxl(m+/p-) mice had reduced fat mass and lipid accumulation in adipose tissue, with increased food intake and metabolic rates. Gene expression profiling was consistent with increased lipid metabolism in adipose tissue. These changes likely result from increased sympathetic nervous system activity rather than adipose cell-autonomous effects, as we found that XL alpha s is not normally expressed in adult adipose tissue, and Gnasxl(m+/p-) mice had increased urinary norepinephrine levels but not increased metabolic responsiveness to a beta 3-adrenergic agonist. Gnasxl(m+/p-) mice were hypolipidemic and had increased glucose tolerance and insulin sensitivity. The similar metabolic profile observed in some prior paternal Gnas knock- out models results from XL alpha s deficiency (or deficiency of the related alternative truncated protein XLN1). XL alpha s ( or XLN1) is a negative regulator of sympathetic nervous system activity in mice. C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Mouse Metab Core Lab, NIH, Bethesda, MD 20892 USA. NICHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. Babraham Inst, Lab Dev Genet & Imprinting, Cambridge CB2 4AT, England. RP Weinstein, LS (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10 Rm,8C101, Bethesda, MD 20892 USA. EM leew@amb.niddk.nih.gov OI Kelsey, Gavin/0000-0002-9762-5634 FU Biotechnology and Biological Sciences Research Council [BBS/E/B/00001169, BBS/E/B/0000C169, BBS/E/B/0000M147]; Intramural NIH HHS; Medical Research Council [G0400155] NR 47 TC 63 Z9 63 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 14 PY 2006 VL 281 IS 28 BP 18989 EP 18999 DI 10.1074/jbc.M511752200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 061BU UT WOS:000238847000012 PM 16672216 ER PT J AU Kobrinsky, E Stevens, L Kazmi, Y Wray, D Soldatov, NM AF Kobrinsky, Evgeny Stevens, Louisa Kazmi, Yasir Wray, Dennis Soldatov, Nikolai M. TI Molecular rearrangements of the K(v)2.1 potassium channel termini associated with voltage gating SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RESONANCE ENERGY-TRANSFER; DEPENDENT K+ CHANNEL; ACTIVATION; DOMAIN; T1; MODULATION; SUBUNITS; TAILS; CELLS AB The voltage-gated K(v)2.1 channel is composed of four identical subunits folded around the central pore and does not inactivate appreciably during short depolarizing pulses. To study voltage-induced relative molecular rearrangements of the channel, K(v)2.1 subunits were genetically fused with enhanced cyan fluorescent protein and/or enhanced yellow fluorescent protein, expressed in COS1 cells, and investigated using fluorescence resonance energy transfer ( FRET) microscopy combined with patch clamp. Fusion of fluorophores to either or both termini of the K(v)2.1 monomer did not significantly affect the gating properties of the channel. FRET between the N- and C-terminal tags fused to the same or different K(v)2.1 monomers decreased upon activation of the channel by depolarization from - 80 to + 60 mV, suggesting voltage-gated relative rearrangement between the termini. Because FRET between the K(v)2.1 N- or C-terminal tags and the membrane-trapped EYFPN-PH pleckstrin homology domains did not change on depolarization, voltage-gated relative movements between the K(v)2.1 termini occurred in a plane parallel to the plasma membrane, within a distance of 1-10 nm. FRET between the N-terminal tags did not change upon depolarization, indicating that the N termini do not rearrange relative to each other, but they could either move cooperatively with the K(v)2.1 tetramer or not move at all. No FRET was detected between the C-terminal tags. Assuming their randomized orientation in the symmetrically arranged K(v)2.1 subunits, C termini may move outwards in order to produce relative rearrangements between N and C termini upon depolarization. C1 NIA, NIH, Baltimore, MD 21224 USA. Univ Leeds, Fac Biol Sci, Leeds LS2 9JT, W Yorkshire, England. RP Soldatov, NM (reprint author), NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM soldatovN@grc.nia.nih.gov FU Intramural NIH HHS NR 28 TC 24 Z9 25 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 JUL 14 PY 2006 VL 281 IS 28 BP 19233 EP 19240 DI 10.1074/jbc.M601231200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 061BU UT WOS:000238847000037 PM 16690619 ER PT J AU Zou, TT Mazan-Mamczarz, K Rao, JN Liu, L Marasa, BS Zhang, AH Xiao, L Pullmann, R Gorospe, M Wang, JY AF Zou, Tongtong Mazan-Mamczarz, Krystyna Rao, Jaladanki N. Liu, Lan Marasa, Bernard S. Zhang, Ai-Hong Xiao, Lan Pullmann, Rudolf Gorospe, Myriam Wang, Jian-Ying TI Polyamine depletion increases cytoplasmic levels of RNA-binding protein HuR leading to stabilization of nucleophosmin and p53 mRNAs SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; GASTROINTESTINAL MUCOSAL GROWTH; KAPPA-B ACTIVATION; CARCINOMA-CELLS; C-MYC; STABILITY; INHIBITION; EXPRESSION; APOPTOSIS; PATHWAY AB Polyamines are essential for maintaining normal intestinal epithelial integrity, an effect that relies, at least in part, on their ability to keep low levels of nucleophosmin (NPM) and p53 mRNAs. The RNA-binding protein HuR associates with the p53 mRNA, as reported previously, and with the NPM mRNA, computationally predicted to be a target of HuR. Here, we show that HuR binds the NPM and p53 3 '-untranslated regions and stabilizes these mRNAs in polyamine-depleted intestinal epithelial cells. Depletion of cellular polyamines by inhibiting ornithine decarboxylase with alpha-difluoromethylornithine dramatically enhanced the cytoplasmic abundance of HuR, whereas ectopic ornithine decarboxylase overexpression decreased cytoplasmic HuR; neither intervention changed whole-cell HuR levels. HuR was found to specifically bind the 3'-untranslated regions of NPN and p53 mRNAs. HuR silencing rendered the NPM and p53 mRNAs unstable and prevented increases in NPM and p53 mRNA and protein in polyamine-deficient cells. These results indicate that polyamines modulate cytoplasmic HuR levels in intestinal epithelial cells, in turn controlling the stability of the NPM and p53 mRNAs and influencing NPM and p53 protein levels. C1 Baltimore Vet Affairs Med Ctr, Surg Serv, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Cell Biol Grp, Dept Surg, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. NIA, IRP, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP Wang, JY (reprint author), Baltimore Vet Affairs Med Ctr, Surg Serv, 10 N Greene St, Baltimore, MD 21201 USA. EM jwang@smail.umaryand.edu FU NIDDK NIH HHS [DK-57819, DK-61972, DK-68491] NR 50 TC 88 Z9 91 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 14 PY 2006 VL 281 IS 28 BP 19387 EP 19394 DI 10.1074/jbc.M602344200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 061BU UT WOS:000238847000054 PM 16690610 ER PT J AU Kovaleski, BJ Kennedy, R Hong, MK Datta, SA Kleiman, L Rein, A Musier-Forsyth, K AF Kovaleski, Brandie J. Kennedy, Robert Hong, Minh K. Datta, Siddhartha A. Kleiman, Lawrence Rein, Alan Musier-Forsyth, Karin TI In vitro characterization of the interaction between HIV-1 Gag and human lysyl-tRNA synthetase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PRIMER TRANSFER-RNAS; ROUS-SARCOMA-VIRUS; ESCHERICHIA-COLI; CAPSID PROTEIN; FLUORESCENCE POLARIZATION; REVERSE TRANSCRIPTION; DIMERIZATION DOMAIN; RECOGNITION; IDENTIFICATION AB Human immunodeficiency virus type 1 (HIV-1) viral assembly is mediated by multiple protein-protein and protein-nucleic acid interactions. Humant RNA(Lys3) is used as the primer for HIV reverse transcription, and HIV Gag and GagPol are required for packaging of the tRNA into virions. Human lysyl-t-RNA synthetase (LysRS) is also specifically packaged into HIV, suggesting a role for LysRS in tRNA packaging. Gag alone is sufficient for packaging of LysRS, and these two proteins have been shown to interact in vitro using glutathione S-transferase pull-down assays. In vitro pull-down assays using truncated constructs have also revealed that residues important for homodimerization of Gag and LysRS are critical for the Gag/LysRS interaction. In this work, we report further in vitro characterization of the interaction between HIV Gag and human LysRS using affinity pull-down assays, fluorescence anisotropy measurements and gel chromatography. An equilibrium binding constant of 310 +/- 80 nM was measured for the Gag/LysRS interaction. We also show that capsid alone binds to LysRS with a similar affinity as full-length Gag. Point mutations that disrupt the homodimerization of LysRS and Gag in vitro do not affect their interaction. These results suggest that dimerization of each protein per se is not required for the interaction but that residues involved in forming the homodimer interfaces contribute to heterodimer formation. Gel chromatography studies further support the formation of a Gag/ LysRS heterodimer. C1 Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA. NCI, Retrovirus Assembly Sect, HIV Drug Resistance Program, NIH, Ft Detrick, MD 21702 USA. Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. Jewish Gen Hosp, McGill Aids Ctr, Montreal, PQ H3T 1E2, Canada. RP Musier-Forsyth, K (reprint author), Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA. EM musier@chem.umn.edu OI Datta, Siddhartha/0000-0002-4098-7490 FU Intramural NIH HHS; NIAID NIH HHS [AI054145]; NIGMS NIH HHS [GM069339, T32-GM08277, T32-GM08700] NR 33 TC 45 Z9 45 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 14 PY 2006 VL 281 IS 28 BP 19449 EP 19456 DI 10.1074/jbc.M601189200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 061BU UT WOS:000238847000060 PM 16702215 ER PT J AU Berezhkovskii, AM Hummer, G Bezrukov, SM AF Berezhkovskii, Alexander M. Hummer, Gerhard Bezrukov, Sergey M. TI Identity of distributions of direct uphill and downhill translocation times for particles traversing membrane channels SO PHYSICAL REVIEW LETTERS LA English DT Article ID TRANSPORT AB We study the distribution of direct translocation times for particles passing through membrane channels connecting two reservoirs. The direct translocation time is a conditional first-passage time defined as the residence time of the particle in the channel while passing to the other side of the membrane directly, i.e., without returning to the reservoir from which it entered. We show that the distributions of direct translocation times are identical for translocation in both directions, independent of any asymmetry in the potential across the channel and, hence, the translocation probabilities. C1 NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Intramural NIH HHS NR 25 TC 32 Z9 32 U1 0 U2 0 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD JUL 14 PY 2006 VL 97 IS 2 AR 020601 DI 10.1103/PhysRevLett.97.020601 PG 4 WC Physics, Multidisciplinary SC Physics GA 063YZ UT WOS:000239057200005 PM 16907424 ER PT J AU Steven, AC Spear, PG AF Steven, Alasdair C. Spear, Patricia G. TI Biochemistry - Viral glycoproteins and an evolutionary conundrum SO SCIENCE LA English DT Editorial Material ID MEMBRANE-FUSION; VIRUS; MECHANISM; ENTRY C1 NIAMSD, Struct Biol Lab, Bethesda, MD 20892 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, 50 South Dr, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov; p-spear@northwestern.edu NR 12 TC 27 Z9 28 U1 3 U2 3 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 JUL 14 PY 2006 VL 313 IS 5784 BP 177 EP 178 DI 10.1126/science.1129761 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 063GZ UT WOS:000239008000027 PM 16840685 ER PT J AU McFarland, EJ Johnson, DC Muresan, P Fenton, T Tomaras, GD McNamara, J Read, JS Douglas, SD Deville, J Gurwith, M Gurunathan, S Lambert, JS AF McFarland, Elizabeth J. Johnson, Daniel C. Muresan, Petronella Fenton, Terence Tomaras, Georgia D. McNamara, James Read, Jennifer S. Douglas, Steven D. Deville, Jaime Gurwith, Marc Gurunathan, Sanjay Lambert, John S. TI HIV-1 vaccine induced immune responses in newborns of HIV-1 infected mothers SO AIDS LA English DT Article; Proceedings Paper CT 12th Conference on Retroviruses and Opportunistic Infections CY FEB 22-25, 2005 CL Boston, MA DE AIDS vaccine; anti-viral antibodies; cellular immunity; newborn infant; viral vaccines; HIV-1; vertical transmission; mother-to-child-transmission of HIV-1 ID HUMAN-IMMUNODEFICIENCY-VIRUS; TO-CHILD TRANSMISSION; RECOMBINANT CANARYPOX VACCINE; CELL RESPONSES; 1ST YEAR; TYPE-1; SAFETY; IMMUNOGENICITY; LYMPHOCYTE; ANTIBODIES AB Objective: Breast milk transmission continues to account for a large proportion of cases of mother-to-child transmission of HIV-1 worldwide. An effective HIV-1 vaccine coupled with either passive immunization or short-term antiretroviral prophylaxis represents a potential strategy to prevent breast milk transmission. This study evaluated the safety and immunogenicity of ALVAC HIV-1 vaccine with and without a subunit envelope boost in infants born to HIV-1-infected women. Design: Placebo-controlled, double-blinded study. Methods: Infants born to HIV-1-infected mothers in the US were immunized with a prime-boost regimen using a canarypox virus HIV-1 vaccine (vCP1452) and a recombinant glycoprotein subunit vaccine (rgp120). Infants (n = 30) were randomized to receive: vCP1452 alone, vCP1452 + rgp120, or corresponding placebos. Results: Local reactions were mild or moderate and no significant systemic toxicities occurred. Subjects receiving both vaccines had gp120-specific binding serum antibodies that were distinguishable from maternal antibody. Repeated gp160-specific lymphoproliferative responses were observed in 75%. Neutralizing activity to HIV-1 homologous to the vaccine strain was observed in 50% of the vCP1452 + rgp-120 subjects who had lost maternal antibody by week 24. In some infants HIV-1-specific proliferative and antibody responses persisted until week 104. HIV-1-specific cytotoxic T lymphocyte responses were detected in two subjects in each treatment group; the frequency of HIV-1 specific cytotoxic T lymphocyte responses did not differ between vaccine and placebo recipients. Conclusion: The demonstration of vaccine-induced immune responses in early infancy supports further study of HIV-1 vaccination as a strategy to reduce breast milk transmission. (c) 2006 Lippincott Williams & Wilkins. C1 Univ Colorado, Hlth Sci Ctr, Dept Pediat Infect Dis, Denver, CO USA. Sinai Childrens Hosp, Chicago, IL USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Ctr Virol, Durham, NC 27710 USA. NIAID, Clin Immunol Branch, Div Allergy & Immunol Transplantat, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Calif Los Angeles, Div Pediat Infect Dis, Los Angeles, CA USA. VaxGen Inc, Brisbane, CA USA. Sanofi Pasteur Inc, Swiftwater, PA USA. Mater Misericordiae Univ Hosp, Dublin, Ireland. Univ Coll Dublin, Dublin 2, Ireland. RP McFarland, EJ (reprint author), Univ Colorado, Sch Med, Dept Pediat, 4200 E 9th Ave, Denver, CO 80262 USA. EM betsy.mcfarland@uchsc.edu RI Tomaras, Georgia/J-5041-2016 FU NIAID NIH HHS [U01 AI41089, U01 AI46725]; NICHD NIH HHS [N01 HD 33162, N01 HD 33345] NR 38 TC 32 Z9 32 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 13 PY 2006 VL 20 IS 11 BP 1481 EP 1489 DI 10.1097/01.aids.0000237363.33994.45 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 076VE UT WOS:000239985400002 PM 16847402 ER PT J AU Silverberg, MJ Wegner, SA Milazzo, MJ McKaig, RG Williams, CF Agan, BK Armstrong, AW Gange, SJ Hawkes, C O'Connell, RJ Ahuja, SK Dolan, MJ AF Silverberg, Michael J. Wegner, Scott A. Milazzo, Mark J. McKaig, Rosemary G. Williams, Carolyn F. Agan, Brian K. Armstrong, Adam W. Gange, Stephen J. Hawkes, Clifton O'Connell, Robert J. Ahuja, Sunil K. Dolan, Matthew J. CA Tri-Service AIDS Clinical TI Effectiveness of highly-active antiretroviral therapy by race/ethnicity SO AIDS LA English DT Article DE highly-active antiretroviral therapy; survival; AIDS; race/ethnicity; HIV seroconversion; effectiveness ID HUMAN-IMMUNODEFICIENCY-VIRUS; DISEASE PROGRESSION; POPULATION EFFECTIVENESS; AFRICAN-AMERICANS; AIDS PROGRESSION; GENE VARIANTS; HIV DISEASE; DRUG-USE; CCR5; RACE AB Objective: To determine the effectiveness of HAART by race/ethnicity. Design: Prospective multicenter cohort study. Methods: We studied 991 African-Americans and 911 European-Americans enrolled in the United States Military's Tri-Service AIDS Clinical Consortium Natural History Study who had dates of HIV seroconversion known within 5 years and followed between 1990 and 2002. We determined the rate of disease progression to AIDS and death for subjects in this cohort. Multivariable models evaluated race, pre-HAART (1990-1995) and HAART (1996-2002) eras, age, gender and military service. Results: In the pre-HAART era, African-Americans had a statistically nonsignificant trend towards better outcomes: the relative hazards (RH) of AIDS and death for African-Americans compared to European-Americans were 0.85 [95% confidence interval (CI), 0.68-1.051 and 0.77 (95% CI, 0.55-1.08), respectively. In the HAART era, outcomes were similar by race: 1.17 (95% CI, 0.86-1.61) for AIDS and 1.11 (95% CI, 0.81-1.53) for death with overlapping Kaplan-Meier curves. Relative to the pre-HAART era, the adjusted RH of AIDS in the HAART era was 0.41 (95% CI, 0.31-0.54) and 0.30 (95% CI, 0.22-0.40) for African-American and European-American participants, respectively. Analogous RH for death were 0.55 (95% CI, 0.38-0.80) and 0.38 (95% CI, 0.27-0.54). The precipitous declines in AIDS and death in the HAART era were not statistically different by race. Conclusions: In a large multi-racial cohort with equal access to health care, HIV treatment outcomes by race/ethnicity were similar. (c) 2006 Lippincott Williams & Wilkins. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. TACC, NHS, Rockville, MD USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Div Retrovirol, Washington, DC 20307 USA. NIAID, Epidemiol Branch, Div AIDS, NIH,DHHS, Bethesda, MD 20892 USA. Wilford Hall USAF Med Ctr, Dept Infect Dis, Lackland AFB, TX 78236 USA. USN, Med Ctr, Portsmouth, VA USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. S Texas Vet Hlth Care Syst, Vet Adm Res Ctr Aids & HIV 1 Infect, San Antonio, TX USA. Univ Texas Hlth Ctr, Dept Med, San Antonio, TX USA. Def Inst Med Operat, Brooks AFB, TX USA. RP Dolan, MJ (reprint author), Kaiser Permanente, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM Matthew.Dolan@brooks.af.mil OI Gange, Stephen/0000-0001-7842-512X; Agan, Brian/0000-0002-5114-1669 FU NIAID NIH HHS [U01-AI-42590] NR 37 TC 35 Z9 36 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 13 PY 2006 VL 20 IS 11 BP 1531 EP 1538 DI 10.1097/01.aids.0000237369.41617.0f PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 076VE UT WOS:000239985400008 PM 16847408 ER PT J AU Habashita, H Kokubo, M Hamano, S Hamanaka, N Toda, M Shibayama, S Tada, H Sagawa, K Fukushima, D Maeda, K Mitsuya, H AF Habashita, Hiromu Kokubo, Masaya Hamano, Shin-ichi Hamanaka, Nobuyuki Toda, Masaaki Shibayama, Shiro Tada, Hideaki Sagawa, Kenji Fukushima, Daikichi Maeda, Kenji Mitsuya, Hiroaki TI Design, synthesis, and biological evaluation of the combinatorial library with a new spirodiketopiperazine scaffold. Discovery of novel potent and selective low-molecular-weight CCR5 antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN INTERLEUKIN-8 RECEPTOR; CHEMOKINE RECEPTOR; HIV-1 ENTRY; AMINO-ACIDS; SOLID-PHASE; IDENTIFICATION; PEPTIDE; RESIN; 1,4-BENZODIAZEPINE-2,5-DIONES; DERIVATIVES AB We previously reported the discovery of several spirodiketopiperazine derivatives as potent CCR5 antagonists with anti-HIV activity. Herein, we describe in detail the identification of these lead compounds using a combinatorial chemistry approach. A novel spirodiketopiperazine scaffold was designed on the basis of the concept of the privileged structure of G-protein-coupled receptors (GPCRs). This new framework was obtained in acceptable yield with high purity from the readily prepared isonitrile resin through the Ugi reaction, sequential transformations, and cyclative cleavage. By measuring the inhibitory activity of each compound in the initial library against the intracellular calcium mobilization stimulated by MIP-1 alpha, several compounds were found to show modest but selective CCR5 antagonistic activity. After the rapid evaluation of these hit compounds, several single-digit nanomolar, low-molecular-weight CCR5 antagonists that can potently block the infectivity and replication of laboratory and clinical strains of HIV as well as those of highly drug-resistant HIV variants with minimal cytotoxicity have been identified. C1 Ono Pharmaceut Co Ltd, Med Chem Res Labs, Osaka 6188585, Japan. Ono Pharmaceut Co Ltd, Exploratory Res Labs, Ibaraki 3004247, Japan. Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 8600811, Japan. NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Habashita, H (reprint author), Ono Pharmaceut Co Ltd, Med Chem Res Labs, Osaka 6188585, Japan. EM habashita@ono.co.jp NR 39 TC 63 Z9 64 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 13 PY 2006 VL 49 IS 14 BP 4140 EP 4152 DI 10.1021/jm060051s PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 060MH UT WOS:000238805800017 PM 16821774 ER PT J AU Clifford, T Boswell, CA Biddlecombe, GB Lewis, JS Brechbiel, MW AF Clifford, Thomas Boswell, C. Andrew Biddlecombe, Grainne B. Lewis, Jason S. Brechbiel, Martin W. TI Validation of a novel CHX-A '' derivative suitable for peptide conjugation: Small animal PET/CT imaging using yttrium-86-CHX-A ''-octreotide SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RECEPTOR-POSITIVE TUMORS; DISSEMINATED PERITONEAL DISEASE; SOLID-PHASE SYNTHESIS; IN-VIVO; MONOCLONAL-ANTIBODIES; SOMATOSTATIN ANALOGS; RADIONUCLIDE THERAPY; CHELATING-AGENT; COMPLEXES; CANCER AB A versatile bifunctional chelating reagent based on a preorganized cyclohexyl derivative of DTPA (CHX-A ") has been developed for the convenient N-terminal labeling of peptides with metal ion radionuclides of Bi(III), In(III), Lu(III), or Y(III). This was achieved via the synthesis of a mono-N-hydroxysuccinimidyl penta-tert-butyl ester derivative of CHX-A" (trans-cyclohexyldiethylenetriaminepenta-acetic acid) featuring a glutaric acid spacer. Commercially obtained octreotide was modified at its N-terminus by this reagent in the solution phase, and its subsequent radiolabeling with In-111 (T-1/2 = 2.8 d) and Y-86 (T-1/2 = 14.7 h) demonstrated. Small animal PET/CT imaging results of Y-86-CHX-A"-octreotide in a somatostatin receptor-positive tumor-bearing rat model are presented for the validation of the novel agent. C1 NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Bldg 10 Ctr Dr, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov OI Boswell, Charles/0000-0002-0426-9846 FU Intramural NIH HHS; NCI NIH HHS [R24 CA86307] NR 55 TC 34 Z9 34 U1 1 U2 8 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 JUL 13 PY 2006 VL 49 IS 14 BP 4297 EP 4304 DI 10.1021/jm060317v PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 060MH UT WOS:000238805800032 PM 16821789 ER PT J AU Shami, PJ Saavedra, JE Bonifant, CL Chu, JX Udupi, V Malaviya, S Carr, BI Kar, S Wang, MF Jia, L Ji, XH Keefer, LK AF Shami, Paul J. Saavedra, Joseph E. Bonifant, Challice L. Chu, Jingxi Udupi, Vidya Malaviya, Swati Carr, Brian I. Kar, Siddhartha Wang, Meifeng Jia, Lee Ji, Xinhua Keefer, Larry K. TI Antitumor activity of JS-K [O-2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] and related O-2-Aryl diazeniumdiolates in vitro and in vivo SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NITRIC-OXIDE; S-TRANSFERASE; GROWTH-FACTOR; CELL GROWTH; KINASE; ACTIVATION; NO; PHOSPHORYLATION; PHOSPHATASES; GLUTATHIONE AB The literature provides evidence that metabolic nitric oxide ( NO) release mediates the cytotoxic activities ( against human leukemia and prostate cancer xenografts in mice) of JS-K, a compound of structure R2N-(O)=NO-Ar for which R2N is 4-(ethoxycarbonyl) piperazin-1-yl and Ar is 2,4-dinitrophenyl. Here we present comparative data on the potencies of JS-K and 41 other O-2-arylated diazeniumdiolates as inhibitors of HL-60 human leukemia cell proliferation, as well as in the NCI 51-cell-line screen for six of them. The data show JS-K to be the most potent of the 42 in both screens and suggest that other features of its structure and metabolism besides NO release may contribute importantly to its activity. Results with control compounds implicate JS-K's arylating ability, and the surprisingly low IC50 value of the N-(ethoxycarbonyl) piperazine byproduct of NO release suggests a role for the R2N moiety. In addition to the above-mentioned in vivo activities, JS-K is shown here to be carcinostatic in a rat liver cancer model. C1 Natl Canc Inst, Basic Res Program, SAIC Frederick, Chem Sect,Lab Comparat Carcinogenesis, Frederick, MD 21702 USA. Natl Canc Inst, Macromol Crystallog Lab, Frederick, MD 21702 USA. Univ Utah, Dept Internal Med, Div Med Oncol, Salt Lake City, UT 84112 USA. Univ Pittsburgh, Liver Canc Ctr, Pittsburgh, PA 15213 USA. Natl Canc Inst, Dev Therapeut Program, Rockville, MD 20852 USA. RP Keefer, LK (reprint author), Natl Canc Inst, Basic Res Program, SAIC Frederick, Chem Sect,Lab Comparat Carcinogenesis, Frederick, MD 21702 USA. EM keefer@ncifcrf.gov RI Ji, Xinhua/C-9664-2012; Keefer, Larry/N-3247-2014 OI Ji, Xinhua/0000-0001-6942-1514; Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO12400, R01 CA84496] NR 33 TC 69 Z9 70 U1 2 U2 11 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 JUL 13 PY 2006 VL 49 IS 14 BP 4356 EP 4366 DI 10.1021/jm060022h PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 060MH UT WOS:000238805800038 PM 16821795 ER PT J AU Thirumurugan, K Sakamoto, T Hammer, JA Sellers, JR Knight, PJ AF Thirumurugan, K Sakamoto, T Hammer, JA Sellers, JR Knight, PJ TI The cargo-binding domain regulates structure and activity of myosin 5 SO NATURE LA English DT Article ID ATPASE ACTIVITY; TAIL DOMAIN; CONFORMATION; CALMODULIN; ACTIVATION; MUSCLE; VA AB Myosin 5 is a two-headed motor protein that moves cargoes along actin filaments(1,2). Its tail ends in paired globular tail domains (GTDs) thought to bind cargo(3). At nanomolar calcium levels, actin-activated ATPase is low and the molecule is folded. Micromolar calcium concentrations activate ATPase and the molecule unfolds(3-6). Here we describe the structure of folded myosin and the GTD's role in regulating activity. Electron microscopy shows that the two heads lie either side of the tail, contacting the GTDs at a lobe of the motor domain (similar to Pro 117 - Pro 137) that contains conserved acidic side chains, suggesting ionic interactions between motor domain and GTD. Myosin 5 heavy meromyosin, a constitutively active fragment lacking the GTDs, is inhibited and folded by a dimeric GST - GTD fusion protein. Motility assays reveal that at nanomolar calcium levels heavy meromyosin moves robustly on actin filaments whereas few myosins bind or move. These results combine to show that with no cargo, the GTDs bind in an intramolecular manner to the motor domains, producing an inhibited and compact structure that binds weakly to actin and allows the molecule to recycle towards new cargoes. C1 Univ Leeds, Inst Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England. Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England. NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Knight, PJ (reprint author), Univ Leeds, Inst Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England. EM p.j.knight@leeds.ac.uk OI Thirumurugan, Kavitha/0000-0002-4673-4099 FU Wellcome Trust [076057, ] NR 24 TC 112 Z9 114 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 13 PY 2006 VL 442 IS 7099 BP 212 EP 215 DI 10.1038/nature04865 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 062XJ UT WOS:000238979700050 PM 16838021 ER PT J AU Lee, DS Pencina, MJ Benjamin, EJ Wang, TJ Levy, D O'Donnell, CJ Nam, B Larson, MG D'Agostino, RB Vasan, RS AF Lee, DS Pencina, MJ Benjamin, EJ Wang, TJ Levy, D O'Donnell, CJ Nam, B Larson, MG D'Agostino, RB Vasan, RS TI Association of parental heart failure with risk of heart failure in offspring SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LEFT-VENTRICULAR MASS; FAMILIAL DILATED CARDIOMYOPATHY; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; MYOCARDIAL-INFARCTION; FRAMINGHAM; GENE; HISTORY; POLYMORPHISM; HYPERTROPHY AB BACKGROUND: The association between heart failure in parents and the prevalence of left ventricular systolic dysfunction and the risk of heart failure in their offspring has not been investigated in a community-based setting. METHODS: We examined the cross-sectional association of heart failure in parents with the prevalence of left ventricular systolic dysfunction, as well as left ventricular mass, internal dimensions, and wall thickness, in 1497 participants of the Framingham Offspring Study (mean age, 57 years; 819 women) who underwent routine echocardiography. We also investigated prospectively whether heart failure in parents increased the risk of heart failure in 2214 offspring (mean age, 44 years; 1150 women). RESULTS: As compared with the 1039 participants whose parents did not have heart failure, the 458 participants in the cross-sectional cohort who had at least one parent with heart failure were more likely to have increased left ventricular mass (17.0 percent vs. 26.9 percent), left ventricular internal dimensions (18.6 percent vs. 23.4 percent), and left ventricular systolic dysfunction (3.1 percent vs. 5.7 percent); the multivariable-adjusted odds ratios were 1.35 (95 percent confidence interval, 0.99 to 1.84), 1.29 (95 percent confidence interval, 0.96 to 1.72), and 2.37 (95 percent confidence interval, 1.22 to 4.61), respectively. In the longitudinal cohort, heart failure developed in 90 offspring during follow-up (mean length of follow-up, 20 years). The age- and sex-adjusted 10-year incidence rates of heart failure were 2.72 percent among offspring with a parent with heart failure, as compared with 1.62 percent among those without a parent with heart failure. This increase in risk persisted after multivariable adjustment (hazard ratio, 1.70; 95 percent confidence interval, 1.11 to 2.60). CONCLUSIONS: Heart failure in parents is associated with an increased prevalence of left ventricular systolic dysfunction cross-sectionally and an elevated risk of heart failure longitudinally. Our data emphasize the contribution of familial factors to the heart-failure burden in the community. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. NHLBI, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. RP Vasan, RS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu RI Lee, Douglas/J-4315-2014; OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [N01-HC-25195, K23 HL074077, K24HL04334, U01 HL 66582] NR 34 TC 78 Z9 80 U1 0 U2 3 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 JUL 13 PY 2006 VL 355 IS 2 BP 138 EP 147 DI 10.1056/NEJMoa052948 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 062UP UT WOS:000238970600005 PM 16837677 ER PT J AU Hewitt, KJ Agarwal, R Morin, PJ AF Hewitt, Kyle J. Agarwal, Rachana Morin, Patrice J. TI The claudin gene family: expression in normal and neoplastic tissues SO BMC CANCER LA English DT Article ID CLOSTRIDIUM-PERFRINGENS ENTEROTOXIN; JUNCTION PROTEINS CLAUDIN-3; OVARIAN-CANCER; PANCREATIC-CANCER; SERIAL ANALYSIS; CARCINOMA; TUMORIGENESIS; MUTATIONS; TARGET; BREAST AB Background: The claudin (CLDN) genes encode a family of proteins important in tight junction formation and function. Recently, it has become apparent that CLDN gene expression is frequently altered in several human cancers. However, the exact patterns of CLDN expression in various cancers is unknown, as only a limited number of CLDN genes have been investigated in a few tumors. Methods: We identified all the human CLDN genes from Genbank and we used the large public SAGE database to ascertain the gene expression of all 21 CLDN in 266 normal and neoplastic tissues. Using real-time RT-PCR, we also surveyed a subset of 13 CLDN genes in 24 normal and 24 neoplastic tissues. Results: We show that claudins represent a family of highly related proteins, with claudin-16, and -23 being the most different from the others. From in silico analysis and RT-PCR data, we find that most claudin genes appear decreased in cancer, while CLDN3, CLDN4, and CLDN7 are elevated in several malignancies such as those originating from the pancreas, bladder, thyroid, fallopian tubes, ovary, stomach, colon, breast, uterus, and the prostate. Interestingly, CLDN5 is highly expressed in vascular endothelial cells, providing a possible target for antiangiogenic therapy. CLDN18 might represent a biomarker for gastric cancer. Conclusion: Our study confirms previously known CLDN gene expression patterns and identifies new ones, which may have applications in the detection, prognosis and therapy of several human cancers. In particular we identify several malignancies that express CLDN3 and CLDN4. These cancers may represent ideal candidates for a novel therapy being developed based on CPE, a toxin that specifically binds claudin-3 and claudin-4. C1 NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. RP Hewitt, KJ (reprint author), NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. EM Hewittkyl@grc.nia.nih.gov; agarwalra@grc.nia.nih.gov; morinp@grc.nia.nih.gov FU Intramural NIH HHS NR 27 TC 266 Z9 281 U1 1 U2 24 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUL 12 PY 2006 VL 6 AR 186 DI 10.1186/1471-2407-6-186 PG 8 WC Oncology SC Oncology GA 073KW UT WOS:000239742700001 PM 16836752 ER PT J AU Rohrbach, P Sanchez, CP Hayton, K Friedrich, O Patel, J Sidhu, ABS Ferdig, MT Fidock, DA Lanzer, M AF Rohrbach, Petra Sanchez, Cecilia P. Hayton, Karen Friedrich, Oliver Patel, Jigar Sidhu, Amar Bir Singh Ferdig, Michael T. Fidock, David A. Lanzer, Michael TI Genetic linkage of pfmdr1 with food vacuolar solute import in Plasmodium falciparum SO EMBO JOURNAL LA English DT Article DE drug transport; Fluo-4; malaria; P-glycoprotein ID ACRIDINE-ORANGE FLUORESCENCE; HUMAN MALARIA PARASITES; P-GLYCOPROTEIN HOMOLOG; CHLOROQUINE RESISTANCE; DIGESTIVE VACUOLE; DRUG-RESISTANCE; INFECTED ERYTHROCYTES; MULTIDRUG-RESISTANCE; MEFLOQUINE RESISTANCE; PFCRT MUTATIONS AB The P-glycoprotein homolog of the human malaria parasite Plasmodium falciparum (Pgh-1) has been implicated in decreased susceptibility to several antimalarial drugs, including quinine, mefloquine and artemisinin. Pgh-1 mainly resides within the parasite's food vacuolar membrane. Here, we describe a surrogate assay for Pgh-1 function based on the subcellular distribution of Fluo-4 acetoxymethylester and its free fluorochrome. We identified two distinct Fluo-4 staining phenotypes: preferential staining of the food vacuole versus a more diffuse staining of the entire parasite. Genetic, positional cloning and pharmacological data causatively link the food vacuolar Fluo-4 phenotype to those Pgh-1 variants that are associated with altered drug responses. On the basis of our data, we propose that Pgh-1 imports solutes, including certain antimalarial drugs, into the parasite's food vacuole. The implications of our findings for drug resistance mechanisms and testing are discussed. C1 Univ Klinikum Heidelberg, Inst Hyg, Abt Parasitol, D-69120 Heidelberg, Germany. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. Univ Heidelberg, Inst Physiol & Pathophysiol, Heidelberg, Germany. Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. RP Lanzer, M (reprint author), Univ Klinikum Heidelberg, Inst Hyg, Abt Parasitol, Neuenheimer Feld 324, D-69120 Heidelberg, Germany. EM michael_lanzer@med.uni-heidelberg.de RI Ferdig, Michael/C-6627-2016; OI Fidock, David/0000-0001-6753-8938 NR 61 TC 77 Z9 82 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JUL 12 PY 2006 VL 25 IS 13 BP 3000 EP 3011 DI 10.1038/sj.emboj.7601203 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 071TP UT WOS:000239625800005 PM 16794577 ER PT J AU Bondy, CA AF Bondy, CA TI Endogenous sex hormones and type 2 diabetes risk SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. EM bondyc@mail.nih.gov NR 6 TC 0 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 12 PY 2006 VL 296 IS 2 BP 169 EP 169 DI 10.1001/jama.296.2.169-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 062LP UT WOS:000238946500019 PM 16835421 ER PT J AU Manini, TM Everhart, JE Patel, KV Schoeller, DA Colbert, LH Visser, M Tylavsky, F Bauer, DC Goodpaster, BH Harris, TB AF Manini, TM Everhart, JE Patel, KV Schoeller, DA Colbert, LH Visser, M Tylavsky, F Bauer, DC Goodpaster, BH Harris, TB TI Daily activity energy expenditure and mortality among older adults SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PHYSICAL-ACTIVITY; WOMEN; MEN; EXERCISE; DISEASE; LIFE; OBESITY; HUMANS; MODEL AB Context Exercise is associated with mortality benefits but simply expending energy through any activity in an individual's free-living environment may confer survival advantages. Objective To determine whether free-living activity energy expenditure is associated with all-cause mortality among older adults. Design, Setting, and Participants Free-living activity energy expenditure was assessed in 302 high-functioning, community-dwelling older adults ( aged 70-82 years). Total energy expenditure was assessed over 2 weeks using doubly labeled water. Resting metabolic rate was measured using indirect calorimetry and the thermic effect of meals was estimated at 10% of total energy expenditure. Free-living activity energy expenditure was calculated as: ( total energy expenditure x 0.90) resting metabolic rate. Participants were followed up over a mean of 6.15 years (1998-2006). Main Outcome Measures Free-living activity energy expenditure ( 3 tertiles: low, < 521 kcal/d; middle, 521- 770 kcal/d; high, > 770 kcal/d) and all-cause mortality. Results Fifty-five participants (18.2%) died during follow-up. As a continuous risk factor, an SD increase in free-living activity energy expenditure ( 287 kcal/d) was associated with a 32% lower risk of mortality after adjusting for age, sex, race, study site, weight, height, percentage of body fat, and sleep duration ( hazard ratio, 0.68; 95% confidence interval, 0.48-0.96). Using the same adjustments, individuals in the highest tertile of free-living activity energy expenditure were at a significantly lower mortality risk compared with the lowest tertile ( hazard ratio, 0.31; 95% confidence interval, 0.14-0.69). Absolute risk of death was 12.1% in the highest tertile of activity energy expenditure vs 24.7% in the lowest tertile; absolute risks were similar to these for tertiles of physical activity level. The effect of free-living activity energy expenditure changed little after further adjustment for self-rated health, education, prevalent health conditions, and smoking behavior. According to self-reports, individuals expending higher levels of free-living activity energy were more likely to work for pay ( P=. 004) and climb stairs ( P=. 01) but self-reported high-intensity exercise, walking for exercise, walking other than for exercise, volunteering, and caregiving did not differ significantly across the activity energy expenditure tertiles. Conclusions Objectively measured free-living activity energy expenditure was strongly associated with lower risk of mortality in healthy older adults. Simply expending energy through any activity may influence survival in older adults. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NIDDKD, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. Univ Wisconsin, Dept Kinesiol, Madison, WI 53706 USA. VU Univ Med Ctr, Fac Earth & Life Sci, Inst Hlth Sci, Amsterdam, Netherlands. VU Univ Med Ctr, Inst Res Extramural Med, Amsterdam, Netherlands. Univ Tennessee, Dept Biostat & Epidemiol, Memphis, TN USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Univ Pittsburgh, Med Ctr, Div Endocrinol & Metab, Pittsburgh, PA USA. RP Manini, TM (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave Gateway Bldg,Suite 3C309, Bethesda, MD 20892 USA. EM maninit@mail.nih.gov FU Intramural NIH HHS; NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 39 TC 286 Z9 292 U1 2 U2 31 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 JUL 12 PY 2006 VL 296 IS 2 BP 171 EP 179 DI 10.1001/jama.296.2.171 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 062LP UT WOS:000238946500022 PM 16835422 ER PT J AU Torborg, CL Berg, AP Jeffries, BW Bayliss, DA McBain, CJ AF Torborg, Christine L. Berg, Allison P. Jeffries, Brian W. Bayliss, Douglas A. McBain, Chris J. TI TASK-like conductances are present within hippocampal CA1 stratum oriens interneuron subpopulations SO JOURNAL OF NEUROSCIENCE LA English DT Article DE potassium channels; interneurons; TASK; KCNK; hippocampus; inhibition ID CHANNELS; SUBUNITS; EXPRESSION; FAMILY; CELLS; RAT AB TASK-1 (KCNK3) and TASK-3 (KCNK9) are members of the two-pore domain potassium channel family and form either homomeric or heteromeric open-rectifier (leak) channels. Recent evidence suggests that these channels contribute to the resting potential and input resistance in several neuron types, including hippocampal CA1 pyramidal cells. However, the evidence for TWIK-related acid-sensitive potassium (TASK)-like conductances in inhibitory interneurons is less clear, and mRNA expression has suggested that TASK channels are expressed in only a subpopulation of interneurons. Here we use immunocytochemistry to demonstrate prominent TASK-3 protein expression in both parvalbumin-positive- and a subpopulation of glutamic acid decarboxylase (GAD)67-positive interneurons. In addition, a TASK-like current (modulated by both pH and bupivacaine) was detected in 30-50% of CA1 stratum oriens interneurons of various morphological classes. In most neurons, basic shifts in pH had a larger effect on the TASK-like current than acidic, suggesting that the current is mediated by TASK-1/TASK-3 heterodimers. These data suggest that TASK-like conductances are more prevalent in inhibitory interneurons than previously supposed. C1 Natl Inst Child Hlth & Human Dev, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA. RP Torborg, CL (reprint author), Natl Inst Child Hlth & Human Dev, Lab Cellular & Synapt Neurophysiol, NIH, Bldg 35,Room 3C907, Bethesda, MD 20892 USA. EM torborgc@mail.nih.gov FU Intramural NIH HHS; NINDS NIH HHS [F31 NS50982, NS33583, R01 NS033583] NR 16 TC 28 Z9 28 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 12 PY 2006 VL 26 IS 28 BP 7362 EP 7367 DI 10.1523/JNEUROSCI.1257-06.2006 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 063AH UT WOS:000238987700005 PM 16837582 ER PT J AU Leng, Y Chuang, DM AF Leng, Yan Chuang, De-Maw TI Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity SO JOURNAL OF NEUROSCIENCE LA English DT Article DE alpha-synuclein; valproate; neuroprotection; excitotoxicity; histone deacetylase; Parkinson's disease ID CEREBRAL CORTICAL-NEURONS; PARKINSONS-DISEASE; MOOD STABILIZER; NEURODEGENERATIVE DISEASES; WILD-TYPE; PROTECTS; CELLS; LITHIUM; MUTATION; PATHWAY AB Emerging evidence suggests that alpha-synuclein (alpha-syn), which is traditionally thought to have a pathophysiological role in neurodegenerative diseases, can have neuroprotective effects. This study aimed to investigate whether endogenous alpha-syn in neurons can be induced by valproic acid (VPA), a mood-stabilizer, anticonvulsant and histone deacetylase (HDAC) inhibitor, and if so, whether the alpha-syn induction is neuroprotective. VPA treatment of rat cerebellar granule cells caused a robust dose- and time-dependent increase in levels of alpha-syn protein and mRNA and in the intensity of alpha-syn immunostaining. Knockdown of VPA-induced alpha-syn overexpression with alpha-syn antisense oligonucleotides or siRNA completely blocked VPA-induced neuroprotection. alpha-Syn knockdown also exacerbated glutamate neurotoxicity, stimulated the expression of the proapoptotic gene ubiquitin-conjugating enzyme E2N, and downregulated the expression of the anti-apoptotic gene Bcl-2. Induction of alpha-syn by VPA was associated with inhibition of HDAC activity, resulting in hyperacetylation of histone H3 in the alpha-syn promoter and a marked increase in alpha-syn promoter activity. Moreover, VPA-induced alpha-syn induction and neuroprotection were mimicked by HDAC inhibitors sodium 4-phenylbutyrate and trichostatin A (TSA). alpha-syn was also induced by VPA in rat cerebral cortical neurons. Additionally, treatment of rats with VPA, sodium butyrate, or TSA markedly increased alpha-syn protein levels in the cortex and cerebellum. Together, our results demonstrate for the first time that VPA induces alpha-syn in neurons through inhibition of HDAC and that this alpha-syn induction is critically involved in neuroprotection against glutamate excitotoxicity. Clinically, VPA may represent a suitable treatment for excitotoxicity-related neurodegenerative diseases. C1 Natl Inst Mental Hlth, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), Natl Inst Mental Hlth, Mol Neurobiol Sect, NIH, Bldg 10,Room 4C206,100 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov FU Intramural NIH HHS NR 58 TC 130 Z9 132 U1 6 U2 13 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 12 PY 2006 VL 26 IS 28 BP 7502 EP 7512 DI 10.1523/JNEUROSCI.0096-06.2006 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 063AH UT WOS:000238987700021 PM 16837598 ER PT J AU Talanov, VS Regino, CAS Kobayashi, H Bernardo, M Choyke, PL Brechbiel, MW AF Talanov, Vladimir S. Regino, Celeste A. S. Kobayashi, Hisataka Bernardo, Marcelino Choyke, Peter L. Brechbiel, Martin W. TI Dendrimer-based nanoprobe for dual modality magnetic resonance and fluorescence imaging SO NANO LETTERS LA English DT Article ID BIOMEDICAL APPLICATIONS; PAMAM DENDRIMERS; QUANTUM YIELDS; NANODEVICE; DELIVERY; THERAPY; CANCER; AGENTS; SIZE AB A novel PAMAM dendrimer-based nanoprobe for dual magnetic resonance and fluorescence imaging modalities was synthesized. Fluorescence studies revealed that Gd(III) complexation to the probe has no effect on the quantum yield; however, increases in the dye content resulted in partial quenching. The potential of the new nanoprobe, G6-(Cy5.5)(1.25)(1B4M-Gd)(145), as a dual modality imaging agent was demonstrated in vivo by the efficient visualization of sentinel lymph nodes in mice by both MRI and fluorescence imaging modalities. C1 NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH,Mol Imaging Program, Bethesda, MD 20892 USA. RP Talanov, VS (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH,Mol Imaging Program, Bldg 10,Room 1B40,10 Ctr Dr, Bethesda, MD 20892 USA. EM vstalanov@msrce.howard.edu; martinwb@mail.nih.gov FU Intramural NIH HHS NR 28 TC 179 Z9 185 U1 5 U2 48 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 J9 NANO LETT JI Nano Lett. PD JUL 12 PY 2006 VL 6 IS 7 BP 1459 EP 1463 DI 10.1021/nl060765q PG 5 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 062VK UT WOS:000238973100029 PM 16834429 ER PT J AU Bravaya, K Bochenkova, A Grigorenko, B Topol, I Burt, S Nemukhin, A AF Bravaya, Ksenia Bochenkova, Anastasia Grigorenko, Bella Topol, Igor Burt, Stanley Nemukhin, Alexander TI Molecular modeling the reaction mechanism of serine-carboxyl peptidases SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID QUANTUM MECHANICS/MOLECULAR MECHANICS; ANGSTROM CRYSTAL-STRUCTURE; AB-INITIO QM/MM; ENZYMATIC-REACTIONS; AUTOMATED DOCKING; FREE-ENERGY; HYDRIDE TRANSFER; GENERAL ACID; PROTEINASE; PROTEASE AB We performed molecular modeling on the mechanism of serine-carboxyl peptidases, a novel class of enzymes active at acidic pH and distinguished by the conserved triad of amino acid residues Ser-Glu-Asp. Catalytic cleavage of a hexapeptide fragment of the oxidized B-chain of insulin by the Pseudomonas sedolisin, a member of the serine-carboxyl peptidases family, was simulated. Following motifs of the crystal structure of the sedolisin-inhibitor complex (PDB accession code 1NLU) we designed the model enzyme-substrate (ES) complex and performed quantum mechanical-molecular mechanical calculations of the energy profile along a reaction route up to the acylenzyme (EA) complex through the tetrahedral intermediate (TI). The energies and forces were computed by using the PBE0 exchange-correlation functional and the basis set 6-31+G** in the quantum part and the AMBER force field parameters in the molecular mechanical part. Analysis of the ES, TI, and AE structures as well as of the corresponding transition states allows us to scrutinize the chemical transformations catalyzed by sedolisin. According to the results of simulations, the reaction mechanism of serine-carboxyl peptidases should be viewed as a special case of carboxyl (aspartic) proteases, with the nucleophilic water molecule being replaced by the Ser residue. The catalytic triad Ser-Glu-Asp in sedolisin functions differently compared to the well-known triad Ser-His-Asp of serine proteases, despite the structural similarity of sedolisin and the serine proteases member, subtilisin. C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia. NCI, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. Russian Acad Sci, Inst Biochem Phys, Moscow 119997, Russia. RP Nemukhin, A (reprint author), Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia. EM anem@lcc.chem.msu.ru RI Nemukhin, Alexander/P-9662-2015; Bochenkova, Anastasia/G-2090-2015 OI Bochenkova, Anastasia/0000-0003-4101-3564 NR 47 TC 8 Z9 8 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD JUL 11 PY 2006 VL 2 IS 4 BP 1168 EP 1175 DI 10.1021/ct6000686 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 062EC UT WOS:000238926400029 PM 26633073 ER PT J AU Traynor, BJ Bruijn, L Conwit, R Beal, F O'Neill, G Fagan, C Cudkowicz, ME AF Traynor, B. J. Bruijn, L. Conwit, R. Beal, F. O'Neill, G. Fagan, C. Cudkowicz, M. E. TI Neuroprotective agents for clinical trials in ALS - A systematic assessment SO NEUROLOGY LA English DT Review ID AMYOTROPHIC-LATERAL-SCLEROSIS; TRANSGENIC MOUSE MODEL; PLACEBO-CONTROLLED TRIAL; MOTOR-NEURON DISEASE; GROWTH-FACTOR-I; PROLONGS SURVIVAL; SPINAL-CORD; VITAMIN-E; CEREBROSPINAL-FLUID; EXTEND SURVIVAL AB Background: Riluzole is currently the only Food and Drug Administration-approved treatment for ALS, but its effect on survival is modest. Objective: To identify potential neuroprotective agents for testing in phase III clinical trials and to outline which data need to be collected for each drug. Methods: The authors identified 113 compounds by inviting input from academic clinicians and researchers and via literature review to identify agents that have been tested in ALS animal models and in patients with ALS. The list was initially narrowed to 24 agents based on an evaluation of scientific rationale, toxicity, and efficacy in previous animal and human studies. These 24 drugs underwent more detailed pharmacologic evaluation. Results: Twenty drugs were selected as suitable for further development as treatments for patients with ALS. Talampanel and tamoxifen have completed early phase II trials and have demonstrated preliminary efficacy. Other agents (ceftriaxone, minocycline, ONO-2506, and IGF-1 polypeptide) are already in phase III trials involving large numbers of patients with ALS. Remaining agents (AEOL 10150, arimoclomol, celastrol, coenzyme Q10, copaxone, IGF-1 viral delivery, memantine, NAALADase inhibitors, nimesulide, scriptaid, sodium phenylbutyrate, thalidomide, trehalose) require additional preclinical animal data, human toxicity and pharmacokinetic data including CNS penetration prior to proceeding to large scale phase III human testing. Further development of riluzole analogues should be considered. Conclusions: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in ALS. C1 Massachusetts Gen Hosp, Dept Neurol, Neurol Clin Trials Unit, Boston, MA 02114 USA. ALS Assoc, Palm Harbor, FL USA. NINDS, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Dept Neurol, New York, NY 10021 USA. Biogen Idec Inc, Cambridge, MA USA. Univ Georgia, Coll Pharm, Augusta, GA USA. Med Coll Georgia, Augusta, GA 30912 USA. RP Traynor, BJ (reprint author), NIMH, Bldg 35,Room 1A110,35 Convent Dr, Bethesda, MD 20892 USA. EM traynorb@mail.nih.gov RI Traynor, Bryan/G-5690-2010 NR 85 TC 126 Z9 140 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 11 PY 2006 VL 67 IS 1 BP 20 EP 27 DI 10.1212/01.wnl.0000223353.34006.54 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 062IB UT WOS:000238936700008 PM 16832072 ER PT J AU Hiroi, T Someya, A Thompson, W Moss, J Vaughan, M AF Hiroi, Toyoko Someya, Akimasa Thompson, Walter Moss, Joel Vaughan, Martha TI GEP(100)/BRAG2: Activator of ADP-ribosylation factor 6 for regulation of cell adhesion and actin cytoskeleton via E-cadherin and alpha-catenin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE adherens junction; F-actin ID ADP-RIBOSYLATION FACTOR; NUCLEOTIDE EXCHANGE FACTOR; PLASMA-MEMBRANE; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; MEDIATED ENDOCYTOSIS; PHOSPHOLIPASE-D; ARF6; PROTEIN; FACTOR-6; EXOCYTOSIS AB GEP(100) (p100) was identified as an ADP-ribosylation factor (ARF) guanine nucleotide-exchange protein (GEP) that partially colocalized with ARF6 in the cell periphery. p100 preferentially accelerated guanosine 5[gamma-thio]triphosphate (GTP gamma S) binding by ARF6, which participates in protein trafficking near the plasma membrane, including receptor recycling, cell adhesion, and cell migration. Here we report that yeast two-hybrid screening of a human fetal brain cDNA library using p100 as bait revealed specific interaction with alpha-catenin, which is known as a regulator of adherens junctions and actin cytoskeleton remodeling. Interaction of p100 with alpha-catenin was confirmed by coimmunoprecipitation of the endogenous proteins from human HepG2 or CaSki cells, although colocalization was difficult to demonstrate microscopically. alpha-Catenin enhanced GTP gamma S binding by ARF6 in vitro in the presence of p100. Depletion of p100 by small interfering RNA (siRNA) treatment in HepG2 cells resulted in E-cadherin content 3-fold that in control cells and blocked hepatocyte growth factor-induced redistribution of E-cadherin, consistent with a known role of ARF6 in this process. F-actin was markedly decreased in normal rat kidney (NRK) cells overexpressing wild-type p100, but not its GEP-inactive mutants, also consistent with the conclusion that p100 has an important role in the activation of ARF6 for its functions in both E-cadherin recycling and actin remodeling. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Hiroi, T (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Room 5N307,MSC 1434, Bethesda, MD 20892 USA. EM hiroit@nhlbi.nih.gov; vaughanm@nih.gov FU Intramural NIH HHS NR 49 TC 38 Z9 39 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 JUL 11 PY 2006 VL 103 IS 28 BP 10672 EP 10677 DI 10.1073/pnas.0604091103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 063VG UT WOS:000239047400025 PM 16807291 ER PT J AU Kurukuti, S Tiwari, VK Tavoosidana, G Pugacheva, E Murrell, A Zhao, ZH Lobanenkov, V Reik, W Ohlsson, R AF Kurukuti, Sreenivasulu Tiwari, Vijay Kumar Tavoosidana, Gholamreza Pugacheva, Elena Murrell, Adele Zhao, Zhihu Lobanenkov, Victor Reik, Wolf Ohlsson, Rolf TI CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genomic imprinting; insulators; chromosome biology ID METHYLATION-FREE DOMAINS; INSULATOR PROTEIN CTCF; MESODERMAL ENHANCERS; BLOCKING ACTIVITY; GENE-EXPRESSION; H19/IGF2 LOCUS; 130 KB; ELEMENT; SITES; TRANSCRIPTION AB It is thought that the H19 imprinting control region (ICR) directs the silencing of the maternally inherited Igf2 allele through a CTCF-dependent chromatin insulator. The ICR has been shown to interact physically with a silencer region in Igf2, differentially methylated region (DMR)1, but the role of CTCF in this chromatin loop and whether it restricts the physical access of distal enhancers to Igf2 is not known. We performed systematic chromosome conformation capture analyses in the Igf2/H19 region over > 160 kb, identifying sequences that interact physically with the distal enhancers and the ICR. We found that, on the paternal chromosome, enhancers interact with the Igf2 promoters but that, on the maternal allele, this is prevented by CTCF binding within the H19 ICR. CTCF binding in the maternal ICR regulates its interaction with matrix attachment region (MAR)3 and DMR1 at Igf2, thus forming a tight loop around the maternal Igf2 locus, which may contribute to its silencing. Mutation of CTCF binding sites in the H19 ICR leads to loss of CTCF binding and de novo methylation of a CTCF target site within Igf2 DMR1, showing that CTCF can coordinate regional epigenetic marks. This systematic chromosome conformation capture analysis of an imprinting cluster reveals that CTCF has a critical role in the epigenetic regulation of higher-order chromatin structure and gene silencing over considerable distances in the genome. C1 Babraham Inst, Lab Dev Genet & Imprinting, Cambridge CB2 4AT, England. Univ Uppsala, Dept Genet & Dev, S-75236 Uppsala, Sweden. NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. Univ Cambridge, Dept Oncol, Cambridge CB2 2XE, England. Univ Cambridge, Hutchison Med Res Council, Res Ctr, Cambridge CB2 2XE, England. RP Reik, W (reprint author), Babraham Inst, Lab Dev Genet & Imprinting, Cambridge CB2 4AT, England. EM wolf.reik@bbsrc.ac.uk; rolf.ohlsson@ebc.uu.se RI Reik, Wolf/I-6794-2012; OI Lobanenkov, Victor/0000-0001-6665-3635; Reik, Wolf/0000-0003-0216-9881 FU Medical Research Council [G0400154]; Wellcome Trust NR 43 TC 314 Z9 331 U1 0 U2 15 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 JUL 11 PY 2006 VL 103 IS 28 BP 10684 EP 10689 DI 10.1073/pnas.0600326103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 063VG UT WOS:000239047400027 PM 16815976 ER PT J AU Folsom, AR Chambless, LE Ballantyne, CM Coresh, J Heiss, G Wu, KK Boerwinkle, E Mosley, TH Sorlie, P Diao, GQ Sharrett, AR AF Folsom, Aaron R. Chambless, Lloyd E. Ballantyne, Christie M. Coresh, Josef Heiss, Gerardo Wu, Kenneth K. Boerwinkle, Eric Mosley, Thomas H., Jr. Sorlie, Paul Diao, Guoqing Sharrett, A. Richey TI An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers - The atherosclerosis risk in communities study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID HEART-DISEASE; STATIN THERAPY; CARDIOVASCULAR EVENTS; CASE-COHORT; CHOLESTEROL; MEN; DESIGN; WOMEN AB Background: There has been interest in recent years in whether additional, and in particular novel, risk factors or blood markers, such as C-reactive protein, can enhance existing coronary heart disease (CHD) prediction models. Methods: Using a series of case-cohort studies, the prospective Atherosclerosis Risk in Communities (ARIC) Study assessed the association of 19 novel risk markers with incident CHD in 15 792 adults followed up since 1987-1989. Novel markers included measures of inflammation, endothelial function, fibrin formation, fibrinolysis, B vitamins, and antibodies to infectious agents. Change in the area under the receiver operating characteristic curve (AUC) was used to assess the additional contribution of novel risk markers to CHD prediction beyond that of traditional risk factors. Results: The basic risk factor model, which included traditional risk factors (age, race, sex, total and high-density lipoprotein cholesterol levels, systolic blood pressure, antihypertensive medication use, smoking status, and diabetes), predicted CHD well, as evidenced by an AUC of approximately 0.8. The C-reactive protein level did not add significantly to the AUC (increase in AUC of 0.003), and neither did most other novel risk factors. Of the 19 markers studied, lipoprotein-associated phospholipase A(2), vitamin B-6, interleukin 6, and soluble thrombomodulin added the most to the AUC (range, 0.006-0.011). Conclusions: Our findings suggest that routine measurement of these novel markers is not warranted for risk assessment. On the other hand, our findings reinforce the utility of major, modifiable risk factor assessment to identify individuals at risk for CHD for preventive action. C1 Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ Texas, Hlth Sci Ctr, Dept Med, Baylor Coll Med, Houston, TX USA. Univ Texas, Hlth Sci Ctr, Hemostasis Lab, Div Hematol, Houston, TX USA. Univ Texas, Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. Univ Texas, Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Med, Baltimore, MD USA. Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Folsom, AR (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Suite 300,1300 S 2nd St, Minneapolis, MN 55454 USA. EM folsom@epi.umn.edu RI Diao, Guoqing/B-9513-2011; Wu, Kenneth Kun-Yu/B-1070-2010 FU NHLBI NIH HHS [N01-HC-55018, N01-HC-55015, N01-HC-55016, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022] NR 27 TC 238 Z9 244 U1 1 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 10 PY 2006 VL 166 IS 13 BP 1368 EP 1373 DI 10.1001/archinte.166.13.1368 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 062AK UT WOS:000238916500005 PM 16832001 ER PT J AU Ferrucci, L Maggio, M Bandinelli, S Basaria, S Lauretani, F Ble, A Valenti, G Ershler, WB Guralnik, JM Longo, DL AF Ferrucci, Luigi Maggio, Marcello Bandinelli, Stefania Basaria, Shehzad Lauretani, Fulvio Ble, Alessandro Valenti, Giorgio Ershler, William B. Guralnik, Jack M. Longo, Dan L. TI Low testosterone levels and the risk of anemia in older men and women SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID HYPOGONADAL MEN; PHYSICAL PERFORMANCE; ANDROGEN DEPRIVATION; HEMOGLOBIN LEVELS; MUSCLE STRENGTH; SKELETAL-MUSCLE; ERYTHROPOIETIN; INCHIANTI; SERUM; EPIDEMIOLOGY AB Background: Anemia is a frequent feature of male hypogonadism and anti-androgenic treatment. We hypothesized that the presence of low testosterone levels in older persons is a risk factor for anemia. Methods: Testosterone and hemoglobin levels were measured in a representative sample of 905 persons 65 years or older without cancer, renal insufficiency, or anti-androgenic treatments. Hemoglobin levels were reassessed after 3 years. Results: At baseline, 31 men and 57 women had anemia. Adjusting for confounders, we found that total and bioavailable testosterone levels were associated with hemoglobin levels in women (P = .001 and P = .02, respectively) and in men (P < .001 and P = .03, respectively). Men and women in the lowest quartile of total and bioavailable testosterone were more likely than those in the highest to have anemia (men, 14/99 vs 3/100; odds ratio [OR], 5.4; 95% confidence interval [CI], 1.4-21.8 for total and 16/99 vs 1/99; OR, 13.1; 95% CI, 1.5-116.9 for bioavailable testosterone; women, 21/129 vs 12/127; OR, 2.1; 95% CI, 0.9-5.0 for total and 24/127 vs 6/127; OR, 3.4; 95% CI, 1.2-9.4 for bioavailable testosterone). Among nonanemic participants and independent of confounders, men and women with low vs normal total and bioavailable testosterone levels had a significantly higher risk of developing anemia at 3-year follow-up (21/167 vs 28/444; relative risk, 2.1; 95% CI, 1.1-4.1 for total and 26/143 vs 23/468; relative risk, 3.9; 95% CI, 1.9-7.8 for bioavailable testosterone). Conclusion: Older men and women with low testosterone levels have a higher risk of anemia. C1 NIH, Clin Res Branch, Baltimore, MD USA. Azienda Sanitaria Firenze, Geriatr Rehabil, Florence, Italy. Johns Hopkins Univ, Sch Med, Bayview Med Ctr, Dept Med,Div Endocrinol, Baltimore, MD USA. Tuscany Reg Hlth Agcy, Florence, Italy. Univ Parma, Dept Internal Med & Biomed Sci, Geriatr Sect, I-43100 Parma, Italy. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, ASTRA Unit,Harbor Hosp, 5th Floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 FU Intramural NIH HHS [Z99 AG999999]; NIA NIH HHS [N01-AG-821336, N01-AG-916413]; NIMHD NIH HHS [263 MD 821336, 263 MD 9164 13, R01 MD009164] NR 41 TC 110 Z9 114 U1 1 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 10 PY 2006 VL 166 IS 13 BP 1380 EP 1388 DI 10.1001/archinte.166.13.1380 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 062AK UT WOS:000238916500007 PM 16832003 ER PT J AU Bibbins-Domingo, K Chertow, GM Fried, LF Odden, MC Newman, AB Kritchevsky, SB Harris, TB Satterfield, S Cummings, SR Shlipak, MG AF Bibbins-Domingo, Kirsten Chertow, Glenn M. Fried, Linda F. Odden, Michelle C. Newman, Anne B. Kritchevsky, Stephen B. Harris, Tamara B. Satterfield, Suzanne Cummings, Steven R. Shlipak, Michael G. TI Renal function and heart failure risk in older black and white individuals - The health, aging, and body composition study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID GLOMERULAR-FILTRATION-RATE; FACTOR INTERVENTION TRIAL; CYSTATIN-C CONCENTRATION; CHRONIC KIDNEY-DISEASE; RACIAL-DIFFERENCES; UNITED-STATES; ATHEROSCLEROSIS RISK; EXPLANATORY FACTORS; AFRICAN-AMERICANS; ATTRIBUTABLE RISK AB Background: Chronic kidney disease is a risk factor for heart failure, an association that may be particularly important in blacks who are disproportionately affected by both processes. Our objective was to determine whether the association of chronic kidney disease with incident heart failure differs between blacks and whites. Methods: The study population comprised participants in the Health, Aging, and Body Composition Study without a diagnosis of heart failure (1124 black and 1676 white community-dwelling older persons). The main predictors were quintiles of cystatin C and creatinine concentrations and estimated glomerular filtration rate. The main outcome measure was incident heart failure. Results: Over a mean 5.7 years, 200 participants developed heart failure. High concentrations of cystatin C and low estimated glomerular filtration rate were each associated with heart failure, but the magnitude was greater for blacks than for whites (cystatin C concentration: adjusted hazard ratio for quintile 5 [>= 1.18 mg/dL] vs quintile 1 [< 0.84 mg/dL] was 3.0 [95% confidence interval 1.4-6.5] in blacks and 1.4 [95% confidence interval, 0.8-2.5] in whites; estimated glomerular filtration rate: adjusted hazard ratio for quintile 5 (< 59.2 mL/min) vs quintile 1 (> 86.7 mL/min) was 2.7 [95% confidence interval, 1.4-4.9] in blacks and 1.8 [95% confidence interval, 0.9-3.6] in whites). For cystatin C, this association was observed at more modest decrements in kidney function among blacks as well. The population attributable risk of heart failure was 47% for blacks with moderate or high concentrations of cystatin C (>= 0.94 mg/dL) (56% prevalence) but only 5% among whites (64% prevalence). Conclusion: The association of kidney dysfunction with heart failure appears stronger in blacks than for whites, particularly when cystatin C is used to measure kidney function. C1 Univ Calif San Francisco, Div Gen Internal Med, SFGH, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. Univ Pittsburgh, Div Renal & Electrolyte, Grad Sch Publ Hlth, Pittsburgh, PA USA. Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA 15261 USA. Vet Affairs Med Ctr, Gen Internal Med Sect, San Francisco, CA 94121 USA. Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN 38163 USA. Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94115 USA. RP Bibbins-Domingo, K (reprint author), Univ Calif San Francisco, Div Gen Internal Med, SFGH, Box 1364, San Francisco, CA 94143 USA. EM bbinsk@medicine.ucsf.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU NHLBI NIH HHS [N01-HC-95095, N01-HL073208-01]; NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIDDK NIH HHS [R01 DK 06648] NR 34 TC 32 Z9 34 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 10 PY 2006 VL 166 IS 13 BP 1396 EP 1402 DI 10.1001/archinte.166.13.1396 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 062AK UT WOS:000238916500009 PM 16832005 ER PT J AU Tomaszewski, JE AF Tomaszewski, J. E. TI Pharmacological (PK/PD) aspects of phase zero clinical trials SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Meeting Abstract CT International Conference on Frontiers of Pharmacology and Toxicology CY AUG 28-31, 2006 CL Chicago, IL SP Univ Illinois, Toxicol Res Lab, Dept Pharmacol & Canc Res Ctr, Appl Biosyst, Elsevier, Soc Toxicol, Labcat, Waters Corp, Hilltop Lab Anim, Bristol Myers Squibb, Marshall Farms, Thermo Electron N Amer LLC, AniLytics, EMKA Technologies, PerkinElmer, Life & Analyt Sci C1 NCI, DCTD, DTP, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUL 10 PY 2006 VL 161 IS 3 SI SI BP 177 EP 177 DI 10.1016/j.cbi.2006.05.014 PG 1 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 076UB UT WOS:000239982200002 ER PT J AU Hollingshead, MG AF Hollingshead, M. G. TI Animal models for cancer treatment and prevention SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Meeting Abstract CT International Conference on Frontiers of Pharmacology and Toxicology CY AUG 28-31, 2006 CL Chicago, IL SP Univ Illinois, Toxicol Res Lab, Dept Pharmacol & Canc Res Ctr, Appl Biosyst, Elsevier, Soc Toxicol, Labcat, Waters Corp, Hilltop Lab Anim, Bristol Myers Squibb, Marshall Farms, Thermo Electron N Amer LLC, AniLytics, EMKA Technologies, PerkinElmer, Life & Analyt Sci C1 NCI, DCTD, DTP, Biol Testing Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUL 10 PY 2006 VL 161 IS 3 SI SI BP 179 EP 179 PG 1 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 076UB UT WOS:000239982200007 ER PT J AU Crowell, JA AF Crowell, J. A. TI Identifying and developing potential cancer preventive agents SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Meeting Abstract CT International Conference on Frontiers of Pharmacology and Toxicology CY AUG 28-31, 2006 CL Chicago, IL SP Univ Illinois, Toxicol Res Lab, Dept Pharmacol & Canc Res Ctr, Appl Biosyst, Elsevier, Soc Toxicol, Labcat, Waters Corp, Hilltop Lab Anim, Bristol Myers Squibb, Marshall Farms, Thermo Electron N Amer LLC, AniLytics, EMKA Technologies, PerkinElmer, Life & Analyt Sci C1 NCI, Div Canc Prevent, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUL 10 PY 2006 VL 161 IS 3 SI SI BP 186 EP 186 PG 1 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 076UB UT WOS:000239982200017 ER PT J AU Krishnaraj, R Arbieva, Z Kapetanovic, IM Lyubimov, A AF Krishnaraj, R. Arbieva, Z. Kapetanovic, I. M. Lyubimov, A. TI Pharmacogenomic evaluation of chemopreventive agents, diindolylmethane and tamoxifen in livers from female rats dosed orally for 13 weeks SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Meeting Abstract CT International Conference on Frontiers of Pharmacology and Toxicology CY AUG 28-31, 2006 CL Chicago, IL SP Univ Illinois, Toxicol Res Lab, Dept Pharmacol & Canc Res Ctr, Appl Biosyst, Elsevier, Soc Toxicol, Labcat, Waters Corp, Hilltop Lab Anim, Bristol Myers Squibb, Marshall Farms, Thermo Electron N Amer LLC, AniLytics, EMKA Technologies, PerkinElmer, Life & Analyt Sci C1 Univ Illinois, Chicago, IL 60680 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUL 10 PY 2006 VL 161 IS 3 SI SI BP 189 EP 190 PG 2 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 076UB UT WOS:000239982200022 ER PT J AU Cassatt, DR Benjamin, JM Maidment, BW AF Cassatt, D. R. Benjamin, J. M. Maidment, B. W. TI NIH/NIAID programs for radiological/nuclear medical countermeasures development SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Meeting Abstract CT International Conference on Frontiers of Pharmacology and Toxicology CY AUG 28-31, 2006 CL Chicago, IL SP Univ Illinois, Toxicol Res Lab, Dept Pharmacol & Canc Res Ctr, Appl Biosyst, Elsevier, Soc Toxicol, Labcat, Waters Corp, Hilltop Lab Anim, Bristol Myers Squibb, Marshall Farms, Thermo Electron N Amer LLC, AniLytics, EMKA Technologies, PerkinElmer, Life & Analyt Sci C1 NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUL 10 PY 2006 VL 161 IS 3 SI SI BP 197 EP 197 PG 1 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 076UB UT WOS:000239982200032 ER PT J AU Kapetanovic, IM AF Kapetanovic, I. M. TI Overview of computer-aided drug design and development (CADDD): in silico-chemico-biological approach SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Meeting Abstract CT International Conference on Frontiers of Pharmacology and Toxicology CY AUG 28-31, 2006 CL Chicago, IL SP Univ Illinois, Toxicol Res Lab, Dept Pharmacol & Canc Res Ctr, Appl Biosyst, Elsevier, Soc Toxicol, Labcat, Waters Corp, Hilltop Lab Anim, Bristol Myers Squibb, Marshall Farms, Thermo Electron N Amer LLC, AniLytics, EMKA Technologies, PerkinElmer, Life & Analyt Sci C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUL 10 PY 2006 VL 161 IS 3 SI SI BP 203 EP 204 PG 2 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 076UB UT WOS:000239982200045 ER PT J AU Birukov, KG Nonas, S Chatchavalvanich, S Miller, I Bocharov, A Garcia, JGN AF Birukov, K. G. Nonas, S. Chatchavalvanich, S. Miller, I. Bocharov, A. V. Garcia, J. G. N. TI Oxidized phospholipids reduce vascular leak and inflammation in the animal models of endotoxin-induced lung injury SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Meeting Abstract CT International Conference on Frontiers of Pharmacology and Toxicology CY AUG 28-31, 2006 CL Chicago, IL SP Univ Illinois, Toxicol Res Lab, Dept Pharmacol & Canc Res Ctr, Appl Biosyst, Elsevier, Soc Toxicol, Labcat, Waters Corp, Hilltop Lab Anim, Bristol Myers Squibb, Marshall Farms, Thermo Electron N Amer LLC, AniLytics, EMKA Technologies, PerkinElmer, Life & Analyt Sci C1 Univ Chicago, Dept Med, Chicago, IL 60637 USA. Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD USA. NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RI Garcia, Joe/E-8862-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUL 10 PY 2006 VL 161 IS 3 SI SI BP 205 EP 205 PG 1 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 076UB UT WOS:000239982200047 ER PT J AU Kapetanovic, IM Crowell, JA AF Kapetanovic, I. M. Crowell, J. A. TI Chemopreventive agent development program: a case study SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Meeting Abstract CT International Conference on Frontiers of Pharmacology and Toxicology CY AUG 28-31, 2006 CL Chicago, IL SP Univ Illinois, Toxicol Res Lab, Dept Pharmacol & Canc Res Ctr, Appl Biosyst, Elsevier, Soc Toxicol, Labcat, Waters Corp, Hilltop Lab Anim, Bristol Myers Squibb, Marshall Farms, Thermo Electron N Amer LLC, AniLytics, EMKA Technologies, PerkinElmer, Life & Analyt Sci C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUL 10 PY 2006 VL 161 IS 3 SI SI BP 214 EP 214 PG 1 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 076UB UT WOS:000239982200066 ER PT J AU Kabirov, KK Kapetanovic, IM Lyubimov, AV AF Kabirov, K. K. Kapetanovic, I. M. Lyubimov, A. V. TI Direct determination of selenium in rat blood plasma by Zeeman atomic absorption spectrometry SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Meeting Abstract CT International Conference on Frontiers of Pharmacology and Toxicology CY AUG 28-31, 2006 CL Chicago, IL SP Univ Illinois, Toxicol Res Lab, Dept Pharmacol & Canc Res Ctr, Appl Biosyst, Elsevier, Soc Toxicol, Labcat, Waters Corp, Hilltop Lab Anim, Bristol Myers Squibb, Marshall Farms, Thermo Electron N Amer LLC, AniLytics, EMKA Technologies, PerkinElmer, Life & Analyt Sci C1 UIC, Toxicol Res Lab, Chicago, IL USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUL 10 PY 2006 VL 161 IS 3 SI SI BP 215 EP 216 PG 2 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 076UB UT WOS:000239982200068 ER PT J AU Lindeblad, M Martin-Jimenez, T Kapetanovic, IM Chen, YF Lyubimov, AV AF Lindeblad, M. Martin-Jimenez, T. Kapetanovic, I. M. Chen, Y. -F. Lyubimov, A. V. TI Lovastatin exposure following gavage versus dietary administration in female rats SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Meeting Abstract CT International Conference on Frontiers of Pharmacology and Toxicology CY AUG 28-31, 2006 CL Chicago, IL SP Univ Illinois, Toxicol Res Lab, Dept Pharmacol & Canc Res Ctr, Appl Biosyst, Elsevier, Soc Toxicol, Labcat, Waters Corp, Hilltop Lab Anim, Bristol Myers Squibb, Marshall Farms, Thermo Electron N Amer LLC, AniLytics, EMKA Technologies, PerkinElmer, Life & Analyt Sci C1 Univ Illinois, Chicago, IL USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUL 10 PY 2006 VL 161 IS 3 SI SI BP 216 EP 217 PG 2 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 076UB UT WOS:000239982200069 ER PT J AU Varticovski, L Hollingshead, MG Anver, MR Robles, AI Barrett, J AF Varticovski, L. Hollingshead, M. G. Anver, M. R. Robles, A. I. Barrett, J. TI Drug testing in transgenic mouse models SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Meeting Abstract CT International Conference on Frontiers of Pharmacology and Toxicology CY AUG 28-31, 2006 CL Chicago, IL SP Univ Illinois, Toxicol Res Lab, Dept Pharmacol & Canc Res Ctr, Appl Biosyst, Elsevier, Soc Toxicol, Labcat, Waters Corp, Hilltop Lab Anim, Bristol Myers Squibb, Marshall Farms, Thermo Electron N Amer LLC, AniLytics, EMKA Technologies, PerkinElmer, Life & Analyt Sci C1 NCI, CCR, Bethesda, MD 20892 USA. NCI, DTP, Frederick, MD 21701 USA. Novartis Oncol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUL 10 PY 2006 VL 161 IS 3 SI SI BP 226 EP 226 PG 1 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 076UB UT WOS:000239982200088 ER PT J AU Jaffe, CC AF Jaffe, C. Carl TI Measures of response: RECIST, WHO, and new alternatives SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID MALIGNANT PLEURAL MESOTHELIOMA; COMPUTER-AIDED DIAGNOSIS; SOLID TUMORS RECIST; PULMONARY NODULES; CLINICAL-TRIALS; VOLUMETRIC MEASUREMENTS; EVALUATION CRITERIA; LUNG LESIONS; END-POINTS; PHASE-II AB RECIST (Response Evaluation Criteria in Solid Tumors) is a widely employed method introduced in 2000 to assess change in tumor size in response to therapy. The simplicity of the technique, however, contrasts sharply with the increasing sophistication of imaging instrumentation. Anatomically based imaging measurement, although supportive of drug development and key to some accelerated drug approvals, is being pressed to improve its methodologic robustness, particularly in the light of more functionally-based imaging that is sensitive to tissue molecular response such as fluorodeoxyglucose positron emission tomography. Nevertheless ready availability of computed tomography and magnetic resonance imaging machines largely assures anatomically based imaging a continuing role in clinical trials for the foreseeable future. Recent advances in image processing enabled by the computational power of modern clinical scanners open a considerable opportunity to characterize tumor response to therapy as a complement to image acquisition. Various alternative quantitative volumetric approaches have been proposed but have yet to gain wide acceptance by clinical and regulatory communities, nor have these more complex techniques shown incontrovertible evidence of greater reproducibility or predictive value of clinical events and outcome. Unless plans are created for clinical trials that incorporate the design needed to prove the added value and unique clinical utility of these novel approaches, any theoretical benefit of these more elaborate methods could remain unfulfilled. C1 NCI, Diagnost Imaging Branch, Canc Imaging Program, Div Canc Treatment & Diag,NIH, Bethesda, MD 20892 USA. RP Jaffe, CC (reprint author), 6130 Execut Blvd,Room 6050, Bethesda, MD 20892 USA. EM jaffec1@mail.nih.gov NR 44 TC 169 Z9 180 U1 0 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2006 VL 24 IS 20 BP 3245 EP 3251 DI 10.1200/JCO.2006.06.5599 PG 7 WC Oncology SC Oncology GA 064HV UT WOS:000239080700004 PM 16829648 ER PT J AU El-Deiry, WS Sigman, CC Kelloff, GJ AF El-Deiry, Wafik S. Sigman, Caroline C. Kelloff, Gary J. TI Imaging and oncologic drug development SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID GROWTH-FACTOR RECEPTOR; MONITORING NEOADJUVANT CHEMOTHERAPY; PROTEIN-PROTEIN INTERACTIONS; CELL LUNG-CANCER; NF-KAPPA-B; IN-VIVO; BREAST-CANCER; CHROMOSOMAL INSTABILITY; COLORECTAL-CANCER; GENE-EXPRESSION AB For decades anatomic imaging with computed tomography or magnetic resonance imaging has facilitated drug development in medical oncology by providing quantifiable and objective evidence of response to cancer therapy. In recent years metabolic imaging with [F-18]fluorodeoxyglucose-positron emission tomography has added an important component to the oncologist's armamentarium for earlier detection of response that is now widely used and appreciated. These modalities along with ultrasound and optical imaging (bioluminescence, fluorescence, near-infrared imaging, multispectral imaging) have become used increasingly in preclinical studies in animal models to document the effects of genetic alterations on cancer progression or metastases, the detection of minimal residual disease, and response to various therapeutics including radiation, chemotherapy, or biologic agents. The field of molecular imaging offers potential to deliver a variety of probes that can image noninvasively drug targets, drug distribution, cancer gene expression, cell surface receptor or oncoprotein levels, and biomarker predictors of prognosis, therapeutic response, or failure. Some applications are best suited to accelerate preclinical anticancer drug development, whereas other technologies may be directly transferable to the clinic. Efforts are underway to apply noninvasive in vivo imaging to specific preclinical or clinical problems to accelerate progress in the field. Because resources are limited, and patient suffering from failed or ineffective therapy continues, a concerted effort is being made to address these issues. Many simultaneous activities involving academia; the pharmaceutical, device, and biotechnology industries; US Food and Drug Administration; National Cancer Institute; Centers for Medicare and Medicaid Services; and specialized networks sponsored by the National Institutes of Health are beginning to address these issues to develop consensus recommendations and progress in this important area. C1 Univ Penn, Sch Med, Abramson Comprehens Canc Ctr, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Lab Mol Oncol & Cell Cycle Regulat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Med Hematol Oncol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. CCS Associates, Mountain View, CA USA. NCI, Canc Imaging Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP El-Deiry, WS (reprint author), Univ Penn, Sch Med, Abramson Comprehens Canc Ctr, 415 Curie Blvd,CRB 437A, Philadelphia, PA 19104 USA. EM wafik@mail.med.upenn.edu FU NCI NIH HHS [U54 CA105008] NR 118 TC 59 Z9 65 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2006 VL 24 IS 20 BP 3261 EP 3273 DI 10.1200/JCO.2006.06.5623 PG 13 WC Oncology SC Oncology GA 064HV UT WOS:000239080700006 PM 16829650 ER PT J AU Loucks, TMJ De Nil, LF AF Loucks, TMJ De Nil, LF TI Anomalous sensorimotor integration in adults who stutter: A tendon vibration study SO NEUROSCIENCE LETTERS LA English DT Article DE stuttering; proprioception; tendon vibration; sensorimotor integration; masseter ID MUSCLE AFFERENTS; FLUENT SPEECH; MOVEMENTS; COORDINATION; KINESTHESIA; INDIVIDUALS; NONSPEECH; ILLUSIONS; MASSETER; POSITION AB Anomalies in oral movement control have been identified in stuttering, which suggest this speech disorder involves a sensorimotor deficit. To test whether adults who stutter (AWS) display aberrant proprioceptive function, masseter tendon vibration was used to manipulate jaw proprioception as AWS and normal speakers performed a jaw-opening task. A movement amplitude reduction in the vibration condition was observed in both groups indicating the movements of AWS and controls were influenced in a similar manner by altering masseter proprioception. However, the undershoot magnitude was reduced in AWS relative to the control participants indicating a subtle difference in proprioceptive integration among the stuttering participants. Our interpretation is that AWS use proprioceptive information less efficiently than normal speakers, which could interfere with sensorimotor integration during speech production. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 NINDS, Laryngeal & Speech Sect, NIH, Bethesda, MD 20892 USA. Univ Toronto, Grad Dept Speech Language Pathol, Toronto, ON, Canada. Toronto Western Res Inst, Toronto, ON, Canada. Sick Kids Res Inst, Toronto, ON, Canada. RP Loucks, TMJ (reprint author), NINDS, Laryngeal & Speech Sect, NIH, Room 5D38,Bldg 10, Bethesda, MD 20892 USA. EM louckst@ninds.nih.gov NR 32 TC 13 Z9 14 U1 0 U2 1 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 JUL 10 PY 2006 VL 402 IS 1-2 BP 195 EP 200 DI 10.1016/j.neulet.2006.04.002 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 055FB UT WOS:000238434300041 PM 16698179 ER PT J AU Chang, HJ Lee, J Poo, H Noda, M Diaz, T Wei, BY Stetler-Stevenson, WG Oh, J AF Chang, HJ Lee, J Poo, H Noda, M Diaz, T Wei, BY Stetler-Stevenson, WG Oh, J TI TIMP-2 promotes cell spreading and adhesion via upregulation of Rap1 signaling SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE TIMP-2; cell spreading; cell adhesion; cell migration; Rap1 ID TISSUE INHIBITOR; TUMOR-GROWTH; ANGIOGENESIS; MIGRATION; INVASION; GENE; ACTIVATION; MECHANISM; LYMPHOMA; COMPLEX AB We previously demonstrated that TIMP-2 treatment of human microvascular endothelial cells (hMVECs) activates Rap1 via the pathway of paxillin-Crk-C3G. Here, we show that TIMP-2 overexpression in hMVECs by adenoviral infection enhances Rap1 expression, leading to further increase in Rap1-GTP. TIMP-2 expression, previously reported to inhibit cell migration, also leads to cell spreading accompanied with increased cell adhesion. HMVECs stably expressing Rapt display a similar phenotype as hMVECs-TIMP-2, whereas the expression of inactive Rap1 mutant, Rap1(38N), leads to elongated appearance with greatly reduced cell adhesion. Furthermore, the phenotype of hMVECs-Rap1(38N) was not reversed by TIMP-2 overexpression. TIMP-2 greatly promotes the association of Rap1 with actin. Therefore, these findings suggest that TIMP-2 mediated alteration in cell morphology requires Rap1, TIMP-2 may recruit Rapt to sites of actin cytoskeleton remodeling necessary for cell spreading, and enhanced cell adhesion by TIMP-2 expression may hinder cell migration. (c) 2006 Elsevier Inc. All rights reserved. C1 Korea Univ, Grad Sch Med, Cellular Oncol Lab, Ansan 425707, Gyeonggi Do, South Korea. Korea Res Inst Biosci & Biotechnol, Proteome Res Lab, Taejon 305600, South Korea. Kyoto Univ, Grad Sch Med, Dept Mol Oncol, Kyoto 6068501, Japan. NCI, Ctr Canc Res, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. RP Oh, J (reprint author), Korea Univ, Grad Sch Med, Cellular Oncol Lab, Ansan 425707, Gyeonggi Do, South Korea. EM ohjs@korea.ac.kr RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 FU Intramural NIH HHS NR 29 TC 4 Z9 4 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 7 PY 2006 VL 345 IS 3 BP 1201 EP 1206 DI 10.1016/j.bbrc.2006.05.044 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 054AA UT WOS:000238346500042 PM 16716258 ER PT J AU Pezza, RJ Petukhova, GV Ghirlando, R Camerini-Otero, RD AF Pezza, RJ Petukhova, GV Ghirlando, R Camerini-Otero, RD TI Molecular activities of meiosis-specific proteins Hop2, Mnd1, and the Hop2-Mnd1 complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOUBLE-STRAND BREAKS; PREDICTING COILED COILS; MEIOTIC RECOMBINATION; SACCHAROMYCES-CEREVISIAE; GENETIC-RECOMBINATION; CHROMOSOME SYNAPSIS; DMC1; DNA; RAD51; SPO11 AB The mouse Hop2 and Mnd1 proteins, which can form a stable heterodimeric complex, ensure the proper synapsis of homologous chromosomes in meiosis by acting in concert with Rad51 and Dmc1 to promote the strand invasion (D-loop formation) step of homologous recombination. Hop2 alone promotes D-loop formation, but Mnd1 and the Hop2-Mnd1 complex do not. Here we show that only the heterodimer complex, but not the individual proteins, can stimulate strand invasion by Dmc1. Furthermore, we demonstrate that the interaction with Mnd1 provokes changes in Hop2 that are responsible not only for abrogating the recombinase activity of Hop2 but also for generating a new molecular interface able to physically interact with and stimulate Dmc1. We also show that coiled-coil motifs in Hop2 and Mnd1 are essential for their interaction with each other and that a clearly delineated region near the COOH terminus of both proteins is necessary for both the DNA binding and single-strand annealing by the Hop-Mnd1 heterodimer. Finally, we describe a point mutation in Hop2 that dissociates its strand invasion activity from its ability to bind and anneal DNA. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Camerini-Otero, RD (reprint author), Bldg 5,Rm 205A,5 Mem Dr,MSC0538, Bethesda, MD 20892 USA. EM camerini@ncifcrf.gov RI Ghirlando, Rodolfo/A-8880-2009 NR 32 TC 44 Z9 47 U1 0 U2 5 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 JUL 7 PY 2006 VL 281 IS 27 BP 18426 EP 18434 DI 10.1074/jbc.M601073200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 058TK UT WOS:000238687300021 PM 16675459 ER PT J AU Lind, MI Missirlis, F Melefors, O Uhrigshardt, H Kirby, K Phillips, JP Soderhall, K Rouault, TA AF Lind, MI Missirlis, F Melefors, O Uhrigshardt, H Kirby, K Phillips, JP Soderhall, K Rouault, TA TI Of two cytosolic aconitases expressed in drosophila, only one functions as an iron-regulatory protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RESPONSIVE-ELEMENT-BINDING; TRANSFERRIN RECEPTOR EXPRESSION; SULFUR CLUSTER BIOGENESIS; RNA-BINDING; MESSENGER-RNA; TRANSLATIONAL REGULATION; CAENORHABDITIS-ELEGANS; 5-UNTRANSLATED REGION; TRYPANOSOMA-BRUCEI; IN-VITRO AB In mammalian cells, iron homeostasis is largely regulated by post-transcriptional control of gene expression through the binding of iron-regulatory proteins (IRP1 and IRP2) to iron-responsive elements (IREs) contained in the untranslated regions of target mRNAs. IRP2 is the dominant iron sensor in mammalian cells under normoxia, but IRP1 is the more ancient protein in evolutionary terms and has an additional function as a cytosolic aconitase. The Caenorhabditis elegans genome does not contain an IRP2 homolog or identifiable IREs; its IRP1 homolog has aconitase activity but does not bind to mammalian IREs. The Drosophila genome offers an evolutionary intermediate containing two IRP1-like proteins (IRP-1A and IRP-1B) and target genes with IREs. Here, we used purified recombinant IRP-1A and IRP-1B from Drosophila melanogaster and showed that only IRP-1A can bind to IREs, although both proteins possess aconitase activity. These results were also corroborated in whole-fly homogenates from transgenic flies that overexpress IRP-1A and IRP-1B in their fat bodies. Ubiquitous and muscle-specific overexpression of IRP-1A, but not of IRP-1B, resulted in pre-adult lethality, underscoring the importance of the biochemical difference between the two proteins. Domain-swap experiments showed that multiple amino acid substitutions scattered throughout the IRP1 domains are synergistically required for conferring IRE binding activity. Our data suggest that as a first step during the evolution of the IRP/IRE system, the ancient cytosolic aconitase was duplicated in insects with one variant acquiring IRE-specific binding. C1 Uppsala Univ, Dept Comparat Physiol, Evolutionary Biol Ctr, S-75236 Uppsala, Sweden. NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. Univ Guelph, Dept Cellular & Mol Biol, Guelph, ON N1G 2W1, Canada. RP Lind, MI (reprint author), Uppsala Univ, Dept Comparat Physiol, Evolutionary Biol Ctr, Norbyvagen 18A, S-75236 Uppsala, Sweden. EM maria.Lind@ebc.uu.se RI Missirlis, Fanis/C-1137-2011 OI Missirlis, Fanis/0000-0003-0467-8444 FU Intramural NIH HHS NR 57 TC 32 Z9 33 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 JUL 7 PY 2006 VL 281 IS 27 BP 18707 EP 18714 DI 10.1074/jbc.M603354200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 058TK UT WOS:000238687300051 PM 16679315 ER PT J AU Gallo, SA Wang, W Rawat, SS Jung, G Waring, AJ Cole, AM Lu, H Yan, XX Daly, NL Craik, DJ Jiang, SB Lehrer, RI Blumenthal, R AF Gallo, SA Wang, W Rawat, SS Jung, G Waring, AJ Cole, AM Lu, H Yan, XX Daly, NL Craik, DJ Jiang, SB Lehrer, RI Blumenthal, R TI theta-defensins prevent HIV-1 Env-mediated fusion by binding gp41 and blocking 6-helix bundle formation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRUNCATED ALPHA-DEFENSINS; ENVELOPE GLYCOPROTEIN; SYNTHETIC PEPTIDE; MONOCLONAL-ANTIBODY; POTENT INHIBITORS; ATOMIC-STRUCTURE; MEMBRANE-FUSION; CORE STRUCTURE; COILED-COIL; TYPE-1 GP41 AB Retrocyclin-1, a 0-defensin, protects target cells from human immunodeficiency virus, type 1 (HIV-1) by preventing viral entry. To delineate its mechanism, we conducted fusion assays between susceptible target cells and effector cells that expressed HIV-1 Env. Retrocyclin-1 (4 mu M) completely blocked fusion mediated by HIV-1 Envs that used CXCR4 or CCR5 but had little effect on cell fusion mediated by HIV-2 and simian immunodeficiency virus Envs. Retrocyclin-1 inhibited HIV-1 Env-mediated fusion without impairing the lateral mobility of CD4, and it inhibited the fusion of CD4-deficient cells with cells bearing CD4-independent HIV-1 Env. Thus, it could act without cross-linking membrane proteins or inhibiting gp120-CD4 interactions. Retrocyclin-1 acted late in the HIV-1 Env fusion cascade but prior to 6-helix bundle formation. Surface plasmon resonance experiments revealed that retrocyclin bound the ectodomain of gp41 with high affinity in a glycan-independent manner and that it bound selectively to the gp41 C-terminal heptad repeat. Native-PAGE, enzyme-linked immunosorbent assay, and CD spectroscopic analyses all revealed that retrocyclin-1 prevented 6-helix bundle formation. This mode of action, although novel for an innate effector molecule, resembles the mechanism of peptidic entry inhibitors based on portions of the gp41 sequence. C1 NCI, CCR Nanobiol Program, NIH, Frederick, MD 21702 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. Univ Cent Florida, Dept Mol Biol & Microbiol, Orlando, FL 32816 USA. New York Blood Ctr, Lindsley F Kimball Res Inst, New York, NY 10021 USA. Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. RP Blumenthal, R (reprint author), NCI, CCR Nanobiol Program, NIH, Frederick, MD 21702 USA. EM blumen@helix.nih.gov RI Daly, Norelle/D-4302-2013; Jiang, Shibo/L-4500-2014; Craik, David/B-1695-2010; OI Craik, David/0000-0003-0007-6796; Gallo, Stephen/0000-0001-6043-2153 FU Intramural NIH HHS; NIAID NIH HHS [AI056921] NR 46 TC 87 Z9 93 U1 0 U2 5 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 JUL 7 PY 2006 VL 281 IS 27 BP 18787 EP 18792 DI 10.1074/jbc.M602422200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 058TK UT WOS:000238687300059 PM 16648135 ER PT J AU Dong, J Tsai-Morris, CH Dufau, ML AF Dong, J Tsai-Morris, CH Dufau, ML TI A novel estradiol/estrogen receptor alpha-dependent transcriptional mechanism controls expression of the human prolactin receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VITAMIN-D-RECEPTOR; NF-KAPPA-B; INTERLEUKIN-6 GENE-EXPRESSION; BREAST-CANCER CELLS; ESTROGEN-RECEPTOR; HORMONE-RECEPTOR; C/EBP-BETA; FACTOR TFIIB; PREINITIATION COMPLEX; PROMOTER UTILIZATION AB Prolactin exerts diverse functions in target tissues through its membrane receptors, and is a potent mitogen in normal and neoplastic breast cells. Estradiol (E-2) induces human prolactin receptor (hPRLR) gene expression through stimulation of its generic promoter (PIII). This study identifies a novel E-2-regulated non-estrogen responsive element-dependent transcriptional mechanism that mediates E-2- induced hPRLR expression. E2 stimulated transcriptional activity in MCF7A(2) cells transfected with PIII lacking an estrogen responsive element, and increased hPRLR mRNA and protein. The abolition of the E2 effect by mutation of Sp1 or C/EBP elements that bind Sp1/Sp3 and C/EBP beta within PIII indicated the cooperation of these transfactors in E-2-induced transcription of the hPRLR. DNA affinity protein assay showed that E-2 induced estrogen receptor alpha (ER alpha) binding to Sp1/Sp3 and C/EBP beta DNA-protein complexes. The ligand-binding domain of ER beta was essential for its physical interaction with C/EBP beta, and E-2 promoted this association, and its DNA binding domain was required for transactivation of PIII. Co-immunoprecipitation studies revealed tethering of C/EBP beta to Sp1 by E-2-activated ER beta. Chromatin immunoprecipitation analysis showed that E-2 induced recruitment of C/EBP beta, ER beta, SRC1, p300, pCAF, TFIIB, and Pol II, with no change in Sp1/Sp3. E-2 also induced promoter-associated acetylation of H3 and H4. These findings demonstrate that an E-2/ER alpha, Sp1, and C/EBP beta complex with recruitment of coactivators and TFIIB and Pol II are required for E-2-activated transcriptional expression of the hPRLR through PIII. Estradiol produced in breast stroma and adipose tissue, which are major sources of estrogen in post-menopausal women, could up-regulate hPRLR gene expression and stimulate breast tumor growth. C1 NICHD, Sect Mol Endocrinol, ERRB, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NICHD, Sect Mol Endocrinol, ERRB, NIH, Bldg 49,Rm 6A-36,49 Convent Dr,MSC 4510, Bethesda, MD 20892 USA. EM dufaum@mail.nih.gov FU Intramural NIH HHS NR 51 TC 53 Z9 53 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 JUL 7 PY 2006 VL 281 IS 27 BP 18825 EP 18836 DI 10.1074/jbc.M512826200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 058TK UT WOS:000238687300063 PM 16651265 ER PT J AU Cardoso, CL Lima, VV Zottis, A Oliva, G Andricopulo, A Wainer, IW Moaddel, R Cass, QB AF Cardoso, CL Lima, VV Zottis, A Oliva, G Andricopulo, A Wainer, IW Moaddel, R Cass, QB TI Development and characterization of an immobilized enzyme reactor (IMER) based on human glyceraldehyde-3-phosphate dehydrogenase for on-line enzymatic studies SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 29th International Symposium on High Performance Liquid Separations and Related Techniques (HPLC 2005) CY JUN 26-30, 2005 CL Stockholm, SWEDEN DE immobilized enzymes; glyceraldehyde-3-phosphate dehydrogenase; IMER; kinetic studies; on-line enzymatic studies ID PERFORMANCE LIQUID-CHROMATOGRAPHY; FUSED-SILICA CAPILLARY; STATIONARY-PHASE; ELECTROPHORESIS; GLYCOLYSIS; RESOLUTION; INHIBITOR; BINDING; PROTEIN; COLUMN AB Immobilized enzyme reactors (IMERs) for on-line enzymatic studies are useful tool to select specific inhibitors and may be used for direct determination of drug-receptor binding interactions and for the rapid on-line screening to identify specific inhibitors. This technique has been shown to increase the stability of enzymes. The enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plays an important role in the life cycle of the Trypanosoma cruzi and it has become a key target in the drug discovery program for Chagas' disease. Crystallographic studies have indicated that there are significant inter-species differences in GAPDH activity and sensitivity. For example the active sites of GAPDH in T cruzi and humans differ by a substitution of ASp(210) (T. cruzi) by Leu(194) in human. Based on this information we initiated the study to develop optimal conditions for the covalent immobilization of the human GAPDH enzyme on a modified capillary support (400 mm x 0.10 nun). The chromatographic separation of NAD from NADH was achieved using a RP-Spherex (R)-diol-OH (10 cm x 0.46 cm, 10 mu m, 100 A) column. By using multidimensional HPLC chromatography system it was possible to investigate the activity and kinetic parameters of the GAPDH-IMER. The values obtained for D-GA3P and NAD were K-m = 3.5 +/- 0.2 mM and 0.75 +/- 0.04 mM, respectively, and were compared with values obtained with the free enzyme. The activity of the immobilized GAPDH has been preserved for over 120 days. (c) 2005 Elsevier B.V. All rights reserved. C1 Univ Fed Sao Carlos, Dept Quim, BR-13565905 Sao Carlos, SP, Brazil. Univ Sao Paulo, Inst Fis & Quim Sao Carlos, Ctr Biotecnol Mol & Estrutural, Sao Paulo, Brazil. NIA, NIH, Baltimore, MD 21224 USA. RP Cass, QB (reprint author), Univ Fed Sao Carlos, Dept Quim, Cx Postal 676, BR-13565905 Sao Carlos, SP, Brazil. EM quezia@dq.ufscar.br RI Andricopulo, Adriano/B-7672-2012; Cass, Quezia/B-8188-2012; Oliva, Glaucius/B-9059-2012; Cardoso, Carmen Lucia/C-4422-2012; Sao Carlos Institute of Physics, IFSC/USP/M-2664-2016 OI Cass, Quezia/0000-0002-6550-1194; Cardoso, Carmen Lucia/0000-0001-6239-6651; NR 29 TC 31 Z9 33 U1 0 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUL 7 PY 2006 VL 1120 IS 1-2 BP 151 EP 157 DI 10.1016/j.chroma.2005.10.063 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 057VN UT WOS:000238623400019 PM 16297925 ER PT J AU Yang, HY Yu, LR Yi, M Lucas, DA Lukes, L Lancaster, M Chan, KC Issaq, HJ Stephens, RM Conrads, TP Veenstra, TD Hunter, KW AF Yang, Haiyan Yu, Li-Rong Yi, Ming Lucas, David A. Lukes, Luanne Lancaster, Mindy Chan, King C. Issaq, Haleem J. Stephens, Robert M. Conrads, Thomas P. Veenstra, Timothy D. Hunter, Kent W. TI Parallel analysis of transcript and translation profiles: Identification of metastasis-related signal pathways differentially regulated by drug and genetic modifications SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE systems biology; biological association network; metastasis; signaling pathway; microarray; isotope-coded affinity tag ID BREAST-CANCER METASTASIS; MAMMARY-TUMOR; EXTRACELLULAR-MATRIX; PROSTATE-CANCER; ACTIVATION; EXPRESSION; PROGRESSION; TRANSDUCER; MICROARRAY; KINASE AB STumor metastasis is a complex multistep process normally involving dysregulation of multiple signal transduction pathways. In this study, we developed a novel approach to efficiently define dysreguated pathways associated with metastasis by comparing global gene and protein expressions of two distinct metastasis-suppressed models. Consequently, we identified common features shared by the two models which are potentially associated with metastasis. The efficiency of metastasis from the highly aggressive polyoma middle T-induced mouse mammary tumors was suppressed by either prolonged caffeine exposure or by breeding the animal to a low metastastic mouse strain. Molecular profiles of the primary tumors from both metastasis-suppressed classes were then derived to identify molecules and pathways that might underlie a common mechanism of metastasis. A number of differentially regulated genes and proteins were identified, including genes encoding basement membrane components, which were inversely related to metastatic efficiency. In addition, the analysis revealed that the Stat signal transduction pathways were potentially associated with metastasis inhibition, as demonstrated by enhanced Stat1 activation, and decreased Stat5 phosphorylation in both genetic and pharmacological modification models. Tumor cells of low-metastatic genotypes also demonstrated anti-apoptotic properties. The common changes of these pathways in all of the metastasis-suppressed systems suggest that they may be critical components in the metastatic cascade, at least in this model system. Our data demonstrate that analysis of common changes in genes and proteins in a metastatic-related context greatly decrease the complexity of data analysis, and may serve as a screening tool to identify biological important factors from large scale data. C1 NCI, Lab Populat Genet, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Lab Proteom & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Hunter, KW (reprint author), NCI, Lab Populat Genet, Ctr Canc Res, 41 Lib Dr, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [Z01 CP010146-06] NR 42 TC 8 Z9 8 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD JUL 7 PY 2006 VL 5 IS 7 BP 1555 EP 1567 DI 10.1021/pr0504283 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 060YP UT WOS:000238838500006 PM 16823962 ER PT J AU Romanyukha, AA Rudnev, SG Sidorov, IA AF Romanyukha, AA Rudnev, SG Sidorov, IA TI Energy cost of infection burden: An approach to understanding the dynamics of host-pathogen interactions SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE infection burden; immune defense; energy cost; adaptation; trade-off ID IMMUNE-RESPONSE; ECOLOGICAL IMMUNOLOGY; DISEASE RESISTANCE; TRADE-OFFS; INFLAMMATION; TUBERCULOSIS; CYTOKINE; DEFENSES; SYSTEM; CELLS AB A mathematical model of long-term immune defense against infection Was used to estimate the energy involved in the principal processes of immune resistance during periods of health and infection. From these values. an optimal level of energy was determined for immune response depending on infection burden. The present findings suggest that weak but prevalent pathogens lead to latent or chronic infection, whereas more virulent but less prevalent pathogens result in acute infection. This energy-based approach offers insight into the mechanisms of immune system adaptation leading to the development of chronic infectious diseases and immune deficiencies. Published by Elsevier Ltd. C1 NCI, Canc Res Ctr, Nanobiol Program, CCR,NIH, Frederick, MD 21702 USA. Russian Acad Sci, Inst Numer Math, Moscow 119991, Russia. RP Sidorov, IA (reprint author), NCI, Canc Res Ctr, Nanobiol Program, CCR,NIH, Bldg 469-110,POB B, Frederick, MD 21702 USA. EM eburg@inm.ras.ru; rudnev@inm.ras.ru; sidorovi@ncifcrf.gov OI Sidorov, Igor/0000-0001-6519-4983 NR 66 TC 24 Z9 28 U1 1 U2 7 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD JUL 7 PY 2006 VL 241 IS 1 BP 1 EP 13 DI 10.1016/j.jtbi.2005.11.004 PG 13 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 059DX UT WOS:000238714600001 PM 16378624 ER PT J AU Krasilnikov, OV Rodrigues, CG Bezrukov, SM AF Krasilnikov, Oleg V. Rodrigues, Claudio G. Bezrukov, Sergey M. TI Single polymer molecules in a protein nanopore in the limit of a strong polymer-pore attraction SO PHYSICAL REVIEW LETTERS LA English DT Article ID ION-CHANNEL; TRANSLOCATION; DYNAMICS; CONDUCTANCE AB The capture and release of single poly(ethylene glycol) molecules by the alpha-Hemolysin pore are observed as time-resolved reversible steps in ion conductance. The capture on rate, inferred from the step frequency, decreases monotonically with polymer size. However, the polymer residence time shows a crossover behavior, first increasing and then decreasing with molecular weight. Our interpretation is that, in the case of polymers which are too large to be accommodated within the pore, the out-of-the-pore part of the molecule pulls on the trapped part, thus acting as an entropic spring. C1 Univ Fed Pernambuco, Dept Biophys & Radiobiol, Recife, PE, Brazil. NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD USA. RP Krasilnikov, OV (reprint author), Univ Fed Pernambuco, Dept Biophys & Radiobiol, Recife, PE, Brazil. FU Intramural NIH HHS NR 26 TC 100 Z9 101 U1 0 U2 8 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD JUL 7 PY 2006 VL 97 IS 1 AR 018301 DI 10.1103/PhysRevLett.97.018301 PG 4 WC Physics, Multidisciplinary SC Physics GA 061CO UT WOS:000238849000061 PM 16907416 ER PT J AU Trifilo, MJ Yajima, T Gu, YS Dalton, N Peterson, KL Race, RE Meade-White, K Portis, JL Masliah, E Knowlton, KU Chesebro, B Oldstone, MBA AF Trifilo, MJ Yajima, T Gu, YS Dalton, N Peterson, KL Race, RE Meade-White, K Portis, JL Masliah, E Knowlton, KU Chesebro, B Oldstone, MBA TI Prion-induced amyloid heart disease with high blood infectivity in transgenic mice SO SCIENCE LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY; DIASTOLIC DYSFUNCTION; SCRAPIE; TRANSFUSION; FAILURE; COMPONENTS; DIAGNOSIS; VARIANT; HUMANS AB We investigated extraneural manifestations in scrapie-infected transgenic mice expressing prion protein lacking the glycophosphatydylinositol membrane anchor. In the brain, blood, and heart, both abnormal protease-resistant prion protein (PrPres) and prion infectivity were readily detected by immunoblot and by inoculation into nontransgenic recipients. The titer of infectious scrapie in blood plasma exceeded 10(7) 50% infectious doses per milliliter. The hearts of these transgenic mice contained PrPres-positive amyloid deposits that led to myocardial stiffness and cardiac disease. C1 Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Scripps Res Inst, Dept Mol & Integrat Neurosci, Viral Immunobiol Lab, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Infectol, Viral Immunobiol Lab, La Jolla, CA 92037 USA. NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. RP Knowlton, KU (reprint author), Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. EM kknowlton@ucsd.edu; bchesebro@niaid.nih.gov; mbaobo@scripps.edu FU NHLBI NIH HHS [5R01HL66424-04]; NIA NIH HHS [P01 AG004342]; NINDS NIH HHS [NS041219-05]; PHS HHS [AGO4342] NR 27 TC 39 Z9 41 U1 0 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 7 PY 2006 VL 313 IS 5783 BP 94 EP 97 DI 10.1126/science.1128635 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 061DA UT WOS:000238850200039 PM 16825571 ER PT J AU Guerreiro, RJ Bras, JM Santana, I Januario, C Santiago, B Morgadinho, AS Ribeiro, MH Hardy, J Singleton, A Oliveira, C AF Guerreiro, Rita J. Bras, Jose M. Santana, Isabel Januario, Cristina Santiago, Beatriz Morgadinho, Ana S. Ribeiro, Maria H. Hardy, John Singleton, Andrew Oliveira, Catarina TI Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort SO BMC NEUROLOGY LA English DT Article ID HEMOCHROMATOSIS GENE HFE; OXIDATIVE STRESS; CLINICAL-DIAGNOSIS; ALLELE; ONSET; EPSILON-4; AGE AB Background: Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD) and Parkinson diseases (PD). Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID: 4886), and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results. Methods: Genotypes were analysed for the two most common variants of HFE in a series of 130 AD, 55 Mild Cognitive Impairment (MCI) and 132 PD patients. Additionally, a series of 115 healthy age-matched controls was also screened. Results: A statistically significant association was found in the PD group when compared to controls, showing that the presence of the C282Y variant allele may confer higher risk for developing the disease. Conclusion: Taken together these results suggest that the common variants in HFE may be a risk factor for PD, but not for AD in the Portuguese population. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal. Univ Coimbra Hosp, Neurol Serv, Coimbra, Portugal. RP Guerreiro, RJ (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM ritajoao@gmail.com; brasjm@gmail.com; isabelsantana@huc.min-saude.pt; cristinajanuario@gmail.com; ubaldo2500@hotmail.com; anamorgadinho@portugalmail.pt; mhgarrucho@huc.min-saude.pt; hardyj@mail.nih.gov; singleta@mail.nih.gov; catarina@cnc.cj.uc.pt RI Singleton, Andrew/C-3010-2009; Bras, Jose/D-3366-2009; Oliveira, Catarina/F-3685-2010; Bras, Jose/A-1428-2011; Hardy, John/C-2451-2009; Guerreiro, Rita/A-1327-2011; OI Oliveira, Catarina/0000-0001-6942-4328; Santana, Isabel/0000-0002-8114-9434 FU Medical Research Council [G0701075] NR 25 TC 46 Z9 48 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD JUL 6 PY 2006 VL 6 AR 24 DI 10.1186/1471-2377-6-24 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 074FZ UT WOS:000239799400001 PM 16824219 ER PT J AU Wang, XP Deavers, M Patenia, R Bassett, RL Mueller, P Ma, Q Wang, E Freedman, RS AF Wang, Xipeng Deavers, Michael Patenia, Rebecca Bassett, Roland L., Jr. Mueller, Peter Ma, Qing Wang, Ena Freedman, Ralph S. TI Monocyte/macrophage and T-cell infiltrates in peritoneum of patients with ovarian cancer or benign pelvic disease SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID LYSOPHOSPHATIDIC ACID; MALIGNANT OVARY; ASCITIC FLUID; GROWTH-FACTOR; IN-VIVO; CARCINOMA; TUMOR; INTERLEUKIN-8; EXPRESSION; IDENTIFICATION AB Background: We previously showed that tumor-free peritoneum of patients with epithelial ovarian cancer (EOC) exhibited enhanced expression of several inflammatory response genes compared to peritoneum of benign disease. Here, we examined peritoneal inflammatory cell patterns to determine their concordance with selected enhanced genes. Methods: Expression patterns of selected inflammatory genes were mined from our previously published data base. Bilateral pelvic peritoneal and subjacent stromal specimens were obtained from 20 women with EOC and 7 women with benign pelvic conditions. Sections were first stained by indirect immunoperoxidase and numbers of monocytes/ macrophages (MO/MA), T cells, B cells, and NK cells counted. Proportions of CD68+ cells and CD3+ cells that coexpressed MO/MA differentiation factors (CD163, CCR1, CXCR8, VCAM1, and phosphorylated cytosolic phospholipase A(2) [pcPLA(2)]), which had demonstrated expression in EOC peritoneal samples, were determined by multicolor immunofluorescence. Results: MO/MA were present on both sides of the pelvic peritoneum in EOC patients, with infiltration of the subjacent stroma and mesothelium. CD68+ MO/MA, the most commonly represented population, and CD3+ T cells were present more often in EOC than in benign pelvic tumors. NK cells, B cells, and granulocytes were rare. CXCL8 (IL-8) and the chemokine receptor CCR1 were coexpressed more frequently on MO/MA than on CD3+ cells contrasting with CD68+/CD163+ cells that coexpressed CXCL8 less often. An important activated enzyme in the eicosanoid pathway, pcPLA(2), was highly expressed on both CD68+ and CD163+ cells. The adherence molecule Vascular Cell Adhesion Molecule-1 (VCAM1) was expressed on CD31+ endothelial cells and on a proportion of CD68+ MO/MA but rarely on CD3+ cells. Conclusion: The pelvic peritoneum in EOC exhibits a general pattern of chronic inflammation, represented primarily by differentiated MO/MA, and distinct from that in benign conditions concordant with previous profiling results. C1 Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. Shanghai Tiao Tong Univ, Renji Hosp, Dept Obstet & Gynecol, Shanghai, Peoples R China. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Biostat & Appl Math, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Blood & Marrow Transplantat, Houston, TX 77030 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Freedman, RS (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM xipengwang@yahoo.com; mdeavers@mdanderson.org; rpatenia@mdanderson.org; rlbasset@mdanderson.org; pm@odin.mdacc.tmc.edu; qma@mdanderson.org; ewang@cc.nih.gov; rfreedma@mdanderson.org NR 37 TC 29 Z9 35 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUL 6 PY 2006 VL 4 AR 30 DI 10.1186/1479-5876-4-30 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 074IO UT WOS:000239806100002 PM 16824216 ER PT J AU Wysocka, J Swigut, T Xiao, H Milne, TA Kwon, SY Landry, J Kauer, M Tackett, AJ Chait, BT Badenhorst, P Wu, C Allis, CD AF Wysocka, J Swigut, T Xiao, H Milne, TA Kwon, SY Landry, J Kauer, M Tackett, AJ Chait, BT Badenhorst, P Wu, C Allis, CD TI A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling SO NATURE LA English DT Article ID TRANSCRIPTION FACTOR; COMPLEX NURF; METHYLATION; H3; BINDING; METHYLTRANSFERASE; ACETYLATION; ASSOCIATION; BROMODOMAIN; DOMAIN AB Lysine methylation of histones is recognized as an important component of an epigenetic indexing system demarcating transcriptionally active and inactive chromatin domains. Trimethylation of histone H3 lysine 4 (H3K4me3) marks transcription start sites of virtually all active genes(1-4). Recently, we reported that the WD40-repeat protein WDR5 is important for global levels of H3K4me3 and control of HOX gene expression(5). Here we show that a plant homeodomain (PHD) finger of nucleosome remodelling factor (NURF), an ISWI-containing ATP-dependent chromatin-remodelling complex, mediates a direct preferential association with H3K4me3 tails. Depletion of H3K4me3 causes partial release of the NURF subunit, BPTF (bromodomain and PHD finger transcription factor), from chromatin and defective recruitment of the associated ATPase, SNF2L (also known as ISWI and SMARCA1), to the HOXC8 promoter. Loss of BPTF in Xenopus embryos mimics WDR5 loss-of-function phenotypes, and compromises spatial control of Hox gene expression. These results strongly suggest that WDR5 and NURF function in a common biological pathway in vivo, and that NURF-mediated ATP-dependent chromatin remodelling is directly coupled to H3K4 trimethylation to maintain Hox gene expression patterns during development. We also identify a previously unknown function for the PHD finger as a highly specialized methyl-lysine-binding domain. C1 Rockefeller Univ, Lab Chromatin Biol, New York, NY 10021 USA. Rockefeller Univ, Lab Mol Vertebrate Embryol, New York, NY 10021 USA. Rockefeller Univ, Lab Mass Spectrometry & Gaseous Ion Chem, New York, NY 10021 USA. NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20814 USA. Univ Birmingham, Inst Biomed Res, Birmingham B15 2TT, W Midlands, England. RP Wu, C (reprint author), Rockefeller Univ, Lab Chromatin Biol, 1230 York Ave, New York, NY 10021 USA. EM carlwu@helix.nih.gov RI Kwon, So Yeon/M-5625-2014; Milne, Tom/E-1872-2016; OI Kwon, So Yeon/0000-0002-8490-9101; Milne, Tom/0000-0002-0413-4271; Badenhorst, Paul/0000-0002-2542-0250 FU Biotechnology and Biological Sciences Research Council [BB/D522470/1]; Intramural NIH HHS NR 28 TC 635 Z9 654 U1 6 U2 74 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 6 PY 2006 VL 442 IS 7098 BP 86 EP 90 DI 10.1038/nature04815 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 059HS UT WOS:000238724500042 PM 16728976 ER PT J AU Dorsey, SG Renn, CL Carim-Todd, L Barrick, CA Bambrick, L Krueger, BK Ward, CW Tessarollo, L AF Dorsey, Susan G. Renn, Cynthia L. Carim-Todd, Laura Barrick, Colleen A. Bambrick, Linda Krueger, Bruce K. Ward, Christopher W. Tessarollo, Lino TI In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model SO NEURON LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; MEDIATING BDNF MODULATION; NEUROTROPHIC FACTOR; NERVOUS-SYSTEM; DOWN-SYNDROME; SIGNAL-TRANSDUCTION; BRAIN; HIPPOCAMPAL; SURVIVAL; MICE AB Imbalances in neurotrophins or their high-affinity Trk receptors have long been reported in neurodegenerative diseases. However, a molecular link between these gene products and neuronal cell death has not been established. In the trisomy 16 (Ts16) mouse there is increased apoptosis in the cortex, and hippocampal neurons undergo accelerated cell death that cannot be rescued by administration of brain-derived neurotrophic factor (BDNF). Ts16 neurons have normal levels of the TrkB tyrosine kinase receptor but an upregulation of the TrkB.T1 truncated receptor isoform. Here we show that restoration of the physiological level of the TrkB.T1 receptor by gene targeting rescues Ts16 cortical cell and hippocampal neuronal death. Moreover, it corrects resting Ca2+ levels and restores BDNF-induced intracellular signaling mediated by full-length TrkB in Ts16 hippocampal neurons. These data provide a direct link between neuronal cell death and abnormalities in Trk neurotrophin receptor levels. C1 NCI, Ctr Canc Res, Mouse Canc Genet Program, Neural Dev Grp, Frederick, MD 21702 USA. Univ Maryland, Sch Med, Sch Nursing, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. RP Dorsey, SG (reprint author), NCI, Ctr Canc Res, Mouse Canc Genet Program, Neural Dev Grp, Frederick, MD 21702 USA. EM sdorsey@son.umaryland.edu; tessarol@ncifcrf.gov FU Intramural NIH HHS; NIAMS NIH HHS [K01-AR02177]; NINDS NIH HHS [R01NS40492]; NINR NIH HHS [K22NR00174] NR 49 TC 57 Z9 59 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 6 PY 2006 VL 51 IS 1 BP 21 EP 28 DI 10.1016/j.neuron.2006.06.009 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 063RQ UT WOS:000239037700007 PM 16815329 ER PT J AU Diatchenko, L Anderson, AD Slade, GD Fillingim, RB Shabalina, SA Higgins, TJ Sama, S Inna, B Goldman, D Max, MB Weir, BS Maixner, W AF Diatchenko, Luda Anderson, Amy D. Slade, Gary D. Fillingim, Roger B. Shabalina, Svetlana A. Higgins, Tomas J. Sama, Swetha Inna, Belfer Goldman, David Max, Mitchell B. Weir, Bruce S. Maixner, William TI Three major haplotypes of the beta 2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE adrenergic receptor beta(2); haplotype; SNPs; chronic pain; blood pressure; somatization; depression; anxiety; negative moods ID BETA-ADRENERGIC-RECEPTORS; TEMPOROMANDIBULAR DISORDERS; GENE-EXPRESSION; REGULATORY SYSTEMS; MYOFASCIAL PAIN; LEADER CISTRON; POLYMORPHISMS; HYPERTENSION; SENSITIVITY; DEPRESSION AB Adrenergic receptor beta(2) (ADR132) is a primary target for epinephrine. It plays a critical role in mediating physiological and psychological responses to environmental stressors. Thus, functional genetic variants of ADRB2 will be associated with a complex array of psychological and physiological phenotypes. These genetic variants should also interact with environmental factors such as physical or emotional stress to produce a phenotype vulnerable to pathological states. In this study, we determined whether common genetic variants of ADRB2 contribute to the development of a common chronic pain condition that is associated with increased levels of psychological distress and low blood pressure, factors which are strongly influenced by the adrenergic system. We genotyped 202 female subjects and examined the relationships between three major ADRB2 haplotypes and psychological factors, resting blood pressure, and the risk of developing a chronic musculoskeletal pain condition-Temporomandibular Joint Disorder (TMD). We propose that the first haplotype codes for lower levels of ADRB2 expression, the second haplotype codes for higher ADRB2 expression, and the third haplotype codes for higher receptor expression and rapid agonist-induced internalization. Individuals who carried one haplotype coding for high and one coding for low ADRB2 expression displayed the highest positive psychological traits, had higher levels of resting arterial pressure, and were about 10 times less likely to develop TMD. Thus, our data suggest that either positive or negative imbalances in ADRB2 function increase the vulnerability to chronic pain conditions such as TMD through different etiological pathways that imply the need for tailored treatment options. (c) 2006 Wiley-Liss, Inc. C1 Univ N Carolina, Ctr Neurosensory Disorders, Chapel Hill, NC 27599 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Adelaide, Australian Res Ctr Populat Oral Hlth, Adelaide, SA, Australia. Univ Florida, Coll Dent, Gainesville, FL USA. NCBI, Computat Biol Branch, NIH, Bethesda, MD USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. NIDCR, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD USA. RP Diatchenko, L (reprint author), Univ N Carolina, Ctr Neurosensory Disorders, Columbia St,CB 7455,2120 Old Dent Bld, Chapel Hill, NC 27599 USA. EM lbdiatch@email.unc.edu RI Shabalina, Svetlana/N-8939-2013; Goldman, David/F-9772-2010 OI Shabalina, Svetlana/0000-0003-2272-7473; Goldman, David/0000-0002-1724-5405 FU NIDCR NIH HHS [R01 DE016558-04, DE016558, DE07509, P01 DE007509-150009, R01 DE016558]; NINDS NIH HHS [NS045688, P01 NS045685, P01 NS045685-05] NR 73 TC 109 Z9 114 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JUL 5 PY 2006 VL 141B IS 5 BP 449 EP 462 DI 10.1002/ajmg.b.30324 PG 14 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 057VC UT WOS:000238622300004 PM 16741943 ER PT J AU Genovesio, A Brasted, PJ Wise, SP AF Genovesio, Aldo Brasted, Peter J. Wise, Steven P. TI Representation of future and previous spatial goals by separate neural populations in prefrontal cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE behavioral neurophysiology; strategies; prospective memory; rules; frontal lobe; output monitoring ID WORKING-MEMORY; NEURONAL-ACTIVITY; FRONTAL-CORTEX; DELAYED ALTERNATION; TEMPORAL-ORDER; UNIT-ACTIVITY; TASK; MONKEY; INFORMATION; MAINTENANCE AB The primate prefrontal cortex plays a central role in choosing goals, along with a wide variety of additional functions, including short-term memory. In the present study, we examined neuronal activity in the prefrontal cortex as monkeys used abstract response strategies to select one of three spatial goals, a selection that depended on their memory of the most recent previous goal. During each trial, the monkeys selected a future goal on the basis of events from the previous trial, including both the symbolic visual cue that had appeared on that trial and the previous goal that the monkeys had selected. When a symbolic visual cue repeated from the previous trial, the monkeys stayed with their previous goal as the next ( future) goal; when the cue changed, the monkeys shifted from their previous goal to one of the two remaining locations as their future goal. We found that prefrontal neurons had activity that reflected either previous goals or future goals, but only rarely did individual cells reflect both. This finding suggests that essentially separate neural networks encode these two aspects of spatial information processing. A failure to distinguish previous and future goals could lead to two kinds of maladaptive behavior. First, wrongly representing an accomplished goal as still pending could cause perseveration or compulsive checking, two disorders commonly attributed to dysfunction of the prefrontal cortex. Second, mistaking a pending goal as already accomplished could cause the failures of omission that occur commonly in dementia. C1 NIMH, Lab Syst Neurosci, NIH, Bethesda, MD 20892 USA. RP Wise, SP (reprint author), NIMH, Lab Syst Neurosci, NIH, Bldg 49,Room B1EE17,49 Convent Dr,MSC 4401, Bethesda, MD 20892 USA. EM stevenwise@mail.nih.gov FU Intramural NIH HHS; NIMH NIH HHS [Z01 MH001092, Z01 MH001092-27, Z01MH-01092-27] NR 68 TC 59 Z9 60 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 5 PY 2006 VL 26 IS 27 BP 7305 EP 7316 DI 10.1523/JNEUROSCI.0699-06.2006 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 060LW UT WOS:000238804700025 PM 16822988 ER PT J AU Ying, JF Bax, A AF Ying, JF Bax, A TI 2 '-hydroxyl proton positions in helical RNA from simultaneously measured heteronuclear scalar couplings and NOEs SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NMR-SPECTROSCOPY; ASSIGNMENT; ORIENTATION; RESONANCE; HYDRATION C1 Natl Inst Diabet & Digest & Kidney Dis, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov FU Intramural NIH HHS NR 16 TC 9 Z9 9 U1 0 U2 2 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 JUL 5 PY 2006 VL 128 IS 26 BP 8372 EP 8373 DI 10.1021/ja0606226 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 057IR UT WOS:000238590000003 PM 16802782 ER PT J AU Tronko, MD Howe, GR Bogdanova, TI Bouville, AC Epstein, OV Brill, AB Likhtarev, IA Fink, DJ Markov, VV Greenebaum, E Oliinyk, VA Masnyk, IJ Shpak, VM McConnell, RJ Tereshchenko, VP Robbins, J Zvinchuk, OV Zablotska, LB Hatch, M Luckyanov, NK Ron, E Thomas, TL Voilleque, PG Beebe, GW AF Tronko, Mykola D. Howe, Geoffrey R. Bogdanova, Tetyana I. Bouville, Andre C. Epstein, Ovsiy V. Brill, Aaron B. Likhtarev, Illya A. Fink, Daniel J. Markov, Valentyn V. Greenebaum, Ellen Oliinyk, Valery A. Masnyk, Ihor J. Shpak, Victor M. McConnell, Robert J. Tereshchenko, Valery P. Robbins, Jacob Zvinchuk, Oleksandr V. Zablotska, Lydia B. Hatch, Maureen Luckyanov, Nickolas K. Ron, Elaine Thomas, Terry L. Voilleque, Paul G. Beebe, Gilbert W. TI A cohort study of thyroid cancer and other thyroid diseases after the chornobyl accident: Thyroid cancer in Ukraine detected during first screening SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RISK; RADIATION; EXPOSURE; BYELARUS; IODINE; CHILDHOOD; I-131 AB Background. The Chornobyl accident in 1986 exposed thousands of people to radioactive iodine isotopes, particularly 1311; this exposure was followed by a large increase in thyroid cancer among those exposed as children and adolescents, particularly in Belarus, the Russian Federation, and Ukraine. Here we report the results of the first cohort study of thyroid cancer among those exposed as children and adolescents following the Chornobyl accident. Methods: A cohort of 32 385 individuals younger than 18 years of age and resident in the most heavily contaminated areas in Ukraine at the time of the accident was invited to be screened for any thyroid pathology by ultrasound and palpation between 1998 and 2000; 13 127 individuals (44%) were actually screened. Individual estimates of radiation dose to the thyroid were available for all screenees based on radioactivity measurements made shortly after the accident and on interview data. The excess relative risk per gray (Gy) was estimated using individual doses and a linear excess relative risk model. Results: Forty-five pathologically confirmed cases of thyroid cancer were found during the 1998-2000 screening. Thyroid cancer showed a strong, monotonic, and approximately linear relationship with individual thyroid dose estimate (P <.001), yielding an estimated excess relative risk of 5.25 per Gy (95% confidence interval [CI] = 1.70 to 27.5). Greater age at exposure was associated with decreased risk of radiation-related thyroid cancer, although this interaction effect was not statistically significant. Conclusion: Exposure to radioactive iodine was strongly associated with increased risk of thyroid cancer among those exposed as children and adolescents. In the absence of Chornobyl radiation, 11.2 thyroid cancer cases would have been expected compared with the 45 observed, i.e., a reduction of 75% (95% CI = 50% to 93%). The study also provides quantitative risk estimates minimally confounded by any screening effects. Caution should be exercised in generalizing these results to any future similar accidents because of the potential differences in the nature of the radioactive iodines involved, the duration and temporal patterns of exposures, and the susceptibility of the exposed population. C1 Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. Inst Endocrinol & Metab, Kiev, Ukraine. Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. Vanderbilt Univ, Sch Med, Dept Radiat & Radiol Sci, Nashville, TN 37212 USA. Ukraine Acad Med Sci, Sci Ctr Radiat Med, Kiev, Ukraine. Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA. Columbia Univ, Coll Phys & Surg, Thyroid Clin, Dept Med, New York, NY USA. NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. MJP Risk Assessment Inc, Denver, CO USA. RP Howe, GR (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, 722 W 168th St,Rm 1104, New York, NY 10032 USA. EM gh68@columbia.edu RI Brill, Aaron/H-3732-2014; OI Brill, Aaron/0000-0001-7538-086X; Zvinchuk, Alexander/0000-0001-7163-1932 FU NCI NIH HHS [N01-CP-21178] NR 33 TC 119 Z9 130 U1 1 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 5 PY 2006 VL 98 IS 13 BP 897 EP 903 DI 10.1093/jnci/djj244 PG 7 WC Oncology SC Oncology GA 060QX UT WOS:000238817800007 PM 16818853 ER PT J AU Boersma, BJ Howe, TM Goodman, JE Yfantis, HG Lee, DH Chanock, SJ Ambs, S AF Boersma, Brenda J. Howe, Tiffany M. Goodman, Julie E. Yfantis, Harry G. Lee, Dong H. Chanock, Stephen J. Ambs, Stefan TI Association of breast cancer outcome with status of p53 and MDM2 SNP309 SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SINGLE NUCLEOTIDE POLYMORPHISM; SAMPLE-SIZE CALCULATIONS; LUNG-CANCER; AFRICAN-AMERICANS; MUTATIONS; PROGNOSIS; EXPRESSION; PATHWAY; PROTEIN; TP53 AB Background. A common single-nucleotide polymorphism (SNP) in the promoter region of the MDM2 gene, known as T-309G and referred to as SNP309 for this study, leads to increased expression of Mdm2 protein and attenuated function of the p53 tumor suppressor protein. We investigated whether genetic variants in MDM2 were associated with breast cancer incidence and survival and whether the variant status could interact with the tumor p53 status to modify breast cancer survival. Methods: We used multivariable logistic and Cox regression analyses to study the relationship of SNP309 status and the status of a second MDM2 SNP in exon 12 at codon 354 (SNP354) with breast cancer incidence and with disease-specific survival among 293 case patients and 317 cancer-free control subjects. Survival analysis included 248 of the 293 case patients who had known tumor p53 status. All statistical tests were two-sided. Results: We did not observe an association between SNP309 status and breast cancer incidence in the unstratified analysis, but we did find a statistically significant association between SNP354 status and breast cancer incidence (odds ratio = 3.34, 95% confidence interval [CI] = 1.88 to 5.93). We also discovered a statistically significant interaction between SNP309 status and tumor p53 expression for breast cancer survival (P-interaction =.002). Among homozygous carriers of the common MDM2 SNP309 allele (T/T), a mutant p53 status (risk ratio [RR] of death = 2.33, 95% CI = 1.08 to 5.03) and aberrant p53 protein expression (RR = 2.61, 95% CI = 1.22 to 5.57) in breast tumors were associated with poor survival. Tumor p53 status was not associated with breast cancer survival among carriers of the variant MDM2 SNP309 allele (G/T or G/G), which is consistent with a dominant effect of the variant allele. Conclusion: A strong interaction between SNP309 status and tumor p53 status appears to modify the association between p53 status and breast cancer survival. C1 NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. Gradient Corp, Cambridge, MA 02138 USA. Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. NCI, Pediat Oncol Branch, Sect Genom Variat, Bethesda, MD 20892 USA. RP Ambs, S (reprint author), NCI, Human Carcinogenesis Lab, Bldg 37-Rm 3050B, Bethesda, MD 20892 USA. EM amnbss@mail.nill.gov RI Boersma, Brenda/A-9270-2009 OI Boersma, Brenda/0000-0002-8992-2735 FU Intramural NIH HHS NR 37 TC 107 Z9 107 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 5 PY 2006 VL 98 IS 13 BP 911 EP 919 DI 10.1093/jnci/djj245 PG 9 WC Oncology SC Oncology GA 060QX UT WOS:000238817800009 PM 16818855 ER PT J AU Moslehi, R Devesa, SS Schairer, C Fraumeni, JF AF Moslehi, Roxana Devesa, Susan S. Schairer, Catherine Fraumeni, Joseph F., Jr. TI Rapidly increasing incidence of ocular non-Hodgkin lymphoma SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID B-CELL LYMPHOMA; CHLAMYDIA-PSITTACI; ADNEXAL LYMPHOMA; CANCER REGISTRY; UNITED-STATES; TRENDS; ASSOCIATION; INFECTION; CLASSIFICATION; POPULATION AB A recent report suggesting that ocular adnexal non-Hodgkin lymphoma (NHL) may be related to Chlamydia psittaci infection underscores the need for reliable epidemiologic data for this malignancy. We examined population-based incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program. During 1992-2001 in the 12 SEER areas, ocular (i.e., eye and adnexa) NHL rates per 100000 person-years for both sexes were highest among Asians/Pacific Islanders, lower in whites, and lower still in blacks. Incidence increased with advancing age and showed little difference by sex, in contrast to other (extranodal and nodal) NHLs, which occurred predominantly in males. From 1975-2001, there was a rapid and steady increase in incidence of ocular NHL, with annual increases of 6.2% and 6.5% among white males and females, respectively, with no evidence of peaking. By contrast, other NHLs showed evidence of peaking in recent years. The distinctive patterns of ocular NHL call for further studies to identify risk factors and mechanisms, including the potential role of C psittaci or other infections. C1 NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD 20852 USA. RP Moslehi, R (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, 6120 Execut Blvd,EPS 8047, Rockville, MD 20852 USA. EM moslehir@mail.nih.gov FU Intramural NIH HHS NR 29 TC 73 Z9 80 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 5 PY 2006 VL 98 IS 13 BP 936 EP 939 DI 10.1093/jnci/djj248 PG 4 WC Oncology SC Oncology GA 060QX UT WOS:000238817800012 PM 16818858 ER PT J AU Richards, JS MacDonald, NJ Eisen, DP AF Richards, Jack S. MacDonald, Nicholas J. Eisen, Damon P. TI Limited polymorphism in Plasmodium falciparum ookinete surface antigen, von Willebrand factor A domain-related protein from clinical isolates SO MALARIA JOURNAL LA English DT Article ID TRANSMISSION-BLOCKING VACCINE; MALARIA TRANSMISSION; MINIMAL VARIATION; SEXUAL STAGE; CANDIDATE; PFS28; ANTIBODIES; PVS28 AB Background: As malaria becomes increasingly drug resistant and more costly to treat, there is increasing urgency to develop effective vaccines. In comparison to other stages of the malaria lifecycle, sexual stage antigens are under less immune selection pressure and hence are likely to have limited antigenic diversity. Methods: Clinical isolates from a wide range of geographical regions were collected. Direct sequencing of PCR products was then used to determine the extent of polymorphisms for the novel Plasmodium falciparum sexual stage antigen von Willebrand Factor A domain-related Protein ( PfWARP). These isolates were also used to confirm the extent of diversity of sexual stage antigen Pfs28. Results: PfWARP was shown to have non-synonymous substitutions at 3 positions and Pfs28 was confirmed to have a single non-synonymous substitution as previously described. Conclusion: This study demonstrates the limited antigenic diversity of two prospective P. falciparum sexual stage antigens, PfWARP and Pfs28. This provides further encouragement for the proceeding with vaccine trials based on these antigens. C1 Royal Melbourne Hosp, Victorian Infect Dis Serv, Melbourne, Vic 3050, Australia. NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD USA. RP Richards, JS (reprint author), Royal Melbourne Hosp, Victorian Infect Dis Serv, Grattan St, Melbourne, Vic 3050, Australia. EM richards@wehi.edu.au; nmacdonald@niaid.nih.gov; damon.eisen@mh.org.au OI Richards, Jack/0000-0001-5786-6989 NR 20 TC 7 Z9 7 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUL 5 PY 2006 VL 5 AR 55 DI 10.1186/1475-2875-5-55 PG 5 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 074IZ UT WOS:000239807200001 PM 16820064 ER PT J AU Dahl, KN Scaffidi, P Islam, MF Yodh, AG Wilson, KL Misteli, T AF Dahl, Kris Noel Scaffidi, Paola Islam, Mohammad F. Yodh, Arjun G. Wilson, Katherine L. Misteli, Tom TI Distinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford progeria syndrome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE laminopathy; mechanics; nucleus; photobleaching; micropipette; aspiration ID MAMMALIAN-CELLS; BUILDING-BLOCKS; PORE COMPLEXES; ENVELOPE; ARCHITECTURE; DISEASE; MECHANOTRANSDUCTION; INTEGRITY; PROTEINS; MODEL AB The nuclear lamina is a network of structural filaments, the A and B type lamins, located at the nuclear envelope and throughout the nucleus. Lamin filaments provide the nucleus with mechanical stability and support many basic activities, including gene regulation. Mutations in LMNA, the gene encoding A type lamins, cause numerous human diseases, including the segmental premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Here we show that structural and mechanical properties of the lamina are altered in HGPS cells. We demonstrate by live-cell imaging and biochemical analysis that lamins A and C become trapped at the nuclear periphery in HGPS patient cells. Using micropipette aspiration, we show that the lamina in HGPS cells has a significantly reduced ability to rearrange under mechanical stress. Based on polarization microscopy results, we suggest that the lamins are disordered in the healthy nuclei, whereas the lamins in HGPS nuclei form orientationally ordered microdomains. The reduced deformability of the HGPS nuclear lamina possibly could be due to the inability of these orientationally ordered microdomains to dissipate mechanical stress. Surprisingly, intact HGPS cells exhibited a degree of resistance to acute mechanical stress similar to that of cells from healthy individuals. Thus, in contrast to the nuclear fragility seen in Imna null cells, the lamina network in HGPS cells has unique mechanical properties that might contribute to disease phenotypes by affecting responses to mechanical force and misregulation of mechanosensitive gene expression. C1 Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Penn, Dept Phys & Astron, Philadelphia, PA 19104 USA. RP Dahl, KN (reprint author), Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA. EM krisdahl@cmu.edu RI Islam, Mohammad/B-7211-2011; Ladoux, Benoit/A-9879-2013 OI Islam, Mohammad/0000-0001-9253-3709; FU Intramural NIH HHS; NIGMS NIH HHS [1F32 GM074502, F32 GM074502, R01 GM048646, R01GM48646] NR 33 TC 177 Z9 180 U1 2 U2 21 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 JUL 5 PY 2006 VL 103 IS 27 BP 10271 EP 10276 DI 10.1073/pnas.0601058103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 064DM UT WOS:000239069400023 PM 16801550 ER PT J AU Devesa, V Adair, BM Liu, J Waalkes, MP Diwan, BA Styblo, M Thomas, DJ AF Devesa, Vicenta Adair, Blakely M. Liu, Jie Waalkes, Michael P. Diwan, Bhalchandra A. Styblo, Miroslav Thomas, David J. TI Arsenicals in maternal and fetal mouse tissues after gestational exposure to arsenite SO TOXICOLOGY LA English DT Article DE arsenic; mouse; in utero; metabolism; transplacental carcinogenesis ID DIMETHYLARSINIC ACID; DRINKING-WATER; ANIMAL-MODELS; IN-UTERO; DEPENDENT DISPOSITION; CACODYLIC ACID; MICE; METABOLISM; CARCINOGENESIS; METHYLATION AB Exposure of pregnant C3H/HeNCR mice to 42.5- or 85-ppm of arsenic as sodium arsenite in drinking water between days 8 and 18 of gestation markedly increases tumor incidence in their offspring. In the work reported here. distribution of inorganic arsenic and its metabolites, methyl arsenic and dimethyl arsenic. were determined in maternal and fetal tissues collected on gestational day 18 of these exposure regimens. Tissues were collected from three females and from associated fetuses exposed to each dosage level. Concentrations of total speciated arsenic (sum of inorganic, methyl, and dimethyl arsenic) were higher in maternal tissues than in placenta and fetal tissues; total speciated arsenic concentration in placenta exceeded those in fetal tissues. significant dosage-dependent (42.5 ppm versus 85 ppm of arsenite in drinking water) differences were found in total speciated arsenic concentrations in maternal lung (p < 0.01) and liver (p < 0.001). Total speciated arsenic concentrations did not differ significantly between dosage levels for maternal blood or for fetal lung. liver. and blood. or for placenta. Percentages of inorganic. methyl. or dimethyl arsenic in maternal or fetal tissues were not dosage-dependent. Over the range of total speciated arsenic concentrations in most maternal and fetal tissues, dimethyl arsenic was the most abundant arsenical. However. in maternal liver at the highest total speciated arsenic concentration, inorganic arsenic was the most abundant arsenical. suggesting that a high tissue burden of arsenic affected formation or retention of methylated species in this organ. Tissue concentration-dependent processes Could affect kinetics of transfer of inorganic arsenic or its metabolites from mother to fetus. Published by Elsevier Ireland Ltd. C1 US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Expt Toxicol Div, Res Triangle Pk, NC 27711 USA. Univ N Carolina, Ctr Environm Med Asthma & Lung Biol, Chapel Hill, NC USA. NIEHS, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. SAIC Frederick, Basic Res Program, Frederick, MD USA. Univ N Carolina, Sch Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA. RP Thomas, DJ (reprint author), US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Expt Toxicol Div, Mail Drop B143-1,109 Alexander Dr, Res Triangle Pk, NC 27711 USA. EM thomas.david@epa.gov RI Devesa, Vicenta/I-2102-2012 OI Devesa, Vicenta/0000-0002-1988-2985 FU FIC NIH HHS [R03 TW007057, R03 TW007057-02]; Intramural NIH HHS; NCI NIH HHS [N01CO12400, N01-CO-12400]; NIDDK NIH HHS [DK 56350, P30 DK056350]; NIEHS NIH HHS [ES09941, R01 ES010845, R01 ES010845-05] NR 54 TC 41 Z9 43 U1 0 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 JUL 5 PY 2006 VL 224 IS 1-2 BP 147 EP 155 DI 10.1016/j.tox.2006.04.041 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 063PH UT WOS:000239031400016 PM 16753250 ER PT J AU Ou, W Silver, J AF Ou, W Silver, J TI Role of protein disulfide isomerase and other thiol-reactive proteins in HIV-1 envelope protein-mediated fusion SO VIROLOGY LA English DT Article DE HIV-1; fusion; protein disulfide isomerase; thioredoxin siRNA ID HUMAN-IMMUNODEFICIENCY-VIRUS; ESCHERICHIA-COLI; INHIBITOR T-20; SOLUBLE CD4; LIPID RAFTS; CELL-FUSION; TYPE-1; ENTRY; ENV; CHOLESTEROL AB Cell-surface protein disulfide isomerase (PDI) has been proposed to promote disulfide bond rearrangements in HIV-1 envelope protein (Env) that accompany Env-mediated fusion. We evaluated the role of PDI in ways that have not been previously tested by downregulating PDI with siRNA and by overexpressing wild-type or variant forms of PDI in transiently and stably transfected cells. These manipulations, as well as treatment with anti-PDI antibodies, had only small effects on infection or cell fusion mediated by NL4-3 or AD8 strains of HIV-1. However, the cell-surface thiol-reactive reagent 5, 5 '-dithiobis(2-nitrobenzoic acid) (DTNB) had a much stronger inhibitory effect in our system, suggesting that cell-surface thiol-containing molecules other than PDI, acting alone or in concert, have a greater effect than PDI on HIV-1 Env-mediated fusion. We evaluated one such candidate, thioredoxin, a PDI family member reported to reduce a labile disulfide bond in CD4. We found that the ability of thioredoxin to reduce the disulfide bond in CD4 is enhanced in the presence of HIV-1 Env gp120 and that thioredoxin also reduces disulfide bonds in gp120 directly in the absence of CD4. We discuss the implications of these observations for identification of molecules involved in disulfide rearrangements in Env during fusion. Published by Elsevier Inc. C1 NIAID, Lab Mol Microbiol, NIH, Bethesda, MD 20892 USA. RP Silver, J (reprint author), NIAID, Lab Mol Microbiol, NIH, Bldg 4,Room 336, Bethesda, MD 20892 USA. EM wou@niaid.nih.gov; jsilver@nih.gov OI Silver, Jonathan/0000-0001-9231-6368 NR 41 TC 57 Z9 60 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 0042-6822 J9 VIROLOGY JI Virology PD JUL 5 PY 2006 VL 350 IS 2 BP 406 EP 417 DI 10.1016/j.virol.2006.01.041 PG 12 WC Virology SC Virology GA 060ET UT WOS:000238785900015 PM 16507315 ER PT J AU Healey, JS Toff, WD Lamas, GA Andersen, HR Thorpe, KE Ellenbogen, KA Lee, KL Skene, AM Schron, EB Skehan, JD Goldman, L Roberts, RS Camm, AJ Yusuf, S Connolly, SJ AF Healey, JS Toff, WD Lamas, GA Andersen, HR Thorpe, KE Ellenbogen, KA Lee, KL Skene, AM Schron, EB Skehan, JD Goldman, L Roberts, RS Camm, AJ Yusuf, S Connolly, SJ TI Cardiovascular outcomes with atrial-based pacing compared with ventricular pacing - Meta-analysis of randomized trials, using individual patient data SO CIRCULATION LA English DT Article DE atrial fibrillation; heart failure; mortality; pacemakers; stroke ID SINUS-NODE DYSFUNCTION; QUALITY-OF-LIFE; TERM-FOLLOW-UP; CANADIAN TRIAL; CHAMBER; FIBRILLATION; PACEMAKER; MODE AB Background - Several randomized trials have compared atrial-based (dual-chamber or atrial) pacing with ventricular pacing in patients with bradycardia. No trial has shown a mortality reduction, and only 1 small trial suggested a reduction in stroke. The goal of this review was to determine whether atrial-based pacing prevents major cardiovascular events. Methods and Results - A systematic review was performed of publications since 1980. For inclusion, trials had to compare an atrial-based with a ventricular-based pacing mode; use a randomized, controlled, parallel design; and have data on mortality, stroke, heart failure, or atrial fibrillation. Individual patient data were obtained from 5 of the 8 identified studies, representing 95% of patients in the 8 trials, and a total of 35 000 patient-years of follow-up. There was no significant heterogeneity among the results of the individual trials. There was no significant reduction in mortality (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.87 to 1.03; P = 0.19) or heart failure (HR, 0.89; 95% CI, 0.77 to 1.03; P = 0.15) with atrial-based pacing. There was a significant reduction in atrial fibrillation (HR, 0.80; 95% CI, 0.72 to 0.89; P = 0.00003) and a reduction in stroke that was of borderline significance (HR, 0.81; 95% CI, 0.67 to 0.99; P = 0.035). There was no convincing evidence that any patient subgroup received special benefit from atrial-based pacing. Conclusions - Compared with ventricular pacing, the use of atrial-based pacing does not improve survival or reduce heart failure or cardiovascular death. However, atrial-based pacing reduces the incidence of atrial fibrillation and may modestly reduce stroke. C1 McMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada. Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. Mt Sinai Med Ctr, Miami Beach, FL 33140 USA. Aarhus Univ Hosp, Skejby, Denmark. Univ Toronto, Toronto, ON, Canada. Virginia Commonwealth Univ Med Coll Virginia, Richmond, VA USA. Duke Univ, Durham, NC USA. Nottingham Clin Res Grp, Nottingham, England. NHLBI, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. McMaster Univ, Henderson Res Ctr, Hamilton, ON, Canada. St Georges Univ London, London, England. RP Healey, JS (reprint author), McMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada. EM healeyj@hhsc.ca NR 28 TC 105 Z9 109 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 4 PY 2006 VL 114 IS 1 BP 11 EP 17 DI 10.1161/CIRCULATIONAHA.105.610303 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 058TV UT WOS:000238688400008 PM 16801463 ER PT J AU Solomon, SD Rice, MM Jablonski, KA Jose, P Domanski, M Sabatine, M Gersh, BJ Rouleau, J Pfeffer, MA Braunwald, E AF Solomon, SD Rice, MM Jablonski, KA Jose, P Domanski, M Sabatine, M Gersh, BJ Rouleau, J Pfeffer, MA Braunwald, E CA PEACE Invest TI Renal function and effectiveness of angiotensin-converting enzyme inhibitor therapy in patients with chronic stable coronary disease in the prevention of events with ACE inhibition (PEACE) trial SO CIRCULATION LA English DT Article DE angiotensin; coronary disease; inhibitors; kidney ID CHRONIC KIDNEY-DISEASE; ACUTE MYOCARDIAL-INFARCTION; VENTRICULAR EJECTION FRACTIONS; CONGESTIVE-HEART-FAILURE; CARDIOVASCULAR EVENTS; ARTERY-DISEASE; RISK; MORTALITY; SURVIVAL; DYSFUNCTION AB Background - Patients with reduced renal function are at increased risk for adverse cardiovascular outcomes. In the post - myocardial infarction setting, angiotensin-converting enzyme ( ACE) inhibitors have been shown to be as effective in patients with impaired renal function as in those with preserved renal function. Methods and Results - We assessed the relation between renal function and outcomes, the influence of ACE inhibition on this relation, and whether renal function modifies the effectiveness of ACE inhibition in patients with stable coronary artery disease and preserved systolic function enrolled in the Prevention of Events with ACE inhibition trial ( PEACE). Patients (n = 8290) were randomly assigned to receive trandolapril (target, 4 mg/d) or placebo. Clinical creatinine measures were available for 8280 patients before randomization. The estimated glomerular filtration rate (eGFR) was calculated with the 4-point Modification of Diet in Renal Disease equation. Renal function was related to outcomes, and the influence of ACE-inhibitor therapy was assessed with formal interaction modeling. The mean eGFR in PEACE was 77.6 +/- 19.4, and 1355 (16.3%) patients had reduced renal function (eGFR < 60 mg (.) mL(-1) (.) 1.73 m(-2)). We observed a significant interaction between eGFR and treatment group with respect to cardiovascular and all-cause mortality (P = 0.02). Trandolapril was associated with a reduction in total mortality in patients with reduced renal function (adjusted HR, 0.73; 95% CI, 0.54 to 1.00) but not in patients with preserved renal function (adjusted HR, 0.94; 95% CI, 0.78 to 1.13). Conclusions - Although trandolapril did not improve survival in the overall PEACE cohort, in which mean eGFR was relatively high, trandolapril reduced mortality in patients with reduced eGFR. These data suggest that reduced renal function may define a subset of patients most likely to benefit from ACE-inhibitor therapy for cardiovascular protection. C1 Harvard Univ, Div Cardiovasc, Sch Med, Brigham & Womens Hosp, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. George Washington Univ, Ctr Biostat, Rockville, MD USA. Univ Montreal, Montreal, PQ, Canada. Mayo Coll Med, Rochester, MN USA. RP Solomon, SD (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM ssolomon@rics.bwh.harvard.edu RI Solomon, Scott/I-5789-2013 FU NHLBI NIH HHS [N01HC65149] NR 23 TC 107 Z9 120 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 4 PY 2006 VL 114 IS 1 BP 26 EP 31 DI 10.1161/CIRCULATIONAHA.105.592733 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 058TV UT WOS:000238688400010 PM 16801465 ER PT J AU Larson, MG AF Larson, MG TI Descriptive statistics and graphical displays SO CIRCULATION LA English DT Article C1 Framingham Heary Study, NHLBI, Framingham, MA 01702 USA. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Larson, MG (reprint author), Framingham Heary Study, NHLBI, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM mlarson@bu.edu OI Larson, Martin/0000-0002-9631-1254 NR 4 TC 16 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 4 PY 2006 VL 114 IS 1 BP 76 EP 81 DI 10.1161/CIRCULATIONAHA.105.584474 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 058TV UT WOS:000238688400016 PM 16818830 ER PT J AU Titus-Ernstoff, L Troisi, R Hatch, EE Palmer, JR Wise, LA Ricker, W Hyer, M Kaufman, R Noller, K Strohsnitter, W Herbst, AL Hartge, P Hoover, RN AF Titus-Ernstoff, L. Troisi, R. Hatch, E. E. Palmer, J. R. Wise, L. A. Ricker, W. Hyer, M. Kaufman, R. Noller, K. Strohsnitter, W. Herbst, A. L. Hartge, P. Hoover, R. N. TI Mortality in women given diethylstilbestrol during pregnancy SO BRITISH JOURNAL OF CANCER LA English DT Article DE DES; oestrogens; breast cancer; mortality ID TERM FOLLOW-UP; BREAST-CANCER; POSTMENOPAUSAL WOMEN; STILBESTROL THERAPY; CONTROLLED-TRIAL; RISK; MOTHERS; ESTROGENS AB We used Cox regression analyses to assess mortality outcomes in a combined cohort of 7675 women who received diethylstilbestrol (DES) through clinical trial participation or prenatal care. In the combined cohort, the RR for DES in relation to all-cause mortality was 1.06 (95% CI = 0.98 - 1.16), and 1.11 ( 95% CI = 1.02 - 1.21) after adjusting for covariates and omitting breast cancer deaths. The RR was 1.07 (95% CI 0.94 - 1.23) for overall cancer mortality, and remained similar after adjusting for covariates and omitting breast cancer deaths. The RR was 1.27 (95% CI = 0.96 - 1.69) for DES and breast cancer, and 1.38 (95% CI = 1.03 - 1.85) after covariate adjustment. The RR was 1.82 in trial participants and 1.12 in the prenatal care cohort, but the DES - cohort interaction was not significant (P = 0.15). Diethylstilbestrol did not increase mortality from gynaecologic cancers. In summary, diethylstilbestrol was associated with a slight but significant increase in all-cause mortality, but was not significantly associated with overall cancer or gynaecological cancer mortality. The association with breast cancer mortality was more evident in trial participants, who received high DES doses. C1 Dartmouth Coll Sch Med, Dept Community & Family Med, Lebanon, NH 03756 USA. Norris Cotton Canc Ctr, Lebanon, NH 03756 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Slone Epidemiol Ctr, Boston, MA 02215 USA. Informat Management Serv Inc, Rockville, MD 20852 USA. Methodist Hosp, Dept Obstet & Gynecol, Houston, TX 77030 USA. Tufts Univ New England Med Ctr, Dept Obstet & Gynecol, Boston, MA 02111 USA. Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. RP Titus-Ernstoff, L (reprint author), Dartmouth Coll Sch Med, Dept Community & Family Med, Lebanon, NH 03756 USA. EM Linda.Titus-Ernstoff@Dartmouth.edu OI Palmer, Julie/0000-0002-6534-335X; Hatch, Elizabeth/0000-0001-7901-3928; Wise, Lauren/0000-0003-2138-3752 FU NCI NIH HHS [CP01012-21, CP50531-21, N01 CP001012]; PHS HHS [33011-21] NR 23 TC 6 Z9 6 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 3 PY 2006 VL 95 IS 1 BP 107 EP 111 DI 10.1038/sj.bjc.6603221 PG 5 WC Oncology SC Oncology GA 057TK UT WOS:000238617900018 PM 16786044 ER PT J AU Garcia-Closas, M Brinton, LA Lissowska, J Chatterjee, N Peplonska, B Anderson, WF Szeszenia-Dabrowska, N Bardin-Mikolajczak, A Zatonski, W Blair, A Kalaylioglu, Z Rymkiewicz, G Mazepa-Sikora, D Kordek, R Lukaszek, S Sherman, ME AF Garcia-Closas, M. Brinton, L. A. Lissowska, J. Chatterjee, N. Peplonska, B. Anderson, W. F. Szeszenia-Dabrowska, N. Bardin-Mikolajczak, A. Zatonski, W. Blair, A. Kalaylioglu, Z. Rymkiewicz, G. Mazepa-Sikora, D. Kordek, R. Lukaszek, S. Sherman, M. E. TI Established breast cancer risk factors by clinically important tumour characteristics SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; epidemiology; aetiologic heterogeneity; histology ID HORMONE-REPLACEMENT THERAPY; HISTOLOGIC TYPES; BODY-WEIGHT; STAGE; CARCINOMA; AGE; PATTERNS; ESTROGEN; DISEASE; OBESITY AB Breast cancer is a morphologically and clinically heterogeneous disease; however, it is less clear how risk factors relate to tumour features. We evaluated risk factors by tumour characteristics ( histopathologic type, grade, size, and nodal status) in a population-based case-control of 2386 breast cancers and 2502 controls in Poland. Use of a novel extension of the polytomous logistic regression permitted simultaneous modelling of multiple tumour characteristics. Late age at first full-term birth was associated with increased risk of large (42 cm) tumours (odds ratios (95% confidence intervals) 1.19 (1.07 - 1.33) for a 5-year increase in age), but not smaller tumours (P for heterogeneity adjusting for other tumour features (P(het)) = 0.007). On the other hand, multiparity was associated with reduced risk for small tumours (0.76 (0.68 - 0.86) per additional birth; P(het) = 0.004). Consideration of all tumour characteristics simultaneously revealed that current or recent use of combined hormone replacement therapy was associated with risk of small (2.29 (1.66 - 3.15)) and grade 1 (3.36 (2.22 - 5.08)) tumours (P(het) = 0.05 for size and 0.0008 for grade 1 vs 3), rather than specific histopathologic types (P(het) = 0.63 for ductal vs lobular). Finally, elevated body mass index was associated with larger tumour size among both pre- and postmenopausal women (P(het) = 0.05 and 0.0001, respectively). None of these relationships were explained by hormone receptor status of the tumours. In conclusion, these data support distinctive risk factor relationships by tumour characteristics of prognostic relevance. These findings might be useful in developing targeted prevention efforts. C1 NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. Ctr Canc, Dept Canc Epidemiol & Prevent, Warsaw, Poland. M Sklodowska Curie Inst Oncol, Warsaw, Poland. Nofer Inst Occupat Med, Lodz, Poland. IMS, Silver Spring, MD USA. Ctr Canc, Dept Pathol, Warsaw, Poland. Med Univ Lodz, Dept Pathol, Lodz, Poland. Polish Mothers Mem Hosp, Res Inst, Dept Clin Pathomorphol, Lodz, Poland. RP Garcia-Closas, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 7076, Rockville, MD 20852 USA. EM montse@nih.gov RI Peplonska, Beata/F-6004-2010; Szeszenia-Dabrowska, Neonila/F-7190-2010; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Kordek, Radzislaw/S-9616-2016; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Lissowska, Jolanta/0000-0003-2695-5799 FU Intramural NIH HHS NR 38 TC 97 Z9 97 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 3 PY 2006 VL 95 IS 1 BP 123 EP 129 DI 10.1038/sj.bjc.6603207 PG 7 WC Oncology SC Oncology GA 057TK UT WOS:000238617900021 PM 16755295 ER PT J AU Ruttens, B Kovac, P AF Ruttens, Bart Kovac, Pavol TI Synthesis of spacer-equipped phosphorylated di-, tri- and tetrasaccharide fragments of the O-specific polysaccharide of Vibrio cholerae O139 SO CARBOHYDRATE RESEARCH LA English DT Article DE glycosylation; 4,6-cyclic phosphate; oligosaccharides; glycoconjugates; Vibrio cholerae O139 ID CAPSULAR POLYSACCHARIDE; STRUCTURAL-ANALYSIS; LIPOPOLYSACCHARIDE; BENGAL; VIRULENCE; STRAIN; REGION AB The synthesis of oligosaccharide fragments of the O-specific polysaccharide of Vibrio cholerae O139 containing a 4.6-cyclic phosphate galactose residue linked to GlcNAc is described. 8-Azido-3,6-dioxaoctyl 2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosvl-(1 -> 3)-2-acetamido-4,6-O-benzylidene-2-deoxy-beta-D-glucopyranoside, obtained by condensation of 2,3,4,6-tetra-O-acetyl-alpha-D-galactopyranosyl bromide and 8-azido-3,6-dioxaoctyl 2-acetamido-4,6-O-benzylidene-2-deoxy-beta-D-glucopyranoside, was converted to 8-azido-3,6-dioxaoctyl 3-O-benzyl-beta-D-galactopyranosyl-(1 -> 3)-2-acetamido-6-O-benzyl-2-deoxy-beta-D-glueopyranoside (6) by reductive opening of the acetal, followed by deacetylation and selective benzylation. Phosphorylation of 6 furnished two isomeric 4,6-cyclic 2,2,2 -trichloroethyl phosphates. Glycosylation of the (S)-phosphate with 2,4-di-O-benzyl-3,6-dideoxy-alpha-L-xylohexopyranosyl bromide under halide-assisted conditions gave the desired tetrasaccharide, together with a trisaccharide. Global deprotection and reduction of the azide to an amine was effected by catalytic hydrogenation/hydrogenolysis to give the deprotected tetrasaccharide, which is functionalized for conjugation. (c) 2006 Published by Elsevier Ltd. C1 NIDDK, LMC, NIH, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIDDK, LMC, NIH, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov FU Intramural NIH HHS NR 21 TC 13 Z9 13 U1 1 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD JUL 3 PY 2006 VL 341 IS 9 BP 1077 EP 1080 DI 10.1016/j.carres.2006.04.007 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 051RL UT WOS:000238178300001 PM 16650390 ER PT J AU Yu, H Kim, W Hatzivassiloglou, V Wilbur, J AF Yu, Hong Kim, Won Hatzivassiloglou, Vasileios Wilbur, John TI A large scale, corpus-based approach for automatically disambiguating biomedical abbreviations SO ACM TRANSACTIONS ON INFORMATION SYSTEMS LA English DT Article DE algorithms; languages; word-sense disambiguation; machine learning; data mining; information retrieval ID INFORMATION AB Abbreviations and acronyms are widely used in the biomedical literature and many of them represent important biomedical concepts. Because many abbreviations are ambiguous (e.g., CAT denotes both chloramphenicol acetyl transferase and computed axial tomography, depending on the context), recognizing the full form associated with each abbreviation is in most cases equivalent to identifying the meaning of the abbreviation. This, in turn, allows us to perform more accurate natural language processing, information extraction, and retrieval. In this study, we have developed supervised approaches to identifying the full forms of ambiguous abbreviations within the context they appear. We first automatically assigned multiple possible full forms for each abbreviation; we then treated the in-context full-form prediction for each specific abbreviation occurrence as a case of word-sense disambiguation. We generated automatically a dictionary of all possible full forms for each abbreviation. We applied supervised machine-learning algorithms for disambiguation. Because some of the links between abbreviations and their corresponding full forms are explicitly given in the text and can be recovered automatically, we can use these explicit links to automatically provide training data for disambiguating the abbreviations that are not linked to a full form within a text. We evaluated our methods on over 150 thousand abstracts and obtain for coverage and precision results of 82% and 92%, respectively, when performed as tenfold cross-validation, and 79% and 80%, respectively, when evaluated against an external set of abstracts in which the abbreviations are not defined. C1 Univ Wisconsin, Dept Hlth Sci, Milwaukee, WI 53211 USA. Univ Texas, Dept Comp Sci, Richardson, TX 75083 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Yu, H (reprint author), Univ Wisconsin, Dept Hlth Sci, Milwaukee, WI 53211 USA. EM yuh9001@dbmi.columbia.edu NR 51 TC 7 Z9 7 U1 0 U2 5 PU ASSOC COMPUTING MACHINERY PI NEW YORK PA 1515 BROADWAY, NEW YORK, NY 10036 USA SN 1046-8188 J9 ACM T INFORM SYST JI ACM Trans. Inf. Syst. PD JUL PY 2006 VL 24 IS 3 BP 380 EP 404 DI 10.1145/1165774.1165778 PG 25 WC Computer Science, Information Systems SC Computer Science GA 097GB UT WOS:000241433900004 ER PT J AU Li, WJ Cooper, JA Mauck, RL Tuan, RS AF Li, WJ Cooper, JA Mauck, RL Tuan, RS TI Fabrication and characterization of six electrospun poly(alpha-hydroxy ester)-based fibrous scaffolds for tissue engineering applications SO ACTA BIOMATERIALIA LA English DT Article DE electrospinning; nanofiber; fiber; mesenchymal stem cell; chondrocyte ID MESENCHYMAL STEM-CELLS; 3-DIMENSIONAL NANOFIBROUS SCAFFOLD; ARTICULAR-CARTILAGE; HUMAN MARROW; DIFFERENTIATION; MORPHOLOGY; POLYMERS; CULTURE; BONE AB The most common synthetic biodegradable polymers being investigated for tissue engineering applications are FDA approved, clinically used poly(alpha-hydroxy esters). To better assess the applicability of the clectrospinning technology for scaffold fabrication, six commonly used poly(alpha-hydroxy esters) were used to prepare clectrospun fibrous scaffolds, and their physical and biological properties were also characterized. Our results suggest that specific, optimized fabrication parameters are required for each polymer to produce scaffolds that consist of uniform structures morphologically similar to native extracellular matrix. Scanning electron microscopy (SEM) revealed a highly porous, three-dimensional structure for all scaffolds, with average fiber diameter ranging from 300 nm to 1.5 mu m, depending on the polymer type used. The poly(glycolic acid) (PGA) and poly(D,L-lactic-co-glycolic acid 50:50) (PLGA5050) fibrous structures were mechanically stiffest, whereas the poly(L-lactic acid) (PLLA) and poly(F-caprolactone) (PCL) scaffolds were most compliant. Upon incubation in physiological solution, severe structural destruction due to polymer degradation was found in the PGA, poly(D,L-lactic acid) (PDLLA), PLGA5050, and poly(D,L-lactic-co-glycolic acid 85:15) (PLGA8515) fibrous scaffolds, whereas PLLA and PCL fibrous scaffolds maintained a robust scaffold structure during the same time period, based oil macroscopic and SEM observations. In addition, PLLA scaffolds supported the highest rate of proliferation of seeded cells (chondrocytes and mesenchymal stem cells) than other polymeric scaffolds. Our findings showed that PLLA and PCL based fibrous scaffolds exhibited the most optimal structural integrity and supported desirable cellular response in culture, suggesting that such scaffolds may be promising candidate biomaterials for tissue engineering applications. (c) 2006 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIST, Div Polymers, Gaithersburg, MD 20899 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Room 1523,Bldg 50,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov RI Li, Wan-Ju/A-7002-2008 FU Intramural NIH HHS; NIAMS NIH HHS [Z01 AR 41113] NR 23 TC 267 Z9 278 U1 16 U2 117 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1742-7061 J9 ACTA BIOMATER JI Acta Biomater. PD JUL PY 2006 VL 2 IS 4 BP 377 EP 385 DI 10.1016/j.actbio.2006.02.005 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 059OT UT WOS:000238742800002 PM 16765878 ER PT J AU Sekar, K Yogavel, M Kanaujia, SP Sharma, A Velmurugan, D Poi, MJ Dauter, Z Tsai, MD AF Sekar, K Yogavel, M Kanaujia, SP Sharma, A Velmurugan, D Poi, MJ Dauter, Z Tsai, MD TI Suggestive evidence for the involvement of the second calcium and surface loop in interfacial binding: monoclinic and trigonal crystal structures of a quadruple mutant of phospholipase A(2) SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID PORCINE PANCREATIC PHOSPHOLIPASE-A2; TRIPLE MUTANT; K-ASTERISK(CAT) ACTIVATION; RESOLUTION REFINEMENT; MOLECULAR REPLACEMENT; ATOMIC-RESOLUTION; ION; CATALYSIS; TERMINUS; PROTEINS AB The crystal structures of the monoclinic and trigonal forms of the quadruple mutant K53,56,120,121M of recombinant bovine pancreatic phospholipase A(2) (PLA(2)) have been solved and refined at 1.9 and 1.1 angstrom resolution, respectively. Interestingly, the monoclinic form reveals the presence of the second calcium ion. Furthermore, the surface-loop residues are ordered and the conformation of residues 62-66 is similar to that observed in other structures containing the second calcium ion. On the other hand, in the trigonal form the surface loop is disordered and the second calcium is absent. Docking studies suggest that the second calcium and residues Lys62 and Asp66 from the surface loop could be involved in the interaction with the polar head group of the membrane phospholipid. It is hypothesized that the two structures of the quadruple mutant, monoclinic and trigonal, represent the conformations of PLA2 at the lipid interface and in solution, respectively. A docked structure with a phospholipid molecule and with a transition-state analogue bound, one at the active site coordinating to the catalytic calcium and the other at the second calcium site, but both at the i-face, is presented. C1 Indian Inst Sci, Bioinformat Ctr, Bangalore 560012, Karnataka, India. Indian Inst Sci, Supercomp Educ & Res Ctr, Bangalore 560012, Karnataka, India. Univ Madras, Dept Crystallog & Biophys, Madras 600025, Tamil Nadu, India. Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. Ohio State Univ, Dept Chem, Columbus, OH 43210 USA. Ohio State Univ, Dept Biochem, Columbus, OH 43210 USA. Ohio State Univ, Ohio State Biochem Program, Columbus, OH 43210 USA. Argonne Natl Lab, Synchrotron Radiat Res Sect, MCL, NCI, Argonne, IL 60439 USA. Acad Sinica, Genom Res Ctr, Taipei, Taiwan. RP Sekar, K (reprint author), Indian Inst Sci, Bioinformat Ctr, Bangalore 560012, Karnataka, India. EM sekar@physics.iisc.ernet.in OI Tsai, Ming-Daw/0000-0003-1374-0414 FU NIGMS NIH HHS [GM 57568] NR 44 TC 5 Z9 5 U1 1 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JUL PY 2006 VL 62 BP 717 EP 724 DI 10.1107/S0907444906014855 PN 7 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 055JV UT WOS:000238447500004 PM 16790927 ER PT J AU Aranda, R Levin, EJ Schotte, F Anfinrud, PA Phillips, GN AF Aranda, R Levin, EJ Schotte, F Anfinrud, PA Phillips, GN TI Time-dependent atomic coordinates for the dissociation of carbon monoxide from myoglobin SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID X-RAY CRYSTALLOGRAPHY; RESOLVED CRYSTALLOGRAPHY; STRUCTURAL DYNAMICS; MOLECULAR-DYNAMICS; HYDROXYMETHYLBILANE SYNTHASE; CRYSTAL-STRUCTURE; LIGAND MIGRATION; SOFTWARE SUITE; PROTEIN; COMPLEX AB Picosecond time-resolved crystallography was used to follow the dissociation of carbon monoxide from the heme pocket of a mutant sperm whale myoglobin and the resultant conformational changes. Electron-density maps have previously been created at various time points and used to describe amino-acid side-chain and carbon monoxide movements. In this work, difference refinement was employed to generate atomic coordinates at each time point in order to create a more explicit quantitative representation of the photo-dissociation process. After photolysis the carbon monoxide moves to a docking site, causing rearrangements in the heme-pocket residues, the coordinate changes of which can be plotted as a function of time. These include rotations of the heme-pocket phenylalanine concomitant with movement of the distal histidine toward the solvent, potentially allowing carbon monoxide movement in and out of the protein and proximal displacement of the heme iron. The degree of relaxation toward the intermediate and deoxy states was probed by analysis of the coordinate movements in the time-resolved models, revealing a non-linear progression toward the unbound state with coordinate movements that begin in the heme-pocket area and then propagate throughout the rest of the protein. C1 Univ Wisconsin, Dept Biochem, Madison, WI 53705 USA. Univ Wisconsin, Dept Biomol Chem, Madison, WI USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Phillips, GN (reprint author), Univ Wisconsin, Dept Biochem, 420 Henry Mall, Madison, WI 53705 USA. EM phillips@biochem.wisc.edu FU Intramural NIH HHS; NIGMS NIH HHS [T32 GM07215-29, 5T32 GM08349] NR 43 TC 44 Z9 45 U1 1 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JUL PY 2006 VL 62 BP 776 EP 783 DI 10.1107/S0907444906017318 PN 7 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 055JV UT WOS:000238447500010 PM 16790933 ER PT J AU Pommier, Y AF Pommier, Yves TI Interfacial inhibition: Topoisomerase I inhibitors, one of nature's paradigms for drug discovery SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract C1 NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 2 EP 2 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590000008 ER PT J AU Gonzalez, FJ Krausz, KW Chen, C Giri, S Idle, JR AF Gonzalez, Frank J. Krausz, Kristopher W. Chen, Chi Giri, Sarbani Idle, Jeffrey R. TI Mouse metabonomics for the analysis and prediction of drug metabolism SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract DE drug metabolism; metabonomics; P450s; UPLC-QTOFMS C1 Charles Univ, Inst Pharmacol, Prague, Czech Republic. NCI, Lab Metab, Bethesda, MD 20892 USA. RI Chen, Chi/B-4618-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 24 EP 24 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590000137 ER PT J AU Kunos, G Osei-Hyiaman, D Wang, L Liu, J Pacher, P Batkai, S Radaeva, S AF Kunos, George Osei-Hyiaman, Douglas Wang, Lei Liu, Jie Pacher, Pal Batkai, Sandor Radaeva, Svetlana TI Endocannabinoids and the control of energy homeostasis SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract DE cannabinoid; appetite; fat metabolism; obesity C1 NIAAA, NIH, Bethesda, MD 20892 USA. RI Batkai, Sandor/G-3889-2010; Batkai, Sandor/H-7983-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 24 EP 24 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590000141 ER PT J AU Pacher, P AF Pacher, Pal TI Pharmacological modulation of oxidative-nitrosative stress and downstream effectors in heart failure. SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract C1 NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 24 EP 24 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590000136 ER PT J AU Jeon, J Gautarn, D Li, HH Cui, Y Deng, C Wess, J AF Jeon, Jongrye Gautarn, Dinesh Li, Jian Hua Cui, Yinghong Deng, Chuxia Wess, J. rgen TI Use of gene targeting technology to understand the roles of CM muscarinic receptors SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract DE acetylcholine; receptor knockout mice; muscarinic receptors C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 39 EP 39 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590000228 ER PT J AU Meshorer, E AF Meshorer, Eran TI Chromatin in embryonic stem cell neuronal differentiation SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract C1 NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 45 EP 45 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590000263 ER PT J AU Figg, WD Price, DK AF Figg, William D. Price, Douglas K. TI Analysis of genetic variations in the androgen receptor and enzymes that regulate androgens SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract DE prostate cancer; polymorphism; androgen C1 NCI, Mol Pharmacol Lab, Med Oncol Branch, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 46 EP 47 PG 2 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590000271 ER PT J AU Murphy, DL Fox, MA Kalueff, A White, C Cromer, K Wendland, J AF Murphy, Dennis L. Fox, Meredith A. Kalueff, Allan White, Charise Cromer, Kiara Wendland, Jens TI Genetic perspectives on SRI actions SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract DE SERT; knockout mice; serotonin syndrome; antidepressants C1 NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. RI Timpano, Kiara/C-8760-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 49 EP 49 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590000287 ER PT J AU Rhee, H Bae, MA Song, BJ AF Rhee, H. Bae, M. A. Song, B. J. TI Pharmacology and toxicology of peroxisome proliferator activated receptor agonists: Differential apoptosis of troglitazone and rosiglitazone SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract DE troglitazone; hepatotoxicity; rosiglitazone C1 US FDA, Rockville, MD 20857 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 50 EP 50 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590000290 ER PT J AU Gardner, E Xi, ZM AF Gardner, Eliot Xi, Zheng-Mong TI Gamma-vinyl GABA inhibits cocaine-primed relapse by a DA-independent mechanism. SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract DE gamma -vinyl GABA; cocaine; dopamine C1 Natl Inst Drug Abuse, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 96 EP 96 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590000568 ER PT J AU Xi, ZX Gardner, E AF Xi, Zheng-Xiong Gardner, Eliot TI Blockade of cannabinoid CB1 receptor by AM251 inhibits cocaine's rewarding effects and cocaine-primed relapse by a DA-independent mechanism. SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract DE cocaine; AM251; dopamine C1 Natl Inst Drug Abuse, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 118 EP 118 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590001034 ER PT J AU Goldstein, J Jackson, J Ferguson, S Negishi, M AF Goldstein, Joyce Jackson, Jonathan Ferguson, Stephen Negishi, Masahiko TI The constitutive androstane receptor mediates induction of murine c cyp2c37 by phenytoin SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract C1 NIEHS, DHHS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 222 EP 222 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590001661 ER PT J AU Sredni-Kenigsbuch, D Chan, CC David, M AF Sredni-Kenigsbuch, Dvora Chan, Chi-Chao David, Michael TI Immunomodulating effect of a tellurium compound AS101 on interleukin-10 and the involvement activation of MAPK signaling pathway in Atopic dermatitis SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract C1 Bar Ilan Univ, Interdisciplinary Dept, IL-52900 Ramat Gan, Israel. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Rabin Med Ctr, Dept Dermatol, Petah Tiqwa, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 271 EP 271 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590002268 ER PT J AU Sun, R Kulkarni, S Wang, L Sun, HY Radaeva, S Gao, B AF Sun, Rui Kulkarni, Shailin Wang, Lei Sun, Hao-Yu Radaeva, Svetlana Gao, Bin TI STAT1 contributes to TLR3 ligand inhibition of liver regeneration and inversely correlates with hepatocyte proliferation in HCV patients SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract C1 Univ Sci & Technol China, NIAAA, Sect Liver Biol, NIH, Hefei 230026, Anhui, Peoples R China. Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Anhui, Peoples R China. NIAAA, Sect Liver Biol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 273 EP 273 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590002280 ER PT J AU Liu, J Wang, L Harvey-White, J Osei-Hyiaman, D Zhou, ZF Huang, B Kim, HY Kunos, G AF Liu, Jie Wang, Lei Harvey-White, Judith Osei-Hyiaman, Douglas Zhou, Zhifeng Huang, Bill Kim, Hee-Yong Kunos, George TI A novel biosynthetic pathway for anandamide SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 303 EP 304 PG 2 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590002449 ER PT J AU Butterweck, V Winterhoff, H Herkenham, M AF Butterweck, Veronika Winterhoff, Hilke Herkenham, Miles TI Effects St. John's wort on HPA axis control in rats after short-term and long-term treatment SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract C1 Univ Florida, Coll Pharm, Dept Pharmaceut, Gainesville, FL 32610 USA. Univ Klinikum Munster, Inst Pharmacol & Toxicol, D-48149 Munster, Germany. NIMH, Sect Funct Neuroanat, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 341 EP 341 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590003061 ER PT J AU Parra, S Rodriguez, C Lin, R Omoluabi, Z Frieske, J Shardonofsky, F Wess, J Knoll, B Bond, R AF Parra, Sergio Rodriguez, Carlos Lin, Rui Omoluabi, Zoma Frieske, Joanna Shardonofsky, Felix Wess, J. rgen Knoll, Brian Bond, Richard TI Muscarinic M2 receptors modulate airway responses to methacholine in a murine model of asthma SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract DE muscarinic receptors C1 Univ Houston, Houston, TX 77004 USA. Univ Antioquia, Dept Farmacol, Medellin, Colombia. Univ Texas, Dallas, TX 75230 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 380 EP 380 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590003292 ER PT J AU Onaivi, E Ishiguro, H Gong, J Patel, S Tagliaferro, P Iwasaki, S Uhl, G AF Onaivi, Emmanuel Ishiguro, Hiroki Gong, Jianping Patel, Sejal Tagliaferro, Patricia Iwasaki, Shinya Uhl, George TI Discovery and functional expression of brain cannabinoid CB2 receptors involved in depression and drug abuse. SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract DE cannabinoid CB2 receptors; brain; depression; drug abuse C1 William Paterson Univ, Wayne, NJ USA. Univ Tsukuba, Ibaraki, Japan. NIH, NI, DA, Baltimore, MD USA. Univ Buenos Aires, RA-1053 Buenos Aires, DF, Argentina. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 417 EP 417 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590003507 ER PT J AU Massi, M Ciccocioppo, R Economidou, D Heilig, M Fedeli, A AF Massi, Maurizio Ciccocioppo, Roberto Economidou, Daina Heilig, Markus Fedeli, Amalia TI Evidence for the involvement of NOP receptor for nociceptin/orphanin FQ (N/OFQ) in the effect of buprenorphine on alcohol intake in rats SO ACTA PHARMACOLOGICA SINICA LA English DT Meeting Abstract DE buprenorphine; NOP receptor; alcohol intake C1 Univ Camerino, Dept Exp Med Pub Hlth, I-62032 Camerino, Italy. NIAAA, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUL PY 2006 VL 27 SU 1 BP 422 EP 422 PG 1 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 071HI UT WOS:000239590003540 ER PT J AU Heishman, SJ Boas, ZP Hager, MC Taylor, RC Singleton, EG Moolchan, ET AF Heishman, Stephen J. Boas, Zachary P. Hager, Marguerite C. Taylor, Richard C. Singleton, Edward G. Moolchan, Eric T. TI Effect of tobacco craving cues on memory encoding and retrieval in smokers SO ADDICTIVE BEHAVIORS LA English DT Article DE craving; cue reactivity; smoking; tobacco; working memory; humans ID SMOKING URGES; DIVIDED ATTENTION; QUESTIONNAIRE; RELIABILITY; PERFORMANCE; VALIDATION; VALIDITY; ABUSERS; IMAGERY AB Previous studies have shown that cue-elicited tobacco craving disrupted performance on cognitive tasks; however, no study has examined directly the effect of cue-elicited craving on memory encoding and retrieval. A distinction between encoding and retireval has been reported such that memory is more impaired when attention is divided at encoding than at retrieval. This study tested the hypothesis that active imagery of smoking situations would impair encoding processes, but have little effect on retrieval. Imagery scripts (cigarette craving and neutral content) were presented either before presentation of a word list (encoding trials) or before word recall (retrieval trials). A working memory task at encoding and free recall of words were assessed. Results indicated that active imagery disrupted working memory on encoding trials, but not on retrieval trials. There was a trend toward impaired working memory following craving scripts compared with neutral scripts. These data support the hypothesis that the cognitive underpinnings of encoding and retrieval processes are distinct. (c) 2005 Elsevier Ltd. All rights reserved. C1 NIDA, Clin Pharmacol & Therapeut Branch, DHHS, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Heishman, SJ (reprint author), NIDA, Clin Pharmacol & Therapeut Branch, DHHS, Intramural Res Program,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM heishman@nih.gov OI Singleton, Edward G./0000-0003-3442-877X FU Intramural NIH HHS NR 15 TC 3 Z9 3 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD JUL PY 2006 VL 31 IS 7 BP 1116 EP 1121 DI 10.1016/j.addbeh.2005.08.007 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 061VF UT WOS:000238900200002 PM 16157458 ER PT J AU Simons-Morton, B Chen, RS AF Simons-Morton, Bruce Chen, Rusan S. TI Over time relationships between early adolescent and peer substance use SO ADDICTIVE BEHAVIORS LA English DT Article DE drug abuse; peer influence; social influence; selection; socialization; latent growth curve modeling; bivariate; lagged; auto-regression latent trajectory analysis ID GROWTH CURVE ANALYSES; ALCOHOL-USE; DRUG-USE; LONGITUDINAL ANALYSIS; PARENT INFLUENCES; SMOKING; SELECTION; FRIENDSHIPS; PROGRESSION; CIGARETTES AB Peer and adolescent substance use are highly correlated, but this relationship is not fully understood. In particular, the relative contributions of selection and socialization to substance use progression have not been established. Students (n = 2453) in the seven middle schools in one school district were assessed at school at the beginning and end of the sixth, seventh, eighth grade and beginning of the 9th grade. Self-reported smoking and drinking and the number of substance using friends were assessed 5 times over 3 years. The relationship between peer and adolescent substance use were assessed in parallel processes as part of an autoregressive latent trajectory model. Substance use and the number of substance using friends increased in linear fashion from T1 to T5. Initial substance use predicted an increase in the number of substance using friends over time, indicating an effect of selection, and the initial number of substance using friends predicted substance use progression, providing evidence of socialization. The magnitudes of these relationships were similar. Bivariate, lagged autoregressive analyses of the successive relationships from one assessment to the next showed consistent, significant associations from peer use to adolescent substance use. The association from adolescent to peer use was significant only from 7th to 8th grade. The findings provide evidence of reciprocal influences, but socialization was a more consistent influence than selection. (c) 2005 Elsevier Ltd. All rights reserved. C1 NICHHD, Bethesda, MD 20892 USA. RP Simons-Morton, B (reprint author), NICHHD, 6100 Bldg,Room 7B13,MSC 7510, Bethesda, MD 20892 USA. EM Bruce_SimonsMorton@nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 NR 35 TC 64 Z9 66 U1 6 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD JUL PY 2006 VL 31 IS 7 BP 1211 EP 1223 DI 10.1016/j.addbeh.2005.09.006 PG 13 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 061VF UT WOS:000238900200011 PM 16229958 ER PT J AU Boasso, A Vaccari, M Nilsson, J Shearer, GM Andersson, J Cecchinato, V Chougnet, C Franchini, G AF Boasso, Adriano Vaccari, Monica Nilsson, Jakob Shearer, Gene M. Andersson, Jan Cecchinato, Valentina Chougnet, Claire Franchini, Genoveffa TI Do regulatory T-cells play a role in AIDS pathogenesis? SO AIDS REVIEWS LA English DT Article DE regulatory T-cell; HIV immune response; T-cell. immune regulatory; antiviral; immunomodulatory ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; ACTIVE ANTIRETROVIRAL THERAPY; PRIMARY HUMAN MACROPHAGES; INDOLEAMINE 2,3-DIOXYGENASE; METASTATIC MELANOMA; IN-VITRO; TRYPTOPHAN CATABOLISM; ANTIGEN-4 BLOCKADE; SIV INFECTION AB The impairment of adaptive immune responses to HIV and abnormalities in the immune regulatory function mechanisms during HIV infection have been regarded as key issues in AIDS pathogenesis since the early years of the pandemic. However, the multiple mechanisms underlying this impairment are still not fully understood. New emerging information shows that alterations in the number and/or function of regulatory T-cells may contribute to HIV pathogenesis. Thus, pharmacologic manipulation of regulatory T-cells as well as blocking the activity of other immunomodulatory molecules, such as indoleamine 2,3-dioxygenase, glucocorticoid-induced tumor necrosis factor receptor and PD1, might provide a valuable approach to redirect the immune system towards an efficient antiviral response. C1 NCI, Anim Models & Retroviral Vaccines Sect, Expt Immunol Branch, Bethesda, MD 20892 USA. NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. Karolinska Univ Hosp, Karolinska Inst, Ctr Infect Med, Stockholm, Sweden. Univ Cincinnati, Coll Med, Div Mol Immunol, Cincinnati Childrens Hosp Res Fdn, Cincinnati, OH USA. Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, Expt Immunol Branch, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov OI Boasso, Adriano/0000-0001-9673-6319 NR 63 TC 29 Z9 31 U1 0 U2 4 PU PERMANYER PUBLICATIONS PI BARCELONA PA MALLORCA, 310, BARCELONA, SPAIN SN 1139-6121 J9 AIDS REV JI Aids Rev. PD JUL-SEP PY 2006 VL 8 IS 3 BP 141 EP 147 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 093AR UT WOS:000241140000003 PM 17078484 ER PT J AU Sullivan, EV Adalsteinsson, E Sood, R Mayer, D Bell, R McBride, W Li, TK Pfefferbaum, A AF Sullivan, EV Adalsteinsson, E Sood, R Mayer, D Bell, R McBride, W Li, TK Pfefferbaum, A TI Longitudinal brain magnetic resonance imaging study of the alcohol-preferring rat. Part I: Adult brain growth SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE brain growth; rat; MRI; morphology; alcohol; age ID CORTICAL GRAY-MATTER; CORPUS-CALLOSUM SIZE; AGE-RELATED-CHANGES; ANIMAL-MODELS; WHITE-MATTER; HIPPOCAMPAL VOLUME; SEX-DIFFERENCES; CELL-PROLIFERATION; PREFRONTAL GRAY; CEREBRAL-CORTEX AB Background: The alcohol-preferring (P) rat, a Wistar strain selectively bred to consume large amounts of alcohol voluntarily, has been used as an animal model of human alcoholism for 3 decades. Heretofore, knowledge about brain morphology has been confined to postmortem examination. Quantitative neuroimaging procedures make it feasible to examine the potential longitudinal effects of alcohol exposure in vivo, while controlling modifying factors, such as age, nutrition, and exercise. To date, few imaging studies have considered what morphological changes occur with age in the rodent brain, and none has systematically applied quantitative neuroimaging approaches to measure volume changes in regional brain structures over extended periods in the adult rat. Methods: We used structural magnetic resonance imaging (MRI) in a longitudinal design to examine 2 cohorts of adult P rats, never exposed to alcohol: Cohort A included 8 rats, 7 of which survived the entire study (578 days) and 4 MRI sessions; Cohort B included 9 rats, all of which survived the study (452 days) and 5 MRI sessions. Results: Growth in whole-brain volume reached maximal levels by about 450 days of age, whereas body weight continued its gain without asymptote. Growth was not uniform across the brain structures measured. Over the initial 12 months of the study, the corpus callosum area expanded 36%, cerebellum 17%, and hippocampus 10%, whereas ventricle size was unchanged. Factors affecting growth rate estimates included litter effects, MR image signal-to-noise ratio, and measurement error. Conclusion: Unlike longitudinal human reports of regional volume declines in aging brain tissue, several brain structures in adult rats continued growing, and some growth patterns were litter-dependent. Determining normal regional growth patterns of brain and of the substantial variance exerted by litter differences, even in selectively bred rats, is essential for establishing baselines against which normal and aberrant dynamic changes can be detected in animal models of aging and disease. C1 Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. Univ New Mexico, Ctr Hlth, Dept Elect Engn & Comp Sci, Albuquerque, NM 87131 USA. Univ New Mexico, Ctr Hlth, Dept Neurol, Albuquerque, NM 87131 USA. Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA. Indiana Univ, Med Ctr, Inst Psychiat, Indianapolis, IN 46204 USA. Indiana Univ, Med Ctr, Dept Psychiat, Indianapolis, IN 46204 USA. NIAAA, Bethesda, MD USA. SRI Int, Neurosci Program, Menlo Pk, CA 94025 USA. RP Pfefferbaum, A (reprint author), SRI Int, Neurosci Program, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM dolf@synapse.sri.com RI Adalsteinsson, Elfar/F-2477-2010 FU NIAAA NIH HHS [AA13522, AA05965, AA13521, U01 AA013522] NR 81 TC 21 Z9 22 U1 4 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUL PY 2006 VL 30 IS 7 BP 1234 EP 1247 DI 10.1111/j.1530-0277.2006.00145.x PG 14 WC Substance Abuse SC Substance Abuse GA 052SB UT WOS:000238253100018 PM 16792572 ER PT J AU Pfefferbaum, A Adalsteinsson, E Sood, R Mayer, D Bell, R McBride, W Li, TK Sullivan, EV AF Pfefferbaum, A Adalsteinsson, E Sood, R Mayer, D Bell, R McBride, W Li, TK Sullivan, EV TI Longitudinal brain magnetic resonance imaging study of the alcohol-preferring rat. Part II: Effects of voluntary chronic alcohol consumption SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Review DE alcohol; rat; MRI; corpus callosum; voluntary drinking; brain ID CEREBRAL GLUCOSE-UTILIZATION; LIFELONG ETHANOL-CONSUMPTION; POPULATION TWIN SAMPLE; FREE-CHOICE DRINKING; WHITE-MATTER; P-RATS; THIAMINE-DEFICIENCY; CORPUS-CALLOSUM; IN-VIVO; HIPPOCAMPAL VOLUME AB Background: Tracking the dynamic course of human alcoholism brain pathology can be accomplished only through naturalistic study and without opportunity for experimental manipulation. Development of an animal model of alcohol-induced brain damage, in which animals consume large amounts of alcohol following cycles of alcohol access and deprivation and are examined regularly with neuroimaging methods, would enable hypothesis testing focused on the degree, nature, and factors resulting in alcohol-induced brain damage and the prospects for recovery or relapse. Methods: We report the results of longitudinal magnetic resonance imaging (MRI) studies of the effects of free-choice chronic alcohol intake on the brains of 2 cohorts of selectively bred alcohol-preferring (P) rats. In the companion paper, we described the MRI acquisition and analysis methods, delineation of brain regions, and growth patterns in total brain and selective structures of the control rats in the present study. Both cohorts were studied as adults for about 1 year and consumed high doses of alcohol for most of the study duration. The paradigm involved a 3-bottle choice with 0, 15 (or 20%), and 30% (or 40%) alcohol available in several different exposure schemes: continuous exposure, cycles of 2 weeks on followed by 2 weeks off alcohol, and binge drinking in the dark. Results: Brain structures of the adult P rats in both the alcohol-exposed and the water control conditions showed significant growth, which was attenuated in a few measures in the alcohol-exposed groups. The region with the greatest demonstrable effect was the corpus callosum, measured on midsagittal images. Conclusion: The P rats showed an age-alcohol interaction different from humans, in that normal growth in selective brain regions that continues in adult rats was retarded. C1 SRI Int, Neurosci Program, Menlo Pk, CA 94025 USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. Univ New Mexico, Ctr Hlth, Dept Elect Engn & Comp Sci, Albuquerque, NM 87131 USA. Univ New Mexico, Ctr Hlth, Dept Neurol, Albuquerque, NM 87131 USA. Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA. Indiana Univ, Med Ctr, Inst Psychiat, Indianapolis, IN 46204 USA. Indiana Univ, Med Ctr, Dept Psychiat, Indianapolis, IN 46204 USA. NIAAA, Bethesda, MD 90034 USA. RP Pfefferbaum, A (reprint author), SRI Int, Neurosci Program, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM dolf@synapse.sri.com RI Adalsteinsson, Elfar/F-2477-2010 FU NIAAA NIH HHS [U01 AA013522, AA05965, AA13521, AA13522] NR 108 TC 16 Z9 16 U1 4 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUL PY 2006 VL 30 IS 7 BP 1248 EP 1261 DI 10.1111/j.1530-0277.2006.00146.x PG 14 WC Substance Abuse SC Substance Abuse GA 052SB UT WOS:000238253100019 PM 16792573 ER PT J AU Scheiblhofer, S Gabler, M Leitner, WW Bauer, R Zoegg, T Ferreira, F Thalhamer, J Weiss, R AF Scheiblhofer, S Gabler, M Leitner, WW Bauer, R Zoegg, T Ferreira, F Thalhamer, J Weiss, R TI Inhibition of type I allergic responses with nanogram doses of replicon-based DNA vaccines SO ALLERGY LA English DT Article DE alphavirus; DNA vaccine; immunotherapy; replicase; type I allergy ID BIRCH-POLLEN ALLERGEN; HUMAN DENDRITIC CELLS; DOUBLE-STRANDED-RNA; PLASMID DNA; TISSUE DISTRIBUTION; IMMUNE-RESPONSES; IMMUNIZATION; IMMUNOTHERAPY; ACTIVATION; EXPRESSION AB Background: Allergic diseases have become a major public health problem in developed countries; yet, no reliable, safe and consistently effective treatment is available. DNA immunization has been shown to prevent and balance established allergic responses, however, the high dose of conventional DNA vaccines necessary for the induction of anti-allergic reactions and their poor immunogenicity in primates require the development of new allergy DNA vaccines. We evaluated protective and therapeutic effects of a Semliki-Forest Virus replicase-based vs a conventional DNA vaccine in BALB/c mice using the model allergen beta-galactosidase. Methods: Immunoglobulin (Ig)E suppression was determined by a basophil release assay as an in vitro correlate for allergen-specific crosslinking capacity of IgE reflecting the in vivo situation in an allergic individual. Th1 memory responses were measured by cytokine detection via enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot assay (ELISPOT). Results: Nanogram amounts of a replicase-based vector triggered a Th1 response comparable with that achieved with the injection of 20 000-times more copies of a conventional DNA plasmid, and induced IgE suppression in both a protective and a therapeutic setting. Conclusion: Replicase-based DNA vaccines fulfill the stringent criteria for an allergy DNA vaccine, i.e. low dose, strong Th1 immunogenicity and memory, lack of 'therapy-induced' IgE production and anaphylactic side effects. Moreover, by triggering apoptosis in transfected cells, their unique 'immunize and disappear' feature minimizes the hypothetical risks of genomic integration or induction of autoimmunity. C1 Salzburg Univ, Dept Mol Biol, Div Allergy & Immunol, A-5020 Salzburg, Austria. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. Christian Doppler Lab Allergy Diagnost & Therapy, Salzburg, Austria. RP Scheiblhofer, S (reprint author), Salzburg Univ, Dept Mol Biol, Div Allergy & Immunol, Hellbrunnerstr 34, A-5020 Salzburg, Austria. RI Leitner, Wolfgang/F-5741-2011; Weiss, Richard/N-7279-2013; Thalhamer, Josef/E-5787-2011; Ferreira, Fatima/E-4889-2011 OI Leitner, Wolfgang/0000-0003-3125-5922; Weiss, Richard/0000-0003-3185-7253; Thalhamer, Josef/0000-0003-2285-6400; Ferreira, Fatima/0000-0003-0989-2335 FU Austrian Science Fund FWF [L 181] NR 35 TC 14 Z9 14 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0105-4538 J9 ALLERGY JI Allergy PD JUL PY 2006 VL 61 IS 7 BP 828 EP 835 DI 10.1111/j.1398-9995.2006.01142.x PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 053KW UT WOS:000238305000006 PM 16792580 ER PT J AU Launer, LJ AF Launer, Lenore J. TI Prevention of AD: the Which, When, and on Whom? SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Editorial Material DE dementia; cardiovascular risk; prevention ID TYPE-2 DIABETES-MELLITUS; POPULATION-BASED COHORT; HUMAN LIFE-SPAN; COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; BLOOD-PRESSURE; RISK-FACTORS; INCIDENT DEMENTIA; ELDERLY PERSONS; MIDDLE-AGE C1 LEDB, IRP, NIA, NIH, Bethesda, MD 20892 USA. RP Launer, LJ (reprint author), LEDB, IRP, NIA, NIH, 7201 Wisconsin Ave,MSC 9205,Room 3C309, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov FU Intramural NIH HHS NR 39 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2006 VL 20 IS 3 SU 2 BP S75 EP S78 DI 10.1097/00002093-200607001-00011 PG 4 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 081MT UT WOS:000240322400011 PM 16917200 ER PT J AU White, L Launer, L AF White, Lon Launer, Lenore TI Relevance of cardiovascular risk factors and ischemic cerebrovascular disease to the pathogenesis of Alzheimer disease - A review of accrued findings from the honolulu-asia aging study SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article; Proceedings Paper CT Conference on Epidemiology of Alzheimers Disease held in honor of Robert Katzman CY APR 28-29, 2006 CL Univ Calif San Diego, San Diego, CA HO Univ Calif San Diego ID MIDLIFE BLOOD-PRESSURE; JAPANESE-AMERICAN MEN; INCIDENT DEMENTIA; ASSOCIATION; POPULATION; WEIGHT; AD C1 Pacific Hlth Res Inst, Honolulu, HI USA. Kuakini Med Ctr, Honolulu, HI USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD USA. RP White, L (reprint author), Suita 306,846 S Hotel St, Honolulu, HI 96813 USA. EM lrwhite@phrihawaii.org FU NIA NIH HHS [U01 AG 019349, R01 AG 017155-S1] NR 17 TC 14 Z9 14 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2006 VL 20 IS 3 SU 2 BP S79 EP S83 DI 10.1097/00002093-200607001-00012 PG 5 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 081MT UT WOS:000240322400012 PM 16917201 ER PT J AU Wattendorf, DJ AF Wattendorf, Daniel J. TI Genetic predisposition of familial Mediterranean fever - Reply SO AMERICAN FAMILY PHYSICIAN LA English DT Letter C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Wattendorf, DJ (reprint author), NHGRI, NIH, Bldg 31,Room 4B09, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD JUL 1 PY 2006 VL 74 IS 1 BP 43 EP 43 PG 1 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 061UG UT WOS:000238897700004 ER PT J AU Cooper, CJ Murphy, TP Matsumoto, A Steffes, M Cohen, DJ Jaff, M Kuntz, R Jamerson, K Reid, D Rosenfield, K Rundback, J D'Agostino, R Henrich, W Dworkin, L AF Cooper, Christopher J. Murphy, Timothy P. Matsumoto, Alan Steffes, Michael Cohen, David J. Jaff, Michael Kuntz, Richard Jamerson, Kenneth Reid, Diane Rosenfield, Kenneth Rundback, John D'Agostino, Ralph Henrich, William Dworkin, Lance TI Stent revascularization for the prevention of cardiovascular and renal events among patients with renal artery stenosis and systolic hypertension: Rationale and design of the CORAL trial SO AMERICAN HEART JOURNAL LA English DT Article ID ATHEROSCLEROTIC RENOVASCULAR DISEASE; BODY-FLUID VOLUMES; RANDOMIZED-TRIAL; ANGIOTENSIN-II; BLOOD-PRESSURE; HEART-FAILURE; CARDIAC-CATHETERIZATION; MYOCARDIAL-INFARCTION; MORPHOLOGIC EVIDENCE; BALLOON ANGIOPLASTY AB Background Atherosclerotic renal artery stenosis is a problem with no consensus on diagnosis or therapy. The consequences of renal ischemia are neuroendocrine activation, hypertension, and renal insufficiency that can potentially result in acceleration of atherosclerosis, further renal dysfunction, myocardial infarction, heart failure, stroke, and death. Whether revascularization improves clinical outcomes when compared with optimum medical therapy is unknown. Methods CORAL is a randomized clinical trial contrasting optimum medical therapy alone to stenting with optimum medical therapy on a composite cardiovascular and renal end point: cardiovascular or renal death, myocardial infarction, hospitalization for congestive heart failure, stroke, doubling of serum creatinine, and need for renal replacement therapy. The secondary end points evaluate the effectiveness of revascularization in important subgroups of patients and with respect to all-cause mortality, kidney function, renal artery potency, microvascular renal function, and blood pressure control. We will also correlate stenosis severity with longitudinal renal function and determine the value of stenting from the perspectives of quality of life and cost-effectiveness. The primary entry criteria are (1) an atherosclerotic renal stenosis of >= 60% with a 20 mm Hg systolic pressure gradient or >= 80% with no gradient necessary and (2) systolic hypertension of >= 155 mm Hg on >= 2 anti hypertensive medications. Randomization will occur in 1080 subjects. The study has 90% power to detect a 28% reduction in primary end point hazard rate. Conclusions CORAL represents a unique opportunity to determine the incremental value of stent revascularization, in addition to optimal medical therapy, for the treatment of atherosclerotic renal artery stenosis. C1 Med Univ Ohio, Dept Med, Toledo, OH 43614 USA. Brown Univ, Rhode Isl Hosp, Providence, RI 02903 USA. Univ Virginia, Charlottesville, VA USA. Univ Minnesota, Minneapolis, MN USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Michigan, Ann Arbor, MI 48109 USA. NHLBI, Bethesda, MD 20892 USA. Holy Name Hosp, Teaneck, NJ USA. Boston Univ, Boston, MA 02215 USA. Univ Maryland, Baltimore, MD 21201 USA. RP Cooper, CJ (reprint author), Med Univ Ohio, Dept Med, 3000 Arlington Ave,Hosp Room 1192, Toledo, OH 43614 USA. EM ccooper@mco.edu RI Schulz, Sandra/F-6238-2012 FU NHLBI NIH HHS [HL071556] NR 70 TC 186 Z9 191 U1 0 U2 8 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JUL PY 2006 VL 152 IS 1 BP 59 EP 66 DI 10.1016/j.ahj.2005.09.011 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 063ZY UT WOS:000239060200008 PM 16824832 ER PT J AU Jaffe, AS Krumholz, HM Catellier, DJ Freedland, KE Bittner, V Blumenthal, JA Calvin, JE Norman, J Sequeira, R O'Connor, C Rich, MW Sheps, D Wu, C AF Jaffe, Allan S. Krumholz, Harlan M. Catellier, Diane J. Freedland, Kenneth E. Bittner, Vera Blumenthal, James A. Calvin, James E. Norman, James Sequeira, Rafael O'Connor, Christopher Rich, Michael W. Sheps, David Wu, Colin CA ENRICHD Invest TI Prediction of medical morbidity and mortality after acute myocardial infarction in patients at increased psychosocial risk in the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) study SO AMERICAN HEART JOURNAL LA English DT Article ID INTERNATIONAL TRIAL; ARTERY DISEASE; DEPRESSION; SURVIVAL; IMPACT; REPERFUSION; PROGNOSIS; SYMPTOMS; SUPPORT; ERA AB Background Patients with myocardial infarction (MI) are at further increased risk for untoward events when patients also exhibit low social support and/or depression. The ENRICHD study was the largest controlled trial in post-Ml patients attempting to treat these psychological comorbidities and provides an opportunity to examine the medical and psychological characteristics that may affect risk in this population. Methods We analyzed the baseline characteristics and their relationship to the primary end point of long-term mortality and recurrent infarction and to the secondary end points of overall mortality and cardiovascular mortality in 2481 post-Ml patients. Cox proportional hazards models were used to predict the risk of these outcomes over a mean of 2.5 years of follow-up. Results Death or nonfatal MI occurred in 24.1%, all-cause mortality in 13.7%, and cardiovascular mortality in 8.4% of the sample (62% of the total). Age, heart failure, pulmonary disease, Killip class, ejection fraction, an elevated creatinine, the use of non-angiotensin-coverting enzyme asodilators, prior MI, diabetes, depression, and bypass surgery after acute MI were all significant multivariable predictors. Conclusions The medical predictors of adverse events in post-MI patients with low social support and/or depression were similar to those of patients with MI in other clinical trials. C1 Mayo Clin & Mayo Fdn, Div Cardiovasc, Rochester, MN 55905 USA. Yale Univ, Sch Med, Div Cardiovasc, New Haven, CT USA. Univ N Carolina, Sch Med, Dept Biostat, Chapel Hill, NC USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Univ Alabama, Div Cardiovasc Dis, Birmingham, AL 35294 USA. Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. Rush Presbyterian St Lukes Med Ctr, Div Cardiovasc, Chicago, IL 60612 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Univ Miami, Jackson Mem Hosp, Sch Med, Miami, FL 33136 USA. Duke Univ, Sch Med, Div Cardiovasc, Durham, NC USA. Washington Univ, Sch Med, Div Cardiovasc, St Louis, MO 63110 USA. Univ Florida, Sch Med, Div Cardiovasc, Gainesville, FL USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Jaffe, AS (reprint author), Mayo Clin & Mayo Fdn, Div Cardiovasc, Gonda 5,200 1st St SW, Rochester, MN 55905 USA. EM jaffe.allan@mayo.edu OI Bittner, Vera/0000-0001-9456-850X FU NHLBI NIH HHS [N01-HC-55140, N01-HC-55141, N01-HC-55142, N01-HC-55143, N01-HC-55144, N01-HC-55145, N01-HC-55146, N01-HC-55147, N01-HC-55148] NR 35 TC 45 Z9 45 U1 1 U2 6 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JUL PY 2006 VL 152 IS 1 BP 126 EP 135 DI 10.1016/j.ahj.2005.10.004 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 063ZY UT WOS:000239060200019 PM 16824842 ER PT J AU Miller, FG AF Miller, Franklin G. TI Equipoise and the ethics of clinical research revisited SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID TRIALS; CRITIQUE C1 NIH, Bethesda, MD USA. RP Miller, FG (reprint author), NIH, Bethesda, MD USA. NR 9 TC 3 Z9 3 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PD JUL-AUG PY 2006 VL 6 IS 4 BP 59 EP 61 DI 10.1080/15265160600755672 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 070OY UT WOS:000239533600020 PM 16885110 ER PT J AU Litton, P AF Litton, Paul TI Defending the distinction between research and medical care SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID CLINICAL-RESEARCH; RESPONSIBILITIES C1 NIH, Bethesda, MD USA. RP Litton, P (reprint author), NIH, Bethesda, MD USA. NR 7 TC 2 Z9 2 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PD JUL-AUG PY 2006 VL 6 IS 4 BP 63 EP 66 DI 10.1080/15265160600755698 PG 5 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 070OY UT WOS:000239533600022 PM 16885112 ER PT J AU Miller, MF Stoltzfus, RJ Iliff, PJ Malaba, LC Humphrey, JH AF Miller, Melissa F. Stoltzfus, Rebecca J. Iliff, Peter J. Malaba, Lucie C. Humphrey, Jean H. CA ZVITAMBO Study Grp TI Effect of maternal and neonatal vitamin A supplementation and other postnatal factors on anemia in Zimbabwean infants: a prospective, randomized study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE vitamin A; infants; hemoglobin; HIV; supplementation; Zimbabwe ID HUMAN-IMMUNODEFICIENCY-VIRUS; TOTAL-BODY IRON; COMPLEMENTARY FOODS; FERRITIN CONCENTRATIONS; FEEDING PRACTICES; BREAST-MILK; HEMOGLOBIN; DEFICIENCY; ABSORPTION; CHILDREN AB Background: Anemia is prevalent in infants in developing countries. Its etiology is multifactorial and includes vitamin A deficiency. Objective: Our primary aim was to measure the effect of maternal or neonatal vitamin A supplementation (or both) on hemoglobin and anemia in Zimbabwean infants. Our secondary aim was to identify the underlying causes of postnatal anemia. Design: A randomized, placebo-controlled trial was conducted in 14 110 mothers and their infants; 2854 infants were randomly selected for the anemia substudy, of whom 1592 were successfully observed for 8-14 mo and formed the study sample. Infants were randomly assigned within 96 h of delivery to 1 of 4 treatment groups: mothers and infants received vitamin A; mothers received vitamin A and infants received placebo; mothers received placebo and infants received vitamin A; and mothers and infants received placebo. The vitamin A doses were 400 000 and 50 000 IU in the mothers and infants, respectively. Results: Vitamin A supplementation had no effect on hemoglobin or anemia (hemoglobin < 105 g/L) in unadjusted or adjusted analyses. Infant HIV infection independently increased anemia risk > 6-fold. Additional predictors of anemia in HIV-negative and -positive infants were male sex and lower total body iron at birth. In addition, in HIV-positive infants, the risk of anemia increased with early infection, low maternal CD4(+) lymphocyte count at recruitment, and frequent morbidity. Six-month plasma ferritin concentrations < 12 mu g/L were a risk factor in HIV-negative but not in HIV-positive infants. Maternal HIV infection alone did not cause anemia. Conclusion: Prevention of infantile anemia should include efforts to increase the birth endowment of iron and prevent HIV infection. C1 NCI, Canc Prevent Fellowship Program, Div Canc Prevent, Bethesda, MD 20892 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. Univ Zimbabwe, Div Nutr, Inst Food Nutr & Family Sci, Harare, Zimbabwe. Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. RP Miller, MF (reprint author), 6116 Execut Blvd,Suite 404, Bethesda, MD 20892 USA. EM millermeli@mail.nih.gov OI Moulton, Lawrence/0000-0001-7041-7387 NR 57 TC 17 Z9 19 U1 0 U2 2 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2006 VL 84 IS 1 BP 212 EP 222 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 064RD UT WOS:000239105900025 PM 16825698 ER PT J AU Mahabir, S Baer, DJ Giffen, C Clevidence, BA Campbell, WS Taylor, PR Hartman, TJ AF Mahabir, Somdat Baer, David J. Giffen, Carol Clevidence, Beverly A. Campbell, William S. Taylor, Philip R. Hartman, Terry J. TI Comparison of energy expenditure estimates from 4 physical activity questionnaires with doubly labeled water estimates in postmenopausal women SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE doubly labeled water; physical activity questionnaires; postmenopausal women ID CULTURAL ACTIVITY PARTICIPATION; ACTIVITY RECALL; CALORIMETRY; VALIDATION; EXERCISE; RISK AB Background: Physical activity energy expenditure (EE) is an important determinant of health, and epidemiologists have used various methods, such as physical activity and energy intake recalls and records, to estimate energy cost. However, most epidemiologic studies have not validated these methods against the doubly labeled water (DLW) technique for measuring EE. Objective: The aim was to compare EE estimated by 4 physical activity questionnaires with that obtained with the DLW technique in free-living postmenopausal women. Design: We measured EE in kcal/d using the DLW method, the Harvard Alumni questionnaire, the Five City Project questionnaire, the Cross-Cultural Activity Participation Study (CAPS) Four Week Activity Recall, and the CAPS Typical Week Activity Survey in 65 healthy postmenopausal women. Results: Compared with DLW, the Harvard Alumni questionnaire, the Five City Project questionnaire, and the CAPS Four Week Activity Recall overestimated (P < 0.05) daily EE by 62%, 16%, and 11%, respectively, whereas the CAPS Typical Week Activity Recall underestimated (P < 0.05) EE by 31%. Both the Harvard Alumni and Five City Project questionnaires overestimated EE in obese and overweight women. Conclusions: When using 3 of the 4 questionnaire methods, postmenopausal women overestimated EEs. Of all women, obese women overestimated daily EE the most. C1 Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. USDA ARS, Beltsville, MD USA. Informat Management Serv Inc, Silver Spring, MD USA. NIH, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. RP Mahabir, S (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Unit 1340,CPB4-3247,1155 Pressler Blvd, Houston, TX 77030 USA. EM smahabir@mdanderson.org RI Mahabir, Somdat/A-9788-2008 FU Intramural NIH HHS NR 31 TC 60 Z9 62 U1 1 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2006 VL 84 IS 1 BP 230 EP 236 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 064RD UT WOS:000239105900027 PM 16825700 ER PT J AU Weiss, JM Saltzman, BS Doherty, JA Voigt, LF Chen, C Beresford, SAA Hill, DA Weiss, NS AF Weiss, JM Saltzman, BS Doherty, JA Voigt, LF Chen, C Beresford, SAA Hill, DA Weiss, NS TI Risk factors for the incidence of endometrial cancer according to the aggressiveness of disease SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE endometrial neoplasms; neoplasm invasiveness ID HORMONE-REPLACEMENT THERAPY; HEALTHY POSTMENOPAUSAL WOMEN; PAPILLARY SEROUS CARCINOMA; ESTROGEN PLUS PROGESTIN; CLEAR-CELL CARCINOMA; EXOGENOUS ESTROGEN; UTERINE CARCINOMAS; ADENOCARCINOMA; INVASION; INFORMATION AB There is a wide range of aggressiveness of endometrial tumors, some being indolent and easily treated while others metastasize and prove fatal. The authors used data from three population-based, case-control studies to determine if etiologic factors differ for aggressive disease. Interview data were obtained from 1,304 female residents of western Washington State who were 45-74 years of age and diagnosed with endometrial cancer during 1985-1991, 1994-1995, and 1997-1999 and from 1,779 controls who were of similar ages and selected primarily by random digit dialing. As a means of gauging aggressiveness, tumor characteristics were abstracted from the population-based cancer registry that serves western Washington State. The risk of endometrial cancer among long-term users (>= 8 years) of unopposed estrogens was particularly high for the least aggressive tumors (odds ratio = 18.6, 95% confidence interval: 12.2, 28.6) but was elevated for moderate and highly aggressive tumors as well (odds ratios = 6.6 and 7.1, respectively). Women who were obese, had a history of diabetes, and had fewer than two children were also at increased risk, regardless of tumor aggressiveness, while oral contraceptive users were at decreased risk of only relatively more aggressive disease. In general, a woman's risk of endometrial cancer appears to be influenced by similar risk factors regardless of disease severity. C1 Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Otolaryngol Head & Neck Surg, Seattle, WA 98195 USA. Univ New Mexico, Sch Med, Dept Internal Med, Albuquerque, NM 87131 USA. RP Weiss, JM (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, 6120 Execut Blvd,EPS 8123,MSC 7240, Bethesda, MD 20892 USA. EM weissjoc@mail.nih.gov FU NCI NIH HHS [K05-CA92002, R01-CA75977, R01-CA47749, R35-CA39779]; NICHD NIH HHS [N01-HD3166] NR 49 TC 18 Z9 21 U1 0 U2 1 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 JUL 1 PY 2006 VL 164 IS 1 BP 56 EP 62 DI 10.1093/aje/kwj152 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 056PF UT WOS:000238536900009 PM 16675538 ER PT J AU Kato, GJ Hsieh, M Machado, R Taylor, J Little, J Butman, JA Lehky, T Tisdale, J Gladwin, MT AF Kato, GJ Hsieh, M Machado, R Taylor, J Little, J Butman, JA Lehky, T Tisdale, J Gladwin, MT TI Cerebrovascular disease associated with sickle cell pulmonary hypertension SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE sickle cell disease; stroke; nitric oxide; hemolysis; vascular disease ID NITRIC-OXIDE; ENDOTHELIAL DYSFUNCTION; ARGININE METABOLISM; PLASMA HEMOGLOBIN; RISK-FACTOR; STROKE; ANEMIA; HEMOLYSIS; DEHYDROGENASE; RESISTANCE AB In patients with sickle cell disease, anemia is a recognized risk factor for stroke, death, and the development of pulmonary hypertension. We have proposed that hemolytic anemia results in endothelial dysfunction and vascular Instability and can ultimately lead to a proliferative vasculopathy leading to pulmonary hypertension. Consistent with this mechanism of disease, we now report a case series of six patients with obliterative central nervous system vasculopathy who also have pulmonary hypertension and high hemolytic rate. These patients, identified in the course of a prospective screening study for pulmonary hypertension, presented with neurological symptoms prompting neuroimaging studies. Compared to 164 other patients of similar age in the screened population, those with newly diagnosed or clinically active cerebrovascular disease have significantly lower hemoglobin levels and higher levels of lactate dehydrogenase. A review of the literature suggests that many clinical, epidemiological, and physiological features of the arteriopathy of pulmonary hypertension closely overlap with those of stroke in sickle cell disease, both known to involve proliferative vascular intimal and smooth muscle hypertrophy and thrombosis. These cases suggest that cerebrovascular disease and pulmonary hypertension in sickle cell disease share common mechanisms, in particular, reduced nitric oxide bioactivity associated with particularly high-grade hemolysis. Clinicians should suspect occult cerebrovascular disease in sickle cell patients with pulmonary hypertension. Am. J. Hematol. 81:503-510, 2006. Published 2006 Wiley-Liss, Inc.dagger C1 NHLBI, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. NINDS, Electromyog Sect, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Kato, GJ (reprint author), 10 Ctr Dr,MSC 1476,Bldg 10-CRC,Room 5-5140, Bethesda, MD 20892 USA. EM gkato@mail.nih.gov RI Butman, John/A-2694-2008; Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Butman, John/0000-0002-1547-9195; Taylor, James/0000-0002-4421-1809 FU Intramural NIH HHS [Z01 CL008070-04, Z99 HL999999, ZIA HL006014-02, Z01 CL001174-07] NR 44 TC 48 Z9 50 U1 0 U2 3 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 JUL PY 2006 VL 81 IS 7 BP 503 EP 510 DI 10.1002/ajh.20642 PG 8 WC Hematology SC Hematology GA 059OO UT WOS:000238742300005 PM 16755569 ER PT J AU Voruganti, VS Cai, GW Freeland-Graves, JH Laston, S Wenger, CR MacCluer, JW Dyke, B Devereux, R Ebbesson, SOE Fabsitz, RR Howard, BV Comuzzie, AG AF Voruganti, VS Cai, GW Freeland-Graves, JH Laston, S Wenger, CR MacCluer, JW Dyke, B Devereux, R Ebbesson, SOE Fabsitz, RR Howard, BV Comuzzie, AG TI Common set of glenes regulates low-density lipoprotein size and obesity-related factors in Alaskan Eskimos: Results from the GOCADAN Study SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Article ID INSULIN-RESISTANCE SYNDROME; CORONARY-HEART-DISEASE; BERING STRAITS REGION; PARTICLE-SIZE; LDL SIZE; CARDIOVASCULAR-DISEASE; PEDIGREE ANALYSIS; HDL CHOLESTEROL; SIBERIA PROJECT; ADIPOSITY AB Increasing incidence of cardiovascular disease in traditionally low-risk Alaskan Eskimos is a cause for concern. The purpose of this study was to examine the genetic and environmental correlations of low-density lipoprotein (LDL) subfractions with obesity-related factors in Alaskan Eskimos, using data from the first 954 participants of the Genetics of Coronary Artery Disease in Alaska Natives Study. Estimates of genetic and environmental influence were calculated using a maximum likelihood variance component method implemented in SOLAR. Mean values of weight, body mass index (BMI), and waist were 73.4 +/- 0.5 kg, 27.6 +/- 0.2 kg/m(2) and 88.0 +/- 0.4 cm, respectively. LDL, and its small (LDL1), medium (LDL2), and large (LDL3) subfractions, had mean values of 115.8 +/- 1.2 mg/dl, 8.3 +/- 0.4 mg/dl, 19.6 +/- 0.8 mg/dl, and 71.5 +/- 1.5 mg/dl, respectively. Bivariate analysis displayed significant genetic correlations between LDL subfractions and obesity-related factors: LDL1 with BMI (rho(G) = 0.67, P < 0.05), waist (rho(G) = 0.80, P < 0.001), and subscapular and tricep skinfolds (rho(G) = 0.93, P < 0.005, and rho(G), = 0.78, P < 0.05, respectively); LDL2 with BMI (rho(G) = 0.52, P < 0.05), waist (rho(G) = 0.46, P < 0.05), and tricep skinfold (rho(G) = 0.60, P < 0.05); and mean LDL size with BMI (rho(G) = -0.36), waist (rho(G) = -0.42), and subscapular and tricep skinfolds (rho(G) = -0.44 and -0.43, respectively) (P < 0.005). These results show that a common set of genes is influencing LDL size and obesity-related factors in Alaskan Eskimos. C1 SW Fdn Biomed Res, Dept Genet, San Antonio, TX 78245 USA. Univ Texas, Div Nutr Sci, Austin, TX 78712 USA. Cornell Univ, Med Ctr, Greenberg Div Cardiol, New York, NY 10021 USA. Norton Sound Hlth Corp, Nome, AK 99709 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Medstar Res Inst, Hyattsville, MD 20783 USA. RP Voruganti, VS (reprint author), SW Fdn Biomed Res, Dept Genet, POB 760549, San Antonio, TX 78245 USA. EM svorugan@darwin.sfbr.org FU NHLBI NIH HHS [U01 HL 64244]; NIMH NIH HHS [MH 59490] NR 38 TC 9 Z9 9 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD JUL-AUG PY 2006 VL 18 IS 4 BP 525 EP 531 DI 10.1002/ajhb.20527 PG 7 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 057VU UT WOS:000238624100010 PM 16788905 ER PT J AU Modi, WS Lautenberger, J An, P Scott, K Goedert, JJ Kirk, GD Buchbinder, S Phair, J Donfield, S O'Brien, SJ Winkler, C AF Modi, WS Lautenberger, J An, P Scott, K Goedert, JJ Kirk, GD Buchbinder, S Phair, J Donfield, S O'Brien, SJ Winkler, C TI Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV type 1 transmission and AIDS disease progression SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ANTIRETROVIRAL THERAPY; CHEMOTACTIC CYTOKINES; VIRUS-REPLICATION; T-CELLS; INFECTION; RANTES; COHORT; MIP-1-ALPHA; HEMOPHILIA; CCR5 AB CCL3 ( MIP-1 alpha), CCL4 ( MIP-1 beta), and CCL18 ( DC-CK1/PARC/AMAC-1) are potent chemoattractants produced by macrophages, natural killer cells, fibroblasts, mast cells, CD4(+) T cells, and CD8(+) T cells. CCL3 and CCL4 are natural ligands for the primary human immunodeficiency virus type 1 ( HIV-1) coreceptor CCR5 and are also known to activate and enhance the cytotoxicity of natural killer cells. Genomic DNAs from 13,000 participants enrolled in five United States based natural-history cohorts with acquired immunodeficiency syndrome ( AIDS) were genotyped for 21 single-nucleotide polymorphisms ( SNPs) in a 47-kb interval on chromosome 17q12 containing the genes CCL3, CCL4, and CCL18. All 21 SNPs were polymorphic in African Americans ( AAs), whereas 7 of the 21 had minor-allele frequencies < 0.01 in European Americans ( EAs). Substantial linkage disequilibrium was observed in a 37-kb interval containing 17 SNPs where many pairwise D' values exceeded 0.70 in both racial groups, but particularly in EAs. Four and three haplotype blocks were observed in AAs and EAs, respectively. Blocks were strongly correlated with each other, and common haplotype diversity within blocks was limited. Two significant associations are reported that replicate an earlier study. First, among AA members of the AIDS Link to the Intravenous Experience cohort of injection drug users, frequencies of three correlated SNPs covering 2,231 bp in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconvertors (). Second, seven highly correlated SNPs spanning P = .02 -. 03 36 kb and containing all three genes were significantly associated with more-rapid disease progression among EAs enrolled in the Multicenter AIDS Cohort Study cohort (). These results reiterate the importance of chemokine gene P = .01 -. 02 variation in HIV-1/AIDS pathogenesis and emphasize that localized linkage disequilibrium makes the identification of causal mutations difficult. C1 NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. NCI, Viral Epidemiol Branch, Rockville, MD USA. San Francisco Dept Publ Hlth, San Francisco, CA USA. Northwestern Univ, Sch Med, Dept Med, Evanston, IL USA. Rho Inc, Chapel Hill, NC USA. RP Winkler, C (reprint author), NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. EM winkler@ncifcrf.gov RI Kirk, Gregory/A-8484-2009 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 39 TC 37 Z9 37 U1 0 U2 6 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL PY 2006 VL 79 IS 1 BP 120 EP 128 DI 10.1086/505331 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 053YD UT WOS:000238341200012 PM 16773571 ER PT J AU Grupe, A Li, YH Rowland, C Hinrichs, T Holmans, P Hardy, J O'Donovan, M Owen, MJ Williams, J Goate, A AF Grupe, A Li, YH Rowland, C Hinrichs, T Holmans, P Hardy, J O'Donovan, M Owen, MJ Williams, J Goate, A TI Single-nucleotide polymorphism rs498055 on chromosome 10q24 is not associated with Alzheimer disease in two independent family samples - Reply SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter C1 Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. Celera Diagnost, Alameda, CA USA. Univ Wales Coll Cardiff, Coll Med, Biostat & Bioinformat Unit, Cardiff, S Glam, Wales. Univ Wales Coll Cardiff, Coll Med, Dept Psychol Med, Cardiff, S Glam, Wales. NIA, Bethesda, MD 20892 USA. RP Goate, A (reprint author), Washington Univ, Sch Med, Dept Psychiat, B8134,660 S Euclid Ave, St Louis, MO 63110 USA. EM goate@icarus.wustl.edu RI turton, miranda/F-4682-2011 NR 5 TC 1 Z9 1 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL PY 2006 VL 79 IS 1 BP 183 EP 184 DI 10.1086/505033 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 053YD UT WOS:000238341200022 ER PT J AU Sharabi, Y Adler, E Shamis, A Nussinovitch, N Markovitz, A Grossman, E AF Sharabi, Yehonatan Adler, Eldad Shamis, Ari Nussinovitch, Naomi Markovitz, Avinoam Grossman, Ehud TI Efficacy of add-on aldosterone receptor blocker in uncontrolled hypertension SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE spironolactone; uncontrolled hypertension; renin; aldosterone; potassium ID LOW-DOSE SPIRONOLACTONE; RESISTANT HYPERTENSION; PRIMARY HYPERALDOSTERONISM; HIGH PREVALENCE; WHITE SUBJECTS; SLEEP-APNEA; RATIO; THERAPY; VALIDITY AB Background: Uncontrolled hypertension (UH) may be caused by hyperaldosteronism, and some experts recommend the routine use of aldosterone antagonists in this condition. The purpose of this study was to evaluate the efficacy of this approach and to characterize those who respond effectively to an add-on aldosterone antagonist. Methods: We retrospectively analyzed the effectiveness of spironolactone, an aldosterone antagonist, used as add-on therapy, compared with a standard add-on treatment, in patients referred to a hypertension clinic with UH despite the use of two or more anti hypertensive drugs. Results: A total of 340 patients (186 male) with an average age of 63 14 years were followed for at least 3 months. Of the patients, 42 received add-on spironolactone and 298 received an additional antihypertensive drug other than spironolactone. Baseline characteristics were similar in both groups. Blood pressure (BP) decreased significantly in both groups. In patients who received spironolactone, BP decreased by 23.2/12.5 mm Hg from 165 +/- 27/94 +/- 15 to 142 +/- 25/81 +/- 9 mm Hg, whereas in patients who received other add-on therapy BP decreased by 7.6/5.8 mm Hg from 160 +/- 24/91 +/- 12 to 152 +/- 20/85 +/- 11 mm Hg (P < .05). Patients who received spironolactone had lower serum potassium levels than those who did not receive spironolactone 3.8 +/- 0.4 v 4.5 +/- 0.5 mmol/L respectively (P <.001). Potassium levels < 4 mmol/L were associated with a greater reduction in BP. Conclusions: Add-on spironolactone is a highly effective add-on treatment in UH, mainly in patients with low serum potassium levels. Further studies assessing serum potassium as a marker for treatment approach are needed to establish the role of aldosterone antagonists in the management of UH. Am J Hypertens 2006;19: 750-755 (c) 2006 American Journal of Hypertension, Ltd. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. Chaim Sheba Med Ctr, Hypertens Unit, IL-52621 Tel Hashomer, Israel. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. RP Sharabi, Y (reprint author), NINDS, Clin Neurocardiol Sect, NIH, 10 Ctr Dr,Bldg 10-6N252, Bethesda, MD 20892 USA. OI Grossman, Ehud/0000-0001-8353-0661 NR 31 TC 46 Z9 47 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD JUL PY 2006 VL 19 IS 7 BP 750 EP 755 DI 10.1016/j.amjhyper.2005.11.016 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 061QJ UT WOS:000238887100017 PM 16814132 ER PT J AU Duarte, G Read, JS Gonin, R Freimanis, L Ivalo, S Melo, VH Marcolin, A Mayoral, C Ceriotto, M de Souza, R Cardoso, E Harris, DR AF Duarte, Geraldo Read, Jennifer S. Gonin, Rene Freimanis, Laura Ivalo, Silvina Melo, Victor H. Marcolin, Alessandra Mayoral, Claudia Ceriotto, Mariana de Souza, Ricardo Cardoso, Edmundo Harris, D. Robert CA NISDI Perinatal Study Grp TI Mode of delivery and postpartum morbidity in Latin American and Caribbean countries among women who are infected with human immunodeficiency virus-1: The NICHD International Site Development Initiative (NISDI) Perinatal Study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 12th Conference on Retroviruses and Opportunistic Infections CY FEB 22-25, 2005 CL Boston, MA DE cesarean delivery; human immunodeficiency virus-1; postpartum morbidity ID HUMAN-IMMUNODEFICIENCY-VIRUS; ELECTIVE CESAREAN DELIVERY; TO-CHILD TRANSMISSION; MATERNAL COMPLICATIONS; VAGINAL DELIVERY; SECTION; PREVENTION; HIV-1 AB Objective: The purpose of this study was to test whether cesarean delivery before labor and before ruptured membranes is associated with a higher risk of postpartum morbidity than vaginal delivery among women who, are infected with human immunodeficiency virus-1 in Latin America and the Caribbean. Study design: Data from a prospective cohort study (National Institute of Child Health and Human Development International Site Development Initiative Perinatal Study) were analyzed. The study population consisted of women who were followed for >= 6 to 12 weeks after delivery, who had singleton infants, and with a known mode of delivery. Results: Of 819 enrollees, 697 women met inclusion criteria (299 vaginal deliveries, 260 cesarean deliveries before labor and before ruptured membranes, 138 cesarean deliveries after labor and/or after ruptured membranes); 36 women (5%) had postpartum morbidity (18 major, 18 minor). Mode of delivery was associated with postpartum morbidity (P =.02). Unadjusted odds ratios (95% CIs) for postpartum morbidity according to mode of delivery were cesarean delivery before labor and before ruptured membranes (odds ratio, 1.16 [95% CI, 0.5, 2.7]), cesarean delivery after labor and/or after ruptured membranes (odds ratio, 2.96 [95% CI, 1.3, 6.7]), and vaginal delivery (reference). These results did not differ appreciably with covariate adjustment. Conclusion: The rate of postpartum morbidity was low. Mode of delivery was associated with postpartum morbidity, possibly reflecting the larger proportion of minor postpartum morbidity events among those with cesarean delivery after labor and/or after ruptured membranes. (c) 2006 Mosby, Inc. All rights reserved. C1 NICHHD, Pediat Adolescent & Maternal AIDS Branch, CRMC, DHHS,NIH, Bethesda, MD 20892 USA. Univ Sao Paulo, Sch Med, BR-14049 Ribeirao Preto, Brazil. WESTAT Corp, Rockville, MD 20850 USA. Hosp Gen Agudos Jose Maria Ramos Mejia, Buenos Aires, DF, Argentina. Univ Fed Minas Gerais, Sch Med, Belo Horizonte, MG, Brazil. HIGA Dr Diego Paroissien, Buenos Aires, DF, Argentina. Hosp Dra Cecilia Grierson, Buenos Aires, DF, Argentina. Univ Caxias Sul, Lab Pesquisa HIV AIDS, Caxias do Sul, Brazil. Na Sa Conceicao Hosp, Porto Alegre, RS, Brazil. RP Read, JS (reprint author), NICHHD, Pediat Adolescent & Maternal AIDS Branch, CRMC, DHHS,NIH, Execut Bldg,Room 4B11F,6100 Execut Blvd,MSC 7510, Bethesda, MD 20892 USA. EM JENNIFER_READ@NIH.GOV RI Mussi-Pinhata, Marisa/G-6568-2012; Duarte, Geraldo/J-7906-2012 FU NICHD NIH HHS [N01-HD-3-3345] NR 31 TC 9 Z9 10 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUL PY 2006 VL 195 IS 1 BP 215 EP 229 DI 10.1016/j.ajog.2006.01.040 PG 15 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 062EF UT WOS:000238926700033 PM 16677591 ER PT J AU Oh, YS Turner, RJ AF Oh, YS Turner, RJ TI Effect of gamma-secretase inhibitors on muscarinic receptor-mediated calcium signaling in human salivary epithelial cells SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE presenilin; carbachol; inositol 1,4,5-trisphosphate; Alzheimer's disease ID ALZHEIMERS-DISEASE; MUTANT PRESENILIN-1; DOWN-REGULATION; MUTATION; ENTRY; MICE; HOMEOSTASIS; FIBROBLASTS; EXPRESSION; MEMBRANE AB Altered intracellular Ca2+ signaling has been observed in cells derived from Alzheimer's disease patients, and a possible link between gamma-secretase activity and the content of intracellular Ca2+ stores has been suggested. To test this hypothesis we studied the effects of several gamma-secretase inhibitors on muscarinic receptor-mediated intracellular calcium release in the human salivary gland cell line HSG. Although several inhibitors in the peptide aldehyde class partially blocked carbachol-induced Ca2+ transients, these effects did not appear to be due to gamma-secretase inhibition, and overall we found no evidence that inhibition of gamma-secretase activity had any significant effect on agonist-induced intracellular calcium release in HSG cells. In complementary experiments with presenilin-null cells we found that the reconstitution of gamma-secretase activity by transfection with wild-type presenilin 1 likewise had no significant effect on thapsigargin-induced Ca2+ release. In a test of the specific hypothesis that the level of APP intracellular domain (AICD), the intracellular fragment of the beta-amyloid precursor protein (APP) resulting from gamma-secretase cleavage, can modulate the Ca2+ content of the endoplasmic reticulum, we were unable to demonstrate any effect of APP small interfering RNA on the magnitude of carbachol-induced intracellular calcium release in HSG cells. Together our data cast considerable doubt on the hypothesis that there is a direct link between gamma-secretase activity and the content of intracellular Ca2+ stores. C1 Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, Gene Therapy & Therapeut Branch, Bethesda, MD 20892 USA. RP Turner, RJ (reprint author), Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, Gene Therapy & Therapeut Branch, Bldg 10,Rm 1A01,GTTB, Bethesda, MD 20892 USA. EM rjturner@mail.nih.gov FU Intramural NIH HHS NR 41 TC 12 Z9 12 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JUL PY 2006 VL 291 IS 1 BP C76 EP C82 DI 10.1152/ajpcell.00508.2005 PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 053EI UT WOS:000238287500010 PM 16467403 ER PT J AU Hall, KD AF Hall, KD TI Computational model of in vivo human energy metabolism during semistarvation and refeeding SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE body composition; mathematical model; weight loss ID BODY-WEIGHT; INDIRECT CALORIMETRY; ADAPTIVE THERMOGENESIS; PHYSICAL-ACTIVITY; NUTRIENT BALANCE; NITROGEN-BALANCE; ACID-METABOLISM; SKELETAL-MUSCLE; FASTING HUMANS; ADIPOSE-TISSUE AB Changes in body weight and composition are the result of complex interactions among metabolic fluxes contributing to macronutrient balances. To better understand these interactions, a mathematical model was constructed that used the measured dietary macronutrient intake during semistarvation and refeeding as model inputs and computed whole body energy expenditure, de novo lipogenesis, and gluconeogenesis as well as turnover and oxidation of carbohydrate, fat, and protein. Published in vivo human data provided the basis for the model components that were integrated by fitting a few unknown parameters to the classic Minnesota human starvation experiment. The model simulated the measured body weight and fat mass changes during semistarvation and refeeding and predicted the unmeasured metabolic fluxes underlying the body composition changes. The resting metabolic rate matched the experimental measurements and required a model of adaptive thermogenesis. Refeeding caused an elevation of de novo lipogenesis that, along with increased fat intake, resulted in a rapid repletion and overshoot of body fat. By continuing the computer simulation with the prestarvation diet and physical activity, the original body weight and composition were eventually restored, but body fat mass was predicted to take more than one additional year to return to within 5% of its original value. The model was validated by simulating a recently published short-term caloric restriction experiment without changing the model parameters. The predicted changes in body weight, fat mass, resting metabolic rate, and nitrogen balance matched the experimental measurements, thereby providing support for the validity of the model. C1 NIDDKD, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Hall, KD (reprint author), NIDDK, NIH, 12 South Dr,Rm 4007, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov RI Hall, Kevin/F-2383-2010; Biguzzi, Felipe/E-4724-2015 FU Intramural NIH HHS [Z01 DK013023-04] NR 72 TC 66 Z9 67 U1 1 U2 13 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JUL PY 2006 VL 291 IS 1 BP E23 EP E37 DI 10.1152/ajpendo.00523.2005 PG 15 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 057FJ UT WOS:000238581400004 PM 16449298 ER PT J AU Jacobson, L Ansari, T Potts, J McGuinness, OP AF Jacobson, L Ansari, T Potts, J McGuinness, OP TI Glucocorticoid-deficient corticotropin-releasing hormone knockout mice maintain glucose requirements but not autonomic responses during repeated hypoglycemia SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE hypoglycemia unawareness; hypoglycemia-associated autonomic failure; catecholamines; adrenal insufficiency ID COUNTERREGULATORY RESPONSES; ANTECEDENT HYPOGLYCEMIA; NORMAL HUMANS; RECURRENT HYPOGLYCEMIA; DIABETES-MELLITUS; ADDISONS-DISEASE; FOOD-INTAKE; CORTISOL; EPINEPHRINE; INSULIN AB Glucocorticoids have been implicated in hypoglycemia-induced autonomic failure but also contribute to normal counterregulation. To determine the influence of normal and hypoglycemia-induced levels of glucocorticoids on counterregulatory responses to acute and repeated hypoglycemia, we compared plasma catecholamines, corticosterone, glucagon, and glucose requirements in male wild-type (WT) and glucocorticoid-deficient, corticotropin-releasing hormone knockout (CRH KO) mice. Conscious, chronically cannulated, unrestrained WT and CRH KO mice underwent a euglycemic (Prior Eu) or hypoglycemic clamp (Prior Hypo) on day 1 followed by a hypoglycemic clamp on day 2 (blood glucose both days, 65 +/- 1 mg/dl). Baseline epinephrine and glucagon were similar, and norepinephrine was elevated, in CRH KO vs. WT mice. CRH KO corticosterone was almost undetectable (< 1.5 mu g/dl) and unresponsive to hypoglycemia. CRH KO glucose requirements were significantly higher during day 1 hypoglycemia despite epinephrine and glucagon responses that were comparable to or greater than those in WT. Hyperinsulinemic euglycemia did not increase hormones or glucose requirements above baseline. On day 2, Prior Hypo WT had significantly higher glucose requirements and significantly lower corticosterone and glucagon responses. Prior Hypo and Prior Eu CRH KO mice had similar day 2 glucose requirements. However, Prior Hypo CRH KO mice had significantly lower day 2 epinephrine and norepinephrine vs. Prior Eu CRH KO and tended to have lower glucagon than on day 1. We conclude that glucocorticoid insufficiency in CRH KO mice correlates with 1) impaired counterregulation during acute hypoglycemia and 2) complex effects after repeated hypoglycemia, neither preventing decreased hormone responses nor worsening glucose requirements. C1 Albany Med Coll, Ctr Neuropharmacol & Neurosci, Albany, NY 12208 USA. Vanderbilt Univ, Mouse Metab Phenotyping Ctr, Nashville, TN USA. Vanderbilt Univ, Dept Physiol & Mol Biophys, Nashville, TN USA. RP Jacobson, L (reprint author), Albany Med Coll, Ctr Neuropharmacol & Neurosci, MC-136, Albany, NY 12208 USA. EM JACOBSL@mail.amc.edu FU NIDDK NIH HHS [DK-59637, DK-62442, R21 DK062442, U24 DK059637] NR 47 TC 12 Z9 13 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JUL PY 2006 VL 291 IS 1 BP E15 EP E22 DI 10.1152/ajpendo.00526.2005 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 057FJ UT WOS:000238581400003 PM 16449297 ER PT J AU Hataishi, R Rodrigues, AC Neilan, TG Morgan, JG Buys, E Shiva, S Tambouret, R Jassal, DS Raher, MJ Furutani, E Ichinose, F Gladwin, MT Rosenzweig, A Zapol, WM Picard, MH Bloch, KD Scherrer-Crosbie, M AF Hataishi, R Rodrigues, AC Neilan, TG Morgan, JG Buys, E Shiva, S Tambouret, R Jassal, DS Raher, MJ Furutani, E Ichinose, F Gladwin, MT Rosenzweig, A Zapol, WM Picard, MH Bloch, KD Scherrer-Crosbie, M TI Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE myocardial infarction; cardiac injury; murine model ID ISCHEMIA/REPERFUSION INJURY; EXTRACORPOREAL-CIRCULATION; NEUTROPHIL ADHESION; LEUKOCYTE ADHESION; SUPEROXIDE ANION; NADPH OXIDASE; NO; INHALATION; THERAPY; ENDOTHELIUM AB To learn whether nitric oxide ( NO) inhalation can decrease myocardial ischemia-reperfusion ( I/R) injury, we studied a murine model of myocardial infarction ( MI). Anesthetized mice underwent left anterior descending coronary artery ligation for 30, 60, or 120 min followed by reperfusion. Mice breathed NO beginning 20 min before reperfusion and continuing thereafter for 24 h. MI size and area at risk were measured, and left ventricular ( LV) function was evaluated using echocardiography and invasive hemodynamic measurements. Inhalation of 40 or 80 ppm, but not 20 ppm, NO decreased the ratio of MI size to area at risk. NO inhalation improved LV systolic function, as assessed by echocardiography 24 h after reperfusion, and systolic and diastolic function, as evaluated by hemodynamic measurements 72 h after reperfusion. Myocardial neutrophil infiltration was reduced in mice breathing NO, and neutrophil depletion prevented inhaled NO from reducing myocardial I/R injury. NO inhalation increased arterial nitrite levels but did not change myocardial cGMP levels. Breathing 40 or 80 ppm NO markedly and significantly decreased MI size and improved LV function after ischemia and reperfusion in mice. NO inhalation may represent a novel method to salvage myocardium at risk of I/R injury. C1 Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Div Cardiol, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Scherrer-Crosbie, M (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Div Cardiol, Dept Med, 55 Fruit St, Boston, MA 02114 USA. EM marielle@crosbie.com OI Picard, Michael/0000-0002-9264-3243 FU NHLBI NIH HHS [HL-42397, HL-70896, HL-57172] NR 49 TC 79 Z9 80 U1 0 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUL PY 2006 VL 291 IS 1 BP H379 EP H384 DI 10.1152/ajpheart.01172.2005 PG 6 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 052VR UT WOS:000238262500047 PM 16443673 ER PT J AU Long, C Chen, MF Sarwinski, SJ Chen, PY Hoffer, BJ Evans, MS Lee, TJF AF Long, C Chen, MF Sarwinski, SJ Chen, PY Hoffer, BJ Evans, MS Lee, TJF TI Monoamine uptake inhibitors block alpha 7-nAChR-mediated cerebral nitrergic neurogenic vasodilation SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE imipramine; desipramine; in vitro tissue bath; porcine basilar artery ID NICOTINIC ACETYLCHOLINE-RECEPTORS; PORCINE BASILAR ARTERIES; RAT HIPPOCAMPAL-NEURONS; TRICYCLIC ANTIDEPRESSANTS; GANGLION NEURONS; BLOOD-FLOW; CHOLINE; RECTIFICATION; DIVERSITY; DILATION AB We have proposed that activation of cerebral perivascular sympathetic alpha 7-nicotinic acetylcholine receptors (alpha 7-nAChRs) by nicotinic agonists releases norepinephrine, which then acts on parasympathetic nitrergic nerves, resulting in release of nitric oxide and vasodilation. Using patch-clamp electrophysiology, immunohistochemistry, and in vitro tissue bath myography, we tested this axo-axonal interaction hypothesis further by examining whether blocking norepinephrine reuptake enhanced alpha 7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. The results indicated that choline- and nicotine-induced alpha 7-nAChR-mediated nitrergic neurogenic relaxation in endothelium-denuded isolated porcine basilar artery rings was enhanced by desipramine and imipramine at lower concentrations (0.03 - 0.1 mu M) but inhibited at higher concentrations (0.3 - 10 mu M). In cultured superior cervical ganglion (SCG) neurons of the pig and rat, choline (0.1 - 30 mM)- evoked inward currents were reversibly blocked by 1 - 30 mu M mecamylamine, 1 - 30 mu M methyllycaconitine, 10 - 300 nM alpha-bungarotoxin, and 0.1 - 10 mu M desipramine and imipramine, providing electrophysiological evidence for the presence of similar functional alpha 7-nAChRs in cerebral perivascular sympathetic neurons of pigs and rats. In alpha 7-nAChR-expressing Xenopus oocytes, choline- elicited inward currents were attenuated by alpha-bungarotoxin, imipramine, and desipramine. These monoamine uptake inhibitors appeared to directly block the alpha 7-nAChR, resulting in diminished nicotinic agonist-induced cerebral nitrergic vasodilation. The enhanced nitrergic vasodilation by lower concentrations of monoamine uptake inhibitors is likely due to a greater effect on monoamine uptake than on alpha 7-nAChR blockade. These results further support the hypothesis of axo-axonal interaction in nitrergic regulation of cerebral vascular tone. C1 Tzu Chi Univ, Coll Life Sci, Ctr Vasc Med, Inst Pharmacol & Toxicol, Hualien 970, Taiwan. So Illinois Univ, Sch Med, Dept Pharmacol, Springfield, IL 62794 USA. So Illinois Univ, Sch Med, Dept Neurol, Springfield, IL 62794 USA. Tzu Chi Gen Hosp, Neuromed Sci Ctr, Hualien, Taiwan. Natl Inst Drug Abuse, NIH, Baltimore, MD USA. RP Lee, TJF (reprint author), Tzu Chi Univ, Coll Life Sci, Ctr Vasc Med, Inst Pharmacol & Toxicol, 701 Chung Yang Rd,Sec 3, Hualien 970, Taiwan. EM tlee@mail.tcu.edu.tw FU NHLBI NIH HHS [HL-27763, HL-47574] NR 29 TC 9 Z9 9 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUL PY 2006 VL 291 IS 1 BP H202 EP H209 DI 10.1152/ajpheart.01192.2005 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 052VR UT WOS:000238262500027 PM 16772524 ER PT J AU Fenton, RA Chou, CL Sowersby, H Smith, CP Knepper, MA AF Fenton, Robert A. Chou, Chung-Lin Sowersby, Holly Smith, Craig P. Knepper, Mark A. TI Gamble's "economy of water" revisited: studies in urea transporter knockout mice SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE vasopressin; passive model; urinary concentrating mechanism ID COLLECTING DUCT; INNER MEDULLA; SYSTEM; URINE AB The Gamble phenomenon (initially described over 70 years ago as "an economy of water in renal function referable to urea") suggested that urea plays a special role in the urinary concentrating mechanism and that the concentrating mechanism depends in some complex way on an interaction between NaCl and urea. In this study, the role of collecting duct urea transporters in the Gamble phenomenon was investigated in wild-type mice and mice in which the inner medulla collecting duct (IMCD) facilitative urea transporters, UT-A1 and UT-A3, had been deleted (UT-A1/3(-/-) mice). The general features of the Gamble phenomenon were confirmed in wild-type mice, namely 1) the water requirement for the excretion of urea is less than for the excretion of an osmotically equivalent amount of NaCl; and 2) when fed various mixtures of urea and salt in the diet, less water is required for the excretion of the two substances together than the amount of water needed for the excretion of the two substances separately. In UT-A1/3(-/-) mice both of these elements of the phenomenon were absent, indicating that IMCD urea transporters play a central role in the Gamble phenomenon. A titration study in which wild-type mice were given progressively increasing amounts of urea showed that the ability of the kidney to reabsorb urea was saturable, resulting in osmotic diuresis above excretion rates of similar to 6,000 mu osmol/day. In the same titration experiments, when increasing amounts of NaCl were added to the diet, mice were unable to increase urinary NaCl concentrations to > 420 mM, resulting in osmotic diuresis at NaCl excretion rates of similar to 3,500 mu osmol/day. Thus both urea and NaCl can induce osmotic diuresis when large amounts are given, supporting the conclusion that the decrease in water excretion with mixtures of urea and NaCl added to the diet (compared with pure NaCl or urea) is due to the separate abilities of urea and NaCl to induce osmotic diuresis, rather than to any specific interaction of urea transport and NaCl transport at an epithelial level. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Univ Manchester, Fac Life Sci, Manchester M13 9PL, Lancs, England. RP Fenton, RA (reprint author), Water & Salt Res Ctr, Inst Anat, Bldg 233-234, DK-8000 Aarhus, Denmark. EM ROFE@ana.au.dk FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [Z01-HL-001285] NR 17 TC 26 Z9 26 U1 1 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUL PY 2006 VL 291 IS 1 BP F148 EP F154 DI 10.1152/ajprenal.00348.2005 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 050XB UT WOS:000238121900016 PM 16478978 ER PT J AU Leibenluft, E AF Leibenluft, E TI Flying almost blind SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID BIPOLAR DISORDER; CHILDREN; MANIA; ADOLESCENTS; DEPRESSION; CARBAMAZEPINE C1 NIMH, Bethesda, MD 20892 USA. RP Leibenluft, E (reprint author), NIMH, Bldg 15K,Room MSC-2670,9000 Rockville Pike, Bethesda, MD 20892 USA. EM leibs@mail.nih.gov NR 12 TC 1 Z9 1 U1 8 U2 8 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 JUL PY 2006 VL 163 IS 7 BP 1129 EP 1131 DI 10.1176/appi.ajp.163.7.1129 PG 3 WC Psychiatry SC Psychiatry GA 059CX UT WOS:000238712000003 PM 16816212 ER PT J AU Fava, M Rush, AJ Wisniewski, SR Nierenberg, AA Alpert, JE McGrath, PJ Thase, ME Warden, D Biggs, M Luther, JF Niederehe, G Ritz, L Trivedi, MH AF Fava, M Rush, AJ Wisniewski, SR Nierenberg, AA Alpert, JE McGrath, PJ Thase, ME Warden, D Biggs, M Luther, JF Niederehe, G Ritz, L Trivedi, MH CA STAR D Study Team TI A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: A STAR*D report SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID SEQUENCED TREATMENT ALTERNATIVES; TREATMENT-RESISTANT DEPRESSION; SEROTONIN REUPTAKE INHIBITORS; QUALITY-OF-LIFE; REPORT QIDS-SR; QUICK INVENTORY; REMISSION RATES; PSYCHOMETRIC EVALUATION; RATING-SCALE; SYMPTOMATOLOGY AB Objective: Few controlled studies have addressed the issue of which antidepressant medications should be recommended for outpatients who have not responded to multiple treatment trials. This study compared the efficacy of switching to mirtazapine to that of switching to a tricyclic antidepressant ( nortriptyline) following two prospective, consecutive, unsuccessful medication treatments for nonpsychotic major depressive disorder. Method: Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks ( first step) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone ( second step), adult outpatients ( N= 235) with nonpsychotic major depressive disorder were randomly assigned to 14 weeks of treatment with mirtazapine ( up to 60 mg/ day) ( N= 114) or nortriptyline ( up to 200 mg/ day) ( N= 121). The primary outcome, symptom remission, was defined a priori as a total exit score of <= 7 on the 17- item Hamilton Rating Scale for Depression. The 16- item Quick Inventory of Depressive Symptomatology - Self- Report ( QIDS- SR16), obtained at treatment visits, provided secondary outcomes of remission ( score = 5 at exit) and response (= 50% reduction in score from baseline). Results: For mirtazapine, remission rates were 12.3% and 8.0% per the Hamilton and QIDS- SR16 scores, respectively. For nortriptyline, remission rates were 19.8% and 12.4%, respectively. QIDS- SR16 response rates were 13.4% for mirtazapine and 16.5% for nortriptyline. Neither response nor remission rates statistically differed by treatment, nor did these two treatments differ in tolerability or adverse events. Conclusions: Switching to a third antidepressant monotherapy regimen after two consecutive unsuccessful antidepressant trials resulted in low remission rates (< 20%) among patients with major depressive disorder. C1 Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75230 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol Data Ctr, Pittsburgh, PA 15260 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Columbia Univ, Coll Phys & Surg, New York, NY 10032 USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. NIMH, Bethesda, MD 20892 USA. RP Fava, M (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, Bullfinch 351,55 Fruit St, Boston, MA 02114 USA. EM MFava@Partners.org RI Biggs, Dr. Melanie/C-1468-2010; McGrath, Patrick/I-6410-2013; OI McGrath, Patrick/0000-0001-7217-7321; Wisniewski, Stephen/0000-0002-3877-9860; Alpert, Jonathan/0000-0002-4332-908X; Rush, Augustus/0000-0003-2004-2382 FU NIMH NIH HHS [N01MH90003] NR 37 TC 152 Z9 153 U1 0 U2 1 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 JUL PY 2006 VL 163 IS 7 BP 1161 EP 1172 DI 10.1176/appi.ajp.163.7.1161 PG 12 WC Psychiatry SC Psychiatry GA 059CX UT WOS:000238712000012 PM 16816220 ER PT J AU Parry, M AF Parry, Manon TI G. Stanley Hall: Psychologist and early gerontologist SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 Natl Lib Med, Hist Med Div, Bethesda, MD 20894 USA. RP Parry, M (reprint author), Natl Lib Med, Hist Med Div, 8600 Rockville Pike,Bldg 38,Room 1E 21, Bethesda, MD 20894 USA. EM parrym@mail.nlm.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 2 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2006 VL 96 IS 7 BP 1161 EP 1161 DI 10.2105/AJPH.2006.090647 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 058IO UT WOS:000238658900011 PM 16735608 ER PT J AU Ladwig, S Fee, E Brown, TM AF Ladwig, S Fee, E Brown, TM TI Contrary to stereotypes, a nursing home resident radiates dignity and joy SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 Univ Rochester, Med Ctr, Ctr Palliat Care & Clin Eth, Rochester, NY 14642 USA. NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. Univ Rochester, Dept Hist, Rochester, NY 14642 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY 14642 USA. RP Ladwig, S (reprint author), Univ Rochester, Med Ctr, Ctr Palliat Care & Clin Eth, 601 Elmwood Ave,Box 601, Rochester, NY 14642 USA. EM susan_ladwig@urmc.rochester.edu NR 4 TC 1 Z9 1 U1 1 U2 2 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2006 VL 96 IS 7 BP 1163 EP 1163 DI 10.2105/AJPH.2006.090506 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 058IO UT WOS:000238658900012 PM 16735609 ER PT J AU Rosen, D Lee, JH Cuttitta, F Rafiqi, F Degan, S Sunday, ME AF Rosen, D Lee, JH Cuttitta, F Rafiqi, F Degan, S Sunday, ME TI Accelerated thymic maturation and autoreactive T cells in bronchopulmonary dysplasia SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE animal model; bombesin; immunohistochemistry; mixed lymphocyte reaction; thymic nurse cells ID GASTRIN-RELEASING-PEPTIDE; CHRONIC LUNG-DISEASE; CIRCULATING DENDRITIC CELLS; HYALINE-MEMBRANE DISEASE; BOMBESIN-LIKE PEPTIDES; BABOON MODEL; MONOCLONAL-ANTIBODY; NURSE CELLS; INVOLUTION; INJURY AB Rationale: Bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns triggered by oxygen and barotrauma, is characterized by arrested alveolarization. Increased levels of bombesin-like peptides shortly after birth mediate lung injury: anti-bombesin antibody 2A11 protects against BPD in two baboon models. The role of adaptive immunity in BPD has not been explored previously. Objectives: Our goal was to test the hypothesis that thymic architecture and/or T-cell function is altered with BPD, leading to autoimmunity and immunodeficiency. Methods: Thymic structure was analyzed by histopathology of thymic architecture and immunohistochemistry for thymic maturation markers (terminal deoxynucleotidyl transferase, proliferating cell nuclear antigen, CD4, and CD8). Thymic cortical epithelial cells (nurse cells) were studied using HLA-DR and protein gene product 9.5 as markers. Functional analysis was performed with "mixed lymphocyte reaction" of thymocyte or splenocyte responder cells with autologous lung cells as the stimulators. Measurements and Main Results: 2A11 treatment attenuates thymic cortical involution in BPD animals, sustaining terminal deoxynucleotidyl transferase-positive prothymocytes and thymocyte proliferation. BIRD animals have increased CD4(+) cells in thymic cortex and lung interstitium, which are reduced by 2A11. Conversely, cortical protein gene product 9.5/HLA-DR-positive thymic nurse cells are depleted in BPD animals, but are preserved by 2A11-treatment. Whereas fetal thymocytes and splenocytes respond to phythemag-glutinin/ionomycin and to a lesser extent, to autologous lung, BPD thymocytes and splenocytes are phythemagglutinin/ionomycin-unresponsive, and yet react strongly to autologous lung. The 2A11 normalizes these responses. Conclusions: These observations suggest that bombesin-like peptides mediate premature thymic maturation and thymic nurse-cell depletion, leading to autoreactive T cells that could contribute to lung injury. C1 Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Childrens Hosp, Div Pulm Med, Dept Med, Boston, MA USA. Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD USA. RP Sunday, ME (reprint author), Duke Univ, Med Ctr, Dept Pathol, Box 3712, Durham, NC 27710 USA. EM mary.sunday@duke.edu RI Cuttitta, Frank/B-4758-2016 FU NCRR NIH HHS [P51RR13986]; NHLBI NIH HHS [U01-HL52636, U01-HL52638] NR 61 TC 22 Z9 25 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 1 PY 2006 VL 174 IS 1 BP 75 EP 83 DI 10.1016/rccm.200511-1784OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 056DX UT WOS:000238502600013 PM 16574933 ER PT J AU Segal, BH Walsh, TJ AF Segal, BH Walsh, TJ TI Untitled SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter ID INVASIVE ASPERGILLOSIS; AMPHOTERICIN-B; ANTIFUNGAL THERAPY; VORICONAZOLE C1 Roswell Pk Canc Inst, Buffalo, NY 14263 USA. NCI, NIH, Bethesda, MD USA. RP Segal, BH (reprint author), Roswell Pk Canc Inst, Buffalo, NY 14263 USA. NR 4 TC 0 Z9 0 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 1 PY 2006 VL 174 IS 1 BP 102 EP 103 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 056DX UT WOS:000238502600017 ER PT J AU Valencia, JC Pacheco-Rodriguez, G Carmona, AK Xavier, J Bruneval, P Riemenschneider, WK Ikeda, Y Yu, ZX Ferrans, VJ Moss, J AF Valencia, Julio C. Pacheco-Rodriguez, Gustavo Carmona, Adriana K. Xavier, Janina Bruneval, Patrick Riemenschneider, William K. Ikeda, Yoshihiko Yu, Zu-Xi Ferrans, Victor J. Moss, Joel TI Tissue-specific renin-angiotensin system in pulmonary lymphangioleiomyomatosis SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE angiotensin II; lymphangioleiomyomatosis; mammalian target of rapamycin; smooth muscle cells; tuberous sclerosis complex ID II TYPE-1 RECEPTOR; SMOOTH-MUSCLE-CELLS; CONVERTING-ENZYME; GROWTH-FACTOR; MOLECULAR-CLONING; MESSENGER-RNA; MAST-CELLS; GENE; EXPRESSION; ESTROGEN AB Lymphangioleiomyomatosis (LAM), a multisystem disease found in middle-aged women, is characterized by cystic lung destruction and abdominal tumors (e.g., angiomyolipomas, lymphangioleimyomas), resulting from proliferation of abnormal-appearing, smooth muscle-like cells (LAM cells). The LAM cells, in combination with other cells, form nodular structures within the lung interstitium and in the walls of the cysts. LAM cells contain mutations in the tuberous sclerosis complex TSC1 and/or TSC2 genes, which lead to dysregulation of the mammalian target of rapamycin, affecting cell growth and proliferation. Proliferation and migration of vascular smooth muscle cells and production of angiogenic factors are regulated, in part, by angiotensin II. To determine whether a LAM-specific renin-angiotensin system might play a role in the pathogenesis of LAM, we investigated the expression of genes and gene products of this system in LAM nodules. mRNA for angiotensinogen was present in RNA isolated by laser-captured microdissection from LAM nodules. Angiotensin I-converting enzyme and chymase-producing mast cells were present within the LAM nodules. We detected renin in LAM cells, as determined by the presence of mRNA and immunohistochemistry. Angiotensin II type I and type II receptors were identified in LAM cells by immunohistochemistry and immunoblotting of microdissected LAM nodules. Angiotensin II is localized in cells containing et-smooth muscle actin (LAM cells). A LAM-specific renin-angiotensin system appears to function within the LAM nodule as an autocrine system that could promote LAM cell proliferation and migration, and could represent a pharmacologic target. C1 Natl Heart Lung & Blood Inst, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. Univ Fed Sao Paulo, Escola Paulista Med, Biophys Dept, Sao Paulo, Brazil. Hop Europeen Georges Pompidou, Lab Anat Pathol, Paris, France. RP Moss, J (reprint author), Natl Heart Lung & Blood Inst, Pulm Crit Care Med Branch, NIH, Bldg 10 Room 6D05 MSC 1590, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov RI Carmona, Adriana/D-2240-2012 FU Intramural NIH HHS NR 46 TC 20 Z9 21 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD JUL PY 2006 VL 35 IS 1 BP 40 EP 47 DI 10.1165/rcmb.2005-03870C PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 060JX UT WOS:000238799600006 PM 16474096 ER PT J AU Kaplan, B Kirk, AD AF Kaplan, B Kirk, AD TI Tacrolimus and sirolimus: When bad things happen to good drugs SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material ID RANDOMIZED MULTICENTER; MYCOPHENOLATE-MOFETIL; TRANSPLANT RECIPIENTS; COMBINATION C1 Univ Illinois, Transplant Inst, Transplantat Branch, NIDDK, Chicago, IL 60607 USA. NIH, Transplantat Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Kaplan, B (reprint author), Univ Illinois, Transplant Inst, Transplantat Branch, NIDDK, Chicago, IL 60607 USA. EM kaplanb@uic.edu RI Kirk, Allan/B-6905-2012; ieong, bee/C-5840-2012 FU Intramural NIH HHS NR 10 TC 3 Z9 3 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUL PY 2006 VL 6 IS 7 BP 1501 EP 1502 DI 10.1111/j.1600-6143.2006.01392.x PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 055QM UT WOS:000238465400001 PM 16827845 ER PT J AU McQueen, PG McKenzie, FE AF McQueen, Philip G. McKenzie, F. Ellis TI Competition for red blood cells can enhance Plasmodium vivax parasitemia in mixed-species malaria infections SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID POLYMERASE CHAIN-REACTION; RETROSPECTIVE EXAMINATION; FALCIPARUM INFECTIONS; STAGE DYNAMICS; ANEMIA; ERYTHROCYTES; THAILAND; HUMANS; SUSCEPTIBILITY; TRANSMISSION AB We assess the consequences of competition for red blood cells (RBCs) in co-infections with the two major agents of human malaria, Plasmodium vivax and Plasmodium falciparum, using differential equations to model the population dynamics of RBCs and parasites. P. vivax parasitizes only the youngest RBCs, but this can reduce the broader RBC population susceptible to P. falciparum. We found that competition for RBCs typically causes one species to suppress the other, depending on their relative reproduction rates and timing of inoculation. However, if the species' reproduction rates are nearly equal, transient increases in RBC production stimulated by the presence of P. falciparum may boost P. vivax parasitemia above its single-species infection level. Conversely, P. falciparum parasitemia is rarely enhanced above its single-species level. Furthermore, transients in RBC production can induce coupled oscillations in the parasitemia of both species. These results are remarkably robust to changes in model parameters. C1 NIH, CIT, Math & Stat Comp Lab, Div Computat Biosci, Bethesda, MD 20892 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP McQueen, PG (reprint author), NIH, CIT, Math & Stat Comp Lab, Div Computat Biosci, 12 S Dr, Bethesda, MD 20892 USA. EM mcqueenp@mail.nih.gov; mckenzel@mail.nih.gov FU Intramural NIH HHS [Z99 TW999999] NR 54 TC 18 Z9 20 U1 2 U2 9 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUL PY 2006 VL 75 IS 1 BP 112 EP 125 PG 14 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 061WA UT WOS:000238902600020 PM 16837717 ER PT J AU Copersino, ML Boyd, SJ Tashkin, DP Huestis, MA Heishman, SJ Dermand, JC Simmons, MS Gorelick, DA AF Copersino, Marc L. Boyd, Susan J. Tashkin, Donald P. Huestis, Marilyn A. Heishman, Stephen J. Dermand, John C. Simmons, Michael S. Gorelick, David A. TI Quitting among non-treatment-seeking marijuana users: Reasons and changes in other substance use SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID EXTRINSIC MOTIVATION; USE DISORDERS; CANNABIS USE; CESSATION; ALCOHOL; PREVALENCE; DEPENDENCE; RECOVERY; SMOKERS AB This study examines the self-reported reasons for quitting marijuana use, changes in other substance use during the quit attempt, and reasons for the resumption of use in 104 non-treatment-seeking adult marijuana smokers. Reasons for quitting were shown to be primarily motivated by concerns about the negative impact of marijuana on health and on self-and social image. The spontaneous quitting of marijuana use is often associated with an increase in the use of legal substances such as alcohol, tobacco, and sleeping aids, but not with the initiation of new substance use. These findings suggest areas for further research on spontaneous recovery from marijuana use. C1 NIDA, IRP, Clin Pharmacol & Therapeut Branch, Intramural Res Program,NIH,Dept Htlh & Human Serv, Baltimore, MD 21224 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90024 USA. RP Gorelick, DA (reprint author), NIDA, IRP, Clin Pharmacol & Therapeut Branch, Intramural Res Program,NIH,Dept Htlh & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM dgorelic@intra.nida.nih.gov FU NIDA NIH HHS [R0-1 DA03018] NR 21 TC 34 Z9 34 U1 2 U2 8 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD JUL-AUG PY 2006 VL 15 IS 4 BP 297 EP 302 DI 10.1080/10550490600754341 PG 6 WC Substance Abuse SC Substance Abuse GA 067BG UT WOS:000239274900006 PM 16867925 ER PT J AU Jacobs, P Blaine, J Borsook, D Katz, N Michel, ME Thomas, D AF Jacobs, Petra Blaine, J. Borsook, D. Katz, N. Michel, M. E. Thomas, D. TI What is the connection between physical and psychological pain and the clinical implications of this relationship? SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Meeting Abstract C1 NIDA, CCTN, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD JUL-AUG PY 2006 VL 15 IS 4 BP 320 EP 321 PG 2 WC Substance Abuse SC Substance Abuse GA 067BG UT WOS:000239274900022 ER PT J AU Skapenko, A Prots, I Wendler, J Mattyasovszky, S Yone, C Burkhardt, H Spriewald, B Rau, R Kalden, JR Lipsky, PE Schulze-Koops, H AF Skapenko, A. Prots, I. Wendler, J. Mattyasovszky, S. Yone, C. Burkhardt, H. Spriewald, B. Rau, R. Kalden, J. R. Lipsky, P. E. Schulze-Koops, H. TI Association of the loss of function IL-4ralpha single nucleotide polymorphism 150V with early erosive rheumatoid arthritis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 Univ Erlangen Nurnberg, Clin Res Grp 3, Nikolaus Fiebiger Ctr Mol Med, Erlangen, Germany. NIAMS, NIH, Bethesda, MD USA. Evangel Fachkrankenhaus, Ratingen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 37 EP 38 PG 2 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372500115 ER PT J AU Skapenko, A Kalden, JR Lipsky, PE Schulze-Koops, H AF Skapenko, A. Kalden, J. R. Lipsky, P. E. Schulze-Koops, H. TI The IL-4RALPHA chain-binding cytokines, IL-4 and IL-13, induce FOXP3 expressing CD25+CD4+ regulatory T cells from CD25-CD4+ precursors SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 Univ Erlangen Nurnberg, Erlangen, Germany. NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 79 EP 79 PG 1 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372500233 ER PT J AU Valencia, X Simone, J Illei, G Yarboro, C Lipsky, P AF Valencia, X. Simone, J. Illei, G. Yarboro, C. Lipsky, P. TI Defective suppressor function of CD4+CD25Hi T regulatory cells in active SLE SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 NIAMS, Autoimmun Branch, Bethesda, MD USA. NIAMS, Off Clin Director, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 84 EP 85 PG 2 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372500249 ER PT J AU Aletaha, D Strand, V Smolen, JS Ward, MM AF Aletaha, D. Strand, V. Smolen, J. S. Ward, M. M. TI Responsiveness of the health assessment questionnaire disability index (HAQ) to biologics in comparison to placebo in clinical trials of rheumatoid arthritis (RA): Effects of RA duration SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 Vienna Med Univ, Dept Rheumatol, Vienna, Austria. Stanford Univ, Div Immunol, Stanford, CA 94305 USA. Hietzing Hosp, Dept Med 2, Vienna, Austria. Natl Inst Hlth, NIAMS, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 95 EP 95 PG 1 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372500281 ER PT J AU Paul, SM Namde, M Hildebrand, H Jain, M Smith, M Canna, S Wiggs, E Comis, L Goldbach-Mansky, R AF Paul, S. M. Namde, M. Hildebrand, H. Jain, M. Smith, M. Canna, S. Wiggs, E. Comis, L. Goldbach-Mansky, R. TI Functional outcomes in neonatal onset multisystem inflammatory disease (NOMID) after 12 months of treatment with the recombinant IL-1 receptor antagonist anakinra SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 100 EP 100 PG 1 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372500297 ER PT J AU Skapenko, A Prots, I Wendler, J Mattyasovszky, S Yone, CL Spriewald, B Burkhardt, H Rau, R Kalden, JR Lipsky, PE Schulze-Koops, H AF Skapenko, A. Prots, I. Wendler, J. Mattyasovszky, S. Yone, C. L. Spriewald, B. Burkhardt, H. Rau, R. Kalden, J. R. Lipsky, P. E. Schulze-Koops, H. TI The IL4R single nucleotide polymorphism 150V is associated with rapidly erosive rheumatoid arthritis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 Univ Erlangen Nurnberg, D-8520 Erlangen, Germany. Univ Erlangen Nurnberg, Ratingen, Germany. NIH, NIAMS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 156 EP 156 PG 1 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372500478 ER PT J AU Grisar, JC Kapral, T Gonda, G Stamm, T Smolen, JS Aletaha, D AF Grisar, J. C. Kapral, T. Gonda, G. Stamm, T. Smolen, J. S. Aletaha, D. TI Short term responsiveness of biomarkers to pheunisolone in patients with active rheumatoid arthritis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 Med Univ Vienna, Div Rheumatol, Vienna, Austria. Hietzing Hosp, Dept Med 2, Vienna, Austria. NIH, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 171 EP 171 PG 1 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372500529 ER PT J AU Illei, G Yarboro, C Austin, H Chitkara, R Klippel, J Balow, J Boumpas, D AF Illei, G. Yarboro, C. Austin, H. Chitkara, R. Klippel, J. Balow, J. Boumpas, D. TI Long-term effects of combination treatment with fludarabine and low-dose pulse cyclophosphamide in patients with lupus nephritis: A lymphoablative regimen for the treatment of severe lupus? SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 NIH, Bethesda, MD 20892 USA. Univ Hosp Heraklion, Iraklion, Greece. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 199 EP 199 PG 1 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372500616 ER PT J AU Goldbach-Mansky, R Snyder, C Pham, T Barham, B Kastner, D Papandoupulos, J Radin, A Mellis, S AF Goldbach-Mansky, R. Snyder, C. Pham, T. Barham, B. Kastner, D. Papandoupulos, J. Radin, A. Mellis, S. TI Differential response to the long acting IL-1 inhibitor IL-1 trap in 2 patients with Adult Onset Still's Disease (AOSD) SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 NIAMSD, Bethesda, MD 20892 USA. Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 262 EP 262 PG 1 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372501109 ER PT J AU Aksentijevich, I Balow, J Barham, B Kastner, DL AF Aksentijevich, I. Balow, J., Jr. Barham, B. Kastner, D. L. TI Gene expression studies in TNF-receptor associated periodic syndrome (TRAPS) SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 Natl Inst Hlth, NIAMS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 286 EP 286 PG 1 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372501184 ER PT J AU Namde, M Canna, S Plass, N Aksentijevich, I Rubin, B Kim, J Brewer, C Snyder, C Pham, T Kastner, D Goldbach-Mansky, R AF Namde, M. Canna, S. Plass, N. Aksentijevich, I. Rubin, B. Kim, J. Brewer, C. Snyder, C. Pham, T. Kastner, D. Goldbach-Mansky, R. TI Twelve months after treating children with neonatal onset mutisystem inflammatory disease (NOMID/CINCA) with the IL-1 receptor antagonist anakinra SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 NIAMS, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 448 EP 448 PG 1 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372501719 ER PT J AU Fritsch-Stork, RD Shen, X Illei, GG Yarboro, CH Prussin, C Hathcock, KS Hodes, RJ Lipsky, RE AF Fritsch-Stork, R. D. Shen, X. Illei, G. G. Yarboro, C. H. Prussin, C. Hathcock, K. S. Hodes, R. J. Lipsky, R. E. TI SLE CD4 T cells display distinct abnormalities in memory cell maturation SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 NIAMS, AKH, KIMIII, Autoimmun Branch, Vienna, Austria. NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. NIAMS, Off Clin Director, Bethesda, MD USA. NIAID, Lab Allerg Dis, Bethesda, MD USA. NCI, NIA, Expt Immunol Branch, Bethesda, MD 20892 USA. NIAMS, Autoimmun Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 473 EP 473 PG 1 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372502021 ER PT J AU Wittkowski, H Frosch, M Wulffraat, N Goldbach-Mansky, R Kuemmerie-Deschner, J Roth, J Pham, T Foell, D AF Wittkowski, H. Frosch, M. Wulffraat, N. Goldbach-Mansky, R. Kuemmerie-Deschner, J. Roth, J. Pham, T. Foell, D. TI S100A12 in the differential diagnosis of fever of unknown origin (FUO) SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2006) CY JUN 21-24, 2006 CL Amsterdam, NETHERLANDS C1 Univ Munster, D-4400 Munster, Germany. Wilhelmina Childrens Hosp, Utrecht, Netherlands. NIAMSD, Bethesda, MD 20892 USA. Univ Childrens Hosp, Tubingen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 SU 2 BP 576 EP 576 PG 1 WC Rheumatology SC Rheumatology GA 209ET UT WOS:000249372502359 ER PT J AU Ozen, S Ruperto, N Dillon, MJ Bagga, A Barron, K Davin, JC Kawasaki, T Lindsley, C Petty, RE Prieur, AM Ravelli, A Woo, P AF Ozen, S Ruperto, N Dillon, MJ Bagga, A Barron, K Davin, JC Kawasaki, T Lindsley, C Petty, RE Prieur, AM Ravelli, A Woo, P TI EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID RHEUMATOLOGY 1990 CRITERIA; SYSTEMIC-LUPUS-ERYTHEMATOSUS; POLYARTERITIS-NODOSA; WEGENER GRANULOMATOSIS; PRELIMINARY DEFINITION; TAKAYASU ARTERITIS; CLINICAL-TRIALS; CHILDREN; NOMENCLATURE; IMPROVEMENT AB Background: There has been a lack of appropriate classification criteria for vasculitis in children. Objective: To develop a widely accepted general classification for the vasculitides observed in children and specific and realistic classification criteria for common childhood vasculitides (Henoch-Schonlein purpura (HSP), Kawasaki disease (KD), childhood polyarteritis nodosa ( PAN), Wegener's granulomatosis (WG), and Takayasu arteritis (TA)). Methods: The project was divided into two phases: (1) the Delphi technique was used to gather opinions from a wide spectrum of paediatric rheumatologists and nephrologists; (2) a consensus conference using nominal group technique was held. Ten international experts, all paediatricians, met for the consensus conference. Agreement of at least 80% of the participants was defined as consensus. Results: Consensus was reached to base the general working classification for childhood vasculitides on vessel size. The small vessel disease was further subcategorised "intogranulomatous'' and `"nongranulomatous.'' Final criteria were developed to classify a child as HSP, KD, childhood PAN, WG, or TA, with changes introduced based on paediatric experience. Mandatory criteria were suggested for all diseases except WG. Conclusions: It is hoped that the suggested criteria will be widely accepted around the world because of the reliable techniques used and the international and multispecialist composition of the expert group involved. C1 Univ Hacettepe, Fac Med, Dept Paediat, TR-06100 Ankara, Turkey. IRCCS, Genoa, Italy. Inst Child Hlth, London, England. Great Ormond St Hosp Children, London WC1N 3JH, England. All India Inst Med Sci, Dept Paediat, New Delhi, India. NIAID, NIH, Bethesda, MD 20892 USA. Emma Childrens Hosp, Acad Med Ctr, Amsterdam, Netherlands. Japan Kawasaki Dis Res Ctr, Tokyo, Japan. Univ Kansas, Med Ctr, Dept Pediat, Lawrence, KS 66045 USA. Univ British Columbia, Dept Pediat, Vancouver, BC V6T 1W5, Canada. Hop Necker Enfants Malad, Unite Immunol Hematol & Rheumatol Pediat, Paris, France. Great Ormond St Hosp Children, Dept Rheumatol, London WC1N 3JH, England. RP Ozen, S (reprint author), Univ Hacettepe, Fac Med, Dept Paediat, TR-06100 Ankara, Turkey. EM sezaozen@hacettepe.edu.tr RI RAVELLI, ANGELO/J-8161-2016 OI RAVELLI, ANGELO/0000-0001-9658-0385 NR 23 TC 297 Z9 362 U1 1 U2 13 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 IS 7 BP 936 EP 941 DI 10.1136/ard.2005.046300 PG 6 WC Rheumatology SC Rheumatology GA 052HH UT WOS:000238223700019 PM 16322081 ER PT J AU Ozen, S Hoffman, HM Frenkel, J Kastner, D AF Ozen, S. Hoffman, H. M. Frenkel, J. Kastner, D. TI Familial Mediterranean fever (FMF) and beyond: a new horizon. Fourth International Congress on the systemic autoinflammatory diseases held in Bethesda, USA, 6-10 November 2005 SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID MUTATIONS; PROTEIN; PYRIN; PATHOGENESIS; INFLAMMATION; DISORDERS; ANAKINRA; RECEPTOR; GENE AB Autoinflammatory diseases are characterised by seemingly unprovoked inflammation. They can be categorised as: hereditary (monogenic) autoinflammatory diseases, complex (polygenic/multifactorial) autoinflammatory diseases, and diseases where the course is affected by mutations in the defined autoinflammatory disease genes. Identification of the inflammatory pathways involved has opened up new areas of research which have implications for the treatment of these disorders and the pathogenesis of common inflammatory diseases. C1 Hacettepe Univ, Dept Paediat, TR-06100 Ankara, Turkey. Univ Calif San Diego, Dept Paediat, La Jolla, CA 92093 USA. Univ Utrecht, Ctr Med, Dept Gen Paediat, Utrecht, Netherlands. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Ozen, S (reprint author), Hacettepe Univ, Dept Paediat, TR-06100 Ankara, Turkey. EM sezaozen@hacettepe.edu.tr NR 20 TC 25 Z9 26 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2006 VL 65 IS 7 BP 961 EP 964 PG 4 WC Rheumatology SC Rheumatology GA 052HH UT WOS:000238223700026 PM 16606647 ER PT J AU Affara, NI Trempus, CS Schanbacher, BL Pei, P Mallery, SR Bauer, JA Robertson, FM AF Affara, Nesrine I. Trempus, Carol S. Schanbacher, Brandon L. Pei, Ping Mallery, Susan R. Bauer, John A. Robertson, Fredika M. TI Activation of Akt and mTOR in CD34(+)/K15(+) keratinocyte stem cells and skin tumors during multi-stage mouse skin carcinogenesis SO ANTICANCER RESEARCH LA English DT Article DE keratinocytes; CD34; cytokeratin 15; stem cells; niche; Akt; protein kinase B; mammalian target of rapamycin (mTOR); skin carcinogenesis; hair follicle; bulge region; papilloma ID LABEL-RETAINING CELLS; HAIR FOLLICLE BULGE; PROTEIN-KINASE-B; EPIDERMAL PROLIFERATIVE UNIT; INTEGRIN-LINKED KINASE; CYCLIN D1 EXPRESSION; MAMMALIAN TARGET; SELF-RENEWAL; PHOSPHATIDYLINOSITOL 3-KINASE; TRANSLATION INITIATION AB Background: The goal of the present studies was to localize two proteins known to be involved in regulation of cell proliferation and survival in specific cell populations in normal SENCAR mouse skin and during multi-stage skin carcinogenesis. The proteins evaluated included activated Akt, as defined by phosphorylation of Akt at Serine-473 (pAkt) and mammalian target of rapamycin (pmTOR), defined by staining of pAkt in the basal cell layer. There were fewer cells within the basal cell layer that contained pm TOR, in addition to the presence of pmTOR in suprabasal cells within papillomas. Conclusion: These results provide first time evidence for pAkt and pmTOR in CD34(+)/K15(+) KSCs localized to the outer root sheath niche of the bulge region of mouse hair follicles. Taken together, the present observations suggest that pAkt and pm TOR may allow this cell population to evade terminal differentiation and to persist for longperiods of time in their specific niche. Strategies that tat-get pAkt and pmTOR may deplete both cells within the CD34(+)/K15(+) KSCs compartment, as well as impacting the survival of non-proliferating suprabasal cells within pre-malignant papillomas. C1 Ohio State Univ, Coll Med, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. Ohio State Univ, Dept Oral Maxillofacial Surg & Oral Pathol, Coll Dent, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. NIEHS, Canc Biol Grp, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. Columbus Childrens Res Inst, Ctr Caridovasc Med, Columbus, OH 43205 USA. RP Robertson, FM (reprint author), Ohio State Univ, Coll Med, Dept Mol Virol Immunol & Med Genet, 2184 Graves Hall,333 W 10th Ave, Columbus, OH 43210 USA. EM robertson.48@osu.edu NR 74 TC 19 Z9 20 U1 0 U2 3 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JUL-AUG PY 2006 VL 26 IS 4B BP 2805 EP 2820 PG 16 WC Oncology SC Oncology GA 096QJ UT WOS:000241391600005 PM 16886599 ER PT J AU Rifkind, JM Nagababu, E Ramasamy, S AF Rifkind, Joseph M. Nagababu, Enika Ramasamy, Somasundaram TI Nitric oxide redox reactions and red cell biology SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID BLOOD-FLOW REGULATION; S-NITROSOHEMOGLOBIN; ELECTRON-TRANSFER; REDUCTIVE NITROSYLATION; NITROGEN MONOXIDE; HEME POCKET; L-ARGININE; HEMOGLOBIN; METABOLISM; OXIDATION AB Three hypotheses explain a role for red blood cells (RBCs) in delivering NO to the vasculature: (a) "the SNOHb hypothesis" involves the uptake of NO by RBCs with NO transferred from the heme to the beta-93 thiol in the R quaternary conformation, followed by the release to membrane thiols in the T quaternary conformation; and (b and c) "the nitrite hypotheses" bypass the intrinsic difficulties of transporting the highly reactive NO, by reutilizing the nitrite formed when NO reacts with oxygen. Deoxyhemoglobin reduces this nitrite back to NO. The distinction between the two nitrite mechanisms depends on the importance of intermediate species formed during nitrite reduction. Without bioactive intermediates, the NO must be immediately released to avoid binding to deoxyhemoglobin. The "nitrite intermediate hypothesis" enables the RBCs to store a pool of potentially bioactive NO until it is released from the cell. In this review, we critically compare these different proposals for the transport/delivery of NO by RBCs. We also compare the redox properties in the RBCs associated with NO with the redox properties associated with oxygen. C1 NIA, Mol Dynam Sect, NIH, Baltimore, MD 21224 USA. RP Rifkind, JM (reprint author), NIA, Mol Dynam Sect, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rifkindj@grc.nia.nih.gov FU Intramural NIH HHS NR 64 TC 22 Z9 23 U1 1 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUL-AUG PY 2006 VL 8 IS 7-8 BP 1193 EP 1203 DI 10.1089/ars.2006.8.1193 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 070DX UT WOS:000239501600011 PM 16910767 ER PT J AU Gius, D Spitz, DR AF Gius, David Spitz, Douglas R. TI Redox signaling in cancer biology SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Editorial Material ID HUMAN TUMOR-CELLS; ACTIVATED PROTEIN-KINASE; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; SUPEROXIDE-DISMUTASE; GLUCOSE DEPRIVATION; IONIZING-RADIATION; THIOREDOXIN; GROWTH; H2O2 AB Over the last three decades, it is has become increasing clear that intracellular signaling pathways are activated via changes in intracellular metabolic oxidation/reduction (redox) reactions involving reactive oxygen species (ROS; i.e., superoxide and hydrogen peroxide). The initial proposals hypothesized that signaling through metabolic oxidation/reduction (redox) reactions involving ROS could contribute to carcinogenesis and progression to malignancy. Strong evidence for this hypothesis was obtained from studies showing that environmental insults (i.e., ionizing radiation) as well as xenobiotics (i.e., polycyclic aromatic hydrocarbons and phorbol esters) capable of inducing steady-state increases in free radical production and ROS could act as both initiators and promoters of carcinogenesis. This Forum is directed at understanding possible redox signaling mechanisms governing cellular radiation response, tumor growth, and response to therapy, as well as the role of nitric oxide in cancer biology. C1 Univ Iowa, Free Rad & Radiat Biol Program, Med Labs B180, Dept Radiat Oncol,Holden Comprehens Canc Ctr, Iowa City, IA 52242 USA. NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Ctr Canc Res,NIH, Bethesda, MD USA. RP Spitz, DR (reprint author), Univ Iowa, Free Rad & Radiat Biol Program, Med Labs B180, Dept Radiat Oncol,Holden Comprehens Canc Ctr, Iowa City, IA 52242 USA. EM douglas-spitz@uiowa.edu FU NCI NIH HHS [P01-CA66081, P30-CA086862, R01-CA100045] NR 40 TC 108 Z9 113 U1 1 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUL-AUG PY 2006 VL 8 IS 7-8 BP 1249 EP 1252 DI 10.1089/ars.2006.8.1249 PG 4 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 070DX UT WOS:000239501600016 PM 16910772 ER PT J AU Cook, JA Chuang, EY Tsai, MH Coffin, D Degraff, W Sowers, AL Mitchell, JB AF Cook, John A. Chuang, Eric Y. Tsai, Mong-Hsun Coffin, Debbie Degraff, William Sowers, Anastasia L. Mitchell, James B. TI Radiation-induced changes in gene-expression profiles for the SCCVII tumor cells grown in vitro and in vivo SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID ALPHA-B-CRYSTALLIN; MURINE TUMORS; HYPOXIA; APOPTOSIS; CANCER; TRANSCRIPTION; INDUCTION; DAMAGE; INHIBITION; RESISTANCE AB SCCVII tumor cells that grow in vitro or in vivo as a solid tumor were used to compare and contrast gene-expression profiles with or without exposure to two doses of ionizing radiation. Exponentially growing SCCVII cell cultures and tumors (1 cm diameter) were treated with 0, 2, or 10 Gy, and RNA was collected 1, 3, 6, 12, and 24 h after treatment. Growth under in vitro conditions increased the expression of genes associated with the unfolded protein response (UPR) including ATF4, Ero-1 like, and cystathionase. Growth in vivo indicated that the HIF-1a genes were not upregulated, whereas genes such as hemoglobin alpha and crystallin alpha B were significantly upregulated. Ninety genes of 16K were found to be significantly modulated under either growth condition by radiation treatment. Gene expression was not dose dependent. Sixty percent of these genes exhibited similar modulation under both in vitro and in vivo conditions; however, 29% of the genes were modulated by radiation under in vivo conditions only. Gene-expression profiles for the same tumor cells can differ, dependent on growth conditions, underscoring the influence that the tumor microenvironment exerts on gene expression for both growth of solid tumors and their response to radiation treatment. C1 NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Natl Taiwan Univ, Dept Elect Engn, Bioengn Grp, Taipei, Taiwan. RP Cook, JA (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. EM cook@helix.nih.gov FU Intramural NIH HHS NR 38 TC 10 Z9 10 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUL-AUG PY 2006 VL 8 IS 7-8 BP 1263 EP 1272 DI 10.1089/ars.2006.8.1263 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 070DX UT WOS:000239501600018 PM 16910774 ER PT J AU Ridnour, LA Thomas, DD Donzelli, S Espey, MG Roberts, DD Wink, DA Isenberg, JS AF Ridnour, Lisa A. Thomas, Douglas D. Donzelli, Sonia Espey, Michael G. Roberts, David D. Wink, David A. Isenberg, Jeffrey S. TI The biphasic nature of nitric oxide responses in tumor biology SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID INDEPENDENT ENOS ACTIVATION; SIGNAL-REGULATED KINASE; PROTEIN-KINASE; CHRONIC INFLAMMATION; CELL-PROLIFERATION; MESANGIAL CELLS; SYNTHASE GENE; THROMBOSPONDIN-1; NO; ANGIOGENESIS AB The dual or biphasic responses of cancer to nitric oxide (NO) arise from its concentration dependent ability to regulate tumor growth, migration, invasion, survival, angiogenesis, and metastasis. The outcome of these various NO-dependent processes is dictated by several factors including NO flux, the chemical redox environment, and the duration of NO exposure. Further, it was recently discovered that an NO-induced redox flux in vascular endothelial cells hypersensitizes these cells to the antiangiogenic effects of thrombospondin-1. This suggests a novel treatment paradigm for targeting tumor-driven angiogenesis that combines redox modulation with mimetic derivatives of thrombospondin-1. This article discusses the biphasic nature of NO in cancer biology and the implications of NO-driven redox flux for modulation of tumor-stimulated angiogenesis, growth, and metastasis. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Ridnour, LA (reprint author), NCI, Radiat Biol Branch, NIH, 10 Ctr Dr,Bldg 10,Room B3-B35, Bethesda, MD 20892 USA. EM ridnourl@mail.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural NIH HHS NR 82 TC 102 Z9 106 U1 0 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUL-AUG PY 2006 VL 8 IS 7-8 BP 1329 EP 1337 DI 10.1089/ars.2006.8.1329 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 070DX UT WOS:000239501600024 PM 16910780 ER PT J AU Donzelli, S Switzer, CH Thomas, DD Ridnour, LA Espey, MG Isenberg, JS Tocchetti, CG King, SB Lazzarino, G Miranda, KM Roberts, DD Feelisch, M Wink, DA AF Donzelli, Sonia Switzer, Christopher H. Thomas, Douglas D. Ridnour, Lisa A. Espey, Michael Graham Isenberg, Jeffrey S. Tocchetti, Carlo G. King, S. Bruce Lazzarino, Giuseppe Miranda, Katrina M. Roberts, David D. Feelisch, Martin Wink, David A. TI The activation of metabolites of nitric oxide synthase by metals is both redox and oxygen dependent: A new feature of nitrogen oxide signaling SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID HYDROXY-L-ARGININE; PROTEIN-TYROSINE NITRATION; IN-VIVO; S-NITROSOTHIOLS; NITROXYL ANION; CARDIOVASCULAR-SYSTEM; SUPEROXIDE-DISMUTASE; ISCHEMIA-REPERFUSION; CEREBROSPINAL-FLUID; MURINE MACROPHAGES AB Nitrite (NO2-), N-G-hydroxy-L-arginine (NOHA), and hydroxylamine (NH2OH) are products of nitric oxide synthase (NOS) activity and can also be formed by secondary reactions of nitric oxide (NO). These compounds are commonly considered to be rather stable and as such to be dosimeters of NO biosynthesis. However, each can be converted via metal-catalyzed reactions into either NO or other reactive nitrogen oxide species (RNOS), such as nitrogen dioxide (NO2) and nitroxyl (HNO), which have biologic activities distinct from those of the parent molecules. Consequently, certain aspects of tissue regulation controlled by RNOS may be dictated to a significant extent by metal-dependent reactions, thereby offering unique advantages for cellular and tissue regulation. For instance, because many metal-catalyzed reactions depend on the redox and oxygen status of the cellular environment, such reactions could serve as redox indicators. Formation of RNOS by metal-mediated pathways would confine the chemistry of these species to specific cellular sites. Additionally, such mechanisms would be independent both of NO and NOS, thus increasing the lifetime of RNOS that react with NO. Thus metal-mediated conversion of nitrite, NOHA, and NH2OH into biologically active agents may provide a unique signaling mechanism. In this review, we discuss the biochemistry of such reactions in the context of their pharmacologic and biologic implications. C1 NCI, Radiat Biol Branch, Tumor Biol Sect, NIH, Bethesda, MD 20892 USA. NCI, Lab Pathol, Biochem Pathol Sect, NIH, Bethesda, MD USA. Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD USA. Wake Forest Univ, Dept Chem, Winston Salem, NC USA. Catania Univ, Biochem Lab, Dept Chem Sci, Catania, Italy. Univ Arizona, Dept Chem, Tucson, AZ USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA USA. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, Tumor Biol Sect, NIH, Bldg 10,Room B3-B35, Bethesda, MD 20892 USA. EM wink@mail.nih.gov RI Roberts, David/A-9699-2008; Miranda, Katrina/B-7823-2009; Switzer, Christopher/D-9203-2013; Feelisch, Martin/C-3042-2008; OI Roberts, David/0000-0002-2481-2981; Feelisch, Martin/0000-0003-2320-1158; tocchetti, carlo gabriele/0000-0001-5983-688X; lazzarino, giuseppe/0000-0002-5917-7279 FU Intramural NIH HHS NR 110 TC 20 Z9 21 U1 0 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUL-AUG PY 2006 VL 8 IS 7-8 BP 1363 EP 1371 DI 10.1089/ars.2006.8.1363 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 070DX UT WOS:000239501600027 PM 16910783 ER PT J AU Bhagwat, AA Tan, J Sharma, M Kothary, M Low, S Tall, BD Bhagwat, M AF Bhagwat, Arvind A. Tan, Jasmine Sharma, Manan Kothary, Mahendra Low, Sharon Tall, Ben D. Bhagwat, Medha TI Functional heterogeneity of RpoS in stress tolerance of enterohemorrhagic Escherichia coli strains SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID ACID-RESISTANCE SYSTEMS; STATIONARY-PHASE; SHIGELLA-FLEXNERI; ENTERIC BACTERIA; MUTATIONS; GLUTAMATE; O157-H7; SURVIVAL; GENES; EXPRESSION AB The stationary-phase sigma factor (RpoS) regulates many cellular responses to environmental stress conditions such as heat, acid, and alkali shocks. On the other hand, mutations at the rpoS locus have frequently been detected among pathogenic as well as commensal strains of Escherichia coli. The objective of this study was to perform a functional analysis of the RpoS-mediated stress responses of enterohemorrhagic E. coli strains from food-borne outbreaks. E. coli strains belonging to serotypes O157:H7, O111:H11, and O26:H11 exhibited polymorphisms for two phenotypes widely used to monitor rpoS mutations, heat tolerance and glycogen synthesis, as well as for two others, alkali tolerance and adherence to Caco-2 cells. However, these strains synthesized the oxidative acid resistance system through an rpoS-dependent pathway. During the transition from mildly acidic growth conditions (pH 5.5) to alkaline stress (pH 10.2), cell survival was dependent on rpoS functionality. Some strains were able to overcome negative regulation by RpoS and induced higher P-galactosidase activity without compromising their acid resistance. There were no major differences in the DNA sequences in the rpoS coding regions among the tested strains. The heterogeneity of rpoS-dependent phenotypes observed for stress-related phenotypes was also evident in the Caco-2 cell adherence assay. Wild-type O157:H7 strains with native rpoS were less adherent than rpoS-complemented counterpart strains, suggesting that rpoS functionality is needed. These results show that some pathogenic E. coli strains can maintain their acid tolerance capability while compromising other RpoS-dependent stress responses. Such adaptation processes may have significant impact on a pathogen's survival in food processing environments, as well in the host's stomach and intestine. C1 USDA ARS, Prod Qual & Safety Lab, Henry A Wallace Beltsville Agr Res Ctr, Beltsville, MD 20705 USA. USDA ARS, Food Technol & Safety Lab, Henry A Wallace Beltsville Agr Res Ctr, Beltsville, MD 20705 USA. US FDA, Div Virulence Assessment, Laurel, MD 20708 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Bhagwat, M (reprint author), USDA ARS, Prod Qual & Safety Lab, Henry A Wallace Beltsville Agr Res Ctr, Bldg 002,10300 Baltimore Ave, Beltsville, MD 20705 USA. EM bhagwata@ba.ars.usda.gov OI Tall, Ben/0000-0003-0399-3629 NR 57 TC 36 Z9 40 U1 0 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD JUL PY 2006 VL 72 IS 7 BP 4978 EP 4986 DI 10.1128/AEM.02842-05 PG 9 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 062RA UT WOS:000238961000060 PM 16820496 ER PT J AU Shaw, P Sporn, A Gogtay, N Overman, GP Greenstein, D Gochman, P Tossell, JW Lenane, M Rapoport, JL AF Shaw, Philip Sporn, Alex Gogtay, Nitin Overman, Gerald P. Greenstein, Deanna Gochman, Peter Tossell, Julia W. Lenane, Marge Rapoport, Judith L. TI Childhood-onset schizophrenia - A double-blind, randomized clozapine-olanzapine comparison SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID TREATMENT-RESISTANT SCHIZOPHRENIA; SCHOOL-AGE-CHILDREN; OPEN-LABEL TRIAL; 2ND-GENERATION ANTIPSYCHOTICS; ADOLESCENT PATIENTS; K-SADS; HALOPERIDOL; RISPERIDONE; METAANALYSIS; RELIABILITY AB Background: Childhood-onset schizophrenia is a rare but severe form of the disorder that is frequently treatment resistant. The psychiatrist has a limited evidence base to guide treatment, particularly as there are no trials in children comparing atypical antipsychotics, the mainstay of current treatment. Objective: To compare the efficacy and safety of olanzapine and clozapine, hypothesizing that clozapine would be more efficacious. Design: Double-blind randomized 8-week controlled trial, with a 2-year open-label follow-up. Setting: National Institute of Mental Health study, January 1998 to June 2005. Patients underwent reassessment 2 years after discharge. Patients: Children and adolescents recruited nationally, aged 7 to 16 years, meeting unmodified DSM-IV criteria for schizophrenia, and resistant to treatment with at least 2 antipsychotics. Interventions: After drug washout and a 1- to 3-week antipsychotic-free period, patients were randomized to treatment with clozapine (n=12) or olanzapine (n=13). Main Outcome Measures: The Clinical Global Impression Severity of Symptoms Scale and Schedule for the Assessment of Negative/Positive Symptoms. Results: Clozapine was associated with a significant reduction in all outcome measures, whereas olanzapine showed a less consistent profile of clinical improvement. While there were moderate to large differential treatment effects in favor of clozapine, these reached significance only in the alleviation of negative symptoms from an antipsychotic-free baseline (P=.04; effect size, 0.89). Clozapine was associated with more overall adverse events. At 2-year follow-up, 15 patients were receiving clozapine with evidence of sustained clinical improvement, but additional adverse events emerged, including lipid anomalies (n=6) and seizures (n=1). Conclusions: While not demonstrating definitively the superiority of clozapine compared with olanzapine in treatment-refractory childhood-onset schizophrenia, the study suggests that clozapine has a more favorable profile of clinical response, which is balanced against more associated adverse events. C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. RP Shaw, P (reprint author), NIMH, Child Psychiat Branch, NIH, Room 3N202,Bldg 10,Ctr Dr, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov RI Gogtay, Nitin/A-3035-2008 NR 43 TC 131 Z9 135 U1 6 U2 14 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 JUL PY 2006 VL 63 IS 7 BP 721 EP 730 DI 10.1001/archpsyc.63.7.721 PG 10 WC Psychiatry SC Psychiatry GA 059RJ UT WOS:000238749600003 PM 16818861 ER PT J AU Cannon, DM Carson, RE Nugent, AC Eckelman, WC Kiesewetter, DO Williams, J Rollis, D Drevets, M Gandhi, S Solorio, G Drevets, WC AF Cannon, Dara M. Carson, Richard E. Nugent, Allison C. Eckelman, William C. Kiesewetter, Dale O. Williams, Joan Rollis, Denise Drevets, Michele Gandhi, Shilpa Solorio, Gerardo Drevets, Wayne C. TI Reduced muscarinic type 2 receptor binding in subjects with bipolar disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID CINGULATE CORTEX; CEREBRAL-CORTEX; KNOCKOUT MICE; CHRM2 GENE; DEPRESSION; M2; COGNITION; AGONIST; SCHIZOPHRENIA; FP-TZTP AB Context: A variety of indirect evidence has implicated the central muscarinic-cholinergic system, and more specifically the type 2 muscarinic (M-2) receptor, in the pathogenesis of depressive symptoms arising in major depressive disorder and bipolar disorder. Objective: To assess the binding potential of muscarinic2 receptors in vivo during depression in subjects with major depressive disorder or bipolar disorder. Design: The M-2 receptor binding was compared between unmedicated subjects with major depressive disorder or bipolar disorder during depression vs healthy controls, using positron emission tomography and [F-18]FP-TZTP (fluorodopa F 18 [3-(3-[3-fluoroproply] thio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine), a selective M-2 receptor radioligand. Setting: Outpatients at the National Institutes of Health. Participants: Unmedicated subjects with current depression meeting DSM-IV criteria for either major depressive disorder (n=17) or bipolar disorder (n=16) and 23 healthy control subjects. Main Outcome Measures: The primary outcome parameter was [F-18] FP-TZTP distribution volume, which is proportional to the product of receptor density and affinity and, in the case of [F-18] FP-TZTP, is known to be sensitive to endogenous acetylcholine concentrations. The relationship between illness severity, as rated using the Montgomery-Asberg Depression and Hamilton Anxiety Rating scales, and distribution volume also was assessed. Results: The mean anterior cingulate cortex distribution volume differed across groups (F-55=3.4; P=.04), and this difference was accounted for by significantly lower binding in bipolar disorder compared with both major depressive disorder and control groups. Conclusions: The mean M-2 receptor binding in subjects with bipolar disorder was reduced relative to both healthy controls and subjects with major depressive disorder, to an extent that correlated with depressive symptoms. The reduction in the bipolar disorder group could be accounted for either by a reduction in M-2 receptor density or affinity or an elevation in endogenous acetylcholine levels. To our knowledge, these data provide the first direct evidence that altered M-2 receptor function contributes to mood dysregulation in bipolar disorder. C1 NIMH, Mood & Anxiety Disorders Program, Mol Imaging Branch, Bethesda, MD 20892 USA. Natl Inst Biomed Imaging & Bioengn, Positron Emiss Tomog Radiochem Grp, NIH, Bethesda, MD USA. Warren Grant Magnuson Clin Ctr, Positron Emiss Tomog Imaging Ctr, NIH, Bethesda, MD USA. Yale Univ, Sch Med, Positron Emiss Tomog Ctr, Phys Dept Diagnost Radiol, New Haven, CT USA. Mol Tracer LLC, Bethesda, MD USA. RP Cannon, DM (reprint author), NIMH, Mood & Anxiety Disorders Program, Mol Imaging Branch, 15K-201 N Dr, Bethesda, MD 20892 USA. EM daracannon@mail.nih.gov RI Cannon, Dara/C-1323-2009; Carson, Richard/H-3250-2011; OI Cannon, Dara/0000-0001-7378-3411; Carson, Richard/0000-0002-9338-7966; Nugent, Allison/0000-0003-2569-2480 NR 40 TC 54 Z9 57 U1 1 U2 3 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 JUL PY 2006 VL 63 IS 7 BP 741 EP 747 DI 10.1001/archpsyc.63.7.741 PG 7 WC Psychiatry SC Psychiatry GA 059RJ UT WOS:000238749600006 PM 16818863 ER PT J AU Zhou, M Gradstein, L Gonzales, JA Tsilou, ET Gahl, WA Chan, CC AF Zhou, Min Gradstein, Libe Gonzales, John A. Tsilou, Ekaterini T. Gahl, William A. Chan, Chi-Chao TI Ocular pathologic features of Hermansky-Pudlak syndrome type 1 in an adult SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID OCULOCUTANEOUS ALBINISM; DEFECTS; TRAFFICKING; PLATELET C1 NEI, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, NIH, Bldg 10,Room 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov FU Intramural NIH HHS [Z01 EY000222-22] NR 10 TC 4 Z9 4 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JUL PY 2006 VL 124 IS 7 BP 1048 EP 1051 DI 10.1001/archopht.124.7.1048 PG 4 WC Ophthalmology SC Ophthalmology GA 064XE UT WOS:000239123200017 PM 16832032 ER PT J AU Wang, MY Zhao, D Spinetti, G Zhang, J Jiang, LQ Pintus, G Monticone, R Lakatta, EG AF Wang, Mingyi Zhao, Di Spinetti, Gaia Zhang, Jing Jiang, Li-Qun Pintus, Gianfranco Monticone, Robert Lakatta, Edward G. TI Matrix metalloproteinase 2 activation of transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta 1-type II receptor signaling within the aged arterial wall SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE aging; metalloproteinases; TGF-beta 1 signaling; arterial remodeling ID GROWTH-FACTOR-BETA; TGF-BETA; ANGIOTENSIN-II; MATRIX METALLOPROTEINASE-2; BINDING-PROTEINS; TISSUE INHIBITOR; EXPRESSION; CELLS; RATS; SYSTEM AB Objective - To study matrix metalloproteinase 2 (MMP-2) effects on transforming growth factor-beta 1 (TGF-beta 1) activation status and downstream signaling during arterial aging. Methods and Results - Western blotting and immunostaining showed that latent and activated TGF-beta 1 are markedly increased within the aorta of aged Fisher 344 cross-bred Brown Norway (30 months of age) rats compared with adult (8 months of age) rats. Aortic TGF-beta 1-type II receptor (T beta RII), its downstream molecules p-similar to mad-mother against decapentaplegic (SMAD)2/3 and SMAD4, fibronectin, and collagen also increased with age. Moreover, TGF-beta 1 staining is colocalized with that of activated MMP-2 within the aged arterial wall and vascular smooth muscle cell (VSMC) in vitro, and this physical association was confirmed by coimmunoprecipitation. Incubation of young aortic rings ex vivo or VSMCs in vitro with activated MMP-2 enhanced active TGF-beta 1, collagen, and fibronectin expression to the level of untreated old counterparts, and this effect was abolished via inhibitors of MMP-2. Interestingly, in old untreated rings or VSMCs, the increased TGF-beta 1, fibronectin, and collagen were also substantially reduced by inhibition of MMP-2. Conclusions - Active TGF-beta 1, its receptor, and receptor-mediated signaling increase within the aortic wall with aging. TGF-beta 1 activation is dependent, in part at least, by a concomitant age-associated increase in MMP-2 activity. Thus, MMP-2 - activated TGF-beta 1, and subsequently T beta RII signaling, is a novel molecular mechanism for arterial aging. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Wang, MY (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, 560 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mingyiw@grc.nia.nih.gov OI Spinetti, Gaia/0000-0001-7996-6809 FU Intramural NIH HHS NR 26 TC 109 Z9 113 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2006 VL 26 IS 7 BP 1503 EP 1509 DI 10.1161/01.ATV.0000225777.58488.f2 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 124YO UT WOS:000243408900015 PM 16690877 ER PT J AU Fritsch, RD Shen, XL Illei, GG Yarboro, CH Prussin, C Hathcock, KS Hodes, RJ Lipsky, PE AF Fritsch, Ruth D. Shen, Xinglei Illei, Gabor G. Yarboro, Cheryl H. Prussin, Calman Hathcock, Karen S. Hodes, Richard J. Lipsky, Peter E. TI Abnormal differentiation of memory T cells in systemic lupus erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Article ID HIGH ENDOTHELIAL VENULES; PERIPHERAL-BLOOD; TELOMERASE ACTIVITY; CHEMOKINE RECEPTOR; LYMPHOCYTE DEVELOPMENT; 2 SUBSETS; IN-VIVO; EXPRESSION; CD27; ACTIVATION AB Objective. The chemokine receptor CCR7 and the tumor necrosis factor receptor family member CD27 define 3 distinct, progressively more differentiated maturational stages of CD4 memory subpopulations in healthy individuals: the CCR7+,CD27+, the CCR7-, CD27+, and the CCR7-,CD27- populations. The goal of this study was to examine maturational disturbances in CD4 T cell differentiation in systemic lupus erythematosus (SLE), using these phenotypic markers. Methods. Phenotypic analysis by flow cytometry, in vitro stimulation experiments, telomere length measurement, and determination of inducible telomerase were carried out. Results. In SLE patients, significant increases of CCR7-,CD27- and CCR7-,CD27+ and a reduction of CCR7+,CD27+ CD4 memory T cells were found. In vitro stimulation of SLE T cells showed a stepwise differentiation from naive to CCR7+,CD27+ to CCR7-,CD27+ to CCR7-,CD27-; telomere length and inducible telomerase decreased in these subsets in the same progressive sequence. The in vitro proliferative response of these populations progressively declined as their susceptibility to apoptosis increased. Interestingly, a significant reduction in inducible telomerase was noted in SLE naive and CCR7+,CD27+ CD4+ memory T cells. Additionally, SLE CCR7-,CD27+ and CCR7-, CD27- CD4 memory T cells proliferated poorly in response to in vitro stimulation and underwent significantly more apoptosis than their normal counterparts. Finally, expression of CXCR4 was significantly reduced in all SLE subsets compared with normal. Conclusion. Together these data indicate an increased degree of in vivo T cell stimulation in SLE, resulting in the accumulation of terminally differentiated memory T cells with a decreased proliferative capacity and an increased tendency to undergo apoptosis upon stimulation. C1 NIAMS, NIH, Bethesda, MD 20892 USA. RP Lipsky, PE (reprint author), NIAMS, NIH, Bldg 10,Room 6D47C,9000 Rockville Pike, Bethesda, MD 20892 USA. EM lipskyp@mail.nih.gov RI Fritsch-sTork, Ruth/G-9702-2012; OI Prussin, Calman/0000-0002-3917-3326 NR 42 TC 50 Z9 55 U1 1 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 JUL PY 2006 VL 54 IS 7 BP 2184 EP 2197 DI 10.1002/art.21943 PG 14 WC Rheumatology SC Rheumatology GA 062IY UT WOS:000238939000017 PM 16802356 ER PT J AU Lipsky, PE AF Lipsky, Peter E. TI Interleukin-6 and rheumatic diseases SO ARTHRITIS RESEARCH & THERAPY LA English DT Article ID C-REACTIVE PROTEIN; COLLAGEN-INDUCED ARTHRITIS; RECOMBINANT HUMAN INTERLEUKIN-6; CORONARY-ARTERY-DISEASE; SOLUBLE IL-6 RECEPTOR; OSTEOCLAST FORMATION; SERUM INTERLEUKIN-6; HEART-DISEASE; INFLAMMATION; RISK AB IL-6 is a pleiotropic cytokine involved in both the initiation and the maintenance of the inflammatory and immunologic responses in certain autoimmune diseases. Blocking of these two complementary functions of IL-6 may confer additive, or even unique, benefits to the patient. The levels of both IL-6 and its soluble receptor (slL-6R alpha) are elevated to various degrees in many rheumatic diseases. IL-6 blockade has been shown to be beneficial both in experimental models and in human disease, and inhibition of IL-6 signaling with a molecule such as tocilizumab could prevent or reverse some of the complications typically associated with rheumatic diseases. C1 NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Lipsky, PE (reprint author), NIAMSD, Autoimmun Branch, NIH, Rockville Pike, Bethesda, MD 20892 USA. EM lipskyp@mail.nih.gov NR 38 TC 57 Z9 59 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PD JUL PY 2006 VL 8 SU 2 AR S4 DI 10.1186/ar1918 PG 5 WC Rheumatology SC Rheumatology GA 091JA UT WOS:000241022000004 PM 16899108 ER PT J AU Kang, HS Beak, JY Kim, YS Petrovich, RM Collins, JB Grissom, SF Jetten, AM AF Kang, HS Beak, JY Kim, YS Petrovich, RM Collins, JB Grissom, SF Jetten, AM TI NABP1, a novel ROR gamma-regulated gene encoding a single-stranded nucleic-acid-binding protein SO BIOCHEMICAL JOURNAL LA English DT Article DE microarray; nucleic acid binding protein 1 (NABP1); nuclear receptor; oligonucleotide/oligosaccharide binding-fold (OB-fold); ROR gamma (retinoid-related orphan receptor gamma); thymopoiesis ID ARCHAEON METHANOCOCCUS-JANNASCHII; ALPHA-DEFICIENT MICE; DNA-BINDING; ORPHAN RECEPTOR; OB-FOLD; IDENTIFICATION; RECOGNITION; EXPRESSION; STAGGERER; DOMAINS AB ROR gamma 2 (retinoid-related orphan receptor gamma 2) plays a critical role in the regulation of thymopoiesis. Microarray analysis was performed in order to uncover differences in gene expression between thymocytes of wild-type and ROR gamma(-/-) mice. This analysis identified a novel gene encoding a 22kDa protein, referred to as NABP1 (nucleic-acid-binding protein 1). This subsequently led to the identification of an additional protein, closely related to NABP1, designated NABP2. Both proteins contain and OB (oligonucleotide/oligosaccharide binding) motif at their N-terminus. This motif is highly conserved between the two proteins. NABP1 is highly expressed in the thymus of wild-type mice and is greatly suppressed in ROR gamma(-/-) mice. During thymopoiesis, NABP1 mRNA expression is restricted to CD4(+)CD8(+) thymocytes, an expression pattern similar to that observed for ROR gamma 2. These observations appear to suggest that NABP1 expression is regulated either directly or indirectly by ROR gamma 2. Confocal microscopic analysis showed that the NABP1 protein localizes to the nucleus. Analysis of nuclear proteins by size-exclusion chromatography indicated that NABP I is part of a high molecular-mass protein complex. Since the OB-fold is frequently involved in the recognition of nucleic acids, the interaction of NABP1 with various nucleic acids was examined. Our results demonstrate that NABP1 binds single-stranded nucleic acids, but not double-stranded DNA, suggesting that it functions as a single-stranded nucleic acid binding protein. C1 NIEHS, Cell Biol Sect, Lab Resp Biol, Div Intramural Res,NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Prot Express Core Facil, Struct Biol Lab, Div Intramural Res,NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Microarray Grp, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Lab Resp Biol, Div Intramural Res,NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU Intramural NIH HHS NR 37 TC 13 Z9 15 U1 0 U2 0 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD JUL 1 PY 2006 VL 397 BP 89 EP 99 DI 10.1042/BJ20051781 PN 1 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 058XZ UT WOS:000238699200011 PM 16533169 ER PT J AU Elberry, M Xiao, KH Esser, L Xia, D Yu, L Yu, CA AF Elberry, Maria Xiao, Kunhung Esser, Lothar Xia, Di Yu, Linda Yu, Chang-An TI Generation, characterization and crystallization of a highly active and stable cytochrome bc(1) complex mutant from Rhodobacter sphaeroides SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Article DE cytochrome bc(1) complex ID IRON-SULFUR PROTEIN; PROTON TRANSLOCATION; ENERGY TRANSDUCTION; RESPIRATORY-CHAIN; ELECTRON-TRANSFER; CRYSTAL-STRUCTURE; MITOCHONDRIAL; INVOLVEMENT; CAPSULATUS; ANTIMYCIN AB The availability of the three dimensional structure of mitochondrial enzyme, obtained by X-ray crystallography, allowed a significant progress in the understanding of the structure-function relation of the cytochrome bc(1) complex. Most of the structural information obtained has been confirmed by molecular genetic studies of the bacterial complex. Despite its small size and simple subunit composition, high quality crystals of the bacterial complex have been difficult to obtain and so far, only low resolution structural data has been reported. The low quality crystal observed is likely associated in part with the low activity and stability of the purified complex. To mitigate this problem, we recently engineered a mutant [S287R(cytb)/V135S(ISP)] from Rhodobacter sphaeroides to produce a highly active and more stable cytochrome bc(1) complex. The purified mutant complex shows a 40% increase in electron transfer activity as compared to that of the wild type enzyme. Differential scanning calorimetric study shows that the mutant is more stable than the wild type complex as indicated by a 4.3 degrees C increase in the thermo-denaturation temperature. Crystals formed from this mutant complex, in the presence of stigmatellin, diffract X-rays up to 2.9 angstrom resolution. (c) 2006 Elsevier B.V. All rights reserved. C1 Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA. NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Yu, CA (reprint author), Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA. EM cayuq@okstate.edu FU NIGMS NIH HHS [GM 30721] NR 22 TC 8 Z9 12 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD JUL PY 2006 VL 1757 IS 7 BP 835 EP 840 DI 10.1016/j.bbabio.2006.05.031 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 077TR UT WOS:000240053700013 PM 16828701 ER PT J AU Bhargava, R Fernandez, DC Hewitt, SM Levin, IW AF Bhargava, Rohit Fernandez, Daniel C. Hewitt, Stephen M. Levin, Ira W. TI High throughput assessment of cells and tissues: Bayesian classification of spectral metrics from infrared vibrational spectroscopic imaging data SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Review DE Fourier transform infrared (FTIR) spectroscopy; imaging; biophotonics; prostate; tissue microarray; Bayesian statistics; likelihood classification; discriminant; cancer; histology; pathology; ROC ID IR MICROSPECTROSCOPY; MICRO-SPECTROSCOPY; BREAST-CANCER; IN-VIVO; RECOGNITION; MICROARRAYS; SYSTEMS; EXPRESSION; RESOLUTION; SPECIMENS AB Vibrational spectroscopy allows a visualization of tissue constituents based on intrinsic chemical composition and provides a potential route to obtaining diagnostic markers of diseases. Characterizations utilizing infrared vibrational spectroscopy, in particular, are conventionally low throughput in data acquisition, generally lacking in spatial resolution with the resulting data requiring intensive numerical computations to extract information. These factors impair the ability of infrared spectroscopic measurements to represent accurately the spatial heterogeneity in tissue, to incorporate robustly the diversity introduced by patient cohorts or preparative artifacts and to validate developed protocols in large population studies. In this manuscript, we demonstrate a combination of Fourier transform infrared (FTIR) spectroscopic imaging, tissue microarrays (TMAs) and fast numerical analysis as a paradigm for the rapid analysis, development and validation of high throughput spectroscopic characterization protocols. We provide an extended description of the data treatment algorithm and a discussion of various factors that may influence decision-making using this approach. Finally, a number of prostate tissue biopsies, arranged in an array modality, are employed to examine the efficacy of this approach in histologic recognition of epithelial cell polarization in patients displaying a variety of normal, malignant and hyperplastic conditions. An index of epithelial cell polarization, derived from a combined spectral and morphological analysis, is determined to be a potentially useful diagnostic marker. (c) 2006 Elsevier B.V. All rights reserved. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Univ Illinois, Dept Bioengn, Urbana, IL 61801 USA. Univ Illinois, Beckman Inst Adv Sci & Technol, Urbana, IL 61801 USA. NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Levin, IW (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM iwl@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Bhargava, Rohit/0000-0001-7360-994X FU Intramural NIH HHS NR 45 TC 84 Z9 87 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 EI 0006-3002 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD JUL PY 2006 VL 1758 IS 7 BP 830 EP 845 DI 10.1016/j.bbamem.2006.05.007 PG 16 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 084ZE UT WOS:000240572100003 PM 16822477 ER PT J AU Boskey, AL Goldberg, M Kulkarni, A Gomez, S AF Boskey, Adele L. Goldberg, Michel Kulkarni, Ashok Gomez, Santiago TI Infrared imaging microscopy of bone: Illustrations from a mouse model of Fabry disease SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Review DE infrared microscopic imaging; bone; hydroxyapatite; Fabry disease ID DEFICIENT MICE; SPECTROSCOPIC CHARACTERIZATION; TARGETED DISRUPTION; MINERALIZED TISSUES; MATRIX; OVEREXPRESSION; HYDROXYAPATITE; CRYSTALLINITY; OSTEOPOROSIS; OSTEOMALACIA AB Bone is a complex tissue whose composition and properties vary with age, sex, diet, tissue type, health and disease. In this review, we demonstrate how infrared spectroscopy and infrared spectroscopic imaging can be applied to the study of these variations. A specific example of mice with Fabry disease (a lipid storage disease) is presented in which it is demonstrated that the bones of these young animals, while showing typical spatial variation in mineral content, mineral crystal size, and collagen maturity, do not differ from the bones of age- and sex-matched wild type animals. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ Paris 05, Fac Chirurg Dent, Grp Matrice Extracellulaires & Biomineralisat, EA 4296,Lab Reparat & Remodelage Tissus Oro Facia, Montrouge, France. Cornell Univ, Hosp Special Surg, Ithaca, NY 14853 USA. Cornell Univ, Weill Med Coll, Ithaca, NY 14853 USA. Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Craniofacial Dev & Regenerat Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Cadiz, Dept Anat Patol, Cadiz, Spain. RP Boskey, AL (reprint author), Univ Paris 05, Fac Chirurg Dent, Grp Matrice Extracellulaires & Biomineralisat, EA 4296,Lab Reparat & Remodelage Tissus Oro Facia, Montrouge, France. EM boskeya@hss.edu OI Boskey, Adele/0000-0002-6181-2219 FU NCRR NIH HHS [C06-RR12538-01, C06 RR012538]; NIAMS NIH HHS [AR041325, AR046121, P30 AR046121, R01 AR041325]; NIDCR NIH HHS [DE04141, R01 DE004141, R37 DE004141] NR 45 TC 17 Z9 18 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD JUL PY 2006 VL 1758 IS 7 BP 942 EP 947 DI 10.1016/j.bbamem.2006.02.019 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 084ZE UT WOS:000240572100015 PM 16697974 ER PT J AU Philpott, CC AF Philpott, Caroline C. TI Iron uptake in fungi: A system for every source SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Review DE yeast; siderophore; transport; iron; fungi; ferrichrome ID YEAST SACCHAROMYCES-CEREVISIAE; MAJOR FACILITATOR SUPERFAMILY; L-ORNITHINE N-5-OXYGENASE; CANDIDA-ALBICANS; SIDEROPHORE BIOSYNTHESIS; MOLECULAR CHARACTERIZATION; FERRICHROME TRANSPORTER; ASPERGILLUS-FUMIGATUS; SCHIZOSACCHAROMYCES-POMBE; TRIACETYLFUSARININE-C AB Fungi have a remarkable capacity to take up iron when present in any of a wide variety of forms, which include free iron ions, low-affinity iron chelates, siderophore-iron chelates, transferrin, heme, and hemoglobin. Appropriately, these unicellular eukaryotes express a variety of iron uptake systems, some of which are unique to fungi and some of which are present in plants and animals, as well. The reductive system of uptake relies upon the external reduction of ferric salts, chelates, and proteins prior to uptake by a high-affinity, ferrous-specific, oxidase/permease complex. This system recognizes a broad range of substrates. The non-reductive system exhibits specificity for siderophore-iron chelates, and transporters of this system exhibit multiple substrate-dependent intracellular trafficking events. (c) 2006 Elsevier B.V. All rights reserved. C1 NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Philpott, CC (reprint author), NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM carolinep@intra.niddk.nih.gov FU Intramural NIH HHS NR 98 TC 91 Z9 97 U1 3 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JUL PY 2006 VL 1763 IS 7 BP 636 EP 645 DI 10.1016/j.bbamcr.2006.05.008 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 084AS UT WOS:000240504500006 PM 16806534 ER PT J AU Kaplan, J Ward, DM Crisp, RJ Philpott, CC AF Kaplan, Jerry Ward, Diane McVey Crisp, Robert J. Philpott, Caroline C. TI Iron-dependent metabolic remodeling in S-cerevisiae SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Review DE iron; heme; metabolism; oxygen; sterol; yeast ID GENE-EXPRESSION; SULFUR PROTEINS; YEAST; TRANSCRIPTION; TRANSPORTER; BIOGENESIS; OXIDASE; AFT1; MITOCHONDRIAL; ACTIVATION AB All eukaryotes require iron although iron is not readily bioavailable. Organisms expend much effort in acquiring iron and in response have evolved multiple mechanisms to acquire iron. Because iron is essential, organisms prioritize the iron use when iron is limiting; iron-sparing enzymes or metabolic pathways are utilized at the expense of iron-rich enzymes. A large percentage of cellular iron containing proteins is devoted to oxygen binding or metabolism, therefore, changes in oxygen availability affect iron usage. Transcriptional and post-transcriptional mechanisms have been shown to affect the concentration of iron-containing proteins under iron or oxygen limiting conditions. In this review, we describe how the budding yeast Saccharomyces cerevisiae utilizes multiple mechanisms to optimize iron usage under iron limiting conditions. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ Utah, Sch Med, SLC, Dept Pathol, Salt Lake City, UT 84132 USA. NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RP Kaplan, J (reprint author), Univ Utah, Sch Med, SLC, Dept Pathol, Salt Lake City, UT 84132 USA. EM jerry.kaplan@path.utah.edu NR 38 TC 75 Z9 80 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JUL PY 2006 VL 1763 IS 7 BP 646 EP 651 DI 10.1016/j.bbamcr.2006.03.008 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 084AS UT WOS:000240504500007 PM 16697062 ER PT J AU Chudasama, Y Robbins, TW AF Chudasama, Y Robbins, TW TI Functions of frontostriatal systems in cognition: Comparative neuropsychopharmacological studies in rats, monkeys and humans SO BIOLOGICAL PSYCHOLOGY LA English DT Review DE frontostriatal systems; comparative neuropsychopharmacological studies; neurocognitive; neuropsychiatric; executive function ID REACTION-TIME-TASK; SPATIAL WORKING-MEMORY; OBSESSIVE-COMPULSIVE DISORDER; MEDIAL PREFRONTAL CORTEX; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; FRONTAL-LOBE DAMAGE; CEREBRAL-BLOOD-FLOW; BORDERLINE PERSONALITY-DISORDER; MODAFINIL IMPROVES COGNITION; STRIATAL DOPAMINE DEPLETION AB A comparative and integrated account is provided of the evidence that implicates frontostriatal systems in neurodegenerative and neuropsychiatric disorders. Specifically, we have made detailed comparisons of performance following basal ganglia disease such as Parkinson's disease, with other informative groups, including Alzheimer's disease, schizophrenia and attention deficit/hyperactivity disorder and structural damage to the frontal lobes themselves. We have reviewed several behavioural paradigms including spatial attention and set-shifting, working memory and decision-making tasks in which optimal performance requires the operation of several cognitive processes that can be successfully dissociated with suitable precision in experimental animals. The role of ascending neurotransmitter systems are analysed from the perspective of different interactions with the prefrontal cortex. In particular, the role of dopamine in attentional control and spatial working memory is surveyed with reference to its deleterious as well as facilitatory effects. Parallels are identified in humans receiving dopaminergic medication, and with monkeys and rats with frontal dopamine manipulations. The effects of serotonergic manipulations are also contrasted with frontal lobe deficits observed in both humans and animals. The main findings are that certain tests of frontal lobe function are very sensitive to several neurocognitive and neuropsychiatric disorders. However, the nature of some of these deficits often differs qualitatively from those produced by frontal lobe lesions, and animal models have been useful in defining various candidate neural systems thus enabling us to translate basic laboratory science to the clinic, as well as in the reverse direction. Published by Elsevier B.V. C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. RP Chudasama, Y (reprint author), NIMH, Neuropsychol Lab, Convent Dr,Bldg 49,Room 1B80, Bethesda, MD 20892 USA. EM Yogita@ln.nimh.nih.gov FU Medical Research Council [G0001354]; Wellcome Trust [, 076274] NR 262 TC 264 Z9 265 U1 13 U2 56 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD JUL PY 2006 VL 73 IS 1 BP 19 EP 38 DI 10.1016/j.biopsycho.2006.01.005 PG 20 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 053JX UT WOS:000238302500003 PM 16546312 ER PT J AU Epstein, DH Preston, KL Jasinski, DR AF Epstein, DH Preston, KL Jasinski, DR TI Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: Lessons from tramadol SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE drug abuse/dependence; cross-species comparison; abuse-liability assessment; oxycodone ID CONDITIONED PLACE PREFERENCE; PATIENT-CONTROLLED ANALGESIA; POSTMARKETING SURVEILLANCE; METHADONE DETOXIFICATION; DISCONTINUATION SYNDROME; BUPRENORPHINE; DRUG; RATS; MORPHINE; HYDROCHLORIDE AB Assessment of abuse potential of opioid analgesics has a long history in both laboratory animals and humans. This article reviews the methods used in animals and in humans and then presents the data collected in the evaluation of tramadol, an atypical centrally acting opioid analgesic approved for marketing in the United States in 1998. Finally, data on the abuse of tramadol from postmarketing surveillance and case reports are presented. The consistency between animal and human study results and the predictive value of both are discussed. Overall, there was substantial agreement between animal and human data, with each having predictive value. Nonetheless, it is suggested that abuse-potential screening of new medications would benefit from an organized, integrated cross-species program. Published by Elsevier B.V. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21224 USA. RP Preston, KL (reprint author), NIDA, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM kpreston@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU Intramural NIH HHS [Z99 DA999999] NR 76 TC 52 Z9 53 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD JUL PY 2006 VL 73 IS 1 BP 90 EP 99 DI 10.1016/j.biopsycho.2006.01.010 PG 10 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 053JX UT WOS:000238302500008 PM 16497429 ER PT J AU Banwell, MG Hamel, E Hockless, DCR Verdier-Pinard, P Willis, AC Wong, DJ AF Banwell, MG Hamel, E Hockless, DCR Verdier-Pinard, P Willis, AC Wong, DJ TI 4,5-Diaryl-1H-pyrrole-2-carboxylates as combretastatin A-4/lamellarin T hybrids: Synthesis and evaluation as anti-mitotic and cytotoxic agents SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE anti-mitotic; cis-stilbene; combretastatin A-4; cytotoxic; lamellarin T ID TUBULIN-BINDING PROPERTIES; RAY CRYSTAL-STRUCTURE; NATURAL-PRODUCTS; ANTIINFLAMMATORY 4,5-DIARYLPYRROLES; ANTINEOPLASTIC AGENTS; ANTIMITOTIC AGENTS; PYRROLE CHEMISTRY; LAMELLARIN-O; ANALOGS; POTENT AB The 4,5-diarylated-1H-pyrrole-2-carboxylates 3-8 have each been prepared as hybrids of the potent anti-mitotic agent combretastatin A-4 (1) and the similarly active marine alkaloid lamellarin T (2). The key steps involved selective lithium-for-halogen exchange at C5 within the N-PMB protected 4,5-dibromopyrrole 22 and Negishi cross-coupling of the derived zincated species with the relevant aryl iodide. The ensuing 5-aryl-4-bromopyrrole then engaged in Suzuki-Miyaura cross-coupling with the appropriate arylboronic acid to give the 4,5-diarylated pyrroles 4, 6 and 8. TFA-promoted removal of the N-PMB group within these last compounds then gave the N-unsubstituted congeners 3, 5 and 7. Compounds 3-8 have all been evaluated for their anti-mitotic and cytotoxic properties and two of them, 3 and 5, display useful activities although they are less potent than combretastatin A-4. Crown Copyright (c) 2006 Published by Elsevier Ltd. All rights reserved. C1 Australian Natl Univ, Inst Adv Studies, Res Sch Chem, Canberra, ACT 0200, Australia. NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis,NIH, Frederick, MD 21702 USA. RP Banwell, MG (reprint author), Australian Natl Univ, Inst Adv Studies, Res Sch Chem, Canberra, ACT 0200, Australia. EM mgb@rse.anu.edu.au RI Banwell, Martin/H-8354-2014; OI Verdier-Pinard, Pascal/0000-0002-6149-6578 NR 39 TC 60 Z9 63 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUL 1 PY 2006 VL 14 IS 13 BP 4627 EP 4638 DI 10.1016/j.bmc.2006.02.018 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 051SZ UT WOS:000238182500028 PM 16510287 ER PT J AU Kulkarni, SS Nightingale, B Dersch, CM Rothman, RB Newman, AH AF Kulkarni, SS Nightingale, B Dersch, CM Rothman, RB Newman, AH TI Design and synthesis of noncompetitive metabotropic glutamate receptor subtype 5 antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE metabotropic glutamate receptor subtype 5; mGluR5; noncompetitive antagonists ID MGLUR5 ANTAGONIST; ANXIOLYTIC ACTIVITY; POTENT; MPEP; 2-METHYL-6-(PHENYLETHYNYL)-PYRIDINE; DISORDERS; DISCOVERY; SIB-1893; COCAINE; ACID AB A series of diaryl amides was designed and synthesized as novel nonethynyl mGluR5 antagonists. The systematic variation of the pharmacophoric groups led to the identification of a lead compound that demonstrated micromolar affinity for the mGluR5. Further optimization resulted in compounds with improved binding affinities and antagonist profiles, in vitro. (c) 2006 Elsevier Ltd. All rights reserved. C1 NIDA, Med Chem Sect, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, NIH,DHHS, 550 Nathan Shock Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov FU Intramural NIH HHS NR 21 TC 15 Z9 15 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUL 1 PY 2006 VL 16 IS 13 BP 3371 EP 3375 DI 10.1016/j.bmcl.2006.04.032 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 051TB UT WOS:000238182700004 PM 16678408 ER PT J AU Raje, S Cornish, J Newman, AH Cao, J Katz, JL Eddington, ND AF Raje, Sangeeta Cornish, Jennifer Newman, Amy H. Cao, Jianjing Katz, Jonathan L. Eddington, Natalie D. TI Investigation of the potential pharmacokinetic and pharmacodynamic drug interaction between AHN 1-055, a potent benztropine analog used for cocaine abuse, and cocaine after dosing in rats using intracerebral microdialysis SO BIOPHARMACEUTICS & DRUG DISPOSITION LA English DT Article DE cocaine; drug interaction; benztropine analogs; dopamine transporter; pharmacokinetics-pharmacodynamics ID DOPAMINE UPTAKE INHIBITORS; TRANSPORTER; BRAIN; POPULATION; AHN-1055; LIGANDS AB Purpose. AHN 1-055, a benztropine (BZT) analog, binds with high affinity to the dopamine transporter (DAT), possesses behavioral, pharmacokinetic (PK) and brain microdialysate dopamine (DA) profiles distinct from cocaine. Accordingly, the objectives of this study were to evaluate the pharmacokinetics and dopamine release of AHN 1-055, in the presence of cocaine. Metliods. Male Sprague Dawley rats (similar to 300 g) were administered 5 mg/kg of AHN 1-055 and cocaine i.v. and blood and brain samples were collected over 36h. In addition, dialysis probes were stereotaxically implanted into the nucleus accumbens and extracellular fluid (ECF) DA levels were measured. PK and PD models were used to describe the relationship between the AHN 1-055, cocaine and DA levels. Results. No significant (p < 0.05) differences were found in the PK parameters of AHN 1-055 alone (V-dss = 18.71/kg, Cl = 1.81/h/kg and t(1/2) = 7.69h) or AHN 1-055 with cocaine (V-dss = 17.41/kg, Cl = 1.91/h/kgand t(1/2) = 6.82h). The brain-to-plasma (B/P) ratios (B/P-AHN (1-055) = 4.8 vs B/P-with (cocaine) = 4.4) and half-lives (t(1/2(AHN 1-055)) = 6-2h vs t(1/2(cocaine)) = 5.6h for AHN 1-055 alone and with cocaine were comparable. AHN 1-055 DA profiles were significantly different after coadministration with cocaine. There were no differences in the IC50 for AHN 1-055, with cocaine, however, the IC50 for cocaine was significantly reduced with AHN 1-055. Conclusions. The PK parameters of AHN 1-055 were not changed, however, the effect on DA levels was affected when cocaine was administered with AHNDA profile is affected when dosed with cocaine. This latter effect is a desirable attribute in the development of a medication as a potential substitute therapeutic medication for the treatment of cocaine abuse. Copyright (c) 2006 John Wiley & Sons, Ltd. C1 Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Pharmacokinet Biopharmaceut Lab, Baltimore, MD 21201 USA. NIDA, Intramural Res Program, NIH, Psychobiol Sect, Baltimore, MD 21224 USA. RP Eddington, ND (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Pharmacokinet Biopharmaceut Lab, 100 Penn St,AHB, Baltimore, MD 21201 USA. EM neddingt@rx.umaryland.edu OI Katz, Jonathan/0000-0002-1068-1159 NR 26 TC 4 Z9 4 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0142-2782 J9 BIOPHARM DRUG DISPOS JI Biopharm. Drug Dispos. PD JUL PY 2006 VL 27 IS 5 BP 229 EP 240 DI 10.1002/bdd.497 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 068FF UT WOS:000239357300003 PM 16586462 ER PT J AU Frolov, VAJ Chizmadzhev, YA Cohen, FS Zimmerberg, J AF Frolov, VAJ Chizmadzhev, YA Cohen, FS Zimmerberg, J TI "Entropic traps"in the kinetics of phase separation in multicomponent membranes stabilize nanodomains SO BIOPHYSICAL JOURNAL LA English DT Article ID BILAYER-LIPID-MEMBRANES; LINE TENSION; 2 DIMENSIONS; CAPILLARY CONDENSATION; SPINODAL DECOMPOSITION; BIOLOGICAL-MEMBRANES; MODEL MEMBRANES; PLASMA-MEMBRANE; GANGLIOSIDE GM1; CELL-SURFACE AB We quantitatively describe the creation and evolution of phase-separated domains in a multicomponent lipid bilayer membrane. The early stages, termed the nucleation stage and the independent growth stage, are extremely rapid ( characteristic times are submillisecond and millisecond, respectively) and the system consists of nanodomains of average radius; similar to 5-50 nm. Next, mobility of domains becomes consequential; domain merger and fission become the dominant mechanisms of matter exchange, and line tension gamma is the main determinant of the domain size distribution at any point in time. For sufficiently small gamma, the decrease in the entropy term that results from domain merger is larger than the decrease in boundary energy, and only nanodomains are present. For large gamma, the decrease in boundary energy dominates the unfavorable entropy of merger, and merger leads to rapid enlargement of nanodomains to radii of micrometer scale. At intermediate line tensions and within finite times, nanodomains can remain dispersed and coexist with a new global phase. The theoretical critical value of line tension needed to rapidly form large rafts is in accord with the experimental estimate from the curvatures of budding domains in giant unilamellar vesicles. C1 Russian Acad Sci, Frumkin Inst Electrochem, Moscow, Russia. Natl Inst Child Hlth & Human Dev, Lab Cellular & Mol Biophys, NIH, Bethesda, MD USA. Rush Univ, Ctr Med, Dept Mol Biophys & Physiol, Chicago, IL USA. RP Zimmerberg, J (reprint author), Russian Acad Sci, Frumkin Inst Electrochem, Moscow, Russia. EM joshz@helix.nih.gov RI Wunder, Stephanie/B-5066-2012; Chizmadzhev, Yuri/L-1984-2013; Zdilla, Michael/B-4145-2011; OI Frolov, Vadim/0000-0002-0653-5669 FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM066837] NR 47 TC 65 Z9 67 U1 5 U2 21 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUL PY 2006 VL 91 IS 1 BP 189 EP 205 DI 10.1529/biophysj.105.068502 PG 17 WC Biophysics SC Biophysics GA 053EN UT WOS:000238288200020 PM 16617071 ER PT J AU Buscaglia, M Lapidus, LJ Eaton, WA Hofrichter, J AF Buscaglia, M Lapidus, LJ Eaton, WA Hofrichter, J TI Effects of denaturants on the dynamics of loop formation in polypeptides SO BIOPHYSICAL JOURNAL LA English DT Article ID DIFFUSION-COLLISION MODEL; INTRAMOLECULAR CONTACT FORMATION; SINGLE-MOLECULE FLUORESCENCE; AMINO-ACIDS; SOLVENT DENATURATION; UNFOLDED PROTEINS; POLYMER CYCLIZATION; EXCLUDED-VOLUME; CHAIN CLOSURE; CYTOCHROME-C AB Quenching of the triplet state of tryptophan by close contact with cysteine has been used to measure the reaction-limited and diffusion-limited rates of loop formation in disordered polypeptides having the sequence cys-(ala-gly-gln)(j)-trp (j=1-9). The decrease in the length-dependence of the reaction-limited rate for short chains in aqueous buffer, previously attributed to chain stiffness, is not observed at high concentrations of chemical denaturant (6 M GdmCl and 8 M urea), showing that denaturants increase chain flexibility. For long chains, both reaction-limited and diffusion-limited rates are significantly smaller in denaturant and exhibit a steeper length dependence. The results can be explained using end-to-end distributions from a wormlike chain model in which excluded volume interactions are incorporated by associating a 0.4-0.5 nm diameter hard sphere with the end of each virtual peptide bond. Fitting the data with this model shows that the denaturants reduce the persistence length from similar to 0.6 nm to similar to 0.4 nm, only slightly greater than the length of a peptide bond. The same model also describes the reported length dependence for the radii of gyration of chemically denatured proteins containing 50-400 residues. The end-to-end diffusion coefficients obtained from the diffusion-limited rates are smaller than the sum of the monomer diffusion coefficients and exhibit significant temperature dependence, suggesting that diffusion is slowed by internal friction arising from barriers to backbone conformational changes. C1 NIDDKD, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. RP Hofrichter, J (reprint author), NIDDKD, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. EM jameshof@niddk.nih.gov RI Buscaglia, Marco/C-2435-2008 OI Buscaglia, Marco/0000-0001-5010-0278 NR 65 TC 71 Z9 71 U1 1 U2 13 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUL PY 2006 VL 91 IS 1 BP 276 EP 288 DI 10.1529/biophysj.105.071167 PG 13 WC Biophysics SC Biophysics GA 053EN UT WOS:000238288200028 PM 16617069 ER PT J AU Smith, DD Kovats, S Lee, TD Cano, L AF Smith, David D. Kovats, Susan Lee, Terry D. Cano, Leticia TI Median filter algorithm for estimating the threshold of detection on custom protein arrays SO BIOTECHNIQUES LA English DT Article ID MICROARRAYS AB We constructed protein arrays according to a titration design to estimate the assay sensitivities over varying concentrations of flu vaccine and human immunoglobulin G (IgG). After imaging, we considered the problem of appropriately distinguishing background noise from foreground signal. We applied the median filter smoothing technique and estimated the differences of the observed signal compared to the smoothed signal. If the absolute value of the difference was large, the feature was easily detectable, indicating that the spot did not blend with its surrounding neighbors. After estimating the residuals, we applied thresholding algorithms to estimate the limits of detection for each assay. At sufficiently large smoothing spans, our median filter approach performed as well or better than visual inspection and two other competing analysis methods. This suggests that a median filter approach has utility in high-throughput arrays where visual inspection is impractical. C1 City Hope Natl Med Ctr, Dept Biostat, Duarte, CA 91010 USA. Beckman Res Inst, Duarte, CA USA. Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Smith, DD (reprint author), City Hope Natl Med Ctr, Dept Biostat, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM dsmith02@coh.org RI Cano, Leticia/B-9908-2009; OI Smith, David/0000-0001-9644-2353; Kovats, Susan/0000-0001-5479-9952 FU NIAID NIH HHS [R01 AI044922] NR 14 TC 0 Z9 0 U1 0 U2 0 PU EATON PUBLISHING CO PI WESTBOROUGH PA ONE RESEARCH DRIVE, SUITE 400A, PO BOX 1070, WESTBOROUGH, MA 01581-6070 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD JUL PY 2006 VL 41 IS 1 BP 74 EP 78 DI 10.2144/000112204 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 062DW UT WOS:000238925800020 PM 16869517 ER PT J AU Trinh, L Phue, JN Jaluria, P Tsai, CW Narum, DL Shiloach, J AF Trinh, Loc Phue, Je-Nie Jaluria, Pratik Tsai, Chiawei W. Narum, David L. Shiloach, Joseph TI Screen-less expanded bed column: new approach for the recovery and purification of a malaria transmission blocking vaccine candidate from Pichia pastoris SO BIOTECHNOLOGY LETTERS LA English DT Article DE expanded bed adsorption; malaria vaccine; Pichia pastoris ID ADSORPTION CHROMATOGRAPHY; PROTEIN-PURIFICATION; MOUSE ENDOSTATIN; SCALE RECOVERY; EXPRESSION; STABILITY; YEAST AB An experimental malaria transmission blocking vaccine antigen, Pfs25H, expressed and secreted from Pichia pastoris was recovered and purified using a screenless expanded bed column equipped with a rotating fluid distribution system. This column was able to accommodate feed stock, containing 30% biomass, at a flow rate of 300-400 cm/h without affecting column stability. This capability is three times higher than the capability of the expanded bed column currently in use, which is equipped with a perforated plate fluid distribution system; this design could accommodate biomass concentrations of only up to 10%. The screen-less design did not affect the binding capacity, purification level or process yield and, therefore, shorten the process. Purified Pfs25H of 6.4 g were recovered from 37 l of Pichia pastoris culture in one step. C1 NIDDK, Biotechnol Unit, Bethesda, MD 20892 USA. NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Unit, NIH Bldg 14A,Room 173, Bethesda, MD 20892 USA. EM yossi@nih.gov NR 20 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-5492 J9 BIOTECHNOL LETT JI Biotechnol. Lett. PD JUL PY 2006 VL 28 IS 13 BP 951 EP 958 DI 10.1007/s10529-006-9029-3 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 060AS UT WOS:000238774200002 PM 16786267 ER PT J AU Park, JH Kim, KL Cho, EW AF Park, Jung-Hyun Kim, Kil Lyong Cho, Eun-Wie TI Detection of surface asialoglycoprotein receptor expression in hepatic and extra-hepatic cells using a novel monoclonal antibody SO BIOTECHNOLOGY LETTERS LA English DT Article DE asialoglycoprotein receptor; monoclonal antibody; flow cytometry; T cells; human peripheral blood lymphocyte ID B-VIRUS; MICE LACKING; HEPATOCYTES; SUBUNIT; BINDING; ORIGIN; LIVER; DEFICIENCY; PROTEINS; DELIVERY AB The asialoglycoprotein receptor (ASGPR) is a heterodimeric membrane protein which is involved in the internalization of desialylated glycoproteins and also in the binding and uptake of various pathogenic viruses. To facilitate the analysis of ASGPR expression, we generated a monoclonal antibody, termed ASSA-1, that is specific to the ASGPR H1 subunit based on ELISA and Western blots analysis. ASSA-1 also reacted to surface-displayed ASGPR in live cells thus enabling analysis of ASGPR expression by immunofluorescence flow cytometry, which we used to analyze established human liver cell lines previously confirmed to be positive for ASGPR mRNA expression. In agreement with previous reports, surface ASGPR was also detected in extra-hepatic cells and, surprisingly, even in human T cell lines, which was then further confirmed in activated, but not in resting, primary human peripheral blood lymphocytes. These observations suggest that ASGPR has a broad pattern of expression that even extends into cells from the immune system, which biological meanings still have to be analyzed. We expect that monoclonal antibody ASSA-1 will serve as a new powerful tool in analyzing the biological role of ASGPR in hepatic and extra-hepatic cells. C1 Korea Res Inst Biosci & Biotechnol, Syst Proteom Res Ctr, Taejon, South Korea. Sungkyunkwan Univ, Dept Biol Sci, Biochem Lab, Suwon, Kyunggi Do, South Korea. NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Cho, EW (reprint author), Korea Res Inst Biosci & Biotechnol, Syst Proteom Res Ctr, Taejon, South Korea. EM ewcho@kribb.re.kr RI Park, Jung Hyun /B-5712-2015 OI Park, Jung Hyun /0000-0002-9547-9055 NR 27 TC 11 Z9 14 U1 2 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-5492 J9 BIOTECHNOL LETT JI Biotechnol. Lett. PD JUL PY 2006 VL 28 IS 14 BP 1061 EP 1069 DI 10.1007/s10529-006-9064-0 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 060VL UT WOS:000238829600002 PM 16799763 ER PT J AU Hughes, T Deininger, M Hochhaus, A Branford, S Radich, J Kaecla, J Baccarani, M Cortes, J Cross, NCP Druker, BJ Gabert, J Grimwade, D Hehlmann, R Kamel-Reid, S Lipton, JH Longtine, J Martinelli, G Saglio, G Soverini, S Stock, W Goldman, JM AF Hughes, T Deininger, M Hochhaus, A Branford, S Radich, J Kaecla, J Baccarani, M Cortes, J Cross, NCP Druker, BJ Gabert, J Grimwade, D Hehlmann, R Kamel-Reid, S Lipton, JH Longtine, J Martinelli, G Saglio, G Soverini, S Stock, W Goldman, JM TI Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results SO BLOOD LA English DT Review ID CHRONIC MYELOID-LEUKEMIA; POLYMERASE-CHAIN-REACTION; CHRONIC MYELOGENOUS LEUKEMIA; MINIMAL RESIDUAL DISEASE; BONE-MARROW-TRANSPLANTATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; STEM-CELL TRANSPLANTATION; TIME QUANTITATIVE PCR; HEPATITIS-C VIRUS; CLONAL CYTOGENETIC ABNORMALITIES AB The introduction in 1998 of imatinib mesylate (IM) revolutionized management of patients with chronic myeloid leukemia (CML) and the second generation of tyrosine kinase inhibitors may prove superior to IM. Real-time quantitative polymerase chain reaction (RQ-PCR) provides an accurate measure of the total leukemia-cell mass and the degree to which BCR-ABL transcripts are reduced by therapy correlates with progression-free survival. Because a rising level of BCR-ABL is an early indication of loss of response and thus the need to reassess therapeutic strategy, regular molecular monitoring of individual patients is clearly desirable. Here we summarize the results of a consensus meeting that took place at the National Institutes of Health (NIH) in Bethesda in October 2005. We make suggestions for (1) harmonizing the differing methodologies for measuring BCR-ABL transcripts in patients with CML undergoing treatment and using a conversion factor whereby individual laboratories can express BCR-ABL transcript levels on an internationally agreed scale; (2) using serial RQ-PCR results rather than bone marrow cytogenetics or fluorescence in situ hybridization (FISH) for the BCR-ABL gene to monitor individual patients responding to treatment; and (3) detecting and reporting Philadelphia (Ph) chromosome-positive subpopulations bearing BCR-ABL kinase domain mutations. We recognize that our recommendations are provisional and will require revision as new evidence emerges. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Inst Canc, Dept Med Hematol Oncol, Portland, OR 97201 USA. Inst Med & Vet Sci, Adelaide, SA 5000, Australia. Univ Heidelberg, Fac Clin Med Mannheim, D-6800 Mannheim, Germany. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Hammersmith Hosp, Imperial Coll, Dept Haematol, London, England. Univ Bologna, Inst Hematol & Med Oncol Seragnoli, I-40126 Bologna, Italy. Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. Univ Southampton, Natl Genet Reference Lab, Salisbury, Wilts, England. Univ Mediterranee, APHM, Marseille, France. Univ Mediterranee, Equipe Rech Technol, Marseille, France. Univ London Kings Coll, Dept Med & Mol Genet, London WC2R 2LS, England. Univ Toronto, Princess Margaret Hosp, Dept Med Oncol & Hematol, Toronto, ON, Canada. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Univ Turin, Dept Clin & Biol Sci, Orbassano, Italy. Univ Chicago, Dept Med, Chicago, IL 60637 USA. RP Goldman, JM (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Rm 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM goldmanj2@nhlbi.nih.gov RI Cross, Nicholas/B-4817-2009; SOVERINI, SIMONA/A-3608-2016; OI Cross, Nicholas/0000-0001-5481-2555; SOVERINI, SIMONA/0000-0002-4508-0353; Hochhaus, Andreas/0000-0003-0626-0834 NR 82 TC 663 Z9 703 U1 5 U2 28 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 JUL 1 PY 2006 VL 108 IS 1 BP 28 EP 37 DI 10.1182/blood-2006-01-0092 PG 10 WC Hematology SC Hematology GA 057LI UT WOS:000238596900013 PM 16522812 ER PT J AU Zhang, N Yang, D Dong, HF Chen, Q Dimitrova, DI Rogers, TJ Sitkovsky, M Oppenheim, JJ AF Zhang, N Yang, D Dong, HF Chen, Q Dimitrova, DI Rogers, TJ Sitkovsky, M Oppenheim, JJ TI Adenosine A2a receptors induce heterologous desensitization of chemokine receptors SO BLOOD LA English DT Article ID STIMULATED HUMAN-NEUTROPHILS; CROSS-DESENSITIZATION; OPIOID RECEPTORS; DENDRITIC CELLS; DOWN-REGULATION; MIP-1 ALPHA; EXPRESSION; PROTEIN; CCR5; BETA AB Adenosine, released by cells in an injurious or hypoxic environment, possesses potent anti-inflammatory effects by inhibiting the production of proinflammatory cytokines and superoxide anions (O-2(-)). We hypothesized that adenosine compounds also induced heterologous desensitization of chemokine receptors, which played a critical role in leukocyte trafficking. Our studies using adenosine receptor subtype-specific agonists revealed that pretreatment with adenosine compounds suppressed RANTES-induced chemotaxis and Ca2+ flux through activation of A2a adenosine receptor. Adenosine compounds also desensitized IL-8- and MCP-1-induced chemotaxis, but not that induced by fMLP. Activation of protein kinase A (PKA), a component of the signaling pathway induced by the A2a receptor, was sufficient to desensitize RANTES-induced chemotaxis. Inhibition of PKA reversed the desensitization effects of adenosine compounds, suggesting that PKA was necessary for A2a receptor-mediated heterologous desensitization. In a mouse model, prior activation of A2a receptors blocked RANTES-induced recruitment of leukocytes in an air pouch. Moreover, the A2a receptor-induced cross-desensitization also reduced the susceptibility of monocytes to infection by an R5 strain of HIV-1. Our results suggest that activation of A2a adenosine receptors suppresses chemokine receptor function, and such receptor cross-talk was based on the simple mechanism of PKA-mediated heterologous desensitization, thus contributing to the anti-inflammatory activity of adenosine. C1 NCI, Mol Immunoregulat Lab, Canc Res Ctr, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Basic Res Program, Sci Applicat Int Frederick, Frederick, MD 21702 USA. Peking Univ, Dept Biol Chem, Beijing 100871, Peoples R China. Peking Univ, State Key Lab Mol Dynam & Stable Struct, Coll Chem, Beijing 100871, Peoples R China. Temple Univ, Sch Med, Dept Pharmacol, Fels Inst Canc Res & Mol Biol,Ctr Subst Abuse Res, Philadelphia, PA 19122 USA. Northeastern Univ, New England Inflammat & Tissue Protect Inst, Boston, MA 02115 USA. RP Oppenheim, JJ (reprint author), NCI, Mol Immunoregulat Lab, Canc Res Ctr, Intramural Res Support Program, Bldg 560,Rm 21-89A, Frederick, MD 21702 USA. EM oppenhei@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400]; NIDA NIH HHS [T32DA07237, DA-06650, DA-13429, DA-16544, DA14230] NR 32 TC 40 Z9 40 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 1 PY 2006 VL 108 IS 1 BP 38 EP 44 DI 10.1182/blood-2005-06-2599 PG 7 WC Hematology SC Hematology GA 057LI UT WOS:000238596900014 PM 16522819 ER PT J AU Cokic, VP Beleslin-Cokic, BB Tomic, M Stojilkovic, SS Noguchi, CT Schechter, AN AF Cokic, VP Beleslin-Cokic, BB Tomic, M Stojilkovic, SS Noguchi, CT Schechter, AN TI Hydroxyurea induces the eNOS-cGMP pathway in endothelial cells SO BLOOD LA English DT Article ID NITRIC-OXIDE SYNTHASE; IRON NITROSYL HEMOGLOBIN; COLONY-STIMULATING FACTORS; DEPENDENT PROTEIN-KINASES; NF-KAPPA-B; CYCLIC-AMP; MYELOPROLIFERATIVE DISORDERS; RIBONUCLEOTIDE REDUCTASE; MYOCARDIAL-INFARCTION; SIGNALING PATHWAYS AB Hydroxyurea is a cell-cycle-specific drug that has been used to treat myeloproliferative diseases and sickle cell anemia. We have recently shown that hydroxyurea, like nitric oxide (NO)-donor compounds, increased cGMP levels in human erythroid cells. We show now that hydroxyurea increases endothelial-cell production of NO; this induction of NO in human umbilical vein endothelial cells (HUVECs) and human bone marrow endothelial cell line (TrHBMEC) is blocked by competitive inhibitors of NO synthase (NOS), such as N-G-nitro-L-arginine-methyl ester (L-NAME) and N-G-nitro-L-arginine. It is dependent on cAMP-dependent protein kinase (PKA) and protein kinase B (PKB/Akt) activity. We found that hydroxyurea dose- and time-dependently induced rapid and transient phosphorylation of eNOS at Ser1177 in a PKA-dependent manner; inhibitors of PKB/Akt could partially abrogate this effect. In addition, hydroxyurea induced cAMP and cGMP levels in a dose-dependent manner, as well as levels of intracellular calcium in HUVECs. These studies established an additional mechanism by which rapid and sustained effects of hydroxyurea may affect cellular NO levels and perhaps enhance the effect of NO in myeloproliferative diseases. C1 NIDDKD, Mol Med Branch, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. Inst Med Res, Belgrade, Serbia Monteneg. Inst Endocrinol Diabet & Dis Metab, Belgrade, Serbia Monteneg. NICHHD, Endocrinol & Reprod Res Branch, Bethesda, MD 20892 USA. RP Schechter, AN (reprint author), NIDDKD, Mol Med Branch, Biol Chem Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 9N307, Bethesda, MD 20892 USA. EM aschecht@helix.nih.gov RI Tomic, Melanija/C-3371-2016; OI Schechter, Alan N/0000-0002-5235-9408 NR 66 TC 43 Z9 43 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 1 PY 2006 VL 108 IS 1 BP 184 EP 191 DI 10.1182/blood-2005-11-4454 PG 8 WC Hematology SC Hematology GA 057LI UT WOS:000238596900033 PM 16527893 ER PT J AU Valencia, X Stephens, G Goldbach-Mansky, R Wilson, M Shevach, EM Lipsky, PE AF Valencia, X Stephens, G Goldbach-Mansky, R Wilson, M Shevach, EM Lipsky, PE TI TNF downmodulates the function of human CD4(+)CD25(hi) T-regulatory cells SO BLOOD LA English DT Article ID TUMOR-NECROSIS-FACTOR; IMMUNOLOGICAL SELF-TOLERANCE; RHEUMATOID-ARTHRITIS; FACTOR RECEPTOR; FACTOR-ALPHA; IMMUNE; FOXP3; SUPPRESSION; LYMPHOCYTES; GENERATION AB CD4(+)CD25(+) T-regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. However, little is known about the exogenous factors that regulate their differentiation and function. Here, we report that TNF inhibits the suppressive function of both naturally occurring CD4(+)CD25(+) Tregs and TGF beta 1-induced CD4(+)CD25(+) T-regulatory cells. The mechanism of this inhibition involves signaling through TNFRII that is constitutively expressed selectively on unstimulated Tregs and that is up-regulated by TNF. TNF-mediated inhibition of suppressive function is related to a decrease in FoxP3 mRNA and protein expression by the Tregs. Notably, CD4(+)CD25(hi) Tregs isolated from patients with active rheumatoid arthritis (RA) expressed reduced levels of FoxP3 mRNA and protein and poorly suppressed the proliferation and cytokine secretion of CD4(+) effector T cells in vitro. Treatment with anti-TNF antibody (infliximab) increased FOXP3 mRNA and protein expression by CD4(+)CD25(hi) Tregs and restored their suppressive function. Thus, TNF has a novel action in modulating autoimmunity, by inhibiting CD4(+)CD25(+) Treg activity. C1 NIAMSD, Autoimmun Branch, Off Clin Director, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Valencia, X (reprint author), NIAMSD, Autoimmun Branch, Off Clin Director, NIH, 10 Ctr Dr,Rm 6D44, Bethesda, MD 20892 USA. EM xvalencia@mail.nih.gov FU Intramural NIH HHS NR 40 TC 470 Z9 500 U1 0 U2 14 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 JUL 1 PY 2006 VL 108 IS 1 BP 253 EP 261 DI 10.1182/blood-2005-11-4567 PG 9 WC Hematology SC Hematology GA 057LI UT WOS:000238596900042 PM 16537805 ER PT J AU Landgren, O Engels, EA Caporaso, NE Gridley, G Mellemkjaer, L Hemminki, K Linet, MS Goldin, LR AF Landgren, O Engels, EA Caporaso, NE Gridley, G Mellemkjaer, L Hemminki, K Linet, MS Goldin, LR TI Patterns of autoimmunity and subsequent chronic lymphocytic leukemia in Nordic countries SO BLOOD LA English DT Article ID FAMILY-CANCER DATABASE; MULTIPLE-MYELOMA; HODGKIN LYMPHOMA; LYMPHOPROLIFERATIVE DISORDERS; MEDICAL CONDITIONS; RISK; HISTORY; DISEASE; RELATIVES; ANEMIA AB A population-based case-control study was conducted to evaluate risk of developing chronic lymphocytic leukemia (CLL) associated with personal and/or family history of autoimmune and related diseases. Data were obtained for all (n = 7764) patients diagnosed with CLL in Sweden and Denmark over a 40-year period and with linkable relatives, 16 658 matched control subjects, and first-degree relatives of patients (n = 17 991) and control subjects (n = 39 388). Odds ratios (ORs) were calculated to quantify risk of CLL in relation to personal/family history of 32 autoimmune and related disorders. The risk of CLL was significantly increased among subjects with a personal history of pernicious anemia (OR = 1.94; 1.18-3.18), mainly in the 0- to 1-year latency period. A significantly decreased risk of CLL was found among individuals with a personal history of chronic rheumatic heart disease (OR = 0.55; 0.33-0.93), particularly persons with a long latency (10+ years) between the 2 conditions. We found no association between personal or familial occurrence of other autoimmune or related disorders and CLL. If our results are confirmed, mechanistic studies examining how pernicious anemia might promote increased occurrence of CLL and how chronic rheumatic heart disease protects against CLL, perhaps related to long-term antibiotics use, may provide insights to the as-yet-unknown etiology of CLL. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. Karolinska Inst, Novum, Dept Biosci, Stockholm, Sweden. German Canc Res Ctr, Div Mol Genet Epidemiol, D-6900 Heidelberg, Germany. RP Landgren, O (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Bldg EPS,Rm 7110, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov FU Intramural NIH HHS NR 40 TC 41 Z9 41 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 1 PY 2006 VL 108 IS 1 BP 292 EP 296 DI 10.1182/blood-2005-11-4620 PG 5 WC Hematology SC Hematology GA 057LI UT WOS:000238596900047 PM 16527887 ER PT J AU Roberts, RA Wright, G Rosenwald, AR Jaramillo, MA Grogan, TM Miller, TP Frutiger, Y Chan, WC Gascoyne, RD Ott, G Muller-Hermelink, K Staudt, LM Rimsza, LM AF Roberts, RA Wright, G Rosenwald, AR Jaramillo, MA Grogan, TM Miller, TP Frutiger, Y Chan, WC Gascoyne, RD Ott, G Muller-Hermelink, K Staudt, LM Rimsza, LM TI Loss of major histocompatibility class II gene and protein expression in primary mediastinal large B-cell lymphoma is highly coordinated and related to poor patient survival SO BLOOD LA English DT Article ID HODGKIN LYMPHOMA; HLA REGION; DELETIONS; CHEMOTHERAPY; LYMPHOCYTES; MICROARRAY; MANAGEMENT; COMPLEX; REGIMEN; LINE AB Loss of major histocompatibility class It (MHC II) expression in diffuse large B-cell lymphoma (DLBCL) correlates with worse outcome, possibly from decreased immunosurveillance. Primary mediastinal B-cell lymphoma (PMBCL) is a subtype of DLBCL which reportedly has frequent loss of MHC II proteins; however, PMBCL has better survival than DLBCL. To investigate this paradox, we used gene-expression profiling (GEP) data and immunohistochemistry to study expression of MHC II and its regulatory genes and to determine their relationship to PMBCL survival. We found that GEP levels correlated between MHC II genes and the transcriptional regulator MHC2TA but not other adjacent genes, implying that transcriptional regulation of MHC II in PMBCL was intact and that MHC II gene deletion was unlikely. MHC II average expression was lower than in certain subtypes of DLBCL; however, only 12% had complete loss of MHC II expression. Poor patient survival in PMBCL correlated with incremental decreases in MHC II expression. Although overall survival was better, survival of the lowest 10% of MHC II expressers was similarly poor in DLBCL and PMBCL. MHC II expression may define a therapeutic target in both these diseases. C1 Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA. Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. NCI, Biomet Res Branch, NIH, Bethesda, MD USA. NCI, Metab Branch, Div Canc Treatment & Diagnosis, NIH, Bethesda, MD USA. Univ Wurzburg, Dept Pathol, Wurzburg, Germany. Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada. RP Rimsza, LM (reprint author), Univ Arizona, Dept Pathol, 1501 N Campbell Ave,POB 245043, Tucson, AZ 85724 USA. EM rimsza@ahsc.arizona.edu FU NCI NIH HHS [U01-CA84967] NR 33 TC 45 Z9 47 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 1 PY 2006 VL 108 IS 1 BP 311 EP 318 DI 10.1182/blood-2005-11-4742 PG 8 WC Hematology SC Hematology GA 057LI UT WOS:000238596900050 PM 16543468 ER PT J AU Bellanne-Chantelot, C Chaumarel, I Labopin, M Bellanger, F Barbu, V De Toma, C Delhommeau, F Casadevall, N Vainchenker, W Thomas, G Najman, A AF Bellanne-Chantelot, C Chaumarel, I Labopin, M Bellanger, F Barbu, V De Toma, C Delhommeau, F Casadevall, N Vainchenker, W Thomas, G Najman, A TI Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders SO BLOOD LA English DT Article ID POLYCYTHEMIA-RUBRA-VERA; TYROSINE KINASE JAK2; ESSENTIAL THROMBOCYTHEMIA; ACTIVATING MUTATION; MYELOID METAPLASIA; V617F MUTATION; OLMSTED COUNTY; EXPRESSION; RECEPTOR; JAK2(V617F) AB To study the prevalence of the Val617Phe JAK2 mutation in familial cases of myeloproliferative disorder (MPD) and its possible implication as a predisposing genetic factor, we analyzed 72 families including 174 patients (81 polycythemia vera [PV], 68 essential thrombocythemia [ET], 11 myelofibrosis with myeloid metaplasia [MMM], 12 chronic myeloid leukemia), 1 systemic mastocytosis, and 1 chronic myelomonocytic leukemia (CMML). The JAK2 mutation was found in three quarters of patients with PV and MMM and in half of patients with ET. Among 46 families with at least 2 cases of PV, ET, or MMM, the JAK2 mutation was absent in 6 families, heterogeneously distributed in 18, and present in all MPD patients in 22. Among these 22 families, the absence of the JAK2 mutation both in purified T and B cells in 13 unrelated patients and the observation of variable ratios of the JAK2 mutant allele in patient leucocytes indicated that the Val617Phe JAK2 mutation was acquired in familial MPDs. The JAK2 mutation was present in natural killer cells in two thirds of tested patients (27 of 40), suggesting its occurrence in a multi-potent hematopoietic progenitor cell. The analysis of the hematologic profile showed that the homozygous JAK2 mutation confers a proliferative advantage and is associated with the progression of the hematologic disease. C1 Hop St Antoine, AP Hp, Cytogenet Serv, F-75012 Paris, France. Univ Paris 06, Paris 6, France. INSERM, Inst Mol Genet, U434, Paris, France. AP HP St Antoine, Dept Hematol, Paris, France. AP HP St Antoine, Dept Mol Biol, Paris, France. Ctr Etud Polymorphisme Humain, Fdn Jean Dausset, F-75010 Paris, France. Hop Hotel Dieu, AP HP, Hematol Lab, Paris, France. Inst Gustave Roussy, INSERM, U790, F-94805 Villejuif, France. Univ Paris 11, Villejuif, France. NCI, Dept Canc Epidemiol & Genet, Gaithersburg, MD USA. RP Bellanne-Chantelot, C (reprint author), Hop St Antoine, AP Hp, Cytogenet Serv, 184 Rue Faubourg, F-75012 Paris, France. EM christine.bellanne@sat.ap-hop-paris.fr NR 31 TC 141 Z9 151 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 JUL 1 PY 2006 VL 108 IS 1 BP 346 EP 352 DI 10.1182/blood-2005-12-4852 PG 7 WC Hematology SC Hematology GA 057LI UT WOS:000238596900054 PM 16537803 ER PT J AU Jung, J Bohn, G Allroth, A Boztug, K Brandes, G Sandrock, I Schaffer, AA Rathinam, C Kollner, I Beger, C Schilke, R Welte, K Grimbacher, B Klein, C AF Jung, J Bohn, G Allroth, A Boztug, K Brandes, G Sandrock, I Schaffer, AA Rathinam, C Kollner, I Beger, C Schilke, R Welte, K Grimbacher, B Klein, C TI Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2 SO BLOOD LA English DT Article ID LYSOSOME-RELATED ORGANELLES; ENCODING NEUTROPHIL ELASTASE; NKT CELL-DEVELOPMENT; ANTIGEN PRESENTATION; BETA-3A SUBUNIT; LINKAGE COMPUTATIONS; AP-3 ADAPTER; MUTATIONS; TRAFFICKING; COMPLEX AB We report on the molecular etiology of an unusual clinical phenotype associating congenital neutropenia, thrombocytopenia, developmental delay, and hypopigmentation. Using genetic linkage analysis and targeted gene sequencing, we defined a homozygous genomic deletion in AP3B1, the gene encoding the beta chain of the adaptor protein-3 (AP-3) complex. The mutation leads to in-frame skipping of exon 15 and thus perturbs proper assembly of the heterotetrameric AP-3 complex. Consequently, trafficking of transmembrane lysosomal proteins is aberrant, as shown for CD63. In basal keratinocytes, the incorporated immature melano-somes were rapidly degraded in large phagolysosomes. Despite distinct ultramorphologic changes suggestive of aberrant vesicular maturation, no functional aberrations were detected in neutrophil granulocytes. However, a comprehensive immunologic assessment revealed that natural killer (NK) and NKT-cell numbers were reduced in AP-3-deficient patients. Our findings extend the clinical and molecular phenotype of human AP-3 deficiency (also known as Hermansky-Pudlak syndrome, type 2) and provide further insights into the role of the AP-3 complex for the innate immune system. C1 Hannover Med Sch, Dept Pediat Hematol, D-30625 Hannover, Germany. Univ Freiburg, Med Ctr, Div Rheumatol & Clin Immunol, Freiburg, Germany. Hannover Med Sch, Dept Cell Biol, D-30625 Hannover, Germany. Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20894 USA. Hannover Med Sch, Inst Cell & Mol Pathol, D-30625 Hannover, Germany. Hannover Med Sch, Dept Conservat Dent & Periodontol, D-30625 Hannover, Germany. RP Klein, C (reprint author), Hannover Med Sch, Dept Pediat Hematol, Carl Neuberg Str, D-30625 Hannover, Germany. EM grimbacher@medizin.ukl.uni-treiburg.de; klein.christoph@mh-hannover.de RI Schaffer, Alejandro/F-2902-2012; OI Jung, Johannes/0000-0003-0137-7929 FU Intramural NIH HHS NR 41 TC 59 Z9 60 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 1 PY 2006 VL 108 IS 1 BP 362 EP 369 DI 10.1182/blood-2005-11-4377 PG 8 WC Hematology SC Hematology GA 057LI UT WOS:000238596900056 PM 16537806 ER PT J AU Wallace, JM Rajachar, RM Chen, XD Shi, ST Allen, MR Bloomfield, SA Les, CM Robey, PG Young, MF Kohn, DH AF Wallace, JM Rajachar, RM Chen, XD Shi, ST Allen, MR Bloomfield, SA Les, CM Robey, PG Young, MF Kohn, DH TI The mechanical phenotype of biglycan-deficient mice is bone- and gender-specific SO BONE LA English DT Article DE transgenic; mechanical properties; mineralization; histomorphometry; pQCT ID QUANTITATIVE TRAIT LOCI; COLLAGEN FIBER ORIENTATION; COMPUTED-TOMOGRAPHY PQCT; GENETIC-REGULATION; C57BL/6J MICE; CORTICAL BONE; TRANSFORMING GROWTH-FACTOR-BETA-1; MINERAL DENSITY; ORGANIC MATRIX; CONGENIC MICE AB Biglycan (bgn) is a small leucine-rich proteoglycan (SLRP) enriched in the extracellular matrix of skeletal tissues. While bgn is known to be involved in the growth and differentiation of osteoblast precursor cells and regulation of collagen fibril formation, it is unclear how these functions impact bone's geometric and mechanical properties, properties which are integral to the structural function of bone. Because the genetic control of bone structure and function is both local- and gender-specific and because there is evidence of gender-specific effects associated with genetic deficiencies, it was hypothesized that the engineered deletion of the gene encoding bgn would result in a cortical bone mechanical phenotype that was bone- and gender-specific. In 11-week-old C57BL6/129 mice, the cortical bone in the mid-diaphyses of the femora and tibiae of both genders was examined. Phenotypic changes in bgn-deficient mice relative to wild type controls were assayed by four-point bending tests to determine mechanical properties at the whole bone (structural) and tissue levels, as well as analyses of bone geometry and bone formation using histomorphometry. Of the bones examined, bgn deficiency most strongly affected the male tibiae, where enhanced cross-sectional geometric properties and bone mineral density were accompanied by decreased tissue-level yield strength and pre-yield structural deformation and energy dissipation. Because pre-yield properties alone were impacted, this implies that the gene deletion causes important alterations in mineral and/or the matrix/mineral ultrastructure and suggests a new understanding of the functional role of bgn in regulating bone mineralization in vivo. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ Michigan, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, US Dept HHS, NIH, Bethesda, MD 20892 USA. Texas A&M Univ, Dept Hlth & Kinesiol, College Stn, TX 77843 USA. Henry Ford Hosp, Ctr Bone & Joint, Detroit, MI 48202 USA. RP Kohn, DH (reprint author), Univ Michigan, Dept Biol & Mat Sci, 1011 N Univ Ave, Ann Arbor, MI 48109 USA. EM jmwallac@umich.edu; rupakr@u.washington.edu; xdchen@uams.edu; sshi@dir.nidcr.nih.gov; matallen@iupui.edu; sbloom@tamu.edu; les@bjc.hfh.edu; probey@dir.nidcr.nih.gov; myoung@dir.nidcr.nih.gov; dhkohn@umich.edu RI Wallace, Joseph/G-7906-2012; Robey, Pamela/H-1429-2011; Allen, Matthew/A-8799-2015 OI Robey, Pamela/0000-0002-5316-5576; Allen, Matthew/0000-0002-1174-9004 FU NIDCR NIH HHS [T32-DE07057]; NIDDK NIH HHS [R90-DK071506] NR 65 TC 28 Z9 29 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD JUL PY 2006 VL 39 IS 1 BP 106 EP 116 DI 10.1016/j.bone.2005.12.081 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 055DD UT WOS:000238429300012 PM 16527557 ER PT J AU Bevans, MF Marden, S Leidy, NK Soeken, K Cusack, G Rivera, P Mayberry, H Bishop, MR Childs, R Barrett, AJ AF Bevans, M. F. Marden, S. Leidy, N. K. Soeken, K. Cusack, G. Rivera, P. Mayberry, H. Bishop, M. R. Childs, R. Barrett, A. J. TI Health-related quality of life in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation SO BONE MARROW TRANSPLANTATION LA English DT Article DE allogeneic transplant; reduced-intensity conditioning; health-related quality of life ID BONE-MARROW-TRANSPLANTATION; LONG-TERM SURVIVORS; ACUTE MYELOGENOUS LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; ADULT SURVIVORS; FUNCTIONAL ASSESSMENT; PSYCHOLOGICAL ADJUSTMENT; COMPLETE REMISSION; FOLLOW-UP; CHEMOTHERAPY AB Reduced-intensity conditioning allogeneic HSCT (RIC) has less regimen-related morbidity and mortality than myeloablative allogeneic HSCT (MT) offering allogeneic transplantation to patients otherwise excluded. Whether these advantages improve health-related quality of life (HRQL) is unknown. We examined the HRQL effects of RIC and MT in patients with hematological diseases pre-transplant (baseline), days 0, 30 100, 1 and 2 years following HSCT. HRQL was measured using the Short Form-36 Health Survey and the Functional Assessment of Cancer Therapy-General and BMT. Data were analyzed using mixed linear modeling adjusting for baseline HRQL differences. Patients (RIC = 41, MT = 35) were predominately male (67%), in remission/stable disease (65%) with an Eastern Cooperative Oncology Group status <= 1 (97%). HRQL progressively improved (P < 0.01) in both groups with higher scores at day 100 compared to days 0 and 30; there was no difference between groups during early recovery. At 2 years, all survivors (n = 43) reported HRQL similar or better than baseline. Results suggest RIC and MT patients experience a similar pattern of HRQL improvement during early recovery. Two-year survivors report a return to baseline or better in HRQL by day 100, with the exception of physical health in MT patients. C1 NIH, Dept Nursing, Bethesda, MD 20892 USA. United Bioresource Corp, Healthcare Analyt Grp, Bethesda, MD USA. Univ Maryland, Baltimore, MD 21201 USA. Natl Canc Inst, Bethesda, MD USA. NHLBI, Stem Cell Allo Transplantat Sect, Bethesda, MD 20892 USA. RP Bevans, MF (reprint author), NIH, Dept Nursing, 10 Ctr Dr,Bldg 10,Rm 12S235B,MSC 1905, Bethesda, MD 20892 USA. EM mbevans@cc.nih.gov NR 41 TC 40 Z9 42 U1 3 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD JUL PY 2006 VL 38 IS 2 BP 101 EP 109 DI 10.1038/sj.bmt.1705406 PG 9 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 061HW UT WOS:000238863200003 PM 16751786 ER PT J AU Falk, RT Brinton, LA Madigan, MP Potischman, N Sturgeon, SR Malone, KE Daling, JR AF Falk, Roni T. Brinton, Louise A. Madigan, M. Patricia Potischman, Nancy Sturgeon, Susan R. Malone, Kathleen E. Daling, Janet R. TI Interrelationships between serum leptin, IGF-1, IGFBP3, C-peptide and prolactin and breast cancer risk in young women SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE breast cancer; c-peptide; insulin; like growth factor I; insulin; like growth factor binding protein 3; leptin; prolactin; premenopausal ID GROWTH-FACTOR-I; POSTMENOPAUSAL WOMEN; INSULIN-RESISTANCE; CIRCULATING LEVELS; BINDING PROTEIN-3; SUBSEQUENT RISK; FACTOR (IGF)-I; SEX-HORMONES; CARCINOMA; METAANALYSIS AB Epidemiologic evidence suggests obese premenopausal women experience a reduced risk of breast cancer. The mechanism underlying this protection is not fully understood although it is well documented that abdominal obesity may impair ovulatory function and reduce gonadal steroidogenesis. We measured levels of several metabolic markers that are modified by obesity [measured by body mass index (BMI, (weight (kg)/height (m(2))))] and play a role in the reproductive axis, including, leptin, insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP3), c-peptide and prolactin in 233 cases and 251 controls participating in a retrospective study of breast cancer in young women conducted in the Seattle/Puget Sound region between 1990 and 1992. Consistent with the finding of a reduced risk with increasing BMI, risks declined with leptin levels, although to a lesser degree with odds ratios ( OR) for the highest vs. lowest quartile of BMI=0.34 (95% C.I. 0.3-0.8) and for leptin = 0.71 (95% C.I. 0.5-1.3). IGF-I, IGFBP3, c-peptide and prolactin were not related to breast cancer risk in a dose-dependent manner. With the possible exception of leptin, our findings do not suggest that these markers explain the breast cancer protection provided by obesity in premenopausal women. C1 NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Appl Res Program, Div Canc Causes & Populat Control, Rockville, MD USA. Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Amherst, MA 01003 USA. Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. RP Falk, RT (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd S Rm 7070, Bethesda, MD 20892 USA. EM falkr@exchange.nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 44 TC 26 Z9 27 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2006 VL 98 IS 2 BP 157 EP 165 DI 10.1007/s10549-9144-005-1 PG 9 WC Oncology SC Oncology GA 071IL UT WOS:000239593700005 PM 16502016 ER PT J AU Kummar, S Gutierrez, M Doroshow, JH Murgo, AJ AF Kummar, S Gutierrez, M Doroshow, JH Murgo, AJ TI Drug development in oncology: classical cytotoxics and molecularly targeted agents SO BRITISH JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE pharmacokinetics; pharmacodynamics; clinical trials; targeted therapeutics; exploratory IND; drug development ID I CLINICAL-TRIALS; GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; RANDOMIZED DISCONTINUATION DESIGN; RECURRENT MALIGNANT GLIOMA; DYSFUNCTION WORKING GROUP; BRAIN-TUMOR CONSORTIUM; SURROGATE END-POINTS; PHASE-I; MAGNETIC-RESONANCE AB There is an apparent need to improve the speed and efficiency of oncological drug development. Furthermore, strategies traditionally applied to the development of standard cytotoxic chemotherapy may not be appropriate for molecularly targeted agents. This is particularly the case for exploratory Phase 1 and 2 trials. Conventional approaches to determine dose based on maximum tolerability and efficacy based on objective tumour response may not be suitable for targeted agents, since many of them have a wide therapeutic index and inhibit tumour growth without demonstrable cytotoxicity. Instead, exploratory trials of targeted agents may have to focus on other end-points such as pharmacological effects and disease stabilization. Thus, there is an increasing interest in making the best possible use of biomarkers and pharmacogenomics in early phases of drug development. C1 NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Med Oncol Branch, Bethesda, MD USA. RP Murgo, AJ (reprint author), NCI, Div Canc Treatment & Diag, Bldg 31,Room 3A44,31 Ctr Dr, Bethesda, MD 20892 USA. EM murgoa@mail.nih.gov NR 61 TC 71 Z9 73 U1 1 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0306-5251 J9 BRIT J CLIN PHARMACO JI Br. J. Clin. Pharmacol. PD JUL PY 2006 VL 62 IS 1 BP 15 EP 26 DI 10.1111/j.1365-2125.2006.02713.x PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 055XW UT WOS:000238485500003 PM 16842375 ER PT J AU Argiris, A Cohen, E Karrison, T Esparaz, B Mauer, A Ansari, R Wong, S Lu, Y Pins, M Dancey, J Vokes, E AF Argiris, Athanassios Cohen, Ezra Karrison, Theodore Esparaz, Benjamin Mauer, Ann Ansari, Rafat Wong, Stuart Lu, Yi Pins, Michael Dancey, Janet Vokes, Everett TI A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer SO CANCER BIOLOGY & THERAPY LA English DT Article DE head and neck cancer; squarnous cell carcinoma; recurrent or metastatic; perifosine; alkylphospholipids; AKT ID SQUAMOUS-CELL CARCINOMA; MITOGENIC SIGNAL-TRANSDUCTION; CISPLATIN PLUS FLUOROURACIL; RADIATION-INDUCED APOPTOSIS; ALKYL-LYSOPHOSPHOLIPIDS; ONCOLOGY-GROUP; PATHWAY; ACTIVATION; AKT; GUIDELINES AB Background: Novel, effective therapies are warranted in the management of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Perifosine is an oral alkylphospholipid that inhibits AKT phosphorylation and has shown preclinical antitumor activity in head and neck cancer cell lines and xenografts. Patients And Methods: We conducted a phase II trial of perifosine in patients with incurable, recurrent or metastatic SCCHN. Previous therapy for recurrent or metastatic disease was limited to no more than one prior chemotherapy and one prior targeted/ biologic agent regimen. Patients had to have measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate laboratory parameters. Perifosine was given as a loading dose of 150 mg every 6 hours x 6 doses orally in the first two days, with antiemetic prophylaxis, followed by 100 mg/day orally without interruption. Administration via gastrostomy tube was allowed. Tumor response was assessed every two cycles (eight weeks). Biomarkers in pathways potentially affected by perifosine, including AKT, P-AKT, P38, p53 and p21 were measured on tumor tissue by immunohistochemistry by manual and automated methods. Results: Nineteen patients were enrolled. No objective responses were observed. One patient had stable disease as best response and 18 patients progressed at first evaluation. The median overall survival time was 5.5 months and the median progression-free survival time was 1.7 months. The most frequent toxicities were gastrointestinal (constipation, nausea, vomiting) and fatigue. One patient developed grade 4 anorexia. Although the sample size was small, a significant correlation was detected between high expression of P38 and AKT in baseline tumor tissue and better survival. Conclusions: Perifosine in the doses and schedule used lacks single-agent activity in SCCHN. Our data do not justify further investigation of perifosine as a single agent in SCCHN. C1 Univ Pittsburgh, Div Hematol Oncol, Pittsburgh, PA 15232 USA. Univ Chicago, Chicago, IL 60637 USA. Phase II Network, Chicago, IL USA. Decatur Mem Hosp, Decatur, GA USA. No Indiana Canc Res Consortium, South Bend, IN USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Northwestern Univ, Chicago, IL 60611 USA. NCI, Bethesda, MD 20892 USA. RP Argiris, A (reprint author), Univ Pittsburgh, Div Hematol Oncol, UPMC Canc Pavil,5th Floor,5150 Ctr Ave, Pittsburgh, PA 15232 USA. EM argirisae@upmc.edu FU NCI NIH HHS [5P30 CA014599-31, N01 CM62201] NR 32 TC 69 Z9 74 U1 0 U2 4 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUL PY 2006 VL 5 IS 7 BP 766 EP 770 DI 10.4161/cbt.5.7.2874 PG 5 WC Oncology SC Oncology GA 086XC UT WOS:000240705300020 PM 16760642 ER PT J AU Birrer, MI AF Birrer, Michael J. TI Ovarian cancer - Not a borderline issue! SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE ovarian cancer; borderline tumors; low malignant potential tumors; BRAF; KRAS ID LOW-GRADE; TUMORS; EXPRESSION; CARCINOMA; MUTATIONS; GENE; P53 C1 NIH, Bethesda, MD 20892 USA. RP Birrer, MI (reprint author), NIH, Bldg 37,Room 1130, Bethesda, MD 20892 USA. EM BirrerM@mail.nih.gov NR 12 TC 1 Z9 1 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUL PY 2006 VL 5 IS 7 BP 786 EP 787 DI 10.4161/cbt.5.7.3022 PG 2 WC Oncology SC Oncology GA 086XC UT WOS:000240705300024 PM 16921259 ER PT J AU Figg, WD Chau, CH AF Figg, William D. Chau, Cindy H. TI Heterogeneity in drug disposition determines interindividual variability of docetaxel pharmacokinetics SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE docetaxel; ketoconazole; cytochrome P450 3A4 ID CYTOCHROME-P450 3A4; CLEARANCE; METABOLISM C1 NCI, Mol Pharmacol Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bldg 10,Rm 5A01,MSC 1910,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 11 TC 1 Z9 1 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUL PY 2006 VL 5 IS 7 BP 840 EP 841 DI 10.4161/cbt.5.7.3025 PG 2 WC Oncology SC Oncology GA 086XC UT WOS:000240705300033 PM 16880730 ER PT J AU Brantley, E Antony, S Kohlhagen, G Meng, LH Agama, K Stinson, SF Sausville, EA Pommier, Y AF Brantley, E Antony, S Kohlhagen, G Meng, LH Agama, K Stinson, SF Sausville, EA Pommier, Y TI Anti-tumor drug candidate 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole induces single-strand breaks and DNA-protein cross-links in sensitive MCF-7 breast cancer cells SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE breast cancer; 5F 203; DNA damage; single-strand breaks; DNA-protein cross-links ID NUCLEOTIDE EXCISION-REPAIR; TOPOISOMERASE-I; TUMOR-CELLS; AMINOFLAVONE NSC-686288; BIOLOGICAL-PROPERTIES; SELECTIVE TOXICITY; CYCLE ARREST; AGENT; LINES; EXPRESSION AB Purpose: The fluorinated benzothiazole analogue 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) exhibits selective and potent anticancer activity, and its lysylamide prodrug (Phortress, NSC 710305) recently entered Phase I clinical trials in the United Kingdom. Only cancer cells sensitive to the anti-proliferative effects of 5F 203 deplete this drug candidate from nutrient media. 5F 203 induces cell cycle arrest, cytochrome P450 1A1 (CYP 1A1) mRNA and protein expression, and is metabolized into reactive electrophilic species that can covalently bind to DNA and form adducts in sensitive (i.e., MCF-7) but not in resistant (i.e., MDA-MB-435) breast cancer cells. Methods: In this present study, we investigated additional anticancer effects of 5F 203 in MCF-7 cells. In addition, we sought to determine if cells deficient in the xeroderma pigmentosum D gene, a gene critical in DNA repair, would show greater sensitivity to the cytotoxic effects of 5F 203 than those complemented with XPD. Results: Alkaline Elution revealed that 5F 203 induced single-strand breaks and DNA-protein cross-links in sensitive MCF-7 cells. In contrast, we detected no double-strand breaks or protein-associated strand breaks typically associated with topoisomerase I (top1) or topoisomerase II (top2) inhibition. In addition, 5F 203 was unable to trap top1- or top2-DNA cleavage complexes in MCF-7 cells. 5F 203 induced cell cycle arrest in MCF-7 cells following DNA damage after brief exposures. Cells deficient in the nucleotide excision repair xeroderma pigmentosum group D (XPD) gene displayed sensitivity to 5F 203 while cells complemented with XPD displayed resistance to 5F 203. Conclusion: These data suggest that the anti-cancer activity of 5F 203 depends upon targets other than top1 or top2 and on the ability of this benzothiazole to form single-strand breaks and DNA-protein cross-links in cancer cells. C1 NCI, Dev Therapeut Program, Frederick, MD 21701 USA. NCI, NIH, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Pommier, Y (reprint author), Loma Linda Univ, Sch Pharm, Dept Pharmaceut Sci, 11262 Campus St W Hall, Loma Linda, CA 92350 USA. EM pommier@nih.gov FU Intramural NIH HHS NR 39 TC 33 Z9 37 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUL PY 2006 VL 58 IS 1 BP 62 EP 72 DI 10.1007/s00280-005-0127-z PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 035AP UT WOS:000236972400007 PM 16331501 ER PT J AU Eder, JP Ryan, DP Appleman, L Zhu, AX Puchalski, T He, XY Sonnichsen, DS Cooper, M Wright, J Clark, JW Supko, JG AF Eder, JP Ryan, DP Appleman, L Zhu, AX Puchalski, T He, XY Sonnichsen, DS Cooper, M Wright, J Clark, JW Supko, JG TI Phase I clinical trial of the farnesyltransferase inhibitor BMS-214662 administered as a weekly 24 h continuous intravenous infusion in patients with advanced solid tumors SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article; Proceedings Paper CT 38th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 18-21, 2002 CL ORLANDO, FL SP Amer Soc Clin Oncol DE cancer; chemotherapy; human; pharmacokinetics; pharmacodynamics ID PRECLINICAL ANTITUMOR-ACTIVITY; CANCER-THERAPY; ONCOGENIC RAS AB Purpose: BMS-214662 is a novel farnesyltransferase ( FT) inhibitor that has shown promising suggestions of single agent activity in patients with advanced solid tumors when administered as a 1 h intravenous (i.v.) infusion every 3 weeks. The degree of FT inhibition in peripheral blood mononuclear cells (PBMCs) was greatest at the end of the infusion and rapidly reversed as the concentration of the drug in the plasma decayed. A second phase I trial of BMS-214662 administered as a weekly 24 h i.v. infusion was initiated to determine if the duration of maximum FT inhibition could be significantly extended by prolonging the infusion time and increasing the frequency of administration. Patients and methods: Infusion of BMS-214662 was prolonged from 2, 4, 8, 16, 24 h in single patient cohorts and repeated weekly for 3 out of 4 weeks. The initial dose was 56 mg/m(2). When the infusion duration reached 24 h, the dose was escalated at a constant multiples of 1.4 in single patient cohorts until the occurrence of toxicity greater than grade 1, upon which groups of at least three patients were evaluated at each dose level. The plasma pharmacokinetics and FT inhibition in PBMCs were measured in all patients at the prospective maximum tolerated dose. Results: Nineteen patients participated in the study ( 11 males/8 females) and the weekly dose was increased to a maximum of 300 mg/m(2) given as a 24 h i.v. infusion. Drug-related toxicity greater than grade 1 first occurred at 300 mg/m(2), with two patients experiencing dose-limiting toxicity. One patient developed a grade 3 hyponatremia and another developed reversible grade 3 diarrhea, grade 2 renal toxicity, and grade 3 transaminitis. A 275 mg/m(2) dose was then evaluated, where one of the three patients treated experienced reversible grade 4 renal toxicity and grade 3 diarrhea. In view of the identical renal toxicity at 275 mg/m(2) in another study and limited drug availability, there was no further accrual to this dose level and the study was closed. No evidence of antitumor activity was observed. The plasma pharmacokinetics of BMS-214662 was linear with high interpatient variability. In the three patients evaluated at the 275 mg/m(2) dose level, the maximum inhibition of FT activity in PBMCs was 47 +/- 23% of the baseline. Conclusion: Administering BMS-214662 as a weekly 24 h continuous i.v. infusion permitted a considerably greater dose intensity to be delivered as compared to a single 1 h infusion given once every 3 weeks. The more prolonged infusion schedule resulted in a much lower degree of maximum FT inhibition in PBMCs than achieved with the 1 h infusion, although the duration of enzyme inhibition was longer, consistent with the lower peak plasma concentration of the drug provided by comparably tolerated doses when given as a 24 h infusion. Similarly, delivering the drug with increased dose intensity permitted by this weekly administration schedule did not appear to enhance its therapeutic benefit, at least in this phase I trial. Continued development of BMS-214662 may depend upon the potential for using it in combination with other anticancer drugs. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Harvard Canc Ctr,Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02115 USA. Bristol Myers Squibb Co, Princeton, NJ USA. NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. RP Eder, JP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Shields Warren Bldg 460,44 Binney St, Boston, MA 02115 USA. EM jeder@partners.org OI Appleman, Leonard/0000-0003-4951-7388 FU NCI NIH HHS [P30-CA-0516, U01-CA-62490] NR 16 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUL PY 2006 VL 58 IS 1 BP 107 EP 116 DI 10.1007/s00280-005-0134-0 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 035AP UT WOS:000236972400012 PM 16362299 ER PT J AU Samanic, C Kogevinas, M Dosemeci, M Malats, N Real, FX Garcia-Closas, M Serra, C Carrato, A Garcia-Closas, R Sala, M Lloreta, J Tardon, A Rothman, N Silverman, DT AF Samanic, Claudine Kogevinas, Manolis Dosemeci, Mustafa Malats, Nuria Real, Francisco X. Garcia-Closas, Montserrat Serra, Consol Carrato, Alfredo Garcia-Closas, Reina Sala, Maria Lloreta, Josep Tardon, Adonina Rothman, Nathaniel Silverman, Debra T. TI Smoking and bladder cancer in Spain: Effects of tobacco type, timing, environmental tobacco smoke, and gender SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID LOWER URINARY-TRACT; CIGARETTE-SMOKING; BLACK TOBACCO; PASSIVE SMOKING; RISK-FACTORS; AROMATIC-AMINES; POOLED ANALYSIS; MEN; OCCUPATION; MUTAGENS AB We examined the effects of dose, type of tobacco, cessation, inhalation, and environmental tobacco smoke exposure on bladder cancer risk among 1,219 patients with newly diagnosed bladder cancer and 1,271 controls recruited from 18 hospitals in Spain. We used unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association between bladder cancer risk and various characteristics of cigarette smoking. Current smokers (men: OR, 7.4; 95% CI, 5.3-10.4; women: OR, 5.1; 95% CI, 1.6-16.4) and former smokers (men: OR, 3.8; 95% CI, 2.85.3; women: OR, 1.8; 95% C1, 0.5-7.2) had significantly increased risks of bladder cancer compared with nonsmokers. We observed a significant positive trend in risk with increasing duration and amount smoked. After adjustment for duration, risk was only 40% higher in smokers of black tobacco than that in smokers of blond tobacco (OR, 1.4; 95% Cl, 0.98-2.0). Compared with risk in current smokers, a significant inverse trend in risk with increasing time since quitting smoking blond tobacco was observed (>= 20 years cessation: OR, 0.2; 95% CI, 0.1-0.9). No trend in risk with cessation of smoking black tobacco was apparent. Compared with men who inhaled into the mouth, risk increased for men who inhaled into the throat (OR, 1.7; 95% CI, 1.1-2.6) and chest (OR, 1.5; 95% CI, 1.1-2.1). Cumulative occupational exposure to environmental tobacco smoke seemed to confer increased risk among female nonsmokers but not among male nonsmokers. After eliminating the effect of cigarette smoking on bladder cancer risk in our study population, the male-to-female incidence ratio decreased from 8.2 to 1.7, suggesting that nearly the entire male excess of bladder cancer observed in Spain is explained by cigarette smoking rather than occupational/environmental exposures to other bladder carcinogens. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Pompeu Fabra, Inst Municipal Invest Med, Barcelona, Spain. Univ Pompeu Fabra, Dept Pathol, Hosp del Mar, IMAS,IMIM, Barcelona, Spain. Corp Parc Tauli, Sabadell, Spain. Dept Hlth, Sabadell, Spain. Hosp Gen Elche, Elche, Spain. Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna, Spain. Univ Oviedo, Oviedo, Spain. RP Samanic, C (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 6120 Execut Blvd,Room 8115, Bethesda, MD 20892 USA. EM samanicc@mail.nih.gov RI sala, maria/A-2593-2011; Serra, C/E-6879-2014; Lloreta, J/I-2112-2014; Garcia-Closas, Montserrat /F-3871-2015; Fernandez , Irene/E-5705-2016; Martinez, Esther/H-2562-2013; Kogevinas, Manolis/C-3918-2017; OI Serra, C/0000-0001-8337-8356; Lloreta, J/0000-0003-1644-9470; Garcia-Closas, Montserrat /0000-0003-1033-2650; Sala Serra, Maria/0000-0002-5516-5967; Malats, Nuria/0000-0003-2538-3784 FU Intramural NIH HHS; NCI NIH HHS [N02-CP-11015] NR 43 TC 97 Z9 100 U1 0 U2 12 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 JUL PY 2006 VL 15 IS 7 BP 1348 EP 1354 DI 10.1158/1055-9965.EPI-06-0021 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 061OB UT WOS:000238880800019 PM 16835335 ER PT J AU Glebov, OK Rodriguez, LM Lynch, P Patterson, S Lynch, H Nakahara, K Jenkins, J Cliatt, J Humbyrd, CJ DeNobile, J Soballe, P Gallinger, S Buchbinder, A Gordon, G Hawk, E Kirsch, IR AF Glebov, Oleg K. Rodriguez, Luz M. Lynch, Patrick Patterson, Sherri Lynch, Henry Nakahara, Kenneth Jenkins, Jean Cliatt, Janet Humbyrd, Casey-Jo DeNobile, John Soballe, Peter Gallinger, Steven Buchbinder, Aby Gordon, Gary Hawk, Ernest Kirsch, Ilan R. TI Celecoxib treatment alters the gene expression profile of normal colonic mucosa SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ABERRANT CRYPT FOCI; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SELECTIVE CYCLOOXYGENASE-2 INHIBITOR; NONPOLYPOSIS COLORECTAL-CANCER; FAMILIAL ADENOMATOUS POLYPOSIS; MESSENGER-RNA AMPLIFICATION; CATENIN-ACCUMULATED CRYPTS; MICROSATELLITE INSTABILITY; PROSTANOID RECEPTOR; CELL-PROLIFERATION AB A clinical trial was recently conducted to evaluate the safety and efficacy of a selective inhibitor of cyclooxygenase-2 (celecoxib) in hereditary nonpolyposis colon cancer patients. In a randomized, placebo-controlled phase I/II multicenter trial, hereditary nonpolyposis colon cancer patients and gene carriers received either celecoxib at one of two doses or placebo. The goal was to evaluate the effects of these treatment arms on a number of endoscopic and tissue-based biomarker end points after 12 months of treatment. As part of this trial, we analyzed gene expression by cDNA array technology in normal descending (rectal) colonic mucosa of patients before and after treatment with celecoxib or placebo. We found that treatment of patients with celecoxib at recommended clinical doses (200 and 400 mg p.o. bid), in contrast to treatment with placebo, leads to changes in expression of > 1,400 genes in the healthy colon, although in general, the magnitude of changes is < 2-fold. Twenty-three of 25 pairs of colon biopsies taken before and after celecoxib treatment can be classified correctly by the pattern of gene expression in a leave-one-out cross-validation. Immune response, particularly T- and B-lymphocyte activation and early steps of inflammatory reaction, cell signaling and cell adhesion, response to stress, transforming growth factor-P signaling, and regulation of apoptosis, are the main biological processes targeted by celecoxib as shown by overrepresentation analysis of the distribution of celecoxib-affected genes across Gene Ontology categories. Analysis of possible cumulative effects of celecoxib-induced changes in gene expression indicates that in healthy colon, celecoxib may suppress the immune response and early steps of inflammation, inhibit formation of focal contacts, and stimulate transforming growth factor-beta signaling. C1 Canc Res Ctr, Genet Branch, Bethesda, MD USA. NCI, Div Canc Prevent, Bethesda, MD USA. Natl Naval Med Ctr, Dept Surg, Bethesda, MD USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Creighton Univ, Omaha, NE 68178 USA. Univ Toronto, Toronto, ON, Canada. Pharmacia, Peapack, NJ USA. Ovat Pharma, Lincoln, IL USA. RP Kirsch, IR (reprint author), Amgen Inc, 1201 Amgen Court W,AW1-J4144, Seattle, WA 98119 USA. EM lkirsch@amgen.com RI Gallinger, Steven/E-4575-2013 FU Intramural NIH HHS NR 84 TC 20 Z9 20 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 JUL PY 2006 VL 15 IS 7 BP 1382 EP 1391 DI 10.1158/1055-9965.EPI-04-0866 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 061OB UT WOS:000238880800024 PM 16835340 ER PT J AU Chung, JY Braunschweig, T Hu, N Roth, M Traicoff, JL Wang, QH Knezevic, V Taylor, PR Hewitt, SM AF Chung, Joon-Yong Braunschweig, Till Hu, Nan Roth, Mark Traicoff, June L. Wang, Quan-Hong Knezevic, Vladimir Taylor, Philip R. Hewitt, Stephen M. TI A multiplex tissue immunoblotting assay for proteomic profiling: A pilot study of the normal to tumor transition of esophageal squamous cell carcinoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BARRETTS-ESOPHAGUS; P53 PROTEIN; EXPRESSION; CANCER; GENE; CYCLOOXYGENASE-2; CARCINOGENESIS; ACCUMULATION; BIOMARKERS; DYSPLASIA AB Esophageal cancer remains a highly lethal malignancy for which the genetic and proteomic events are poorly understood. Studies have reported dysregulated proteins in esophageal carcinoma; however, the magnitude of these changes remains largely uncharacterized. Little is known about alterations early in the neoplastic pathway. Using multiplex tissue immunoblotting, we quantified the expression of seven proteins in esophageal carcinogenesis. Regions of normal, dysplasia, and invasive carcinoma of the squamous esophagus in six patients were characterized. Pan-cytokeratin WK) was essentially unchanged across the transition (0.96 in dysplasia and 0.69 in tumor). Expression levels of annexin 1, CK-4, and CK-14 were all decreased in dysplasia and tumor compared with normal (reference, 1.00): annexin 1, 0.30 in dysplasia and 0.15 in tumor; CK-4, 0.20 in dysplasia and 0.16 in tumor; and CK-14, 0.54 in dysplasia and 0.40 in tumor. Expression of two proteins was increased in dysplasia and tumor versus normal: cyclooxygenase-2,1.35 in dysplasia and 2.32 in tumor and p53,1.29 in dysplasia and 2.37 in tumor. Secreted protein, acidic and rich in cysteine, which is expressed in the adjacent stroma, was 1.56-fold higher in stroma underlying dysplasia and 6.20-fold increased in dysplastic stroma surrounding invasive tumor. These findings suggest that changes in protein expression can be detected during the transition to dysplasia and maybe useful biomarkers. C1 Canc Res Ctr, Tissue Array Res Program, Pathol Lab, Bethesda, MD USA. NCI, Canc Prevent Studies Branch, NIH, Bethesda, MD USA. Inje Univ, Coll Med, PharmacoGenom Res Ctr, Pusan, South Korea. Inje Univ, Coll Med, Mol Cell Physiol Res Grp, Pusan, South Korea. 20 20 GeneSyst Inc, Rockville, MD USA. Shanxi Canc Hosp, Pathol Lab, Shanxi, Peoples R China. RP Hewitt, SM (reprint author), Ctr Adv Technol, Tissue Array Res Program Lab, MSC 4605, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU Intramural NIH HHS NR 23 TC 30 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 JUL PY 2006 VL 15 IS 7 BP 1403 EP 1408 DI 10.1158/1055-9965.EPT-05-0651 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 061OB UT WOS:000238880800028 PM 16835344 ER PT J AU Perera, FP Tang, DL Brandt-Rauf, P Santella, RM Mooney, LVA Tu, YH Bendkowska, I Bell, DA AF Perera, Frederica P. Tang, Deliang Brandt-Rauf, Paul Santella, Regina M. Mooney, La Verne A. Tu, Yi-Hsuan Bendkowska, Ivona Bell, Douglas A. TI Lack of associations among cancer and albumin adducts, ras p21 oncoprotein levels, and CYP1A1, CYP2D6, NAT1. and, NAT2 in a nested case-control study of lung cancer within the Physicians' Health Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID AROMATIC HYDROCARBON-DNA; RISK; ONCOGENE; GENOTYPE; ADENOCARCINOMA; POLYMORPHISMS; METAANALYSIS; ACTIVATION C1 Columbia Univ, Dept Environm Hlth Sci, Columbia Ctr Childrens Environm Hlth, Mailman Sch Publ Hlth, New York, NY 10032 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Perera, FP (reprint author), Columbia Univ, Dept Environm Hlth Sci, Columbia Ctr Childrens Environm Hlth, Mailman Sch Publ Hlth, 100 Haven Ave,Tower III,25F, New York, NY 10032 USA. EM fpp1@columbia.edu FU Intramural NIH HHS; NCI NIH HHS [5R01 CA 53772]; NIEHS NIH HHS [P30 ES009089]; PHS HHS [1R01 1019650595] NR 24 TC 11 Z9 11 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 JUL PY 2006 VL 15 IS 7 BP 1417 EP 1419 DI 10.1158/1055-9965.EPI-05-0691 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 061OB UT WOS:000238880800032 PM 16835348 ER PT J AU Schatzkin, A AF Schatzkin, Arthur TI Sir Richard Doll on chance and genetic susceptibility in carcinogenesis, or, why not all smokers get lung cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Letter C1 NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. RP Schatzkin, A (reprint author), NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2006 VL 15 IS 7 BP 1420 EP 1420 DI 10.1158/1055-9965.EPI-06-0325 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 061OB UT WOS:000238880800033 PM 16835349 ER PT J AU Kimchi-Sarfaty, C D Vieira, W Dodds, D Sherman, A Kreitman, RJ Shinar, S Gottesman, MM AF Kimchi-Sarfaty, C. D Vieira, W. Dodds, D. Sherman, A. Kreitman, R. J. Shinar, S. Gottesman, M. M. TI SV40 pseudovirion gene delivery of a toxin to treat human adenocarcinomas in mice SO CANCER GENE THERAPY LA English DT Article DE gene delivery; SV40 pseudovirions; in vitro packaging; Pseudomonas exotoxin; doxorubicin; adenocarcinoma ID HIGHLY EFFICIENT VECTORS; DISULFIDE-STABILIZED FV; PSEUDOMONAS EXOTOXIN; IN-VITRO; RECOMBINANT IMMUNOTOXIN; CANCER-THERAPY; FUSION PROTEIN; CELL LEUKEMIA; GROWTH; TUMORS AB SV40 vectors packaged in vitro (pseudovirions) are an efficient delivery system for plasmids up to 17.7 kb, with or without SV40 sequences. A truncated Pseudomonas exotoxin gene (PE38) was delivered into various human cells (HeLa, KB-3-1, human lymphoblastoids, and erythroleukemia cells), in vitro using pseudovirions. The number of viable cells was reduced significantly in the PE38-transduced cells. Human KB adenocarcinomas growing in mice were treated with intratumoral injection of PE38 packaged in vitro, and tumor size decreased significantly. Intraperitoneal treatments were as effective in reducing tumor size as intratumoral treatments. To check the viability of mock- or PE38-treated mice, every 4 days they were weighed, their blood was tested, and various tissues were screened for pathology. All parameters showed that the in vitro-packaged vectors, injected into tumors or intraperitoneally, caused no abnormalities in mice. The combined treatment of doxorubicin with in vitro-packaged PE38 reduced tumor size slightly more than each of the treatments separately. However, the combined treatment did not cause the weight loss seen with doxorubicin alone. These results indicate that SV40 in vitro packaging is an effective system for cancer gene delivery using two different routes of injection and in combination with chemotherapy. C1 NCI, Lab Cell Biol, NIH, Bethesda, MD 20892 USA. NCI, Lab Mol Biol, NIH, Bethesda, MD USA. RP Gottesman, MM (reprint author), NCI, Lab Cell Biol, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU Intramural NIH HHS; NCI NIH HHS [Z01 BC005598-16] NR 38 TC 10 Z9 12 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD JUL PY 2006 VL 13 IS 7 BP 648 EP 657 DI 10.1038/sj.cgt.7700943 PG 10 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 054KX UT WOS:000238376700002 PM 16498428 ER PT J AU White, JS Becker, RL McLean, IW Director-Myska, AE Nath, J AF White, Jason S. Becker, Robert L. McLean, Ian W. Director-Myska, Alison E. Nath, Joginder TI Molecular cytogenetic evaluation of 10 uveal melanoma cell lines SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; IN-SITU HYBRIDIZATION; ACQUIRED HOMOZYGOSITY ISODISOMY; OCULAR MELANOMA; COPY NUMBER; MALIGNANT-MELANOMA; SOLID TUMORS; CHROMOSOME-3; IDENTIFICATION; ABNORMALITIES AB Uveal melanoma is the most common intraocular tumor in adults and often results in unilateral blindness and/or death. Previous cytogenetic characterizations of this tumor consistently revealed chromosomal abnormalities involving chromosomes 3, 6, and 8; reports of other abnormalities vary in frequency. We defined cytogenetic abnormalities of this tumor using complementary in situ hybridization techniques on 10 uveal melanoma cell lines. Synthesis of comparative genomic hybridization (CGH) and spectral karyotyping (SKY) results revealed that chromosomal rearrangement is involved in DNA sequence copy number abnormalities throughout the genome but monosomy 3 was not found. Monosomy 3 is thought to be a significant prognostic indicator. so its absence vas investigated further. Fluorescence in situ hybridization (FISH) for chromosome 3 revealed approximately 1 centromere signal per cell, but probes for 3p and 3q revealed multiple telomere signals per cell. suggesting chromosomal rearrangement without whole-chromosome loss. Based on combined CGH. SKY. and FISH data, we propose that chromosome 3 is more frequently involved in chromosomal rearrangements than whole-chromosome loss in uveal melanoma. Future approaches should be designed to confirm and enhance the resolution of regions of imbalance in primary tumors. Once identified. conserved chromosomal alterations that contribute to uveal melanoma may reveal the underlying aspects of uveal melanoma onset, metastasis and resistance to current treatment modalities. (c) 2006 Elsevier Inc. All rights reserved. C1 W Virginia Univ, Genet & Dev Biol Program, Morgantown, WV 26505 USA. Armed Forces Inst Pathol, Dept Cellular Pathol & Genet, Rockville, MD 20850 USA. Armed Forces Inst Pathol, Dept Ophthalm Pathol, Washington, DC 20306 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Nath, J (reprint author), W Virginia Univ, Genet & Dev Biol Program, 1120 Agr Sci Bldg, Morgantown, WV 26505 USA. EM jnath@wvu.edu NR 48 TC 9 Z9 9 U1 0 U2 1 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 JUL 1 PY 2006 VL 168 IS 1 BP 11 EP 21 DI 10.1016/j.cancergencyto.2005.11.016 PG 11 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 059MG UT WOS:000238736300002 PM 16772116 ER PT J AU Nguyen, DM Yeow, WS Ziauddin, MF Baras, A Tsai, W Reddy, RM Chua, A Cole, GW Schrump, DS AF Nguyen, Dao M. Yeow, Wen-Shuz Ziauddin, M. Firdos Baras, Aris Tsai, Wilson Reddy, Rishindra M. Chua, Alex Cole, George W., Jr. Schrump, David S. TI The essential role of the mitochondria-dependent death-signaling cascade in chemotherapy-induced potentiation of Apo2L/TRAIL cytotoxicity in cultured thoracic cancer cells: Amplified caspase 8 is indispensable for combination-mediated massive cell death SO CANCER JOURNAL LA English DT Article DE Apo2L/TRAIL; mitochondria; caspase; Bcl-2; primary thoracic cancers; cisplatin; paclitaxel; type II pathway ID TRAIL-INDUCED APOPTOSIS; CYTOCHROME-C; BCL-2 OVEREXPRESSION; DECOY RECEPTORS; LUNG-CANCER; IN-VIVO; LIGAND; NECROSIS; ACTIVATION; RESISTANCE AB PURPOSE Despite adequately expressing functional receptors for tumor necrosis factor receptor apoptosis-inducing ligand (TRAIL), many cultured tumor cells are refractory to the cytotoxic effect of this ligand. Cytotoxic chemotherapeutic drugs have been shown to synergize with Apo2L/TRAIL to mediate apoptosis in cancer cells. The main goal of this study was to evaluate the effect of either cisplatin or paclitaxel, two common used chemotherapeutic agents for solid tumors, on enhancing Apo2L/TRAIL cytotoxicity in a panel-cultured thoracic cancer cells and to examine the role of the mitochondria-dependent caspase activation cascade in mediating apoptosis of combination-treated cells. METHODS Cultured thoracic cancer cells were treated with cisplatin/Apo2L/TRAIL or paclitaxel/Apo2L/TRAIL sequential combinations in vitro. Cell viability and apoptosis were determined by 4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays. Stable transfectants expressing high levels of Bcl-2 were created by retroviral gene transfer. Specific proteolytic activity of caspases 3, 6, 8, and 9 were measured by commercially available kits using fluorescent substrates. RESULTS All cell lines preferentially expressed high levels of DR4 and/or DR5 and low levels of DcR1/DcR2; all of which were not altered by chemotherapeutic drug treatments. Pretreatment of these cancer cells with sublethal concentrations of either cisplatin or paclitaxel increased their susceptibility to Apo2L/TRAIL by twofold to > 20-fold. Profound synergistic induction of apoptosis was observed in combination-treated cells. Viability of primary normal cells was affected by neither Apo2L/TRAIL nor the combinations of chemotherapy and Apo2L/TRAIL. Overexpression of Bcl-2 or inhibition of caspase 9 activity completely abrogated combination-induced cytotoxicity and apoptosis, indicating the essential role of the mitochondria-dependent death signaling cascade in this process. Robust activation of caspase 8 in combination-treated cells was completely suppressed either by Bcl-2 overexpression or by blocking of the activity of the mitochondria-regulated caspase 9, thus identifying the amplification feedback loop as the source of elevated caspase 8 activity. Finally, mitochondria-mediated amplification of caspase 8 activity was indispensable for complete caspase activation and full execution of apoptosis, because suppression of its activity using the selective caspase 6 inhibitor (located downstream of the caspase 3 but upstream of the caspase 8 in the feedback loop) resulted in profound suppression of not only caspase 8 activity but also those of caspases 9 and 3, as well as complete protection of cancer cells from combination-induced cytotoxicity. CONCLUSION Cisplatin or paclitaxel synergistically interacts with Apo2L/TRAIL to mediate profound induction of apoptosis. The mitochondria-dependent caspase activation cascade and the amplification feedback loop are essential for the complete execution of the cell death program. Furthermore, our data identify mitochondria as the direct target for the development of more refined strategies to enhance the therapeutic effect of Apo2L/TRAIL as an anticancer agent. C1 NCI, Sect Thorac Oncol, Surg Branch, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. RP Nguyen, DM (reprint author), NCI, Sect Thorac Oncol, Surg Branch, Canc Res Ctr,NIH, Bldg 10,Room 4W-4-3390,10 Ctr Dr, Bethesda, MD 20892 USA. EM Dao_Nguyen@nih.gov NR 44 TC 26 Z9 31 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 EI 1540-336X J9 CANCER J JI Cancer J. PD JUL-AUG PY 2006 VL 12 IS 4 BP 257 EP 273 DI 10.1097/00130404-200607000-00004 PG 17 WC Oncology SC Oncology GA 078BF UT WOS:000240075400004 PM 16925970 ER PT J AU Miao, ZH Rao, VA Agama, K Antony, S Kohn, KW Pommier, Y AF Miao, Ze-Hong Rao, V. Ashutosh Agama, Keli Antony, Smitha Kohn, Kurt W. Pommier, Yves TI 4-nitroquinoline-1-oxide induces the formation of cellular topoisomerase I-DNA cleavage complexes SO CANCER RESEARCH LA English DT Article ID DIOL EPOXIDE ADDUCTS; BLOOM-SYNDROME; CHROMOSOMAL INSTABILITY; STRAND BREAKS; MAMMALIAN-CELLS; WERNER-SYNDROME; PYLORIC MUCOSA; FILTER ELUTION; HISTONE H2AX; RAT STOMACH AB RecQ helicase BLM-deficient cells are characteristically hypersensitive to 4-nitroquinoline-1-oxide (4NQO). We recently reported that isogenic BLM-deficient cells (PNSG13) are more sensitive than BLM-complemented cells (PNSF5) to camptothecin, which specifically traps topoisomerase I cleavage complexes (Top1cc). We now report that PNSG13 are also 3.5-fold more sensitive to 4NQO compared with PNSF5 and that 4NQO induces higher levels of Top1cc and reduced histone gamma-H2AX in PSNG13 than in PNSF5. Similarly, 4NQO induces more Top1cc in primary fibroblasts from a patient with Bloom syndrome than in normal human fibroblasts. 4NQO also induces Top1cc in colon cancer HCT116 and HT29 cells in a time- and concentration-dependent fashion. Of note, distinct from camptothecin, the Top1cc produced by 4NQO accumulate progressively after 4NQO addition and persist following 4NQO removal. The Top1cc induced by 4NQO are detectable by alkaline elution. To examine the functional relevance of the Top1cc induced by 4NQO, we used two stable topoisomerase I small interfering RNA (siRNA) cell lines derived from HCT116 and MCF7 cells. Both topoisomerase I siRNA cell lines are resistant to 4NQO, indicating that Top1cc contribute to the cellular activity of 4NQO. Collectively, these data show that 4NQO is an effective inducer of cellular Top1cc. Because 4NQO does not directly trap Top1cc in biochemical assays, we propose that active metabolites of 4NQO trap Top1cc by forming DNA adducts. Induction of Top1cc and histone gamma-H2AX by 4NQO may contribute to the cellular effects of 4NQO, including its selective activity toward RecQ helicase BLM-deficient cells. C1 NCI, Lab Mol Pharmacol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Lab Mol Pharmacol, Ctr Canc Res, NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Intramural NIH HHS NR 54 TC 15 Z9 16 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2006 VL 66 IS 13 BP 6540 EP 6545 DI 10.1158/0008-5472.CAN-05-4471 PG 6 WC Oncology SC Oncology GA 060TZ UT WOS:000238825800014 PM 16818625 ER PT J AU Yu, M Yeh, J Van Waes, C AF Yu, Mng Yeh, Jason Van Waes, Carter TI Protein kinase casein kinase 2 mediates inhibitor-kappa B kinase and aberrant nuclear factor-kappa B activation by serum factor(s) in head and neck squamous carcinoma cells SO CANCER RESEARCH LA English DT Article ID NECROSIS-FACTOR-ALPHA; PROINFLAMMATORY CYTOKINE EXPRESSION; BREAST-CANCER CELLS; TUMOR-GROWTH; CK2 ACTIVITY; CONSTITUTIVE ACTIVATION; TRANSCRIPTION FACTORS; RESPONSE FACTOR; SURVIVAL; PHOSPHORYLATION AB We showed previously that the signal transcription factor nuclear factor-kappa B (NF-kappa B) is aberrantly activated and that inhibition of NF-kappa B induces cell death and inhibits tumorigenesis in head and neck squamous cell carcinomas (HNSCC). Thus, identification of specific kinases underlying the activation of NF-kappa B could provide targets for selective therapy. Inhibitor-kappa B (I kappa B) kinase (IKK) is known to activate NF-kappa B by inducing NH2-terminal phosphorylation and degradation of its endogenous inhibitor, I kappa B. Casein kinase 2 (CK2) was previously reported to be overexpressed in HNSCC cells and to be a COOH-terminal IKK, but its relationship to NF-kappa B activation in HNSCC cells is unknown. In this study, we examined the contribution of IKK and CK2 in the regulation of NF-kappa B in HNSCC in vitro. NF-kappa B activation was specifically inhibited by kinase-dead mutants of the IKK1 and IKK2 subunits or small interfering RNA targeting the 0 subunit of CK2. CK2 and IKK kinase activity, as well as NF-kappa B transcriptional activity, was shown to be serum responsive, indicating that these kinases mediate aberrant activation of NF-kappa B in response to serum' factor(s) in vitro. Recombinant CK2 alpha was shown to phosphorylate recombinant IKK2 as well as to promote immunoprecipitated IKK complex from HNSCC to phosphorylate the NH2-terminal S32/S36 of I kappa B alpha. We conclude that the aberrant NF-kappa B activity in HNSCC cells in response to serum is partially through a novel mechanism involving CK2-mediated activation of IKK2, making these kinases candidates for selective therapy to target the NF-kappa B pathway in HNSCC. C1 Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. RP Van Waes, C (reprint author), Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov FU NIDCD NIH HHS [Z01 DC 00016, Z01 DC000016, Z01 DC000016-12] NR 51 TC 47 Z9 47 U1 0 U2 0 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 JUL 1 PY 2006 VL 66 IS 13 BP 6722 EP 6731 DI 10.1158/0008-5472.CAN-05-3758 PG 10 WC Oncology SC Oncology GA 060TZ UT WOS:000238825800036 PM 16818647 ER PT J AU Joshi, N Johnson, LL Wei, WQ Abnet, CC Dong, ZW Taylor, PR Limburg, PJ Dawsey, SM Hawk, ET Qiao, YL Kirsch, IR AF Joshi, Nina Johnson, Laura Lee Wei, Wen-Qiang Abnet, Christian C. Dong, Zhi-Wei Taylor, Philip R. Limburg, Paul J. Dawsey, Sanford M. Hawk, Ernest T. Qiao, You-Lin Kirsch, Ilan R. TI Gene expression differences in normal esophageal mucosa associated with regression and progression of mild and moderate squamous dysplasia in a high-risk Chinese population SO CANCER RESEARCH LA English DT Article ID RECEPTOR TYROSINE KINASES; CELL CARCINOMA; CANCER VACCINES; BASIC-PROTEIN; TGF-ALPHA; LIGAND; MECHANISMS; INHIBITION; ANTIBODIES; SELENIUM AB A randomized, double-blinded, placebo-controlled 2 X 2 factorial chemoprevention trial was conducted in Linxian, China to assess the effects of selenomethionine and celecoxib on the natural history of esophageal squamous dysplasia. Results from this study indicated that asymptomatic adults with mild dysplasia were more likely to show an improvement when treated with selenomethionine compared with placebo (P = 0.02). Prompted by this finding, we examined the molecular profiles associated with regression and progression of dysplastic lesions in normal mucosa from 29 individuals, a subset of the Linxian cohort, using the Affymetrix U133A chip. Twenty differentially expressed genes were associated with regression and 129 were associated with progression when we compared the change in gene expression over time. Genes associated with immune response (n = 15), cell cycle (n = 15), metabolism (n = 15), calcium transport or calcium ion activity (n = 10), regulation of transcription (n = 9), signal transduction (n = 7), cytoskeleton and microtubules (n = 5), nucleotide processing and biosynthesis (n = 4), G-coupled signaling (n = 4), and apoptosis (n = 3) were present in the list of 149 genes. Using the Expression Analysis Systematic Explorer pathway analysis program, only the immune response pathway was significantly overrepresented among these 149 genes. Individuals whose lesions regressed seemed to have higher expression of genes associated with immune stimulation, such as antigen presentation, survival of T cells, and T-cell activation (HLA-DRA, HLA-DPAI, HLA-DBQ1, CD58, and MERIA). In contrast, individuals whose lesions progressed had higher expression of genes involved in immune suppression and inflammation (CNR2, NFATC4, NFRKB, MBP, INHBB, CMKLR1, CRP, ORMS, SERPINA7, and SERPINA1). These data suggest that local and systemic immune responses may influence the natural history of esophageal squamous dysplasia. C1 NCI, Div Canc Epidemiol & Genet, NIH, EPS,Nutr Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Genet Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NIH, Off Clin & Regulatory Affairs, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. NIH, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Off Ctr Training & Resources, NIH, Bethesda, MD 20892 USA. Chinese Acad Med Sci, Beijing 100037, Peoples R China. Mayo Clin & Mayo Fdn, Coll Med, Rochester, MN USA. RP Taylor, PR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, EPS,Nutr Epidemiol Branch, 6120 Execut Blvd,Room 7006, Bethesda, MD 20892 USA. EM ptaylor@mail.nih.gov RI Qiao, You-Lin/B-4139-2012; OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843 NR 51 TC 16 Z9 16 U1 0 U2 1 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 JUL 1 PY 2006 VL 66 IS 13 BP 6851 EP 6860 DI 10.1158/0008-5472.CAN-06-0662 PG 10 WC Oncology SC Oncology GA 060TZ UT WOS:000238825800052 PM 16818663 ER PT J AU Woditschka, S Haag, JD Waller, JL Monson, DM Hitt, AA Brose, HL Hu, R Zheng, Y Watson, PA Kim, K Lindstrom, MJ Mau, B Steele, VE Lubet, RA Gould, MN AF Woditschka, Stephan Haag, Jill D. Waller, Jordy L. Monson, Dinelli M. Hitt, Andrew A. Brose, Heidi L. Hu, Rong Zheng, Yun Watson, Philip A. Kim, Kwanghee Lindstrom, Mary J. Mau, Bob Steele, Vernon E. Lubet, Ronald A. Gould, Michael N. TI Neu-induced retroviral rat mammary carcinogenesis: A novel chemoprevention model for both hormonally responsive and nonresponsive mammary carcinomas SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER; TRANSGENIC MICE; CELL-PROLIFERATION; EPITHELIAL-CELLS; IN-SITU; PREVENTION; EXPRESSION; TAMOXIFEN; TUMORS; APOPTOSIS AB Clinically relevant animal models of mammary carcinogenesis are crucial for the development and evaluation of new breast cancer chemopreventive agents. The neu-induced retroviral rat mammary carcinogenesis model is based on the direct in situ transfer of the activated neu oncogene into the mammary epithelium using a replication-defective retroviral vector. The resulting mammary carcinomas in intact Wistar-Furth rats exhibit a mixed hormonal response in the same proportion as has been observed in women. In intact rats, similar to 50% of mammary carcinomas can be prevented by tamoxifen treatment. In ovariectomized animals, the mammary carcinomas are hormonally nonresponsive and cannot be prevented by tamoxifen. We evaluated the efficacy of retinoic X receptor-selective retinoids (rexinoids) in this novel model of mammary carcinogenesis. The rexinoids LG100268 and bexarotene (LG1069, Targretin) were highly efficacious in the prevention of neu-induced mammary carcinomas. Dietary LG100268 at 100 mg/kg diet decreased tumor multiplicity by 32% (P = 0.0114) in intact rats and 50% (P < 0.0001) in ovariectomized rats. Bexarotene treatment at a dose of 250 mg/kg diet was associated with reductions in tumor multiplicity of 84% (P < 0.0001) and 86% (P < 0.0001) in intact and ovariectomized animals, respectively. In addition to tumor multiplicity, proliferation and apoptosis were modulated by bexarotene treatment independently of estrogen signaling. The neu-induced retroviral rat mammary carcinogenesis model represents a valuable addition to existing rodent chemoprevention models. The model is useful for assessing the efficacy of chemopreventive agents, specifically those compounds that target hormonally nonresponsive tumors. C1 Univ Wisconsin, Canc Res Lab, Madison, WI 53706 USA. Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53706 USA. Univ Wisconsin, Ctr Biotechnol, Madison, WI 53705 USA. NCI, Chemoprevent Agent Dev Grp, Rockville, MD USA. RP Gould, MN (reprint author), Univ Wisconsin, Canc Res Lab, 1400 Univ Ave, Madison, WI 53706 USA. EM gould@oncology.wisc.edu RI Gould, Michael/C-7414-2014 FU NCI NIH HHS [CA 101201, CN 05116, CN 15124, CN 85176] NR 35 TC 10 Z9 10 U1 0 U2 1 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 JUL 1 PY 2006 VL 66 IS 13 BP 6884 EP 6891 DI 10.1158/0008-5472.CAN-05-1823 PG 8 WC Oncology SC Oncology GA 060TZ UT WOS:000238825800056 PM 16818667 ER PT J AU Hodge, DR Farrar, WL AF Hodge, David R. Farrar, William L. TI p53 expression after treatment with zebularine is not due to demethylation - In response SO CANCER RESEARCH LA English DT Letter C1 NCI, Frederick, MD 21701 USA. RP Hodge, DR (reprint author), NCI, Frederick, MD 21701 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 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 JUL 1 PY 2006 VL 66 IS 13 BP 6893 EP 6893 PG 1 WC Oncology SC Oncology GA 060TZ UT WOS:000238825800058 ER PT J AU Mechanic, LE Millikan, RC Player, J de Cotret, AR Winkel, S Worley, K Heard, K Heard, K Tse, CK Keku, T AF Mechanic, Leah E. Millikan, Robert C. Player, Jon de Cotret, Allan Rene Winkel, Scott Worley, Kendra Heard, Kristin Heard, Kimberley Tse, Chiu-Kit Keku, Temitope TI Polymorphisms in nucleotide excision repair genes, smoking and breast cancer in African Americans and whites: a population-based case-control study SO CARCINOGENESIS LA English DT Article ID OXIDATIVE DNA-DAMAGE; BASAL-CELL CARCINOMA; PRIMARY LUNG-CANCER; CIGARETTE-SMOKING; XPD POLYMORPHISMS; PASSIVE SMOKING; LYS751GLN POLYMORPHISM; CYTOCHROME P4501A1; BLADDER-CANCER; ACTIVE SMOKING AB Polymorphisms exist in several genes involved in nucleotide excision repair (NER), the principal pathway for removal of smoking-induced DNA damage. An epidemiologic study was conducted to determine whether these polymorphisms modify the association between smoking and breast cancer. DNA samples and exposure histories were analyzed as part of a large population-based case-control study of breast cancer in North Carolina. The study population included 2311 cases (894 African Americans, 1417 whites) and 2022 controls (788 African Americans, 1234 whites). Odds ratios (ORs) were calculated for breast cancer and smoking, and for breast cancer and nine non-synonymous coding polymorphisms in six NER genes (XPD codons 312 and 751, RAD23B codon 249, XPG codon 1104, XPC codon 939, XPF codons 415 and 662, and ERCC6 codons 1213 and 1230). Modification of ORs for smoking by single and combined NER genotypes was investigated. In this study population, smoking was more strongly associated with breast cancer in African American women compared with white women. Among African American women, the association of breast cancer and smoking was strongest among women with specific combinations of NER genotypes. Evidence for multiplicative interaction was found between combined NER genotypes and smoking dose (likelihood ratio test P = 0.06), duration (P = 0.09), time since cessation (P = 0.02), age at initiation (P = 0.04) and former smoking (P = 0.03). No interactions were observed in white women. Therefore, polymorphisms in NER genes may modify the relationship between breast cancer and smoking. These results are consistent with previous evidence of exposure-specific p53 mutations in breast tumors from current and former smokers, suggesting that smoking may play a role in breast cancer etiology. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC 27599 USA. RP Millikan, RC (reprint author), NCI, Human Carcinogenesis Lab, NIH, 37 Convent Dr MSC 4255,Bldg 37,Rm 3060, Bethesda, MD 20892 USA. EM mechanil@mail.nih.gov FU NCI NIH HHS [P30-CA16086, P50-CA58223]; NIEHS NIH HHS [P42-ES05948, P30-ES10126] NR 83 TC 67 Z9 69 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 JUL PY 2006 VL 27 IS 7 BP 1377 EP 1385 DI 10.1093/carcin/bgi330 PG 9 WC Oncology SC Oncology GA 061XD UT WOS:000238906200010 PM 16399771 ER PT J AU Yao, RS Wang, Y Lu, Y Lemon, WJ End, DW Grubbs, CJ Lubet, RA You, M AF Yao, Ruisheng Wang, Yian Lu, Yan Lemon, William J. End, David W. Grubbs, Clinton J. Lubet, Ronald A. You, Ming TI Efficacy of the farnesyltransferase inhibitor R115777 in a rat mammary tumor model: role of Ha-ras mutations and use of microarray analysis in identifying potential targets SO CARCINOGENESIS LA English DT Article ID PROTEIN TRANSFERASE INHIBITOR; TRANSGENIC MICE; CARCINOMAS; EXPRESSION; P53; APOPTOSIS; BREAST; CANCER; ONCOGENES; PATHWAYS AB Rats treated with the alkylating agent methylnitrosourea (MNU) develop multiple, hormonally dependent mammary tumors. Roughly 50% of the tumors have Ha-ras mutation, whereas 50% do not. The MNU-induced rat mammary tumor model was employed to examine the therapeutic efficacy of the farnesyltransferase inhibitor (FTI), R115777, and to examine the use of genomics in identifying susceptible tumors as well as identifying genes whose expression are modulated by FTI treatment. In animals bearing palpable mammary tumors (< 7 mm diameter), we performed a surgical biopsy, and 3 days following the biopsy, rats were treated with R115777 (50 mg/kg body wt/day) by gavage. Tumors with Ha-ras mutations underwent profound regression, with nearly 90% showing complete regressions within 4 weeks. In contrast, the non-Ha-ras mutation-bearing tumors yielded a more variable response, although roughly half of the non-Ha-ras mutation tumors underwent significant regression. These results show that although all tumors appear to respond to the FTI inhibitor the tumors with Ha-ras mutations were exquisitely sensitive. We employed a microarray approach to define potential targets and the mechanism of action of R115777 in Ha-ras mutant or wildtype tumors following treatment with FTI. In addition, we determined whether gene expression prior to FTI treatment can be used to differentiate highly sensitive tumors (Ha-ras mutant) and tumors with variable sensitivity (Ha-ras wildtype). Untreated or FTI-treated (4 days at 50 mg/kg body wt) tumors (Ha-ras mutant or wildtype) were examined using oligonucleotide arrays. A significant number of genes were differentially expressed in control rat mammary tumors with or without an activated Ha-ras mutation, suggesting that a microarray analysis might differentiate highly sensitive and variably sensitive tumors. Most of the genes whose expressions were modulated by FTI in tumors were independent of Ha-ras status and were presumably modulated by effects on farnesylation of proteins other than Ha-ras. However, treatment of Ha-ras-mutated mammary tumors with R155777 results in preferential modulation of genes involved in ras-MAP kinase signal transduction pathway and in decreased expression of many genes involved with cell proliferation. In contrast, several classes of genes are altered in rat mammary tumors without a mutated Ha-ras, suggesting that non-ras targets are involved. Ras pathway related genes, p53, WT1 and PCNA, were preferentially modulated in Ha-ras-mutated tumors, whereas modulation of genes in the G-protein pathway, various cytochrome p450s and RB1 are involved in Ha-ras wildtype tumors. Elucidation of gene expression changes in FTI-treated or control rat mammary adenocarcinomas will help in identifying potential pharmacodynamic markers of FTI treatment as well as potential molecular targets of R115777 and other FTIs. C1 Washington Univ, Sch Med, Dept Surg, St Louis, MO 63103 USA. Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 63103 USA. Janssen Res Fdn, Spring House, PA 19477 USA. Univ Alabama, Birmingham, AL 35294 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Washington Univ, Sch Med, Dept Surg, Campus Box 8109,660 S Euclid Ave, St Louis, MO 63103 USA. EM youm@msnotes.wustl.edu FU NCI NIH HHS [R01 CA1133793, R01 CA96103, N01-CN-43308] NR 31 TC 5 Z9 6 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 JUL PY 2006 VL 27 IS 7 BP 1420 EP 1431 DI 10.1093/carcin/bgi341 PG 12 WC Oncology SC Oncology GA 061XD UT WOS:000238906200016 PM 16403772 ER PT J AU Fenton, JI Hursting, SD Perkins, SN Hord, NG AF Fenton, Jenifer I. Hursting, Stephen D. Perkins, Susan N. Hord, Norman G. TI Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc ((Min/+)) colon epithelial cell line SO CARCINOGENESIS LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; INTESTINAL TUMORIGENESIS; COLORECTAL TUMORIGENESIS; IN-VITRO; CANCER; MICE; GROWTH; EXPRESSION; OBESITY; MECHANISMS AB Increased visceral adipose tissue results in elevated plasma leptin, which are associated with increased risk of a number of obesity-related cancers. However, research is contradictory regarding the role of elevated plasma leptin in colon cancer risk. Having established that leptin induced proliferation in a murine model of preneoplastic (Apc(Min/+); IMCE) colon epithelial cells but not normal (Apc(+/+); YAMC) cells, we hypothesized that the leptin-associated IMCE cell proliferation was a result of autocrine interleukin-6 (IL-6) production and ensuing IL-6 receptor (IL-6R) signaling. Here we show, for the first time, that leptin induces elevated IL-6 production in IMCE cells but not in YAMC cells. IL-6 treatment induced cell proliferation in IMCE cells, but not in YAMC cells, in a concentration-dependent manner from 0.1 to 100 ng/ml (P < 0.05). Interleukin-6-induced IMCE cell proliferation was blocked by the addition of a neutralizing anti-IL-6R antibody. In addition, leptin-induced IMCE cell proliferation was blocked by the addition of an anti-IL-6R neutralizing antibody. Further, we elucidate a novel mechanism by which leptin activates TACE/ADAM17-associated IL-6R shedding and trans-IL-6 signaling in IMCE by induction of IL-6 production. IL-6 treatment of IMCE cells was associated with STAT3, ERK, p38, MEK and JAK2 activation and associated STAT3 nuclear activation and translocation. These data implicate leptin-induced IL-6 production, signaling and subsequent STAT3 activation as early events promoting the survival/proliferation of colon epithelial preneoplastic cells. The elucidation of the leptin-initiated mechanism of preneoplastic cell proliferation establishes a biologically plausible link between the adipoctye-specific cytokine leptin and obesity-associated colon cancer. C1 NCI, Canc Prevent Fellowship Program, Div Canc Prevent, 6130 Execut Blvd,MSC 7361, Bethesda, MD 20892 USA. NCI, Lab Biosyst & Canc, Bethesda, MD 20892 USA. Michigan State Univ, Dept Food Sci & Human Nutr, E Lansing, MI 48824 USA. RP Fenton, JI (reprint author), NCI, Canc Prevent Fellowship Program, Div Canc Prevent, 6130 Execut Blvd,MSC 7361, Bethesda, MD 20892 USA. EM imigjeni@msu.edu OI Fenton, Jenifer/0000-0002-8875-3239 NR 49 TC 52 Z9 54 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2006 VL 27 IS 7 BP 1507 EP 1515 DI 10.1093/carcin/bgl018 PG 9 WC Oncology SC Oncology GA 061XD UT WOS:000238906200026 PM 16597643 ER PT J AU Willems, L Reichelt, ME Molina, JG Sun, CX Chunn, JL Ashton, KJ Schnermann, J Blackburn, MR Headrick, JP AF Willems, Laura Reichelt, Melissa E. Molina, Jose G. Sun, Chun-Xiao Chunn, Janci L. Ashton, Kevin J. Schnermann, Jurgen Blackburn, Michael R. Headrick, John P. TI Effects of adenosine deaminase and A(1) receptor deficiency in non-noxic and ischaemic mouse hearts SO CARDIOVASCULAR RESEARCH LA English DT Article DE experimental; heart; organ; biochemistry; general physiology; pharmacology; adenosine deaminase; adenosine receptor; gene knockout; ischemia ID RAT-HEART; ENDOGENOUS ADENOSINE; INFARCT SIZE; FUNCTIONAL IMPLICATIONS; REPERFUSION INJURY; ANGINA-PECTORIS; MICE; PROTEIN; CARDIOPROTECTION; INHIBITION AB Objective: Adenosine deaminase (ADA) may be multifunctional, regulating adenosine levels and adenosine receptor (AR) agonism, and potentially modifying AR functionality. Herein we assess effects of ADA (and A(1)AR) deficiency on AR-mediated responses and ischaemic tolerance. Methods: Normoxic function and responses to 20 or 25 min ischaemia and 45 min reperfusion were studied in isolated hearts from wild-type mice and from mice deficient in ADA and/or A(1)ARs. Results: Neither ADA or A(1)AR deficiency significantly modified basal contractility, although ADA deficiency reduced resting heart rate (an effect abrogated by A(1)AR deficiency). Bradycardia and vasodilation in response to AR agonism (2-chloroadenosine) were unaltered by ADA deficiency, while A(1)AR deficiency eliminated the heart rate response. Adenosine efflux increased 10- to 20-fold with ADA deficiency (at the expense of inosine). Deletion of ADA improved outcome from 25 min ischaemia, reducing ventricular diastolic pressure (by 45%; 21 +/- 4 vs. 38 +/- 3mm Hg) and lactate dehydrogenase (LDH) efflux (by 40%; 0.12 +/- 0.01 vs. 0.21 +/- 0.02U/g/min ischaemia), and enhancing pressure development (by 35%; 89 6 vs. 66 5mm Hg). Similar protection was evident after 20min ischaemia, and was mimicked by the ADA inhibitor EHNA (5 mu M). Deletion of ADA also enhanced tolerance in A(1)AR deficient hearts, though effects on diastolic pressure were eliminated. Conclusions: Deficiency of ADA does not alter sensitivities of cardiovascular A(1) or A(2)ARs (despite markedly elevated [adenosine]), but significantly improves ischaemic tolerance. Conversely, AIAR deficiency impairs ischaemic tolerance. Effects of ADA deficiency on diastolic pressure appear solely A(1)AR-dependent while other ARs or processes additionally contribute to improved contractile recovery and reduced cell death. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. C1 Griffith Univ, Heart Fdn Res Ctr, Southport, Qld 4217, Australia. Univ Texas, Hlth Sci Ctr, Sch Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Headrick, JP (reprint author), Griffith Univ, Heart Fdn Res Ctr, Southport, Qld 4217, Australia. EM J.Headrick@griffith.edu.au RI Willems, Laura/B-6259-2009; Reichelt, Melissa/C-9579-2014; Ashton, Kevin/R-2147-2016 OI Reichelt, Melissa/0000-0002-5059-2046; Ashton, Kevin/0000-0001-6106-3425 FU NIAID NIH HHS [AI-43572] NR 56 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD JUL 1 PY 2006 VL 71 IS 1 BP 79 EP 87 DI 10.1016/j.cardiores.2006.03.006 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 061OH UT WOS:000238881500012 PM 16626672 ER PT J AU Lal, A Gorospe, M AF Lal, Ashish Gorospe, Myriam TI Egad, more forms of gene regulation: The gadd45a story SO CELL CYCLE LA English DT Article DE posttranscriptional gene expression; mRNA turnover; translation; DNA damage; ribonucleoprotein complex; RNA-binding protein; AUF1; TIAR ID P53-REGULATED PROTEIN GADD45; TRANSCRIPTION FACTORS OCT-1; CELL-CYCLE CHECKPOINT; DNA-DAMAGING AGENTS; MESSENGER-RNA; POSTTRANSCRIPTIONAL REGULATION; P53-INDEPENDENT INDUCTION; GENOTOXIC STRESS; CARCINOMA CELLS; NUCLEAR ANTIGEN AB Despite the historical hegemony of transcription, mounting evidence supports the importance of posttranscriptional gene regulation via processes such as mRNA splicing, localization, turnover, and translation. However, each of these steps is still largely viewed as an exclusive proposition, whereby a particular gene under given circumstances is controlled by a single specific regulatory mechanism. Our recent investigation of gadd45a expression in response to genotoxic stress illustrates a more complex scenario, wherein transcriptional changes operate in concert with mRNA turnover and translational regulation. gadd45a thus joins a handful of reported genes whose levels are potently altered in response to cellular damage or mitogenic cues through the coordinated action of DNA- and RNA-binding proteins. Eliciting cellular responses that are strong, swift, and versatile, gene regulation by multiple factors acting on different levels is emerging as the norm, rather than the exception, for a growing collection of gene products which critically influence cellular homeostasis. C1 NIA, IRP, LCMB, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, IRP, LCMB, NIH, Box 12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov FU Intramural NIH HHS NR 39 TC 15 Z9 15 U1 0 U2 1 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUL 1 PY 2006 VL 5 IS 13 BP 1422 EP 1425 DI 10.4161/cc.5.13.2902 PG 4 WC Cell Biology SC Cell Biology GA 071PR UT WOS:000239614600013 PM 16775423 ER PT J AU Insel, TR AF Insel, Thomas R. TI Introduction - Julius Axelrod SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Biographical-Item C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, NIH, 6001 Execut Blvd,Room 8235, Bethesda, MD 20892 USA. EM insel@mail.nih.gov NR 1 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUL-AUG PY 2006 VL 26 IS 4-6 BP 349 EP 350 DI 10.1007/s10571-006-9074-4 PG 2 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 118VP UT WOS:000242971900002 ER PT J AU Saavedra, JM AF Saavedra, Juan M. TI Introduction SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUL-AUG PY 2006 VL 26 IS 4-6 BP 351 EP 354 DI 10.1007/s1057-006-9075-3 PG 4 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 118VP UT WOS:000242971900003 ER PT J AU Saavedra, JM Pavel, J AF Saavedra, Juan M. Pavel, Jaroslav TI The discovery of a novel macrophage binding site SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE brain; inflammation; renin-angiotensin system; angiotensin II receptors; lipopolysaccharide; cytokinins; brain lesion; activated microglia; spleen; immune reaction ID II RECEPTOR SUBTYPES; I-125 CGP-42112 BINDING; UNILATERAL NODOSE GANGLIONECTOMY; BRAIN ANGIOTENSIN-II; RAT-BRAIN; QUANTITATIVE AUTORADIOGRAPHY; CEREBELLAR CORTEX; HYPERTENSIVE-RATS; CGP42112 BINDING; GENE-EXPRESSION AB 1. During the course of studies directed to determine the transport of Angiotensin II AT(2) receptors in the rat brain, we found that stab wounds to the brain revealed a binding site recognized by the AT(2) receptor ligand CGP42112 but not by Angiotensin II. 2. We localized this novel site to macrophages/microglia associated with physical or chemical injuries of the brain. 3. The non-Angiotensin II site was also highly localized to inflammatory lesions of peripheral arteries. 4. In rodent tissues, high binding expression was limited to the spleen and to circulating monocytes. A high-affinity binding site was also characterized in human monocytes. 5. Lack of affinity for many ligands binding to known macrophage receptors indicated the possibility that the non-Angiotensin II CGP42112 binding corresponds to a novel site. 6. CGP42112 enhanced cell attachment to fibronectin and collagen and metalloproteinase-9 secretion from human monocytes incubated in serum-free medium but did not promote cytokine secretion. 7. When added in the presence of lipopolysaccharicle, CGP42112 reduced the lipopolysaccharide-stimulated secretion of the pro-inflammatory cytokines TNF-alpha, IL-1, IL-1 beta, and IL-6, and increased protein kinase A. 8. Molecular modeling revealed that a CGP42112 derivative was selective for the novel macrophage site and did not recognize the Angiotensin II AT(2) receptor. 9. These results demonstrate that CGP42112, previously considered as a selective Angiotensin II AT(2) ligand, recognizes an additional non-Angiotensin II site different from AT(2) receptors. 10. Our observations indicate that CGP42112 or related molecules could be considered of interest as potential anti-inflammatory compounds. C1 NIMH, DIRP, Pharmacol Sect, NIH,DHHS, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, DIRP, Pharmacol Sect, NIH,DHHS, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Saavedrj@mail.nih.gov FU Intramural NIH HHS NR 32 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUL-AUG PY 2006 VL 26 IS 4-6 BP 509 EP 526 DI 10.1007/s10571-006-9044-x PG 18 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 118VP UT WOS:000242971900014 PM 16633892 ER PT J AU Weihe, E Depboylu, C Schutz, B Schafer, MKH Eiden, LE AF Weihe, Eberhard Depboylu, Candan Schuetz, Burkhard Schaefer, Martin K.-H. Eiden, Lee E. TI Three types of tyrosine hydroxylase-positive CNS neurons distinguished by dopa decarboxylase and VMAT2 co-expression SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE aromatic amino acid decarboxylase/dopa decarboxylase; CNS neuronal phenotypes; dopaergic; dopaminergic; tyrosine hydroxylase; vesicular monoamine transporter ID VESICULAR MONOAMINE TRANSPORTER; AMINO-ACID DECARBOXYLASE; CENTRAL-NERVOUS-SYSTEM; MESSENGER-RNAS VMAT1; DOPAMINERGIC-NEURONS; ARCUATE NUCLEUS; MEDIOBASAL HYPOTHALAMUS; IMMUNOREACTIVE NEURONS; NONDOPAMINERGIC NEURONS; FUNCTIONAL-SIGNIFICANCE AB 1. We investigate here for the first time in primate brain the combinatorial expression of the three major functionally relevant proteins for catecholaminergic neurotransmission tyrosine hydroxylase (TH), aromatic acid acid decarboxylase (AADC), and the brain-specific isoform of the vesicular monoamine transporter, VMAT2, using highly specific antibodies and immunofluorescence with confocal microscopy to visualize combinatorial expression of these proteins. 2. In addition to classical TH, AADC, and VMAT2-copositive catecholaminergic neurons, two unique kinds of TH-positive neurons were identified based on co-expression of AADC and VMAT2. 3. TH and AADC co-positive, but VMAT2-negative neurons, are termed "nonexocytotic catecholaminergic TH neurons." These were found in striatum, olfactory bulb, cerebral cortex, area postrema, nucleus tractus solitarius, and in the dorsal motor nucleus of the vagus. 4. TH-positive neurons expressing neither AADC nor VMAT2 are termed "dopaergic TH neurons." We identified these neurons in supraoptic, paraventricular and periventricular hypothalamic nuclei, thalamic paraventicular nucleus, habenula, parabrachial nucleus, cerebral cortex and spinal cord. We were unable to identify any dopaergic (TH-positive, AADC-negative) neurons that expressed VMAT2, suggesting that regulatory mechanisms exist for shutting off VMAT2 expression in neurons that fail to biosynthesize its substrates. 5. In several cases, the corresponding TH phenotypes were identified in the adult rat, suggesting that this rodent is an appropriate experimental model for further investigation of these TH-positive neuronal cell groups in the adult central nervous system. Thus, no examples of TH and VMAT2 co-positive neurons lacking AADC expression were found in rodent adult nervous system. 6. In conclusion, the adult mammalian nervous system contains in addition to classical catecholaminergic neurons, cells that can synthesize dopamine, but cannot transport and store it in synaptic vesicles, and neurons that can synthesize only L-dopa and lack VMAT2 expression. The presence of these additional populations of TH-positive neurons in the adult primate CNS has implications for functional catecholamine neurotransmission, its derangement in disease and drug abuse, and its rescue by gene therapeutic maneuvers in neurodegenerative diseases such as Parkinson's disease. C1 NIMH, Sect Mol Neurosci, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. Univ Marburg, Inst Anat & Cell Biol, Dept Mol Neurosci, D-35032 Marburg, Germany. RP Eiden, LE (reprint author), NIMH, Sect Mol Neurosci, Lab Cellular & Mol Regulat, NIH, Bldg 49,Room 5A-68,9000 Rockville Pike, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov OI Eiden, Lee/0000-0001-7524-944X FU Intramural NIH HHS [Z01 MH002386-21, Z01 MH002386-22, ZIA MH002386-23] NR 54 TC 47 Z9 47 U1 0 U2 8 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUL-AUG PY 2006 VL 26 IS 4-6 BP 659 EP 678 DI 10.1007/s10571-006-9053-9 PG 20 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 118VP UT WOS:000242971900023 PM 16741673 ER PT J AU Goldstein, DS Eisenhofer, G Kopin, IJ AF Goldstein, David S. Eisenhofer, Graeme Kopin, Irwin J. TI Clinical catecholamine neurochemistry: A legacy of Julius Axelrod SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE catecholamine; norepinephrine; epinephrine; adrenaline; metanephrine; normetanephrine; positron emission tomography; pheochromocytoma; dihydroxy phenylglycol; phenylethanolamine-N-methyltransferase; catechol-O-methyltransferase; sympathetic nervous system ID CARDIAC SYMPATHETIC DENERVATION; ENZYMATIC SYNTHESIS; PARKINSON-DISEASE; EPINEPHRINE; PLASMA; PHEOCHROMOCYTOMA; NOREPINEPHRINE; LOCALIZATION; DIAGNOSIS; HUMANS AB 1. Discoveries, insights, and concepts that Julius Axelrod introduced about the disposition and metabolism of catecholamines provided the scientific basis and spurred the development of clinical catecholamine neurochemistry. 2. Here, we provide examples of this aspect of Axelrod's scientific legacy. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov NR 27 TC 9 Z9 10 U1 0 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUL-AUG PY 2006 VL 26 IS 4-6 BP 695 EP 702 DI 10.1007/s10571-006-9041-0 PG 8 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 118VP UT WOS:000242971900025 PM 16871444 ER PT J AU Harashima, C Jacobowitz, DM Stoffel, M Chakrabarti, L Haydar, TF Siarey, RJ Galdzicki, Z AF Harashima, Chie Jacobowitz, David M. Stoffel, Markus Chakrabarti, Lina Haydar, Tarik F. Siarey, Richard J. Galdzicki, Zygmunt TI Elevated expression of the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) in cerehellar unipolar brush cells of a Down syndrome mouse model SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE unipolar brush cells; trisomy; cerebellum; Ts65Dn; dorsal cochlear nucleus; vestibulocerebellum; Girk2 knockout mouse; GIRK; Down syndrome; potassium channel; G-protein activated inwardly rectifying potassium channel ID RAT CEREBELLAR GRANULE; TS65DN MOUSE; COCHLEAR NUCLEUS; HEARING-LOSS; K+ CHANNELS; IMMUNOHISTOCHEMICAL LOCALIZATION; CALRETININ; CORTEX; GLUTAMATE; BRAIN AB 1. Down syndrome (DS) arises from the presence of three copies of chromosome (Chr.) 21. Fine motor learning deficits found in DS from childhood to adulthood result from expression of extra genes on Chr. 21, however, it remains unclear which if any of these genes are the specific causes of the cognitive and motor dysfunction. DS cerebellum displays morphological abnormalities that likely contribute to the DS motor phenotype. 2. The G-protein-activated inwardly rectifying potassium channel subunit 2 (GIRK2) is expressed in cerebellum and can shunt dendritic conductance and attenuate postsynaptic potentials. We have used an interbreeding approach to cross a genetic mouse model of DS (Ts65Dn) with Girk2 knockout mice and examined its relative expression level by quantitative real-time RT-PCR, Western blotting and immunohistochemistry. 3. We report here for the first time that GIRK2 is expressed in unipolar brush cells, which are excitatory interneurons of the vestibulocerebellum and dorsal cochlear nucleus. Analysis of disomic-Ts65Du/Girk2((+/+/-)) and lieterozygous-Diploid/Girk2((+/-)) mice shows that GIRK2 expression in Ts65Dn lobule X follows gene dosage. The lobule X of Ts65Dn mice contain greater numbers of unipolar brush cells co-expressing GIRK2 and calretinin than the control mouse groups. C1 Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Lab Metab Dis & Mol Cell Biol, New York, NY 10021 USA. Childrens Natl Med Ctr, Childrens Res Inst, Neurosci Res Ctr, Washington, DC USA. RP Jacobowitz, DM (reprint author), Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. EM djacobowitz@usuhs.mil FU Intramural NIH HHS; NICHD NIH HHS [HD38417] NR 55 TC 21 Z9 21 U1 2 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUL-AUG PY 2006 VL 26 IS 4-6 BP 719 EP 734 DI 10.1007/s10571-006-9066-4 PG 16 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 118VP UT WOS:000242971900027 PM 16783527 ER PT J AU Ren-Patterson, RF Cochran, LW Holmes, A Lesch, KP Lu, B Murphy, DL AF Ren-Patterson, Renee F. Cochran, Lauren W. Holmes, Andrew Lesch, Klaus-Peter Lu, Bai Murphy, Dennis L. TI Gender-dependent modulation of brain monoamines and anxiety-like behaviors in mice with genetic serotonin transporter and BDNF deficiencies SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Review DE neurotrophins; serotonin; knockout; gene interaction; estrogen; TrkB; dopamine ID NEUROTROPHIC FACTOR BDNF; FACTOR MESSENGER-RNA; ADULT-RAT BRAIN; FAMILY-BASED ASSOCIATION; KNOCKOUT MICE; IN-VITRO; MUTANT MICE; MOTOR-NEURONS; VAL66MET POLYMORPHISM; SOMATOSTATIN NEURONS AB 1. Brain-derived neurotrophic factor (BDNF) supports serotonergic neuronal development and our recent study found that heterozygous mice lacking one BDNF gene allele interbred with male serotonin transporter (SERT) knockout mice had greater reductions in brain tissue serotonin concentrations, greater increases in anxiety-like behaviors and greater ACTH responses to stress than found in the SERT knockout mice alone. 2. We investigated here whether there might be gender differences in these consequences of combined SERT and BDNF deficiencies by extending the original studies to female mice, and also to an examination of the effects of ovariectomy and tamoxifen in these female mice, and of 21-day 17-beta estradiol implantation to male mice. 3. We found that unlike the male SERT x BDNF-deficient mice, female SERT x BDNF mice appeared protected by their gender in having significantly lesser reductions in serotonin concentrations in hypothalamus and other brain regions than males, relative to controls. Likewise, in the elevated plus maze, female SERT x BDNF-deficient mice demonstrated no increases in the anxiety-like behaviors previously found in males. 4. Furthermore, female SERT x BDNF mice did not manifest the similar to 40% reduction in the expression of TrkB receptors or the similar to 30% reductions in dopamine and its metabolites that male SERT x BDNF did. After estradiol implantation in male SERT x BDNF mice, hypothalamic serotonin was significantly increased compared to vehicle-implanted mice. These findings support the hypothesis that estrogen may enhance BDNF function via its TrkB receptor, leading to alterations in the serotonin circuits, which modulate anxiety-like behaviors. 5. This double-mutant mouse model contributes to the knowledge base that will help in understanding gene x gene x gender interactions in studies of SERT and BDNF gene polymorphisms in human genetic diseases such as anxiety disorders and depression. C1 NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. NIAAA, Sect Behav Genom, Bethesda, MD USA. Univ Wurzburg, D-97070 Wurzburg, Germany. NICHD, Dev Neurobiol Lab, Rockville, MD USA. RP Murphy, DL (reprint author), NIMH, Clin Sci Lab, Bldg 10,Room 3D41, Bethesda, MD 20892 USA. EM Dennis.Murphy@mail.nih.gov RI Lu, Bai/A-4018-2012; Lesch, Klaus-Peter/J-4906-2013 OI Lesch, Klaus-Peter/0000-0001-8348-153X FU Intramural NIH HHS NR 122 TC 60 Z9 62 U1 2 U2 12 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUL-AUG PY 2006 VL 26 IS 4-6 BP 755 EP 780 DI 10.1007/s10571-006-9048-6 PG 26 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 118VP UT WOS:000242971900029 PM 17029036 ER PT J AU Drgon, T Lin, ZC Wang, GJ Fowler, J Pablo, J Mash, DC Volkow, N Uhl, GR AF Drgon, Tomas Lin, Zhicheng Wang, Gene-Jack Fowler, Joanna Pablo, Johnfn Mash, Deborah C. Volkow, Nora Uhl, George R. TI Common human 5 ' dopamine transporter (SLC6A3) haplotypes yield varying expression levels in vivo SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE haplotype; dopamine transporter; cocaine; Parkinson's disease; PET; postmortem brain ID DEFICIT HYPERACTIVITY DISORDER; REPORTER GENE-EXPRESSION; VARIABLE NUMBER; RADIOLIGAND BINDING; COCAINE REWARD; REGION; ASSOCIATION; DENSITY; SITES; ADHD AB 1. Individuals display significant differences in their levels of expression of the dopamine transporter (DAT; SLC6A3). These differences in DAT are strong candidates to contribute to individual differences in motor, mnemonic and reward functions. To identify "cis"-acting genetic mechanisms for these individual differences, we have sought variants in 5' aspects of the human DAT gene and identified the haplotypes that these variants define. 2. We report (i) significant relationships between 5' DAT haplotypes and human individual differences in ventral striatal DAT expression assessed it? vivo using [C-11] cocaine PET and (ii) apparent confirmation of these results in studies of DAT expression in postmortem striatum Using [H-3] carboxyflurotropane binding. 3. These observations support the idea that cis-acting variation in 5' aspects of the human DAT/SLC6A3 locus contributes to individual differences in levels of DAT expression in vivo. 5' DAT variation is thus a good candidate to contribute to individual differences in a number of human phenotypes. C1 NIDA, Mol Neurobiol Branch, IRP, DHSS, Baltimore, MD 21224 USA. Brookhaven Natl Lab, Upton, NY 11973 USA. Univ Miami, Sch Med, Dept Neurol, Miami, FL 33152 USA. NIDA, Off Director, NIH, DHSS, Rockville, MD 21224 USA. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, IRP, DHSS, Box 5180, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov FU NIDA NIH HHS [DA 06227, DA 7092-01, DA00280, DA09490-01] NR 38 TC 30 Z9 30 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUL-AUG PY 2006 VL 26 IS 4-6 BP 875 EP 889 DI 10.1007/s10571-006-9014-3 PG 15 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 118VP UT WOS:000242971900036 PM 16710758 ER PT J AU Yue, CM Mutsuga, N Verbalis, J Gainer, H AF Yue, Chunmei Mutsuga, Noriko Verbalis, Joseph Gainer, Harold TI Microarray analysis of gene expression in the supraoptic nucleus of normoosmotic and hypoosmotic rats SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE hyponatremia; hypoosmotic; vasopressin; oxytocin; microarray; laser microdissection ID MESSENGER RIBONUCLEIC-ACIDS; CHRONIC HYPOOSMOLALITY; PHOSPHOFRUCTOKINASE-C; MAGNOCELLULAR NEURONS; HYPOTHALAMONEUROHYPOPHYSEAL SYSTEM; PYRIMIDINE DEGRADATION; VASOPRESSIN; RNA; PROTEIN; BRAIN AB 1. Hypoosmolality produces a dramatic inhibition of vasopressin (VP) and oxytocin (OT) gene expression in the supraoptic nucleus (SON). This study examines the effect of sustained hypoosmolality on global gene expression in the OT and VP magnocellular neurons (MCNs) of the hypothalamo-neurohypophysial system (HNS), in order to detect novel genes in this system that might be involved in osmoregulation in the MCNs. 2. For this purpose, we used Affymetrix oligonucleotide arrays to analyze the expression of specific genes in laser microdissected rat SONS, and their changes in expression during chronic hypoosmolality. We identified over 40 genes that had three-fold or more greater expression in the SON versus total hypothalamus, and that also changed more than two fold in expression as a result of the chronic hypoosmolar treatment. These genes contained both novel as well as genes previously known to be present in the SON. All of the raw data for the genes that are expressed in the SON and altered by hypoosmolality can be found on the following NINDS website URL address: http://data.ninds.nih.gov/Gainer/Publications. C1 Natl Inst Neurol Disorder & Stroke, Mol Neurosci Sect, Lab Neurochem, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Med, Div Endocrinol & Metab, Washington, DC 20007 USA. RP Gainer, H (reprint author), Natl Inst Neurol Disorder & Stroke, Mol Neurosci Sect, Lab Neurochem, NIH, Bldg 49,Rm 5A78, Bethesda, MD 20892 USA. EM gainerh@ninds.nih.gov FU Intramural NIH HHS NR 55 TC 14 Z9 14 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUL-AUG PY 2006 VL 26 IS 4-6 BP 959 EP 978 DI 10.1007/s10571-006-9017-0 PG 20 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 118VP UT WOS:000242971900042 PM 16699879 ER PT J AU Hoffmann, KM Tapia, JA Jensen, RT AF Hoffmann, KM Tapia, JA Jensen, RT TI Activation of GaB1 in pancreatic acinar cells: Effects of gastrointestinal growth factors/hormones on stimulation, phosphospecific phosphorylation, translocation and interaction with downstream signaling molecules SO CELLULAR SIGNALLING LA English DT Article DE Gab1 pancreas; pancreatic growth factors; pancreatic secretagogues; cholecystokinin; hepatocyte growth factor; tyrosine phosphorylation ID C-DEPENDENT MECHANISM; FACTOR RECEPTOR; TYROSINE PHOSPHORYLATION; GRB2-ASSOCIATED BINDER-1; EPITHELIAL MORPHOGENESIS; DOCKING PROTEIN; EGF-RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; LYSOPHOSPHATIDIC ACID AB The scaffolding/adapter protein, Gab1, is a key signaling molecule for numerous stimuli including growth factors and G protein-coupled-receptors (GPCRs). A number of questions about Gab1 signaling remain and little is known about the ability of gastrointestinal (GI) hormones/neurotransmitters/growth factors to activate Gab1. Therefore, we examined their ability to activate Gab1 and explored the mechanisms involved using rat pancreatic acini. HGF and EGF stimulated total Gab1 tyrosine phosphorylation (TyrP) and TyrP of Gab1 phospho-specific sites (Y307, Y627), but not other pancreatic growth factors, GI GPCRs (CCK, bombesin, carbachol, VIP, secretin), or agents directly activating PKC or increasing Ca2+. HGF-stimulated Y307 Gab1 TyrP differed in kinetics from total and Y627. Neither GF109203X, nor inhibition of Ca2+ increases altered HGF's effect. In unstimulated cells > 95% of Gab1 was cytosolic and HGF stimulated a 3-fold increase in membrane Gab1. HGF stimulated equal increases in pY307 and pY627 Gab1 in cytosol/membrane. HGF stimulated Gab1 association with c-Met, Grb2, SHP2, PI3K, She, Crk isoforms and CrkL, but not with PLC gamma 1. These results demonstrate that only a subset of pancreatic growth factors (HGF/EGF) stimulates Gab1 signaling and no pancreatic hormones/neurotransmitters. Our results with Gab I activation with different growth factors, the role of PKC, and its interaction with distant signaling molecules suggest the cellular mechanisms of Gab1 signaling show important differences in different cells. These results show that Gab1 activation plays a central role in HGF's ability to stimulate intracellular transduction cascades in pancreatic acinar cells and this action likely plays a key role in HGF's ability to alter pancreatic cell function (i.e., growth/regeneration). (c) 2005 Elsevier Inc. All rights reserved. C1 NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Extremadura, Dept Fisiol, Caceres 10071, Spain. RP Jensen, RT (reprint author), NIDDKD, Digest Dis Branch, NIH, Bldg 10,Room 9C-103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov RI Tapia, Jose/C-5181-2008 OI Tapia, Jose/0000-0002-3614-6867 NR 50 TC 7 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD JUL PY 2006 VL 18 IS 7 BP 942 EP 954 DI 10.1016/j.cellsig.2005.08.013 PG 13 WC Cell Biology SC Cell Biology GA 032EN UT WOS:000236756800003 PM 16185843 ER PT J AU Riley, AM Trusselle, M Kuad, P Borkovec, M Cho, J Choi, JH Qian, X Shears, SB Spiess, B Potter, BVL AF Riley, Andrew M. Trusselle, Melanie Kuad, Paul Borkovec, Michal Cho, Jaiesoon Choi, Jae H. Qian, Xun Shears, Stephen B. Spiess, Bernard Potter, Barry V. L. TI scyllo-inositol pentakisphosphate as an analogue of myo-inositol 1,3,4,5,6-pentakisphosphate: Chemical synthesis, physicochemistry and biological applications SO CHEMBIOCHEM LA English DT Article DE cyclitols; enzymes; inositol phosphates; protecting groups; structure-activity relationships ID D-MYO-INOSITOL; INFRAMOLECULAR PROTONATION PROCESS; PROTEIN-TYROSINE PHOSPHATASES; 3-PHOSPHATASE ACTIVITY; POSSIBLE REGIOISOMERS; HEXAKISPHOSPHATE; PTEN; INHIBITORS; 1,3,4,5-TETRAKISPHOSPHATE; INS(1,3,4,5,6)P-5 AB myo-Inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P-5), an inositol polyphosphate of emerging significance in cellular signalling, and its C-2 epimer scyllo-inositol pentakisphosphate (scyllo-InsP(5)) were synthesised from the same myo-inositol-based precursor. Potentiometric and NMR titrations show that both pentakisphosphates undergo a conformational ring-flip at higher pH, beginning at pH 8 for scyllo-InsP(5) and pH 9 for Ins(1,3,4,5,6)P-5. Over the physiological pH range, however, the conformation of the inositol rings and the microprotonation patterns of the phosphate groups in Ins(1,3,4,5,6)P-5 and scyllo-InsP(5) are similar. Thus scyllo-InsP(5) should be a useful tool for identifying biologically relevant actions of Ins(1,3,4,5,6)P-5, mediated by specific binding sites, and distinguishing them from nonspecific electrostatic effects. We also demonstrate that, although scyllo-InsP(5) and Ins(1,3,4,5,6)P-5 are both hydrolysed by multiple inositol polyphosphate phosphatase (MINPP), scyllo-InsP(5) is not dephosphorylated by PTEN or phosphorylated by Ins(1,3,4,5,6)P-5 2-kinases. This finding both reinforces the value of scyllo-InsP(5) as a biological control and shows that the axial 2-OH group of Ins(1,3,4,5,6)P-5 plays a part in substrate recognition by PTEN and the Ins(1,3,4,5,6)P-5 2-kinases. C1 Univ Bath, Dept Pharm & Pharmacol, Wolfson Lab Med Chem, Bath BA2 7AY, Avon, England. ULP, Dept Pharmacochim Commun Cellulaire, UMR 7175, LC1,CNRS,Fac Pharm, F-67401 Illkirch Graffenstaden, France. Univ Geneva, Dept Inorgan Analyt & Appl Chem, CH-1211 Geneva, Switzerland. Lab Signal Transduct, Inositide Signaling Grp, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Potter, BVL (reprint author), Univ Bath, Dept Pharm & Pharmacol, Wolfson Lab Med Chem, Claverton Down, Bath BA2 7AY, Avon, England. EM B.V.L.Potter@bath.oc.uk RI Potter, Barry/A-1845-2012; Borkovec, Michal/C-6022-2014; Riley, Andrew/F-3526-2013 OI Borkovec, Michal/0000-0002-1114-4865; FU Intramural NIH HHS [Z01 ES080046-19]; Wellcome Trust [060554] NR 47 TC 12 Z9 12 U1 0 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD JUL PY 2006 VL 7 IS 7 BP 1114 EP 1122 DI 10.1002/cbic.200600037 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 061NP UT WOS:000238879600018 PM 16755629 ER PT J AU Hershkowitz, I Orbach, Y Lamb, ME Sternberg, KJ Horowitz, D AF Hershkowitz, Irit Orbach, Yael Lamb, Michael E. Sternberg, Kathleen J. Horowitz, Dvora TI Dynamics of forensic interviews with suspected abuse victims who do not disclose abuse SO CHILD ABUSE & NEGLECT LA English DT Article DE child abuse; forensic interviews; disclosure; non-disclosure; reluctance; supportiveness ID CHILD SEXUAL-ABUSE; INVESTIGATIVE INTERVIEWS; RESPONSES; ALLEGATIONS; MEMORIES; QUESTION; ISRAEL; TELL; US AB Objectives: The present study was designed to explore structural differences between forensic interviews in which children made allegations and those in which children did not make allegations. Methodology: Fifty forensic interviews of 4- to 13-year-old suspected victims of abuse who did not disclose abuse during the interview were compared with the same number of forensic interviews of alleged victims who made allegations of sexual or physical abuse. Only cases in which there was substantial reason to believe that abuse had taken place were included in the study. Audiotapes of the interviews were examined with a focus on interviewer utterances and children's responses during the pre-substantive rapport-building, episodic memory training, and I getting the allegation' phases of the interviews, which all employed the NICHD Investigative Interview Guide. Findings: Forensic interviews which yielded allegations of child abuse were characterized by quite different dynamics than interviews with children who did not make allegations. When interviewing non-disclosers, interviewers made less frequent use of free recall prompts and offered fewer supportive comments than when interviewing children who made allegations of abuse. Children who did not disclose abuse were somewhat uncooperative, offered fewer details, and gave more uninformative responses, even at the very beginning of the interview, before the interviewers focused on substantive issues and before the interviewers themselves began to behave differently. Conclusions: A premature focus on substantive issues may prevent children who are not responsive in the episodic memory training phase from disclosing abuse. Identifying reluctant disclosers and making more extensive efforts to build rapport before substantive issues are broached, or interviewing such children in more than one session, may help suspected victims disclose their experiences. Published by Elsevier Ltd. C1 Univ Cambridge, Fac Social & Polit Sci, Cambridge CB2 3RQ, England. Univ Haifa, IL-31999 Haifa, Israel. Natl Inst Child Hlth & Human Dev, Bethesda, MD USA. Israeli Minist Labour & Social Affairs, Jerusalem, Israel. RP Lamb, ME (reprint author), Univ Cambridge, Fac Social & Polit Sci, Free Sch Lane, Cambridge CB2 3RQ, England. NR 41 TC 52 Z9 54 U1 3 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2134 J9 CHILD ABUSE NEGLECT JI Child Abuse Negl. PD JUL PY 2006 VL 30 IS 7 BP 753 EP 769 DI 10.1016/j.chiabu.2005.10.016 PG 17 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA 070SO UT WOS:000239544400003 PM 16846642 ER PT J AU Bornstein, MH Putnick, DL Suwalsky, JTD Gini, M AF Bornstein, Marc H. Putnick, Diane L. Suwalsky, Joan T. D. Gini, Motti TI Maternal chronological age, prenatal and perinatal history, social support, and parenting of infants SO CHILD DEVELOPMENT LA English DT Review ID ADULT SINGLE MOTHERS; ADOLESCENT MOTHERS; UNITED-STATES; PERSONALITY-INVENTORY; DELAYED CHILDBEARING; PRESCHOOL-CHILDREN; PREGNANT TEENAGERS; OLDER MOTHERS; BIRTH; LIFE AB The role of maternal chronological age in prenatal and perinatal history, social support, and parenting practices of new mothers (N=335) was examined. Primiparas of 5-month-old infants ranged in age from 13 to 42 years. Age effects were zero, linear, and nonlinear. Nonlinear age effects were significantly associated up to a certain age with little or no association afterward; by spline regression, estimated points at which the slope of the regression line changed were 25 years for prenatal and perinatal history, 31 years for social supports, and 27 years for parenting practices. Given the expanding age range of first-time parents, these findings underscore the importance of incorporating maternal age as a factor in studies of parenting and child development. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), NICHHD, NIH, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov RI Putnick, Diane/B-1707-2009 FU Intramural NIH HHS NR 152 TC 43 Z9 45 U1 0 U2 10 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-3920 J9 CHILD DEV JI Child Dev. PD JUL-AUG PY 2006 VL 77 IS 4 BP 875 EP 892 DI 10.1111/j.1467-8624.2006.00908.x PG 18 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 066UU UT WOS:000239256400005 PM 16942495 ER PT J AU Wakschlag, LS Leventhal, BL Pine, DS Pickett, KE Carter, AS AF Wakschlag, Lauren S. Leventhal, Bennett L. Pine, Daniel S. Pickett, Kate E. Carter, Alice S. TI Elucidating early mechanisms of developmental psychopathology: The case of prenatal smoking and disruptive behavior SO CHILD DEVELOPMENT LA English DT Article ID MOTHER-CHILD-RELATIONSHIP; MATERNAL SMOKING; EXTERNALIZING BEHAVIOR; CONDUCT PROBLEMS; 2-YEAR-OLD CHILDREN; ANTISOCIAL-BEHAVIOR; TOBACCO EXPOSURE; PREGNANCY; DISORDER; TODDLERS AB There is a robust association between prenatal smoking and disruptive behavior disorders, but little is known about the emergence of such behaviors in early development. The association of prenatal smoking and hypothesized behavioral precursors to disruptive behavior in toddlers (N=93) was tested. Exposed toddlers demonstrated atypical behavioral patterns, including (1) escalating externalizing problems from 18 to 24 months and (2) observed difficulty modulating behavior in response to social cues. Specification of exposure-related behaviors is a first step toward generating testable hypotheses about putative mechanisms of effect. While it remains unclear whether prenatal exposure plays an etiologic role in the emergence of disruptive behavior, atypical exposure-related behavioral patterns are evident in the first years of life and demonstrate developmental coherence. C1 Univ Illinois, Inst Juvenile Res, Dept Psychiat, Chicago, IL 60608 USA. NIMH, Bethesda, MD 20892 USA. Univ York, York YO10 5DD, N Yorkshire, England. Univ Massachusetts, Boston, MA 02125 USA. RP Wakschlag, LS (reprint author), Univ Illinois, Inst Juvenile Res, Dept Psychiat, 1747 W Roosevelt Rd,MC 747,Room 155, Chicago, IL 60608 USA. EM lwakschlag@psych.uic.edu FU NIDA NIH HHS [K08 DA00330, R01 DA15223] NR 82 TC 50 Z9 50 U1 5 U2 9 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-3920 J9 CHILD DEV JI Child Dev. PD JUL-AUG PY 2006 VL 77 IS 4 BP 893 EP 906 DI 10.1111/j.1467-8624.2006.00909.x PG 14 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 066UU UT WOS:000239256400006 PM 16942496 ER PT J AU Morante, MP Briones, J Canto, E Sabzevari, H Martino, R Sierra, J Rodriguez-Sanchez, JL Vidal, S AF Morante, MP Briones, J Canto, E Sabzevari, H Martino, R Sierra, J Rodriguez-Sanchez, JL Vidal, S TI Activation-associated phenotype of CD3(+) T cells in acute graft-versus-host disease SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE activation; CD4(+) lymphocytes; CD8+lymphocytes; GvHD; phenotype ID BONE-MARROW-TRANSPLANTATION; LYMPHOCYTE-ACTIVATION; IMMUNE RECONSTITUTION; ACUTE GVHD; EXPRESSION; CD4(+); DEPLETION; ANTIBODY; LIGAND; BLOOD AB During the effector phase of graft-versus-host disease (GvHD) response, donor T cells play an essential role and they are believed to change the expression of activation and co-stimulatory markers associated with functional alloreactivity. We analysed the expression of CD25, CD69, HLA-DR, CD154 and CD134 on CD4(+) and CD8(+) T cells by flow cytometry during acute GvHD (aGvHD) in 24 patients receiving human leucocyte antigen (HLA)-identical stem cell transplants. Expression of these molecules in nine patients with stages I-IV aGvHD was compared with 15 patients without aGvHD (n = 15). Serial analysis showed that peripheral blood of aGvHD patients presented a significant increase of CD4(+) CD25(+) cells (P < 0.03), CD4+ CD69(+) (P < 0.04) and CD4(+) CD134(+) cells (P < 0.01). Additionally, there was a significant increase in CD8(+) cells expressing CD134 (P = 0.007) and CD154 (P = 0.02). After resolution of aGvHD, the increased expression of these molecules returned to values comparable to patients without aGvHD. Only two of the 15 patients without clinical signs of aGvHD presented activated T cells that could not be attributed to development of aGvHD. In summary, our data show that multiple activation molecules are preferentially up-regulated on CD4(+) and CD8(+) T cells from patients with aGvHD. These patients had a significant increase in the expression of the co-stimulatory molecules CD134 and CD154. C1 Hosp Sant Pau, Inst Rec, Dept Immunol, Barcelona 08025, Spain. Hosp Sant Pau, Dept Clin Haematol, Barcelona 08025, Spain. Hosp Sant Pau, Tumor Immunol & Biol Lab, Barcelona 08025, Spain. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Vidal, S (reprint author), Hosp Sant Pau, Inst Rec, Dept Immunol, Pare Claret 167, Barcelona 08025, Spain. EM svidal@santpau.es RI Lopez, Dulce/A-7700-2013 NR 33 TC 7 Z9 7 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD JUL PY 2006 VL 145 IS 1 BP 36 EP 43 DI 10.1111/j.1365-2249.2006.03104.x PG 8 WC Immunology SC Immunology GA 053LT UT WOS:000238307300006 ER PT J AU Finzi, D Plaeger, SF Dieffenbach, CW AF Finzi, Diana Plaeger, Susan F. Dieffenbach, Carl W. TI Defective virus drives human immunodeficiency virus infection, persistence, and pathogenesis SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Review ID CD4(+) T-CELLS; FOLLICULAR DENDRITIC CELLS; ACUTE SIV INFECTION; HIV-1 INFECTION; IN-VIVO; TYPE-1 INFECTION; REVERSE-TRANSCRIPTASE; NEUTRALIZING ANTIBODIES; HIV-1-INFECTED SUBJECTS; LYMPHOCYTE-RESPONSES C1 NIAID, Basic Sci Program, Div AIDS, Bethesda, MD 20892 USA. RP Dieffenbach, CW (reprint author), NIAID, Basic Sci Program, Div AIDS, Bethesda, MD 20892 USA. EM cdieffenba@mail.nih.gov NR 94 TC 14 Z9 14 U1 0 U2 0 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 JUL PY 2006 VL 13 IS 7 BP 715 EP 721 DI 10.1128/CVI.00052-06 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 069BT UT WOS:000239420400001 PM 16829607 ER PT J AU Bates, SE Rosing, DR Fojo, T Piekarz, RL AF Bates, Susan E. Rosing, Douglas R. Fojo, Tito Piekarz, Richard L. TI Challenges of evaluating the cardiac effects of anticancer agents SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID MODERATELY EMETOGENIC CHEMOTHERAPY; SUBEROYLANILIDE HYDROXAMIC ACID; HISTONE DEACETYLASE INHIBITOR; T-CELL LYMPHOMA; PHASE-II TRIAL; INDUCED NAUSEA; SUDDEN-DEATH; QT INTERVAL; DRUGS; PALONOSETRON C1 NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Med Oncol Branch, Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov NR 27 TC 28 Z9 28 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 1 PY 2006 VL 12 IS 13 BP 3871 EP 3874 DI 10.1158/1078-0432.CCR-06-1017 PG 4 WC Oncology SC Oncology GA 062FR UT WOS:000238930500001 PM 16818679 ER EF