FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Joedicke, JJ Gibbert, K Myers, L Hasenkrug, K Dittmer, U AF Joedicke, J. J. Gibbert, K. Myers, L. Hasenkrug, K. Dittmer, U. TI Characterisation of regulatory T cells in Friend retrovirus infection SO IMMUNOLOGY LA English DT Meeting Abstract CT 1st Biennial Symposium on Regulatory T Cells and T Helper Cells CY MAR 30, 2012 CL Royal Vet Coll (RVC), London, ENGLAND HO Royal Vet Coll (RVC) C1 [Joedicke, J. J.; Gibbert, K.; Dittmer, U.] Univ Duisburg Essen, Inst Virol, Univ Hosp Essen, Essen, Germany. [Myers, L.; Hasenkrug, K.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD JUN PY 2012 VL 136 SU 1 SI SI MA 18 BP 8 EP 8 PG 1 WC Immunology SC Immunology GA 952VB UT WOS:000304820100019 ER PT J AU Rondon, C Campo, P Togias, A Fokkens, WJ Durham, SR Powe, DG Mullol, J Blanca, M AF Rondon, Carmen Campo, Paloma Togias, Alkis Fokkens, Wytske J. Durham, Stephen R. Powe, Desmond G. Mullol, Joaquim Blanca, Miguel TI Local allergic rhinitis: Concept, pathophysiology, and management SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Allergic rhinitis; eosinophil cationic protein; entopy; local allergic rhinitis; local specific IgE; nasal polyps; nonallergic rhinitis; nasal allergen provocation test; tryptase ID PERSISTENT NONALLERGIC RHINITIS; IDIOPATHIC RHINITIS; PROVOCATION TEST; NASAL POLYPOSIS; IGE ANTIBODIES; MESSENGER-RNA; MAST-CELLS; ABSENCE; ASTHMA; ATOPY AB Local allergic rhinitis (LAR) is a localized nasal allergic response in the absence of systemic atopy characterized by local production of specific IgE (sIgE) antibodies, a T(H)2 pattern of mucosal cell infiltration during natural exposure to aeroallergens, and a positive nasal allergen provocation test response with release of inflammatory mediators (tryptase and eosinophil cationic protein). Although the prevalence remains to be established, a number of patients previously given a diagnosis of nonallergic rhinitis or idiopathic rhinitis are now being classified as having LAR. Culprit allergens responsible include house dust mite, grass and olive pollens, and many others. For the diagnosis of LAR, neither skin prick testing nor determination of the presence of serum sIgE antibodies is useful, and a nasal allergen provocation test is needed to identify the culprit allergen or allergens. In a certain proportion of cases, local sIgE can be detected, and conjunctivitis, asthma, or both can be associated. Whether patients with LAR will have systemic atopy in the future is a matter of debate. Further studies are needed for examine the prevalence of this phenomenon in different areas, to improve the diagnostic methods to better identify these patients, and to develop therapeutic approaches, including the use of immunotherapy. (J Allergy Clin Immunol 2012;129:1460-7.) C1 [Rondon, Carmen; Campo, Paloma; Blanca, Miguel] Carlos Haya Hosp, Allergy Serv, Malaga, Spain. [Togias, Alkis] NIAID, Asthma Allergy & Inflammat Branch, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Fokkens, Wytske J.] Univ Amsterdam, Acad Med Ctr, Dept Otorhinolaryngol, NL-1105 AZ Amsterdam, Netherlands. [Durham, Stephen R.] Imperial Coll Sch Med, Natl Heart & Lung Inst, London, England. [Powe, Desmond G.] Nottingham Trent Univ, John Van Geest Canc Res Ctr, Nottingham, England. [Powe, Desmond G.] Nottingham Trent Univ, Nottingham Univ Hosp NHS Trust, Queens Med Ctr, Dept Cellular Pathol, Nottingham, England. [Mullol, Joaquim] CIBERES, Hosp Clin IDIBAPS, ENT Dept, Rhinol Unit, Barcelona, Spain. [Mullol, Joaquim] CIBERES, Hosp Clin IDIBAPS, ENT Dept, Smell Clin, Barcelona, Spain. RP Rondon, C (reprint author), Hosp Civil, Lab Invest, Pabellon 5,Plaza Hosp Civil, Malaga 29009, Spain. EM carmenrs61@gmail.com FU GlaxoSmithKline; Medtronic FX W. J. Fokkens has received research support from GlaxoSmithKline and Medtronic and has served as an advisor to GlaxoSmith Kline, MSD, and Stallergenes. The rest of the authors declare that they have no relevant conflicts of interest. NR 27 TC 81 Z9 84 U1 1 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2012 VL 129 IS 6 BP 1460 EP 1467 DI 10.1016/j.jaci.2012.02.032 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 952BL UT WOS:000304764600004 PM 22516477 ER PT J AU Hancock, DB Romieu, I Chiu, GY Sienra-Monge, JJ Li, HL del Rio-Navarro, BE London, SJ AF Hancock, Dana B. Romieu, Isabelle Chiu, Grace Y. Sienra-Monge, Juan-Jose Li, Huiling Estela del Rio-Navarro, Blanca London, Stephanie J. TI STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID SEVERITY C1 [Hancock, Dana B.; London, Stephanie J.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Div Intramural Res, Res Triangle Pk, NC USA. [Li, Huiling; London, Stephanie J.] Natl Inst Environm Hlth Sci, Lab Resp Biol, Div Intramural Res, Res Triangle Pk, NC USA. [Hancock, Dana B.] Res Triangle Inst Int, Behav Hlth Epidemiol Program, Res Triangle Pk, NC USA. [Romieu, Isabelle] Int Agcy Res Canc, F-69372 Lyon, France. [Chiu, Grace Y.] Westat Corp, Res Triangle Pk, NC USA. [Sienra-Monge, Juan-Jose; Estela del Rio-Navarro, Blanca] Hosp Infantil Mexico Dr Federico Gomez, Mexico City, DF, Mexico. RP Hancock, DB (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, Div Intramural Res, Res Triangle Pk, NC USA. EM london2@niehs.nih.gov OI Hancock, Dana/0000-0003-2240-3604; London, Stephanie/0000-0003-4911-5290 FU Intramural NIH HHS [ZIA ES049019-16]; NIEHS NIH HHS [Z01 ES049019] NR 11 TC 5 Z9 5 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2012 VL 129 IS 6 BP 1673 EP 1676 DI 10.1016/j.jaci.2012.03.012 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA 952BL UT WOS:000304764600032 PM 22534531 ER PT J AU Palayoor, ST J-Aryankalayil, M Makinde, AY Cerna, D Falduto, MT Magnuson, SR Coleman, CN AF Palayoor, Sanjeewani T. J-Aryankalayil, Molykutty Makinde, Adeola Y. Cerna, David Falduto, Michael T. Magnuson, Scott R. Coleman, C. Norman TI Gene Expression Profile of Coronary Artery Cells Treated With Nonsteroidal Anti-inflammatory Drugs Reveals Off-target Effects SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY LA English DT Article DE NSAIDs; HCAEC; CASMC; microarray; cardiovascular genes ID HUMAN PANCREATIC-CANCER; SELECTIVE COX-2 INHIBITORS; VIOXX INDUCES EXPRESSION; SLOWS TUMOR-GROWTH; CYCLE ARREST GENES; GASTROINTESTINAL TOXICITY; CYCLO-OXYGENASE-2 INHIBITORS; MYOCARDIAL-INFARCTION; RHEUMATOID-ARTHRITIS; ACTIVATED RECEPTORS AB Nonsteroidal anti-inflammatory drugs (NSAIDs) have come under scrutiny because of the gastrointestinal, renal, and cardiovascular toxicity associated with prolonged use of these drugs. The purpose of this study was to identify molecular targets for NSAIDs related to cellular toxicity with a view to optimize drug efficacy in the clinic. Coronary artery smooth muscle cells and endothelial cells were treated with low (clinically achievable) and high (typically used in preclinical studies) concentrations of celecoxib, NS398, and ibuprofen for 24 hours. NSAIDs-induced gene expression changes were evaluated by microarray analysis and validated by real-time reverse-transcription polymerase chain reaction and western blotting. The functional significance of differentially expressed genes was evaluated by Ingenuity Pathway Analysis. At high concentrations, NSAIDs altered the expression of genes regulating cell proliferation and cell death. NSAIDs also altered genes associated with cardiovascular functions including inflammation, thrombosis, fibrinolysis, coronary artery disease, and hypertension. The gene expression was most impacted by ibuprofen, celecoxib, and NS398, in that order. This study revealed that NSAIDs altered expression of an array of genes associated with cardiovascular events and emphasizes the potential for fingerprinting drugs in preclinical studies to assess the potential drug toxicity and to optimize the drug efficacy in clinical settings. C1 [Palayoor, Sanjeewani T.; J-Aryankalayil, Molykutty; Makinde, Adeola Y.; Cerna, David; Coleman, C. Norman] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Falduto, Michael T.; Magnuson, Scott R.] GenUs Biosyst Inc, Northbrook, IL USA. RP Palayoor, ST (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room B3B406, Bethesda, MD 20892 USA. EM palayoor@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Supported by the Intramural Research Program of National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 44 TC 7 Z9 7 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0160-2446 J9 J CARDIOVASC PHARM JI J. Cardiovasc. Pharmacol. PD JUN PY 2012 VL 59 IS 6 BP 487 EP 499 DI 10.1097/FJC.0b013e31824ba6b5 PG 13 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 956IF UT WOS:000305082600001 PM 22668799 ER PT J AU Veronese, M Schmidt, KC Smith, CB Bertoldo, A AF Veronese, Mattia Schmidt, Kathleen C. Smith, Carolyn Beebe Bertoldo, Alessandra TI Use of spectral analysis with iterative filter for voxelwise determination of regional rates of cerebral protein synthesis with L-[1-C-11]leucine PET SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE [C-11]leucine; cerebral protein synthesis; parametric imaging; positron emission tomography; spectral analysis ID POSITRON-EMISSION-TOMOGRAPHY; TISSUE AMINO-ACIDS; DYNAMIC PET; BRAIN; (CO2)-C-11; VALIDATION; RESOLUTION; MODEL; PH AB A spectral analysis approach was used to estimate kinetic parameters of the L-[1-C-11]leucine positron emission tomography (PET) method and regional rates of cerebral protein synthesis (rCPS) on a voxel-by-voxel basis. Spectral analysis applies to both heterogeneous and homogeneous tissues; it does not require prior assumptions concerning number of tissue compartments. Parameters estimated with spectral analysis can be strongly affected by noise, but numerical filters improve estimation performance. Spectral analysis with iterative filter (SAIF) was originally developed to improve estimation of leucine kinetic parameters and rCPS in region-of-interest (ROI) data analyses. In the present study, we optimized SAIF for application at the voxel level. In measured L-[1-C-11]leucine PET data, voxel-level SAIF parameter estimates averaged over all voxels within a ROI (mean voxel-SAIF) generally agreed well with corresponding estimates derived by applying the originally developed SAIF to ROI time-activity curves (ROI-SAIF). Region-of-interest-SAIF and mean voxel-SAIF estimates of rCPS were highly correlated. Simulations showed that mean voxel-SAIF rCPS estimates were less biased and less variable than ROI-SAIF estimates in the whole brain and cortex; biases were similar in white matter. We conclude that estimation of rCPS with SAIF is improved when the method is applied at voxel level than in ROI analysis. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 1073-1085; doi:10.1038/jcbfm.2012.27; published online 7 March 2012 C1 [Veronese, Mattia; Bertoldo, Alessandra] Univ Padua, DEI, I-35131 Padua, Italy. [Schmidt, Kathleen C.; Smith, Carolyn Beebe] NIMH, Sect Neuroadaptat & Prot Metab, Bethesda, MD 20892 USA. RP Bertoldo, A (reprint author), Univ Padua, DEI, Via G Gradenigo 6-B, I-35131 Padua, Italy. EM bertoldo@dei.unipd.it RI Veronese, Mattia/A-6012-2013; OI Veronese, Mattia/0000-0003-3562-0683; Bertoldo, Alessandra/0000-0002-6262-6354 FU National Institute of Mental Health FX This research was supported in part by the Intramural Research Program, National Institute of Mental Health. Portions of this work were presented in preliminary form at The Eighth International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM2010) (Veronese et al, 2010b). NR 23 TC 6 Z9 6 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2012 VL 32 IS 6 BP 1073 EP 1085 DI 10.1038/jcbfm.2012.27 PG 13 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 951RS UT WOS:000304738300016 PM 22395209 ER PT J AU Welch, WP Yang, WY Taylor-Zapata, P Flynn, JT AF Welch, W. Pete Yang, Wenya Taylor-Zapata, Perdita Flynn, Joseph T. TI Antihypertensive Drug Use By Children: Are the Drugs Labeled and Indicated? SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Article ID HIGH BLOOD-PRESSURE; ADOLESCENTS; EFFICACY; SAFETY AB J Clin Hypertens (Greenwich). 2012; 14:388395. (C) 2012 Wiley Periodicals, Inc. As a result of the Food and Drug Administration (FDA) Modernization Act and the Best Pharmaceuticals for Children Act, the number of medications with FDA-approved pediatric labeling has increased. To assess the success of these initiatives, we examined whether antihypertensive drugs used by children with hypertension in 2008 had FDA-approved pediatric labeling and indications. Using a nationwide commercial insurer database, 2915 children with primary (n=2607) and secondary (n=308) hypertension were identified. Drug user rate and days of supply were calculated from pharmacy claims. Drugs were categorized based on pediatric labeling and indication and whether they were recommended for pediatric use. Antihypertensive drugs were used by 889 (34%) children with primary hypertension and 200 children (65%) with secondary hypertension. User rates were 44.3% in hypertensive children younger than 6 years, 30.9% in those 6 years to older than 12 years, and 38.1% in those 12 years to older than 18 years. Seven percent of drugs were neither labeled for pediatric use nor considered recommended for use in children. In children younger than 6 years, 29% of drugs used were not indicated for use in that age group. Despite recent legislative initiatives, many drugs used by hypertensive children still lack pediatric labeling. Additional efforts are needed to close the gap between the availability of drugs that are labeled and indicated for pediatric use and actual drug usage in children. C1 [Flynn, Joseph T.] Seattle Childrens Hosp, Div Nephrol, Seattle, WA 98105 USA. [Welch, W. Pete] Lewin Grp, Falls Church, VA USA. [Yang, Wenya; Taylor-Zapata, Perdita] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Flynn, JT (reprint author), Seattle Childrens Hosp, Div Nephrol, Seattle, WA 98105 USA. EM joseph.flynn@seattlechildrens.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX This study was performed by the Lewin Group, Inc, with funding by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). NR 15 TC 15 Z9 17 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1524-6175 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD JUN PY 2012 VL 14 IS 6 BP 388 EP 395 DI 10.1111/j.1751-7176.2012.00656.x PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 952OY UT WOS:000304803000008 PM 22672093 ER PT J AU Motegi, S Ishikawa, O Udey, M AF Motegi, Seiichiro Ishikawa, Osamu Udey, Mark TI Expression of MFG-E8 in murine and human skin SO JOURNAL OF DERMATOLOGY LA English DT Meeting Abstract C1 [Motegi, Seiichiro; Udey, Mark] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Motegi, Seiichiro; Ishikawa, Osamu] Gunma Univ, Dept Dermatol, Grad Sch Med, Maebashi, Gumma 371, Japan. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0385-2407 J9 J DERMATOL JI J. Dermatol. PD JUN PY 2012 VL 39 SU 1 SI SI BP 39 EP 39 PG 1 WC Dermatology SC Dermatology GA 956AL UT WOS:000305061900086 ER PT J AU Jager, J Bornstein, MH Putnick, DL Hendricks, C AF Jager, Justin Bornstein, Marc H. Putnick, Diane L. Hendricks, Charlene TI Family Members' Unique Perspectives of the Family: Examining Their Scope, Size, and Relations to Individual Adjustment SO JOURNAL OF FAMILY PSYCHOLOGY LA English DT Article DE multiple perspectives; unique perspectives; family system; adolescence; multitrait-multimethod ID MULTITRAIT-MULTIMETHOD MATRIX; CONFIRMATORY FACTOR-ANALYSES; ASSESSMENT DEVICE; MULTIPLE PERSPECTIVES; REARING BEHAVIORS; LATENT-VARIABLES; SAMPLE-SIZE; CHILD; MODELS; PARENT AB Using the McMaster Family Assessment Device (Epstein, Baldwin, & Bishop, 1983) and incorporating the perspectives of adolescent, mother, and father, this study examined each family member's "unique perspective" or nonshared, idiosyncratic view of the family. We used a modified multitrait-multimethod confirmatory factor analysis that (a) isolated for each family member's 6 reports of family dysfunction the nonshared variance (a combination of variance idiosyncratic to the individual and measurement error) from variance shared by 1 or more family members and (b) extracted common variance across each family member's set of nonshared variances. The sample included 128 families from a U.S. East Coast metropolitan area. Each family member's unique perspective generalized across his or her different reports of family dysfunction and accounted for a sizable proportion of his or her own variance in reports of family dysfunction. In addition, after holding level of dysfunction constant across families and controlling for a family's shared variance (agreement regarding family dysfunction), each family member's unique perspective was associated with his or her own adjustment. Future applications and competing alternatives for what these "unique perspectives" reflect about the family are discussed. RP Jager, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth, Child & Family Res Sect, 6705 Rockledge Dr, Bethesda, MD 20892 USA. EM jagerjo@mail.nih.gov OI Putnick, Diane/0000-0002-6323-749X FU Intramural NIH HHS [ZIA HD001119-24, Z99 HD999999] NR 57 TC 9 Z9 9 U1 17 U2 25 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0893-3200 J9 J FAM PSYCHOL JI J. Fam. Psychol. PD JUN PY 2012 VL 26 IS 3 BP 400 EP 410 DI 10.1037/a0028330 PG 11 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA 952ID UT WOS:000304785300012 PM 22545933 ER PT J AU Zinocker, S Sviland, L Dressel, R Rolstad, B AF Zinoecker, Severin Sviland, Lisbet Dressel, Ralf Rolstad, Bent TI Kinetics of lymphocyte reconstitution after allogeneic bone marrow transplantation: markers of graft-versus-host disease (vol 90, pg 177, 2011) SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Correction C1 [Zinoecker, Severin] NIAID, Immunogenet Lab, Rockville, MD 20852 USA. RP Zinocker, S (reprint author), NIAID, Immunogenet Lab, Twinbrook 2,12441 Parklawn Dr, Rockville, MD 20852 USA. EM zinockers@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUN PY 2012 VL 91 IS 6 BP 1003 EP 1003 DI 10.1189/jlb.0211067.add PG 1 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 952DL UT WOS:000304770200017 ER PT J AU Mizuhiki, T Richmond, BJ Shidara, M AF Mizuhiki, Takashi Richmond, Barry J. Shidara, Munetaka TI Encoding of reward expectation by monkey anterior insular neurons SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE reward expectation; reward seeking; single neuron ID DECISION-MAKING; NEURAL ACTIVITY; RISK-TAKING; CORTEX; STRIATUM; SIGNALS; BRAIN; ADDICTION; SCHEDULES; RESPONSES AB Mizuhiki T, Richmond BJ, Shidara M. Encoding of reward expectation by monkey anterior insular neurons. J Neurophysiol 107: 2996-3007, 2012. First published March 7, 2012; doi:10.1152/jn.00282.2011.-The insula, a cortical brain region that is known to encode information about autonomic, visceral, and olfactory functions, has recently been shown to encode information during reward-seeking tasks in both single neuronal recording and functional magnetic resonance imaging studies. To examine the reward-related activation, we recorded from 170 single neurons in anterior insula of 2 monkeys during a multitrial reward schedule task, where the monkeys had to complete a schedule of 1, 2, 3, or 4 trials to earn a reward. In one block of trials a visual cue indicated whether a reward would or would not be delivered in the current trial after the monkey successfully detected that a red spot turned green, and in other blocks the visual cue was random with respect to reward delivery. Over one-quarter of 131 responsive neurons were activated when the current trial would (certain or uncertain) be rewarded if performed correctly. These same neurons failed to respond in trials that were certain, as indicated by the cue, to be unrewarded. Another group of neurons responded when the reward was delivered, similar to results reported previously. The dynamics of population activity in anterior insula also showed strong signals related to knowing when a reward is coming. The most parsimonious explanation is that this activity codes for a type of expected outcome, where the expectation encompasses both certain and uncertain rewards. C1 [Mizuhiki, Takashi; Shidara, Munetaka] Univ Tsukuba, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058577, Japan. [Mizuhiki, Takashi; Shidara, Munetaka] Natl Inst Adv Ind Sci & Technol, Neurosci Res Inst, Tsukuba, Ibaraki, Japan. [Richmond, Barry J.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Shidara, M (reprint author), Univ Tsukuba, Grad Sch Comprehens Human Sci, 1-1-1 Tennoudai, Tsukuba, Ibaraki 3058577, Japan. EM mshidara@md.tsukuba.ac.jp FU Ministry of Education, Culture, Sports, Science, and Technology of Japan [17022052]; Japan Society for the Promotion of Science (JSPS) [23700701]; 21st Century Center of Excellence/JSPS; National Institute of Advanced Industrial Science and Technology of Japan; U.S. National Institute of Mental Health FX The work was supported by a Grant-in-Aid for Scientific Research on Priority Areas-System Study on Higher-Order Brain Functions (17022052) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Grant-in-Aid for Young Scientists (B) (23700701) from the Japan Society for the Promotion of Science (JSPS), 21st Century Center of Excellence Program/JSPS, and the National Institute of Advanced Industrial Science and Technology of Japan. B. J. Richmond is supported by the U.S. National Institute of Mental Health intramural program. We thank JSPS for providing support for B. J. Richmond in Japan. NR 50 TC 17 Z9 17 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUN PY 2012 VL 107 IS 11 BP 2996 EP 3007 DI 10.1152/jn.00282.2011 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 952TC UT WOS:000304814300008 PM 22402653 ER PT J AU Karabanov, A Jin, SH Joutsen, A Poston, B Aizen, J Ellenstein, A Hallett, M AF Karabanov, Anke Jin, Seung-Hyun Joutsen, Atte Poston, Brach Aizen, Joshua Ellenstein, Aviva Hallett, Mark TI Timing-dependent modulation of the posterior parietal cortex-primary motor cortex pathway by sensorimotor training SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE paired-pulse tms; EEG coherence; motor learning; functional connectivity ID TRANSCRANIAL MAGNETIC STIMULATION; EVENT-RELATED DESYNCHRONIZATION; SEQUENTIAL FINGER MOVEMENTS; FUNCTIONAL CONNECTIONS; HUMAN BRAIN; AREAS; RHYTHMS; ACTIVATION; COHERENCE; SYNCHRONIZATION AB Karabanov A, Jin S, Joutsen A, Poston B, Aizen J, Ellenstein A, Hallett M. Timing-dependent modulation of the posterior parietal cortex-primary motor cortex pathway by sensorimotor training. J Neurophysiol 107: 3190-3199, 2012. First published March 21, 2012; doi:10.1152/jn.01049.2011.-Interplay between posterior parietal cortex (PPC) and ipsilateral primary motor cortex (M1) is crucial during execution of movements. The purpose of the study was to determine whether functional PPC-M1 connectivity in humans can be modulated by sensorimotor training. Seventeen participants performed a sensorimotor training task that involved tapping the index finger in synchrony to a rhythmic sequence. To explore differences in training modality, one group (n = 8) learned by visual and the other (n = 9) by auditory stimuli. Transcranial magnetic stimulation (TMS) was used to assess PPC-M1 connectivity before and after training, whereas electroencephalography (EEG) was used to assess PPC-M1 connectivity during training. Facilitation from PPC to M1 was quantified using paired-pulse TMS at conditioning-test intervals of 2, 4, 6, and 8 ms by measuring motor-evoked potentials (MEPs). TMS was applied at baseline and at four time points (0, 30, 60, and 180 min) after training. For EEG, task-related power and coherence were calculated for early and late training phases. The conditioned MEP was facilitated at a 2-ms conditioning-test interval before training. However, facilitation was abolished immediately following training, but returned to baseline at subsequent time points. Regional EEG activity and interregional connectivity between PPC and M1 showed an initial increase during early training followed by a significant decrease in the late phases. The findings indicate that parietal-motor interactions are activated during early sensorimotor training when sensory information has to be integrated into a coherent movement plan. Once the sequence is encoded and movements become automatized, PPC-M1 connectivity returns to baseline. C1 [Jin, Seung-Hyun] Seoul Natl Univ Hosp, Dept Neurosurg, Seoul 110744, South Korea. [Joutsen, Atte] Tampere Univ Technol, Dept Biomed Engn, FIN-33101 Tampere, Finland. [Karabanov, Anke] Hvidovre Univ Hosp, Danish Res Ctr Magnet Resonance, Copenhagen, Denmark. [Karabanov, Anke; Jin, Seung-Hyun; Joutsen, Atte; Poston, Brach; Aizen, Joshua; Ellenstein, Aviva; Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bethesda, MD USA. RP Karabanov, A (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Rm 7D42, Bethesda, MD 20892 USA. EM ankenk@drcmr.dk OI Karabanov, Anke Ninija/0000-0003-1874-393X FU National Institute of Neurological Disorders and Stroke FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Program. NR 51 TC 11 Z9 11 U1 0 U2 13 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUN PY 2012 VL 107 IS 11 BP 3190 EP 3199 DI 10.1152/jn.01049.2011 PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 952TC UT WOS:000304814300026 PM 22442568 ER PT J AU Kramer-Marek, G Bernardo, M Kiesewetter, DO Bagci, U Kuban, M Omer, A Zielinski, R Seidel, J Choyke, P Capala, J AF Kramer-Marek, Gabriela Bernardo, Marcelino Kiesewetter, Dale O. Bagci, Ulas Kuban, Monika Omer, Aras Zielinski, Rafal Seidel, Jurgen Choyke, Peter Capala, Jacek TI PET of HER2-Positive Pulmonary Metastases with F-18-Z(HER2:342) Affibody in a Murine Model of Breast Cancer: Comparison with F-18-FDG SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE HER2; PET imaging; Affibody molecules; F-18-FDG ID HER2 EXPRESSION; THERAPY; TRASTUZUMAB; MOLECULES; XENOGRAFTS; PROTEIN; SITES; MICE AB Targeted therapies often depend on the expression of the target present in the tumor. This expression can be difficult to ascertain in widespread metastases. F-18-FDG PET/CT, although sensitive, is nonspecific for particular tumor markers. Here, we compare the use of a human epidermal growth factor receptor 2 (HER2)-specific F-18-(ZHER2):(342)-Affibody and F-18-FDG in HER2-expressing pulmonary metastases in a murine model of breast cancer. Methods: The lung metastasis model was established by intravenous injection of MDA-MB-231(HER2)-Luc human breast cancer cells into the tail vein. Bioluminescence imaging was used to evaluate metastasis progression. Uptake of F-18-Z(HER2:342)-Affibody and F-18-FDG was confirmed by coregistration of the PET images with MR and CT images. At the end of the study, the presence of neoplastic cells and HER2 expression in lung tissues, and distribution of the tracer, were assessed ex vivo by immunohistochemistry and autoradiography. Results: F-18-Z(HER2:342)-Affibody successfully targeted HER2-positive lesions in the lung and allowed detection of metastases as early as 9 wk after injection of cells. In contrast, F-18-FDG uptake was often masked by surrounding inflammatory changes and was nonspecific for HER2 expression. HER2 expression at a cellular level correlated well with tracer uptake on autoradiography. Conclusion: F-18-Z(HER2:342)-Affibody is a promising tracer for evaluation of HER2 status of breast cancer metastases and is more specific for detecting HER2-positive lesions than F-18-FDG. C1 [Kramer-Marek, Gabriela; Kuban, Monika; Capala, Jacek] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Bernardo, Marcelino; Omer, Aras; Seidel, Jurgen; Choyke, Peter] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Kiesewetter, Dale O.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Zielinski, Rafal] UT MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX USA. RP Kramer-Marek, G (reprint author), Indiana Univ, Sch Med, Div Endocrinol, 980 W Walnut,Room C549, Indianapolis, IN 46202 USA. EM gkramerm@iupui.edu RI Bagci, Ulas/A-4225-2012; OI Bagci, Ulas/0000-0001-7379-6829 FU Affibody AB; Center for Cancer Research; National Cancer Institute; Imaging Probe Development Center; National Heart, Lung, and Blood Institute; National Institute of Biomedical Imaging and Bioengineering; Breast Cancer Research Stamp Fund; National Cancer Institute, National Institutes of Health [N01-CO-12400, N01-CO-12401, HHSN261200800001E] FX We appreciate the support of Affibody AB. We owe special thanks to Elaine Jagoda and Steven Adler for continuous constructive discussions. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. This research was supported in part by the Center for Cancer Research, an Intramural Research Program of the National Cancer Institute, Imaging Probe Development Center; National Heart, Lung, and Blood Institute; National Institute of Biomedical Imaging and Bioengineering; and the Breast Cancer Research Stamp Fund awarded through competitive peer review. In addition, the study was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contracts N01-CO-12400 and N01-CO-12401, and HHSN261200800001E. No other potential conflict of interest relevant to this article was reported. NR 23 TC 9 Z9 9 U1 0 U2 6 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD JUN PY 2012 VL 53 IS 6 BP 939 EP 946 DI 10.2967/jnumed.111.100354 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 955SJ UT WOS:000305040900038 PM 22582046 ER PT J AU Kiselev, E Empey, N Agama, K Pommier, Y Cushman, M AF Kiselev, Evgeny Empey, Nicholas Agama, Keli Pommier, Yves Cushman, Mark TI Dibenzo[c,h][1,5]naphthyridinediones as Topoisomerase I Inhibitors: Design, Synthesis, and Biological Evaluation SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ANTICANCER AGENTS; CAMPTOTHECIN; NITIDINE; CHLORIDE AB Dibenzo[c,h][1,5]naphthyridinediones were prepared via a novel synthetic pathway. The compounds were designed as topoisomerase I (Top 1) inhibitors based on the indenoisoquinoline series of drugs. The results of biological evaluation demonstrate that, unlike very closely related dibenzo[c,h][1,6]naphthyridinediones, dibenzo[c,h][1,5]naphthyridinediones retain the Top1 inhibitory activity of similarly substituted indenoisoquinolines. C1 [Kiselev, Evgeny; Empey, Nicholas; Cushman, Mark] Purdue Univ, Dept Med Chem & Mol Pharmacol, Coll Pharm, W Lafayette, IN 47907 USA. [Kiselev, Evgeny; Empey, Nicholas; Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Agama, Keli; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Cushman, M (reprint author), Purdue Univ, Dept Med Chem & Mol Pharmacol, Coll Pharm, W Lafayette, IN 47907 USA. EM cushman@purdue.edu FU National Institutes of Health (NIH) [UO1 CA89566]; Purdue Research Foundation; Center for Cancer Research, National Cancer Institute FX This work was made possible by the National Institutes of Health (NIH) through support of this work with Research Grant No. UO1 CA89566, by a Purdue Research Foundation Research Grant, and by the Center for Cancer Research, Intramural Program of the National Cancer Institute. NR 30 TC 11 Z9 11 U1 1 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD JUN 1 PY 2012 VL 77 IS 11 BP 5167 EP 5172 DI 10.1021/jo3006039 PG 6 WC Chemistry, Organic SC Chemistry GA 950WP UT WOS:000304682400033 PM 22587603 ER PT J AU Miller, PE Morey, MC Hartman, TJ Snyder, DC Sloane, R Cohen, HJ Demark-Wahnefried, W AF Miller, Paige E. Morey, Miriam C. Hartman, Terry J. Snyder, Denise C. Sloane, Richard Cohen, Harvey Jay Demark-Wahnefried, Wendy TI Dietary Patterns Differ between Urban and Rural Older, Long-Term Survivors of Breast, Prostate, and Colorectal Cancer and Are Associated with Body Mass Index SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Dietary patterns; Cancer survivors; Body mass index; Geographic residence ID HEALTH BEHAVIORS; NUTRIENT INTAKE; UNITED-STATES; RISK; ADULTS; OBESITY; FOOD; WOMEN; OVERWEIGHT; OUTCOMES AB Background Older adult cancer survivors are at greater risk of cancer recurrence and other comorbidities that can be prevented through improved diet and weight management. The tertiary prevention needs of rural-dwelling survivors can be even greater, yet little is known about rural and urban differences in lifestyle factors among this high-risk population. Objectives To compare dietary patterns of urban and rural cancer survivors and to examine associations of dietary patterns with body mass index (BMI). Design A secondary analysis was performed of baseline data from the Reach Out to Enhance Wellness (RENEW) trial, a diet and exercise intervention among overweight, long-term (>= 5 years), older survivors of colorectal, breast, and prostate cancer. Survivors in the present analysis (n=729) underwent two 45- to 60-minute telephone surveys, which included two 24-hour dietary recalls. Principal components analysis and multivariable general linear models were used to derive dietary patterns and to evaluate associations between dietary patterns and BMI, respectively. Results Principal components analysis identified three primary dietary patterns among rural dwellers (high sweets and starches, high reduced-fat dairy, cereal, nuts, and fruits, and mixed) and three among urban dwellers (high fruits and vegetables, high meat and refined grains, and high sugar-sweetened beverages). Among rural survivors, greater adherence to the high reduced-fat dairy, cereal, nuts, and fruits pattern was positively associated with lower BMI (P trend < 0.05), whereas higher scores on the mixed pattern was associated with greater BMI (P trend < 0.05). Greater adherence to the high fruits and vegetables pattern among urban survivors was inversely associated with BMI (P trend < 0.05). Conclusions Urban and rural differences in dietary intake behavior should be considered in designing public health interventions among the increasing population of older cancer survivors. In addition, targeting overall dietary patterns might be one approach to help reduce the burden of obesity among this population. J Acad Nutr Diet. 2012;112:824-831. C1 [Miller, Paige E.] NCI, NIH, Canc Prevent Fellowship Program, Rockville, MD 20852 USA. [Morey, Miriam C.] Duke Univ, Sch Med, Geriatr Res Educ & Clin Ctr, Durham VA Med Ctr, Durham, NC USA. [Morey, Miriam C.; Cohen, Harvey Jay] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Hartman, Terry J.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Snyder, Denise C.] Duke Univ, Res Management Team, Sch Nursing, Durham, NC USA. [Cohen, Harvey Jay] Duke Univ, Duke Ctr Study Aging & Human Dev, Sch Med, Durham, NC USA. [Demark-Wahnefried, Wendy] UAB, Dept Nutr Sci, Birmingham, W Midlands, England. [Demark-Wahnefried, Wendy] UAB Comprehens Canc Ctr, Birmingham, W Midlands, England. RP Miller, PE (reprint author), NCI, NIH, Canc Prevent Fellowship Program, 6130 Execut Blvd,EPN 4081, Rockville, MD 20852 USA. EM paige.miller@nih.gov FU National Institutes of Health (NIH) [CA106919, P30AG028716]; National Center for Research Resources, NIH [1 UL1 RR024128-01]; Veterans Affairs Research and Development [E3386R]; Duke University Pepper Center [AG028716]; Veterans Affairs [HSRD-IIR-06-252-3] FX Research related to this abstract was funded by the following grants: CA106919 from the National Institutes of Health (NIH), P30AG028716 (NIH), no. 1 UL1 RR024128-01 from the National Center for Research Resources, NIH, grant no. E3386R from the Veterans Affairs Research and Development, and grant no. AG028716 from the Duke University Pepper Center, and HSRD-IIR-06-252-3 from Veterans Affairs. NR 48 TC 5 Z9 5 U1 2 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD JUN PY 2012 VL 112 IS 6 BP 824 EP 831 DI 10.1016/j.jand.2012.02.021 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 951QU UT WOS:000304735900006 PM 22709810 ER PT J AU Giaccone, G AF Giaccone, G. TI DEVELOPMENTS IN SMALL CELL LUNG CANCER SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract CT 3rd European Lung Cancer Conference (ELCC) CY APR 18-21, 2012 CL Geneva, SWITZERLAND SP Lilly Oncol, AstraZeneca, Daiichi Sankyo, Pfizer Oncol, Roche, Abbott Oncol, Lets Work, Boehringer Ingelheim, Merck Serono, Merck C1 [Giaccone, G.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD JUN PY 2012 VL 7 IS 6 SU S BP S18 EP S18 PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 951NM UT WOS:000304727300043 ER PT J AU Bugge, TH AF Bugge, T. H. TI Membrane-anchored serine proteases and their inhibitors SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Bugge, T. H.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2012 VL 10 IS 6 BP E26 EP E26 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 950PM UT WOS:000304661200088 ER PT J AU Larsen, BR Steffensen, SDR Nielsen, NVL Friis, S Godiksen, S Bornholdt, J Sondergaard, C Andersen, MN Poulsen, SS Szabo, R Bugge, TH Lin, CY Skovbjerg, H Jensen, JK Vogel, LK AF Larsen, B. R. Steffensen, S. D. R. Nielsen, N. V. L. Friis, S. Godiksen, S. Bornholdt, J. Sondergaard, C. Andersen, M. N. Poulsen, S. S. Szabo, R. Bugge, T. H. Lin, C. Y. Skovbjerg, H. Jensen, J. K. Vogel, L. K. TI Hepatocyte growth factor activator inhibitor-2 resides primarily intracellularly to facilitate cell surface transport of matriptase SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Larsen, B. R.; Steffensen, S. D. R.; Friis, S.; Godiksen, S.; Bornholdt, J.; Sondergaard, C.; Andersen, M. N.; Poulsen, S. S.; Skovbjerg, H.; Vogel, L. K.] Univ Copenhagen, Copenhagen, Denmark. [Nielsen, N. V. L.] Univ Aarhus, Aarhus, Denmark. [Szabo, R.; Bugge, T. H.] NIH, Bethesda, MD 20892 USA. [Lin, C. Y.] Univ Maryland, Baltimore, MD 21201 USA. [Jensen, J. K.] Aarhus Univ, Aarhus, Denmark. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2012 VL 10 IS 6 BP E18 EP E18 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 950PM UT WOS:000304661200060 ER PT J AU Abi-Jaoudeh, N Mielekamp, P Noordhoek, N Venkatesan, AM Millo, C Radaelli, A Carelsen, B Wood, BJ AF Abi-Jaoudeh, Nadine Mielekamp, Peter Noordhoek, Niels Venkatesan, Aradhana M. Millo, Corina Radaelli, Alessandro Carelsen, Bart Wood, Bradford J. TI Cone-Beam Computed Tomography Fusion and Navigation for Real-Time Positron Emission Tomography-guided Biopsies and Ablations: A Feasibility Study SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID INTERVENTIONAL RADIOLOGY; PET-CT; CANCER; ACCURACY; GUIDANCE; LESIONS; SUITE AB Purpose: To describe a novel technique for multimodality positron emission tomography (PET) fusion guided interventions that combines cone-beam computed tomography (CT) with PET/CT before the procedure. Materials and Methods: Subjects were selected among patients scheduled for a biopsy-or ablation procedure. The lesions were not visible with conventional imaging methods or did not have uniform uptake on PET. Clinical success was defined by adequate histopathologic specimens for molecular profiling or diagnosis and by lack of enhancement on follow-up imaging for ablation procedures. Time to target (time elapsed between the completion of the initial cone-beam CT scan and first tissue sample or treatment), total procedure time (time from the moment the patient was on the table until the patient was off the table), and number of times the needle was repositioned were recorded. Results: Seven patients underwent eight procedures (two ablations and six biopsies). Registration and procedures were completed successfully in all cases. Clinical success was achieved in all biopsy procedures and in one of the two ablation procedures. The needle was repositioned once in one biopsy procedure only. On average, the time to target was 38 minutes (range 13-54 min). Total procedure time was 95 minutes (range 51-240 min, which includes composite ablation). On average, fluoroscopy time was 2.5 minutes (range 1.3-6.2 min). Conclusions: An integrated cone-beam CT software platform can enable PET-guided biopsies and ablation procedures without the need for additional specialized hardware. C1 [Abi-Jaoudeh, Nadine; Venkatesan, Aradhana M.; Millo, Corina; Wood, Bradford J.] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Mielekamp, Peter; Noordhoek, Niels; Radaelli, Alessandro; Carelsen, Bart] Philips Healthcare, iXR Div, Best, Netherlands. RP Abi-Jaoudeh, N (reprint author), NIH, Dept Radiol & Imaging Sci, Bldg 10 MSC 1182,9000 Rockville Pike, Bethesda, MD 20892 USA. EM naj@mail.nih.gov FU Philips Healthcare FX P.M., N.N., A.R., and B.C. are employees of and receive a salary from Philips Healthcare. None of the other authors have identified a conflict of interest. NR 28 TC 17 Z9 17 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JUN PY 2012 VL 23 IS 6 BP 737 EP 743 DI 10.1016/j.jvir.2012.02.006 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 950ZW UT WOS:000304691400002 PM 22494658 ER PT J AU Venkatesan, AM Partanen, A Pulanic, TK Dreher, MR Fischer, J Zurawin, RK Muthupillai, R Sokka, S Nieminen, HJ Sinaii, N Merino, M Wood, BJ Stratton, P AF Venkatesan, Aradhana M. Partanen, Ari Pulanic, Tajana Klepac Dreher, Matthew R. Fischer, John Zurawin, Robert K. Muthupillai, Raja Sokka, Sham Nieminen, Heikki J. Sinaii, Ninet Merino, Maria Wood, Bradford J. Stratton, Pamela TI Magnetic Resonance Imaging-guided Volumetric Ablation of Symptomatic Leiomyomata: Correlation of Imaging with Histology SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID FOCUSED ULTRASOUND SURGERY; TEMPORAL TEMPERATURE CONTROL; UTERINE LEIOMYOMAS; THERMAL ABLATION; MR THERMOMETRY; PHASED-ARRAY; FOCAL POINT; FEASIBILITY; DOSIMETRY; CARCINOMA AB Purpose: To describe the preliminary safety and accuracy of a magnetic resonance (MR) imaging-guided high-intensity focused ultrasound (HIFU) system employing new technical developments, including ablation control via volumetric thermal feedback, for the treatment of uterine leiomyomata with histopathologic correlation. Materials and Methods: In this phase I clinical trial, 11 women underwent MR-guided HIFU ablation (Sonalleve 1.5T; Philips Medical Systems, Vantaa, Finland), followed by hysterectomy within 30 days. Adverse events, imaging findings, and pathologic confirmation of ablation were assessed. The relationship between MR imaging findings, thermal dose estimates, and pathology and HIFU spatial accuracy were assessed using Bland-Altman analyses and intraclass correlations. Results: There were 12 leiomyomata treated. No serious adverse events were observed. Two subjects decided against having hysterectomy and withdrew from the study before surgery. Of 11 women, 9 underwent hysterectomy; all leiomyomata demonstrated treatment in the expected location. A mean ablation volume of 6.92 cm(3) +/- 10.7 was observed at histopathologic examination. No significant differences between MR imaging nonperfused volumes, thermal dose estimates, and histopathology ablation volumes were observed (P>.05). Mean misregistration values perpendicular to the ultrasound beam axis were 0.8 mm +/- 1.2 in feet-head direction and 0.1 mm +/- 1.0 in and left-right direction and -0.7 mm +/- 3.1 along the axis. Conclusions: Safe, accurate ablation of uterine leiomyomata was achieved with an MR-guided HIFU system with novel treatment monitoring capabilities, including ablation control via volumetric thermal feedback. C1 [Venkatesan, Aradhana M.; Dreher, Matthew R.; Wood, Bradford J.] NIH, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Partanen, Ari] Philips Med Syst, Cleveland, OH USA. [Partanen, Ari] Univ Helsinki, Dept Phys, Helsinki, Finland. [Pulanic, Tajana Klepac; Stratton, Pamela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol Branch, Bethesda, MD USA. [Fischer, John; Zurawin, Robert K.; Muthupillai, Raja] St Lukes Episcopal Hosp, Dept Radiol, Houston, TX 77030 USA. [Zurawin, Robert K.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Sokka, Sham; Nieminen, Heikki J.] Philips Med Syst, Vantaa, Finland. [Sinaii, Ninet] NIH, Ctr Clin, Biostat & Clin Epidemiol Serv, Bethesda, MD 20892 USA. [Merino, Maria] NCI, NIH, Surg Pathol Branch, Bethesda, MD 20892 USA. RP Venkatesan, AM (reprint author), NIH, Ctr Intervent Oncol, 10 Ctr Dr,Bldg 10,Rm 1C369,MSC 1182, Bethesda, MD 20892 USA. EM VenkatesanA@cc.nih.gov OI Partanen, Ari/0000-0003-1985-149X FU NIH [CL04040011-03] FX A.P., S.S., and H.J.N. are salaried employees of Philips Healthcare. Philips has market interest and intellectual property in this field. B.J.W. has NIH Intramural Research funding Z01/ZIA #CL04040011-03. NR 25 TC 16 Z9 20 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JUN PY 2012 VL 23 IS 6 BP 786 EP 794 DI 10.1016/j.jvir.2012.02.015 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 950ZW UT WOS:000304691400009 PM 22626269 ER PT J AU Reynolds, SJ Makumbi, F Newell, K Kiwanuka, N Ssebbowa, P Mondo, G Boaz, I Wawer, MJ Gray, RH Serwadda, D Quinn, TC AF Reynolds, Steven J. Makumbi, Fred Newell, Kevin Kiwanuka, Noah Ssebbowa, Paschal Mondo, George Boaz, Iga Wawer, Maria J. Gray, Ronald H. Serwadda, David Quinn, Thomas C. TI Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: a randomised, double-blind placebo-controlled trial SO LANCET INFECTIOUS DISEASES LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; REVERSE-TRANSCRIPTASE; VIRAL LOAD; HETEROSEXUAL TRANSMISSION; ANTIRETROVIRAL TREATMENT; THERAPY; ACQUISITION; PLASMA; IMPACT; MEN AB Background Daily suppression of herpes simplex virus type 2 (HSV-2) reduces plasma HIV-1 concentrations and modestly delayed HIV-1 disease progression in one clinical trial. We investigated the effect of daily suppressive aciclovir on HIV-1 disease progression in Rakai, Uganda. Methods We did a single site, parallel, randomised, controlled trial of HIV-1, HSV-2 dually infected adults with CD4 cell counts of 300-400 cells per pL. We excluded individuals who had an AIDS-defining illness or active genital ulcer disease, and those that were taking antiretroviral therapy. Participants were randomly assigned (1:1) with computer-generated random numbers in blocks of four to receive either aciclovir 400 mg orally twice daily or placebo; participants were followed up for 24 months. All study staff and participants were masked to treatment, except for the two statisticians. The primary outcome was CD4 cell count less than 250 cells per pL or initiation of antiretroviral therapy for WHO stage 4 disease. Our intention-to-treat analysis used Cox proportional hazards models, adjusting for baseline log(10), viral load, CD4 cell count, sex, and age to assess the risk of disease progression. We also investigated the effect of suppressive HSV-2 treatment stratified by baseline HIV viral load with a Cox proportional hazards model. This trial is registered with ClinicalTrials.gov, number NCT00405821. Findings 440 participants were randomly assigned, 220 to each group. 110 participants in the placebo group and 95 participants in the treatment group reached the primary endpoint (adjusted hazard ratio [HR] 0.75, 95% CI 0.58-099; p=0 040). 24 participants in the placebo group and 22 in the treatment group were censored, but all contributed data for the final analysis. In a subanalysis stratified by baseline HIV viral load, participants with a baseline viral load of 50000 copies mL or more in the treatment group had a reduced HIV disease progression compared with those in the placebo group (0.62, 0.43-0.96; p=0. 03). No significant difference in HIV disease progression existed between participants in the treatment group and those in the placebo group who had baseline HIV viral loads of less than 50 000 copies per mL (0.90, 0-54-1.5; p=0 688). No safety issues related to aciclovir treatment were identified. Interpretation Aciclovir reduces the rate of disease progression, with the greatest effect in individuals with a high baseline viral load. Suppressive aciclovir might be warranted for individuals dually infected with HSV-2 and HIV-1 with viral loads of 50 000 copies per mL or more before initiation of antiretroviral treatment. C1 [Reynolds, Steven J.; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Reynolds, Steven J.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Makumbi, Fred; Kiwanuka, Noah; Serwadda, David] Makerere Univ, Sch Publ Hlth, Coll Hlth Sci, Kampala, Uganda. [Newell, Kevin] NCI, Clin Monitoring Res Program, SAIC Frederick, Frederick, MD 21701 USA. [Ssebbowa, Paschal; Mondo, George; Boaz, Iga] Rakai Hlth Sci Program, Kalisizo, Uganda. [Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Reynolds, SJ (reprint author), US Embassy, NIAID, ICER Program, NIH, POB 7007, Kampala, Uganda. EM sreynol6@jhmi.edu FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases, National Cancer Institute (National Institutes of Health, USA); [PO1 AI-30731-19] FX This research was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. This project was funded partly with federal funds from the National Cancer Institute, National Institutes of Health, contract number HHSN261200800001E, and partly through programme project grant PO1 AI-30731-19. The content of this report does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government. We thank the trial participants, the staff of the Rakai Health Sciences Program, and Larry Corey for his design input and support. We also thank the NI H Data Safety and Monitoring Board and the institutional review boards (Uganda Virus Research Institute Science and Ethics Committee and the National Institute of Allergy and Infectious Diseases institutional review board) for their technical advice and oversight of this study.; Funding National Institute of Allergy and Infectious Diseases, National Cancer Institute (National Institutes of Health, USA). NR 29 TC 26 Z9 26 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUN PY 2012 VL 12 IS 6 BP 441 EP 448 DI 10.1016/S1473-3099(12)70037-3 PG 8 WC Infectious Diseases SC Infectious Diseases GA 952JR UT WOS:000304789300016 PM 22433279 ER PT J AU Taylor, SM Parobek, CM Fairhurst, RM AF Taylor, Steve M. Parobek, Christian M. Fairhurst, Rick M. TI Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis SO LANCET INFECTIOUS DISEASES LA English DT Review ID SICKLE-CELL TRAIT; PLASMODIUM-FALCIPARUM MALARIA; VARIANT SURFACE-ANTIGENS; BETA-THALASSEMIA TRAIT; PAPUA-NEW-GUINEA; HUMAN RED-CELLS; IMMUNE-RESPONSES; ALPHA(+)-THALASSEMIA PROTECTS; ALPHA-THALASSEMIA; AFRICAN CHILDREN AB Background Haemoglobinopathies can reduce the risk of malaria syndromes. We aimed to quantify the relation between different haemoglobin mutations and malaria protection to strengthen the foundation for translational studies of malaria pathogenesis and immunity. Methods We systematically searched the Med line and Embase databases for studies that estimated the risk of malaria in patients with and without haemoglobinopathies up to Sept 9, 2011, and identified additional studies from reference lists. We included studies that enrolled mainly children or pregnant women and had the following outcomes: Plasmodium falciparum severe malaria, uncomplicated malaria, asymptomatic parasitaemia, or pregnancy-associated malaria, and Plasmodium vivax malaria. Two reviewers identified studies independently, assessed quality of the studies, and extracted data. We produced odds ratios (ORs; 95% CIs) for case-control studies and incidence rate ratios (IRRs; 95% CIs) for prospective studies. We did the meta-analysis with a random-effects model when equivalent outcomes were reported in more than one study. Findings Of 62 identified studies, 44 reported data for haemoglobin AS, 19 for haemoglobin AC and CC, and 18 for alpha -thalassaemia. Meta-analysis of case-control studies showed a decreased risk of severe P falciparum malaria in individuals with haemoglobin AS (OR 0.09, 95% CI 0.06-0.12), haemoglobin CC (0 27, 0.11-0.63), haemoglobin AC (0.83, 67-0.96), homozygous a-thalassaemia (0.63, 0.48-0.83), and heterozygous alpha- thalassaemia (0.83, 0.74-0.92). In meta-analysis of prospective trials only haemoglobin AS was consistently associated with protection from uncomplicated malaria (IRR 0.69, 95% CI 0.61-0.79); no haemoglobinopathies led to consistent protection from asymptomatic parasitaemia. Few clinical studies have investigated beta-thalassaemia, haemoglobin E, P vivax malaria, or pregnancy-associated malaria. Interpretation Haemoglobin AS, CC, and AC genotypes and homozygous and heterozygous alpha-thalassaemia provide significant protection from severe malaria syndromes, but these haemoglobinopathies differ substantially in the degree of protection provided and confer mild or no protection against uncomplicated malaria and asymptomatic parasitaemia. Through attenuation of severity of malaria, haemoglobinopathies could serve as a model for investigation of the mechanisms of malaria pathogenesis and immunity. C1 [Taylor, Steve M.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Taylor, Steve M.] Duke Univ, Med Ctr, Div Infect Dis & Int Hlth, Durham, NC USA. [Parobek, Christian M.] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. [Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Taylor, SM (reprint author), Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Campus Box 7435, Chapel Hill, NC 27599 USA. EM taylo115@email.unc.edu OI Parobek, Christian/0000-0002-4511-3493 FU US National Institute of Allergy and Infectious Diseases, National Institutes of Health; US National Institute of Allergy and Infectious Diseases FX This research was supported in part by the Intramural Research Programme of the US National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank Peter Crompton (US National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA) for providing access to unpublished data, and Steven Meshnick and Jonathan Juliano (University of North Carolina, Chapel Hill, NC, USA) for providing material support. These individuals received no compensation for their assistance. We also thank our anonymous reviewers whose input greatly enhanced this report. Ultimately, we are indebted to the investigators from whose work we have drawn and the patients for whom they cared.; Funding US National Institute of Allergy and Infectious Diseases. NR 101 TC 75 Z9 76 U1 7 U2 55 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUN PY 2012 VL 12 IS 6 BP 457 EP 468 DI 10.1016/S1473-3099(12)70055-5 PG 12 WC Infectious Diseases SC Infectious Diseases GA 952JR UT WOS:000304789300018 PM 22445352 ER PT J AU Nayyar, GML Breman, JG Newton, PN Herrington, J AF Nayyar, Gaurvika M. L. Breman, Joel G. Newton, Paul N. Herrington, James TI Poor-quality antimalarial drugs in southeast Asia and sub-Saharan Africa SO LANCET INFECTIOUS DISEASES LA English DT Review ID ARTEMISININ RESISTANCE; PLASMODIUM-FALCIPARUM; COUNTERFEIT DRUGS; FAKE ARTESUNATE; TABLETS SOLD; MALARIA; PHARMACIES; PYRIMETHAMINE; AMODIAQUINE; MEDICINES AB Poor-quality antimalarial drugs lead to drug resistance and inadequate treatment, which pose an urgent threat to vulnerable populations and jeopardise progress and investments in combating malaria. Emergence of artemisinin resistance or tolerance in Plasmodium falciparum on the Thailand Cambodia border makes protection of the effectiveness of the drug supply imperative. We reviewed published and unpublished studies reporting chemical analyses and assessments of packaging of antimalarial drugs. Of 1437 samples of drugs in five classes from seven countries in southeast Asia, 497 (35%) failed chemical analysis, 423 (46%) of 919 failed packaging analysis, and 450 (36%) of 1260 were classified as falsified. In 21 surveys of drugs from six classes from 21 countries in sub-Saharan Africa, 796 (35%) of 2297 failed chemical analysis, 28 (36%) of 77 failed packaging analysis, and 79 (20%) of 389 were classified as falsified. Data were insufficient to identify the frequency of substandard (products resulting from poor manufacturing) antimalarial drugs, and packaging analysis data were scarce. Concurrent interventions and a multifaceted approach are needed to define and eliminate criminal production, distribution, and poor manufacturing of antimalarial drugs. Empowering of national medicine regulatory authorities to protect the global drug supply is more important than ever. C1 [Nayyar, Gaurvika M. L.; Breman, Joel G.; Herrington, James] NIAID, Fogarty Int Ctr, NIH, Bethesda, MD 20892 USA. [Newton, Paul N.] Univ Oxford, Wellcome Trust MahosotHosp, Trop Med Res Collaborat, Microbiol Lab,Mahosot Hosp, Viangchan, Laos. [Newton, Paul N.] Univ Oxford, Ctr Clin Vaccinol & Trop Med, Churchill Hosp, Oxford, Laos. RP Nayyar, GML (reprint author), NIAID, Fogarty Int Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gaurvika@gmail.com FU Wellcome Trust of Great Britain; Fogarty International Center, National Institutes of Health FX We thank Stacey)(nobler (Fogarty International Center), Pascal Ringwald (Global Malaria Programme, WHO), and Tom Wellems (National Institute of Allergy and Infectious Disease) for their advice and support. PNN is supported by the Wellcome Trust of Great Britain. This study was funded by the Fogarty International Center, National Institutes of Health. NR 81 TC 111 Z9 116 U1 1 U2 58 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUN PY 2012 VL 12 IS 6 BP 488 EP 496 PG 9 WC Infectious Diseases SC Infectious Diseases GA 952JR UT WOS:000304789300021 PM 22632187 ER PT J AU Lai, JP Robbins, PF Raffeld, M Aung, PP Tsokos, M Rosenberg, SA Miettinen, MM Lee, CCR AF Lai, Jin-Ping Robbins, Paul F. Raffeld, Mark Aung, Phyu Phyu Tsokos, Maria Rosenberg, Steven A. Miettinen, Markku M. Lee, Chyi-Chia Richard TI NY-ESO-1 expression in synovial sarcoma and other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential diagnosis SO MODERN PATHOLOGY LA English DT Article DE NY-ESO-1; sarcoma; targeted therapy AB A promising targeted therapy against NY-ESO-1 (CTAG 1B) using genetically modified T-cells in synovial sarcomas was recently demonstrated in a clinical trial at the NCI. To investigate the role of NY-ESO-1 immunohistochemistry in patient selection and gain better insight into the incidence of NY-ESO-1 expression in synovial sarcomas and other mesenchymal tumors, we evaluated NY-ESO-1 expression by immunohistochemistry in 417 tumors. This collection of samples included: 50 SS18/SSX1/2 fusion positive synovial sarcomas, 155 gastrointestinal stromal tumors (GIST), 135 other spindle cell sarcomas as well as 77 other sarcomas (chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, rhabdomyosarcoma, angiosarcoma, malignant mesothelioma, and Ewing's sarcoma). We report that 76% of synovial sarcomas expressed NY-ESO-1 in a strong and diffuse pattern (2-3 +, >50-70% of tumor cells). In contrast, only rare cases of other spindle cell mesenchymal tumor expressed NY-ESO-1 (GIST (2/155), malignant peripheral nerve sheath tumors (1/34), and dermatofibrosarcoma protuberans (2/20)). Individual cases of other sarcomas (angiosarcoma, malignant mesothelioma, chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, and Ewing's sarcoma) were positive for NY-ESO-1. However, no positive cases were identified amongst our cohort of leiomyosarcomas (0/24), hemangiopericytoma/solitary fibrous tumors (0/40), and cellular schwannomas (0/17). In summary, we find that NY-ESO-1 is strongly and diffusely expressed in a majority of synovial sarcomas, but only rarely in other mesenchymal lesions. Beyond its role in patient selection for targeted therapy, immunohistochemistry for NY-ESO-1 may be diagnostically useful for the distinction of synovial sarcoma from other spindle cell neoplasms. Modern Pathology (2012) 25, 854-858; doi:10.1038/modpathol.2012.31; published online 2 March 2012 C1 [Lai, Jin-Ping; Raffeld, Mark; Aung, Phyu Phyu; Tsokos, Maria; Miettinen, Markku M.; Lee, Chyi-Chia Richard] NCI, NIH, Pathol Lab, Bethesda, MD 20892 USA. [Robbins, Paul F.; Rosenberg, Steven A.] NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. RP Lee, CCR (reprint author), NCI, NIH, Pathol Lab, Bldg 10-2B50,10 Ctr Dr, Bethesda, MD 20892 USA. EM leechy@mail.nih.gov RI Lee, Chyi-Chia/I-1938-2013 OI Lee, Chyi-Chia/0000-0002-5306-7781 NR 8 TC 25 Z9 28 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD JUN PY 2012 VL 25 IS 6 BP 854 EP 858 DI 10.1038/modpathol.2012.31 PG 5 WC Pathology SC Pathology GA 953AM UT WOS:000304839300009 PM 22388761 ER PT J AU Antao, JM Mason, JM Dejardin, J Kingston, RE AF Antao, Jose M. Mason, James M. Dejardin, Jerome Kingston, Robert E. TI Protein Landscape at Drosophila melanogaster Telomere-Associated Sequence Repeats SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID POSITION-EFFECT VARIEGATION; DISTINCT CHROMATIN DOMAINS; GENE-EXPRESSION; GAGA FACTOR; IN-VIVO; ENCODES; COMPLEX; WOC; HP1; LOCALIZATION AB The specific set of proteins bound at each genomic locus contributes decisively to regulatory processes and to the identity of a cell. Understanding of the function of a particular locus requires the knowledge of what factors interact with that locus and how the protein composition changes in different cell types or during the response to internal and external signals. Proteomic analysis of isolated chromatin segments (PICh) was developed as a tool to target, purify, and identify proteins associated with a defined locus and was shown to allow the purification of human telomeric chromatin. Here we have developed this method to identify proteins that interact with the Drosophila telomere-associated sequence (TAS) repeats. Several of the purified factors were validated as novel TAS-bound proteins by chromatin immunoprecipitation, and the Brahma complex was confirmed as a dominant modifier of telomeric position effect through the use of a genetic test. These results offer information on the efficacy of applying the PICh protocol to loci with sequence more complex than that found at human telomeres and identify proteins that bind to the TAS repeats, which might contribute to TAS biology and chromatin silencing. C1 [Antao, Jose M.; Kingston, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Antao, Jose M.; Kingston, Robert E.] Harvard Univ, Harvard Med Sch, Dept Genet, Cambridge, MA 02138 USA. [Antao, Jose M.] Inst Gulbenkian Ciencias, Gulbenkian PhD Program Biomed, Oeiras, Portugal. [Mason, James M.] Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC USA. [Dejardin, Jerome] CNRS UPR 1142, Inst Human Genet, INSERM AVENIR Team, Montpellier, France. RP Kingston, RE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM masonj@niehs.nih.gov; kingston@molbio.mgh.harvard.edu FU National Institutes of Health [GM43901]; National Institute of Environmental Health Sciences, National Institutes of Health; Fundacao para a Ciencia e Tecnologia [SFRH/BD/11800/2003] FX Funding for this work was provided by the National Institutes of Health (GM43901) and by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. J.M.A. was supported in part by a fellowship from the Fundacao para a Ciencia e Tecnologia (SFRH/BD/11800/2003). NR 57 TC 19 Z9 19 U1 0 U2 17 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2012 VL 32 IS 12 BP 2170 EP 2182 DI 10.1128/MCB.00010-12 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 953SV UT WOS:000304894400001 PM 22493064 ER PT J AU Liu, HH Hu, YJ Zheng, M Suhoski, MM Engleman, EG Dill, DL Hudnall, M Wang, JM Spolski, R Leonard, WJ Peltz, G AF Liu, Hong-Hsing Hu, Yajing Zheng, Ming Suhoski, Megan M. Engleman, Edgar G. Dill, David L. Hudnall, Matt Wang, Jianmei Spolski, Rosanne Leonard, Warren J. Peltz, Gary TI Cd14 SNPs regulate the innate immune response SO MOLECULAR IMMUNOLOGY LA English DT Article DE CD14; Monocyte; Genetics ID RESPIRATORY SYNCYTIAL VIRUS; TOLL-LIKE RECEPTOR-2; DOUBLE-STRANDED-RNA; RUNX1 BINDING-SITE; SOLUBLE CD14; GENE-EXPRESSION; ARTICULAR CHONDROCYTES; RHEUMATOID-ARTHRITIS; TRANSGENIC MICE; INTERFERON-BETA AB CD14 is a monocytic differentiation antigen that regulates innate immune responses to pathogens. Here, we show that murine Cd14 SNPs regulate the length of Cd14 mRNA and CD14 protein translation efficiency, and consequently the basal level of soluble CD14 (sCD14) and type I IFN production by murine macrophages. This has substantial downstream consequences for the innate immune response; the level of expression of at least 40 IFN-responsive murine genes was altered by this mechanism. We also observed that there was substantial variation in the length of human CD14 mRNAs and in their translation efficiency. sCD14 increased cytokine production by human dendritic cells (DCs), and sCD14-primed DCs augmented human CD4T cell proliferation. These findings may provide a mechanism for exploring the complex relationship between CD14 SNPs, serum sCD14 levels, and susceptibility to human infectious and allergic diseases. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Liu, Hong-Hsing; Hu, Yajing; Zheng, Ming; Hudnall, Matt; Peltz, Gary] Stanford Univ, Sch Med, Dept Anesthesia, Stanford, CA 94305 USA. [Suhoski, Megan M.; Engleman, Edgar G.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Dill, David L.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Wang, Jianmei] Roche, Dept Genet & Genom, Palo Alto, CA 94304 USA. [Spolski, Rosanne; Leonard, Warren J.; Peltz, Gary] NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. [Spolski, Rosanne; Leonard, Warren J.; Peltz, Gary] NHLBI, Ctr Immunol, Bethesda, MD 20892 USA. RP Peltz, G (reprint author), Stanford Univ, Sch Med, Dept Anesthesia, 300 Pasteur Dr Lane,Bldg Room 232, Stanford, CA 94305 USA. EM gpeltz@stanford.edu OI Liu, Hong-Hsing/0000-0002-3745-7202 FU NIDDK [1R01DK090992-01]; Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health FX G.P. was partially supported by funding from a transformative RO1 award (1R01DK090992-01) from the NIDDK. This work was also supported in part by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health (R.S. and W.J.L.). NR 83 TC 6 Z9 6 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD JUN PY 2012 VL 51 IS 2 BP 112 EP 127 DI 10.1016/j.molimm.2012.02.112 PG 16 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 950YJ UT WOS:000304687500002 PM 22445606 ER PT J AU Shen, DW Pouliot, LM Gillet, JP Ma, WT Johnson, AC Hall, MD Gottesman, MM AF Shen, Ding-Wu Pouliot, Lynn M. Gillet, Jean-Pierre Ma, Wenting Johnson, Alfred C. Hall, Matthew D. Gottesman, Michael M. TI The Transcription Factor GCF2 Is an Upstream Repressor of the Small GTPAse RhoA, Regulating Membrane Protein Trafficking, Sensitivity to Doxorubicin, and Resistance to Cisplatin SO MOLECULAR PHARMACEUTICS LA English DT Article DE chemotherapy; trafficking; cytoskeleton; cisplatin resistance; doxorubicin; cisplatin ID CARCINOMA-CELL-LINES; HUMAN OVARIAN-CANCER; MULTIDRUG-RESISTANCE; REDUCED EXPRESSION; MOLECULAR-CLONING; BINDING FACTOR; GENE; IDENTIFICATION; ACCUMULATION; ACTIN AB Our aim was to explore the involvement of the transcriptional suppressor GCF2 in silencing RhoA, disorganization of the cytoskeleton, mislocalization of MRP1, and sensitivity to anticancer agents as an upstream gene target in cancer therapy. Increased expression of GCF2 was found in human cisplatin-resistant cells, and overexpression in GCF2-transfected cells results in loss of RhoA expression and disruption of the actin/filamin network. In consequence, the membrane transporter MRP1 was internalized from the cell surface into the cytoplasm, rendering cells sensitive to doxorubicin by more than 10-fold due to increased accumulation of doxorubicin in the cells. The GCF2 transfectants also showed reduced accumulation of cisplatin and increased resistance. siRNA targeted to GCF2 suppressed the expression of GCF2 in cisplatin-resistant cells, reactivated RhoA expression, and restored the fine structure of actin microffiaments. MRP1 was also relocated to the cell surface. siRNA targeted to RhoA increased resistance 3-fold in KB-3-1 and KB-CP.5 cells. These data for the first time demonstrate a novel complex regulatory pathway downstream from GCF2 involving the small GTPase RhoA, actin/filamin dynamics, and membrane protein trafficking. This pathway mediates diverse responses to cytotoxic compounds, and also provides a molecular basis for further investigation into the pleiotropic resistance mechanism at play in cisplatin-resistant cells. C1 [Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Johnson, Alfred C.] NIH, Off Director, Bethesda, MD 20892 USA. [Pouliot, Lynn M.] Georgetown Univ, Dept Microbiol & Immunol, Washington, DC USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Ctr Canc Res, 37 Convent Dr,Rm 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov RI gillet, jean-pierre/A-3714-2012 FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 45 TC 8 Z9 9 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD JUN PY 2012 VL 9 IS 6 BP 1822 EP 1833 DI 10.1021/mp300153z PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 951OA UT WOS:000304728700028 PM 22571463 ER PT J AU Saccardi, R Freedman, MS Sormani, MP Atkins, H Farge, D Griffith, LM Kraft, G Mancardi, GL Nash, R Pasquini, M Martin, R Muraro, PA AF Saccardi, R. Freedman, M. S. Sormani, M. P. Atkins, H. Farge, D. Griffith, L. M. Kraft, G. Mancardi, G. L. Nash, R. Pasquini, M. Martin, R. Muraro, P. A. CA European Blood Marrow Ctr Int Blood Marrow Res CIBMTR HSCT MS Int Study GrP TI A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE autologous hematopoietic cell transplantation; prospective clinical trial; multiple sclerosis; consensus ID PLACEBO-CONTROLLED TRIAL; DOSE IMMUNOSUPPRESSIVE THERAPY; AUTOIMMUNE-DISEASES; DOUBLE-BLIND; MARROW-TRANSPLANTATION; INTERFERON BETA-1A; MULTICENTER TRIAL; BLOOD; CYCLOPHOSPHAMIDE; MITOXANTRONE AB Background: Haematopoietic stem cell transplantation (HSCT) has been tried in the last 15 years as a therapeutic option in patients with poor-prognosis autoimmune disease who do not respond to conventional treatments. Worldwide, more than 600 patients with multiple sclerosis (MS) have been treated with HSCT, most of them having been recruited in small, single-centre, phase 1-2 uncontrolled trials. Clinical and magnetic resonance imaging outcomes from case series reports or Registry-based analyses suggest that a major response is achieved in most patients; quality and duration of response are better in patients transplanted during the relapsing-remitting phase than in those in the secondary progressive stage. Objectives: An interdisciplinary group of neurologists and haematologists has been formed, following two international meetings supported by the European and American Blood and Marrow Transplantation Societies, for the purpose of discussing a controlled clinical trial, to be designed within the new scenarios of evolving MS treatments. Conclusions: Objectives of the trial, patient selection, transplant technology and outcome assessment were extensively discussed. The outcome of this process is summarized in the present paper, with the goal of establishing the background and advancing the development of a prospective, randomized, controlled multicentre trial to assess the clinical efficacy of HSCT for the treatment of highly active MS. C1 [Saccardi, R.] Careggi Univ Hosp, Dept Hematol, Florence, Italy. [Freedman, M. S.] Univ Ottawa, Dept Med Neurol, Ottawa, ON K1N 6N5, Canada. [Freedman, M. S.] Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Sormani, M. P.] Univ Genoa, Dept Hlth Sci, I-16126 Genoa, Italy. [Atkins, H.] Ottawa Hosp, Blood & Marrow Transplant Programme, Ottawa, ON, Canada. [Farge, D.] Hop St Louis, Dept Internal Med, Paris, France. [Griffith, L. M.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Kraft, G.] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Mancardi, G. L.] Univ Genoa, Dept Neurosci Ophthalmol & Genet, I-16126 Genoa, Italy. [Nash, R.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Pasquini, M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Martin, R.] Univ Zurich Hosp, Dept Clin Neuroimmunol & MS Res, Neurol Clin, Zurich, Switzerland. [Muraro, P. A.] Imperial Coll London, Ctr Neurosci, London, England. RP Saccardi, R (reprint author), Careggi Hosp, Largo Brambilla 3, I-50134 Florence, Italy. EM riccardo.saccardi@aouc.unifi.it RI mancardi, giovanni luigi/K-8656-2016 OI Muraro, Paolo/0000-0002-3822-1218; mancardi, giovanni luigi/0000-0001-8427-118X FU UK MS society [938/10] FX P.A.M. received funding support from the UK MS society (ref. no. 938/10). NR 50 TC 29 Z9 30 U1 1 U2 11 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER J JI Mult. Scler. J. PD JUN PY 2012 VL 18 IS 6 BP 825 EP 834 DI 10.1177/1352458512438454 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 951FH UT WOS:000304705700010 PM 22383228 ER PT J AU Peinado, H Aleckovic, M Lavotshkin, S Matei, I Costa-Silva, B Moreno-Bueno, G Hergueta-Redondo, M Williams, C Garcia-Santos, G Ghajar, CM Nitadori-Hoshino, A Hoffman, C Badal, K Garcia, BA Callahan, MK Yuan, JD Martins, VR Skog, J Kaplan, RN Brady, MS Wolchok, JD Chapman, PB Kang, YB Bromberg, J Lyden, D AF Peinado, Hector Aleckovic, Masa Lavotshkin, Simon Matei, Irina Costa-Silva, Bruno Moreno-Bueno, Gema Hergueta-Redondo, Marta Williams, Caitlin Garcia-Santos, Guillermo Ghajar, Cyrus M. Nitadori-Hoshino, Ayuko Hoffman, Caitlin Badal, Karen Garcia, Benjamin A. Callahan, Margaret K. Yuan, Jianda Martins, Vilma R. Skog, Johan Kaplan, Rosandra N. Brady, Mary S. Wolchok, Jedd D. Chapman, Paul B. Kang, Yibin Bromberg, Jacqueline Lyden, David TI Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET SO NATURE MEDICINE LA English DT Article ID PREMETASTATIC NICHE; RELEASED EXOSOMES; SIGNALING PATHWAY; C-MET; CANCER; MICROVESICLES; GROWTH; RECRUITMENT; EXPRESSION; MECHANISM AB Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA- 4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process. C1 [Callahan, Margaret K.; Wolchok, Jedd D.; Chapman, Paul B.; Bromberg, Jacqueline] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Peinado, Hector; Matei, Irina; Costa-Silva, Bruno; Williams, Caitlin; Garcia-Santos, Guillermo; Nitadori-Hoshino, Ayuko; Badal, Karen; Lyden, David] Weill Cornell Med Coll, Dept Pediat, Childrens Canc & Blood Fdn Labs, New York, NY USA. [Peinado, Hector; Matei, Irina; Costa-Silva, Bruno; Williams, Caitlin; Garcia-Santos, Guillermo; Nitadori-Hoshino, Ayuko; Badal, Karen; Lyden, David] Weill Cornell Med Coll, Dept Cell, Childrens Canc & Blood Fdn Labs, New York, NY USA. [Peinado, Hector; Matei, Irina; Costa-Silva, Bruno; Williams, Caitlin; Garcia-Santos, Guillermo; Nitadori-Hoshino, Ayuko; Badal, Karen; Lyden, David] Weill Cornell Med Coll, Dept Dev Biol, Childrens Canc & Blood Fdn Labs, New York, NY USA. [Aleckovic, Masa; Garcia, Benjamin A.; Kang, Yibin] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. [Lavotshkin, Simon] Columbia Univ, Coll Phys & Surg, Dept Surg, New York, NY USA. [Costa-Silva, Bruno; Martins, Vilma R.] AC Camargo Hosp, Int Ctr Res & Educ, Sao Paulo, Brazil. [Moreno-Bueno, Gema; Hergueta-Redondo, Marta] Univ Autonoma Madrid, Inst Invest Biomed Alberto Sols, IdiPAZ Inst Invest Sanitaria La Paz, CSIC,Dept Bioquim, Madrid, Spain. [Moreno-Bueno, Gema; Hergueta-Redondo, Marta] Fdn MD Anderson Canc Ctr, Madrid, Spain. [Ghajar, Cyrus M.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. [Hoffman, Caitlin] Weill Cornell Med Coll, Dept Neurosurg, New York, NY USA. [Yuan, Jianda; Wolchok, Jedd D.] Sloan Kettering Inst, Ludwig Ctr Canc Immunotherapy, Dept Immunol, New York, NY USA. [Skog, Johan] Exosome Diagnost Inc, New York, NY USA. [Kaplan, Rosandra N.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Brady, Mary S.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Kang, Yibin] Canc Inst New Jersey, Genom Instabil & Tumor Progress Program, New Brunswick, NJ USA. [Kang, Yibin; Lyden, David] Champalimaud Metastasis Programme, Lisbon, Portugal. [Lyden, David] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. RP Bromberg, J (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. EM bromberj@mskcc.org; dcl2001@med.cornell.edu RI Peinado, Hector/A-6417-2013; Oncogenomica, Inct/H-9999-2013; Neurociencia, Inct/I-1011-2013; Francisco, Suely/D-9065-2014; Martins, Vilma/E-2547-2012; Moreno-Bueno, Gema/K-9354-2016; OI Martins, Vilma/0000-0002-2909-8502; Moreno-Bueno, Gema/0000-0002-5030-6687; Aleckovic, Masa/0000-0001-5653-8502 FU Children's Cancer and Blood Foundation; Manning Foundation; Hartwell Foundation; Pediatric Oncology Experimental Therapeutics Investigators Consortium; Stavros S. Niarchos Foundation; Champalimaud Foundation; Nancy C. and Daniel P. Paduano Foundation; Mary Kay Foundation; American Hellenic Educational Progressive Association; Malcolm Hewitt Wiener Foundation; George Best Costacos Foundation; NCI [NCI-R01CA 098234-01]; National Foundation for Cancer Research; Susan G. Komen for the Cure; Fundacion para el Fomento en Asturias de la Investigacion Cientifica Aplicada y la Tecnologia; Fundacion Universidad de Oviedo; Beth C. Tortolani Foundation; Sussman Family Fund; Charles and Marjorie Holloway Foundation; Manhassat Breast Cancer Fund; NIH [CA87637, R01-CA134519, R01-CA141062]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); National Science Foundation [CBET-0941143]; American Society; [NCI-U54-CA143836] FX We dedicate this work to the memory of James A. Paduano. We thank M. J. Bissell, A. Cano, J. Wels and S.R. Granitto for critical reading of this paper and suggestions. We also thank the members of our laboratories for helpful discussions and the members of the Weill Cornell Medical College electron microscopy and microarray core facilities for their support. We thank V. Hearing, (US National Institutes of Health (NIH), National Cancer Institute (NCI)) for providing the antibody to TYRP2 and D.C. Bennett (St. George's University of London) for providing the melan-a cell line. Our work is supported by grants from the Children's Cancer and Blood Foundation (H.P. and D.L.), The Manning Foundation (B.C.-S. and D.L.), The Hartwell Foundation (D.L.), Pediatric Oncology Experimental Therapeutics Investigators Consortium (H.P. and D.L.), Stavros S. Niarchos Foundation (D.L.), Champalimaud Foundation (H.P., Y.K. and D.L.), The Nancy C. and Daniel P. Paduano Foundation (H.P. and D.L.), The Mary Kay Foundation (A.N.-H. and D.L.), American Hellenic Educational Progressive Association 5th District (D.L.), The Malcolm Hewitt Wiener Foundation (D.L.), The George Best Costacos Foundation (D.L.), NCI (D.L., grant NCI-R01CA 098234-01), National Foundation for Cancer Research (D.L.), Susan G. Komen for the Cure (H.P. and D.L.), NCI-U54-CA143836 training grant (C.M.G. and D.L.), Fundacion para el Fomento en Asturias de la Investigacion Cientifica Aplicada y la Tecnologia (G.G.-S.), Fundacion Universidad de Oviedo (G.G.-S.), The Beth C. Tortolani Foundation (H.P., D.L. and J.B.), Sussman Family Fund (J.B.), Charles and Marjorie Holloway Foundation (J.B.), Manhassat Breast Cancer Fund (J.B.), NIH-CA87637 (J.B.), Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, V.R.M. and B.C.-S.), NIH (Y.K., grants R01-CA134519 and R01-CA141062), National Science Foundation grant CBET-0941143 and an American Society for Mass Spectrometry research award (B.A.G.). NR 58 TC 807 Z9 836 U1 45 U2 212 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUN PY 2012 VL 18 IS 6 BP 883 EP + DI 10.1038/nm.2753 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 956VD UT WOS:000305116600025 PM 22635005 ER PT J AU Avraham-Davidi, I Ely, Y Pham, VN Castranova, D Grunspan, M Malkinson, G Gibbs-Bar, L Mayseless, O Allmog, G Lo, B Warren, CM Chen, TT Ungos, J Kidd, K Shaw, K Rogachev, I Wan, WZ Murphy, PM Farber, SA Carmel, L Shelness, GS Iruela-Arispe, ML Weinstein, BM Yaniv, K AF Avraham-Davidi, Inbal Ely, Yona Pham, Van N. Castranova, Daniel Grunspan, Moshe Malkinson, Guy Gibbs-Bar, Liron Mayseless, Oded Allmog, Gabriella Lo, Brigid Warren, Carmen M. Chen, Tom T. Ungos, Josette Kidd, Kameha Shaw, Kenna Rogachev, Ilana Wan, Wuzhou Murphy, Philip M. Farber, Steven A. Carmel, Liran Shelness, Gregory S. Iruela-Arispe, M. Luisa Weinstein, Brant M. Yaniv, Karina TI ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1 SO NATURE MEDICINE LA English DT Article ID TRIGLYCERIDE TRANSFER PROTEIN; LOW-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-B; ENDOTHELIAL-CELLS; LIPID-METABOLISM; ZEBRAFISH; ABETALIPOPROTEINEMIA; HYPERCHOLESTEROLEMIA; HYPERLIPIDEMIA; PLASMA AB Despite the clear major contribution of hyperlipidemia to the prevalence of cardiovascular disease in the developed world, the direct effects of lipoproteins on endothelial cells have remained obscure and are under debate. Here we report a previously uncharacterized mechanism of vessel growth modulation by lipoprotein availability. Using a genetic screen for vascular defects in zebrafish, we initially identified a mutation, stalactite (stl), in the gene encoding microsomal triglyceride transfer protein (mtp), which is involved in the biosynthesis of apolipoprotein B (ApoB)-containing lipoproteins. By manipulating lipoprotein concentrations in zebrafish, we found that ApoB negatively regulates angiogenesis and that it is the ApoB protein particle, rather than lipid moieties within ApoB-containing lipoproteins, that is primarily responsible for this effect. Mechanistically, we identified downregulation of vascular endothelial growth factor receptor 1 (VEGFR1), which acts as a decoy receptor for VEGF, as a key mediator of the endothelial response to lipoproteins, and we observed VEGFR1 downregulation in hyperlipidemic mice. These findings may open new avenues for the treatment of lipoprotein-related vascular disorders. C1 [Avraham-Davidi, Inbal; Ely, Yona; Grunspan, Moshe; Malkinson, Guy; Gibbs-Bar, Liron; Mayseless, Oded; Allmog, Gabriella; Yaniv, Karina] Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel. [Pham, Van N.; Castranova, Daniel; Lo, Brigid; Ungos, Josette; Kidd, Kameha; Shaw, Kenna; Weinstein, Brant M.] NICHHD, Mol Genet Lab, US Natl Inst Hlth NIH, Bethesda, MD USA. [Warren, Carmen M.; Chen, Tom T.; Iruela-Arispe, M. Luisa] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA USA. [Rogachev, Ilana] Weizmann Inst Sci, Dept Plant Sci, IL-76100 Rehovot, Israel. [Wan, Wuzhou; Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD USA. [Farber, Steven A.] Carnegie Inst Sci, Dept Embryol, Baltimore, MD USA. [Carmel, Liran] Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Genet, Jerusalem, Israel. [Shelness, Gregory S.] Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol, Winston Salem, NC 27103 USA. RP Yaniv, K (reprint author), Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel. EM karina.yaniv@weizmann.ac.il RI Farber, Steven/G-5851-2012; Wan, Wuhzou/H-8556-2013 OI Farber, Steven/0000-0002-8037-7312; FU Israel Science Foundation [748/2009]; Marie Curie Actions-International Reintegration [FP7-PEOPLE-2009-RG 256393]; Yeda-Sela Center; Israel Cancer Research Foundation; US National Institutes of Health (NIH) [RO1CA126935]; NIH [T32HL069766, HL049373, R56DK093399, R01GM063904]; Carnegie Institution for Science endowment; G. Harold and Leila Y. Mathers Charitable Foundation; National Institute of Child Health and Human Development, NIH,; Foundation Leducq FX The authors would like to thank G. Palardy, R. Miyares, N. Nevo, I. Harel, T. Berkutzki, I. Raviv, R. Oren and C. Rot for technical assistance; A. Aharoni for help with GC-MS analyses; E. Zelzer (Weizmann Institute, Israel) for providing the Ldlr-null mice, K. Tordjman (Sourasky Medical Center, Israel) for providing the ApoE-null mice, S. Schulte-Merker (Hubrecht Institute) for providing the vegfr1 plasmid and the Tg(flt1: YFP)hu4624 transgenic line; J. Berliner (University of California Los Angeles, California) for providing human aortic endothelial cells (HAECs); D. Haratz, I. Groskop and A. Shaish for advice regarding lipid analyses; A. Harmelin and N. Stettner for animal care; and I. B. Dawid, E. Tzahor, A. Gross, B. Shilo and J. Torres-Vazquez for critical reading of the manuscript. The authors are grateful to all the members of the Yaniv and Weinstein labs for discussion, technical assistance and continuous support. This work was supported in part by Israel Science Foundation 748/2009 (to K.Y.), Marie Curie Actions-International Reintegration grants FP7-PEOPLE-2009-RG 256393 (to K.Y.), the Yeda-Sela Center (to K.Y.), the Israel Cancer Research Foundation Postdoctoral Fellowship (to I.A.-D.), US National Institutes of Health (NIH) RO1CA126935 (to M. L. I.-A.), NIH T32HL069766 (training grant for T. T. C. and C. M. W.) and NIH HL049373 (to G. S. S.). S. A. F. is funded by the NIH (R56DK093399 and R01GM063904), the Carnegie Institution for Science endowment and the G. Harold and Leila Y. Mathers Charitable Foundation. B. M. W. is supported by the intramural program of the National Institute of Child Health and Human Development, NIH, and by the Foundation Leducq. NR 53 TC 45 Z9 46 U1 1 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUN PY 2012 VL 18 IS 6 BP 967 EP + DI 10.1038/nm.2759 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 956VD UT WOS:000305116600036 PM 22581286 ER PT J AU Baur, JA Ungvari, Z Minor, RK Le Couteur, DG de Cabo, R AF Baur, Joseph A. Ungvari, Zoltan Minor, Robin K. Le Couteur, David G. de Cabo, Rafael TI Are sirtuins viable targets for improving healthspan and lifespan? SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID SMOOTH-MUSCLE-CELLS; SMALL-MOLECULE ACTIVATORS; NITRIC-OXIDE SYNTHASE; FATTY-ACID OXIDATION; STIMULATED INSULIN-SECRETION; APOLIPOPROTEIN E-DEFICIENT; CORONARY-ARTERY-DISEASE; PANCREATIC BETA-CELLS; RED WINE CONSTITUENT; AGGREGATION IN-VIVO AB Although the increased lifespan of our populations illustrates the success of modern medicine, the risk of developing many diseases increases exponentially with old age. Caloric restriction is known to retard ageing and delay functional decline as well as the onset of disease in most organisms. Studies have implicated the sirtuins (SIRT1-SIRT7) as mediators of key effects of caloric restriction during ageing. Two unrelated molecules that have been shown to increase SIRT1 activity in some settings, resveratrol and SRT1720, are excellent protectors against metabolic stress in mammals, making SIRT1 a potentially appealing target for therapeutic interventions. This Review covers the current status and controversies surrounding the potential of sirtuins as novel pharmacological targets, with a focus on SIRT1. C1 [Baur, Joseph A.] Univ Penn, Dept Physiol, Philadelphia, PA 19104 USA. [Baur, Joseph A.] Univ Penn, Inst Diabet Obes & Metab, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ungvari, Zoltan] Univ Oklahoma, Hlth Sci Ctr, Reynolds Oklahoma Ctr Aging, Stanton L Young Biomed Res Ctr 1303, Oklahoma City, OK 74104 USA. [Minor, Robin K.; de Cabo, Rafael] NIA, Lab Expt Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Le Couteur, David G.] Univ Sydney, CERA, Sydney, NSW 2139, Australia. [Le Couteur, David G.] Univ Sydney, ANZAC Res Inst, Sydney, NSW 2139, Australia. [Le Couteur, David G.] Concord RG Hosp, Sydney, NSW 2139, Australia. RP Baur, JA (reprint author), Univ Penn, Dept Physiol, Philadelphia, PA 19104 USA. EM baur@mail.med.upenn.edu; decabora@mail.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Baur, Joseph/0000-0001-8262-6549; , rafael/0000-0003-2830-5693 FU US National Institutes of Health (NIH); US National Institute on Aging; NIH [AT006526, AG031182]; Ellison Medical Foundation; National Health and Medical Research Council of Australia; Ageing and Alzheimer's Research Foundation FX The preparation of this manuscript was supported by the Intramural Research Program of the US National Institutes of Health (NIH), the US National Institute on Aging, research grants from the NIH (AT006526 to Z.U. and AG031182 to J.A.B.), the Ellison Medical Foundation, the National Health and Medical Research Council of Australia, and the Ageing and Alzheimer's Research Foundation. NR 291 TC 181 Z9 185 U1 3 U2 54 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 JUN PY 2012 VL 11 IS 6 BP 443 EP 461 DI 10.1038/nrd3738 PG 19 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 952AU UT WOS:000304762900020 PM 22653216 ER PT J AU Cella, D Lai, JS Nowinski, CJ Victorson, D Peterman, A Miller, D Bethoux, F Heinemann, A Rubin, S Cavazos, JE Reder, AT Sufit, R Simuni, T Holmes, GL Siderowf, A Wojna, V Bode, R McKinney, N Podrabsky, T Wortman, K Choi, S Gershon, R Rothrock, N Moy, C AF Cella, D. Lai, J-S. Nowinski, C. J. Victorson, D. Peterman, A. Miller, D. Bethoux, F. Heinemann, A. Rubin, S. Cavazos, J. E. Reder, A. T. Sufit, R. Simuni, T. Holmes, G. L. Siderowf, A. Wojna, V. Bode, R. McKinney, N. Podrabsky, T. Wortman, K. Choi, S. Gershon, R. Rothrock, N. Moy, C. TI Neuro-QOL Brief measures of health-related quality of life for clinical research in neurology SO NEUROLOGY LA English DT Article ID PATIENT-REPORTED OUTCOMES; DISEASE AB Objective: To address the need for brief, reliable, valid, and standardized quality of life (QOL) assessment applicable across neurologic conditions. Methods: Drawing from larger calibrated item banks, we developed short measures (8-9 items each) of 13 different QOL domains across physical, mental, and social health and evaluated their validity and reliability. Three samples were utilized during short form development: general population (Internet-based, n = 2,113); clinical panel (Internet-based, n = 553); and clinical outpatient (clinic-based, n = 581). All short forms are expressed as T scores with a mean of 50 and SD of 10. Results: Internal consistency (Cronbach alpha) of the 13 short forms ranged from 0.85 to 0.97. Correlations between short form and full-length item bank scores ranged from 0.88 to 0.99 (0.82-0.96 after removing common items from banks). Online respondents were asked whether they had any of 19 different chronic health conditions, and whether or not those reported conditions interfered with ability to function normally. All short forms, across physical, mental, and social health, were able to separate people who reported no health condition from those who reported 1-2 or 3 or more. In addition, scores on all 13 domains were worse for people who acknowledged being limited by the health conditions they reported, compared to those who reported conditions but were not limited by them. Conclusion: These 13 brief measures of self-reported QOL are reliable and show preliminary evidence of concurrent validity inasmuch as they differentiate people based upon number of reported health conditions and whether those reported conditions impede normal function. Neurology (R) 2012;78:1860-1867 C1 [Cella, D.; Lai, J-S.; Nowinski, C. J.; Victorson, D.; Heinemann, A.; Sufit, R.; Simuni, T.; Bode, R.; McKinney, N.; Podrabsky, T.; Wortman, K.; Choi, S.; Gershon, R.; Rothrock, N.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Peterman, A.] Univ N Carolina, Charlotte, NC 28223 USA. [Miller, D.; Bethoux, F.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Heinemann, A.] Rehabil Inst Chicago, Chicago, IL 60611 USA. [Rubin, S.] Northshore Univ Hlth Syst, Evanston, IL USA. [Cavazos, J. E.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Reder, A. T.] Univ Chicago, Chicago, IL 60637 USA. [Holmes, G. L.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Hanover, NH 03756 USA. [Siderowf, A.] Univ Penn, Philadelphia, PA 19104 USA. [Wojna, V.] Univ Puerto Rico, San Juan, PR 00936 USA. [Moy, C.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP Cella, D (reprint author), Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. EM d-cella@northwestern.edu RI Cavazos, Jose/J-4122-2016; OI Cavazos, Jose/0000-0001-5777-2608; Wojna, Valerie/0000-0002-4014-9921; Heinemann, Allen/0000-0003-2782-7326 FU National Institute of Neurological Disorders and Stroke (NINDS) [HHSN265200423601C, U01 NS 056 975 02, NHLBI K23: K23HL085766]; NIH [HHSN265200423601C, HHSN260200600007C, HHS-N-260-2006-00007-C, R01HD054569-02NIDRR, 1U01NS056975-01, R01 CA104883, HHSN26520043601C, 2U54NS43011, U54RR022762, S11NS46278, N01-AG-6-0007, 1U5AR057943-01, HHSN260200600007, 1U01DK082342-01, AG-260-06-01, HD05469]; Teva Pharmaceuticals; American Cancer Society (national and Illinois Division); TEVA Neuro-Sciences; Biogen Idec; Consortium of Multiple Sclerosis Centers; Enhancing Quality of Prosthetic and Orthotic Services with Process and Outcome Information, National Institute on Disability and Rehabilitation Research [H133E080009]; Rehabilitation Research and Training Center on Improving Measurement of Medical Rehabilitation Outcomes [H133B090024]; National Institute on Disability and Rehabilitation Research; Midwest Regional Spinal Cord Injury Care System [H133N060014]; Midwest Regional Traumatic Brain Injury Care System, National Institute on Disability and Rehabilitation Research [H133A080045]; Morris K. Udall Parkinson's Disease Research Center of Excellence from NINDS [NS-053488]; Department of Health of the Commonwealth of Pennsylvania [SAP4100027296]; NIA [1RC2AG036498-01]; NIDRR [H133B090024, OppNet: N01-AG-6-0007]; Center for Disease Control and Prevention FX The Neuro-QOL project was supported by the National Institute of Neurological Disorders and Stroke (NINDS) contract number HHSN265200423601C (PI: David Cella).; Dr. Cella has received research support from the National Institute of Neurological Disorders and Stroke (NINDS) contract number HHSN265200423601C. Dr. Lai reports no disclosures. Dr. Nowinski receives or has received research support from the NIH (contracts #HHSN265200423601C and #HHSN260200600007C) and Teva Pharmaceuticals. She has also received honoraria for writing an article for Medlink. Dr. Victorson holds stock options in Eli Lily and Company, received an honoraria for serving on the Steering Committee of the Reeve Neuro-Recovery Network, was funded by NIH contracts #HHSN265200423601C and #HHS-N-260-2006-00007-C and grants #R01HD054569-02NIDRR, #1U01NS056975-01, and #R01 CA104883, received support from the American Cancer Society (national and Illinois Division) for research in prostate cancer, received institutional support from NorthShore University HealthCare System for research in prostate cancer, received institutional support from the Medical University of South Carolina for sarcoidosis research, and received institutional support from the Northwestern Medical Faculty Foundation for urology research. Dr. Peterman receives royalties from an online entry in UpToDate; was supported by NIH Contract # HHSN265200423601C for the study on which this manuscript reports; and received institutional funding for research on spirituality and health. Dr. Miller has received research support from NIH contract HHSN26520043601C and TEVA Neuro-Sciences. She has received consulting fees from Biogen Idec and the Consortium of Multiple Sclerosis Centers. She serves on the editorial board of Quality of Life Research. Dr. Bethoux receives honoraria for consulting from Medtronic Inc., Biogen Idec, and IMPAX Laboratories. Dr. Heinemann receives salary support from a variety of federal research and training grants: Enhancing Quality of Prosthetic and Orthotic Services with Process and Outcome Information, National Institute on Disability and Rehabilitation Research (H133E080009); Rehabilitation Research and Training Center on Improving Measurement of Medical Rehabilitation Outcomes (H133B090024), National Institute on Disability and Rehabilitation Research; Midwest Regional Spinal Cord Injury Care System (H133N060014), National Institute on Disability and Rehabilitation Research; Midwest Regional Traumatic Brain Injury Care System, National Institute on Disability and Rehabilitation Research (H133A080045); Development of Quality Measures for Post-Stroke Rehabilitation, NIDRR/USDE. Dr. Rubin, Dr. Cavazos, and Dr. Reder report no disclosures. Dr. Sufit has served on Data Safety and Monitoring Boards for the NINDS and Pfizer Pharmaceuticals. He has received honoraria for speaking engagements from Hill-Rom. He has served as an expert in medical malpractice litigation. Dr. Simuni reports no disclosures. Dr. Holmes serves on the Advisory Board for Questcor Pharmaceuticals, Sunovion Pharmaceuticals, and Upsher-Smith Laboratories. Dr. Siderowf is supported by a Morris K. Udall Parkinson's Disease Research Center of Excellence grant from NINDS (NS-053488), and has been supported by SAP4100027296, a health research grant awarded by the Department of Health of the Commonwealth of Pennsylvania from the Tobacco Master Settlement Agreement under Act 2001-77. Dr. Wojna has received personal compensation for activities with GlaxoSmithKline as a speaker and research support from Biogen Idec. and is funded by NIH grants #2U54NS43011, #U54RR022762 (pilot study), and #S11NS46278. Dr. Bode, N. McKinney, T. Podrabsky, K. Wortman, and Dr. Choi report no disclosures. Dr.; Gershon has received personal compensation for activities as a speaker and consultant with Sylvan Learning, Rockman, and the American Board of Podiatric Surgery. He has several grants awarded by NIH: N01-AG-6-0007, 1U5AR057943-01, HHSN260200600007, 1U01DK082342-01, AG-260-06-01, HD05469, NINDS: U01 NS 056 975 02, NHLBI K23: K23HL085766, NIA: 1RC2AG036498-01, NIDRR: H133B090024, OppNet: N01-AG-6-0007 (PI: David Cella). Dr. Rothrock receives royalties from the publication of "Evaluation of Health-Related Quality of Life" in UpToDate. She receives research support from the National Institutes of Health and previously the Center for Disease Control and Prevention. Dr. Moy reports no disclosures. Go to Neurology.org for full disclosures. NR 19 TC 51 Z9 51 U1 5 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN PY 2012 VL 78 IS 23 BP 1860 EP 1867 DI 10.1212/WNL.0b013e318258f744 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 953XC UT WOS:000304906100014 PM 22573626 ER PT J AU Graybeal, C Kiselycznyk, C Holmes, A AF Graybeal, C. Kiselycznyk, C. Holmes, A. TI STRESS-INDUCED IMPAIRMENTS IN PREFRONTAL-MEDIATED BEHAVIORS AND THE ROLE OF THE N-METHYL-D-ASPARTATE RECEPTOR SO NEUROSCIENCE LA English DT Review DE stress; prefrontal cortex; cognition; extinction; glutamate; N-methyl-D-aspartate ID SPATIAL WORKING-MEMORY; DORSAL RAPHE NUCLEUS; NR2B-CONTAINING NMDA RECEPTORS; CHRONIC UNPREDICTABLE STRESS; MAJOR DEPRESSIVE DISORDER; REACTION-TIME-TASK; MORRIS WATER-MAZE; FEAR EXTINCTION; CONDITIONED FEAR; PSYCHOTOMIMETIC PHENCYCLIDINE AB The prefrontal cortex (PFC) mediates higher-order cognitive and executive functions that subserve various complex, adaptable behaviors, such as cognitive flexibility, attention, and working memory. Deficits in these functions typify multiple neuropsychiatric disorders that are caused or exacerbated by exposure to psychological stress. Here we review recent evidence examining the effects of stress on executive and cognitive functions in rodents and discuss an emerging body of evidence that implicates the N-methyl-D-aspartate receptor (NMDAR) as a potentially critical molecular mechanism mediating these effects. Future work in this area could open up new avenues for developing pharmacotherapies for ameliorating cognitive dysfunction in neuropsychiatric disease. This article is part of a Special Issue entitled: Neuroscience Disease Models. (c) 2012 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Graybeal, C.; Kiselycznyk, C.; Holmes, A.] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD 20892 USA. RP Graybeal, C (reprint author), NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD 20892 USA. EM graybealc@mail.nih.gov FU Intramural NIH HHS [ZIA AA000411-08] NR 160 TC 12 Z9 12 U1 1 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUN 1 PY 2012 VL 211 SI SI BP 28 EP 38 DI 10.1016/j.neuroscience.2012.02.042 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 955WA UT WOS:000305050400004 PM 22414923 ER PT J AU Li, P Deng, SS Wang, JB Iwata, A Qiao, YL Dai, XB Boffetta, P AF Li, P. Deng, S-S Wang, J-B Iwata, A. Qiao, Y-L Dai, X-B Boffetta, P. TI Occupational and environmental cancer incidence and mortality in China SO OCCUPATIONAL MEDICINE-OXFORD LA English DT Article DE Cancer; environmental agents; occupational agents; population attributable fraction ID LUNG-CANCER; RISK; RADON; MESOTHELIOMA; ASBESTOS AB Background Most cancers are due to environmental, occupational or other non-genetic factors and are potentially preventable. Aims To provide an evidence-based assessment of the burden of occupational and environmental-related cancers in China in 2005. Methods The population attributable fraction (PAF) was calculated based on the assumption of no occupational agent exposure. Relative risk estimates for specific cancers of interest and prevalence of exposure were mainly derived from large-scale studies. Data on cancer incidence and mortality was obtained from the Third National Death Cause Survey and cancer registries in China. Results We estimated that a total of 48 511 deaths of cancer were attributable to occupational agents in China in 2005, with 34 975 among men (3.1% of all cancer deaths) and 13 536 among women (2.1%). A total of 59 410 incident cases of cancer were attributable to occupational agents in China in 2005, with 42 724 among men (2.8% of all cancer incident cases) and 16 686 among women (1.6%). The highest PAF was observed for mesothelioma with asbestos, followed by leukaemia, bladder and lung cancers. Indoor radon was responsible for 0.2% of lung cancer-related deaths among men and women. Conclusions Occupational agents represent an important cause of cancer, but indoor radon plays a relatively limited role in cancer causes in China. Our report provides strong evidence of the need for policy makers to develop strategies to reduce the risk of occupational cancers. C1 [Wang, J-B; Qiao, Y-L] Chinese Acad Med Sci, Dept Canc Epidemiol, Inst Canc, Beijing 100021, Peoples R China. [Li, P.; Dai, X-B] Chongqing Med Univ, Dept Occupat & Environm Hlth, Sch Publ Hlth, Chongqing 400016, Peoples R China. [Li, P.] Xian Ctr Dis Control & Prevent, Xian 710054, Peoples R China. [Deng, S-S] Sichuan Univ, Dept Occupat Hlth, Sch Publ Hlth, Chengdu 610041, Peoples R China. [Wang, J-B] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. [Iwata, A.] NYU, Sch Med, New York, NY 10021 USA. [Boffetta, P.] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, P.] Int Prevent Res Inst, F-69006 Lyon, France. RP Qiao, YL (reprint author), Chinese Acad Med Sci, Dept Canc Epidemiol, Inst Canc, 17 S Panjiayuan Lane, Beijing 100021, Peoples R China. EM qiaoy@cicams.ac.cn; mayvivian2004@yahoo.com.cn RI Qiao, You-Lin/B-4139-2012 OI Qiao, You-Lin/0000-0001-6380-0871 FU International Agency for Research on Cancer (Lyon, France) [GEE/08/19] FX Funding; International Agency for Research on Cancer (Lyon, France) (CRA No GEE/08/19). NR 30 TC 5 Z9 6 U1 1 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0962-7480 EI 1471-8405 J9 OCCUP MED-OXFORD JI Occup. Med.-Oxf. PD JUN PY 2012 VL 62 IS 4 BP 281 EP 287 DI 10.1093/occmed/kqs016 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 952YT UT WOS:000304833100011 PM 22411970 ER PT J AU Ramulu, PY Maul, E Hochberg, C Chan, ES Ferrucci, L Friedman, DS AF Ramulu, Pradeep Y. Maul, Eugenio Hochberg, Chad Chan, Emilie S. Ferrucci, Luigi Friedman, David S. TI Real-World Assessment of Physical Activity in Glaucoma Using an Accelerometer SO OPHTHALMOLOGY LA English DT Article ID MOBILITY PERFORMANCE; VISUAL IMPAIRMENT; LENS OPACITIES; UNITED-STATES; EYE; DISABILITY; DISEASE; PROJECT; FALLS; RISK AB Objective: To determine the association between glaucomatous visual field (VF) loss and the amount of physical activity and walking in normal life. Design: Prospective, observational study. Participants: Glaucoma suspects without significant VF or visual acuity loss (controls) and glaucoma subjects with bilateral VF loss between 60 and 80 years of age. Methods: Participants wore an accelerometer over 7 days of normal activity. Main Outcome Measures: Daily minutes of moderate or vigorous physical activity (MVPA) was the primary measure. Steps per day was a secondary measure. Results: Fifty-eight controls and 83 glaucoma subjects provided sufficient study days for analysis. Control and glaucoma subjects were similar in age, race, gender, employment status, cognitive ability, and comorbid illness (P>0.1 for all). Better-eye VF mean deviation (MD) averaged 0.0 decibels (dB) in controls and -11.1 dB in glaucoma subjects. The median control subject engaged in 16.1 minutes of MVPA daily and walked 5891 steps/day, as compared with 12.9 minutes of MVPA daily (P = 0.25) and 5004 steps/day (P = 0.05) for the median glaucoma subject. In multivariate models, glaucoma was associated with 21% less MVPA (95% confidence interval [CI], -53% to 32%; P = 0.37) and 12% fewer steps per day (95% CI, -22% to 9%; P = 0.21) than controls, although differences were not statistically significant. There was a significant dose response relating VF loss to decreased activity, with each 5 dB decrement in the better-eye VF associated with 17% less MVPA (95% CI, -30% to -2%; P = 0.03) and 10% fewer steps per day (95% CI, -16% to -5%; P = 0.001). Glaucoma subjects in the most severe tertile of VF damage (better-eye VF MD worse than -13.5 dB) engaged in 66% less MVPA than controls (95% CI, -82% to -37%; P = 0.001) and took 31% fewer steps per day (95% CI, -44% to -15%; P = 0.001). Other significant predictors of decreased physical activity included older age, comorbid illness, depressive symptoms, and higher body mass index. Conclusions: Overall, no significant difference in physical activity was found between individuals with and without glaucoma, although substantial reductions in physical activity and walking were noted with greater levels of VF loss. Further study is needed to characterize better the relationship between glaucoma and physical activity. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2012;119:1159-1166 (C) 2012 by the American Academy of Ophthalmology. C1 [Ramulu, Pradeep Y.; Maul, Eugenio; Hochberg, Chad; Chan, Emilie S.; Friedman, David S.] Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Bethesda, MD 20892 USA. RP Ramulu, PY (reprint author), Johns Hopkins Univ, Wilmer Eye Inst, 600 N Wolfe St,Maumenee B-110, Baltimore, MD 21287 USA. EM pramulu1@jhmi.edu FU American Geriatrics Society, New York, NY; National Institutes of Health, Bethesda, Maryland [EY018595]; Research to Prevent Blindness, New York, New York; National Institute of Aging, National Institutes of Health FX Supported in part by the Dennis W. Jahnigen Memorial Award, the American Geriatrics Society, New York, NY; the National Institutes of Health, Bethesda, Maryland (grant no.: EY018595); the Robert and Helen Schaub Special Scholar Award, Research to Prevent Blindness, New York, New York; and the Intramural Research Program of the National Institute of Aging, National Institutes of Health. All funding organizations had no role in the design or conduct of this research. NR 37 TC 26 Z9 26 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD JUN PY 2012 VL 119 IS 6 BP 1159 EP 1166 DI 10.1016/j.ophtha.2012.01.013 PG 8 WC Ophthalmology SC Ophthalmology GA 951JP UT WOS:000304717100011 PM 22386950 ER PT J AU Nielsen-Saines, K Komarow, L Cu-Uvin, S Jourdain, G Klingman, KL Shapiro, DE Mofenson, L Moran, L Campbell, TB Hitti, J Fiscus, S Currier, J AF Nielsen-Saines, Karin Komarow, Lauren Cu-Uvin, Susan Jourdain, Gonzague Klingman, Karin L. Shapiro, David E. Mofenson, Lynne Moran, Laura Campbell, Thomas B. Hitti, Jane Fiscus, Susan Currier, Judith CA ACTG 5190 PACTG Study Team TI Infant Outcomes After Maternal Antiretroviral Exposure in Resource-Limited Settings SO PEDIATRICS LA English DT Article DE maternal ARV exposure; infant safety; ARV toxicities; A5190; P1054; MTCT; HIV ID UNINFECTED CHILDREN BORN; HIV-INFECTED MOTHERS; MORTALITY; THERAPY; NEVIRAPINE; TRANSMISSION; PREGNANCY; MORBIDITY; ZAMBIA; MALAWI AB BACKGROUND AND OBJECTIVE: The impact of maternal antiretrovirals (ARVs) during pregnancy, labor, and postpartum on infant outcomes is unclear. METHODS: Infants born to HIV-infected mothers in ARV studies were followed for 18 months. RESULTS: Between June 2006 and December 2008, 236 infants enrolled from Africa (n = 36), India (n = 47), Thailand (n = 152), and Brazil (n = 1). Exposure to ARVs in pregnancy included >= 3 ARVs (10%), zidovudine/intrapartum ARV (81%), and intrapartum ARV (9%). There were 4 infant infections (1 in utero, 3 late postpartum) and 4 deaths with 1.8% mortality (95% confidence interval [CI], 0.1%-3.5%) and 96.4% HIV-1-free survival (95% CI, 94.0%-98.9%). Birth weight was >= 2.5 kg in 86%. In the first 6 months, Indian infants (nonbreastfed) had lowest median weights and lengths and smallest increases in growth. After 6 months, African infants had the lowest median weight and weight-for-age z scores. Infants exposed to highest maternal viral load had the lowest height and height-for-age z scores. Serious adverse events occurred in 38% of infants, did not differ by country, and correlated with less maternal ARV exposure. Clinical diagnoses were seen in 84% of Thai, 31% of African, and 9% of Indian infants. Congenital defects/inborn errors of metabolism were seen in 18 (7.6%) infants, of which 17 were Thai (11%: 95% CI, 6.7%-17.0%); none had first trimester ARV exposure. CONCLUSIONS: Infant follow-up in large international cohorts is feasible and provides important safety and HIV transmission data following maternal ARV exposure. Increased surveillance increases identification of congenital/inborn errors. Pediatrics 2012;129:e1525-e1532 C1 [Nielsen-Saines, Karin] David Geffen UCLA Sch Med, Div Infect Dis, Dept Pediat, Los Angeles, CA 90095 USA. [Currier, Judith] David Geffen UCLA Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Komarow, Lauren; Shapiro, David E.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Cu-Uvin, Susan] Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Jourdain, Gonzague] Inst Rech Dev, Chiang Mai, Thailand. [Klingman, Karin L.] NIAID, Bethesda, MD 20892 USA. [Mofenson, Lynne] NICHHD, Bethesda, MD 20892 USA. [Moran, Laura] Ctr Infect Dis Res Social & Sci Syst, Silver Spring, MD USA. [Campbell, Thomas B.] Univ Colorado Denver, Dept Med, Aurora, CO USA. [Hitti, Jane] Univ Washington, Sch Med, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Fiscus, Susan] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. RP Nielsen-Saines, K (reprint author), David Geffen UCLA Sch Med, Div Infect Dis, Dept Pediat, MDCC 22-442,10833 LeConte Ave, Los Angeles, CA 90095 USA. EM knielsen@mednet.ucla.edu OI Mofenson, Lynne/0000-0002-2818-9808 FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068636, U01 AI068632]; National Institute of Mental Health (NIMH) [AI068632]; National Institute of Dental and Craniofacial Research (NIDCR); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Statistical and Data Analysis Center at the Harvard School of Public Health, under NIAID [5 U01 AI41110]; Pediatric AIDS Clinical Trials Group (PACTG); IMPAACT Group [1 U01 AI068616]; NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network; NICHD [N01-DK-9-01/HHSN267200800001C, N01-HD-3-3345]; HIV Prevention Trials Network (HPTN); National Institute on Drug Abuse; Office of AIDS Research, of the National Institutes of Health, US Department of Health and Human Services [U01 AI046749]; NIH/NIAID [U01 AI047986]; IMPAACT CTU [U01 AI069401, 5 U01 AI069450]; Statistical and Data Management Center of the AIDS Clinical Trials Group [ACTG]; Siriraj Hospital Mahidol University [U01AI069512]; YRG CARE Medical Center VHS Chennai CRS [U01 AI069432]; Bhumibol Adulyadej Hospital CRS [U01 AI069429]; Chiang Mai University Pediatrics-Obstetrics CRS [5 U01 AI069399-05]; Prapokklao Hospital CRS [U01 AI069429]; Chonburi Hospital CRS [U01 AI069429]; College of Medical JHU CRS [1 U01 AI069518]; Provincial Hospital CRS [U01 AI069429]; University of North Carolina Lilongwe CRS [1 U01 AI069518]; Parirenyatwa CRS, UZ-UCSF CTU, Harare Zimbabwe CRS [5 U01 AI069436-02]; Wits HIV CRS [1 U01 AI069463-01]; Chiang Rai Regional Hospital CRS [U01 AI069429]; [AI68634] FX The project described was supported by award U01 AI068636 from the National Institute of Allergy and Infectious Diseases (NIAID) and supported by the National Institute of Mental Health (NIMH) and the National Institute of Dental and Craniofacial Research (NIDCR). Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the NIAID (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the NIMH (AI068632). This work was supported by the Statistical and Data Analysis Center at the Harvard School of Public Health, under NIAID cooperative agreement 5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and 1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the NIAID and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract N01-DK-9-01/HHSN267200800001C). This study was also supported by the HIV Prevention Trials Network (HPTN) and sponsored by the NIAID, NICHD, National Institute on Drug Abuse, NIMH, and Office of AIDS Research, of the National Institutes of Health, US Department of Health and Human Services, under award U01 AI046749. The UCLA HPTU was supported through U01 AI047986, NIH/NIAID, and the IMPAACT CTU through U01 AI069401, NIH/NIAID. The University of Colorado CTU was supported through award 5 U01 AI069450, NIH/NIAID. Additional support was provided by grants AI68634 (Statistical and Data Management Center of the AIDS Clinical Trials Group [ACTG]); U01AI069512 (Siriraj Hospital Mahidol University, Site 8251); U01 AI069432 (YRG CARE Medical Center VHS Chennai CRS, Site 11701); U01 AI069429 (Bhumibol Adulyadej Hospital CRS, Site 8355); 5 U01 AI069399-05 (Chiang Mai University Pediatrics-Obstetrics CRS, Site 20101); U01 AI069429 (Prapokklao Hospital CRS, Site 8354); U01 AI069429 (Chonburi Hospital CRS, Site 8356); 1 U01 AI069518 (College of Medical JHU CRS, Site 30301); U01 AI069429 (Provincial Hospital CRS, Site 8353); 1 U01 AI069518 (University of North Carolina Lilongwe CRS, Site 12001); 5 U01 AI069436-02 (Parirenyatwa CRS, UZ-UCSF CTU, Harare Zimbabwe CRS, Site 30313); 1 U01 AI069463-01 (Wits HIV CRS, Site 11101); U01 AI069429 (Chiang Rai Regional Hospital CRS, Site 8352); NICHD contract N01-HD-3-3345 (Hospital dos Servidores Rio de Janeiro NICHD CRS, Site 5072). Funded by the National Institutes of Health (NIH). NR 21 TC 8 Z9 8 U1 1 U2 6 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2012 VL 129 IS 6 BP E1525 EP E1532 DI 10.1542/peds.2011-2340 PG 8 WC Pediatrics SC Pediatrics GA 951FT UT WOS:000304707000020 PM 22585772 ER PT J AU O'Shea, CJ Sloan, JL Wiggs, EA Pao, M Gropman, A Baker, EH Manoli, I Venditti, CP Snow, J AF O'Shea, Colin J. Sloan, Jennifer L. Wiggs, Edythe A. Pao, Maryland Gropman, Andrea Baker, Eva H. Manoli, Irini Venditti, Charles P. Snow, Joseph TI Neurocognitive Phenotype of Isolated Methylmalonic Acidemia SO PEDIATRICS LA English DT Article DE basal ganglia; cognition; FSIQ; hyperammonemia; IQ; methylmalonic acidemia; MMA; neuropsychology ID EARLY-TREATED PHENYLKETONURIA; WHITE-MATTER ABNORMALITIES; SYRUP-URINE-DISEASE; GLOBUS-PALLIDUS; INBORN ERROR; ACIDURIA; CHILDREN; MANAGEMENT; MUT(-); NEURODEGENERATION AB OBJECTIVE: Methylmalonic acidemia (MMA) is a metabolic disorder with a poorly defined long-term neurocognitive phenotype. We studied the neuropsychological outcomes of patients and examined clinical covariates that influenced cognition. METHODS: A diverse cohort with mut, cblA, or cblB subtypes of isolated MMA (N = 43), ages 2 to 32 years, were evaluated at a single center over a 6-year period. The influence of clinical, laboratory, and metabolic parameters on neuropsychological testing results was determined. RESULTS: Early-onset mut patients (n = 21) manifested the most severe neurocognitive impairments, with a mean +/- SD full-scale IQ (FSIQ) of 71.1 +/- 14.75. Late-onset mut patients (n = 6) had a mean FSIQ of 88.5 +/- 27.62. cblA (n = 7), cblB (n = 6), and mut patients diagnosed prenatally or by newborn screening (n = 3) obtained mean FSIQs in the average range (100.7 +/- 10.95, 96.6 +/- 10.92, and 106.7 +/- 6.66, respectively). Hyperammonemia at diagnosis and the presence of a seizure disorder were associated with a lower FSIQ (P = .001 and P = .041, respectively), but other clinical variables, including basal ganglia injury and mutation status, did not. FSIQ remained stable over longitudinal testing (n = 10). Decreased scores on processing speed, compared with all other intellectual domains, emerged as a specific neurocognitive manifestation. CONCLUSIONS: The neurocognitive outcomes seen in isolated MMA are highly variable. An earlier age of disease onset, the presence of hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairment. In all patient subtypes, selective deficits in processing speed were present. Pediatrics 2012;129:e1541-e1551 C1 [O'Shea, Colin J.; Pao, Maryland; Snow, Joseph] NIMH, Off Clin Director, Bethesda, MD 20892 USA. [Sloan, Jennifer L.; Gropman, Andrea; Manoli, Irini; Venditti, Charles P.] NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Wiggs, Edythe A.] NINDS, Off Clin Director, Bethesda, MD 20892 USA. [Baker, Eva H.] NIH, Bethesda, MD 20892 USA. [Gropman, Andrea] Childrens Natl Med Ctr, Div Neurol, Washington, DC 20010 USA. RP Venditti, CP (reprint author), NIH, Bldg 49,Room 4A18, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov OI Manoli, Irini/0000-0003-1543-2941 FU National Human Genome Research Institute, National Institutes of Health (NIH); National Institute of Mental Health, NIH; National Institute of Neurological Disorders and Stroke, NIH; National Institutes of Health Clinical Center; National Institutes of Health (NIH) FX Drs Sloan, Gropman, Manoli, and Venditti were supported, in part, by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (NIH). Mr O'Shea, Dr Pao, and Dr Snow were supported, in part, by the Intramural Research Program of the National Institute of Mental Health, NIH. Dr Wiggs was supported, in part, by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH. Dr Baker was supported, in part, by the National Institutes of Health Clinical Center. Funded by the National Institutes of Health (NIH). NR 38 TC 10 Z9 10 U1 1 U2 7 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2012 VL 129 IS 6 BP E1541 EP E1551 DI 10.1542/peds.2011-1715 PG 11 WC Pediatrics SC Pediatrics GA 951FT UT WOS:000304707000022 PM 22614770 ER PT J AU Smith, PB Ambalavanan, N Li, L Cotten, CM Laughon, M Walsh, MC Das, A Bell, EF Carlo, WA Stoll, BJ Shankaran, S Laptook, AR Higgins, RD Goldberg, RN AF Smith, P. Brian Ambalavanan, Namasivayam Li, Lei Cotten, C. Michael Laughon, Matthew Walsh, Michele C. Das, Abhik Bell, Edward F. Carlo, Waldemar A. Stoll, Barbara J. Shankaran, Seetha Laptook, Abbot R. Higgins, Rosemary D. Goldberg, Ronald N. CA Generic Database Subcomm Eunice Kennedy Shriver Natl Inst C Neonatal Res Network TI Approach to Infants Born at 22 to 24 Weeks' Gestation: Relationship to Outcomes of More-Mature Infants SO PEDIATRICS LA English DT Article DE low-birth weight infant; NICUs; treatment; patient outcome assessment ID NEONATAL RESEARCH NETWORK; BIRTH-WEIGHT; ANTENATAL CORTICOSTEROIDS; PRETERM INFANTS; AGE ESTIMATION; UNITED-STATES; VIABILITY; MORTALITY; VOLUME; RATES AB OBJECTIVE: We sought to determine if a center's approach to care of premature infants at the youngest gestational ages (22-24 weeks' gestation) is associated with clinical outcomes among infants of older gestational ages (25-27 weeks' gestation). METHODS: Inborn infants of 401 to 1000 g birth weight and 22 0/7 to 27 6/7 weeks' gestation at birth from 2002 to 2008 were enrolled into a prospectively collected database at 20 centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Markers of an aggressive approach to care for 22- to 24-week infants included use of antenatal corticosteroids, cesarean delivery, and resuscitation. The primary outcome was death before postnatal day 120 for infants of 25 to 27 weeks' gestation. Secondary outcomes were the combined outcomes of death or a number of morbidities associated with prematurity. RESULTS: Our study included 3631 infants 22 to 24 weeks' gestation and 5227 infants 25 to 27 weeks' gestation. Among the 22- to 24-week infants, use of antenatal corticosteroids ranged from 28% to 100%, cesarean delivery from 13% to 65%, and resuscitation from 30% to 100% by center. Centers with higher rates of antenatal corticosteroid use in 22-to 24-week infants had reduced rates of death, death or retinopathy of prematurity, death or late-onset sepsis, death or necrotizing enterocolitis, and death or neurodevelopmental impairment in 25- to 27-week infants. CONCLUSIONS: This study suggests that physicians' willingness to provide care to extremely low gestation infants as measured by frequency of use of antenatal corticosteroids is associated with improved outcomes for more-mature infants. Pediatrics 2012;129:e1508-e1516 C1 [Smith, P. Brian; Cotten, C. Michael; Goldberg, Ronald N.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Ambalavanan, Namasivayam; Carlo, Waldemar A.] Univ Alabama Birmingham, Div Neonatol, Birmingham, AL USA. [Li, Lei; Das, Abhik] RTI Int, Res Triangle Pk, NC USA. [Laughon, Matthew] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Walsh, Michele C.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, Barbara J.] Childrens Healthcare Atlanta, Dept Pediat, Atlanta, GA USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Laptook, Abbot R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Smith, PB (reprint author), Duke Clin Res Inst, Box 17969, Durham, NC 27715 USA. EM brian.smith@duke.edu RI Smith, Phillip/I-5565-2014; OI Ambalavanan, Namasivayam/0000-0003-0731-9092 FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Child Health and Human Development [1K23HD060040-01, DHHS-1R18AE000028-01, 5U10 HD040492-10, SBIR 2RRHD057713-02] FX The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development provided grant support for the Neonatal Research Network's Generic Database Study. Dr Smith received support from National Institute of Child Health and Human Development 1K23HD060040-01 and DHHS-1R18AE000028-01. Dr Cotten received support from National Institute of Child Health and Human Development 5U10 HD040492-10 and SBIR 2RRHD057713-02. Funded by the National Institutes of Health (NIH). NR 26 TC 37 Z9 38 U1 0 U2 8 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD JUN PY 2012 VL 129 IS 6 BP E1508 EP E1516 DI 10.1542/peds.2011-2216 PG 9 WC Pediatrics SC Pediatrics GA 951FT UT WOS:000304707000018 PM 22641761 ER PT J AU Solomon, BD Hadley, DW Pineda-Alvarez, DE Kamat, A Teer, JK Cherukuri, PF Hansen, NF Cruz, P Young, AC Berkman, BE Chandrasekharappa, SC Mullikin, JC AF Solomon, Benjamin D. Hadley, Donald W. Pineda-Alvarez, Daniel E. Kamat, Aparna Teer, Jamie K. Cherukuri, Praveen F. Hansen, Nancy F. Cruz, Pedro Young, Alice C. Berkman, Benjamin E. Chandrasekharappa, Settara C. Mullikin, James C. CA NISC Comparative Sequencing TI Incidental Medical Information in Whole-Exome Sequencing SO PEDIATRICS LA English DT Article DE whole-exome sequencing; incidental medical information ID SINGLE-NUCLEOTIDE POLYMORPHISMS; CONGENITAL MUSCULAR-DYSTROPHY; OXYGENASE-1 GENE PROMOTER; BETA-HYDROXYLASE GENE; PRDM9 MEISETZ GENE; MICROSATELLITE POLYMORPHISM; MISSENSE MUTATION; GENOMIC MEDICINE; PROTEASE-26 GENE; MALE-INFERTILITY AB Genomic technologies, such as whole-exome sequencing, are a powerful tool in genetic research. Such testing yields a great deal of incidental medical information, or medical information not related to the primary research target. We describe the management of incidental medical information derived from whole-exome sequencing in the research context. We performed whole-exome sequencing on a monozygotic twin pair in which only 1 child was affected with congenital anomalies and applied an institutional review board-approved algorithm to determine what genetic information would be returned. Whole-exome sequencing identified 79 525 genetic variants in the twins. Here, we focus on novel variants. After filtering artifacts and excluding known single nucleotide polymorphisms and variants not predicted to be pathogenic, the twins had 32 novel variants in 32 genes that were felt to be likely to be associated with human disease. Eighteen of these novel variants were associated with recessive disease and 18 were associated with dominantly manifesting conditions (variants in some genes were potentially associated with both recessive and dominant conditions), but only 1 variant ultimately met our institutional review board-approved criteria for return of information to the research participants. Pediatrics 2012; 129: e1605-e1611 C1 [Solomon, Benjamin D.; Pineda-Alvarez, Daniel E.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Hadley, Donald W.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [NISC Comparative Sequencing] NHGRI, Natl Inst Hlth Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Kamat, Aparna; Cherukuri, Praveen F.; Hansen, Nancy F.; Cruz, Pedro; Young, Alice C.; Mullikin, James C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Teer, Jamie K.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Berkman, Benjamin E.] NHGRI, Dept Bioeth, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Berkman, Benjamin E.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Chandrasekharappa, Settara C.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Solomon, BD (reprint author), NHGRI, Med Genet Branch, NIH, MSC 3717,Bldg 35,Room 1B-207, Bethesda, MD 20892 USA. EM solomonb@mail.nih.gov FU Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services; National Institutes of Health (NIH) FX Supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services. Funded by the National Institutes of Health (NIH). NR 75 TC 20 Z9 20 U1 0 U2 7 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2012 VL 129 IS 6 BP E1605 EP E1611 DI 10.1542/peds.2011-0080 PG 7 WC Pediatrics SC Pediatrics GA 951FT UT WOS:000304707000029 PM 22585771 ER PT J AU Lin, CJ DeRoo, LA Jacobs, SR Sandler, DP AF Lin, Cynthia J. DeRoo, Lisa A. Jacobs, Sara R. Sandler, Dale P. TI Accuracy and reliability of self-reported weight and height in the Sister Study SO PUBLIC HEALTH NUTRITION LA English DT Article DE Self-report; Weight; Height; Accuracy; Reliability; Women ID EATING-DISORDERS; UNITED-STATES; WOMEN; HEALTH; PREVALENCE; VALIDITY; RISK; OVERWEIGHT; TELEPHONE; SYMPTOMS AB Objective: To assess the accuracy and reliability of self-reported weight and height and identify the factors associated with reporting accuracy. Design: Analysis of self-reported and measured weight and height from participants in the Sister Study (2003-2009), a nationwide cohort of 50 884 women aged 35-74 years in the USA with a sister with breast cancer. Setting: Weight and height were reported via computer-assisted telephone interview (CATI) and self-administered questionnaires, and measured by examiners. Subjects: Early enrolees in the Sister Study. There were 18 639 women available for the accuracy analyses and 13 316 for the reliability analyses. Results: Using weighted kappa statistics, comparisons were made between CATI responses and examiner measures to assess accuracy and CATI and questionnaire responses to assess reliability. Polytomous logistic regression evaluated factors associated with over- or under-reporting. Compared with measured values, agreement: was 96% for reported height (+/- 1 inch (+/- 2.5 cm); weighted kappa = 0.84) and 67% for weight (+/- 3 lb (+/- 1.36 kg); weighted kappa = 0.92). Obese women (BMI >= 30 kg/m(2)) were more likely than normal-weight women to under-report weight by >= 5% and underweight women (BMI < 18.5 kg/m(2)) were more likely to over-report. Among normal-weight and overweight women (18.5 kg/m(2) <= BMI < 30 kg/m(2)), weight cycling and lifetime weight difference >= 50 lb (>= 22.68 kg) were associated with over-reporting. Conclusions: US women in the Sister Study were reasonably reliable and accurate in reporting weight and height. Women with normal-range BMI reported most accurately. Overweight and obese women and those with weight fluctuations were less accurate, but even among obese women, few under-reported their weight by >10%. C1 [Lin, Cynthia J.; DeRoo, Lisa A.; Jacobs, Sara R.; Sandler, Dale P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Sandler, DP (reprint author), NIEHS, Epidemiol Branch, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. EM sandler@niehs.nih.gov OI Sandler, Dale/0000-0002-6776-0018 FU National Institute of Environmental Health Sciences [Z01 ES044005]; National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01 ES044005), National Institutes of Health. The authors have no conflict of interest regarding this manuscript. C.J.L. carried out the data analysis and drafted the paper. L.A.D. supervised data collection, contributed to the development of the research topic and analysis strategy, supervised the analysis and edited the paper. D.P.S., Principal Investigator of the Sister Study, collected and provided the primary data, contributed to the development of the research topic and analysis strategy, supervised the analysis and edited the paper. S.R.J. participated in early evaluation of the data, literature review, data analysis and drafting of the paper. NR 28 TC 23 Z9 23 U1 2 U2 4 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD JUN PY 2012 VL 15 IS 6 BP 989 EP 999 DI 10.1017/S1368980011003193 PG 11 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA 951TF UT WOS:000304742200007 PM 22152926 ER PT J AU George, SM Thompson, FE Midthune, D Subar, AF Berrigan, D Schatzkin, A Potischman, N AF George, Stephanie M. Thompson, Frances E. Midthune, Douglas Subar, Amy F. Berrigan, David Schatzkin, Arthur Potischman, Nancy TI Strength of the relationships between three self-reported dietary intake instruments and serum carotenoids: the Observing Energy and Protein Nutrition (OPEN) Study SO PUBLIC HEALTH NUTRITION LA English DT Article DE Diet; Carotenoids; Diet surveys; Biological markers ID FOOD FREQUENCY QUESTIONNAIRES; HEALTH INTERVIEW SURVEY; HISTORY QUESTIONNAIRE; MEASUREMENT ERROR; NATIONAL-HEALTH; 24-HOUR RECALL; BIOMARKERS; ADULTS; VEGETABLES; SAMPLE AB Objective: To assess the strength of the relationships between serum carotenoids and three self-reported dietary intake instruments often used to characterize carotenoid intake in studies of diet and disease. Design: Participants completed a Diet History Questionnaire (DHQ), two 24 h dietary recalls (24HR), a fruit and vegetable screener and a fasting blood draw. We derived dietary intake estimates of alpha-carotene, beta-carotene, cryptoxanthin, lutein, zeaxanthin and lycopene from each diet instrument and calculated sex-specific multivariate correlations between dietary intake estimates and their corresponding serum values. Setting: Montgomery County, Maryland, USA. Subjects: Four hundred and seventy women and men aged 40-69 years in the National Cancer Institute's Observing Protein and Energy Nutrition (OPEN) Study. Results: Serum carotenoids correlated more strongly with the DHQ (r = 0.34-0.54 for women; r = 0.38-0.56 for men) than with the average of two recalls (r = 0.26-0.47 for women; r = 0.26-0.40 for men) with the exception of zeaxanthin, for which the correlations using recalls were higher. With adjustment for within-person variation, correlations between serum carotenoids and recalls were greatly improved (r = 0.38-0.83 for women; r = 0.42-0.74 for men). In most cases, correlations between serum carotenoids and the fruit and vegetable screener resembled serum-DHQ correlations. Conclusions: Evidence from the study provides support for the use of the DHQ, fruit and vegetable screener and deattenuated recalls for estimating carotenoid status in studies without serum measures, and draws attention to the importance of adjusting for intra-individual variability when using recalls to estimate carotenoid values. C1 [George, Stephanie M.; Thompson, Frances E.; Subar, Amy F.; Berrigan, David; Potischman, Nancy] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Midthune, Douglas] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP George, SM (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4017A, Bethesda, MD 20892 USA. EM stephanie.george@nih.gov FU National Cancer Institute, National Institutes of Health, US Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. The authors have no conflicts of interest to disclose. S.M.G. analysed the data. All authors played a role in the writing of the manuscript, and S.M.G., F.E.T. and N.P. had primary responsibility for final content. All authors read and approved the final manuscript. NR 44 TC 10 Z9 10 U1 1 U2 10 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 EI 1475-2727 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD JUN PY 2012 VL 15 IS 6 BP 1000 EP 1007 DI 10.1017/S1368980011003272 PG 8 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA 951TF UT WOS:000304742200008 PM 22230252 ER PT J AU Irrechukwu, ON Reiter, DA Lin, PC Roque, RA Fishbein, KW Spencer, RG AF Irrechukwu, Onyi N. Reiter, David A. Lin, Ping-Chang Roque, Remigio A. Fishbein, Kenneth W. Spencer, Richard G. TI Characterization of Engineered Cartilage Constructs Using Multiexponential T-2 Relaxation Analysis and Support Vector Regression SO TISSUE ENGINEERING PART C-METHODS LA English DT Article ID BOVINE NASAL CARTILAGE; MAGNETIC-RESONANCE MICROSCOPY; ARTICULAR-CARTILAGE; AGGREGATING PROTEOGLYCANS; KERATAN SULFATE; HYALURONIC-ACID; AGAROSE GELS; TISSUE; PROTON; WATER AB Increased sensitivity in the characterization of cartilage matrix status by magnetic resonance (MR) imaging, through the identification of surrogate markers for tissue quality, would be of great use in the noninvasive evaluation of engineered cartilage. Recent advances in MR evaluation of cartilage include multiexponential and multiparametric analysis, which we now extend to engineered cartilage. We studied constructs which developed from chondrocytes seeded in collagen hydrogels. MR measurements of transverse relaxation times were performed on samples after 1, 2, 3, and 4 weeks of development. Corresponding biochemical measurements of sulfated glycosaminoglycan (sGAG) were also performed. sGAG per wet weight increased from 7.74 +/- 1.34 mu g/mg in week 1 to 21.06 +/- 4.14 mu g/mg in week 4. Using multiexponential T-2 analysis, we detected at least three distinct water compartments, with T-2 values and weight fractions of (45 ms, 3%), (200 ms, 4%), and (500 ms, 97%), respectively. These values are consistent with known properties of engineered cartilage and previous studies of native cartilage. Correlations between sGAG and MR measurements were examined using conventional univariate analysis with T-2 data from monoexponential fits with individual multiexponential compartment fractions and sums of these fractions, through multiple linear regression based on linear combinations of fractions, and, finally, with multivariate analysis using the support vector regression (SVR) formalism. The phenomenological relationship between T-2 from monoexponential fitting and sGAG exhibited a correlation coefficient of r(2)=0.56, comparable to the more physically motivated correlations between individual fractions or sums of fractions and sGAG; the correlation based on the sum of the two proteoglycan-associated fractions was r(2)=0.58. Correlations between measured sGAG and those calculated using standard linear regression were more modest, with r(2) in the range 0.43-0.54. However, correlations using SVR exhibited r(2) values in the range 0.68-0.93. These results indicate that the SVR-based multivariate approach was able to determine tissue sGAG with substantially higher accuracy than conventional monoexponential T-2 measurements or conventional regression modeling based on water fractions. This combined technique, in which the results of multiexponential analysis are examined with multivariate statistical techniques, holds the potential to greatly improve the accuracy of cartilage matrix characterization in engineered constructs using noninvasive MR data. C1 [Irrechukwu, Onyi N.; Reiter, David A.; Lin, Ping-Chang; Roque, Remigio A.; Fishbein, Kenneth W.; Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Spencer, RG (reprint author), NIA, Magnet Resonance Imaging & Spect Sect, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. EM spencer@helix.nih.gov OI Lin, Ping-Chang/0000-0003-0918-4072 FU NIH National Institute on Aging FX This work was supported by the Intramural Research Program of the NIH National Institute on Aging. NR 48 TC 7 Z9 8 U1 1 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3384 J9 TISSUE ENG PART C-ME JI Tissue Eng. Part C-Methods PD JUN PY 2012 VL 18 IS 6 BP 433 EP 443 DI 10.1089/ten.tec.2011.0509 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 952MV UT WOS:000304797500004 PM 22166112 ER PT J AU Guo, DL Cain, JP O'Connell, S Gardner, ER Pisle, S Figg, WD Tabibi, SE Yalkowsky, SH AF Guo, Duoli Cain, James P. O'Connell, Sean Gardner, Erin R. Pisle, Steven Figg, William D. Tabibi, S. Esmail Yalkowsky, Samuel H. TI Preformulation Study of NSC-726796 SO AAPS PHARMSCITECH LA English DT Article DE CPS49; NSC-726796; NSC-749820; preformulation; stability ID THALIDOMIDE ANALOGS; CPS49 AB A stability-indicating high-performance liquid chromatography method to quantify 2-(2,4-difluorophenyl)-4,5,6,7-tetrafluoroisoindoline-1,3-dione (NSC-726796) and its three main degradation products was developed. This method was used to investigate its degradation kinetics and mechanism. The reaction follows first-order kinetics and appears to be base catalyzed with the maximum stability at pH 1. The products were identified as 2-(2,4-difluorophenylcarbamoyl)-3,4,5,6-tetrafluorobenzoic acid (NSC-749820), 2,4-difluoroaniline, and tetrafluorophthalic acid. The parent drug, NSC-726796, was also found to react with methanol and ethanol. NSC-726796 demonstrates antiangiogenic activity, however, when its degradant NSC749820 does not show antiangiogenic activity. C1 [Guo, Duoli; O'Connell, Sean; Yalkowsky, Samuel H.] Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. [Cain, James P.] Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. [Gardner, Erin R.] NCI, Clin Pharmacol Program, SAIC Frederick, Frederick, MD 21702 USA. [Pisle, Steven; Figg, William D.] NCI, Clin Pharmacol Program, Bethesda, MD 20892 USA. [Tabibi, S. Esmail] NCI, Pharmaceut Resources Branch, Bethesda, MD 20892 USA. RP Guo, DL (reprint author), Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. EM duoliguo@gmail.com RI Figg Sr, William/M-2411-2016 FU National Cancer Institute, National Institutes of Health [N01-CM-27142, HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contracts N01-CM-27142 and HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 8 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD JUN PY 2012 VL 13 IS 2 BP 661 EP 673 DI 10.1208/s12249-012-9784-5 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 950LX UT WOS:000304651900034 PM 22552929 ER PT J AU Laughon, SK Zhang, J Grewal, J Sundaram, R Beaver, J Reddy, UM AF Laughon, S. Katherine Zhang, Jun Grewal, Jagteshwar Sundaram, Rajeshwari Beaver, Julie Reddy, Uma M. TI Induction of labor in a contemporary obstetric cohort SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE indication for induction; induction and cesarean; labor induction; method of induction ID PREGNANCY; RISK; OUTCOMES; TERM AB OBJECTIVE: We sought to describe details of labor induction, including precursors and methods, and associated vaginal delivery rates. STUDY DESIGN: This was a retrospective cohort study of 208,695 electronic medical records from 19 hospitals across the United States, 2002 through 2008. RESULTS: Induction occurred in 42.9% of nulliparas and 31.8% of multiparas and elective or no recorded indication for induction at term occurred in 35.5% and 44.1%, respectively. Elective induction at term in multiparas was highly successful (vaginal delivery 97%) compared to nulliparas (76.2%). For all precursors, cesarean delivery was more common in nulliparas in the latent compared to active phase of labor. Regardless of method, vaginal delivery rates were higher with a ripe vs unripe cervix, particularly for multiparas (86.6-100%). CONCLUSION: Induction of labor was a common obstetric intervention. Selecting appropriate candidates and waiting longer for labor to progress into the active phase would make an impact on decreasing the national cesarean delivery rate. C1 [Laughon, S. Katherine; Grewal, Jagteshwar; Sundaram, Rajeshwari; Beaver, Julie; Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Childrens Environm Hlth, Xinhua Hosp, Shanghai 200030, Peoples R China. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, MOE, Xinhua Hosp, Shanghai 200030, Peoples R China. RP Laughon, SK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. OI Grewal, Jagteshwar/0000-0002-0141-4876; Sundaram, Rajeshwari/0000-0002-6918-5002; Grantz, Katherine/0000-0003-0276-8534 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C] FX The data included in this paper were obtained from the Consortium on Safe Labor, which was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through Contract No. HHSN267200603425C. NR 18 TC 0 Z9 1 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUN PY 2012 VL 206 IS 6 AR 486.e1 DI 10.1016/j.ajog.2012.03.014 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 947PV UT WOS:000304442900016 PM 22520652 ER PT J AU Weathers, JD Stringaris, A Deveney, CM Brotman, MA Zarate, CA Connolly, ME Fromm, SJ LeBourdais, SB Pine, DS Leibenluft, E AF Weathers, Judah D. Stringaris, Argyris Deveney, Christen M. Brotman, Melissa A. Zarate, Carlos A., Jr. Connolly, Megan E. Fromm, Stephen J. LeBourdais, Stephanie B. Pine, Daniel S. Leibenluft, Ellen TI A Developmental Study of the Neural Circuitry Mediating Motor Inhibition in Bipolar Disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; GO/NO-GO TASK; RESPONSE-INHIBITION; ANTERIOR CINGULATE; PREFRONTAL CORTEX; FUNCTIONAL MRI; RATING-SCALE; MANIA; ACTIVATION; BRAIN AB Objective: Despite increased interest in the developmental trajectory of the pathophysiology mediating bipolar disorder, few studies have compared adults and youths with bipolar disorder. Deficits in motor inhibition are thought to play an important role in the pathophysiology of the illness across the age spectrum. The authors compared the neural circuitry mediating this process in bipolar youths relative to bipolar adults and in healthy volunteers. Method: Participants were pediatric (N=16) and adult (N=23) patients with bipolar disorder and healthy child (N=21) and adult (N=29) volunteers. Functional MRI (fMRI) data were acquired while participants performed the stop-signal task. Results: During failed inhibition, an age group-by-diagnosis interaction manifested in the anterior cingulate cortex, with bipolar youths exhibiting hypoactivation relative to both healthy youths and bipolar adults, and bipolar adults exhibiting hyperactivation relative to healthy adults. During successful inhibition, a main effect of diagnosis emerged in the right nucleus accumbens and the left ventral prefrontal cortex, with bipolar patients in both age groups showing less activation than healthy subjects. Conclusions: Anterior cingulate cortex dysfunction during failed motor inhibition was observed in both bipolar youths and adults, although the nature of this dysfunction differed between the two groups. Adults and youths with bipolar disorder exhibited similar deficits in activation of the nucleus accumbens and the ventral prefrontal cortex during successful inhibition. Therefore, while subcortical and ventral prefrontal cortex hypoactivation was present in bipolar patients across the lifespan, anterior cingulate cortex dysfunction varied developmentally, with reduced activation in youths and increased activation in adults during failed inhibition. Longitudinal fMRI studies of the developmental trajectory of the neural circuitry mediating motor inhibition in bipolar disorder are warranted. C1 [Weathers, Judah D.] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, Bethesda, MD 20892 USA. Kings Coll London, Inst Psychiat, Dept Adolescent & Child Psychiat, London WC2R 2LS, England. NIMH, Expt Therapeut & Pathophysiol Branch, Div Intramural Res, Bethesda, MD 20892 USA. NIMH, Emot & Dev Branch, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. NIMH, Sect Dev & Affect Neurosci, Emot & Dev Branch, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Worcester, MA USA. RP Weathers, JD (reprint author), NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, Bethesda, MD 20892 USA. EM judah.weathers@nih.gov RI Brotman, Melissa/H-7409-2013 FU NIMH FX Supported by the NIMH Intramural Research Program. NR 40 TC 17 Z9 17 U1 1 U2 6 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 JUN PY 2012 VL 169 IS 6 BP 633 EP 641 DI 10.1176/appi.ajp.2012.11081244 PG 9 WC Psychiatry SC Psychiatry GA 948PK UT WOS:000304514900014 PM 22581312 ER PT J AU Kim, P Thomas, LA Rosen, BH Moscicki, AM Brotman, MA Zarate, CA Blair, RJR Pine, DS Leibenluft, E AF Kim, Pilyoung Thomas, Laura A. Rosen, Brooke H. Moscicki, Alexander M. Brotman, Melissa A. Zarate, Carlos A., Jr. Blair, R. James R. Pine, Daniel S. Leibenluft, Ellen TI Differing Amygdala Responses to Facial Expressions in Children and Adults With Bipolar Disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID SPECTRUM DISORDERS; LABELING DEFICITS; ANXIETY DISORDER; NEURAL RESPONSES; RATING-SCALE; ADOLESCENTS; EMOTION; MANIA; METAANALYSIS; DEPRESSION AB Objective: Child and adult bipolar patients show both behavioral deficits in face emotion processing and abnormal amygdala activation. However, amygdala function in pediatric relative to adult bipolar patients has not been compared directly. The authors used functional MRI to compare amygdala activity during a face processing task in children and adults with bipolar disorder and in healthy comparison subjects. Method: Amygdala responses to emotional facial expressions were examined in pediatric (N=18) and adult (N=17) bipolar patients and in healthy child (N=15) and adult (N=22) volunteers. Participants performed a gender identification task while viewing fearful, angry, and neutral faces. Results: In response to fearful faces, bipolar patients across age groups exhibited right amygdala hyperactivity relative to healthy volunteers. However, when responses to all facial expressions were combined, pediatric patients exhibited greater right amygdala activation than bipolar adults and healthy children. Conclusions: Amygdala hyperactivity in response to fearful faces is present in both youths and adults with bipolar disorder. However, compared with bipolar adults and healthy child volunteers, pediatric bipolar patients showed amygdala hyperactivity in response to a broad array of emotional faces. Thus, abnormal amygdala activation during face processing appears to be more pervasive in children than in adults with bipolar disorder. Longitudinal studies are needed to elucidate the mechanisms of this developmental difference, thus facilitating developmentally sensitive diagnosis and treatment. C1 [Kim, Pilyoung; Thomas, Laura A.; Rosen, Brooke H.; Moscicki, Alexander M.; Brotman, Melissa A.; Zarate, Carlos A., Jr.; Blair, R. James R.; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Bethesda, MD 20892 USA. RP Kim, P (reprint author), NIMH, Bethesda, MD 20892 USA. EM pilyoung.kim@nih.gov RI Brotman, Melissa/H-7409-2013; OI Thomas, Laura/0000-0002-4106-1358 FU NIH; NIMH FX Supported by the Intramural Research Program of NIMH and NIH. NR 36 TC 20 Z9 22 U1 2 U2 7 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 JUN PY 2012 VL 169 IS 6 BP 642 EP 649 DI 10.1176/appi.ajp.2012.11081245 PG 8 WC Psychiatry SC Psychiatry GA 948PK UT WOS:000304514900015 PM 22535257 ER PT J AU Etemadi, A Golozar, A Kamangar, F Freedman, ND Shakeri, R Matthews, C Islami, F Boffetta, P Brennan, P Abnet, CC Malekzadeh, R Dawsey, SM AF Etemadi, A. Golozar, A. Kamangar, F. Freedman, N. D. Shakeri, R. Matthews, C. Islami, F. Boffetta, P. Brennan, P. Abnet, C. C. Malekzadeh, R. Dawsey, S. M. TI Large body size and sedentary lifestyle during childhood and early adulthood and esophageal squamous cell carcinoma in a high-risk population SO ANNALS OF ONCOLOGY LA English DT Article DE esophagus; obesity; physical activity; squamous cell carcinoma ID NESTED CASE-CONTROL; GASTRIC CARDIA; MASS INDEX; PHYSICAL-ACTIVITY; CANCER-RISK; COHORT; ADENOCARCINOMA; EPIDEMIOLOGY; ALCOHOL; OBESITY AB Background: Little is known about the association of obesity and physical activity at young ages with subsequent risk of esophageal squamous cell carcinoma (ESCC). Patients and methods: Between 2003 and 2007, we conducted a case-control study in a high-risk population in northeastern Iran. Three hundred ESCC cases and 571 matched controls were recruited. Each individual was shown a standard pictogram, to report body size at ages 15 and 30. Demographic and health-related information, including physical activity at these ages was also collected. Results: In the fully adjusted models, very obese body size (last two pictograms) at age 15 [odds ratio (OR) 3.2, 95% confidence interval (CI) 1.3-7.7] and age 30 (OR 3.1; 95% CI 1.1-8.5) were associated with ESCC in women, but not in men. Sedentary work at age 15 (OR 3.3, 95% CI 1.3-8.3) and 30 (OR 18.2, 95% CI 3.9-86.2) were also associated with ESCC risk in women only. The increased risk in women at age 15 remained high after later reduction in body size, while women who became very obese only at age 30 did not show a significantly increased risk. Conclusion: These results highlight the importance of early lifestyle modifications in the context of cancer prevention, particularly in women. C1 [Etemadi, A.; Golozar, A.; Shakeri, R.; Islami, F.; Malekzadeh, R.] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Inst, Tehran, Iran. [Etemadi, A.; Golozar, A.; Kamangar, F.; Freedman, N. D.; Matthews, C.; Abnet, C. C.; Dawsey, S. M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kamangar, F.] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Islami, F.; Brennan, P.] Int Agcy Res Canc, F-69372 Lyon, France. [Boffetta, P.] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, P.] Int Prevent Res Inst, Lyon, France. RP Etemadi, A (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Suite 320, Rockville, MD 20852 USA. EM arash.etemadi@nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; Etemadi, Arash/C-1386-2016; OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Etemadi, Arash/0000-0002-3458-1072; , Ramin/0000-0003-0487-3629; Malekzadeh, Reza/0000-0003-1043-3814 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Digestive Disease Research Center of Tehran University of Medical Sciences [82-603]; International Agency for Research on Cancer FX This study was supported in part by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Digestive Disease Research Center of Tehran University of Medical Sciences (82-603); and the International Agency for Research on Cancer. NR 46 TC 9 Z9 10 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JUN PY 2012 VL 23 IS 6 BP 1593 EP 1600 DI 10.1093/annonc/mdr494 PG 8 WC Oncology SC Oncology GA 948WO UT WOS:000304534000034 PM 22052987 ER PT J AU England, K Boshoff, HIM Arora, K Weiner, D Dayao, E Schimel, D Via, LE Barry, CE AF England, Kathleen Boshoff, Helena I. M. Arora, Kriti Weiner, Danielle Dayao, Emmanuel Schimel, Daniel Via, Laura E. Barry, Clifton E., III TI Meropenem-Clavulanic Acid Shows Activity against Mycobacterium tuberculosis In Vivo SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID BETA-LACTAMASE; STABILITY; ANTIBIOTICS; ANIMALS AB The carbapenems imipenem and meropenem in combination with clavulanic acid reduced the bacterial burden in Mycobacterium tuberculosis-infected macrophages by 2 logs over 6 days. Despite poor stability in solution and a short half-life in rodents, treatment of chronically infected mice revealed significant reductions of bacterial burden in the lungs and spleens. Our results show that meropenem has activity in two in vivo systems, but stability and pharmacokinetics of long-term administration will offer significant challenges to clinical evaluation. C1 [England, Kathleen; Boshoff, Helena I. M.; Arora, Kriti; Weiner, Danielle; Dayao, Emmanuel; Schimel, Daniel; Via, Laura E.; Barry, Clifton E., III] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. RP Barry, CE (reprint author), NIAID, TB Res Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM cbarry@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012; OI Via, Laura/0000-0001-6074-9521 NR 20 TC 39 Z9 39 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUN PY 2012 VL 56 IS 6 BP 3384 EP 3387 DI 10.1128/AAC.05690-11 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 947LZ UT WOS:000304432800079 PM 22450968 ER PT J AU Demidowich, AP Freeman, AF Kuhns, DB Aksentijevich, I Gallin, JI Turner, ML Kastner, DL Holland, SM AF Demidowich, Andrew P. Freeman, Alexandra F. Kuhns, Douglas B. Aksentijevich, Ivona Gallin, John I. Turner, Maria L. Kastner, Daniel L. Holland, Steven M. TI Genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) SO ARTHRITIS AND RHEUMATISM LA English DT Article ID ETANERCEPT; MUTATIONS; EFFICACY; DISORDER; ANAKINRA; RECEPTOR; PSTPIP1; PROTEIN; DISEASE AB Objective To describe the genotypes, phenotypes, immunophenotypes, and treatments of PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), a rare autoinflammatory disease, in 5 patients. Methods Clinical information was gathered from medical records and through interviews with 5 patients from 4 kindreds. PSTPIP1 (CD2BP1) exon 10 and exon 11 sequencing was performed in each patient. Neutrophil granule content and cytokine levels were determined in plasma and stimulated peripheral blood mononuclear cells (PBMCs) from patients and controls. Results We identified 2 previously described PAPA syndromeassociated PSTPIP1 mutations, A230T and E250Q, and a novel change, E250K. Disease penetrance was incomplete, with variable expressivity. The cutaneous manifestations included pathergy, cystic acne, and pyoderma gangrenosum. Interleukin-1 beta (IL-1 beta) and circulating neutrophil granule enzyme levels were markedly elevated in patients compared to those in controls. PBMC stimulation studies demonstrated impaired production of IL-10 and enhanced production of granulocytemacrophage colony-stimulating factor. Good resolution of pyoderma gangrenosum was achieved in 3 patients with tumor necrosis factor a (TNFa) blockade treatment. Conclusion This analysis of 5 patients demonstrates that mutations in PSTPIP1 are incompletely penetrant and variably expressed in the PAPA syndrome. Neutrophil granule proteins are markedly elevated ex vivo and in the plasma, and elevated levels might be compatible with a diagnosis of PAPA syndrome. TNFa blockade appears to be effective in treating the cutaneous manifestations of PAPA syndrome. C1 [Demidowich, Andrew P.; Freeman, Alexandra F.; Gallin, John I.; Holland, Steven M.] NIAID, NIH, Bethesda, MD 20892 USA. [Kuhns, Douglas B.] NCI, SAIC Frederick Inc, Frederick, MD USA. [Aksentijevich, Ivona; Kastner, Daniel L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Turner, Maria L.] NCI, NIH, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, NIH, Bldg 10,CRC B3-4141,10 Ctr Dr MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH; National Cancer Institute, NIH [HHSN-261200800001E]; Pfizer Foundation; Foundation for the NIH FX Supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, and with funds from the National Cancer Institute, NIH, under contract HHSN-261200800001E. Dr. Demidowich was a Clinical Research Training Program fellow at the NIH. His fellowship was supported by a joint partnership between the Pfizer Foundation and the Foundation for the NIH. NR 16 TC 58 Z9 59 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD JUN PY 2012 VL 64 IS 6 BP 2022 EP 2027 DI 10.1002/art.34332 PG 6 WC Rheumatology SC Rheumatology GA 948SE UT WOS:000304522100035 PM 22161697 ER PT J AU Bartolucci, C Stojan, J Yu, QS Greig, NH Lamba, D AF Bartolucci, Cecilia Stojan, Jure Yu, Qian-sheng Greig, Nigel H. Lamba, Doriano TI Kinetics of Torpedo californica acetylcholinesterase inhibition by bisnorcymserine and crystal structure of the complex with its leaving group SO BIOCHEMICAL JOURNAL LA English DT Article DE acetylcholinesterase (AChE); Alzheimer's disease (AD); bisnorcymserine; bisnoreseroline; carbamate; enzyme kinetics; X-ray crystal structure ID ACTIVE-SITE GORGE; ALZHEIMERS-DISEASE; X-RAY; MOLECULAR-DYNAMICS; REVERSIBLE INHIBITION; AROMATIC RESIDUES; NMR SYSTEM; BACK DOOR; BUTYRYLCHOLINESTERASE; CRYSTALLOGRAPHY AB Natural and synthetic carbamates act as pseudo-irreversible inhibitors of AChE (acetylcholinesterase) as well as BChE (butyrylcholinesterase), two enzymes involved in neuronal function as well as in the development and progression of AD (Alzheimer's disease). The AChE mode of action is characterized by a rapid carbamoylation of the active-site Ser(200) with release of a leaving group followed by a slow regeneration of enzyme action due to subsequent decarbamoylation. The experimental AD therapeutic bisnorcymserine, a synthetic carbamate, shows an interesting activity and selectivity for BChE, and its clinical development is currently being pursued. We undertook detailed kinetic studies on the activity of the carbamate bisnorcymserine with Tc (Torpedo californica) AChE and, on the basis of the results, crystallized the complex between TcAChE and bisnorcymserine. The X-ray crystal structure showed only the leaving group, bisnoreseroline, trapped at the bottom of the aromatic enzyme gorge. Specifically, bisnoreseroline interacts in a non-covalent way with Ser(200) and His(440), disrupting the existing interactions within the catalytic triad, and it stacks with Trp(84) at the bottom of the gorge, giving rise to an unprecedented hydrogen-bonding contact. These interactions point to a dominant reversible inhibition mechanism attributable to the leaving group, bisnoreseroline, as revealed by kinetic analysis. C1 [Bartolucci, Cecilia] CNR, Ist Cristallog, Area Ric Roma, I-00015 Rome, Italy. [Stojan, Jure] Univ Ljubljana, Inst Biochem, Fac Med, SI-1000 Ljubljana, Slovenia. [Yu, Qian-sheng; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Lamba, Doriano] CNR, Ist Cristallog, I-34149 Trieste, Italy. RP Bartolucci, C (reprint author), CNR, Ist Cristallog, Area Ric Roma, Via Salaria Km 29-300, I-00015 Rome, Italy. EM cecilia.bartolucci@ic.cnr.it RI Lamba, Doriano/B-2961-2011 OI Lamba, Doriano/0000-0001-6859-7868 FU Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Roma, Italy; Slovenian Research Agency [P1-0170]; National Institute on Aging, National Institutes Of Health, U.S.A.; Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Trieste, Italy FX This research was supported in part by the Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Roma, Italy, the Slovenian Research Agency [grant number P1-0170], the Intramural Research Program, National Institute on Aging, National Institutes Of Health, U.S.A., and the Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Trieste, Italy. NR 51 TC 10 Z9 11 U1 0 U2 15 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 JUN 1 PY 2012 VL 444 BP 269 EP 277 DI 10.1042/BJ20111675 PN 2 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 950IQ UT WOS:000304643200013 PM 22390827 ER PT J AU Shen, Y Ning, J Qin, J AF Shen, Yu Ning, Jing Qin, Jing TI Likelihood approaches for the invariant density ratio model with biased-sampling data SO BIOMETRIKA LA English DT Article DE Conditional likelihood; Density ratio model; em algorithm; Length-biased sampling; Maximum likelihood approach ID SEMIPARAMETRIC REGRESSION; NONPARAMETRIC-ESTIMATION; EMPIRICAL LIKELIHOOD; SURVIVAL-DATA; CENSORED-DATA AB The full likelihood approach in statistical analysis is regarded as the most efficient means for estimation and inference. For complex length-biased failure time data, computational algorithms and theoretical properties are not readily available, especially when a likelihood function involves infinite-dimensional parameters. Relying on the invariance property of length-biased failure time data under the semiparametric density ratio model, we present two likelihood approaches for the estimation and assessment of the difference between two survival distributions. The most efficient maximum likelihood estimators are obtained by the em algorithm and profile likelihood. We also provide a simple numerical method for estimation and inference based on conditional likelihood, which can be generalized to k-arm settings. Unlike conventional survival data, the mean of the population failure times can be consistently estimated given right-censored length-biased data under mild regularity conditions. To check the semiparametric density ratio model assumption, we use a test statistic based on the area between two survival distributions. Simulation studies confirm that the full likelihood estimators are more efficient than the conditional likelihood estimators. We analyse an epidemiological study to illustrate the proposed methods. C1 [Shen, Yu; Ning, Jing] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Qin, Jing] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. RP Shen, Y (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. EM yshen@mdanderson.org; jning@mdanderson.org; jingqin@niaid.nih.gov OI Shen, Yu/0000-0002-3899-7868 FU National Institutes of Health FX This work was supported in part by grants from the National Institutes of Health. We are grateful to three referees, an associate editor and the editor for helpful comments and suggestions. We thank Professors Asgharian and Wolfson and the investigators from the Canadian Study of Health and Aging for providing us with the dementia data. NR 27 TC 4 Z9 4 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-3444 J9 BIOMETRIKA JI Biometrika PD JUN PY 2012 VL 99 IS 2 BP 363 EP 378 DI 10.1093/biomet/ass008 PG 16 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 948XP UT WOS:000304537400008 PM 23843663 ER PT J AU Komatsu, DE Thanos, PK Mary, MN Janda, HA John, CM Robison, L Ananth, M Swanson, JM Volkow, ND Hadjiargyrou, M AF Komatsu, David E. Thanos, Panayotis K. Mary, Michelle N. Janda, Haden A. John, Christine M. Robison, Lisa Ananth, Mala Swanson, James M. Volkow, Nora D. Hadjiargyrou, Michael TI Chronic exposure to methylphenidate impairs appendicular bone quality in young rats SO BONE LA English DT Article DE Methylphenidate; Growth suppression; Biomechanics; DXA; Testosterone ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT-HYPERACTIVITY DISORDER; FOLLOW-UP; STIMULANT MEDICATION; GROWTH-RATES; CHILDREN; ADHD; ASSOCIATIONS; BEHAVIOR; WEIGHT AB Methylphenidate (MP) is a psychostimulant widely prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD). Although generally well tolerated, growth deficits have been reported in children and adolescents undergoing MP treatment. This study was designed to elucidate the skeletal effects of chronic MP administration in adolescent rats. Male, 4-week-old rats received one of two doses of MP (MP-Low or MP-High) delivered for 8 h a day via drinking water, or were untreated (water only). After 13 weeks, half were sacrificed (N = 12/group) and the remaining rats were left to recover, untreated for 5 additional weeks. Femora, tibiae, and L5 vertebra were analyzed using calipers, DXA, and mechanical testing. Immediately following treatment, MP decreased femoral anterior-posterior diameter (5% and 9% for MP-Low and MP-High, respectively), femoral and tibial bone mineral density (BMD) (6% and 5% for MP-High femora and tibiae, respectively), and bone mineral content (BMC) (9% for MP-High femora and tibiae). In addition, femora from MP treated rats had reduced ultimate force (20% for MP-High) and energy to failure (20% and 33% for MP-Low and MP-High, respectively). However, after recovery, there were no statistically significant differences for any measured parameters. Despite these effects on the appendicular skeleton, no differences were identified between vertebral samples at either time-point. In summary, MP treatment resulted in smaller, less mineralized, and weaker bones at appendicular sites, but did not affect the axial site. Although these effects were ameliorated within 5 weeks, these data suggest that adolescents undergoing MP treatment may be at an increased risk for long bone fractures. (C) 2012 Elsevier Inc. All rights reserved. C1 [Komatsu, David E.] SUNY Stony Brook, Dept Orthopaed, Stony Brook, NY 11794 USA. [Thanos, Panayotis K.; Robison, Lisa; Ananth, Mala] Brookhaven Natl Lab, Behav Neuropharmacol & Neuroimaging Lab, Upton, NY 11973 USA. [Thanos, Panayotis K.; Volkow, Nora D.] NIAAA, Lab Neuroimaging, NIH, Bethesda, MD 20892 USA. [Mary, Michelle N.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Janda, Haden A.; John, Christine M.] InMot Orthopaed Res Ctr, Memphis, TN 38103 USA. [Swanson, James M.] Univ Calif Irvine, Child Dev Ctr, Irvine, CA 92612 USA. [Hadjiargyrou, Michael] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. RP Komatsu, DE (reprint author), SUNY Stony Brook, Dept Orthopaed, HSC Level 18,Room 085, Stony Brook, NY 11794 USA. EM david.komatsu@sbumed.org; thanos@bnl.gov; michellenmary@yahoo.com; haden.janda@smith-nephew.com; csnearly@gmail.com; lrobison@bnl.gov; mananth@bnl.gov; jmswanso@uci.edu; nvolkow@nida.nih.gov; michael.hadjiargyrou@sunysb.edu FU NIDA, NIAAA (LNI); InMotion Orthopaedic Research Center in Memphis, TN FX The authors gratefully acknowledge support by: NIDA, NIAAA (Intramural Research Program, LNI), as well as the InMotion Orthopaedic Research Center in Memphis, TN. In addition, the authors thank R.J. Schroeder and G.J. Wang who provided assistance in the early phases of these studies. NR 29 TC 9 Z9 9 U1 1 U2 2 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 JUN PY 2012 VL 50 IS 6 BP 1214 EP 1222 DI 10.1016/j.bone.2012.03.011 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 948LC UT WOS:000304503700002 PM 22465849 ER PT J AU Stamelou, M Edwards, MJ Hallett, M Bhatia, KP AF Stamelou, Maria Edwards, Mark J. Hallett, Mark Bhatia, Kailash P. TI The non-motor syndrome of primary dystonia: clinical and pathophysiological implications SO BRAIN LA English DT Review DE primary dystonia; non-motor; sensory; depression; endophenotypes; pathophysiology; quality of life ID FOCAL HAND DYSTONIA; QUALITY-OF-LIFE; DEEP-BRAIN-STIMULATION; OBSESSIVE-COMPULSIVE DISORDER; IDIOPATHIC TORSION DYSTONIA; VIBRATION-INDUCED ILLUSION; BOTULINUM TOXIN TREATMENT; HUMAN MOTOR CORTEX; CONTINGENT NEGATIVE-VARIATION; PRIMARY GENERALIZED DYSTONIA AB Dystonia is typically considered a movement disorder characterized by motor manifestations, primarily involuntary muscle contractions causing twisting movements and abnormal postures. However, growing evidence indicates an important non-motor component to primary dystonia, including abnormalities in sensory and perceptual functions, as well as neuropsychiatric, cognitive and sleep domains. Here, we review this evidence and discuss its clinical and pathophysiological implications. C1 [Stamelou, Maria; Edwards, Mark J.; Bhatia, Kailash P.] UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorde, London WC1N 3BG, England. [Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD USA. RP Bhatia, KP (reprint author), UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorde, Queen Sq, London WC1N 3BG, England. EM k.bhatia@ion.ucl.ac.uk RI Edwards, Mark/F-1052-2012; OI Bhatia, Kailash/0000-0001-8185-286X FU NINDS; EFNS; NIHR; Department of Health's NIHR Biomedical Research Centres; Ipsen; Halley Stewart Trust through Dystonia Society UK; Wellcome Trust MRC strategic neurodegenerative disease initiative [WT089698]; Parkinson's UK [G-1009] FX NINDS Intramural Program (to M. H.); EFNS scientific grant (to M.S.); NIHR Clinician Scientist Fellowship (to M.J.E.); The work was performed at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. K.P.B. received research support from Ipsen and from the Halley Stewart Trust through Dystonia Society UK, and the Wellcome Trust MRC strategic neurodegenerative disease initiative award (Ref. number WT089698), and a grant from Parkinson's UK (Ref. number G-1009). NR 211 TC 70 Z9 71 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD JUN PY 2012 VL 135 BP 1668 EP 1681 DI 10.1093/brain/awr224 PN 6 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 948YC UT WOS:000304538900004 PM 21933808 ER PT J AU Goldstein, DS Holmes, C Sharabi, Y AF Goldstein, David S. Holmes, Courtney Sharabi, Yehonatan TI Cerebrospinal fluid biomarkers of central catecholamine deficiency in Parkinson's disease and other synucleinopathies SO BRAIN LA English DT Article DE Parkinson's; dopamine; norepinephrine; DHPG; DOPAC; biomarker ID MULTIPLE SYSTEM ATROPHY; PURE AUTONOMIC FAILURE; 3,4-DIHYDROXYPHENYLACETIC ACID DOPAC; NEUROGENIC ORTHOSTATIC HYPOTENSION; PERFORMANCE LIQUID-CHROMATOGRAPHY; CENTRAL DOPAMINE DEFICIENCY; CARDIAC SYMPATHETIC-NERVE; ALPHA-SYNUCLEIN; SUBSTANTIA-NIGRA; ELECTROCHEMICAL DETECTION AB Central catecholamine deficiency characterizes alpha-synucleinopathies such as Parkinson's disease. We hypothesized that cerebrospinal fluid levels of neuronal metabolites of catecholamines provide neurochemical biomarkers of these disorders. To test this hypothesis we measured cerebrospinal fluid levels of catechols including dopamine, norepinephrine and their main respective neuronal metabolites dihydroxyphenylacetic acid and dihydroxyphenylglycol in Parkinson's disease and two other synucleinopathies, multiple system atrophy and pure autonomic failure. Cerebrospinal fluid catechols were assayed in 146 subjects-108 synucleinopathy patients (34 Parkinson's disease, 54 multiple system atrophy, 20 pure autonomic failure) and 38 controls. In 14 patients cerebrospinal fluid was obtained before or within 2 years after the onset of parkinsonism. The Parkinson's disease, multiple system atrophy and pure autonomic failure groups all had lower cerebrospinal fluid dihydroxyphenylacetic acid [0.86 +/- 0.09 (SEM), 1.00 +/- 0.09, 1.32 +/- 0.12 nmol/l] than controls (2.15 +/- 0.18 nmol/l; P < 0.0001; P < 0.0001; P = 0.0002). Dihydroxyphenylglycol was also lower in the three synucleinopathies (8.82 +/- 0.44, 7.75 +/- 0.42, 5.82 +/- 0.65 nmol/l) than controls (11.0 +/- 0.62 nmol/l; P = 0.009, P < 0.0001, P < 0.0001). Dihydroxyphenylacetic acid was lower and dihydroxyphenylglycol higher in Parkinson's disease than in pure autonomic failure. Dihydroxyphenylacetic acid was 100% sensitive at 89% specificity in separating patients with recent onset of parkinsonism from controls but was of no value in differentiating Parkinson's disease from multiple system atrophy. Synucleinopathies feature cerebrospinal fluid neurochemical evidence for central dopamine and norepinephrine deficiency. Parkinson's disease and pure autonomic failure involve differential dopaminergic versus noradrenergic lesions. Cerebrospinal fluid dihydroxyphenylacetic acid seems to provide a sensitive means to identify even early Parkinson's disease. C1 [Goldstein, David S.; Holmes, Courtney; Sharabi, Yehonatan] Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, NIH, 10 Ctr Dr MSC 1620,Bldg 10,Room 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke, NIH; Division of Intramural Research, NINDS, NIH; [1ZIANS003034-05] FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH. Division of Intramural Research, NINDS, NIH. Project No. 1ZIANS003034-05. NR 70 TC 27 Z9 28 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD JUN PY 2012 VL 135 BP 1900 EP 1913 DI 10.1093/brain/aws055 PN 6 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 948YC UT WOS:000304538900021 PM 22451506 ER PT J AU Lerner, A Bagic, A Simmons, JM Mari, Z Bonne, O Xu, B Kazuba, D Herscovitch, P Carson, RE Murphy, DL Drevets, WC Hallett, M AF Lerner, Alicja Bagic, Anto Simmons, Janine M. Mari, Zoltan Bonne, Omer Xu, Ben Kazuba, Diane Herscovitch, Peter Carson, Richard E. Murphy, Dennis L. Drevets, Wayne C. Hallett, Mark TI Widespread abnormality of the gamma-aminobutyric acid-ergic system in Tourette syndrome SO BRAIN LA English DT Article DE Tourette syndrome; tics; GABA(A) receptors; flumazenil; PET ID OBSESSIVE-COMPULSIVE DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEEP BRAIN-STIMULATION; BASAL GANGLIA; FUNCTIONAL NEUROANATOMY; BENZODIAZEPINE-RECEPTOR; STRIATAL INTERNEURONS; THALAMIC-STIMULATION; TIC GENERATION; IN-VIVO AB Dysfunction of the gamma-aminobutyric acid-ergic system in Tourette syndrome may conceivably underlie the symptoms of motor disinhibition presenting as tics and psychiatric manifestations, such as attention deficit hyperactivity disorder and obsessive-compulsive disorder. The purpose of this study was to identify a possible dysfunction of the gamma-aminobutyric acid-ergic system in Tourette patients, especially involving the basal ganglia-thalamo-cortical circuits and the cerebellum. We studied 11 patients with Tourette syndrome and 11 healthy controls. Positron emission tomography procedure: after injection of 20 mCi of [C-11]flumazenil, dynamic emission images of the brain were acquired. Structural magnetic resonance imaging scans were obtained to provide an anatomical framework for the positron emission tomography data analysis. Images of binding potential were created using the two-step version of the simplified reference tissue model. The binding potential images then were spatially normalized, smoothed and compared between groups using statistical parametric mapping. We found decreased binding of GABA(A) receptors in Tourette patients bilaterally in the ventral striatum, globus pallidus, thalamus, amygdala and right insula. In addition, the GABA(A) receptor binding was increased in the bilateral substantia nigra, left periaqueductal grey, right posterior cingulate cortex and bilateral cerebellum. These results are consistent with the longstanding hypothesis that circuits involving the basal ganglia and thalamus are disinhibited in Tourette syndrome patients. In addition, the abnormalities in GABA(A) receptor binding in the insula and cerebellum appear particularly noteworthy based upon recent evidence implicating these structures in the generation of tics. C1 [Lerner, Alicja] US FDA, Ctr Drug Evaluat & Res, Controlled Substance Staff, Silver Spring, MD 20993 USA. [Bagic, Anto] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. [Simmons, Janine M.] NIMH, Affect Social Behav & Social Cognit Program, NIH, Bethesda, MD 20892 USA. [Mari, Zoltan] Johns Hopkins Univ, Dept Neurol, Sch Med, Baltimore, MD 21287 USA. [Bonne, Omer] Hadassah Hebrew Univ, Dept Psychiat, Med Ctr, IL-91120 Jerusalem, Israel. [Xu, Ben; Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Bethesda, MD 20892 USA. [Kazuba, Diane; Murphy, Dennis L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Herscovitch, Peter] NIH, Positron Emiss Tomog Dept, Ctr Clin, Bethesda, MD 20892 USA. [Carson, Richard E.] Yale Univ, Sch Med, Dept Diagnost Radiol, Yale PET Ctr, New Haven, CT 06520 USA. [Carson, Richard E.] Yale Univ, Sch Med, Dept Biomed Engn, Yale PET Ctr, New Haven, CT 06520 USA. [Drevets, Wayne C.] Univ Oklahoma, Coll Med, Tulsa, OK 74136 USA. [Drevets, Wayne C.] Laureate Inst Brain Res, Tulsa, OK 74136 USA. RP Lerner, A (reprint author), US FDA, Ctr Drug Evaluat & Res, Controlled Substance Staff, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM alicja.lerner@fda.hhs.gov RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 FU NINDS; NIMH, National Institutes of Health FX The Intramural Research Programs of the NINDS and NIMH, National Institutes of Health. NR 85 TC 49 Z9 50 U1 4 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD JUN PY 2012 VL 135 BP 1926 EP 1936 DI 10.1093/brain/aws104 PN 6 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 948YC UT WOS:000304538900023 PM 22577221 ER PT J AU McCarty, CA Reding, DJ Commins, J Williams, C Yeager, M Burmester, JK Schairer, C Ziegler, RG AF McCarty, Catherine A. Reding, Douglas J. Commins, John Williams, Craig Yeager, Meredith Burmester, James K. Schairer, Catherine Ziegler, Regina G. TI Alcohol, genetics and risk of breast cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Alcohol; Metabolizing enzyme; Genetics; Risk factors ID PROGESTERONE-RECEPTOR STATUS; ADH3 GENOTYPE; CONSUMPTION; ESTROGEN; DEHYDROGENASE; EXPRESSION; CYTOCHROME-P450; QUESTIONNAIRES; POLYMORPHISMS; HISTOLOGY AB We tested the hypothesis that genes involved in the alcohol oxidation pathway modify the association between alcohol intake and breast cancer. Subjects were women aged 55-74 at baseline from the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Incident breast cancers were identified through annual health surveys. Controls were frequency matched to cases by age and year of entry into the trial. A self-administered food frequency questionnaire queried frequency and usual serving size of beer, wine or wine coolers, and liquor. Three SNPs in genes in the alcohol metabolism pathway were genotyped: alcohol dehydrogenase 2, alcohol dehydrogenase 3, and CYP2E1. The study included 1,041 incident breast cancer cases and 1,070 controls. In comparison to non-drinkers, the intake of any alcohol significantly increased the risk of breast cancer, and this risk increased with each category of daily alcohol intake (OR 2.01, 95% CI 1.14, 3.53) for women who drank three or more standard drinks per day. Stratification by genotype revealed significant gene/environment interactions. For the ADH1B gene, there were statistically significant associations between all levels of alcohol intake and risk of breast cancer (all OR > 1.34 and all lower CI > 1.01), while for women with the GA or AA genotype, there were no significant associations between alcohol intake and risk of breast cancer. Alcohol intake, genes involved in alcohol metabolism and their interaction increase the risk of breast cancer in post-menopausal women. This information could be useful for primary care providers to personalize information about breast cancer risk reduction. C1 [McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN 55805 USA. [McCarty, Catherine A.; Reding, Douglas J.; Burmester, James K.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Commins, John; Williams, Craig] Informat Management Serv Inc, Rockville, MD USA. [Yeager, Meredith; Schairer, Catherine; Ziegler, Regina G.] NCI, Bethesda, MD 20892 USA. RP McCarty, CA (reprint author), Essentia Inst Rural Hlth, Maildrop 5AV-2,502 E 2nd St, Duluth, MN 55805 USA. EM cmccarty@eirh.org FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health, and Human Services FX Supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health, and Human Services. NR 29 TC 8 Z9 8 U1 0 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUN PY 2012 VL 133 IS 2 BP 785 EP 792 DI 10.1007/s10549-012-1972-1 PG 8 WC Oncology SC Oncology GA 949XJ UT WOS:000304610600038 PM 22331481 ER PT J AU Lu, VB Smith, PA Rashiq, S AF Lu, Van B. Smith, Peter A. Rashiq, Saifee TI The excitability of dorsal horn neurons is affected by cerebrospinal fluid from humans with osteoarthritis SO CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY LA English DT Article DE neuropathic pain; electrophysiology; organotypic culture; cytokine ID SUBSTANTIA-GELATINOSA NEURONS; UNDERLYING NEUROPATHIC PAIN; NEUROTROPHIC FACTOR; NERVE INJURY; SPINAL-CORD; RAT MODEL; EXCITATORY INTERNEURONS; SYNAPTIC-TRANSMISSION; CENTRAL SENSITIZATION; SENSORY NEURONS AB Changes in central neural processing are thought to contribute to the development of chronic osteoarthritis pain. This may be reflected as the presence of inflammatory mediators in the cerebral spinal fluid (CSF). We therefore exposed organotypically cultured slices of rat spinal cord to CSF from human subjects with osteoarthritis (OACSF) at a ratio of 1 part CSF in 9 parts culture medium for 5-6 days, and measured changes in neuronal electrophysiological properties by means of whole-cell recording. Although OACSF had no effect on the membrane properties and excitability of neurons in the substantia gelatinosa, synaptic transmission was clearly altered. The frequency of spontaneous excitatory postsynaptic currents (sEPSC) in delay-firing putative excitatory neurons was increased, as was sEPSC amplitude and frequency in tonic-firing inhibitory neurons. These changes could affect sensory processing in the dorsal horn, and may affect the transfer of nociceptive information. Although OACSF also affected inhibitory synaptic transmission (frequency of spontaneous inhibitory synaptic currents; sIPSC), this may have little bearing on sensory processing by substantia gelatinosa neurons, as sEPSC frequency is >3x greater than sIPSC frequency in this predominantly excitatory network. These results support the clinical notion that changes in nociceptive processing at the spinal level contribute to the generation of chronic osteoarthritis pain. C1 [Smith, Peter A.] Univ Alberta, Ctr Neurosci, Edmonton, AB T6G 2H7, Canada. [Smith, Peter A.] Univ Alberta, Dept Pharmacol, Edmonton, AB T6G 2H7, Canada. [Lu, Van B.] NIAAA, NIH, Rockville, MD 20849 USA. [Rashiq, Saifee] Univ Alberta, Dept Anesthesiol & Pain Med, Edmonton, AB T6G 2G3, Canada. RP Smith, PA (reprint author), Univ Alberta, Ctr Neurosci, 9-75 Med Sci Bldg, Edmonton, AB T6G 2H7, Canada. EM peter.a.smith@ualberta.ca OI Lu, Van/0000-0002-4880-6455 FU Canadian Institutes of Health Research (CIHR); Alberta Heritage Foundation for Medical Research (AHFMR) FX This research was supported by the Canadian Institutes of Health Research (CIHR). V. B. L. was a recipient of a studentship award from the Alberta Heritage Foundation for Medical Research (AHFMR) and CIHR. We also thank Briana Napier for assistance with data analysis, and Dr. Kathryn Jamieson-Lega for assistance with patient samples. None of the authors are engaged in financial or other relationships that might lead to a conflict of interest. NR 32 TC 0 Z9 0 U1 0 U2 1 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 1200 MONTREAL ROAD, BUILDING M-55, OTTAWA, ON K1A 0R6, CANADA SN 0008-4212 J9 CAN J PHYSIOL PHARM JI Can. J. Physiol. Pharmacol. PD JUN PY 2012 VL 90 IS 6 BP 783 EP 790 DI 10.1139/Y2012-014 PG 8 WC Pharmacology & Pharmacy; Physiology SC Pharmacology & Pharmacy; Physiology GA 948VU UT WOS:000304531700044 PM 22506885 ER PT J AU Rayburn, E Wang, W Li, M Zhang, X Xu, HX Li, HB Qin, JJ Jia, L Covey, J Lee, M Zhang, RW AF Rayburn, Elizabeth Wang, Wei Li, Mao Zhang, Xu Xu, Hongxia Li, Haibo Qin, Jiang-Jiang Jia, Lee Covey, Joseph Lee, Moses Zhang, Ruiwen TI Preclinical pharmacology of novel indolecarboxamide ML-970, an investigative anticancer agent SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE ML-970 (NSC 716970); Indolecarboxamide; HPLC; Protein binding; Pharmacokinetics; Enterohepatic circulation ID TOXICITY; SAFETY AB ML-970 (AS-I-145; NSC 716970) is an indolecarboxamide synthesized as a less toxic analog of CC-1065 and duocarmycin, a natural product that binds the A-T-rich DNA minor groove and alkylates DNA. The NCI60 screening showed that ML-970 had potent cytotoxic activity, with an average GI(50) of 34 nM. The aim of this study is to define the pharmacological properties of this novel anticancer agent. We established an HPLC method for the compound, examined its stability, protein binding, and metabolism by S9 enzymes, and conducted pharmacokinetic studies of the compound in two strains of mice using two different formulations. ML-970 was relatively stable in plasma, being largely intact after an 8-h incubation in mouse plasma at 37A degrees C. The compound was extensively bound to plasma proteins. ML-970 was only minimally metabolized by the enzymes present in S9 preparation and was not appreciably excreted in the urine or feces. The solution formulation provided higher C (max), AUC, F values, and greater bioavailability, although the suspension formulation resulted in a later T (max) and a slightly longer T (1/2). To determine the fate of the compound, we accomplished in-depth studies of tissue distribution; the results indicated that the compound undergoes extensive enterohepatic circulation. The results obtained from this study will be relevant to the further development of the compound and may explain the lower myelotoxicity of this analog compared to CC-1065. C1 [Wang, Wei; Zhang, Xu; Xu, Hongxia; Qin, Jiang-Jiang; Zhang, Ruiwen] Texas Tech Univ, Hlth Sci Ctr, Dept Pharmaceut Sci, Amarillo, TX 79106 USA. [Rayburn, Elizabeth; Wang, Wei; Li, Mao; Zhang, Xu; Xu, Hongxia; Li, Haibo; Zhang, Ruiwen] Univ Alabama Birmingham, Div Clin Pharmacol, Dept Pharmacol & Toxicol, Canc Pharmacol Lab,Comprehens Canc Ctr, Birmingham, AL 35294 USA. [Wang, Wei; Zhang, Ruiwen] Texas Tech Univ, Hlth Sci Ctr, Canc Biol Ctr, Sch Pharm, Amarillo, TX 79106 USA. [Jia, Lee; Covey, Joseph] NCI, Dev Therapeut Program, DCTD, Rockville, MD USA. [Lee, Moses] Hope Coll, Dept Chem, Holland, MI 49423 USA. RP Zhang, RW (reprint author), Texas Tech Univ, Hlth Sci Ctr, Dept Pharmaceut Sci, 1300 Coulter Dr, Amarillo, TX 79106 USA. EM ruiwen.zhang@ttuhsc.edu OI Qin, Jiangjiang/0000-0002-8559-616X FU NIH NCI [N01-CM-52207] FX This work was supported by NIH NCI contract N01-CM-52207. We thank Dr. Silvana Grau, Dr. Scharri Ezell, and Ms. Charnell Sommers for excellent technical assistance, and Dr. Donald Hill for helpful discussion. NR 11 TC 5 Z9 5 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUN PY 2012 VL 69 IS 6 BP 1423 EP 1431 DI 10.1007/s00280-012-1851-9 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 950BB UT WOS:000304622600004 PM 22367116 ER PT J AU Bose, P Perkins, EB Honeycut, C Wellons, MD Stefan, T Jacobberger, JW Kontopodis, E Beumer, JH Egorin, MJ Imamura, CK Figg, WD Karp, JE Koc, ON Cooper, BW Luger, SM Colevas, AD Roberts, JD Grant, S AF Bose, Prithviraj Perkins, Edward B. Honeycut, Connie Wellons, Martha D. Stefan, Tammy Jacobberger, James W. Kontopodis, Emmanouil Beumer, Jan H. Egorin, Merrill J. Imamura, Chiyo K. Figg, W. Douglas, Sr. Karp, Judith E. Koc, Omer N. Cooper, Brenda W. Luger, Selina M. Colevas, A. Dimitrios Roberts, John D. Grant, Steven TI Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl(+) hematological malignancies SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Imatinib; Flavopiridol; Cyclin-dependent kinase inhibitor; CDK inhibitor; Bcr-Abl; Tyrosine kinase inhibitor; Alvocidib ID DEPENDENT KINASE INHIBITOR; CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; DNA-BINDING ACTIVITY; CANCER-THERAPY; BREAST-CANCER; TYROSINE; TRANSCRIPTION; NEOPLASMS; CELLS AB Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, down-regulates short-lived anti-apoptotic proteins via inhibition of transcription. In preclinical studies, flavopiridol synergizes with imatinib to induce apoptosis. We investigated this novel combination regimen in patients with Bcr-Abl(+) malignancies. In a phase I dose-escalation study, imatinib was administered orally daily, and flavopiridol by 1 h intravenous infusion weekly for 3 weeks every 4 weeks. Adults with chronic myelogenous leukemia or Philadelphia chromosome-positive acute leukemia were eligible. Patients were divided into two strata based on peripheral blood and bone marrow blast counts. The primary objective was to identify the recommended phase II doses for the combination. Correlative pharmacokinetic and pharmacodynamic studies were also performed. A total of 21 patients received study treatment. Four dose levels were evaluated before the study was closed following the approval of the second-generation Bcr-Abl tyrosine kinase inhibitors (TKIs). Five patients responded, including four sustained responses. Four patients had stable disease. All but one responder, and all patients with stable disease had previously been treated with imatinib. One patient had a complete response sustained for 30 months. Changes in expression of phospho-Bcr/Abl, -Stat5, and Mcl-1 were monitored. No major pharmacokinetic interaction was observed. This is the first study to evaluate the combination of a CDK inhibitor and a TKI in humans. The combination of flavopiridol and imatinib is tolerable and produces encouraging responses, including in some patients with imatinib-resistant disease. C1 [Grant, Steven] Virginia Commonwealth Univ, Inst Mol Med, Richmond, VA 23284 USA. [Bose, Prithviraj; Perkins, Edward B.; Honeycut, Connie; Wellons, Martha D.; Roberts, John D.; Grant, Steven] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Bose, Prithviraj; Perkins, Edward B.; Roberts, John D.; Grant, Steven] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA USA. [Stefan, Tammy; Jacobberger, James W.; Cooper, Brenda W.] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Kontopodis, Emmanouil] Univ Hosp Herakl, Dept Med Oncol, Iraklion, Greece. [Kontopodis, Emmanouil; Beumer, Jan H.; Egorin, Merrill J.] Univ Pittsburgh, Inst Canc, Mol Therapeut Drug Discovery Program, Pittsburgh, PA USA. [Beumer, Jan H.] Univ Pittsburgh, Inst Canc, Mol Therapeut Melanoma Program, Pittsburgh, PA USA. [Beumer, Jan H.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Egorin, Merrill J.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Egorin, Merrill J.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Imamura, Chiyo K.] Keio Univ, Sch Med, Dept Clin Pharmacokinet & Pharmacodynam, Tokyo, Japan. [Figg, W. Douglas, Sr.] NCI, Mol Pharmacol Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Figg, W. Douglas, Sr.] NCI, Clin Pharmacol Program, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Karp, Judith E.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Div Hematol Malignancies, Baltimore, MD USA. [Koc, Omer N.] Cleveland Clin, Taussig Canc Inst, Dept Reg Oncol, Cleveland, OH 44106 USA. [Luger, Selina M.] Univ Penn, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Colevas, A. Dimitrios] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Grant, Steven] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA. [Grant, Steven] Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Richmond, VA USA. RP Grant, S (reprint author), Virginia Commonwealth Univ, Inst Mol Med, Richmond, VA 23284 USA. EM stgrant@vcu.edu RI Figg Sr, William/M-2411-2016 FU NIH [R01 CA93738-05, CA 100866, R21 CA106139]; NCI [U01 CA70095, P30-CA47904]; Massey Cancer Center [P30 CA016059]; General Clinical Research Center [M01 RR00065]; Leukemia and Lymphoma Society of America [6181-10]; Multiple Myeloma Research Foundation; Myeloma SPORE [1P50CA142509]; Lymphoma SPORE [1P50CA130805]; Hellenic Society of Medical Oncology; American Society of Clinical Oncology Cancer Foundation FX The authors would like to acknowledge Mary Beth Tombes, R. N., M. N. for assistance in preparing the manuscript tables, Lora Kramer for the Western blot figure, Sookyung Woo and Shawn Spencer for the manuscript and supplemental sections on flavopiridol pharmacokinetics and Brian J. Druker, Director, Knight Cancer Institute, Oregon Health and Science University, for performing correlative studies on characterization of mechanisms of resistance to imatinib in patients previously treated with imatinib. This work was supported by the following NIH grants: R01 CA93738-05, CA 100866, and R21 CA106139, NCI Cooperative Agreement U01 CA70095, Massey Cancer Center Support Grant P30 CA016059, General Clinical Research Center Grant M01 RR00065, Leukemia and Lymphoma Society of America award 6181-10, Multiple Myeloma Research Foundation, Myeloma SPORE award 1P50CA142509, and Lymphoma SPORE award 1P50CA130805. EK was supported by a scholarship from the Hellenic Society of Medical Oncology. JHB and MJE were supported by grant P30-CA47904 from the National Cancer Institute. MJE was the recipient of an American Society of Clinical Oncology Cancer Foundation Translational Research Professorship. NR 45 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUN PY 2012 VL 69 IS 6 BP 1657 EP 1667 DI 10.1007/s00280-012-1839-5 PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 950BB UT WOS:000304622600028 PM 22349810 ER PT J AU Wang, E Tomei, S Marincola, FM AF Wang, Ena Tomei, Sara Marincola, Francesco M. TI Reflections upon human cancer immune responsiveness to T cell-based therapy SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE CIMT 2011; Melanoma; Tumor immunotherapy; Immunoresponsiveness; Cancer vaccines ID TUMOR-INFILTRATING LYMPHOCYTES; MELANOMA PATIENTS; GENE-EXPRESSION; METASTATIC MELANOMA; IMMUNOLOGICAL CONSTANT; PERIPHERAL-BLOOD; IN-VIVO; IMMUNOTHERAPY; ANTIGENS; REJECTION AB Immune-mediated rejection of human cancer is a relatively rare but well-documented phenomenon. Its rate of occurrence progressively increases from the occasional observation of spontaneous regressions to the high rate of complete remissions observed in response to effective treatments. For two decades, our group has focused its interest in understanding this phenomenon by studying humans following an inductive approach. Sticking to a sequential logic, we dissected the phenomenon by studying to the best of our capability both peripheral and tumor samples and reached the conclusion that immune-mediated cancer rejection is a facet of autoimmunity where the target tissue is the cancer itself. As we are currently defining the strategy to effectively identify the mechanisms leading in individual patients to rejection of their own tumors, we considered useful to summarize the thought process that guided us to our own interpretation of the mechanisms of immune responsiveness. C1 [Wang, Ena; Tomei, Sara; Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Tomei, Sara; Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, IDIS, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C711,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tomeis@mail.nih.gov; fmarincola@mail.cc.nih.gov NR 73 TC 5 Z9 5 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD JUN PY 2012 VL 61 IS 6 BP 761 EP 770 DI 10.1007/s00262-012-1274-9 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA 950AU UT WOS:000304621900002 PM 22576055 ER PT J AU Shaw, P Gilliam, M Malek, M Rodriguez, N Greenstein, D Clasen, L Evans, A Rapoport, J Giedd, J AF Shaw, P. Gilliam, M. Malek, M. Rodriguez, N. Greenstein, D. Clasen, L. Evans, A. Rapoport, J. Giedd, J. TI Parental Age Effects on Cortical Morphology in Offspring SO CEREBRAL CORTEX LA English DT Article DE cognition; cortex; neuroimaging; neuropsychiatric disorder; parental age ID POSTTRAUMATIC-STRESS-DISORDER; AUTOMATED 3-D EXTRACTION; ADVANCING PATERNAL AGE; CEREBRAL-CORTEX; SURFACE-AREA; HUMAN BRAIN; PREFRONTAL CORTEX; EARLY DEPRIVATION; CORPUS-CALLOSUM; MATERNAL AGE AB The age at which a parent has a child impacts the child's cognition and risk for mental illness. It appears that this risk is curvilinear, with both age extremes associated with lower intelligence and increased prevalence of some neuropsychiatric disorders. Little is known of the neural mechanisms underpinning this phenomenon. We extracted lobar volumes, surface areas, and cortical thickness from 489 neuroanatomic magnetic resonance images acquired on 171 youth. Using linear mixed model regression, we determined the association between parental age and offspring's neuroanatomy, adjusting for offspring's age, sex, intelligence, and parental socioeconomic class. For gray matter volumes, quadratic paternal and maternal age terms contributed significantly (maternal quadratic age effect: t = -2.2, P = 0.03; paternal quadratic age effect: t = -2.4, P = 0.02) delineating an inverted "U" relationship between parental age and gray matter volume. Cortical volume increased with both advancing paternal and maternal age until around the early 30s after which it fell. Paternal age effects were more pronounced on cortical surface area, whereas maternal age impacted more on cortical thickness. There were no significant effects of parental age on white matter volumes. These parental age effects on cerebral morphology may form part of the link between parental age extremes and suboptimal neurocognitive outcomes. C1 [Shaw, P.; Gilliam, M.; Malek, M.; Rodriguez, N.; Greenstein, D.; Clasen, L.; Rapoport, J.; Giedd, J.] NIMH, Child Psychiat Branch, Intramural Program, Bethesda, MD 20892 USA. [Evans, A.] McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. RP Shaw, P (reprint author), NIMH, Child Psychiat Branch, Intramural Program, Room 3N202,Bldg 10,Ctr Dr, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov RI Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU National Institute of Mental Health FX Intramural Program of the National Institute of Mental Health. NR 66 TC 7 Z9 7 U1 3 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD JUN PY 2012 VL 22 IS 6 BP 1256 EP 1262 DI 10.1093/cercor/bhr194 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 948YJ UT WOS:000304539700004 PM 21817090 ER PT J AU Tomasi, D Volkow, ND AF Tomasi, Dardo Volkow, Nora D. TI Laterality Patterns of Brain Functional Connectivity: Gender Effects SO CEREBRAL CORTEX LA English DT Article DE connectivity; functional connectomes; laterality ID ANTERIOR CINGULATE CORTEX; CEREBRAL ASYMMETRY; HEMISPHERIC-ASYMMETRY; SEX-DIFFERENCES; DEVELOPMENTAL DYSLEXIA; PLANUM-TEMPORALE; AUDITORY-CORTEX; SCHIZOPHRENIA; LANGUAGE; NETWORKS AB Lateralization of brain connectivity may be essential for normal brain function and may be sexually dimorphic. Here, we study the laterality patterns of short-range (implicated in functional specialization) and long-range (implicated in functional integration) connectivity and the gender effects on these laterality patterns. Parallel computing was used to quantify short- and long-range functional connectivity densities in 913 healthy subjects. Short-range connectivity was rightward lateralized and most asymmetrical in areas around the lateral sulcus, whereas long-range connectivity was rightward lateralized in lateral sulcus and leftward lateralizated in inferior prefrontal cortex and angular gyrus. The posterior inferior occipital cortex was leftward lateralized (short- and long-range connectivity). Males had greater rightward lateralization of brain connectivity in superior temporal (short- and long-range), inferior frontal, and inferior occipital cortices (short-range), whereas females had greater leftward lateralization of long-range connectivity in the inferior frontal cortex. The greater lateralization of the male's brain (rightward and predominantly short-range) may underlie their greater vulnerability to disorders with disrupted brain asymmetries (schizophrenia, autism). C1 [Tomasi, Dardo; Volkow, Nora D.] NIAAA, Lab Neuroimaging, LNI, Dept Med,Brookhaven Natl Lab, Upton, NY 11973 USA. [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. RP Tomasi, D (reprint author), NIAAA, Lab Neuroimaging, LNI, Dept Med,Brookhaven Natl Lab, Bldg 490,30 Bell Ave, Upton, NY 11973 USA. EM tomasi@bnl.gov RI Tomasi, Dardo/J-2127-2015 FU National Institutes of Alcohol Abuse and Alcoholism [2RO1AA09481] FX National Institutes of Alcohol Abuse and Alcoholism (2RO1AA09481). NR 58 TC 53 Z9 55 U1 4 U2 34 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD JUN PY 2012 VL 22 IS 6 BP 1455 EP 1462 DI 10.1093/cercor/bhr230 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 948YJ UT WOS:000304539700021 PM 21878483 ER PT J AU Pavan, WJ Raible, DW AF Pavan, William J. Raible, David W. TI Specification of neural crest into sensory neuron and melanocyte lineages SO DEVELOPMENTAL BIOLOGY LA English DT Review DE Neural crest; Dorsal root ganglion; Melanocyte ID DORSAL-ROOT GANGLION; ENDOTHELIN RECEPTOR-B; TRANSCRIPTION FACTOR SOX9; 2 DISTINCT WAVES; C-KIT ANTIBODY; GENE-EXPRESSION; CHICK-EMBRYO; TRIGEMINAL GANGLION; CELL FATE; REGULATES DEVELOPMENT AB Elucidating the mechanisms by which multipotent cells differentiate into distinct lineages is a common theme underlying developmental biology investigations. Progress has been made in understanding some of the essential factors and pathways involved in the specification of different lineages from the neural crest. These include gene regulatory networks involving transcription factor hierarchies and input from signaling pathways mediated from environmental cues. In this review, we examine the mechanisms for two lineages that are derived from the neural crest, peripheral sensory neurons and melanocytes. Insights into the specification of these cell types may reveal common themes in the specification processes that occur throughout development. (C) 2012 Elsevier Inc. All rights reserved. C1 [Raible, David W.] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. [Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Raible, DW (reprint author), Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. EM bpavan@mail.nih.gov; draible@u.washington.edu FU Intramural NIH HHS [ZIA HG000070-15, ZIA HG000136-11, Z01 HG000136-09, ZIA HG000136-13, ZIA HG000070-16, ZIA HG000136-12, Z01 HG000136-10]; NINDS NIH HHS [R01 NS057220-01A1, R01 NS057220-05, R01 NS057220-02, R01 NS057220-03, R01 NS057220-04, R01 NS057220] NR 202 TC 24 Z9 24 U1 0 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2012 VL 366 IS 1 SI SI BP 55 EP 63 DI 10.1016/j.ydbio.2012.02.038 PG 9 WC Developmental Biology SC Developmental Biology GA 948KH UT WOS:000304501600006 PM 22465373 ER PT J AU Maeda, K Das, D Nakata, H Mitsuya, H AF Maeda, Kenji Das, Debananda Nakata, Hirotomo Mitsuya, Hiroaki TI CCR5 inhibitors: emergence, success, and challenges SO EXPERT OPINION ON EMERGING DRUGS LA English DT Review DE AIDS; antiretroviral therapy; CCR5; CCR5 inhibitor; chemokine; HIV ID TREATMENT-EXPERIENCED PATIENTS; ACTIVE ANTIRETROVIRAL THERAPY; CCR5-TROPIC HIV-1 INFECTION; SMALL-MOLECULE INHIBITOR; CHEMOKINE RECEPTOR CCR5; SHORT-TERM MONOTHERAPY; CLINICAL-TRIALS; ENVELOPE GLYCOPROTEIN; FUSION COFACTORS; HIGHLY POTENT AB Introduction: The discovery of CC-chemokine receptor 5 (CCR5) as a human immunodeficiency virus type 1 (HIV-1) coreceptor opened a new avenue to exploit CCR5 as a potential target for the intervention of HIV-1's cellular entry. Areas covered: Various small-molecule CCR5 inhibitors were identified in the last decade; however, maraviroc (MVC) is the only CCR5 inhibitor currently used in the clinic. Concerns and challenges that exist for wider clinical use of CCR5 inhibitors are discussed. Expert opinion: Although MVC-containing regimens have been recommended for treatment-naive patients, MVC appears to have been used as one of drugs for salvage therapy rather than for treating drug-naive patients. This is apparently due to MVC's twice-daily dosing schedule. Another significant disadvantage is that a costly tropism assay must be performed prior to MVC treatment. The access to inexpensive, sensitive, and rapid tropism tests should be made easily available. Only a few novel CCR5 inhibitors are presently in the pipeline. Development of potent and metabolically-stable novel CCR5 inhibitors allowing once-daily dosing regimens is needed. Development of CXCR4 inhibitors should greatly improve the treatment options available to patients infected with X4-and/or dual-tropic HIV-1 strains in combination with a CCR5 inhibitor. C1 [Maeda, Kenji; Das, Debananda; Nakata, Hirotomo; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Nakata, Hirotomo; Mitsuya, Hiroaki] Kumamoto Univ, Dept Hematol, Grad Sch Biomed Sci, Kumamoto 8608556, Japan. [Nakata, Hirotomo; Mitsuya, Hiroaki] Kumamoto Univ, Dept Infect Dis, Grad Sch Biomed Sci, Kumamoto 8608556, Japan. RP Maeda, K (reprint author), NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, 9000 Rockville Pike,Bldg 10,Room 5A11, Bethesda, MD 20892 USA. EM maedak@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, NIH; Ministry of Health, Welfare, and Labor of Japan FX The authors of this article have no conflict of interest with entry inhibitors including CCR5 inhibitors that are now in clinical use or in clinical/preclinical development. This work was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, and in part by a Grant for global education and research center aiming at the control of AIDS (Global Center of Excellence supported by Monbu-Kagakusho), Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan. NR 96 TC 17 Z9 18 U1 0 U2 19 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8214 J9 EXPERT OPIN EMERG DR JI Expert Opin Emerg. Drugs PD JUN PY 2012 VL 17 IS 2 BP 135 EP 145 DI 10.1517/14728214.2012.673584 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 947TB UT WOS:000304452400002 PM 22533737 ER PT J AU Adler, MJ Dimitrov, DS AF Adler, Mark J. Dimitrov, Dimiter S. TI Therapeutic Antibodies Against Cancer SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Therapeutics; Antibodies; Cancer; Immunogenicity; Safety; Efficacy ID CHRONIC LYMPHOCYTIC-LEUKEMIA; METASTATIC COLORECTAL-CANCER; PHASE-III TRIAL; GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; BRENTUXIMAB VEDOTIN SGN-35; CETUXIMAB PLUS IRINOTECAN; PROGRESSION-FREE SURVIVAL; HUMAN MONOCLONAL-ANTIBODIES; IN-SITU HYBRIDIZATION AB Antibody-based therapeutics against cancer are highly successful and currently enjoy unprecedented recognition of their potential; 13 monoclonal antibodies (mAbs) have been approved for clinical use in the European Union and in the United States. Bevacizumab, rituximab, and trastuzumab had sales in 2010 of more than $5 billion each. Hundreds of mAbs, including bispecific mAbs and multispecific fusion proteins, mAbs conjugated with small-molecule drugs, and mAbs with optimized pharmacokinetics, are in clinical trials. However, deeper understanding of mechanisms is needed to overcome major problems including resistance to therapy, access to targets, complexity of biological systems, and individual variations. C1 [Adler, Mark J.] Univ Calif Hlth Syst, Dept Med, UC San Diego Canc Ctr, Encinitas, CA 92024 USA. [Adler, Mark J.] San Diego Canc Res Inst, Encinitas, CA 92024 USA. [Dimitrov, Dimiter S.] NIH, Frederick Natl Labs Canc Res, Frederick, MD 21702 USA. RP Adler, MJ (reprint author), Univ Calif Hlth Syst, Dept Med, UC San Diego Canc Ctr, 1200 Garden View, Encinitas, CA 92024 USA. EM oncologic@gmail.com FU NIH NCI CCR FX This study was supported by the NIH NCI CCR intramural program. NR 234 TC 17 Z9 18 U1 0 U2 17 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 EI 1558-1977 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD JUN PY 2012 VL 26 IS 3 BP 447 EP + DI 10.1016/j.hoc.2012.02.013 PG 36 WC Oncology; Hematology SC Oncology; Hematology GA 949JF UT WOS:000304571800002 PM 22520975 ER PT J AU Arnaldez, FI Heiman, LJ AF Arnaldez, Fernanda I. Heiman, Lee J. TI Targeting the Insulin Growth Factor Receptor 1 SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE IGF1R; IGF1; IGF2; Insulin; Kinase; Cancer ID FACTOR-I RECEPTOR; GASTROINTESTINAL-STROMAL-TUMORS; HUMAN-BREAST-CANCER; CELL LUNG-CANCER; POTENTIAL THERAPEUTIC TARGET; SMALL-MOLECULE INHIBITORS; TYPE-2 DIABETIC-PATIENTS; IGF-BINDING PROTEIN-3; COLORECTAL-CANCER; PROSTATE-CANCER AB The IGF axis is a tightly controlled endocrine system that regulates cell growth and development, known to have an important function in cancer biology. IGF1 and IGF2 can promote cancer growth in a GH-independent manner both through paracrine and autocrine secretion and can also confer resistance to chemotherapy and radiation. Many alterations of this system have been found in neoplasias, including increased expression of ligands and receptors, loss of heterozygosity of the IGF2 locus and increased IGF1R gene copy number. The IGF1 network is an attractive candidate for targeted therapy, including receptor blockade with monoclonal antibodies and small molecule inhibitors of receptor downstream signaling. This article reviews the role of the IGF axis in the initiation and progression of cancer, and describes the recent advances in IGF inhibition as a therapeutic tool. C1 [Arnaldez, Fernanda I.; Heiman, Lee J.] NCI, NIH, Mol Oncol Sect, Pediat Oncol Branch,Ctr Canc Res, Bethesda, MD 20892 USA. RP Arnaldez, FI (reprint author), NCI, NIH, Mol Oncol Sect, Pediat Oncol Branch,Ctr Canc Res, 9000 Rockville Pike,Bldg 10-Room 1W-3816, Bethesda, MD 20892 USA. EM arnaldezf@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 128 TC 44 Z9 47 U1 1 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD JUN PY 2012 VL 26 IS 3 BP 527 EP + DI 10.1016/j.hoc.2012.01.004 PG 18 WC Oncology; Hematology SC Oncology; Hematology GA 949JF UT WOS:000304571800005 PM 22520978 ER PT J AU Thomas, A Rajan, A Giaccone, G AF Thomas, Anish Rajan, Arun Giaccone, Giuseppe TI Tyrosine Kinase Inhibitors in Lung Cancer SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Non-small cell lung cancer; Tyrosine kinase inhibitor; Epidermal growth factor receptor; Anaplastic lymphoma kinase translocation; Vascular endothelial growth factor ID GROWTH-FACTOR RECEPTOR; PHASE-III TRIAL; IRREVERSIBLE EGFR INHIBITOR; PREVIOUSLY TREATED PATIENTS; EML4-ALK FUSION GENE; ACQUIRED-RESISTANCE; ANAPLASTIC LYMPHOMA; ANTITUMOR-ACTIVITY; JAPANESE PATIENTS; KRAS MUTATIONS AB Identification of driver mutations in growth related protein kinases, especially tyrosine kinases, has led to clinical development of an array of tyrosine kinase inhibitors in various malignancies, including lung cancer. Improved understanding of tyrosine kinase biology has led to faster drug development, identification of resistance mechanisms, and ways to overcome resistance. This review discusses the clinical data supporting the use and practical aspects of management of patients on epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors. C1 [Thomas, Anish; Rajan, Arun; Giaccone, Giuseppe] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, Room 12N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 FU National Cancer Institute FX Funding support: Intramural Research Program, National Cancer Institute. NR 97 TC 4 Z9 4 U1 0 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 EI 1558-1977 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD JUN PY 2012 VL 26 IS 3 BP 589 EP + DI 10.1016/j.hoc.2012.02.001 PG 18 WC Oncology; Hematology SC Oncology; Hematology GA 949JF UT WOS:000304571800008 PM 22520981 ER PT J AU Park, SR Chen, A AF Park, Sook Ryun Chen, Alice TI Poly(Adenosine Diphosphate-Ribose) Polymerase Inhibitors in Cancer Treatment SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Poly(ADP-ribose) polymerase; Inhibitor; Synthetic lethality; BRCA ID HOMOLOGOUS RECOMBINATION REPAIR; EPITHELIAL OVARIAN-CANCER; POPULATION-BASED SAMPLE; NEGATIVE BREAST-CANCER; BRCA1 PROMOTER REGION; ADVANCED SOLID TUMORS; DOUBLE-STRAND BREAKS; DNA MISMATCH REPAIR; POLY(ADP-RIBOSE) POLYMERASE; PARP INHIBITOR AB Recently, the development of poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors as a synthetic lethality approach has brought a major breakthrough in the treatment of breast cancer susceptibility gene (BRCA)-mutant cancers. Because sporadic cancers have also been found to commonly have other defects in DNA repair, PARP inhibitors are under active clinical investigation in combination with DNA-damaging therapeutics in a wide range of sporadic cancers. In this review, the authors discuss DNA repair mechanisms and PARP as a therapeutic target and summarize an update on clinical trials of available PARP inhibitors and predictive biomarkers for their efficacy. C1 [Park, Sook Ryun] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Chen, Alice] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD 20852 USA. RP Chen, A (reprint author), 6130 Execut Blvd,EPN 7131, Rockville, MD 20852 USA. EM chenali@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 94 TC 15 Z9 17 U1 0 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD JUN PY 2012 VL 26 IS 3 BP 649 EP + DI 10.1016/j.hoc.2012.02.012 PG 23 WC Oncology; Hematology SC Oncology; Hematology GA 949JF UT WOS:000304571800011 PM 22520984 ER PT J AU Sharara-Chami, RI Zhou, YJ Ebert, S Pacak, K Ozcan, U Majzoub, JA AF Sharara-Chami, Rana I. Zhou, Yingjiang Ebert, Steven Pacak, Karel Ozcan, Umut Majzoub, Joseph A. TI Epinephrine deficiency results in intact glucose counter-regulation, severe hepatic steatosis and possible defective autophagy in fasting mice SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE Brown adipose tissue; Epinephrine; Autophagy; Fasting; Steatosis; Metabolism ID ADRENERGIC-MECHANISMS; GLYCEMIC THRESHOLDS; CELLULAR AUTOPHAGY; INSULIN-RESISTANCE; RAT LIVER; GLUCAGON; DISEASE; HUMANS; ALPHA; COUNTERREGULATION AB Epinephrine is one of the major hormones involved in glucose counter-regulation and gluconeogenesis. However, little is known about its importance in energy homeostasis during fasting. Our objective is to study the specific role of epinephrine in glucose and lipid metabolism during starvation. In our experiment, we subject regular mice and epinephrine-deficient mice to a 48-h fast then we evaluate the different metabolic responses to fasting. Our results show that epinephrine is not required for glucose counter-regulation: epinephrine-deficient mice maintain their blood glucose at normal fasting levels via glycogenolysis and gluconeogenesis, with normal fasting-induced changes in the peroxisomal activators: peroxisome proliferator activated receptor gamma coactivator alpha (PGC-1 alpha), fibroblast growth factor 21 (FGF-21), peroxisome proliferator activated receptor alpha (PPAR-alpha), and sterol regulatory element binding protein (SREBP-1c). However, fasted epinephrine-deficient mice develop severe ketosis and hepatic steatosis, with evidence for inhibition of hepatic autophagy, a process that normally provides essential energy via degradation of hepatic triglycerides during starvation. We conclude that, during fasting, epinephrine is not required for glucose homeostasis, lipolysis or ketogenesis. Epinephrine may have an essential role in lipid handling, possibly via an autophagy-dependent mechanism. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Sharara-Chami, Rana I.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Crit Care Med,Dept Anesthesiol, Boston, MA 02115 USA. [Zhou, Yingjiang; Ozcan, Umut; Majzoub, Joseph A.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Endocrinol,Dept Med, Boston, MA 02115 USA. [Ebert, Steven] Univ Cent Florida, Coll Med, Burnett Sch Biomed Sci, Orlando, FL 32816 USA. [Pacak, Karel] NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. RP Sharara-Chami, RI (reprint author), Amer Univ Beirut, Med Ctr, Dept Pediat & Adolescent Med, Div Pediat Crit Care Med, Beirut, Lebanon. EM rsharara@aub.edu.lb FU Timothy Murphy Fund FX The research was supported by the Timothy Murphy Fund. NR 41 TC 7 Z9 7 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD JUN PY 2012 VL 44 IS 6 BP 905 EP 913 DI 10.1016/j.biocel.2012.02.016 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 948GD UT WOS:000304490700013 PM 22405854 ER PT J AU Siberry, GK Harris, DR Oliveira, RH Krauss, MR Hofer, CB Tiraboschi, AA Marques, H Succi, RC Abreu, T Della Negra, M Mofenson, LM Hazra, R AF Siberry, George K. Harris, D. Robert Oliveira, Ricardo Hugo Krauss, Margot R. Hofer, Cristina B. Tiraboschi, Adriana Aparecida Marques, Heloisa Succi, Regina C. Abreu, Thalita Della Negra, Marinella Mofenson, Lynne M. Hazra, Rohan CA NISDI PLACES Protocol TI Evaluation of Viral Load Thresholds for Predicting New World Health Organization Stage 3 and 4 Events in HIV-Infected Children Receiving Highly Active Antiretroviral Therapy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE pediatric HIV infection; viral load monitoring; viral load threshold; Latin America ID IMMUNODEFICIENCY-VIRUS TYPE-1; INFANTS; RNA AB Background: This study evaluated a wide range of viral load (VL) thresholds to identify a cut-point that best predicts new clinical events in children on stable highly active antiretroviral therapy (HAART). Methods: Cox proportional hazards modeling was used to assess the adjusted risk for World Health Organization stage 3 or 4 clinical events (WHO events) as a function of time-varying CD4, VL, and hemoglobin values in a cohort study of Latin American children on HAART >= 6 months. Models were fit using different VL cut-points between 400 and 50,000 copies per milliliter, with model fit evaluated on the basis of the minimum Akaike information criterion value, a standard model fit statistic. Results: Models were based on 67 subjects with WHO events out of 550 subjects on study. The VL cut-points of >2600 and >32,000 copies per milliliter corresponded to the lowest Akaike information criterion values and were associated with the highest hazard ratios (2.0, P = 0.015; and 2.1, P = 0.0058, respectively) for WHO events. Conclusions: In HIV-infected Latin American children on stable HAART, 2 distinct VL thresholds (>2600 and >32,000 copies/mL) were identified for predicting children at significantly increased risk for HIV-related clinical illness, after accounting for CD4 level, hemoglobin level, and other significant factors. C1 [Siberry, George K.; Mofenson, Lynne M.; Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Brach, NIH, Bethesda, MD 20892 USA. [Harris, D. Robert; Krauss, Margot R.] Westat Corp, Rockville, MD USA. [Oliveira, Ricardo Hugo; Hofer, Cristina B.; Abreu, Thalita] Univ Fed Rio de Janeiro, Inst Puericultura & Pediat Martagao Gesteira, Rio De Janeiro, Brazil. [Tiraboschi, Adriana Aparecida] Univ Sao Paulo, Fac Med Ribeirao Preto, Sao Paulo, Brazil. [Marques, Heloisa] Univ Sao Paulo, Fac Med Sao Paulo, Sao Paulo, Brazil. [Succi, Regina C.] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Della Negra, Marinella] Inst Infectol Emilio Ribas, Sao Paulo, Brazil. RP Siberry, GK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Brach, NIH, 6100 Execut Blvd,Room 4B11H, Bethesda, MD 20892 USA. EM siberryg@mail.nih.gov RI Mussi-Pinhata, Marisa/G-6568-2012; OI Mofenson, Lynne/0000-0002-2818-9808 FU National Institute of Child Health and Human Development (NICHD) [N01-HD-3-3345, HHSN267200800001C, N01-HD-8-0001] FX Supported by National Institute of Child Health and Human Development Contracts N01-HD-3-3345 (2002-2007) and HHSN267200800001C (NICHD Control: N01-HD-8-0001) (2007-2012). NR 10 TC 2 Z9 2 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2012 VL 60 IS 2 BP 214 EP 218 DI 10.1097/QAI.0b013e31824e4da6 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 947NL UT WOS:000304436600025 PM 22343177 ER PT J AU Baum, SJ Kris-Etherton, PM Willett, WC Lichtenstein, AH Rudel, LL Maki, KC Whelan, J Ramsden, CE Block, RC AF Baum, Seth J. Kris-Etherton, Penny M. Willett, Walter C. Lichtenstein, Alice H. Rudel, Lawrence L. Maki, Kevin C. Whelan, Jay Ramsden, Christopher E. Block, Robert C. TI Fatty acids in cardiovascular health and disease: A comprehensive update SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Article DE Cardiovascular disease; Coronary heart disease; Monounsaturated fatty acids; Polyunsaturated fatty acids; Saturated fat ID CORONARY-HEART-DISEASE; RANDOMIZED CONTROLLED-TRIALS; PLACEBO-CONTROLLED TRIAL; DIETARY LINOLEIC-ACID; AFRICAN-GREEN MONKEYS; MIDDLE-AGED MEN; MYOCARDIAL-INFARCTION; SATURATED FAT; MONOUNSATURATED FAT; SERUM-LIPIDS AB Research dating back to the 1950s reported an association between the consumption of saturated fatty acids (SFAs) and risk of coronary heart disease. Recent epidemiological evidence, however, challenges these findings. It is well accepted that the consumption of SFAs increases low-density lipoprotein cholesterol (LDL-C), whereas carbohydrates, monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) do not. High-density lipoprotein (HDL)-C increases with SFA intake. Among individuals who are insulin resistant, a low-fat, high-carbohydrate diet typically has an adverse effect on lipid profiles (in addition to decreasing HDL-C, it also increases triglyceride and LDL particle concentrations). Consequently, a moderate fat diet in which unsaturated fatty acids replace SFAs and carbohydrates are not augmented is advised to lower LDL-C; compared with a low-fat diet, a moderate-fat diet will lower triglycerides and increase HDL-C. Now, there is some new evidence that is questioning the health benefits of even MUFAs and PUFAs. In addition, in a few recent studies investigators have also failed to demonstrate expected cardiovascular benefits of marine-derived omega-3 fatty acids. To clarify the clinical pros and cons of dietary fats, the National Lipid Association held a fatty acid symposium at the 2011 National Lipid Association Scientific Sessions. During these sessions, the science regarding the effects of different fatty acid classes on coronary heart disease risk was reviewed. (C) 2012 National Lipid Association. All rights reserved. C1 [Baum, Seth J.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Kris-Etherton, Penny M.] Penn State Univ, University Pk, PA 16802 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Lichtenstein, Alice H.] Tufts Univ, Medford, MA 02155 USA. [Rudel, Lawrence L.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Maki, Kevin C.] Biofortis Provident Clin Res, Addison, IL USA. [Whelan, Jay] Univ Tennessee, Knoxville, TN USA. [Ramsden, Christopher E.] NIH, Bethesda, MD 20892 USA. [Block, Robert C.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. RP Baum, SJ (reprint author), Univ Miami, Miller Sch Med, Miami, FL 33136 USA. EM sjbaum@fpim.org NR 87 TC 90 Z9 93 U1 10 U2 85 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD JUN PY 2012 VL 6 IS 3 BP 216 EP 234 DI 10.1016/j.jacl.2012.04.077 PG 19 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 951NI UT WOS:000304726900004 PM 22658146 ER PT J AU Fisch, MJ Lee, JW Weiss, M Wagner, LI Chang, VT Cella, D Manola, JB Minasian, LM McCaskill-Stevens, W Mendoza, TR Cleeland, CS AF Fisch, Michael J. Lee, Ju-Whei Weiss, Matthias Wagner, Lynne I. Chang, Victor T. Cella, David Manola, Judith B. Minasian, Lori M. McCaskill-Stevens, Worta Mendoza, Tito R. Cleeland, Charles S. TI Prospective, Observational Study of Pain and Analgesic Prescribing in Medical Oncology Outpatients With Breast, Colorectal, Lung, or Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RACIAL-DIFFERENCES; PREVALENCE; MANAGEMENT; CARE; COMMUNICATION; PERCEPTIONS; VALIDATION; PHYSICIANS; ATTITUDES; RELIEF AB Purpose Pain is prevalent among patients with cancer, yet pain management patterns in outpatient oncology are poorly understood. Patients and Methods A total of 3,123 ambulatory patients with invasive cancer of the breast, prostate, colon/rectum, or lung were enrolled onto this prospective study regardless of phase of care or stage of disease. At initial assessment and 4 to 5 weeks later, patients completed a 25-item measure of pain, functional interference, and other symptoms. Providers recorded analgesic prescribing. The pain management index was calculated to assess treatment adequacy. Results Of the 3,023 patients we identified to be at risk for pain, 2,026 (67%) reported having pain or requiring analgesics at initial assessment; of these 2,026 patients, 670 (33%) were receiving inadequate analgesic prescribing. We found no difference in treatment adequacy between the initial and follow-up visits. Multivariable analysis revealed that the odds of a non-Hispanic white patient having inadequate pain treatment were approximately half those of a minority patient after adjusting for other explanatory variables (odds ratio, 0.51; 95% CI, 0.37 to 0.70; P = .002). Other significant predictors of inadequate pain treatment were having a good performance status, being treated at a minority treatment site, and having nonadvanced disease without concurrent treatment. Conclusion Most outpatients with common solid tumors must confront issues related to pain and the use of analgesics. There is significant disparity in pain treatment adequacy, with the odds of undertreatment twice as high for minority patients. These findings persist over 1 month of follow-up, highlighting the complexity of these problems. C1 [Fisch, Michael J.] Univ Texas MD Anderson Canc Ctr, Dept Gen Oncol, Houston, TX 77030 USA. [Lee, Ju-Whei; Manola, Judith B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Weiss, Matthias] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI USA. [Wagner, Lynne I.; Cella, David] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Chang, Victor T.] New Jersey Hlth Care Syst, Dept Vet Affairs, E Orange, NJ USA. [Chang, Victor T.] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [Minasian, Lori M.; McCaskill-Stevens, Worta] NCI, Bethesda, MD 20892 USA. RP Fisch, MJ (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Gen Oncol, Unit 410,1515 Holcombe Blvd, Houston, TX 77030 USA. EM mfisch@mdanderson.org FU Public Health Service [CA37604, CA23318, CA026582, CA17145]; National Cancer Institute, National Institutes of Health; Department of Health and Human Services FX Supported in part by Public Health Service Grants No. CA37604, CA23318, CA026582, and CA17145 and grants from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. NR 29 TC 89 Z9 91 U1 4 U2 17 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 1 PY 2012 VL 30 IS 16 BP 1980 EP 1988 DI 10.1200/JCO.2011.39.2381 PG 9 WC Oncology SC Oncology GA 949SS UT WOS:000304596800020 PM 22508819 ER PT J AU Brody, H Colloca, L Miller, FG AF Brody, Howard Colloca, Luana Miller, Franklin G. TI The Placebo Phenomenon: Implications for the Ethics of Shared Decision-Making SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article ID INFORMED PATIENT CHOICE; HEALTH OUTCOMES; PRIMARY-CARE; RISK; COMMUNICATION; TRANSPARENCY; EXPECTATIONS; CONSENT; LESSONS; TRIAL AB Recent research into the placebo effect has implications for the ethics of shared decision-making (SDM). The older biomedical model views SDM as affecting which therapy is chosen, but not the nature or likelihood of any health outcomes produced by the therapy. Research indicates, however, that both the content and manner in which information is shared with the patient, and the patient's experience of being involved in the decision, can directly alter therapeutic outcomes via placebo responses. An ethical tension is thereby created between SDM aimed strictly and solely at conveying accurate information, and "outcome engineering" in which SDM is adapted toward therapeutic goals. Several practical strategies mitigate this tension and promote respect for autonomous decision-making while still utilizing the therapeutic potential of SDM. C1 [Brody, Howard] Univ Texas Med Branch, Inst Med Humanities, Galveston, TX USA. [Brody, Howard] Univ Texas Med Branch, Dept Family Med, Galveston, TX USA. [Colloca, Luana] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Miller, Franklin G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Brody, H (reprint author), Univ Texas Med Branch, Inst Med Humanities, Galveston, TX USA. EM habrody@utmb.edu OI Colloca, Luana/0000-0002-6503-4709 NR 36 TC 12 Z9 12 U1 2 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUN PY 2012 VL 27 IS 6 BP 739 EP 742 DI 10.1007/s11606-011-1977-1 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 947BZ UT WOS:000304402900019 PM 22258918 ER PT J AU Balaban, RS AF Balaban, Robert S. TI Metabolic homeostasis of the heart SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Editorial Material ID MITOCHONDRIAL ATP SYNTHASE; PERFUSED RAT HEARTS; IN-VIVO; OXIDATIVE-PHOSPHORYLATION; P-31 NMR; OXYGEN-CONSUMPTION; ENERGY-METABOLISM; DEHYDROGENASE-ACTIVITY; PHOSPHATE METABOLITES; CARDIAC METABOLISM C1 NHLBI, Cardiac Energet Lab, Natl Inst Hlth, Bethesda, MD 20817 USA. RP Balaban, RS (reprint author), NHLBI, Cardiac Energet Lab, Natl Inst Hlth, Bethesda, MD 20817 USA. EM rsb@nih.gov FU Intramural NIH HHS NR 64 TC 19 Z9 19 U1 0 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1295 EI 1540-7748 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD JUN PY 2012 VL 139 IS 6 BP 407 EP 414 DI 10.1085/jgp.201210783 PG 8 WC Physiology SC Physiology GA 948YR UT WOS:000304540800003 PM 22641635 ER PT J AU Budhu, A Wang, XW AF Budhu, Anuradha Wang, Xin Wei TI At the cancer steering wheel: Defining key genomic drivers of liver cancer with next generation sequencing SO JOURNAL OF HEPATOLOGY LA English DT Article DE Hepatocellular carcinoma; Next generation sequencing; Gene mutation; Liver cancer; DNA sequencing ID HEPATOCELLULAR-CARCINOMA; MUTATIONS AB Through exomic sequencing of 10 hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCC) and subsequent evaluation of additional affected individuals, we discovered novel inactivating mutations of ARID2 in four major subtypes of HCC (HCV-associated HCC, hepatitis B virus (HBV)-associated HCC, alcohol-associated HCC and HCC with no known etiology). Notably, 18.2% of individuals with HCV-associated HCC in the United States and Europe harbored ARID2 inactivation mutations, suggesting that ARID2 is a tumor suppressor gene that is relatively commonly mutated in this tumor subtype. C1 [Budhu, Anuradha; Wang, Xin Wei] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wang, XW (reprint author), 37 Convent Dr,Bldg 37,Rm 3044A, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI Wang, Xin/B-6162-2009 NR 10 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD JUN PY 2012 VL 56 IS 6 BP 1412 EP 1414 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 948OK UT WOS:000304512300029 PM 22286003 ER PT J AU Hoffman, GE Le, WW Entezam, A Otsuka, N Tong, ZB Nelson, L Flaws, JA McDonald, JH Jafar, S Usdin, K AF Hoffman, Gloria E. Le, Wei Wei Entezam, Ali Otsuka, Noriyuki Tong, Zhi-Bin Nelson, Lawrence Flaws, Jodi A. McDonald, John H. Jafar, Sanjeeda Usdin, Karen TI Ovarian Abnormalities in a Mouse Model of Fragile X Primary Ovarian Insufficiency SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE knockin; immunocytochemistry; ovarian follicles; gene expression; oocyte; granulosa cells ID FOLLICLE-STIMULATING-HORMONE; CEREBELLAR-TREMOR/ATAXIA-SYNDROME; PREMUTATION CARRIERS; MESSENGER-RNA; MEDIATED NEURODEGENERATION; OXIDATIVE STRESS; DROSOPHILA MODEL; GENE-EXPRESSION; NEUROPEPTIDE-Y; RCGG REPEATS AB FMR1 premutation (PM) alleles have 55-200 CGGCCG-repeats in their 5' UTR. PM carriers are at risk of fragile X-associated tremor and ataxia syndrome (FXTAS). Females are also at risk for FX primary ovarian insufficiency (FXPOI). PM pathology is generally attributed to deleterious properties of transcripts with long CGG-tracts. For FXPOI, hormone changes suggest a reduced residual follicle pool. Whether this is due to a smaller than normal original follicle pool or an increased rate of follicle depletion is unclear. A FX-PM mouse the authors generated with 130 CGG.CCG-repeats in the endogenous Fmr1 gene recapitulates features of FXTAS. Here the authors demonstrate that the gross development of the ovary and the establishment of the primordial follicle pool is normal in these mice. However, these animals show a faster loss of follicles of all follicle classes, suggesting that the problem is intrinsic to the ovary. In addition, many oocytes show aberrant nuclear accumulation of FMRP and elevated levels of ubiquitination. Furthermore, PM follicles are smaller and have fewer granulosa cells (GCs) than normal. Thus, these animals have ovarian abnormalities involving both the oocytes and GCs that may shed light on the molecular basis of FXPOI in humans. (J Histochem Cytochem 60:439-456, 2012) C1 [Hoffman, Gloria E.; Le, Wei Wei; Jafar, Sanjeeda] Morgan State Univ, Dept Biol, Baltimore, MD 21251 USA. [Entezam, Ali; Usdin, Karen] NIDDK, Lab Mol & Cell Biol, NIH, Bethesda, MD USA. [Otsuka, Noriyuki] Hokkaido Univ, Dept Pathol, Grad Sch Med, Sapporo, Hokkaido, Japan. [Tong, Zhi-Bin; Nelson, Lawrence] NICHD, Implantat & Oocyte Physiol Sect, NIH, Bethesda, MD USA. [Flaws, Jodi A.] Univ Illinois, Dept Comparat Biosci, Urbana, IL 61801 USA. [McDonald, John H.] Univ Delaware, Dept Biol Sci, Newark, DE USA. RP Hoffman, GE (reprint author), Morgan State Univ, Dept Biol, Spencer G-12,1700 E Cold Spring Lane, Baltimore, MD 21251 USA. EM gl042@verizon.net FU NIDDK (NIH) FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Institutional grants to support research: Funding for this work came in part from a grant to KU from the Intramural program of the NIDDK (NIH). NR 64 TC 32 Z9 36 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD JUN PY 2012 VL 60 IS 6 BP 439 EP 456 DI 10.1369/0022155412441002 PG 18 WC Cell Biology SC Cell Biology GA 950QJ UT WOS:000304663500003 PM 22470123 ER PT J AU Clark, HB Hekman, K Yu, GY Gomez, C AF Clark, H. Brent Hekman, Katherine Yu, Guo-Yun Gomez, Christopher TI Spinocerebellar Ataxia 26: Neuropathological Findings and an Association with a Mutation in Eukaryotic Elongation Factor 2 SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 88th Annual Meeting of the American-Association-of-Neuropathologists CY JUN 21-24, 2012 CL Chicago, IL SP Amer Assoc Neuropathol C1 [Clark, H. Brent] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Hekman, Katherine; Gomez, Christopher] Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. [Yu, Guo-Yun] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2012 VL 71 IS 6 MA 32 BP 556 EP 556 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 949QB UT WOS:000304589600039 ER PT J AU Pletnikova, O Sloane, K Traynor, B Crain, B Troncoso, J Rabins, P Onyike, C AF Pletnikova, Olga Sloane, Kelly Traynor, Bryan Crain, Barbara Troncoso, Juan Rabins, Peter Onyike, Chiadi TI C9ORF72 Expansion in Hippocampal Sclerosis Reaffirms its Classification within the Spectrum of Frontotemporal Dementias SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 88th Annual Meeting of the American-Association-of-Neuropathologists CY JUN 21-24, 2012 CL Chicago, IL SP Amer Assoc Neuropathol C1 [Pletnikova, Olga; Sloane, Kelly; Crain, Barbara; Troncoso, Juan; Rabins, Peter; Onyike, Chiadi] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Traynor, Bryan] NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2012 VL 71 IS 6 MA 68 BP 565 EP 566 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 949QB UT WOS:000304589600075 ER PT J AU Bellad, MB Goudar, SS Edlavitch, SA Mahantshetti, NS Naik, V Hemingway-Foday, JJ Gupta, M Nalina, HR Derman, R Moss, N Kodkany, BS AF Bellad, M. B. Goudar, S. S. Edlavitch, S. A. Mahantshetti, N. S. Naik, V. Hemingway-Foday, J. J. Gupta, M. Nalina, H. R. Derman, R. Moss, N. Kodkany, B. S. TI Consanguinity, prematurity, birth weight and pregnancy loss: a prospective cohort study at four primary health center areas of Karnataka, India SO JOURNAL OF PERINATOLOGY LA English DT Article DE intermarriage; miscarriage; stillbirth; low birth weight; gestation ID CONGENITAL-MALFORMATIONS; PARENTAL CONSANGUINITY; REPRODUCTIVE WASTAGE; FETAL GROWTH; ASSOCIATION; POPULATION; JERUSALEM; MORTALITY; PAKISTAN; DEATHS AB Objective: To determine whether consanguinity adversely influences pregnancy outcome in South India, where consanguinity is a common means of family property retention. Study Design: Data were collected from a prospective cohort of 647 consenting women, consecutively registered for antenatal care between 14 and 18 weeks gestation, in Belgaum district, Karnataka in 2005. Three-generation pedigree charts were drawn for consanguineous participants. chi(2)-Test and Student's t-test were used to assess categorical and continuous data, respectively, using SPSS version 14. Multivariate logistic regression adjusted for confounding variables. Result: Overall, 24.1% of 601 women with singleton births and outcome data were consanguineous. Demographic characteristics between study groups were similar. Non-consanguineous couples had fewer stillbirths (2.6 vs 6.9% P = 0.017; adjusted P = 0.050), miscarriages (1.8 vs 4.1%, P = 0.097; adjusted P = 0.052) and lower incidence of birth weight <2500 g (21.8 vs 29.5%, P = 0.071, adjusted P = 0.044). Gestation <37 weeks was 6.2% in both the groups. Adjusted for consanguinity and other potential confounders, age <20 years was protective of stillbirth (P = 0.01), pregnancy loss (P = 0.023) and preterm birth (P = 0.013), whereas smoking (P = 0.015) and poverty (P = 0.003) were associated with higher rates of low birth weight. Conclusion: Consanguinity significantly increases pregnancy loss and birth weight <2500 g. Journal of Perinatology (2012) 32, 431-437; doi:10.1038/jp.2011.115; published online 18 August 2011 C1 [Bellad, M. B.; Goudar, S. S.; Mahantshetti, N. S.; Naik, V.; Gupta, M.; Nalina, H. R.; Kodkany, B. S.] Jawaharlal Nehru Med Coll, Dept Med Educ, Belgaum 590010, Karnataka, India. [Edlavitch, S. A.] Univ Missouri, UKMC Sch Med, Dept Psychiat, Kansas City, MO 64110 USA. [Hemingway-Foday, J. J.] Res Triangle Inst Int, StatEpi, Int Studies Program, Washington, DC USA. [Derman, R.] Christiana Care Hlth Syst, Womens & Childrens Hlth Res, Dept Obstet & Gynecol, Newark, DE USA. [Moss, N.] NIH, Global Network Womens & Children Hlth, Bethesda, MD 20892 USA. RP Goudar, SS (reprint author), Jawaharlal Nehru Med Coll, Dept Med Educ, Belgaum 590010, Karnataka, India. EM sgoudar@jnmc.edu OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053 FU Department of Obstetrics and Gynecology, JN Medical College, Belgaum, India; Fogarty International Center UMKC-JNMC Global Network for Women's and Children Health Research Unit [5U01HD042372-08]; Bill and Melinda Gates Foundation FX This study was conducted as part of the Junior Scholar Programme of the Global Network for Women's and Children's Health Research, National Institute for Child Health and Human Development, Bethesda, MD, USA and JN Medical College, Belgaum, India and the University of Missouri at Kansas City, USA. We thank all participating auxiliary nurse midwives, field research officers and Global Network Site 8 research unit staff for their efforts. We thank Dr Nancy L Sloan for editing the manuscript. Support was provided by the Department of Obstetrics and Gynecology, JN Medical College, Belgaum, India. The Eunice Kennedy Shriver National Institutes of Child Health and Human Development and the Fogarty International Center provided funding through the UMKC-JNMC Global Network for Women's and Children Health Research Unit (grant number 5U01HD042372-08) and by the Bill and Melinda Gates Foundation. NR 35 TC 5 Z9 5 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0743-8346 J9 J PERINATOL JI J. Perinatol. PD JUN PY 2012 VL 32 IS 6 BP 431 EP 437 DI 10.1038/jp.2011.115 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 949UY UT WOS:000304602700007 PM 21852769 ER PT J AU Mori, T Hayashi, T Su, TP AF Mori, Tomohisa Hayashi, Teruo Su, Tsung-Ping TI Compromising sigma-1 Receptors at the Endoplasmic Reticulum Render Cytotoxicity to Physiologically Relevant Concentrations of Dopamine in a Nuclear Factor-kappa B/Bcl-2-Dependent Mechanism: Potential Relevance to Parkinson's Disease SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NF-KAPPA-B; UNFOLDED PROTEIN RESPONSE; ER-OVERLOAD RESPONSE; ACTIVATION; STRESS; PATHWAYS; BRAIN; CELLS; CHAPERONES; TOXICITY AB The endoplasmic reticulum (ER) chaperone sigma-1 receptor (Sig-1R) is cytoprotective against ER stress-induced apoptosis. The level of Sig-1Rs in the brain was reported to be lower in early parkinsonian patients. Because dopamine (DA) toxicity is well known to be involved in the etiology of Parkinson's disease, we tested in this study whether a relationship might exist between Sig-1Rs and DA-induced cytotoxicity in a cellular model by using Chinese hamster ovary (CHO) cells. DA in physiological concentrations (e. g., lower than 10 mu M) does not cause apoptosis. However, the same concentrations of DA cause apoptosis in Sig-1R knockdown CHO cells. In search of a mechanistic explanation, we found that unfolded protein response is not involved. Rather, the level of protective protein Bcl-2 is critically involved in this DA/Sig-1R knockdown-induced apoptosis. Specifically, the DA/Sig-1R knockdown causes a synergistic proteasomal conversion of nuclear factor kappa B (NF-kappa B) p105 to the active form of p50, which is known to down-regulate the transcription of Bcl-2. It is noteworthy that the DA/Sig-1R knockdown-induced apoptosis is blocked by the overexpression of Bcl-2. Our results therefore indicate that DA is involved in the activation of NF-kappa B and suggest that endogenous Sig-1Rs are tonically inhibiting the proteasomal conversion/activation of NF-kappa B caused by physiologically relevant concentrations of DA that would otherwise cause apoptosis. Thus, Sig-1Rs and associated ligands may represent new therapeutic targets for the treatment of parkinsonism. C1 [Mori, Tomohisa; Hayashi, Teruo; Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, Integrat Neurosci Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Sect, Integrat Neurosci Res Branch, Intramural Res Program,NIH, Triad Suite 3304,333 Cassell Dr, Baltimore, MD 21224 USA. EM tsu@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 23 TC 15 Z9 18 U1 0 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 JUN PY 2012 VL 341 IS 3 BP 663 EP 671 DI 10.1124/jpet.111.190868 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 947QQ UT WOS:000304445000011 PM 22399814 ER PT J AU Moody, TW Osefo, N Nuche-Berenguer, B Ridnour, L Wink, D Jensen, RT AF Moody, Terry W. Osefo, Nauramy Nuche-Berenguer, Bernardo Ridnour, Lisa Wink, David Jensen, Robert T. TI Pituitary Adenylate Cyclase-Activating Polypeptide Causes Tyrosine Phosphorylation of the Epidermal Growth Factor Receptor in Lung Cancer Cells SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID SPLICE VARIANTS; SIGNAL-TRANSDUCTION; PACAP RECEPTOR; EGFR MUTATIONS; MESSENGER-RNAS; PEPTIDE; GEFITINIB; KINASE; TRANSACTIVATION; PROLIFERATION AB Pituitary adenylate cyclase-activating polypeptide (PACAP) is an autocrine growth factor for some lung cancer cells. The activated PACAP receptor (PAC1) causes phosphatidylinositol turnover, elevates cAMP, and increases the proliferation of lung cancer cells. PAC1 and epidermal growth factor receptor (EGFR) are present in non-small-cell lung cancer (NSCLC) cells, and the growth of NSCLC cells is inhibited by the PAC1 antagonist PACAP(6-38) and the EGFR tyrosine kinase inhibitor gefitinib. Here, the ability of PACAP to transactivate the EGFR was investigated. Western blot analysis indicated that the addition of PACAP but not the structurally related vasoactive intestinal peptide increased EGFR tyrosine phosphorylation in NCI-H838 or H345 cells. PACAP-27, in a concentration-dependent manner, increased EGFR transactivation 4-fold 2 min after addition to NCI-H838 cells. The ability of 100 nM PACAP-27 to increase EGFR or extracellular signal-regulated kinase tyrosine phosphorylation in NCI-H838 cells was inhibited by PACAP(6-38), gefitinib, 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d] pyrimidine (PP2; Src inhibitor), (R)-N4-hydroxy-N1-[(S)-2-(1H-indol-3-yl)-1-methylcarbamoyl-ethyl]-2- isobutyl-succinamide (GM6001; matrix metalloprotease inhibitor), or antibody to transforming growth factor alpha (TGF alpha). By enzyme-linked immunosorbent assay, PACAP addition to NCI-H838 cells increased TGF alpha secretion into conditioned media. EGFR transactivation caused by the addition of PACAP to NCI-H838 cells was inhibited by N-acetyl-cysteine (antioxidant), tiron (superoxide scavenger), diphenylene iodonium (NADPH oxidase inhibitor), or 1-[6-[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl] amino] hexyl]-1H-pyrrole-2,5-dione (U73122; phospholipase C inhibitor), but not N-[2-[[3-(4-bromophenyl)-2-propenyl]amino] ethyl]-5-isoquinolinesulfonamide (H89; protein kinase A inhibitor). PACAP addition to NCI-H838 cells significantly increased reactive oxygen species, and the increase was inhibited by tiron. The results indicate that PACAP causes transactivation of the EGFR in NSCLC cells in an oxygen-dependent manner that involves phospholipase C but not protein kinase A. C1 [Moody, Terry W.; Osefo, Nauramy] NCI, Ctr Canc Res, Off Director, NIH, Bethesda, MD 20892 USA. [Nuche-Berenguer, Bernardo; Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD USA. [Ridnour, Lisa; Wink, David] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Moody, TW (reprint author), NCI, Ctr Canc Res, Off Director, NIH, Bldg 31,Room 4A48,31 Ctr Dr, Bethesda, MD 20892 USA. EM moodyt@mail.nih.gov FU National Institutes of Health (National Cancer Institute and National Institute of Diabetes, Digestive, and Kidney Disease) FX This research was supported by the Intramural Research Program of the National Institutes of Health (National Cancer Institute and National Institute of Diabetes, Digestive, and Kidney Disease). NR 37 TC 12 Z9 13 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 JUN PY 2012 VL 341 IS 3 BP 873 EP 881 DI 10.1124/jpet.111.190033 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 947QQ UT WOS:000304445000033 PM 22389426 ER PT J AU Bora, A Anderson, C Bachani, M Nath, A Cotter, RJ AF Bora, Adriana Anderson, Carol Bachani, Muznabanu Nath, Avindra Cotter, Robert J. TI Robust Two-Dimensional Separation of Intact Proteins for Bottom-Up Tandem Mass Spectrometry of the Human CSF Proteome SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE CSF proteome; LC-MS; cerebrospinal fluid; Gelfree ID VENTRICULAR CEREBROSPINAL-FLUID; ION-EXCHANGE CHROMATOGRAPHY; PAROTID SALIVARY PROTEINS; GEL-ELECTROPHORESIS; SIZE; PHASE; IDENTIFICATION; MIXTURES AB Cerebrospinal fluid (CSF) is produced in the brain by cells in the choroid plexus at a rate of 500 mL/day. It is the only body fluid in direct contact with the brain. Thus, any changes in the CSF composition will reflect pathological processes and make CSF a potential source of biomarkers for different disease states. Proteomics offers a comprehensive view of the proteins found in CSF. In this study, we use a recently developed nongel based method of sample preparation of CSF followed by liquid chromatography high accuracy mass spectrometry (LC-MS) for MS and MS/MS analyses, allowing unambiguous identification of peptides/proteins. Gel-eluted liquid fraction entrapment electrophoresis (Gelfree) is used to separate a CSF complex protein mixture in 12 user-selectable liquid-phase molecular weight fractions. Using this high throughput workflow, we have been able to separate CSF intact proteins over a broad mass range (3.5-100 kDa) with high resolution (between 15 and 100 kDa) in 2 h and 40 min. We have completely eliminated albumin and were able to interrogate the low abundance CSF proteins in a highly reproducible manner from different CSF samples at the same time. Using LC-MS as a downstream analysis, we identified 368 proteins using MidiTrap G-10 desalting columns and 166 proteins (including 57 unique proteins) using Zeba spin columns with a 5% false discovery rate (FDR). Prostaglandin D2 synthase, Chromogranin A, Apolipoprotein E, Chromogranin B, Secretogranin III, Cystatin C, VGF nerve growth factor, and Cadherin 2 are a few of the proteins that were characterized. Gelfree-LC-MS is a robust method for the analysis of the human proteome that we will use to develop biomarkers for several neurodegenerative diseases and to quantitate these markers using multiple reaction monitoring. C1 [Bora, Adriana; Cotter, Robert J.] Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD USA. [Anderson, Carol; Bachani, Muznabanu; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. RP Cotter, RJ (reprint author), Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD USA. EM rcotter@jhmi.edu FU National Institutes of Neurological Disorders and Stroke (NINDS) [R01NS039253] FX This work was supported in part by Grant R01NS039253 to R.J.C. from the National Institutes of Neurological Disorders and Stroke (NINDS). Many thanks to John Tran and the Kelleher Lab at Northwestern University for occasional feedback and advice during our sample preparation. NR 28 TC 11 Z9 11 U1 1 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD JUN PY 2012 VL 11 IS 6 BP 3143 EP 3149 DI 10.1021/pr300057v PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 950WQ UT WOS:000304682500008 PM 22537003 ER PT J AU Barbacci, D Jackson, SN Muller, L Egan, T Lewis, EK Schultz, JA Woods, AS AF Barbacci, Damon Jackson, Shelley N. Muller, Ludovic Egan, Thomas Lewis, Ernest K. Schultz, J. Albert Woods, Amina S. TI Cellular Membrane Phospholipids Act as a Depository for Quaternary Amine Containing Drugs thus Competing with the Acetylcholine/Nicotinic Receptor SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE drug-protein interactions; drug-lipid interactions; MALDI-IM-TOF MS; noncovalent complexes; phospholipids; quaternary amines; guanidinium ID MOBILITY-MASS-SPECTROMETRY; AMAZING STABILITY; LIPID-MEMBRANES; MALDI-TOFMS; IMS-MS; PHOSPHATE; DISCOVERY; ARGININE; CHLORISONDAMINE; SEPARATION AB We previously demonstrated that ammonium- or guanidinium-phosphate interactions are key to forming noncovalent complexes (NCXs) through salt bridge formation with G-protein coupled receptors (GPCR), which are immersed in the cell membrane's lipids. The present work highlights MALDI ion mobility coupled to orthogonal time-of-flight mass spectrometry (MALDI IM oTOF MS) as a method to determine qualitative and relative quantitative affinity of drugs to form NCXs with targeted GPCRs' epitopes in a model system using, bis-quaternary amine based drugs, alpha- and beta- subunit epitopes of the nicotinic acetylcholine receptor' (nAChR) and phospholipids. Bis-quaternary amines proved to have a strong affinity for all nAChR epitopes and negatively charged phospholipids, even in the presence of the physiological neurotransmitter acetylcholine. Ion mobility baseline separated isobaric phosphatidyl ethanolamine and a matrix cluster, providing an accurate estimate for phospholipid counts. Overall this technique is a powerful method for screening drugs' interactions with targeted lipids and protein respectively containing quaternary amines and guanidinium moieties. C1 [Barbacci, Damon; Jackson, Shelley N.; Muller, Ludovic; Woods, Amina S.] NIDA IRP, NIH, Baltimore, MD 21224 USA. [Barbacci, Damon; Egan, Thomas; Lewis, Ernest K.; Schultz, J. Albert] Ionwerks Inc, Houston, TX 77002 USA. RP Woods, AS (reprint author), NIDA IRP, NIH, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov FU ONDCP; Henry M. Jackson Foundation; National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, under SBIR [HHSN271200900009C, 1RC3DA031431-01] FX The authors gratefully thank the ONDCP for instrument funding. A.S.W. acknowledges the Henry M. Jackson Foundation for funding and Gregg Shieffer for technical support. We thank NIDA-IRP for ongoing support for our lab personnel and space. This project has also been funded in part at Ionwerks with federal funds from the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, under SBIR Phase II Contract No. HHSN271200900009C and SBIR Phase II Grant No. 1RC3DA031431-01. NR 41 TC 2 Z9 2 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD JUN PY 2012 VL 11 IS 6 BP 3382 EP 3389 DI 10.1021/pr300184g PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 950WQ UT WOS:000304682500028 PM 22506649 ER PT J AU Fumagalli, D Bedard, PL Nahleh, Z Michiels, S Sotiriou, C Loi, S Sparano, JA Ellis, M Hylton, N Zujewski, JA Hudis, C Esserman, L Piccart, M AF Fumagalli, Debora Bedard, Philippe L. Nahleh, Zeina Michiels, Stefan Sotiriou, Christos Loi, Sherene Sparano, Joseph A. Ellis, Matthew Hylton, Nola Zujewski, Jo Anne Hudis, Clifford Esserman, Laura Piccart, Martine CA BIG-NABCG Collaboration TI A common language in neoadjuvant breast cancer clinical trials: proposals for standard definitions and endpoints SO LANCET ONCOLOGY LA English DT Review ID GENE-EXPRESSION PROFILES; PROGNOSTIC-SIGNIFICANCE; PRIMARY CHEMOTHERAPY; ENDOCRINE THERAPY; PREOPERATIVE CHEMOTHERAPY; INDUCTION CHEMOTHERAPY; MOLECULAR PORTRAITS; ADJUVANT BREAST; TAMOXIFEN; KI67 AB The neoadjuvant setting provides a unique opportunity to study the effect of systemic treatments on breast cancer biology and to identify clinically useful prognostic and predictive biomarkers. Discrepancies and inconsistencies in the use of definitions and endpoint assessments in this setting confound the analysis and interpretation of results across clinical trials and hinder research progress. This Review represents a joint effort of the Breast International Group and the National Cancer Institute-sponsored North American Breast Cancer Group to provide clinicians and researchers with a series of standardised definitions and endpoints that could be implemented in future neoadjuvant clinical trials. Definitions of the setting of interest and of survival endpoints are recommended, together with proposals for standard assessment of the response to treatment, use of functional and molecular imaging endpoints, and characterisation and selection of the population to treat. We expect that implementation of these recommendations will improve the conduct, reporting, and effectiveness of clinical trials and fully exploit the clinical and scientific potential of the neoadjuvant setting in breast cancer. C1 [Piccart, Martine] Inst Jules Bordet, Breast Int Grp, B-1000 Brussels, Belgium. [Fumagalli, Debora; Michiels, Stefan; Sotiriou, Christos; Loi, Sherene] Univ Libre Brussels, Inst Jules Bordet, Fac Med, Breast Canc Translat Res Lab, Brussels, Belgium. [Bedard, Philippe L.] Univ Toronto, Princess Margaret Hosp, Dept Med, Div Med Oncol & Hematol, Toronto, ON, Canada. [Nahleh, Zeina] TTUHSC Paul L Foster Sch Med, Dept Internal Med, Div Hematol Oncol, El Paso, TX USA. [Sparano, Joseph A.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Ellis, Matthew] Washington Univ St Louis, Siteman Canc Ctr, St Louis, MO USA. [Hylton, Nola] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Zujewski, Jo Anne] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Hudis, Clifford] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Esserman, Laura] Univ Calif San Francisco, Dept Surg & Radiol, San Francisco, CA USA. RP Piccart, M (reprint author), Inst Jules Bordet, Breast Int Grp, Blvd Waterloo 121, B-1000 Brussels, Belgium. EM martine.piccart@bordet.be RI Michiels, Stefan/L-1516-2013; Loi, Sherene/H-1979-2016 OI Michiels, Stefan/0000-0002-6963-2968; FU Breast Cancer Research Foundation FX We thank Carolyn Straehle for editorial assistance. The BIG and NABCG collaboration is supported by a Breast Cancer Research Foundation grant. NR 73 TC 26 Z9 28 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD JUN PY 2012 VL 13 IS 6 BP E240 EP E248 PG 9 WC Oncology SC Oncology GA 948YV UT WOS:000304541200018 PM 22652232 ER PT J AU Terrault, NA Roland, ME Schiano, T Dove, L Wong, MT Poordad, F Ragni, MV Barin, B Simon, D Olthoff, KM Johnson, L Stosor, V Jayaweera, D Fung, J Sherman, KE Subramanian, A Millis, JM Slakey, D Berg, CL Carlson, L Ferrell, L Stablein, DM Odim, J Fox, L Stock, PG AF Terrault, Norah A. Roland, Michelle E. Schiano, Thomas Dove, Lorna Wong, Michael T. Poordad, Fred Ragni, Margaret V. Barin, Burc Simon, David Olthoff, Kim M. Johnson, Lynt Stosor, Valentina Jayaweera, Dushyantha Fung, John Sherman, Kenneth E. Subramanian, Aruna Millis, J. Michael Slakey, Douglas Berg, Carl L. Carlson, Laurie Ferrell, Linda Stablein, Donald M. Odim, Jonah Fox, Lawrence Stock, Peter G. CA Solid Organ Transplantation In HIV TI Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection SO LIVER TRANSPLANTATION LA English DT Article ID HIV; IMPACT; INFECTION; SURVIVAL; THERAPY; CIRRHOSIS; DISEASE; RECURRENCE; TACROLIMUS; ALLOGRAFTS AB Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in human immunodeficiency virus (HIV)infected patients because of reportedly poor outcomes. This prospective, multicenter US cohort study compared patient and graft survival for 89 HCV/HIV-coinfected patients and 2 control groups: 235 HCV-monoinfected LT controls and all US transplant recipients who were 65 years old or older. The 3-year patient and graft survival rates were 60% [95% confidence interval (CI) = 47%-71%] and 53% (95% CI = 40%-64%) for the HCV/HIV patients and 79% (95% CI = 72%-84%) and 74% (95% CI = 66%-79%) for the HCV-infected recipients (P < 0.001 for both), and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among the HCV/HIV patients, older donor age [hazard ratio (HR) = 1.3 per decade], combined kidney-liver transplantation (HR = 3.8), an anti-HCVpositive donor (HR = 2.5), and a body mass index < 21 kg/m2 (HR = 3.2) were independent predictors of graft loss. For the patients without the last 3 factors, the patient and graft survival rates were similar to those for US LT recipients. The 3-year incidence of treated acute rejection was 1.6-fold higher for the HCV/HIV patients versus the HCV patients (39% versus 24%, log rank P = 0.02), but the cumulative rates of severe HCV disease at 3 years were not significantly different (29% versus 23%, P = 0.21). In conclusion, patient and graft survival rates are lower for HCV/HIV-coinfected LT patients versus HCV-monoinfected LT patients. Importantly, the rates of treated acute rejection (but not the rates of HCV disease severity) are significantly higher for HCV/HIV-coinfected recipients versus HCV-infected recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients, but recipient and donor selection and the management of acute rejection strongly influence outcomes. Liver Transpl 18:716726, 2012. (C) 2012 AASLD. C1 [Terrault, Norah A.; Roland, Michelle E.; Carlson, Laurie; Ferrell, Linda; Stock, Peter G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Schiano, Thomas] Mt Sinai Sch Med, New York, NY USA. [Dove, Lorna] New York Presbyterian Hosp Columbia, New York, NY USA. [Wong, Michael T.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Poordad, Fred] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Ragni, Margaret V.] Univ Pittsburgh, Pittsburgh, PA USA. [Barin, Burc; Stablein, Donald M.] EMMES Corp, Rockville, MD USA. [Simon, David] Rush Univ, Chicago, IL 60612 USA. [Olthoff, Kim M.] Univ Penn, Philadelphia, PA 19104 USA. [Johnson, Lynt] Georgetown Med Ctr, Washington, DC USA. [Stosor, Valentina] Northwestern Univ, Chicago, IL 60611 USA. [Jayaweera, Dushyantha] Univ Miami, Miami, FL USA. [Fung, John] Cleveland Clin, Cleveland, OH 44106 USA. [Sherman, Kenneth E.] Univ Cincinnati, Cincinnati, OH USA. [Subramanian, Aruna] Johns Hopkins Univ, Baltimore, MD USA. [Millis, J. Michael] Univ Chicago, Chicago, IL 60637 USA. [Slakey, Douglas] Tulane Univ, New Orleans, LA 70118 USA. [Berg, Carl L.] Univ Virginia, Charlottesville, VA USA. [Odim, Jonah; Fox, Lawrence] NIAID, Bethesda, MD 20892 USA. RP Terrault, NA (reprint author), Univ Calif San Francisco, 513 Parnassus Ave,S357,Box 0538, San Francisco, CA 94143 USA. EM norah.terrault@ucsf.edu RI Fung, John/A-2679-2012 FU Solid Organ Transplantation in HIV: Multi-Site Study [AI052748]; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX This work was supported by the Solid Organ Transplantation in HIV: Multi-Site Study (AI052748), which was funded by the National Institute of Allergy and Infectious Diseases. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.; All the authors completed and submitted copyright assignment, authorship responsibility, National Institutes of Health funding, financial disclosure, institutional review board/animal care committee approval, and sponsorship forms, and no conflicts were reported. NR 27 TC 104 Z9 104 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD JUN PY 2012 VL 18 IS 6 BP 716 EP 726 DI 10.1002/lt.23411 PG 11 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 948SX UT WOS:000304524000012 PM 22328294 ER PT J AU Tanpure, RP George, CS Sriram, M Strecker, TE Tidmore, JK Hamel, E Charlton-Sevcik, AK Chaplin, DJ Trawick, ML Pinney, KG AF Tanpure, Rajendra P. George, Clinton S. Sriram, Madhavi Strecker, Tracy E. Tidmore, Justin K. Hamel, Ernest Charlton-Sevcik, Amanda K. Chaplin, David J. Trawick, Mary Lynn Pinney, Kevin G. TI An amino-benzosuberene analogue that inhibits tubulin assembly and demonstrates remarkable cytotoxicity SO MEDCHEMCOMM LA English DT Article ID VASCULAR DISRUPTING AGENTS; ANTINEOPLASTIC AGENTS; BIOLOGICAL EVALUATION; COMBRETASTATIN A-1; RING-EXPANSION; BLOOD-VESSELS; CELL-GROWTH; DERIVATIVES; COLCHICINE; CANCER AB The recent discovery of a small-molecule benzosuberene-based phenol that demonstrates remarkable picomolar cytotoxicity against selected human cancer cell lines and strongly inhibits tubulin polymerization (1-2 mu M) inspired the design and synthesis of a variety of new, structurally diverse benzosuberene derivatives. An efficient synthetic route to functionalized benzosuberenes was developed. This methodology utilized a Wittig reaction, followed by a selective alkene reduction and ring-closing cyclization to form the core benzosuberone structure. This synthetic route facilitated the preparation of a 4-nitro-1-(3',4',5'-trimethoxyphenyl) benzosuberene derivative and its corresponding 4-amino analogue in good yield. The 4-amino analogue was a strong inhibitor of tubulin polymerization (1.2 mu M), demonstrated enhanced cytotoxicity against the human cancer cell lines examined (GI(50) = 33 pM against SK-OV-3 ovarian cancer, for example), and exhibited a concentration dependent disruption of a pre-established capillary-like network of tubules formed from human umbilical vein endothelial cells. C1 [Tanpure, Rajendra P.; George, Clinton S.; Sriram, Madhavi; Strecker, Tracy E.; Tidmore, Justin K.; Charlton-Sevcik, Amanda K.; Trawick, Mary Lynn; Pinney, Kevin G.] Baylor Univ, Dept Chem & Biochem, Waco, TX 76798 USA. [Hamel, Ernest] NCI, NIH, Div Canc Treatment & Diag, Dev Therapeut Program,Screening Technol Branch, Frederick, MD 21702 USA. [Chaplin, David J.] OXiGENE Inc, San Francisco, CA 94080 USA. RP Pinney, KG (reprint author), Baylor Univ, Dept Chem & Biochem, 1 Bear Pl 97348, Waco, TX 76798 USA. EM Kevin_Pinney@baylor.edu OI Pinney, Kevin/0000-0003-1262-8631; George, Clinton/0000-0003-0322-2103; Sevcik, Amanda/0000-0003-4057-6429 FU Cancer Prevention and Research Institute of Texas (CPRIT) [RP100406]; Oxigene Inc.; Welch Foundation [AA-1278]; National Cancer Institute [5R01CA140674]; NSF [CHE-0420802] FX The authors are grateful to the Cancer Prevention and Research Institute of Texas (CPRIT (RP100406), to K. G. P. and M. L. T.), Oxigene Inc. (to K. G. P. and M. L. T), the Welch Foundation (grant no. AA-1278 to K. G. P.), and the National Cancer Institute Award Number 5R01CA140674 (to K. G. P and M. L. T) for their financial support of this project, and to the NSF for funding the Varian 500 MHz NMR spectrometer (grant no. CHE-0420802). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The authors also thank Dr. Alejandro Ramirez (Mass Spectrometry Core Facility, Baylor University) for mass spectroscopic analysis, Dr. Craig Moehnke for assistance with NMR studies, and Dr. James Karban and Dr. Michelle Nemec (Director) for use of the shared Molecular Biosciences Center at Baylor University. NR 38 TC 8 Z9 8 U1 0 U2 6 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-2503 EI 2040-2511 J9 MEDCHEMCOMM JI MedChemComm PD JUN PY 2012 VL 3 IS 6 BP 720 EP 724 DI 10.1039/c2md00318j PG 5 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 950OW UT WOS:000304659600013 PM 23772309 ER PT J AU Fitzgerald, PJ AF Fitzgerald, Paul J. TI Neurodrinking: Is alcohol a substrate in a novel, endogenous synthetic pathway for norepinephrine? SO MEDICAL HYPOTHESES LA English DT Article ID CHRONIC ETHANOL TREATMENT; PREFERRING RATS; CATECHOLAMINE SYNTHESIS; BETA-ENDORPHIN; BRAIN; DRINKING; NORADRENALINE; HYDROXYLASE; METABOLITE; WITHDRAWAL AB A number of preclinical and clinical studies indicate multiple types of interaction between ethanol intake and the mood-related neurotransmitter, norepinephrine (NE). For example, ethanol interacts with dopamine beta-hydroxylase (DBH), an enzyme that plays an essential role in the only well-established endogenous synthetic pathway for NE, whereby dopamine is hydroxylated to form NE. While the DBH pathway may indeed be the only endogenous mechanism for producing NE, another possibility is that multiple means have evolved for the biosynthesis of this very important neurotransmitter, where some pathways may be independent of DBH. If so, such redundancy would provide greater assurance that enough NE is available for the body to use in this neurotransmitter's various physiological roles. This paper puts forth the hypothesis ethanol is a substrate in a novel, endogenous synthetic pathway for NE, consistent with some studies showing that intake of ethanol increases the concentration of endogenous NE. Also consistent with this hypothesis, the molecular structure of ethanol is a physical subset of the structure of NE itself. If the hypothesis is correct, it may have important implications for understanding the physiological basis of alcohol use, abuse, and dependence in humans, as well as modeling these phenomena in animals. Importantly, the hypothesis is directly testable in rodents by presenting ethanol to DBH knockout mice, which are thought to lack NE, and then measuring if NE is synthesized in these animals. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Fitzgerald, Paul J.] Johns Hopkins Univ, Zanvyl Krieger Mind Brain Inst, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA. RP Fitzgerald, PJ (reprint author), NIAAA, 5625 Fishers Lane,Room 2N09, Bethesda, MD 20852 USA. EM pfitz@mbi.mb.jhu.edu NR 26 TC 1 Z9 5 U1 0 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0306-9877 J9 MED HYPOTHESES JI Med. Hypotheses PD JUN PY 2012 VL 78 IS 6 BP 760 EP 762 DI 10.1016/j.mehy.2012.02.025 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 948RC UT WOS:000304519300013 PM 22425177 ER PT J AU Srivastava, K Hu, P Solomon, BD Ming, JE Roessler, E Muenke, M AF Srivastava, Kshitij Hu, Ping Solomon, Benjamin D. Ming, Jeffrey E. Roessler, Erich Muenke, Maximilian TI Molecular analysis of the Noggin (NOG) gene in holoprosencephaly patients SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Holoprosencephaly (HPE); Noggin (NOG); Forebrain; Mutation; Modifier ID FOREBRAIN DEVELOPMENT; ANTAGONISM; MOUSE; MICE; BMP; SYMPHALANGISM; PATHOGENESIS; MUTATIONS; MICROFORM; ORGANIZER AB Holoprosencephaly (HPE) is the most common structural anomaly of the human forebrain. Various genetic and teratogenic causes have been implicated in its pathogenesis. A recent report in mice described Noggin (NOG) as a candidate gene involved in the etiogenesis of microform HPE. Here, we present for the first time genetic analysis of a large HPE cohort for sequence variations in NOG. On the basis of our study, we conclude that mutations in the coding region of NOG are rare, and play at most an uncommon role in human HPE. Published by Elsevier Inc. C1 [Srivastava, Kshitij; Hu, Ping; Solomon, Benjamin D.; Roessler, Erich; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Ming, Jeffrey E.] Childrens Hosp Philadelphia, Div Human Genet & Mol Biol, Philadelphia, PA 19104 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov FU NIH [5RO1DEO15874]; Division of Intramural Research (DIR), National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, USA FX We appreciate the many participating families who have enabled physicians and researchers to advance our understanding of holoprosencephaly. We would also like to thank the NINDS DNA Sequencing Facility for assistance with DNA sequencing. J.E.M. was supported in part by NIH grant 5RO1DEO15874. This research was supported by the Division of Intramural Research (DIR), National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, USA. The funding body had no role in study design, collection, analysis and interpretation of data, writing of the report and in the decision to submit the article for publication. NR 29 TC 1 Z9 1 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2012 VL 106 IS 2 BP 241 EP 243 DI 10.1016/j.ymgme.2012.03.008 PG 3 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 949MT UT WOS:000304581000014 PM 22503063 ER PT J AU Hirvonen, J Goodwin, RS Li, CT Terry, GE Zoghbi, SS Morse, C Pike, VW Volkow, ND Huestis, MA Innis, RB AF Hirvonen, J. Goodwin, R. S. Li, C-T Terry, G. E. Zoghbi, S. S. Morse, C. Pike, V. W. Volkow, N. D. Huestis, M. A. Innis, R. B. TI Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers SO MOLECULAR PSYCHIATRY LA English DT Article DE addiction; cannabis; CB1 receptor; positron emission tomography; receptor imaging ID RAT-BRAIN; DELTA(9)-TETRAHYDROCANNABINOL; DEPENDENCE; BINDING; TOLERANCE; MARIJUANA; USERS; DELTA-9-TETRAHYDROCANNABINOL; ADAPTATION; SINGLE AB Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB1 (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After similar to 4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB1 receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB1 receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain. Molecular Psychiatry (2012) 17, 642-649; doi:10.1038/mp.2011.82; published online 12 July 2011 C1 [Hirvonen, J.; Li, C-T; Terry, G. E.; Zoghbi, S. S.; Morse, C.; Pike, V. W.; Innis, R. B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Goodwin, R. S.; Huestis, M. A.] NIDA, Chem & Drug Metab Sect, NIH, Baltimore, MD USA. [Volkow, N. D.] NIDA, Off Director, NIH, Bethesda, MD 20892 USA. RP Innis, RB (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B1D43,10 Ctr Dr,MSC 1026, Bethesda, MD 20892 USA. EM robert.innis@nih.gov FU NIMH [Z01-MH-002852-04]; NIDA [Z01-DA000413-13]; Academy of Finland; Finnish Cultural Foundation; Finnish Foundation for Alcohol Studies; Finnish Medical Foundation; Instrumentarium Foundation; Jalmari and Rauha Ahokas Foundation; Paulo Foundation; Research Foundation of Orion Corporation; Yrjo Jahnsson Foundation FX We thank Kimberly Jenko, Kacey Anderson, and David Clark for measurements of radioligand in plasma; Maria D Ferraris Araneta, Yulin Chu, Denise Rallis-Frutos, Gerald Hodges, William C Kreisl, Christina Hines and Barbara Scepura as well as Kathleen Demuth and the NIDA and BPRU nursing staff for subject recruitment and care; the NIH PET Department for imaging; and PMOD Technologies for providing its image analysis and modeling software. This research was supported by the Intramural Programs of the NIMH (project no. Z01-MH-002852-04) and the NIDA (project no. Z01-DA000413-13). Jussi Hirvonen was supported by personal grants from The Academy of Finland; The Finnish Cultural Foundation; The Finnish Foundation for Alcohol Studies; The Finnish Medical Foundation; The Instrumentarium Foundation; The Jalmari and Rauha Ahokas Foundation; The Paulo Foundation; The Research Foundation of Orion Corporation; and The Yrjo Jahnsson Foundation. NR 42 TC 120 Z9 121 U1 43 U2 64 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUN PY 2012 VL 17 IS 6 BP 642 EP 649 DI 10.1038/mp.2011.82 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 947TU UT WOS:000304454700010 PM 21747398 ER PT J AU Gonzalez, S Rangel-Barajas, C Peper, M Lorenzo, R Moreno, E Ciruela, F Borycz, J Ortiz, J Lluis, C Franco, R McCormick, PJ Volkow, ND Rubinstein, M Floran, B Ferre, S AF Gonzalez, S. Rangel-Barajas, C. Peper, M. Lorenzo, R. Moreno, E. Ciruela, F. Borycz, J. Ortiz, J. Lluis, C. Franco, R. McCormick, P. J. Volkow, N. D. Rubinstein, M. Floran, B. Ferre, S. TI Dopamine D-4 receptor, but not the ADHD-associated D-4.7 variant, forms functional heteromers with the dopamine D-2S receptor in the brain SO MOLECULAR PSYCHIATRY LA English DT Article DE dopamine receptors; receptor heteromers; ADHD; striatum; glutamate ID DEFICIT-HYPERACTIVITY DISORDER; RAT NUCLEUS-ACCUMBENS; SUBSTANTIA-NIGRA; PARS RETICULATA; GENE LOCUS; RELEASE; LOCALIZATION; ALLELE; SHELL; POLYMORPHISM AB Polymorphic variants of the dopamine D-4 receptor have been consistently associated with attention-deficit hyperactivity disorder (ADHD). However, the functional significance of the risk polymorphism (variable number of tandem repeats in exon 3) is still unclear. Here, we show that whereas the most frequent 4-repeat (D-4.4) and the 2-repeat (D-4.2) variants form functional heteromers with the short isoform of the dopamine D-2 receptor (D-2S), the 7-repeat risk allele (D-4.7) does not. D-2 receptor activation in the D-2S-D-4 receptor heteromer potentiates D-4 receptor-mediated MAPK signaling in transfected cells and in the striatum, which did not occur in cells expressing D-4.7 or in the striatum of knockin mutant mice carrying the 7 repeats of the human D-4.7 in the third intracellular loop of the D-4 receptor. In the striatum, D-4 receptors are localized in corticostriatal glutamatergic terminals, where they selectively modulate glutamatergic neurotransmission by interacting with D-2S receptors. This interaction shows the same qualitative characteristics than the D-2S-D-4 receptor heteromer-mediated mitogen-activated protein kinase (MAPK) signaling and D-2S receptor activation potentiates D-4 receptor-mediated inhibition of striatal glutamate release. It is therefore postulated that dysfunctional D-2S-D-4.7 heteromers may impair presynaptic dopaminergic control of corticostriatal glutamatergic neurotransmission and explain functional deficits associated with ADHD. Molecular Psychiatry (2012) 17, 650-662; doi:10.1038/mp.2011.93; published online 16 August 2011 C1 [Borycz, J.; Ferre, S.] NIDA, Intramural Res Program, NIH, CNS Receptor Receptor Interact Unit, Baltimore, MD 21224 USA. [Gonzalez, S.; Moreno, E.; Lluis, C.; McCormick, P. J.] Univ Barcelona, Dept Biochem & Mol Biol, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain. [Rangel-Barajas, C.; Floran, B.] Inst Politecn Nacl, Dept Fisiol Biofis & Neurociencia, Ctr Invest & Estudios Avanzados, Mexico City, DF, Mexico. [Peper, M.; Lorenzo, R.; Rubinstein, M.] Consejo Nacl Invest Cient & Tecn, Dept Fisiol & Biol Mol & Celular, Inst Invest Ingn Genet & Biol Mol, Buenos Aires, DF, Argentina. [Ciruela, F.] Univ Barcelona, Unitat Farmacol, Dept Patol & Terapeut Expt, Barcelona, Spain. [Ortiz, J.] Univ Autonoma Barcelona, Dept Biochem & Mol Biol, Inst Neurosci, Bellaterra, Spain. [Franco, R.] Univ Navarra, Dept Neurociencias, Ctr Invest Med Aplicada, E-31080 Pamplona, Spain. [Volkow, N. D.] NIDA, NIH, Bethesda, MD 20892 USA. RP Ferre, S (reprint author), NIDA, Intramural Res Program, NIH, CNS Receptor Receptor Interact Unit, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Ortiz, Jordi/E-9018-2011; McCormick, Peter/E-7387-2012; Ferre, Sergi/K-6115-2014; Ciruela, Francisco/A-5096-2013; Franco, Rafael/C-3694-2015 OI Ortiz, Jordi/0000-0002-9748-2290; McCormick, Peter/0000-0002-2225-5181; Ferre, Sergi/0000-0002-1747-1779; Ciruela, Francisco/0000-0003-0832-3739; Moreno, Estefania/0000-0002-2491-5753; Franco, Rafael/0000-0003-2549-4919 FU NIDA IRP; Spanish Ministerio de Ciencia y Tecnologia [SAF2008-03229-E, SAF2009-07276, SAF2010-18472, SAF2008-01462, CSD2008-00005]; Consejo Nacional de Ciencia y Tecnologia de Mexico [50428-M] FX We thank the technical help from Jasmina Jimenez (University of Barcelona). The study was supported by the NIDA IRP funds and from Grants from Spanish Ministerio de Ciencia y Tecnologia (SAF2008-03229-E, SAF2009-07276, SAF2010-18472, SAF2008-01462 and Consolider-Ingenio CSD2008-00005) and from Consejo Nacional de Ciencia y Tecnologia de Mexico (50428-M). PJM is a Ramon y Cajal Fellow. NR 34 TC 35 Z9 35 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUN PY 2012 VL 17 IS 6 BP 650 EP 662 DI 10.1038/mp.2011.93 PG 13 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 947TU UT WOS:000304454700011 PM 21844870 ER PT J AU Corrigan-Curay, J Cohen-Haguenauer, O O'Reilly, M Ross, SR Fan, H Rosenberg, N Somia, N King, N Friedmann, T Dunbar, C Aiuti, A Naldini, L Baum, C von Kalle, C Kiem, HP Montini, E Bushman, F Sorrentino, BP Carrondo, M Malech, H Gahrton, G Shapiro, R Wolff, L Rosenthal, E Jambou, R Zaia, J Kohn, DB AF Corrigan-Curay, Jacqueline Cohen-Haguenauer, Odile O'Reilly, Marina Ross, Susan R. Fan, Hung Rosenberg, Naomi Somia, Nikunj King, Nancy Friedmann, Theodore Dunbar, Cynthia Aiuti, Alessandro Naldini, Luigi Baum, Christopher von Kalle, Christof Kiem, Hans-Peter Montini, Eugenio Bushman, Frederic Sorrentino, Brian P. Carrondo, Manuel Malech, Harry Gahrton, Gosta Shapiro, Robyn Wolff, Linda Rosenthal, Eugene Jambou, Robert Zaia, John Kohn, Donald B. TI Challenges in Vector and Trial Design Using Retroviral Vectors for Long-Term Gene Correction in Hematopoietic Stem Cell Gene Therapy SO MOLECULAR THERAPY LA English DT News Item ID CHRONIC GRANULOMATOUS-DISEASE; INTEGRATION SITES; LENTIVIRAL VECTOR; INSERTIONAL ACTIVATION; PROGENITOR CELLS; BETA-THALASSEMIA; CLINICAL-TRIALS; C-MYB; MICE; IMMUNODEFICIENCY C1 [Kohn, Donald B.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Corrigan-Curay, Jacqueline; O'Reilly, Marina; Rosenthal, Eugene; Jambou, Robert] NIH, Off Biotechnol Act, Off Director, Bethesda, MD 20892 USA. [Cohen-Haguenauer, Odile] Univ Paris 07, Ecole Normale Super Cachan, LBPA CNRS UMR 8113, Biotechnol & Pharmacol Lab, F-94235 Cachan, France. [Cohen-Haguenauer, Odile] Univ Paris 07, Dept Clin Oncol, Hop St Louis, F-94235 Cachan, France. [Ross, Susan R.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Fan, Hung] Univ Calif Irvine, Canc Res Inst, Irvine, CA USA. [Rosenberg, Naomi] Tufts Univ, Sackler Sch Grad Biomed Sci, Sch Med, Dept Pathol, Boston, MA 02111 USA. [Somia, Nikunj] Univ Minnesota Twin Cities, Dept Genet Cell Biol & Dev, Inst Mol Genet, Minneapolis, MN USA. [King, Nancy] Wake Forest Univ, Dept Social Sci & Hlth Policy, Ctr Bioeth Hlth & Soc, Winston Salem, NC 27109 USA. [Friedmann, Theodore] Univ Calif San Diego, Sch Med, Dept Pediat, Ctr Mol Genet, La Jolla, CA 92093 USA. [Dunbar, Cynthia] NHLBI, Mol Hematopoiesis Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Aiuti, Alessandro; Naldini, Luigi; Montini, Eugenio] San Raffaele TeleThon Inst Gene Therapy HSR TIGET, Milan, Italy. [Aiuti, Alessandro; Naldini, Luigi] Bambino Gesu Pediat Hosp, DPUO, Univ Dept Pediat, Rome, Italy. [Aiuti, Alessandro; Naldini, Luigi] Univ Roma Tor Vergata, Sch Med, Rome, Italy. Univ Vita Salute San Raffaele, Milan, Italy. [Baum, Christopher] Hannover Med Sch, Dept Expt Hematol, D-3000 Hannover, Germany. [von Kalle, Christof] German Canc Res Ctr, Dept Translat Oncol, Natl Ctr Tumor Dis, D-6900 Heidelberg, Germany. [Kiem, Hans-Peter] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Bushman, Frederic] Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Sorrentino, Brian P.] St Jude Childrens Hosp, Expt Hematol Div, Memphis, TN 38105 USA. [Carrondo, Manuel] Univ Nova Lisboa, Inst Tecnol Quim & Biol, IBET, Estacao Agron Nacl, Oeiras, Portugal. [Malech, Harry] NIAID, Host Def Lab, Genet Immunotherapy Sect, NIH, Bethesda, MD 20892 USA. [Gahrton, Gosta] Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden. [Shapiro, Robyn] Drinker Biddle & Reath LLP, Milwaukee, WI USA. [Wolff, Linda] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Zaia, John] City Hope Natl Med Ctr, Dept Virol, Clin Res Comprehens Canc Ctr, Beckman Res Inst, Duarte, CA USA. RP Kohn, DB (reprint author), Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, David Geffen Sch Med, Box 957243,3163 Terasaki SLB, Los Angeles, CA 90095 USA. EM odile.cohen@lbpa.ens-cachan.fr; dkohn@mednet.ucla.edu RI Naldini, Luigi/E-9083-2012; Carrondo, Manuel/C-8155-2011; AIUTI, ALESSANDRO/K-3918-2016; Kohn, Donald/N-5085-2016; OI AIUTI, ALESSANDRO/0000-0002-5398-1717; Kohn, Donald/0000-0003-1840-6087; Malech, Harry/0000-0001-5874-5775; Carrondo, Manuel/0000-0002-4550-4574; Montini, Eugenio/0000-0003-1771-6067; Bushman, Frederic/0000-0003-4740-4056 FU Telethon [TGT11A01] NR 65 TC 27 Z9 27 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD JUN PY 2012 VL 20 IS 6 BP 1084 EP 1094 DI 10.1038/mt.2012.93 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 951ZC UT WOS:000304758500003 PM 22652996 ER PT J AU Berezhnoy, A Stewart, CA Mcnamara, JO Thiel, W Giangrande, P Trinchieri, G Gilboa, E AF Berezhnoy, Alexey Stewart, C. Andrew Mcnamara, James O., II Thiel, William Giangrande, Paloma Trinchieri, Giorgio Gilboa, Eli TI Isolation and Optimization of Murine IL-10 Receptor Blocking Oligonucleotide Aptamers Using High-throughput Sequencing SO MOLECULAR THERAPY LA English DT Article ID T-CELL EXHAUSTION; HEPATITIS-C VIRUS; INTERLEUKIN-10 RECEPTOR; IN-VIVO; INFECTION; PERSISTENCE; CLEARANCE; REJECTION; RESPONSES; SELECTION AB Interleukin-10 (IL-10) is a key suppressor of inflammation in chronic infections and in cancer. In mice, the inability of the immune system to clear viral infections or inhibit tumor growth can be reversed by antibody-mediated blockade of IL-10 action. We used a modified selection protocol to isolate RNA-based, nuclease- resistant, aptamers that bind to the murine IL-10 receptor. After 5 rounds of selection high-throughput sequencing (HTS) was used to analyze the library. Using distribution statistics on about 11 million sequences, aptamers were identified which bound to IL-10 receptor in solution with low K-d. After 12 rounds of selection the predominant IL-10 receptor-binding aptamer identified in the earlier rounds remained, whereas other high-affinity aptamers were not detected. Prevalence of certain nucleotide (nt) substitutions in the sequence of a high-affinity aptamer present in round 5 was used to deduce its secondary structure and guide the truncation of the aptamer resulting in a shortened 48-nt long aptamer with increased affinity. The aptamer also bound to IL-10 receptor on the cell surface and blocked IL-10 function in vitro. Systemic administration of the truncated aptamer was capable of inhibiting tumor growth in mice to an extent comparable to that of an anti-IL-10 receptor antibody. C1 [Berezhnoy, Alexey; Gilboa, Eli] Univ Miami, Dept Microbiol & Immunol, Dodson Interdisciplinary Immunotherapy Inst, Miller Sch Med, Miami, FL 33136 USA. [Berezhnoy, Alexey; Gilboa, Eli] Univ Miami, Sylvester Comprehens Canc Ctr, Miller Sch Med, Miami, FL 33136 USA. [Stewart, C. Andrew; Trinchieri, Giorgio] NCI, Canc Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Mcnamara, James O., II] Roy J & Lucille A Carver Coll Med, Dept Internal Med, Iowa City, IA USA. [Thiel, William; Giangrande, Paloma] Univ Iowa, Dept Internal Med, Mol & Cellular Biol Program, Iowa City, IA 52242 USA. [Thiel, William; Giangrande, Paloma] Univ Iowa, Dept Radiat Oncol, Mol & Cellular Biol Program, Iowa City, IA USA. RP Gilboa, E (reprint author), Univ Miami, Dept Microbiol & Immunol, Dodson Interdisciplinary Immunotherapy Inst, Miller Sch Med, 1550 NW 10th Ave Med Campus,Fox Bldg 200H,M710, Miami, FL 33136 USA. EM egilboa@med.miami.edu RI Stewart, Charles/G-2470-2012 FU Dodson estate; Sylvester Comprehensive Cancer Center (Medical School, University of Miami) FX We thank Nadezhda Tarasova for advice PEG conjugations. Authors declare no commercial affiliation, consulting arrangements, stock, equity, or any other potential financial conflict of interest. Funding was provided by a bequest from the Dodson estate and the Sylvester Comprehensive Cancer Center (Medical School, University of Miami). NR 25 TC 38 Z9 38 U1 5 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD JUN PY 2012 VL 20 IS 6 BP 1242 EP 1250 DI 10.1038/mt.2012.18 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 951ZC UT WOS:000304758500021 PM 22434135 ER PT J AU Uchiyama, T Adriani, M Jagadeesh, GJ Paine, A Candotti, F AF Uchiyama, Toru Adriani, Marsilio Jagadeesh, G. Jayashree Paine, Adam Candotti, Fabio TI Foamy Virus Vector-mediated Gene Correction of a Mouse Model of Wiskott-Aldrich Syndrome SO MOLECULAR THERAPY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; NOD/SCID-REPOPULATING CELLS; SYNDROME PROTEIN-DEFICIENCY; LONG-TERM; T-CELL; TRANSGENE EXPRESSION; LENTIVIRAL VECTORS; SELECTIVE ADVANTAGE; WASP; THERAPY AB The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by eczema, thrombocytopenia and immunodeficiency. Hematopoietic cell transplantation can cure the disease and gene therapy is being tested as an alternative treatment option. In this study, we assessed the use of foamy virus (FV) vectors as a gene transfer system for WAS, using a Was knockout (KO) mouse model. Preliminary experiments using FV vectors expressing the green fluorescent protein under the transcriptional control of the endogenous WAS promoter or a ubiquitously acting chromatin opening element allowed us to define transduction conditions resulting in high (>40%) and long-term in-vivo marking of blood cells after transplantation. In following experiments, Was KO mice were treated with FV vectors containing the human WAS complementary DNA (cDNA). Transplanted animals expressed the WAS protein (WASp) in T and B lymphocytes, as well as platelets and showed restoration of both T-cell receptor-mediated responses and B-cell migration. We also observed recovery of platelet adhesion and podosome formation in dendritic cells (DCs) of treated mice. These data demonstrate that FV vectors can be effective for hematopoietic stem cell (HSC)-directed gene correction of WAS. C1 [Uchiyama, Toru; Adriani, Marsilio; Jagadeesh, G. Jayashree; Paine, Adam; Candotti, Fabio] NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Candotti, F (reprint author), NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM fabio@nhgri.nih.gov RI Adriani, Marsilio/F-2553-2013 FU NHGRI; Japanese Society for Promotion of Science (JSPS) FX The authors are grateful to David W. Russell (University of Washington, Seattle, WA) and Adrian J. Thrasher (University College of London, London, UK) for sharing reagents, Julia Fekecs (NHGRI/NIH, Bethesda, MD) for artwork, and the NIH Building 49 Animal Care Staff for excellent and humane care of laboratory animals. This research was supported by funding from the NHGRI intramural program and the Japanese Society for Promotion of Science (JSPS). The authors declared no conflict of interest. NR 49 TC 11 Z9 11 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD JUN PY 2012 VL 20 IS 6 BP 1270 EP 1279 DI 10.1038/mt.2011.282 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 951ZC UT WOS:000304758500024 PM 22215016 ER PT J AU Perciavalle, RM Stewart, DP Koss, B Lynch, J Milasta, S Bathina, M Temirov, J Cleland, MM Pelletier, S Schuetz, JD Youle, RJ Green, DR Opferman, JT AF Perciavalle, Rhonda M. Stewart, Daniel P. Koss, Brian Lynch, John Milasta, Sandra Bathina, Madhavi Temirov, Jamshid Cleland, Megan M. Pelletier, Stephane Schuetz, John D. Youle, Richard J. Green, Douglas R. Opferman, Joseph T. TI Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration SO NATURE CELL BIOLOGY LA English DT Article ID CYTOCHROME-C-OXIDASE; CELL-DEATH; COMPLEX-I; SUPRAMOLECULAR ORGANIZATION; ANTIAPOPTOTIC MCL-1; SKELETAL-MUSCLE; PROTEIN IMPORT; ATP SYNTHASE; SURVIVAL; BCL-2 AB MCL-1, an anti-apoptotic BCL-2 family member that is essential for the survival of multiple cell lineages, is also among the most highly amplified genes in cancer. Although MCL-1 is known to oppose cell death, precisely how it functions to promote survival of normal and malignant cells is poorly understood. Here, we report that different forms of MCL-1 reside in distinct mitochondrial locations and exhibit separable functions. On the outer mitochondrial membrane, an MCL-1 isoform acts like other anti-apoptotic BCL-2 molecules to antagonize apoptosis, whereas an amino-terminally truncated isoform of MCL-1 that is imported into the mitochondrial matrix is necessary to facilitate normal mitochondrial fusion, ATP production, membrane potential, respiration, cristae ultrastructure and maintenance of oligomeric ATP synthase. Our results provide insight into how the surprisingly diverse salutary functions of MCL-1 may control the survival of both normal and cancer cells. C1 [Perciavalle, Rhonda M.; Stewart, Daniel P.; Koss, Brian; Bathina, Madhavi; Pelletier, Stephane; Opferman, Joseph T.] St Jude Childrens Res Hosp, Dept Biochem, Memphis, TN 38105 USA. [Perciavalle, Rhonda M.] Univ Tennessee, Ctr Hlth Sci, Integrated Program Biomed Sci, Memphis, TN 38163 USA. [Temirov, Jamshid] St Jude Childrens Res Hosp, Cell & Tissue Imaging Facil, Memphis, TN 38105 USA. [Cleland, Megan M.; Youle, Richard J.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Opferman, JT (reprint author), St Jude Childrens Res Hosp, Dept Biochem, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM Joseph.Opferman@stjude.org RI BATHINA, MADHAVI/G-3200-2012 FU Pew Scholars Program in the Biomedical Sciences; National Institutes of Health [HL-102175]; American Cancer Society [RSG-10-255-01-LIB]; Cancer Center [P30CA021765]; American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital FX We thank the St Jude Cell and Tissue Imaging Facility for assistance with live-cell imaging and S. Erase for assistance with electron micrographs; the W. M. Keck Foundation Biotechnology Resource Laboratory at Yale University for Edman sequencing; B. Xia, E. Parganas and D. Gable for technical assistance; C. Shaner for animal husbandry; and members of the St Jude Biochemistry Department, S. Oakes, J. Ihle and C. Sherr for helpful discussions. J.T.O. is supported by the Pew Scholars Program in the Biomedical Sciences; the National Institutes of Health HL-102175; the American Cancer Society RSG-10-255-01-LIB; a Cancer Center Support Grant P30CA021765; and the American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital. NR 62 TC 116 Z9 118 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUN PY 2012 VL 14 IS 6 BP 575 EP + DI 10.1038/ncb2488 PG 17 WC Cell Biology SC Cell Biology GA 949TW UT WOS:000304599900007 PM 22544066 ER PT J AU Kiezun, A Garimella, K Do, R Stitziel, NO Neale, BM McLaren, PJ Gupta, N Sklar, P Sullivan, PF Moran, JL Hultman, CM Lichtenstein, P Magnusson, P Lehner, T Shugart, YY Price, AL de Bakker, PIW Purcell, SM Sunyaev, SR AF Kiezun, Adam Garimella, Kiran Do, Ron Stitziel, Nathan O. Neale, Benjamin M. McLaren, Paul J. Gupta, Namrata Sklar, Pamela Sullivan, Patrick F. Moran, Jennifer L. Hultman, Christina M. Lichtenstein, Paul Magnusson, Patrik Lehner, Thomas Shugart, Yin Yao Price, Alkes L. de Bakker, Paul I. W. Purcell, Shaun M. Sunyaev, Shamil R. TI Exome sequencing and the genetic basis of complex traits SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; ALLELE FREQUENCY-SPECTRUM; RARE VARIANTS; POPULATION-STRUCTURE; PROTEIN FUNCTION; COMMON DISEASES; PLASMA-LEVELS; MUTATIONS; SELECTION C1 [Kiezun, Adam; McLaren, Paul J.; de Bakker, Paul I. W.; Sunyaev, Shamil R.] Harvard Univ, Sch Med, Dept Med, Div Genet,Brigham & Womens Hosp, Boston, MA 02114 USA. [Kiezun, Adam; Garimella, Kiran; Do, Ron; Stitziel, Nathan O.; Neale, Benjamin M.; McLaren, Paul J.; Gupta, Namrata; Moran, Jennifer L.; Price, Alkes L.; de Bakker, Paul I. W.; Sunyaev, Shamil R.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Do, Ron; Neale, Benjamin M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Stitziel, Nathan O.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Neale, Benjamin M.; Purcell, Shaun M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Sklar, Pamela] Mt Sinai Sch Med, Dept Psychiat, Friedman Brain Inst, New York, NY USA. [Sklar, Pamela] Mt Sinai Sch Med, Inst Genom & Multiscale Biol, New York, NY USA. [Sullivan, Patrick F.] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC USA. [Hultman, Christina M.; Lichtenstein, Paul; Magnusson, Patrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Shugart, Yin Yao] NIMH, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. [Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. RP Sunyaev, SR (reprint author), Harvard Univ, Sch Med, Dept Med, Div Genet,Brigham & Womens Hosp, Boston, MA 02114 USA. EM ssunyaev@rics.bwh.harvard.edu RI de Bakker, Paul/B-8730-2009; Magnusson, Patrik/C-4458-2017; OI de Bakker, Paul/0000-0001-7735-7858; lichtenstein, paul/0000-0003-3037-5287; Stitziel, Nathan/0000-0002-4963-8211; Moran, Jennifer/0000-0002-5664-4716 FU US National Institutes of Health (NIH) [5R01 MH084676]; Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation; NIH [AI069474, AI069428, AI69467, AI069415, Al32782, AI27661, AI25859, AI28568, AI30914, AI069495, AI069471, AI069532, AI069452, AI069450, AI069556]; Herman Foundation; Stanley Medical Research Institute; National Institute of Mental Health (NIMH) [1R01MH089208-01]; Canadian Institutes of Health Research FX The authors are grateful to S. Pollack for assistance with EIGENSOFT. This work was made possible, in part, by the US National Institutes of Health (NIH; grant 5R01 MH084676) and, in part, by the International HIV Controllers Study, supported by the Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation (to P.I.W.d.B.), and the AIDS Clinical Trials Group, supported by the NIH (grants AI069513, AI34835, AI069432, AI069423, AI069477, AI069501, AI069474, AI069428, AI69467, AI069415, Al32782, AI27661, AI25859, AI28568, AI30914, AI069495, AI069471, AI069532, AI069452, AI069450, AI069556, AI069484, AI069472, AI34853, AI069465, AI069511, AI38844, AI069424, AI069434, AI46370, AI68634, AI069502, AI069419, AI068636, RR024975 and AI077505). Sequencing of the SCZ control individuals was funded by the NIH (grant RC2MH089905), the Herman Foundation and the Stanley Medical Research Institute. N.O.S. was supported, in part, by an NIH Training Grant (T32-HL07604-25; Division of Cardiovascular Medicine, Brigham and Women's Hospital). B.M.N. was supported by a National Institute of Mental Health (NIMH) grant (1R01MH089208-01). R. D. is supported by a Canadian Institutes of Health Research Banting Postdoctoral Fellowship. The views expressed in this paper do not necessarily represent the views of the NIMH, NIH, Department of Health and Human Services (HHS) or the US government. NR 97 TC 195 Z9 199 U1 1 U2 35 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2012 VL 44 IS 6 BP 623 EP 630 DI 10.1038/ng.2303 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 949BT UT WOS:000304551100006 PM 22641211 ER PT J AU Laurie, CC Laurie, CA Rice, K Doheny, KF Zelnick, LR McHugh, CP Ling, H Hetrick, KN Pugh, EW Amos, C Wei, QY Wang, LE Lee, JE Barnes, KC Hansel, NN Mathias, R Daley, D Beaty, TH Scott, AF Ruczinski, I Scharpf, RB Bierut, LJ Hartz, SM Landi, MT Freedman, ND Goldin, LR Ginsburg, D Li, J Desch, KC Strom, SS Blot, WJ Signorello, LB Ingles, SA Chanock, SJ Berndt, SI Le Marchand, L Henderson, BE Monroe, KR Heit, JA de Andrade, M Armasu, SM Regnier, C Lowe, WL Hayes, MG Marazita, ML Feingold, E Murray, JC Melbye, M Feenstra, B Kang, JH Wiggs, JL Jarvik, GP McDavid, AN Seshan, VE Mirel, DB Crenshaw, A Sharopova, N Wise, A Shen, J Crosslin, DR Levine, DM Zheng, XW Udren, JI Bennett, S Nelson, SC Gogarten, SM Conomos, MP Heagerty, P Manolio, T Pasquale, LR Haiman, CA Caporaso, N Weir, BS AF Laurie, Cathy C. Laurie, Cecelia A. Rice, Kenneth Doheny, Kimberly F. Zelnick, Leila R. McHugh, Caitlin P. Ling, Hua Hetrick, Kurt N. Pugh, Elizabeth W. Amos, Chris Wei, Qingyi Wang, Li-E Lee, Jeffrey E. Barnes, Kathleen C. Hansel, Nadia N. Mathias, Rasika Daley, Denise Beaty, Terri H. Scott, Alan F. Ruczinski, Ingo Scharpf, Rob B. Bierut, Laura J. Hartz, Sarah M. Landi, Maria Teresa Freedman, Neal D. Goldin, Lynn R. Ginsburg, David Li, Jun Desch, Karl C. Strom, Sara S. Blot, William J. Signorello, Lisa B. Ingles, Sue A. Chanock, Stephen J. Berndt, Sonja I. Le Marchand, Loic Henderson, Brian E. Monroe, Kristine R. Heit, John A. de Andrade, Mariza Armasu, Sebastian M. Regnier, Cynthia Lowe, William L. Hayes, M. Geoffrey Marazita, Mary L. Feingold, Eleanor Murray, Jeffrey C. Melbye, Mads Feenstra, Bjarke Kang, Jae H. Wiggs, Janey L. Jarvik, Gail P. McDavid, Andrew N. Seshan, Venkatraman E. Mirel, Daniel B. Crenshaw, Andrew Sharopova, Nataliya Wise, Anastasia Shen, Jess Crosslin, David R. Levine, David M. Zheng, Xiuwen Udren, Jenna I. Bennett, Siiri Nelson, Sarah C. Gogarten, Stephanie M. Conomos, Matthew P. Heagerty, Patrick Manolio, Teri Pasquale, Louis R. Haiman, Christopher A. Caporaso, Neil Weir, Bruce S. TI Detectable clonal mosaicism from birth to old age and its relationship to cancer SO NATURE GENETICS LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; COPY-NUMBER VARIATION; POLYMORPHISM ARRAY ANALYSIS; B-CELL LYMPHOCYTOSIS; STEM-CELLS; GENOME; MALIGNANCIES; ASSOCIATION; GENE; POPULATIONS AB We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5-10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2-3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6-18). C1 [Laurie, Cathy C.; Laurie, Cecelia A.; Rice, Kenneth; Zelnick, Leila R.; McHugh, Caitlin P.; Shen, Jess; Crosslin, David R.; Levine, David M.; Zheng, Xiuwen; Udren, Jenna I.; Bennett, Siiri; Nelson, Sarah C.; Gogarten, Stephanie M.; Conomos, Matthew P.; Heagerty, Patrick; Weir, Bruce S.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Doheny, Kimberly F.; Ling, Hua; Hetrick, Kurt N.; Pugh, Elizabeth W.] Johns Hopkins Univ, Ctr Inherited Dis Res, Baltimore, MD USA. [Amos, Chris; Wei, Qingyi; Wang, Li-E] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. [Lee, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Div Surg, Houston, TX 77030 USA. [Barnes, Kathleen C.; Hansel, Nadia N.; Mathias, Rasika] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Daley, Denise] Univ British Columbia, Dept Med, Vancouver, BC, Canada. [Beaty, Terri H.] Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Scott, Alan F.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Ruczinski, Ingo] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Scharpf, Rob B.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Bierut, Laura J.; Hartz, Sarah M.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Landi, Maria Teresa; Freedman, Neal D.; Goldin, Lynn R.; Chanock, Stephen J.; Berndt, Sonja I.; Caporaso, Neil] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Ginsburg, David] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. [Ginsburg, David] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Li, Jun] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Desch, Karl C.] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Blot, William J.; Signorello, Lisa B.] Vanderbilt Univ, Dept Med, Vanderbilt Epidemiol Ctr, Div Epidemiol, Nashville, TN USA. [Ingles, Sue A.; Henderson, Brian E.; Monroe, Kristine R.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Heit, John A.] Mayo Clin, Dept Internal Med, Rochester, MN USA. [de Andrade, Mariza; Armasu, Sebastian M.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Regnier, Cynthia] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. [Regnier, Cynthia] Mayo Clin, Mayo Hyperoxaluria Ctr, Rochester, MN USA. [Lowe, William L.; Hayes, M. Geoffrey] Northwestern Univ, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. [Marazita, Mary L.] Univ Pittsburgh, Sch Dent Med, Dept Oral Biol, Ctr Craniofacial & Dent Genet, Pittsburgh, PA USA. [Feingold, Eleanor] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Melbye, Mads; Feenstra, Bjarke] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Kang, Jae H.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Wiggs, Janey L.; Pasquale, Louis R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jarvik, Gail P.] Univ Washington, Div Med Genet, Seattle, WA 98195 USA. [McDavid, Andrew N.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Seshan, Venkatraman E.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Mirel, Daniel B.; Crenshaw, Andrew] Broad Inst Harvard & MIT, Cambridge, MA USA. [Sharopova, Nataliya] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Wise, Anastasia; Manolio, Teri] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. RP Laurie, CC (reprint author), Univ Washington, Dept Biostat, Seattle, WA 98195 USA. EM cclaurie@u.washington.edu RI Weir, Bruce/A-2894-2013; Rice, Kenneth/A-4150-2013; Jarvik, Gail/N-6476-2014; Freedman, Neal/B-9741-2015; OI Rice, Kenneth/0000-0001-5779-4495; Jarvik, Gail/0000-0002-6710-8708; Freedman, Neal/0000-0003-0074-1098; Feenstra, Bjarke/0000-0003-1478-649X; Feingold, Eleanor/0000-0003-2898-6484; McDavid, Andrew/0000-0002-6581-1213; Zheng, Xiuwen/0000-0002-1390-0708; Gogarten, Stephanie/0000-0002-7231-9745; Hartz, Sarah/0000-0002-5429-3799 FU US National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI); NIH (NCI) [R29CA70334, R01CA100264, P50CA093459, U10AA008401, CA63464, CA54281, CA1326792, RC2 CA148085]; NIH [U01HG004738, HHSN268200782096C, U01HG004726, U01HG004735, U01HG004415, U01HG004423]; NIH (National Institute Dental and Craniofacial Research (NIDCR) [U01DE018993]; NIH, National Institute on Alcohol Abuse and Alcoholism (NIAAA) [U01HG004422]; NIH, National Institute on Drug Abuse (NIDA) [P01CA089392, R01DA013423, R01DA019963]; NIH (NIDCR) [U01DE018903, R01DE014899]; NIH, NIH Center for Inherited Disease Research (CIDR) [HHSN268200-782096C]; NIH, National Eye Institute (NEI) [U01HG004728, R01EY015473, R01EY015872]; NIH, GENEVA Coordinating Center [U01 HG004446]; NIG, CIDR [HHSN268200782096C, U01HG004438]; NIH, Broad Center for Genotyping and Analysis [U01HG04424]; NIH, the National Library of Medicine; Division of Cancer Epidemiology and Genetics, NCI, NIH; Research to Prevent Blindness in NYC; Harvard Medical School; Harvard Glaucoma Center of Excellence; NCI [T32 CA09168] FX The GENEVA Consortium thanks the subjects and the staff of all GENEVA studies for their important contributions. We thank the following state cancer registries for their help: Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Nebraska, New Hampshire, New Jersey, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, Washington and Wyoming. We thank C. Laird and G. Marti for helpful comments on the manuscript and B. Wakimoto and D. Gottschling for enlightening discussions. We also thank K. Jacobs for exchanging ideas and for working with us to estimate cross-method concordance of mosaic detection using the PLCO/GENEVA Lung Cancer study. Support for the GENEVA genome-wide association studies was provided through the US National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI). Some studies also received support from individual NIH Institutes. The grant numbers are: Melanoma (NCI R29CA70334, R01CA100264 and P50CA093459); Lung Health (U01HG004738); Cleft Lip/Palate (National Institute Dental and Craniofacial Research (NIDCR): U01DE018993 and NIH contract: HHSN268200782096C); Addiction (U01HG004422, National Institute on Alcohol Abuse and Alcoholism (NIAAA): U10AA008401, National Cancer Institute (NCI): P01CA089392, National Institute on Drug Abuse (NIDA): R01DA013423 and R01DA019963); Lung Cancer (Z01CP010200); Blood Clotting (R37 HL 039693); Prostate Cancer (U01HG004726, NCI: CA63464, CA54281, CA1326792 and RC2 CA148085); Venous Thromboembolism (U01HG004735); Birth Weight (U01HG004415); Dental Caries (NIDCR: U01DE018903 and R01DE014899, NIH Center for Inherited Disease Research (CIDR) contract: HHSN268200-782096C); Prematurity (U01HG004423); Glaucoma (U01HG004728, National Eye Institute (NEI): R01EY015473 and R01EY015872); GENEVA Coordinating Center (U01 HG004446); CIDR (U01HG004438 and HHSN268200782096C); Broad Center for Genotyping and Analysis (U01HG04424); the Intramural Research Program of the NIH, the National Library of Medicine; and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH. L. R. P. was also supported by a Physician Scientist award from Research to Prevent Blindness in NYC and an Ophthalmology Scholar Award from Harvard Medical School and from the Harvard Glaucoma Center of Excellence. L.R.Z. was supported by the NCI (T32 CA09168). NR 53 TC 161 Z9 161 U1 6 U2 36 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUN PY 2012 VL 44 IS 6 BP 642 EP U58 DI 10.1038/ng.2271 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 949BT UT WOS:000304551100010 PM 22561516 ER PT J AU Jacobs, KB Yeager, M Zhou, WY Wacholder, S Wang, ZM Rodriguez-Santiago, B Hutchinson, A Deng, X Liu, CW Horner, MJ Cullen, M Epstein, CG Burdett, L Dean, MC Chatterjee, N Sampson, J Chung, CC Kovaks, J Gapstur, SM Stevens, VL Teras, LT Gaudet, MM Albanes, D Weinstein, SJ Virtamo, J Taylor, PR Freedman, ND Abnet, CC Goldstein, AM Hu, N Yu, K Yuan, JM Liao, LD Ding, T Qiao, YL Gao, YT Koh, WP Xiang, YB Tang, ZZ Fan, JH Aldrich, MC Amos, C Blot, WJ Bock, CH Gillanders, EM Harris, CC Haiman, CA Henderson, BE Kolonel, LN Le Marchand, L McNeill, LH Rybicki, BA Schwartz, AG Signorello, LB Spitz, MR Wiencke, JK Wrensch, M Wu, XF Zanetti, KA Ziegler, RG Figueroa, JD Garcia-Closas, M Malats, N Marenne, G Prokunina-Olsson, L Baris, D Schwenn, M Johnson, A Landi, MT Goldin, L Consonni, D Bertazzi, PA Rotunno, M Rajaraman, P Andersson, U Freeman, LEB Berg, CD Buring, JE Butler, MA Carreon, T Feychting, M Ahlbom, A Gaziano, JM Giles, GG Hallmans, G Hankinson, SE Hartge, P Henriksson, R Inskip, PD Johansen, C Landgren, A McKean-Cowdin, R Michaud, DS Melin, BS Peters, U Ruder, AM Sesso, HD Severi, G Shu, XO Visvanathan, K White, E Wolk, A Zeleniuch-Jacquotte, A Zheng, W Silverman, DT Kogevinas, M Gonzalez, JR Villa, O Li, DH Duell, EJ Risch, HA Olson, SH Kooperberg, C Wolpin, BM Jiao, L Hassan, M Wheeler, W Arslan, AA Bueno-de-Mesquita, HB Fuchs, CS Gallinger, S Gross, MD Holly, EA Klein, AP LaCroix, A Mandelson, MT Petersen, G Boutron-Ruault, MC Bracci, PM Canzian, F Chang, K Cotterchio, M Giovannucci, EL Goggins, M Bolton, JAH Jenab, M Khaw, KT Krogh, V Kurtz, RC McWilliams, RR Mendelsohn, JB Rabe, KG Riboli, E Tjonneland, A Tobias, GS Trichopoulos, D Elena, JW Yu, H Amundadottir, L Stolzenberg-Solomon, RZ Kraft, P Schumacher, F Stram, D Savage, SA Mirabello, L Andrulis, IL Wunder, JS Garcia, AP Sierrasesumaga, L Barkauskas, DA Gorlick, RG Purdue, M Chow, WH Moore, LE Schwartz, KL Davis, FG Hsing, AW Berndt, SI Black, A Wentzensen, N Brinton, LA Lissowska, J Peplonska, B McGlynn, KA Cook, MB Graubard, BI Kratz, CP Greene, MH Erickson, RL Hunter, DJ Thomas, G Hoover, RN Real, FX Fraumeni, JF Caporaso, NE Tucker, M Rothman, N Perez-Jurado, LA Chanock, SJ AF Jacobs, Kevin B. Yeager, Meredith Zhou, Weiyin Wacholder, Sholom Wang, Zhaoming Rodriguez-Santiago, Benjamin Hutchinson, Amy Deng, Xiang Liu, Chenwei Horner, Marie-Josephe Cullen, Michael Epstein, Caroline G. Burdett, Laurie Dean, Michael C. Chatterjee, Nilanjan Sampson, Joshua Chung, Charles C. Kovaks, Joseph Gapstur, Susan M. Stevens, Victoria L. Teras, Lauren T. Gaudet, Mia M. Albanes, Demetrius Weinstein, Stephanie J. Virtamo, Jarmo Taylor, Philip R. Freedman, Neal D. Abnet, Christian C. Goldstein, Alisa M. Hu, Nan Yu, Kai Yuan, Jian-Min Liao, Linda Ding, Ti Qiao, You-Lin Gao, Yu-Tang Koh, Woon-Puay Xiang, Yong-Bing Tang, Ze-Zhong Fan, Jin-Hu Aldrich, Melinda C. Amos, Christopher Blot, William J. Bock, Cathryn H. Gillanders, Elizabeth M. Harris, Curtis C. Haiman, Christopher A. Henderson, Brian E. Kolonel, Laurence N. Le Marchand, Loic McNeill, Lorna H. Rybicki, Benjamin A. Schwartz, Ann G. Signorello, Lisa B. Spitz, Margaret R. Wiencke, John K. Wrensch, Margaret Wu, Xifeng Zanetti, Krista A. Ziegler, Regina G. Figueroa, Jonine D. Garcia-Closas, Montserrat Malats, Nuria Marenne, Gaelle Prokunina-Olsson, Ludmila Baris, Dalsu Schwenn, Molly Johnson, Alison Landi, Maria Teresa Goldin, Lynn Consonni, Dario Bertazzi, Pier Alberto Rotunno, Melissa Rajaraman, Preetha Andersson, Ulrika Freeman, Laura E. Beane Berg, Christine D. Buring, Julie E. Butler, Mary A. Carreon, Tania Feychting, Maria Ahlbom, Anders Gaziano, J. Michael Giles, Graham G. Hallmans, Goran Hankinson, Susan E. Hartge, Patricia Henriksson, Roger Inskip, Peter D. Johansen, Christoffer Landgren, Annelie McKean-Cowdin, Roberta Michaud, Dominique S. Melin, Beatrice S. Peters, Ulrike Ruder, Avima M. Sesso, Howard D. Severi, Gianluca Shu, Xiao-Ou Visvanathan, Kala White, Emily Wolk, Alicja Zeleniuch-Jacquotte, Anne Zheng, Wei Silverman, Debra T. Kogevinas, Manolis Gonzalez, Juan R. Villa, Olaya Li, Donghui Duell, Eric J. Risch, Harvey A. Olson, Sara H. Kooperberg, Charles Wolpin, Brian M. Jiao, Li Hassan, Manal Wheeler, William Arslan, Alan A. Bueno-de-Mesquita, H. Bas Fuchs, Charles S. Gallinger, Steven Gross, Myron D. Holly, Elizabeth A. Klein, Alison P. LaCroix, Andrea Mandelson, Margaret T. Petersen, Gloria Boutron-Ruault, Marie-Christine Bracci, Paige M. Canzian, Federico Chang, Kenneth Cotterchio, Michelle Giovannucci, Edward L. Goggins, Michael Bolton, Judith A. Hoffman Jenab, Mazda Khaw, Kay-Tee Krogh, Vittorio Kurtz, Robert C. McWilliams, Robert R. Mendelsohn, Julie B. Rabe, Kari G. Riboli, Elio Tjonneland, Anne Tobias, Geoffrey S. Trichopoulos, Dimitrios Elena, Joanne W. Yu, Herbert Amundadottir, Laufey Stolzenberg-Solomon, Rachael Z. Kraft, Peter Schumacher, Fredrick Stram, Daniel Savage, Sharon A. Mirabello, Lisa Andrulis, Irene L. Wunder, Jay S. Patino Garcia, Ana Sierrasesumaga, Luis Barkauskas, Donald A. Gorlick, Richard G. Purdue, Mark Chow, Wong-Ho Moore, Lee E. Schwartz, Kendra L. Davis, Faith G. Hsing, Ann W. Berndt, Sonja I. Black, Amanda Wentzensen, Nicolas Brinton, Louise A. Lissowska, Jolanta Peplonska, Beata McGlynn, Katherine A. Cook, Michael B. Graubard, Barry I. Kratz, Christian P. Greene, Mark H. Erickson, Ralph L. Hunter, David J. Thomas, Gilles Hoover, Robert N. Real, Francisco X. Fraumeni, Joseph F., Jr. Caporaso, Neil E. Tucker, Margaret Rothman, Nathaniel Perez-Jurado, Luis A. Chanock, Stephen J. TI Detectable clonal mosaicism and its relationship to aging and cancer SO NATURE GENETICS LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; GENOMIC IMBALANCES; MAFFUCCI SYNDROME; OLLIER DISEASE; MUTATIONS; SUSCEPTIBILITY; ASSOCIATION; ABERRATIONS; MECHANISMS; ANEUPLOIDY AB In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of > 2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases. C1 [Jacobs, Kevin B.; Yeager, Meredith; Zhou, Weiyin; Wacholder, Sholom; Wang, Zhaoming; Hutchinson, Amy; Deng, Xiang; Liu, Chenwei; Horner, Marie-Josephe; Cullen, Michael; Epstein, Caroline G.; Burdett, Laurie; Chatterjee, Nilanjan; Sampson, Joshua; Chung, Charles C.; Kovaks, Joseph; Albanes, Demetrius; Weinstein, Stephanie J.; Taylor, Philip R.; Freedman, Neal D.; Abnet, Christian C.; Goldstein, Alisa M.; Hu, Nan; Yu, Kai; Liao, Linda; Ziegler, Regina G.; Figueroa, Jonine D.; Garcia-Closas, Montserrat; Prokunina-Olsson, Ludmila; Baris, Dalsu; Landi, Maria Teresa; Goldin, Lynn; Rotunno, Melissa; Rajaraman, Preetha; Freeman, Laura E. Beane; Hartge, Patricia; Inskip, Peter D.; Landgren, Annelie; Silverman, Debra T.; Mendelsohn, Julie B.; Tobias, Geoffrey S.; Amundadottir, Laufey; Stolzenberg-Solomon, Rachael Z.; Savage, Sharon A.; Mirabello, Lisa; Purdue, Mark; Chow, Wong-Ho; Moore, Lee E.; Hsing, Ann W.; Berndt, Sonja I.; Black, Amanda; Wentzensen, Nicolas; Brinton, Louise A.; McGlynn, Katherine A.; Cook, Michael B.; Graubard, Barry I.; Kratz, Christian P.; Greene, Mark H.; Hoover, Robert N.; Fraumeni, Joseph F., Jr.; Caporaso, Neil E.; Tucker, Margaret; Rothman, Nathaniel; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Jacobs, Kevin B.; Yeager, Meredith; Zhou, Weiyin; Wang, Zhaoming; Hutchinson, Amy; Deng, Xiang; Liu, Chenwei; Cullen, Michael; Burdett, Laurie] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Rodriguez-Santiago, Benjamin; Villa, Olaya; Real, Francisco X.; Perez-Jurado, Luis A.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Rodriguez-Santiago, Benjamin; Villa, Olaya; Perez-Jurado, Luis A.] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain. [Rodriguez-Santiago, Benjamin; Villa, Olaya] qGenomics, Quantitat Genom Med Lab, Barcelona, Spain. [Dean, Michael C.] NCI, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Gapstur, Susan M.; Stevens, Victoria L.; Teras, Lauren T.; Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Yuan, Jian-Min] Univ Minnesota, Sch Publ Hlth, Dept Epidemiol & Community Hlth, Minneapolis, MN USA. [Yuan, Jian-Min] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Ding, Ti; Tang, Ze-Zhong] Shanxi Canc Hosp, Taiyuan, Peoples R China. [Qiao, You-Lin; Fan, Jin-Hu] Chinese Acad Med Sci, Dept Epidemiol, Canc Inst Hosp, Beijing 100730, Peoples R China. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Canc Inst, Shanghai, Peoples R China. [Koh, Woon-Puay] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Aldrich, Melinda C.] Vanderbilt Univ, Sch Med, Dept Thorac Surg, Nashville, TN 37212 USA. [Aldrich, Melinda C.; Blot, William J.; Signorello, Lisa B.; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol,Vanderbilt Epidemiol Ctr, Nashville, TN USA. [Amos, Christopher; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. [Blot, William J.; Signorello, Lisa B.] Int Epidemiol Inst, Rockville, MD USA. [Bock, Cathryn H.; Schwartz, Ann G.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Bock, Cathryn H.; Schwartz, Ann G.] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI USA. [Gillanders, Elizabeth M.; Zanetti, Krista A.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Harris, Curtis C.; Zanetti, Krista A.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Haiman, Christopher A.; Henderson, Brian E.; McKean-Cowdin, Roberta; Schumacher, Fredrick; Stram, Daniel; Barkauskas, Donald A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [McNeill, Lorna H.] Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar Res, Div Off Vice President Canc Prevent & Populat Sci, Houston, TX 77030 USA. [McNeill, Lorna H.] Univ Texas MD Anderson Canc Ctr, Ctr Community Engaged & Translat Res, Duncan Family Inst, Houston, TX 77030 USA. [Rybicki, Benjamin A.] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Signorello, Lisa B.; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Spitz, Margaret R.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Wiencke, John K.; Wrensch, Margaret] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Malats, Nuria; Marenne, Gaelle] CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Consonni, Dario; Bertazzi, Pier Alberto] Univ Milan, Dept Occupat & Environm Hlth, Milan, Italy. [Consonni, Dario; Bertazzi, Pier Alberto] Osped Maggiore Policlin Mangiagalli & Regina Elen, Unit Epidemiol, Fdn Ist Ricevero & Cura Carattere Sci IRCCS, Milan, Italy. [Andersson, Ulrika; Henriksson, Roger; Melin, Beatrice S.] Umea Univ, Dept Radiat Sci, Umea, Sweden. [Berg, Christine D.; Elena, Joanne W.] NCI, Clin & Translat Epidemiol Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. 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EM chanocks@mail.nih.gov RI Consonni, Dario/K-7943-2016; Amundadottir, Laufey/L-7656-2016; Tobias, Geoffrey/M-4135-2016; Beane Freeman, Laura/C-4468-2015; Kogevinas, Manolis/C-3918-2017; bertazzi, pietro alberto/D-5039-2017; Tucker, Margaret/B-4297-2015; Albanes, Demetrius/B-9749-2015; Abnet, Christian/C-4111-2015; Garcia-Closas, Montserrat /F-3871-2015; Boutron-Ruault, Marie-Christine/H-3936-2014; Brinton, Louise/G-7486-2015; Freedman, Neal/B-9741-2015; Malats, Nuria/H-7041-2015; Perez Jurado, Luis Alberto/M-7706-2015; Real Arribas, Francisco/H-5275-2015; Savage, Sharon/B-9747-2015; Krogh, Vittorio/K-2628-2016; Berg , Christine/K-1047-2014; Qiao, You-Lin/B-4139-2012; Dean, Michael/G-8172-2012; Ruder, Avima/I-4155-2012; Patino-Garcia, Ana/I-4299-2012; Peplonska, Beata/F-6004-2010; Aldrich, Melinda/C-7783-2013; Cook, Michael/A-5641-2009; Gallinger, Steven/E-4575-2013; Andrulis, Irene/E-7267-2013; Boutron Ruault, Marie-Christine/G-3705-2013; Boutron, Marie-Christine/K-8168-2013; Michaud, Dominique/I-5231-2014 OI Lissowska, Jolanta/0000-0003-2695-5799; Yuan, Jian-Min/0000-0002-4620-3108; Giles, Graham/0000-0003-4946-9099; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Consonni, Dario/0000-0002-8935-3843; Amundadottir, Laufey/0000-0003-1859-8971; Tobias, Geoffrey/0000-0002-2878-8253; Beane Freeman, Laura/0000-0003-1294-4124; bertazzi, pietro alberto/0000-0003-3475-2449; Duell, Eric J/0000-0001-5256-0163; Rodriguez-Santiago, Benjamin/0000-0003-1167-3852; Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Liao, Linda/0000-0002-1923-5294; Abnet, Christian/0000-0002-3008-7843; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Freedman, Neal/0000-0003-0074-1098; Malats, Nuria/0000-0003-2538-3784; Real Arribas, Francisco/0000-0001-9501-498X; Savage, Sharon/0000-0001-6006-0740; Krogh, Vittorio/0000-0003-0122-8624; Qiao, You-Lin/0000-0001-6380-0871; Dean, Michael/0000-0003-2234-0631; Ruder, Avima/0000-0003-0419-6664; Cook, Michael/0000-0002-0533-7302; FU Intramural Research Program; US National Institutes of Health (NIH), NCI [HHSN261200800001E] FX This research was supported by the Intramural Research Program and by contract number HHSN261200800001E of the US National Institutes of Health (NIH), NCI. Support for each contributing study is listed in the Supplementary Note. We thank C. Laurie and B. Weir for constructive discussion and a comparison of methodology and results for the GENEVA study. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Cancer Institute, the National Institute for Occupational Safety and Health or the Maryland Cancer Registry. NR 43 TC 169 Z9 170 U1 2 U2 61 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUN PY 2012 VL 44 IS 6 BP 651 EP U68 DI 10.1038/ng.2270 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 949BT UT WOS:000304551100011 PM 22561519 ER PT J AU Manning, AK Hivert, MF Scott, RA Grimsby, JL Bouatia-Naji, N Chen, H Rybin, D Liu, CT Bielak, LF Prokopenko, I Amin, N Barnes, D Cadby, G Hottenga, JJ Ingelsson, E Jackson, AU Johnson, T Kanoni, S Ladenvall, C Lagou, V Lahti, J Lecoeur, C Liu, YM Martinez-Larrad, MT Montasser, ME Navarro, P Perry, JRB Rasmussen-Torvik, LJ Salo, P Sattar, N Shungin, D Strawbridge, RJ Tanaka, T van Duijn, CM An, P de Andrade, M Andrews, JS Aspelund, T Atalay, M Aulchenko, Y Balkau, B Bandinelli, S Beckmann, JS Beilby, JP Bellis, C Bergman, RN Blangero, J Boban, M Boehnke, M Boerwinkle, E Bonnycastle, LL Boomsma, DI Borecki, IB Boettcher, Y Bouchard, C Brunner, E Budimir, D Campbell, H Carlson, O Chines, PS Clarke, R Collins, FS Corbaton-Anchuelo, A Couper, D de Faire, U Dedoussis, GV Deloukas, P Dimitriou, M Egan, JM Eiriksdottir, G Erdos, MR Eriksson, JG Eury, E Ferrucci, L Ford, I Forouhi, NG Fox, CS Franzosi, MG Franks, PW Frayling, TM Froguel, P Galan, P de Geus, E Gigante, B Glazer, NL Goel, A Groop, L Gudnason, V Hallmans, G Hamsten, A Hansson, O Harris, TB Hayward, C Heath, S Hercberg, S Hicks, AA Hingorani, A Hofman, A Hui, J Hung, J Jarvelin, MR Jhun, MA Johnson, PCD Jukema, JW Jula, A Kao, WH Kaprio, J Kardia, SLR Keinanen-Kiukaanniemi, S Kivimaki, M Kolcic, I Kovacs, P Kumari, M Kuusisto, J Kyvik, KO Laakso, M Lakka, T Lannfelt, L Lathrop, GM Launer, LJ Leander, K Li, G Lind, L Lindstrom, J Lobbens, S Loos, RJF Luan, JA Lyssenko, V Magi, R Magnusson, PKE Marmot, M Meneton, P Mohlke, KL Mooser, V Morken, MA Miljkovic, I Narisu, N O'Connell, J Ong, KK Oostra, BA Palmer, LJ Palotie, A Pankow, JS Peden, JF Pedersen, NL Pehlic, M Peltonen, L Penninx, B Pericic, M Perola, M Perusse, L Peyser, PA Polasek, O Pramstaller, PP Province, MA Raikkonen, K Rauramaa, R Rehnberg, E Rice, K Rotter, JI Rudan, I Ruokonen, A Saaristo, T Sabater-Lleal, M Salomaa, V Savage, DB Saxena, R Schwarz, P Seedorf, U Sennblad, B Serrano-Rios, M Shuldiner, AR Sijbrands, EJG Siscovick, DS Smit, JH Small, KS Smith, NL Smith, AV Stancakova, A Stirrups, K Stumvoll, M Sun, YV Swift, AJ Toenjes, A Tuomilehto, J Trompet, S Uitterlinden, AG Uusitupa, M Vikstrom, M Vitart, V Vohl, MC Voight, BF Vollenweider, P Waeber, G Waterworth, DM Watkins, H Wheeler, E Widen, E Wild, SH Willems, SM Willemsen, G Wilson, JF Witteman, JCM Wright, AF Yaghootkar, H Zelenika, D Zemunik, T Zgaga, L Wareham, NJ McCarthy, MI Barroso, I Watanabe, RM Florez, JC Dupuis, J Meigs, JB Langenberg, C AF Manning, Alisa K. Hivert, Marie-France Scott, Robert A. Grimsby, Jonna L. Bouatia-Naji, Nabila Chen, Han Rybin, Denis Liu, Ching-Ti Bielak, Lawrence F. Prokopenko, Inga Amin, Najaf Barnes, Daniel Cadby, Gemma Hottenga, Jouke-Jan Ingelsson, Erik Jackson, Anne U. Johnson, Toby Kanoni, Stavroula Ladenvall, Claes Lagou, Vasiliki Lahti, Jari Lecoeur, Cecile Liu, Yongmei Martinez-Larrad, Maria Teresa Montasser, May E. Navarro, Pau Perry, John R. B. Rasmussen-Torvik, Laura J. Salo, Perttu Sattar, Naveed Shungin, Dmitry Strawbridge, Rona J. Tanaka, Toshiko van Duijn, Cornelia M. An, Ping de Andrade, Mariza Andrews, Jeanette S. Aspelund, Thor Atalay, Mustafa Aulchenko, Yurii Balkau, Beverley Bandinelli, Stefania Beckmann, Jacques S. Beilby, John P. Bellis, Claire Bergman, Richard N. Blangero, John Boban, Mladen Boehnke, Michael Boerwinkle, Eric Bonnycastle, Lori L. Boomsma, Dorret I. Borecki, Ingrid B. Boettcher, Yvonne Bouchard, Claude Brunner, Eric Budimir, Danijela Campbell, Harry Carlson, Olga Chines, Peter S. Clarke, Robert Collins, Francis S. Corbaton-Anchuelo, Arturo Couper, David de Faire, Ulf Dedoussis, George V. Deloukas, Panos Dimitriou, Maria Egan, Josephine M. Eiriksdottir, Gudny Erdos, Michael R. Eriksson, Johan G. Eury, Elodie Ferrucci, Luigi Ford, Ian Forouhi, Nita G. Fox, Caroline S. Franzosi, Maria Grazia Franks, Paul W. Frayling, Timothy M. Froguel, Philippe Galan, Pilar de Geus, Eco Gigante, Bruna Glazer, Nicole L. Goel, Anuj Groop, Leif Gudnason, Vilmundur Hallmans, Goeran Hamsten, Anders Hansson, Ola Harris, Tamara B. Hayward, Caroline Heath, Simon Hercberg, Serge Hicks, Andrew A. Hingorani, Aroon Hofman, Albert Hui, Jennie Hung, Joseph Jarvelin, Marjo-Riitta Jhun, Min A. Johnson, Paul C. D. Jukema, J. Wouter Jula, Antti Kao, W. H. Kaprio, Jaakko Kardia, Sharon L. R. Keinanen-Kiukaanniemi, Sirkka Kivimaki, Mika Kolcic, Ivana Kovacs, Peter Kumari, Meena Kuusisto, Johanna Kyvik, Kirsten Ohm Laakso, Markku Lakka, Timo Lannfelt, Lars Lathrop, G. Mark Launer, Lenore J. Leander, Karin Li, Guo Lind, Lars Lindstrom, Jaana Lobbens, Stephane Loos, Ruth J. F. Luan, Jian'an Lyssenko, Valeriya Magi, Reedik Magnusson, Patrik K. E. Marmot, Michael Meneton, Pierre Mohlke, Karen L. Mooser, Vincent Morken, Mario A. Miljkovic, Iva Narisu, Narisu O'Connell, Jeff Ong, Ken K. Oostra, Ben A. Palmer, Lyle J. Palotie, Aarno Pankow, James S. Peden, John F. Pedersen, Nancy L. Pehlic, Marina Peltonen, Leena Penninx, Brenda Pericic, Marijana Perola, Markus Perusse, Louis Peyser, Patricia A. Polasek, Ozren Pramstaller, Peter P. Province, Michael A. Raikkonen, Katri Rauramaa, Rainer Rehnberg, Emil Rice, Ken Rotter, Jerome I. Rudan, Igor Ruokonen, Aimo Saaristo, Timo Sabater-Lleal, Maria Salomaa, Veikko Savage, David B. Saxena, Richa Schwarz, Peter Seedorf, Udo Sennblad, Bengt Serrano-Rios, Manuel Shuldiner, Alan R. Sijbrands, Eric J. G. Siscovick, David S. Smit, Johannes H. Small, Kerrin S. Smith, Nicholas L. Smith, Albert Vernon Stancakova, Alena Stirrups, Kathleen Stumvoll, Michael Sun, Yan V. Swift, Amy J. Toenjes, Anke Tuomilehto, Jaakko Trompet, Stella Uitterlinden, Andre G. Uusitupa, Matti Vikstrom, Max Vitart, Veronique Vohl, Marie-Claude Voight, Benjamin F. Vollenweider, Peter Waeber, Gerard Waterworth, Dawn M. Watkins, Hugh Wheeler, Eleanor Widen, Elisabeth Wild, Sarah H. Willems, Sara M. Willemsen, Gonneke Wilson, James F. Witteman, Jacqueline C. M. Wright, Alan F. Yaghootkar, Hanieh Zelenika, Diana Zemunik, Tatijana Zgaga, Lina Wareham, Nicholas J. McCarthy, Mark I. Barroso, Ines Watanabe, Richard M. Florez, Jose C. Dupuis, Josee Meigs, James B. Langenberg, Claudia CA DIAGRAM Consortium MUTHER Consortium TI A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance SO NATURE GENETICS LA English DT Article ID CORONARY-ARTERY-DISEASE; TYPE-2 DIABETES RISK; ASSOCIATION ANALYSIS; ENVIRONMENT INTERACTION; COMMON VARIANTS; LOCI; OBESITY; SUSCEPTIBILITY; GLUCOSE; POLYMORPHISM AB Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 x 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology. C1 [Hivert, Marie-France; Grimsby, Jonna L.; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Manning, Alisa K.; Chen, Han; Liu, Ching-Ti; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Manning, Alisa K.; Palotie, Aarno; Saxena, Richa; Voight, Benjamin F.; Florez, Jose C.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Manning, Alisa K.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. 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E.; Pedersen, Nancy L.; Rehnberg, Emil] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Johnson, Toby] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol & Genome Ctr, London, England. [Wheeler, Eleanor; Barroso, Ines] Wellcome Trust Sanger Inst, Metab Dis Grp, Cambridge, England. [Ladenvall, Claes; Shungin, Dmitry; Franks, Paul W.; Groop, Leif; Hansson, Ola; Lyssenko, Valeriya] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Ladenvall, Claes; Shungin, Dmitry; Franks, Paul W.; Groop, Leif; Hansson, Ola; Lyssenko, Valeriya] Lund Univ, Ctr Diabet, Malmo, Sweden. [Lahti, Jari; Raikkonen, Katri] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. 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[Lindstrom, Jaana; Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Diabet Prevent Unit, Helsinki, Finland. [Sattar, Naveed] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Shungin, Dmitry; Franks, Paul W.] Umea Univ Hosp, Genet Epidemiol & Clin Res Grp, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden. [Shungin, Dmitry] Umea Univ, Dept Odontol, Umea, Sweden. [Strawbridge, Rona J.; Hamsten, Anders; Sabater-Lleal, Maria; Sennblad, Bengt] Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, Stockholm, Sweden. [Ferrucci, Luigi] NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. [van Duijn, Cornelia M.] Netherlands Genom Initiat, Ctr Med Syst Biol, The Hague, Netherlands. [van Duijn, Cornelia M.; Hofman, Albert; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.] Netherlands Genom Initiat, Netherlands Consortium Hlth Aging, Rotterdam, Netherlands. [An, Ping; Borecki, Ingrid B.; Province, Michael A.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [de Andrade, Mariza] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Andrews, Jeanette S.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur; Smith, Albert Vernon] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor; Gudnason, Vilmundur; Smith, Albert Vernon] Univ Iceland, Reykjavik, Iceland. [Atalay, Mustafa; Lakka, Timo] Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland. [Balkau, Beverley] INSERM, Ctr Res Epidemiol & Populat Hlth, Ctr Rech Epidemiol & Sante Populat CESP, Villejuif, France. [Balkau, Beverley] Univ Paris 11, UMRS 1018, Villejuif, France. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Beckmann, Jacques S.] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. 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[Penninx, Brenda] Vrije Univ Amsterdam Med Ctr, Inst Res Extramural Med EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Pericic, Marijana] Inst Anthropol Res, Zagreb, Croatia. [Perusse, Louis] Univ Laval, Dept Prevent Med, Quebec City, PQ, Canada. [Rice, Ken] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Rudan, Igor] Univ Split, Ctr Global Hlth, Split, Croatia. [Ruokonen, Aimo] Univ Oulu, Inst Clin Med, Oulu, Finland. [Saaristo, Timo] Finnish Diabet Assoc, Tampere, Finland. [Saaristo, Timo] Pirkanmaa Hosp Dist & Diabet Ctr, Tampere, Finland. [Savage, David B.; Barroso, Ines] Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 2QQ, England. [Saxena, Richa; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Schwarz, Peter] Univ Dresden, Dept Med, Div Prevent & Care Diabet, Dresden, Germany. [Seedorf, Udo] Univ Munster, Leibniz Inst Arteriosclerosis Res, Munster, Germany. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Sijbrands, Eric J. G.; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Siscovick, David S.; Smith, Nicholas L.] Univ Washington, Dept Med, Seattle, WA USA. [Siscovick, David S.; Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Smith, Nicholas L.] Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Stumvoll, Michael; Toenjes, Anke] Univ Leipzig, Div Endocrinol & Diabet, Dept Med, Leipzig, Germany. [Sun, Yan V.] Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Tuomilehto, Jaakko] Hosp Univ La Paz, Madrid, Spain. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Uusitupa, Matti] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Uusitupa, Matti] Kuopio Univ Hosp, Res Unit, SF-70210 Kuopio, Finland. [Vohl, Marie-Claude] Univ Laval, Dept Food Sci & Nutr, Quebec City, PQ, Canada. [Vollenweider, Peter; Waeber, Gerard] CHU Vaudois, Dept Internal Med, Lausanne, Switzerland. [Zgaga, Lina] Univ Zagreb, Dept Med Stat Epidemiol & Med Informat, Zagreb 41000, Croatia. [McCarthy, Mark I.] Churchill Hosp, Oxford Natl Inst Hlth Res NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. EM jmeigs@partners.org; claudia.langenberg@mrc-epid.cam.ac.uk RI Leander, Karin/C-7261-2017; Boban, Mladen/E-2777-2017; Kolcic, Ivana/E-2713-2017; Hicks, Andrew/E-9518-2017; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; de Geus, Eco/M-9318-2015; Meitinger, Thomas/O-1318-2015; Prokopenko, Inga/H-3241-2014; Perusse, Louis/A-3444-2012; Bouchard, Claude/A-7637-2009; Smith, Albert/K-5150-2015; Kyvik, Kirsten /K-5680-2016; Hayward, Caroline/M-8818-2016; BOUATIA-NAJI, NABILA/D-5863-2013; Schwarz, Peter/B-5127-2013; Magnusson, Patrik/C-4458-2017; Aulchenko, Yurii/M-8270-2013; Altshuler, David/A-4476-2009; Lagou, Vasiliki/N-8451-2013; Corbaton-Anchuelo, Arturo/I-4390-2013; Pramstaller, Peter/C-2357-2008; Zondervan, Krina/M-1143-2013; Palmer, Lyle/K-3196-2014; Johnson, Paul/O-9695-2014; Hansson, Ola/F-1793-2011; Boehm, Bernhard/F-8750-2015; Gudnason, Vilmundur/K-6885-2015; Li, Guo/E-5613-2012; Elliott, Amanda/G-5120-2012; Strawbridge, Rona/H-5422-2012; Rudan, Igor/I-1467-2012; Gigante, Bruna/I-9252-2012; Heath, Simon/J-4138-2012; Rice, Kenneth/A-4150-2013; Hui, Jennie/A-9543-2013; Deloukas, Panos/B-2922-2013; Beckmann, Jacques S /A-9772-2008; Aspelund, Thor/C-5983-2008; Colaus, PsyColaus/K-6607-2013 OI Sabater Lleal, Maria/0000-0002-0128-379X; Eriksson, Johan/0000-0002-2516-2060; Lahti, Jari/0000-0002-4310-5297; Kaprio, Jaakko/0000-0002-3716-2455; Pankow, James/0000-0001-7076-483X; Raikkonen, Katri/0000-0003-3124-3470; Kumari, Meena/0000-0001-9716-1035; Forouhi, Nita/0000-0002-5041-248X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Chen, Han/0000-0002-9510-4923; Navarro, Pau/0000-0001-5576-8584; Jorgensen, Torben/0000-0001-9453-2830; Watkins, Hugh/0000-0002-5287-9016; Small, Kerrin/0000-0003-4566-0005; Perola, Markus/0000-0003-4842-1667; Marmot, Michael/0000-0002-2431-6419; Hide, Winston/0000-0002-8621-3271; Zgaga, Lina/0000-0003-4089-9703; Lakka, Timo/0000-0002-9199-2871; Dupuis, Josee/0000-0003-2871-3603; Franks, Paul/0000-0002-0520-7604; Sijbrands, Eric/0000-0001-8857-7389; Miljkovic, Iva/0000-0002-3155-9777; Rybin, Denis/0000-0002-3657-4829; Barnes, Daniel/0000-0002-3781-7570; Kivimaki, Mika/0000-0002-4699-5627; Johnson, Toby/0000-0002-5998-3270; Leander, Karin/0000-0002-1404-9222; Kolcic, Ivana/0000-0001-7918-6052; Hicks, Andrew/0000-0001-6320-0411; Seedorf, Udo/0000-0003-4652-5358; Shungin, Dmitry/0000-0001-7900-5856; Zeggini, Eleftheria/0000-0003-4238-659X; Bouatia-Naji, Nabila/0000-0001-5424-2134; Magi, Reedik/0000-0002-2964-6011; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; de Geus, Eco/0000-0001-6022-2666; Prokopenko, Inga/0000-0003-1624-7457; Smith, Albert/0000-0003-1942-5845; Kyvik, Kirsten /0000-0003-2981-0245; Hayward, Caroline/0000-0002-9405-9550; Schwarz, Peter/0000-0001-6317-7880; Aulchenko, Yurii/0000-0002-7899-1575; Altshuler, David/0000-0002-7250-4107; Corbaton-Anchuelo, Arturo/0000-0002-8775-4766; Zondervan, Krina/0000-0002-0275-9905; Palmer, Lyle/0000-0002-1628-3055; Johnson, Paul/0000-0001-6663-7520; Hansson, Ola/0000-0002-7394-7639; Gudnason, Vilmundur/0000-0001-5696-0084; Strawbridge, Rona/0000-0001-8506-3585; Rudan, Igor/0000-0001-6993-6884; Rice, Kenneth/0000-0001-5779-4495; Hui, Jennie/0000-0002-1653-2496; Deloukas, Panos/0000-0001-9251-070X; Beckmann, Jacques S /0000-0002-9741-1900; Aspelund, Thor/0000-0002-7998-5433; FU British Heart Foundation [RG/07/008/23674]; Chief Scientist Office [CZB/4/710]; Medical Research Council [G0100222, G0701863, G0900339, G0902037, G1002084, G19/35, G8802774, MC_PC_U127592696, MC_U106179471, MC_U106179472, MC_U127561128, MC_U127592696, MC_U137686857, MC_UP_A100_1003]; NCATS NIH HHS [UL1 TR000124]; NCRR NIH HHS [S10 RR029392]; NHLBI NIH HHS [R01 HL105756]; NIDDK NIH HHS [P30 DK063491, K24 DK080140, P30 DK020572, R01 DK072193, R01 DK078616]; NIMH NIH HHS [R37 MH059490]; Wellcome Trust [090532, 091551] NR 79 TC 236 Z9 240 U1 7 U2 80 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUN PY 2012 VL 44 IS 6 BP 659 EP U81 DI 10.1038/ng.2274 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 949BT UT WOS:000304551100012 PM 22581228 ER PT J AU Ellinor, PT Lunetta, KL Albert, CM Glazer, NL Ritchie, MD Smith, AV Arking, DE Muller-Nurasyid, M Krijthe, BP Lubitz, SA Bis, JC Chung, MK Doerr, M Ozaki, K Roberts, JD Smith, JG Pfeufer, A Sinner, MF Lohman, K Ding, JZ Smith, NL Smith, JD Rienstra, M Rice, KM Van Wagoner, DR Magnani, JW Wakili, R Clauss, S Rotter, JI Steinbeck, G Launer, LJ Davies, RW Borkovich, M Harris, TB Lin, HH Volker, U Volzke, H Milan, DJ Hofman, A Boerwinkle, E Chen, LY Soliman, EZ Voight, BF Li, G Chakravarti, A Kubo, M Tedrow, UB Rose, LM Ridker, PM Conen, D Tsunoda, T Furukawa, T Sotoodehnia, N Xu, SY Kamatani, N Levy, D Nakamura, Y Parvez, B Mahida, S Furie, KL Rosand, J Muhammad, R Psaty, BM Meitinger, T Perz, S Wichmann, HE Witteman, JCM Kao, WHL Kathiresan, S Roden, DM Uitterlinden, AG Rivadeneira, F McKnight, B Sjogren, M Newman, AB Liu, YM Gollob, MH Melander, O Tanaka, T Stricker, BHC Felix, SB Alonso, A Darbar, D Barnard, J Chasman, DI Heckbert, SR Benjamin, EJ Gudnason, V Kaab, S AF Ellinor, Patrick T. Lunetta, Kathryn L. Albert, Christine M. Glazer, Nicole L. Ritchie, Marylyn D. Smith, Albert V. Arking, Dan E. Mueller-Nurasyid, Martina Krijthe, Bouwe P. Lubitz, Steven A. Bis, Joshua C. Chung, Mina K. Doerr, Marcus Ozaki, Kouichi Roberts, Jason D. Smith, J. Gustav Pfeufer, Arne Sinner, Moritz F. Lohman, Kurt Ding, Jingzhong Smith, Nicholas L. Smith, Jonathan D. Rienstra, Michiel Rice, Kenneth M. Van Wagoner, David R. Magnani, Jared W. Wakili, Reza Clauss, Sebastian Rotter, Jerome I. Steinbeck, Gerhard Launer, Lenore J. Davies, Robert W. Borkovich, Matthew Harris, Tamara B. Lin, Honghuang Voelker, Uwe Voelzke, Henry Milan, David J. Hofman, Albert Boerwinkle, Eric Chen, Lin Y. Soliman, Elsayed Z. Voight, Benjamin F. Li, Guo Chakravarti, Aravinda Kubo, Michiaki Tedrow, Usha B. Rose, Lynda M. Ridker, Paul M. Conen, David Tsunoda, Tatsuhiko Furukawa, Tetsushi Sotoodehnia, Nona Xu, Siyan Kamatani, Naoyuki Levy, Daniel Nakamura, Yusuke Parvez, Babar Mahida, Saagar Furie, Karen L. Rosand, Jonathan Muhammad, Raafia Psaty, Bruce M. Meitinger, Thomas Perz, Siegfried Wichmann, H-Erich Witteman, Jacqueline C. M. Kao, W. H. Linda Kathiresan, Sekar Roden, Dan M. Uitterlinden, Andre G. Rivadeneira, Fernando McKnight, Barbara Sjogren, Marketa Newman, Anne B. Liu, Yongmei Gollob, Michael H. Melander, Olle Tanaka, Toshihiro Stricker, Bruno H. Ch Felix, Stephan B. Alonso, Alvaro Darbar, Dawood Barnard, John Chasman, Daniel I. Heckbert, Susan R. Benjamin, Emelia J. Gudnason, Vilmundur Kaeaeb, Stefan TI Meta-analysis identifies six new susceptibility loci for atrial fibrillation SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CHROMOSOME 4Q25; DILATED CARDIOMYOPATHY; PACEMAKER CHANNEL; COMMON VARIANTS; PR INTERVAL; CAVEOLIN-1; REPLICATION; MUTATIONS; PROTEINS AB Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death(1). We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 x 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules. C1 [Ellinor, Patrick T.; Lubitz, Steven A.; Sinner, Moritz F.; Rienstra, Michiel; Milan, David J.; Mahida, Saagar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Ellinor, Patrick T.; Milan, David J.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Ellinor, Patrick T.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Ellinor, Patrick T.; Albert, Christine M.; Tedrow, Usha B.; Ridker, Paul M.; Furie, Karen L.; Rosand, Jonathan; Chasman, Daniel I.] Harvard Univ, Sch Med, Boston, MA USA. [Lunetta, Kathryn L.; Xu, Siyan] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lunetta, Kathryn L.; Sinner, Moritz F.; Magnani, Jared W.; Levy, Daniel; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Lunetta, Kathryn L.; Sinner, Moritz F.; Magnani, Jared W.; Levy, Daniel; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Albert, Christine M.; Lubitz, Steven A.; Tedrow, Usha B.; Rose, Lynda M.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Albert, Christine M.; Tedrow, Usha B.; Ridker, Paul M.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Glazer, Nicole L.; Bis, Joshua C.; Smith, Nicholas L.; Li, Guo; Sotoodehnia, Nona; Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Ritchie, Marylyn D.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Arking, Dan E.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Mueller-Nurasyid, Martina; Sinner, Moritz F.; Wakili, Reza; Clauss, Sebastian; Steinbeck, Gerhard; Kaeaeb, Stefan] Univ Munich, Dept Med 1, Univ Hosp Grosshadern, Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Mueller-Nurasyid, Martina; Stricker, Bruno H. Ch] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Krijthe, Bouwe P.; Hofman, Albert; Witteman, Jacqueline C. M.; Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Chung, Mina K.; Smith, Jonathan D.; Van Wagoner, David R.] Cleveland Clin, Dept Cardiovasc Med, Inst Heart & Vasc, Cleveland, OH 44106 USA. [Chung, Mina K.; Van Wagoner, David R.] Cleveland Clin, Lerner Res Inst, Dept Mol Cardiol, Cleveland, OH 44106 USA. [Doerr, Marcus; Felix, Stephan B.] Ernst Moritz Arndt Univ Greifswald, Dept Internal Med B, Greifswald, Germany. [Ozaki, Kouichi; Tanaka, Toshihiro] RIKEN Ctr Genom Med, Lab Cardiovasc Dis, Kanagawa, Japan. [Roberts, Jason D.; Borkovich, Matthew; Gollob, Michael H.] Univ Ottawa, Inst Heart, Arrhythmia Res Lab, Ottawa, ON, Canada. [Smith, J. Gustav] Lund Univ, Dept Cardiol, Lund, Sweden. [Smith, J. Gustav; Voight, Benjamin F.; Kathiresan, Sekar] Broad Inst Harvard & MIT, Cambridge, MA USA. [Pfeufer, Arne; Meitinger, Thomas] German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Pfeufer, Arne; Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Lohman, Kurt] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Ding, Jingzhong] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Smith, Nicholas L.] Dept Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Smith, Nicholas L.; Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Smith, Nicholas L.; Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Jonathan D.] Cleveland Clin, Dept Cell Biol, Lerner Res Inst, Cleveland, OH 44106 USA. [Rienstra, Michiel] Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, Groningen, Netherlands. [Rice, Kenneth M.; McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Magnani, Jared W.; Lin, Honghuang; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, US NIH, Bethesda, MD 20892 USA. [Davies, Robert W.] Univ Ottawa, Inst Heart, Cardiovasc Res Methods Ctr, Ottawa, ON, Canada. [Voelker, Uwe] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Chen, Lin Y.] Univ Minnesota, Sch Med, Dept Med, Cardiac Arrhythmia Ctr,Cardiovasc Div, Minneapolis, MN 55455 USA. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. [Kubo, Michiaki] RIKEN Ctr Genom Med, Lab Genotyping Dev, Kanagawa, Japan. [Conen, David] Univ Basel Hosp, Dept Med, CH-4031 Basel, Switzerland. [Tsunoda, Tatsuhiko] RIKEN Ctr Genom Med, Lab Med Informat, Kanagawa, Japan. [Furukawa, Tetsushi] Tokyo Med & Dent Univ, Med Res Inst, Dept Bioinformat Pharmacol, Tokyo, Japan. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [Xu, Siyan; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Kamatani, Naoyuki] RIKEN Ctr Genom Med, Lab Stat Anal, Kanagawa, Japan. [Nakamura, Yusuke] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Mol Med Lab, Tokyo, Japan. [Parvez, Babar; Muhammad, Raafia; Roden, Dan M.; Darbar, Dawood] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Furie, Karen L.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Perz, Siegfried] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Neuherberg, Germany. [Wichmann, H-Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Epidemiol, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Kao, W. H. Linda] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Kao, W. H. Linda] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Roden, Dan M.] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA. [Uitterlinden, Andre G.; Rivadeneira, Fernando; Stricker, Bruno H. Ch] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Sjogren, Marketa; Melander, Olle] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA USA. [Liu, Yongmei] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Stricker, Bruno H. Ch] Inspectorate Hlth Care, The Hague, Netherlands. [Stricker, Bruno H. Ch] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Barnard, John] Cleveland Clin, Dept Quantitat Hlth Sci, Lerner Res Inst, Cleveland, OH 44106 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. [Kaeaeb, Stefan] Munich Heart Alliance, Munich, Germany. RP Ellinor, PT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. EM pellinor@partners.org; skaab@med.uni-muenchen.de RI Alonso, Alvaro/A-4917-2010; Kaab, Stefan/H-3915-2012; Rice, Kenneth/A-4150-2013; Pfeufer, Arne/B-6634-2013; Ritchie, Marylyn/C-1114-2012; Van Wagoner, David/C-6783-2008; Wakili, Reza/F-1619-2014; Newman, Anne/C-6408-2013; Tsunoda, Tatsuhiko/K-2061-2014; Darbar, Dawood/C-9079-2015; Gudnason, Vilmundur/K-6885-2015; Li, Guo/E-5613-2012; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Tanaka, Toshihiro/J-9310-2014; Kubo, Michiaki/N-7947-2015; Smith, Albert Vernon/K-5150-2015; OI Alonso, Alvaro/0000-0002-2225-8323; Rice, Kenneth/0000-0001-5779-4495; Van Wagoner, David/0000-0001-8250-9828; Newman, Anne/0000-0002-0106-1150; Darbar, Dawood/0000-0002-4103-5977; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Tanaka, Toshihiro/0000-0001-6201-9784; Lunetta, Kathryn/0000-0002-9268-810X; Lin, Honghuang/0000-0003-3043-3942; Smith, Albert Vernon/0000-0003-1942-5845; Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU NCATS NIH HHS [UL1 TR000124]; NHLBI NIH HHS [R01 HL105756, K24 HL105780, L30 HL097675, R01 HL090620, R01 HL092217, R01 HL092217-04, R01 HL104156, R21 HL106092, U19 HL065962, U19 HL065962-12]; NIDA NIH HHS [R21 DA027021] NR 30 TC 232 Z9 239 U1 2 U2 41 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2012 VL 44 IS 6 BP 670 EP U88 DI 10.1038/ng.2261 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 949BT UT WOS:000304551100013 PM 22544366 ER PT J AU Hu, JH Yang, LL Kammermeier, PJ Moore, CG Brakeman, PR Tu, JC Yu, SY Petralia, RS Li, Z Zhang, PW Park, JM Dong, XZ Xiao, B Worley, PF AF Hu, Jia-Hua Yang, Linlin Kammermeier, Paul J. Moore, Chester G. Brakeman, Paul R. Tu, Jiancheng Yu, Shouyang Petralia, Ronald S. Li, Zhe Zhang, Ping-Wu Park, Joo Min Dong, Xinzhong Xiao, Bo Worley, Paul F. TI Preso1 dynamically regulates group I metabotropic glutamate receptors SO NATURE NEUROSCIENCE LA English DT Article ID LONG-TERM DEPRESSION; X MENTAL-RETARDATION; PROTEIN-KINASES; HOMER PROTEINS; IP3 RECEPTORS; SPINAL-CORD; ACTIVATION; MICE; PLASTICITY; CHANNELS AB Group I metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, are G protein-coupled receptors (GPCRs) that are expressed at excitatory synapses in brain and spinal cord. GPCRs are often negatively regulated by specific G protein-coupled receptor kinases and subsequent binding of arrestin-like molecules. Here we demonstrate an alternative mechanism in which group I mGluRs are negatively regulated by proline-directed kinases that phosphorylate the binding site for the adaptor protein Homer, and thereby enhance mGluR-Homer binding to reduce signaling. This mechanism is dependent on a multidomain scaffolding protein, Preso1, that binds mGluR, Homer and proline-directed kinases and that is required for their phosphorylation of mGluR at the Homer binding site. Genetic ablation of Preso1 prevents dynamic phosphorylation of mGluR5, and Preso1(-/-) mice exhibit sustained, mGluR5-dependent inflammatory pain that is linked to enhanced mGluR signaling. Preso1 creates a microdomain for proline-directed kinases with broad substrate specificity to phosphorylate mGluR and to mediate negative regulation. C1 [Hu, Jia-Hua; Yang, Linlin; Moore, Chester G.; Brakeman, Paul R.; Tu, Jiancheng; Li, Zhe; Zhang, Ping-Wu; Park, Joo Min; Dong, Xinzhong; Xiao, Bo; Worley, Paul F.] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA. [Kammermeier, Paul J.] Univ Rochester, Med Ctr, Dept Pharmacol & Physiol, Rochester, NY 14642 USA. [Yu, Shouyang; Xiao, Bo] Sichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610064, Peoples R China. [Petralia, Ronald S.] US Natl Inst Hlth, Nat Inst Deafness & Other Commun Disorders, Bethesda, MD USA. [Dong, Xinzhong] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD USA. [Worley, Paul F.] Johns Hopkins Univ Hosp, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. RP Worley, PF (reprint author), Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA. EM pworley@jhmi.edu FU US National Institutes of Health from the National Institute on Drug Abuse [DA010309]; National Institute of Mental Health [MH084020]; National Institute of Neurological Disorders and Stroke [NS050274, NS054791, GM087369]; National 973 Basic Research Program of China [20009CB941400]; National Institute on Deafness and Other Communication Disorders FX We thank J. Roder of University of Toronto for Grm5-/- mice, J. Worley for help with behavioral experiments and Y.-X. Wang for help with the immunogold. This work was supported by US National Institutes of Health grants from the National Institute on Drug Abuse (DA010309), National Institute of Mental Health (MH084020) and National Institute of Neurological Disorders and Stroke (NS050274 (P.F.W.); NS054791 and GM087369 (X.D.)); National 973 Basic Research Program of China (20009CB941400; B.X.); and the National Institute on Deafness and Other Communication Disorders Intramural Research Program (R.S.P.). NR 53 TC 25 Z9 25 U1 2 U2 13 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 JUN PY 2012 VL 15 IS 6 BP 836 EP U55 DI 10.1038/nn.3103 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 949AI UT WOS:000304546700010 PM 22561452 ER PT J AU Jain, S Goldstein, DS AF Jain, Samay Goldstein, David S. TI Cardiovascular dysautonomia in Parkinson disease: From pathophysiology to pathogenesis SO NEUROBIOLOGY OF DISEASE LA English DT Review DE Parkinson disease; Orthostasis; Dysautonomia; Catecholamine; Neurodegeneration; Autonomic dysfunction; Non-motor features ID NEUROGENIC ORTHOSTATIC HYPOTENSION; MULTIPLE SYSTEM ATROPHY; SYMPATHETIC DENERVATION; AUTONOMIC FAILURE; METABOLIC STRESS; ALPHA-SYNUCLEIN; PC12 CELLS; DOPAMINE; 3,4-DIHYDROXYPHENYLACETALDEHYDE; NEURONS AB Signs or symptoms of impaired autonomic regulation of circulation often attend Parkinson disease (PD). This review covers biomarkers and mechanisms of autonomic cardiovascular abnormalities in PD and related alpha-synucleinopathies. The clearest clinical laboratory correlate of dysautonomia in PD is loss of myocardial noradrenergic innervation, detected by cardiac sympathetic neuroimaging. About 30-40% of PD patients have orthostatic hypotension (OH), defined as a persistent, consistent fall in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 3 min of change in position from supine to standing. Neuroimaging evidence of cardiac sympathetic denervation is universal in PD with OH (PD + OH). In PD without OH about half the patients have diffuse left ventricular myocardial sympathetic denervation, a substantial minority have partial denervation confined to the inferolateral or apical walls, and a small number have normal innervation. Among patients with partial denervation the neuronal loss invariably progresses over time, and in those with normal innervation at least some loss eventually becomes evident. Thus, cardiac sympathetic denervation in PD occurs independently of the movement disorder. PD + OH also entails extra-cardiac noradrenergic denervation, but this is not as severe as in pure autonomic failure. PD + OH patients have failure of both the parasympathetic and sympathetic components of the arterial baroreflex. OH in PD therefore seems to reflect a "triple whammy" of cardiac and extra-cardiac noradrenergic denervation and baroreflex failure. In contrast, most patients with multiple system atrophy, which can resemble PD + OH clinically, do not have evidence for cardiac or extra-cardiac noradrenergic denervation. Catecholamines in the neuronal cytoplasm are potentially toxic, via spontaneous and enzyme-catalyzed oxidation. Normally cytoplasmic catecholamines are efficiently taken up into vesicles via the vesicular monoamine transporter. The recent finding of decreased vesicular uptake in Lewy body diseases therefore suggests a pathogenetic mechanism for loss of catecholaminergic neurons in the periphery and brain. Parkinson disease (PD) is one of the most common chronic neurodegenerative diseases of the elderly, and it is likely that as populations age PD will become even more prevalent and more of a public health burden. Severe depletion of dopaminergic neurons of the nigrostriatal system characterizes and likely produces the movement disorder (rest tremor, slowness of movement, rigid muscle tone, and postural instability) in PD. Over the past two decades, compelling evidence has accrued that PD also involves loss of noradrenergic neurons in the heart. This finding supports the view that loss of catecholaminergic neurons, both in the nigrostriatal system and the heart, is fundamental in PD. By the time PD manifests clinically, most of the nigrostriatal dopaminergic neurons are already lost Identifying laboratory measures biomarkers of the disease process is therefore crucial for advances in treatment and prevention. Deposition of the protein, alpha-synuclein, in the form of Lewy bodies in catecholaminergic neurons is a pathologic hallmark of PD. Alpha-synucleinopathy in autonomic neurons may occur early in the pathogenetic process. The timing of cardiac noradrenergic denervation in PD is therefore a key issue. This review updates the field of autonomic cardiovascular abnormalities in PD and related disorders, with emphasis on relationships among striatal dopamine depletion, sympathetic noradrenergic denervation, and alpha-synucleinopathy. (C) 2011 Elsevier Inc. All rights reserved. C1 [Jain, Samay] Univ Pittsburgh, Med Ctr, Dept Neurol, Pittsburgh, PA 15213 USA. [Goldstein, David S.] NINDS, Clin Neurocardiol Sect, CNP, DIR,NIH, Bethesda, MD 20892 USA. RP Jain, S (reprint author), Univ Pittsburgh, Med Ctr, Dept Neurol, 3471 5th Ave,Suite 811,Kaufmann Med Bldg, Pittsburgh, PA 15213 USA. EM jains@upmc.edu; goldsteind@ninds.nih.gov FU NIA NIH HHS [P30 AG024827]; NINDS NIH HHS [K23 NS070867, K23 NS070867-01A1] NR 52 TC 67 Z9 72 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD JUN PY 2012 VL 46 IS 3 BP 572 EP 580 DI 10.1016/j.nbd.2011.10.025 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 950DK UT WOS:000304629300007 PM 22094370 ER PT J AU Moussouttas, M Lai, EW Khoury, J Huynh, TT Dombrowski, K Pacak, K AF Moussouttas, Michael Lai, Edwin W. Khoury, John Huynh, Thanh T. Dombrowski, Keith Pacak, Karel TI Determinants of Central Sympathetic Activation in Spontaneous Primary Subarachnoid Hemorrhage SO NEUROCRITICAL CARE LA English DT Article DE Subarachnoid hemorrhage; Sympathetic nervous system; Catecholamines; Cerebrospinal fluid ID HYPOTHALAMIC-STIMULATION; CEREBROSPINAL-FLUID; NERVOUS ACTIVITY; INSULAR CORTEX; DYSFUNCTION; STRESS; PLASMA; STROKE; INJURY; 3,4-DIHYDROXYPHENYLGLYCOL AB Subarachnoid hemorrhage (SAH) has been associated with pronounced acute sympathetic activation. The purpose of this investigation is to identify demographic, clinical, radiological, and anatomical features of SAH that relate to sympathetic activation. Observational study of consecutive Grades 3-5 SAH patients requiring ventriculostomy and undergoing endovascular aneurysmal obliteration. All patients underwent cerebrospinal fluid (CSF) sampling within 48 h of SAH onset, and samples were assayed for various catecholamine compounds and metabolites. Univariate analyses were performed to identify variables associated with catecholamine levels, and to correlate linearity among catecholamine compounds and metabolites. Variables demonstrating a possible association and variables of interest were entered into linear regression models to determine predictors of catecholamine elevations. Of the 102 patients, mean age was 58 years and 74% were female; 42% were Hunt-Hess (H/H) grade 4/5, 61% had a computed tomography (CT) score of 3/4, 57% had anterior cerebral or communicating artery (ACA/ACom) aneursysms, and 23% had aneurysms in the posterior circulation. In the univariate analysis, age, gender, H/H grade, CT score, and aneurysm location demonstrated various associations with catecholamine levels, and substantial positive correlations existed between the various catecholamine compounds and metabolites. Linear regression analyses revealed H/H grade to be an independent predictor of elevated CSF epinephrine (EPI), 3,4-dihydroxyphenylalanine (DOPA) and 3,4-dihydroxyphenyl acetic acid (DOPAC) levels, and of the norepinephrine/3,4-dihydroxyphenylglycol (NE/DHPG) ratio (p < 0.05 for all analyses). Female gender independently predicted increased dopamine (DA) and DOPAC levels (p < 0.05 for two analyses), as well as possibly DOPA levels (p < 0.1). Age, CT score and aneurysm location demonstrated only inconsistent associations and trends. Central sympathetic activation relates to clinical severity and female gender. No definitive associations were found for age, hemorrhage amount, or aneurysm location. C1 [Moussouttas, Michael] Thomas Jefferson Med Ctr, Dept Neurol, Cerebrovasc & Neurocrit Care Div, Philadelphia, PA 19107 USA. [Lai, Edwin W.; Huynh, Thanh T.; Pacak, Karel] NIH, Sect Med Neuroendocrinol, Reprod & Adult Endocrinol Program, Bethesda, MD 20892 USA. [Khoury, John; Dombrowski, Keith] Thomas Jefferson Med Ctr, Dept Neurol, Philadelphia, PA USA. RP Moussouttas, M (reprint author), Thomas Jefferson Med Ctr, Dept Neurol, Cerebrovasc & Neurocrit Care Div, 900 Walnut St,Suite 200, Philadelphia, PA 19107 USA. EM arista1@pol.net FU NIH/NICHD FX The authors express gratitude to the nurses of the neurological intensive care unit from the Jefferson Hospital of Neurosciences at Thomas Jefferson University Medical Center for their assistance in this project. This project represents a collaboration between the Neurocritical Care Division in the Department of Neurology at Thomas Jefferson Medical Center, and the Section on Neuroendocrinology of the Reproductive and Adult Endocrinology Program at the National Institutes of Health. This research study was supported in part by the Intramural Research Program of the NIH/NICHD. NR 33 TC 10 Z9 10 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 J9 NEUROCRIT CARE JI Neurocrit. Care PD JUN PY 2012 VL 16 IS 3 BP 381 EP 388 DI 10.1007/s12028-012-9673-5 PG 8 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA 949ZX UT WOS:000304619000006 PM 22311230 ER PT J AU Machha, A Schechter, AN AF Machha, Ajay Schechter, Alan N. TI Inorganic nitrate: a major player in the cardiovascular health benefits of vegetables? SO NUTRITION REVIEWS LA English DT Review DE cardiovascular; diet; nitrate; nitric oxide; vegetables ID CORONARY-ARTERY-DISEASE; NITRIC-OXIDE PATHWAY; DIETARY NITRATE; BLOOD-PRESSURE; ENDOTHELIAL DYSFUNCTION; HYPOXIC VASODILATION; MYOCARDIAL-ISCHEMIA; REPERFUSION INJURY; FRUIT; PHYSIOLOGY AB Epidemiological evidence suggests a higher consumption of vegetables confers a protective effect against the risk of cardiovascular disease. Impaired bioavailability of nitric oxide (NO), which is a critical regulator of vascular homeostasis, in the vasculature is thought to be a major problem in cardiovascular disease. Classically, vascular endothelium is suggested to be the sole source of bioactive NO in the vasculature. Emerging literature, however, associates the nitrate-nitrite-NO pathway, in which endogenous nitrate undergoes reduction to nitrite and then to NO in various tissues, including blood, with the production of bioactive NO. Indeed, NO generated from the nitrate-nitrite-NO pathway has recently been associated with the maintenance of NO homeostasis in the body. Endogenous nitrate originates mostly from NO oxidation in the biological milieu and from exposure to dietary nitrate. Consumption of vegetables accounts for approximately 8085% of daily nitrate exposure in humans, thereby establishing inorganic nitrate as a promising factor in the cardiovascular health benefits of vegetables. At this point in time, however, the benefit : hazard ratio of inorganic nitrate and its active metabolite nitrite remains less clear and must be studied in prospective controlled studies. This brief review discusses the potential role of inorganic dietary nitrate in the cardiovascular health benefits of vegetables. C1 [Schechter, Alan N.] NIDDKD, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Machha, Ajay] Calif Northstate Univ, Coll Pharm, Dept Pharmaceut, Rancho Cordova, CA USA. RP Schechter, AN (reprint author), NIDDKD, Mol Med Branch, NIH, Bldg 10,Room 9N314B,10 Ctr Dr, Bethesda, MD 20892 USA. EM alans@intra.niddk.nih.gov OI Schechter, Alan N/0000-0002-5235-9408 FU Intramural NIH HHS [ZIA DK025104-04] NR 57 TC 13 Z9 14 U1 1 U2 24 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0029-6643 EI 1753-4887 J9 NUTR REV JI Nutr. Rev. PD JUN PY 2012 VL 70 IS 6 BP 367 EP 372 DI 10.1111/j.1753-4887.2012.00477.x PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 949SG UT WOS:000304595600007 PM 22646129 ER PT J AU Lear, SA Chockalingam, A Kohli, S Richardson, CG Humphries, KH AF Lear, Scott A. Chockalingam, Arun Kohli, Simi Richardson, Chris G. Humphries, Karin H. TI Elevation in Cardiovascular Disease Risk in South Asians Is Mediated by Differences in Visceral Adipose Tissue SO OBESITY LA English DT Article ID BODY-FAT DISTRIBUTION; SIMPLE ANTHROPOMETRIC INDEXES; TRIAL M-CHAT; INSULIN-RESISTANCE; COMPUTED-TOMOGRAPHY; WAIST CIRCUMFERENCE; HEALTH-ASSESSMENT; CENTRAL OBESITY; METABOLIC SYNDROME; ABDOMINAL OBESITY AB South Asians have a higher risk for cardiovascular disease (CVD) that remains largely unexplained. We hypothesized that the increased CVD risk in South Asians compared to Europeans is mediated through higher levels of visceral adipose tissue (VAT) in South Asians compared to total body fat and subcutaneous abdominal adipose tissue (SAT). South Asians (207) and Europeans (201) underwent assessment for demographics, body fat, and risk factors. Linear regression models were created by sex for each risk factor to explore mediation effects of total body fat, SAT, and VAT adjusted for age, income, smoking, and BMI (menopausal status for women). Mediation was based on changes in the ethnicity p coefficient due to additional adjustment for our adipose variable of interest and the Sobel test for mediation. South Asians had worse lipid, glucose, insulin, and C-reactive protein (CRP) levels than Europeans after adjusting for confounders. Most of these differences remained even after further adjustment by either total body fat or SAT. In contrast, VAT attenuated the ethnic differences in risk factors by 16%-52%. After adjusting for VAT, there were no longer ethnic differences in total cholesterol (TC), LDL-C, TC/HDL-C, glucose, and diastolic blood pressure (BP) in men, and in HDL-C, triglycerides (TG), TC/HDL-C, and homeostasis model (HOMA) in women, and VAT was a significant mediator for these risk factors. Higher levels of risk factors for CVD in,South Asians are predominantly because of the unique phenotype of South Asians having greater VAT than Europeans even at the same BMI. C1 [Lear, Scott A.; Kohli, Simi] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Lear, Scott A.; Humphries, Karin H.] Univ British Columbia, Dept Med, Div Cardiol, Vancouver, BC, Canada. [Chockalingam, Arun] NHLBI, Off Global Hlth, Bethesda, MD 20892 USA. [Richardson, Chris G.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. RP Lear, SA (reprint author), Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. EM slear@providencehealth.bc.ca FU Canadian Institutes of Health Research: Institute of Nutrition, Metabolism and Diabetes; Michael Smith Foundation for Health Research FX This research was funded by the Canadian Institutes of Health Research: Institute of Nutrition, Metabolism and Diabetes. Dr Lear is a Canadian Institutes of Health Research New Investigator and the Pfizer/Heart & Stroke Foundation Chair in Cardiovascular Prevention Research at St. Paul's Hospital. Dr Richardson holds a Scholar Award from the Michael Smith Foundation for Health Research. NR 40 TC 23 Z9 23 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD JUN PY 2012 VL 20 IS 6 BP 1293 EP 1300 DI 10.1038/oby.2011.395 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 948QO UT WOS:000304517900029 PM 22282045 ER PT J AU Zoppoli, G Bianchi, F Bruzzone, A Calvia, A Oneto, C Passalia, C Balleari, E Bedognetti, D Ponomareva, E Nazzari, E Castelletti, L Castellan, L Minuto, F Ghio, R Ferone, D AF Zoppoli, Gabriele Bianchi, Federico Bruzzone, Andrea Calvia, Alessandro Oneto, Caterina Passalia, Caterina Balleari, Enrico Bedognetti, Davide Ponomareva, Elena Nazzari, Elena Castelletti, Lara Castellan, Lucio Minuto, Francesco Ghio, Riccardo Ferone, Diego TI Polycythemia as rare secondary direct manifestation of acromegaly: management and single-centre epidemiological data SO PITUITARY LA English DT Article DE Acromegaly; Polycythemia; Polycythemia Vera; GH; IGF-I ID GROWTH-HORMONE; RECEPTOR; VERA AB Polycythemia associated with acromegaly is usually caused by the systemic manifestations of the disease, such as sleep-apnea or concomitant erythropoietin-secreting kidney tumors. The recognition of underlying pathologies requires a thorough diagnostic process. We report a unique case of acromegaly with polycythemia, not caused by commonly described manifestations of the disease, and receding with octreotide therapy. The medical history of 141 acromegalic patients followed by the Endocrinology Unit of the San Martino University Hospital in Genoa has been also reviewed, together with the literature evidence for similar cases. The diagnostic workflow and 2-years follow-up of a 43-years old acromegalic, polycythemic man with a history of past smoking, moderate hypertension, and mental retardation are described. The hematological parameters of our cohort was retrospectively compared with those of a healthy, age/gender-related control group as well. Therapy with octreotide LAR, 20 mg i.m. q28d was begun soon after diagnosis of acromegaly in the polycythemic patient. Haematocrit level, hormonal setting, as well as pituitary tumor size and visual perimetry during treatment were recorded. Octreotide LAR treatment normalized hormonal alterations, as well as hematological parameters. Polycythemia has not recurred after 2 years of therapy. The median hemoglobin and hematocrit levels of the retrospectively analyzed cohort of acromegalic were significantly lower than normal ranges of a healthy, age/sex- related control population. In conclusions, polycythemia can be a direct, albeit rare, secondary manifestation of acromegaly, that must be considered during the diagnostic work-up of acromegalic patients presenting with such disorder. C1 [Bianchi, Federico; Nazzari, Elena; Minuto, Francesco; Ferone, Diego] Univ Genoa, Dept Endocrine & Med Sci, I-16132 Genoa, Italy. [Bianchi, Federico; Nazzari, Elena; Minuto, Francesco; Ferone, Diego] Univ Genoa, Ctr Excellence Biomed Res, I-16132 Genoa, Italy. [Zoppoli, Gabriele; Bruzzone, Andrea; Calvia, Alessandro; Oneto, Caterina; Passalia, Caterina; Balleari, Enrico; Ghio, Riccardo] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Zoppoli, Gabriele] NCI, Mol Pharmacol Lab, CCR, Natl Inst Hlth, Bethesda, MD 20892 USA. [Bedognetti, Davide] Natl Inst Hlth, Infect Dis Sect, DTM, CC, Bethesda, MD USA. [Bedognetti, Davide] Natl Inst Canc Res, Genoa, Italy. [Ponomareva, Elena] Dept Hematol, Genoa, Italy. [Ponomareva, Elena] Stem Cell Ctr, Genoa, Italy. [Castelletti, Lara; Castellan, Lucio] San Martino Hosp, Neuroradiol Unit, Genoa, Italy. RP Ferone, D (reprint author), Univ Genoa, Dept Endocrine & Med Sci, Viale Benedetto 15 6, I-16132 Genoa, Italy. EM ferone@unige.it RI Zoppoli, Gabriele/B-6935-2016; Balleari, Enrico/R-3119-2016; OI Zoppoli, Gabriele/0000-0003-3890-5588; Balleari, Enrico/0000-0003-2186-8012; Bedognetti, Davide/0000-0002-5857-773X FU Italian Minister of Instruction, University and Research [2008LFK7J5_004]; University of Genoa, Genoa, Italy FX This study was partially supported by grant from Italian Minister of Instruction, University and Research [PRIN 2008 n. 2008LFK7J5_004]. G.Z.' s Ph.D. Fellowship was sponsored by the University of Genoa, Genoa, Italy. NR 21 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1386-341X J9 PITUITARY JI Pituitary PD JUN PY 2012 VL 15 IS 2 BP 209 EP 214 DI 10.1007/s11102-011-0311-6 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 947CW UT WOS:000304405400014 PM 21503687 ER PT J AU Butler, PW Cochran, CS Merino, MJ Nguyen, DM Schrump, DS Gorden, P AF Butler, Peter W. Cochran, Craig S. Merino, Maria J. Nguyen, Dao M. Schrump, David S. Gorden, Phillip TI Ectopic growth hormone-releasing hormone secretion by a bronchial carcinoid tumor: clinical experience following tumor resection and long-acting octreotide therapy SO PITUITARY LA English DT Article DE Acromegaly; Ectopic acromegaly; Growth hormone-releasing hormone; Neuroendocrine tumor; Carcinoid; Somatostatin analogue; Octreotide ID SOMATOTROPH HYPERPLASIA; SOMATOSTATIN ANALOGS; IN-VITRO AB Acromegaly resulting from the ectopic secretion of growth hormone-releasing hormone (GHRH) is rare. We present a case of acromegaly secondary to proven GHRH-secretion by a bronchial carcinoid tumor in a type 1 diabetic subject and document the clinical course pre- and post-resection of the tumor and of subsequent octreotide therapy. A 54-year-old Caucasian man was referred for evaluation of acromegalic symptoms and significantly increased insulin requirements. He had a history of left lung surgery 20 years prior for hemoptysis. Initial laboratory results indicated acromegaly. Fasting serum growth hormone (GH): 26.1 ng/mL (0-5 ng/mL), insulin-like growth factor 1 (IGF-1): 635 ng/mL (87-283 ng/mL), GH at 60 min post-ingestion of 75 grams of oral glucose during a glucose tolerance test: 8.3 ng/mL (normal < 1 ng/mL). Pituitary magnetic resonance imaging (MRI) revealed diffuse pituitary enlargement without adenoma. A 4.4 cm left hilar mass was noted on chest computed tomography (CT) scan. Further evaluation for a suspected GHRH-secreting neuroendocrine tumor was pursued. Plasma GHRH level was elevated: 198 pg/mL (< 50 pg/mL). Octreoscan showed radiolabelled-octreotide uptake in the left lung mass and pituitary gland. Surgical resection of the lung mass was performed. Immunohistochemical study of the tumor tissue indicated a neuroendocrine tumor secreting GHRH. Postoperatively, serum GHRH, GH and IGF-1 levels fell precipitously. At 10 months, IGF-1 levels were mildly elevated and 7 months of 10 mg long-acting octreotide therapy (Sandostatin(A (R)) LAR(A (R))) was trialed. At 20 months, off octreotide, serum IGF-1 levels had normalized, acromegalic features were receding, and the patient's daily insulin requirements had decreased by 57%. C1 [Butler, Peter W.; Cochran, Craig S.; Gorden, Phillip] Natl Inst Diabet & Digest & Kidney Dis NIDDK, Clin Endocrinol Branch, Bethesda, MD USA. [Butler, Peter W.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Merino, Maria J.; Nguyen, Dao M.; Schrump, David S.] NCI, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Gorden, P (reprint author), Natl Inst Diabet & Digest & Kidney Dis NIDDK, Clin Endocrinol Branch, Bethesda, MD USA. EM phillipg@intra.niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; Eunice Kennedy Shriver National Institutes of Child Health and Human Development at the National Institutes of Health FX The authors wish to acknowledge the generous assistance of Lawrence A. Frohman, M.D., University of Illinois at Chicago, in providing the anti-GHRH antibodies used in immunohistochemical analysis. This work was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and the Eunice Kennedy Shriver National Institutes of Child Health and Human Development at the National Institutes of Health. NR 23 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1386-341X J9 PITUITARY JI Pituitary PD JUN PY 2012 VL 15 IS 2 BP 260 EP 265 DI 10.1007/s11102-010-0226-7 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 947CW UT WOS:000304405400022 PM 20379782 ER PT J AU Yu, SJ Airavaara, M Shen, H Chou, J Harvey, BK Wang, Y AF Yu, Seong-Jin Airavaara, Mikko Shen, Hui Chou, Jenny Harvey, Brandon K. Wang, Yun TI Suppression of endogenous PPAR gamma increases vulnerability to methamphetamine-induced injury in mouse nigrostriatal dopaminergic pathway SO PSYCHOPHARMACOLOGY LA English DT Article DE Methamphetamine; Dopamine; Neurodegeneration; Virus; Striatum ID ADENOASSOCIATED VIRAL VECTOR; TRANSIENT FOCAL ISCHEMIA; FREELY-MOVING RATS; PARKINSONS-DISEASE; CEREBRAL-ISCHEMIA; SUBSTANTIA-NIGRA; GENE-EXPRESSION; ROTAROD TEST; BRAIN; MODEL AB Rationale Methamphetamine is a commonly abused drug and dopaminergic neurotoxin. Repeated administration of high doses of methamphetamine induces programmed cell death, suppression of dopamine release, and reduction in locomotor activity. Previous studies have shown that pretreatment with peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist reduced methamphetamine-induced neurodegeneration. Objectives The purpose of this study was to examine the role of endogenous PPAR gamma in protecting against methamphetamine toxicity. Methods Adeno-associated virus (AAV) encoding the Cre recombinase gene was unilaterally injected into the left substantia nigra of loxP-PPAR gamma or control wild-type mice. Animals were treated with high doses of methamphetamine 1 month after viral injection. Behavioral tests were examined using rotarod and rotometer. In vivo voltammetry was used to examine dopamine release/clearance and at 2 months after methamphetamine injection. Results Administration of AAV-Cre selectively removed PPAR gamma in left nigra in loxP-PPAR gamma mice but not in the wild-type mice. The loxP-PPAR gamma/AAV-Cre mice that received methamphetamine showed a significant reduction in time on the rotarod and exhibited increased ipsilateral rotation using a rotometer. The peak of dopamine release induced by local application of KCl and the rate of dopamine clearance were significantly attenuated in the left striatum of loxP-PPAR gamma/AAV-Cre animals. Tyrosine hydroxylase immunoreactivity was reduced in the left, compared to right, nigra, and dorsal striatum in loxP-PPAR gamma/AAV-Cre mice receiving high doses of methamphetamine. Conclusion A deficiency in PPAR gamma increases vulnerability to high doses of methamphetamine. Endogenous PPAR gamma may play an important role in reducing methamphetamine toxicity in vivo. C1 [Yu, Seong-Jin; Airavaara, Mikko; Shen, Hui; Chou, Jenny; Harvey, Brandon K.; Wang, Yun] Natl Inst Drug Abuse, IRP, Neural Protect & Regenerat Sect, Baltimore, MD 21224 USA. RP Wang, Y (reprint author), Natl Inst Drug Abuse, IRP, Neural Protect & Regenerat Sect, 251 Bayview Blvd,06-721A, Baltimore, MD 21224 USA. EM ywang@intra.nida.nih.gov FU NIDA IRP FX This study was supported by NIDA IRP. We thank Dr. Barry Hoffer for his critical suggestions. NR 46 TC 6 Z9 6 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 2012 VL 221 IS 3 BP 479 EP 492 DI 10.1007/s00213-011-2595-7 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 949YT UT WOS:000304615200009 PM 22160138 ER PT J AU Jindrichova, M Kuzyk, P Li, S Stojilkovic, SS Zemkova, H AF Jindrichova, Marie Kuzyk, Pavlo Li, Shuo Stojilkovic, Stanko S. Zemkova, Hana TI Conserved ectodomain cysteines are essential for rat P2X7 receptor trafficking SO PURINERGIC SIGNALLING LA English DT Article DE Purinergic P2X receptors; ATP-gated channels; Disulfide bonds; Trafficking; BzATP ID N-LINKED GLYCOSYLATION; P2X(7) RECEPTOR; EXTRACELLULAR ATP; CELL-SURFACE; PORE FORMATION; IMMUNE CELLS; ION-CHANNEL; EXPRESSION; IDENTIFICATION; RESIDUES AB The P2X7 receptor (P2X7R) is a member of the ATP-gated ion channel family that exhibits distinct electro-physiological and pharmacological properties. This includes low sensitivity to ATP, lack of desensitization, a sustained current growth during prolonged receptor stimulation accompanied with development of permeability to large organic cations, and the coupling of receptor activation to cell blebbing and death. The uniquely long C-terminus of P2X7R accounts for many of these receptor-specific functions. The aim of this study was to understand the role of conserved ectodomain cysteine residues in P2X7R function. Single-and double-point threonine mutants of C119-C168, C129-C152, C135-C162, C216-C226, and C260-C269 cysteine pairs were expressed in HEK293 cells and studied using whole-cell current recording. All mutants other than C119T-P2X7R responded to initial and subsequent application of 300-mu M BzATP and ATP with small amplitude monophasic currents or were practically nonfunctional. The mutagenesis-induced loss of function was due to decreased cell-surface receptor expression, as revealed by assessing levels of biotinylated mutants. Coexpression of all double mutants with the wild-type receptor had a transient or, in the case of C119T/C168T double mutant, sustained inhibitory effect on receptor trafficking. The C119T-P2X7R mutant was expressed on the plasma membrane and was fully functional with a slight decrease in the sensitivity for BzATP, indicating that interaction of liberated Cys168 with another residue rescues the trafficking of receptor. Thus, in contrast to other P2XRs, all disulfide bonds of P2X7R are individually essential for the proper receptor trafficking. C1 [Jindrichova, Marie; Kuzyk, Pavlo; Zemkova, Hana] Acad Sci Czech Republic, Inst Physiol, Dept Cellular & Mol Neuroendocrinol, CR-14220 Prague, Czech Republic. [Li, Shuo; Stojilkovic, Stanko S.] NICHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD USA. RP Zemkova, H (reprint author), Acad Sci Czech Republic, Inst Physiol, Dept Cellular & Mol Neuroendocrinol, Videnska 1083, CR-14220 Prague, Czech Republic. EM zemkova@biomed.cas.cz RI Zemkova, Hana/C-1844-2012; Jindrichova, Marie/C-3401-2012; Jindrichova, Marie/H-4320-2014 FU Internal Grant Agency of Academy of Sciences [IAA500110910]; Grant Agency of the Czech Republic [305/07/0681, 305/08/H037, P304/12/P371]; Academy of Sciences of the Czech Republic [AVOZ 50110509]; Centrum for Neuroscience [LC554]; NICHD, NIH FX This study was supported by the Internal Grant Agency of Academy of Sciences (Grant No. IAA500110910), the Grant Agency of the Czech Republic (305/07/0681, 305/08/H037 and P304/12/P371), the Academy of Sciences of the Czech Republic (Research Project No. AVOZ 50110509), the Centrum for Neuroscience (Research Project No. LC554), and the Intramural Research Program of the NICHD, NIH. NR 52 TC 6 Z9 6 U1 2 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD JUN PY 2012 VL 8 IS 2 BP 317 EP 325 DI 10.1007/s11302-012-9291-x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 949QZ UT WOS:000304592200016 PM 22286664 ER PT J AU Skrok, J Shehata, ML Mathai, S Girgis, RE Zaiman, A Mudd, JO Boyce, D Lechtzin, N Lima, JAC Bluemke, DA Hassoun, PM Vogel-Claussen, J AF Skrok, Jan Shehata, Monda L. Mathai, Stephen Girgis, Reda E. Zaiman, Ari Mudd, James O. Boyce, Danielle Lechtzin, Noah Lima, Joao A. C. Bluemke, David A. Hassoun, Paul M. Vogel-Claussen, Jens TI Pulmonary Arterial Hypertension: MR Imaging-derived First-Pass Bolus Kinetic Parameters Are Biomarkers for Pulmonary Hemodynamics, Cardiac Function, and Ventricular Remodeling SO RADIOLOGY LA English DT Article ID CARDIOPULMONARY TRANSIT TIMES; MAGNETIC-RESONANCE; HEART-DISEASE; REPRODUCIBILITY; QUANTIFICATION; ANGIOGRAPHY; CAPACITANCE; PRESSURE; FIBROSIS; FAILURE AB Purpose: To prospectively compare contrast material-enhanced (CE) magnetic resonance (MR) imaging-derived right-to-left ventricle pulmonary transit time (PTT), left ventricular (LV) full width at half maximum (FWHM), and LV time to peak (TTP) between patients with pulmonary arterial hypertension (PAH) and healthy volunteers and to correlate these measurements with survival markers in patients with PAH. Materials and Methods: This HIPAA-compliant study received institutional review board approval. Written informed consent was obtained from all participants. Forty-three patients (32 with PAH [29 women; median age, 55.4 years], 11 with scleroderma but not PAH [seven women; median age, 58.9 years]) underwent right-sided heart catheterization and 3-T CE cardiac MR imaging. Eighteen age- and sex-matched healthy control subjects (12 women; median age, 51.7 years) underwent only CE MR imaging. A short-axis saturation-recovery gradient-echo section was acquired in the basal third of both ventricles, and right-to-left-ventricle PTT, LV FWHM, and LV TTP were calculated. Statistical analysis included Kruskal-Wallis test, Wilcoxon rank sum test, Spearman correlation coefficient, multiple linear regression analysis, and Lin correlation coefficient analysis. Results: Patients had significantly longer PTT (median, 8.2 seconds; 25th-75th percentile, 6.9-9.9 seconds), FWHM (median, 8.2 seconds; 25th-75th percentile, 5.7-11.4 seconds), and TTP (median, 4.8 seconds; 25th-75th percentile, 3.9-6.5 seconds) than did control subjects (median, 6.4 seconds; 25th-75th percentile, 5.7-7.1 seconds; median, 5.2 seconds; 25th-75th percentile, 4.1-6.1 seconds; median, 3.2 seconds; 25th-75th percentile, 2.8-3.8 seconds, respectively; P < .01 for each) and subjects with scleroderma but not PAH (median, 6.5 seconds; 25th-75th percentile, 5.6-7.0 seconds; median, 5.0 seconds; 25th-75th percentile, 4.0-7.3 seconds; median, 3.6 seconds; 25th-75th percentile, 2.7-4.0 seconds, respectively; P < .02 for each). PTT, LV FWHM, and LV TTP correlated with pulmonary vascular resistance index (P < .01), right ventricular stroke volume index (P <= .01), and pulmonary artery capacitance (P <= .02). In multiple linear regression models, PTT, FWHM, and TTP were associated with mean pulmonary arterial pressure and cardiac index. Conclusion: CE MR-derived PTT, LV FWHM, and LV TTP are noninvasive compound markers of pulmonary hemodynamics and cardiac function in patients with PAH. Their predictive value for patient outcome warrants further investigation. (c) RSNA, 2012 C1 [Skrok, Jan; Shehata, Monda L.; Vogel-Claussen, Jens] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Mathai, Stephen; Girgis, Reda E.; Zaiman, Ari; Boyce, Danielle; Lechtzin, Noah; Hassoun, Paul M.] Johns Hopkins Univ, Sch Med, Dept Med, Div Pulm & Crit Care Med, Baltimore, MD 21287 USA. [Mudd, James O.; Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD 21287 USA. [Vogel-Claussen, Jens] Hannover Med Sch, Dept Radiol, D-3000 Hannover, Germany. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Dept Radiol & Imaging Sci, NIH, Ctr Clin, Bethesda, MD USA. RP Vogel-Claussen, J (reprint author), Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Nelson Basement MRI 110,600 N Wolfe St, Baltimore, MD 21287 USA. EM jclauss1@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU NHLBI NIH HHS [1P50 HL084946-01, P50 HL084946] NR 35 TC 25 Z9 27 U1 0 U2 3 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUN PY 2012 VL 263 IS 3 BP 678 EP 687 DI 10.1148/radiol.12111001 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 947GK UT WOS:000304416900008 PM 22509050 ER PT J AU Gilliam, BE Ombrello, AK Burlingame, RW Pepmueller, PH Moore, TL AF Gilliam, Brooke E. Ombrello, Amanda K. Burlingame, Rufus W. Pepmueller, Peri H. Moore, Terry L. TI Measurement of Autoantibodies in Pediatric-Onset Systemic Lupus Erythematosus and Their Relationship with Disease-Associated Manifestations SO SEMINARS IN ARTHRITIS AND RHEUMATISM LA English DT Review DE systemic lupus erythematosus; anti-double-stranded DNA antibodies; anti-C1q antibodies; nephritis ID ANTI-C1Q ANTIBODY-LEVELS; PROGNOSTIC-SIGNIFICANCE; DSDNA ANTIBODIES; REVISED CRITERIA; PREDICTIVE-VALUE; CLINICAL-VALUE; NEPHRITIS; SLE; C1Q; PREVALENCE AB Objective: To evaluate an autoantibody profile in pediatric-onset systemic lupus erythematosus (SLE) patients to determine clinical and statistical associations with disease-associated manifestations. Methods: Sera from 53 SLE patients and 22 healthy individuals were collected. Antibodies to C1q, histone, chromatin, ribosomal P, dsDNA, and high-avidity dsDNA were measured by enzyme-linked immunosorbent assays. Patient records were evaluated for clinical and laboratory associations. Results: The most prevalent autoantibodies found in the SLE cohort were anti-C1q antibodies (n = 32, 60%), which correlated significantly with proteinuria and decreased complement levels (P < 0.05). Anti-C1q and antihistone antibodies were significantly elevated in patients with class III/IV nephritis compared with class I/II/V nephritis (P = 0.041). SLE patients with active nephritis at the time of sample collection demonstrated significantly elevated levels of anti-C1q antibodies compared with those without active nephritis, also exhibiting 100% sensitivity for active nephritis, proteinuria, and urinary casts. Antibodies to Gig, dsDNA, histone, and chromatin were significantly elevated in patients with active disease (P < 0.01). Chart-documented anti-dsDNA antibodies were positive in 28 SLE patients, INOVA anti-dsDNA antibodies in 25 patients, and high-avidity anti-dsDNA antibodies in 8 patients. Antihistone correlated significantly with leukopenia and hemolytic anemia (P < 0.05). Conclusions: This study indicates the importance of measuring anti-C1q antibodies in pediatric-onset SLE patients because elevated anti-C1q antibodies may be more indicative of renal disease activity, showing significant correlation with proteinuria, urinary casts, and active nephritis. Antibodies to C1q, histone, chromatin, and dsDNA exhibited the strongest association with clinical features, indicating the importance of measuring all of these antibodies in pediatric-onset SLE patients. (C) 2012 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:840-848 C1 [Gilliam, Brooke E.; Moore, Terry L.] St Louis Univ, Sch Med, Div Adult & Pediat Rheumatol, St Louis, MO 63104 USA. [Ombrello, Amanda K.] NHGRI, NIH, Bethesda, MD 20892 USA. [Burlingame, Rufus W.] INOVA Diagnost Inc, Technol & Dev, San Diego, CA USA. RP Moore, TL (reprint author), St Louis Univ, Sch Med, Div Adult & Pediat Rheumatol, Room 211A Doisy Hall,1402 S Grand Blvd, St Louis, MO 63104 USA. EM mooretl@slu.edu FU Campbell-Avery Charitable Trust; Dorr Family Charitable Trust; Lupus/Juvenile Arthritis Research Groups of St. Louis FX Funding was provided by Campbell-Avery Charitable Trust, the Dorr Family Charitable Trust, and the Lupus/Juvenile Arthritis Research Groups of St. Louis. NR 46 TC 8 Z9 9 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0049-0172 EI 1532-866X J9 SEMIN ARTHRITIS RHEU JI Semin. Arthritis Rheum. PD JUN PY 2012 VL 41 IS 6 BP 840 EP 848 DI 10.1016/j.semarthrit.2011.09.009 PG 9 WC Rheumatology SC Rheumatology GA 950XL UT WOS:000304685100010 PM 22177108 ER PT J AU Hong, CW Luckey, MA Park, JH AF Hong, Changwan Luckey, Megan A. Park, Jung-Hyun TI Intrathymic IL-7: The where, when, and why of IL-7 signaling during T cell development SO SEMINARS IN IMMUNOLOGY LA English DT Review DE Thymus; IL-7 receptor; Thymocytes; SOCS; Positive selection ID RECEPTOR-DEFICIENT MICE; DEFECTIVE LYMPHOID DEVELOPMENT; DOUBLE-POSITIVE THYMOCYTES; INTERLEUKIN-7 RECEPTOR; IN-VIVO; HOMEOSTATIC PROLIFERATION; TRANSCRIPTION FACTORS; GENE REARRANGEMENT; LACKING JAK3; GAMMA CHAIN AB The thymus is the birthplace of all T lineage cells. But the thymus is also a cradle as it provides the environment for further maturation and differentiation of immature thymocytes. While many factors contribute to make the thymus a unique place for T cell development, here we review the essential role of intrathymic interleukin-7 (IL-7). In the absence of IL-7 signaling, survival, proliferation and differentiation of immature thymocytes are all severely impaired. Consequently, IL-7 is critical to nurture and guide T precursor cells through the diverse steps of thymic maturation. Interestingly, even as IL-7 signaling is such a critical factor, IL-7 signaling must be also actively suppressed during specific stages of T cell differentiation. These contradictory observations are puzzling but can be satisfactorily explained when understanding the developmental context of IL-7 signaling. In this regard, here we will discuss the spatiotemporal expression of intrathymic IL-7 and address the stage-specific effects of IL-7 signaling in developing thymocytes. Specifically, we will review other facets of intrathymic IL-7 beyond its role as a pro-survival factor and so clarify and reaffirm the unique role of IL-7 as a prime factor in T cell development and differentiation. Published by Elsevier Ltd. C1 [Hong, Changwan; Luckey, Megan A.; Park, Jung-Hyun] NCI, Exp Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Park, JH (reprint author), Bldg 10,Room 5B17,10 Ctr Dr, Bethesda, MD 20892 USA. EM parkhy@mail.nih.gov RI Park, Jung Hyun /B-5712-2015; Davis, Megan/F-5339-2015 OI Park, Jung Hyun /0000-0002-9547-9055; FU US National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We are grateful to Dr. Alfred Singer and Dr. James Di Santo for insightful discussions and critical review of this manuscript. This study was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 106 TC 19 Z9 22 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD JUN PY 2012 VL 24 IS 3 BP 151 EP 158 DI 10.1016/j.smim.2012.02.002 PG 8 WC Immunology SC Immunology GA 949OA UT WOS:000304584300002 PM 22421571 ER PT J AU Lundstrom, W Fewkes, NM Mackall, CL AF Lundstroem, Wangko Fewkes, Natasha M. Mackall, Crystal L. TI IL-7 in human health and disease SO SEMINARS IN IMMUNOLOGY LA English DT Review DE Interleukin-7; Interleukin-7 receptor; Cancer; Autoimmunity ID ACUTE LYMPHOBLASTIC-LEUKEMIA; VERSUS-HOST-DISEASE; SEVERE COMBINED IMMUNODEFICIENCY; IMMATURE/TRANSITIONAL B-CELLS; BONE-MARROW TRANSPLANT; T-CELL; IN-VIVO; INTERLEUKIN-7 RECEPTOR; HOMEOSTATIC PROLIFERATION; MULTIPLE-SCLEROSIS AB IL-7 plays many essential roles in human health and disease. Congenital deficiencies in IL-7 signaling result in profound immunodeficiency, polymorphisms in IL7R alpha modulate susceptibility to autoimmune disease, and acquired somatic activating mutations in IL7R alpha contribute to neoplastic transformation in B cell and T cell leukemia. In response to lymphopenia, IL-7 accumulates to supranormal levels, which alters T cell homeostasis by augmenting T cell reactivity toward self and cognate antigens. This physiologic response is now routinely exploited to improve the efficacy of adoptive cell therapies for cancer. Clinical trials of recombinant IL-7 have demonstrated safety and potent immunorestorative effects, and current studies are investigating whether rhIL-7 therapy can improve outcomes in chronic viral infection and in the context of cancer immunotherapies. Building upon the large fund of knowledge regarding the basic biology of IL-7, this review will discuss the many and varied roles of IL-7 in human health and disease. Published by Elsevier Ltd. C1 [Lundstroem, Wangko; Fewkes, Natasha M.; Mackall, Crystal L.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM lundstromwp@mail.nih.gov; fewkesnm@mail.nih.gov; mackallc@mail.nih.gov FU Intramural NIH HHS [Z01 BC011069-01] NR 92 TC 40 Z9 40 U1 0 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD JUN PY 2012 VL 24 IS 3 BP 218 EP 224 DI 10.1016/j.smim.2012.02.005 PG 7 WC Immunology SC Immunology GA 949OA UT WOS:000304584300009 PM 22410365 ER PT J AU Mazzucchelli, RI Riva, A Durum, SK AF Mazzucchelli, Renata I. Riva, Agostino Durum, Scott K. TI The human IL-7 receptor gene: Deletions, polymorphisms and mutations SO SEMINARS IN IMMUNOLOGY LA English DT Review DE IL-7R; IL-7; T244I ID ACUTE LYMPHOBLASTIC-LEUKEMIA; SEVERE COMBINED IMMUNODEFICIENCY; INFLAMMATORY-BOWEL-DISEASE; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; INTERLEUKIN-7 TRANSGENIC MICE; MULTIPLE-SCLEROSIS PATIENTS; GENOME-WIDE ASSOCIATION; OF-FUNCTION MUTATIONS; T-CELL DEVELOPMENT; CHRONIC COLITIS AB Most T cell subsets depend on IL-7 for survival. IL-7 binds to IL-7R alpha and gamma c, initiating the signaling cascade. Deletion of IL-7Ra in humans has, for some time, been known to cause severe combined immunodeficiency. More recently, polymorphisms in IL-7R have been shown be a risk factor for a number of diseases that are autoimmune or involve excess immune and inflammatory responses including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, primary biliary cirrhosis, inflammatory bowel disease, atopic dermatitis, inhalation allergy, sarcoidosis and graft-versus host disease. The polymorphism that affects risk to most of these immunopathologies is T244I at the border of the extracellular domain and the transmembrane region. The same region has recently been shown to harbor gain-of-function mutations in acute lymphoblastic leukemia. These studies have suggested new therapies that target the IL-7 pathway. Published by Elsevier Ltd. C1 [Durum, Scott K.] NCI, Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21701 USA. [Mazzucchelli, Renata I.] San Raffaele Telethon Inst Gene Therapy, Lab Gene Therapy & Primary Immunodeficiency, I-20132 Milan, Italy. [Riva, Agostino] Univ Milan, Infect Dis & Immunopathol Sect, DISC L Sacco Hosp, I-20157 Milan, Italy. RP Durum, SK (reprint author), NCI, Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21701 USA. EM durums@mail.nih.gov NR 100 TC 15 Z9 15 U1 1 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD JUN PY 2012 VL 24 IS 3 BP 225 EP 230 DI 10.1016/j.smim.2012.02.007 PG 6 WC Immunology SC Immunology GA 949OA UT WOS:000304584300010 PM 22425228 ER PT J AU Schlom, J Hodge, JW AF Schlom, Jeffrey Hodge, James W. TI Introduction: Therapeutic Cancer Vaccines SO SEMINARS IN ONCOLOGY LA English DT Editorial Material C1 [Schlom, Jeffrey; Hodge, James W.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 0 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD JUN PY 2012 VL 39 IS 3 BP 243 EP 244 PG 2 WC Oncology SC Oncology GA 948KW UT WOS:000304503100001 PM 22595046 ER PT J AU Madan, RA Bilusic, M Heery, C Schlom, J Gulley, JL AF Madan, Ravi A. Bilusic, Marijo Heery, Christopher Schlom, Jeffrey Gulley, James L. TI Clinical Evaluation of TRICOM Vector Therapeutic Cancer Vaccines SO SEMINARS IN ONCOLOGY LA English DT Review ID RESISTANT PROSTATE-CANCER; LONG-TERM SURVIVAL; CYCLOOXYGENASE-2 INHIBITOR CELECOXIB; METASTATIC COLORECTAL-CANCER; COLONY-STIMULATING FACTOR; ANTIGEN-PRESENTING CELLS; RANDOMIZED PHASE-II; CARCINOEMBRYONIC ANTIGEN; HEPATIC RESECTION; COSTIMULATORY MOLECULES C1 [Schlom, Jeffrey] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09,MSC 1750, Bethesda, MD 20892 USA. EM schlomj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Center for Cancer Research, National Cancer Institute (NCI), NIH FX The authors are supported by funds from the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), NIH. In addition, there is a Collaborative Research and Development Agreement between the NCI/Laboratory of Tumor Immunology and Biology (LTIB) and Bavarian Nordic. Dr. Schlom is an inventor on several patents and patent applications related to therapeutic cancer vaccines. NR 67 TC 38 Z9 38 U1 0 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD JUN PY 2012 VL 39 IS 3 BP 296 EP 304 DI 10.1053/j.seminoncol.2012.02.010 PG 9 WC Oncology SC Oncology GA 948KW UT WOS:000304503100007 PM 22595052 ER PT J AU Hodge, JW Ardiani, A Farsaci, B Kwilas, AR Gameiro, SR AF Hodge, James W. Ardiani, Andressa Farsaci, Benedetto Kwilas, Anna R. Gameiro, Sofia R. TI The Tipping Point for Combination Therapy: Cancer Vaccines With Radiation, Chemotherapy, or Targeted Small Molecule Inhibitors SO SEMINARS IN ONCOLOGY LA English DT Review ID MEDIATED ANTITUMOR IMMUNITY; RENAL-CELL CARCINOMA; T-REGULATORY CELLS; INDUCED LEUKOCYTE ADHESION; TYROSINE KINASE INHIBITOR; LOW-DOSE CYCLOPHOSPHAMIDE; COLONY-STIMULATING FACTOR; METASTATIC BREAST-CANCER; CONTROLLED PHASE-III; TUMOR-CELLS C1 [Hodge, James W.; Ardiani, Andressa; Farsaci, Benedetto; Kwilas, Anna R.; Gameiro, Sofia R.] NCI, Recombinant Vaccine Grp, Tumor Immunol & Biol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Hodge, JW (reprint author), NCI, Recombinant Vaccine Grp, Tumor Immunol & Biol Lab, Ctr Canc Res,NIH, 10 Ctr Dr,Room 8B13, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Farsaci, Benedetto/L-9837-2014; Hodge, James/D-5518-2015 OI Farsaci, Benedetto/0000-0001-8275-2561; Hodge, James/0000-0001-5282-3154 FU Intramural NIH HHS [Z01 BC010661-03, Z01 BC010661-04, Z99 CA999999]; NCI NIH HHS [Z01 BC010661-04] NR 116 TC 52 Z9 55 U1 0 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD JUN PY 2012 VL 39 IS 3 BP 323 EP 339 DI 10.1053/j.seminoncol.2012.02.006 PG 17 WC Oncology SC Oncology GA 948KW UT WOS:000304503100010 PM 22595055 ER PT J AU Berzofsky, JA Terabe, M Wood, LV AF Berzofsky, Jay A. Terabe, Masaki Wood, Lauren V. TI Strategies to Use Immune Modulators in Therapeutic Vaccines Against Cancer SO SEMINARS IN ONCOLOGY LA English DT Review ID GROWTH-FACTOR-BETA; T-CELL-RECEPTOR; COLONY-STIMULATING FACTOR; ALTERNATE READING FRAME; HIGH-AVIDITY CTL; TUMOR IMMUNOSURVEILLANCE; MYELOID CELLS; BREAST-CANCER; REGULATORY T; PROSTATE-CANCER C1 [Berzofsky, Jay A.] NCI, Vaccine Branch, CCR, NIH, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Vaccine Branch, CCR, NIH, Bldg 10,Room 6B-04,10 Ctr Dr, Bethesda, MD 20892 USA. EM berzofsj@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD FX Supported by funds of the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. NR 96 TC 19 Z9 20 U1 1 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD JUN PY 2012 VL 39 IS 3 BP 348 EP 357 DI 10.1053/j.seminoncol.2012.02.002 PG 10 WC Oncology SC Oncology GA 948KW UT WOS:000304503100012 PM 22595057 ER PT J AU Hamilton, DH Litzinger, MT Fernando, RI Huang, B Palena, C AF Hamilton, Duane H. Litzinger, Mary T. Fernando, Romaine I. Huang, Bruce Palena, Claudia TI Cancer Vaccines Targeting the Epithelial-Mesenchymal Transition: Tissue Distribution of Brachyury and Other Drivers of the Mesenchymal-Like Phenotype of Carcinomas SO SEMINARS IN ONCOLOGY LA English DT Review ID E-CADHERIN EXPRESSION; RESISTANT PROSTATE-CANCER; TRANSCRIPTION FACTOR SLUG; STEM-CELLS; ALDEHYDE DEHYDROGENASE; TRANSGENIC ADENOCARCINOMA; TUMOR PROGRESSION; BREAST-CARCINOMA; PROGENITOR CELLS; SNAIL C1 [Hamilton, Duane H.; Litzinger, Mary T.; Fernando, Romaine I.; Huang, Bruce; Palena, Claudia] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Palena, C (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B14,MSC 1750, Bethesda, MD 20892 USA. EM palenac@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 63 TC 24 Z9 24 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD JUN PY 2012 VL 39 IS 3 BP 358 EP 366 DI 10.1053/j.seminoncol.2012.02.005 PG 9 WC Oncology SC Oncology GA 948KW UT WOS:000304503100013 PM 22595058 ER PT J AU Beason-Held, LL Thambisetty, M Deib, G Sojkova, J Landman, BA Zonderman, AB Ferrucci, L Kraut, MA Resnick, SM AF Beason-Held, Lori L. Thambisetty, Madhav Deib, Gerard Sojkova, Jitka Landman, Bennett A. Zonderman, Alan B. Ferrucci, Luigi Kraut, Michael A. Resnick, Susan M. TI Baseline Cardiovascular Risk Predicts Subsequent Changes in Resting Brain Function SO STROKE LA English DT Article DE aging; cholesterol; diabetes; hypertension; positron emission tomography ID CEREBRAL-BLOOD-FLOW; ALZHEIMERS-DISEASE; COGNITIVE IMPAIRMENT; LONGITUDINAL CHANGES; MATTER VOLUME; OLDER-ADULTS; DEMENTIA; CORTEX; MRI; VASOREACTIVITY AB Background and Purpose-The Framingham Heart Study group cardiovascular disease risk profile (FCRP) score was used to assess the relationship between baseline cardiovascular risk and subsequent changes in resting state cerebral blood flow (CBF) in cognitively normal older participants from the Baltimore Longitudinal Study of Aging. Methods-Ninty-seven cognitively normal participants underwent annual resting-state positron emission tomography scans at baseline and over a period of up to 8 years (mean interval, 7.4 years). Images quantifying voxel-wise longitudinal rates of CBF change were calculated and used to examine the relationship between baseline FCRP score and changes over time in regional CBF. Individual components of the FCRP score (age, cholesterol, blood pressure, smoking status, and type 2 diabetes) were also correlated with changes in regional CBF to examine the independent contributions of each component to the overall pattern of change. Results-Higher baseline FCRP scores were associated with accelerated longitudinal decline in CBF in orbitofrontal, medial frontal/anterior cingulate, insular, precuneus, and brain stem regions. Of the components that comprise the FCRP score, higher diastolic blood pressure and diabetes were associated independently with greater decline in the medial frontal/anterior cingulate and insular regions, respectively. Conclusions-Baseline cardiovascular risk factors are associated with greater rates of decline in resting state regional brain function. The regions showing accelerated decline participate in higher-order cognitive processes and are also vulnerable to age-related neuropathology. These results, in conjunction with other studies, encourage early treatment of cardiovascular risk factors in older individuals. (Stroke. 2012; 43: 1542-1547.) C1 [Beason-Held, Lori L.; Thambisetty, Madhav; Sojkova, Jitka; Zonderman, Alan B.; Ferrucci, Luigi; Resnick, Susan M.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Deib, Gerard; Sojkova, Jitka; Kraut, Michael A.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Landman, Bennett A.] Vanderbilt Univ, Dept Elect Engn, Nashville, TN 37235 USA. RP Beason-Held, LL (reprint author), NIA LBN, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM heldlo@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institutes of Health, National Institute on Aging; Research and Development Contract [N01-AG-3-2124]; National Institute on Aging [N01-AG-3-2124] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging and by Research and Development Contract N01-AG-3-2124.; Drs Sojkova and Kraut receive salary support from National Institute on Aging Research and Development Contract N01-AG-3-2124. NR 45 TC 13 Z9 13 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2012 VL 43 IS 6 BP 1542 EP 1547 DI 10.1161/STROKEAHA.111.638437 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 948SV UT WOS:000304523800023 PM 22492519 ER PT J AU Fiebach, JB Al-Rawi, Y Wintermark, M Furlan, AJ Rowley, HA Lindsten, A Smyej, J Eng, P Warach, S Pedraza, S AF Fiebach, Jochen B. Al-Rawi, Yasir Wintermark, Max Furlan, Anthony J. Rowley, Howard A. Lindsten, Annika Smyej, Jamal Eng, Paul Warach, Steven Pedraza, Salvador TI Vascular Occlusion Enables Selecting Acute Ischemic Stroke Patients for Treatment With Desmoteplase SO STROKE LA English DT Article DE computed tomography angiography; desmoteplase; magnetic resonance angiography; occlusion; stroke ID TISSUE-PLASMINOGEN-ACTIVATOR; ACUTE HEMISPHERIC STROKE; THROMBOLYSIS; MRI; RECANALIZATION; ANGIOGRAPHY; CRITERIA; TRIAL AB Background and Purpose-Desmoteplase is a novel and highly fibrin-specific thrombolytic agent. Evidence of safety and efficacy was obtained in 2 phase II trials (Desmoteplase In Acute Ischemic Stroke [DIAS] and Desmoteplase for Acute Ischemic Stroke [DEDAS]). The DIAS-2 phase III trial did not replicate the positive phase II efficacy findings. Post hoc analyses were performed with the aim of predicting treatment responders based on CTA and MRA. Methods-Patients were grouped according to vessel status (Thrombolysis In Myocardial Infarction [TIMI] grade) for logistic regression of clinical response, applying the data from DIAS-2 as well as the pooled data from DIAS, DEDAS, and DIAS-2. Results-In DIAS-2, a substantial number of mismatch-selected patients (126/179; 70%) presented with a normal flow/low-grade stenosis (TIMI 2-3) at screening, with the majority having a favorable outcome at day 90. In contrast, favorable outcome rates in patients with vessel occlusion/high-grade stenosis (TIMI 0-1) were 18% with placebo versus 36% and 27% with desmoteplase 90 and 125 mu g/kg, respectively. The clinical effect based on the pooled data from DIAS, DEDAS, and DIAS-2 was favorable for desmoteplase-treated patients presenting with TIMI 0 to 1 at baseline (OR, 4.144; 95% CI, 1.40-12.23; P = 0.010). There was no desmoteplase treatment benefit in patients presenting with TIMI 2 to 3 (OR, 1.109). Conclusions-In this sample of patients with a mismatch diagnosed, proximal vessel occlusion or severe stenosis was associated with clinically beneficial treatment effects of desmoteplase. Selecting patients using CTA or MRA in clinical trials of thrombolytic therapy is justifiable. C1 [Fiebach, Jochen B.] Charite, Ctr Stroke Res Berlin, D-12200 Berlin, Germany. [Al-Rawi, Yasir] Signen Biomed Consulting FZE, Abu Dhabi, U Arab Emirates. [Furlan, Anthony J.] Case Western Reserve Univ, Dept Neurol, Univ Hosp Case Med Ctr, Neurol Inst, Cleveland, OH 44106 USA. [Rowley, Howard A.] Univ Wisconsin, Dept Radiol, Madison, WI 53706 USA. [Lindsten, Annika; Smyej, Jamal] H Lundbeck & Co AS, Valby, Denmark. [Eng, Paul] Forest Res Inst, Jersey City, NJ USA. [Warach, Steven] NINDS, Bethesda, MD 20892 USA. [Pedraza, Salvador] IDI Hosp Dr Josep Trueta de Girona, Dept Radiol, Girona, Spain. RP Fiebach, JB (reprint author), Charite, Ctr Stroke Res Berlin CSB, Dept Neurol, Hindenburgdamm 30, D-12200 Berlin, Germany. EM jochen.fiebach@charite.de OI Fiebach, Jochen B./0000-0002-7936-6958; Wintermark, Max/0000-0002-6726-3951 FU H. Lundbeck A/S, Valby, Denmark FX Supported, in part, by H. Lundbeck A/S, Valby, Denmark. NR 22 TC 46 Z9 46 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2012 VL 43 IS 6 BP 1561 EP 1566 DI 10.1161/STROKEAHA.111.642322 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 948SV UT WOS:000304523800026 PM 22474060 ER PT J AU Siberry, GK Williams, PL Mendez, H Seage, GR Jacobson, DL Hazra, R Rich, KC Griner, R Tassiopoulos, K Kacanek, D Mofenson, LM Miller, T DiMeglio, LA Watts, DH AF Siberry, George K. Williams, Paige L. Mendez, Hermann Seage, George R., III Jacobson, Denise L. Hazra, Rohan Rich, Kenneth C. Griner, Raymond Tassiopoulos, Katherine Kacanek, Deborah Mofenson, Lynne M. Miller, Tracie DiMeglio, Linda A. Watts, D. Heather CA PHACS TI Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants SO AIDS LA English DT Article; Proceedings Paper CT 18th International AIDS Conference CY JUL 13-23, 2010 CL Vienna, AUSTRIA DE antiretroviral drugs; infant growth; perinatal HIV exposure; pregnancy; tenofovir disoproxil fumarate ID OPTIMIZED BACKGROUND REGIMEN; BONE-MINERAL DENSITY; DISOPROXIL FUMARATE; ANTIRETROVIRAL TREATMENT; ABACAVIR-LAMIVUDINE; PERINATAL EXPOSURE; NUCLEOSIDE ANALOGS; SALVAGE THERAPY; RHESUS MACAQUES; INFECTED WOMEN AB Objective: To evaluate the association of tenofovir disoproxil fumarate (TDF) use during pregnancy with early growth parameters in HIV-exposed, uninfected (HEU) infants. Design: US-based prospective cohort study of HEU children to examine potential adverse effects of prenatal TDF exposure. Methods: We evaluated the association of maternal TDF use during pregnancy with small for gestational age (SGA); lowbirth weight (LBW, <2.5 kg); weight-for-age z-scores (WAZ), length-for-age z-scores (LAZ), and head circumference-for-age (HCAZ) z-scores at newborn visit; and LAZ, HCAZ, and WAZ at age 1 year. Logistic regression models for LBW and SGA were fit, adjusting for maternal and sociodemographic factors. Adjusted linear regression models were used to evaluate LAZ, WAZ, and HCAZ by TDF exposure. Results: Of 2029 enrolled children with maternal antiretroviral information, TDF was used by 449 (21%) HIV-infected mothers, increasing from 14% in 2003 to 43% in 2010. There was no difference between those exposed to combination regimens with vs. without TDF for SGA, LBW, and newborn LAZ and HCAZ. However, at age 1 year, infants exposed to combination regimens with TDF had significantly lower adjusted mean LAZ and HCAZ than those without TDF (LAZ: -0.17 vs. -0.03, P = 0.04; HCAZ: 0.17 vs. 0.42, P = 0.02). Conclusion: TDF use during pregnancy was not associated with increased risk for LBW or SGA. The slightly lower mean LAZ and HCAZ observed at age 1 year in TDF-exposed infants are of uncertain significance but underscore the need for additional studies of growth outcomes after TDF use during pregnancy. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Siberry, George K.; Hazra, Rohan; Mofenson, Lynne M.; Watts, D. Heather] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent Maternal AIDS Branch, NIH, Bethesda, MD USA. [Williams, Paige L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Mendez, Hermann] SUNY Downstate, Dept Pediat, Brooklyn, NY USA. [Seage, George R., III; Tassiopoulos, Katherine] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Williams, Paige L.; Jacobson, Denise L.; Griner, Raymond; Kacanek, Deborah] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Rich, Kenneth C.; Miller, Tracie] Univ Miami, Miller Sch Med, Dept Pediat, Div Pediat Clin Res, Miami, FL 33136 USA. [DiMeglio, Linda A.] Indiana Univ Sch Med, Dept Pediat, Sect Pediat Endocrinol & Diabetol, Indianapolis, IN USA. RP Siberry, GK (reprint author), 6100 Execut Blvd, Bethesda, MD 20892 USA. EM siberryg@mail.nih.gov OI Mofenson, Lynne/0000-0002-2818-9808; DiMeglio, Linda/0000-0002-8033-6078 FU Intramural NIH HHS [Z99 HD999999]; NICHD NIH HHS [U01 HD052102, U01 HD052102-04, U01 HD052104, U01 HD052104-01] NR 28 TC 67 Z9 69 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 1 PY 2012 VL 26 IS 9 BP 1151 EP 1159 DI 10.1097/QAD.0b013e328352d135 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 946PK UT WOS:000304364900011 PM 22382151 ER PT J AU Thapa, DR Bhatia, K Bream, JH D'Souza, G Rinaldo, CR Wolinsky, S Detels, R Martinez-Maza, O AF Thapa, Dharma R. Bhatia, Kishor Bream, Jay H. D'Souza, Gypsyamber Rinaldo, Charles R. Wolinsky, Steven Detels, Roger Martinez-Maza, Otoniel TI B-cell activation induced microRNA-21 is elevated in circulating B cells preceding the diagnosis of AIDS-related non-Hodgkin lymphomas SO AIDS LA English DT Article ID SERUM-LEVELS; EXPRESSION; INFECTION; LEUKEMIA; DISEASE AB We show that microRNA-21 is significantly elevated in peripheral B cells of HIV-infected individuals who go on to develop AIDS-related non-Hodgkin lymphoma (n=13, <3 years prior to diagnosis) when compared with HIV-negative (n=18) or HIV-positive controls (n=21) (P<0.01). Moreover, miR-21 is overexpressed in activated B cells and can be induced by interleukin 4 alone, or with CD40 or immunoglobulin M co-stimulation, and lipopolysaccharides, suggesting that miR-21 may help maintain B-cell hyperactivation, contributing to lymphomagenesis. C1 [Detels, Roger; Martinez-Maza, Otoniel] Univ Calif Los Angeles, UCLA AIDS Inst, UCLA Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. [Detels, Roger; Martinez-Maza, Otoniel] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Thapa, Dharma R.; Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA. [Thapa, Dharma R.; Martinez-Maza, Otoniel] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Bhatia, Kishor] NCI, Bethesda, MD 20892 USA. [Bream, Jay H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Rinaldo, Charles R.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Infect Dis & Microbiol, Pittsburgh, PA 15261 USA. [Wolinsky, Steven] Northwestern Univ, Div Infect Dis, Feinberg Sch Med, Chicago, IL 60611 USA. RP Martinez-Maza, O (reprint author), Univ Calif Los Angeles, UCLA AIDS Inst, UCLA Sch Publ Hlth, Dept Epidemiol, 173 BSRB,615 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM omartinez@mednet.ucla.edu RI Wolinsky, Steven/B-2893-2012; Thapa, Dharma/C-2854-2012; Martinez-Maza, Otoniel/B-2667-2009; OI Martinez-Maza, Otoniel/0000-0003-1364-0675; Wolinsky, Steven/0000-0002-9625-6697 FU Margaret E. Early Trust; National Institute of Health (NCI) [U01-AI35040, R01-CA57152, P30-AI28697]; California HIV/AIDS Research Program [D08-LA-311]; James B. Pendleton Charitable Trust; McCarthy Family Foundation; NIH [AI-028697: UCLA] FX This work was supported by grants from the Margaret E. Early Trust, the National Institute of Health (NCI supplement to U01-AI35040, R01-CA57152, P30-AI28697), and fellowship support from California HIV/AIDS Research Program (D08-LA-311) to D. R. T. This work was carried out in the facilities of the UCLA AIDS Institute, which were supported, in part, by funds from the James B. Pendleton Charitable Trust and the McCarthy Family Foundation, and by NIH grant AI-028697: UCLA Center for AIDS Research (CFAR). NR 25 TC 14 Z9 17 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 1 PY 2012 VL 26 IS 9 BP 1177 EP 1180 DI 10.1097/QAD.0b013e3283543e0e PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 946PK UT WOS:000304364900016 PM 22487708 ER PT J AU Goldspiel, BR AF Goldspiel, Barry R. TI Oncology pharmacy practice as a model for international collaborations SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article C1 [Goldspiel, Barry R.] NIH, Clin Pharm Specialist Sect, Dept Pharm, Bethesda, MD 20892 USA. [Goldspiel, Barry R.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. RP Goldspiel, BR (reprint author), NIH, Clin Pharm Specialist Sect, Dept Pharm, Bldg 10,Room 1C-240, Bethesda, MD 20892 USA. EM bgoldspiel@nih.gov NR 15 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD JUN 1 PY 2012 VL 69 IS 11 BP 951 EP 957 DI 10.2146/ajhp110739 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 948IX UT WOS:000304497900014 PM 22610027 ER PT J AU Mbulaiteye, SM Anderson, WF Ferlay, J Bhatia, K Chang, C Rosenberg, PS Devesa, SS Parkin, DM AF Mbulaiteye, Sam M. Anderson, William F. Ferlay, Jacques Bhatia, Kishor Chang, Cindy Rosenberg, Philip S. Devesa, Susan S. Parkin, Donald M. TI Pediatric, elderly, and emerging adult-onset peaks in Burkitt's lymphoma incidence diagnosed in four continents, excluding Africa SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID UNITED-STATES; AGE; RATES; COHORT; PATTERNS; PERIOD; DISEASE AB Burkitt's lymphoma (BL) in the general population and immunosuppressed persons with AIDS in the United States was characterized by three age-specific incidence peaks near 10, 40, and 70 years. We hypothesized that BL from different geographical areas may exhibit pediatric, adult, and elderly age incidence peaks. We investigated this hypothesis using data on 3,403 cases obtained from the International Agency for Research on Cancer (19632002). Data from Africa were sparse or incomplete, and thus were excluded. Age-standardized rates (ASRs) and age-specific incidence rates were calculated, supplemented with the calculations performed using ageperiodcohort (APC) models. The ASR rose 5.3% (95% confidence interval [CI], 5.05.6) per year in males and 4.6% (95% CI, 4.54.8) in females. The ASR increased gradually in children, steeply in adults and most rapidly in the elderly both in males and in females. Overall, BL male/female ASR ratio was 2.5, but it declined from 3.1 (95% CI, 3.03.3) for pediatric BL to 2.3 (95% CI, 2.22.4) for adult BL and 1.5 (95% CI, 1.41.6) for elderly BL. Age-specific incidence peaks occurred near 10 and 70 years in all regions and periods. A peak near 40 years of age emerged in the mid-1990s, particularly in men. Findings using APC models confirmed those based on the standard analyses. Our findings, based on the international BL cases, support our hypothesis that BL is multimodal and that BL peaks at different ages may be clues to differences in the etiology and/or biology of BL at those ages. Am. J. Hematol. 87:573578, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Mbulaiteye, Sam M.; Bhatia, Kishor; Chang, Cindy] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Anderson, William F.; Rosenberg, Philip S.; Devesa, Susan S.] NCI, Biostat Branch, DCEG, Bethesda, MD 20892 USA. [Ferlay, Jacques] Int Agcy Res Canc, F-69372 Lyon, France. [Parkin, Donald M.] Univ Oxford, Clin Trial Serv Unit, Oxford, England. RP Mbulaiteye, SM (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Execut Plaza S,Rm 7080,MSC 7248, Rockville, MD 20852 USA. EM mbulaits@mail.nih.gov FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX Contract grant sponsor: The Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 38 TC 17 Z9 18 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JUN PY 2012 VL 87 IS 6 BP 573 EP 578 DI 10.1002/ajh.23187 PG 6 WC Hematology SC Hematology GA 945CC UT WOS:000304249400002 PM 22488262 ER PT J AU Adam, MP Fechner, PY Ramsdell, LA Badaru, A Grady, RE Pagon, RA McCauley, E Cheng, EY Parisi, MA Shnorhavorian, M AF Adam, Margaret P. Fechner, Patricia Y. Ramsdell, Linda A. Badaru, Angela Grady, Richard E. Pagon, Roberta A. McCauley, Elizabeth Cheng, Edith Y. Parisi, Melissa A. Shnorhavorian, Margarett TI Ambiguous genitalia: What prenatal genetic testing is practical? SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE ambiguous genitalia; disorders of sex development; prenatal diagnosis; intersex; hypospadias ID CLASSIFY INTERSEX DISORDERS; CONSENSUS STATEMENT; DIAGNOSIS; DIFFERENTIATION; MANAGEMENT AB Concern for ambiguous genitalia or chromosome-phenotype discordance detected in a prenatal setting has increased over the last two decades. Practitioners faced with this prenatal finding have a variety of genetic tests available to them; however, it is unclear to what extent prenatal testing for disorders of sex development (DSD) is useful or practical. We undertook a retrospective review of the medical records of 140 individuals evaluated through the DSD clinic at Seattle Children's Hospital with birthdates from 01/01/1994 through 08/16/2011 to determine the rate of prenatal detection of ambiguous genitalia in individuals with DSD, what prenatal diagnostic workup was undertaken, and the postnatal outcome, including whether a postnatal genetic diagnosis was confirmed. Of all 140 subjects, 34 (24%) were identified prenatally. The most common postnatal diagnoses were penoscrotal hypospadias with transposition of the scrotum with no known genetic cause (24/140; 17%) and 21-hydroxylase deficiency (20/140; 14%). Apart from these, no single diagnosis comprised more than a few cases. Prenatal diagnostic testing varied widely, from no tests to multiple molecular tests with amniotic fluid hormone concentrations. In the absence of other fetal anomalies or growth retardation on ultrasound, prenatal karyotype with fluorescence in situ hybridization for the SRY gene is the most useful test when ambiguous genitalia is suspected. Further prenatal testing for Smith-Lemli-Opitz syndrome in 46,XY individuals and congenital adrenal hyperplasia in 46,XX individuals may be considered. However, targeted molecular testing for rare DSD conditions in the absence of a family history of DSD has a low yield. (c) 2012 Wiley Periodicals, Inc. C1 [Adam, Margaret P.; Fechner, Patricia Y.; Badaru, Angela; Pagon, Roberta A.; McCauley, Elizabeth] Seattle Childrens Hosp, Seattle, WA 98105 USA. [Adam, Margaret P.; Fechner, Patricia Y.; Ramsdell, Linda A.; Badaru, Angela; Grady, Richard E.; Pagon, Roberta A.; McCauley, Elizabeth; Shnorhavorian, Margarett] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Grady, Richard E.; Shnorhavorian, Margarett] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Cheng, Edith Y.] Univ Washington, Sch Med, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Parisi, Melissa A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Adam, MP (reprint author), Seattle Childrens Hosp, 4800 Sand Point Way NE,POB 5371-A7937, Seattle, WA 98105 USA. EM margaret.adam@seattlechildrens.org NR 21 TC 6 Z9 6 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUN PY 2012 VL 158A IS 6 BP 1337 EP 1343 DI 10.1002/ajmg.a.35338 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 943OM UT WOS:000304133700014 PM 22581420 ER PT J AU Guatelli-Steinberg, D Ferrell, RJ Spence, J AF Guatelli-Steinberg, Debbie Ferrell, Rebecca J. Spence, Jennifer TI Linear enamel hypoplasia as an indicator of physiological stress in great apes: Reviewing the evidence in light of enamel growth variation SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Article DE enamel defects; primate teeth; growth; perikymata ID BRIEF COMMUNICATION; FRUIT AVAILABILITY; DENTAL DEVELOPMENT; CANINE DIMORPHISM; SEXUAL-DIMORPHISM; GORILLA-GORILLA; PRIMATES; CHILDREN; PREVALENCE; MORPHOLOGY AB Physiological stress, such as malnutrition or illness, can disrupt normal enamel growth, resulting in linear enamel hypoplasias (LEHs). Although ecological factors may contribute to LEH expression, other factors, such as surface abrasion and enamel growth variables, are also likely to be involved. Attention to these other factors is necessary before we can begin to understand what LEH might signify in terms of ecological sources of physiological stress in non-human primates. This study focuses on assessing the contribution of these other factors to variation in LEH expression within and across great ape taxa. Here, we present LEH data from unabraded crown regions in samples of seven great ape species. We analyze these data with respect to lateral enamel formation time and the angles that striae of Retzius make with the enamel surface, as these variables are expected to affect variation in LEH expression. We find that although the duration of enamel formation is associated with sex differences in LEH expression, it is not clearly related to taxonomic variation in LEH expression, and does not explain the low frequency of LEH in mountain gorillas found in this and a previous study. Our data on striae of Retzius angles suggest that these influence LEH expression along the tooth crown and may contribute to the consistently high frequencies of LEH seen in Pongo in this and previous studies. We suggest that future work aimed at understanding species variation in these angles is crucial to evaluating taxonomic patterns of LEH expression in great apes. Am J Phys Anthropol 148:191204, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Guatelli-Steinberg, Debbie] Ohio State Univ, Dept Anthropol, Smith Lab 4034, Columbus, OH 43210 USA. [Guatelli-Steinberg, Debbie] Ohio State Univ, Dept Ecol Evolut & Organismal Biol, Columbus, OH 43210 USA. [Ferrell, Rebecca J.] NIA, NIH, Bethesda, MD 20892 USA. RP Guatelli-Steinberg, D (reprint author), Ohio State Univ, Dept Anthropol, Smith Lab 4034, 174 W 18th Ave, Columbus, OH 43210 USA. EM guatelli-steinbe.1@osu.edu FU National Science Foundation [BCS-0607520] FX Grant sponsor: National Science Foundation; Grant number: BCS-0607520. NR 70 TC 14 Z9 14 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD JUN PY 2012 VL 148 IS 2 BP 191 EP 204 DI 10.1002/ajpa.21619 PG 14 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 945CF UT WOS:000304249700005 PM 22610895 ER PT J AU Miller, AC Gladwin, MT AF Miller, Andrew C. Gladwin, Mark T. TI Pulmonary Complications of Sickle Cell Disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE sickle cell disease; hemolytic anemia; pulmonary hypertension; sudden death; nitric oxide ID ACUTE CHEST SYNDROME; PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; THALASSEMIA MAJOR PATIENTS; NITRIC-OXIDE; ARTERIAL-HYPERTENSION; EXERCISE CAPACITY; INCREASED RISK; HEART-DISEASE; CHILDREN; ANEMIA AB Sickle cell disease (SCD) is a common monogenetic disorder with high associated morbidity and mortality. The pulmonary complications of SCD are of particular importance, as acute chest syndrome and pulmonary hypertension have the highest associated mortality rates within this population. This article reviews the pathophysiology, diagnosis, and treatment of clinically significant pulmonary manifestations of SCD, including acute chest syndrome, asthma, and pulmonary hypertension in adult and pediatric patients. Clinicians should be vigilant in screening and treating such comorbidities to improve patient outcomes. C1 [Miller, Andrew C.; Gladwin, Mark T.] Univ Pittsburgh, Med Ctr, Div Pulm Allergy & Crit Care Med, Dept Med, Pittsburgh, PA 15213 USA. [Gladwin, Mark T.] Univ Pittsburgh, Med Ctr, Vasc Med Inst, Pittsburgh, PA 15213 USA. [Miller, Andrew C.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), Univ Pittsburgh, Med Ctr, Div Pulm Allergy & Crit Care Med, Dept Med, 3459 5th Ave,628 NW, Pittsburgh, PA 15213 USA. EM gladwinmt@upmc.edu OI Miller, Andrew/0000-0001-8474-5090 FU National Institutes of Health [R01HL098032, RO1HL096973, PO1HL103455]; Institute for Transfusion Medicine; Hemophilia Center of Western Pennsylvania; Actelion Pharmaceuticals; Akaria (INO) Therapeutics; National Institutes of Health FX Supported by National Institutes of Health grants R01HL098032, RO1HL096973, and PO1HL103455, the Institute for Transfusion Medicine, and the Hemophilia Center of Western Pennsylvania (M.T.G.). As a National Institutes of Health government employee, M.T.G. received grant support in the form of government clinical trials agreements from Actelion Pharmaceuticals and Akaria (INO) Therapeutics. Pfizer supplied sildenafil to the National Institutes of Health and National Heart, Lung, and Blood Institute for the Walk-PHASST trial. A.C.M. receives salary support from the National Institutes of Health. NR 111 TC 35 Z9 37 U1 0 U2 7 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUN 1 PY 2012 VL 185 IS 11 BP 1154 EP 1165 DI 10.1164/rccm.201111-2082CI PG 12 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 946VC UT WOS:000304384600007 PM 22447965 ER PT J AU Verma, S Turkbey, B Muradyan, N Rajesh, A Cornud, F Haider, MA Choyke, PL Harisinghani, M AF Verma, Sadhna Turkbey, Baris Muradyan, Naira Rajesh, Arumugam Cornud, Francois Haider, Masoom A. Choyke, Peter L. Harisinghani, Mukesh TI Overview of Dynamic Contrast-Enhanced MRI in Prostate Cancer Diagnosis and Management SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE diffusion-weighted imaging; MR spectroscopy; prostate cancer; prostate MRI; tumor angiogenesis ID EXTERNAL-BEAM RADIOTHERAPY; RADICAL PROSTATECTOMY; PHARMACOKINETIC PARAMETERS; LOCAL RECURRENCE; PERIPHERAL ZONE; DCE-MRI; LOCALIZATION; DIFFUSION; TUMOR; GLAND AB OBJECTIVE. This article is a primer on the technical aspects of performing a high-quality dynamic contrast-enhanced MRI (DCE-MRI) examination of the prostate gland. CONCLUSION. DCE-MRI is emerging as a useful clinical technique as part of a multiparametric approach for evaluating the extent of primary and recurrent prostate cancer. Performing a high-quality DCE-MRI examination requires a good understanding of the technical aspects and limitations of image acquisition and postprocessing techniques. C1 [Verma, Sadhna] Univ Cincinnati, Med Ctr, Dept Radiol, Cincinnati, OH 45267 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Muradyan, Naira] iCAD Inc, Nashua, NH USA. [Rajesh, Arumugam] Univ Hosp Leicester NHS Trust, Leicester Gen Hosp, Leicester, Leics, England. [Cornud, Francois] Hop Cochin, F-75674 Paris, France. [Haider, Masoom A.] Univ Toronto, Dept Radiol, Toronto, ON M5S 1A1, Canada. [Haider, Masoom A.] Univ Hlth Network, Toronto, ON, Canada. [Harisinghani, Mukesh] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. RP Verma, S (reprint author), Univ Cincinnati, Med Ctr, Dept Radiol, 234 Goodman St,POB 670761, Cincinnati, OH 45267 USA. EM drsadhnaverma@gmail.com NR 67 TC 81 Z9 88 U1 1 U2 11 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUN PY 2012 VL 198 IS 6 BP 1277 EP 1288 DI 10.2214/AJR.12.8510 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 946ZX UT WOS:000304397500030 PM 22623539 ER PT J AU Zhang, F Niu, G Lin, X Jacobson, O Ma, Y Eden, HS He, YL Lu, GM Chen, XY AF Zhang, Fan Niu, Gang Lin, Xin Jacobson, Orit Ma, Ying Eden, Henry S. He, Yulong Lu, Guangming Chen, Xiaoyuan TI Imaging tumor-induced sentinel lymph node lymphangiogenesis with LyP-1 peptide SO AMINO ACIDS LA English DT Article DE Lymphangiogenesis; Lymph node; LyP-1 peptide; Optical imaging ID POSITRON-EMISSION-TOMOGRAPHY; BREAST-CANCER PATIENTS; IN-VIVO; HOMING PEPTIDE; METASTASIS; CELLS; PROMOTES; VESSELS; LYVE-1; FLOW AB Lymphangiogenesis in tumor-draining lymph nodes (LNs) starts before the onset of metastasis and is associated with metastasis to distant LNs and organs. In this study, we aimed to visualize tumor-induced lymphangiogenesis with a tumor lymphatics-specific peptide LyP-1. The LyP-1 peptide was labeled with a near-infrared fluorophore (Cy5.5) for optical imaging. At days 3, 7, 14 and 21 after subcutaneous 4T1 tumor inoculation, Cy5.5-LyP-1 was administered through the middle phalanges of the upper extremities of the tumor-bearing mice. At 45 min and 24 h postinjection, brachial LN fluorescence imaging was performed. Ex vivo fluorescence images were acquired for quantitative analysis of the fluorescence intensity. Tumor-induced lymphangiogenesis was confirmed by LYVE-1 immunostaining and increased size of tumor side brachial LNs. Cy5.5-LyP-1 staining in LNs co-localized with LYVE-1, suggesting lymphatics-specific binding of LyP-1 peptide. The brachial LNs were clearly visualized by optical imaging at both time points. The tumor side LNs showed significantly higher fluorescence intensities than the contralateral brachial LNs at days 7, 14, and 21, but not day 3 after tumor inoculation. At day 21 after tumor inoculation, the average signal of tumor-draining LNs was 78.0 +/- A 2.44, 24.3 +/- A 5.43, 25.6 +/- A 0.25 (x10(3) photon/cm(2)/s) using Cy5.5-LyP-1, Cy5.5-LyP-1 with blocking, and Cy5.5 only, respectively. Tumor-draining brachial LNs showed extensive growth of lymphatic sinuses throughout the cortex and medulla. Use of LyP-1 based imaging probes with optical imaging offers a useful tool for the study of tumor-induced lymphangiogenesis. LyP-1 may serve as a marker of lymphangiogenesis useful in detecting "high risk" LNs before tumor metastasis and after micro-metastasis, as well as for screening potential anti-lymphatic therapies. C1 [Zhang, Fan; He, Yulong; Lu, Guangming] Nanjing Univ, Coll Med, Sch Clin, Dept Radiol,Nanjing Jinling Hosp, Nanjing 210002, Jiangsu, Peoples R China. [Zhang, Fan; Niu, Gang; Lin, Xin; Jacobson, Orit; Ma, Ying; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Niu, Gang] Ctr Clin, Imaging Sci Training Program, Bethesda, MD 20892 USA. [Eden, Henry S.] Natl Inst Biomed Imaging & Bioengn, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Lu, GM (reprint author), Nanjing Univ, Coll Med, Sch Clin, Dept Radiol,Nanjing Jinling Hosp, Nanjing 210002, Jiangsu, Peoples R China. EM cjr.luguangming@vip.163.com; shawn.chen@nih.gov OI HE, YULONG/0000-0002-0099-3749 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Science Foundation of China (NSFC) [81028009, 30930028]; Radiology and Imaging Sciences Department, NIH Clinical Center FX This project was supported in part by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), the International Cooperative Program of the National Science Foundation of China (NSFC) (81028009). F.Z and G.L. are partially supported by the NSFC grant No. 30930028. G.N. currently is an Imaging Sciences Training Program (ISTP) Fellow jointly supported by the Radiology and Imaging Sciences Department, NIH Clinical Center and the Intramural Research Program, NIBIB, NIH. NR 32 TC 7 Z9 7 U1 0 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PD JUN PY 2012 VL 42 IS 6 BP 2343 EP 2351 DI 10.1007/s00726-011-0976-1 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 943UH UT WOS:000304150300032 PM 21769497 ER PT J AU Webb, R Mathur, A Chang, R Baid, S Nilubol, N Libutti, SK Stratakis, CA Kebebew, E AF Webb, Richard Mathur, Aarti Chang, Richard Baid, Smita Nilubol, Naris Libutti, Steven K. Stratakis, Constantine A. Kebebew, Electron TI What is the Best Criterion for the Interpretation of Adrenal Vein Sample Results in Patients with Primary Hyperaldosteronism? SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID PRIMARY ALDOSTERONISM; COMPUTED-TOMOGRAPHY; DIAGNOSIS; LATERALIZATION; STIMULATION; ADENOMA AB In patients with primary hyperaldosteronism, adrenal vein sampling (AVS) has emerged as a gold standard for distinguishing between unilateral and bilateral disease, but multiple criteria have been used and no consensus exists as to the most accurate criterion. The objective of this study was to determine which AVS criteria most accurately identify patients with unilateral surgical disease and are associated with significant clinical improvement after adrenalectomy. This is a retrospective analysis of AVS results in 108 patients with primary hyperaldosteronism treated at a single institution. Literature review of AVS criteria was used to distinguish between unilateral and bilateral disease. Of the 10 AVS criteria identified in the literature, one criterion (ACTH stimulation, positioning: cortisol [adrenal]/cortisol [periphery] [Ca/Cp] > 5.0 and lateralization: aldosterone/cortisol [A/C] [dominant {D}]: A/C [nondominant {ND}] > 4:1) was the most accurate in identifying and correctly predicting lateralization of disease ( value range: < 0.001-0.0369). For this criterion, the true positive rate was 88%. The second most accurate criterion was no ACTH stimulation, positioning Ca/Cp > 1.1 and lateralization: A/C (D): A/C (ND) > 2:1. For this criterion, the overall true positive was 85%. However, we found no significant difference in clinical outcome based on individual criteria fulfillment. Of the multiple criteria used for AVS evaluation, one criterion has the best accuracy. With the increasing use of AVS, there should be a consensus by which these results are evaluated and surgeons recommend adrenalectomy. C1 [Webb, Richard; Mathur, Aarti; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Sect, Surg Branch, Bethesda, MD 20892 USA. [Chang, Richard] Warren F Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD USA. [Baid, Smita; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Bethesda, MD USA. [Libutti, Steven K.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Libutti, Steven K.] Montefiore Med Ctr, Dept Surg, Bronx, NY 10467 USA. RP Webb, R (reprint author), NCI, Endocrine Oncol Sect, Surg Branch, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU Intramural NIH HHS [ZIA HD008920-01] NR 22 TC 11 Z9 11 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JUN PY 2012 VL 19 IS 6 BP 1881 EP 1886 DI 10.1245/s10434-011-2121-5 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA 944NF UT WOS:000304209800023 PM 22048631 ER PT J AU Weisbrod, AB Liewehr, DJ Steinberg, SM Patterson, EE Libutti, SK Linehan, WM Nilubol, N Kebebew, E AF Weisbrod, Allison B. Liewehr, David J. Steinberg, Seth M. Patterson, Erin E. Libutti, Steven K. Linehan, W. Marston Nilubol, Naris Kebebew, Electron TI Association of Type O Blood with Pancreatic Neuroendocrine Tumors in Von Hippel-Lindau Syndrome SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID GROUP ANTIGENS; GROUP ALLELES; LEWIS-B; CANCER; EXPRESSION; DISEASE; CARCINOMA; TISSUE; RISK; ABH AB ABO blood type antigens are expressed not only on human red blood cells, but also throughout the gastrointestinal tract and in normal pancreatic tissue. Previous studies have identified an association between ABO blood type and various malignancies. We analyzed the association of ABO blood type with pancreatic neuroendocrine tumors (PNETs) in a high-risk cohort of patients with Von Hippel-Lindau (VHL) syndrome. A retrospective review was performed of 798 patients with VHL syndrome. Blood type was confirmed for 181 patients. Fisher's exact test and Mehta's modification to Fisher's exact test were used to test for an association between ABO blood type and manifestations of VHL syndrome. We found a strong trend for association between O blood type and pancreatic disease manifestation in patients with VHL syndrome ( = 0.047). More importantly, there was a significant association of O blood type with solid pancreatic lesions consistent with PNETs ( = 0.0084). Patients with solid pancreatic lesions who met criteria for surgical resection at the National Institutes of Health also had a higher rate of O blood type than those who did not require surgery ( = 0.051). Our findings suggest an association between O blood type and pancreatic manifestation of disease in patients with VHL syndrome, especially for PNETs. Screening and surveillance approaches for pancreatic lesions in patients with VHL syndrome should also consider patient blood type. The possibility of A, B, H misexpression in PNETs should also be explored to determine whether the serologic association with disease translates into a relationship with tissue pathology. C1 [Weisbrod, Allison B.; Patterson, Erin E.; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Libutti, Steven K.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Surg, Bronx, NY 10467 USA. [Linehan, W. Marston] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Weisbrod, AB (reprint author), NCI, Endocrine Oncol Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. EM Allison.Weisbrod@nih.gov NR 26 TC 5 Z9 5 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JUN PY 2012 VL 19 IS 6 BP 2054 EP 2059 DI 10.1245/s10434-012-2276-8 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA 944NF UT WOS:000304209800045 PM 22350603 ER PT J AU Theken, KN Schuck, RN Edin, ML Tran, B Ellis, K Bass, A Lih, FB Tomer, KB Poloyac, SM Wu, MC Hinderliter, AL Zeldin, DC Stouffer, GA Lee, CR AF Theken, Katherine N. Schuck, Robert N. Edin, Matthew L. Tran, Bryant Ellis, Kyle Bass, Almasa Lih, Fred B. Tomer, Kenneth B. Poloyac, Samuel M. Wu, Michael C. Hinderliter, Alan L. Zeldin, Darryl C. Stouffer, George A. Lee, Craig R. TI Evaluation of cytochrome P450-derived eicosanoids in humans with stable atherosclerotic cardiovascular disease SO ATHEROSCLEROSIS LA English DT Article DE Soluble epoxide hydrolase; Arachidonic acid; Epoxyeicosatrienoic acid; Dihydroxyeicosatrienoic acid; 20-Hydroxyeicosatetraenoic acid; Coronary artery disease ID SOLUBLE EPOXIDE HYDROLASE; CORONARY-HEART-DISEASE; GENETIC-VARIATION; ARACHIDONIC-ACID; 20-HYDROXYEICOSATETRAENOIC ACID; ENDOTHELIAL EXPRESSION; ESSENTIAL-HYPERTENSION; BLOOD-PRESSURE; EPOXYGENASE; RISK AB Objective: Preclinical and genetic epidemiologic studies suggest that modulating cytochrome P450 (CYP)-mediated arachidonic acid metabolism may have therapeutic utility in the management of coronary artery disease (CAD). However, predictors of inter-individual variation in CYP-derived eicosanoid metabolites in CAD patients have not been evaluated to date. Therefore, the primary objective was to identify clinical factors that influence CYP epoxygenase, soluble epoxide hydrolase (sEH), and CYP omega-hydroxylase metabolism in patients with established CAD. Methods: Plasma levels of epoxyeicosatrienoic acids (EETs), dihydroxyeicosatrienoic acids (DHETs), and 20-hydroxyeicosatetraenoic acid (20-HETE) were quantified by HPLC-MS/MS in a population of patients with stable, angiographically confirmed CAD (N = 82) and healthy volunteers from the local community (N = 36). Predictors of CYP epoxygenase, sEH, and CYP omega-hydroxylase metabolic function were evaluated by regression. Results: Obesity was significantly associated with low plasma EET levels and 14,15-EET:14,15-DHET ratios. Age, diabetes, and cigarette smoking also were significantly associated with CYP epoxygenase and sEH metabolic activity, while only renin-angiotensin system inhibitor use was associated with CYP omega-hydroxylase metabolic activity. Compared to healthy volunteers, both obese and non-obese CAD patients had significantly higher plasma EETs (P<0.01) and epoxide: diol ratios (P<0.01), whereas no difference in 20-HETE levels was observed (P = NS). Conclusions: Collectively, these findings suggest that CYP-mediated eicosanoid metabolism is dysregulated in certain subsets of CAD patients, and demonstrate that biomarkers of CYP epoxygenase and sEH, but not CYP omega-hydroxylase, metabolism are altered in stable CAD patients relative to healthy individuals. Future studies are necessary to determine the therapeutic utility of modulating these pathways in patients with CAD. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Theken, Katherine N.; Schuck, Robert N.; Tran, Bryant; Ellis, Kyle; Bass, Almasa; Lee, Craig R.] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Wu, Michael C.] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Hinderliter, Alan L.; Stouffer, George A.] Univ N Carolina, Sch Med, Div Cardiol, Chapel Hill, NC USA. [Hinderliter, Alan L.; Stouffer, George A.; Lee, Craig R.] Univ N Carolina, McAllister Heart Inst, Chapel Hill, NC USA. [Edin, Matthew L.; Lih, Fred B.; Tomer, Kenneth B.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Poloyac, Samuel M.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. RP Lee, CR (reprint author), 2317 Kerr Hall,CB 7569, Chapel Hill, NC 27599 USA. EM craig_lee@unc.edu RI Theken, Katherine/H-1098-2012; Tomer, Kenneth/E-8018-2013; OI Edin, Matthew/0000-0002-7042-500X; Lee, Craig/0000-0003-3595-5301; Wu, Michael C./0000-0002-3357-6570 FU American Foundation for Pharmaceutical Education; National Institutes of Health (NIH) National Heart, Lung, and Blood Institute [T32 HL069768]; American Heart Association; North Carolina Translational and Clinical Sciences Institute; NIH/NIEHS [Z01 ES050167, Z01 ES025034]; NIH National Center for Research Resources [KL2RR025746]; National Center for Advancing Translational Sciences FX This publication was made possible by a predoctoral fellowship from the American Foundation for Pharmaceutical Education to Dr. Theken, a predoctoral training program in Integrative Vascular Biology supported by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (T32 HL069768) to Dr. Schuck, a Beginning Grant-in-Aid from the American Heart Association and a pilot grant from the North Carolina Translational and Clinical Sciences Institute to Dr. Lee, funds from the Intramural Research Program of the NIH/NIEHS to Dr. Tomer (Z01 ES050167) and Dr. Zeldin (Z01 ES025034), and by grant KL2RR025746 from the NIH National Center for Research Resources and the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 30 TC 35 Z9 35 U1 1 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JUN PY 2012 VL 222 IS 2 BP 530 EP 536 DI 10.1016/j.atherosclerosis.2012.03.022 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 947OJ UT WOS:000304439000036 PM 22503544 ER PT J AU Liu, YM Nguyen, P Baris, TZ Poirier, MC AF Liu, Yongmin Phuonggiang Nguyen Baris, Tara Z. Poirier, Miriam C. TI Molecular Analysis of Mitochondrial Compromise in Rodent Cardiomyocytes Exposed Long Term to Nucleoside Reverse Transcriptase Inhibitors (NRTIs) SO CARDIOVASCULAR TOXICOLOGY LA English DT Article DE HL-1; H9c2; Nucleoside reverse transcriptase inhibitors; Mitochondrial toxicity; Oxygen consumption rate; Extracellular acidification rate; Mitochondrial biogenesis; Electron microscopy; Mitochondrial protein expression ID HUMAN LYMPHOBLASTOID-CELLS; IN-VITRO EXPOSURE; PERINATAL EXPOSURE; ANTIRETROVIRAL THERAPY; PATAS MONKEYS; TOXICITY; AZT; GENOTOXICITY; DYSFUNCTION; BIOGENESIS AB Despite the highly effective impact of NRTI therapy in patients infected with the human immunodeficiency virus type 1 (HIV-1), long-term treatment has revealed cardiotoxicity, considered to be due to mitochondrial dysfunction. To evaluate mitochondrial damage, and design therapeutic interventions, we established cultures of rat H9c2 and mouse HL-1 cardiomyocytes and exposed them to the NRTIs zidovudine (AZT), and AZT plus didanosine (ddI). Proliferation assays showed that H9c2 cells grew well in 50 mu M AZT and 50 mu M AZT/50 mu M ddI and that HL-1 cells grew well in 10 mu M AZT and 10 mu M AZT/10 mu M ddI. Both types of cells were exposed to the drugs for 39 passages (P), and mitochondrial integrity in the form of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) was examined by Seahorse XF24 analyzer. In NRTI-exposed H9c2 cells at most passages, OCR was reduced, in both the basal and uncoupled states, compared to unexposed controls ( < 0.05). NRTI-exposed HL-1 cells showed a different pattern of mitochondrial compromise, with inhibition of OCR, in basal and uncoupled cells, occurring largely before P14 and after P17 ( < 0.05). The ECAR response in uncoupled cells of both types was unchanged at early passages, but increased after P18 ( < 0.05). Evaluation of mitochondrial biogenesis in H9c2 cells revealed reduction before P29, no change at P29, and reduction at P39 in NRTI-exposed cells, compared to unexposed cells ( < 0.05). Western blotting of transcription factors critical for mitochondrial biogenesis, PGC-1 alpha, Nrf-1 and mtTFA, showed downregulation in NRTI-exposed H9c2 cells compared to unexposed controls. In addition, electron microscopy (EM) revealed increasing mitochondrial morphological damage in H9c2 cells over passages. For both cell types, AZT/ddI was more damaging than AZT alone. These studies demonstrate progressive mitochondrial compromise in cardiomyocytes-exposed long term, and the model will be used to evaluate potentially protective intervention strategies. C1 [Liu, Yongmin; Phuonggiang Nguyen; Baris, Tara Z.; Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, CCR,NIH, Bethesda, MD 20892 USA. RP Liu, YM (reprint author), NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, CCR,NIH, Bldg 37,Rm 4032,37 Convent Dr,MSC-4255, Bethesda, MD 20892 USA. EM yongminl@mail.nih.gov OI Nguyen, Phuonggiang/0000-0003-1638-1584 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We wish to thank Dr. Aleksandra Michalowski for statistical consultation. We would also like to thank Dr. Kevin Bittman and Tony Nardei of Seahorse Bioscience Inc. for their help. This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 40 TC 7 Z9 8 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1530-7905 J9 CARDIOVASC TOXICOL JI Cardiovasc. Toxicol. PD JUN PY 2012 VL 12 IS 2 BP 123 EP 134 DI 10.1007/s12012-011-9148-5 PG 12 WC Cardiac & Cardiovascular Systems; Toxicology SC Cardiovascular System & Cardiology; Toxicology GA 944BH UT WOS:000304172800004 PM 22170576 ER PT J AU Stirling, PC Crisp, MJ Basrai, MA Tucker, CM Dunham, MJ Spencer, FA Hieter, P AF Stirling, Peter C. Crisp, Matthew J. Basrai, Munira A. Tucker, Cheryl M. Dunham, Maitreya J. Spencer, Forrest A. Hieter, Philip TI Mutability and mutational spectrum of chromosome transmission fidelity genes SO CHROMOSOMA LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; SISTER-CHROMATID COHESION; CELL-DIVISION CYCLE; COLORECTAL CANCERS; SYNTHETIC LETHAL; FUNCTIONAL-CHARACTERIZATION; DNA-DAMAGE; GENOME; INSTABILITY; MUTANTS AB It has been more than two decades since the original chromosome transmission fidelity (Ctf) screen of was published. Since that time the spectrum of mutations known to cause Ctf and, more generally, chromosome instability (CIN) has expanded dramatically as a result of systematic screens across yeast mutant arrays. Here we describe a comprehensive summary of the original Ctf genetic screen and the cloning of the remaining complementation groups as efforts to expand our knowledge of the CIN gene repertoire and its mutability in a model eukaryote. At the time of the original screen, it was impossible to predict either the genes and processes that would be overrepresented in a pool of random mutants displaying a Ctf phenotype or what the entire set of genes potentially mutable to Ctf would be. We show that in a collection of 136 randomly selected Ctf mutants, > 65% of mutants map to 13 genes, 12 of which are involved in sister chromatid cohesion and/or kinetochore function. Extensive screening of systematic mutant collections has shown that 350 genes with functions as diverse as RNA processing and proteasomal activity mutate to cause a Ctf phenotype and at least 692 genes are required for faithful chromosome segregation. The enrichment of random Ctf alleles in only 13 of 350 possible Ctf genes suggests that these genes are more easily mutable to cause genome instability than the others. These observations inform our understanding of recurring CIN mutations in human cancers where presumably random mutations are responsible for initiating the frequently observed CIN phenotype of tumors. C1 [Stirling, Peter C.; Hieter, Philip] Univ British Columbia, Michael Smith Labs, Vancouver, BC V6T 1Z4, Canada. [Crisp, Matthew J.; Basrai, Munira A.] NCI, Genet Branch Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Tucker, Cheryl M.] Princeton Univ, Lewis Sigler Inst, Princeton, NJ 08544 USA. [Dunham, Maitreya J.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. [Spencer, Forrest A.] Johns Hopkins Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. RP Hieter, P (reprint author), Univ British Columbia, Michael Smith Labs, Vancouver, BC V6T 1Z4, Canada. EM hieter@msl.ubc.ca OI Dunham, Maitreya/0000-0001-9944-2666 FU National Institutes of Health (NIH) [P50 GM071508, GM077456, CA016519]; National Cancer Institute, NIH; Canadian Institutes of Health Research [MOP-38096] FX PCS is a fellow of the Terry Fox Foundation (#700044) and acknowledges the additional support of the Michael Smith Foundation for Health Research. MJD is a Rita Allen Scholar and was supported in part by National Institutes of Health (NIH) grant P50 GM071508 to the Lewis Sigler Institute at Princeton University. MB is supported by the Intramural Research Program of the National Cancer Institute, NIH. FS is supported by NIH GM077456. PH is supported by grants from the NIH CA016519 and Canadian Institutes of Health Research MOP-38096. NR 79 TC 11 Z9 11 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-5915 J9 CHROMOSOMA JI Chromosoma PD JUN PY 2012 VL 121 IS 3 BP 263 EP 275 DI 10.1007/s00412-011-0356-3 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 943PL UT WOS:000304136600004 PM 22198145 ER PT J AU Parkman, HP Hasler, WL Nguyen, L Pasricha, PJ Snape, WJ Farrugia, G Koch, KL Calles, J Abell, TL McCallum, RW Yates, K Lee, L Unalp-Arida, A Tonascia, J Hamilton, F AF Parkman, Henry P. Hasler, William L. Linda Nguyen Pasricha, Pankaj J. Snape, William J. Farrugia, Gianrico Koch, Kenneth L. Calles, Jorge Abell, Thomas L. McCallum, Richard W. Yates, Katherine Lee, Linda Unalp-Arida, Aynur Tonascia, James Hamilton, Frank TI Diabetic Gastroparesis: Myth or Reality? Reply SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Letter C1 [Parkman, Henry P.] Temple Univ, Philadelphia, PA 19122 USA. [Hasler, William L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Linda Nguyen; Pasricha, Pankaj J.] Stanford Univ, Palo Alto, CA 94304 USA. [Snape, William J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Farrugia, Gianrico] Mayo Clin, Rochester, MN USA. [Koch, Kenneth L.; Calles, Jorge] Wake Forest Univ, Winston Salem, NC 27109 USA. [Abell, Thomas L.] Univ Mississippi, Jackson, MS 39216 USA. [McCallum, Richard W.] Texas Tech Univ, El Paso, TX USA. [Yates, Katherine; Lee, Linda; Unalp-Arida, Aynur; Tonascia, James] Johns Hopkins Univ, Baltimore, MD USA. [Hamilton, Frank] NIDDK, Bethesda, MD USA. RP Parkman, HP (reprint author), Temple Univ, Philadelphia, PA 19122 USA. NR 8 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD JUN PY 2012 VL 10 IS 6 BP 686 EP 687 DI 10.1016/j.cgh.2012.02.024 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 948QJ UT WOS:000304517400026 ER PT J AU Harpaz, R DuMouchel, W Shah, NH Madigan, D Ryan, P Friedman, C AF Harpaz, R. DuMouchel, W. Shah, N. H. Madigan, D. Ryan, P. Friedman, C. TI Novel Data-Mining Methodologies for Adverse Drug Event Discovery and Analysis SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Review ID MEDICAL-PRODUCT-SAFETY; SIGNAL-DETECTION; MYOCARDIAL-INFARCTION; HOSPITALIZED-PATIENTS; SURVEILLANCE; DATABASES; SYSTEMS; NETWORK; DESIGN; INFORMATION AB An important goal of the health system is to identify new adverse drug events (ADEs) in the postapproval period. Data-mining methods that can transform data into meaningful knowledge to inform patient safety have proven essential for this purpose. New opportunities have emerged to harness data sources that have not been used within the traditional framework. This article provides an overview of recent methodological innovations and data sources used to support ADE discovery and analysis. C1 [Harpaz, R.; Friedman, C.] Columbia Univ, Med Ctr, Dept Biomed Informat, New York, NY 10027 USA. [DuMouchel, W.] Oracle Hlth Sci, Burlington, MA USA. [DuMouchel, W.; Madigan, D.; Ryan, P.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Shah, N. H.] Stanford Univ, Stanford Ctr Biomed Informat Res, Stanford, CA 94305 USA. [Madigan, D.] Columbia Univ, Dept Stat, New York, NY USA. [Ryan, P.] Janssen Res & Dev, Titusville, NJ USA. RP Harpaz, R (reprint author), Columbia Univ, Med Ctr, Dept Biomed Informat, New York, NY 10027 USA. EM rave.harpaz@dbmi.columbia.edu FU National Library of Medicine [1R01LM010016, 3R01LM010016-01S1, 3R01LM010016-02S1, 5T15-LM007079-19(HS)]; National Center for Biomedical Ontology [U54-HG004028]; i2b2 National Center for Biomedical Computing [2U54LM008748] FX This work was supported in part by grants 1R01LM010016, 3R01LM010016-01S1, 3R01LM010016-02S1, and 5T15-LM007079-19(HS) from the National Library of Medicine; U54-HG004028 from the National Center for Biomedical Ontology; and 2U54LM008748 from the i2b2 National Center for Biomedical Computing. We thank Nicholas Tatonetti of Stanford University and Roee Sa'adon of First Life Research for their valuable comments. We are grateful to Oracle's Health Sciences Division for supplying data and figures. NR 72 TC 86 Z9 90 U1 3 U2 46 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUN PY 2012 VL 91 IS 6 BP 1010 EP 1021 DI 10.1038/clpt.2012.50 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 945AS UT WOS:000304245800019 PM 22549283 ER PT J AU Chertow, DS O'Grady, NP AF Chertow, Daniel S. O'Grady, Naomi P. TI Room for improvement in central venous catheter postinsertion care SO CRITICAL CARE MEDICINE LA English DT Editorial Material ID BLOOD-STREAM INFECTIONS; RANDOMIZED CONTROLLED-TRIAL; CRITICALLY-ILL PATIENTS; PREVENTION C1 [Chertow, Daniel S.; O'Grady, Naomi P.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Chertow, DS (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 9 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JUN PY 2012 VL 40 IS 6 BP 1962 EP 1963 DI 10.1097/CCM.0b013e31825466cc PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 946EZ UT WOS:000304335600038 PM 22610199 ER PT J AU Chattopadhyay, PK Gaylord, B Palmer, A Jiang, N Raven, MA Lewis, G Reuter, MA Rahman, AKMNU Price, DA Betts, MR Roederer, M AF Chattopadhyay, Pratip K. Gaylord, Brent Palmer, Adrian Jiang, Nan Raven, Mary A. Lewis, Geoff Reuter, Morgan A. Rahman, A. K. M. Nur-ur Price, David A. Betts, Michael R. Roederer, Mario TI Brilliant violet fluorophores: A new class of ultrabright fluorescent compounds for immunofluorescence experiments SO CYTOMETRY PART A LA English DT Article DE brilliant violet; fluorochromes; dyes; immunofluorescence; violet laser; conductive polymers ID SOLUBLE CONJUGATED POLYMERS; FLOW-CYTOMETRY; DNA DETECTION; T-CELLS; IDENTIFICATION; DEGRANULATION; NANOCRYSTALS; SENSITIVITY; PROBES; ASSAY AB The Nobel Prize in Chemistry was awarded in 2000 for the discovery of conductive organic polymers, which have subsequently been adapted for applications in ultrasensitive biological detection. Here, we report the first use of this new class of fluorescent probes in a diverse range of cytometric and imaging applications. We demonstrate that these Brilliant Violet reporters are dramatically brighter than other UV-violet excitable dyes, and are of similar utility to phycoerythrin (PE) and allophycocyanin (APC). They are thus ideally suited for cytometric assays requiring high sensitivity, such as MHC-multimer staining or detection of intracellular antigens. Furthermore, these reporters are sensitive and spectrally distinct options for fluorescence imaging, two-photon microscopy and imaging cytometry. These ultra-bright materials provide the first new high-sensitivity fluorescence probes in over 25 years and will have a dramatic impact on the design and implementation of multicolor panels for high-sensitivity immunofluorescence assays. Published 2012 Wiley Periodicals, Inc. C1 [Chattopadhyay, Pratip K.; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gaylord, Brent; Palmer, Adrian] Sirigen, Ringwood, Hants, England. [Jiang, Nan] BioLegend, San Diego, CA USA. [Raven, Mary A.; Lewis, Geoff] Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA. [Raven, Mary A.; Lewis, Geoff] Univ Calif Santa Barbara, Dept Mol Cellular, Santa Barbara, CA 93106 USA. [Reuter, Morgan A.; Rahman, A. K. M. Nur-ur; Betts, Michael R.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff, Whales, Wales. RP Chattopadhyay, PK (reprint author), NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pchattop@mail.nih.gov RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Chattopadhyay, Pratip/0000-0002-5457-9666 FU NIAID, NIH FX Grant sponsors: Intramural Research Program of the NIAID, NIH. NR 21 TC 30 Z9 31 U1 6 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD JUN PY 2012 VL 81A IS 6 BP 456 EP 466 DI 10.1002/cyto.a.22043 PG 11 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 945FO UT WOS:000304258400007 PM 22489009 ER PT J AU Gregg, EW Cheng, YLJ Saydah, S Cowie, C Garfield, S Geiss, L Barker, L AF Gregg, Edward W. Cheng, Yiling J. Saydah, Sharon Cowie, Catherine Garfield, Sanford Geiss, Linda Barker, Lawrence TI Trends in Death Rates Among US Adults With and Without Diabetes Between 1997 and 2006 Findings from the National Health Interview Survey SO DIABETES CARE LA English DT Article ID HEART-DISEASE; UNITED-STATES; MORTALITY; POPULATION; MELLITUS; RISK; PREVALENCE; INDIVIDUALS; DECLINE; BURDEN AB OBJECTIVE-To determine whether all-cause and cardiovascular disease (CVD) death rates declined between 1997 and 2006, a period of continued advances in treatment approaches and risk factor control, among U.S. adults with and without diabetes. RESEARCH DESIGN AND METHODS-We compared 3-year death rates of four consecutive nationally representative samples (1997-1998, 1999-2000, 2001-2002, and 2003-2004) of U.S. adults aged 18 years and older using data from the National Health Interview Surveys linked to National Death Index. RESULTS-Among diabetic adults, the CVD death rate declined by 40% (95% CI 23-54) and all-cause mortality declined by 23% (10-35) between the earliest and latest samples. There was no difference in the rates of decline in mortality between diabetic men and women. The excess CVD mortality rate associated with diabetes (i.e., compared with nondiabetic adults) decreased by 60% (from 5.8 to 2.3 CVD deaths per 1,000) while the excess all-cause mortality rate declined by 44% (from 10.8 to 6.1 deaths per 1,000). CONCLUSIONS-Death rates among both U.S. men and women with diabetes declined substantially between 1997 and 2006, reducing the absolute difference between adults with and without diabetes. These encouraging findings, however, suggest that diabetes prevalence is likely to rise in the future if diabetes incidence is not curtailed. C1 [Gregg, Edward W.; Cheng, Yiling J.; Saydah, Sharon; Geiss, Linda; Barker, Lawrence] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Cowie, Catherine; Garfield, Sanford] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Gregg, EW (reprint author), Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. EM edg7@cdc.gov NR 26 TC 124 Z9 129 U1 2 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2012 VL 35 IS 6 BP 1252 EP 1257 DI 10.2337/dc11-1162 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 950DY UT WOS:000304631000011 PM 22619288 ER PT J AU Zhao, H Pearson, EK Brooks, DC Coon, JS Chen, D Demura, M Zhang, M Clevenger, CV Xu, X Veenstra, TD Chatterton, RT DeMayo, FJ Bulun, SE AF Zhao, Hong Pearson, Elizabeth K. Brooks, David C. Coon, John S. Chen, Dong Demura, Masashi Zhang, Ming Clevenger, Charles V. Xu, Xia Veenstra, Timothy D. Chatterton, Robert T. DeMayo, Francesco J. Bulun, Serdar E. TI A Humanized Pattern of Aromatase Expression Is Associated with Mammary Hyperplasia in Mice SO ENDOCRINOLOGY LA English DT Article ID BREAST ADIPOSE FIBROBLASTS; RAT LUTEINIZING-HORMONE; TRANSGENIC MICE; EPITHELIAL-CELLS; GENE-EXPRESSION; ESTROGEN; CANCER; GLAND; OVEREXPRESSION; PROMOTERS AB Aromatase is essential for estrogen production and is the target of aromatase inhibitors, the most effective endocrine treatment for postmenopausal breast cancer. Peripheral tissues in women, including the breast, express aromatase via alternative promoters. Female mice lack the promoters that drive aromatase expression in peripheral tissues; thus, we generated a transgenic humanized aromatase (Arom(hum)) mouse line containing a single copy of the human aromatase gene to study the link between aromatase expression in mammary adipose tissue and breast pathology. Aromhum mice expressed human aromatase, driven by the proximal human promoters II and I. 3 and the distal promoter I. 4, in breast adipose fibroblasts and myoepithelial cells. Estrogen levels in the breast tissue of Aromhum mice were higher than in wild-type mice, whereas circulating levels were similar. Aromhum mice exhibited accelerated mammary duct elongation at puberty and an increased incidence of lobuloalveolar breast hyperplasia associated with increased signal transducer and activator of transcription-5 phosphorylation at 24 and 64 wk. Hyperplastic epithelial cells showed remarkably increased proliferative activity. Thus, we demonstrated that the human aromatase gene can be expressed via its native promoters in a wide variety of mouse tissues and in a distribution pattern nearly identical to that of humans. Locally increased tissue levels, but not circulating levels, of estrogen appeared to exert hyperplastic effects on the mammary gland. This novel mouse model will be valuable for developing tissue-specific aromatase inhibition strategies. (Endocrinology 153: 2701-2713, 2012) C1 [Zhao, Hong; Pearson, Elizabeth K.; Brooks, David C.; Coon, John S.; Chen, Dong; Demura, Masashi; Chatterton, Robert T.; Bulun, Serdar E.] Northwestern Univ, Div Reprod Biol Res, Dept Obstet & Gynecol, Feinberg Sch Med, Chicago, IL 60611 USA. [Zhang, Ming] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Clevenger, Charles V.] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. [Chatterton, Robert T.] Northwestern Univ, Dept Physiol, Feinberg Sch Med, Chicago, IL 60611 USA. [Xu, Xia; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Sci Applicat Int Corp Frederick, NIH, Frederick, MD 21702 USA. [DeMayo, Francesco J.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. RP Zhao, H (reprint author), Northwestern Univ, Div Reprod Biol Res, Dept Obstet & Gynecol, Feinberg Sch Med, 303 E Super St,Suite 4-250, Chicago, IL 60611 USA. EM h-zhao@northwestern.edu RI DEMURA, Masashi/E-1278-2011 OI DEMURA, Masashi/0000-0003-4156-1640 FU National Institutes of Health [CA67167]; Lynn Sage Cancer Research Foundation FX This work was supported by National Institutes of Health Grant CA67167 and Lynn Sage Cancer Research Foundation Grant. NR 49 TC 7 Z9 8 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2012 VL 153 IS 6 BP 2701 EP 2713 DI 10.1210/en.2011-1761 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 946RF UT WOS:000304370700021 PM 22508516 ER PT J AU Moslehi, R Kumar, A Mills, JL Ambroggio, X Signore, C Dzutsev, A AF Moslehi, Roxana Kumar, Anil Mills, James L. Ambroggio, Xavier Signore, Caroline Dzutsev, Amiran TI Phenotype-specific adverse effects of XPD mutations on human prenatal development implicate impairment of TFIIH-mediated functions in placenta SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE trichothiodystrophy; xeroderma pigmentosum; XPD; TFIIH; human fetal development ID COMPLEMENTATION GROUP-D; NUCLEOTIDE-EXCISION-REPAIR; PIGMENTOSUM GROUP-D; MULTIPLE SEQUENCE ALIGNMENT; GROUP-D PATIENT; XERODERMA-PIGMENTOSUM; DNA-REPAIR; TRANSCRIPTION INITIATION; BASAL TRANSCRIPTION; CLINICAL-FEATURES AB Mutations in XPD (ERCC2), XPB (ERCC3), and TTD-A (GTF2H5), genes involved in nucleotide excision repair and transcription, can cause several disorders including trichothiodystrophy (TTD) and xeroderma pigmentosum (XP). In this study, we tested the hypothesis that mutations in the XPD gene affect placental development in a phenotype-specific manner. To test our hypothesis and decipher potential biologic mechanisms, we compared all XPD-associated TTD (n=43) and XP (n=37) cases reported in the literature with respect to frequencies of gestational complications. Our genetic epidemiologic investigations of TTD and XP revealed that the exact genetic abnormality was relevant to the mechanism leading to gestational complications such as preeclampsia. Through structural mapping, we localized the preeclampsia-associated mutations to a C-terminal motif and the helicase surfaces of XPD, most likely affecting XPD's binding to cdk-activating kinase (CAK) and p44 subunits of transcription factor (TF) IIH. Our results suggested a link between TTD-but not XP-associated XPD mutations, placental maldevelopment and risk of pregnancy complications, possibly due to impairment of TFIIH-mediated functions in placenta. Our findings highlight the importance of the fetal genotype in development of gestational complications, such as preeclampsia. Therefore, future studies of genetic associations of preeclampsia and other placental vascular complications may benefit from focusing on genetic variants within the fetal DNA. European Journal of Human Genetics (2012) 20, 626-631; doi:10.1038/ejhg.2011.249; published online 11 January 2012 C1 [Moslehi, Roxana; Kumar, Anil] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Albany, NY 12144 USA. [Moslehi, Roxana] SUNY Albany, Canc Res Ctr, Albany, NY 12144 USA. [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH,DHHS, Bethesda, MD USA. [Ambroggio, Xavier] NIAID, BCBB, NIH, DHHS, Bethesda, MD 20892 USA. [Signore, Caroline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH,DHHS, Bethesda, MD USA. [Dzutsev, Amiran] NCI, SAIC, Canc Inflammat Program, NIH, Frederick, MD 21701 USA. RP Moslehi, R (reprint author), SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Albany, NY 12144 USA. EM rmoslehi@albany.edu FU Center for Social and Demographic Analysis (CSDA) at the University at Albany; National Institute of Child Health and Human Development at the National Institutes of Health; Junior Faculty Researcher Award FX This study was supported in part by the Junior Faculty Researcher Award granted to RM through Center for Social and Demographic Analysis (CSDA) at the University at Albany; this award was made possible through a grant (R24 HD044943) from National Institute of Child Health and Human Development at the National Institutes of Health to CSDA. NR 58 TC 8 Z9 8 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD JUN PY 2012 VL 20 IS 6 BP 626 EP 631 DI 10.1038/ejhg.2011.249 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 944KK UT WOS:000304200000010 PM 22234153 ER PT J AU Pan, XB Zhu, XD Li, QQ AF Pan, Xinbin Zhu, Xiaodong Li, Qingdi Quentin TI Syphilis manifesting as a nasopharyngeal carcinoma with cervical lymphadenopathy: A case report SO EXPERIMENTAL AND THERAPEUTIC MEDICINE LA English DT Article DE syphilis; cervical lymphadenopathy; nasopharyngeal carcinoma; differential diagnosis ID SECONDARY SYPHILIS AB The present case report describes a case of syphilitic lymphadenopathy and raises the awareness of the differential diagnosis of cervical lymphadenopathy. A 50-year-old male worker presented with a 6-month history of enlarged and growing lymph nodes in the right upper neck and a blood-tinged post-nasal drip. Physical examination showed multiple enlarged lymph nodes located in the right upper neck. On nasopharyngoscopy, a mass was found in the nasopharynx. The histopathology of both the nasopharyngeal mass and the enlarged lymph nodes revealed non-specific inflammation. Rapid plasma reagin test results (titer, 1:1280) and Treponema pallidum particle assay results (titer, 1:2560) were positive. Subsequently, a diagnosis of syphilis was confirmed clinically and serologically. The reaction after penicillin treatment further confirmed the syphilis diagnosis. Thus, syphilis should be considered as a possibility in the differential diagnosis of cervical lymphadenopathy. C1 [Pan, Xinbin; Zhu, Xiaodong] Guangxi Med Univ, Canc Hosp, Dept Radiat Oncol, Nanning 530021, Peoples R China. [Li, Qingdi Quentin] NIH, Bethesda, MD 20892 USA. RP Zhu, XD (reprint author), Guangxi Med Univ, Canc Hosp, Dept Radiat Oncol, Nanning 530021, Peoples R China. EM zhuxiaodong1966@yahoo.com.cn; liquenti@mail.nih.gov NR 14 TC 2 Z9 2 U1 0 U2 0 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1792-0981 J9 EXP THER MED JI Exp. Ther. Med. PD JUN PY 2012 VL 3 IS 6 BP 1023 EP 1025 DI 10.3892/etm.2012.535 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 944EP UT WOS:000304182400019 ER PT J AU Shin, HW Kang, SY Hallett, M Sohn, YH AF Shin, Hae-Won Kang, Suk Y. Hallett, Mark Sohn, Young H. TI Reduced surround inhibition in musicians SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE Transcranial magnetic stimulation; Surround inhibition; Motor evoked potential; Musician; Dystonia ID FOCAL HAND DYSTONIA; INTRACORTICAL INHIBITION; MOTOR CORTEX; PLASTICITY; MODULATION; ACTIVATION; MUSCLE; REPRESENTATION; PLAYERS; FINGERS AB To investigate whether surround inhibition (SI) in the motor system is altered in professional musicians, we performed a transcranial magnetic stimulation (TMS) study in 10 professional musicians and 15 age-matched healthy non-musicians. TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1,000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the abductor digiti minimi (ADM) muscles were compared between the musicians and non-musicians with the primary analysis being the intervals between 3 and 80 ms (during the movement). A mixed-design ANOVA revealed a significant difference in normalized ADM MEPs during the index finger flexion between groups, with less SI in the musicians. This study demonstrated that the functional operation of SI is less strong in musicians than non-musicians, perhaps due to practice of movement synergies involving both muscles. Reduced SI, however, could lead susceptible musicians to be prone to develop task-specific dystonia. C1 [Sohn, Young H.] Yonsei Univ, Coll Med, Dept Neurol, Seoul 120752, South Korea. [Sohn, Young H.] Yonsei Univ, Coll Med, Brain Res Inst, Seoul 120752, South Korea. [Shin, Hae-Won] Chung Ang Univ, Coll Med, Dept Neurol, Seoul 156755, South Korea. [Kang, Suk Y.] Hallym Univ, Coll Med, Kangnam Sacred Heart Hosp, Dept Neurol, Seoul 150950, South Korea. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Sohn, YH (reprint author), Yonsei Univ, Coll Med, Dept Neurol, 250 Seongsanno, Seoul 120752, South Korea. EM heather@gmail.com; sukyunkang@daum.net; hallettm@ninds.nih.gov; yhsohn62@yuhs.ac FU Yonsei University; NINDS FX This work was supported by the Brain Korea 21 Project for Medical Science, Yonsei University. Dr. Hallett is supported by the NINDS Intramural Program. We thank Hye S. Lee, MS, for her helpful assistance in statistical analysis. NR 22 TC 14 Z9 14 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD JUN PY 2012 VL 219 IS 3 BP 403 EP 408 DI 10.1007/s00221-012-3102-z PG 6 WC Neurosciences SC Neurosciences & Neurology GA 947QX UT WOS:000304445700009 PM 22543743 ER PT J AU Bagci, U Yao, JH Wu, A Caban, J Palmore, TN Suffredini, AF Aras, O Mollura, DJ AF Bagci, Ulas Yao, Jianhua Wu, Albert Caban, Jesus Palmore, Tara N. Suffredini, Anthony F. Aras, Omer Mollura, Daniel J. TI Automatic Detection and Quantification of Tree-in-Bud (TIB) Opacities From CT Scans SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Computer-assisted detection (CAD); infectious diseases; lung; tree-in-bud (TIB); Willmore energy ID COMPUTER-AIDED DIAGNOSIS; INFLUENZA-A H1N1; LUNG SEGMENTATION; SCALE; CLASSIFICATION; ALGORITHMS; FEATURES; SHAPE AB This study presents a novel computer-assisted detection (CAD) system for automatically detecting and precisely quantifying abnormal nodular branching opacities in chest computed tomography (CT), termed tree-in-bud (TIB) opacities by radiology literature. The developed CAD system in this study is based on 1) fast localization of candidate imaging patterns using local scale information of the images, and 2) Mobius invariant feature extraction method based on learned local shape and texture properties of TIB patterns. For fast localization of candidate imaging patterns, we use ball-scale filtering and, based on the observation of the pattern of interest, a suitable scale selection is used to retain only small size patterns. Once candidate abnormality patterns are identified, we extract proposed shape features from regions where at least one candidate pattern occupies. The comparative evaluation of the proposed method with commonly used CAD methods is presented with a dataset of 60 chest CTs (laboratory confirmed 39 viral bronchiolitis human parainfluenza CTs and 21 normal chest CTs). The quantitative results are presented as the area under the receiver operator characteristics curves and a computer score (volume affected by TIB) provided as an output of the CAD system. In addition, a visual grading scheme is applied to the patient data by three well-trained radiologists. Interobserver and observer-computer agreements are obtained by the relevant statistical methods over different lung zones. Experimental results demonstrate that the proposed CAD system can achieve high detection rates with an overall accuracy of 90.96%. Moreover, correlations of observer-observer (R-2 = 0.8848, p < 0.01) and observer-CAD agreements (R-2 = 0.824, p < 0.01) validate the feasibility of the use of the proposed CAD system in detecting and quantifying TIB patterns. C1 [Bagci, Ulas; Wu, Albert; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Caban, Jesus] USN, Med Ctr, Bethesda, MD 20889 USA. [Palmore, Tara N.] NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Suffredini, Anthony F.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Aras, Omer] NCI, NIH, Bethesda, MD 20892 USA. RP Bagci, U (reprint author), NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. EM ulasbagci@ieee.org; jyao@cc.nih.gov; albywu@gmail.com; cabanj@cc.nih.gov; tpalmore@cc.nih.gov; asuffredini@cc.nih.gov; dromeraras@gmail.com; daniel.mollura@nih.gov RI Bagci, Ulas/A-4225-2012; OI Bagci, Ulas/0000-0001-7379-6829 FU Imaging Sciences Training Program; Center for Infectious Disease Imaging; National Institutes of Allergy and Infectious Diseases; National Institutes of Bio-imaging and Bioengineering, National Institutes of Health FX This work was supported in part by the Imaging Sciences Training Program, the Center for Infectious Disease Imaging, the Intramural Program of the National Institutes of Allergy and Infectious Diseases, and the Intramural Research Program of the National Institutes of Bio-imaging and Bioengineering, National Institutes of Health. NR 43 TC 8 Z9 8 U1 0 U2 13 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD JUN PY 2012 VL 59 IS 6 BP 1620 EP 1632 DI 10.1109/TBME.2012.2190984 PG 13 WC Engineering, Biomedical SC Engineering GA 944ZQ UT WOS:000304242700014 PM 22434795 ER PT J AU Nyante, SJ Graubard, BI Li, Y McQuillan, GM Platz, EA Rohrmann, S Bradwin, G McGlynn, KA AF Nyante, S. J. Graubard, B. I. Li, Y. McQuillan, G. M. Platz, E. A. Rohrmann, S. Bradwin, G. McGlynn, K. A. TI Trends in sex hormone concentrations in US males: 1988-1991 to 1999-2004 SO INTERNATIONAL JOURNAL OF ANDROLOGY LA English DT Article DE androstanediol glucuronide; epidemiology; estradiol; National Health and Nutrition Examination Survey; sex hormone-binding globulin; testosterone ID TESTICULAR DYSGENESIS SYNDROME; LIFE-STYLE FACTORS; SERUM TESTOSTERONE LEVELS; COMMUNITY-DWELLING MEN; OLDER AFRICAN-AMERICAN; CARDIA MALE HORMONE; IN-UTERO EXPOSURE; MIDDLE-AGED MEN; BODY-MASS INDEX; BINDING GLOBULIN AB Previous studies suggest that male testosterone concentrations have declined over time. To explore this in a large US population, we examined testosterone and free testosterone concentrations in National Health and Nutrition Examination Surveys (NHANES) from 19881991 and 19992004. We also examined sex hormone-binding globulin (SHBG), estradiol, and androstanediol glucuronide (3a-diol-G) over the same period. Non-Hispanic white, non-Hispanic black, and Mexican-American men from 19881991 and 19992004 NHANES surveys who were =20 years old and had serum from morning blood draws were included in this analysis (19881991: N = 1,413; 19992004: N = 902). Testosterone, estradiol and SHBG were measured by competitive electrochemiluminescence immunoassays and 3a-diol-G was measured by enzyme immunoassay. Free testosterone was calculated using testosterone and SHBG values. Adjusted mean hormone concentrations were estimated using linear regression, accounting for NHANES sampling weights and design, age, race/ethnicity, body mass index, waist circumference, alcohol use and smoking. Differences in adjusted mean concentrations (?) and two-sided p-values were calculated; p < 0.05 was statistically significant. Overall, 3a-diol-G and estradiol declined between 19881991 and 19992004, but there was little change in testosterone, free testosterone, or SHBG (?: 3a-diol-G = -1.83 ng/mL, p < 0.01; estradiol = -6.07 pg/mL, p < 0.01; testosterone = -0.03 ng/mL, p = 0.75; free testosterone = -0.001 ng/mL, p = 0.67; SHBG = -1.17 nmol/L, p = 0.19). Stratification by age and race revealed that SHBG and 3a-diol-G declined among whites 2044 years old (?: SHBG = -5.14 nmol/L, p < 0.01; 3a-diol-G = -2.89 ng/mL, p < 0.01) and free testosterone increased among blacks 2044 years old (?: 0.014 ng/mL, p = 0.03). Estradiol declined among all ages of whites and Mexican-Americans. In conclusion, there was no evidence for testosterone decline between 19881991 and 19992004 in the US general population. Subgroup analyses suggest that SHBG and 3a-diol-G declined in young white men, estradiol declined in white and Mexican-American men, and free testosterone increased in young black men. These changes may be related to the increasing prevalence of reproductive disorders in young men. C1 [Nyante, S. J.; Graubard, B. I.; McGlynn, K. A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Li, Y.] Univ Texas Arlington, Dept Math, Arlington, TX 76019 USA. [McQuillan, G. M.] Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Platz, E. A.] Johns Hopkins Univ, Dept Epidemiol, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Rohrmann, S.] Univ Zurich, Inst Social & Prevent Med, Div Canc Epidemiol & Prevent, CH-8006 Zurich, Switzerland. [Bradwin, G.] Harvard Univ, Sch Med, Dept Lab Med, Boston, MA USA. [Bradwin, G.] Childrens Hosp, Boston, MA 02115 USA. RP Nyante, SJ (reprint author), 6120 Execut Blvd,EPS 5029,MSC 7234, Rockville, MD 20852 USA. EM sarah.nyante@nih.gov FU National Cancer Institute, USA; Johns Hopkins Medical Institutions FX This research was supported by the Intramural Research Program of the National Cancer Institute, USA. The measurement of sex steroid hormone concentrations in 1988-1991 NHANES participants was supported by the Maryland Cigarette Restitution Fund Research Grant Program at the Johns Hopkins Medical Institutions. NR 37 TC 14 Z9 14 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-6263 J9 INT J ANDROL JI Int. J. Androl. PD JUN PY 2012 VL 35 IS 3 BP 456 EP 466 DI 10.1111/j.1365-2605.2011.01230.x PG 11 WC Andrology SC Endocrinology & Metabolism GA 946IB UT WOS:000304343800025 PM 22150314 ER PT J AU von Marschall, Z Mok, S Phillips, MD McKnight, DA Fisher, LW AF von Marschall, Zofia Mok, Seeun Phillips, Matthew D. McKnight, Dianalee A. Fisher, Larry W. TI Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects in both dentinogenesis imperfecta and dentin dysplasia by entrapping normal DSPP SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE DENTINOGENESIS IMPERFECTA; DENTIN DYSPLASIA; DENTIN SIALOPHOSPHOPROTEIN; DSPP; ENDOPLASMIC RETICULUM TRAFFICKING; DMP1; OSTEOPONTIN; SPP1 ID PHOSPHOPROTEIN FRAMESHIFT MUTATIONS; GENE; EXPRESSION; DEFECTS; BONE; HUMAN-CHROMOSOME-4; OSTEOPONTIN; DISORDERS; PRODUCTS; PROTEINS AB Families with nonsyndromic dentinogenesis imperfecta (DGI) and the milder, dentin dysplasia (DD), have mutations in one allele of the dentin sialophosphoprotein (DSPP) gene. Because loss of a single Dspp allele in mice (and likely, humans) causes no dental phenotype, the mechanism(s) underling the dominant negative effects were investigated. DSPP mutations occur in three classes. (The first class, the mid-leader missense mutation, Y6D, was not investigated in this report.) All other 5' mutations of DSPP result in changes/loss in the first three amino acids (isoleucine-proline-valine [IPV]) of mature DSPP or, for the A15V missense mutation, some retention of the hydrophobic leader sequence. All of this second class of mutations caused mutant DSPP to be retained in the rough endoplasmic reticulum (rER) of transfected HEK293 cells. Trafficking out of the rER by coexpressed normal DSPP was reduced in a dose-responsive manner, probably due to formation of Ca2+-dependent complexes with the retained mutant DSPP. IPV-like sequences begin many secreted Ca2+-binding proteins, and changing the third amino acid to the charged aspartate (D) in three other acidic proteins also caused increased rER accumulation. Both the leader-retaining A15V and the long string of hydrophobic amino acids resulting from all known frameshift mutations within the 3'-encoded Ca2+-binding repeat domain (third class of mutations) caused retention by association of the mutant proteins with rER membranes. More 5' frameshift mutations result in longer mutant hydrophobic domains, but the milder phenotype, DD, probably due to lower effectiveness of the remaining, shorter Ca2+-binding domain in capturing normal DSPP protein within the rER. This study presents evidence of a shared underlying mechanism of capturing of normal DSPP by two different classes of DSPP mutations and offers an explanation for the mild (DD-II) versus severe (DGI-II and III) nonsyndromic dentin phenotypes. Evidence is also presented that many acidic, Ca2+-binding proteins may use the same IPV-like receptor/pathway for exiting the rER. (C) 2012 American Society for Bone and Mineral Research. C1 [von Marschall, Zofia; Mok, Seeun; Phillips, Matthew D.; McKnight, Dianalee A.; Fisher, Larry W.] NIDCR, Craniofacial & Skeletal Dis Branch, NIH, DHHS, Bethesda, MD USA. FU NIH, NIDCR FX This work was supported by the Intramural Research Program of the NIH, NIDCR. NR 39 TC 15 Z9 17 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUN PY 2012 VL 27 IS 6 BP 1309 EP 1321 DI 10.1002/jbmr.1573 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 943QY UT WOS:000304141500009 PM 22392858 ER PT J AU Friedman, DB Johnson, KM Owens, OL Thomas, TL Dawkins, DS Gansauer, L Bartelt, S Waddell, NM Talley, PJ Bearden, JD Hebert, JR AF Friedman, Daniela B. Johnson, Kim M. Owens, Otis L. Thomas, Tracey L. Dawkins, DeLisa S. Gansauer, Lucy Bartelt, Sharon Waddell, Nancy M. Talley, Pastor J. Bearden, James D., III Hebert, James R. TI Developing Partnerships and Recruiting Dyads for a Prostate Cancer Informed Decision Making Program: Lessons Learned From a Community-Academic-Clinical Team SO JOURNAL OF CANCER EDUCATION LA English DT Article DE African-American men and women; Community-based participatory research; Research partnerships; Recruitment; Cancer communication; Multi-media ID PREVENTION TRIAL; MINORITY RECRUITMENT; AFRICAN-AMERICANS; SCREENING TRIAL; PARTICIPATION; MORTALITY; WOMEN; POPULATIONS; RETENTION; COUPLES AB Prostate cancer (PrCA) is the most commonly diagnosed non-skin cancer among men. PrCA mortality in African-American (AA) men in South Carolina is similar to 50% higher than for AAs in the U.S as a whole. AA men also have low rates of participation in cancer research. This paper describes partnership development and recruitment efforts of a Community-Academic-Clinical research team for a PrCA education intervention with AA men and women that was designed to address the discordance between high rates of PrCA mortality and limited participation in cancer research. Guided by Vesey's framework on recruitment and retention of minority groups in research, recruitment strategies were selected and implemented following multiple brainstorming sessions with partners having established community relationships. Based on findings from these sessions culturally appropriate strategies are recommended for recruiting AA men and women for PrCA education research. Community-based research recruitment challenges and lessons learned are presented. C1 [Friedman, Daniela B.; Owens, Otis L.; Thomas, Tracey L.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Hlth Promot Educ & Behav, Columbia, SC 29208 USA. [Friedman, Daniela B.; Owens, Otis L.; Thomas, Tracey L.; Hebert, James R.] Univ S Carolina, Statewide Canc Prevent & Control Program, Columbia, SC 29208 USA. [Johnson, Kim M.; Dawkins, DeLisa S.; Gansauer, Lucy; Bartelt, Sharon; Waddell, Nancy M.; Talley, Pastor J.; Bearden, James D., III] Gibbs Canc Ctr, Spartanburg Reg Healthcare Syst, Natl Canc Inst Community Canc Ctr Program, Spartanburg, SC USA. [Hebert, James R.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. RP Friedman, DB (reprint author), Univ S Carolina, Arnold Sch Publ Hlth, Dept Hlth Promot Educ & Behav, 800 Sumter St,Room 220B, Columbia, SC 29208 USA. EM dbfriedman@sc.du FU National Cancer Institute (NCI) [U54 CA153461-01]; Cancer Training Branch of the NCI [K05 CA136975] FX Funded by the National Cancer Institute (NCI) Community Networks Program Centers U54 CA153461-01 (PI: Hebert; Project Leader: Friedman). Partially supported by an Established Investigator Award in Cancer Prevention and Control from the Cancer Training Branch of the NCI to J.R. Hebert (K05 CA136975). We acknowledge the community advisory panel, Spartanburg Regional Gibbs Cancer Center, NCI Community Clinical Oncology Program and NCI Community Cancer Centers Program partners, Dawn Skaggs, Bruce Grant, RN, and study participants. NR 39 TC 16 Z9 16 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD JUN PY 2012 VL 27 IS 2 BP 243 EP 249 DI 10.1007/s13187-012-0353-0 PG 7 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 943SC UT WOS:000304144500006 PM 22528633 ER PT J AU Nguyen, AB Belgrave, FZ AF Nguyen, Anh B. Belgrave, Faye Z. TI Health Sources of Cancer Screening Knowledge for Vietnamese Women SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Health sources; Cancer screening; Vietnamese women ID CERVICAL-CANCER; BREAST; COMMUNICATION; MAMMOGRAPHY; PERCEPTIONS; ATTITUDES; OUTREACH; RISK AB The study examined sources of health information among Vietnamese women and whether these sources were associated with cancer screening outcomes. One hundred eleven participants completed a questionnaire with measures of breast and cervical cancer screening attitudes, efficacy, and behavior. A factor analysis of items that measured sources for information on cancer screening produced three factors: English media sources, Vietnamese media sources, and informal sources. These sources were included along with demographic variables in regression analyses to predict cancer screening outcomes. Results indicated that using informal sources for breast screening information predicted positive attitudes toward breast cancer screening and efficacy for breast and cervical cancer screening. Reliance on Vietnamese media sources was associated with lower cervical screening efficacy. Being older, having health insurance, and a higher income were associated with favorable cancer screening outcomes. The findings suggest that cancer screening programs for Vietnamese women should take into consideration preferred mediums for receiving health information. C1 [Nguyen, Anh B.] Harvard Univ, Canc Prevent Fellowship Program, Natl Canc Inst, Sch Publ Hlth, Boston, MA 02115 USA. [Belgrave, Faye Z.] Virginia Commonwealth Univ, Richmond, VA 23220 USA. RP Nguyen, AB (reprint author), Harvard Univ, Canc Prevent Fellowship Program, Natl Canc Inst, Sch Publ Hlth, 677 Huntington Ave,Box 656, Boston, MA 02115 USA. EM Anguyen@hsph.harvard.edu; fzbelgra@vcu.edu FU Ruth L. Kirschstein National Research Service Award [F31]; National Cancer Institute (NCI) [5F31CA136235] FX This study was supported by a Ruth L. Kirschstein National Research Service Award (F31), the National Cancer Institute (NCI), awarded to the first author. Grant #: 5F31CA136235. NR 25 TC 2 Z9 2 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD JUN PY 2012 VL 27 IS 2 BP 320 EP 326 DI 10.1007/s13187-011-0299-7 PG 7 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 943SC UT WOS:000304144500018 PM 22160818 ER PT J AU Malati, CY Robertson, SM Hunt, JD Chairez, C Alfaro, RM Kovacs, JA Penzak, SR AF Malati, Christine Y. Robertson, Sarah M. Hunt, Jennifer D. Chairez, Cheryl Alfaro, Raul M. Kovacs, Joseph A. Penzak, Scott R. TI Influence of Panax ginseng on Cytochrome P450 (CYP)3A and P-glycoprotein (P-gp) Activity in Healthy Participants SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE HIV; Panax ginseng; cytochrome P450; drug interaction; midazolam; herb ID ST-JOHNS-WORT; FEXOFENADINE PHARMACOKINETICS; FUNCTIONAL-CHARACTERIZATION; ALTERNATIVE MEDICINE; PHENOTYPING PROBES; DRUG-INTERACTIONS; HEPATIC-UPTAKE; CYP3A ACTIVITY; GINKGO-BILOBA; CACO-2 CELLS AB A number of herbal preparations have been shown to interact with prescription medications secondary to modulation of cytochrome P450 (CYP) and/or P-glycoprotein (P-gp). The purpose of this study was to determine the influence of Panax ginseng on CYP3A and P-gp function using the probe substrates midazolam and fexofenadine, respectively. Twelve healthy participants (8 men) completed this open-label, single-sequence pharmacokinetic study. Healthy volunteers received single oral doses of midazolam 8 mg and fexofenadine 120 mg, before and after 28 days of P ginseng 500 mg twice daily. Midazolam and fexofenadine pharmacokinetic parameter values were calculated and compared before and after P ginseng administration. Geometric mean ratios (postginseng/preginseng) for midazolam area under the concentration-time curve from zero to infinity (AUC(0-infinity)), half-life (t(1/2)), and maximum concentration (C-max) were significantly reduced at 0.66 (0.55-0.78), 0.71 (0.53-0.90), and 0.74 (0.56-0.93), respectively. Conversely, fexofenadine pharmacokinetics were unaltered by P ginseng administration. Based on these results, P ginseng appeared to induce CYP3A activity in the liver and possibly the gastrointestinal tract. Patients taking P ginseng in combination with CYP3A substrates with narrow therapeutic ranges should be monitored closely for adequate therapeutic response to the substrate medication. C1 [Malati, Christine Y.; Alfaro, Raul M.; Penzak, Scott R.] NIH, Clin Pharmacokinet Res Lab, Dept Pharm, Clin Res Ctr, Bethesda, MD 20892 USA. [Robertson, Sarah M.] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Dept Hlth & Human Serv, Silver Spring, MD USA. [Hunt, Jennifer D.; Chairez, Cheryl] NIAID, NIH, Bethesda, MD 20892 USA. [Kovacs, Joseph A.] NIH, Dept Crit Care Med, Clin Res Ctr, Bethesda, MD 20892 USA. RP Penzak, SR (reprint author), NIH, Ctr Clin, Dept Pharm, Bldg 10,1N 257, Bethesda, MD 20892 USA. EM spenzak@mail.cc.nih.gov FU National Institutes of Health (NIH) Clinical Center Pharmacy Department; National Institute of Allergy and Infectious Diseases (NIAID) FX This research was financially supported by the Intramural Research Programs of the National Institutes of Health (NIH) Clinical Center Pharmacy Department and the National Institute of Allergy and Infectious Diseases (NIAID). NR 45 TC 31 Z9 36 U1 2 U2 20 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JUN PY 2012 VL 52 IS 6 BP 932 EP 939 DI 10.1177/0091270011407194 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 944UI UT WOS:000304228900015 PM 21646440 ER PT J AU Huestis, DL Yaro, AS Traore, AI Dieter, KL Nwagbara, JI Bowie, AC Adamou, A Kassogue, Y Diallo, M Timbine, S Dao, A Lehmann, T AF Huestis, Diana L. Yaro, Alpha S. Traore, Adama I. Dieter, Kathryne L. Nwagbara, Juliette I. Bowie, Aleah C. Adamou, Abdoulaye Kassogue, Yaya Diallo, Moussa Timbine, Seydou Dao, Adama Lehmann, Tovi TI Seasonal variation in metabolic rate, flight activity and body size of Anopheles gambiae in the Sahel SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Article DE aestivation; gonotrophic cycle; malaria vector; metabolism; respiration; seasonality; temperature ID MALARIA VECTOR CONTROL; SUMMER DIAPAUSE; CULEX-PIPIENS; DRY SEASON; DESICCATION RESISTANCE; WATER-LOSS; TEMPERATURE; FLY; PHYSIOLOGY; MOSQUITOS AB Malaria in Africa is vectored primarily by the Anopheles gambiae complex. Although the mechanisms of population persistence during the dry season are not yet known, targeting dry season mosquitoes could provide opportunities for vector control. In the Sahel, it appears likely that M-form A. gambiae survive by aestivation (entering a dormant state). To assess the role of eco-physiological changes associated with dry season survival, we measured body size, flight activity and metabolic rate of wild-caught mosquitoes throughout 1. year in a Sahelian locality, far from permanent water sources, and at a riparian location adjacent to the Niger River. We found significant seasonal variation in body size at both the Sahelian and riparian sites, although the magnitude of the variation was greater in the Sahel. For flight activity, significant seasonality was only observed in the Sahel, with increased flight activity in the wet season when compared with that just prior to and throughout the dry season. Whole-organism metabolic rate was affected by numerous biotic and abiotic factors, and a significant seasonal component was found at both locations. However, assay temperature accounted completely for seasonality at the riparian location, while significant seasonal variation remained after accounting for all measured variables in the Sahel. Interestingly, we did not find that mean metabolic rate was lowest during the dry season at either location, contrary to our expectation that mosquitoes would conserve energy and increase longevity by reducing metabolism during this time. These results indicate that mosquitoes may use mechanisms besides reduced metabolic rate to enable survival during the Sahelian dry season. C1 [Huestis, Diana L.; Dieter, Kathryne L.; Nwagbara, Juliette I.; Bowie, Aleah C.; Lehmann, Tovi] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Yaro, Alpha S.; Traore, Adama I.; Adamou, Abdoulaye; Kassogue, Yaya; Diallo, Moussa; Timbine, Seydou; Dao, Adama] Univ Bamako, Malaria Res & Training Ctr, Bamako, Mali. RP Huestis, DL (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM diana.huestis@nih.gov OI Huestis, Diana/0000-0001-6649-4785 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health [107816] FX This research was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (Project 107816). Deposited in PMC for release after 12 months. NR 63 TC 17 Z9 17 U1 1 U2 15 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 JUN PY 2012 VL 215 IS 12 BP 2013 EP 2021 DI 10.1242/jeb.069468 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 947IH UT WOS:000304423200007 PM 22623189 ER PT J AU Pandiyan, P Lenardo, M AF Pandiyan, Pushpa Lenardo, Michael TI Comment on "Cutting Edge: Regulatory T Cells Do Not Mediate Suppression via Programmed Cell Death Pathways" SO JOURNAL OF IMMUNOLOGY LA English DT Letter C1 [Pandiyan, Pushpa; Lenardo, Michael] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Pandiyan, P (reprint author), NIAID, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ppandiyan@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 8 TC 1 Z9 1 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2012 VL 188 IS 11 BP 5203 EP 5204 DI 10.4049/jimmunol.1290023 PG 2 WC Immunology SC Immunology GA 945NC UT WOS:000304282200001 PM 22611245 ER PT J AU Draper, DW Gowdy, KM Madenspacher, JH Wilson, RH Whitehead, GS Nakano, H Pandiri, AR Foley, JF Remaley, AT Cook, DN Fessler, MB AF Draper, David W. Gowdy, Kymberly M. Madenspacher, Jennifer H. Wilson, Rhonda H. Whitehead, Gregory S. Nakano, Hideki Pandiri, Arun R. Foley, Julie F. Remaley, Alan T. Cook, Donald N. Fessler, Michael B. TI ATP Binding Cassette Transporter G1 Deletion Induces IL-17-Dependent Dysregulation of Pulmonary Adaptive Immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ALLERGIC AIRWAY INFLAMMATION; LIVER-X-RECEPTOR; T-CELLS; CHOLESTEROL ACCUMULATION; ALVEOLAR MACROPHAGES; HOST-DEFENSE; EXPRESSION; ABCG1; ACTIVATION; ASTHMA AB Mice with genetic deletion of the cholesterol transporter ATP binding cassette G1 (ABCG1) have pulmonary lipidosis and enhanced innate immune responses in the airway. Whether ABCG1 regulates adaptive immune responses to the environment is unknown. To this end, Abcg1(+/+) and Abcg1(-/-) mice were sensitized to OVA via the airway using low-dose LPS as an adjuvant, and then challenged with OVA aerosol. Naive Abcg1(-/-) mice displayed increased B cells, CD4(+) T cells, CD8(+) T cells, and dendritic cells (DCs) in lung and lung-draining mediastinal lymph nodes, with lung CD11b(+) DCs displaying increased CD80 and CD86. Upon allergen sensitization and challenge, the Abeg1(-/-) airway, compared with Abcgr1(+), displayed reduced Th2 responses (IL-4, IL-5, eosinophils), increased neutrophils and IL-17, but equivalent airway hyperresponsiveness. Reduced Th2 responses were also found using standard i.p. OVA sensitization with aluminum hydroxide adjuvant. Mediastinal lymph nodes from airway-sensitized Abcg1(-/-) mice produced reduced IL-5 upon ex vivo OVA challenge. Abeg1(-/-) CD4(+) T cells displayed normal ex vivo differentiation, whereas Abcg1(-/-) DCs were found paradoxically to promote Th2 polarization. Th17 cells, IL-17(+) gamma delta T cells, and IL-17(+) neutrophils were all increased in Abcg1(-/-) lungs, suggesting Th17 and non-Th17 sources of IL-17 excess. Neutralization of IL-17 prior to challenge normalized eosinophils and reduced neutrophilia in the Abcg1(-/-) airway. We conclude that Abcg1(-/-) mice display IL-17 mediated suppression of eosinophilia and enhancement of neutrophilia in the airway following allergen sensitization and challenge. These findings identify ABCG1 as a novel integrator of cholesterol homeostasis and adaptive immune programs. The Journal of Immunology, 2012, 188: 5327-5336. C1 [Draper, David W.; Gowdy, Kymberly M.; Madenspacher, Jennifer H.; Wilson, Rhonda H.; Whitehead, Gregory S.; Nakano, Hideki; Cook, Donald N.; Fessler, Michael B.] NIEHS, Lab Resp Biol, Div Intramural Res, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Pandiri, Arun R.; Foley, Julie F.] NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Pulm & Vasc Med Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Fessler, MB (reprint author), NIEHS, Lab Resp Biol, Div Intramural Res, NIH,Dept Hlth & Human Serv, 111 TW Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, NC 27709 USA. EM fesslerm@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES102005] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Grant Z01 ES102005). NR 43 TC 12 Z9 12 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2012 VL 188 IS 11 BP 5327 EP 5336 DI 10.4049/jimmunol.1101605 PG 10 WC Immunology SC Immunology GA 945NC UT WOS:000304282200019 PM 22539789 ER PT J AU Ito, T Smrz, D Jung, MY Bandara, G Desai, A Smrzova, S Kuehn, HS Beaven, MA Metcalfe, DD Gilfillan, AM AF Ito, Tomonobu Smrz, Daniel Jung, Mi-Yeon Bandara, Geethani Desai, Avanti Smrzova, Sarka Kuehn, Hye Sun Beaven, Michael A. Metcalfe, Dean D. Gilfillan, Alasdair M. TI Stem Cell Factor Programs the Mast Cell Activation Phenotype SO JOURNAL OF IMMUNOLOGY LA English DT Article ID C-KIT LIGAND; WISKOTT-ALDRICH-SYNDROME; CONNECTIVE-TISSUE-TYPE; FAMILY KINASE HCK; MEDIATOR RELEASE; ACTIN CYTOSKELETON; IMMUNOGLOBULIN-E; BONE-MARROW; SIGNALING PATHWAYS; RBL-2H3 CELLS AB Mast cells, activated by Ag via Fc epsilon RI, release an array of proinflammatory mediators that contribute to allergic disorders, such as asthma and anaphylaxis. The KIT ligand, stem cell factor (SCF), is critical for mast cell expansion, differentiation, and survival, and under acute conditions, it enhances mast cell activation. However, extended SCF exposure in vivo conversely protects against fatal Ag-mediated anaphylaxis. In investigating this dichotomy, we identified a novel mode of regulation of the mast cell activation phenotype through SCF-mediated programming. We found that mouse bone marrow-derived mast cells chronically exposed to SCF displayed a marked attenuation of Fc epsilon RI-mediated degranulation and cytokine production. The hyporesponsive phenotype was not a consequence of altered signals regulating calcium flux or protein kinase C, but of ineffective cytoskeletal reorganization with evidence implicating a downregulation of expression of the Src kinase Hck. Collectively, these findings demonstrate a major role for SCF in the homeostatic control of mast cell activation with potential relevance to mast cell-driven disease and the development of novel approaches for the treatment of allergic disorders. The Journal of Immunology, 2012, 188: 5428-5437. C1 [Ito, Tomonobu; Smrz, Daniel; Jung, Mi-Yeon; Bandara, Geethani; Desai, Avanti; Smrzova, Sarka; Kuehn, Hye Sun; Metcalfe, Dean D.; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Gilfillan, AM (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C206,10 Ctr Dr MSC 1881, Bethesda, MD 20892 USA. EM agilfillan@niaid.nih.gov RI Smrz, Daniel/D-4853-2014 OI Smrz, Daniel/0000-0003-0143-8744 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute within the National Institutes of Health FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute within the National Institutes of Health. NR 52 TC 25 Z9 27 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2012 VL 188 IS 11 BP 5428 EP 5437 DI 10.4049/jimmunol.1103366 PG 10 WC Immunology SC Immunology GA 945NC UT WOS:000304282200029 PM 22529299 ER PT J AU Daly, J Bebenek, K Watt, DL Richter, K Jiang, CC Zhao, ML Ray, M McGregor, WG Kunkel, TA Diaz, M AF Daly, Janssen Bebenek, Katarzyna Watt, Danielle L. Richter, Kathleen Jiang, Chuancang Zhao, Ming-Lang Ray, Madhumita McGregor, W. Glenn Kunkel, Thomas A. Diaz, Marilyn TI Altered Ig Hypermutation Pattern and Frequency in Complementary Mouse Models of DNA Polymerase zeta Activity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CLASS SWITCH RECOMBINATION; CYTIDINE DEAMINASE AID; SOMATIC HYPERMUTATION; IMMUNOGLOBULIN GENES; EMBRYONIC LETHALITY; CATALYTIC SUBUNIT; LUPUS NEPHRITIS; MRL/LPR MICE; REV31 GENE; B-CELLS AB To test the hypothesis that DNA polymerase zeta participates in Ig hypermutation, we generated two mouse models of Pol zeta function: a B cell-specific conditional knockout and a knock-in strain with a Pol zeta mutagenesis-enhancing mutation. Pol zeta-deficient B cells had a reduction in mutation frequency at Ig loci in the spleen and in Peyer's patches, whereas knock-in mice with a mutagenic Pol zeta displayed a marked increase in mutation frequency in Peyer's patches, revealing a pattern that was similar to mutations in yeast strains with a homologous mutation in the gene encoding the catalytic subunit of Pol zeta. Combined, these data are best explained by a direct role for DNA polymerase zeta in Ig hypermutation. The Journal of Immunology, 2012, 188: 5528-5537. C1 [Diaz, Marilyn] NIEHS, Somat Hypermutat Grp, Mol Genet Lab, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Bebenek, Katarzyna; Watt, Danielle L.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Bebenek, Katarzyna; Watt, Danielle L.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [McGregor, W. Glenn] Univ Louisville, Sch Med, James Graham Brown Canc Ctr, Dept Pharmacol & Toxicol, Louisville, KY 40202 USA. RP Diaz, M (reprint author), NIEHS, Somat Hypermutat Grp, Mol Genet Lab, NIH,Dept Hlth & Human Serv, D3-01,Bldg 101,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM diaz@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences, Division of Intramural Research [Z01 ES101603, Z01 ES065070] FX This work was supported by the National Institutes of Health, National Institute of Environmental Health Sciences, Division of Intramural Research, Project Z01 ES101603 (to M.D.) and Project Z01 ES065070 (to T.A.K.). NR 40 TC 19 Z9 19 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2012 VL 188 IS 11 BP 5528 EP 5537 DI 10.4049/jimmunol.1102629 PG 10 WC Immunology SC Immunology GA 945NC UT WOS:000304282200039 PM 22547703 ER PT J AU Derive, M Bouazza, Y Sennoun, N Marchionni, S Quigley, L Washington, V Massin, F Max, JP Ford, J Alauzet, C Levy, B McVicar, DW Gibot, S AF Derive, Marc Bouazza, Youcef Sennoun, Nacira Marchionni, Sandra Quigley, Laura Washington, Valance Massin, Frederic Max, Jean-Pierre Ford, Jill Alauzet, Corentine Levy, Bruno McVicar, Daniel W. Gibot, Sebastien TI Soluble Trem-like Transcript-1 Regulates Leukocyte Activation and Controls Microbial Sepsis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MYELOID CELLS-1 TREM-1; SEPTIC SHOCK; PATHWAY MODULATION; CRYSTAL-STRUCTURE; CUTTING EDGE; INFLAMMATION; PLATELETS; MACROPHAGES; NEUTROPHILS; EXPRESSION AB The triggering receptor expressed on myeloid cells (TREM)-1 plays a crucial role during the onset of sepsis by amplifying the host immune response. The TREM-like transcript-1 (TLT-1) belongs to the TREM family, is selectively expressed on activated platelets, and is known to facilitate platelet aggregation through binding to fibrinogen. In this study, we show that a soluble form of TLT-1 is implicated in the regulation of inflammation during sepsis by dampening leukocyte activation and modulating platelet-neutrophil crosstalk. A 17-aa sequence of the TLT-1 extracellular domain (LR17) is responsible for this activity through competition with the TREM-1 ligand. Whereas early or late LR17 treatment of septic mice improves survival, trem1-1(-/-) animals are highly susceptible to polymicrobial infection. The present findings identify platelet-derived soluble TLT-1 as a potent endogenous regulator of sepsis-associated inflammation and open new therapeutic perspectives. We anticipate soluble TLT-1 to be important in regulating leukocyte activation during other noninfectious inflammatory disorders. The Journal of Immunology, 2012, 188: 5585-5592. C1 [Gibot, Sebastien] Ctr Hosp Univ Nancy, Serv Reanimat Med, Hop Cent, F-54000 Nancy, France. [Derive, Marc; Bouazza, Youcef; Sennoun, Nacira; Levy, Bruno; Gibot, Sebastien] Nancy Univ, Fac Med, Contrat Avenir INSERM, Grp Choc, F-54000 Nancy, France. [Marchionni, Sandra; Massin, Frederic] Ctr Hosp Univ Nancy, Immunol Lab, Hop Brabois, F-54000 Nancy, France. [Quigley, Laura; Ford, Jill; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Washington, Valance] Cent Caribbean Univ, Lab Anat & Cell Biol, Bayamon, PR 00960 USA. [Max, Jean-Pierre] Nancy Univ, Fac Med, INSERM U961, F-54000 Nancy, France. [Alauzet, Corentine] Nancy Univ, Fac Med, Bacteriol Lab, EA 4369, F-54000 Nancy, France. RP Gibot, S (reprint author), Ctr Hosp Univ Nancy, Serv Reanimat Med, Hop Cent, 29 Blvd Marechal Lattre de Tassigny, F-54000 Nancy, France. EM s.gibot@chu-nancy.fr RI McVicar, Daniel/G-1970-2015 NR 31 TC 20 Z9 20 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2012 VL 188 IS 11 BP 5585 EP 5592 DI 10.4049/jimmunol.1102674 PG 8 WC Immunology SC Immunology GA 945NC UT WOS:000304282200044 PM 22551551 ER PT J AU Cai, SS Batra, S Wakamatsu, N Pacher, P Jeyaseean, S AF Cai, Shanshan Batra, Sanjay Wakamatsu, Nobuko Pacher, Pal Jeyaseean, Samithamby TI NLRC4 Inflammasome-Mediated Production of IL-1 beta Modulates Mucosal Immunity in the Lung against Gram-Negative Bacterial Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; PULMONARY HOST-DEFENSE; ESCHERICHIA-COLI PNEUMONIA; COLONY-STIMULATING FACTOR; III SECRETION APPARATUS; TOLL-LIKE RECEPTORS; NEUTROPHIL RECRUITMENT; KLEBSIELLA-PNEUMONIAE; CASPASE-1 ACTIVATION; NALP3 INFLAMMASOME AB Bacterial flagellin is critical to mediate NLRC4 inflammasome-dependent caspase-1 activation. However, Shigella flexneri, a nonflagellated bacterium, and a flagellin (fliC) knockout strain of Pseudomonas aeruginosa are known to activate NLRC4 in bone marrow-derived macrophages. Furthermore, the flagellin-deficient fliC strain of P aeruginosa was used in a mouse model of peritonitis to show the requirement of NLRC4. In a model of pulmonary P aeruginosa infection, flagellin was shown to be essential for the induction of NLRC4-dependent caspase-1 activation. Moreover, in all P aeruginosa studies, IL-1 beta production was attenuated in NLRC4(-/-) mice; however, the role of IL-1 beta in NLRC4-mediated innate immunity in the lungs against a nonflagellated bacterium was not explored. In this article, we report that NLRC4 is important for host survival and bacterial clearance, as well as neutrophil-mediated inflammation in the lungs following Klebsiella pneumoniae infection. NLRC4 is essential for K. pneumoniae-induced production of IL-1 beta, IL-17A, and neutrophil chemoattractants (keratinocyte cell-derived chemokines, MIP-2, and LPS-induced CXC chemokines) in the lungs. NLRC4 signaling in hematopoietic cells contributes to K. pneumoniae-induced lung inflammation. Furthermore, exogenous IL-1 beta, but not IL-18 or IL-17A, partially rescued survival, neutrophil accumulation, and cytokine/chemokine expression in the lungs of NLRC4(-/-) mice following infectious challenge. Furthermore, IL-1R1(-/-) mice displayed a decrease in neutrophilic inflammation in the lungs postinfection. Taken together, these findings provide novel insights into the role of NLRC4 in host defense against K. pneumoniae infection. The Journal of Immunology, 2012, 188: 5623-5635. C1 [Cai, Shanshan; Batra, Sanjay; Wakamatsu, Nobuko; Jeyaseean, Samithamby] Louisiana State Univ, Dept Pathobiol Sci, Lab Lung Biol, Ctr Expt Infect Dis Res, Baton Rouge, LA 70820 USA. [Pacher, Pal] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Jeyaseean, Samithamby] Louisiana State Univ, Hlth Sci Ctr, Sect Pulm & Crit Care, Dept Med, New Orleans, LA 70112 USA. RP Jeyaseean, S (reprint author), Louisiana State Univ, Dept Pathobiol Sci, Lab Lung Biol, Ctr Expt Infect Dis Res, Skip Bertman Dr, Baton Rouge, LA 70820 USA. EM jey@lsu.edu RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Flight Attendant Medical Research Institute [YCSA-062466]; National Institutes of Health (via the American Recovery and Reinvestment Act) [R01 HL-091958, R01 HL-091958S1] FX This work was supported by a Scientist Award from the Flight Attendant Medical Research Institute (YCSA-062466) and grants from the National Institutes of Health (R01 HL-091958 and R01 HL-091958S1 via the American Recovery and Reinvestment Act to S.J.). NR 88 TC 46 Z9 47 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2012 VL 188 IS 11 BP 5623 EP 5635 DI 10.4049/jimmunol.1200195 PG 13 WC Immunology SC Immunology GA 945NC UT WOS:000304282200048 PM 22547706 ER PT J AU Kwon, JH Lee, JH Kim, KS Chung, YW Kim, IY AF Kwon, Joon Hyun Lee, Jea Hwang Kim, Ki Soon Chung, Youn Wook Kim, Ick Young TI Regulation of Cytosolic Phospholipase A(2) Phosphorylation by Proteolytic Cleavage of Annexin A1 in Activated Mast Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROTEIN-KINASE-C; FC-EPSILON-RI; ARACHIDONIC-ACID; MEMBRANE TRANSLOCATION; EICOSANOID PRODUCTION; INTERACTION-MODEL; CALCIUM; RELEASE; RAT; DEGRANULATION AB Annexin A1 (ANXA1) is cleaved at the N terminal in some activated cells, such as macrophages, neutrophils, and epithelial cells. We previously observed that ANXA1 was proteolytically cleaved in lung extracts prepared from a murine OVA-induced asthma model. However, the cleavage and regulatory mechanisms of ANXA1 in the allergic response remain unclear. In this study, we found that ANXA1 was cleaved in both Ag-induced activated rat basophilic leukemia 2H3 (RBL-2H3) cells and bone marrow-derived mast cells. This cleavage event was inhibited when intracellular Ca2+ signaling was blocked. ANXA1-Knockdown RBL-2H3 cells produced a greater amount of eicosanoids with simultaneous upregulation of cytosolic phospholipase A(2) (cPLA(2)) activity. However, there were no changes in degranulation activity or cytokine production in the knockdown cells. We also found that cPLA(2) interacted with either full-length or cleaved ANXA1 in activated mast cells. cPLA(2) mainly interacted with full-length ANXA1 in the cytosol and cleaved ANXA1 in the membrane fraction. In addition, introduction of a cleavage-resistant ANXA1 mutant had inhibitory effects on both the phosphorylation of cPLA(2) and release of eicosanoids during the activation of RBL-2H3 cells and bone marrow-derived mast cells. These data suggest that cleavage of ANXA1 causes proinflammatory reactions by increasing the phosphorylation of cPLA(2) and production of eicosanoids during mast-cell activation. The Journal of Immunology, 2012, 188: 5665-5673. C1 [Kwon, Joon Hyun; Lee, Jea Hwang; Kim, Ki Soon; Kim, Ick Young] Korea Univ, Sch Life Sci & Biotechnol, Lab Cellular & Mol Biochem, Seoul 136701, South Korea. [Chung, Youn Wook] NHLBI, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Kim, IY (reprint author), Korea Univ, Sch Life Sci & Biotechnol, Lab Cellular & Mol Biochem, 1,5-Ka Anam Dong, Seoul 136701, South Korea. EM ickkim@korea.ac.kr FU National Research Foundation of Korea; Ministry of Education, Science and Technology [KRF-2008-313-C00548] FX This work was supported by the Basic Science Research Program through the National Research Foundation of Korea supported by the Ministry of Education, Science and Technology (KRF-2008-313-C00548). NR 50 TC 15 Z9 15 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2012 VL 188 IS 11 BP 5665 EP 5673 DI 10.4049/jimmunol.1102306 PG 9 WC Immunology SC Immunology GA 945NC UT WOS:000304282200052 PM 22539796 ER PT J AU Gai, ND Butman, JA AF Gai, Neville D. Butman, John A. TI Fast T1 mapping determined using incomplete inversion recovery look-locker 3D balanced SSFP acquisition and a simple two-parameter model fit SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE T1 map; two-parameter model; incomplete inversion recovery ID QUANTIFICATION; T-1; TRUEFISP; PULSES; TIME; MRI AB Purpose: To evaluate a fast T1 mapping technique using incomplete inversion recovery 3D balanced steady-state free precession acquisition along with a two-parameter model fit. Materials and Methods: Using Bloch simulations, we explored the two-parameter model fit for data acquired using such an acquisition scheme. The parameter space over which the fit holds good was determined through simulations. A linear correction was derived for the R1* (1/T1*) values so determined. Two phantoms and six volunteers were scanned using the described technique. Comparison scans using full recovery as well as gold standard inversion recovery spin echo were also performed. Results: The two-parameter fit works exceedingly well over a large parameter space. T1 values in the phantoms showed an error of 4.9% and 39% before correction and 0.9% and 1.6% after correction. For the six volunteers, error in T1 value was 5.3% for white matter (WM) and 2.4% for gray matter (GM) after correction, while it was 11.2% and 18.2% before correction. Conclusion: The work presented here allows for T1 map determination with higher resolution and shorter acquisition time than previously possible. The technique is especially well suited for GM/WM T1 mapping. J. Magn. Reson. Imaging 2012;. (c) 2012 Wiley Periodicals Inc. C1 [Gai, Neville D.] NIH, Radiol & Imaging Sci RAD & IS, Ctr Clin, Bethesda, MD 20892 USA. RP Gai, ND (reprint author), NIH, Radiol & Imaging Sci RAD & IS, Ctr Clin, 9000 Rockville Pike,Bldg 10,Room 1C502X, Bethesda, MD 20892 USA. EM gaind@cc.nih.gov RI Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU NIH FX Contract grant sponsor: Intramural Research Program of NIH. NR 12 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD JUN PY 2012 VL 35 IS 6 BP 1437 EP 1444 DI 10.1002/jmri.23576 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 942HP UT WOS:000304035100022 PM 22282318 ER PT J AU Mandava, A Pace, C Campbell, B Emanuel, E Grady, C AF Mandava, Amulya Pace, Christine Campbell, Benjamin Emanuel, Ezekiel Grady, Christine TI The quality of informed consent: mapping the landscape. A review of empirical data from developing and developed countries SO JOURNAL OF MEDICAL ETHICS LA English DT Review ID CLINICAL-TRIALS; RESEARCH PARTICIPANTS; PARENTAL CONSENT; MEDICAL-RESEARCH; VACCINE TRIAL; WEST-AFRICA; COMPREHENSION; INFORMATION; PERCEPTIONS; CANCER AB Objective Some researchers claim that the quality of informed consent of clinical research participants in developing countries is worse than in developed countries. To evaluate this assumption, we reviewed the available data on the quality of consent in both settings. Methods We conducted a comprehensive PubMed search, examined bibliographies and literature reviews, and consulted with international experts on informed consent in order to identify studies published from 1966 to 2010 that used quantitative methods, surveyed participants or parents of paediatric participants in actual trials, assessed comprehension and/or voluntariness, and did not involve testing particular consent interventions. Forty-seven studies met these criteria. We compared data about participant comprehension and voluntariness. The paucity of data and variation in study methodology limit comparison and preclude statistical aggregation of the data. Results and Discussion This review shows that the assertion that informed consent is worse in developing countries than in developed countries is a simplification of a complex picture. Despite the limitations of comparison, the data suggest that: (1) comprehension of study information varies among participants in both developed and developing countries, and comprehension of randomisation and placebo controlled designs is poorer than comprehension of other aspects of trials in both settings; and (2) participants in developing countries appear to be less likely than those in developed countries to say they can refuse participation in or withdraw from a trial, and are more likely to worry about the consequences of refusal or withdrawal. C1 [Mandava, Amulya; Emanuel, Ezekiel; Grady, Christine] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Pace, Christine] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Campbell, Benjamin] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. RP Grady, C (reprint author), NIH, Dept Bioeth, Bethesda, MD 20892 USA. EM cgrady@cc.nih.gov FU Department of Bioethics of the NIH Clinical Center FX This research was supported by the Department of Bioethics of the NIH Clinical Center. NR 68 TC 39 Z9 43 U1 1 U2 15 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 J9 J MED ETHICS JI J. Med. Ethics PD JUN PY 2012 VL 38 IS 6 BP 356 EP 365 DI 10.1136/medethics-2011-100178 PG 10 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 947RN UT WOS:000304447500007 PM 22313664 ER PT J AU Chen, SL Tao, PL Chu, CH Chen, SH Wu, HE Tseng, LF Hong, JS Lu, RB AF Chen, Shiou-Lan Tao, Pao-Luh Chu, Chun-Hsien Chen, Shih-Heng Wu, Hsiang-En Tseng, Leon F. Hong, Jau-Shyong Lu, Ru-Band TI Low-Dose Memantine Attenuated Morphine Addictive Behavior Through its Anti-Inflammation and Neurotrophic Effects in Rats SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Article DE Addiction; BDNF; Cytokine; Memantine; Morphine ID CONDITIONED PLACE PREFERENCE; SERUM CONCENTRATIONS; NUCLEUS-ACCUMBENS; TNF-ALPHA; BRAIN; NEURONS; EXPRESSION; BDNF; ACTIVATION; HEROIN AB Opioid abuse and dependency are international problems. Studies have shown that neuronal inflammation and degeneration might be related to the development of opioid addiction. Thus, using neuroprotective agents might be beneficial for treating opioid addiction. Memantine, an Alzheimer's disease medication, has neuroprotective effects in vitro and in vivo. In this study, we evaluated whether a low dose of memantine prevents opioid-induced drug-seeking behavior in rats and analyzed its mechanism. A conditioned-place-preference test was used to investigate the morphine-induced drug-seeking behaviors in rats. We found that a low-dose (0.2-1 mg/kg) of subcutaneous memantine significantly attenuated the chronic morphine-induced place-preference in rats. To clarify the effects of chronic morphine and low-dose memantine, serum and brain levels of cytokines and brain-derived neurotrophic factor (BDNF) were measured. After 6 days of morphine treatment, cytokine (IL-1 beta, IL-6) levels had significantly increased in serum; IL-1 beta and IL-6 mRNA levels had significantly increased in the nucleus accumbens and medial prefrontal cortex, both addiction-related brain areas; and BDNF levels had significantly decreased, both in serum and in addiction-related brain areas. Pretreatment with low-dose memantine significantly attenuated chronic morphine-induced increases in serum and brain cytokines. Low-dose memantine also significantly potentiated serum and brain BDNF levels. We hypothesize that neuronal inflammation and BDNF downregulation are related to the progression of opioid addiction. We hypothesize that the mechanism low-dose memantine uses to attenuate morphine-induced addiction behavior is its anti-inflammatory and neurotrophic effects. C1 [Chen, Shiou-Lan; Chu, Chun-Hsien; Lu, Ru-Band] Natl Cheng Kung Univ, Dept Psychiat, Coll Med & Hosp, Addict Res Ctr, Tainan 70428, Taiwan. [Tao, Pao-Luh] Natl Hlth Res Inst, Div Mental Hlth & Addict Med, Inst Populat Hlth Sci, Zhunan, Taiwan. [Wu, Hsiang-En; Tseng, Leon F.] Med Coll Wisconsin, Dept Anesthesiol, Milwaukee, WI 53226 USA. [Chu, Chun-Hsien; Chen, Shih-Heng; Hong, Jau-Shyong] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Lu, RB (reprint author), Natl Cheng Kung Univ, Dept Psychiat, Coll Med & Hosp, Addict Res Ctr, 138 Sheng Li Rd, Tainan 70428, Taiwan. EM rblu@mail.ncku.edu.tw RI Tao, Pao-Luh/F-6085-2010 FU Taiwan National Science Council [NSC 98-2627-B-006-017]; Taiwan Department of Health [DOH98-TD-I-111-DD004]; Taiwan National Health Research Institute [NHRI-EX97-9738NI]; National Cheng Kung University FX This study was supported in part by grant NSC 98-2627-B-006-017 from the Taiwan National Science Council (to RBL), grant DOH98-TD-I-111-DD004 from the Taiwan Department of Health (to RBL), grant NHRI-EX97-9738NI from the Taiwan National Health Research Institute (to RBL), and by a grant from the National Cheng Kung University Project Promote Academic Excellence and Develop a World Class Research Centers. NR 47 TC 22 Z9 22 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD JUN PY 2012 VL 7 IS 2 SI SI BP 444 EP 453 DI 10.1007/s11481-011-9337-9 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 943YQ UT WOS:000304164400015 PM 22205542 ER PT J AU Daniel, CR Sinha, R Park, Y Graubard, BI Hollenbeck, AR Morton, LM Cross, AJ AF Daniel, Carrie R. Sinha, Rashmi Park, Yikyung Graubard, Barry I. Hollenbeck, Albert R. Morton, Lindsay M. Cross, Amanda J. TI Meat Intake Is Not Associated with Risk of Non-Hodgkin Lymphoma in a Large Prospective Cohort of US Men and Women SO JOURNAL OF NUTRITION LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; CANCER-RISK; NATIONAL-INSTITUTES; POOLED ANALYSIS; CONSUMPTION; EXPOSURE; PROTEIN; MODULE AB Meat intake has been inconsistently associated with risk of non-Hodgkin lymphoma (NHL), a heterogeneous group of malignancies of the lymphoid tissue etiologically linked to immunomodulatory factors. In a large U.S. cohort, we prospectively investigated several biologically plausible mechanisms related to meat intake, including meat-cooking and meat-processing compounds, in relation to NHL risk by histologic subtype. At baseline (1995-1996), participants of the NIH-AARP Diet and Health Study completed a diet and lifestyle questionnaire (n = 492,186), and a subcohort (n = 302,162) also completed a questionnaire on meat-cooking methods and doneness levels. Over a mean of 9 y of follow-up, we identified 3611 incident cases of NHL. In multivariable Cox proportional hazards regression models, we found no association between intake of red meat, processed meat, fish, poultry, heme iron, nitrite, nitrate, animal fat, or protein and NHL risk. MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline) and DiMeIQx (2-amino-3,4,8-trimethylimidazo[4,5-f] quinoxaline), heterocyclic amines formed in meats cooked to well done at high temperatures, were inversely associated with chronic lymphocytic leukemia/small lymphocytic lymphoma [n = 979; HR (95% Cl) for the highest vs. lowest quintile of intake: 0.73 (0.55, 0.96) and 0.77 (0.61, 0.98), respectively]. In this large U.S. cohort, meat intake was not associated with NHL or any histologic subtypes of NHL. Contrary to findings in animal models and other cancer sites, meat-cooking and -processing compounds did not increase NHL risk. J. Nutr. 142: 1074-1080, 2012. C1 [Daniel, Carrie R.; Sinha, Rashmi; Park, Yikyung; Graubard, Barry I.; Morton, Lindsay M.; Cross, Amanda J.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Hollenbeck, Albert R.] AARP, Res & Strateg Anal Dept, Washington, DC USA. RP Daniel, CR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. EM carrie.daniel@nih.hhs.gov RI Morton, Lindsay/B-5234-2015; Sinha, Rashmi/G-7446-2015; OI Morton, Lindsay/0000-0001-9767-2310; Sinha, Rashmi/0000-0002-2466-7462; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute FX Supported by the Intramural Research Program of the National Cancer Institute. None of the authors had any conflicts of interest. NR 43 TC 12 Z9 12 U1 0 U2 8 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUN PY 2012 VL 142 IS 6 BP 1074 EP 1080 DI 10.3945/jn.112.158113 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 946EY UT WOS:000304335500015 PM 22535761 ER PT J AU Foreyt, J Kleinman, R Brown, RJ Lindstrom, R AF Foreyt, John Kleinman, Ronald Brown, Rebecca J. Lindstrom, Rachel TI The Use of Low-Calorie Sweeteners by Children: Implications for Weight Management SO JOURNAL OF NUTRITION LA English DT Article ID FOOD-INTAKE; BEVERAGE CONSUMPTION; ENERGY-INTAKE; TASTE RECEPTORS; CHILDHOOD OBESITY; SELF-REGULATION; UNITED-STATES; BODY-WEIGHT; ARTIFICIAL SWEETENERS; INTENSE SWEETENERS AB The rise in pediatric obesity since the 1970s has been well established in the United States and is becoming a major concern worldwide. As a potential means to help slow the obesity epidemic, low-calorie sweeteners (LCS) have gained attention as dietary tools to assist in adherence to weight loss plans or prevention of excess weight gain. Observational studies tend to show positive correlations between LCS consumption and weight gain in children and adolescents. Although the data are intriguing, these epidemiologic studies do not establish that LCS cause weight gain, because there are likely many lifestyle and genetic differences between children and families who choose to consume LCS and those who do not. Short-term randomized controlled trials have shown LCS use to be BMI neutral or to have modest weight-reducing effects in overweight and obese adolescents. The long-term effects of LCS in children and adolescents are unknown. Some compelling research is currently underway and may provide needed insight into the potential role of LCS in weight management. The paucity of data regarding the effects of LCS use in children and adolescents creates challenges in decision-making for health care providers and parents. J. Nutr. 142: 1155S-1162S, 2012. C1 [Foreyt, John] Baylor Coll Med, Houston, TX 77030 USA. [Kleinman, Ronald] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Massachusetts Gen Hosp Children, Boston, MA USA. [Brown, Rebecca J.] NIH, Bethesda, MD 20892 USA. [Lindstrom, Rachel] Amer Move Fdn, Aurora, CO USA. RP Foreyt, J (reprint author), Baylor Coll Med, Houston, TX 77030 USA. EM jforeyt@bcm.edu FU Kellogg Company; Committee on Low-Calorie Sweeteners of the North American Branch of the International Life Sciences Institute; National Institute of Diabetes, Digestive, and Kidney Diseases FX Published in a supplement to The Journal of Nutrition. Presented at the conference Low-Calorie Sweeteners, Appetite and Weight Control: What the Science Tells Us, held in Washington, DC, April 7-8, 2011. The conference was sponsored by the Committee on Low-calorie Sweeteners of the International Life Sciences Institute North America. The views expressed in these papers are not necessarily those of the supplement coordinator or guest editors. The supplement coordinator for this supplement was Adam Drewnowski, University of Washington. Supplement Coordinator disclosures: Adam Drewnowski received travel reimbursement for participation in the Low-Calorie Sweeteners Conference. The supplement is the responsibility of the Guest Editor to whom the Editor of The Journal of Nutrition has delegated supervision of both technical conformity to the published regulations of The Journal of Nutrition and general oversight of the scientific merit of each article. The Guest Editor for this supplement was Sibylle Kranz. Guest Editor disclosure: Sibylle Kranz has received funding from The Kellogg Company to conduct research projects unrelated to this supplement material. She has also been an invited speaker at a roundtable discussion funded by The Kellogg Company. Publication costs for this supplement were defrayed in part by the payment of page charges. This publication must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, Editor, or Editorial Board of The Journal of Nutrition.; Supported by the Committee on Low-Calorie Sweeteners of the North American Branch of the International Life Sciences Institute. J. Foreyt, R. Kleinman, and R. Lindstrom received a modest honorarium for their participation in the workshop and development of the manuscript, as well as travel funding to attend the workshop.; Author disclosures: R. Kleinman has served on an advisory committee for Ajinomoto. J. Foreyt has received consulting fees, honoraria, and unrestricted grants from food, beverage, and pharmaceutical companies and from government and nonprofit sources. R. J. Brown's research was supported in part by the Intramural Research Program of the National Institute of Diabetes, Digestive, and Kidney Diseases. R. Lindstrom, no conflicts of interest. NR 64 TC 10 Z9 10 U1 10 U2 56 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUN PY 2012 VL 142 IS 6 BP 1155S EP 1162S DI 10.3945/jn.111.149609 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 946EY UT WOS:000304335500028 PM 22573780 ER PT J AU Swanson, CA Zimmermann, MB Skeaff, S Pearce, EN Dwyer, JT Trumbo, PR Zehaluk, C Andrews, KW Carriquiry, A Caldwel, KL Egan, SK Long, SE Bailey, RL Sullivan, KM Holden, JM Betz, JM Phinney, KW Brooks, SPJ Johnson, CL Haggans, CJ AF Swanson, Christine A. Zimmermann, Michael B. Skeaff, Sheila Pearce, Elizabeth N. Dwyer, Johanna T. Trumbo, Paula R. Zehaluk, Christina Andrews, Karen W. Carriquiry, Alicia Caldwel, Kathleen L. Egan, S. Kathleen Long, Stephen E. Bailey, Regan Lucas Sullivan, Kevin M. Holden, Joanne M. Betz, Joseph M. Phinney, Karen W. Brooks, Stephen P. J. Johnson, Clifford L. Haggans, Carol J. TI Summary of an NIH Workshop to Identify Research Needs to Improve the Monitoring of Iodine Status in the United States and to Inform the DRI SO JOURNAL OF NUTRITION LA English DT Article ID URINARY IODINE; THYROID-FUNCTION; DIETARY-SUPPLEMENTS; PREGNANT-WOMEN; IODIZED SALT; BREAST-MILK; NATIONAL-HEALTH; DOUBLE-BLIND; DEFICIENCY; NUTRITION AB The Office of Dietary Supplements (ODS) at the NIH sponsored a workshop on May 12-13, 2011, to bring together representatives from various NIH institutes and centers as a first step in developing an NIH iodine research initiative. The workshop also provided an opportunity to identify research needs that would inform the dietary reference intakes for iodine, which were last revised in 2001. Iodine is required throughout the life cycle, but pregnant women and infants are the populations most at risk of deficiency, because iodine is required for normal brain development and growth. The CDC monitors iodine status of the population on a regular basis, but the status of the most vulnerable populations remains uncertain. The NIH funds very little investigator-initiated research relevant to iodine and human nutrition, but the ODS has worked for several years with a number of other U.S. government agencies to develop many of the resources needed to conduct iodine research of high quality (e.g., validated analytical methods and reference materials for multiple types of samples). Iodine experts, scientists from several U.S. government agencies, and NIH representatives met for 2 d to identify iodine research needs appropriate to the NIH mission. J. Nutr. 142: 1175S-1185S, 2012. C1 [Swanson, Christine A.; Dwyer, Johanna T.; Bailey, Regan Lucas; Betz, Joseph M.; Haggans, Carol J.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Zimmermann, Michael B.] ETH, Inst Food & Nutr, Zurich, Switzerland. [Skeaff, Sheila] Univ Otago, Dept Human Nutr, Dunedin, New Zealand. [Pearce, Elizabeth N.] Boston Univ, Sch Med, Evans Ctr Interdisciplinary Biomed Res, Boston, MA 02118 USA. [Trumbo, Paula R.; Egan, S. Kathleen] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Zehaluk, Christina; Brooks, Stephen P. J.] Hlth Canada, Bur Nutr Sci, Ottawa, ON K1A 0L2, Canada. [Andrews, Karen W.; Holden, Joanne M.] ARS, USDA, Beltsville, MD USA. [Carriquiry, Alicia] Iowa State Univ, Dept Stat, Ames, IA USA. [Caldwel, Kathleen L.; Sullivan, Kevin M.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. [Long, Stephen E.; Phinney, Karen W.] Natl Inst Stand & Technol, Div Analyt Chem, Gaithersburg, MD 20899 USA. [Johnson, Clifford L.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Swanson, CA (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Room 3B01, Bethesda, MD 20892 USA. EM swansonc@od.nih.gov RI Zimmermann, Michael/C-3062-2016; OI Dwyer, Johanna/0000-0002-0783-1769 FU NIH Office of Dietary Supplements FX Published in a supplement to The Journal of Nutrition. Presented at the Office of Dietary Supplements Iodine Workshop, held in Rockville, Maryland, May 12-13, 2011. The workshop was organized and sponsored by the NIH Office of Dietary Supplements. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or other government agencies. The views expressed in these papers are not necessarily those of the Supplement Coordinator or Guest Editors. The Supplement Coordinator for this supplement was Christine A. Swanson, Office of Dietary Supplements, NIH. Supplement Coordinator disclosures: Christine A. Swanson had no conflicts to disclose. This supplement is the responsibility of the Guest Editor to whom the Editor of The Journal of Nutrition has delegated supervision of both technical conformity to the published regulations of The Journal of Nutrition and general oversight of the scientific merit of each article. The Guest Editor for this supplement was A. Catharine Ross, Guest Editor disclosure: A. Catharine Ross had no conflicts to disclose. Publication costs for this supplement were defrayed in part by the payment of page charges. This publication must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, Editor, or Editorial Board of The Journal of Nutrition. NR 92 TC 13 Z9 14 U1 2 U2 19 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUN PY 2012 VL 142 IS 6 BP 1175S EP 1185S DI 10.3945/jn.111.156448 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 946EY UT WOS:000304335500030 PM 22551802 ER PT J AU Perrault, LP Moskowitz, AJ Kron, IL Acker, MA Miller, MA Horvath, KA Thourani, VH Argenziano, M D'Alessandro, DA Blackstone, EH Moy, CS Mathew, JP Hung, J Gardner, TJ Parides, MK AF Perrault, Louis P. Moskowitz, Alan J. Kron, Irving L. Acker, Michael A. Miller, Marissa A. Horvath, Keith A. Thourani, Vinod H. Argenziano, Michael D'Alessandro, David A. Blackstone, Eugene H. Moy, Claudia S. Mathew, Joseph P. Hung, Judy Gardner, Timothy J. Parides, Michael K. TI Optimal surgical management of severe ischemic mitral regurgitation: To repair or to replace? SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID VALVULAR HEART-DISEASE; PAPILLARY-MUSCLE; NORMATIVE DATA; VALVE REPAIR; ANNULOPLASTY; RELIABILITY; DYSFUNCTION AB Background: Ischemic mitral regurgitation, a complication of myocardial infarction and coronary artery disease more generally, is associated with a high mortality rate and is estimated to affect 2.8 million Americans. With 1-year mortality rates as high as 40%, recent practice guidelines of professional societies recommend repair or replacement, but there remains a lack of conclusive evidence supporting either intervention. The choice between therapeutic options is characterized by the trade-off between reduced operative morbidity and mortality with repair versus a better long-term correction of mitral insufficiency with replacement. The long-term benefits of repair versus replacement remain unknown, which has led to significant variation in surgical practice. Methods and Results: This article describes the design of a prospective randomized clinical trial to evaluate the safety and effectiveness of mitral valve repair and replacement in patients with severe ischemic mitral regurgitation. This trial is being conducted as part of the Cardiothoracic Surgical Trials Network. This article addresses challenges in selecting a feasible primary end point, characterizing the target population (including the degree of mitral regurgitation) and analytical challenges in this high mortality disease. Conclusions: The article concludes by discussing the importance of information on functional status, survival, neurocognition, quality of life, and cardiac physiology in therapeutic decision making. (J Thorac Cardiovasc Surg 2012;143:1396-403) C1 [Moskowitz, Alan J.; Parides, Michael K.] Mt Sinai Sch Med, Dept Hlth Evidence & Policy, InCHOIR, New York, NY USA. [Perrault, Louis P.] Univ Montreal, Montreal Heart Inst, Dept Surg, Montreal, PQ, Canada. [Kron, Irving L.] Univ Virginia, Sch Med, Div Thorac & Cardiovasc Surg, Charlottesville, VA 22908 USA. [Acker, Michael A.] Univ Penn, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [Miller, Marissa A.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Horvath, Keith A.] Suburban Hosp, NIH Heart Ctr, Bethesda, MD USA. [Thourani, Vinod H.] Emory Univ Hosp Midtown, Div Cardiothorac Surg, Atlanta, GA USA. [Argenziano, Michael] Columbia Univ, Med Ctr, Div Cardiothorac Surg, New York, NY USA. [D'Alessandro, David A.] Montefiore Einstein Heart Ctr, Dept Cardiovasc & Thorac Surg, New York, NY USA. [Blackstone, Eugene H.] Cleveland Clin, Dept Thorac & Cardiovasc Surg, Cleveland, OH 44106 USA. [Moy, Claudia S.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Mathew, Joseph P.] Duke Univ, Med Ctr, Dept Anesthesiol, Durham, NC 27710 USA. [Hung, Judy] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Gardner, Timothy J.] Christiana Care Hlth Syst, Ctr Heart & Vasc Hlth, Newark, DE USA. RP Parides, MK (reprint author), Mt Sinai Sch Med, Dept Hlth Evidence & Policy, InCHOIR, New York, NY USA. EM michael.parides@mssm.edu OI Moskowitz, Alan/0000-0002-4412-9450 FU NHLBI NIH HHS [U01 HL088942, R01 HL092101] NR 31 TC 18 Z9 22 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD JUN PY 2012 VL 143 IS 6 BP 1396 EP 1403 DI 10.1016/j.jtcvs.2011.05.030 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 943HE UT WOS:000304110700025 PM 22054660 ER PT J AU Jain, A Liu, K Ferrucci, L Criqui, MH Tian, L Guralnik, JM Tao, HM McDermott, MM AF Jain, Atul Liu, Kiang Ferrucci, Luigi Criqui, Michael H. Tian, Lu Guralnik, Jack M. Tao, Huimin McDermott, Mary M. TI The Walking Impairment Questionnaire stair-climbing score predicts mortality in men and women with peripheral arterial disease SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID LOWER-EXTREMITY FUNCTION; ANKLE-BRACHIAL INDEX; INTERMITTENT CLAUDICATION; FUNCTIONAL STATUS; PHYSICAL-ACTIVITY; ASSOCIATION; RISK; PERFORMANCE; DISABILITY; EXERCISE AB Objective: The Walking Impairment Questionnaire (WIQ) measures self-reported walking distance, walking speed, and stair-climbing ability in men and women with lower extremity peripheral arterial disease (PAD). We determined whether poorer WIQ scores are associated with higher all-cause and cardiovascular disease (CVD) mortality in individuals with and without PAD. Methods: We identified 1048 men and women with and without PAD from Chicago-area medical centers. Participants completed the WIQ at baseline and were monitored for a median of 4.5 years. Cox proportional hazards models were used to relate baseline WIQ scores with death, adjusting for age, sex, race, the ankle-brachial index (ABI), comorbidities, and other covariates. Results: During follow-up, 461 participants (44.0%) died, including 158 deaths from CVD. PAD participants in the lowest baseline quartile of the WIQ stair-climbing scores had higher all-cause mortality (hazard ratio, 1.70; 95% confidence interval, 1.08-2.66, P = .02) and higher CVD mortality (hazard ratio, 3.11; 95% confidence interval, 1.30-7.47, P = .01) compared with those with the highest baseline WIQ stair-climbing score. Among PAD participants, there were no significant associations of lower baseline WIQ distance or speed scores with rates of all-cause mortality (P = .20 and P = .07 for trend, respectively) or CVD mortality (P = .51 and P = .33 for trend, respectively). Among non-PAD participants there were no significant associations of lower baseline WIQ stair-climbing, distance, or speed score with rates of all-cause mortality (P = .94, P = .69, and P = .26, for trend, respectively) or CVD mortality (P = .28, P = .68, and P = .78, for trend, respectively). Conclusions: Among participants with PAD, lower WIQ stair-climbing scores are associated with higher all-cause and CVD mortality, independently of the ABI and other covariates. (J Vasc Surg 2012;55:1662-73.) C1 [Jain, Atul] Northwestern Univ, Feinberg Sch Med, Div Gen Internal Med, Chicago, IL 60611 USA. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Tian, Lu] Stanford Univ, Palo Alto, CA 94304 USA. [Guralnik, Jack M.] Univ Maryland, Baltimore, MD 21201 USA. RP Jain, A (reprint author), Northwestern Univ, Feinberg Sch Med, Div Gen Internal Med, 750 N Lake Shore Dr,10th Flr, Chicago, IL 60611 USA. EM atul-jain@md.northwestern.edu FU National Heart, Lung, and Blood Institute [K12-HL083790, R01-HL083064, R01-HL64739, R01-HL71223]; National Center for Research Resources, National Institutes of Health [RR-00048]; National Institute on Aging FX This study was supported by grants K12-HL083790, R01-HL083064, R01-HL64739, and R01-HL71223 from the National Heart, Lung, and Blood Institute, and by grant RR-00048 from the National Center for Research Resources, National Institutes of Health. This study was also supported by the National Institute on Aging. NR 23 TC 16 Z9 16 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUN PY 2012 VL 55 IS 6 BP 1662 EP U440 DI 10.1016/j.jvs.2011.12.010 PG 14 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 944MF UT WOS:000304206000017 PM 22608041 ER PT J AU Burbelo, PD Dubovi, EJ Simmonds, P Medina, JL Henriquez, JA Mishra, N Wagner, J Tokarz, R Cullen, JM Ladarola, MJ Rice, CM Lipkin, WI Kapoor, A AF Burbelo, Peter D. Dubovi, Edward J. Simmonds, Peter Medina, Jan L. Henriquez, Jose A. Mishra, Nischay Wagner, Jason Tokarz, Rafal Cullen, John M. Ladarola, Michael J. Rice, Charles M. Lipkin, W. Ian Kapoor, Amit TI Serology-Enabled Discovery of Genetically Diverse Hepaciviruses in a New Host SO JOURNAL OF VIROLOGY LA English DT Article ID HEPATITIS-C VIRUS; ORDERED RNA STRUCTURE; CELL-CULTURE; AGENT; INFECTION; GENOMES; MODEL; PATHOGENESIS; REPLICATION; PERSISTENT AB Genetic and biological characterization of new hepaciviruses infecting animals contributes to our understanding of the ultimate origins of hepatitis C virus (HCV) infection in humans and dramatically enhances our ability to study its pathogenesis using tractable animal models. Animal homologs of HCV include a recently discovered canine hepacivirus (CHV) and GB virus B (GBV-B), both viruses with largely undetermined natural host ranges. Here we used a versatile serology-based approach to determine the natural host of the only known nonprimate hepacivirus (NPHV), CHV, which is also the closest phylogenetic relative of HCV. Recombinant protein expressed from the helicase domain of CHV NS3 was used as antigen in the luciferase immunoprecipitation system (LIPS) assay to screen several nonprimate animal species. Thirty-six samples from 103 horses were immunoreactive, and viral genomic RNA was present in 8 of the 36 seropositive animals and none of the seronegative animals. Complete genome sequences of these 8 genetically diverse NPHVs showed 14% (range, 6.4% to 17.2%) nucleotide sequence divergence, with most changes occurring at synonymous sites. RNA secondary structure prediction of the 383-base 5' untranslated region of NPHV was refined and extended through mapping of polymorphic sites to unpaired regions or (semi)covariant pairings. Similar approaches were adopted to delineate extensive RNA secondary structures in the coding region of the genome, predicted to form 27 regularly spaced, thermodynamically stable stem-loops. Together, these findings suggest a promising new nonprimate animal model and provide a database that will aid creation of functional NPHV cDNA clones and other novel tools for hepacivirus studies. C1 [Medina, Jan L.; Henriquez, Jose A.; Mishra, Nischay; Tokarz, Rafal; Lipkin, W. Ian; Kapoor, Amit] Columbia Univ, Ctr Infect & Immun, New York, NY 10027 USA. [Burbelo, Peter D.; Wagner, Jason; Ladarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, Natl Inst Hlth, Bethesda, MD USA. [Dubovi, Edward J.] Coll Vet Med Cornell, Anim Hlth Diagnost Ctr, Ithaca, NY USA. [Simmonds, Peter] Univ Edinburgh, Ctr Immun Infect & Evolut, Ashworth Labs, Edinburgh, Midlothian, Scotland. [Cullen, John M.] N Carolina State Univ, Coll Vet Med, Raleigh, NC USA. [Rice, Charles M.] Rockefeller Univ, Lab Virol & Infect Dis, Ctr Study Hepatitis C, New York, NY 10021 USA. RP Kapoor, A (reprint author), Columbia Univ, Ctr Infect & Immun, New York, NY 10027 USA. EM ak3117@columbia.edu FU National Institutes of Health [AI090196, AI081132, AI079231, AI57158, AI070411, EY017404]; Defense Threat Reduction Agency (Department of Defense); USDA [8-1275-7-370]; Division of Intramural Research, National Institute of Dental and Craniofacial Research FX This work was supported by National Institutes of Health grants (AI090196, AI081132, AI079231, AI57158, AI070411, and EY017404), by an award from the Defense Threat Reduction Agency (Department of Defense) and USDA 58-1275-7-370, and by the Division of Intramural Research, National Institute of Dental and Craniofacial Research. NR 41 TC 87 Z9 91 U1 1 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2012 VL 86 IS 11 BP 6171 EP 6178 DI 10.1128/JVI.00250-12 PG 8 WC Virology SC Virology GA 944UM UT WOS:000304229300018 PM 22491452 ER PT J AU Cerhan, JR Natkunam, Y Morton, LM Maurer, MJ Asmann, Y Habermann, TM Vasef, MA Cozen, W Lynch, CF Allmer, C Slager, SL Lossos, IS Chanock, SJ Rothman, N Hartge, P Dogan, A Wang, SS AF Cerhan, James R. Natkunam, Yasodha Morton, Lindsay M. Maurer, Matthew J. Asmann, Yan Habermann, Thomas M. Vasef, Mohammad A. Cozen, Wendy Lynch, Charles F. Allmer, Cristine Slager, Susan L. Lossos, Izidore S. Chanock, Stephen J. Rothman, Nathaniel Hartge, Patricia Dogan, Ahmet Wang, Sophia S. TI LIM domain only 2 protein expression, LMO2 germline genetic variation, and overall survival in diffuse large B-cell lymphoma in the pre-rituximab era SO LEUKEMIA & LYMPHOMA LA English DT Article DE Diff use large B-cell lymphoma; LMO2; prognosis; single nucleotide polymorphisms ID TRANSCRIPTION FACTOR LMO2; R-CHOP; LEUKEMIA; PREDICTS; RBTN2; MICE; POLYMORPHISMS; ASSOCIATION; ALIGNMENTS; ELEMENTS AB Both LMO2 (LIM domain only 2) mRNA and protein expression in diffuse large B-cell lymphoma (DLBCL) have been associated with superior survival. However, a role for germline genetic variation in LMO2 has not been previously reported. Immunohistochemistry (IHC) for LMO2 was conducted on tumor tissue from diagnostic biopsies, and 20 tag single nucleotide polymorphisms (SNPs) from LMO2 were genotyped from germline DNA. LMO2 IHC positivity was associated with superior survival (hazard ratio [HR] = 0.55; 95% confi dence interval [CI] 0.31 - 0.97). Four LMO2 SNPs (rs10836127, rs941940, rs750781, rs1885524) were associated with survival after adjusting for LMO2 IHC and clinical factors (p < 0.05), and one of these SNPs (rs941940) was also associated with IHC positivity (p = 0.02). Compared to a model with clinical factors only (c-statistic = 0.676), adding the four SNPs (c-statistic = 0.751) or LMO2 IHC (c-statistic = 0.691) increased the predictive ability of the model, while inclusion of all three factors (c-statistic = 0.754) did not meaningfully add predictive ability above a model with clinical factors and the four SNPs. In conclusion, germline genetic variation in LMO2 was associated with DLBCL prognosis and provided slightly stronger predictive ability relative to LMO2 IHC status. C1 [Cerhan, James R.] Mayo Clin, Coll Med, Div Epidemiol, Rochester, MN 55905 USA. [Maurer, Matthew J.; Asmann, Yan; Allmer, Cristine; Slager, Susan L.] Mayo Clin, Coll Med, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Habermann, Thomas M.] Mayo Clin, Coll Med, Div Hematol, Rochester, MN 55905 USA. [Dogan, Ahmet] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Natkunam, Yasodha] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Morton, Lindsay M.; Chanock, Stephen J.; Rothman, Nathaniel; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Vasef, Mohammad A.] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Cozen, Wendy] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Lossos, Izidore S.] Univ Miami, Dept Med, Div Hematol Oncol, Miami, FL USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Dept Populat Sci, Duarte, CA USA. RP Cerhan, JR (reprint author), Mayo Clin, Coll Med, Div Epidemiol, 200 1st St SW, Rochester, MN 55905 USA. EM cerhan.james@mayo.edu RI Morton, Lindsay/B-5234-2015; OI Morton, Lindsay/0000-0001-9767-2310; Cerhan, James/0000-0002-7482-178X FU National Cancer Institute [R01 CA96704, R01 CA129539, P50 CA97274, P01 CA17054, P30 CA014089]; National Cancer Institute (SEER) [N01-PC35139, N01-PC67008, N01-PC67009, N01-PC65064, N01-PC71105] FX This work was supported by the National Cancer Institute (grants R01 CA96704, R01 CA129539, P50 CA97274, P01 CA17054 and P30 CA014089; NCI Intramural Program; SEER contracts N01-PC35139, N01-PC67008, N01-PC67009, N01-PC65064, N01-PC71105). NR 35 TC 3 Z9 3 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUN PY 2012 VL 53 IS 6 BP 1105 EP 1112 DI 10.3109/10428194.2011.638717 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 945XZ UT WOS:000304311500016 PM 22066713 ER PT J AU Xue, H Shah, S Greiser, A Guetter, C Littmann, A Jolly, MP Arai, AE Zuehlsdorff, S Guehring, J Kellman, P AF Xue, Hui Shah, Saurabh Greiser, Andreas Guetter, Christoph Littmann, Arne Jolly, Marie-Pierre Arai, Andrew E. Zuehlsdorff, Sven Guehring, Jens Kellman, Peter TI Motion correction for myocardial T1 mapping using image registration with synthetic image estimation SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE cardiac MRI; T1 mapping; image registration; motion correction; MOLLI ID CARDIOVASCULAR MAGNETIC-RESONANCE; CARDIAC CINE MRI; ENHANCEMENT; INFARCTION; RESOLUTION; VALIDATION; FIBROSIS AB Quantification of myocardial T1 relaxation has potential value in the diagnosis of both ischemic and nonischemic cardiomyopathies. Image acquisition using the modified Look-Locker inversion recovery technique is clinically feasible for T1 mapping. However, respiratory motion limits its applicability and degrades the accuracy of T1 estimation. The robust registration of acquired inversion recovery images is particularly challenging due to the large changes in image contrast, especially for those images acquired near the signal null point of the inversion recovery and other inversion times for which there is little tissue contrast. In this article, we propose a novel motion correction algorithm. This approach is based on estimating synthetic images presenting contrast changes similar to the acquired images. The estimation of synthetic images is formulated as a variational energy minimization problem. Validation on a consecutive patient data cohort shows that this strategy can perform robust nonrigid registration to align inversion recovery images experiencing significant motion and lead to suppression of motion induced artifacts in the T1 map. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc. C1 [Shah, Saurabh; Zuehlsdorff, Sven] Siemens Med Solut USA Inc, CMR R&D, Chicago, IL USA. [Greiser, Andreas; Littmann, Arne; Guehring, Jens] Siemens AG, Healthcare Sect, Imaging & IT Div, Erlangen, Germany. [Arai, Andrew E.; Kellman, Peter] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Xue, Hui; Guetter, Christoph; Jolly, Marie-Pierre] Siemens Corp Res, Princeton, NJ USA. RP Xue, H (reprint author), Siemens Corp, Corp Res, 755 Coll Rd E, Princeton, NJ 08540 USA. EM hui-xue@siemens.com FU Intramural NIH HHS [ZIA HL006136-01, Z99 HL999999, ZIA HL006136-02, ZIA HL004607-14] NR 33 TC 62 Z9 62 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2012 VL 67 IS 6 BP 1644 EP 1655 DI 10.1002/mrm.23153 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 942XX UT WOS:000304086000016 PM 22135227 ER PT J AU Lin, PC Irrechukwu, O Roque, R Hancock, B Fishbein, KW Spencer, RG AF Lin, Ping-Chang Irrechukwu, Onyi Roque, Remy Hancock, Brynne Fishbein, Kenneth W. Spencer, Richard G. TI Multivariate analysis of cartilage degradation using the support vector machine algorithm SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE classification; osteoarthritis; MRI; discriminant analysis; clustering ID MAGNETIC-RESONANCE MICROSCOPY; HUMAN ARTICULAR-CARTILAGE; IN-VIVO; T-2 RELAXATION; MR-IMAGES; CLASSIFICATION; KERNEL; TISSUE; KNEE; TIME AB An important limitation in MRI studies of early osteoarthritis is that measured MRI parameters exhibit substantial overlap between different degrees of cartilage degradation. We investigated whether multivariate support vector machine analysis would permit improved tissue characterization. Bovine nasal cartilage samples were subjected to pathomimetic degradation and their T1, T2, magnetization transfer rate (km), and apparent diffusion coefficient (ADC) were measured. Support vector machine analysis performed using certain parameter combinations exhibited particularly favorable classification properties. The areas under the receiver operating characteristic (ROC) curve for detection of extensive and mild degradation were 1.00 and 0.94, respectively, using the set (T1, km, ADC), compared with 0.97 and 0.60 using T1, the best univariate classifier. Furthermore, a degradation probability for each sample, derived from the support vector machine formalism using the parameter set (T1, km, ADC), demonstrated much stronger correlations (r2 = 0.790.88) with direct measurements of tissue biochemical components than did even the best-performing individual MRI parameter, T1 (r2 = 0.530.64). These results, combined with our previous investigation of Gaussian cluster-based tissue discrimination, indicate that the combinations (T1, km) and (T1, km, ADC) may emerge as particularly useful for characterization of early cartilage degradation. Magn Reson Med, 2011. (c) 2011 Wiley Periodicals, Inc. C1 [Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. RP Spencer, RG (reprint author), NIA, Magnet Resonance Imaging & Spect Sect, Clin Invest Lab, NIH, GRC 4D-06, Baltimore, MD 21224 USA. EM spencer@helix.nih.gov OI Lin, Ping-Chang/0000-0003-0918-4072; Fishbein, Kenneth/0000-0002-6353-4603 FU National Institutes of Health; National Institute on Aging FX Grant sponsors: National Institutes of Health, National Institute on Aging (Intramural Research Program) NR 41 TC 15 Z9 15 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2012 VL 67 IS 6 BP 1815 EP 1826 DI 10.1002/mrm.23189 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 942XX UT WOS:000304086000035 PM 22179972 ER PT J AU Chesler, EJ Plitt, A Fisher, D Hurd, B Lederle, L Bubier, JA Kiselycznyk, C Holmes, A AF Chesler, Elissa J. Plitt, Aaron Fisher, Daniel Hurd, Benita Lederle, Lauren Bubier, Jason A. Kiselycznyk, Carly Holmes, Andrew TI Quantitative trait loci for sensitivity to ethanol intoxication in a C57BL/6J x 129S1/SvImJ inbred mouse cross SO MAMMALIAN GENOME LA English DT Article ID ALCOHOL-RELATED BEHAVIORS; ACUTE FUNCTIONAL TOLERANCE; CHRONIC SWIM STRESS; SHORT-SLEEP MICE; PREFERENCE DRINKING; GENETIC-ANALYSIS; NEUROTENSIN MEASURES; CANDIDATE GENE; LONG-SLEEP; RAT LINES AB Individual variation in sensitivity to acute ethanol (EtOH) challenge is associated with alcohol drinking and is a predictor of alcohol abuse. Previous studies have shown that the C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mouse strains differ in responses on certain measures of acute EtOH intoxication. To gain insight into genetic factors contributing to these differences, we performed quantitative trait locus (QTL) analysis of measures of EtOH-induced ataxia (accelerating rotarod), hypothermia, and loss of righting reflex (LORR) duration in a B6 x S1 F2 population. We confirmed that S1 showed greater EtOH-induced hypothermia (specifically at a high dose) and longer LORR compared to B6. QTL analysis revealed several additive and interacting loci for various phenotypes, as well as examples of genotype interactions with sex. QTLs for different EtOH phenotypes were largely non-overlapping, suggesting separable genetic influences on these behaviors. The most compelling main-effect QTLs were for hypothermia on chromosome 16 and for LORR on chromosomes 4 and 6. Several QTLs overlapped with loci repeatedly linked to EtOH drinking in previous mouse studies. The architecture of the traits we examined was complex but clearly amenable to dissection in future studies. Using integrative genomics strategies, plausible functional and positional candidates may be found. Uncovering candidate genes associated with variation in these phenotypes in this population could ultimately shed light on genetic factors underlying sensitivity to EtOH intoxication and risk for alcoholism in humans. C1 [Chesler, Elissa J.; Bubier, Jason A.] Jackson Lab, Bar Harbor, ME 04609 USA. [Plitt, Aaron; Fisher, Daniel; Hurd, Benita; Lederle, Lauren; Kiselycznyk, Carly; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. RP Chesler, EJ (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM Elissa.Chesler@jax.org OI Bubier, Jason/0000-0001-5013-1234 FU National Institute of Alcohol Abuse and Alcoholism [Z01 AA000411]; Jackson Laboratory; [R01 AA18776] FX This research was supported by the National Institute of Alcohol Abuse and Alcoholism Intramural Research Program (Z01 AA000411). EJC was supported by The Jackson Laboratory and R01 AA18776. NR 74 TC 10 Z9 10 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD JUN PY 2012 VL 23 IS 5-6 BP 305 EP 321 DI 10.1007/s00335-012-9394-2 PG 17 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 945WB UT WOS:000304306000001 PM 22371272 ER PT J AU Zhu, BK Khozoie, C Bility, MT Ferry, CH Blazanin, N Glick, AB Gonzalez, FJ Peters, JM AF Zhu, Bokai Khozoie, Combiz Bility, Moses T. Ferry, Christina H. Blazanin, Nicholas Glick, Adam B. Gonzalez, Frank J. Peters, Jeffrey M. TI Peroxisome Proliferator-Activated Receptor beta/delta Cross Talks with E2F and Attenuates Mitosis in HRAS-Expressing Cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID INDUCED SKIN TUMORIGENESIS; PPAR-BETA/DELTA; LIGAND ACTIVATION; MICROARRAY ANALYSIS; RAS ONCOGENE; METABOLIC SYNDROME; CYCLE PROGRESSION; TARGET GENES; COLON-CANCER; TUMOR-CELLS AB The role of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) in Harvey sarcoma ras (Hras)-expressing cells was examined. Ligand activation of PPARI beta/delta caused a negative selection with respect to cells expressing higher levels of the Hras oncogene by inducing a mitotic block. Mitosis-related genes that are predominantly regulated by E2F were induced to a higher level in HRAS-expressing Ppar beta/delta-null keratinocytes compared to HRAS-expressing wild-type keratinocytes. Ligand-activated PPAR beta/delta repressed expression of these genes by direct binding with p130/p107, facilitating nuclear translocation and increasing promoter recruitment of p130/p107. These results demonstrate a novel mechanism of PPAR beta/delta cross talk with E2F signaling. Since cotreatment with a PPAR beta/delta ligand and various mitosis inhibitors increases the efficacy of increasing G(2)/M arrest, targeting PPAR beta/delta in conjunction with mitosis inhibitors could become a suitable option for development of new multitarget strategies for inhibiting RAS-dependent tumorigenesis. C1 [Zhu, Bokai; Khozoie, Combiz; Bility, Moses T.; Ferry, Christina H.; Blazanin, Nicholas; Glick, Adam B.; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Zhu, Bokai; Khozoie, Combiz; Bility, Moses T.; Ferry, Christina H.; Blazanin, Nicholas; Glick, Adam B.; Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. EM jmp21@psu.edu OI Zhu, Bokai/0000-0003-0827-5757 FU National Institutes of Health [CA124533, CA126826, CA141029, CA140369, AA018863, CA122109, CAL117957]; National Cancer Institute Intramural [ZIABC005561, ZIABC005562, ZIABC005708] FX We gratefully acknowledge Andrew Billin and Timothy Willson for providing the GW0742 and the Center for Quantitative Cell Analysis and the Genomic Core Facility at the Huck Institutes of Life Sciences of The Pennsylvania State University for their technical support with flow cytometry and data analysis.; This work was supported by National Institutes of Health grants CA124533, CA126826, CA141029, CA140369, and AA018863 to J.M.P. and CA122109 and CAL117957 to A.B.G. and by grants from the National Cancer Institute Intramural Research Program (ZIABC005561, ZIABC005562, and ZIABC005708) to F.J.G. NR 70 TC 7 Z9 7 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 JUN PY 2012 VL 32 IS 11 BP 2065 EP 2082 DI 10.1128/MCB.00092-12 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 945RF UT WOS:000304293000003 PM 22473992 ER PT J AU Tripathi, V Popescu, NC Zimonjic, DB AF Tripathi, Veenu Popescu, Nicholas C. Zimonjic, Drazen B. TI DLC1 Interaction with alpha-Catenin Stabilizes Adherens Junctions and Enhances DLC1 Antioncogenic Activity SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GTPASE-ACTIVATING PROTEIN; TUMOR-SUPPRESSOR PROTEIN; SQUAMOUS-CELL CARCINOMA; E-CADHERIN; PROSTATE-CANCER; BETA-CATENIN; HEPATOCELLULAR-CARCINOMA; CYTOPLASMIC ACCUMULATION; REDUCED EXPRESSION; PATIENT SURVIVAL AB The DLC1 (for deleted in liver cancer 1) tumor suppressor gene encodes a RhoGAP protein that inactivates Rho GTPases, which are implicated in regulation of the cytoskeleton and adherens junctions (AJs), a cell-cell adhesion protein complex associated with the actin cytoskeleton. Malignant transformation and tumor progression to metastasis are often associated with changes in cytoskeletal organization and cell-cell adhesion. Here we have established in human cells that the AJ-associated protein alpha-catenin is a new binding partner of DLC1. Their binding was mediated by the N-terminal amino acids 340 to 435 of DLC1 and the N-terminal amino acids 117 to 161 of alpha-catenin. These proteins colocalized in the cytosol and in the plasma membrane, where together they associated with E-cadherin and beta-catenin, constitutive AJ proteins. Binding of DLC1 to alpha-catenin led to their accumulation at the plasma membrane and required DLC1 GAP activity. Knocking down alpha-catenin in DLC1-positive cells diminished DLC1 localization at the membrane. The DLC1-alpha-catenin complex reduced the Rho GTP level at the plasma membrane, increased E-cadherin's mobility, affected actin organization, and stabilized AJs. This process eventually contributed to a robust oncosuppressive effect of DLC1 in metastatic prostate carcinoma cells. Together, these results unravel a new mechanism through which DLC1 exerts its strong oncosuppressive function by positively influencing AJ stability. C1 [Tripathi, Veenu; Popescu, Nicholas C.; Zimonjic, Drazen B.] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Popescu, NC (reprint author), NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. EM popescun@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 70 TC 17 Z9 18 U1 2 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2012 VL 32 IS 11 BP 2145 EP 2159 DI 10.1128/MCB.06580-11 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 945RF UT WOS:000304293000009 PM 22473989 ER PT J AU Allicock, OM Lemey, P Tatem, AJ Pybus, OG Bennett, SN Mueller, BA Suchard, MA Foster, JE Rambaut, A Carrington, CVF AF Allicock, Orchid M. Lemey, Philippe Tatem, Andrew J. Pybus, Oliver G. Bennett, Shannon N. Mueller, Brandi A. Suchard, Marc A. Foster, Jerome E. Rambaut, Andrew Carrington, Christine V. F. TI Phylogeography and Population Dynamics of Dengue Viruses in the Americas SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE dengue virus; gene flow; Bayesian phylogeography; Americas; population dynamics; evolution; coalescent ID AEDES-AEGYPTI; MOLECULAR EVOLUTION; HEMORRHAGIC-FEVER; YELLOW-FEVER; DISPERSAL; INFERENCE; SELECTION; MAINTENANCE; ALIGNMENTS; THAILAND AB Changes in Dengue virus (DENV) disease patterns in the Americas over recent decades have been attributed, at least in part, to repeated introduction of DENV strains from other regions, resulting in a shift from hypoendemicity to hyperendemicity. Using newly sequenced DENV-1 and DENV-3 envelope (E) gene isolates from 11 Caribbean countries, along with sequences available on GenBank, we sought to document the population genetic and spatiotemporal transmission histories of the four main invading DENV genotypes within the Americas and investigate factors that influence the rate and intensity of DENV transmission. For all genotypes, there was an initial invasion phase characterized by rapid increases in genetic diversity, which coincided with the first confirmed cases of each genotype in the region. Rapid geographic dispersal occurred upon each genotype's introduction, after which individual lineages were locally maintained, and gene flow was primarily observed among neighboring and nearby countries. There were, however, centers of viral diversity (Barbados, Puerto Rico, Colombia, Suriname, Venezuela, and Brazil) that were repeatedly involved in gene flow with more distant locations. For DENV-1 and DENV-2, we found that a "distance-informed" model, which posits that the intensity of virus movement between locations is inversely proportional to the distance between them, provided a better fit than a model assuming equal rates of movement between all pairs of countries. However, for DENV-3 and DENV-4, the more stochastic "equal rates" model was preferred. C1 [Allicock, Orchid M.; Foster, Jerome E.; Carrington, Christine V. F.] Univ W Indies, Dept Preclin Sci, Fac Med Sci, St Augustine, Trinid & Tobago. [Lemey, Philippe] Katholieke Univ Leuven, Dept Microbiol & Immunol, Louvain, Belgium. [Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL 32611 USA. [Tatem, Andrew J.; Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Bennett, Shannon N.; Mueller, Brandi A.] Univ Hawaii Manoa, Dept Trop Med Med Microbiol & Pharmacol, John A Burns Sch Med, Honolulu, HI 96822 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Ashworth Labs, Edinburgh, Midlothian, Scotland. RP Carrington, CVF (reprint author), Univ W Indies, Dept Preclin Sci, Fac Med Sci, St Augustine, Trinid & Tobago. EM christine.carrington@sta.uwi.edu OI Pybus, Oliver/0000-0002-8797-2667; Rambaut, Andrew/0000-0003-4337-3707 FU Caribbean Health Research Council; University of the West Indies, St Augustine Campus; Commonwealth Scholarship Commission; European Research Council (ERC) under the European Community [260864]; COBRE [NIH-RR018727]; NSF-IGERT [054 9514]; RAPIDD of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; [NIH-AI065 359]; [NIH-RR003061]; [DOD-06187000] FX This work was supported by grants from the Caribbean Health Research Council to C.V.F.C. O.M.A. is a member of the Tropical Medicine Cluster (University of the West Indies) and was supported by grants and scholarships from the University of the West Indies, St Augustine Campus Research and Publications Fund, and the Commonwealth Scholarship Commission. P.L., M.A.S., and A.R. acknowledge support from the European Research Council (ERC) under the European Community's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 260864. S.B. and B.M. acknowledge support from NIH-RR018727 COBRE Bioinformatics Facility, NIH-AI065 359, NIH-RR003061, DOD-06187000, and NSF-IGERT 054 9514. A.J.T. acknowledges support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. The authors would like to acknowledge the CAREC for providing the viral isolates included in the study, and the National Institute of Allergy NR 56 TC 48 Z9 50 U1 2 U2 25 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD JUN PY 2012 VL 29 IS 6 BP 1533 EP 1543 DI 10.1093/molbev/msr320 PG 11 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 944KO UT WOS:000304200600006 PM 22319149 ER PT J AU Forrest, D Swaroop, A AF Forrest, Douglas Swaroop, Anand TI The Role of Nuclear Receptors in Photoreceptor Differentiation and Disease SO MOLECULAR ENDOCRINOLOGY LA English DT Review ID CONE OPSIN EXPRESSION; CAUSES RETINAL DEGENERATION; DEVELOPING MOUSE RETINA; CELL-FATE DETERMINATION; THYROID-HORMONE; TRANSCRIPTION FACTOR; ROR-BETA; TYPE-3 DEIODINASE; VERTEBRATE RETINA; MAMMALIAN RETINA AB Rod and cone photoreceptors are specialized sensory cells that mediate vision. Transcriptional controls are critical for the development and long-term survival of photoreceptors; when these controls become ineffective, retinal dysfunction or degenerative disease may result. This review discusses the role of nuclear receptors, a class of ligand-regulated transcription factors, at key stages of photoreceptor life in the mammalian retina. Nuclear receptors with known ligands, such as retinoids or thyroid hormone, together with several orphan receptors without identified physiological ligands, complement other classes of transcription factors in directing the differentiation and functional maintenance of photoreceptors. The potential of nuclear receptors to respond to ligands introduces versatility into the control of photoreceptor development and function and may suggest new opportunities for treatments of photoreceptor disease. (Molecular Endocrinology 26: 905-915, 2012) C1 [Forrest, Douglas] NIDDKD, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. RP Forrest, D (reprint author), NIDDKD, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. EM forrestd@niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; National Eye Institute at National Institutes of Health FX This work was supported by the intramural research programs at the National Institute of Diabetes and Digestive and Kidney Diseases and at the National Eye Institute at National Institutes of Health. NR 94 TC 25 Z9 25 U1 1 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUN PY 2012 VL 26 IS 6 BP 905 EP 915 DI 10.1210/me.2012-1010 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 946PM UT WOS:000304365100003 PM 22556342 ER PT J AU Carreno, CA Clifton, RG Hauth, JC Myatt, L Roberts, JM Spong, CY Varner, MW Thorp, JM Mercer, BM Peaceman, AM Ramin, SM Carpenter, MW Sciscione, A Tolosa, JE Sorokin, Y AF Carreno, Carlos A. Clifton, Rebecca G. Hauth, John C. Myatt, Leslie Roberts, James M. Spong, Catherine Y. Varner, Michael W. Thorp, John M., Jr. Mercer, Brian M. Peaceman, Alan M. Ramin, Susan M. Carpenter, Marshall W. Sciscione, Anthony Tolosa, Jorge E. Sorokin, Yoram CA Eunice Kennedy Shriver Natl Inst TI Excessive Early Gestational Weight Gain and Risk of Gestational Diabetes Mellitus in Nulliparous Women SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID BODY-MASS INDEX; PREGNANCY; COMPLICATIONS; OBESE; OUTCOMES; TRIAL AB OBJECTIVE: To estimate whether there is an association between excessive early gestational weight gain and the development of gestational diabetes mellitus (GDM) and excessive fetal growth. METHODS: This is a secondary analysis of a randomized controlled trial of vitamins C and E in nulliparous low-risk women. Maternal weight gain from prepregnancy (self-reported) to 15-18 weeks of gestation was measured, and expected gestational weight gain was determined using the Institute of Medicine 2009 guidelines for each prepregnancy body mass index category. Excessive early gestational weight gain was defined as gestational weight gain greater than the upper range of the Institute of Medicine guidelines. Rates of GDM, birth weight greater than 4,000 g, and large for gestational age (LGA, birth weight 90th percentile or higher) were calculated and compared between women with excessive early gestational weight gain and early nonexcessive gestational weight gain (within or below Institute of Medicine guidelines). RESULTS: A total of 7,985 women were studied. Excessive early gestational weight gain occurred in 47.5% of women. Ninety-three percent of women with excessive early gestational weight gain had total gestational weight gain greater than Institute of Medicine guidelines. In contrast, only 55% of women with nonexcessive early gestational weight gain had total gestational weight gain greater than Institute of Medicine guidelines (P<.001). Rates of GDM, LGA, and birth weight greater than 4,000 g were higher in women with excessive early gestational weight gain. CONCLUSION: In our population, excessive early gestational weight gain occurred in 93% of women who had total gestational weight gain greater than the Institute of Medicine guidelines. In low-risk nulliparous women, excessive early gestational weight gain is associated with the development of GDM and excessive fetal growth. (Obstet Gynecol 2012;119:1227-33) DOI: 10.1097/AOG.0b013e318256cf1a C1 Univ Texas Hlth Sci Ctr Houston, Dept Obstet & Gynecol, Houston, TX 77030 USA. Univ Alabama Birmingham, Birmingham, AL USA. Univ Cincinnati, Cincinnati, OH USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Utah, Salt Lake City, UT USA. Univ N Carolina, Chapel Hill, NC USA. Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. Northwestern Univ, Chicago, IL 60611 USA. Brown Univ, Providence, RI 02912 USA. Drexel Univ, Philadelphia, PA 19104 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Univ Texas Med Branch, Galveston, TX USA. Wayne State Univ, Detroit, MI USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Carreno, CA (reprint author), Univ Texas Hlth Sci Ctr Houston, Div Maternal Fetal Med, Dept Obstet Gynecol & Reprod Sci, 6431 Fannin St,Suite 3-262, Houston, TX 77030 USA. EM carlos.carreno@uth.tmc.edu RI Varner, Michael/K-9890-2013 OI Peaceman, Alan/0000-0002-4515-4850; Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD34208, HD27869, HD40485, HD40560, HD40544, HD34116, HD40512, HD21410, HD40545, HD40500, HD27915, HD34136, HD27860, HD53118, HD53097, HD27917, HD36801]; National Heart, Lung, and Blood Institute; National Center for Research Resources [M01 RR00080, UL1 RR024153, UL1 RR024989] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD34208, HD27869, HD40485, HD40560, HD40544, HD34116, HD40512, HD21410, HD40545, HD40500, HD27915, HD34136, HD27860, HD53118, HD53097, HD27917, and HD36801); the National Heart, Lung, and Blood Institute; and the National Center for Research Resources (M01 RR00080, UL1 RR024153, UL1 RR024989). Its contents do not necessarily represent the official view of NICHD, National Heart, Lung and Blood Institute, National Center for Research Resources, or the National Institutes of Health. NR 25 TC 45 Z9 47 U1 0 U2 7 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 JUN PY 2012 VL 119 IS 6 BP 1227 EP 1233 DI 10.1097/AOG.0b013e318256cf1a PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 946OC UT WOS:000304360700021 PM 22617588 ER PT J AU Myatt, L Clifton, RG Roberts, JM Spong, CY Hauth, JC Varner, MW Thorp, JM Mercer, BM Peaceman, AM Ramin, SM Carpenter, MW Iams, JD Sciscione, A Harper, M Tolosa, JE Saade, G Sorokin, Y Anderson, GD AF Myatt, Leslie Clifton, Rebecca G. Roberts, James M. Spong, Catherine Y. Hauth, John C. Varner, Michael W. Thorp, John M., Jr. Mercer, Brian M. Peaceman, Alan M. Ramin, Susan M. Carpenter, Marshall W. Iams, Jay D. Sciscione, Anthony Harper, Margaret Tolosa, Jorge E. Saade, George Sorokin, Yoram Anderson, Garland D. CA Eunice Kennedy Shriver Natl Inst TI First-Trimester Prediction of Preeclampsia in Nulliparous Women at Low Risk SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Invest ID UTERINE ARTERY DOPPLER; MEAN PLATELET VOLUME; SERUM PAPP-A; MATERNAL SERUM; NORMAL-PREGNANCY; HYPERTENSION; PLACENTAL-PROTEIN-13; DISINTEGRIN; PRESSURE; INDEXES AB OBJECTIVE: To identify clinical characteristics and biochemical markers in first-trimester samples that would possibly predict the subsequent development of preeclampsia. METHODS: We conducted a multicenter observational study in 2,434 nulliparous women at low risk to identify biomarkers that possibly predict preeclampsia. Clinical history, complete blood count, and biochemical markers were assessed in the first trimester. The trophoblast and angiogenesis markers ADAM-12, pregnancy-associated plasma protein-A, placental protein 13, placental growth factor, soluble fms-like tyrosine kinase-1, and endoglin were measured in a case-control subset of 174 women with preeclampsia and 509 women in the control group. RESULTS: Univariable analysis revealed maternal age, race, marital status, years of education, source of medical payment, prenatal caregiver, body mass index (BMI, calculated as weight (kg)/[height (m)] 2), and systolic blood pressure at enrollment were significantly associated with preeclampsia. Mean platelet volume was greater at enrollment in women who later had development of preeclampsia (median 9.4 compared with 9.0 femtoliter (fl); P=.02). First-trimester concentrations (multiples of the median) of ADAM-12 (1.14 compared with 1.04; P=.003), pregnancy-associated plasma protein-A (0.94 compared with 0.98; P=.04), and placental growth factor (0.83 compared with 1.04; P<.001) were significantly different in women who had development of preeclampsia compared with women in the control group. The optimal multivariable model included African American race, systolic blood pressure, BMI, education level, ADAM-12, pregnancy-associated plasma protein-A, and placental growth factor, and yielded an area under the curve of 0.73 (95% confidence interval 0.69-0.77) and a sensitivity of 46.1% (95% confidence interval 38.3-54.0) for 80% specificity. CONCLUSION: A multivariable analysis of clinical data and biochemical markers in the first trimester did not identify a model that had clinical utility for predicting preeclampsia in a nulliparous population at low risk. (Obstet Gynecol 2012; 119: 1234-42) DOI: 10.1097/AOG.0b013e3182571669 C1 Univ Cincinnati, Dept Obstet & Gynecol, Cincinnati, OH USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Alabama Birmingham, Birmingham, AL USA. Univ Utah, Salt Lake City, UT USA. Univ N Carolina, Chapel Hill, NC USA. Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. Brown Univ, Providence, RI 02912 USA. Ohio State Univ, Columbus, OH 43210 USA. Drexel Univ, Philadelphia, PA 19104 USA. Wake Forest Univ Hlth Sci, Winston Salem, NC USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Univ Texas Med Branch, Galveston, TX USA. Univ Texas Med Ctr, Galveston, TX USA. Wayne State Univ, Detroit, MI USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Myatt, L (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Mail Code 7836,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM Myattl@uthscsa.edu RI Varner, Michael/K-9890-2013 OI Peaceman, Alan/0000-0002-4515-4850; Varner, Michael/0000-0001-9455-3973 FU NCATS NIH HHS [UL1 TR000005, UL1 TR000090]; NCRR NIH HHS [M01 RR000080, M01 RR00080, UL1 RR024153, UL1 RR024989]; NICHD NIH HHS [HD21410, HD27860, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD36801, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, HD53097, HD53118, R24 HD050924, U01 HD036801, U10 HD021410, U10 HD027860, U10 HD027869, U10 HD027915, U10 HD027917, U10 HD034116, U10 HD034136, U10 HD034208, U10 HD036801, U10 HD040485, U10 HD040500, U10 HD040512, U10 HD040544, U10 HD040545, U10 HD040560, U10 HD053097, U10 HD053118, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560, UG1 HD053097] NR 36 TC 87 Z9 89 U1 1 U2 12 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 JUN PY 2012 VL 119 IS 6 BP 1234 EP 1242 DI 10.1097/AOG.0b013e3182571669 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 946OC UT WOS:000304360700022 PM 22617589 ER PT J AU Dworkin, RH Turk, DC Peirce-Sandner, S Burke, LB Farrar, JT Gilron, I Jensen, MP Katz, NP Raja, SN Rappaport, BA Rowbotham, MC Backonja, MM Baron, R Bellamy, N Bhagwagar, Z Costello, A Cowan, P Fang, WC Hertz, S Jay, GW Junor, R Kerns, RD Kerwin, R Kopecky, EA Lissin, D Malamut, R Markman, JD McDermott, MP Munera, C Porter, L Rauschkolb, C Rice, ASC Sampaio, C Skljarevski, V Sommerville, K Stacey, BR Steigerwald, I Tobias, J Trentacosti, AM Wasan, AD Wells, GA Williams, J Witter, J Ziegler, D AF Dworkin, Robert H. Turk, Dennis C. Peirce-Sandner, Sarah Burke, Laurie B. Farrar, John T. Gilron, Ian Jensen, Mark P. Katz, Nathaniel P. Raja, Srinivasa N. Rappaport, Bob A. Rowbotham, Michael C. Backonja, Misha-Miroslav Baron, Ralf Bellamy, Nicholas Bhagwagar, Zubin Costello, Ann Cowan, Penney Fang, Weikai Christopher Hertz, Sharon Jay, Gary W. Junor, Roderick Kerns, Robert D. Kerwin, Rosemary Kopecky, Ernest A. Lissin, Dmitri Malamut, Richard Markman, John D. McDermott, Michael P. Munera, Catherine Porter, Linda Rauschkolb, Christine Rice, Andrew S. C. Sampaio, Cristina Skljarevski, Vladimir Sommerville, Kenneth Stacey, Brett R. Steigerwald, Ilona Tobias, Jeffrey Trentacosti, Ann Marie Wasan, Ajay D. Wells, George A. Williams, Jim Witter, James Ziegler, Dan TI Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations SO PAIN LA English DT Review ID CONCENTRATION CAPSAICIN PATCH; RANDOMIZED CONTROLLED-TRIALS; PLACEBO-CONTROLLED TRIALS; PERIPHERAL NEUROPATHIC PAIN; LONG-TERM TRIALS; LEAD-IN PERIOD; LOW-BACK-PAIN; DOUBLE-BLIND; POSTHERPETIC NEURALGIA; ENRICHED ENROLLMENT AB A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo ("assay sensitivity"). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety. (C) 2012 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved. C1 [Dworkin, Robert H.] Univ Rochester, Med Ctr, Dept Anesthesiol, Rochester, NY 14642 USA. [Dworkin, Robert H.] Univ Rochester, Dept Neurol, Rochester, NY 14642 USA. [Dworkin, Robert H.] Univ Rochester, Ctr Human Expt Therapeut, Rochester, NY 14642 USA. [Turk, Dennis C.; Jensen, Mark P.] Univ Washington, Seattle, WA 98195 USA. [Burke, Laurie B.; Rappaport, Bob A.; Costello, Ann; Hertz, Sharon; Trentacosti, Ann Marie] US FDA, Silver Spring, MD USA. [Farrar, John T.] Univ Penn, Philadelphia, PA 19104 USA. [Gilron, Ian] Queens Univ, Kingston, ON, Canada. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. [Katz, Nathaniel P.] Tufts Univ, Boston, MA 02111 USA. [Raja, Srinivasa N.] Johns Hopkins Univ, Baltimore, MD USA. [Rowbotham, Michael C.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Backonja, Misha-Miroslav] Univ Wisconsin, Madison, WI USA. [Baron, Ralf] Univ Kiel, Kiel, Germany. [Bellamy, Nicholas] Univ Queensland, Brisbane, Qld, Australia. [Bhagwagar, Zubin] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Cowan, Penney] Amer Chron Pain Assoc, Rocklin, CA USA. [Fang, Weikai Christopher] DePuy Spine, Raynham, MA USA. [Jay, Gary W.] Pfizer, New London, CT USA. [Junor, Roderick] Eisai Ltd, Hatfield, Herts, England. [Kerns, Robert D.] Dept Vet Affairs, West Haven, CT USA. [Kerns, Robert D.] Yale Univ, New Haven, CT USA. [Kerwin, Rosemary] Nuvo Res, W Chester, PA USA. [Kopecky, Ernest A.] Endo Pharmaceut Inc, Chadds Ford, PA USA. [Lissin, Dmitri] Durect Corp, Cupertino, CA USA. [Malamut, Richard; Witter, James] AstraZeneca, Wilmington, DE USA. [Munera, Catherine] Purdue Pharma, Stamford, CT USA. [Porter, Linda] NIH, Bethesda, MD 20892 USA. [Rauschkolb, Christine] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. [Rice, Andrew S. C.] Univ London Imperial Coll Sci Technol & Med, London, England. [Sampaio, Cristina] Fac Med Lisbon, Lisbon, Portugal. [Skljarevski, Vladimir] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Sommerville, Kenneth] King Pharmaceut, Cary, NC USA. [Stacey, Brett R.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Steigerwald, Ilona] Grunenthal GmbH, Aachen, Germany. [Tobias, Jeffrey] NeurogesX Inc, San Carlos, CA USA. [Wasan, Ajay D.] Harvard Univ, Sch Med, Boston, MA USA. [Wells, George A.] Univ Ottawa, Ottawa, ON, Canada. [Williams, Jim] Smith & Nephew, Durham, NC USA. [Ziegler, Dan] Univ Dusseldorf, German Diabet Ctr, D-40225 Dusseldorf, Germany. RP Dworkin, RH (reprint author), Univ Rochester, Med Ctr, Dept Anesthesiol, 601 Elmwood Ave,Box 604, Rochester, NY 14642 USA. EM robert_dworkin@urmc.rochester.edu RI Bhagwagar, Zubin/H-1071-2012; Rice, Andrew/I-7501-2012; Bellamy, Nicholas/G-3631-2010 OI Bhagwagar, Zubin/0000-0002-1101-768X; Yang, Shuman/0000-0002-9638-0890; FU AstraZeneca; Bristol-Myers Squibb; DePuy Spine; Durect; Eisai; Eli Lilly; Endo; Forest; Grunenthal; Johnson Johnson; King; NeurogesX; Nuvo; Pfizer; Purdue; Smith Nephew; US Department of Veterans Affairs; US Food and Drug Administration; US National Institutes of Health FX The views expressed in this article are those of the authors, none of whom have financial conflicts of interest related to the specific issues discussed in this manuscript. At the time of the consensus meeting on which this article is based, 15 of the authors were employed by one of the companies that provided unrestricted grants to the University of Rochester Office of Continuing Professional Education to support the activities of IMMPACT, including the consensus meeting; these companies were AstraZeneca, Bristol-Myers Squibb, DePuy Spine, Durect, Eisai, Eli Lilly, Endo, Forest, Grunenthal, Johnson & Johnson, King, NeurogesX, Nuvo, Pfizer, Purdue, and Smith & Nephew.; No official endorsement by the US Department of Veterans Affairs, US Food and Drug Administration, US National Institutes of Health, or the pharmaceutical companies that provided unrestricted grants to the University of Rochester Office of Continuing Professional Education should be inferred. The authors thank Paul J. Lambiase and Mary Gleichauf for their invaluable assistance in the organization of the IMMPACT meeting. NR 108 TC 98 Z9 100 U1 0 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUN PY 2012 VL 153 IS 6 BP 1148 EP 1158 DI 10.1016/j.pain.2012.03.003 PG 11 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 945BZ UT WOS:000304249100009 PM 22494920 ER PT J AU Barchowsky, A Buckley, LA Carlson, GP Fitsanakis, VA Ford, SM Genter, MB Germolec, DR Leavens, TL Lehman-McKeeman, LD Safe, SH Sulentic, CEW Eidemiller, BJ AF Barchowsky, Aaron Buckley, Lorrene A. Carlson, Gary P. Fitsanakis, Vanessa A. Ford, Sue M. Genter, Mary Beth Germolec, Dori R. Leavens, Teresa L. Lehman-McKeeman, Lois D. Safe, Stephen H. Sulentic, Courtney E. W. Eidemiller, Betty J. TI The Toxicology Education Summit: Building the Future of Toxicology Through Education SO TOXICOLOGICAL SCIENCES LA English DT Article DE toxicology; education AB Toxicology and careers in toxicology, as well as many other scientific disciplines, are undergoing rapid and dramatic changes as new discoveries, technologies, and hazards advance at a blinding rate. There are new and ever increasing demands on toxicologists to keep pace with expanding global economies, highly fluid policy debates, and increasingly complex global threats to public health. These demands must be met with new paradigms for multidisciplinary, technologically complex, and collaborative approaches that require advanced and continuing education in toxicology and associated disciplines. This requires paradigm shifts in educational programs that support recruitment, development, and training of the modern toxicologist, as well as continued education and retraining of the midcareer professional to keep pace and sustain careers in industry, government, and academia. The Society of Toxicology convened the Toxicology Educational Summit to discuss the state of toxicology education and to strategically address educational needs and the sustained advancement of toxicology as a profession. The Summit focused on core issues of: building for the future of toxicology through educational programs; defining education and training needs; developing the "Total Toxicologist"; continued training and retraining toxicologists to sustain their careers; and, finally, supporting toxicology education and professional development. This report summarizes the outcomes of the Summit, presents examples of successful programs that advance toxicology education, and concludes with strategies that will insure the future of toxicology through advanced educational initiatives. C1 [Barchowsky, Aaron] Univ Pittsburgh, Dept Environm & Occupat Hlth, Grad Sch Publ Hlth, Pittsburgh, PA 15219 USA. [Buckley, Lorrene A.] Eli Lilly & Co, Indianapolis, IN 46240 USA. [Carlson, Gary P.] Purdue Univ, W Lafayette, IN 47906 USA. [Fitsanakis, Vanessa A.] King Coll, Bristol, TN 37620 USA. [Ford, Sue M.] St Johns Univ, Jamaica, NY 11439 USA. [Genter, Mary Beth] Univ Cincinnati, Cincinnati, OH 45267 USA. [Germolec, Dori R.] NIEHS, Res Triangle Pk, NC 27709 USA. [Leavens, Teresa L.] N Carolina State Univ, Raleigh, NC 27607 USA. [Lehman-McKeeman, Lois D.] Bristol Myers Squibb Co, Princeton, NJ 08543 USA. [Safe, Stephen H.] Texas A&M Univ, College Stn, TX 77845 USA. [Sulentic, Courtney E. W.] Wright State Univ, Dayton, OH 45435 USA. [Eidemiller, Betty J.] Soc Toxicol, Reston, VA 20190 USA. RP Barchowsky, A (reprint author), Univ Pittsburgh, Dept Environm & Occupat Hlth, Grad Sch Publ Hlth, Suite 332,100 Technol Dr, Pittsburgh, PA 15219 USA. EM aab20@pitt.edu FU National Institute of Environmental Health Sciences (NIEHS) [R13 ES021130]; Society of Toxicology Council FX The Toxicology Educational Summit was supported by National Institute of Environmental Health Sciences (NIEHS) grant R13 ES021130 and NIEHS Director's Funds, as well as by the Society of Toxicology Council. NR 0 TC 1 Z9 1 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 2012 VL 127 IS 2 BP 331 EP 338 DI 10.1093/toxsci/kfs111 PG 8 WC Toxicology SC Toxicology GA 944JY UT WOS:000304198400002 PM 22461448 ER PT J AU Oli, GG Ayele, FT Petros, B AF Oli, Geleta Geshere Ayele, Fasil Tekola Petros, Beyene TI Parasitological, serological and clinical evidence for high prevalence of podoconiosis (non-filarial elephantiasis) in Midakegn district, central Ethiopia SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Article DE podoconiosis; non-filarial elephantiasis; prevalence; Wuchereria bancrofti; serology; Ethiopia; podoconiose; elephantiasis non filaire; prevalence; Wuchereria bancrofti; serologie; Ethiopie; Podoconiosis; elefantiasis no filariasica; Prevalencia; Wuchereria bancrofti; Serologia; Etiopia ID SOUTHERN ETHIOPIA; LOWER LEGS; ENDEMIC ELEPHANTIASIS; LYMPHATIC FILARIASIS; STIGMA AB Objective To determine whether the elephantiasis in Midakegn district, central Ethiopia, is filarial or non-filarial (podoconiosis) using serological, parasitological and clinical examinations, and to estimate its prevalence. Methods At house-to-house visits in 330 randomly selected households, all household members who had elephantiasis were interviewed and clinically examined at the nearby health centre to confirm the presence of elephantiasis, check the presence of scrotal swelling and rule out the other causes of lymphoedema. A midnight blood sample was obtained from each participant with elephantiasis for microscopic examination of Wuchereria bancrofti microfilaria. A daytime blood sample was obtained from half of the participants for serological confirmation using the immuno-chromatographic test card. Results Consistent with the features of podoconiosis, none of the elephantiasis cases had consistently worn shoes since childhood; 94.3% had bilateral swelling limited below the level of the knees; no individual had thigh or scrotal elephantiasis; parasitological test for microfilariae and serological tests for W. bancrofti antigen were negative in all samples. The prevalence of the disease was 7.4% and it peaked in the third decade of life, the most economically active age. Conclusion Midakegn District has a high prevalence of podoconiosis and no filarial elephantiasis. Prevention, treatment and control of podoconiosis must be among the top priorities of public health programmes. C1 [Ayele, Fasil Tekola] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Oli, Geleta Geshere] Jimma Univ, Coll Nat Sci, Dept Biol, Jimma, Ethiopia. [Petros, Beyene] Univ Addis Ababa, Microbial Cellular & Mol Biol Program Unit, Addis Ababa, Ethiopia. RP Ayele, FT (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bldg 12A,Room 4044,12 S Dr,MSC 5635, Bethesda, MD 20892 USA. EM ayeleft@mail.nih.gov OI Tekola-Ayele, Fasil/0000-0003-4194-9370 FU School of Graduate Studies of Addis Ababa University FX The study was financed by the School of Graduate Studies of Addis Ababa University. We thank Midakegn District Health Office and the Health Center professional staff (health extension workers and nurses), and the study participants. We would also like to thank Professor Asrat Hailu for providing the ICT cards used in the study. NR 22 TC 11 Z9 11 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1360-2276 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD JUN PY 2012 VL 17 IS 6 BP 722 EP 726 DI 10.1111/j.1365-3156.2012.02978.x PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 945ZE UT WOS:000304316100007 ER PT J AU Haller, ST Kennedy, DJ Shidyak, A Budny, GV Malhotra, D Fedorova, OV Shapiro, JI Bagrov, AY AF Haller, Steven T. Kennedy, David J. Shidyak, Amjad Budny, George V. Malhotra, Deepak Fedorova, Olga V. Shapiro, Joseph I. Bagrov, Alexei Y. TI Monoclonal Antibody Against Marinobufagenin Reverses Cardiac Fibrosis in Rats With Chronic Renal Failure SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; chronic kidney disease; collagen; digitalis-like factors; fibrosis; hypertension; marinobufagenin; monoclonal antibody; Na/K-ATPase; uremic cardiomyopathy ID ENDOGENOUS CARDIOTONIC STEROIDS; REMNANT KIDNEY; UREMIC CARDIOMYOPATHY; NA+/K+-ATPASE; PREECLAMPSIA; HYPERTROPHY; FIBROBLASTS; EXPRESSION; DIGITALIS; PRESSURE AB BACKGROUND Cardiotonic steroids (CTS) are implicated in pathophysiology of uremic cardiomyopathy. In the present study, we tested whether a monoclonal antibody (mAb) against the bufadienolide CTS, marinobufagenin (MBG), alleviates cardiac hypertrophy and fibrosis in partially nephrectomized (PNx) rats. METHODS In PNx rats, we compared the effects of 3E9 anti-MBG mAb and of Digibind, an affinity-purified digoxin antibody, on blood pressure and cardiac hypertrophy and fibrosis following 4 weeks after the surgery. RESULTS In PNx rats, a fourfold elevation in plasma MBG levels was associated with hypertension, increased cardiac levels of carbonylated protein, cardiac hypertrophy, a reduction in cardiac expression of a nuclear transcription factor which is a negative regulator of collagen synthesis, Friend leukemia integration-1 (Fli-1), and an increase in the levels of collagen-1. A single intraperitoneal administration of 3E9 mAb to PNx rats reduced blood pressure by 59 mm Hg for 7 days and produced a significant reduction in cardiac weight and cardiac levels of oxidative stress, an increase in the expression of Fli-1, and a reduction in cardiac fibrosis. The effects of Digibind were similar to those of 3E9 mAb, but were less pronounced. CONCLUSIONS In experimental chronic renal failure, elevated levels of MBG contribute to hypertension and induce cardiac fibrosis via suppression of Fli-1, representing a potential target for therapy. C1 [Haller, Steven T.; Kennedy, David J.; Budny, George V.; Malhotra, Deepak; Shapiro, Joseph I.] Univ Toledo, Coll Med, Toledo, OH 43606 USA. [Kennedy, David J.; Shidyak, Amjad] Cleveland Clin Lerner Res Inst, Dept Cell Biol, Cleveland, OH USA. [Fedorova, Olga V.; Bagrov, Alexei Y.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Bagrov, AY (reprint author), NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. EM bagrova@mail.nih.gov FU National Institute on Aging, NIH; NIH [HL071556] FX These studies were supported by Intramural Research Program, National Institute on Aging, NIH (O.V.F., and A.Y.B.) and by NIH grant HL071556 (J.I.S.). NR 23 TC 29 Z9 31 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD JUN PY 2012 VL 25 IS 6 BP 690 EP 696 DI 10.1038/ajh.2012.17 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 944GZ UT WOS:000304188600012 PM 22378033 ER PT J AU Khoury, MJ Gwinn, ML Glasgow, RE Kramer, BS AF Khoury, Muin J. Gwinn, Marta L. Glasgow, Russell E. Kramer, Barnett S. TI A Population Approach to Precision Medicine SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID GENOMIC MEDICINE; PUBLIC-HEALTH; PERSONALIZED MEDICINE; CANCER; PREVENTION; AGENDA; CARE; OPPORTUNITIES; 21ST-CENTURY; EPIDEMIOLOGY AB The term P4 medicine is used to denote an evolving field of medicine that uses systems biology approaches and information technologies to enhance wellness rather than just treat disease. Its four components include predictive, preventive, personalized, and participatory medicine. In the current paper, it is argued that in order to fulfill the promise of P4 medicine, a "fifth P" must be integrated-the population perspective-into each of the other four components. A population perspective integrates predictive medicine into the ecologic model of health; applies principles of population screening to preventive medicine; uses evidence-based practice to personalize medicine; and grounds participatory medicine on the three core functions of public health: assessment, policy development, and assurance. Population sciences-including epidemiology; behavioral, social, and communication sciences; and health economics, implementation science, and outcomes research-are needed to show the value of P4 medicine. Balanced strategies that implement both population-and individual-level interventions can best maximize health benefits, minimize harm, and avoid unnecessary healthcare costs. (Am J Prev Med 2012; 42(6): 639-645) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Khoury, Muin J.; Gwinn, Marta L.] CDC, Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Khoury, Muin J.; Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Kramer, Barnett S.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Khoury, MJ (reprint author), CDC, Off Publ Hlth Genom, 1600 Clifton Rd, Atlanta, GA 30333 USA. EM muk1@cdc.gov FU Intramural NIH HHS [Z99 CA999999] NR 64 TC 41 Z9 44 U1 6 U2 31 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD JUN PY 2012 VL 42 IS 6 BP 639 EP 645 DI 10.1016/j.amepre.2012.02.012 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 942ZT UT WOS:000304090900015 PM 22608383 ER PT J AU Glasgow, RE Green, LW Taylor, MV Stange, KC AF Glasgow, Russell E. Green, Lawrence W. Taylor, Martina V. Stange, Kurt C. TI An Evidence Integration Triangle for Aligning Science with Policy and Practice SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID PUBLIC-HEALTH SERVICES; CENTERED MEDICAL HOME; PARTICIPATORY RESEARCH; RESEARCH NETWORKS; SYSTEMS RESEARCH; TEAM SCIENCE; CARE; COMMUNITY; INTERVENTIONS; TRANSLATION AB Over-reliance on decontextualized, standardized implementation of efficacy evidence has contributed to slow integration of evidence-based interventions into health policy and practice. This article describes an "evidence integration triangle" (EIT) to guide translation, implementation, prevention efforts, comparative effectiveness research, funding, and policy-making. The EIT emphasizes interactions among three related components needed for effective evidence implementation: (1) practical evidence-based interventions; (2) pragmatic, longitudinal measures of progress; and (3) participatory implementation processes. At the center of the EIT is active engagement of key stakeholders and scientific evidence and attention to the context in which a program is implemented. The EIT model is a straightforward framework to guide practice, research, and policy toward greater effectiveness and is designed to be applicable across multiple levels-from individual-focused and patient-provider interventions, to health systems and policy-level change initiatives. (Am J Prev Med 2012; 42(6): 646-654) (C) 2012 Elsevier Inc C1 [Glasgow, Russell E.; Taylor, Martina V.; Stange, Kurt C.] NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD 20852 USA. [Green, Lawrence W.] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA USA. [Stange, Kurt C.] Case Western Reserve Univ, Dept Family Med, Cleveland, OH 44106 USA. [Stange, Kurt C.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Stange, Kurt C.] Case Western Reserve Univ, Dept Sociol, Cleveland, OH 44106 USA. [Stange, Kurt C.] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Stange, Kurt C.] Case Western Reserve Univ, Cleveland Clin & Translat Sci Collaborat, Cleveland, OH 44106 USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 6130 Execut Blvd,Room 6144, Rockville, MD 20852 USA. EM glasgowre@mail.nih.gov FU Division of Cancer Control and Population Sciences at the National Cancer Institute; American Cancer Society; Clinical & Translational Science Award (CTSA) [UL1 RR024989]; National Center for Research Resources FX KCS's time is supported by the Intergovernmental Personnel Act Mobility Program through the Division of Cancer Control and Population Sciences at the National Cancer Institute, by a Clinical Research Professorship from the American Cancer Society, and by a Clinical & Translational Science Award (CTSA) to Case Western Reserve University/Cleveland Clinic, CTSA Grant Number UL1 RR024989, from the National Center for Research Resources. NR 84 TC 56 Z9 58 U1 8 U2 41 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD JUN PY 2012 VL 42 IS 6 BP 646 EP 654 DI 10.1016/j.amepre.2012.02.016 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 942ZT UT WOS:000304090900016 PM 22608384 ER PT J AU Nweeia, MT Eichmiller, FC Hauschka, PV Tyler, E Mead, JG Potter, CW Angnatsiak, DP Richard, PR Orr, JR Black, SR AF Nweeia, Martin T. Eichmiller, Frederick C. Hauschka, Peter V. Tyler, Ethan Mead, James G. Potter, Charles W. Angnatsiak, David P. Richard, Pierre R. Orr, Jack R. Black, Sandie R. TI Vestigial Tooth Anatomy and Tusk Nomenclature for Monodon Monoceros SO ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY LA English DT Article DE Monodon monoceros; narwhal; vestigial teeth; osteoanatomy; nomenclature ID ELEPHANT LOXODONTA-AFRICANA; MAMMALIA; PROBOSCIDEA; NARWHAL; EVOLUTION; PATTERN; EOCENE; DENTIN; IVORY; INDIA AB Narwhal tusks, although well described and characterized within publications, are clouded by contradictory references, which refer to them as both incisors and canines. Vestigial teeth are briefly mentioned in the scientific literature with limited descriptions and no image renderings. This study first examines narwhal maxillary osteoanatomy to determine whether the erupted tusks are best described as incisiform or caniniform teeth. The study also offers evidence to support the evolutionary obsolescence of the vestigial teeth through anatomic, morphologic, and histologic descriptions. Examination of 131 skull samples, including 110 museum skull specimens and 21 harvested skulls, revealed the erupted tusks surrounded by maxillary bone over the entire length of their bone socket insertion, and are thus more accurately termed caniniform or canine teeth. The anatomy, morphology, and development of vestigial teeth in five skull samples are more fully described and documented. Vestigial tooth samples included 14 embedded pairs or individual teeth that were partially exposed or removed from the maxillary bone. Their location was posterior, ventral, and lateral to the tusks, although male vestigial teeth often exfoliate in the mouth lodging between the palatal tissue and underlying maxillary bone. Their myriad morphologies, sizes, and eruption patterns suggest that these teeth are no longer guided by function but rather by random germ cell differentiation and may eventually cease expression entirely. The conclusions reached are that the narwhal tusks are the expression of canine teeth and that vestigial teeth have no apparent functional characteristics and are following a pattern consistent with evolutionary obsolescence. Anat Rec, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Nweeia, Martin T.] Harvard Univ, Sch Dent Med, Dept Restorat Dent & Biomat Sci, Boston, MA 02115 USA. [Nweeia, Martin T.] Smithsonian Inst, Dept Vertebrate Zool, Washington, DC 20560 USA. [Nweeia, Martin T.; Potter, Charles W.] Harvard Museum Comparat Zool, Dept Mammals, Boston, MA USA. [Eichmiller, Frederick C.] Delta Dent Wisconsin, Stevens Point, WI USA. [Hauschka, Peter V.] Childrens Hosp Boston, Dept Orthopaed Surg, Boston, MA USA. [Tyler, Ethan] NIH, Med Arts Design Sect, Washington, DC USA. [Angnatsiak, David P.] Inuit Hunter, Pond Inlet, NU, Canada. [Richard, Pierre R.; Orr, Jack R.] Fisheries & Oceans Canada, Arctic Res Div, Winnipeg, MB, Canada. [Black, Sandie R.] Calgary Zoo Anim Hlth Ctr, Vet Serv, Calgary, AB, Canada. RP Nweeia, MT (reprint author), Harvard Univ, Sch Dent Med, Dept Restorat Dent & Biomat Sci, 188 Longwood Ave, Boston, MA 02115 USA. EM martin_nweeia@hsdm.harvard.edu FU National Science Foundation; Harvard School of Medicine; Harvard School of Dental Medicine; Explorers Club; World Center for Exploration; National Geographic Society; Smithsonian Institution; Harvard Museum of Comparative Zoology FX Grant sponsors: National Science Foundation, Harvard Schools of Medicine and Dental Medicine, The Explorers Club, World Center for Exploration, The National Geographic Society, the Smithsonian Institution, the Harvard Museum of Comparative Zoology. NR 79 TC 10 Z9 10 U1 13 U2 98 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1932-8486 J9 ANAT REC JI Anat. Rec. PD JUN PY 2012 VL 295 IS 6 BP 1006 EP 1016 DI 10.1002/ar.22449 PG 11 WC Anatomy & Morphology SC Anatomy & Morphology GA 940SY UT WOS:000303914600014 PM 22467529 ER PT J AU Bhondwe, RS Kang, DW Kim, MS Kim, HS Park, SG Son, K Choi, S Kuhs, KAL Pavlyukovets, VA Pearce, LV Blumberg, PM Lee, J AF Bhondwe, Rahul S. Kang, Dong Wook Kim, Myeong Seop Kim, Ho Shin Park, Seul-gi Son, Karam Choi, Sun Kuhs, Krystle A. Lang Pavlyukovets, Vladimir A. Pearce, Larry V. Blumberg, Peter M. Lee, Jeewoo TI Structure-activity relationships and molecular modeling of the N-(3-pivaloyloxy-2-benzylpropyl)-N '-[4-(methylsulfonylamino)benzyl] thiourea template for TRPV1 antagonism SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Vanilloid receptor 1; TRPV1 antagonist; Capsaicin; Resiniferatoxin; Molecular modeling ID VANILLOID RECEPTOR; CAPSAICIN RECEPTORS; ANALGESICS; AGONISTS; ANALOGS; POTENT AB The structure-activity relationships of N-(3-acyloxy-2-benzylpropyl)-N'-4-[(methylsulfonylamino) benzyl] thioureas, which represent simplified RTX-based vanilloids, were investigated by varying the distances between the four principal pharmacophores and assessing binding and antagonistic activity on rTRPV1. The analysis indicated that a 3-pivaloyloxy-2-benzylpropyl C-region conferred the best potency in binding affinity and antagonism. The molecular modeling of this best template with the tetrameric homology model of rTRPV1 was performed to identify its binding interactions with the receptor. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Bhondwe, Rahul S.; Kim, Myeong Seop; Kim, Ho Shin; Lee, Jeewoo] Seoul Natl Univ, Res Inst Pharmaceut Sci, Coll Pharm, Seoul 151742, South Korea. [Kang, Dong Wook] Catholic Univ Deagu, Dept Pharmaceut Sci & Technol, Coll Hlth & Med Sci, Gyongsan 712702, Gyeongsangbuk D, South Korea. [Park, Seul-gi; Son, Karam; Choi, Sun] Ewha Womans Univ, Natl Leading Res Lab NLRL Mol Modeling & Drug Des, Coll Pharm, Div Life & Pharmaceut Sci, Seoul 120750, South Korea. [Park, Seul-gi; Son, Karam; Choi, Sun] Ewha Womans Univ, Natl Core Res Ctr Cell Signaling & Drug Discovery, Seoul 120750, South Korea. [Kuhs, Krystle A. Lang; Pavlyukovets, Vladimir A.; Pearce, Larry V.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Res Inst Pharmaceut Sci, Coll Pharm, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU National Research Foundation of Korea (NRF) [R11-2007-107-02001-0]; NLRL [2011-0028885]; Brain Research Center of the 21st Century Frontier Research Program [2011-K000289]; MEST; NRF; Ewha Womans University; National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z1A BC 005270] FX This research was supported by Grants from the National Research Foundation of Korea (NRF) (R11-2007-107-02001-0), Grants from the NLRL program (2011-0028885), Brain Research Center of the 21st Century Frontier Research Program (2011-K000289) funded by MEST and NRF, the Ewha Global Top 5 Grant 2011 of Ewha Womans University, and was supported in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Project Z1A BC 005270). NR 21 TC 4 Z9 4 U1 1 U2 7 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 JUN 1 PY 2012 VL 22 IS 11 BP 3656 EP 3660 DI 10.1016/j.bmcl.2012.04.034 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 941RK UT WOS:000303980600014 PM 22546668 ER PT J AU Hollenhorst, MI Lips, KS Wolff, M Wess, J Gerbig, S Takats, Z Kummer, W Fronius, M AF Hollenhorst, Monika I. Lips, Katrin S. Wolff, Miriam Wess, Juergen Gerbig, Stefanie Takats, Zoltan Kummer, Wolfgang Fronius, Martin TI Luminal cholinergic signalling in airway lining fluid: a novel mechanism for activating chloride secretion via Ca2+-dependent Cl- and K+ channels SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE airway epithelium; acetylcholine; acetylcholine receptors; muscarinic receptors; nicotinic receptors; non-neuronal cholinergic system; transepithelial ion transport; auto-; paracrine ID NICOTINIC ACETYLCHOLINE-RECEPTORS; TRANSMEMBRANE CONDUCTANCE REGULATOR; POLYSPECIFIC CATION TRANSPORTERS; BRONCHIAL EPITHELIAL-CELLS; INTERMEDIATE-CONDUCTANCE; CYSTIC-FIBROSIS; NONNEURONAL ACETYLCHOLINE; TRACHEAL EPITHELIUM; PHARMACOLOGICAL CHARACTERIZATION; DOWN-REGULATION AB BACKGROUND AND PURPOSE Recent studies detected the expression of proteins involved in cholinergic metabolism in airway epithelial cells, although the function of this non-neuronal cholinergic system is not known in detail. Thus, this study focused on the effect of luminal ACh as a regulator of transepithelial ion transport in epithelial cells. EXPERIMENTAL APPROACH RT-PCR experiments were performed using mouse tracheal epithelial cells for ChAT and organic cation transporter (OCT) transcripts. Components of tracheal airway lining fluid were analysed with desorption electrospray ionization (DESI) MS. Effects of nicotine on mouse tracheal epithelial ion transport were examined with Ussing-chamber experiments. KEY RESULTS Transcripts encoding ChAT and OCT13 were detected in mouse tracheal epithelial cells. The DESI experiments identified ACh in the airway lining fluid. Luminal ACh induced an immediate, dose-dependent increase in the transepithelial ion current (EC50: 23.3 mu M), characterized by a transient peak and sustained plateau current. This response was not affected by the Na+-channel inhibitor amiloride. The Cl--channel inhibitor niflumic acid or the K+-channel blocker Ba2+ attenuated the ACh effect. The calcium ionophore A23187 mimicked the ACh effect. Luminal nicotine or muscarine increased the ion current. Experiments with receptor gene-deficient animals revealed the participation of muscarinic receptor subtypes M1 and M3. CONCLUSIONS AND IMPLICATIONS The presence of luminal ACh and activation of transepithelial ion currents by luminal ACh receptors identifies a novel non-neuronal cholinergic pathway in the airway lining fluid. This pathway could represent a novel drug target in the airways. C1 [Hollenhorst, Monika I.; Fronius, Martin] Univ Giessen, Inst Anim Physiol, D-35392 Giessen, Germany. [Lips, Katrin S.] Univ Giessen, Lab Expt Trauma Surg, D-35392 Giessen, Germany. [Lips, Katrin S.; Wolff, Miriam; Kummer, Wolfgang] Univ Giessen, Inst Anat & Cell Biol, D-35392 Giessen, Germany. [Lips, Katrin S.; Wolff, Miriam; Kummer, Wolfgang] Univ Giessen, Marburg Lung Ctr, D-35392 Giessen, Germany. [Wess, Juergen] NIDDK, Bioorgan Chem Lab, US Dept HHS, Bethesda, MD 20892 USA. [Gerbig, Stefanie; Takats, Zoltan] Univ Giessen, Inst Inorgan & Analyt Chem, D-35392 Giessen, Germany. RP Fronius, M (reprint author), Univ Giessen, Inst Anim Physiol, Wartweg 95, D-35392 Giessen, Germany. EM martin.fronius@bio.uni-giessen.de RI Gerbig, Stefanie/F-9483-2012 FU Konrad-Adenauer-Stiftung; Universities of Giessen; Marburg Lung Center FX The authors would like to thank Martin Bodenbenner for excellent technical support. The present study was supported by a scholarship from the Konrad-Adenauer-Stiftung to MI Hollenhorst and the Universities of Giessen and Marburg Lung Center. NR 67 TC 7 Z9 7 U1 1 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD JUN PY 2012 VL 166 IS 4 BP 1388 EP 1402 DI 10.1111/j.1476-5381.2012.01883.x PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 943OS UT WOS:000304134400015 PM 22300281 ER PT J AU Ding, JL Liu, YY Peden, DB Kleeberger, SR Zhou, HB AF Ding, Jieli Liu, Yanyan Peden, David B. Kleeberger, Steven R. Zhou, Haibo TI Regression analysis for a summed missing data problem under an outcome-dependent sampling scheme SO CANADIAN JOURNAL OF STATISTICS-REVUE CANADIENNE DE STATISTIQUE LA English DT Article DE Biased sampling; empirical likelihood; missing data; semiparametric ID EMPIRICAL LIKELIHOOD METHOD; BINARY RESPONSE DATA; INFERENCE; DESIGN AB In this paper, we consider a regression analysis for a missing data problem in which the variables of primary interest are unobserved under a general biased sampling scheme, an outcome-dependent sampling (ODS) design. We propose a semiparametric empirical likelihood method for accessing the association between a continuous outcome response and unobservable interesting factors. Simulation study results show that ODS design can produce more efficient estimators than the simple random design of the same sample size. We demonstrate the proposed approach with a data set from an environmental study for the genetic effects on human lung function in COPD smokers. The Canadian Journal of Statistics 40: 282303; 2012 (c) 2012 Statistical Society of Canada C1 [Ding, Jieli; Zhou, Haibo] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Ding, Jieli; Liu, Yanyan] Wuhan Univ, Sch Math & Stat, Wuhan 430072, Hubei, Peoples R China. [Peden, David B.] Univ N Carolina, Dept Pediat, Chapel Hill, NC 27599 USA. [Peden, David B.; Zhou, Haibo] Univ N Carolina, Sch Med, Ctr Environm Med Asthma & Lung Biol, Chapel Hill, NC 27599 USA. [Kleeberger, Steven R.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Zhou, HB (reprint author), Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. EM zhou@bios.unc.edu FU National Science Foundation of China [11101314, 11171263]; U.S. National Institutes of Health [R01CA79949, P50HL084934, U19AI077437]; Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services FX The authors thank the Editor, Associate Editor, and two referees for their valuable comments and suggestions that have led to further improvement of this paper. This research is funded in part by the National Science Foundation of China grants 11101314 (Ding) and 11171263 (Liu), U.S. National Institutes of Health grants R01CA79949 (Zhou and Ding), P50HL084934 and U19AI077437 (Peden), the Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services (Kleeberger). NR 25 TC 2 Z9 2 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0319-5724 J9 CAN J STAT JI Can. J. Stat.-Rev. Can. Stat. PD JUN PY 2012 VL 40 IS 2 BP 282 EP 303 DI 10.1002/cjs.11131 PG 22 WC Statistics & Probability SC Mathematics GA 943OU UT WOS:000304134600005 ER PT J AU Barry, KH Koutros, S Lubin, JH Coble, JB Barone-Adesi, F Freeman, LEB Sandler, DP Hoppin, JA Ma, XM Zheng, TZ Alavanja, MCR AF Barry, Kathryn Hughes Koutros, Stella Lubin, Jay H. Coble, Joseph B. Barone-Adesi, Francesco Freeman, Laura E. Beane Sandler, Dale P. Hoppin, Jane A. Ma, Xiaomei Zheng, Tongzhang Alavanja, Michael C. R. TI Methyl bromide exposure and cancer risk in the Agricultural Health Study SO CANCER CAUSES & CONTROL LA English DT Article DE Methyl bromide; Fumigant; Pesticide; Cancer ID PROSTATE-CANCER; PESTICIDE EXPOSURE; FARM-WORKERS; CALIFORNIA; FORESTOMACH; INHALATION; RATS; CARCINOGENICITY; TOXICITY AB Methyl bromide is a genotoxic soil fumigant with high acute toxicity, but unknown human carcinogenicity. Although many countries have reduced methyl bromide use because of its ozone depleting properties, some uses remain in the United States and other countries, warranting further investigation of human health effects. We used Poisson regression to calculate rate ratios (RR) and 95 % confidence intervals (CI) for associations between methyl bromide use and all cancers combined, as well as 12 specific sites, among 53,588 Agricultural Health Study pesticide applicators with follow-up from 1993 to 2007. We also evaluated interactions with a family history for four common cancers (prostate, lung, colon, and lymphohematopoietic). We categorized methyl bromide exposure based on lifetime days applied weighted by an intensity score. A total of 7,814 applicators (14.6 %) used methyl bromide, predominantly before enrollment. Based on 15 exposed cases, stomach cancer risk increased monotonically with increasing methyl bromide use (RR = 1.42; 95 % CI, 0.51-3.95 and RR = 3.13; 95 % CI, 1.25-7.80 for low and high use compared with no use; (trend) = 0.02). No other sites displayed a significant monotonic pattern. Although we previously observed an association with prostate cancer (follow-up through 1999), the association did not persist with longer follow-up. We observed a nonsignificant elevated risk of prostate cancer with methyl bromide use among those with a family history of prostate cancer, but the interaction with a family history did not achieve statistical significance. Our results provide little evidence of methyl bromide associations with cancer risk for most sites examined; however, we observed a significant exposure-dependent increase in stomach cancer risk. Small numbers of exposed cases and declining methyl bromide use might have influenced our findings. Further study is needed in more recently exposed populations to expand on these results. C1 [Barry, Kathryn Hughes; Koutros, Stella; Coble, Joseph B.; Barone-Adesi, Francesco; Freeman, Laura E. Beane; Alavanja, Michael C. R.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Barry, Kathryn Hughes; Ma, Xiaomei; Zheng, Tongzhang] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Lubin, Jay H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Sandler, Dale P.; Hoppin, Jane A.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Barry, KH (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 8111,MSC 7240, Bethesda, MD 20892 USA. EM barrykh@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Sandler, Dale/0000-0002-6776-0018 FU National Cancer Institute, Division of Cancer Epidemiology and Genetics [Z01CP010119]; National Institute of Environmental Health Sciences [Z01ES049030]; National Institutes of Health; National Cancer Institute [T32 CA105666] FX This research was supported by the Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics (Z01CP010119), and National Institute of Environmental Health Sciences (Z01ES049030), National Institutes of Health. Additionally, support for K. H. B. was provided by National Cancer Institute grant T32 CA105666. NR 29 TC 13 Z9 14 U1 2 U2 23 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2012 VL 23 IS 6 BP 807 EP 818 DI 10.1007/s10552-012-9949-2 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 943FK UT WOS:000304105700002 PM 22527160 ER PT J AU Gulati, R Tsodikov, A Wever, EM Mariotto, AB Heijnsdijk, EAM Katcher, J de Koning, HJ Etzioni, R AF Gulati, Roman Tsodikov, Alex Wever, Elisabeth M. Mariotto, Angela B. Heijnsdijk, Eveline A. M. Katcher, Jeffrey de Koning, Harry J. Etzioni, Ruth TI The impact of PLCO control arm contamination on perceived PSA screening efficacy SO CANCER CAUSES & CONTROL LA English DT Article DE Computer simulation; Early detection of cancer; Mortality; Prostate-specific antigen; Prostatic neoplasms; Randomized controlled trial ID PROSTATE-CANCER; UNITED-STATES; TRIAL; LUNG; BIOPSY; MORTALITY; DESIGN; ERSPC; MODEL AB To quantify the extent to which a clinically significant prostate cancer mortality reduction due to screening could have been masked by control arm screening (contamination) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial. We used three independently developed models of prostate cancer natural history to conduct a virtual PLCO trial. Simulated participants underwent pre-trial screening based on population patterns. The intervention arm followed observed compliance during the trial then resumed population screening. A contaminated control arm followed observed contamination during the trial then resumed population screening, while an uncontaminated control arm discontinued screening upon entry. We assumed a clinically significant screening benefit, applied population treatments and survival patterns, and calculated mortality rate ratios relative to the contaminated and uncontaminated control arms. The virtual trial reproduced observed incidence, including stage and grade distributions, and control arm mortality after 10 years of complete follow-up. Under the assumed screening benefit, the three models found that contamination increased the mortality rate ratio from 0.68-0.77 to 0.86-0.91, increased the chance of excess mortality in the intervention arm from 0-4 % to 15-28 %, and decreased the power of the trial to detect a mortality difference from 40-70 % to 9-25 %. Our computer simulation models indicate that contamination substantially limited the ability of the PLCO to identify a clinically significant screening benefit. While the trial shows annual screening does not reduce mortality relative to population screening, contamination prevents concluding whether screening reduces mortality relative to no screening. C1 [Gulati, Roman; Katcher, Jeffrey; Etzioni, Ruth] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Tsodikov, Alex] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Wever, Elisabeth M.; Heijnsdijk, Eveline A. M.; de Koning, Harry J.] Erasmus Univ, Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands. [Mariotto, Angela B.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Gulati, R (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,M2-B230,POB 19024, Seattle, WA 98109 USA. EM rgulati@fhcrc.org FU National Cancer Institute [U01CA157224-01, U01CA157224]; Centers for Disease Control; Beckman Coulter FX We are grateful to Dr. Paul F. Pinsky for careful reading and helpful comments on an earlier draft. Any remaining errors are our own. This research was supported by U01CA157224-01 from the National Cancer Institute and U01CA157224 from the National Cancer Institute and the Centers for Disease Control. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, the National Institutes of Health, or the Centers for Disease Control.; HJK received partial funding from Beckman Coulter to evaluate cost-effectiveness of the prostate health index. All other authors declare that they have no conflict of interest. NR 31 TC 28 Z9 28 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2012 VL 23 IS 6 BP 827 EP 835 DI 10.1007/s10552-012-9951-8 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 943FK UT WOS:000304105700004 PM 22488488 ER PT J AU Torfadottir, JE Valdimarsdottir, UA Mucci, L Stampfer, M Kasperzyk, JL Fall, K Tryggvadottir, L Aspelund, T Olafsson, O Harris, TB Jonsson, E Tulinius, H Adami, HO Gudnason, V Steingrimsdottir, L AF Torfadottir, Johanna E. Valdimarsdottir, Unnur A. Mucci, Lorelei Stampfer, Meir Kasperzyk, Julie L. Fall, Katja Tryggvadottir, Laufey Aspelund, Thor Olafsson, Orn Harris, Tamara B. Jonsson, Eirikur Tulinius, Hrafn Adami, Hans-Olov Gudnason, Vilmundur Steingrimsdottir, Laufey TI Rye bread consumption in early life and reduced risk of advanced prostate cancer SO CANCER CAUSES & CONTROL LA English DT Article DE Adolescent; Diet; Epidemiology; Rye bread; Prostatic neoplasms; Whole grain; AGES-Reykjavik study ID IGF BINDING PROTEIN-3; NESTED CASE-CONTROL; WHOLE GRAIN; SERUM ENTEROLACTONE; METABOLIC SYNDROME; NORDIC COUNTRIES; PLANT FOODS; INSULIN; REYKJAVIK; SWEDEN AB To determine whether consumption of whole-grain rye bread, oatmeal, and whole-wheat bread, during different periods of life, is associated with risk of prostate cancer (PCa). From 2002 to 2006, 2,268 men, aged 67-96 years, reported their dietary habits in the AGES-Reykjavik cohort study. Dietary habits were assessed for early life, midlife, and current life using a validated food frequency questionnaire. Through linkage to cancer and mortality registers, we retrieved information on PCa diagnosis and mortality through 2009. We used regression models to estimate odds ratios (ORs) and hazard ratios (HRs) for PCa according to whole-grain consumption, adjusted for possible confounding factors including fish, fish liver oil, meat, and milk intake. Of the 2,268 men, 347 had or were diagnosed with PCa during follow-up, 63 with advanced disease (stage 3+ or died of PCa). Daily rye bread consumption in adolescence (vs. less than daily) was associated with a decreased risk of PCa diagnosis (OR = 0.76, 95 % confidence interval (CI): 0.59-0.98) and of advanced PCa (OR = 0.47, 95 % CI: 0.27-0.84). High intake of oatmeal in adolescence (a parts per thousand yen5 vs. a parts per thousand currency sign4 times/week) was not significantly associated with risk of PCa diagnosis (OR = 0.99, 95 % CI: 0.77-1.27) nor advanced PCa (OR = 0.67, 95 % CI: 0.37-1.20). Midlife and late life consumption of rye bread, oatmeal, or whole-wheat bread was not associated with PCa risk. Our results suggest that rye bread consumption in adolescence may be associated with reduced risk of PCa, particularly advanced disease. C1 [Torfadottir, Johanna E.; Valdimarsdottir, Unnur A.; Fall, Katja; Aspelund, Thor; Olafsson, Orn] Univ Iceland, Ctr Publ Hlth Sci, IS-101 Reykjavik, Iceland. [Valdimarsdottir, Unnur A.; Mucci, Lorelei; Stampfer, Meir; Kasperzyk, Julie L.; Adami, Hans-Olov] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mucci, Lorelei; Stampfer, Meir; Kasperzyk, Julie L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Fall, Katja] Orebro Univ Hosp, Orebro, Sweden. [Tryggvadottir, Laufey; Tulinius, Hrafn] Iceland Canc Registry, Reykjavik, Iceland. [Tryggvadottir, Laufey; Tulinius, Hrafn; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Jonsson, Eirikur] Landspitali Univ Hosp, Reykjavik, Iceland. [Adami, Hans-Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Steingrimsdottir, Laufey] Univ Iceland, Unit Nutr Res, Fac Food Sci & Nutr, IS-101 Reykjavik, Iceland. RP Torfadottir, JE (reprint author), Univ Iceland, Ctr Publ Hlth Sci, IS-101 Reykjavik, Iceland. EM jet1@hi.is RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015; OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; Tryggvadottir, Laufey/0000-0001-8067-9030; Fall, Katja/0000-0002-3649-2639 FU Framfor (Progress), an Icelandic organization; HELGA; NIH [5 T32 CA09001-36]; American Institute for Cancer Research; National Institute on Aging [N01-AG-1-2100]; National Institute on Aging; Icelandic Heart Association; Althingi (the Icelandic Parliament); Framfor FX We wish to thank Oddur Benediktsson (1937-2010) and the organization Framfor for their support and interest in the study. JET is supported by Framfor (Progress), an Icelandic organization that aims to fund research and education initiatives related to prostate cancer, the Icelandic Cancer Society and NordForsk, Nordic Centre of Excellence programme: HELGA: Nordic Health Whole Grain Food. JLK is supported by HELGA, in part by training grant NIH 5 T32 CA09001-36 and by the American Institute for Cancer Research. This study was also funded in part by the National Institute on Aging contract N01-AG-1-2100, in part by the Intramural Research Program of the National Institute on Aging, the Icelandic Heart Association, and the Althingi (the Icelandic Parliament). NR 49 TC 10 Z9 10 U1 1 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2012 VL 23 IS 6 BP 941 EP 950 DI 10.1007/s10552-012-9965-2 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 943FK UT WOS:000304105700015 PM 22527172 ER PT J AU Andaya, AA Enewold, L Horner, MJ Jatoi, I Shriver, CD Zhu, KM AF Andaya, Abegail A. Enewold, Lindsey Horner, Marie-Josephe Jatoi, Ismail Shriver, Craig D. Zhu, Kangmin TI Socioeconomic disparities and breast cancer hormone receptor status SO CANCER CAUSES & CONTROL LA English DT Article DE Breast cancer; Estrogen receptor; Hormone receptor; Progesterone receptor; Poverty; Socioeconomic status ID ESTROGEN-RECEPTOR; GEOCODING PROJECT; PHYSICAL-ACTIVITY; AARP DIET; RISK; HEALTH; MORTALITY; WOMEN; RACE/ETHNICITY; ASSOCIATION AB Recent research, although inconsistent, indicates that socioeconomic status (SES) may be associated with hormone receptor (HR) status. This study aims to examine the association between SES and breast cancer HR status within and across racial/ethnic groups stratified by age at diagnosis and tumor stage. The study subjects were 184,602 women with incident breast cancer diagnosed during 2004-2007 and identified from the National Cancer Institute's Surveillance, Epidemiology and End Results program. Log-binomial regression assessed the risk of having breast tumors that were (1) HR-negative versus HR-positive and (2) HR-unknown versus HR-known between women who, at the time of diagnosis, were residing in high or medium poverty areas compared to low poverty areas. High poverty areas tended to have a greater prevalence of HR-negative tumors compared to more affluent areas. Although not always significant, this was observed among non-Hispanic white and Hispanic women regardless of age-tumor stage category, and only among young, non-Hispanic black women and non-Hispanic Asian/Pacific Islander women with regional and distant stage. High poverty areas also tended to have a greater prevalence of HR-unknown tumors compared to more affluent areas. Furthermore, significant trends between HR status and poverty level varied by race/ethnicity, age, and tumor stage. Poverty may be related to breast cancer negative and unknown HR status. These findings suggest the effects of non-genetic factors on biochemical features of breast cancer, as well as imply a clinical importance to improve HR measurement or recording for low socioeconomic breast cancer patients. C1 [Andaya, Abegail A.; Enewold, Lindsey; Shriver, Craig D.; Zhu, Kangmin] US Mil Canc Inst, Rockville, MD 20852 USA. [Horner, Marie-Josephe] NCI, NIH, Rockville, MD USA. [Jatoi, Ismail] UT Hlth Sci Ctr San Antonio, Dept Surg, San Antonio, TX USA. [Shriver, Craig D.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Shriver, Craig D.; Zhu, Kangmin] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Zhu, KM (reprint author), US Mil Canc Inst, 11300 Rockville Pike,Suite 1215, Rockville, MD 20852 USA. EM kangmin.zhu@usuhs.edu FU United States Military Cancer Institute (USMCI) via the Uniformed Services University of the Health Sciences under Henry M. Jackson Foundation for the Advancement of Military Medicine; Walter Reed National Military Medical Center FX This project was supported by the United States Military Cancer Institute (USMCI) via the Uniformed Services University of the Health Sciences under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine, and by the Clinical Breast Care Project, Walter Reed National Military Medical Center. The authors declare no conflict of interests. NR 40 TC 13 Z9 13 U1 1 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2012 VL 23 IS 6 BP 951 EP 958 DI 10.1007/s10552-012-9966-1 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 943FK UT WOS:000304105700016 PM 22527173 ER PT J AU Mahabir, S Aagaard, K Anderson, LM Herceg, Z Hiatt, RA Hoover, RN Linet, MS Medina, D Potischman, N Tretli, S Trichopoulos, D Troisi, R AF Mahabir, Somdat Aagaard, Kjersti Anderson, Lucy M. Herceg, Zdenko Hiatt, Robert A. Hoover, Robert N. Linet, Martha S. Medina, Daniel Potischman, Nancy Tretli, Steinar Trichopoulos, Dimitrios Troisi, Rebecca TI Challenges and opportunities in research on early-life events/exposures and cancer development later in life SO CANCER CAUSES & CONTROL LA English DT Article ID PREGNANCY OUTCOME HAPO; ATOMIC-BOMB SURVIVORS; TESTICULAR CANCER; BREAST-CANCER; PERINATAL CARCINOGENESIS; RISK; METAANALYSIS; EXPOSURES; HEALTH; WOMEN AB It is becoming increasingly evident that early-life events and exposures have important consequences for cancer development later in life. However, epidemiological studies of early-life factors and cancer development later in life have had significant methodological challenges such as the long latency period, the distinctiveness of each cancer, and large number of subjects that must be studied, all likely to increase costs. These traditional hurdles might be mitigated by leveraging several existing large-scale prospective studies in the United States (US) and globally, as well as birth databases and birth cohorts, in order to launch both association and mechanistic studies of early-life exposures and cancer development later in life. Dedicated research funding will be needed to advance this paradigm shift in cancer research, and it seems justified by its potential to produce transformative understanding of how cancer develops over the life-course. This in turn has the potential to transform cancer prevention strategies through interventions in early-life rather than later in life, as is the current practice, where it is perhaps less effective. C1 [Mahabir, Somdat] NCI, Modifiable Risk Factors Branch, Epidemiol & Genet Res Program, DCCPS, Bethesda, MD 20892 USA. [Aagaard, Kjersti] Baylor Coll Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Houston, TX 77030 USA. [Anderson, Lucy M.] NCI, Comparat Carcinogenesis Lab, Bethesda, MD 20892 USA. [Herceg, Zdenko] Int Agcy Res Canc, Epigenet Grp, San Francisco, CA USA. [Hiatt, Robert A.] UCSF Comprehens Canc Ctr, Dept Epidemiol & Biostat, San Francisco, CA USA. [Hoover, Robert N.; Troisi, Rebecca] NCI, Epidemiol & Biostat Program, DCEG, Bethesda, MD 20892 USA. [Linet, Martha S.] NCI, Radiat Epidemiol Branch, DCEG, Bethesda, MD 20892 USA. [Medina, Daniel] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Potischman, Nancy] NCI, Appl Res Program, DCCPS, Bethesda, MD 20892 USA. [Tretli, Steinar] Canc Registry Norway, Dept Etiol Canc Res, Montebello, Norway. [Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Mahabir, S (reprint author), NCI, Modifiable Risk Factors Branch, Epidemiol & Genet Res Program, DCCPS, 6130 Execut Blvd, Bethesda, MD 20892 USA. EM mahabir@mail.nih.gov FU NCI FX Within NCI, there is no established grant funding mechanism geared toward early-life events/exposures and cancer development. To date, excluding childhood cancers, only a few grants investigating early-life factors and cancer risk in adults have been funded by the NCI. Research on early-life factors has the potential to produce transformative understanding of how cancer develops over the life-course, potentially leading to prevention strategies through interventions in early-life. Clinical partnerships with obstetric and pediatric groups also can be forged, and existing NIH Roadmap Initiatives can be leveraged. This sort of approach likely will have cross-institute appeal. Considering the limited number of funded grants investigating the role of early-life factors and cancer development later in life and the potentially transformative nature of this research paradigm, dedicated research funding should be prioritized by the NCI to encourage this type of research. NR 38 TC 10 Z9 10 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2012 VL 23 IS 6 BP 983 EP 990 DI 10.1007/s10552-012-9962-5 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 943FK UT WOS:000304105700019 PM 22527169 ER PT J AU Stauffer, JK Orentas, RJ Lincoln, E Khan, T Salcedo, R Hixon, JA Back, TC Wei, JS Patidar, R Song, Y Hurd, L Tsokos, M Lai, EW Eisenhofer, G Weiss, W Khan, J Wigginton, JM AF Stauffer, Jimmy K. Orentas, Rimas J. Lincoln, Erin Khan, Tahira Salcedo, Rosalba Hixon, Julie A. Back, Timothy C. Wei, Jun S. Patidar, Rajesh Song, Young Hurd, Laura Tsokos, Maria Lai, Edwin W. Eisenhofer, Graeme Weiss, William Khan, Javed Wigginton, Jon M. TI High-Throughput Molecular and Histopathologic Profiling of Tumor Tissue in a Novel Transplantable Model of Murine Neuroblastoma: New Tools for Pediatric Drug Discovery SO CANCER INVESTIGATION LA English DT Article DE Neuroblastoma; Mouse model; MYCN; Microenvironment ID HIGH-RISK NEUROBLASTOMA; BONE-MARROW-TRANSPLANTATION; ANTITUMOR IMMUNE-RESPONSE; N-MYC; INTERFERON-GAMMA; CELL-LINES; IFN-GAMMA; BETA-2-MICROGLOBULIN EXPRESSION; AGGRESSIVE NEUROBLASTOMA; MEDIATED APOPTOSIS AB Using two MYCN transgenic mouse strains, we established 10 transplantable neuroblastoma cell lines via serial orthotopic passage in the adrenal gland. Tissue arrays demonstrate that by histochemistry, vascularity, immunohistochemical staining for neuroblastoma markers, catecholamine analysis, and concurrent cDNA microarray analysis, there is a close correspondence between the transplantable lines and the spontaneous tumors. Several genes closely associated with the pathobiology and immune evasion of neuroblastoma, novel targets that warrant evaluation, and decreased expression of tumor suppressor genes are demonstrated. These studies describe a unique and generalizable approach to expand the utility of transgenic models of spontaneous tumor, providing new tools for preclinical investigation. C1 [Khan, Javed] Natl Canc Inst, Ctr Canc Res, Adv Technol Ctr, Pediat Oncol Branch,Oncogenom Sect, Gaithersburg, MD 20877 USA. [Stauffer, Jimmy K.; Orentas, Rimas J.; Khan, Tahira; Salcedo, Rosalba; Hixon, Julie A.; Khan, Javed; Wigginton, Jon M.] Ctr Canc Res, Natl Canc Inst, Pediat Oncol Branch, Bethesda, MD USA. [Lincoln, Erin; Back, Timothy C.] SAIC Frederick Inc, Basic Res Program, NCI Frederick, Frederick, MD USA. [Wei, Jun S.; Patidar, Rajesh; Song, Young; Hurd, Laura; Khan, Javed] Adv Technol Ctr, Pediat Oncol Branch, Oncogen Sect, Bethesda, MD USA. [Tsokos, Maria] Natl Canc Inst, Ctr Canc Res, Pathol Lab, Bethesda, MD USA. [Lai, Edwin W.; Eisenhofer, Graeme] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Weiss, William] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Khan, J (reprint author), Natl Canc Inst, Ctr Canc Res, Adv Technol Ctr, Pediat Oncol Branch,Oncogenom Sect, 8717 Grovemont Circle,Room 134E, Gaithersburg, MD 20877 USA. EM khanjav@mail.nih.gov RI Xiao, Yang/B-5668-2012; Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU National Institutes of Health, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Children's Cancer Foundation; National Cancer Institute, National Institutes of Health [N01-CO-12400] FX The authors would like to thank Ms. Susan Charbonneau and Lin Grove, for assistance with manuscript preparation, and Rimas Orentas for editing the manuscript. These studies were supported (in part) by the Intramural Program, National Institutes of Health, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. The generous support of these studies by the Children's Cancer Foundation is also gratefully acknowledged. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract no. N01-CO-12400. Animal care was provided in accordance with the procedures outlined in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, Publication No. 86-23, 1985). NR 111 TC 5 Z9 5 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0735-7907 J9 CANCER INVEST JI Cancer Invest. PD JUN PY 2012 VL 30 IS 5 BP 343 EP 363 DI 10.3109/07357907.2012.664670 PG 21 WC Oncology SC Oncology GA 942SR UT WOS:000304067800002 PM 22571338 ER PT J AU Ong, RC Stopfer, M AF Ong, Rose C. Stopfer, Mark TI Peripheral and Central Olfactory Tuning in a Moth SO CHEMICAL SENSES LA English DT Article DE innate preference; insect; mushroom body; odor; olfactory learning; olfactory receptor neuron ID MANDUCA-SEXTA; ANTENNAL LOBE; SPHINX MOTH; BEHAVIORAL-RESPONSES; HELIOTHIS-VIRESCENS; NICOTIANA-ATTENUATA; PROJECTION NEURONS; INNATE PREFERENCES; APIS-MELLIFERA; PLANT ODORS AB Animals can be innately attracted to certain odorants. Because these attractants are particularly salient, they might be expected to induce relatively strong responses throughout the olfactory pathway, helping animals detect the most relevant odors but limiting flexibility to respond to other odors. Alternatively, specific neural wiring might link innately preferred odors to appropriate behaviors without a need for intensity biases. How nonpheromonal attractants are processed by the general olfactory system remains largely unknown. In the moth Manduca sexta, we studied this with a set of innately preferred host plant odors and other, neutral odors. Electroantennogram recordings showed that, as a population, olfactory receptor neurons (ORNs) did not respond with greater intensity to host plant odors, and further local field potential recordings showed that no specific amplification of signals induced by host plant odors occurred between the first olfactory center and the second. Moreover, when odorants were mutually diluted to elicit equally intense output from the ORNs, moths were able to learn to associate all tested odorants equally well with food reward. Together, these results suggest that, although nonpheromonal host plant odors activate broadly distributed responses, they may be linked to attractive behaviors mainly through specific wiring in the brain. C1 [Stopfer, Mark] NICHHD, Unit Sensory Coding & Neural Ensembles, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Ong, Rose C.] Chinese Univ Hong Kong, Dept Biochem, Shatin, Hong Kong, Peoples R China. RP Stopfer, M (reprint author), NICHHD, Unit Sensory Coding & Neural Ensembles, NIH, Porter Neurosci Res Ctr, 35 Lincoln Dr,Rm 3A-102,Msc 3715, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov FU National Institute of Child Health and Human Development at the National Institutes of Health FX This work was supported by an intramural grant from National Institute of Child Health and Human Development at the National Institutes of Health to M.S. NR 40 TC 0 Z9 0 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0379-864X J9 CHEM SENSES JI Chem. Senses PD JUN PY 2012 VL 37 IS 5 BP 455 EP 461 DI 10.1093/chemse/bjr127 PG 7 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA 942OU UT WOS:000304055700007 PM 22362866 ER PT J AU McLeod, R Boyer, KM Lee, D Mui, E Wroblewski, K Karrison, T Noble, AG Withers, S Swisher, CN Heydemann, PT Sautter, M Babiarz, J Rabiah, P Meier, P Grigg, ME AF McLeod, Rima Boyer, Kenneth M. Lee, Daniel Mui, Ernest Wroblewski, Kristen Karrison, Theodore Noble, A. Gwendolyn Withers, Shawn Swisher, Charles N. Heydemann, Peter T. Sautter, Mari Babiarz, Jane Rabiah, Peter Meier, Paul Grigg, Michael E. CA Toxoplasmosis Study Grp TI Prematurity and Severity Are Associated With Toxoplasma gondii Alleles (NCCCTS, 1981-2009) SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID TREATED CONGENITAL TOXOPLASMOSIS; EPIGENETIC FACTORS; GENE-EXPRESSION; EYE LESIONS; INFANTS; INFECTION; CHILDREN; STRAINS; VIRULENCE; PEPTIDES AB Background. Congenital toxoplasmosis is a severe, life-altering disease in the United States. A recently developed enzyme-linked immunosorbent assay ( ELISA) distinguishes Toxoplasma gondii parasite types (II and not exclusively II [NE-II]) by detecting antibodies in human sera that recognize allelic peptide motifs of distinct parasite types. Methods. ELISA determined parasite serotype for 193 congenitally infected infants and their mothers in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS), 1981-2009. Associations of parasite serotype with demographics, manifestations at birth, and effects of treatment were determined. Results. Serotypes II and NE-II occurred in the United States with similar proportions during 3 decades. For persons diagnosed before or at birth and treated in infancy, and persons diagnosed after 1 year of age who missed treatment in infancy, proportions were similar (P = .91). NE-II serotype was more common in hot, humid regions (P = .02) but was also present in other regions. NE-II serotype was associated with rural residence (P < .01), lower socioeconomic status (P < .001), and Hispanic ethnicity (P < .001). Prematurity (P = .03) and severe disease at birth (P < .01) were associated with NE-II serotype. Treatment with lower and higher doses of pyrimethamine with sulfadizine improved outcomes relative to those outcomes of persons in the literature who did not receive such treatment. Conclusions. Type II and NE-II parasites cause congenital toxoplasmosis in North America. NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth. Both type II and NE-II infections improved with treatment. Clinical Trials Registration. NCT00004317. C1 [McLeod, Rima; Lee, Daniel; Mui, Ernest; Noble, A. Gwendolyn; Sautter, Mari; Babiarz, Jane] Univ Chicago, Dept Ophthalmol & Visual Sci, Chicago, IL 60637 USA. [McLeod, Rima] Univ Chicago, Dept Pediat, Div Infect Dis, Chicago, IL 60637 USA. [McLeod, Rima] Michael Reese Hosp & Med Ctr, Div Infect Dis, Dept Med, Chicago, IL USA. [Boyer, Kenneth M.] Rush Univ, Med Ctr, Dept Pediat, Chicago, IL USA. [Boyer, Kenneth M.] Rush Univ, Med Ctr, Div Pediat Infect Dis, Chicago, IL USA. [Wroblewski, Kristen; Karrison, Theodore; Withers, Shawn; Meier, Paul] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Noble, A. Gwendolyn; Rabiah, Peter] Childrens Mem Hosp, Dept Ophthalmol, Westchester, NY USA. [Swisher, Charles N.] Childrens Mem Hosp, Div Pediat Neurol, Westchester, NY USA. [Heydemann, Peter T.] Rush Univ, Med Ctr, Dept Neurol, Chicago, IL 60612 USA. [Meier, Paul] Columbia Univ, Dept Biostat, New York, NY USA. [Grigg, Michael E.] Mol Parasitol Unit, Natl Inst Hlth, Bethesda, MD USA. RP McLeod, R (reprint author), Univ Chicago, Dept Ophthalmol & Visual Sci, 5841 S Maryland Ave,MC 2114, Chicago, IL 60637 USA. EM rmcleod@midway.uchicago.edu FU National Institute of Allergy and Infectious Diseases (NIAID) [R01AI027530]; Research to Prevent Blindness Foundation; Stanley Foundation; Medical Research Institute [07R-1890]; National Institutes of Health; NIAID FX This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) (grant number R01AI027530 to R. M.), the Research to Prevent Blindness Foundation, The Stanley Foundation and Medical Research Institute (grant number 07R-1890 to R. M.), the Intramural Research Program of the National Institutes of Health and NIAID (to M. E. G.); and gifts from the Blackmon, Brennan, Cornwell, Cussen, Dougiello, Jackson, Kapnick, Kiewiet, Koshland, Langel, Lipskar, Mann, Morel, Rooney-Alden, Rosenstein, Samuel, and Taub families. NR 40 TC 67 Z9 68 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 1 PY 2012 VL 54 IS 11 BP 1595 EP 1605 DI 10.1093/cid/cis258 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 942MO UT WOS:000304048400012 PM 22499837 ER PT J AU Carroll, MW Choi, H Min, S Hwang, S Park, H Song, T Park, Y Jeon, HS Goldfeder, LC Via, LE Lebron, J Jin, B Cai, Y Barry, CE Lee, M AF Carroll, Matthew W. Choi, Hongjo Min, Seonyeong Hwang, Soohee Park, Hyeeun Song, Taeksun Park, Yumi Jeon, Han-Seung Goldfeder, Lisa C. Via, Laura E. Lebron, Janette Jin, Boyoung Cai, Ying Barry, Clifton E., III Lee, Myungsun TI Rhabdomyolysis in a Patient Treated With Linezolid for Extensively Drug-Resistant Tuberculosis SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID MITOCHONDRIAL PROTEIN-SYNTHESIS; INHIBITION; OXAZOLIDINONES; TOXICITY; THERAPY C1 [Choi, Hongjo; Min, Seonyeong; Park, Hyeeun; Song, Taeksun; Park, Yumi; Jeon, Han-Seung; Jin, Boyoung; Barry, Clifton E., III; Lee, Myungsun] Int TB Res Ctr, Chang Won 631710, South Korea. [Hwang, Soohee] Natl Masan Hosp, Chang Won 631710, South Korea. [Carroll, Matthew W.; Goldfeder, Lisa C.; Via, Laura E.; Lebron, Janette; Cai, Ying; Barry, Clifton E., III] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, TB Res Sect, Bethesda, MD USA. RP Lee, M (reprint author), Int TB Res Ctr, 475-1 Gapo Dong, Chang Won 631710, South Korea. EM drsunny21c@gmail.com RI Barry, III, Clifton/H-3839-2012; OI Via, Laura/0000-0001-6074-9521 FU Intramural NIH HHS NR 15 TC 7 Z9 8 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 1 PY 2012 VL 54 IS 11 BP 1624 EP 1627 DI 10.1093/cid/cis293 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 942MO UT WOS:000304048400018 PM 22423128 ER PT J AU Kim, KY Sack, MN AF Kim, Kye-Young Sack, Michael N. TI Parkin in the regulation of fat uptake and mitochondrial biology: emerging links in the pathophysiology of Parkinson's disease SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review DE CD36; fat uptake; Parkin; peroxisome proliferator-activated receptor gamma coactivator-1 alpha ID COACTIVATOR 1-ALPHA PGC-1-ALPHA; DEFICIENT MICE; INDEPENDENT UBIQUITINATION; DOPAMINERGIC-NEURONS; PROTEIN-DEGRADATION; ALPHA-SYNUCLEIN; BRAIN; CELLS; ACIDS; RISK AB Purpose of review Perturbations in fatty acid levels and in regulatory proteins linked to fat and mitochondrial homeostasis are associated with modifying the risk of Parkinson's disease. Findings, that are not surprising, based on the high fat content of the brain, the myriad of neurological functions dependent on polyunsaturated fatty acids and the role of mitochondria in energy supply and stress amelioration. Nevertheless, dissecting out the molecular links between lipid biology, mitochondrial regulation and Parkinson's disease is complicated by the divergent causes underpinning Parkinson's disease pathophysiology. Here, we summarize aspects of fatty acid biology relevant to Parkinson's disease; the known links between the modulation of fat and Parkinson's disease and introduce mechanisms whereby the E3-ubiquitin ligase, Parkin known to be mutated as a genetic predisposing factor in Parkinson's disease, modulates fat uptake and mitochondrial control. Recent findings Prior evidence supports that Parkin, under mitochondrial stress conditions, plays a pivotal role in the mitophagy mitochondrial housekeeping program. Recent evidence now demonstrates a broader role of Parkin in controlling fat uptake and mitochondrial regulatory programs. Summary The identification that Parkin has a multifunctional role in modulating cellular fatty acid uptake and mitochondrial biology further strengthens the pathophysiologic link between fat metabolism, mitochondria and Parkinson's disease. C1 [Kim, Kye-Young; Sack, Michael N.] Ctr Mol Med, Natl Heart Lung & Blood Inst, Bethesda, MD USA. RP Sack, MN (reprint author), 10-CRC Room 5-3150,10 Ctr Dr, Bethesda, MD 20892 USA. EM sackm@nhlbi.nih.gov FU Division of Intramural Research of the National Heart, Lung and Blood Institute of the NIH; Division of Intramural Research of the NHLBI FX This work was funded by the Division of Intramural Research of the National Heart, Lung and Blood Institute of the NIH.; K.Y.K. and M.N.S. are funded by the Division of Intramural Research of the NHLBI. NR 35 TC 8 Z9 9 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0957-9672 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD JUN PY 2012 VL 23 IS 3 BP 201 EP 205 DI 10.1097/MOL.0b013e328352dc5d PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA 941CI UT WOS:000303939900006 PM 22488424 ER PT J AU Marlatt, MW Potter, MC Lucassen, PJ van Praag, H AF Marlatt, Michael W. Potter, Michelle C. Lucassen, Paul J. van Praag, Henriette TI Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE neurogenesis; BDNF; cognition; locomotor activity; exercise ID LONG-TERM POTENTIATION; DENTATE GYRUS; SYNAPTIC PLASTICITY; ADULT NEUROGENESIS; PHYSICAL-EXERCISE; GLUTAMATE RECEPTORS; NEUROTROPHIC FACTOR; CELL-PROLIFERATION; VOLUNTARY EXERCISE; ESTROUS CYCLICITY AB Age-related memory loss is considered to commence at middle-age and coincides with reduced adult hippocampal neurogenesis and neurotrophin levels. Consistent physical activity at midlife may preserve brain-derived neurotrophic factor (BDNF) levels, new cell genesis, and learning. In the present study, 9-month-old female C57Bl/6J mice were housed with or without a running wheel and injected with bromodeoxyuridine (BrdU) to label newborn cells. Morris water maze learning, open field activity and rotarod behavior were tested 1 and 6 months after exercise onset. Here we show that long-term running improved retention of spatial memory and modestly enhanced rotarod performance at 15 months of age. Both hippocampal neurogenesis and mature BDNF peptide levels were elevated after long-term running. Thus, regular exercise from the onset and during middle-age may maintain brain function. (C) 2011 Wiley Periodicals, Inc. Develop Neurobiol 72: 943952, 2012 C1 [Marlatt, Michael W.; Potter, Michelle C.; van Praag, Henriette] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Marlatt, Michael W.; Lucassen, Paul J.] Univ Amsterdam, Swammerdam Inst Life Sci, Ctr Neurosci, Amsterdam, Netherlands. RP van Praag, H (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM vanpraagh@mail.nih.gov RI van Praag, Henriette/F-3939-2015 OI van Praag, Henriette/0000-0002-5727-434X FU National Institute on Aging, NIH; EU (NEURAD), HSN, NWO, ISAO FX Contract grant sponsors: Intramural Research Program, National Institute on Aging, NIH; EU (NEURAD), HSN, NWO, ISAO. NR 53 TC 90 Z9 93 U1 5 U2 35 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8451 J9 DEV NEUROBIOL JI Dev. Neurobiol. PD JUN PY 2012 VL 72 IS 6 SI SI BP 943 EP 952 DI 10.1002/dneu.22009 PG 10 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 941SQ UT WOS:000303985400016 PM 22252978 ER PT J AU Dufer, M Horth, K Wagner, R Schittenhelm, B Prowald, S Wagner, TFJ Oberwinkler, J Lukowski, R Gonzalez, FJ Krippeit-Drews, P Drews, G AF Duefer, Martina Hoerth, Katrin Wagner, Rebecca Schittenhelm, Bjoern Prowald, Susanne Wagner, Thomas F. J. Oberwinkler, Johannes Lukowski, Robert Gonzalez, Frank J. Krippeit-Drews, Peter Drews, Gisela TI Bile Acids Acutely Stimulate Insulin Secretion of Mouse beta-Cells via Farnesoid X Receptor Activation and K-ATP Channel Inhibition SO DIABETES LA English DT Article ID GLUCOSE-HOMEOSTASIS; DIABETES-MELLITUS; FXR; METABOLISM; SENSITIVITY; LIVER; EXPRESSION; PROTECTS; ISLETS; LIGAND AB Type 2 diabetes mellitus is associated with alterations in bile acid (BA) signaling. The aim of our study was to test whether pancreatic beta-cells contribute to BA-dependent regulation of glucose homeostasis. Experiments were performed with islets from wild-type, farnesoid X receptor (FXR) knockout (KO), and beta-cell ATP-dependent K+ (K-ATP) channel gene SUR1 (ABCC8) KO mice, respectively. Sodium taurochenodeoxycholate (TCDC) increased glucose-induced insulin secretion. This effect was mimicked by the FXR agonist GW4064 and suppressed by the FXR antagonist guggulsterone. TCDC and GW4064 stimulated the electrical activity of beta-cells and enhanced cytosolic Ca2+ concentration ([Ca2+](c)). These effects were blunted by guggulsterone. Sodium ursodeoxycholate, which has a much lower affinity to FXR than TCDC, had no effect on [Ca2+](c) and insulin secretion. FXR activation by TCDC is suggested to inhibit K-ATP current. The decline in K-ATP channel activity by TCDC was only observed in beta-cells with intact metabolism and was reversed by guggulsterone. TCDC did not alter insulin secretion in islets of SUR1-KO or FXR-KO mice. TCDC did not change islet cell apoptosis. This is the first study showing an acute action of BA on beta-cell function. The effect is mediated by FXR by nongenomic elements, suggesting a novel link between FXR activation and K-ATP channel inhibition. Diabetes 61:1479-1489, 2012 C1 [Duefer, Martina; Hoerth, Katrin; Wagner, Rebecca; Schittenhelm, Bjoern; Prowald, Susanne; Lukowski, Robert; Krippeit-Drews, Peter; Drews, Gisela] Univ Tubingen, Inst Pharm, Dept Pharmacol, Tubingen, Germany. [Wagner, Thomas F. J.] Scripps Res Inst, Dorris Neurosci Ctr, Dept Cell Biol, La Jolla, CA 92037 USA. [Oberwinkler, Johannes] Univ Marburg, Inst Physiol & Pathophysiol, Marburg, Germany. [Gonzalez, Frank J.] NCI, NIH, Bethesda, MD 20892 USA. RP Dufer, M (reprint author), Univ Tubingen, Inst Pharm, Dept Pharmacol, Tubingen, Germany. EM martina.duefer@uni-tuebingen.de FU Deutsche Forschungsgemeinschaft; Emmy Noether-programme FX This work was supported by grants from the Deutsche Forschungsgemeinschaft (to M.D. and G.D.) and Emmy Noether-programme (to J.O.). NR 48 TC 51 Z9 54 U1 2 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2012 VL 61 IS 6 BP 1479 EP 1489 DI 10.2337/db11-0815 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 948FX UT WOS:000304490100025 PM 22492528 ER PT J AU Haiman, CA Fesinmeyer, MD Spencer, KL Buzkova, P Voruganti, VS Wan, P Haessler, J Franceschini, N Monroe, KR Howard, BV Jackson, RD Florez, JC Kolonel, LN Buyske, S Goodloe, RJ Liu, SM Manson, JE Meigs, JB Waters, K Mukamal, KJ Pendergrass, SA Shrader, P Wilkens, LR Hindorff, LA Ambite, JL North, KE Peters, U Crawford, DC Le Marchand, L Pankow, JS AF Haiman, Christopher A. Fesinmeyer, Megan D. Spencer, Kylee L. Buzkova, Petra Voruganti, V. Saroja Wan, Peggy Haessler, Jeff Franceschini, Nora Monroe, Kristine R. Howard, Barbara V. Jackson, Rebecca D. Florez, Jose C. Kolonel, Laurence N. Buyske, Steven Goodloe, Robert J. Liu, Simin Manson, JoAnn E. Meigs, James B. Waters, Kevin Mukamal, Kenneth J. Pendergrass, Sarah A. Shrader, Peter Wilkens, Lynne R. Hindorff, Lucia A. Ambite, Jose Luis North, Kari E. Peters, Ulrike Crawford, Dana C. Le Marchand, Loic Pankow, James S. TI Consistent Directions of Effect for Established Type 2 Diabetes Risk Variants Across Populations SO DIABETES LA English DT Article ID GENOME-WIDE ASSOCIATION; LARGE-SCALE ASSOCIATION; TCF7L2 GENE; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS RISK; SUSCEPTIBILITY LOCI; AFRICAN-AMERICANS; DESIGN; INDIANS; CDKAL1 AB Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P-heterogeneity < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations. Diabetes 61:1642-1647, 2012 C1 [Haiman, Christopher A.; Wan, Peggy; Monroe, Kristine R.; Waters, Kevin] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Fesinmeyer, Megan D.; Haessler, Jeff; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Spencer, Kylee L.; Goodloe, Robert J.; Pendergrass, Sarah A.; Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. [Buzkova, Petra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Voruganti, V. Saroja] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Howard, Barbara V.] Georgetown Univ, Washington, DC USA. [Howard, Barbara V.] Medstar Hlth Res Inst, Washington, DC USA. [Jackson, Rebecca D.] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Florez, Jose C.; Manson, JoAnn E.; Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Kolonel, Laurence N.; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Buyske, Steven] Rutgers State Univ, Dept Genet & Stat, Piscataway, NJ USA. [Liu, Simin] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Manson, JoAnn E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Meigs, James B.; Shrader, Peter] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NHGRI, NIH, Off Populat Gen, Bethesda, MD 20892 USA. [Ambite, Jose Luis] Univ So Calif, Inst Informat Sci, Los Angeles, CA USA. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Haiman, CA (reprint author), Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. EM haiman@usc.edu RI Crawford, Dana/C-1054-2012; Liu, Simin/I-3689-2014; OI Liu, Simin/0000-0003-2098-3844; Pankow, James/0000-0001-7076-483X FU National Human Genome Research Institute; [U01HG004803]; [U01HG004798]; [U01HG004802]; [U01HG004790]; [U01HG004801] FX The PAGE program is funded by the National Human Genome Research Institute, supported by U01HG004803 (CALiCo [Causal Variants Across the Life Course]), U01HG004798 (EAGLE [Epidemiologic Architecture of Genes Linked to Environment]), U01HG004802 (MEG [Multiethnic Cohort]), U01HG004790 ('WHI [Women's Health Initiative]), and UO1HG004801 (Coordinating Center). NR 44 TC 30 Z9 30 U1 0 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2012 VL 61 IS 6 BP 1642 EP 1647 DI 10.2337/db11-1296 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 948FX UT WOS:000304490100043 PM 22474029 ER PT J AU Cecchi, F Rabe, DC Bottaro, DP AF Cecchi, Fabiola Rabe, Danie C. Bottaro, Donald P. TI Targeting the HGF/Met signaling pathway in cancer therapy SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE hepatocyte growth factor; MET ID HEPATOCYTE GROWTH-FACTOR; RECEPTOR TYROSINE KINASE; CELL LUNG-CANCER; C-MET RECEPTOR; EPITHELIAL TRANSITION MET; SCATTER FACTOR; GEFITINIB RESISTANCE; LIVER-REGENERATION; INVASIVE GROWTH; TUMOR-GROWTH AB Introduction: Under normal conditions, hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase (TK), is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand-activated receptor internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis and tumor progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis. Area covered: The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programs. The authors review Met structure and function, the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development, as well as the latest clinical trial results. Expert opinion: Clinical trials with HGF/Met pathway antagonists show that as a class these agents are well tolerated. Although widespread efficacy was not seen in several completed Phase II studies, promising results have been reported in lung, gastric, prostate and papillary renal cancer patients treated with these agents. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment are optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents, and model systems available concerning HGF/Met oncogenic signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control. C1 [Cecchi, Fabiola; Rabe, Danie C.; Bottaro, Donald P.] NCI, NIH, Ctr Canc Res, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Cecchi, F (reprint author), NCI, NIH, Ctr Canc Res, Urol Oncol Branch, Bldg 10 CRC,Rm 1W-5832,10 Ctr Dr,MSC 1107, Bethesda, MD 20892 USA. EM cecchif@mail.nih.gov RI Bottaro, Donald/F-8550-2010; OI Bottaro, Donald/0000-0002-5057-5334; Cecchi, Franco/0000-0002-2035-5621 FU NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 137 TC 84 Z9 91 U1 2 U2 22 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8222 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD JUN PY 2012 VL 16 IS 6 BP 553 EP 572 DI 10.1517/14728222.2012.680957 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 942ZY UT WOS:000304091400003 PM 22530990 ER PT J AU Cheung, GYC Otto, M AF Cheung, Gordon Y. C. Otto, Michael TI The potential use of toxin antibodies as a strategy for controlling acute Staphylococcus aureus infections SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE alpha-hemolysin; immunotherapy; leukotoxins; methicillin-resistant Staphylococcus aureus; monoclonal antibody; Panton-Valentine leukocidin; phenol-soluble modulins; superantigens; toxin; vaccine ID PANTON-VALENTINE LEUKOCIDIN; GENE REGULATOR AGR; SHOCK-SYNDROME TOXIN-1; COMMUNITY-ASSOCIATED MRSA; ENTEROTOXIN-B GENE; METHICILLIN-RESISTANT; ALPHA-TOXIN; MONOCLONAL-ANTIBODIES; VIRULENCE DETERMINANTS; GAMMA-HEMOLYSIN AB Introduction: The pandemic human pathogen, Staphylococcus aureus, displays high levels of antibiotic resistance and is a major cause of hospital- and community-associated infections. S. aureus disease manifestation is to a great extent due to the production of a large arsenal of virulence factors, which include a series of secreted toxins. Antibodies to S. aureus toxins are found in people who are infected or asymptomatically colonized with S. aureus. Immunotherapies consisting of neutralizing anti-toxin antibodies could provide immediate aid to patients with impaired immune systems or in advanced stages of disease. Areas covered: Important S. aureus toxins, their roles in pathogenesis, rationales for selecting S. aureus toxins for immunization efforts, and caveats associated with monoclonal antibody-based passive immunization are discussed. This review will focus on hyper-virulent community-associated methicillin-resistant S. aureus because of their recent surge and clinical importance. Expert opinion: Antibodies against genome-encoded toxins may be more broadly applicable than those directed against toxins found only in a sub-population of S. aureus isolates. Furthermore, there is substantial functional redundancy among S. aureus toxins. Thus, an optimal anti-S. aureus formulation may consist of multiple antibodies directed against a series of key S. aureus genome-encoded toxins. C1 [Cheung, Gordon Y. C.; Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), NIAID, Lab Human Bacterial Pathogenesis, NIH, Bldg 33,Room 1W10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov RI Cheung, Yiu Chong /K-3565-2012; OI Otto, Michael/0000-0002-2222-4115 FU National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 153 TC 19 Z9 21 U1 2 U2 21 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8222 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD JUN PY 2012 VL 16 IS 6 BP 601 EP 612 DI 10.1517/14728222.2012.682573 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 942ZY UT WOS:000304091400006 PM 22530584 ER PT J AU Volkow, ND Muenke, M AF Volkow, Nora D. Muenke, Maximilian TI The genetics of addiction SO HUMAN GENETICS LA English DT Editorial Material C1 [Volkow, Nora D.] NIDA, Natl Human Res Inst, NIH, US Dept HHS, Rockville, MD 20892 USA. [Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, Natl Human Res Inst, NIH, US Dept HHS, Rockville, MD 20892 USA. EM nvolkow@nida.nih.gov; mamuenke@mail.nih.gov FU Intramural NIH HHS [ZIA HG000175-14] NR 26 TC 4 Z9 4 U1 1 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD JUN PY 2012 VL 131 IS 6 SI SI BP 773 EP 777 DI 10.1007/s00439-012-1173-3 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 943RL UT WOS:000304142800001 PM 22562404 ER PT J AU Merikangas, KR McClair, VL AF Merikangas, Kathleen R. McClair, Vetisha L. TI Epidemiology of substance use disorders SO HUMAN GENETICS LA English DT Review ID NATIONAL-COMORBIDITY-SURVEY; POPULATION-BASED SAMPLE; ENVIRONMENTAL RISK-FACTORS; WORLD-HEALTH-ORGANIZATION; SUPPLEMENT NCS-A; IV ALCOHOL-ABUSE; DRUG-ABUSE; MENTAL-DISORDERS; SURVEY REPLICATION; ADOLESCENT-SUPPLEMENT AB Epidemiological studies of substance use and substance use disorders (SUDs) have provided an abundance of data on the patterns of substance use in nationally representative samples across the world (Degenhardt et al. in PLoS Med 5(7):e141, 2008; Johnston et al. in Monitoring the future national survey results on drug use, 1975-2010, vol I, secondary school students. Institute for Social Research, Ann Arbor, MI, 2011; SAMHSA in Results from the 2010 national survey on drug use and health: summary of national findings, vol NSDUH, series H-41, HHS Publication No. (SMA) 11-4658. Substance Abuse and Mental Health Services Administration, Rockville, 2011). This paper presents a summary of the goals, methods, and recent findings on the epidemiology of substance use and disorders in the general population of adults and adolescents and describes the methods and findings on the genetic epidemiology of drug use disorders. The high 12-month prevalence rates of substance dependence in US adults (about 12 % for alcohol and 2-3 % for illicit drugs) approximate those of other mental disorders as well as chronic physical disorders with major public health impact. New findings from the nationally representative samples of US youth reveal that the lifetime prevalence of alcohol use disorders is approximately 8 % and illicit drug use disorders is 2-3 % (Merikangas et al. in J Am Acad Child Adolesc Psychiatry 49(10):980-989, 2010; Swendsen et al. in Arch Gen Psychiatry 69(4):390-398, 2012; SAMHSA in Results from the 2010 national survey on drug use and health: summary of national findings, vol NSDUH, Series H-41, HHS Publication No. (SMA) 11-4658. Substance Abuse and Mental Health Services Administration, Rockville, 2011). The striking increase in prevalence rates from ages 13 to 18 highlight adolescence as the key period of development of SUDs. The application of genetic epidemiological studies has consistently demonstrated that genetic factors have a major influence on progression of substance use to dependence, whereas environmental factors unique to the individual play an important role in exposure and initial use of substances. Identification of specific susceptibility genes and environmental factors that influence exposure and progression of drug use may enhance our ability to prevent and treat SUDs. C1 [Merikangas, Kathleen R.; McClair, Vetisha L.] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. EM merikank@mail.nih.gov FU National Institutes of Health, National Institute of Mental Health, Genetic Epidemiology Research Branch FX This work was supported in part by the National Institutes of Health, National Institute of Mental Health, Intramural Research Program, Genetic Epidemiology Research Branch. The views and opinions expressed in this article are those of the authors and should not be construed to represent the views of any of the US Government. NR 82 TC 64 Z9 67 U1 11 U2 60 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD JUN PY 2012 VL 131 IS 6 SI SI BP 779 EP 789 DI 10.1007/s00439-012-1168-0 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 943RL UT WOS:000304142800002 PM 22543841 ER PT J AU Arcos-Burgos, M Velez, JI Solomon, BD Muenke, M AF Arcos-Burgos, Mauricio Velez, Jorge I. Solomon, Benjamin D. Muenke, Maximilian TI A common genetic network underlies substance use disorders and disruptive or externalizing disorders SO HUMAN GENETICS LA English DT Review ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; GENOME-WIDE ASSOCIATION; DEFICIT HYPERACTIVITY DISORDER; ADDICTION MOLECULAR-GENETICS; PEDIGREE DISEQUILIBRIUM TEST; ALCOHOL DEPENDENCE; ABUSE-VULNERABILITY; GENERALIZED VITILIGO; SUSCEPTIBILITY LOCI; HAPLOTYPIC VARIANTS AB Here we summarize evidence obtained by our group during the last two decades, and contrasted it with a review of related data from the available literature to show that behavioral syndromes involving attention deficit/hyperactivity disorder (ADHD), externalizing disorders, and substance-use disorder (SUD) share similar signs and symptoms (i.e., have a biological basis as common syndromes), physiopathological and psychopathological mechanisms, and genetic factors. Furthermore, we will show that the same genetic variants harbored in different genes are associated with different syndromes and that non-linear interactions between genetic variants (epistasis) best explain phenotype severity, long-term outcome, and response to treatment. These data have been depicted in our studies by extended pedigrees, where ADHD, externalizing symptoms, and SUD segregate and co-segregate. Finally, we applied here a new formal network analysis using the set of significantly replicated genes that have been shown to be either associated and/or linked to ADHD, disruptive behaviors, and SUD in order to detect significantly enriched gene categories for protein and genetic interactions, pathways, co-expression, co-localization, and protein domain similarity. We found that networks related to pathways involved in axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse are overrepresented. In summary, we provide compiled evidence of complex networks of genotypes underlying a wide phenotype that involves SUD and externalizing disorders. C1 [Arcos-Burgos, Mauricio; Velez, Jorge I.; Solomon, Benjamin D.; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Arcos-Burgos, Mauricio] Australian Natl Univ, Translat Genom Grp, Dept Translat Med, John Curtin Sch Med Res,ANU Coll Med Biol & Envir, Canberra, ACT, Australia. RP Arcos-Burgos, M (reprint author), NHGRI, Med Genet Branch, NIH, Bldg 35,Room 1B-209, Bethesda, MD 20892 USA. EM arcosburgosm@mail.nih.gov; mamuenke@mail.nih.gov FU Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, USA FX The authors would like to extend their deepest gratitude to all patients and families who took part in our research on ADHD. The authors want to especially thank Julia Fekecs who provided invaluable graphical assistance with figures. This research was supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, USA. NR 59 TC 17 Z9 17 U1 5 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD JUN PY 2012 VL 131 IS 6 SI SI BP 917 EP 929 DI 10.1007/s00439-012-1164-4 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 943RL UT WOS:000304142800011 PM 22492058 ER PT J AU Lin, XL Lu, DR Gao, Y Tao, S Yang, XB Feng, JJ Tan, AH Zhang, HY Hu, YL Qin, X Kim, ST Peng, T Li, L Mo, LJ Zhang, SJ Trent, JM Mo, ZN Zheng, SL Xu, JF Sun, JL AF Lin, Xiaoling Lu, Daru Gao, Yong Tao, Sha Yang, Xiaobo Feng, Junjie Tan, Aihua Zhang, Haiying Hu, Yanling Qin, Xue Kim, Seong-Tae Peng, Tao Li, Li Mo, Linjian Zhang, Shijun Trent, Jeffrey M. Mo, Zengnan Zheng, S. Lilly Xu, Jianfeng Sun, Jielin TI Genome-wide association study identifies novel loci associated with serum level of vitamin B12 in Chinese men SO HUMAN MOLECULAR GENETICS LA English DT Article ID TRANSCOBALAMIN-I HAPTOCORRIN; AFFINITY IGE RECEPTOR; INTRINSIC-FACTOR GENE; HELICOBACTER-PYLORI; BETA-SUBUNIT; DEFICIENCY; HTM4; ABSORPTION; EXPRESSION; MUTATIONS AB Vitamin B12 (VitB12 or cobalamin) is an essential cofactor in several metabolic pathways. Clinically, VitB12 deficiency is associated with pernicious anemia, neurodegenerative disorder, cardiovascular disease and gastrointestinal disease. Although previous genome-wide association studies (GWAS) identified several genes, including FUT2, CUBN, TCN1 and MUT, that may influence VitB12 levels in European populations, common genetic determinants of VitB12 remain largely unknown, especially in Asian populations. Here we performed a GWAS in 1999 healthy Chinese men and replicated the top findings in an independent Chinese sample with 1496 subjects. We identified four novel genomic loci that were significantly associated with serum level of VitB12 at a genome-wide significance level of 5.00 10(8). These four loci were MS4A3 (11q12.1; rs2298585; P 2.64 10(15)), CLYBL (13q32; rs41281112; P 9.23 10(10)), FUT6 (19p13.3; rs3760776; P 3.68 10(13)) and 5q32 region (rs10515552; P 3.94 10(8)). In addition, we also confirmed the association with the serum level of VitB12 for the previously reported FUT2 gene and identified one novel non-synonymous single-nucleotide polymorphism in FUT2 gene in this Chinese population (19q13.33; rs1047781; P 3.62 10(36)). The new loci identified offer new insights into the biochemical pathways involved in determining the serum level of VitB12 and provide opportunities to better delineate the role of VitB12 in health and disease. C1 [Gao, Yong; Yang, Xiaobo; Tan, Aihua; Zhang, Haiying; Hu, Yanling; Qin, Xue; Zhang, Shijun; Mo, Zengnan] Guangxi Med Univ, Ctr Genom & Personalized Med, Nanning, Guangxi, Peoples R China. [Lin, Xiaoling; Xu, Jianfeng] Fudan Univ, Huashan Hosp, Fudan Inst Urol, Shanghai 200433, Peoples R China. [Lin, Xiaoling; Gao, Yong; Xu, Jianfeng] Fudan Univ, Sch Life Sci, Fudan VARI Ctr Genet Epidemiol, Shanghai 200433, Peoples R China. [Lu, Daru] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Yang, Xiaobo; Zhang, Haiying] Guangxi Med Univ, Sch Publ Hlth, Dept Occupat Hlth & Environm Hlth, Nanning, Guangxi, Peoples R China. [Hu, Yanling; Li, Li] Guangxi Med Univ, Med Sci Res Ctr, Nanning, Guangxi, Peoples R China. [Qin, Xue] Guangxi Med Univ, Affiliated Hosp 1, Dept Clin Lab, Nanning, Guangxi, Peoples R China. [Peng, Tao] Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Nanning, Guangxi, Peoples R China. [Mo, Linjian; Mo, Zengnan] Guangxi Med Univ, Affiliated Hosp 1, Inst Urol & Nephrol, Nanning, Guangxi, Peoples R China. [Tao, Sha; Trent, Jeffrey M.; Xu, Jianfeng] Van Andel Res Inst, Ctr Genet Epidemiol, Grand Rapids, MI USA. [Feng, Junjie; Kim, Seong-Tae; Zheng, S. Lilly; Xu, Jianfeng; Sun, Jielin] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Peng, Tao] NCI, Lab Genom Div, NIH, Frederick, MD 21701 USA. RP Mo, ZN (reprint author), Guangxi Med Univ, Ctr Genom & Personalized Med, Nanning, Guangxi, Peoples R China. EM zengnanmo@hotmail.com RI tao, sha/B-7750-2012; Yang, Xiaobo/G-3854-2016; Kim, Seong-Tae/E-4474-2017 OI Kim, Seong-Tae/0000-0001-7436-1405 FU National Natural Science Foundation of China [30945204, 30360124, 30260110]; Guangxi Provincial Department of Finance and Education [2009GJCJ150]; Fudan-VARI Center for genetic Epidemiology; Fudan University Institute of Urology FX This work was partially supported by the General Program of National Natural Science Foundation of China (30945204, 30360124, 30260110), the Guangxi Provincial Department of Finance and Education (2009GJCJ150) and intramural funding from Fudan-VARI Center for genetic Epidemiology and intramural funding from Fudan University Institute of Urology. NR 26 TC 17 Z9 18 U1 3 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 1 PY 2012 VL 21 IS 11 BP 2610 EP 2617 DI 10.1093/hmg/dds062 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 942NZ UT WOS:000304053100020 PM 22367966 ER PT J AU Moore, C Sidney, J English, AM Wriston, A Hunt, DF Shabanowitz, J Southwood, S Bradley, K Lafont, BAP Mothe, BR Sette, A AF Moore, Carrie Sidney, John English, A. Michelle Wriston, Amanda Hunt, Donald F. Shabanowitz, Jeffrey Southwood, Scott Bradley, Kate Lafont, Bernard A. P. Mothe, Bianca R. Sette, Alessandro TI Identification of the peptide-binding motif recognized by the pigtail macaque class I MHC molecule Mane-A1*082:01 (Mane A*0301) SO IMMUNOGENETICS LA English DT Article DE MHC; Macaques; Peptide binding motif; T cell epitope; Class I ID SIMIAN IMMUNODEFICIENCY VIRUS; T-CELL EPITOPES; RHESUS MACAQUES; HIGH-FREQUENCY; HLA-A; MASS-SPECTROMETRY; SPECIFICITY; PROTEINS; DISEASE; DEFINITION AB Rhesus and pigtail macaques have proven to be valuable animal models for several important human diseases, including HIV, where they exhibit similar pathology and disease progression. Because rhesus macaques have been extensively characterized in terms of their major histocompatibility complex (MHC) class I alleles, their demand has soared, making them increasingly difficult to obtain for research purposes. This problem has been exacerbated by a continued export ban in place since 1978. Pigtail macaques represent a potential alternative animal model. However, because their MHC class I alleles have not been characterized in detail, their use has been hindered. To address this, in the present study, we have characterized the peptide binding specificity of the pigtail macaque class I allele Mane-A1*082:01 (formerly known as Mane A*0301), representative of the second most common MHC class I antigen detected across several cohorts. The motif was defined on the basis of binding studies utilizing purified MHC protein and panels of single amino acid substitution analog peptides, as well as sequences of peptide ligands eluted from Mane-A1*082:01. Based on these analyses, Mane-A1*082:01 was found to recognize a motif with H in position 2 and the aromatic residues F and Y, or the hydrophobic/aliphatic residue M, at the C-terminus. Finally, analysis of the binding of a combinatorial peptide library allowed the generation of a detailed quantitative motif that proved effective in the prediction of a set of high-affinity binders derived from chimeric SIV/HIV, an important model virus for studying HIV infection in humans. C1 [Moore, Carrie; Sidney, John; Southwood, Scott; Bradley, Kate; Sette, Alessandro] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. [English, A. Michelle; Wriston, Amanda; Shabanowitz, Jeffrey] Univ Virginia, Dept Chem, Charlottesville, VA 22908 USA. [Hunt, Donald F.] Univ Virginia, Dept Chem & Pathol, Charlottesville, VA 22908 USA. [Lafont, Bernard A. P.] NIAID, Nonhuman Primate Immunogenet & Cellular Immunol U, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Mothe, Bianca R.] Calif State Univ San Marcos, Dept Biol Sci, San Marcos, CA 92069 USA. RP Sette, A (reprint author), La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. EM alex@liai.org RI Hunt, Donald/I-6936-2012; Lafont, Bernard/B-7236-2014 OI Hunt, Donald/0000-0003-2815-6368; FU National Institute of Allergy and Infectious Diseases, National Institutes of Health NIH NIAID [HHSN272200900042C]; NIH [AI33993] FX This study was supported in part by the Intramural Research program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health NIH NIAID contract HHSN272200900042C (A. S.), and NIH grant AI33993 (DFH). NR 50 TC 2 Z9 2 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD JUN PY 2012 VL 64 IS 6 BP 461 EP 468 DI 10.1007/s00251-012-0600-x PG 8 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 943HA UT WOS:000304110200006 PM 22278177 ER PT J AU Amer, A Abu Madi, M Dabbagh, M Kamal, M Almarzouqi, S Almulla, S Osman, M Salam, WA Shebl, F AF Amer, Aliaa Abu Madi, Marawan Dabbagh, Muhamad Kamal, Madeeha Almarzouqi, Sheikha Almulla, Somaya Osman, Mariam Salam, Wafaa Abdel Shebl, Fatma TI EARLY DIAGNOSIS OF IRON DEFICIENCY IN SCHOOLCHILDREN: A QATARI EXPERIENCE SO INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY LA English DT Meeting Abstract C1 [Amer, Aliaa; Almarzouqi, Sheikha; Almulla, Somaya] Hamad Med Corp DOHA Qatar, Dept Lab Med & Pathol, Haematol Sect, Doha, Qatar. [Abu Madi, Marawan; Osman, Mariam; Salam, Wafaa Abdel] Qatar Univ DOHA Qatar, Dept Hlth Sci, Coll Arts & Sci, Doha, Qatar. [Dabbagh, Muhamad] Hamad Med Corp DOHA Qatar, Dept Pediat, Doha, Qatar. [Kamal, Madeeha] Hamad Med Corp DOHA Qatar, Dept Sch Hlth, Doha, Qatar. [Shebl, Fatma] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1751-5521 J9 INT J LAB HEMATOL JI Int. J. Lab. Hematol. PD JUN PY 2012 VL 34 SU 1 SI SI BP 106 EP 106 PG 1 WC Hematology SC Hematology GA 942YH UT WOS:000304087100169 ER PT J AU Britton, JC Bar-Haim, Y Carver, FW Holroyd, T Norcross, MA Detloff, A Leibenluft, E Ernst, M Pine, DS AF Britton, Jennifer C. Bar-Haim, Yair Carver, Frederick W. Holroyd, Tom Norcross, Maxine A. Detloff, Allison Leibenluft, Ellen Ernst, Monique Pine, Daniel S. TI Isolating neural components of threat bias in pediatric anxiety SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE magnetoencephalography; ventrolateral prefrontal cortex; attention ID PREFRONTAL CORTEX ACTIVATION; ATTENTIONAL BIAS; ANGRY FACES; HUMAN BRAIN; DISORDER; CHILDREN; ADOLESCENTS; SUPPRESSION; AMYGDALA; SIGNAL AB Background: Attention biases toward threat are often detected in individuals with anxiety disorders. Threat biases can be measured experimentally through dot-probe paradigms, in which individuals detect a probe following a stimulus pair including a threat. On these tasks, individuals with anxiety tend to detect probes that occur in a location previously occupied by a threat (i.e., congruent) faster than when opposite threats (i.e., incongruent). In pediatric anxiety disorders, dot-probe paradigms detect abnormal attention biases toward threat and abnormal ventrolateral prefrontal cortex (vlPFC) function. However, it remains unclear if this aberrant vlPFC activation occurs while subjects process threats (e.g., angry faces) or, alternatively, while they process and respond to probes. This magnetoencephalography (MEG) study was designed to answer this question. Methods: Adolescents with either generalized anxiety disorder (GAD, n = 17) or no psychiatric diagnosis (n = 25) performed a dot-probe task involving angry and neutral faces while MEG data were collected. Synthetic Aperture Magnetometry (SAM) beamformer technique was used to determine whether there were group differences in power ratios while subjects processed threats (i.e., angry vs. neutral faces) or when subjects responded to incongruent versus. congruent probes. Results: Group differences in vlPFC activation during the response period emerged with a 130 Hz frequency band. No group differences in vlPFC activation were detected in response to angry-face cues. Conclusions: In the dot-probe task, anxiety-related perturbations in vlPFC activation reflect abnormal attention control when responding to behaviorally relevant probes, but not to angry faces. Given that motor responses to these probes are used to calculate threat bias, this study provides insight into the pathophysiology reflected in this commonly used marker of anxiety. In addition, this finding may inform the development of novel anxiety-disorder treatments targeting the vlPFC to enhance attention control to task-relevant demands. C1 [Britton, Jennifer C.; Norcross, Maxine A.; Detloff, Allison; Ernst, Monique; Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Bar-Haim, Yair] Tel Aviv Univ, Dept Psychol, Adler Ctr Res Child Dev & Psychopathol, IL-69978 Tel Aviv, Israel. [Carver, Frederick W.; Holroyd, Tom] NIMH, Magnetoencephal MEG Core Facil, Bethesda, MD 20892 USA. [Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Bethesda, MD 20892 USA. RP Britton, JC (reprint author), NIMH, Sect Dev & Affect Neurosci, 9000 Rockville Pike,Bldg 15K, Bethesda, MD 20892 USA. EM brittonjen@mail.nih.gov RI Britton, Jennifer/J-4501-2013 FU National Institute of Mental Health, National Institutes of Health [K99-MH091183-01]; National Alliance of Research on Schizophrenia and Depression (NARSAD) FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (K99-MH091183-01 awarded to J.C.B.) and the National Alliance of Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (J.C.B.). A previous version of these findings was presented at the Society of Biological Psychiatry annual conference in May 2009. All authors declare no potential conflicts of interest or financial interests related to this manuscript. The current affiliation of A. D. is with the Psychology Department, Duke University. We thank Nina Shiffrin and Michelle Goldwin for their assistance in data acquisition. NR 29 TC 24 Z9 24 U1 5 U2 21 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD JUN PY 2012 VL 53 IS 6 BP 678 EP 686 DI 10.1111/j.1469-7610.2011.02503.x PG 9 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 942YP UT WOS:000304087900009 PM 22136196 ER PT J AU Friedman, KM Prieto, PA Devillier, LE Gross, CA Yang, JC Wunderlich, JR Rosenberg, SA Dudley, ME AF Friedman, Kevin M. Prieto, Peter A. Devillier, Laura E. Gross, Colin A. Yang, James C. Wunderlich, John R. Rosenberg, Steven A. Dudley, Mark E. TI Tumor-specific CD4(+) Melanoma Tumor-infiltrating Lymphocytes SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE tumor-infiltration lymphocytes (TIL); CD4(+); immunotherapy; T-helper cell (Th); HLA DR ID REGULATORY T-CELLS; METASTATIC MELANOMA; CANCER REGRESSION; ADOPTIVE TRANSFER; TRANSFER THERAPY; ANTIGEN; SURVIVAL; IMMUNOTHERAPY; IDENTIFICATION; AUTOIMMUNITY AB Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) can mediate objective and durable tumor regressions in patients with metastatic melanoma. CD8(+) tumor-reactive TIL are well studied in humans and animals, yet the function of tumor-infiltrating CD4(+) T lymphocytes in patient treatments remains controversial. We recently demonstrated that CD4(+) TILs are not necessary for objective responses in patients. Coinfusion with tumor-specific CD4 TIL may enhance or increase the durability of tumor regressions, but the number of patients with tumor-reactive CD4 TIL is unknown. We screened 44 CD8(+)-depleted TIL for in vitro reactivity against autologous tumor. Nine (20%) showed specific reactivity by interferon-gamma release assay, of which 8 were specifically blocked by an anti-HLA-DR antibody. Flow-cytometric analysis of these reactive TIL confirmed a high CD4(+) composition (median 89%). Highlighting the contribution of CD4(+) TIL to tumor regression, a patient with widespread metastatic disease was administered TIL containing HLA class II-restricted tumor activity with high-dose interleukin-2 therapy after lymphodepletion that mediated regression of extensive metastatic disease in the liver and spleen. These results demonstrate that at least 20% of metastatic melanomas contain CD4(+) lymphocytes with specific tumor recognition and suggest a possible role for CD4(+) cells in the effectiveness of adoptive cell therapy. C1 [Friedman, Kevin M.; Devillier, Laura E.; Gross, Colin A.; Yang, James C.; Wunderlich, John R.; Rosenberg, Steven A.; Dudley, Mark E.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Prieto, Peter A.] Yale Univ, Dept Surg, New Haven, CT USA. RP Dudley, ME (reprint author), NCI, Surg Branch, NIH, CRC 3W Room 3-5752,10 Ctr Dr, Bethesda, MD 20892 USA. EM med@nih.gov OI Gross, Colin/0000-0002-7061-5073 FU Cell Processing Laboratory Immunotherapy clinical team; Surgery Branch Protocol Support Office of Surgery Branch, NCI FX The authors thank the members of the Cell Processing Laboratory the Immunotherapy clinical team and the Surgery Branch Protocol Support Office of the Surgery Branch, NCI for their tireless work in support of these clinical efforts. NR 43 TC 30 Z9 31 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD JUN PY 2012 VL 35 IS 5 BP 400 EP 408 DI 10.1097/CJI.0b013e31825898c5 PG 9 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 942LM UT WOS:000304045500005 PM 22576345 ER PT J AU Zhang, L Feldman, SA Zheng, ZL Chinnasamy, N Xu, H Nahvi, AV Dudley, ME Rosenberg, SA Morgan, RA AF Zhang, Ling Feldman, Steven A. Zheng, Zhili Chinnasamy, Nachimuthu Xu, Hui Nahvi, Azam V. Dudley, Mark E. Rosenberg, Steven A. Morgan, Richard A. TI Evaluation of gamma-Retroviral Vectors That Mediate the Inducible Expression of IL-12 for Clinical Application SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE NFAT-responsive promoter; IL-12; adoptive T-cell therapy ID T-CELLS; METASTATIC MELANOMA; INTERLEUKIN-12; THERAPY; LYMPHOCYTES AB The clinical application of interleukin-12 (IL-12) has been hindered by the toxicity associated with its systemic administration. To potentially overcome this problem, we developed a promoter designed to direct IL-12 expression within the tumor environment using an inducible composite promoter containing binding motifs for the nuclear factor of activated T cells (NFAT) linked to a minimal IL-2 promoter. In this study, the NFAT promoter was coupled to a single-chain human IL-12 gene and inserted into 2 gamma-retroviral self-inactivating vectors (SERS.NFAT.hIL12 and SERS.NFAT.hIL12.PA2) and 1 gamma-retroviral vector (MSGV1.NFAT.hIL.12PA2). Peripheral blood lymphocytes (PBLs) were double transduced with an antigen-specific T-cell receptor and the 3 NFAT.hIL12 vectors. Evaluation of inducible IL-12 expression, transduction efficiency, and vector production considerations led to the choice of the MSGV1.NFAT.hIL12.PA2 vector for clinical application. MSGV1.NFAT.hIL12.PA2 PG13 retroviral vector producer cell clones were screened by transduction of tumor antigen-specific PBLs. On the basis of expression studies in PBL, clone D3 was chosen to produce clinical-grade viral vector supernatant and was demonstrated to efficiently transduce young tumor-infiltrating lymphocytes (TIL). The vector-transduced young TIL with known tumor recognition demonstrated specific inducible IL-12 production after coculture with HLA-matched tumor targets and had augmented effector function as demonstrated by increased IFN-gamma secretion. These results support the clinical application of adoptive transfer of young TIL engineered with the NFAT.hIL12 vector as a new approach for cancer immunotherapy. C1 [Zhang, Ling; Feldman, Steven A.; Zheng, Zhili; Chinnasamy, Nachimuthu; Xu, Hui; Nahvi, Azam V.; Dudley, Mark E.; Rosenberg, Steven A.; Morgan, Richard A.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), 10 Ctr Dr,Bldg 10,CRC 3W-3864, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov FU National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This work is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and Center for Cancer Research. NR 24 TC 15 Z9 15 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD JUN PY 2012 VL 35 IS 5 BP 430 EP 439 DI 10.1097/CJI.0b013e31825898e8 PG 10 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 942LM UT WOS:000304045500008 PM 22576348 ER PT J AU Norouzi, S Aghamohammadi, A Mamishi, S Rosenzweig, SD Rezaei, N AF Norouzi, Sayna Aghamohammadi, Asghar Mamishi, Setareh Rosenzweig, Sergio D. Rezaei, Nima TI Bacillus Calmette-Guerin (BCG) complications associated with primary immunodeficiency diseases SO JOURNAL OF INFECTION LA English DT Review DE BCG vaccination; Complications; Primary immunodeficiency diseases; Severe combined immunodeficiency; Mendelian susceptibility to mycobacterial diseases ID CHRONIC GRANULOMATOUS-DISEASE; BONE-MARROW-TRANSPLANTATION; RECEPTOR BETA-1 DEFICIENCY; HYPER-IGM SYNDROME; MENDELIAN SUSCEPTIBILITY; MYCOBACTERIUM-BOVIS; GENETIC-HETEROGENEITY; CLINICAL-FEATURES; SCID PATIENT; IFN-GAMMA AB Primary immunodeficiency diseases (PIDs) are a group of inherited disorders, characterized by defects of the immune system predisposing individuals to variety of manifestations, including recurrent infections and unusual vaccine complications. There are a number of PIDs prone to Bacillus Calmette-Guerin (BCG) complications. This review presents an update on our understanding about the BCGosis-susceptible PIDs, including severe combined immunodeficiency, chronic granulomatous disease, and Mendelian susceptibility to mycobacterial diseases. (c) 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved. C1 [Norouzi, Sayna; Mamishi, Setareh] Univ Tehran Med Sci, Pediat Infect Dis Res Ctr, Tehran, Iran. [Aghamohammadi, Asghar; Rezaei, Nima] Univ Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Res Ctr Immunodeficiencies, Tehran, Iran. [Rosenzweig, Sergio D.] NIAID, Infect Dis Susceptibil Unit, Lab Host Def, Primary Immunodeficiency Clin,NIH, Bethesda, MD 20892 USA. [Rezaei, Nima] Univ Tehran Med Sci, Sch Med, Dept Immunol, Mol Immunol Res Ctr, Tehran, Iran. [Rezaei, Nima] Univ Sheffield, Sch Med & Biomed Sci, Dept Infect & Immun, Sheffield, S Yorkshire, England. RP Rezaei, N (reprint author), Childrens Med Ctr Hosp, Res Ctr Immunodeficiencies, Dr Qarib St,Keshavarz Blvd, Tehran 14194, Iran. EM rezaei_nima@yahoo.com RI Rezaei, Nima/B-4245-2008 OI Rezaei, Nima/0000-0002-3836-1827 FU Tehran University of Medical Sciences and Health Services [90-03-30-15173] FX This study was supported by grant from Tehran University of Medical Sciences and Health Services (90-03-30-15173). NR 149 TC 49 Z9 52 U1 0 U2 13 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0163-4453 EI 1532-2742 J9 J INFECTION JI J. Infect. PD JUN PY 2012 VL 64 IS 6 BP 543 EP 554 DI 10.1016/j.jinf.2012.03.012 PG 12 WC Infectious Diseases SC Infectious Diseases GA 941YR UT WOS:000304006200001 PM 22430715 ER PT J AU Ray, A Marshall, V Uldrick, T Leighty, R Labo, N Wyvill, K Aleman, K Polizzotto, MN Little, RF Yarchoan, R Whitby, D AF Ray, Alex Marshall, Vickie Uldrick, Thomas Leighty, Robert Labo, Nazzarena Wyvill, Kathy Aleman, Karen Polizzotto, Mark N. Little, Richard F. Yarchoan, Robert Whitby, Denise TI Sequence Analysis of Kaposi Sarcoma-Associated Herpesvirus (KSHV) MicroRNAs in Patients with Multicentric Castleman Disease and KSHV-Associated Inflammatory Cytokine Syndrome SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; VIRUS-ENCODED MICRORNAS; DNA-SEQUENCES; EXPRESSION; INTERLEUKIN-6; CELLS; HUMAN-HERPESVIRUS-8; AFRICA; HIV; IDENTIFICATION AB Background. Kaposi sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs that yield 25 mature microRNAs. We previously reported phylogenetic analysis of the microRNA-coding region of KSHV from Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD) patients. We observed a high level of conservation for most sequences but also a divergent cluster of 5 KSHV sequences, including 2 from MCD patients. Methods. KSHV microRNA sequences from 23 MCD patients and 7 patients with a newly described KSHV-associated inflammatory cytokine syndrome (KICS) were examined by amplification, cloning, and sequencing of a 646-bp fragment of K12/T0.7 encoding microRNA-K12-10 and microRNA-K12-12 and a 2.8-kbp fragment containing the remaining 10 pre-microRNAs. Results. Phylogenetic analysis showed a distinct variant cluster consisting exclusively of MCD and KICS patients in all trees. Pearson chi(2) analysis revealed that 40 single-nucleotide polymorphisms (SNPs) at various loci were significantly associated with MCD and KICS risk. Cluster analysis of these SNPs generated several combinations of 3 SNPs as putative indicators of MCD and KICS risk. Conclusions. These findings show that MCD and KICS patients frequently have unusual KSHV microRNA sequences and suggest an association between the observed sequence variation and risk of MCD and KICS. C1 [Ray, Alex; Marshall, Vickie; Labo, Nazzarena; Whitby, Denise] NCI, Viral Oncol Sect, AIDS & Canc Virus Program, SAIC Frederick, Frederick, MD 21702 USA. [Uldrick, Thomas; Wyvill, Kathy; Aleman, Karen; Polizzotto, Mark N.; Little, Richard F.; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Leighty, Robert] NCI, Data Management Serv Inc, Frederick, MD 21702 USA. RP Whitby, D (reprint author), NCI, Viral Oncol Sect, AIDS & Canc Virus Program, SAIC Frederick, POB B,Bldg 535,4th Floor, Frederick, MD 21702 USA. EM whitbyd@mail.nih.gov RI Labo, Nazzarena/H-8655-2012 OI Labo, Nazzarena/0000-0001-5953-4064 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the National Cancer Institute, National Institutes of Health (contract number HHSN261200800001E). NR 50 TC 13 Z9 13 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2012 VL 205 IS 11 BP 1665 EP 1676 DI 10.1093/infdis/jis249 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 942RV UT WOS:000304065600011 PM 22448005 ER PT J AU Zhang, GL Zhou, BP Wang, WF Zhang, MX Zhao, YH Wang, Z Yang, L Zhai, JN Feng, CG Wang, JW Chen, XC AF Zhang, Guoliang Zhou, Boping Wang, Wenfei Zhang, Mingxia Zhao, Yahua Wang, Zheng Yang, Lin Zhai, Jingnan Feng, Carl G. Wang, Junwen Chen, Xinchun TI A Functional Single-Nucleotide Polymorphism in the Promoter of the Gene Encoding Interleukin 6 Is Associated With Susceptibility to Tuberculosis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HAN CHINESE POPULATION; NECROSIS-FACTOR-ALPHA; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; IMMUNE-RESPONSES; T-CELLS; IL-6; DISEASE; GAMMA; RISK AB Genetic variation influences susceptibility or resistance to tuberculosis. Interleukin 6 (IL-6) contributes to protection against tuberculosis in mice. However, its role in regulating susceptibility or resistance to tuberculosis in humans is unclear. Genotyping of polymorphisms in IL-6 and IL-6R (CD126) genes was performed in 2 independent cohorts, an experimental population (495 cases and 358 controls) and a validation population (1383 cases and 1149 controls). The associations of the variants with tuberculosis were tested using 2 case-control association studies. In addition, the regulatory effects of single-nucleotide polymorphism rs1800796 (-572C > G) on IL-6 production in plasma and CD14(+) monocyte cultures stimulated with a Mycobacterium tuberculosis (M. tuberculosis) product were assessed. The rs1800796 polymorphism is associated with increased resistance to tuberculosis (odds ratio [OR], 0.771; 95% confidential interval, .684-.870). The rs1800796GG genotype is strongly associated with reduced risk to tuberculosis (OR, 0.621; 95% CI, .460-.838). Interestingly, CD14(+) monocytes isolated from individuals with rs1800796GG genotype produced significantly less IL-6 in response to M. tuberculosis 19-kDa lipoprotein than those with CC or CG genotype. We identified a genetic polymorphism in the IL-6 promoter that regulates cytokine production and host resistance to pulmonary tuberculosis in Chinese populations. C1 [Zhang, Guoliang; Zhou, Boping; Wang, Wenfei; Zhang, Mingxia; Zhai, Jingnan; Chen, Xinchun] Shenzhen Third Peoples Hosp, Guangdong Med Coll, Guangdong Key Lab Emerging Infect Dis, Shenzhen 518112, Peoples R China. [Wang, Wenfei; Zhao, Yahua] S China Agr Univ, Coll Life Sci, Dept Biol Chem, Guangzhou, Guangdong, Peoples R China. [Wang, Zheng; Yang, Lin] Shenzhen Peoples Hosp, Dept Thorac Surg, Shenzhen, Peoples R China. [Feng, Carl G.] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Wang, Junwen] Univ Hong Kong, LKS Fac Med, Dept Biochem, Pokfulam, Hong Kong, Peoples R China. RP Chen, XC (reprint author), Shenzhen Third Peoples Hosp, Guangdong Med Coll, Guangdong Key Lab Emerging Infect Dis, 29 Bulan Rd, Shenzhen 518112, Peoples R China. EM chenxinchun@gmail.com RI Wang, Junwen/C-4432-2009; Wang, Junwen/D-3700-2011 OI Wang, Junwen/0000-0002-4432-4707 FU Eleven-Fifth Mega-Scientific Project on the "prevention and treatment of AIDS, viral hepatitis and other infectious diseases" [2008ZX10003-005]; Natural Science Foundation of China [30872258, 81172732]; Department of Health and Human Services, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Food and Health Bureau of Hong Kong [10091262] FX This work was supported by Eleven-Fifth Mega-Scientific Project on the "prevention and treatment of AIDS, viral hepatitis and other infectious diseases" (2008ZX10003-005), the Natural Science Foundation of China (grants 30872258 and 81172732), the Intramural Research Program, Department of Health and Human Services, National Institute of Allergy and Infectious Diseases, National Institutes of Health (to C. G. F.), and the Food and Health Bureau of Hong Kong (10091262 to J. W.). NR 42 TC 16 Z9 18 U1 2 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2012 VL 205 IS 11 BP 1697 EP 1704 DI 10.1093/infdis/jis266 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 942RV UT WOS:000304065600014 PM 22457277 ER PT J AU Falanga, V AF Falanga, Vincent TI Stem Cells in Tissue Repair and Regeneration SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID WOUND BED PREPARATION; VENOUS ULCERS; BONE-MARROW AB The field of tissue repair and wound healing has blossomed in the past 30 years. We have gone from recombinant growth factors, to living tissue engineering constructs, to stem cells. The task now is to pursue true regeneration, thus achieving complete restoration of structure and function. C1 [Falanga, Vincent] Roger Williams Med Ctr, Dept Dermatol & Skin Surg, Providence, RI 02908 USA. [Falanga, Vincent] Roger Williams Med Ctr, NIH Ctr Biomed Res Excellence, Providence, RI 02908 USA. [Falanga, Vincent] Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA. [Falanga, Vincent] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. RP Falanga, V (reprint author), Roger Williams Med Ctr, Dept Dermatol & Skin Surg, Elmhurst Bldg,50 Maude St, Providence, RI 02908 USA. EM vfalanga@bu.edu FU NCRR NIH HHS [P20 RR018757, #P20RR018757-10]; NIAMS NIH HHS [R01 AR060342, R01 #AR060342]; NIGMS NIH HHS [P20 GM103414, 8 P20 GM103414-10] NR 11 TC 10 Z9 10 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUN PY 2012 VL 132 IS 6 BP 1538 EP 1541 DI 10.1038/jid.2012.77 PG 5 WC Dermatology SC Dermatology GA 942HO UT WOS:000304035000004 PM 22584501 ER PT J AU Weinstock, MA Bingham, SF DiGiovanna, JJ Rizzo, AE Marcolivio, K Hall, R Eilers, D Naylor, M Kirsner, R Kalivas, J Cole, G Vertrees, JE AF Weinstock, Martin A. Bingham, Stephen F. DiGiovanna, John J. Rizzo, Amilcar E. Marcolivio, Kim Hall, Russell Eilers, David Naylor, Mark Kirsner, Robert Kalivas, James Cole, Gary Vertrees, Julia E. CA Vet Affairs Topical Tretinoin TI Tretinoin and the Prevention of Keratinocyte Carcinoma (Basal and Squamous Cell Carcinoma of the Skin): A Veterans Affairs Randomized Chemoprevention Trial SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID RENAL-TRANSPLANT RECIPIENTS; LOW-DOSE ISOTRETINOIN; OF-LIFE IMPACT; TOPICAL TRETINOIN; ACTINIC KERATOSES; VATTC TRIAL; LONG-TERM; CANCER; RISK; RELIABILITY AB Keratinocyte carcinoma (KC) is the most common cancer in the United States, with no proven means for prevention other than systemic retinoids, which have significant toxicity, and sunscreen. Topical tretinoin has been used for KC chemoprevention, although this use is unproven. Hence, we conducted the randomized Veterans Affairs Topical Tretinoin Chemoprevention Trial of high-dose topical tretinoin for KC prevention. We randomized 1,131 patients to topical 0.1% tretinoin or a matching vehicle control for 1.5-5.5 years. The primary outcomes were time to development of new basal cell carcinoma (BCC) and new invasive squamous cell carcinoma (SCC) on the face or ears. The effects were not significant (P = 0.3 for BCC and P = 0.4 for SCC). The proportions of the tretinoin and control groups who developed a BCC at 5 years were 53 and 54% and an invasive SCC at 5 years were 28 and 31%. These differences (95% confidence intervals) were: for BCC, 1.0% (-6.5, 8.6%); for SCC, 3.6% (-3.1, 10.3%). No differences were observed in any cancer-related end points or in actinic keratosis counts. The only quality of life difference was worse symptoms in the tretinoin group at 12 months after randomization. This trial in high-risk patients demonstrates that high-dose topical tretinoin is ineffective at reducing risk of KCs. C1 [Weinstock, Martin A.; Rizzo, Amilcar E.; Marcolivio, Kim] VA Med Ctr, Dermatoepidemiol Unit, Providence, RI USA. [Weinstock, Martin A.; DiGiovanna, John J.] Rhode Isl Hosp, Dept Dermatol, Providence, RI USA. [Weinstock, Martin A.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Bingham, Stephen F.] VA Maryland Hlth Care Syst, Cooperat Studies Program, Perry Point, MD USA. [DiGiovanna, John J.] NCI, DNA Repair Sect, Dermatol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Hall, Russell] Duke Univ, Sch Med, Dept Med, VA Med Ctr,Div Dermatol, Durham, NC 27706 USA. [Eilers, David] Edward Hines Jr VA Med Ctr, Dept Dermatol, Hines, IL USA. [Naylor, Mark] VA Med Ctr, Oklahoma City, OK USA. [Kirsner, Robert] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr,VA Med Ctr, Dept Dermatol & Cutaneous Surg,Dept Epidemiol & P, Miami, FL 33136 USA. [Kalivas, James] VA Med Ctr, Phoenix, AZ USA. [Cole, Gary] VA Med Ctr, Dept Dermatol, Long Beach, CA USA. [Vertrees, Julia E.] Clin Res Pharm Coordinating Ctr, VA Cooperat Studies Program, Albuquerque, NM USA. RP Weinstock, MA (reprint author), VA Med Ctr 111D, Dermatoepidemiol Unit, 830 Chalkstone Ave, Providence, RI 02908 USA. EM maw@brown.edu FU Office of Research and Development, Department of Veterans Affairs [CSP 402]; American Cancer Society FX This study was supported by the VA Cooperative Studies Program (CSP 402), Office of Research and Development, Department of Veterans Affairs, and the American Cancer Society. The tretinoin, 0.1%, and the vehicle creams were donated by OrthoNeutrogena, a division of Ortho-McNeil Pharmaceutical. NR 29 TC 29 Z9 29 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUN PY 2012 VL 132 IS 6 BP 1583 EP 1590 DI 10.1038/jid.2011.483 PG 8 WC Dermatology SC Dermatology GA 942HO UT WOS:000304035000010 PM 22318383 ER PT J AU Romero, R Chaiworapongsa, T Savasan, ZA Hussein, Y Dong, Z Kusanovic, JP Kim, CJ Hassan, SS AF Romero, Roberto Chaiworapongsa, Tinnakorn Savasan, Zeynep Alpay Hussein, Youssef Dong, Zhong Pedro Kusanovic, Juan Kim, Chong Jai Hassan, Sonia S. TI Clinical chorioamnionitis is characterized by changes in the expression of the alarmin HMGB1 and one of its receptors, sRAGE SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE danger signal; intra-amniotic inflammation; sterile inflammation; pregnancy; neuroinflammation; neuro-immune reflex; amniotic fluid; DAMPs; damage-associated molecular patterns; intra-amniotic infection; term labor ID GLYCATION END-PRODUCTS; MOBILITY GROUP BOX-1; PRETERM PREMATURE RUPTURE; TOLL-LIKE RECEPTORS; FACTOR-KAPPA-B; INFLAMMATORY CELL RECRUITMENT; AMNIOTIC-FLUID CONCENTRATIONS; HUMAN GESTATIONAL TISSUES; VEIN ENDOTHELIAL-CELLS; NUCLEAR-PROTEIN HMGB1 AB Objective: High mobility group box-1 (HMGB1) protein is an alarmin, a normal cell constituent, which is released into the extracellular environment upon cellular stress/damage and capable of activating inflammation and tissue repair. The receptor for advanced glycation end products (RAGE) can bind HMGB1. RAGE, in turn, can induce the production of pro-inflammatory cytokines; this may be modulated by the soluble truncated forms of RAGE, including soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE). The objectives of this study were to determine whether: 1) clinical chorioamnionitis at term is associated with changes in amniotic fluid concentrations of HMGB1, sRAGE and esRAGE; and 2) the amniotic fluid concentration of HMGB1 changes with labor or as a function of gestational age. Methods: Amniotic fluid samples were collected from the following groups: 1) mid-trimester (n=45); 2) term with (n=48) and without labor (n=22) without intra-amniotic infection; and 3) term with clinical chorioamnionitis (n=46). Amniotic fluid concentrations of HMGB1, sRAGE and esRAGE concentrations were determined by ELISA. Results: 1) the median amniotic fluid HMGB1 concentration was higher in patients at term with clinical chorioamnionitis than in those without this condition (clinical chorioamnionitis: median 3.8 ng/mL vs. term in labor: median 1.8 ng/mL, p=0.007; and vs. term not in labor: median 1.1 ng/mL, p=0.003); 2) in contrast, patients with clinical chorioamnionitis had a lower median sRAGE concentration than those without this condition (clinical chorioamnionitis: median 9.3 ng/mL vs. term in labor: median 18.6 ng/mL, p=0.001; and vs. term not in labor median: 28.4 ng/mL, p<0.001); 3) amniotic fluid concentrations of esRAGE did not significantly change in patients with clinical chorioamnionitis at term (clinical chorioamnionitis: median 5.4 ng/mL vs. term in labor: median 6.1 ng/mL, p=0.9; and vs. term not in labor: median 9.5 ng/mL, p=0.06); and 4) there was no significant difference in the median AF HMGB1 concentration between women at term in labor and those not in labor (p=0.4) and between women in the mid-trimester and those at term not in labor (mid-trimester: median 1.5 ng/mL; p=0.2). Conclusion: An increase in the amniotic fluid HMGB1 concentration and a decrease in sRAGE were observed in clinical chorioamnionitis at term. This finding provides evidence that an alarmin, HMGB1, and one of its receptors, sRAGE, are engaged in the process of clinical chorioamnionitis at term. These changes are quite different from those observed in cases of intra-amniotic infection/inflammation in preterm gestations. C1 [Romero, Roberto] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, Detroit, MI 48201 USA. [Romero, Roberto; Chaiworapongsa, Tinnakorn; Savasan, Zeynep Alpay; Hussein, Youssef; Dong, Zhong; Kim, Chong Jai; Hassan, Sonia S.] NICHD NIH DHHS, Perinatol Res Branch, Bethesda, MD USA. [Chaiworapongsa, Tinnakorn; Savasan, Zeynep Alpay; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Pedro Kusanovic, Juan] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. [Pedro Kusanovic, Juan] Hosp Dr Sotero del Rio, Ctr Perinatal Res, Santiago, Chile. [Kim, Chong Jai] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. Presented at the 56th annual meeting of the Society for Gynecologic Investigation. March 16-19, 2011, Miami, FL. NR 164 TC 36 Z9 36 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD JUN PY 2012 VL 25 IS 6 BP 558 EP 567 DI 10.3109/14767058.2011.599083 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 943CH UT WOS:000304097600003 PM 22578261 ER PT J AU Mullin, PM Ching, CY Schoenberg, F MacGibbon, K Romero, R Goodwin, TM Fejzo, MS AF Mullin, Patrick M. Ching, ChunYu Schoenberg, Frederic MacGibbon, Kimber Romero, Roberto Goodwin, T. Murphy Fejzo, Marlena S. TI Risk factors, treatments, and outcomes associated with prolonged hyperemesis gravidarum SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE hyperemesis gravidarum; outcomes; risk factors; treatments ID PLASMA ADENOSINE CONCENTRATIONS; WERNICKES ENCEPHALOPATHY; ADDISONS-DISEASE; DAIRY-PRODUCTS; LARGE COHORT; PREGNANCY; WOMEN; PREECLAMPSIA; SEVERITY AB Objective: To identify factors associated with prolonged Hyperemesis Gravidarum (HG). Study Design: About 395 women completed a survey regarding pre-existing conditions, treatments and outcomes. Responses were compared using two-sided t-tests or the F-test. Results: Participants with prolonged HG are slightly younger and weigh more. Pre-existing factors associated with prolonged HG include allergies and a restrictive diet. Prolonged HG is associated with hematemesis, dizziness, fainting and antiemetic treatment. Following pregnancy, those with prolonged HG reported more posttraumatic stress, motion sickness, muscle weakness and infants with irritability, severe colic and growth restriction. Conclusion: Multiple pre-existing conditions and poor maternal and infant outcomes were associated with prolonged HG. The most significant condition prior to pregnancy was allergies suggesting a possible autoimmune component affecting duration of HG. In addition, the most significant lifestyle choice linked to prolonged HG was a restrictive diet. Future research is needed to determine whether a change in diet prior to pregnancy may lead to a shorter duration of HG and its associated outcomes. C1 [Mullin, Patrick M.; Goodwin, T. Murphy; Fejzo, Marlena S.] Univ So Calif, Keck Sch Med, Dept Maternal Fetal Med, Los Angeles, CA 90095 USA. [Ching, ChunYu; Schoenberg, Frederic] Univ Calif Los Angeles, Dept Stat, Los Angeles, CA USA. [MacGibbon, Kimber] Hyperemesis Educ & Res Fdn, Leesburg, VA USA. [Romero, Roberto] NICHD, NIH, DHHS, Perinatol Res Branch, Bethesda, MD USA. [Romero, Roberto] NICHD, NIH, DHHS, Perinatol Res Branch, Detroit, MI USA. [Fejzo, Marlena S.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. RP Fejzo, MS (reprint author), Univ So Calif, Keck Sch Med, Dept Maternal Fetal Med, 5535 MRL BLDG,675 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM mfejzo@mednet.ucla.edu OI MacGibbon, Kimber/0000-0002-6534-3114 FU Intramural NIH HHS [ZIA HD002401-17] NR 34 TC 8 Z9 9 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD JUN PY 2012 VL 25 IS 6 BP 632 EP 636 DI 10.3109/14767058.2011.598588 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 943CH UT WOS:000304097600014 PM 21916750 ER PT J AU Cornman-Homonoff, J Kuehn, D Aros, S Carter, TC Conley, MR Troendle, J Cassorla, F Mills, JL AF Cornman-Homonoff, Joshua Kuehn, Devon Aros, Sofia Carter, Tonia C. Conley, Mary R. Troendle, James Cassorla, Fernando Mills, James L. TI Heavy prenatal alcohol exposure and risk of stillbirth and preterm delivery SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE alcohol; pregnancy; stillbirth; preterm delivery; binge drinking ID PREGNANCY; DEATH; CONSUMPTION; MORTALITY; DRINKING; BIRTH; CHILE AB We prospectively identified 96 women consuming at least 4 drinks/day during pregnancy by screening 9628 pregnant women. In these women with heavy prenatal alcohol use, there were three stillbirths and one preterm delivery; 98 matched nondrinking women had no stillbirths and two preterm births. Preterm rates did not differ significantly. The stillbirth rate was higher in the exposed group (p = 0.06). Additional investigation showed the stillbirth rate in the exposed population (3.1%) was significantly higher (p = 0.019) than the reported Chilean population rate (0.45%). Our data suggest that heavy alcohol consumption may increase the risk for stillbirth but not preterm delivery. C1 [Cornman-Homonoff, Joshua; Kuehn, Devon; Carter, Tonia C.; Conley, Mary R.; Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Cornman-Homonoff, Joshua] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Kuehn, Devon] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. [Aros, Sofia] Univ Chile, Fac Med, Dept Pediat, San Borja Arriaran Clin Hosp, Santiago 7, Chile. [Troendle, James] NHLBI, Div Cardiovasc Sci, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Cassorla, Fernando] Univ Chile, Fac Med, Inst Maternal & Child Res IDIMI, Santiago 7, Chile. RP Mills, JL (reprint author), NICHD NIH, Room 7B03,6100 Execut Blvd, Bethesda, MD 20892 USA. EM jamesmills@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 10 TC 6 Z9 6 U1 1 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD JUN PY 2012 VL 25 IS 6 BP 860 EP 863 DI 10.3109/14767058.2011.587559 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 943CH UT WOS:000304097600059 PM 21728738 ER PT J AU Meyers, CA Rock, EP Fine, HA AF Meyers, Christina A. Rock, Edwin P. Fine, Howard A. TI Refining endpoints in brain tumor clinical trials SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Brain cancer; Clinical trials; Neurocognitive function ID NEUROCOGNITIVE FUNCTION; COGNITIVE FUNCTION; PROGRESSION; RADIATION; CANCER; GLIOMA AB As targeted therapies advance treatment for brain tumors, standard clinical trial endpoints of survival, progression free survival and radiographic response have become insufficient to capture clinical benefit. Brain cancer is a malignancy with neurodegenerative features. In this setting prolongation of life and/or radiographic stability are less clinically meaningful if neurocognitive function substantially declines. Hence evaluation of new therapeutic strategies should routinely include periodic assessment of neurocognitive function. C1 [Meyers, Christina A.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Rock, Edwin P.] Otsuka Pharmaceut Dev & Commercializat Inc, Rockville, MD USA. [Fine, Howard A.] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. RP Meyers, CA (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. EM cameyers53@yahoo.com NR 15 TC 13 Z9 13 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JUN PY 2012 VL 108 IS 2 SI SI BP 227 EP 230 DI 10.1007/s11060-012-0813-8 PG 4 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 943TH UT WOS:000304147600003 PM 22451194 ER PT J AU Shaikh, Q Kamal, AK AF Shaikh, Quratulain Kamal, Ayeesha Kamran TI HDL cholesterol - How do I raise my patients good cholesterol? SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material ID DENSITY-LIPOPROTEIN CHOLESTEROL; DISEASE C1 [Kamal, Ayeesha Kamran] Aga Khan Univ Hosp, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. Aga Khan Univ Hosp, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ Hosp, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. EM ayeesha.kamal@aku.edu OI Shaikh, Quratulain/0000-0001-6106-2713 FU FIC NIH HHS [D43TW008660, D43 TW008660] NR 6 TC 2 Z9 2 U1 0 U2 0 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD JUN PY 2012 VL 62 IS 6 BP 623 EP 624 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 943NF UT WOS:000304129800027 PM 22755358 ER PT J AU Sonntag, WE Csiszar, A deCabo, R Ferrucci, L Ungvari, Z AF Sonntag, William E. Csiszar, Anna deCabo, Raphael Ferrucci, Luigi Ungvari, Zoltan TI Diverse Roles of Growth Hormone and Insulin-Like Growth Factor-1 in Mammalian Aging: Progress and Controversies SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE IGF-1; Longevity; Growth hormone ID LIFE-SPAN EXTENSION; AGE-RELATED PATHOLOGY; PLASMA-PROTEIN-A; IGF-I; HUMAN LONGEVITY; C-ELEGANS; DWARF MICE; CAENORHABDITIS-ELEGANS; EXTENDED LONGEVITY; MUSCLE HYPERTROPHY AB Because the initial reports demonstrating that circulating growth hormone and insulin-like growth factor-1 decrease with age in laboratory animals and humans, there have been numerous studies related to the importance of these hormones for healthy aging. Nevertheless, the role of these potent anabolic hormones in the genesis of the aging phenotype remains controversial. In this chapter, we review the studies demonstrating the beneficial and deleterious effects of growth hormone and insulin-like growth factor-1 deficiency and explore their effects on specific tissues and pathology as well as their potentially unique effects early during development. Based on this review, we conclude that the perceived contradictory roles of growth hormone and insulin-like growth factor-1 in the genesis of the aging phenotype should not be interpreted as a controversy on whether growth hormone or insulin-like growth factor-1 increases or decreases life span but rather as an opportunity to explore the complex roles of these hormones during specific stages of the life span. C1 [Sonntag, William E.] Univ Oklahoma, Reynolds Oklahoma Ctr Aging, Hlth Sci Ctr,Donald W Reynolds Dept Geriatr Med, Stanton L Young Biomed Res Ctr 1303, Oklahoma City, OK 74104 USA. [deCabo, Raphael; Ferrucci, Luigi] NIA, Bethesda, MD 20892 USA. RP Sonntag, WE (reprint author), Univ Oklahoma, Reynolds Oklahoma Ctr Aging, Hlth Sci Ctr,Donald W Reynolds Dept Geriatr Med, Stanton L Young Biomed Res Ctr 1303, 975 NE 10th St, Oklahoma City, OK 74104 USA. EM william-sonntag@ouhsc.edu RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU National Institutes of Health [NS056218, AG11370, AG27147, AG031085, AT006526]; American Federation for Aging Research; Oklahoma Center for the Advancement of Science and Technology; American Heart Association; Ellison Medical Foundation; Donald W. Reynolds Foundation FX This work was supported by grants from the National Institutes of Health (NS056218, AG11370, AG27147, AG031085, AT006526), the American Federation for Aging Research, the Oklahoma Center for the Advancement of Science and Technology, the American Heart Association, the Ellison Medical Foundation, and Donald W. Reynolds Foundation. NR 91 TC 31 Z9 31 U1 2 U2 13 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUN PY 2012 VL 67 IS 6 BP 587 EP 598 DI 10.1093/gerona/gls115 PG 12 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 942OM UT WOS:000304054700005 PM 22522510 ER PT J AU Cesari, M Kritchevsky, SB Nicklas, B Kanaya, AM Patrignani, P Tacconelli, S Tranah, GJ Tognoni, G Harris, TB Incalzi, RA Newman, AB Pahor, M AF Cesari, Matteo Kritchevsky, Stephen B. Nicklas, Barbara Kanaya, Alka M. Patrignani, Paola Tacconelli, Stefania Tranah, Gregory J. Tognoni, Gianni Harris, Tamara B. Incalzi, Raffaele Antonelli Newman, Anne B. Pahor, Marco CA Hlth ABC Study TI Oxidative Damage, Platelet Activation, and Inflammation to Predict Mobility Disability and Mortality in Older Persons: Results From the Health Aging and Body Composition Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Oxidative damage; Platelet activation; Inflammation; Disability; Mortality ID OXIDANT STRESS; CARDIOVASCULAR-DISEASE; OBESE WOMEN; IN-VIVO; INTERLEUKIN-6; ISOPROSTANES; PEROXIDATION; MARKERS; RISK; AGE AB Inflammation, oxidative damage, and platelet activation are hypothesized biological mechanisms driving the disablement process. The aim of the present study is to assess whether biomarkers representing these mechanisms predicted major adverse health-related events in older persons. Data are from 2,234 community-dwelling nondisabled older persons enrolled in the Health Aging and Body Composition study. Biomarkers of lipid peroxidation (ie, urinary levels of 8-iso-prostaglandin F-2 alpha), platelet activation (ie, urinary levels of 11-dehydro-thromboxane B-2), and inflammation (serum concentrations of interleukin-6) were considered as independent variables of interest and tested in Cox proportional hazard models as predictors of (severe) mobility disability and overall mortality. The sample's (women 48.0%, whites 64.3%) mean age was 74.6 (SD 2.9) years. During the follow-up (median 11.4 years), 792 (35.5%), 269 (12.0%), and 942 (42.2%) events of mobility disability, severe mobility disability, and mortality occurred, respectively. Only interleukin-6 showed significant independent associations with the onset of all the study outcomes. Higher levels of urinary 8-iso-prostaglandin F-2 alpha and 11-dehydro-thromboxane B-2 independently predicted increased risk of death (hazard ratio 1.10, 95% confidence interval 1.03-1.19 and hazard ratio 1.14, 95% confidence interval 1.06-1.23, respectively). No significant interactions of gender, race, cardiovascular disease, diabetes, and antiplatelet drugs were detected on the studied relationships. The inflammatory marker interleukin-6 is confirmed to be a robust predictor for the onset of negative health-related events. Participants with higher urinary levels of 8-iso-prostaglandin F-2 alpha and 11-dehydro-thromboxane B-2 presented a higher mortality risk. C1 [Cesari, Matteo] Univ Toulouse, Inst Vieillissement, F-31000 Toulouse, France. [Cesari, Matteo; Pahor, Marco] Univ Florida, Inst Aging, Dept Aging & Geriatr Res, Gainesville, FL USA. [Kritchevsky, Stephen B.; Nicklas, Barbara] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Gainesville, NC USA. [Kanaya, Alka M.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Patrignani, Paola; Tacconelli, Stefania] Gabriele D Annunzio Univ, Ctr Excellent Aging, Chieti, Italy. [Tranah, Gregory J.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Tognoni, Gianni] Consorzio Mario Negri Sud, Chieti, Italy. [Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Incalzi, Raffaele Antonelli] Univ Campus Biomed, Area Geriatria, Rome, Italy. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Cesari, M (reprint author), Univ Toulouse, Inst Vieillissement, 37 Allees Jules Guesde, F-31000 Toulouse, France. EM macesari@gmail.com RI Antonelli Incalzi, Raffaele/G-3978-2012; Newman, Anne/C-6408-2013; Cesari, Matteo/A-4649-2008; OI Kritchevsky, Stephen/0000-0003-3336-6781; Newman, Anne/0000-0002-0106-1150; Cesari, Matteo/0000-0002-0348-3664; Antonelli Incalzi, Raffaele/0000-0003-2100-2075 FU National Institutes of Health-National Institute on Aging [R01AG26556]; Wake Forest University [P30-AG21332]; University of Florida-Institute on Aging Claude D. Pepper Older Americans Independence Centers [P30AG028740]; National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute of Nursing Research [R01-NR012459] FX The present study is funded by the National Institutes of Health-National Institute on Aging (R01AG26556) and by the Wake Forest University (P30-AG21332) and University of Florida-Institute on Aging (P30AG028740) Claude D. Pepper Older Americans Independence Centers. The Health ABC study is supported by the National Institute on Aging (contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, and grant R01-AG028050), the National Institute of Nursing Research (grant R01-NR012459), and partly by the Intramural Research Program of the National Institutes of Health-National Institute on Aging. NR 40 TC 26 Z9 29 U1 2 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUN PY 2012 VL 67 IS 6 BP 671 EP 676 DI 10.1093/gerona/glr246 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 942OM UT WOS:000304054700012 PM 22389462 ER PT J AU Semba, RD Chang, SS Sun, K Cappola, AR Ferrucci, L Fried, LP AF Semba, Richard D. Chang, Sandy S. Sun, Kai Cappola, Anne R. Ferrucci, Luigi Fried, Linda P. TI Serum 25-Hydroxyvitamin D and Pulmonary Function in Older Disabled Community-Dwelling Women SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; Lung function; Parathyroid hormone; Vitamin D; Women ID VITAMIN-D DEFICIENCY; 3RD NATIONAL-HEALTH; RANDOMIZED CONTROLLED-TRIALS; NUTRITION EXAMINATION SURVEY; LUNG-FUNCTION; D SUPPLEMENTATION; PHYSICAL PERFORMANCE; MUSCLE STRENGTH; METAANALYSIS; ASSOCIATION AB Recent studies have expanded the functions of vitamin D to a possible role in pulmonary function. Our objective was to examine the relationship between serum 25-hydroxyvitamin D (25[OH]D), serum parathyroid hormone, and pulmonary function in older women. We examined the relationship of serum 25(OH)D and parathyroid hormone with pulmonary function (forced expiratory volume in one second [FEV1], forced vital capacity [FVC], and FEV1/FVC ratio) in a cross-sectional study of 646 moderately to severely disabled women, 65 years or more, living in the community in Baltimore, Maryland, who participated in the Women's Health and Aging Study I. Overall, median (25th, 75th percentile) serum 25-hydroxyvitamin D concentrations were 19.9 (14.7, 26.7) ng/mL. Serum 25(OH)D was positively associated with FEV1 (p = .03), FVC (p = .18), and FEV1/FVC (p = .04) in multivariable linear regression models adjusting for age, race, education, smoking, height, physical activity, cognition, interleukin-6, chronic diseases, and other potential confounders. In the same models, serum parathyroid hormone was not significantly associated with FEV1, FVC, or FEV1/FVC. These findings support the idea that vitamin D deficiency is independently associated with poor pulmonary function in older disabled women. C1 [Semba, Richard D.; Sun, Kai] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21287 USA. [Chang, Sandy S.] Yale Univ, Sch Med, Dept Internal Med, Sect Geriatr, New Haven, CT 06510 USA. [Cappola, Anne R.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Smith Bldg,M015,400 N Broadway, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu FU NIA NIH HHS [R01 AG027012, R37 AG019905] NR 43 TC 1 Z9 1 U1 2 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUN PY 2012 VL 67 IS 6 BP 683 EP 689 DI 10.1093/gerona/glr213 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 942OM UT WOS:000304054700014 PM 22156439 ER PT J AU Yewdell, JW Lu, XJ AF Yewdell, Jonathan W. Lu, Xiuju TI Don't mess with ERAAP! SO NATURE IMMUNOLOGY LA English DT Editorial Material ID CLASS IB MOLECULES; ENDOPLASMIC-RETICULUM; HLA-E; AMINOPEPTIDASE; PEPTIDES; ERAP1; EXPRESSION; QA-1 C1 [Yewdell, Jonathan W.; Lu, Xiuju] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@nih.gov FU Intramural NIH HHS [ZIA AI000542-25] NR 17 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2012 VL 13 IS 6 BP 526 EP 528 DI 10.1038/ni.2306 PG 4 WC Immunology SC Immunology GA 944LO UT WOS:000304203900004 PM 22610241 ER PT J AU Pobezinsky, LA Angelov, GS Tai, XG Jeurling, S Van Laethem, F Feigenbaum, L Park, JH Singer, A AF Pobezinsky, Leonid A. Angelov, Georgi S. Tai, Xuguang Jeurling, Susanna Van Laethem, Francois Feigenbaum, Lionel Park, Jung-Hyun Singer, Alfred TI Clonal deletion and the fate of autoreactive thymocytes that survive negative selection SO NATURE IMMUNOLOGY LA English DT Article ID DOUBLE-POSITIVE THYMOCYTES; T-CELL DIFFERENTIATION; CD28 COSTIMULATION; INTRAEPITHELIAL LYMPHOCYTES; CD4(+)CD8(+) THYMOCYTES; CENTRAL TOLERANCE; RUNX PROTEINS; THYMUS; EXPRESSION; APOPTOSIS AB Clonal deletion of autoreactive thymocytes is important for self-tolerance, but the intrathymic signals that induce clonal deletion have not been clearly identified. We now report that clonal deletion during negative selection required CD28-mediated costimulation of autoreactive thymocytes at the CD4(+)CD8(lo) intermediate stage of differentiation. Autoreactive thymocytes were prevented from undergoing clonal deletion by either a lack of CD28 costimulation or transgenic overexpression of the antiapoptotic factors Bcl-2 or Mcl-1, with surviving thymocytes differentiating into anergic CD4(-)CD8(-) double-negative thymocytes positive for the T cell antigen receptor alpha beta subtype (TCR alpha beta) that 'preferentially' migrated to the intestine, where they re-expressed CD8 alpha and were sequestered as CD8 alpha alpha(+) intraepithelial lymphocytes (IELs). Our study identifies costimulation by CD28 as the intrathymic signal required for clonal deletion and identifies CD8 alpha alpha(+) IELs as the developmental fate of autoreactive thymocytes that survive negative selection. C1 [Pobezinsky, Leonid A.; Tai, Xuguang; Jeurling, Susanna; Van Laethem, Francois; Park, Jung-Hyun; Singer, Alfred] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Angelov, Georgi S.] Univ Lausanne, Ludwig Ctr Canc Res, CH-1066 Epalinges, Switzerland. [Feigenbaum, Lionel] NCI, Sci Applicat Int Corp Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM singera@nih.gov RI Park, Jung Hyun /B-5712-2015 OI Park, Jung Hyun /0000-0002-9547-9055 FU National Cancer Institute Center for Cancer Research of the US National Institutes of Health FX We thank N. Taylor, J. DiSanto and R. Hodes for critical reading of the manuscript; A. Sharpe (Harvard University) for B7-deficient mice, T. Honjo (Kyoto University) for PD-1-deficient mice; D. Littman (New York University) for Runx3-YFP reporter mice; and S. Sharrow, A. Adams and L. Granger for flow cytometry. Supported by the Intramural Research Program of the National Cancer Institute Center for Cancer Research of the US National Institutes of Health. NR 50 TC 52 Z9 53 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2012 VL 13 IS 6 BP 569 EP + DI 10.1038/ni.2292 PG 11 WC Immunology SC Immunology GA 944LO UT WOS:000304203900011 PM 22544394 ER PT J AU Takahashi, H Kanno, T Nakayamada, S Hirahara, K Sciume, G Muljo, SA Kuchen, S Casellas, R Wei, L Kanno, Y O'Shea, JJ AF Takahashi, Hayato Kanno, Tomohiko Nakayamada, Shingo Hirahara, Kiyoshi Sciume, Giuseppe Muljo, Stefan A. Kuchen, Stefan Casellas, Rafael Wei, Lai Kanno, Yuka O'Shea, John J. TI TGF-beta and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells SO NATURE IMMUNOLOGY LA English DT Article ID GERMINAL CENTER RESPONSE; ROR-GAMMA-T; IN-VIVO; INTERFERON-GAMMA; TH17 CELLS; DIFFERENTIATION; LINEAGE; GENERATION; T(H)17; ABSENCE AB Distinct CD4(+) T cell subsets are critical for host defense and immunoregulation. Although these subsets can act as terminally differentiated lineages, they have been increasingly noted to demonstrated plasticity. MicroRNAs are factors that control T cell stability and plasticity. Here we report that naturally occurring regulatory T cells (T-reg cells) had high expression of the microRNA miR-10a and that miR-10a was induced by retinoic acid and transforming growth factor-beta (TGF-beta) in inducible T-reg cells. By simultaneously targeting the transcriptional repressor Bcl-6 and the corepressor Ncor2, miR-10a attenuated the phenotypic conversion of inducible T-reg cells into follicular helper T cells. We also found that miR-10a limited differentiation into the T(H)17 subset of helper T cells and therefore represents a factor that can fine-tune the plasticity and fate of helper T cells. C1 [Takahashi, Hayato; Nakayamada, Shingo; Hirahara, Kiyoshi; Sciume, Giuseppe; Wei, Lai; Kanno, Yuka; O'Shea, John J.] Natl Inst Arthrit Musculoskeletal & Skin Dis, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Kanno, Tomohiko] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Muljo, Stefan A.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Kuchen, Stefan; Casellas, Rafael] Natl Inst Arthrit Musculoskeletal & Skin Dis, Immunogenet Mol Lab, NIH, Bethesda, MD USA. RP O'Shea, JJ (reprint author), Natl Inst Arthrit Musculoskeletal & Skin Dis, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov RI Kanno, Yuka/B-5802-2013; Wei, Lai/D-1088-2014; Muljo, Stefan/F-5671-2015; Sciume, Giuseppe/K-8985-2016; Hirahara, Kiyoshi/E-2460-2017; OI Muljo, Stefan/0000-0003-1013-446X; Sciume, Giuseppe/0000-0003-0131-512X; Hirahara, Kiyoshi/0000-0002-9128-9449; Kanno, Yuka/0000-0001-5668-9319 FU Japan Society for the Promotion of Science; Instituto Pasteur-Fondazione Cenci-Bolognetti; National Institute of Arthritis, Musculoskeletal and Skin Diseases FX We thank Y. Belkaid, W. Chen and A. Villarino for reading this manuscript; K. Moro and T. Tamachi for advice on manipulating Peyer's patches; L. Naldini (San Raffaele Institute) for the LV-SFFV lentiviral vector; and J. Simone and J. Lay for cell sorting. Supported by the Japan Society for the Promotion of Science (Research Fellowship for Japanese Biomedical and Behavioral Researchers at the US National Institutes of Health to H. T. and K. H.), the Instituto Pasteur-Fondazione Cenci-Bolognetti (G. S.) and the Intramural Research Program of the National Institute of Arthritis, Musculoskeletal and Skin Diseases. NR 54 TC 115 Z9 132 U1 1 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2012 VL 13 IS 6 BP 587 EP + DI 10.1038/ni.2286 PG 11 WC Immunology SC Immunology GA 944LO UT WOS:000304203900013 PM 22544395 ER PT J AU Grover, M Bernard, CE Pasricha, PJ Lurken, MS Faussone-Pellegrini, MS Smyrk, TC Parkman, HP Abell, TL Snape, WJ Hasler, WL Mccallum, RW Nguyen, L Koch, KL Calles, J Lee, L Tonascia, J Unalp-Arida, A Hamilton, FA Farrugia, G AF Grover, M. Bernard, C. E. Pasricha, P. J. Lurken, M. S. Faussone-Pellegrini, M. S. Smyrk, T. C. Parkman, H. P. Abell, T. L. Snape, W. J. Hasler, W. L. Mccallum, R. W. Nguyen, L. Koch, K. L. Calles, J. Lee, L. Tonascia, J. Uenalp-Arida, A. Hamilton, F. A. Farrugia, G. CA NIDDK Gastroparesis Clinical Res TI Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Article DE clinical symptoms; enteric nervous system; gastric emptying; gastroparesis; interstitial cells of Cajal; macrophages ID NITRIC-OXIDE SYNTHASE; GASTRIC-EMPTYING SCINTIGRAPHY; ENTERIC NERVOUS-SYSTEM; INTERSTITIAL-CELLS; DIABETIC GASTROPARESIS; PATHOLOGICAL FINDINGS; FUNCTIONAL DYSPEPSIA; CAJAL; SYMPTOMS; MELLITUS AB Background Cellular changes associated with diabetic (DG) and idiopathic gastroparesis (IG) have recently been described from patients enrolled in the Gastroparesis Clinical Research Consortium. The association of these cellular changes with gastroparesis symptoms and gastric emptying is unknown. The aim of this study was to relate cellular changes to symptoms and gastric emptying in patients with gastroparesis. Methods Earlier, using full thickness gastric body biopsies from 20 DG, 20 IG, and 20 matched controls, we found decreased interstitial cells of Cajal (ICC) and enteric nerves and an increase in immune cells in both DG and IG. Here, demographic, symptoms [gastroparesis cardinal symptom index score (GCSI)], and gastric emptying were related to cellular alterations using Pearsons correlation coefficients. Key Results Interstitial cells of Cajal counts inversely correlated with 4 h gastric retention in DG but not in IG (r = -0.6, P = 0.008, DG, r = 0.2, P = 0.4, IG). There was also a significant correlation between loss of ICC and enteric nerves in DG but not in IG (r = 0.5, P = 0.03 for DG, r = 0.3, P = 0.16, IG). Idiopathic gastroparesis with a myenteric immune infiltrate scored higher on the average GCSI (3.6 +/- 0.7 vs 2.7 +/- 0.9, P = 0.05) and nausea score (3.8 +/- 0.9 vs 2.6 +/- 1.0, P = 0.02) as compared to those without an infiltrate. Conclusions & Inferences In DG, loss of ICC is associated with delayed gastric emptying. Interstitial cells of Cajal or enteric nerve loss did not correlate with symptom severity. Overall clinical severity and nausea in IG is associated with a myenteric immune infiltrate. Thus, full thickness gastric biopsies can help define specific cellular abnormalities in gastroparesis, some of which are associated with physiological and clinical characteristics of gastroparesis. C1 [Grover, M.; Bernard, C. E.; Lurken, M. S.; Smyrk, T. C.; Farrugia, G.] Mayo Clin, Rochester, MN 55905 USA. [Pasricha, P. J.; Nguyen, L.] Stanford Univ, Palo Alto, CA 94304 USA. [Faussone-Pellegrini, M. S.] Univ Florence, Florence, Italy. [Parkman, H. P.] Temple Univ, Philadelphia, PA 19122 USA. [Abell, T. L.] Univ Mississippi, Jackson, MS 39216 USA. [Snape, W. J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Hasler, W. L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Mccallum, R. W.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79409 USA. [Koch, K. L.; Calles, J.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Lee, L.; Tonascia, J.; Uenalp-Arida, A.] Johns Hopkins Univ, Baltimore, MD USA. [Hamilton, F. A.] NIDDKD, Bethesda, MD 20892 USA. RP Farrugia, G (reprint author), Mayo Clin, 200 1st St SW, Rochester, MN 55905 USA. EM farrugia.gianrico@mayo.edu RI Vaughn, Ivana/B-6138-2016 OI Vaughn, Ivana/0000-0002-7201-0289 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008]; NIDDK [DK57061, DK84567, PO1 DK68055] FX The Gastroparesis Clinical Research Consortium (GpCRC) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008). This work was also supported by NIDDK DK57061, DK84567, and PO1 DK68055. NR 42 TC 49 Z9 52 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD JUN PY 2012 VL 24 IS 6 BP 531 EP + DI 10.1111/j.1365-2982.2012.01894.x PG 10 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 941VT UT WOS:000303995700006 PM 22339929 ER PT J AU Luis, AD Douglass, RJ Hudson, PJ Mills, JN Bjornstad, ON AF Luis, Angela D. Douglass, Richard J. Hudson, Peter J. Mills, James N. Bjornstad, Ottar N. TI Sin Nombre hantavirus decreases survival of male deer mice SO OECOLOGIA LA English DT Article DE Sin Nombre virus; Hantavirus; Peromyscus; Critical host density; Mark-capture-recapture; Disease-induced mortality ID MOUSE PEROMYSCUS-MANICULATUS; POPULATION-DYNAMICS; VIRUS-INFECTION; ELEVATED TESTOSTERONE; MATERNAL ANTIBODIES; LONG-TERM; TRANSMISSION; MONTANA; HOST; PARASITES AB How pathogens affect their hosts is a key question in infectious disease ecology, and it can have important influences on the spread and persistence of the pathogen. Sin Nombre virus (SNV) is the etiological agent of hantavirus pulmonary syndrome (HPS) in humans. A better understanding of SNV in its reservoir host, the deer mouse, could lead to improved predictions of the circulation and persistence of the virus in the mouse reservoir, and could help identify the factors that lead to increased human risk of HPS. Using mark-recapture statistical modeling on longitudinal data collected over 15 years, we found a 13.4% decrease in the survival of male deer mice with antibodies to SNV compared to uninfected mice (both male and female). There was also an additive effect of breeding condition, with a 21.3% decrease in survival for infected mice in breeding condition compared to uninfected, non-breeding mice. The data identified that transmission was consistent with density-dependent transmission, implying that there may be a critical host density below which SNV cannot persist. The notion of a critical host density coupled with the previously overlooked disease-induced mortality reported here contribute to a better understanding of why SNV often goes extinct locally and only seems to persist at the metapopulation scale, and why human spillover is episodic and hard to predict. C1 [Luis, Angela D.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. [Luis, Angela D.; Hudson, Peter J.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Luis, Angela D.; Bjornstad, Ottar N.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Douglass, Richard J.] Univ Montana, Montana Tech, Dept Biol, Butte, MT USA. [Mills, James N.] Ctr Dis Control & Prevent, Div High Consequence Pathogens & Pathogenesis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA USA. [Bjornstad, Ottar N.] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. RP Luis, AD (reprint author), Colorado State Univ, Dept Biol, Campus Delivery 1878, Ft Collins, CO 80523 USA. EM Angela.Luis@colostate.edu RI Bjornstad, Ottar/I-4518-2012 FU Pennsylvania State University; National Institute of Health (NIH) from the INBRE-BRIN [P20RR16455-05]; US Centers for Disease Control and Prevention, Atlanta, GA [US3/CCU813599]; Research and Policy for Infectious Disease Dynamics (RAPIDD) of the Science and Technology Directorate (Department of Homeland Security); Fogarty International Center (NIH) FX We thank Dave Cameron and Dana Ranch Inc. and the Confederated Salish and Kootenai Tribes at Polson for unlimited access to their properties. S. Carver, K. Hughes, K Coffin, B. Lonner, D. Waltee, R. Van Horn, W. Semmens, and T. Wilson provided valuable assistance in the field. S. Zanto provided serologic testing at the Montana State Department of Public Health and Human Services Laboratory; P. Rollin and A. Comer arranged serologic testing at the Special Pathogens Branch Laboratory, US Centers for Disease Control and Prevention. ADL was supported in part by the Academic Computing Fellowship of the Pennsylvania State University. Financial support was provided by the National Institute of Health (NIH) grant # P20RR16455-05 from the INBRE-BRIN program and the US Centers for Disease Control and Prevention, Atlanta, GA, through cooperative agreement # US3/CCU813599, and the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate (Department of Homeland Security) and the Fogarty International Center (NIH). NR 50 TC 17 Z9 17 U1 3 U2 43 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0029-8549 J9 OECOLOGIA JI Oecologia PD JUN PY 2012 VL 169 IS 2 BP 431 EP 439 DI 10.1007/s00442-011-2219-2 PG 9 WC Ecology SC Environmental Sciences & Ecology GA 943ZJ UT WOS:000304166600014 PM 22218940 ER PT J AU Barbour, KE Zmuda, JM Boudreau, R Strotmeyer, ES Horwitz, MJ Evans, RW Kanaya, AM Harris, TB Cauley, JA AF Barbour, K. E. Zmuda, J. M. Boudreau, R. Strotmeyer, E. S. Horwitz, M. J. Evans, R. W. Kanaya, A. M. Harris, T. B. Cauley, J. A. TI The effects of adiponectin and leptin on changes in bone mineral density SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Adiponectin; BMD change; Hip aBMD; Leptin; Trabecular lumbar spine vBMD; Whole-body aBMD ID TYPE-2 DIABETES-MELLITUS; SERUM LEPTIN; ELDERLY-MEN; POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; INSULIN-RESISTANCE; HUMAN OSTEOBLASTS; OLDER WOMEN; PREDICTOR; GHRELIN AB We tested the hypothesis that low leptin and high adiponectin levels are associated with higher rates of bone mineral density (BMD) loss among 3,075 men and women, aged 70-79, from the Health Aging and Body Composition Study. Results suggest that adiponectin, but not leptin, is a risk factor for bone loss in women. Adiponectin and leptin are hormones secreted by adipose cells that may impact BMD. Few studies have evaluated the longitudinal association of leptin and adiponectin levels with rates of BMD change. Hip and whole-body areal BMD (aBMD) were measured five times using dual-energy X-ray absorptiometry over 10 years (average follow-up time, 7.95 +/- 1.92 years). Trabecular lumbar spine volumetric BMD (vBMD) was measured using quantitative computed topography at baseline and year 6 in the Pittsburgh cohort only. Random slope and intercept models were used to account for within person correlation as a result of repeated measures of hip and whole-body aBMD. Linear regression was used to model changes in spine trabecular vBMD. Among women, the annualized rate of hip aBMD loss in the highest tertile of adiponectin was -0.67% (95% CI -0.77, -0.58) compared to [-0.43% (95% CI -0.51, -0.35)] in the lowest tertile ( trend = 0.019) after adjusting for age, race, BMI, diabetes, baseline hip aBMD, and weight change. In men, hip aBMD loss was greatest in the high adiponectin group (tertile 3), however this association was not significant ( trend = 0.148). After adjusting for weight change in women, the association between higher leptin and lower hip aBMD loss was attenuated and no longer significant ( trend = 0.134). Leptin and adiponectin levels were not associated with whole-body aBMD or trabecular lumbar spine vBMD loss. Adiponectin was associated with increased hip aBMD loss in women only, supporting evidence that adiponectin may have an important role in bone health. C1 [Barbour, K. E.] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15213 USA. [Barbour, K. E.; Zmuda, J. M.; Boudreau, R.; Strotmeyer, E. S.; Evans, R. W.; Cauley, J. A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Horwitz, M. J.] Univ Pittsburgh, Sch Med, Div Endocrinol & Metab, Pittsburgh, PA 15213 USA. [Kanaya, A. M.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Barbour, KE (reprint author), Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, 130 N Bellefield Ave, Pittsburgh, PA 15213 USA. EM barbourk@edc.pitt.edu; zmudaj@edc.pitt.edu; boudreaur@edc.pitt.edu; strotmeyere@edc.pitt.edu; HorwMx@UPMC.EDU; evansr@edc.pitt.edu; alka.kanaya@ucsf.edu; harrist@gw.nia.nih.gov; jcauley@edc.pitt.edu RI Strotmeyer, Elsa/F-3015-2014; OI Strotmeyer, Elsa/0000-0002-4093-6036; Boudreau, Robert/0000-0003-0162-5187; Cauley, Jane A/0000-0003-0752-4408 FU Health Aging and Body Composition Study (Health ABC) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; NIH, National Institute on Aging FX The Health Aging and Body Composition Study (Health ABC) includes the contract numbers: N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, and R01-AG028050. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 39 TC 20 Z9 22 U1 1 U2 8 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD JUN PY 2012 VL 23 IS 6 BP 1699 EP 1710 DI 10.1007/s00198-011-1768-x PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 943ZN UT WOS:000304167300007 PM 21877199 ER PT J AU Ledet, EM Sartor, O Rayford, W Bailey-Wilson, JE Mandal, DM AF Ledet, Elisa M. Sartor, Oliver Rayford, Walter Bailey-Wilson, Joan E. Mandal, Diptasri M. TI Suggestive evidence of linkage identified at chromosomes 12q24 and 2p16 in African American prostate cancer families from louisiana SO PROSTATE LA English DT Article DE cancer; prostate; linkage; African American; Louisiana ID GENOME-WIDE LINKAGE; GERMLINE MUTATIONS; INTERNATIONAL CONSORTIUM; SUSCEPTIBILITY LOCUS; COMPLEX TRAITS; BRCA2 MUTATION; RISK VARIANTS; GENE; 8Q24; CONFIRMATION AB BACKGROUND In the United States, incidence of prostate cancer in African American men is more than twice than that of any other race. Thus far, numerous disease susceptibility loci have been identified for this cancer but definite locus-specific information is not yet established due to the tremendous amount of genetic and disease heterogeneity; additionally, despite high prevalence of prostate cancer amongst African American men, this population has been under represented in genetic studies of prostate cancer. METHODS In order to identify the susceptible locus (loci) for prostate cancer in African Americans, we have performed linkage analyses on members of 15 large high-risk families. Specifically, these families were recruited from Louisiana and represent a uniquely admixed African American population exclusive to Southern Louisiana. In addition to geographical constraints, these families were clinically homogeneous creating a well-characterized collection of large pedigrees. The families were genotyped with Illumina Infinium II SNP HumanLinkage-12 panel and extensive demographic and clinical information was documented from the hospital pathological reports and family interviews. RESULTS We identified two novel regions, 12q24 and 2p16, with suggestive evidence of linkage under the dominant model of inheritance. CONCLUSIONS This is the first time that chromosome 12q24 (HLOD?=?2.21) and 2p16 (HLOD?=?1.97) has been shown to be associated with prostate cancer in high-risk African American families. These results provide insight to prostate cancer in an exceptional, well-characterized African American population, and illustrate the significance of utilizing large unique, but homogenous pedigrees. Prostate 72:938947, 2012. (c) 2011 Wiley Periodicals, Inc. C1 [Ledet, Elisa M.; Mandal, Diptasri M.] Louisiana State Univ, Hlth Sci Ctr, Dept Genet, New Orleans, LA 70112 USA. [Sartor, Oliver] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Sartor, Oliver] Tulane Univ, Sch Med, Dept Urol, New Orleans, LA 70112 USA. [Rayford, Walter] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Bailey-Wilson, Joan E.] NHGRI, NIH, Baltimore, MD USA. RP Mandal, DM (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Genet, 533 Bolivar St,CSRB 6-16, New Orleans, LA 70112 USA. EM dmanda@lsuhsc.edu OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU Louisiana' Board of Regents [LEQSF (2002-05)-RD-A-15, PFund-2008]; NCI [1 RO3 CA97778-01]; Cancer Research Foundation of America; Centers for Disease Control and Prevention [H57/CCH 624034-01]; Louisiana Cancer Research Consortium; Louisiana State University School of Medicine; National Human Genome Research Institute, National Institutes of Health FX Grant sponsor: Louisiana' Board of Regents; Grant numbers: LEQSF (2002-05)-RD-A-15; PFund-2008; Grant sponsor: NCI; Grant number: 1 RO3 CA97778-01; Grant sponsor: Cancer Research Foundation of America; Grant sponsor: Centers for Disease Control and Prevention; Grant number: H57/CCH 624034-01; Grant sponsor: Louisiana Cancer Research Consortium; Grant sponsor: Louisiana State University School of Medicine; Grant sponsor: Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 44 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-4137 J9 PROSTATE JI Prostate PD JUN PY 2012 VL 72 IS 9 BP 938 EP 947 DI 10.1002/pros.21496 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 940UJ UT WOS:000303918300002 PM 22615067 ER PT J AU Chokkalingam, AP Yeboah, ED DeMarzo, A Netto, G Yu, K Biritwum, RB Tettey, Y Adjei, A Jadallah, S Li, Y Chu, LW Chia, D Niwa, S Partin, A Thompson, IM Roehrborn, C Hoover, RN Hsing, AW AF Chokkalingam, A. P. Yeboah, E. D. DeMarzo, A. Netto, G. Yu, K. Biritwum, R. B. Tettey, Y. Adjei, A. Jadallah, S. Li, Y. Chu, L. W. Chia, D. Niwa, S. Partin, A. Thompson, I. M. Roehrborn, C. Hoover, R. N. Hsing, A. W. TI Prevalence of BPH and lower urinary tract symptoms in West Africans SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article DE BPH; DRE; PSA; Africa ID BENIGN PROSTATIC HYPERPLASIA; QUALITY-OF-LIFE; MEN; HEALTH; SEVERITY; AMERICAN; VOLUME; OLDER; AGE; DYSFUNCTION AB BACKGROUND: BPH and lower urinary tract symptoms (LUTS) are very common among older men in Western countries. However, the prevalence of these two conditions in the developing countries is less clear. METHODS: We assessed the age-standardized prevalence of BPH and/or LUTS among West Africans in a probability sample of 950 men aged 50-74 in Accra, Ghana, with no evidence of biopsy-confirmed prostate cancer after screening with PSA and digital rectal examination (DRE). Information on LUTS was based on self-reports of the International Prostate Symptom Score (IPSS). BPH was estimated using DRE, PSA levels and imputed prostate volume. RESULTS: The prevalence of DRE-detected enlarged prostate was 62.3%, while that of PSA >= 1.5 ng ml(-1) (an estimate of prostate volume >= 30cm(3)) was 35.3%. The prevalence of moderate-to-severe LUTS (IPSS >= 8) was 19.9%. The prevalence of IPSS >= 8 and an enlarged prostate on DRE was 13.3%. Although there is no universally agreed-upon definition of BPH/LUTS, making comparisons across populations difficult, BPH and/or LUTS appear to be quite common among older Ghanaian men. CONCLUSIONS: We found that after age standardization, the prevalence of DRE-detected enlarged prostate in Ghanaian men is higher than previously reported for American men, but the prevalence of LUTS was lower than previously reported for African Americans. Further studies are needed to confirm these findings and identify the risk factors for BPH in both Africans and African Americans. C1 [Chokkalingam, A. P.] Univ Calif Berkeley, UC Berkeley Sch Publ Hlth, Berkeley, CA 94704 USA. [Yeboah, E. D.; Biritwum, R. B.; Tettey, Y.; Adjei, A.] Univ Ghana, Sch Med, Accra, Ghana. [DeMarzo, A.; Netto, G.; Jadallah, S.; Partin, A.] Johns Hopkins Univ, Brady Urol Inst, Baltimore, MD USA. [Yu, K.; Li, Y.; Chu, L. W.; Hoover, R. N.; Hsing, A. W.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. [Chia, D.] Univ Calif Los Angeles, Rockville, MD USA. [Niwa, S.] WESTAT Corp, Rockville, MD 20850 USA. [Thompson, I. M.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Roehrborn, C.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Chokkalingam, AP (reprint author), Univ Calif Berkeley, UC Berkeley Sch Publ Hlth, 1995 Univ Ave,Suite 460, Berkeley, CA 94704 USA. EM anandc@berkeley.edu; hsinga@mail.nih.gov FU Westat; National Cancer Institute, National Institutes of Health FX We thank Ms Evelyn Tay and Ms Vicky Okyne for their expert help in coordinating the study; consultants/resident urologists, pathologists, nurses and interviewers of Korle-Bu Hospital and University of Ghana Medical School for their assistance with subject enrollment, screening and clinical examination; the study participants for their contribution toward a better understanding of prostate disease; Ms Violet Devairakkam, Ms Norma Kim and Mr John Heinrich of Research Triangle Institute (RTI) for their expert study management; and Ms Ann Truelove of Westat for study support and data management. This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 28 TC 9 Z9 9 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD JUN PY 2012 VL 15 IS 2 BP 170 EP 176 DI 10.1038/pcan.2011.43 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 942LA UT WOS:000304044300009 PM 21912428 ER PT J AU Hsu, HS Benjauthrit, V Zheng, F Chen, RM Huang, YH Zhou, QF Shung, KK AF Hsu, Hsiu-Sheng Benjauthrit, Vatcharee Zheng, Fan Chen, Rumin Huang, Yuhong Zhou, Qifa Shung, K. Kirk TI PMN-PT-PZT composite films for high frequency ultrasonic transducer applications SO SENSORS AND ACTUATORS A-PHYSICAL LA English DT Article DE PMN-PT; PZT; Composite films; Ultrasonic transducer ID THICK-FILMS; DEPOSITION AB We have successfully fabricated x(0.65PMN-0.35PT)-(1 - x)PZT (xPMN-PT-(1 - x)PZT), where x is 0.1, 0.3, 0.5, 0.7 and 0.9, thick films with a thickness of approximately 9 mu m on platinized silicon substrate by employing a composite sol-gel technique. X-ray diffraction analysis and scanning electron microscopy revealed that these films are dense and creak-free with well-crystallized perovskite phase in the whole composition range. The dielectric constant can be controllably adjusted by using different compositions. Higher PZT content of xPMN-PT-(1 - x)PZT films show better ferroelectric properties. A representative 0.9PMN-PT-0.1 PZT thick film transducer is built. It has 200 MHz center frequency with a -6 dB bandwidth of 38% (76 MHz). The measured two-way insertion loss is 65 dB. Published by Elsevier B.V. C1 [Hsu, Hsiu-Sheng; Benjauthrit, Vatcharee; Zheng, Fan; Chen, Rumin; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Hsu, Hsiu-Sheng; Benjauthrit, Vatcharee; Zheng, Fan; Chen, Rumin; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Hsu, Hsiu-Sheng] Univ So Calif, Mork Family Dept Chem Engn & Mat Sci, Los Angeles, CA 90089 USA. [Huang, Yuhong] Chemat Technol Inc, Northridge, CA 91324 USA. RP Zhou, QF (reprint author), Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu FU NIH [P41-EB218]; NSF [1026215] FX This work has been supported by NIH P41-EB218 and NSF 1026215. NR 22 TC 15 Z9 16 U1 2 U2 32 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0924-4247 J9 SENSOR ACTUAT A-PHYS JI Sens. Actuator A-Phys. PD JUN PY 2012 VL 179 BP 121 EP 124 DI 10.1016/j.sna.2012.02.031 PG 4 WC Engineering, Electrical & Electronic; Instruments & Instrumentation SC Engineering; Instruments & Instrumentation GA 942VC UT WOS:000304077100018 PM 23750072 ER PT J AU Ziadloo, A Burks, SR Gold, EM Lewis, BK Chaudhry, A Merino, MJ Frenkel, V Frank, JA AF Ziadloo, Ali Burks, Scott R. Gold, Eric M. Lewis, Bobbi K. Chaudhry, Aneeka Merino, Maria J. Frenkel, Victor Frank, Joseph A. TI Enhanced Homing Permeability and Retention of Bone Marrow Stromal Cells by Noninvasive Pulsed Focused Ultrasound SO STEM CELLS LA English DT Article DE Mesenchymal stem cells; Pulsed focused ultrasound; High-intensity focused ultrasound; Mechanotransduction; Stem cell migration; Cytokines; Enhanced homing permeability and retention; ICAM; VCAM; Integrins; Ferumoxides; Protamine ID MESENCHYMAL STEM-CELLS; IN-VIVO; ENDOTHELIAL-CELLS; SOLID TUMORS; TRANSPLANTATION; INFLAMMATION; DELIVERY; MECHANISMS; THERAPY; KIDNEY AB Bone marrow stromal cells (BMSCs) have shown significant promise in the treatment of disease, but their therapeutic efficacy is often limited by inefficient homing of systemically administered cells, which results in low number of cells accumulating at sites of pathology. BMSC home to areas of inflammation where local expression of integrins and chemokine gradients is present. We demonstrated that nondestructive pulsed focused ultrasound (pFUS) exposures that emphasize the mechanical effects of ultrasound-tissue interactions induced local and transient elevations of chemoattractants (i.e., cytokines, integrins, and growth factors) in the murine kidney. pFUS-induced upregulation of cytokines occurred through approximately 1 day post-treatment and returned to contralateral kidney levels by day 3. This window of significant increases in cytokine expression was accompanied by local increases of other trophic factors and integrins that have been shown to promote BMSC homing. When BMSCs were intravenously administered following pFUS treatment to a single kidney, enhanced homing, permeability, and retention of BMSC was observed in the treated kidney versus the contralateral kidney. Histological analysis revealed up to eight times more BMSC in the peritubular regions of the treated kidneys on days 1 and 3 post-treatment. Furthermore, cytokine levels in pFUS-treated kidneys following BMSC administration were found to be similar to controls, suggesting modulation of cytokine levels by BMSC. pFUS could potentially improve cell-based therapies as a noninvasive modality to target homing by establishing local chemoattractant gradients and increasing expression of integrins to enhance tropism of cells toward treated tissues. STEM CELLS2012;30:12161227 C1 [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Ziadloo, Ali; Burks, Scott R.; Gold, Eric M.; Lewis, Bobbi K.; Chaudhry, Aneeka; Frank, Joseph A.] NCI, Frank Lab, Ctr Clin, Bethesda, MD 20892 USA. [Ziadloo, Ali; Burks, Scott R.; Gold, Eric M.; Lewis, Bobbi K.; Chaudhry, Aneeka; Frank, Joseph A.] NCI, Lab Diagnost Radiol Res Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Frenkel, Victor] Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA. RP Frank, JA (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Room B1N256,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. EM jafrank@helix.nih.gov FU Clinical Center at the National Institutes of Health FX This work was supported by the Intramural Research Program in the Clinical Center at the National Institutes of Health. BMSCs were provided by the Center for Bone Marrow Stromal Cell Transplantation at the NIH. NR 52 TC 20 Z9 21 U1 1 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD JUN PY 2012 VL 30 IS 6 BP 1216 EP 1227 DI 10.1002/stem.1099 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 942YJ UT WOS:000304087300018 PM 22593018 ER PT J AU Himes, SK Goodwin, RS Rock, CM Jones, HE Johnson, RE Wilkins, DG Huestis, MA AF Himes, Sarah K. Goodwin, Robert S. Rock, Colleen M. Jones, Hendree E. Johnson, Rolley E. Wilkins, Diana G. Huestis, Marilyn A. TI Methadone and Metabolites in Hair of Methadone-Assisted Pregnant Women and Their Infants SO THERAPEUTIC DRUG MONITORING LA English DT Article DE methadone; EDDP; hair; in utero exposure; neonatal outcomes ID NEONATAL ABSTINENCE SYNDROME; SOLID-PHASE MICROEXTRACTION; MASS-SPECTROMETRY; MATERNAL HEROIN; HUMAN PLACENTA; BIRTH-WEIGHT; DRUGS; ABUSE; BUPRENORPHINE; MAINTENANCE AB Introduction: Methadone is the recommended pharmacotherapy for opioid-dependent pregnant women. The primary aims of this study were to determine whether a dose-concentration relationship exists between cumulative maternal methadone dose, methadone and metabolite concentrations in maternal hair during pregnancy and whether maternal hair methadone and metabolite concentrations predict neonatal outcomes. Materials and Methods: Hair specimens were collected monthly from opioid-dependent mothers enrolled in methadone treatment and 4 of their infants. Hair specimens were segmented (3 cm), washed (maternal hair only), and analyzed for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), and 2-ethyl-5-methyl-3,3-diphenylpyrroline by liquid chromatography tandem mass spectrometry. Results: There was large intersubject variability and no dose-concentration relationship for cumulative methadone dose and methadone, EDDP, 2-ethyl-5-methyl-3,3-diphenylpyrroline, or total concentrations in hair. For individual women, a positive trend was noted for cumulative methadone dose and methadone and EDDP concentrations in hair. There was a positive linear trend for cumulative methadone dose and EDDP/methadone ratio in maternal hair, perhaps reflecting methadone's induction of its own metabolism. Maternal methadone concentrations were higher than those in infant hair, and infant EDDP hair concentrations were higher than those in maternal hair. Maternal methadone dose, and methadone and EDDP hair concentrations were not correlated with peak infant neonatal abstinence syndrome (NAS) scores, days to peak NAS, duration of NAS, time to NAS onset, birth length, head circumference, or amount of neonatal morphine pharmacotherapy. Maternal cumulative third trimester methadone dose was positively correlated with infant birth weight. Conclusions: Methadone and EDDP in pregnant women's hair are markers of methadone exposure and do not predict total methadone dose, nor neonatal outcomes from in utero methadone exposure. C1 [Himes, Sarah K.; Goodwin, Robert S.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Rock, Colleen M.; Wilkins, Diana G.] Univ Utah, Dept Pharmacol & Toxicol, Ctr Human Toxicol, Salt Lake City, UT 84112 USA. [Jones, Hendree E.] RTI Int, Subst Abuse Treatment Evaluat & Intervent, Res Triangle Pk, NC USA. [Jones, Hendree E.; Johnson, Rolley E.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Johnson, Rolley E.] Reckitt Benckiser Pharmaceut Inc, Richmond, VA USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse (NIDA) [DA 12220, DA 12403, DA 09096]; General Clinical Research Centers of the National Center for Research Resources of the National Institutes of Health [M01RR-02719]; National Institutes of Health at NIDA FX Supported by grants DA 12220, DA 12403, and DA 09096 from the National Institute on Drug Abuse (NIDA) and M01RR-02719 from the General Clinical Research Centers of the National Center for Research Resources of the National Institutes of Health and by the National Institutes of Health Intramural Research Program at NIDA. NR 51 TC 7 Z9 7 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD JUN PY 2012 VL 34 IS 3 BP 337 EP 344 DI 10.1097/FTD.0b013e3182512b26 PG 8 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 942LU UT WOS:000304046300016 PM 22495425 ER PT J AU Hoffert, JD Pisitkun, T Miller, RL AF Hoffert, Jason D. Pisitkun, Trairak Miller, R. Lance TI Conditional Allele Mouse Planner (CAMP): software to facilitate the planning and design of breeding strategies involving mice with conditional alleles SO TRANSGENIC RESEARCH LA English DT Article DE Transgenics; Conditional knockout; Cre; Floxed; Frt; Flp; Gfp; Tet; Java program; Software ID COLONY MANAGEMENT; PHENOTYPE DATA AB Transgenic and conditional knockout mouse models play an important role in biomedical research and their use has grown exponentially in the last 5-10 years. Generating conditional knockouts often requires breeding multiple alleles onto the background of a single mouse or group of mice. Breeding these mice depends on parental genotype, litter size, transmission frequency, and the number of breeding rounds. Therefore, a well planned breeding strategy is critical for keeping costs to a minimum. However, designing a viable breeding strategy can be challenging. With so many different variables this would be an ideal task for a computer program. To facilitate this process, we created a Java-based program called Conditional Allele Mouse Planner (CAMP). CAMP is designed to provide an estimate of the number of breeders, amount of time, and costs associated with generating mice of a particular genotype. We provide a description of CAMP, how to use it, and offer it freely as an application. C1 [Hoffert, Jason D.; Pisitkun, Trairak; Miller, R. Lance] NHLBI, Epithelial Syst Biol Grp, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. RP Miller, RL (reprint author), NHLBI, Epithelial Syst Biol Grp, Epithelial Syst Biol Lab, NIH, Bldg 10,6N312, Bethesda, MD 20892 USA. EM Lance.miller@nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271 NR 4 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 J9 TRANSGENIC RES JI Transgenic Res. PD JUN PY 2012 VL 21 IS 3 BP 665 EP 669 DI 10.1007/s11248-011-9545-3 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 943CF UT WOS:000304097400018 PM 21870117 ER PT J AU Nilubol, N Weinstein, L Simonds, WF Jensen, RT Phan, GQ Hughes, MS Libutti, SK Marx, S Kebebew, E AF Nilubol, Naris Weinstein, Lee Simonds, William F. Jensen, Robert T. Phan, Giao Q. Hughes, Marybeth S. Libutti, Steven K. Marx, Stephen Kebebew, Electron TI Preoperative Localizing Studies for Initial Parathyroidectomy in MEN1 Syndrome: Is There Any Benefit? SO WORLD JOURNAL OF SURGERY LA English DT Article ID ENDOCRINE-NEOPLASIA TYPE-1; PRIMARY HYPERPARATHYROIDISM; SUBTOTAL PARATHYROIDECTOMY; SECONDARY HYPERPARATHYROIDISM; RENAL HYPERPARATHYROIDISM; SURGICAL-MANAGEMENT; SESTAMIBI SCAN; IMAGING TESTS; FOLLOW-UP; GLANDS AB The objective of the present study was to evaluate the utility of preoperative localizing studies in patients with MEN1 undergoing initial bilateral neck exploration (BNE) and parathyroidectomy for pHPT. We performed a retrospective analysis of patients diagnosed with MEN1 who underwent initial parathyroidectomy between December 1993 and December 2010. Results of preoperative localizing studies were compared with intraoperative findings and outcome. Sixty patients with MEN1 (32 females and 28 males) underwent initial subtotal parathyroidectomy. The median age at the time of surgery was 33 years (range: 13-78 years). Fifty-three patients had one or more positive localizing study results. Neck ultrasonography, sestamibi scan, parathyroid protocol computed tomography scan, and neck and mediastinum magnetic resonance imaging were performed in 93, 91, 32, and 19% of patients, respectively. Fifty-three patients (88%) had cervical thymectomy. Twenty patients had 24 ectopic parathyroid glands; 18 glands were in the thymus (75%). Preoperative localizing studies identified 9 of 24 ectopic parathyroid glands (38%), including 4 ectopic glands outside the thymus in 4 patients (7%); 3 were detected by ultrasonography. There were no supernumerary glands identified on preoperative localizing studies. In patients with MEN1, preoperative localizing studies identified a subset of ectopic glands (38%). Preoperative localizing studies may alter the operative approach in 7% of patients. Ultrasonography can detect most ectopic parathyroid glands outside thymus. This suggests that routine preoperative localizing studies to identify ectopic and supernumerary enlarged parathyroid glands is not useful in the majority of patients with MEN1 undergoing bilateral neck exploration and subtotal parathyroidectomy with cervical thymectomy. C1 [Nilubol, Naris; Phan, Giao Q.; Hughes, Marybeth S.; Kebebew, Electron] NCI, Endocrine Oncol Sect, Surg Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Weinstein, Lee; Simonds, William F.; Marx, Stephen] NIDDK, Metab Dis Branch, NIH, Bethesda, MD USA. [Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD USA. [Libutti, Steven K.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Surg, Bronx, NY 10467 USA. RP Nilubol, N (reprint author), NCI, Endocrine Oncol Sect, Surg Branch, Ctr Canc Res,NIH, 10 Ctr Dr,MSC1201,Rm 3-3940, Bethesda, MD 20892 USA. EM niluboln@mail.nih.gov FU National Cancer Institute; Intramural Division of The National Institute of Diabetes, Digestive and Kidney Diseases, The National Institutes of Health FX This study was supported in part by (1) the Intramural Program of The Center for Cancer Research, The National Cancer Institute, and (2) the Intramural Division of The National Institute of Diabetes, Digestive and Kidney Diseases, The National Institutes of Health. The authors are grateful to Craig Cochran, R.N. (Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD) for his dedication to the service and patient care. NR 34 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 J9 WORLD J SURG JI World J.Surg. PD JUN PY 2012 VL 36 IS 6 BP 1368 EP 1374 DI 10.1007/s00268-012-1451-1 PG 7 WC Surgery SC Surgery GA 943CA UT WOS:000304096800023 PM 22350475 ER PT J AU Illei, G AF Illei, G. TI MICRORNA IN CONNECTIVE TISSUE DISEASE SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Illei, G.] Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome Clin, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2012 VL 71 SU 3 BP 14 EP 14 PG 1 WC Rheumatology SC Rheumatology GA V31QQ UT WOS:000208898500056 ER PT J AU Goldbach-Mansky, R AF Goldbach-Mansky, R. TI NEW GENES IN AUTOINFLAMMATION ... PROVIDE NEW INSIGHTS INTO DISEASE PATHOGENESIS BEYOND IL-1 SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Goldbach-Mansky, R.] Natl Inst Arthrit Musculoskeletal & Skin Dis NIAM, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2012 VL 71 SU 3 BP 38 EP 38 PG 1 WC Rheumatology SC Rheumatology GA V31QQ UT WOS:000208898500156 ER PT J AU Aksentijevich, I Zhou, Q Lee, GS Katan, M Datta, S Milner, J Khan, J Kastner, DL AF Aksentijevich, I. Zhou, Q. Lee, G. -S. Katan, M. Datta, S. Milner, J. Khan, J. Kastner, D. L. TI EXOME SEQUENCING IDENTIFIES A HYPERMORPHIC MISSENSE MUTATION IN THE PLCG2 GENE AS THE CAUSE OF A DOMINANTLY INHERITED AUTOINFLAMMATORY DISEASE WITH IMMUNODEFICIENCY SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Aksentijevich, I.; Zhou, Q.; Lee, G. -S.; Kastner, D. L.] NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA. [Katan, M.] UCL, Dept Struct & Mol Biol, London, England. [Datta, S.; Milner, J.] NIAID, Lab Allerg Dis, Bethesda, MD 20892 USA. [Khan, J.] NCI, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2012 VL 71 SU 3 BP 113 EP 114 PG 2 WC Rheumatology SC Rheumatology GA V31QQ UT WOS:000208898500379 ER PT J AU Austermann, J Fassl, S Holzinger, D Chae, JJ Tilmann, K Keitzer, R Roth, J Foell, D Wittkowski, H AF Austermann, J. Fassl, S. Holzinger, D. Chae, J. J. Tilmann, K. Keitzer, R. Roth, J. Foell, D. Wittkowski, H. TI THE PATHOPHYSIOLOGY OF S100A8/A9 IN FAMILIAL MEDITERRANEAN FEVER (FMF) SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Austermann, J.; Fassl, S.; Holzinger, D.; Roth, J.; Foell, D.; Wittkowski, H.] Univ Munster, Inst Immunol, Munster, Germany. [Chae, J. J.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Tilmann, K.; Keitzer, R.] Charite, Berlin, Germany. NR 3 TC 0 Z9 0 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2012 VL 71 SU 3 BP 144 EP 144 PG 1 WC Rheumatology SC Rheumatology GA V31QQ UT WOS:000208898500466 ER PT J AU Tjarnlund, A Rider, L Miller, F Werth, VP Lundberg, IE AF Tjarnlund, A. Rider, L. Miller, F. Werth, V. P. Lundberg, I. E. CA Int Myositis Classification Criter TI ETHNIC BUT NOT GENDER DIFFERENCES IN DISEASE MANIFESTATIONS IN DERMATOMYOSITIS PATIENTS SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Tjarnlund, A.; Lundberg, I. E.] Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Solna, Sweden. [Tjarnlund, A.; Lundberg, I. E.] Karolinska Inst, Stockholm, Sweden. [Rider, L.; Miller, F.] NIEHS, Environm Autoimmun Grp, Program Clin Res, NIH, Bethesda, MD USA. [Werth, V. P.] Philadelphia VAMC, Dept Dermatol, Philadelphia, PA USA. [Werth, V. P.] Hosp Univ Penn, Philadelphia, PA 19104 USA. OI Miller, Frederick/0000-0003-2831-9593; Rider, Lisa/0000-0002-6912-2458 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2012 VL 71 SU 3 BP 236 EP 236 PG 1 WC Rheumatology SC Rheumatology GA V31QQ UT WOS:000208898501175 ER PT J AU Zimmer, C Moll, M Rieber, N Goldbach-Mansky, R Aksentijevich, I Kuemmerle-Deschner, J AF Zimmer, C. Moll, M. Rieber, N. Goldbach-Mansky, R. Aksentijevich, I. Kuemmerle-Deschner, J. TI IL-1 INHIBITION IN A PATIENT WITH POLYMORPHISM IN THE INTERLEUKIN 1-RECEPTOR TYPE 1 GENE AND CLINICAL PHENOTYPE OF CRMO/DIRA SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Zimmer, C.] OSK Childrens Hosp, Ravensburg, Germany. [Zimmer, C.; Moll, M.; Rieber, N.; Kuemmerle-Deschner, J.] Univ Childrens Hosp, Dept Pediat Rheumatol, Tubingen, Germany. [Goldbach-Mansky, R.] NIAMSD, Bethesda, MD 20892 USA. [Aksentijevich, I.] Natl Human Res Genome Inst, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2012 VL 71 SU 3 BP 257 EP 257 PG 1 WC Rheumatology SC Rheumatology GA V31QQ UT WOS:000208898501233 ER PT J AU Efthimiou, P Petryna, O Mehta, B Kontzias, A Cush, J AF Efthimiou, P. Petryna, O. Mehta, B. Kontzias, A. Cush, J. TI SUCCESSFUL USE OF CANAKINUMAB IN ADULT-ONSET STILL'S DISEASE REFRACTORY TO SHORT ACTING IL-1 INHIBITORS SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Efthimiou, P.] Weill Cornell Med Coll, Lincoln Med & Mental Hlth Ctr, New York, NY USA. [Petryna, O.] Columbia Univ, New York, NY 10027 USA. [Mehta, B.] Lincoln Med & Mental Hlth Ctr, New York, NY USA. [Kontzias, A.] NIH, Bethesda, MD 20892 USA. [Cush, J.] Baylor Univ, Med Ctr, Dallas, TX USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2012 VL 71 SU 3 BP 291 EP 291 PG 1 WC Rheumatology SC Rheumatology GA V31QQ UT WOS:000208898501335 ER PT J AU Goldbach-Mansky, R Sibley, C Felix, SD Brewer, C King, K Zalewski, C Kim, HJ Bishop, R Chakraborty, A Colin, L Chioato, A AF Goldbach-Mansky, R. Sibley, C. Felix, S. D. Brewer, C. King, K. Zalewski, C. Kim, H. J. Bishop, R. Chakraborty, A. Colin, L. Chioato, A. TI EFFICACY AND SAFETY OF CANAKINUMAB IN PATIENTS WITH NOMID/CINCA SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Goldbach-Mansky, R.; Sibley, C.] NIAMS, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD USA. [Felix, S. D.; Colin, L.; Chioato, A.] Novartis Inst Biomed Res, Basel, Switzerland. [Brewer, C.; King, K.; Zalewski, C.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. [Kim, H. J.] Georgetown Univ Hosp, Dept Otolaryngol Head & Neck Surg, Washington, DC 20007 USA. [Bishop, R.] NEI, NIH, Bethesda, MD 20892 USA. [Chakraborty, A.] Novartis Pharmaceut, E Hanover, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2012 VL 71 SU 3 BP 291 EP 291 PG 1 WC Rheumatology SC Rheumatology GA V31QQ UT WOS:000208898501336 ER PT J AU Maksymowych, W Learch, T Lambert, R Ward, M Haroon, N Salonen, D Inman, R Weisman, M AF Maksymowych, W. Learch, T. Lambert, R. Ward, M. Haroon, N. Salonen, D. Inman, R. Weisman, M. TI THE SPARCC/SPARTAN (SPAR) REFERENCE IMAGING MODULE FOR CALIBRATION OF READERS SCORING WITH THE MSASSS: PRELIMINARY VALIDATION SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Maksymowych, W.; Lambert, R.] Univ Alberta, Edmonton, AB, Canada. [Learch, T.; Weisman, M.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Ward, M.] Niams, Bethesda, MD USA. [Salonen, D.; Inman, R.; Weisman, M.] Univ Toronto, Toronto, ON, Canada. NR 0 TC 1 Z9 1 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2012 VL 71 SU 3 BP 405 EP 406 PG 2 WC Rheumatology SC Rheumatology GA V31QQ UT WOS:000208898502162 ER PT J AU Maksymowych, W Weisman, M Lambert, R Haroon, N Inman, R Salonen, D Ward, M Learch, T AF Maksymowych, W. Weisman, M. Lambert, R. Haroon, N. Inman, R. Salonen, D. Ward, M. Learch, T. TI WHAT IS THE CONTRIBUTION OF THE ANTERO-POSTERIOR RADIOGRAPH OF THE LUMBAR SPINE TO THE ASSESSMENT OF RADIOGRAPHIC SEVERITY AND PROGRESSION USING THE MODIFIED STOKE ANKYLOSING SPONDYLITIS SPINE SCORE? SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Maksymowych, W.; Lambert, R.] Univ Alberta, Edmonton, AB, Canada. [Weisman, M.; Learch, T.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Haroon, N.; Inman, R.; Salonen, D.] Univ Toronto, Toronto, ON, Canada. [Ward, M.] Niams, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2012 VL 71 SU 3 BP 414 EP 415 PG 2 WC Rheumatology SC Rheumatology GA V31QQ UT WOS:000208898502188 ER PT J AU Gensler, LS Yoon, G Learch, TJ Ward, MM AF Gensler, L. S. Yoon, G. Learch, T. J. Ward, M. M. TI LOWER SOCIOECONOMIC STATUS AND SMOKING ARE ASSOCIATED WITH GREATER RADIOGRAPHIC DISEASE SEVERITY IN AXIAL SPONDYLOARTHRITIS SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Gensler, L. S.; Yoon, G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Learch, T. J.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Ward, M. M.] NIAMSD, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2012 VL 71 SU 3 BP 564 EP 564 PG 1 WC Rheumatology SC Rheumatology GA V31QQ UT WOS:000208898503128 ER PT J AU Bekker, LG Beyrer, C Quinn, TC AF Bekker, Linda-Gail Beyrer, Chris Quinn, Thomas C. TI Behavioral and Biomedical Combination Strategies for HIV Prevention SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID SEXUALLY-TRANSMITTED INFECTIONS; SUB-SAHARAN AFRICA; ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED-TRIAL; FEMALE SEX WORKERS; HOMOSEXUAL BISEXUAL MEN; HERPES-SIMPLEX-VIRUS; MALE CIRCUMCISION; HETEROSEXUAL TRANSMISSION AB Around 2.5 million people become infected with HIV each year. This extraordinary toll on human life and public health worldwide will only be reversed with effective prevention. What's more, in the next few years, it is likely at least, that no single prevention strategy will be sufficient to contain the spread of the disease. There is a need for combination prevention as there is for combination treatment, including biomedical, behavioral, and structural interventions. Expanded HIV prevention must be grounded in a systematic analysis of the epidemic's dynamics in local contexts. Although85% of HIV is transmitted sexually, effective combinations of prevention have been shown for people who inject drugs. Combination prevention should be based on scientifically derived evidence, with input and engagement from local communities that fosters the successful integration of care and treatment. C1 [Bekker, Linda-Gail] Univ Cape Town, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. [Bekker, Linda-Gail] Univ Cape Town, Dept Med, ZA-7925 Cape Town, South Africa. [Beyrer, Chris] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Quinn, Thomas C.] NIAID, NIH, Sect Int HIV STD Res, Bethesda, MD 20892 USA. RP Bekker, LG (reprint author), Univ Cape Town, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. EM Linda-gail.bekker@hiv-research.org.za NR 146 TC 0 Z9 0 U1 1 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD JUN PY 2012 VL 4 IS 6 AR a007435 DI 10.1101/cshperspect.a007435 PG 23 WC Cell Biology SC Cell Biology GA 995QZ UT WOS:000308028500006 ER PT J AU Lifson, JD Haigwood, NL AF Lifson, Jeffrey D. Haigwood, Nancy L. TI Lessons in Nonhuman Primate Models for AIDS Vaccine Research: From Minefields to Milestones SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CD8(+) T-CELLS; COMPLEX CLASS-I; NEUTRALIZING MONOCLONAL-ANTIBODIES; LYMPHADENOPATHY-ASSOCIATED VIRUS; PNEUMOCYSTIS-CARINII PNEUMONIA; HIV-1/SIV CHIMERIC VIRUS; HUMORAL IMMUNE-RESPONSES; NEWBORN RHESUS MACAQUES; EXPRESSING HIV ENVELOPE AB Nonhuman primate (NHP) disease models for AIDS have made important contributions to the search for effective vaccines for AIDS. Viral diversity, persistence, capacity for immune evasion, and safety considerations have limited development of conventional approaches using killed or attenuated vaccines, necessitating the development of novel approaches. Here we highlight the knowledge gained and lessons learned in testing vaccine concepts in different virus/NHP host combinations. C1 [Lifson, Jeffrey D.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. [Haigwood, Nancy L.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. [Haigwood, Nancy L.] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Beaverton, OR 97006 USA. RP Haigwood, NL (reprint author), Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. EM haigwoon@ohsu.edu FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Center for Research Resources [P51-RR000163] FX This article is dedicated to Harvey Crystal, MD, dedicated clinician and inspired teacher (J.D.L.) and to Marshall Hall Edgell, PhD, whose insight and creativity inspired two generations of scientists (N.L.H.). Preparation of this material was supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E (J.D.L.), and from the National Center for Research Resources, and under grant P51-RR000163 (N.L.H.). The authors thank Jeremy Smedley, DVM, for helpful insight and contributions to early drafts of this manuscript. NR 169 TC 31 Z9 32 U1 2 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD JUN PY 2012 VL 2 IS 6 AR a007310 DI 10.1101/cshperspect.a007310 PG 20 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 080XW UT WOS:000314278600006 PM 22675663 ER PT J AU Taveira-DaSilva, AM Moss, J AF Taveira-DaSilva, Angelo M. Moss, Joel TI Optimizing treatments for lymphangioleiomyomatosis SO EXPERT REVIEW OF RESPIRATORY MEDICINE LA English DT Article DE chylous effusions; lung function decline; lymphangioleiomyomas; lymphangioleiomyomatosis; sirolimus; tuberous sclerosis complex ID TUBEROUS SCLEROSIS COMPLEX; TUMOR-SUPPRESSOR GENE; S6 KINASE ACTIVATION; GROWTH FACTOR-D; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; LUNG-FUNCTION; CELL-GROWTH; SPORADIC LYMPHANGIOLEIOMYOMATOSIS; LYMPHATIC INVOLVEMENT; TSC2-NULL CELLS AB Lymphangioleiomyomatosis (LAM), a multisystem disease predominantly affecting premenopausal women, is associated with cystic lung destruction and lymphatic and kidney tumors. LAM results from the proliferation of a neoplastic cell that has mutations in the tuberous sclerosis complex 1 or 2 genes, leading to activation of a critical regulatory protein, mammalian target of rapamycin. In this report, we discuss the molecular mechanisms regulating LAM cell growth and report the results of therapeutic trials employing new targeted agents. At present, inhibitors of mammalian target of rapamycin such as sirolimus appear to be the most promising therapeutic agents, although drug toxicity and development of resistance are potential problems. As the pathogenesis of LAM is being further recognized, other therapeutic agents such as matrix metalloproteinase inhibitors, statins, interferon, VEGF inhibitors, chloroquine analogs and cyclin-dependent kinase inhibitors, along with sirolimus or a combination of several of these agents, may offer the best hope for effective therapy. C1 [Taveira-DaSilva, Angelo M.; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Rm 6D05,MSC 1590, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov FU Intramural Research Program, National Institutes of Health, National Heart, Lung and Blood Institute FX The authors were supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung and Blood Institute. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 106 TC 7 Z9 8 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1747-6348 EI 1747-6356 J9 EXPERT REV RESP MED JI Expert Rev. Respir. Med. PD JUN PY 2012 VL 6 IS 3 BP 267 EP 276 DI 10.1586/ERS.12.26 PG 10 WC Respiratory System SC Respiratory System GA 213LL UT WOS:000324058600011 PM 22788941 ER PT J AU Aravind, L Anantharaman, V Zhang, DP de Souza, RF Iyer, LM AF Aravind, L. Anantharaman, Vivek Zhang, Dapeng de Souza, Robson F. Iyer, Lakshminarayan M. TI Gene flow and biological conflict systems in the origin and evolution of eukaryotes SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Article DE antibiotics; biological conflict; endosymbiosis; immunity proteins; restriction-modfication; RNAi; selfish elements; toxins ID RESTRICTION-MODIFICATION SYSTEMS; REVEALS COMMON MECHANISMS; AMEBA-ASSOCIATED BACTERIA; UBIQUITIN-LIKE PROTEINS; HOST-CELL INTERACTION; COMPARATIVE GENOMICS; NATURAL-HISTORY; APICOMPLEXAN PARASITES; TRANSCRIPTION FACTORS; ALPHA-PROTEOBACTERIA AB The endosymbiotic origin of eukaryotes brought together two disparate genomes in the cell. Additionally, eukaryotic natural history has included other endosymbiotic events, phagotrophic consumption of organisms, and intimate interactions with viruses and endoparasites. These phenomena facilitated large-scale lateral gene transfer and biological conflicts. We synthesize information from nearly two decades of genomics to illustrate how the interplay between lateral gene transfer and biological conflicts has impacted the emergence of new adaptations in eukaryotes. Using apicomplexans as example, we illustrate how lateral transfer from animals has contributed to unique parasite-host interfaces comprised of adhesion- and O-linked glycosylation-related domains. Adaptations, emerging due to intense selection for diversity in the molecular participants in organismal and genomic conflicts, being dispersed by lateral transfer, were subsequently exapted for eukaryote-specific innovations. We illustrate this using examples relating to eukaryotic chromatin, RNAi and RNA-processing systems, signaling pathways, apoptosis and immunity. We highlight the major contributions from catalytic domains of bacterial toxin systems to the origin of signaling enzymes (e.g., ADP-ribosylation and small molecule messenger synthesis), mutagenic enzymes for immune receptor diversification and RNA-processing. Similarly, we discuss contributions of bacterial antibiotic/siderophore synthesis systems and intra-genomic and intra-cellular selfish elements (e.g., restriction-modification, mobile elements and lysogenic phages) in the emergence of chromatin remodeling/modifying enzymes and RNA-based regulation. We develop the concept that biological conflict systems served as evolutionary "nurseries" for innovations in the protein world, which were delivered to eukaryotes via lateral gene flow to spur key evolutionary innovations all the way from nucleogenesis to lineage-specific adaptations. C1 [Aravind, L.; Anantharaman, Vivek; Zhang, Dapeng; de Souza, Robson F.; Iyer, Lakshminarayan M.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [de Souza, Robson F.] Univ Sao Paulo, Inst Ciencias Biomed, Dept Microbiol, BR-05508 Sao Paulo, Brazil. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov FU intramural funds of the US Department of Health and Human Services (National Library of Medicine, NIH) FX The authors' research is supported by the intramural funds of the US Department of Health and Human Services (National Library of Medicine, NIH). NR 184 TC 30 Z9 30 U1 1 U2 21 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD JUN PY 2012 VL 2 AR UNSP 89 DI 10.3389/fcimb.2012.00089 PG 21 WC Immunology; Microbiology SC Immunology; Microbiology GA 221AI UT WOS:000324628800015 PM 22919680 ER PT J AU Whirledge, S Dixon, D Cidlowski, JA AF Whirledge, Shannon Dixon, Darlene Cidlowski, John A. TI Glucocorticoids Regulate Gene Expression and Repress Cellular Proliferation in Human Uterine Leiomyoma Cells SO HORMONES & CANCER LA English DT Article AB Sex hormones and growth factors have been implicated in the pathogenesis of uterine leiomyomas. The uterus is also an abundant source of the glucocorticoid receptor but its role and function have been largely ignored. Human samples of uterine leiomyomas and matched myometrium retain expression of the glucocorticoid receptor (GR) suggesting a potential role for GR in leiomyoma function. However, hormone responsive gene expression varies between normal myometrium and leiomyoma cells. We now employ genome-wide microarray studies comparing glucocorticoid and estrogen-treated human uterine leiomyoma cells to those treated with both steroids to identify the potential role of glucocorticoids in uterine leiomyoma cells. Treatment with the synthetic glucocorticoid dexamethasone (Dex) regulated 3,128 probes. Estrogen (E-2) treatment identified 2,094 probes, and in the presence of both hormones, 4,626 probes were regulated. Of the 552 probes identified, the majority of genes co-regulated by Dex, E-2, and Dex + E-2 exhibited co-downregulation. Interestingly, a small group of 17 genes displayed antagonistic regulation by Dex and E-2, where all genes in this group, Dex reversed the E-2 effect with. Ingenuity Pathway Analysis of the data identified cell growth, development, and differentiation as significant glucocorticoid regulated pathways. Flow cytometry confirmed that glucocorticoids regulated cell proliferation and significantly reduced the percentage of S-phase cells either in the presence or absence of estrogen in leiomyomas but not smooth muscle cells. Translation of our results suggest that glucocorticoids may play a significant role in regulating uterine leiomyoma gene expression and cell growth, and thus may have implications for therapeutic development of uterine leiomyoma treatment. RP Cidlowski, JA (reprint author), NIEHS, NIH, MD F3-07,POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU Intramural NIH HHS [Z01 ES090057-13, Z01 ES090057-12] NR 35 TC 14 Z9 14 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-8497 EI 1868-8500 J9 HORM CANCER-US JI Horm. Cancer PD JUN PY 2012 VL 3 IS 3 BP 79 EP 92 DI 10.1007/s12672-012-0103-0 PG 14 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 935NA UT WOS:000303524600002 PM 22311344 ER PT J AU Volkow, N AF Volkow, N. TI Addiction: From molecules to neuronal circuits SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Volkow, N.] NIDA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2012 VL 15 SU 1 MA PL-02-001 BP 1 EP 1 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V34BS UT WOS:000209062500003 ER PT J AU Zarate, C AF Zarate, C. TI Modulating the NMDA receptor complex in developing therapeutics for bipolar disorder and major depressive disorder SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Zarate, C.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2012 VL 15 SU 1 MA S-06-002 BP 9 EP 10 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V34BS UT WOS:000209062500031 ER PT J AU Cannon, D McMahon, FJ Drevets, WC AF Cannon, D. McMahon, F. J. Drevets, W. C. TI Genetic variation in Cholinergic-Muscarinic-2 Receptor gene modulates Muscarinic2-Receptor binding in vivo and accounts for reduced binding in bipolar disorder SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Cannon, D.] Natl Univ Ireland, Dept Psychiat, Galway, Ireland. [McMahon, F. J.] NIMH, Mood & Anxiety Disorders Prog, Bethesda, MD 20892 USA. [Drevets, W. C.] Univ Oklahoma, Laureate Inst Brain, Coll Med, Tulsa, OK USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2012 VL 15 SU 1 MA S-26-003 BP 31 EP 31 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V34BS UT WOS:000209062500115 ER PT J AU Singewald, N Hauschild, M Sartori, S Muigg, P Landgraf, R Hefner, K Camp, M Neumann, I Holmes, A Whittle, N AF Singewald, N. Hauschild, M. Sartori, S. Muigg, P. Landgraf, R. Hefner, K. Camp, M. Neumann, I. Holmes, A. Whittle, N. TI Rodent models of vulnerability to emotional trauma : Neural correlates and novel treatment options SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Singewald, N.] Univ Innsbruck, Dept Pharmacol & Toxico, A-6020 Innsbruck, Austria. [Hauschild, M.; Sartori, S.; Whittle, N.] Univ Innsbruck, A-6020 Innsbruck, Austria. [Landgraf, R.] MPI Psychiat, Munich, Germany. [Hefner, K.; Camp, M.; Holmes, A.] NIAAA, Rockville, MD 20852 USA. [Neumann, I.] Univ Regensburg, D-93053 Regensburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2012 VL 15 SU 1 MA S-37-003 BP 42 EP 42 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V34BS UT WOS:000209062500158 ER PT J AU Sierakowiak, A Bonito-Oliva, A Ferre, S Olson, L Carlsson, A Fisone, G Brene, S AF Sierakowiak, A. Bonito-Oliva, A. Ferre, S. Olson, L. Carlsson, A. Fisone, G. Brene, S. TI (-)-OSU6162 potentiates amphetamine-mediated effects in habituated but not in novel environments SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Sierakowiak, A.] Karolinska Inst, Dept Neurobiol, Solna, Sweden. [Bonito-Oliva, A.; Olson, L.; Fisone, G.] Karolinska Inst, Stockholm, Sweden. [Ferre, S.] NIDA, NIH, Baltimore, MD USA. [Carlsson, A.] Gothenburg Univ, Inst Neurosci & Physiol, Gothenburg, Sweden. [Brene, S.] Karalinska Inst, NVC, Stockholm, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2012 VL 15 SU 1 MA P-02-037 BP 76 EP 76 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V34BS UT WOS:000209062500283 ER PT J AU Sibley, D Free, RB Southall, N Doyle, T Roof, R Conroy, J Han, Y Javitch, J Ferrer, M AF Sibley, D. Free, R. B. Southall, N. Doyle, T. Roof, R. Conroy, J. Han, Y. Javitch, J. Ferrer, M. TI High-throughput screening for allosteric modulators of the D2 dopamine receptor SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Sibley, D.; Doyle, T.; Ferrer, M.] NIH, Bethesda, MD 20892 USA. [Free, R. B.; Roof, R.; Conroy, J.] NINDS, NIH, Bethesda, MD 20892 USA. [Southall, N.] NCGC, NIH, Bethesda, MD USA. [Han, Y.] Columbia Univ, Dept Psychiat, New York, NY USA. [Javitch, J.] NIH, Dept Psychiat, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2012 VL 15 SU 1 MA P-10-035 BP 167 EP 167 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V34BS UT WOS:000209062500614 ER PT J AU Su, TP Mori, T Hayashi, T AF Su, T. P. Mori, T. Hayashi, T. TI Compromising sigma-1 receptors at the ER renders cytotoxicity to physiologically relevant concentrations of dopamine in a NF-kB/Bcl-2-dependent mechanism : Potential relevance to Parkinson's disease SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Su, T. P.; Mori, T.; Hayashi, T.] NIDA, IRP, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2012 VL 15 SU 1 MA P-10-036 BP 168 EP 168 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V34BS UT WOS:000209062500615 ER PT J AU Tsai, SY Hayashi, T Su, TP AF Tsai, S. -Y. Hayashi, T. Su, T. -P. TI The Sigma-1 receptor chaperone plays an essential role in neural circuits SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Tsai, S. -Y.] NIH, Baltimore, MD USA. [Hayashi, T.; Su, T. -P.] NIH, Cellular Pathobiol Sect, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2012 VL 15 SU 1 MA P-10-039 BP 168 EP 168 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V34BS UT WOS:000209062500618 ER PT J AU Kiselycznyk, C Svenningsson, P Holmes, A AF Kiselycznyk, C. Svenningsson, P. Holmes, A. TI Local G1uN2B antagonism in responses to stress and anxiety- and depression-related behavior SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Kiselycznyk, C.; Holmes, A.] NIH, Rockville, MD USA. [Svenningsson, P.] Karolinska Inst, Stockholm, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2012 VL 15 SU 1 MA P-15.022 BP 205 EP 205 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V34BS UT WOS:000209062500753 ER PT J AU Moya, P Prochazkova, M Utreras, E Kulkarni, A Murphy, D AF Moya, P. Prochazkova, M. Utreras, E. Kulkarni, A. Murphy, D. TI Functional studies of altered Eaat3 expression in obsessive-compulsive disorder SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Moya, P.] NIMH, Bethesda, MD 20892 USA. [Prochazkova, M.; Utreras, E.; Kulkarni, A.] NIDCR, Bethesda, MD USA. [Murphy, D.] NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2012 VL 15 SU 1 MA P-15-029 BP 206 EP 207 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V34BS UT WOS:000209062500759 ER PT J AU Shrestha, S AF Shrestha, S. TI PET imaging of serotoninergic system in monkeys: Effects of maternal separation, and chronic fluoxetine treatment during development SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Shrestha, S.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2012 VL 15 SU 1 MA P-16-019 BP 218 EP 218 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V34BS UT WOS:000209062500797 ER PT J AU Watkins, SK Zhu, ZQ Watkins, KE Hurwitz, AA AF Watkins, Stephanie K. Zhu, Ziqiang Watkins, Keith E. Hurwitz, Arthur A. TI Isolation of Immune Cells from Primary Tumors (Retracted article. See 2016) SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article; Retracted Publication DE Cancer Biology; Issue 64; Immunology; Prostate; tumor; immune cell isolation; mouse; TRAMP; B16 melanoma; leukocyte; dendritic cell; T cell AB Tumors create a unique immunosuppressive microenvironment (tumor microenvironment, TME) whereby leukocytes are recruited into the tumor by various chemokines and growth factors (1,2). However, once in the TME, these cells lose the ability to promote anti-tumor immunity and begin to support tumor growth and down-regulate anti-tumor immune responses (3-4). Studies on tumor-associated leukocytes have mainly focused on cells isolated from tumor-draining lymph nodes or spleen due to the inherent difficulties in obtaining sufficient cell numbers and purity from the primary tumor. While identifying the mechanisms of cell activation and trafficking through the lymphatic system of tumor bearing mice is important and may give insight to the kinetics of immune responses to cancer, in our experience, many leukocytes, including dendritic cells (DCs), in tumor-draining lymph nodes have a different phenotype than those that infiltrate tumors (5,6). Furthermore, we have previously demonstrated that adoptively-transferred T cells isolated from the tumor-draining lymph nodes are not tolerized and are capable of responding to secondary stimulation in vitro unlike T cells isolated from the TME, which are tolerized and incapable of proliferation or cytokine production (7,8). Interestingly, we have shown that changing the tumor microenvironment, such as providing CD4(+) T helper cells via adoptive transfer, promotes CD8(+) T cells to maintain pro-inflammatory effector functions (5). The results from each of the previously mentioned studies demonstrate the importance of measuring cellular responses from TME-infiltrating immune cells as opposed to cells that remain in the periphery. To study the function of immune cells which infiltrate tumors using the Miltenyi Biotech isolation system(9), we have modified and optimized this antibody-based isolation procedure to obtain highly enriched populations of antigen presenting cells and tumor antigen-specific cytotoxic T lymphocytes. The protocol includes a detailed dissection of murine prostate tissue from a spontaneous prostate tumor model (TRansgenic Adenocarcinoma of the Mouse Prostate -TRAMP) (10) and a subcutaneous melanoma (B16) tumor model followed by subsequent purification of various leukocyte populations. C1 [Watkins, Stephanie K.; Zhu, Ziqiang; Hurwitz, Arthur A.] Natl Canc Inst Frederick, Tumor Immun & Tolerance Sect, Mol Immunoregulat Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. [Watkins, Keith E.] KEWB Prod, Frederick, MD USA. RP Hurwitz, AA (reprint author), Natl Canc Inst Frederick, Tumor Immun & Tolerance Sect, Mol Immunoregulat Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. EM hurwitza@mail.nih.gov FU NIH, NCI FX The authors would like to thank Dr. Scott Durham for review of the manuscript and video. This work is supported in-part by the intramural research program of the NIH, NCI. NR 10 TC 5 Z9 5 U1 1 U2 9 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD JUN PY 2012 IS 64 AR e3952 DI 10.3791/3952 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36PI UT WOS:000209223100031 PM 22733225 ER PT J AU Moore, LE Jaeger, E Nickerson, ML Brennan, P De Vries, S Roy, R Toro, J Li, H Karami, S Lenz, P Zaridze, D Janout, V Bencko, V Navratilova, M Szeszenia-Dabrowska, N Mates, D Linehan, WM Merino, M Simko, J Pfeiffer, R Boffetta, P Hewitt, S Rothman, N Chow, WH Waldman, FM AF Moore, L. E. Jaeger, E. Nickerson, M. L. Brennan, P. De Vries, S. Roy, R. Toro, J. Li, H. Karami, S. Lenz, P. Zaridze, D. Janout, V. Bencko, V. Navratilova, M. Szeszenia-Dabrowska, N. Mates, D. Linehan, W. M. Merino, M. Simko, J. Pfeiffer, R. Boffetta, P. Hewitt, S. Rothman, N. Chow, W-H Waldman, F. M. TI Genomic copy number alterations in clear cell renal carcinoma: associations with case characteristics and mechanisms of VHL gene inactivation SO ONCOGENESIS LA English DT Article DE renal cancer; epidemiology; VHL AB Array comparative genomic hybridization was used to identify copy number alterations in clear cell renal cell carcinoma (ccRCC) patient tumors to identify associations with patient/clinical characteristics. Of 763 ccRCC patients, 412 (54%) provided frozen biopsies. Clones were analyzed for significant copy number differences, adjusting for multiple comparisons and covariates in multivariate analyses. Frequent alterations included losses on: 3p (92.2%), 14q (46.8%), 8p (38.1%), 4q (35.4%), 9p (32.3%), 9q (31.8%), 6q (30.8%), 3q (29.4%), 10q (25.7%), 13q (24.5%), 1p (23.5%) and gains on 5q (60.2%), 7q (39.6%), 7p (30.6%), 5p (26.5%), 20q (25.5%), 12q (24.8%), 12p (22.8%). Stage and grade were associated with 1p, 9p, 9q, 13q and 14q loss and 12q gain. Males had more alterations compared with females, independent of stage and grade. Significant differences in the number/types of alterations were observed by family cancer history, age at diagnosis and smoking status. Von Hippel-Lindau (VHL) gene inactivation was associated with 3p loss (P 0.15). In a meta-analysis combining all five samples, the best haplotype remained significantly associated with longevity after adjustment for multiple testing in the initial and follow-up samples (OR = 1.18, P = 7.5 x 10-4, multiple-testing-adjusted P = 0.037). These results suggest that LMNA variants may play a role in human lifespan. C1 [Conneely, Karen N.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. [Capell, Brian C.; Erdos, Michael R.; Swift, Amy J.; Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Sebastiani, Paola; Solovieff, Nadia] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Baldwin, Clinton T.; Perls, Thomas T.] Boston Med Ctr, Dept Med, New England Centenarian Study, Geriatr Sect, Boston, MA 02118 USA. [Baldwin, Clinton T.; Perls, Thomas T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Budagov, Temuri; Barzilai, Nir; Atzmon, Gil] Albert Einstein Coll Med, Dept Med & Genet, Bronx, NY 10461 USA. [Puca, Annibale A.] CNR, Ist Tecnol Biomed, Segrate, Italy. [Puca, Annibale A.] Ist Ricovero Cura Carattere Scientifico Multimed, Milan, Italy. [Geesaman, Bard J.] Elixir Pharmaceut, Cambridge, MA 02139 USA. [Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. RP Conneely, KN (reprint author), 615 Michael St,Suite 301, Atlanta, GA 30322 USA. EM kconnee@emory.edu OI Perls, Thomas/0000-0002-2492-4334; Capell, Brian/0000-0002-7036-8359; sebastiani, paola/0000-0001-6419-1545 FU National Human Genome Research Institute; Glenn Award for Research in Biological Mechanisms of Aging; NIH [PO1 AG027734]; NIH/NIA Longevity Consortium [U19 AG023122]; NIH/NIA [R56 AG027216]; NIH/NHLBI [R01 HL87681-01] FX This work has been supported by the intramural program of the National Human Genome Research Institute and by grants from Glenn Award for Research in Biological Mechanisms of Aging (N.B.), the NIH PO1 AG027734 (N.B.), the NIH/NIA Longevity Consortium U19 AG023122 (G. A., T. P), the NIH/NIA R56 AG027216 (C. B.), and NIH/NHLBI R01 HL87681-01 (N.S.). We thank Drs. Gilles Thomas, Helene Blanche, and Valerie Morel for genotyping the French samples analyzed in this study and Narisu Narisu for providing technical assistance with the genotyping of the Stage 1 samples. NR 43 TC 14 Z9 15 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD JUN PY 2012 VL 11 IS 3 BP 475 EP 481 DI 10.1111/j.1474-9726.2012.00808.x PG 7 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 940RG UT WOS:000303910100013 PM 22340368 ER PT J AU Wang, MY Fu, ZM Wu, J Zhang, J Jiang, LQ Khazan, B Telljohann, R Zhao, MM Krug, AW Pikilidou, M Monticone, RE Wersto, R Van Eyk, J Lakatta, EG AF Wang, Mingyi Fu, Zongming Wu, James Zhang, Jing Jiang, Liqun Khazan, Benjamin Telljohann, Richard Zhao, Mingming Krug, Alexander W. Pikilidou, Maria Monticone, Robert E. Wersto, Robert Van Eyk, Jennifer Lakatta, Edward G. TI MFG-E8 activates proliferation of vascular smooth muscle cells via integrin signaling SO AGING CELL LA English DT Article DE MFG-E8; aging; VSMC proliferation; cell cycle; vascular remodeling ID SUBCLINICAL ARTERIAL-DISEASE; EPIDERMAL-GROWTH FACTOR-8; ANGIOTENSIN-II; MILK; RAT; MOUSE; HYPERTENSION; PROTEIN; YOUNG; AGE AB An accumulation of milk fat globule EGF-8 protein (MFG-E8) occurs within the context of arterial wall inflammatory remodeling during aging, hypertension, diabetes mellitus, or atherosclerosis. MFG-E8 induces VSMC invasion, but whether it affects VSMC proliferation, a salient feature of arterial inflammation, is unknown. Here, we show that in the rat arterial wall in vivo, PCNA and Ki67, markers of cell cycle activation, increase with age between 8 and 30 months. In fresh and early passage VSMC isolated from old aortae, an increase in CDK4 and PCNA, an increase in the acceleration of cell cycle S and G2 phases, decrease in the G1/G0 phase, and an increase in PDGF and its receptors confer elevated proliferative capacity, compared to young VSMC. Increased coexpression and physical interaction of MFG-E8 and integrin av beta 5 occur with aging in both the rat aortic wall in vivo and in VSMC in vitro. In young VSMC in vitro, MFG-E8 added exogenously, or overexpressed endogenously, triggers phosphorylation of ERK1/2, augmented levels of PCNA and CDK4, increased BrdU incorporation, and promotes proliferation, via av beta 5 integrins. MFG-E8 silencing, or its receptor inhibition, or the blockade of ERK1/2 phosphorylation in these cells reduces PCNA and CDK4 levels and decelerates the cell cycle S phase, conferring a reduction in proliferative capacity. Collectively, these results indicate that MFG-E8 in a dose-dependent manner coordinates the expression of cell cycle molecules and facilitates VSMC proliferation via integrin/ERK1/2 signaling. Thus, an increase in MFG-E8 signaling is a mechanism of the age-associated increase in aortic VSMC proliferation. C1 [Wang, Mingyi; Wu, James; Zhang, Jing; Jiang, Liqun; Khazan, Benjamin; Telljohann, Richard; Zhao, Mingming; Krug, Alexander W.; Pikilidou, Maria; Monticone, Robert E.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Fu, Zongming; Van Eyk, Jennifer] Hopkins NHLBI Prote Ctr, John Hopkins Med Sch, Div Cardiol, Baltimore, MD 21224 USA. [Wersto, Robert] NIA, Res Resource Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Wang, MY (reprint author), NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM mingyiw@grc.nia.nih.gov FU National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institute on Aging. NR 45 TC 20 Z9 22 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD JUN PY 2012 VL 11 IS 3 BP 500 EP 508 DI 10.1111/j.1474-9726.2012.00813.x PG 9 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 940RG UT WOS:000303910100016 PM 22385834 ER PT J AU Zuo, LJ Zhang, FY Zhang, HP Zhang, XY Wang, F Li, CSR Lu, LG Hong, J Lu, L Krystal, J Deng, HW Luo, XG AF Zuo, Lingjun Zhang, Fengyu Zhang, Heping Zhang, Xiang-Yang Wang, Fei Li, Chiang-Shan R. Lu, Lingeng Hong, Jiang Lu, Lin Krystal, John Deng, Hong-Wen Luo, Xingguang TI Genome-wide search for replicable risk gene regions in alcohol and nicotine co-dependence SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE GWAS; alcohol and nicotine co-dependence; risk region ID SMOKING-CESSATION; RECEPTOR GENES; ASSOCIATION; POLYMORPHISM; METAANALYSIS; SUBUNIT; LOCI; POPULATIONS; LINKAGE; CLUSTER AB The present study searched for replicable risk genomic regions for alcohol and nicotine co-dependence using a genome-wide association strategy. The data contained a total of 3,143 subjects including 818 European-American (EA) cases with alcohol and nicotine co-dependence, 1,396 EA controls, 449 African-American (AA) cases, and 480 AA controls. We performed separate genome-wide association analyses in EAs and AAs and a meta-analysis to derive combined P-values, and calculated the genome-wide false discovery rate (FDR) for each SNP. Regions with P?= 16 weeks). Results Ten patients with gastric carcinoma and 11 with adenocarcinoma of the gastroesophageal junction received a median of 2 cycles (range 1-10 cycles) of treatment per patient. 17 patients were evaluable for response. No objective response was seen. One patient experienced prolonged Stable disease (pSD). Three patients had SD and 13 progressive disease. Median overall survival was 7.8 months (95% CI, 3.9-12.2 months) and median time to progression was 1.8 months (95% CI: 1.51.9 months). Grade 3 events possibly related to saracatinib included: fatigue (2 patients), hypoxia (2) anemia (3) and lymphopenia (2). Conclusion Saracatinib has insufficient activity as a single agent in patients with advanced gastric adenocarcinoma to warrant further investigation. Further development in gastric cancer would require rational drug combinations or identification of a tumor phenotype sensitive to Src inhibition. C1 [Mackay, Helen J.; Jarvi, Andrea; MacAlpine, Katrina; Oza, Amit M.] Univ Toronto, Princess Margaret Hosp, Dept Med Oncol, Drug Dev Program, Toronto, ON M5G 2M9, Canada. [Au, Heather J.] Univ Alberta, Cross Canc Inst, Edmonton, AB, Canada. [McWhirter, Elaine] Juravinski Canc Ctr, Hamilton, ON, Canada. [Alcindor, Thierry] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Wright, John J.] NCI, Rockville, MD USA. RP Mackay, HJ (reprint author), Univ Toronto, Princess Margaret Hosp, Dept Med Oncol, Drug Dev Program, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. EM helen.mackay@uhn.on.ca FU US National Cancer Institute FX This trial was supported by funding from, and drug was supplied by the Cancer Therapeutics Evaluation Program, US National Cancer Institute NR 26 TC 21 Z9 21 U1 1 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD JUN PY 2012 VL 30 IS 3 BP 1158 EP 1163 DI 10.1007/s10637-011-9650-4 PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 940GT UT WOS:000303878700033 PM 21400081 ER PT J AU El-Khoueiry, AB Ramanathan, RK Yang, DY Zhang, W Shibata, S Wright, JJ Gandara, D Lenz, HJ AF El-Khoueiry, A. B. Ramanathan, R. K. Yang, D. Y. Zhang, W. Shibata, S. Wright, J. J. Gandara, D. Lenz, H. J. TI A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Pancreatic cancer; Sorafenib; Gemcitabine; Ribonulceotide reductase ID CELL LUNG-CANCER; RAF/MEK/ERK PATHWAY; CLINICAL-TRIALS; GENE; POLYMORPHISM; ASSOCIATION; POPULATION; EXPRESSION; CARCINOMA; SURVIVAL AB Purpose Patients with metastatic pancreatic cancer have limited therapeutic options. The role of the Ras-Raf-MAPK pathway and of vascular endothelial growth factor in pancreatic carcinogenesis provided the rational to evaluate the efficacy of sorafenib with or without gemcitabine in a randomized phase II study. Methods Patients with metastatic pancreatic cancer were randomized to sorafenib alone (arm A) or sorafenib with gemcitabine (arm B). Results Arm A was closed to accrual at interim analysis due to the lack of objective response. Median PFS and OS were 2.3 and 4.3 months respectively. There was one partial response among the 37 patients in arm B. Median PFS and OS were 2.9 and 6.5 months respectively. There were more grade 3 and 4 toxicities in arm B with the most common being neutropenia (17%), thrombocytopenia (8%), alkaline phosphatase elevation (14%), venous thromboembolism (8%), diarrhea, hypokalemia and ALT elevation (5%) each. Several associations were noted between single nucleotide polymorphisms in ribonucleotide reductase, Cox-2, vascular endothelial growth factor and survival in patients treated with gemcitabine and sorafenib. Conclusions Neither sorafenib alone or sorafenib in combination with gemcitabine manifested promising activity in metastatic pancreatic cancer. C1 [El-Khoueiry, A. B.; Zhang, W.; Lenz, H. J.] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Div Med Oncol, Los Angeles, CA 90033 USA. [Ramanathan, R. K.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Yang, D. Y.; Lenz, H. J.] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Shibata, S.] City Hope Natl Med Ctr, Ctr Canc, Duarte, CA USA. [Wright, J. J.] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MA USA. [Gandara, D.] UC Davis, Ctr Canc, Sacramento, CA USA. RP El-Khoueiry, AB (reprint author), Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Div Med Oncol, 1441 Eastlake Ave,Suite 3440, Los Angeles, CA 90033 USA. EM elkhouei@usc.edu FU National Institutes of Health [NO1 CM-62209, P30CA033572, P30CA14089]; Bayer Phrmaceuticals FX Supported in part by Grants No. NO1 CM-62209, P30CA033572 and P30CA14089 from the National Institutes of Health.; Dr. Heinz-Josef Lenz receives clinical trial funding from Bayer Phrmaceuticals. Dr. Anthony El-Khoueiry is on the speaker's bureau for Bayer Pharmaceuticals. No other authors have conflicts of interest. NR 29 TC 18 Z9 18 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD JUN PY 2012 VL 30 IS 3 BP 1175 EP 1183 DI 10.1007/s10637-011-9658-9 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 940GT UT WOS:000303878700035 PM 21424698 ER PT J AU Gharib, AM Abd-Elmoniem, KZ Ho, VB Fodi, E Herzka, DA Ohayon, J Stuber, M Pettigrew, RI AF Gharib, Ahmed M. Abd-Elmoniem, Khaled Z. Ho, Vincent B. Foedi, Eszter Herzka, Daniel A. Ohayon, Jacques Stuber, Matthias Pettigrew, Roderic I. TI The Feasibility of 350 mu m Spatial Resolution Coronary Magnetic Resonance Angiography at 3 T in Humans SO INVESTIGATIVE RADIOLOGY LA English DT Article DE coronary MRA; cardiac MR; 3 T ID COMPUTED-TOMOGRAPHY; NAVIGATOR CORRECTION; ARTERY STENOSIS; CONTRAST; TIME; VISUALIZATION; LOCATIONS; DISEASE; MRA AB Purpose: The purposes of this study were to (1) develop a high-resolution 3-T magnetic resonance angiography (MRA) technique with an in-plane resolution approximate to that of multidetector coronary computed tomography (MDCT) and a voxel size of 0.35 x 0.35 x 1.5 mm(3) and to (2) investigate the image quality of this technique in healthy participants and preliminarily in patients with known coronary artery disease (CAD). Materials and Methods: A 3-T coronary MRA technique optimized for an image acquisition voxel as small as 0.35 x 0.35 x 1.5 mm(3) (high-resolution coronary MRA [HRC]) was implemented and the coronary arteries of 22 participants were imaged. These included 11 healthy participants (average age, 28.5 years; 5 men) and 11 participants with CAD (average age, 52.9 years; 5 women) as identified on MDCT. In addition, the 11 healthy participants were imaged using a method with a more common spatial resolution of 0.7 x 1 x 3 mm(3) (regular-resolution coronary MRA [RRC]). Qualitative and quantitative comparisons were made between the 2 MRA techniques. Results: Normal vessels and CAD lesions were successfully depicted at 350 x 350 mu m(2) in-plane resolution with adequate signal-to-noise ratio (SNR) and contrast-to-noise ratio. The CAD findings were consistent among MDCT and HRC. The HRC showed a 47% improvement in sharpness despite a reduction in SNR (by 72%) and in contrast-to-noise ratio (by 86%) compared with the regular-resolution coronary MRA. Conclusion: This study, as a first step toward substantial improvement in the resolution of coronary MRA, demonstrates the feasibility of obtaining at 3 T a spatial resolution that approximates that of MDCT. The acquisition in-plane pixel dimensions are as small as 350 x 350 mu m(2) with a 1.5-mm slice thickness. Although SNR is lower, the images have improved sharpness, resulting in image quality that allows qualitative identification of disease sites on MRA consistent with MDCT. C1 [Gharib, Ahmed M.] NIDDK, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. [Ho, Vincent B.] Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. [Herzka, Daniel A.] Johns Hopkins Sch Med, Baltimore, MD USA. [Stuber, Matthias] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. RP Gharib, AM (reprint author), NIDDK, NIH, Clin Res Ctr, Bldg 10,Rm 3-5340,MSC 1263,10 Ctr Dr, Bethesda, MD 20892 USA. EM agharib@mail.nih.gov RI Ohayon, Jacques/M-6576-2014; Stuber, Matthias/B-2949-2010; Gharib, Ahmed/O-2629-2016; Abd-Elmoniem, Khaled/B-9289-2008 OI Stuber, Matthias/0000-0001-9843-2028; Gharib, Ahmed/0000-0002-2476-481X; Abd-Elmoniem, Khaled/0000-0002-1001-1702 FU Intramural NIH HHS [Z99 DK999999] NR 29 TC 9 Z9 9 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD JUN PY 2012 VL 47 IS 6 BP 339 EP 345 DI 10.1097/RLI.0b013e3182479ec4 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 941RC UT WOS:000303979500003 PM 22551651 ER PT J AU Cameron, LD Marteau, TM Brown, PM Klein, WMP Sherman, KA AF Cameron, Linda D. Marteau, Theresa M. Brown, Paul M. Klein, William M. P. Sherman, Kerry A. TI Communication strategies for enhancing understanding of the behavioral implications of genetic and biomarker tests for disease risk: The role of coherence SO JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Health communication; Genetic testing; Common-sense model; Risk perception; Cancer ID CANCER SUSCEPTIBILITY; SMOKING-CESSATION; INFORMING WOMEN; IMPACT; INFORMATION; CONSEQUENCES; FEEDBACK; SMOKERS AB Individuals frequently have difficulty understanding how behavior can reduce genetically-conferred risk for diseases such as colon cancer. With increasing opportunities to purchase genetic tests, communication strategies are needed for presenting information in ways that optimize comprehension and adaptive behavior. Using the Common-Sense Model, we tested the efficacy of a strategy for providing information about the relationships (links) among the physiological processes underlying disease risk and protective action on understanding, protective action motivations, and willingness to purchase tests. We tested the generalizability of the strategy's effects across varying risk levels, for genetic tests versus tests of a non-genetic biomarker, and when using graphic and numeric risk formats. In an internet-based experiment, 749 adults from four countries responded to messages about a hypothetical test for colon cancer risk. Messages varied by Risk-Action Link Information (provision or no provision of information describing how a low-fat diet reduces risk given positive results, indicating presence of a gene fault), Risk Increment (20%, 50%, or 80% risk given positive results), Risk Format (numeric or graphic presentation of risk increments), and Test Type (genetic or enzyme). Providing risk-action link information enhanced beliefs of coherence (understanding how a low-fat diet reduces risk) and response efficacy (low-fat diets effectively reduce risk) and lowered appraisals of anticipated risk of colon cancer given positive results. These effects held across risk increments, risk formats, and test types. For genetic tests, provision of risk-action link information reduced the amount individuals were willing to pay for testing. Brief messages explaining how action can reduce genetic and biomarker-detected risks can promote beliefs motivating protective action. By enhancing understanding of behavioral control, they may reduce the perceived value of genetic risk information. C1 [Cameron, Linda D.; Brown, Paul M.] Univ Calif, Merced, CA USA. [Marteau, Theresa M.] Kings Coll London, London WC2R 2LS, England. [Klein, William M. P.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Sherman, Kerry A.] Macquarie Univ, Sydney, NSW 2109, Australia. [Sherman, Kerry A.] Westmead Breast Canc Inst, Sydney, NSW, Australia. RP Cameron, LD (reprint author), Univ Calif, Merced, CA USA. EM lcameron@ucmerced.edu; theresa.marteau@kcl.ac.uk; pbrown3@ucmerced.edu; kleinwm@mail.nih.gov; kerry.sherman@mq.edu.au OI Sherman, Kerry/0000-0001-7780-6668; Marteau, Theresa/0000-0003-3025-1129 NR 32 TC 18 Z9 18 U1 0 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0160-7715 J9 J BEHAV MED JI J. Behav. Med. PD JUN PY 2012 VL 35 IS 3 BP 286 EP 298 DI 10.1007/s10865-011-9361-5 PG 13 WC Psychology, Clinical SC Psychology GA 940BT UT WOS:000303865700004 PM 21698440 ER PT J AU Collie-Akers, VL Warrick, C Zhu, L Granado, M Ingram, K AF Collie-Akers, Vicki L. Warrick, Cynthia Zhu, Li Granado, Misha Ingram, Kymeiria TI Assessment of Characteristics of Capacity Among Breast Cancer Screening Facilities SO JOURNAL OF COMMUNITY HEALTH LA English DT Article DE Mammography; Breast cancer detection and prevention; Capacity; Facilities ID MAMMOGRAPHY USE; BARRIERS; ACCESS; ADHERENCE; MEDICARE; SERVICES AB Use of mammograms to detect presence of breast cancer is influenced by many factors, including ability to access mammography services. Access to services is often affected by the capacity of mammography facilities to serve women. We sought to describe the capacity of mammography facilities to conduct mammograms in a largely urban area of Texas. We used a 24-item survey to all mammography facilities in Texas Public Health Region 6/5 South. The survey contained questions across six domains: facility type, scheduling, staffing, mechanical capacity, cost/payment methods, and patient reminders. We received or completed 60 surveys (43%). Most of the facilities were open only Monday through Friday (61.7%) and were open only during typical business hours (51.7%). About 83% of the facilities had one or two machines. Most facilities had only one or two staff to conduct mammograms. The results of this survey indicate that the capacity of mammography facilities vary dramatically across many characteristics of capacity. As these indicators are tied to the ability of women to access necessary preventive services, it is important to determine how these characteristics are associated with mammography utilization. C1 [Collie-Akers, Vicki L.] Univ Kansas, Work Grp Community Hlth & Dev, Dole Ctr, Lawrence, KS 66045 USA. [Warrick, Cynthia] Howard Univ, Ctr Minor Hlth Serv Res, Washington, DC 20059 USA. [Zhu, Li] NCI, Bethesda, MD 20892 USA. [Granado, Misha] Univ Texas Hlth Sci Ctr, Houston, TX USA. [Ingram, Kymeiria] Duke VA Med Ctr, Durham, NC USA. RP Collie-Akers, VL (reprint author), Univ Kansas, Work Grp Community Hlth & Dev, Dole Ctr, 1000 Sunnyside Ave,Rm 4082, Lawrence, KS 66045 USA. EM vcollie@ku.edu FU NCI NIH HHS [5K01CA106565, K01 CA106565] NR 17 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0094-5145 J9 J COMMUN HEALTH JI J. Community Health PD JUN PY 2012 VL 37 IS 3 BP 626 EP 631 DI 10.1007/s10900-011-9493-0 PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 936LB UT WOS:000303590800011 PM 22119996 ER PT J AU Singleton, A Erby, LH Foisie, KV Kaphingst, KA AF Singleton, Amanda Erby, Lori Hamby Foisie, Kathryn V. Kaphingst, Kimberly A. TI Informed Choice in Direct-to-Consumer Genetic Testing (DTCGT) Websites: A Content Analysis of Benefits, Risks, and Limitations SO JOURNAL OF GENETIC COUNSELING LA English DT Article DE Direct-to-consumer; Genetic testing; Internet; Informed choice; Persuasion; Content analysis ID UNITED-STATES; HEALTH; GENOME; PREDICTION; SERVICES AB An informed choice about health-related direct-to-consumer genetic testing (DTCGT) requires knowledge of potential benefits, risks, and limitations. To understand the information that potential consumers of DTCGT services are exposed to on company websites, we conducted a content analysis of 23 health-related DTCGT websites. Results revealed that benefit statements outweighed risk and limitation statements 6 to 1. The most frequently described benefits were: 1) disease prevention, 2) consumer education, 3) personalized medical recommendations, and 4) the ability to make health decisions. Thirty-five percent of websites also presented at least one risk of testing. Seventy-eight percent of websites mentioned at least one limitation of testing. Based on this information, potential consumers might get an inaccurate picture of genetic testing which could impact their ability to make an informed decision. Practices that enhance the presentation of balanced information on DTCGT company websites should be encouraged. C1 [Kaphingst, Kimberly A.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Singleton, Amanda] GeneDx, Gaithersburg, MD USA. [Erby, Lori Hamby] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Singleton, Amanda; Foisie, Kathryn V.] NHGRI, Bethesda, MD 20892 USA. RP Kaphingst, KA (reprint author), Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, 660 S Euclid Ave,Campus Box 8100, St Louis, MO 63110 USA. EM kkaphingst@gwbmail.wustl.edu FU National Human Genome Research Institute, National Institutes of Health FX The design and conduct of this study was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health in partial fulfillment of the requirements of the first author's ScM degree at the Johns Hopkins Bloomberg School of Public Health. All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. No authors had any conflicts of interest, including financial interests or affiliations relevant to the subject of this manuscript. These results were presented in part at the National Society of Genetic Counselors Annual Education Conference, Dallas, TX, 2010. NR 23 TC 17 Z9 17 U1 3 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 J9 J GENET COUNS JI J. Genet. Couns. PD JUN PY 2012 VL 21 IS 3 SI SI BP 433 EP 439 DI 10.1007/s10897-011-9474-6 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 940KG UT WOS:000303887800012 PM 22194036 ER PT J AU Bakalar, M Schroeder, JL Pursley, R Pohida, TJ Glancy, B Taylor, J Chess, D Kellman, P Xue, H Balaban, RS AF Bakalar, M. Schroeder, J. L. Pursley, R. Pohida, T. J. Glancy, B. Taylor, J. Chess, D. Kellman, P. Xue, H. Balaban, R. S. TI Three-dimensional motion tracking for high-resolution optical microscopy, in vivo SO JOURNAL OF MICROSCOPY LA English DT Article DE Two-photon excitation microscopy; intravital; fluorescence; three-dimensional microscopy; motion tracking; real-time; GPU; mouse skeletal muscle; feedback control ID MULTIPHOTON EXCITATION MICROSCOPY; FLUORESCENCE MICROSCOPY; 2-PHOTON MICROSCOPY; MUSCLE; ANIMALS; HYPOXIA; CALCIUM; TISSUE AB When conducting optical imaging experiments, in vivo, the signal to noise ratio and effective spatial and temporal resolution is fundamentally limited by physiological motion of the tissue. A three-dimensional (3D) motion tracking scheme, using a multiphoton excitation microscope with a resonant galvanometer, (512 x 512 pixels at 33 frames s-1) is described to overcome physiological motion, in vivo. The use of commercially available graphical processing units permitted the rapid 3D cross-correlation of sequential volumes to detect displacements and adjust tissue position to track motions in near real-time. Motion phantom tests maintained micron resolution with displacement velocities of up to 200 mu m min-1, well within the drift observed in many biological tissues under physiologically relevant conditions. In vivo experiments on mouse skeletal muscle using the capillary vasculature with luminal dye as a displacement reference revealed an effective and robust method of tracking tissue motion to enable (1) signal averaging over time without compromising resolution, and (2) tracking of cellular regions during a physiological perturbation. C1 [Bakalar, M.; Schroeder, J. L.; Glancy, B.; Taylor, J.; Chess, D.; Kellman, P.; Balaban, R. S.] NHLBI, Princeton, NJ USA. [Pursley, R.; Pohida, T. J.] CIT Signal Proc Grp, Princeton, NJ USA. [Xue, H.] Siemens Corp Res, Princeton, NJ USA. RP Bakalar, M (reprint author), 2127 1-2 Haste St, Berkeley, CA 94704 USA. EM Matthew.bakalar@berkeley.edu RI Glancy, Brian/P-3163-2016 OI Glancy, Brian/0000-0002-8571-244X FU Intramural NIH HHS [ZIA HL004610-05] NR 17 TC 11 Z9 11 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-2720 J9 J MICROSC-OXFORD JI J. Microsc.. PD JUN PY 2012 VL 246 IS 3 BP 237 EP 247 DI 10.1111/j.1365-2818.2012.03613.x PG 11 WC Microscopy SC Microscopy GA 941VD UT WOS:000303993700004 PM 22582797 ER PT J AU FitzGerald, MP Payne, CK Lukacz, ES Yang, CC Peters, KM Chai, TC Nickel, JC Hanno, PM Kreder, KJ Burks, DA Mayer, R Kotarinos, R Fortman, C Allen, TM Fraser, L Mason-Cover, M Furey, C Odabachian, L Sanfield, A Chu, J Huestis, K Tata, GE Dugan, N Sheth, H Bewyer, K Anaeme, A Newton, K Featherstone, W Halle-Podell, R Cen, L Landis, JR Propert, KJ Foster, HE Kusek, JW Nyberg, LM AF FitzGerald, M. P. Payne, C. K. Lukacz, E. S. Yang, C. C. Peters, K. M. Chai, T. C. Nickel, J. C. Hanno, P. M. Kreder, K. J. Burks, D. A. Mayer, R. Kotarinos, R. Fortman, C. Allen, T. M. Fraser, L. Mason-Cover, M. Furey, C. Odabachian, L. Sanfield, A. Chu, J. Huestis, K. Tata, G. E. Dugan, N. Sheth, H. Bewyer, K. Anaeme, A. Newton, K. Featherstone, W. Halle-Podell, R. Cen, L. Landis, J. R. Propert, K. J. Foster, H. E., Jr. Kusek, J. W. Nyberg, L. M. CA Interstitial Cystitis TI Randomized Multicenter Clinical Trial of Myofascial Physical Therapy in Women With Interstitial Cystitis/Painful Bladder Syndrome and Pelvic Floor Tenderness SO JOURNAL OF UROLOGY LA English DT Article DE pelvic pain; cystitis, interstitial; physical therapy modalities ID PAIN SYNDROME; MEN; BIOFEEDBACK; DYSFUNCTION; INDEX AB Purpose: We determined the efficacy and safety of pelvic floor myofascial physical therapy compared to global therapeutic massage in women with newly symptomatic interstitial cystitis/painful bladder syndrome. Materials and Methods: A randomized controlled trial of 10 scheduled treatments of myofascial physical therapy vs global therapeutic massage was performed at 11 clinical centers in North America. We recruited women with interstitial cystitis/painful bladder syndrome with demonstrable pelvic floor tenderness on physical examination and a limitation of no more than 3 years' symptom duration. The primary outcome was the proportion of responders defined as moderately improved or markedly improved in overall symptoms compared to baseline on a 7-point global response assessment scale. Secondary outcomes included ratings for pain, urgency and frequency, the O'Leary-Sant IC Symptom and Problem Index, and reports of adverse events. We compared response rates between treatment arms using the exact conditional version of the Mantel-Haenszel test to control for clustering by clinical center. For secondary efficacy outcomes cross-sectional descriptive statistics and changes from baseline were calculated. Results: A total of 81 women randomized to the 2 treatment groups had similar symptoms at baseline. The global response assessment response rate was 26% in the global therapeutic massage group and 59% in the myofascial physical therapy group (p = 0.0012). Pain, urgency and frequency ratings, and O'Leary-Sant IC Symptom and Problem Index decreased in both groups during followup, and were not significantly different between the groups. Pain was the most common adverse event, occurring at similar rates in both groups. No serious adverse events were reported. Conclusions: A significantly higher proportion of women with interstitial cystitis/painful bladder syndrome responded to treatment with myofascial physical therapy than to global therapeutic massage. Myofascial physical therapy may be a beneficial therapy in women with this syndrome. C1 [FitzGerald, M. P.; Kotarinos, R.] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. [Halle-Podell, R.] Massage Therapy Oak Pk, Oak Pk, IL USA. [Payne, C. K.; Allen, T. M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Lukacz, E. S.; Fraser, L.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Yang, C. C.; Mason-Cover, M.] Univ Washington, Seattle, WA 98195 USA. [Peters, K. M.; Odabachian, L.; Sanfield, A.] William Beaumont Hosp, Royal Oak, MI 48072 USA. [Burks, D. A.; Anaeme, A.; Newton, K.] Henry Ford Hosp, Detroit, MI 48202 USA. [Chai, T. C.; Nickel, J. C.; Huestis, K.] Univ Maryland, Baltimore, MD 21201 USA. [Kusek, J. W.; Nyberg, L. M.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Nickel, J. C.; Tata, G. E.] Queens Univ, Kingston, ON, Canada. [Hanno, P. M.; Dugan, N.; Sheth, H.] Univ Penn Hlth Syst, Philadelphia, PA USA. [Cen, L.; Landis, J. R.; Propert, K. J.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kreder, K. J.; Bewyer, K.] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Mayer, R.; Featherstone, W.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Foster, H. E., Jr.] Yale Univ, Dept Surg, Urol Sect, New Haven, CT USA. RP FitzGerald, MP (reprint author), Hines VA Med Ctr, 5000 S 5th Ave, Hines, IL 60141 USA. EM mary.fitzgerald6@va.gov FU NIDDK NIH HHS [U01 DK065192-05, U01 DK065214-05, U01 DK065209, U01 DK065202-04S2, U01 DK065255-06, U01 DK065267-06, U01 DK065190-06, U01 DK065215-05, U01 DK065271, U01 DK065213-06, U01 DK065267, U01 DK065271-05, U01 DK065209-06, U01 DK065214, U01 DK065178-05, U01 DK065178, U01 DK065192, U01 DK065215] NR 15 TC 42 Z9 43 U1 0 U2 26 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUN PY 2012 VL 187 IS 6 BP 2113 EP 2118 DI 10.1016/j.juro.2012.01.123 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 939OK UT WOS:000303821300051 PM 22503015 ER PT J AU Morishima, C Di Bisceglie, AM Rothman, AL Bonkovsky, HL Lindsay, KL Lee, WM Koziel, MJ Fontana, RJ Kim, HY Wright, EC AF Morishima, C. Di Bisceglie, A. M. Rothman, A. L. Bonkovsky, H. L. Lindsay, K. L. Lee, W. M. Koziel, M. J. Fontana, R. J. Kim, H. -Y. Wright, E. C. CA HALT-C Trial Grp TI Antigen-specific T lymphocyte proliferation decreases over time in advanced chronic hepatitis C SO JOURNAL OF VIRAL HEPATITIS LA English DT Article DE cirrhosis; fibrosis; hepatitis C virus; interferon-alpha; lymphoproliferation; T cell ID ANTIVIRAL THERAPY; BACTERIAL-INFECTIONS; VIRUS-INFECTION; INTERFERON-ALPHA; CELL RESPONSE; CUTTING EDGE; CIRRHOSIS; PEGINTERFERON; RIBAVIRIN; GENOTYPE AB . To evaluate T cell immunity in advanced liver disease, antigen-specific lymphoproliferative (LP) responses were prospectively studied in the context of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial. Peripheral blood responses to hepatitis C virus (HCV), tetanus and Candida protein antigens were measured at baseline, month 12 (M12), M24, M36 and M48 in 186 patients randomized to either low-dose peginterferon-alfa-2a (PEG-IFN) only or observation. Liver histology was evaluated at baseline, M24 and M48. Patients with cirrhosis (Ishak 56) were less likely to have positive LP responses to HCV at baseline than patients with fibrosis (15%vs 29%, P = 0.03) and had lower levels of HCV c100 responses at baseline, M24 and M48 (P = 0.11, P = 0.05, P = 0.02, respectively). For 97 patients with complete longitudinal data, the frequency of positive LP responses to HCV, tetanus and Candida antigens declined over time (P < 0.003), and the slope of this decline was greater in the PEG-IFN treatment group than the observation group (P < 0.02). Lower levels of tetanus LP responses were associated with fibrosis progression and clinical outcomes (P = 0.009). Poorer CD4+ T cell proliferative function was associated with more advanced liver disease in chronic hepatitis C and may be further affected by long-term PEG-IFN treatment. C1 [Morishima, C.] Univ Washington, Div Virol, Dept Lab Med, Seattle, WA 98109 USA. [Di Bisceglie, A. M.] St Louis Univ, Sch Med, Div Gastroenterol & Hepatol, St Louis, MO USA. [Rothman, A. L.] Univ Massachusetts, Sch Med, Ctr Infect Dis & Vaccine Res, Worcester, MA USA. [Rothman, A. L.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Bonkovsky, H. L.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Bonkovsky, H. L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Lindsay, K. L.] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Lee, W. M.] Univ Texas SW Med Ctr Dallas, Div Digest & Liver Dis, Dallas, TX 75390 USA. [Koziel, M. J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Fontana, R. J.] Univ Michigan, Sch Med, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI USA. [Kim, H. -Y.] New England Res Inst, Watertown, MA 02172 USA. [Wright, E. C.] NIDDKD, Off Director, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Morishima, C (reprint author), Univ Washington, Div Virol, Dept Lab Med, Seattle, WA 98109 USA. EM chihiro@u.washington.edu FU Hoffmann-La Roche, Inc.; Bristol Myers Squibb; National Institute of Diabetes & Digestive & Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Center for Minority Health and Health Disparities; General Clinical Research Center from the National Center for Research Resources, National Institutes of Health; Clinical and Translational Science Center from the National Center for Research Resources, National Institutes of Health; University of Massachusetts Medical Center, Worcester, MA [N01-DK-9-2326]; Beth Israel Deaconess Medical Center, Boston, MA [M01RR-06192]; Saint Louis University School of Medicine, St Louis, MO [N01-DK-9-2324]; University of Texas Southwestern Medical Center, Dallas, TX [N01-DK-9-2321, M01RR-00633, 1 UL1 RR024982-01]; University of Southern California, Los Angeles, CA [N01-DK-9-2325, M01RR-00043]; University of Washington, Seattle, WA [N01-DK-9-2318]; New England Research Institutes, Watertown, MA [N01-DK-9-2328] FX The authors disclose the following: A.M. Di Bisceglie is a consultant and receives research support from Hoffmann-La Roche, Inc.; H. L. Bonkovsky receives research support from Hoffmann-La Roche, Inc.; K. L. Lindsay was a consultant and received research support from Hoffmann-La Roche, Inc. during this study and is now an employee of Tibotec, Inc. (a subsidiary of Johnson and Johnson), Titusville, NJ; W. M. Lee receives research support from Hoffmann-La Roche, Inc.; M.J. Koziel received an unrestricted research grant from Bristol Myers Squibb and is currently an employee of Vertex Pharmaceuticals, Cambridge, MA; R.J. Fontana is on the speaker's bureau for Hoffmann-La Roche, Inc. Authors with no financial relationships related to this project are: C. Morishima, A.L. Rothman, H-Y Kim, and E.C. Wright.; This study was supported by the National Institute of Diabetes & Digestive & Kidney Diseases (contract numbers are listed later). Additional support was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed later). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc., through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health. We also gratefully acknowledge the generous gift of HCV protein antigens from Michael Houghton and Kevin Crawford (Chiron Corporation).; The authors wish to thank Jee-Hang Tse (University of Washington, Seattle, WA) for creating the figures. In addition to the authors of this manuscript, the following individuals were instrumental in the planning, conduct and/or care of patients enrolled in this study at each of the participating institutions as follows: University of Massachusetts Medical Center, Worcester, MA: (Contract N01-DK-9-2326) Gyongyi Szabo, MD, Barbara F. Banner, MD, Maureen Cormier, RN, Donna Giansiracusa, RN. Beth Israel Deaconess Medical Center, Boston, MA: Qi He, MD. University of Connecticut Health Center, Farmington, CT: (Grant M01RR-06192) Gloria Borders, RN, Michelle Kelley, RN, ANP. Saint Louis University School of Medicine, St Louis, MO: (Contract N01-DK-9-2324) Bruce Bacon, MD, Brent Neuschwander-Tetri, MD, Elizabeth M. Brunt, MD, Debra King, RN. University of Texas Southwestern Medical Center, Dallas, TX: (Contract N01-DK-9-2321, Grant M01RR-00633, Grant 1 UL1 RR024982-01, North and Central Texas Clinical and Translational Science Initiative) Thomas E. Rogers, MD, Peter F. Malet, MD, Janel Shelton, Nicole Crowder, LVN, Rivka Elbein, RN, BSN, Nancy Liston, MPH. University of Southern California, Los Angeles, CA: (Contract N01-DK-9-2325, Grant M01RR-00043) Sugantha Govindarajan, MD, Carol B. Jones, RN, Susan L. Milstein, RN. National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, MD: James E. Everhart, MD, Leonard B. Seeff, MD, Patricia R. Robuck, PhD, Jay H. Hoofnagle, MD. University of Washington, Seattle, WA: (Contract N01-DK-9-2318) David R. Gretch, MD, PhD, Minjun Chung Apodaca, BS, ASCP, Rohit Shankar, BS, ASCP, Natalia Antonov, M. Ed, Megan Allison, BS, Michelle Gano, BS, and Christina Yoshihara, BS. New England Research Institutes, Watertown, MA: (Contract N01-DK-9-2328) Kristin K. Snow, MSc, ScD, Anne M. Stoddard, ScD, Margaret C. Bell, MS, MPH. Armed Forces Institute of Pathology, Washington, DC: Zachary D. Goodman, MD, PhD. Data and Safety Monitoring Board Members: (Chair) Gary L. Davis, MD, Guadalupe Garcia-Tsao, MD, Michael Kutner, PhD, Stanley M. Lemon, MD, Robert P. Perrillo, MD. NR 32 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1352-0504 J9 J VIRAL HEPATITIS JI J. Viral Hepatitis PD JUN PY 2012 VL 19 IS 6 BP 404 EP 413 DI 10.1111/j.1365-2893.2011.01562.x PG 10 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA 939ZE UT WOS:000303858900004 PM 22571902 ER PT J AU Koontongkaew, S Amornphimoltham, P Monthanpisut, P Saensuk, T Leelakriangsak, M AF Koontongkaew, Sittichai Amornphimoltham, Panomwat Monthanpisut, Paopanga Saensuk, Theeranuch Leelakriangsak, Montira TI Fibroblasts and extracellular matrix differently modulate MMP activation by primary and metastatic head and neck cancer cells SO MEDICAL ONCOLOGY LA English DT Article DE Head and neck cancer; Metastasis; Matrix metalloproteinases; Fibroblast; Extracellular matrix; CXCR4; CCL12; Integrin; Mitogen-activated protein kinase ID HUMAN ORAL KERATINOCYTES; PROTEIN-KINASE; CARCINOMA-CELLS; I COLLAGEN; TYROSINE PHOSPHORYLATION; PROSTATE-CANCER; STROMAL CELLS; TUMOR-CELLS; INVASION; INTEGRIN AB A genetically related pair of human head and neck cancer (HNSCC) cell lines derived from the same patient at different stages of disease was used to investigate the role of extracellular matrix, integrin, and CXCL12-CXCR4 receptor interactions and their signal pathways in MMP-2 and MMP-9 activation and cell invasion. We found that collagen I enhanced MMP-2 and MMP-9 secretion in both primary and metastatic HNSCC cells. Collagen I acted through alpha(2)beta(1) integrin to activate tyrosine kinases, protein kinase C, ERK1/2, and p38, which in turn activated MMP-2 and MMP-9 production. The signaling function was also involved in the enhancement of cell invasion. Experiments using cocultures between live and fixed cells demonstrated that direct contact between tumor and fibroblast cells was required to activate MMP-2 and MMP-9 secretion in both tumor cells and fibroblasts. The augmentation appears specific for MMP-2. Fibroblasts seem to be responsible for the increased MMP-2 in the coculture. In addition, fibroblast or tumor cell-conditioned media upregulated the secretion of MMP-2 and MMP-9 in HNSCC cells. These findings indicate that autocrine and paracrine factors are involved in the augmented secretion of MMPs in coculture. We also found that CXCL12-enhanced HNSCC cell invasion through paracrine-activated CXCR4, which triggered MMP-dependent cell invasion. Together, our results suggest that cell-matrix and cell-cell interactions including autocrine and paracrine factors play important roles in the invasive behavior of HNSCC via upregulation of MMP-2 and MMP-9. C1 [Koontongkaew, Sittichai; Monthanpisut, Paopanga; Saensuk, Theeranuch] Thammasat Univ, Fac Dent, Klongluang 12121, Pratum Thani, Thailand. [Koontongkaew, Sittichai] Thammasat Univ, Med Herb Res Unit, Bangkok, Thailand. [Amornphimoltham, Panomwat] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20882 USA. [Leelakriangsak, Montira] Prince Songkla Univ, Fac Sci & Technol, Muang 94000, Pattani, Thailand. RP Koontongkaew, S (reprint author), Thammasat Univ, Fac Dent, Klongluang 12121, Pratum Thani, Thailand. EM koontongkaew@yahoo.com FU Thailand Research Foundation (TRF); Thammasat University FX This work was supported by research grants from Thailand Research Foundation (TRF) and Thammasat University. We thank Dr. Silvio Gutkind (NIDCR, Bethesda, MD, USA) for the HNSCC cell lines used in our studies. We also thank Dr. Matthew J Cheesman for editing the manuscript. NR 34 TC 10 Z9 10 U1 0 U2 6 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 J9 MED ONCOL JI Med. Oncol. PD JUN PY 2012 VL 29 IS 2 BP 690 EP 703 DI 10.1007/s12032-011-9871-6 PG 14 WC Oncology SC Oncology GA 935RX UT WOS:000303539000047 PM 21380786 ER PT J AU Haller, JL Panyutin, I Chaudhry, A Zeng, CB Mach, RH Frank, JA AF Haller, Jodi L. Panyutin, Irina Chaudhry, Aneeka Zeng, Chenbo Mach, Robert H. Frank, Joseph A. TI Sigma-2 Receptor as Potential Indicator of Stem Cell Differentiation SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Sigma 2 receptor; Embryonic stem cell; Amniotic fluid stem cell; Bone marrow stromal cells; Hematopoietic stem cell; Differentiation; Proliferation; EdU; Ki 67 ID IN-VIVO; TERATOMA FORMATION; BREAST-CANCER; TRACKING; PROLIFERATION; SIRAMESINE; PROMOTER; SURVIVAL; LIGANDS; MODELS AB The sigma-2 (sigma(2)) receptor is a potential biomarker of proliferative status of solid tumors. Specific synthetic probes using -substituted-9-azabicyclo [3.3.1]nonan-3 alpha-yl carbamate analogs have been designed and implemented for experimental cancer diagnosis and therapy. We employed the fluorescently labeled sigma(2) receptor probe, SW120, to evaluate sigma(2) receptor expression in human stem cells (SC), including: bone marrow stromal, neural progenitor, amniotic fluid, hematopoetic, and embryonic stem cells. We concurrently evaluated the intensity of SW120 and 5-ethynyl-2'-deoxyuridine (EdU) relative to passage number and multi-potency. We substantiated significantly higher sigma(2) receptor density among proliferating SC relative to lineage-restricted cell types. Additionally, cellular internalization of the sigma(2) receptor in SC was consistent with receptor-mediated endocytosis and confocal microscopy indicated SW120 specific co-localization with a fluorescent marker of lysosomes in all SC imaged. These results suggest that sigma(2) receptors may serve to monitor stem cell differentiation in future experimental studies. C1 [Haller, Jodi L.; Chaudhry, Aneeka; Frank, Joseph A.] NIH, Frank Lab, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Panyutin, Irina] NIH, Neumann Lab, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Zeng, Chenbo; Mach, Robert H.] Washington Univ, Sch Med, Dept Radiol, Div Radiol Sci, St Louis, MO 63110 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Haller, JL (reprint author), NIH, Frank Lab, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10,Room BIN256, Bethesda, MD 20892 USA. EM hallerjod@cc.nih.gov; jafrank@helix.nih.gov FU Clinical Center at the National Institutes of Health FX This work was supported by the Intramural Research Program in the Clinical Center at the National Institutes of Health. NR 40 TC 9 Z9 9 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD JUN PY 2012 VL 14 IS 3 BP 325 EP 335 DI 10.1007/s11307-011-0493-3 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 940IY UT WOS:000303884400007 PM 21614680 ER PT J AU Kwon-Chung, KJ Perfect, JR Levitz, SM AF Kwon-Chung, Kyung J. Perfect, John R. Levitz, Stuart M. TI A Chronological History of the International Conference on Cryptococcus and Cryptococcosis (ICCC), an Invaluable Forum for Growth of the Cryptococcal Research Field and Clinical Practice SO MYCOPATHOLOGIA LA English DT Article DE History of ICCC AB Cryptococcologists meet every 3 years to present their new research data and discuss the current state of cryptococcosis therapy at the International Conference on Cryptococcus and Cryptococcosis (ICCC). The ICCC has served as a unique forum where mycologists could interact and share their research data in a setting exclusively devoted to the study of Cryptococcus and cryptococcosis. This article presents an historical perspective on the ICCC meetings, beginning with the first ICCC that was held in Jerusalem, Israel in 1989. Subsequent ICCC meetings have grown, in terms of attendance and submitted abstracts. The history of the ICCC serves as a testimony to the remarkable progress that has been made in our basic understanding of the molecular biology, biochemistry, ecology, and taxonomy of Cryptococcus as well as the epidemiology, immunology, clinical manifestations, and treatment for cryptococcosis. C1 [Kwon-Chung, Kyung J.] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Perfect, John R.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Levitz, Stuart M.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. EM june_kwon-chung@nih.gov NR 0 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-486X J9 MYCOPATHOLOGIA JI Mycopathologia PD JUN PY 2012 VL 173 IS 5-6 SI SI BP 287 EP 293 DI 10.1007/s11046-011-9481-z PG 7 WC Mycology SC Mycology GA 936JO UT WOS:000303586900002 PM 22038679 ER PT J AU Park, YD Williamson, PR AF Park, Yoon-Dong Williamson, Peter R. TI 'Popping the Clutch': Novel Mechanisms Regulating Sexual Development in Cryptococcus neoformans SO MYCOPATHOLOGIA LA English DT Article DE Cryptococcus neoformans; Mating pheromone; Signaling pathway; Sexual development ID CALCINEURIN-BINDING-PROTEIN; MESSENGER-RNA TURNOVER; SACCHAROMYCES-CEREVISIAE; TRANSCRIPTION FACTOR; ADENYLYL-CYCLASE; MATING-TYPE; FILOBASIDIELLA-NEOFORMANS; SIGNAL-TRANSDUCTION; HYPHAL ELONGATION; STRESS-RESPONSE AB Sexual reproduction in fungal pathogens such as Cryptococcus provides natural selection and adaptation of the organisms to environmental conditions by allowing beneficial mutations to spread. However, successful mating in these fungi requires a time-critical induction of signaling pheromones when appropriate partners become available. Recently, it has been shown that the fungus uses the transcriptional equivalent of the racing technique: 'popping the clutch'aEuro"pushing in the clutch pedal, putting the car in gear, revving with the gas pedal, and then dropping the clutch pedal to accelerate rapidly. In the same way, Cryptococcus during vegetative growth constitutively matches a high rate of pheromone synthesis with a high rate of degradation to produce repressed levels of transcript. Then, when mating is required, the fungus drops the degradative machinery, resulting in a rapid induction of the pheromone. Pairing with this novel regulatory cycle is a host of mitogen-activated protein kinase cascades, cyclic AMP-dependent, and calcium-calcineurin signaling pathways that maintain these high rates of pheromone synthesis and prime downstream pathways for an effective mating response. The intersection of a number of virulence-associated traits with sexual development such as the synthesis of an immune-disruptive laccase as well as a protective polysaccharide capsule makes these rapid regulatory strategies a formidable foe in the battle against human disease. C1 [Park, Yoon-Dong; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Williamson, PR (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike,Bldg 10,Rm 11N116,MSC 1888, Bethesda, MD 20892 USA. EM williamsonpr@mail.nih.gov FU NIH, NIAID FX This work was supported, in part, by the Intramural Research Program of the NIH, NIAID. We also would like to acknowledge the helpful manuscript review by KJ Kwon-Chung and J Abbott. NR 75 TC 3 Z9 3 U1 1 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-486X J9 MYCOPATHOLOGIA JI Mycopathologia PD JUN PY 2012 VL 173 IS 5-6 SI SI BP 359 EP 366 DI 10.1007/s11046-011-9464-0 PG 8 WC Mycology SC Mycology GA 936JO UT WOS:000303586900010 PM 21912854 ER PT J AU Kalra, N Ashai, A Xi, LQ Zhang, JL Avital, I Raffeld, M Hassan, R AF Kalra, Neetu Ashai, Ali Xi, Liqiang Zhang, Jingli Avital, Itzhak Raffeld, Mark Hassan, Raffit TI Patients with peritoneal mesothelioma lack epidermal growth factor receptor tyrosine kinase mutations that would make them sensitive to tyrosine kinase inhibitors SO ONCOLOGY REPORTS LA English DT Article DE EGFR; peritoneal mesothelioma; somatic mutation; tyrosine kinase inhibitor; erlotinib ID MALIGNANT PLEURAL MESOTHELIOMA; CELL LUNG-CANCER; EGFR MUTATIONS; ADENOSQUAMOUS CARCINOMA; PHASE-II; GEFITINIB; DOMAIN; POLYMORPHISM; EXPRESSION; ERLOTINIB AB The epidermal growth factor receptor (EGFR) is a promising target for cancer therapy. The presence of certain somatic mutations in the tyrosine kinase (TK) domain of the EGFR gene is associated with clinical response to TK inhibitors (TKI) in patients with lung adenocarcinoma. In this study we evaluated the status of somatic mutations in the entire TK domain of the EGFR gene by direct sequencing using early passage peritoneal mesothelioma cells, established cell lines as well as 33 peritoneal mesothelioma tumor samples. No novel mutations were found in the cell lines. Sequence analysis of the EGER TK domain revealed the presence of a silent polymorphism (c.2607G -> A, Q787Q) at exon 20 of both peritoneal mesothelioma cell lines as well as tumor specimens. The frequency of genotypes AA and GA was 42.8 and 57.2% in the cell lines and 33.3 and 57.6% in tumor specimens, respectively. The TKI erlotinib showed an IC50 in the range of 10-50 mu M in five out of the seven cell lines with a GA genotype while all five cell lines with the AA genotype had an IC50 >50 mu M. Of the 33 peritoneal mesothelioma tumor samples analyzed none had an EGFR TKI sensitizing mutation and only one specimen showed an earlier reported somatic mutation at codon 850 in exon 21 of the EGFR gene. Our data show that patients with peritoneal mesothelioma do not harbor somatic mutations in the EGFR TK domain that would make them sensitive to EGFR TKI. C1 [Kalra, Neetu; Ashai, Ali; Zhang, Jingli; Hassan, Raffit] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Xi, Liqiang; Raffeld, Mark] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Avital, Itzhak] NCI, GI & Hepatobiliary Malignancy Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5116, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 28 TC 5 Z9 6 U1 0 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD JUN PY 2012 VL 27 IS 6 BP 1794 EP 1800 DI 10.3892/or.2012.1725 PG 7 WC Oncology SC Oncology GA 939BY UT WOS:000303783100014 PM 22426987 ER PT J AU Keil, MF Briassoulis, G Gokarn, N Nesterova, M Wu, TJ Stratakis, CA AF Keil, Margaret F. Briassoulis, George Gokarn, Nirmal Nesterova, Maria Wu, T. John Stratakis, Constantine A. TI Anxiety phenotype in mice that overexpress protein kinase A SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Protein kinase A; Transgenic mouse model; Anxiety; Behavioral phenotype; Amygdala ID ELEVATED PLUS-MAZE; RII-BETA-SUBUNIT; GENOME-WIDE ANALYSIS; REGULATORY SUBUNIT; GENE-EXPRESSION; CARNEY COMPLEX; MUTANT MICE; DEFICIENT MICE; MESSENGER-RNA; MOUSE MODEL AB The role of cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling in the molecular pathways involved in fear and memory is well established. Prior studies in our lab reported that transgenic mice with an inactivating mutation in Prkar1a gene (codes for the 1-alpha regulatory subunit (R1 alpha) of PKA) exhibited behavioral abnormalities including anxiety and depression. In the present study, we examined the role of altered PKA signaling on anxiety-like behaviors in Prkar1a(+/-) mice compared to wild-type (WT) littermates. The elevated plus maze (EPM) and marble bury (MB) tests were used to assess anxiety-like behavior. The hotplate test was performed to evaluate analgesia. We further examined the impact of the Prkar1a inactivating mutation on PKA activity in specific nuclei of the brain associated with anxiety-like behavior. Results for the MB test showed a genotype effect, with increased anxiety-like behavior in Prkar1a(+/-) mice, compared to WT littermates (p < 0.05). MANOVA analysis showed a significant genotype difference in anxiety-like behavior in the EPM between WT and Prkar1a(+/-) mice on combined dependent variables (open arm time and open to total time ratio; p < 0.05). Results of hotplate testing showed no genotype effect however; the expected sex difference was noted. Analysis of PKA activity showed the loss of one Prkar1a allele led to an increase in basal and cAMP-stimulated kinase activity in both the basolateral and central amygdala. These results suggest that the alteration in PICA signaling in Prkar1a(+/-) mice is not a ubiquitous effect; and supports the importance of cAMP/PKA pathway in neurobiological processes involved in anxiety and fear sensitization. Published by Elsevier Ltd. C1 [Keil, Margaret F.; Briassoulis, George; Gokarn, Nirmal; Nesterova, Maria; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Keil, Margaret F.] Uniformed Serv Univ Hlth Sci, Grad Sch Nursing, Bethesda, MD 20814 USA. [Wu, T. John] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Wu, T. John] Uniformed Serv Univ Hlth Sci, Program Neurosci, Bethesda, MD 20814 USA. RP Keil, MF (reprint author), NICHD, NIH, PDEGEN, 10 Ctr Dr,Bldg 10 CRC,Room 1 E3330, Bethesda, MD 20892 USA. EM keilm@mail.nih.gov; stratakc@cc1.nichd.nih.gov FU NICHD, NIH [Z01-HD-000642-04]; Uniformed Services University of the Health Sciences; Department of Defense [CO85DP] FX This work was supported by NICHD, NIH intramural project Z01-HD-000642-04 to Dr. C.A. Stratakis. This study was supported in part by intramural graduate student grant from the Uniformed Services University of the Health Sciences (MFK) and Department of Defense grant CO85DP (TJW). NR 58 TC 8 Z9 8 U1 2 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD JUN PY 2012 VL 37 IS 6 BP 836 EP 843 DI 10.1016/j.psyneuen.2011.09.016 PG 8 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 939VI UT WOS:000303846800012 PM 22024111 ER PT J AU Jasmin, K Casasanto, D AF Jasmin, Kyle Casasanto, Daniel TI The QWERTY Effect: How typing shapes the meanings of words. SO PSYCHONOMIC BULLETIN & REVIEW LA English DT Article DE Motor action; Meaning; Orthography; Typing; QWERTY; Valence ID LANGUAGE AB The QWERTY keyboard mediates communication for millions of language users. Here, we investigated whether differences in the way words are typed correspond to differences in their meanings. Some words are spelled with more letters on the right side of the keyboard and others with more letters on the left. In three experiments, we tested whether asymmetries in the way people interact with keys on the right and left of the keyboard influence their evaluations of the emotional valence of the words. We found the predicted relationship between emotional valence and QWERTY key position across three languages (English, Spanish, and Dutch). Words with more right-side letters were rated as more positive in valence, on average, than words with more left-side letters: the . This effect was strongest in new words coined after QWERTY was invented and was also found in pseudowords. Although these data are correlational, the discovery of a similar pattern across languages, which was strongest in neologisms, suggests that the QWERTY keyboard is shaping the meanings of words as people filter language through their fingers. Widespread typing introduces a new mechanism by which semantic changes in language can arise. C1 [Jasmin, Kyle] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Jasmin, Kyle; Casasanto, Daniel] MPI Psycholinguist, Neurobiol Language Dept, Nijmegen, Netherlands. [Casasanto, Daniel] Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands. [Casasanto, Daniel] New Sch Social Res, Dept Psychol, New York, NY 10011 USA. [Jasmin, Kyle] UCL, Inst Cognit Neurosci, London, England. RP Casasanto, D (reprint author), New Sch Social Res, Dept Psychol, 80 5th Ave,7th Floor, New York, NY 10011 USA. EM casasanto@alum.mit.edu NR 16 TC 17 Z9 20 U1 0 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1069-9384 EI 1531-5320 J9 PSYCHON B REV JI Psychon. Bull. Rev. PD JUN PY 2012 VL 19 IS 3 BP 499 EP 504 DI 10.3758/s13423-012-0229-7 PG 6 WC Psychology, Mathematical; Psychology, Experimental SC Psychology GA 940JV UT WOS:000303886700016 PM 22391999 ER PT J AU Kim, YS Brechbiel, MW AF Kim, Young-Seung Brechbiel, Martin W. TI An overview of targeted alpha therapy SO TUMOR BIOLOGY LA English DT Article DE Radioimmunotherapy; Alpha particles; Antibody; Actinium; Astatine; Bismuth; Lead; Radium; Thorium; Alpha targeted therapy; Alpha emitters ID DISSEMINATED PERITONEAL DISEASE; BIFUNCTIONAL CHELATING-AGENT; PARTICLE-EMITTING AT-211; MONOCLONAL-ANTIBODY U36; SQUAMOUS-CELL CARCINOMA; OVARIAN-CANCER; BREAST-CANCER; NUDE-MICE; AC-225/BI-213 GENERATOR; RADIONUCLIDE GENERATOR AB The effectiveness of targeted alpha-therapy (TAT) can be explained by the properties of alpha-particles. Alpha particles are helium nuclei and are similar to 8,000 times larger than beta(-)-particles (electrons). When emitted from radionuclides that decay via an alpha-decay pathway, they release enormous amounts of energy over a very short distance. Typically, the range of alpha-particles in tissue is 50-100 mu m and they have high linear energy transfer (LET) with a mean energy deposition of 100 keV/mu m, providing a more specific tumor cell killing ability without damage to the surrounding normal tissues than beta(-)-emitters. Due to these properties, the majority of pre-clinical and clinical trials have demonstrated that alpha-emitters such as Ac-225, At-211, Bi-212, Bi-213, Pb-212, Ra-223, and Th-227 are ideal for the treatment of smaller tumor burdens, micrometastatic disease, and disseminated disease. Even though these alpha-emitters have favorable properties, the development of TAT has been limited by high costs, unresolved chemistry, and limited availability of the radionuclides. To overcome these limitations, more potent isotopes, additional sources, and more efficient isotope production methods should be addressed. Furthermore, better chelation and labeling methods with the improvements of isotope delivery, targeting vehicles, molecular targets, and identification of appropriate clinical applications are still required. C1 [Kim, Young-Seung; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Rm B3B69, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We also thank Diane Milenic for assistance in assembling the manuscript. NR 122 TC 48 Z9 48 U1 5 U2 65 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1010-4283 J9 TUMOR BIOL JI Tumor Biol. PD JUN PY 2012 VL 33 IS 3 SI SI BP 573 EP 590 DI 10.1007/s13277-011-0286-y PG 18 WC Oncology SC Oncology GA 935PA UT WOS:000303530200002 PM 22143940 ER PT J AU Kramer-Marek, G Capala, J AF Kramer-Marek, Gabriela Capala, Jacek TI The role of nuclear medicine in modern therapy of cancer SO TUMOR BIOLOGY LA English DT Article DE Nuclear medicine; Molecular imaging; PET; SPECT; Cancer diagnosis; Cancer therapy ID POSITRON-EMISSION-TOMOGRAPHY; PROLIFERATIVE ACTIVITY; AFFIBODY MOLECULES; MEMBRANE ANTIGEN; PROSTATE-CANCER; BREAST-CANCER; TUMOR HYPOXIA; NECK-CANCER; PET; RADIOIMMUNOTHERAPY AB Nuclear medicine is a multidisciplinary field that develops and uses instrumentation and tracers (radiopharmaceuticals) to study physiological processes and noninvasively diagnose, stage, and treat diseases. Particularly, it offers a unique means to study cancer biology in vivo and to optimize cancer therapy for individual patients. A tracer is either a radionuclide alone, such as iodine-131 or a radiolabel in a carrier molecule such as F-18 in fluorodeoxyglucose (F-18-FDG), or other feasible radionuclide attached to a drug, a protein, or a peptide, which when introduced into the body, would accumulate in the tissue of interest. Nuclear medicine imaging, including single-photon emission computer tomography and positron emission tomography, can provide important quantitative and functional information about normal tissues or disease conditions, in contrast to conventional, anatomical imaging techniques such as ultrasound, computed tomography, or magnetic resonance imaging. For treatment, tumor-targeting agents, conjugated with therapeutic radionuclides, may be used to deposit lethal radiation at tumor sites. This review outlines the role of nuclear medicine in modern cancer therapy. C1 [Capala, Jacek] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Kramer-Marek, Gabriela] Univ Silesia, August Chelkowski Inst Phys, Katowice, Poland. [Kramer-Marek, Gabriela] Indiana Univ, Sch Med, Div Endocrinol, Indianapolis, IN USA. RP Capala, J (reprint author), NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. EM capalaj@mail.nih.gov NR 59 TC 8 Z9 8 U1 1 U2 13 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1010-4283 J9 TUMOR BIOL JI Tumor Biol. PD JUN PY 2012 VL 33 IS 3 SI SI BP 629 EP 640 DI 10.1007/s13277-012-0373-8 PG 12 WC Oncology SC Oncology GA 935PA UT WOS:000303530200007 PM 22446937 ER PT J AU Yu, DK Shi, J Sun, T Du, XL Liu, L Zhang, XJ Lu, C Tang, XH Li, M Xiao, LC Zhang, ZW Yuan, QP Yang, M AF Yu, Dianke Shi, Juan Sun, Tong Du, Xiaoli Liu, Li Zhang, Xiaojiao Lu, Chao Tang, Xiaohu Li, Meng Xiao, Lingchen Zhang, Zhouwei Yuan, Qipeng Yang, Ming TI Pharmacogenetic role of ERCC1 genetic variants in treatment response of platinum-based chemotherapy among advanced non-small cell lung cancer patients SO TUMOR BIOLOGY LA English DT Article DE Chemotherapy; ERCC1; Meta-analysis; Pharmacogenetics; Platinum ID NUCLEOTIDE EXCISION-REPAIR; DNA-REPAIR; POLYMORPHISMS; CISPLATIN; SURVIVAL; XPD; ENDONUCLEASE; METAANALYSIS; ASSOCIATION; EXPRESSION AB The excision repair cross-complementation group 1 (ERCC1) plays an essential role in DNA repair and has been linked to resistance to platinum-based anticancer drugs among advanced non-small cell lung cancer (NSCLC) patients. We systematically evaluate whether ERCC1 Asn118Asn and C8092A genetic variants are associated with treatment response of platinum chemotherapy. We preformed a meta-analysis using ten eligible cohort studies (including 11 data-sets) with a total of 1,252 NSCLC patients to summarize the existing data on the association between the ERCC1 Asn118Asn and C8092A polymorphisms and response to platinum regiments. Odds ratio or hazard ratio with 95% confidence interval were calculated to estimate the correlation. We found that neither ERCC1 C8092A polymorphism nor Asn118Asn variant is associated with different response of platinum-based treatment among advanced NSCLC patients. Additionally, these two genetic variants are not related to treatment response in either Caucasian patients or Asian patients. Our meta-analysis indicates that the ERCC1 Asn118Asn and C8092A polymorphisms may not be good prognostic biomarkers for platinum-based chemotherapy in patients with stage III-IV NSCLC. C1 [Yuan, Qipeng; Yang, Ming] Beijing Univ Chem Technol, Coll Life Sci & Technol, Beijing 100029, Peoples R China. [Yu, Dianke] Chinese Acad Med Sci, State Key Lab Mol Oncol, Dept Etiol & Carcinogenesis, Canc Inst & Hosp, Beijing 100730, Peoples R China. [Yu, Dianke] Peking Union Med Coll, Beijing 100021, Peoples R China. [Shi, Juan; Liu, Li; Zhang, Xiaojiao; Lu, Chao; Tang, Xiaohu; Li, Meng; Xiao, Lingchen; Zhang, Zhouwei; Yuan, Qipeng; Yang, Ming] Beijing Univ Chem Technol, Coll Life Sci & Technol, Beijing, Peoples R China. [Sun, Tong] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sun, Tong] Harvard Univ, Sch Med, Boston, MA USA. [Du, Xiaoli] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Yuan, QP (reprint author), Beijing Univ Chem Technol, Coll Life Sci & Technol, POB 53, Beijing 100029, Peoples R China. EM yuanqp@mail.buct.edu.cn; yangm@mail.buct.edu.cn RI Yang, Ming/G-4705-2012 OI Yang, Ming/0000-0002-7722-7487 FU Beijing Nova Program [2010B013]; Fundamental Research Funds for the Central Universities [ZZ1234]; National Natural Science Foundation of China [30872968] FX This work was supported by Beijing Nova Program (no. 2010B013 to M. Yang), the Fundamental Research Funds for the Central Universities (no. ZZ1234 to M. Yang) and National Natural Science Foundation of China (no. 30872968). NR 29 TC 13 Z9 14 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1010-4283 J9 TUMOR BIOL JI Tumor Biol. PD JUN PY 2012 VL 33 IS 3 SI SI BP 877 EP 884 DI 10.1007/s13277-011-0314-y PG 8 WC Oncology SC Oncology GA 935PA UT WOS:000303530200033 PM 22249976 ER PT J AU Gara, N Zhao, X Collins, MT Chong, WH Kleiner, DE Liang, TJ Ghany, MG Hoofnagle, JH AF Gara, N. Zhao, X. Collins, M. T. Chong, W. H. Kleiner, D. E. Liang, T. Jake Ghany, M. G. Hoofnagle, J. H. TI Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID LAMIVUDINE; OSTEOMALACIA; DIPIVOXIL; FIBROBLAST-GROWTH-FACTOR-23; RESISTANCE; ENTECAVIR; DISEASE AB Background Adefovir and tenofovir are nucleotide analogues used as long-term therapy of chronic hepatitis B. Side effects are few, but prolonged and high-dose therapy has been associated with proximal renal tubular dysfunction (RTD). Aim To assess the incidence of RTD during long-term nucleotide therapy of chronic hepatitis B. Methods A total of 51 patients being treated at the Clinical Center, National Institutes of Health were studied. Diagnosis of RTD required de novo appearance of at least three of five features: hypophosphataemia, hypouricaemia, serum creatinine elevation, proteinuria or glucosuria. Results Among 51 patients treated for 110 (mean 7.4) years with adefovir (n = 42), tenofovir (n = 4) or adefovir followed by tenofovir (n = 5), 7 (14%) developed RTD. Time to onset ranged from 22 to 94 (mean 49) months with an estimated 10-year cumulative rate of 15%. All seven had low urinary percent maximal tubular reabsorption of phosphate (<82%). Patients with RTD were older (58 vs. 44 years; P = 0.01) and had lower baseline glomerular filtration rates (82 vs. 97 cc/min; P = 0.08) compared to those without; but did not differ in other features. Six patients with RTD were switched to entecavir, all subsequently had improvements in serum phosphate (2.03.0 mg/dL), creatinine (1.61.1 mg/dL), uric acid (2.73.8 mg/dL) and proteinuria. Conclusions Renal tubular dysfunction develops in 15% of patients treated with adefovir or tenofovir for 29 years and is partially reversible with change to other antivirals. Monitoring for serum phosphate, creatinine and urinalysis is prudent during long-term adefovir and tenofovir therapy. C1 [Gara, N.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Collins, M. T.; Chong, W. H.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. [Kleiner, D. E.] NCI, Pathol Branch, NIH, Bethesda, MD 20892 USA. RP Gara, N (reprint author), NIDDK, Liver Dis Branch, NIH, CRC 4-5722,10 Ctr Dr, Bethesda, MD 20892 USA. EM naveen.gara@nih.gov OI Kleiner, David/0000-0003-3442-4453 FU Intramural Divisions of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Dental and Craniofacial Research; National Cancer Institute of the National Institutes of Health FX Declaration of funding interests: This study was supported by the Intramural Divisions of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Dental and Craniofacial Research, and National Cancer Institute of the National Institutes of Health. NR 30 TC 57 Z9 65 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JUN PY 2012 VL 35 IS 11 BP 1317 EP 1325 DI 10.1111/j.1365-2036.2012.05093.x PG 9 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 934IF UT WOS:000303437000008 PM 22506503 ER PT J AU Rostovtseva, TK AF Rostovtseva, Tatiana K. TI VDAC structure, function, and regulation of Mitochondrial and Cellular Metabolism SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Editorial Material C1 NICHD, Program Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Rostovtseva, TK (reprint author), NICHD, Program Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 3 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 JUN PY 2012 VL 1818 IS 6 SI SI BP 1437 EP 1437 DI 10.1016/j.bbamem.2012.03.018 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 933KI UT WOS:000303359900001 PM 22502648 ER PT J AU Das, S Steenbergen, C Murphy, E AF Das, Samarjit Steenbergen, Charles Murphy, Elizabeth TI Does the voltage dependent anion channel modulate cardiac ischemia-reperfusion injury? SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Review DE Mitochondrion; Ischemia; Cardioprotection; Phosphotylation ID MITOCHONDRIAL PERMEABILITY TRANSITION; APOPTOTIC CELL-DEATH; GLYCOGEN-SYNTHASE KINASE-3-BETA; RAT-LIVER MITOCHONDRIA; HEXOKINASE-II; CYTOCHROME-C; MEMBRANE-PROTEINS; VDAC CHANNELS; BINDING; TUBULIN AB The voltage dependent anion channel (VDAC) provides exchange of metabolites, anions, and cations across the outer mitochondrial membrane. VDAC provides substrates and adenine nucleotides necessary for electron transport and therefore plays a key role in regulating mitochondrial bioenergetics. VDAC has also been suggested to regulate the response to cell death signaling. Emerging data show that VDAC is regulated by protein-protein interactions as well as by post-translational modifications. This review will focus on the regulation of VDAC and its potential role in regulating cell death in cardiac ischemia-reperfusion. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondria! metabolism. Published by Elsevier B.V. C1 [Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. NHLBI, Dept Pathol, Johns Hopkins Med Inst, NIH, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), NHLBI, Syst Biol Ctr, NIH, Room 8N202,Build 10,MSC 1770,10 Ctr Dr, Bethesda, MD 20892 USA. EM murphyl@mail.nih.gov FU Intramural NIH HHS [ZIA HL006059-02, ZIA HL002065-04, ZIA HL002066-04]; NHLBI NIH HHS [R01 HL039752-25, R01 HL039752] NR 65 TC 7 Z9 7 U1 0 U2 4 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 JUN PY 2012 VL 1818 IS 6 SI SI BP 1451 EP 1456 DI 10.1016/j.bbamem.2011.11.008 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 933KI UT WOS:000303359900004 PM 22100866 ER PT J AU Rostovtseva, TK Bezrukov, SM AF Rostovtseva, Tatiana K. Bezrukov, Sergey M. TI VDAC inhibition by tubulin and its physiological implications SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Review DE Voltage-dependent anion channel; Mitochondria; Microtubule; phosphorylation; Signaling network; Selectivity ID DEPENDENT ANION CHANNEL; MITOCHONDRIAL OUTER-MEMBRANE; ADENINE-NUCLEOTIDE TRANSPORT; BETA-TUBULIN; NEUROSPORA-CRASSA; MESSENGER-RNA; CYCLIC-AMP; CELL-DEATH; IN-VIVO; VOLTAGE AB Regulation of mitochondrial outer membrane (MOM) permeability has dual importance: in normal metabolite and energy exchange between mitochondria and cytoplasm, and thus in control of respiration, and in apoptosis by release of apoptogenic factors into the cytosol. However, the mechanism of this regulation involving the voltage-dependent anion channel (VDAC), the major channel of MOM, remains controversial. For example, one of the long-standing puzzles was that in permeabilized cells, adenine nucleotide translocase is less accessible to cytosolic ADP than in isolated mitochondria. Still another puzzle was that according to channel-reconstitution experiments, voltage regulation of VDAC is limited to potentials exceeding 30 mV, which are believed to be much too high for MOM. We have solved these puzzles and uncovered multiple new functional links by identifying a missing player in the regulation of VDAC and, hence, MOM permeability the cytoskeletal protein tubulin. We have shown that depending on VDAC phosphorylation state and applied voltage, nanomolar to micromolar concentrations of dimeric tubulin induce functionally important reversible blockage of VDAC reconstituted into planar phospholipid membranes. The voltage sensitivity of the blockage equilibrium is truly remarkable. It is described by an effective "gating charge" of more than ten elementary charges, thus making the blockage reaction as responsive to the applied voltage as the most voltage-sensitive channels of electrophysiology are. Analysis of the tubulin-blocked state demonstrated that although this state is still able to conduct small ions, it is impermeable to ATP and other multi-charged anions because of the reduced aperture and inversed selectivity. The findings, obtained in a channel reconstitution assay, were supported by experiments with isolated mitochondria and human hepatoma cells. Taken together, these results suggest a previously unknown mechanism of regulation of mitochondrial energetics, governed by VDAC interaction with tubulin at the mitochondria-cytosol interface. Immediate physiological implications include new insights into serine/threonine kinase signaling pathways, Ca2+ homeostasis, and cytoskeleton/microtubule activity in health and disease, especially in the case of the highly dynamic microtubule network which is characteristic of cancerogenesis and cell proliferation. In the present review, we speculate how these findings may help to identify new mechanisms of mitochondria-associated action of chemotherapeutic microtubule-targeting drugs, and also to understand why and how cancer cells preferentially use inefficient glycolysis rather than oxidative phosphorylation (Warburg effect). This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism. Published by Elsevier B.V. C1 [Rostovtseva, Tatiana K.; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Phys & Struct Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Rostovtseva, TK (reprint author), NICHD, Lab Phys & Struct Biol, PPB, NIH, 9000 Rockville Pike,Bldg 9,Rm 1E-106, Bethesda, MD 20892 USA. EM rostovtt@mail.nih.gov FU NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX These studies were supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development The authors thank Philip Gurney and Kely Sheldon for fruitful discussions. NR 79 TC 48 Z9 48 U1 2 U2 14 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 JUN PY 2012 VL 1818 IS 6 SI SI BP 1526 EP 1535 DI 10.1016/j.bbamem.2011.11.004 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 933KI UT WOS:000303359900011 PM 22100746 ER PT J AU Shuch, B Bratslavsky, G Shih, J Vourganti, S Finley, D Castor, B Treat, E Linehan, WM Pantuck, AJ Said, JW Belldegrun, AS AF Shuch, Brian Bratslavsky, Gennady Shih, Joanna Vourganti, Srinivas Finley, David Castor, Brandon Treat, Eric Linehan, W. Marston Pantuck, Allan J. Said, Jonathan W. Belldegrun, Arie S. TI Impact of pathological tumour characteristics in patients with sarcomatoid renal cell carcinoma SO BJU INTERNATIONAL LA English DT Article DE sarcomatoid; kidney cancer; adjuvant; prognosis; RCC ID RADICAL NEPHRECTOMY; HISTOLOGIC SUBTYPES; THERAPY; CLASSIFICATION; EXPERIENCE; SURVIVAL; INVASION; STAGE AB Study Type Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Sarcomatoid renal cell carcinoma can occur in the setting of all histological subtypes of kidney cancer. These tumours are very aggressive and many patients present with disseminated disease. Long-term survival is poor and the durable responses to systemic therapy are infrequent. Our large cohort analyses the influence of pathological tumour characteristics in determining prognosis for patients with sarcomatoid renal cell carcinoma undergoing surgical resection. This series helps define the prognostic influence of histological subtype, type of sarcomatoid morphology, the percentage necrosis and sarcomatoid features, and the presence of microvascular invasion. OBJECTIVES To examine the influence of pathological tumour characteristics on survival to aid prognostication and clinical trial design. Patients with sarcomatoid renal cell carcinoma (sRCC) are known to have poor prognosis and response to systemic therapy. PATIENTS AND METHODS A single-centre database was reviewed to identify all patients with sRCC. Clinical variables and pathological information, including histology, necrosis, percentage of sarcomatoid features (PSF) and microvascular invasion (MVI), were recorded and correlated to outcome. RESULTS Analyses of 104 patients with sRCC found that the median (range) size of tumours was 9.5 cm (2.530), 65% of patients had areas of clear cell histology, and 69.2% had metastatic disease at presentation. The PSF did not influence tumour size, stage, necrosis, MVI, nodes or metastasis. A total of 85 patients (81.7%) died during the follow-up period with a median (95% confidence interval [CI]) survival of 5.9 months (4.78.9). In the overall cohort, Eastern Cooperative Group performance status (ECOGPS), tumour size and metastatic disease were independent predictors of poor survival. MVI, PSF and percentage necrosis were strongly associated with outcome but were not independent predictors of outcome. A multivariate risk model was established that incorporated six covariates (tumour size, MVI, ECOGPS, PSF, necrosis, and metastatic disease) to produce a predictive tool. CONCLUSIONS Both patients with localized and metastatic sRCC have very poor survival outcomes. Pathological features MVI, PSF and necrosis are important predictors of survival and could be used in a prognostic model while grade and histology do not influence prognosis. A prognostic model, if validated, could aid in patient counselling and/or clinical trial design. C1 [Shuch, Brian] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Shuch, Brian; Finley, David; Treat, Eric; Pantuck, Allan J.; Said, Jonathan W.; Belldegrun, Arie S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Shih, Joanna] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. [Castor, Brandon; Said, Jonathan W.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol, Los Angeles, CA 90095 USA. RP Shuch, B (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr MSC 1107,Bldg 10,CRC,Room 1-5848, Bethesda, MD 20892 USA. EM brian.shuch@nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX A proportion of research support was provided by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 28 TC 29 Z9 32 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 J9 BJU INT JI BJU Int. PD JUN PY 2012 VL 109 IS 11 BP 1600 EP 1606 DI 10.1111/j.1464-410X.2011.10785.x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 936NX UT WOS:000303598400010 PM 22221668 ER PT J AU Hansen, KA Hillenbrand, SF Ungerleider, LG AF Hansen, Kathleen A. Hillenbrand, Sarah F. Ungerleider, Leslie G. TI Human Brain Activity Predicts Individual Differences in Prior Knowledge Use during Decisions SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID HUMAN VISUAL-CORTEX; EVENT-RELATED FMRI; PREFRONTAL CORTEX; PARIETAL CORTEX; PERCEPTUAL CATEGORIZATION; NEURAL REPRESENTATION; PRIOR PROBABILITY; FUNCTIONAL MRI; STROOP TASK; PERFORMANCE AB Studies by cognitive psychologists, psychophysicists, neuroscientists, and economists provide ample evidence that humans use prior knowledge to bias decisions adaptively. In this study, we sought to locate and investigate the brain areas mediating this behavior. Participants viewed ambiguous abstract shapes and decided whether a shape was of Category A (smoother) or B (bumpier). The decision was made in the context of one of two prior knowledge cues, 80/20 and 50/50. The 80/20 cue indicated that upcoming shapes had an 80% probability of being of one category, for example, B, and a 20% probability of being of the other. The 50/50 cue indicated that upcoming shapes had an equal probability of being of either category. The shift in bias produced by the 80/20 cue relative to the 50/50 cue was of the predicted sign for every subject but varied in magnitude. We searched for brain regions in which activity changes correlated with the extent of the bias shift; these were dorsolateral pFC (middle frontal gyrus), inferior frontal junction, anterior insula, inferior parietal lobule, intraparietal sulcus, head of the caudate, posterior cingulate cortex, and fusiform gyrus. The findings indicate that an individual's brain activity in these regions reflects the extent to which that individual makes use of prior knowledge to bias decisions. We also created within-ROI tuning curves by binning the shape curvature levels and plotting brain activity levels at each of the nine bins. In the fronto-parietal and anterior insula ROIs, the tuning curves peaked at targets contraindicated by the prior knowledge cue (e.g., Category B targets if the 80/20 cue meant 20% probability B). The increased activity in these regions likely indicates a no-go response when sufficient perceptual evidence favored the alternative contraindicated by the 80/20 cue. C1 [Hansen, Kathleen A.; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Hillenbrand, Sarah F.] Univ Calif Berkeley, Berkeley, CA 94720 USA. RP Hansen, KA (reprint author), NIMH, Lab Brain & Cognit, NIH, Bldg 10,Room 4C104, Bethesda, MD 20892 USA. EM hansenka@mail.nih.gov FU National Institute of Mental Health FX We thank Chris Baker, Hauke Heekeren, Shruti Japee, Sean Marrett, Alex Martin, and Lionel Rauth for helpful comments. This work was supported by the National Institute of Mental Health Intramural Research Program. NR 58 TC 2 Z9 2 U1 3 U2 16 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD JUN PY 2012 VL 24 IS 6 BP 1462 EP 1475 PG 14 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 935EK UT WOS:000303501600016 PM 22401286 ER PT J AU Strand, BH Murray, ET Guralnik, J Hardy, R Kuh, D AF Strand, Bjorn Heine Murray, Emily T. Guralnik, Jack Hardy, Rebecca Kuh, Diana TI Childhood social class and adult adiposity and blood-pressure trajectories 36-53 years: gender-specific results from a British birth cohort SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; BODY-MASS INDEX; SOCIOECONOMIC POSITION; PHYSICAL-ACTIVITY; YOUNG FINNS; EDUCATIONAL-ATTAINMENT; WEIGHT-GAIN; LIFE-STYLE; AGE 53; OBESITY AB Background In this study, the authors investigate gender-specific effects of childhood socio-economic position (SEP) on adiposity and blood pressure at three time points in adulthood. Methods Mixed models were used to assess the association of childhood SEP with body mass index (BMI), waist circumference, systolic blood pressure (SBP) and diastolic blood pressure (DBP) at ages 36, 43 and 53 years in a British birth cohort. Results The adverse effect of lower childhood SEP on adiposity increased between ages 36 and 53 years in women (BMI: trend test: p=0.03) and remained stable in men, but the opposite was seen for SBP, where inequalities increased in men (p=0.01). Childhood SEP inequalities in DBP were stable with age in both men and women. Educational attainment mediated some but not all of the effects of childhood SEP on adiposity and SBP, and their rate of change; adult social class was a less important mediator. Conclusion Childhood SEP is important for adult adiposity and blood pressure across midlife, especially for BMI in women and for blood pressure in men. Thus, pathways to adult health differ for men and women, and public health policies aimed at reducing social inequalities need to start early in life and take account of gender. C1 [Strand, Bjorn Heine; Murray, Emily T.; Hardy, Rebecca; Kuh, Diana] MRC Natl Survey Hlth & Dev, MRC Unit Lifelong Hlth & Ageing, London, England. [Strand, Bjorn Heine; Murray, Emily T.; Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Strand, BH (reprint author), Norwegian Inst Publ Hlth, Marcus Thranes Gt 6,POB 4404, N-0403 Oslo, Norway. EM heine@fhi.no OI Strand, Bjorn/0000-0003-4385-8886 FU MRC Unit for Lifelong Health and Ageing in UK; National Institute on Aging, NIH in USA; Research Council of Norway FX The manuscript is funded by MRC Unit for Lifelong Health and Ageing in UK and supported in part by the Intramural Research Program, National Institute on Aging, NIH in USA, and the Research Council of Norway. NR 47 TC 10 Z9 10 U1 0 U2 6 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD JUN PY 2012 VL 66 IS 6 BP 512 EP 518 DI 10.1136/jech.2010.115220 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 936RX UT WOS:000303608800019 PM 21098826 ER PT J AU Bulken-Hoover, JD Jackson, WM Ji, YM Volger, JA Tuan, RS Nesti, LJ AF Bulken-Hoover, Jamie D. Jackson, Wesley M. Ji, Youngmi Volger, Jared A. Tuan, Rocky S. Nesti, Leon J. TI Inducible Expression of Neurotrophic Factors by Mesenchymal Progenitor Cells Derived from Traumatically Injured Human Muscle SO MOLECULAR BIOTECHNOLOGY LA English DT Article DE Mesenchymal stem cells; Nerve regeneration; Tissue engineering; BDNF; Traumatized muscle; Neurotrophic induction ID PERIPHERAL-NERVE REGENERATION; MARROW STROMAL CELLS; STEM-CELLS; SCIATIC-NERVE; RETINOIC ACID; TISSUE; DIFFERENTIATION; REPAIR; TRANSPLANTATION; ANTIBODIES AB Peripheral nerve damage frequently accompanies musculoskeletal trauma and repair of these nerves could be enhanced by the targeted application of neurotrophic factors (NTFs), which are typically expressed by endogenous cells that support nerve regeneration. Injured muscle tissues express NTFs to promote reinnervation as the tissue regenerates, but the source of these factors from within the muscles is not fully understood. We have previously identified a population of mesenchymal progenitor cells (MPCs) in traumatized muscle tissue with properties that support tissue regeneration, and our hypothesis was that MPCs also secrete the NTFs that are associated with muscle tissue reinnervation. We determined that MPCs express genes associated with neurogenic function and measured the protein-level expression of specific NTFs with known functions to support nerve regeneration. We also demonstrated the effectiveness of a neurotrophic induction protocol to enhance the expression of the NTFs, which suggests that the expression of these factors may be modulated by the cellular environment. Finally, neurotrophic induction affected the expression of cell surface markers and proliferation rate of the MPCs. Our findings indicate that traumatized muscle-derived MPCs may be useful as a therapeutic cell type to enhance peripheral nerve regeneration following musculoskeletal injury. C1 [Bulken-Hoover, Jamie D.; Jackson, Wesley M.; Volger, Jared A.; Nesti, Leon J.] NIAMSD, Cartilage Biol & Orthopaed Branch, US Dept HHS, NIH, Bethesda, MD 20892 USA. [Bulken-Hoover, Jamie D.; Jackson, Wesley M.; Ji, Youngmi; Volger, Jared A.; Nesti, Leon J.] NIAMSD, Clin & Expt Orthopaed Lab, US Dept HHS, NIH, Bethesda, MD 20892 USA. [Bulken-Hoover, Jamie D.; Volger, Jared A.; Nesti, Leon J.] Walter Reed Army Med Ctr, Dept Orthopaed & Rehabil, Washington, DC 20307 USA. [Tuan, Rocky S.] Univ Pittsburgh, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, Dept Bioengn,Sch Med, Pittsburgh, PA 15219 USA. RP Nesti, LJ (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, US Dept HHS, NIH, 50 South Dr,Room 1525,MSC 8022, Bethesda, MD 20892 USA. EM rst13@pitt.edu; nestil@mail.nih.gov FU NIH [Z01 AR41131, 1ZIAAR041191]; Department of Defense Military Amputee Research at WRAMC [PO5-A011]; Comprehensive Neurosciences Program [CNP-2008-CR01]; Peer-Reviewed Orthopaedic Research Program [W81XWH-10-2-0084]; Commonwealth of Pennsylvania Department of Health FX The study was supported in part by the NIH Intramural Research Program (Z01 AR41131 and 1ZIAAR041191), grants from the Department of Defense Military Amputee Research Program at WRAMC (PO5-A011), Comprehensive Neurosciences Program (CNP-2008-CR01) and Peer-Reviewed Orthopaedic Research Program (W81XWH-10-2-0084), and the Commonwealth of Pennsylvania Department of Health was obtained. The authors thank Dr. Paul Manner, University of Washington, for providing human skeletal tissues, James Simone, NIAMS Flow Cytometry Group, for assistance with immunotyping, and Ibardo Zambrano and Richard Booth for technical assistance. NR 40 TC 2 Z9 2 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1073-6085 J9 MOL BIOTECHNOL JI Mol. Biotechnol. PD JUN PY 2012 VL 51 IS 2 BP 128 EP 136 DI 10.1007/s12033-011-9445-z PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 936JQ UT WOS:000303587100004 PM 21904958 ER PT J AU Purswani, MU Chernoff, MC Mitchell, CD Seage, GR Zilleruelo, G Abitbol, C Andiman, WA Kaiser, KA Spiegel, H Oleske, JM AF Purswani, Murli U. Chernoff, Miriam C. Mitchell, Charles D. Seage, George R., III Zilleruelo, Gaston Abitbol, Carolyn Andiman, Warren A. Kaiser, Kathleen A. Spiegel, Hans Oleske, James M. CA IMPAACT 219 219C Study Team TI Chronic kidney disease associated with perinatal HIV infection in children and adolescents SO PEDIATRIC NEPHROLOGY LA English DT Article DE HIVAN; HIV immune complex kidney disease; FSGS; Renal; Youth; Proteinuria; Biopsy ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; TUBULAR EPITHELIAL-CELLS; RENAL-DISEASE; IGA NEPHROPATHY; GLOMERULONEPHRITIS; BIOPSY; GLOMERULOPATHY; PATHOGENESIS; MORTALITY AB This study describes the incidence, clinical and demographic characteristics, and spectrum of chronic kidney disease (CKD) in youths with perinatal HIV-1 infection. Retrospective analysis between May 1993 and December 2006 of subjects with renal disease followed in the Pediatric AIDS Clinical Trials Group 219/219C multicenter study examining the long-term consequences of perinatal HIV infection. Diagnosis confirmation was made utilizing a questionnaire mailed to research sites. Participants with CKD of other etiology than HIV were excluded. Outcome measures were biopsy-diagnosed CKD and, in the absence of biopsy, HIV-associated nephropathy (HIVAN) using established clinical criteria. Questionnaires on 191 out of 2,102 participants identified 27 cases of CKD: 14 biopsy-diagnosed and 6 clinical cases of HIVAN, and 7 biopsy-diagnosed cases of immune complex-mediated kidney disease (lupus-like nephritis, 3; IgA nephropathy, 2; membranous nephropathy, 2). Incidence rates for CKD associated with HIV in pre-highly active antiretroviral therapy (HAART) (1993-1997) and HAART (1998-2002, 2003-2006) eras were 0.43, 2.84, and 2.79 events per 1,000 person years respectively. In multivariate analysis, black race and viral load a parts per thousand yen100,000 copies/mL (rate ratios 3.28 and 5.05, p a parts per thousand currency signaEuro parts per thousand 0.02) were associated with CKD. A variety of immune complex-mediated glomerulonephritides and HIVAN occurs in this population. Black race and uncontrolled viral replication are risk factors for CKD associated with HIV. C1 [Purswani, Murli U.] Bronx Lebanon Hosp Ctr, Dept Pediat, Albert Einstein Coll Med, Bronx, NY 10457 USA. [Chernoff, Miriam C.; Seage, George R., III] Harvard Univ, Sch Med, Ctr Biostat AIDS Res, Boston, MA USA. [Mitchell, Charles D.] Univ Miami, Miller Sch Med, Div Infect Dis & Immunol, Dept Pediat,Batchelor Childrens Res Inst, Miami, FL 33136 USA. [Seage, George R., III] Harvard Univ, Sch Med, Dept Epidemiol, Boston, MA USA. [Zilleruelo, Gaston; Abitbol, Carolyn] Univ Miami, Miller Sch Med, Dept Pediat, Div Pediat Nephrol, Miami, FL 33136 USA. [Andiman, Warren A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Andiman, Warren A.] Yale Univ, Dept Pediat, Sch Publ Hlth, New Haven, CT 06520 USA. [Kaiser, Kathleen A.] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Spiegel, Hans] NIAID, Microbicide Res Branch, Prevent Sci Program, Div AIDS DAIDS, Bethesda, MD 20892 USA. [Oleske, James M.] Univ Med & Dent New Jersey, Dept Pediat, New Jersey Med Sch, Newark, NJ 07103 USA. [Andiman, Warren A.] Yale Univ, Dept Epidemiol, Sch Publ Hlth, New Haven, CT USA. RP Purswani, MU (reprint author), Bronx Lebanon Hosp Ctr, Dept Pediat, Albert Einstein Coll Med, 1685 Morris Ave,Suite 1G, Bronx, NY 10457 USA. EM mpurswan@bronxleb.org RI Oleske, James/C-1951-2016 OI Oleske, James/0000-0003-2305-5605 FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [AI068632]; Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases [5 U01 AI41110]; Pediatric AIDS Clinical Trials Group (PACTG); IMPAACT Group [1 U01 AI068616]; NICHD [N01-DK-9-001/HHSN267200800001C] FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID; U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH; AI068632). This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and #1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by the NICHD (contract number N01-DK-9-001/HHSN267200800001C). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders were not involved in the design and conducting of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. NR 48 TC 6 Z9 6 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUN PY 2012 VL 27 IS 6 BP 981 EP 989 DI 10.1007/s00467-011-2097-1 PG 9 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 934OC UT WOS:000303452700015 PM 22366874 ER PT J AU Vytal, K Cornwell, B Arkin, N Grillon, C AF Vytal, Katherine Cornwell, Brian Arkin, Nicole Grillon, Christian TI Describing the interplay between anxiety and cognition: From impaired performance under low cognitive load to reduced anxiety under high load SO PSYCHOPHYSIOLOGY LA English DT Article DE Anxiety; Cognition; Emotion; Startle blink; Healthy volunteers; Working memory ID N-BACK TASKS; WORKING-MEMORY; SELECTIVE ATTENTION; PREFRONTAL CORTEX; EMOTION; DISORDERS; AMYGDALA; INTEGRATION; EFFICIENCY; CONTEXT AB Anxiety impairs the ability to think and concentrate, suggesting that the interaction between emotion and cognition may elucidate the debilitating nature of pathological anxiety. Using a verbal n-back task that parametrically modulated cognitive load, we explored the effect of experimentally induced anxiety on task performance and the startle reflex. Findings suggest there is a crucial inflection point between moderate and high cognitive load, where resources shift from anxious apprehension to focus on task demands. Specifically, we demonstrate that anxiety impairs performance under low load, but is reduced when subjects engage in a difficult task that occupies executive resources. We propose a two-component model of anxiety that describes a cognitive mechanism behind performance impairment and an automatic response that supports sustained anxiety-potentiated startle. Implications for therapeutic interventions and emotional pathology are discussed. C1 [Vytal, Katherine; Cornwell, Brian; Arkin, Nicole; Grillon, Christian] NIMH, NIH, Bethesda, MD 20892 USA. RP Vytal, K (reprint author), NIMH, NIH, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. EM katye.vytal@nih.gov FU National Institute of Mental Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health. NR 47 TC 42 Z9 43 U1 6 U2 35 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD JUN PY 2012 VL 49 IS 6 BP 842 EP 852 DI 10.1111/j.1469-8986.2012.01358.x PG 11 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 935DC UT WOS:000303498100012 PM 22332819 ER PT J AU Wiener, L Battles, H Zadeh, S Smith, CJ Helman, LJ Kim, SY AF Wiener, Lori Battles, Haven Zadeh, Sima Smith, Carly J. Helman, Lee J. Kim, Su Young TI Gastrointestinal stromal tumor: psychosocial characteristics and considerations SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Gastrointestinal stromal tumor (GIST); Psychosocial; Pain; Body image; Posttraumatic stress symptoms; Anxiety ID QUALITY-OF-LIFE; IMATINIB MESYLATE; ABDOMINAL-PAIN; MUTATIONS; DISTRESS; CHILDREN; CANCER; TRIAL; GIST; KIT AB Gastrointestinal stromal tumors (GIST) are very rare, especially within the pediatric population. The National Institutes of Health initiated a multidisciplinary clinic to bring together a worldwide group of healthcare providers with experience in the study and treatment of GIST in order to better understand the disease and to examine whether this is a population at psychosocial risk. Seven GIST clinics have been held to date. Participants completed a GIST Psychosocial Assessment containing items covering demographic factors, family stressors, general health, psychosocial concerns, psychiatric history, and self-identified needs. Our sample consists of 60 adult patients (ages 18-66) and 18 pediatric patients (ages 9-17). Living with pain at least a few days a week was endorsed by those whose self-reported health status was good to excellent (49% of the adult cohort and 25% of the pediatric cohort). Pain was significantly associated with anxiety, difficulties with family relationships, behavior problems, and psychotropic medication use. Body image and appearance concerns were endorsed by over half of the cohort. Post-trauma symptoms were prevalent for those newly diagnosed and those living with GIST for over 15 years. This is the first study to explore the psychosocial impact of GIST. Individuals living with GIST experience chronic pain, post-trauma symptoms and significant anxiety along with an expressed need for interventions to help them manage their anxiety. Due to the chronic nature of this disease, the GIST population is at risk for long-term psychological distress. Psychosocial interventions in pediatric and adult care settings are offered. C1 [Wiener, Lori; Battles, Haven; Zadeh, Sima] NCI, Psychosocial Support & Res Program, Pediat Oncol Branch, Ctr Canc Res,NIH,Pediat Clin, Bethesda, MD 20892 USA. [Smith, Carly J.; Helman, Lee J.; Kim, Su Young] NCI, Mol Oncol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Wiener, L (reprint author), NCI, Psychosocial Support & Res Program, Pediat Oncol Branch, Ctr Canc Res,NIH,Pediat Clin, 10 Ctr Dr,Room 1-6466, Bethesda, MD 20892 USA. EM wienerl@mail.nih.gov FU Center for Cancer Research, National Cancer Institute; GIST Cancer Awareness Foundation; GIST; GIST Support International; Life Raft Group FX This research was supported by the Center for Cancer Research, National Cancer Institute. We would like to thank the patients and their families who attended the NIH pediatric and wildtype GIST clinic (http://www.pediatricgist.cancer.gov). We also appreciate the support of GIST support group organizations including: GIST Cancer Awareness Foundation, GIST Cancer Research Fund, GIST Support International, and Life Raft Group. We would also like to acknowledge Shannon Dier, MA for her assistance with the data coding and analyses following the first four GIST clinics. NR 18 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD JUN PY 2012 VL 20 IS 6 BP 1343 EP 1349 DI 10.1007/s00520-012-1426-7 PG 7 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 935PN UT WOS:000303532000028 PM 22426502 ER PT J AU Hurley, CK Wang, T Spellman, SR Umejiego, J Aljurf, M Askar, M Battiwalla, M Dehn, J Horan, J Marino, SR Marsh, SGE Maurer, D Oudshoorn, M Pidala, J Saber, W Schultz, KR Turner, V Lee, SJ Woolfrey, A AF Hurley, Carolyn K. Wang, Tao Spellman, Stephen R. Umejiego, John Aljurf, Mahmoud Askar, Medhat Battiwalla, Minoo Dehn, Jason Horan, John Marino, Susana R. Marsh, Steven G. E. Maurer, David Oudshoorn, Machteld Pidala, Joseph Saber, Wael Schultz, Kirk R. Turner, Victoria Lee, Stephanie J. Woolfrey, Ann TI IMPACT OF HLA UNIDIRECTIONAL MISMATCHES ON THE OUTCOME OF UNRELATED DONOR HEMATOPOIETIC STEM CELL TRANSPLANTATION SO TISSUE ANTIGENS LA English DT Meeting Abstract CT Joint 16th International HLA and Immunogenetics Workshop/26th European Federation for Immunogenetics Conference/23rd British-Society-of-Histocompatibility-and-Immunogenetics Conference CY MAY 31-JUN 03, 2012 CL Liverpool, ENGLAND SP British Soc Histocompatibil & Immunogenet C1 [Hurley, Carolyn K.] Georgetown Univ Hosp, Washington, DC 20007 USA. [Wang, Tao; Saber, Wael] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Spellman, Stephen R.; Umejiego, John] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Aljurf, Mahmoud] King Faisal Specialist Hosp & Res Ctr, Riyadh 11211, Saudi Arabia. [Askar, Medhat] Cleveland Clin, Allogen Labs, Cleveland, OH 44106 USA. [Battiwalla, Minoo] NHLBI, NIH, Bethesda, MD 20892 USA. [Dehn, Jason] Natl Marrow Donor Program, Minneapolis, MN USA. [Horan, John] Childrens Healthcare Atlanta Egleston, Atlanta, GA USA. [Marino, Susana R.] Univ Chicago Med, Chicago, IL USA. [Marsh, Steven G. E.] Anthony Nolan Res Inst, London, England. [Maurer, David] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Oudshoorn, Machteld] Leiden Univ, Med Ctr, Leiden, Netherlands. [Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Schultz, Kirk R.] British Columbia Childrens Hosp, Vancouver, BC V6H 3V4, Canada. [Turner, Victoria] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Lee, Stephanie J.; Woolfrey, Ann] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. EM sspellma@nmdp.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD JUN PY 2012 VL 79 IS 6 BP 407 EP 407 PG 1 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 935DT UT WOS:000303499800013 ER PT J AU dos Santos, EJM Maia, MHT Maia, A Lima, F Vasconcelos, JM Sena, L Single, R Martin, MP Carrington, M AF dos Santos, Eduardo Jose Melo Maia, Maria H. T. Maia, Andreza Lima, Fabio Vasconcelos, Janaina M. Sena, Leonardo Single, Richard Martin, Maureen P. Carrington, Mary TI KIR POLYMORPHISM IN SOUTH AMERICAN INDIANS SO TISSUE ANTIGENS LA English DT Meeting Abstract CT Joint 16th International HLA and Immunogenetics Workshop/26th European Federation for Immunogenetics Conference/23rd British-Society-of-Histocompatibility-and-Immunogenetics Conference CY MAY 31-JUN 03, 2012 CL Liverpool, ENGLAND SP British Soc Histocompatibil & Immunogenet C1 [dos Santos, Eduardo Jose Melo; Maia, Maria H. T.; Maia, Andreza; Lima, Fabio; Vasconcelos, Janaina M.; Sena, Leonardo] Fed Univ Para, BR-66059 Belem, Para, Brazil. [Single, Richard] Univ Vermont, Burlington, MA USA. [Martin, Maureen P.; Carrington, Mary] NCI Frederick, SAIC Frederick, Frederick, MD USA. EM ejmsantos@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD JUN PY 2012 VL 79 IS 6 BP 562 EP 562 PG 1 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 935DT UT WOS:000303499800388 ER PT J AU Kumar, G Waters, MS Farooque, TM Young, MF Simon, CG AF Kumar, Girish Waters, Michael S. Farooque, Tanya M. Young, Marian F. Simon, Carl G., Jr. TI Freeform fabricated scaffolds with roughened struts that enhance both stem cell proliferation and differentiation by controlling cell shape SO BIOMATERIALS LA English DT Article DE Cell proliferation; Cell spreading; Osteogenesis; Scaffold; Topography; Stem cell ID PROTEIN ADSORPTION; BONE REGENERATION; ARCHITECTURE; INTERFACE; BACTERIA AB We demonstrate that freeform fabricated (FFF) scaffolds with a roughened surface topography can support hBMSC proliferation, while also inducing osteogenic differentiation, for maximized generation of calcified, bone-like tissue. Previously, hBMSCs rapidly proliferated, without osteogenic differentiation, during culture in FFF scaffolds. In contrast, hBMSCs underwent osteogenic differentiation, with slow proliferation, during culture in nanofiber scaffolds. Analysis of cell morphology showed that the topography presented by the nanofiber scaffolds drove hBMSC differentiation by guiding them into a morphology that induced osteogenic differentiation. Herein, we hypothesized that using the high-surface area architecture of FFF scaffolds to present a surface roughness that drives hBMSCs into a morphology that induces osteogenic differentiation would yield a maximum amount differentiated hBMSCs and bone-like tissue. Thus, a solvent etching method was developed that imparted a 5-fold increase in roughness to the surface of the struts of poly(epsilon-caprolactone) (PCL) FFF scaffolds. The etched scaffolds induced osteogenic differentiation of the hBMSCs while un-etched scaffolds did not. The etched scaffolds also supported the same high levels of hBMSC proliferation that un-etched scaffolds supported. Finally, hBMSCs on un-etched scaffolds had a large spread area, while hBMSCs on etched scaffolds has a smaller area and were more rounded, indicating that the surface roughness from the etched scaffolds dictated the morphology of the hBMSCs. The results demonstrate that FFF scaffolds with surface roughness can support hBMSC proliferation, while also inducing osteogenic differentiation, to maximize generation of calcified tissue. This work validates a rational approach to scaffold fabrication where the structure of the scaffold was designed to optimize stem cell function by controlling cell morphology. Published by Elsevier Ltd. C1 [Kumar, Girish; Waters, Michael S.; Farooque, Tanya M.; Simon, Carl G., Jr.] NIST, Div Polymers, Gaithersburg, MD 20899 USA. [Kumar, Girish; Young, Marian F.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Kumar, Girish] US FDA, Div Biol, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Simon, CG (reprint author), NIST, Div Polymers, 100 Bur Dr, Gaithersburg, MD 20899 USA. EM carl.simon@nist.gov FU NIH-NIBIB/NIST NRC; NIST-ARRA NRC; NIST; NIH/NIDCR (National Institute of Dental and Craniofacial Research); Tulane Center for Gene Therapy through NCRR of the NIH [P40RR017447] FX G.K., M.S.W. and T.M.F. were supported by postdoctoral fellowships from NIH-NIBIB/NIST NRC, NIST-ARRA NRC and NIST-ARRA NRC, respectively. This work was supported by NIST and the Intramural Program of the NIH/NIDCR (National Institute of Dental and Craniofacial Research). The hBMSCs employed in this work were provided by the Tulane Center for Gene Therapy through a grant from NCRR of the NIH P40RR017447. The "standard deviation" (S.D.) is the same as the "combined standard uncertainty of the mean" for the purposes of this work. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH, NIBIB, NIDCR or NIST. This article, a contribution of NIST, is not subject to US copyright. Certain equipment and instruments or materials are identified in the paper to adequately specify the experimental details. Such identification does not imply recommendation by NIST, nor does it imply the materials are necessarily the best available for the purpose. NR 33 TC 42 Z9 43 U1 2 U2 23 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD JUN PY 2012 VL 33 IS 16 BP 4022 EP 4030 DI 10.1016/j.biomaterials.2012.02.048 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 929WL UT WOS:000303096300002 PM 22417619 ER PT J AU Huang, XL Zhang, F Lee, S Swierczewska, M Kiesewetter, DO Lang, LX Zhang, GF Zhu, L Gao, HK Choi, HS Niu, G Chen, XY AF Huang, Xinglu Zhang, Fan Lee, Seulki Swierczewska, Magdalena Kiesewetter, Dale O. Lang, Lixin Zhang, Guofeng Zhu, Lei Gao, Haokao Choi, Hak Soo Niu, Gang Chen, Xiaoyuan TI Long-term multimodal imaging of tumor draining sentinel lymph nodes using mesoporous silica-based nanoprobes SO BIOMATERIALS LA English DT Article DE Mesoporous silica nanoparticles; Multimodality imaging; Tumor metastasis; Magnetic resonance imaging; Positron emission tomography; Near-infrared fluorescence imaging ID INTEGRIN ALPHA(V)BETA(3) EXPRESSION; IN-VIVO; QUANTUM DOTS; GAMMA-PROBE; NANOPARTICLES; LYMPHANGIOGENESIS; CANCER; CELLS; FLUORESCENCE; NANORODS AB The imaging of sentinel lymph nodes (SLNs), the first defense against primary tumor metastasis, has been considered as an important strategy for noninvasive tracking tumor metastasis in clinics. In this study, we report the development and application of mesoporous silica-based triple-modal nanoprobes that integrate multiple functional moieties to facilitate near-infrared optical, magnetic resonance (MR) and positron emission tomography (PET) imaging. After embedding near-infrared dye ZW800, the nanoprobe was labeled with T-1 contrast agent Gd3+ and radionuclide Cu-64 through chelating reactions. High stability and long intracellular retention time of the nanoprobes was confirmed by in vitro characterization, which facilitate long-term in vivo imaging. Longitudinal multimodal imaging was subsequently achieved to visualize tumor draining SLNs up to 3 weeks in a 4T1 tumor metastatic model. Obvious differences in uptake rate, amount of particles, and contrast between metastatic and contralateral sentinel lymph nodes were observed. These findings provide very helpful guidance for the design of robust multifunctional nanomaterials in SLNs' mapping and tumor metastasis diagnosis. Published by Elsevier Ltd. C1 [Huang, Xinglu; Zhang, Fan; Lee, Seulki; Swierczewska, Magdalena; Kiesewetter, Dale O.; Lang, Lixin; Zhu, Lei; Gao, Haokao; Niu, Gang; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [Zhang, Guofeng] NIBIB, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Choi, Hak Soo] Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA. RP Niu, G (reprint author), NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. EM gang.niu@nih.gov; shawn.chen@nih.gov RI Choi, Hak Soo/C-9954-2011; Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU NIBIB, NIH; Henry M. Jackson Foundation FX This work was supported by the Intramural Research Program of the NIBIB, NIH and the Henry M. Jackson Foundation (X. H., M. S.). NR 48 TC 58 Z9 59 U1 5 U2 74 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD JUN PY 2012 VL 33 IS 17 BP 4370 EP 4378 DI 10.1016/j.biomaterials.2012.02.060 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 930YT UT WOS:000303181500014 PM 22425023 ER PT J AU Waring, AC Rodondi, N Harrison, S Kanaya, AM Simonsick, EM Miljkovic, I Satterfield, S Newman, AB Bauer, DC AF Waring, Avantika C. Rodondi, Nicolas Harrison, Stephanie Kanaya, Alka M. Simonsick, Eleanor M. Miljkovic, Iva Satterfield, Suzanne Newman, Anne B. Bauer, Douglas C. CA Hlth Ageing Body Composition Hlth TI Thyroid function and prevalent and incident metabolic syndrome in older adults: the health, ageing and body composition study SO CLINICAL ENDOCRINOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; SUBCLINICAL HYPOTHYROIDISM; CARDIOVASCULAR-DISEASE; EUTHYROID SUBJECTS; STIMULATING HORMONE; SERUM THYROTROPIN; REFERENCE RANGE; BLOOD-PRESSURE; RISK; POPULATION AB Objective Both subclinical hypothyroidism and the metabolic syndrome have been associated with increased risk of coronary heart disease events. It is unknown whether the prevalence and incidence of metabolic syndrome is higher as TSH levels increase, or in individuals with subclinical hypothyroidism. We sought to determine the association between thyroid function and the prevalence and incidence of the metabolic syndrome in a cohort of older adults. Design Data were analysed from the Health, Ageing and Body Composition Study, a prospective cohort of 3075 community-dwelling US adults. Participants Two thousand one hundred and nineteen participants with measured TSH and data on metabolic syndrome components were included in the analysis. Measurements TSH was measured by immunoassay. Metabolic syndrome was defined per revised ATP III criteria. Results At baseline, 684 participants met criteria for metabolic syndrome. At 6-year follow-up, incident metabolic syndrome developed in 239 individuals. In fully adjusted models, each unit increase in TSH was associated with a 3% increase in the odds of prevalent metabolic syndrome (OR, 1.03; 95% CI, 1.011.06; P = 0.02), and the association was stronger for TSH within the normal range (OR, 1.16; 95% CI, 1.031.30; P = 0.02). Subclinical hypothyroidism with a TSH > 10 mIU/l was significantly associated with increased odds of prevalent metabolic syndrome (OR, 2.3; 95% CI, 1.05.0; P = 0.04); the odds of incident MetS was similar (OR 2.2), but the confidence interval was wide (0.67.5). Conclusions Higher TSH levels and subclinical hypothyroidism with a TSH > 10 mIU/l are associated with increased odds of prevalent but not incident metabolic syndrome. C1 [Waring, Avantika C.; Kanaya, Alka M.; Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Rodondi, Nicolas] Univ Bern, Inselspital, Dept Gen Internal Med, CH-3010 Bern, Switzerland. [Harrison, Stephanie] Calif Pacific Med Ctr, San Francisco Coordinating Ctr, Res Inst, San Francisco, CA USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, NIH, Bethesda, MD 20892 USA. [Simonsick, Eleanor M.] Johns Hopkins Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Miljkovic, Iva; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. RP Waring, AC (reprint author), 400 Parnassus Ave,A-550, San Francisco, CA 94143 USA. EM avantika.waring@ucsf.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Miljkovic, Iva/0000-0002-3155-9777 FU NIH, National Institute on Aging; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; NINR [R01-NR012459] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. NR 35 TC 39 Z9 43 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD JUN PY 2012 VL 76 IS 6 BP 911 EP 918 DI 10.1111/j.1365-2265.2011.04328.x PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 930DV UT WOS:000303118300022 PM 22187968 ER PT J AU Bennett, EP Mandel, U Clausen, H Gerken, TA Fritz, TA Tabak, LA AF Bennett, Eric P. Mandel, Ulla Clausen, Henrik Gerken, Thomas A. Fritz, Timothy A. Tabak, Lawrence A. TI Control of mucin-type O-glycosylation: A classification of the polypeptide GalNAc-transferase gene family SO GLYCOBIOLOGY LA English DT Review DE GalNAc-T; GalNAc-transferase; GALNT; monoclonal antibodies; O-glycoproteins; O-glycosylation ID ALPHA-D-GALACTOSAMINE; N-ACETYLGALACTOSAMINYLTRANSFERASE FAMILY; ACETYL-D-GALACTOSAMINE; FIBROBLAST GROWTH-FACTORS; WHOLE-GENOME DUPLICATION; CORONARY-ARTERY-DISEASE; BREAST-CANCER CELLS; BOVINE UDP-GALNAC; TUMORAL CALCINOSIS; LINKED GLYCOSYLATION AB Glycosylation of proteins is an essential process in all eukaryotes and a great diversity in types of protein glycosylation exists in animals, plants and microorganisms. Mucin-type O-glycosylation, consisting of glycans attached via O-linked N-acetylgalactosamine (GalNAc) to serine and threonine residues, is one of the most abundant forms of protein glycosylation in animals. Although most protein glycosylation is controlled by one or two genes encoding the enzymes responsible for the initiation of glycosylation, i.e. the step where the first glycan is attached to the relevant amino acid residue in the protein, mucin-type O-glycosylation is controlled by a large family of up to 20 homologous genes encoding UDP-GalNAc:polypeptide GalNAc-transferases (GalNAc-Ts) (EC 2.4.1.41). Therefore, mucin-type O-glycosylation has the greatest potential for differential regulation in cells and tissues. The GalNAc-T family is the largest glycosyltransferase enzyme family covering a single known glycosidic linkage and it is highly conserved throughout animal evolution, although absent in bacteria, yeast and plants. Emerging studies have shown that the large number of genes (GALNTs) in the GalNAc-T family do not provide full functional redundancy and single GalNAc-T genes have been shown to be important in both animals and human. Here, we present an overview of the GalNAc-T gene family in animals and propose a classification of the genes into subfamilies, which appear to be conserved in evolution structurally as well as functionally. C1 [Bennett, Eric P.; Mandel, Ulla] Univ Copenhagen, Copenhagen Ctr Glyc, Dept Odontol, DK-2200 Copenhagen N, Denmark. [Clausen, Henrik] Univ Copenhagen, Copenhagen Ctr Glyc, Dept Cellular & Mol Med, DK-2200 Copenhagen N, Denmark. [Gerken, Thomas A.] Case Western Reserve Univ, Sch Med, Dept Pediat, Cleveland, OH 44106 USA. [Gerken, Thomas A.] Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. [Gerken, Thomas A.] Case Western Reserve Univ, Sch Med, Dept Chem, Cleveland, OH 44106 USA. [Fritz, Timothy A.] US FDA, Ctr Biol Evaluat & Res, Off Vaccines Res & Review, Div Vaccines & Related Prod Applicat, Rockville, MD 20852 USA. [Tabak, Lawrence A.] Natl Inst Dent & Craniofacial Res, Dept Hlth & Human Serv, Sect Biol Chem, NIH, Bethesda, MD 20892 USA. RP Bennett, EP (reprint author), Univ Copenhagen, Copenhagen Ctr Glyc, Dept Odontol, Norre Alle 20, DK-2200 Copenhagen N, Denmark. EM epb@sund.ku.dk OI Bennett, Eric Paul/0000-0002-4976-0647 FU University of Copenhagen; Danish Research councils; Carlsberg Foundation FX This work was supported by funds from the University of Copenhagen (Excellence program), Danish Research councils and the Carlsberg Foundation. NR 181 TC 168 Z9 170 U1 6 U2 66 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD JUN PY 2012 VL 22 IS 6 BP 736 EP 756 DI 10.1093/glycob/cwr182 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 933BO UT WOS:000303334400001 PM 22183981 ER PT J AU Raman, J Guan, Y Perrine, CL Gerken, TA Tabak, LA AF Raman, Jayalakshmi Guan, Yu Perrine, Cynthia L. Gerken, Thomas A. Tabak, Lawrence A. TI UDP-N-acetyl-alpha-d-galactosamine:polypeptide N-acetylgalactosaminyltransferases: Completion of the family tree SO GLYCOBIOLOGY LA English DT Article DE GaNAcT; splice variants; enzyme activity; expression analysis ID GALNAC TRANSFERASE; O-GLYCOSYLATION; LECTIN DOMAINS; POLYPEPTIDE; EXPRESSION; CLONING; MUCINS; BIOSYNTHESIS; SITE; IDENTIFICATION AB The formation of mucin-type O-glycans is initiated by an evolutionarily conserved family of enzymes, the UDP-N-acetyl-alpha-d-galactosamine:polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). The human genome encodes 20 transferases; 17 of which have been characterized functionally. The complexity of the GalNAc-T family reflects the differential patterns of expression among the individual enzyme isoforms and the unique substrate specificities which are required to form the dense arrays of glycans that are essential for mucin function. We report the expression patterns and enzymatic activity of the remaining three members of the family and the further characterization of a recently reported isoform, GalNAc-T17. One isoform, GalNAcT-16 that is most homologous to GalNAc-T14, is widely expressed (abundantly in the heart) and has robust polypeptide transferase activity. The second isoform GalNAc-T18, most similar to GalNAc-T8, -T9 and -T19, completes a discrete subfamily of GalNAc-Ts. It is widely expressed and has low, albeit detectable, activity. The final isoform, GalNAc-T20, is most homologous to GalNAc-T11 but lacks a lectin domain and has no detectable transferase activity with the panel of substrates tested. We have also identified and characterized enzymatically active splice variants of GalNAc-T13 that differ in the sequence of their lectin domain. The variants differ in their affinities for glycopeptide substrates. Our findings provide a comprehensive view of the complexities of mucin-type O-glycan formation and provide insight into the underlying mechanisms employed to heavily decorate mucins and mucin-like domains with carbohydrate. C1 [Raman, Jayalakshmi; Guan, Yu; Tabak, Lawrence A.] Natl Inst Dent & Craniofacial Res, Dept Hlth & Human Serv, Sect Biol Chem, NIH, Bethesda, MD 20892 USA. [Perrine, Cynthia L.; Gerken, Thomas A.] Case Western Reserve Univ, Sch Med, Dept Chem, Cleveland, OH 44106 USA. [Gerken, Thomas A.] Case Western Reserve Univ, Sch Med, Dept Pediat & Biochem, Cleveland, OH 44106 USA. RP Tabak, LA (reprint author), Natl Inst Dent & Craniofacial Res, Dept Hlth & Human Serv, Sect Biol Chem, NIH, Bethesda, MD 20892 USA. EM lawrence.tabak@nih.gov FU NIDDK, NIH; National Cancer Institute [R01-CA-78834] FX Supported by funds of the intramural program of NIDDK, NIH to LAT and the National Cancer Institute grant R01-CA-78834 to TAG. NR 37 TC 27 Z9 29 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD JUN PY 2012 VL 22 IS 6 BP 768 EP 777 DI 10.1093/glycob/cwr183 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 933BO UT WOS:000303334400003 PM 22186971 ER PT J AU Zhao, F Hoechst, B Duffy, A Gamrekelashvili, J Fioravanti, S Manns, MP Greten, TF Korangy, F AF Zhao, Fei Hoechst, Bastian Duffy, Austin Gamrekelashvili, Jaba Fioravanti, Suzanne Manns, Michael P. Greten, Tim F. Korangy, Firouzeh TI S100A9 a new marker for monocytic human myeloid-derived suppressor cells SO IMMUNOLOGY LA English DT Article DE cancer; flow cytometry; FACS; immune response; tolerance; tumour immunology ID HEPATOCELLULAR-CARCINOMA; CANCER-PATIENTS; T-CELLS; PROTEINS; IMMUNOSUPPRESSION; SUBPOPULATIONS; GRANULOCYTES; ACCUMULATION; INHIBITION; PATHOLOGY AB Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that negatively regulate the immune response during tumour progression, inflammation and infection. Only limited data are available on human MDSC because of the lack of specific markers. We have identified members of the S100 protein family S100A8, S100A9 and S100A12 specifically expressed in CD14+ HLA-DR-/low MDSC. S100A9 staining in combination with anti-CD14 could be used to identify MDSC in whole blood from patients with colon cancer. An increase in the population of CD14+ S100A9high MDSC was observed in the peripheral blood from colon cancer patients in comparison with healthy controls. Finally, nitric oxide synthase expression, a hallmark of MDSC, was induced in CD14+ S100A9high upon lipopolysaccharide/interferon-? stimulation. We propose S100 proteins as useful markers for the analysis and further characterization of human MDSC. C1 [Zhao, Fei; Duffy, Austin; Gamrekelashvili, Jaba; Fioravanti, Suzanne; Greten, Tim F.; Korangy, Firouzeh] NCI, NIH, Med Oncol Branch, Bethesda, MD 20892 USA. [Hoechst, Bastian] Univ Bonn, Inst Mol Med, Bonn, Germany. [Hoechst, Bastian] Univ Bonn, Inst Expt Immunol, Bonn, Germany. [Manns, Michael P.] Hannover Med Sch, Dept Gastroenterol, D-3000 Hannover, Germany. [Manns, Michael P.] Hannover Med Sch, Dept Hepatol, D-3000 Hannover, Germany. [Manns, Michael P.] Hannover Med Sch, Dept Endocrinol, D-3000 Hannover, Germany. RP Korangy, F (reprint author), NCI, NIH, Med Oncol Branch, Bldg 10-12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov; firouzeh.korangy@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU National institutes of Health, National Cancer Institute, Center for Cancer Research; Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer FX This research was supported (in part) by the Intramural Research Program of the National institutes of Health, National Cancer Institute, Center for Cancer Research. This work was supported by a grant to MPM from the Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer. We would like to thank the Experimental Transplantation and Immunology Branch cell sorting facility for technical assistance with cell sorting. NR 27 TC 42 Z9 46 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD JUN PY 2012 VL 136 IS 2 BP 176 EP 183 DI 10.1111/j.1365-2567.2012.03566.x PG 8 WC Immunology SC Immunology GA 930CO UT WOS:000303114300007 PM 22304731 ER PT J AU Bennett, LM Gadlin, H AF Bennett, L. Michelle Gadlin, Howard TI Collaboration and Team Science: From Theory to Practice SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Article DE collaboration; trust; translational research; managing conflict while promoting disagreement; sharing credit AB Interdisciplinary efforts are becoming more critical for scientific discovery and translational research efforts. Highly integrated and interactive research teams share a number of features that contribute to their success in developing and sustaining their efforts over time. Through analysis of in-depth interviews with members of highly successful research teams and others who did not meet their goals or ended because of conflicts, we identified key elements that are critical for team success and effectiveness. There is no debate that the scientific goal sits at the center of the collaborative effort. However, supporting features need to be in place to avoid the derailment of the team. Among the most important of these is trust: without trust, the team dynamic runs the risk of deteriorating over time. Other critical factors of which both leaders and participants need to be aware include developing a shared vision, strategically identifying team members and purposefully building the team, promoting disagreement while containing conflict, and setting clear expectations for sharing credit and authorship. Self-awareness and strong communication skills contribute greatly to effective leadership and management strategies of scientific teams. While all successful teams share the characteristic of effectively carrying out these activities, there is no single formula for execution with every leader exemplifying different strengths and weaknesses. Successful scientific collaborations have strong leaders who are self-aware and are mindful of the many elements critical for supporting the science at the center of the effort. C1 [Bennett, L. Michelle] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Gadlin, Howard] NIH, Ctr Cooperat Resolut, Off Director, Bethesda, MD 20892 USA. RP Bennett, LM (reprint author), NHLBI, Div Intramural Res, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM LMBennett@nih.gov FU Intramural NIH HHS [Z99 HL999999]; NCRR NIH HHS [R13 RR023236] NR 28 TC 26 Z9 27 U1 0 U2 27 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD JUN PY 2012 VL 60 IS 5 BP 768 EP 775 PG 8 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 933FG UT WOS:000303344800013 PM 22525233 ER PT J AU Loewinger, GC Beckert, MV Tejeda, HA Cheer, JF AF Loewinger, Gabriel C. Beckert, Michael V. Tejeda, Hugo A. Cheer, Joseph F. TI Methamphetamine-induced dopamine terminal deficits in the nucleus accumbens are exacerbated by reward-associated cues and attenuated by CB1 receptor antagonism SO NEUROPHARMACOLOGY LA English DT Article DE Methamphetamine; Dopamine; Endocannabinoids; Voltammetry ID RAT STRIATUM; SUBSTITUTED AMPHETAMINES; INDUCED NEUROTOXICITY; TRANSPORTER FUNCTION; VENTRAL TEGMENTUM; FREE-RADICALS; RELEASE; BRAIN; MICE; CANNABINOIDS AB Methamphetamine (METH) exposure is primarily associated with deleterious effects to dopaminergic neurons. While several studies have implicated the endocannabinoid system in METH's locomotor, rewarding and neurochemical effects, a role for this signaling system in METH's effects on dopamine terminal dynamics has not been elucidated. Given that CB1 receptor blockade reduces the acute potentiation of phasic extracellular dopamine release from other psychomotor stimulant drugs and that the degree of acute METH-induced increases in extracellular dopamine levels is related to the severity of dopamine depletion, we predicted that pretreatment with the CB1 receptor antagonist rimonabant would reduce METH-induced alterations at dopamine terminals. Furthermore, we hypothesized that administration of METH in environments where reward associated-cues were present would potentiate METH's acute effects on dopamine release in the nucleus accumbens and exacerbate changes in dopamine terminal activity. Fast-scan cyclic voltammetry was used to measure electrically-evoked dopamine release in the nucleus accumbens and revealed markers of compromised dopamine terminal integrity nine days after a single dose of METH. These were exacerbated in animals that received METH in the presence of reward-associated cues, and attenuated in rimonabant-pretreated animals. While these deficits in dopamine dynamics were associated with reduced operant responding on days following METH administration in animals treated with only METH, rimonabant-pretreated animals exhibited levels of operant responding comparable to control. Moreover, dopamine release correlated significantly with changes in lever pressing behavior that occurred on days following METH administration. Together these data suggest that the endocannabinoid system is involved in the subsecond dopaminergic response to METH. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Loewinger, Gabriel C.; Beckert, Michael V.; Tejeda, Hugo A.; Cheer, Joseph F.] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Cheer, Joseph F.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Tejeda, Hugo A.] Natl Inst Drug Abuse, Integrat Neurosci Sect, NIH, Baltimore, MD USA. [Tejeda, Hugo A.; Cheer, Joseph F.] Univ Maryland, Sch Med, Program Neurosci, Baltimore, MD 21201 USA. RP Cheer, JF (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, 20 Penn St, Baltimore, MD 21201 USA. EM jchee001@umaryland.edu FU NIH [DA022340] FX The authors would like to thank Mr. David Bernstein for expert technical assistance and Drs Bryan Yamamoto and Kristen Keefe for valuable input and comments. This research was funded by NIH grant DA022340 to JFC. NR 66 TC 9 Z9 9 U1 3 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JUN PY 2012 VL 62 IS 7 BP 2192 EP 2201 DI 10.1016/j.neuropharm.2012.01.013 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 931MG UT WOS:000303223400006 PM 22306525 ER PT J AU Kozma, E Kumar, TS Federico, S Phan, K Balasubramanian, R Gao, ZG Paoletta, S Moro, S Spalluto, G Jacobson, KA AF Kozma, Eszter Kumar, T. Santhosh Federico, Stephanie Khai Phan Balasubramanian, Ramachandran Gao, Zhan-Guo Paoletta, Silvia Moro, Stefano Spalluto, Giampiero Jacobson, Kenneth A. TI Novel fluorescent antagonist as a molecular probe in A(3) adenosine receptor binding assays using flow cytometry SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Purines; Fluorescence; G protein-coupled receptor; A(3) adenosine receptor; Flow cytometry ID GPCR LIGANDS; DERIVATIVES; THERAPY; DISEASE; CELLS AB The physiological role of the A(3) adenosine receptor (AR) was explored in cardiac ischaemia, inflammatory diseases and cancer. We report a new fluorophore-conjugated human (h) A(3)AR antagonist for application to cell-based assays in ligand discovery and for receptor imaging. Fluorescent pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine (pyrazolo-triazolo-pyrimidine, PTP) and triazolo[1,5-c]quinazolin-5-yl)amine (triazolo-quinazoline, TQ) AR antagonists were compared. A chain-extended and click-conjugated Alexa Fluor-488 TQ derivative (MRS5449) displayed a radioligand binding K-i value of 6.4 +/- 2.5 nM in hA(3)AR-expressing CHO cell membranes. MRS5449 antagonized hA(3)AR agonist-induced inhibition of cyclic AMP accumulation in a concentration-dependent manner (K-B = 4.8 nM). Using flow cytometry (FCM), MRS5449 saturated hA(3)ARs with very high specific-to-nonspecific binding ratio with an equilibrium binding constant 5.15 nM, comparable to the K-d value of 6.65 nM calculated from kinetic experiments. K-i values of known AR antagonists in inhibition of MRS5449 binding in whole cell FCM were consistent with radioligand binding in membranes, but agonist binding was 5-20 fold weaker than obtained with agonist radioligand [I-125]I-AB-MECA. Further binding analysis of MRS5549 suggested multiple agonist binding states of the A(3)AR. Molecular docking predicted binding modes of these fluorescent antagonists. Thus, MRS5449 is a useful tool for hA(3)AR characterization. Published by Elsevier Inc. C1 [Kozma, Eszter; Kumar, T. Santhosh; Khai Phan; Balasubramanian, Ramachandran; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Federico, Stephanie; Spalluto, Giampiero] Univ Trieste, Dipartimento Sci Farmaceut, I-34127 Trieste, Italy. [Paoletta, Silvia; Moro, Stefano] Univ Padua, Dipartimento Sci Farmaceut, MMS, I-35131 Padua, Italy. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; Moro, Stefano/A-2979-2012; OI Jacobson, Kenneth/0000-0001-8104-1493; Moro, Stefano/0000-0002-7514-3802; Federico, Stephanie/0000-0003-2800-5287 FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases; Hungarian-American Enterprise Scholarship Foundation (HAESF); University of Padova, Italy; Italian Ministry for University and Research (MIUR), Rome, Italy FX This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. EK thanks the Hungarian-American Enterprise Scholarship Foundation (HAESF) for financial support. The work coordinated by SM was carried out with financial support from the University of Padova, Italy, and the Italian Ministry for University and Research (MIUR), Rome, Italy. SM is very grateful to Chemical Computing Group Inc. (Montreal, Quebec, Canada) for a scientific and technical partnership. NR 32 TC 16 Z9 16 U1 1 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JUN 1 PY 2012 VL 83 IS 11 BP 1552 EP 1561 DI 10.1016/j.bcp.2012.02.019 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 929PU UT WOS:000303078700009 PM 22402302 ER PT J AU Silverio, KG Davidson, KC James, RG Adams, AM Foster, BL Nociti, FH Somerman, MJ Moon, RT AF Silverio, K. G. Davidson, K. C. James, R. G. Adams, A. M. Foster, B. L. Nociti, F. H., Jr. Somerman, M. J. Moon, R. T. TI Wnt/beta-catenin pathway regulates bone morphogenetic protein (BMP2)-mediated differentiation of dental follicle cells SO JOURNAL OF PERIODONTAL RESEARCH LA English DT Article DE bone morphogenetic protein (BMP); cementoblast; dental follicle cells; maturation; Wnt ID TRANSCRIPTION FACTOR OSTERIX; OSTEOBLAST DIFFERENTIATION; BETA-CATENIN; PROMOTES PROLIFERATION; TOOTH MORPHOGENESIS; SIGNAL-TRANSDUCTION; MICROARRAY ANALYSIS; C3H10T1/2 CELLS; DIRECT TARGET; STEM-CELLS AB Background and Objective: Bone morphogenetic protein 2 (BMP2)-induced osteogenic differentiation has been shown to occur through the canonical Wnt/ bcatenin pathway, whereas factors promoting canonical Wnt signaling in cementoblasts inhibit cell differentiation and promote cell proliferation in vitro. The aim of this study was to investigate whether putative precursor cells of cementoblasts, dental follicle cells (murine SVF4 cells), when stimulated with BMP2, would exhibit changes in genes/ proteins associated with the Wnt/ b-catenin pathway. Material and Methods: SVF4 cells were stimulated with BMP2, and the following assays were carried out: (i) Wnt/ b-catenin pathway activation assessed by western blotting, b-catenin/ transcription factor (TCF) reporter assays and expression of the lymphoid enhancer-binding factor-1 (Lef1), transcription factor 7 (Tcf 7), Wnt inhibitor factor 1 (Wif1) and Axin2 (Axin2) genes; and (ii) cementoblast/ osteoblast differentiation assessed by mineralization in vitro, and by the mRNA levels of runt-related transcription factor 2 (Runx2), osterix (Osx), alkaline phosphatase (Alp), osteocalcin (Ocn) and bone sialoprotein (Bsp), determined by quantitative PCR after treatment with wingless-type MMTV integration site family, member 3A (WNT3A) and knockdown of b-catenin. Results: WNT3A induced b-catenin nuclear translocation and up-regulated the transcriptional activity of a canonical Wnt-responsive reporter, suggesting that the Wnt/ b-catenin pathway functions in SVF4 cells. Activation of Wnt signaling with WNT3A suppressed BMP2-mediated induction of cementoblast/ osteoblast maturation of SVF4 cells. However, b-catenin knockdown showed that the BMP2induced expression of cementoblast/ osteoblast differentiation markers requires endogenous b-catenin. WNT3A down-regulated transcripts for Runx2, Alp and Ocn in SVF4 cells compared with untreated cells. In contrast, BMP2 induction of Bsp transcripts occurred independently of Wnt/ b-catenin signaling. Conclusion: These data suggest that stabilization of b-catenin by WNT3A inhibits BMP2-mediated induction of cementoblast/ osteoblast differentiation in SVF4 cells, although BMP2 requires endogenous Wnt/ b-catenin signaling to promote cell maturation. C1 [Silverio, K. G.; Nociti, F. H., Jr.] Univ Estadual Campinas, Dept Prosthodont & Periodont, Sch Dent, BR-13414903 Piracicaba, SP, Brazil. [Davidson, K. C.; James, R. G.; Adams, A. M.; Moon, R. T.] Univ Washington, Sch Med, Inst Stem Cells & Regenerat Med, Seattle, WA USA. Univ Washington, Sch Dent, Dept Periodont, Seattle, WA 98195 USA. [Davidson, K. C.; James, R. G.; Adams, A. M.; Moon, R. T.] Univ Washington, Sch Med, Dept Pharmacol, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Foster, B. L.; Nociti, F. H., Jr.; Somerman, M. J.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Silverio, KG (reprint author), Univ Estadual Campinas, Dept Prosthodont & Periodont, Sch Dent Piracicaba, Ave Limeira,901 Bairro Areiao, BR-13414903 Piracicaba, SP, Brazil. EM kgsilverio@fop.unicamp.br RI Nociti, Francisco/G-4907-2015; Silverio, Karina/E-9424-2013; Moon, Randall/B-1743-2014; Foster, Brian/H-8375-2015 OI Moon, Randall/0000-0002-9352-1408; Foster, Brian/0000-0003-3444-0576 FU CAPES [130508/5] FX Dra Silverio was supported by CAPES (Grant # 130508/5). The authors wish to thank Travis Biechele for the beta-catenin/Tcf transcriptional reporter plasmids (pBARV and pfuBARV). This work was completed while MJS and BLF were affiliated with the Department of Periodontics, University of Washington School of Dentistry, Seattle, WA, USA. NR 52 TC 20 Z9 24 U1 0 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3484 J9 J PERIODONTAL RES JI J. Periodont. Res. PD JUN PY 2012 VL 47 IS 3 BP 309 EP 319 DI 10.1111/j.1600-0765.2011.01433.x PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 928RA UT WOS:000302999400005 PM 22150562 ER PT J AU Datrice, NM Langan, RC Ripley, RT Kemp, CD Steinberg, SM Wood, BJ Libutti, SK Fojo, T Schrump, DS Avital, I AF Datrice, Nicole M. Langan, Russell C. Ripley, R. Taylor Kemp, Clinton D. Steinberg, Seth M. Wood, Bradford J. Libutti, Steven K. Fojo, Tito Schrump, David S. Avital, Itzhak TI Operative management for recurrent and metastatic adrenocortical carcinoma SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE metastatic adrenocortical carcinoma; liver resection; and lung resection ID ADRENAL-CORTICAL CARCINOMA; PROGNOSTIC-FACTORS; MITOTANE; RESECTION; FEATURES; SURGERY; CANCER; SERIES AB Objective A review of all resections for recurrent or metastatic ACC was performed to identify patients who might benefit from a surgical approach, and to identify factors that might aid in prognosis among patients with metastatic disease. Summary Background Data: Adrenocortical carcinoma (ACC) is a rare tumor, with frequent recurrences and metastases even after complete resection. Chemotherapy has limited efficacy, and surgical resection of metastatic ACC remains controversial. Methods: A retrospective review was performed of all patients who underwent surgical intervention for metastatic ACC in a single tertiary center from 1977 to 2009. All available clinicopathologic data were analyzed to determine potential factors associated with response to treatment and survival. Results: Fifty-seven patients underwent 116 procedures for recurrent or metastatic disease. Twenty-three resections were for liver metastases, 48 for pulmonary metastases, 22 for abdominal disease including local recurrences, and 13 were for metastases at other sites. Median and 5-year survivals from time of first metastasectomy were 2.5 years, and 41%, respectively. The median survival of patients with DFI <12 months was 1.7 years, compared to 6.6 years for patients with DFI >12 months (P = 0.015). Median survival for right versus left-sided primaries was 1.9 years versus 3.8 years (P = 0.03). Liver metastases were more common with right-sided primaries (67% vs. 41%, P = 0.05). Chemotherapy had no impact on survival. Conclusions: Resection of recurrent or metastatic ACC is safe, and may result in prolongation of survival in selected patients with DFI greater than 1 year. J. Surg. Oncol. 2012; 105: 709-713. (C) 2011 Wiley Periodicals, Inc. C1 [Datrice, Nicole M.; Langan, Russell C.; Ripley, R. Taylor; Kemp, Clinton D.; Schrump, David S.; Avital, Itzhak] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NIH, Biostat & Data Management Sect, Off Clin Director, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Dept Diagnost Radiol, NIH, Bethesda, MD 20892 USA. [Libutti, Steven K.] Montefiore Med Ctr, Dept Surg, Bronx, NY 10467 USA. [Fojo, Tito] NIH, Med Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Fojo, Tito] Univ Texas MD Anderson Canc Ctr, Div Surg, Dept Surg Oncol, Houston, TX 77030 USA. RP Avital, I (reprint author), NCI, Surg Branch, NIH, Bldg 10,Hatfield CRC Room 4-3961,10 Ctr Dr, Bethesda, MD 20892 USA. EM avitali@mail.nih.gov FU Intramural NIH HHS [ZIA CL040011-05, ZIA CL040015-04, ZID BC011242-04] NR 20 TC 27 Z9 29 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-4790 J9 J SURG ONCOL JI J. Surg. Oncol. PD JUN PY 2012 VL 105 IS 7 BP 709 EP 713 DI 10.1002/jso.23015 PG 5 WC Oncology; Surgery SC Oncology; Surgery GA 927XQ UT WOS:000302944300016 PM 22189845 ER PT J AU Raju, TNK AF Raju, Tonse N. K. TI Developmental physiology of late and moderate prematurity SO SEMINARS IN FETAL & NEONATAL MEDICINE LA English DT Article DE Apnea; Hypoglycemia; Hypothermia; Infection; Preterm; Respiratory distress ID LATE PRETERM INFANT; EXTRACORPOREAL MEMBRANE-OXYGENATION; NEAR-TERM INFANTS; RESPIRATORY-FAILURE; CESAREAN DELIVERY; COLD STRESS; MATURATION; MORBIDITY; NUTRITION; ADMISSION AB This is a brief review of the developmental physiology of selected organ and functional systems in moderate and late preterm infants. This outline provides a discussion of the physiological underpinnings for some of the clinical conditions seen in this group of infants, including hypothermia, hypoglycemia, respiratory distress syndrome, transient tachypnea, severe respiratory failure, apnea, feeding difficulties, jaundice, and increased susceptibility to infections. Published by Elsevier Ltd. C1 [Raju, Tonse N. K.] NIH, Ctr Dev Biol & Perinatal Med, Bethesda, MD 20892 USA. [Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Raju, TNK (reprint author), 6100 Execut Blvd,Room 4B03, Bethesda, MD 20952 USA. EM rajut@mail.nih.gov NR 39 TC 21 Z9 21 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1744-165X EI 1878-0946 J9 SEMIN FETAL NEONAT M JI Semin. Fetal Neonatal Med. PD JUN PY 2012 VL 17 IS 3 BP 126 EP 131 DI 10.1016/j.siny.2012.01.010 PG 6 WC Pediatrics SC Pediatrics GA 927FG UT WOS:000302891900003 PM 22317884 ER PT J AU Onozawa, M Aplan, PD AF Onozawa, Masahiro Aplan, Peter D. TI Illegitimate V(D)J recombination involving nonantigen receptor loci in lymphoid malignancy SO GENES CHROMOSOMES & CANCER LA English DT Review ID ACUTE LYMPHOBLASTIC-LEUKEMIA; MOUSE THYMIC LYMPHOMAS; T-CELL MALIGNANCIES; TRANSCRIPTION FACTOR; TUMOR-SUPPRESSOR; CHROMOSOMAL TRANSLOCATIONS; IKAROS GENE; INTRAGENIC DELETIONS; ABERRANT METHYLATION; TRANSGENIC MICE AB V(D)J recombination of antigen receptor loci (IGH, IGK, IGL, TCRA, TCRB, TCRG, and TCRD) is an essential mechanism that confers enormous diversity to the mammalian immune system. However, there are now at least six examples of intrachromosomal interstitial deletions caused by aberrant V(D)J recombination between nonantigen receptor loci; five of out these six are associated with lymphoid malignancy. The SIL-SCL fusion and deletions of CDKN2A, IKZF1, Notch1, and Bcl11b are all associated with lymphoid malignancy. These interstitial deletions seem to be species specific, as the deletions seen in mice are not seen in humans; the converse is true as well. Nucleotide sequence analysis of these rearrangements reveals the hallmarks of V(D)J recombination, including site specificity near cryptic heptamer signal sequences, exonucleolytic nibbling at the junction site, and nontemplated N-region nucleotide insertion at the junction site. Two of these interstitial deletions (murine Notch1 and Bcl11b deletions) have been detected, at low frequency, in tissues from healthy mice with no evidence of malignancy, similar to the finding of chromosomal translocations in the peripheral blood or tonsils of healthy individuals. The contention that these are mediated via V(D)J recombination is strengthened by in vivo assays using extrachromosomal substrates, and chromatin immunoprecipitation-sequence analysis which shows Rag2 binding at the sites of rearrangement. Although the efficiency of these illegitimate recombination events is several orders of magnitude less than that at bona fide antigen receptor loci, the consequence of such deletions, namely activation of proto-oncogenes or deletion of tumor suppressor genes, is devastating, and a major cause for lymphoid malignancy. (c) 2012 Wiley Periodicals, Inc. C1 [Onozawa, Masahiro; Aplan, Peter D.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Aplan, PD (reprint author), NCI, NIH NCI CCR Genet Branch, Ctr Canc Res, NIH, 41 Ctr Dr,Room B900, Bethesda, MD 20892 USA. EM aplanp@mail.nih.gov RI Aplan, Peter/K-9064-2016 FU NCI, NIH; Japan Society for the Promotion of Science (JSPS) FX Supported by: The Intramural Program of the NCI, NIH, The Japan Society for the Promotion of Science (JSPS), Postdoctoral Fellowships for Research Abroad program. NR 76 TC 16 Z9 16 U1 0 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD JUN PY 2012 VL 51 IS 6 BP 525 EP 535 DI 10.1002/gcc.21942 PG 11 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 922LL UT WOS:000302548500001 PM 22334400 ER PT J AU Park, JH Lee, KS Lim, HJ Kim, H Kwak, HJ Park, HY AF Park, Jin-Hee Lee, Kuy-Sook Lim, Hyun-Joung Kim, Hanna Kwak, Hyun-Jeong Park, Hyun-Young TI The PPAR delta ligand L-165041 inhibits VEGF-induced angiogenesis, but the antiangiogenic effect is not related to PPAR delta SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE ANGIOGENESIS; CELL CYCLE; ENDOTHELIAL CELL; PPARd ID PROLIFERATOR-ACTIVATED RECEPTORS; ENDOTHELIAL-CELL PROLIFERATION; SMOOTH-MUSCLE PROLIFERATION; GROWTH-FACTOR; PEROXISOME; EXPRESSION; GAMMA; AGONIST; MIGRATION; CANCER AB Peroxisome proliferator-activated receptor (PPAR)d is known to be expressed ubiquitously and involved in lipid and glucose metabolism. Recent studies have demonstrated that PPARd is expressed in endothelial cells (ECs) and plays a potential role in endothelial survival and proliferation. Although PPARa and PPAR? are well recognized to play anti-inflammatory, antiproliferative, and antiangiogenic roles in ECs, the general effect of PPARd on angiogenesis in ECs remains unclear. Thus, we investigated the effect of the PPARd ligand L-165041 on vascular EC proliferation and angiogenesis in vitro as well as in vivo. Our data show that L-165041 inhibited VEGF-induced cell proliferation and migration in human umbilical vein ECs (HUVECs). L-165041 also inhibited angiogenesis in the Matrigel plug assay and aortic ring assay. Flow cytometric analysis indicated that L-165041 reduced the number of ECs in the S phase and the expression levels of cell cycle regulatory proteins such as cyclin A, cyclin E, CDK2, and CDK4; phosphorylation of the retinoblastoma protein was suppressed by pretreatment with L-165041. We confirmed whether these antiangiogenic effects of L-165041 were PPARd-dependent using GW501516 and PPARd siRNA. GW501516 treatment did not inhibit VEGF-induced angiogenesis, and transfection of PPARd siRNA did not reverse this antiangiogenic effect of L-165041, suggesting that the antiangiogenic effect of L-165041 on ECs is PPARd-independent. Together, these data indicate that the PPARd ligand L-165041 inhibits VEGF-stimulated angiogenesis by suppressing the cell cycle progression independently of PPARd. This study highlights the therapeutic potential of L-165041 in the treatment of many disorders related to pathological angiogenesis. J. Cell. Biochem. 113: 19471954, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Park, Jin-Hee; Lee, Kuy-Sook; Lim, Hyun-Joung; Kim, Hanna; Kwak, Hyun-Jeong; Park, Hyun-Young] Natl Inst Hlth, Ctr Biomed Sci, Div Cardiovasc & Rare Dis, Bethesda, MD USA. RP Park, HY (reprint author), Korea Natl Inst Hlth, Ctr Biomed Sci, Osong Hlth Technol Adm Complex, Cheongwon Gun 363951, Chungcheongbuk, South Korea. EM hypark65@nih.go.kr FU Korea National Institute of Health [2007-N63001-00, 2010-N63002-00] FX This work was supported by Korea National Institute of Health intramural research grants (2007-N63001-00 and 2010-N63002-00). NR 44 TC 9 Z9 9 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD JUN PY 2012 VL 113 IS 6 BP 1947 EP 1954 DI 10.1002/jcb.24063 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 923IN UT WOS:000302613100014 PM 22234939 ER PT J AU Haleem-Smith, H Argintar, E Bush, C Hampton, D Postma, WF Chen, FH Rimington, T Lamb, J Tuan, RS AF Haleem-Smith, Hana Argintar, Evan Bush, Curtis Hampton, Daniel Postma, William F. Chen, Faye H. Rimington, Todd Lamb, Joshua Tuan, Rocky S. TI Biological responses of human mesenchymal stem cells to titanium wear debris particles SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE adult stem cells; implant wear; endocytosis; apoptosis; cytoskeleton; cell adhesion; cell proliferation; cytokines ID TOTAL HIP-ARTHROPLASTY; HUMAN TRABECULAR BONE; REVISION TOTAL HIP; ON-METAL BEARINGS; POLYMETHYLMETHACRYLATE PARTICLES; OSTEOGENIC DIFFERENTIATION; UNITED-STATES; IN-VITRO; EXPRESSION; OSTEOBLASTS AB Wear debris-induced osteolysis is a major cause of orthopedic implant aseptic loosening, and various cell types, including macrophages, monocytes, osteoblasts, and osteoclasts, are involved. We recently showed that mesenchymal stem/osteoprogenitor cells (MSCs) are another target, and that endocytosis of titanium (Ti) particles causes reduced MSC proliferation and osteogenic differentiation. Here we investigated the mechanistic aspects of the endocytosis-mediated responses of MSCs to Ti particulates. Dose-dependent effects were observed on cell viability, with doses >300 Ti particles/cell resulting in drastic cell death. To maintain cell viability and analyze particle-induced effects, doses <300 particles/cell were used. Increased production of interleukin-8 (IL-8), but not IL-6, was observed in treated MSCs, while levels of TGF-beta, IL-1 beta, and TNF-a were undetectable in treated or control cells, suggesting MSCs as a likely major producer of IL-8 in the periprosthetic zone. Disruptions in cytoskeletal and adherens junction organization were also observed in Ti particles-treated MSCs. However, neither IL-8 and IL-6 treatment nor conditioned medium from Ti particle-treated MSCs failed to affect MSC osteogenic differentiation. Among other Ti particle-induced cytokines, only GM-CSF appeared to mimic the effects of reduced cell viability and osteogenesis. Taken together, these results strongly suggest that MSCs play both responder and initiator roles in mediating the osteolytic effects of the presence of wear debris particles in periprosthetic zones. (c) 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:853863, 2012 C1 [Haleem-Smith, Hana; Argintar, Evan; Bush, Curtis; Hampton, Daniel; Postma, William F.; Chen, Faye H.; Rimington, Todd; Lamb, Joshua; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Argintar, Evan; Bush, Curtis; Hampton, Daniel; Postma, William F.; Rimington, Todd; Lamb, Joshua; Tuan, Rocky S.] Georgetown Univ, Sch Med, Dept Orthopaed Surg, Washington, DC 20007 USA. [Tuan, Rocky S.] Univ Pittsburgh, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, Sch Med, Pittsburgh, PA 15219 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM rst13@pitt.edu FU National Institutes of Health [ZO1 AR41131]; Commonwealth of Pennsylvania Department of Health FX The authors thank Dr. Paul Manner, George Washington University and University of Washington, for providing total joint arthroplasty human tissues. Supported in part by the Intramural Research Program of the National Institutes of Health (ZO1 AR41131), and the Commonwealth of Pennsylvania Department of Health. NR 51 TC 21 Z9 24 U1 0 U2 17 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD JUN PY 2012 VL 30 IS 6 BP 853 EP 863 DI 10.1002/jor.22002 PG 11 WC Orthopedics SC Orthopedics GA 921GS UT WOS:000302466700002 PM 22083964 ER PT J AU Kato, GJ AF Kato, Gregory J. TI TRV: A physiological biomarker in sickle cell disease SO PEDIATRIC BLOOD & CANCER LA English DT Editorial Material ID REGURGITANT JET VELOCITY; PULMONARY-HYPERTENSION; EXERCISE CAPACITY; LEG ULCERS; CHILDREN; ANEMIA; ADOLESCENTS; HEMOGLOBIN; PREVALENCE; SILDENAFIL C1 NHLBI, Sickle Cell Vasc Dis Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Kato, GJ (reprint author), NHLBI, Sickle Cell Vasc Dis Sect, Hematol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gkato@mail.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [ZIA HL006014-04] NR 23 TC 3 Z9 3 U1 0 U2 2 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2012 VL 58 IS 6 BP 831 EP 832 DI 10.1002/pbc.23399 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 910QQ UT WOS:000301656300001 PM 22180092 ER PT J AU Lock, RB Carol, H Morton, CL Keir, ST Reynolds, CP Kang, MH Maris, JM Wozniak, AW Gorlick, R Kolb, EA Houghton, PJ Smith, MA AF Lock, Richard B. Carol, Hernan Morton, Christopher L. Keir, Stephen T. Reynolds, C. Patrick Kang, Min H. Maris, John M. Wozniak, Amy W. Gorlick, Richard Kolb, E. Anders Houghton, Peter J. Smith, Malcolm A. TI Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; GSK923295A; preclinical testing ID MITOTIC CHECKPOINT; AURORA KINASES; ANTICANCER DRUG; CANCER MODELS; PHASE-II; IN-VIVO; KINETOCHORES; ANEUPLOIDY; KINESIN; AGENTS AB Background The centromere kinesin motor protein CENP-E plays a crucial role in mitosis, and is an appealing molecular target in cancer. GSK923295A is an allosteric inhibitor of CENP-E that is undergoing clinical evaluation. Procedures. GSK923295A was evaluated against the 23 cell lines in the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96 hr exposures to concentrations ranging from 1.0 mu M to 10.0 mu M. GSK923295A was also tested in vivo against the PPTP acute lymphoblastic leukemia (ALL) and solid tumor xenograft panels using a days 1-3 and 8-10 schedule that was repeated at day 21. The agent was administered via the intraperitoneal (i. p.) route at a daily dose of 125 mg/kg. Results. The median IC50 for all PPTP cell lines was 27 nM, with the median IC50 for the ALL panel being the lowest (18 nM) and for the neuroblastoma panel the highest (39 nM). Excessive toxicity was observed for each of the 8 xenografts of the ALL panel in NOD/ SCID mice. Thirty-five solid tumor xenograft models were considered evaluable. GSK923295A induced significant differences in event-free survival distribution compared to controls in 32 of 35 evaluable solid tumor xenografts tested. Objective responses were noted in 13 of 35 solid tumor xenografts, including 9 with maintained complete responses, and 3 with complete response (CR). Conclusions. GSK923295A demonstrated significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts. These results suggest that CENP-E may be a valuable therapeutic target in pediatric cancer. Pediatr Blood Cancer 2012; 58: 916-923. (C) 2011 Wiley Periodicals, Inc. C1 [Lock, Richard B.; Carol, Hernan] Childrens Canc Inst Australia Med Res, Lowy Canc Res Ctr, Randwick, NSW, Australia. [Morton, Christopher L.; Wozniak, Amy W.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Lock, RB (reprint author), Univ New S Wales, Lowy Canc Res Ctr, Leukaemia Biol Program, Childrens Canc Inst Australia, Sydney, NSW 2052, Australia. EM rlock@ccia.unsw.edu.au RI Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786]; Cytokinetics, Inc. [GSK923295A] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216, CA21765, CA108786; Grant sponsor: Cytokinetics, Inc.; Grant number: GSK923295A. NR 34 TC 12 Z9 13 U1 0 U2 2 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2012 VL 58 IS 6 BP 916 EP 923 DI 10.1002/pbc.23176 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 910QQ UT WOS:000301656300016 PM 21584937 ER PT J AU Altirriba, J Garcia, A Sanchez, B Haba, L Altekruse, S Stratmann, T Bombi, JA Mezquita, C Gomis, R Mora, C AF Altirriba, Jordi Garcia, Ainhoa Sanchez, Begona Haba, Laura Altekruse, Sean Stratmann, Thomas Antoni Bombi, Josep Mezquita, Cristobal Gomis, Ramon Mora, Conchi TI The sole presence of CDK4 is not a solid criterion for discriminating between tumor and healthy pancreatic tissues SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter DE CDK4; pancreatic tumor marker; pancreatic endocrine tumors; pancreatic ductal adenocarcinoma; pancreatic intraepithelial neoplasia; cell cycle progression ID DEPENDENT KINASES; EXPRESSION; CANCER C1 [Sanchez, Begona; Mora, Conchi] Univ Lleida, IRB Lleida, Dept Expt Med, Sch Med, Lleida 25008, Spain. [Altirriba, Jordi; Garcia, Ainhoa; Haba, Laura; Gomis, Ramon] Hosp Clin Barcelona, Diabet & Obes Lab, Endocrinol & Nutr Unit, IDIBAPS, Barcelona, Spain. [Altirriba, Jordi; Garcia, Ainhoa; Haba, Laura; Gomis, Ramon] CIBER Diabet & Enfermedades Metab Asociadas CIBER, Barcelona 08017, Spain. [Altirriba, Jordi] Univ Geneva, Dept Internal Med, Div Endocrinol Diabetol & Nutr, Lab Metab,Fac Med, Geneva, Switzerland. [Altekruse, Sean] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Stratmann, Thomas] Univ Barcelona, Dept Physiol, Barcelona, Spain. [Antoni Bombi, Josep] Univ Barcelona, Hosp Clin Barcelona, IDIBAPS, Dept Pathol,CDB, Barcelona, Spain. [Mezquita, Cristobal] Univ Barcelona, Dept Physiol 1, Barcelona, Spain. [Gomis, Ramon] Univ Barcelona, Dept Med, Barcelona, Spain. RP Mora, C (reprint author), Univ Lleida, Inst Biomed Res IRB Lleida, Basic & Clin Immunol & Endocrinol Res Grp, Immunol Unit,Dept Expt Med,Sch Med, C Montserrat Roig 2, Lleida 25008, Spain. EM conchi.mora@mex.udl.cat RI Mora, Conchi/A-8280-2010; OI Mora, Conchi/0000-0002-5644-0537; Altirriba, Jordi/0000-0002-8922-2333 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [N01PC35143, N01PC35139, N01PC35137] NR 8 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUN 1 PY 2012 VL 130 IS 11 BP 2743 EP 2745 DI 10.1002/ijc.26313 PG 3 WC Oncology SC Oncology GA 915GX UT WOS:000302013200030 PM 21792898 ER PT J AU Talbert, PB Ahmad, K Almouzni, G Ausio, J Berger, F Bhalla, PL Bonner, WM Cande, WZ Chadwick, BP Chan, SWL Cross, GAM Cui, LW Dimitrov, SI Doenecke, D Eirin-Lopez, JM Gorovsky, MA Hake, SB Hamkalo, BA Holec, S Jacobsen, SE Kamieniarz, K Khochbin, S Ladurner, AG Landsman, D Latham, JA Loppin, B Malik, HS Marzluff, WF Pehrson, JR Postberg, J Schneider, R Singh, MB Smith, MM Thompson, E Torres-Padilla, ME Tremethick, DJ Turner, BM Waterborg, JH Wollmann, H Yelagandula, R Zhu, B Henikoff, S AF Talbert, Paul B. Ahmad, Kami Almouzni, Genevieve Ausio, Juan Berger, Frederic Bhalla, Prem L. Bonner, William M. Cande, W. Zacheus Chadwick, Brian P. Chan, Simon W. L. Cross, George A. M. Cui, Liwang Dimitrov, Stefan I. Doenecke, Detlef Eirin-Lopez, Jose M. Gorovsky, Martin A. Hake, Sandra B. Hamkalo, Barbara A. Holec, Sarah Jacobsen, Steven E. Kamieniarz, Kinga Khochbin, Saadi Ladurner, Andreas G. Landsman, David Latham, John A. Loppin, Benjamin Malik, Harmit S. Marzluff, William F. Pehrson, John R. Postberg, Jan Schneider, Robert Singh, Mohan B. Smith, M. Mitchell Thompson, Eric Torres-Padilla, Maria-Elena Tremethick, David John Turner, Bryan M. Waterborg, Jakob Harm Wollmann, Heike Yelagandula, Ramesh Zhu, Bing Henikoff, Steven TI A unified phylogeny-based nomenclature for histone variants SO EPIGENETICS & CHROMATIN LA English DT Review ID LYSINE-RICH HISTONES; AMINO-ACID-SEQUENCES; CALF THYMUS; DROSOPHILA-MELANOGASTER; CORE HISTONE; H3 VARIANTS; SEA-URCHIN; PLASMODIUM-FALCIPARUM; TRYPANOSOMA-BRUCEI; MESSENGER-RNA AB Histone variants are non-allelic protein isoforms that play key roles in diversifying chromatin structure. The known number of such variants has greatly increased in recent years, but the lack of naming conventions for them has led to a variety of naming styles, multiple synonyms and misleading homographs that obscure variant relationships and complicate database searches. We propose here a unified nomenclature for variants of all five classes of histones that uses consistent but flexible naming conventions to produce names that are informative and readily searchable. The nomenclature builds on historical usage and incorporates phylogenetic relationships, which are strong predictors of structure and function. A key feature is the consistent use of punctuation to represent phylogenetic divergence, making explicit the relationships among variant subtypes that have previously been implicit or unclear. We recommend that by default new histone variants be named with organism-specific paralog-number suffixes that lack phylogenetic implication, while letter suffixes be reserved for structurally distinct clades of variants. For clarity and searchability, we encourage the use of descriptors that are separate from the phylogeny-based variant name to indicate developmental and other properties of variants that may be independent of structure. C1 [Talbert, Paul B.; Latham, John A.; Malik, Harmit S.; Henikoff, Steven] Howard Hughes Med Inst, Div Basic Sci, Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Ahmad, Kami] Harvard Univ, Sch Med, Dept BCMP, Boston, MA 02115 USA. [Almouzni, Genevieve] Ctr Rech, Inst Curie, UMR 218, CNRS, F-75248 Paris 05, France. [Ausio, Juan] Univ Victoria, Dept Biochem & Microbiol, Victoria, BC V8W 3P6, Canada. [Berger, Frederic; Holec, Sarah; Wollmann, Heike; Yelagandula, Ramesh] Natl Univ Singapore, Res Link 1, Temasek Lifesci Lab, Singapore 117604, Singapore. [Bhalla, Prem L.; Singh, Mohan B.] Univ Melbourne, Melbourne Sch Land & Environm, Plant Mol Biol & Biotechnol Grp, Parkville, Vic 3010, Australia. [Bonner, William M.] NCI, Mol Pharmacol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Cande, W. Zacheus] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Chadwick, Brian P.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Chan, Simon W. L.] UC Davis HHMI, Dept Plant Biol, Davis, CA 95616 USA. [Cross, George A. M.] Rockefeller Univ, Mol Parasitol Lab, New York, NY 10065 USA. [Cui, Liwang] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Dimitrov, Stefan I.] INSERM UJF U821, Inst Albert Bonniot, Lab Biol Mol & Cellulaire Differenciat, Grenoble, France. [Doenecke, Detlef] Univ Gottingen, Dept Biochem, D-37073 Gottingen, Germany. [Eirin-Lopez, Jose M.] Univ A Coruna, Dept Cell & Mol Biol, E-15071 La Coruna, Spain. [Gorovsky, Martin A.] Univ Rochester, Dept Biol, Rochester, NY 14627 USA. [Hake, Sandra B.] Univ Munich, Dept Mol Biol, Adolf Butenandt Inst, Ctr Integrated Prot Sci Munich, D-80336 Munich, Germany. [Hamkalo, Barbara A.] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. [Jacobsen, Steven E.] Univ Calif Los Angeles, Dept Mol Cellular & Dev Biol, Howard Hughes Med Inst, Los Angeles, CA 90095 USA. [Kamieniarz, Kinga; Schneider, Robert] Max Planck Inst Immunbiol & Epigenet, D-79108 Freiburg, Germany. [Khochbin, Saadi] Univ Grenoble 1, U823, INSERM, F-38706 La Tronche, France. [Ladurner, Andreas G.] Univ Munich, Butenandt Inst, Dept Physiol Chem, D-81377 Munich, Germany. [Ladurner, Andreas G.] Univ Munich, Biomed Ctr, D-81377 Munich, Germany. [Landsman, David] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Loppin, Benjamin] Univ Lyon 1, CGphiMC CNRS UMR5534, F-69622 Villeurbanne, France. [Marzluff, William F.] Univ N Carolina, Program Mol Biol & Biotechnol, Chapel Hill, NC 27599 USA. [Pehrson, John R.] Univ Penn, Dept Anim Biol, Philadelphia, PA 19104 USA. [Postberg, Jan] Univ Witten Herdecke, Paediat Ctr, HELIOS Med Ctr Wuppertal, D-42283 Wuppertal, Germany. [Smith, M. Mitchell] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22908 USA. [Thompson, Eric] Univ Bergen, Sars Int Ctr Marine Mol Biol, N-5008 Bergen, Norway. [Thompson, Eric] Univ Bergen, Dept Biol, N-5008 Bergen, Norway. [Torres-Padilla, Maria-Elena] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire, CNRS INSERM U964, CU Strasbourg, F-67404 Illkirch Graffenstaden, France. [Tremethick, David John] Australian Natl Univ, Genome Biol Dept, John Curtin Sch Med Res, Canberra, ACT 2601, Australia. [Turner, Bryan M.] Univ Birmingham, Coll Med & Dent Sci, Birmingham B15 2TT, W Midlands, England. [Waterborg, Jakob Harm] Univ Missouri, Sch Biol Sci, Kansas City, MO 64110 USA. [Zhu, Bing] Natl Inst Biol Sci, Chromatin Lab, Beijing 102206, Peoples R China. RP Henikoff, S (reprint author), Howard Hughes Med Inst, Div Basic Sci, Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. EM steveh@fhcrc.org RI Malik, Harmit/E-8519-2012; Waterborg, Jakob/J-5479-2013; dimitrov, stefan/M-7697-2013; Khochbin, Saadi/M-8090-2013; Cross, George/B-7444-2011; OI Postberg, Jan/0000-0002-8562-3316; Waterborg, Jakob/0000-0002-2881-4634; Eirin-Lopez, Jose Maria/0000-0002-8041-9770; Berger, Frederic/0000-0002-3609-8260; Cross, George/0000-0003-1374-6955; Landsman, David/0000-0002-9819-6675; Bhalla, Prem/0000-0002-2910-0393; Malik, Harmit/0000-0001-6005-0016; Singh, Mohan/0000-0001-9427-8975 FU EMBO; Howard Hughes Medical Institute; Intramural Research Program of the NIH, National Library of Medicine FX This project was initiated during the EMBO Workshop on Histone variants and genome regulation held in Strasbourg, France, 12-14 October 2011. We are grateful for support from EMBO, the Howard Hughes Medical Institute, and the Intramural Research Program of the NIH, National Library of Medicine. NR 94 TC 115 Z9 118 U1 4 U2 34 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8935 J9 EPIGENET CHROMATIN JI Epigenetics Chromatin PD MAY 31 PY 2012 VL 5 AR 7 DI 10.1186/1756-8935-5-7 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA 963LK UT WOS:000305622000001 PM 22650316 ER PT J AU Chen, HY Yao, K Nadas, J Bode, AM Malakhova, M Oi, N Li, HT Lubet, RA Dong, ZG AF Chen, Hanyong Yao, Ke Nadas, Janos Bode, Ann M. Malakhova, Margarita Oi, Naomi Li, Haitao Lubet, Ronald A. Dong, Zigang TI Prediction of Molecular Targets of Cancer Preventing Flavonoid Compounds Using Computational Methods SO PLOS ONE LA English DT Article ID RIBOSOMAL S6 KINASE; LEUKOTRIENE A(4) HYDROLASE; INDUCED COX-2 EXPRESSION; CELL-PROLIFERATION; PROTEIN-KINASES; LIGAND DOCKING; PI-3 KINASE; RED WINE; TRANSFORMATION; INHIBITOR AB Plant-based polyphenols (i.e., phytochemicals) have been used as treatments for human ailments for centuries. The mechanisms of action of these plant-derived compounds are now a major area of investigation. Thousands of phytochemicals have been isolated, and a large number of them have shown protective activities or effects in different disease models. Using conventional approaches to select the best single or group of best chemicals for studying the effectiveness in treating or preventing disease is extremely challenging. We have developed and used computational-based methodologies that provide efficient and inexpensive tools to gain further understanding of the anticancer and therapeutic effects exerted by phytochemicals. Computational methods involving virtual screening, shape and pharmacophore analysis and molecular docking have been used to select chemicals that target a particular protein or enzyme and to determine potential protein targets for well-characterized as well as for novel phytochemicals. C1 [Chen, Hanyong; Yao, Ke; Nadas, Janos; Bode, Ann M.; Malakhova, Margarita; Oi, Naomi; Li, Haitao; Dong, Zigang] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [Lubet, Ronald A.] NCI, Bethesda, MD 20892 USA. RP Chen, HY (reprint author), Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA. EM zgdong@hi.umn.edu FU Hormel Foundation; National Institutes of Health [R37 CA081064, CA120388, ES016548, CA0227501]; National Cancer Institute [HHSN-261200533001C-NO1-CN-53301] FX This work was supported by the Hormel Foundation and National Institutes of Health grants R37 CA081064, CA120388, ES016548, CA0227501 and National Cancer Institute Contract No. HHSN-261200533001C-NO1-CN-53301. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 20 Z9 20 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 31 PY 2012 VL 7 IS 5 AR e38261 DI 10.1371/journal.pone.0038261 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TY UT WOS:000305338500119 PM 22693608 ER PT J AU Cohen, HS Cox, C Springer, G Hoffman, HJ Young, MA Margolick, JB Plankey, MW AF Cohen, Helen S. Cox, Christopher Springer, Gayle Hoffman, Howard J. Young, Mary A. Margolick, Joseph B. Plankey, Michael W. TI Prevalence of Abnormalities in Vestibular Function and Balance among HIV-Seropositive and HIV-Seronegative Women and Men SO PLOS ONE LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; PAROXYSMAL POSITIONAL VERTIGO; ACTIVE ANTIRETROVIRAL THERAPY; MULTICENTER AIDS COHORT; SENSORY INTERACTION; VESTIBULOOCULAR REFLEX; POSTURAL CONTROL; INTERAGENCY HIV; CLINICAL-TEST; VIRUS AB Background: Most HIV-seropositive subjects in western countries receive highly active antiretroviral therapy (HAART). Although many aspects of their health have been studied, little is known about their vestibular and balance function. The goals of this study were to determine the prevalences of vestibular and balance impairments among HIV-seropositive and comparable seronegative men and women and to determine if those groups differed. Methods: Standard screening tests of vestibular and balance function, including head thrusts, Dix-Hallpike maneuvers, and Romberg balance tests on compliant foam were performed during semiannual study visits of participants who were enrolled in the Baltimore and Washington, D. C. sites of the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study. Results: No significant differences by HIV status were found on most tests, but HIV-seropositive subjects who were using HAART had a lower frequency of abnormal Dix-Hallpike nystagmus than HIV-seronegative subjects. A significant number of nonclassical Dix-Hallpike responses were found. Age was associated with Romberg scores on foam with eyes closed. Sex was not associated with any of the test scores. Conclusion: These findings suggest that HAART-treated HIV infection has no harmful association with vestibular function in community-dwelling, ambulatory men and women. The association with age was expected, but the lack of association with sex was unexpected. The presence of nonclassical Dix-Hallpike responses might be consistent with central nervous system lesions. C1 [Cohen, Helen S.] Baylor Coll Med, Bobby R Alford Dept Otolaryngol Head & Neck Surg, Houston, TX 77030 USA. [Cox, Christopher; Springer, Gayle] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, NIH, Bethesda, MD USA. [Young, Mary A.; Plankey, Michael W.] Georgetown Univ, Med Ctr, Dept Med, Div Infect Dis, Washington, DC 20007 USA. [Margolick, Joseph B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. RP Cohen, HS (reprint author), Baylor Coll Med, Bobby R Alford Dept Otolaryngol Head & Neck Surg, Houston, TX 77030 USA. EM mwp23@georgetown.edu FU National Institute on Deafness and Other Communication Disorders (NIDCD) [U01 AI-035042-18, U01 AI-034994-17]; Baltimore-Washington, D.C.; National Cancer Institute [UO1-AI-35042, UL1RR025005]; Metropolitan Washington, D.C.; National Institute on Drug Abuse FX This study was supported by the National Institute on Deafness and Other Communication Disorders (NIDCD) via interagency agreement with NIAID for Cooperative Agreements U01 AI-035042-18 (MACS) and U01 AI-034994-17 (WIHS). Support of the Baltimore-Washington, D.C. MAC site was provided by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (UO1-AI-35042, UL1RR025005)(GCRC). Support of the Metropolitan Washington, D.C. WIHS site was provided by the National Institute of Allergy and Infectious Diseases (UO1-AI34994) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UO1-HD-32632). The study was co-funded by the National Cancer Institute, the National Institute on Drug Abuse. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 4 Z9 4 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 31 PY 2012 VL 7 IS 5 AR e38419 DI 10.1371/journal.pone.0038419 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TY UT WOS:000305338500146 PM 22675462 ER PT J AU Fu, LZ Sun, GH Fiorentino, M Shi, YB AF Fu, Liezhen Sun, Guihong Fiorentino, Maria Shi, Yun-Bo TI Characterization of Xenopus Tissue Inhibitor of Metalloproteinases-2: A Role in Regulating Matrix Metalloproteinase Activity during Development SO PLOS ONE LA English DT Article ID DUPLICATED MATRIX-METALLOPROTEINASE-9 GENES; IMPLICATES DISTINCT FUNCTIONS; HORMONE RESPONSE GENES; THYROID-HORMONE; AMPHIBIAN METAMORPHOSIS; TRANSCRIPTIONAL REGULATION; ANURAN METAMORPHOSIS; EXPRESSION PROFILES; STROMELYSIN-3 GENE; FROG METAMORPHOSIS AB Background: Frog metamorphosis is totally dependent on thyroid hormone (T3) and mimics the postembryonic period around birth in mammals. It is an excellent model to study the molecular basis of postembryonic development in vertebrate. We and others have shown that many, if not all, matrix metalloproteinases (MMPs), which cleave proteins of the extracellular matrix as well as other substrates, are induced by T3 and important for metamorphosis. MMP activity can be inhibited by tissue inhibitors of metalloproteinase (TIMPs). There are 4 TIMPs in vertebrates and their roles in postembryonic development are poorly studied. Methodology/Principal Findings: We analyzed the TIMP2 genes in Xenopus laevis and the highly related species Xenopus tropicalis and discovered that TIMP2 is a single copy gene in Xenopus tropicalis as in mammals but is duplicated in Xenopus laevis. Furthermore, the TIMP2 locus in Xenopus tropicalis genome is different from that in human, suggesting an evolutionary reorganization of the locus. More importantly, we found that the duplicated TIMP2 genes were similarly regulated in the developing limb, remodeling intestine, resorbing tail during metamorphosis. Unexpectedly, like its MMP target genes, the TIMP2 genes were upregulated by T3 during both natural and T3-induced metamorphosis. Conclusions/Significance: Our results indicate that TIMP2 is highly conserved among vertebrates and that the TIMP2 locus underwent a chromosomal reorganization during evolution. Furthermore, the unexpected upregulation of TIMP2 genes during metamorphosis suggests that proper balance of MMP activity is important for metamorphosis. C1 [Fu, Liezhen; Sun, Guihong; Fiorentino, Maria; Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, PCRM, NIH, Bethesda, MD USA. [Sun, Guihong] Wuhan Univ, Sch Med, Key Lab Allergy & Immune Related Dis, Wuhan 430072, Peoples R China. [Sun, Guihong] Wuhan Univ, Sch Med, Med Res Ctr, Wuhan 430072, Peoples R China. RP Fu, LZ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, PCRM, NIH, Bethesda, MD USA. EM Shi@helix.nih.gov OI Fiorentino, Maria R/0000-0001-5318-7313 FU Intramural Research Program of National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Program of National Institute of Child Health and Human Development, National Institutes of Health. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 4 Z9 5 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 31 PY 2012 VL 7 IS 5 AR e36707 DI 10.1371/journal.pone.0036707 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TY UT WOS:000305338500016 PM 22693555 ER PT J AU Kottgen, A Yang, Q Shimmin, LC Tin, A Schaeffer, C Coresh, J Liu, X Rampoldi, L Hwang, SJ Boerwinkle, E Hixson, JE Kao, WHL Fox, CS AF Koettgen, Anna Yang, Qiong Shimmin, Lawrence C. Tin, Adrienne Schaeffer, Celine Coresh, Josef Liu, Xuan Rampoldi, Luca Hwang, Shih-Jen Boerwinkle, Eric Hixson, James E. Kao, W. H. Linda Fox, Caroline S. TI Association of Estimated Glomerular Filtration Rate and Urinary Uromodulin Concentrations with Rare Variants Identified by UMOD Gene Region Sequencing SO PLOS ONE LA English DT Article ID CHRONIC KIDNEY-DISEASE; RISK POPULATION COHORTS; COLLABORATIVE METAANALYSIS; HIGHER ALBUMINURIA; SERUM CREATININE; INCIDENT CKD; ALL-CAUSE; FRAMINGHAM; MUTATIONS; DESIGN AB Background: Recent genome-wide association studies (GWAS) have identified common variants in the UMOD region associated with kidney function and disease in the general population. To identify novel rare variants as well as common variants that may account for this GWAS signal, the exons and 4 kb upstream region of UMOD were sequenced. Methodology/Principal Findings: Individuals (n = 485) were selected based on presence of the GWAS risk haplotype and chronic kidney disease (CKD) in the ARIC Study and on the extremes of of the UMOD gene product, uromodulin, in urine (Tamm Horsfall protein, THP) in the Framingham Heart Study (FHS). Targeted sequencing was conducted using capillary based Sanger sequencing (3730 DNA Analyzer). Variants were tested for association with THP concentrations and estimated glomerular filtration rate (eGFR), and identified non-synonymous coding variants were genotyped in up to 22,546 follow-up samples. Twenty-four and 63 variants were identified in the 285 ARIC and 200 FHS participants, respectively. In both studies combined, there were 33 common and 54 rare (MAF<0.05) variants. Five non-synonymous rare variants were identified in FHS; borderline enrichment of rare variants was found in the extremes of THP (SKAT p-value = 0.08). Only V458L was associated with THP in the FHS general-population validation sample (p = 9* 10(-3), n = 2,522), but did not show directionconsistent and significant association with eGFR in both the ARIC (n = 14,635) and FHS (n = 7,520) validation samples. Pooling all non-synonymous rare variants except V458L together showed non-significant associations with THP and eGFR in the FHS validation sample. Functional studies of V458L revealed no alternations in protein trafficking. Conclusions/Significance: Multiple novel rare variants in the UMOD region were identified, but none were consistently associated with eGFR in two independent study samples. Only V458L had modest association with THP levels in the general population and thus could not account for the observed GWAS signal. C1 [Koettgen, Anna; Tin, Adrienne; Coresh, Josef; Kao, W. H. Linda] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Koettgen, Anna] Freiburg Univ Clin, Div Renal, Freiburg, Germany. [Yang, Qiong; Liu, Xuan] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Shimmin, Lawrence C.; Boerwinkle, Eric; Hixson, James E.] UT Houston Sch Publ Hlth, Div Epidemiol & Dis Control, Ctr Human Genet, Houston, TX USA. [Schaeffer, Celine; Rampoldi, Luca] Ist Sci San Raffaele, Dulbecco Telethon Inst, I-20132 Milan, Italy. [Schaeffer, Celine; Rampoldi, Luca] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy. [Coresh, Josef; Kao, W. H. Linda] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP Kottgen, A (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. EM foxca@nhlbi.nih.gov RI Yang, Qiong/G-5438-2014; OI SCHAEFFER, Celine/0000-0001-5883-3951; Rampoldi, Luca/0000-0002-0544-7042 FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Institute of Diabetes and Digestive and Kidney Diseases [1 R01 DK076770-01]; Emmy Noether Programme of the German Research Foundation [KO 3598/2-1]; National Human Genome Research Institute [RC2 HG005697]; National Institutes of Health/National Heart, Lung, and Blood Institute [N01-HC-25195]; NHLBI; Fondazione Telethon Italy [TCR08006] FX ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The authors thank the staff and participants of the ARIC study for their important contributions. This study was additionally funded by the National Institute of Diabetes and Digestive and Kidney Diseases (1 R01 DK076770-01), the Emmy Noether Programme of the German Research Foundation (KO 3598/2-1 to A.K.), and the National Human Genome Research Institute (RC2 HG005697 to JEH). FHS: This work was supported through National Institutes of Health/National Heart, Lung, and Blood Institute Contract N01-HC-25195 and the NHLBI division of intra- mural research. Functional studies: This work was supported by the Fondazione Telethon Italy (TCR08006 to LR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 11 Z9 11 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 31 PY 2012 VL 7 IS 5 AR e38311 DI 10.1371/journal.pone.0038311 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TY UT WOS:000305338500128 PM 22693617 ER PT J AU Sahu, SN Lewis, J Patel, I Bozdag, S Lee, JH LeClerc, JE Cinar, HN AF Sahu, Surasri N. Lewis, Jada Patel, Isha Bozdag, Serdar Lee, Jeong H. LeClerc, Joseph E. Cinar, Hediye Nese TI Genomic Analysis of Immune Response against Vibrio cholerae Hemolysin in Caenorhabditis elegans SO PLOS ONE LA English DT Article ID UNFOLDED PROTEIN RESPONSE; EL-TOR HEMOLYSIN; INNATE IMMUNITY; BACTERIAL PATHOGENESIS; VIRULENCE FACTORS; CELL VACUOLATION; C-ELEGANS; GENES; RECEPTOR; EXPRESSION AB Vibrio cholerae cytolysin (VCC) is among the accessory V. cholerae virulence factors that may contribute to disease pathogenesis in humans. VCC, encoded by hlyA gene, belongs to the most common class of bacterial toxins, known as pore-forming toxins (PFTs). V. cholerae infects and kills Caenorhabditis elegans via cholerae toxin independent manner. VCC is required for the lethality, growth retardation and intestinal cell vacuolation during the infection. However, little is known about the host gene expression responses against VCC. To address this question we performed a microarray study in C. elegans exposed to V. cholerae strains with intact and deleted hlyA genes. Many of the VCC regulated genes identified, including C-type lectins, Prion-like (glutamine [Q]/asparagine [N]-rich)-domain containing genes, genes regulated by insulin/IGF-1-mediated signaling (IIS) pathway, were previously reported as mediators of innate immune response against other bacteria in C. elegans. Protective function of the subset of the genes up-regulated by VCC was confirmed using RNAi. By means of a machine learning algorithm called FastMEDUSA, we identified several putative VCC induced immune regulatory transcriptional factors and transcription factor binding motifs. Our results suggest that VCC is a major virulence factor, which induces a wide variety of immune response-related genes during V. cholerae infection in C. elegans. C1 [Sahu, Surasri N.; Lee, Jeong H.; Cinar, Hediye Nese] US FDA, Div Virulence Assessment, Laurel, MD USA. [Lewis, Jada; Patel, Isha; LeClerc, Joseph E.] US FDA, Div Mol Biol, Laurel, MD USA. [Bozdag, Serdar] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. [Sahu, Surasri N.] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Lee, Jeong H.] Kyungpook Natl Univ, Taegu, South Korea. RP Sahu, SN (reprint author), US FDA, Div Virulence Assessment, Laurel, MD USA. EM hediye.cinar@fda.hhs.gov NR 66 TC 16 Z9 16 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 31 PY 2012 VL 7 IS 5 AR e38200 DI 10.1371/journal.pone.0038200 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TY UT WOS:000305338500108 PM 22675448 ER PT J AU Wang, SP Dorsey, TH Terunuma, A Kittles, RA Ambs, S Kwabi-Addo, B AF Wang, Songping Dorsey, Tiffany H. Terunuma, Atsushi Kittles, Rick A. Ambs, Stefan Kwabi-Addo, Bernard TI Relationship between Tumor DNA Methylation Status and Patient Characteristics in African-American and European-American Women with Breast Cancer SO PLOS ONE LA English DT Article ID RACIAL DISPARITIES; PROSTATE TISSUES; CARCINOMA; SURVIVAL; SUBTYPES; HYPERMETHYLATION; BIOLOGY; RACE; PROGNOSIS; ETHNICITY AB Aberrant DNA methylation is critical for development and progression of breast cancer. We investigated the association of CpG island methylation in candidate genes and clinicopathological features in 65 African-American (AA) and European-American (EA) breast cancer patients. Quantitative methylation analysis was carried out on bisulfite modified genomic DNA and sequencing (pyrosequencing) for promoter CpG islands of p16, ESR1, RASSF1A, RAR beta 2, CDH13, HIN1, SFRP1 genes and the LINE1 repetitive element using matched paired non-cancerous and breast tumor specimen (32 AA and 33 EA women). Five of the genes, all known tumor suppressor genes (RASSF1A, RAR beta 2, CDH13, HIN1 and SFRP1), were found to be frequently hypermethylated in breast tumor tissues but not in the adjacent non-cancerous tissues. Significant differences in the CDH13 methylation status were observed by comparing DNA methylation between AA and EA patients, with more obvious CDH13 methylation differences between the two patient groups in the ER-disease and among young patients (age<50). In addition, we observed associations between CDH13, SFRP1, and RASSF1A methylation and breast cancer subtypes and between SFRP1 methylation and patient's age. Furthermore, tumors that received neoadjuvant therapy tended to have reduced RASSF1A methylation when compared with chemotherapy naive tumors. Finally, Kaplan Meier survival analysis showed a significant association between methylation at 3 loci (RASSF1A, RAR beta 2 and CDH13) and reduced overall disease survival. In conclusion, the DNA methylation status of breast tumors was found to be significantly associated with clinicopathological features and race/ethnicity of the patients. C1 [Wang, Songping; Kwabi-Addo, Bernard] Howard Univ, Dept Biochem & Mol Biol, Washington, DC 20059 USA. [Dorsey, Tiffany H.; Terunuma, Atsushi; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res & Epidemiol, NIH, Bethesda, MD 20892 USA. [Dorsey, Tiffany H.; Terunuma, Atsushi; Ambs, Stefan] NCI, Genet Res Program, NIH, Bethesda, MD 20892 USA. [Kittles, Rick A.] Univ Illinois, Dept Med, Chicago, IL USA. RP Wang, SP (reprint author), Howard Univ, Dept Biochem & Mol Biol, Washington, DC 20059 USA. EM bkwabi-addo@howard.edu RI Kwabi-Addo, Bernard/A-6993-2016 OI Kwabi-Addo, Bernard/0000-0003-3692-6350 FU Department of Defense Program Idea Award [PC073828] FX This work was supported by grant PC073828 from the Department of Defense Program Idea Award to BKA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 22 Z9 25 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 31 PY 2012 VL 7 IS 5 AR e37928 DI 10.1371/journal.pone.0037928 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TY UT WOS:000305338500067 PM 22701537 ER PT J AU Tai, XG Van Laethem, F Pobezinsky, L Guinter, T Sharrow, SO Adams, A Granger, L Kruhlak, M Lindsten, T Thompson, CB Feigenbaum, L Singer, A AF Tai, Xuguang Van Laethem, Francois Pobezinsky, Leonid Guinter, Terry Sharrow, Susan O. Adams, Anthony Granger, Larry Kruhlak, Michael Lindsten, Tullia Thompson, Craig B. Feigenbaum, Lionel Singer, Alfred TI Basis of CTLA-4 function in regulatory and conventional CD4(+) T cells SO BLOOD LA English DT Article ID IMMUNOLOGICAL SELF-TOLERANCE; DENDRITIC CELLS; COSTIMULATORY MOLECULES; TRYPTOPHAN CATABOLISM; IN-VIVO; EXPRESSION; FOXP3; ACTIVATION; RECEPTOR; CD28 AB CTLA-4 proteins contribute to the suppressor function of regulatory T cells (Tregs), but the mechanism by which they do so remains incompletely understood. In the present study, we assessed CTLA-4 protein function in both Tregs and conventional (Tconv) CD4(+) T cells. We report that CTLA-4 proteins are responsible for all 3 characteristic Treg functions of suppression, TCR hyposignaling, and anergy. However, Treg suppression and anergy only required the external domain of CTLA-4, whereas TCR hyposignaling required its internal domain. Surprisingly, TCR hyposignaling was neither required for Treg suppression nor anergy because costimulatory blockade by the external domain of CTLA-4 was sufficient for both functions. We also report that CTLA-4 proteins were localized in Tregs in sub-membrane vesicles that rapidly recycled to/from the cell surface, whereas CTLA-4 proteins in naive Tconv cells were retained in Golgi vesicles away from the cell membrane and had no effect on Tconv cell function. However, TCR signaling of Tconv cells released CTLA-4 proteins from Golgi retention and caused activated Tconv cells to acquire suppressor function. Therefore, the results of this study demonstrate the importance of intracellular localization for CTLA-4 protein function and reveal that CTLA-4 protein externalization imparts suppressor function to both regulatory and conventional CD4(+) T cells. (Blood. 2012; 119(22): 5155-5163) C1 [Tai, Xuguang; Van Laethem, Francois; Pobezinsky, Leonid; Guinter, Terry; Sharrow, Susan O.; Adams, Anthony; Granger, Larry; Kruhlak, Michael; Singer, Alfred] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Lindsten, Tullia; Thompson, Craig B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Feigenbaum, Lionel] SAIC Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, Bldg 10,Rm 4B36,10 Ctr Dr, Bethesda, MD 20892 USA. EM singera@mail.nih.gov FU Intramural Research Program of National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD. NR 39 TC 76 Z9 81 U1 0 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 31 PY 2012 VL 119 IS 22 BP 5155 EP 5163 DI 10.1182/blood-2011-11-388918 PG 9 WC Hematology SC Hematology GA 959DM UT WOS:000305291800018 PM 22403258 ER PT J AU Suthaus, J Stuhlmann-Laeisz, C Tompkins, VS Rosean, TR Klapper, W Tosato, G Janz, S Scheller, J Rose-John, S AF Suthaus, Jan Stuhlmann-Laeisz, Christiane Tompkins, Van S. Rosean, Timothy R. Klapper, Wolfram Tosato, Giovanna Janz, Siegfried Scheller, Juergen Rose-John, Stefan TI HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice SO BLOOD LA English DT Article ID INTERLEUKIN-6 TRANSGENIC MICE; NF-KAPPA-B; KAPOSIS-SARCOMA; DNA-SEQUENCES; HERPESVIRUS; RECEPTOR; EXPRESSION; ANTIBODY; GP130; CELL AB Human herpes virus 8 (HHV-8) or Kaposi sarcoma-associated herpes virus is the etiologic agent of Kaposi sarcoma, primary effusion lymphoma, and plasma cell-type multicentric Castleman disease (MCD). HHV-8 encodes a viral homolog of human IL-6, called viral IL-6 (vIL-6), which does not require the cellular IL-6 receptor for binding to the ubiquitously expressed gp130 receptor subunit and subsequent JAK-STAT signaling. Thus, in contrast to IL-6, vIL-6 can stimulate virtually all cells in the body. To elucidate the mechanism by which vIL-6 drives human diseases, we generated transgenic mice that constitutively express vIL-6 under control of the MHC class I promoter. The mice were found to exhibit vIL-6 serum levels comparable with those observed in HHV-8-infected patients, to contain elevated amounts of phosphorylated STAT3 in spleen and lymph nodes, where vIL-6 was produced, and to spontaneously develop key features of human plasma cell-type MCD, including splenomegaly, multifocal lymphadenopathy, hypergammaglobulinemia, and plasmacytosis. Transfer of the vIL-6 transgene onto an IL-6-deficient genetic background abrogated MCD-like phenotypes, indicating that endogenous mouse IL-6 is a crucial cofactor in the natural history of the disease. Our results in mice suggest that human IL-6 plays an important role in the pathogenesis of HHV-8-associated MCD. (Blood. 2012; 119(22): 5173-5181) C1 [Suthaus, Jan; Rose-John, Stefan] Univ Kiel, Inst Biochem, D-2300 Kiel, Germany. [Stuhlmann-Laeisz, Christiane; Klapper, Wolfram] Univ Kiel, Inst Pathol, D-2300 Kiel, Germany. [Tompkins, Van S.; Rosean, Timothy R.; Janz, Siegfried] Univ Iowa, Dept Pathol, Carver Coll Med, Iowa City, IA 52242 USA. [Rosean, Timothy R.; Janz, Siegfried] Univ Iowa, Interdisciplinary Grad Program Immunol, Iowa City, IA USA. [Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Scheller, Juergen] Univ Dusseldorf, Fac Med, Inst Biochem & Mol Biol 2, D-40225 Dusseldorf, Germany. RP Rose-John, S (reprint author), Univ Kiel, Inst Biochem, Olshausenstr 40, D-2300 Kiel, Germany. EM jscheller@uni-duesseldorf.de; rosejohn@biochem.uni-kiel.de RI Scheller, Jurgen/K-5290-2015; Klapper, Wolfram/S-6314-2016; Rose-John, Stefan/A-7998-2010; OI Rose-John, Stefan/0000-0002-7519-3279; Tompkins, Van/0000-0003-1279-8075 FU Multiple Myeloma Research foundation; International Waldenstrom's Macroglobulinemia foundation; National Institutes of Health [R01CA151354, T32-HL07734, 5T32AI007485-17]; Deutsche Forschungsgemeinschaft, Bonn, Germany [SFB415, B5, C6, SFB877, A1, A2]; Cluster of Excellence Inflammation at Interfaces FX This work was supported in part by the Multiple Myeloma Research and International Waldenstrom's Macroglobulinemia foundations (research awards; S.J.), the National Institutes of Health (R01CA151354, S.J.; T32-HL07734, V. S. T.; and 5T32AI007485-17, T. R. R.), the Deutsche Forschungsgemeinschaft, Bonn, Germany (J. Scheller and S.R.-J.; SFB415, projects B5, C6; SFB877, projects A1, A2), and the Cluster of Excellence Inflammation at Interfaces. NR 50 TC 42 Z9 47 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 31 PY 2012 VL 119 IS 22 BP 5173 EP 5181 DI 10.1182/blood-2011-09-377705 PG 9 WC Hematology SC Hematology GA 959DM UT WOS:000305291800020 PM 22490805 ER PT J AU Jin, H Li, L Xu, J Zhen, FH Zhu, L Liu, PP Zhang, MJ Zhang, WQ Wen, ZL AF Jin, Hao Li, Li Xu, Jin Zhen, Fenghua Zhu, Lu Liu, P. Paul Zhang, Mingjie Zhang, Wenqing Wen, Zilong TI Runx1 regulates embryonic myeloid fate choice in zebrafish through a negative feedback loop inhibiting Pu.1 expression SO BLOOD LA English DT Article ID CCAAT/ENHANCER-BINDING-PROTEIN; HEMATOPOIETIC STEM/PROGENITOR CELLS; TRANSCRIPTION FACTOR; ADULT HEMATOPOIESIS; DEFINITIVE HEMATOPOIESIS; TRANSGENIC ZEBRAFISH; LINEAGE COMMITMENT; EARLY MACROPHAGES; GENE-EXPRESSION; DANIO-RERIO AB Proper cell fate choice in myelopoiesis is essential for generating correct numbers of distinct myeloid subsets manifesting a wide spectrum of subset-specific activities during development and adulthood. Studies have suggested that myeloid fate choice is primarily regulated by transcription factors; however, new intrinsic regulators and their underlying mechanisms remain to be elucidated. Zebrafish embryonic myelopoiesis gives rise to neutrophils and macrophages and represents a promising system to derive new regulatory mechanisms for myeloid fate decision in vertebrates. Here we present an in vivo study of cell fate specification during zebrafish embryonic myelopoiesis through characterization of the embryos with altered Pu.1, Runx1 activity alone, or their combinations. Genetic analysis shows that low and high Pu.1 activities determine embryonic neutrophilic granulocyte and macrophage fate, respectively. Inactivation and overexpression of Runx1 in zebrafish uncover Runx1 as a key embryonic myeloid fate determinant that favors neutrophil over macrophage fate. Runx1 is induced by high Pu.1 level and in turn transrepresses pu.1 expression, thus constituting a negative feedback loop that fashions a favorable Pu.1 level required for balanced fate commitment to neutrophils versus macrophages. Our findings define a Pu.1-Runx1 regulatory loop that governs the equilibrium between distinct myeloid fates by assuring an appropriate Pu.1 dosage. (Blood. 2012; 119(22):5239-5249) C1 [Jin, Hao; Li, Li; Xu, Jin; Zhen, Fenghua; Zhu, Lu; Zhang, Mingjie; Wen, Zilong] Hong Kong Univ Sci & Technol, State Key Lab Mol Neurosci, Div Life Sci, Kowloon, Hong Kong, Peoples R China. [Liu, P. Paul] NHGRI, Natl Inst Hlth, Bethesda, MD 20892 USA. [Zhang, Wenqing] So Med Univ, Dept Cell Biol, Lab Zebrafish Modeling & Drug Screening Human Dis, Guangdong Higher Educ Inst, Guangzhou, Peoples R China. RP Wen, ZL (reprint author), Hong Kong Univ Sci & Technol, State Key Lab Mol Neurosci, Div Life Sci, Kowloon, Hong Kong, Peoples R China. EM zzwwqq@smu.edu.cn; zilong@ust.hk RI Liu, Paul/A-7976-2012; OI Liu, Paul/0000-0002-6779-025X; Zhang, Mingjie/0000-0001-9404-0190 FU Research Grants Council of the HKSAR [HKUST6/CRF/09]; National Basic Research Program of China [2012CB945102]; National Natural Science Foundation of China [31171403, 30828020]; National Human Genome Research Institute, National Institutes of Health FX This work was supported by the General Research Fund (Research Grants Council of the HKSAR, grant HKUST6/CRF/09), the National Basic Research Program of China (grant 2012CB945102), the National Natural Science Foundation of China (grants 31171403 and 30828020), and the Intramural Research Program of National Human Genome Research Institute, National Institutes of Health. NR 50 TC 29 Z9 30 U1 1 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 31 PY 2012 VL 119 IS 22 BP 5239 EP 5249 DI 10.1182/blood-2011-12-398362 PG 11 WC Hematology SC Hematology GA 959DM UT WOS:000305291800028 PM 22493295 ER PT J AU Lombardi, F Herrmann, HJ Perrone-Capano, C Plenz, D de Arcangelis, L AF Lombardi, F. Herrmann, H. J. Perrone-Capano, C. Plenz, D. de Arcangelis, L. TI Balance between Excitation and Inhibition Controls the Temporal Organization of Neuronal Avalanches SO PHYSICAL REVIEW LETTERS LA English DT Article ID CORTICAL-NEURONS; IN-VITRO; NETWORKS; DYNAMICS; STATE; OSCILLATIONS; CRITICALITY; MECHANISMS; CULTURES; ORIGIN AB Neuronal avalanches, measured in vitro and in vivo, exhibit a robust critical behavior. Their temporal organization hides the presence of correlations. Here we present experimental measurements of the waiting time distribution between successive avalanches in the rat cortex in vitro. This exhibits a nonmonotonic behavior not usually found in other natural processes. Numerical simulations provide evidence that this behavior is a consequence of the alternation between states of high and low activity, named up and down states, leading to a balance between excitation and inhibition controlled by a single parameter. During these periods, both the single neuron state and the network excitability level, keeping memory of past activity, are tuned by homeostatic mechanisms. C1 [Lombardi, F.; Herrmann, H. J.] ETH, Inst Computat Phys Engn Mat, Zurich, Switzerland. [Herrmann, H. J.] Univ Fed Ceara, Dept Fis, BR-60451970 Fortaleza, Ceara, Brazil. [Perrone-Capano, C.] Univ Naples Federico II, Dept Biol Sci, Naples, Italy. [Perrone-Capano, C.] IGB CNR, Naples, Italy. [Plenz, D.] NIH, Sect Crit Brain Dynam, Bethesda, MD 20892 USA. [de Arcangelis, L.] Univ Naples 2, Dept Informat Engn, Aversa, CE, Italy. RP Lombardi, F (reprint author), ETH, Inst Computat Phys Engn Mat, Zurich, Switzerland. RI Sistemas Complexos, Inct/J-8597-2013; Perrone-Capano, Carla/O-7708-2015; UFC, DF/E-1564-2017; Universidade Federal do Ceara, Physics Department/J-4630-2016 OI Perrone-Capano, Carla/0000-0002-6327-9753; Universidade Federal do Ceara, Physics Department/0000-0002-9247-6780 FU SNF [205321-13874]; NIMH; NIH FX We thank the SNF for funding within project 205321-13874. D. P. is supported by the Intramural Research Program of the NIMH and NIH. NR 33 TC 40 Z9 40 U1 1 U2 13 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 MAY 31 PY 2012 VL 108 IS 22 AR 228703 DI 10.1103/PhysRevLett.108.228703 PG 5 WC Physics, Multidisciplinary SC Physics GA 950OK UT WOS:000304658400026 PM 23003665 ER PT J AU Jackson, WM Nesti, LJ Tuan, RS AF Jackson, Wesley M. Nesti, Leon J. Tuan, Rocky S. TI Mesenchymal stem cell therapy for attenuation of scar formation during wound healing SO STEM CELL RESEARCH & THERAPY LA English DT Review ID HEPATOCYTE GROWTH-FACTOR; MARROW-DERIVED CELLS; HUMAN TRABECULAR BONE; SYNGENEIC MURINE MODEL; NITRIC-OXIDE SYNTHASE; GLOBAL HEART-FAILURE; PROGENITOR CELLS; STROMAL CELLS; INTERLEUKIN-10-DEFICIENT MICE; INFLAMMATORY RESPONSE AB Scars are a consequence of cutaneous wound healing that can be both unsightly and detrimental to the function of the tissue. Scar tissue is generated by excessive deposition of extracellular matrix tissue by wound healing fibroblasts and myofibroblasts, and although it is inferior to the uninjured skin, it is able to restore integrity to the boundary between the body and its environment. Scarring is not a necessary process to repair the dermal tissues. Rather, scar tissue forms due to specific mechanisms that occur during the adult wound healing process and are modulated primarily by the inflammatory response at the site of injury. Adult tissue-derived mesenchymal stem cells, which participate in normal wound healing, are trophic mediators of tissue repair. These cells participate in attenuating inflammation in the wound and reprogramming the resident immune and wound healing cells to favor tissue regeneration and inhibit fibrotic tissue formation. As a result, these cells have been considered and tested as a likely candidate for a cellular therapy to promote scar-less wound healing. This review identifies specific mechanisms by which mesenchymal stem cells can limit tissue fibrosis and summarizes recent in vivo studies where these cells have been used successfully to limit scar formation. C1 [Tuan, Rocky S.] Univ Pittsburgh, Sch Med, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, Pittsburgh, PA 15219 USA. [Jackson, Wesley M.; Nesti, Leon J.] Uniformed Serv Univ Hlth Sci, Dept Surg, Clin & Expt Orthopaed Lab, Bethesda, MD 20814 USA. [Jackson, Wesley M.] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD 20817 USA. [Nesti, Leon J.] NIAMSD, Orthopaed Res Grp, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), Univ Pittsburgh, Sch Med, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, 450 Technol Dr,Room 221, Pittsburgh, PA 15219 USA. EM rst13@pitt.edu FU National Institutes of Health [Z01 AR41131]; Commonwealth of Pennsylvania Department of Health; Department of Defense at the Walter Reed Army Medical Center (Department of the Army) [PO5 A011]; Department of the Army [W81XWH 10 2 0084, W81XWH 10 2 0085, D10_I_AR_J8_981] FX Supported in part by the National Institutes of Health Intramural Research Program (Z01 AR41131) and from the Commonwealth of Pennsylvania Department of Health. Additional support provided by the Department of Defense Military Amputee Research Program at the Walter Reed Army Medical Center (Department of the Army, Grant No. PO5 A011), the Peer reviewed Orthopedic Research Program (Department of the Army, Grants No. W81XWH 10 2 0084 and W81XWH 10 2 0085), and the Defense Medical Research Development Program (Department of the Army, Grant No. D10_I_AR_J8_981), for which the U. S. Army Medical Research Acquisition Activity 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. The views expressed in this manuscript are those of the authors alone and do not represent the views, policies or official positions of, nor should any official endorsement be inferred on the part of, the United States Government, the United States Army, the Uniformed Services University of the Health Sciences (USU), or the Department of Defense. Nor do they represent those of the National Institutes of Health or the Department of Health and Human Services. Figure one was produced using Sevier Medical Art. NR 122 TC 66 Z9 70 U1 2 U2 38 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-6512 J9 STEM CELL RES THER JI Stem Cell Res. Ther. PD MAY 31 PY 2012 VL 3 AR 20 DI 10.1186/scrt111 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 952CZ UT WOS:000304768800001 PM 22668751 ER PT J AU Brick, K Smagulova, F Khil, P Camerini-Otero, RD Petukhova, GV AF Brick, Kevin Smagulova, Fatima Khil, Pavel Camerini-Otero, R. Daniel Petukhova, Galina V. TI Genetic recombination is directed away from functional genomic elements in mice SO NATURE LA English DT Article ID HISTONE H3 METHYLTRANSFERASE; MEIOTIC RECOMBINATION; PRDM9; INITIATION; HOTSPOTS; SITES; MOUSE; IDENTIFICATION; LANDSCAPE; MEIOSIS AB Genetic recombination occurs during meiosis, the key developmental programme of gametogenesis. Recombination in mammals has been recently linked to the activity of a histone H3 methyltransferase, PR domain containing 9 (PRDM9)(1-6), the product of the only known speciation-associated gene in mammals(7). PRDM9 is thought to determine the preferred recombination sites-recombination hotspots-through sequence-specific binding of its highly polymorphic multi-Zn-finger domain(8). Nevertheless, Prdm9 knockout mice are proficient at initiating recombination(9). Here we map and analyse the genome-wide distribution of recombination initiation sites in Prdm9 knockout mice and in two mouse strains with different Prdm9 alleles and their F-1 hybrid. We show that PRDM9 determines the positions of practically all hotspots in the mouse genome, with the exception of the pseudo-autosomal region (PAR)-the only area of the genome that undergoes recombination in 100% of cells(10). Surprisingly, hotspots are still observed in Prdm9 knockout mice, and as in wild type, these hotspots are found at H3 lysine 4 (H3K4) trimethylation marks. However, in the absence of PRDM9, most recombination is initiated at promoters and at other sites of PRDM9-independent H3K4 trimethylation. Such sites are rarely targeted in wild-type mice, indicating an unexpected role of the PRDM9 protein in sequestering the recombination machinery away from gene-promoter regions and other functional genomic elements. C1 [Smagulova, Fatima; Petukhova, Galina V.] Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. [Brick, Kevin; Khil, Pavel; Camerini-Otero, R. Daniel] Natl Inst Diabet Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. RP Petukhova, GV (reprint author), Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. EM rdcamerini@mail.nih.gov; gpetukhova@usuhs.mil RI Smagulova, Fatima/K-5459-2015; OI Brick, Kevin/0000-0002-9596-6400; Smagulova, Fatima/0000-0001-6883-1968; Khil, Pavel/0000-0002-4903-8777 FU NIDDK; March of Dimes Foundation [5-FY07-667]; NIH from NIGMS [1R01GM084104-01A1]; USUHS [FS71HU, R071HU, CS71HU] FX We thank S. Sharmeen and H. Smith for assistance with high-throughput sequencing. We also thank M. Lichten and P. Hsieh for critical discussion of the manuscript. This research was supported by the NIDDK Intramural Research Program; Basil O'Connor Starter Scholar Research Award Grant No. 5-FY07-667 from the March of Dimes Foundation (G.V.P.); NIH grant 1R01GM084104-01A1 from NIGMS (G.V.P.); and New Investigator Start-up Grants FS71HU, R071HU and CS71HU from USUHS (G.V.P.). NR 30 TC 115 Z9 115 U1 4 U2 56 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 31 PY 2012 VL 485 IS 7400 BP 642 EP 645 DI 10.1038/nature11089 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 949WP UT WOS:000304608000048 PM 22660327 ER PT J AU Steeg, PS AF Steeg, Patricia S. TI PERSPECTIVE The right trials SO NATURE LA English DT Editorial Material ID METASTASIS C1 NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Steeg, PS (reprint author), NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM steegp@mail.nih.gov NR 5 TC 42 Z9 43 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 31 PY 2012 VL 485 IS 7400 BP S58 EP S59 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 949WP UT WOS:000304608000005 PM 22648501 ER PT J AU Shankaran, S Pappas, A McDonald, SA Vohr, BR Hintz, SR Epi, MS Yolton, K Gustafson, KE Leach, TM Green, C Bara, R Huitema, CMP Ehrenkranz, RA Tyson, JE Das, A Hammond, J Peralta-Carcelen, M Evans, PW Heyne, RJ Wilson-Costello, DE Vaucher, YE Bauer, CR Dusick, AM Adams-Chapman, I Goldstein, RF Guillet, R Papile, LA Higgins, RD AF Shankaran, Seetha Pappas, Athina McDonald, Scott A. Vohr, Betty R. Hintz, Susan R. Epi, M. S. Yolton, Kimberly Gustafson, Kathryn E. Leach, Theresa M. Green, Charles Bara, Rebecca Huitema, Carolyn M. Petrie Ehrenkranz, Richard A. Tyson, Jon E. Das, Abhik Hammond, Jane Peralta-Carcelen, Myriam Evans, Patricia W. Heyne, Roy J. Wilson-Costello, Deanne E. Vaucher, Yvonne E. Bauer, Charles R. Dusick, Anna M. Adams-Chapman, Ira Goldstein, Ricki F. Guillet, Ronnie Papile, Lu-Ann Higgins, Rosemary D. CA Eunice Kennedy Shriver NICHD Neona TI Childhood Outcomes after Hypothermia for Neonatal Encephalopathy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HYPOXIC-ISCHEMIC ENCEPHALOPATHY; EMERGENCY CARDIOVASCULAR CARE; WHOLE-BODY HYPOTHERMIA; CEREBRAL-PALSY; CARDIOPULMONARY-RESUSCITATION; SYSTEMIC HYPOTHERMIA; PERINATAL ASPHYXIA; SCHOOL-AGE; TERM; ASSOCIATION AB BACKGROUND We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available. METHODS In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5 degrees C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70. RESULTS Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P = 0.06); death occurred in 27 (28%) and 41 (44%) (P = 0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P = 0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P = 0.87). Attention-executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P = 0.19), and visuospatial dysfunction occurred in 4% and 3% (P = 0.80). CONCLUSIONS The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; ClinicalTrials.gov number, NCT00005772.) C1 [Shankaran, Seetha; Pappas, Athina; Bara, Rebecca] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [McDonald, Scott A.; Das, Abhik; Hammond, Jane] Res Triangle Inst, Stat & Epidemiol Unit, Res Triangle Pk, NC 27709 USA. [Huitema, Carolyn M. Petrie] Res Triangle Inst, Stat & Epidemiol Unit, Rockville, MD USA. [Vohr, Betty R.; Leach, Theresa M.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Hintz, Susan R.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Yolton, Kimberly] Univ Cincinnati, Dept Pediat, Cincinnati, OH 45221 USA. [Gustafson, Kathryn E.; Goldstein, Ricki F.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Green, Charles; Tyson, Jon E.; Evans, Patricia W.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Peralta-Carcelen, Myriam] Univ Alabama Birmingham, Div Neonatol, Birmingham, AL USA. [Heyne, Roy J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Wilson-Costello, Deanne E.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Vaucher, Yvonne E.] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Bauer, Charles R.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Dusick, Anna M.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN USA. [Adams-Chapman, Ira] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Adams-Chapman, Ira] Childrens Healthcare Atlanta, Atlanta, GA USA. [Guillet, Ronnie] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Papile, Lu-Ann] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Neonatal Res Network, NIH, Bethesda, MD USA. RP Shankaran, S (reprint author), Childrens Hosp Michigan, Div Neonatal Perinatal Med, 3901 Beaubien Blvd, Detroit, MI 48201 USA. EM sshankar@med.wayne.edu FU National Institutes of Health; Eunice Kennedy Shriver NICHD Neonatal Research Network FX Supported by grants from the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network. NR 20 TC 180 Z9 186 U1 2 U2 15 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 31 PY 2012 VL 366 IS 22 BP 2085 EP 2092 DI 10.1056/NEJMoa1112066 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 949YE UT WOS:000304613400008 PM 22646631 ER PT J AU Wersto, RP Koss, LG AF Wersto, Robert P. Koss, Leopold G. TI Intratumor Heterogeneity and Branched Evolution SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Wersto, Robert P.] NIA, Baltimore, MD 21224 USA. [Koss, Leopold G.] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Wersto, RP (reprint author), NIA, Baltimore, MD 21224 USA. EM werstor@nih.gov NR 1 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 31 PY 2012 VL 366 IS 22 BP 2132 EP 2132 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 949YE UT WOS:000304613400024 PM 22646643 ER PT J AU Bonds, DE Miller, ME Dudl, J Feinglos, M Ismail-Beigi, F Malozowski, S Seaquist, E Simmons, DL Sood, A AF Bonds, Denise E. Miller, Michael E. Dudl, Jim Feinglos, Mark Ismail-Beigi, Faramarz Malozowski, Saul Seaquist, Elizabeth Simmons, Debra L. Sood, Ajay TI Severe hypoglycemia symptoms, antecedent behaviors, immediate consequences and association with glycemia medication usage: Secondary analysis of the ACCORD clinical trial data SO BMC ENDOCRINE DISORDERS LA English DT Article DE Hypoglycemia; Type 2 diabetes ID TYPE-2 DIABETES-MELLITUS; BETA-CELL FUNCTION; INSULIN; RISK; FREQUENCY; DRUGS; ROSIGLITAZONE AB Background: Hypoglycemia is a common complication of diabetes treatment. This paper describes symptoms, predecessors, consequences and medications associated with the first episode of severe hypoglycemia among ACCORD participants with type 2 diabetes, and compares these between intensive (Int: goal A1C < 6.0%) and standard (Std, goal A1C 7-7.9%) glycemia intervention groups. Methods: Information about symptoms, antecedents, and consequences was collected at the time participants reported an episode of severe hypoglycemia. Data on medications prescribed during the clinical trial was used to determine the association of particular diabetes drug classes and severe hypoglycemia. Results: The most frequently reported symptoms in both glycemia group were weakness/fatigue (Int 29%; Std 30%) and sweating (Int 26%; Std 27%), followed by confusion/disorientation (Int 22%; Std 29%) and shakiness (Int 21%; Std 19%). Approximately half of all events were preceded by a variation in food intake (Int 48%; Std 58%). The most common consequences were confusion (Int 37%; Std 34%), loss of consciousness (Int 25%; Std 25%), and hospitalization (Int 18%; Std 24%). The highest rates of hypoglycemia were found among those participants treated with insulin only (Int 6.09/100 person yrs; Std 2.64/100 person yrs) while the lowest were among those prescribed oral agents only (Int 1.93/100 person yrs; Std 0.20/100 person yrs). Conclusions: Severe hypoglycemia episodes were frequently preceded by a change in food intake, making many episodes potentially preventable. Symptoms of confusion/disorientation and loss of consciousness were frequently seen. The highest rates of hypoglycemia were seen with prescription of insulin, either alone or in combination with other medications. C1 [Bonds, Denise E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Miller, Michael E.] Wake Forest Univ, Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Dudl, Jim] Kaiser Permanente, Care Management Inst, Oakland, CA USA. [Feinglos, Mark] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Malozowski, Saul] NIDDK, Div Diabet Endocrinol & Metab Dis, Bethesda, MD USA. [Seaquist, Elizabeth] Univ Minnesota, Sch Med, Dept Med, Div Endocrinol & Diabet, Minneapolis, MN 55455 USA. [Simmons, Debra L.] Cent Arkansas Vet Healthcare Syst, Div Med, Little Rock, AR USA. [Simmons, Debra L.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Sood, Ajay] Case Western Reserve Univ, Dept Med, Div Endocrinol, Cleveland, OH 44106 USA. RP Bonds, DE (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM bondsde@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute [N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010]; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; General Clinical Research Centers FX The ACCORD Trial was supported by contracts (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; and by General Clinical Research Centers. Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, Sanofi-Aventis US, and Takeda Pharmaceuticals provided study medications, equipment, or supplies. NR 18 TC 20 Z9 20 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6823 J9 BMC ENDOCR DISORD JI BMC Endocr. Disord. PD MAY 30 PY 2012 VL 12 AR 5 DI 10.1186/1472-6823-12-5 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 999ZI UT WOS:000308354800001 PM 22646230 ER PT J AU Agarwal, SK Jothi, R AF Agarwal, Sunita K. Jothi, Raja TI Genome-Wide Characterization of Menin-Dependent H3K4me3 Reveals a Specific Role for Menin in the Regulation of Genes Implicated in MEN1-Like Tumors SO PLOS ONE LA English DT Article ID EMBRYONIC STEM-CELLS; ENDOCRINE-NEOPLASIA TYPE-1; HISTONE METHYLTRANSFERASE COMPLEX; PANCREATIC NEUROENDOCRINE TUMORS; SUPPRESSOR MENIN; EXPRESSED GENES; IN-VITRO; DIFFERENTIATION; MICE; LEUKEMIA AB Inactivating mutations in the MEN1 gene predisposing to the multiple endocrine neoplasia type 1 (MEN1) syndrome can also cause sporadic pancreatic endocrine tumors. MEN1 encodes menin, a subunit of MLL1/MLL2-containing histone methyltransferase complexes that trimethylate histone H3 at lysine 4 (H3K4me3). The importance of menin-dependent H3K4me3 in normal and transformed pancreatic endocrine cells is unclear. To study the role of menin-dependent H3K4me3, we performed in vitro differentiation of wild-type as well as menin-null mouse embryonic stem cells (mESCs) into pancreatic islet-like endocrine cells (PILECs). Gene expression analysis and genome-wide H3K4me3 ChIP-Seq profiling in wild-type and menin-null mESCs and PILECs revealed menin-dependent H3K4me3 at the imprinted Dlk1-Meg3 locus in mESCs, and all four Hox loci in differentiated PILECs. Specific and significant loss of H3K4me3 and gene expression was observed for genes within the imprinted Dlk1-Meg3 locus in menin-null mESCs and the Hox loci in menin-null PILECs. Given that the reduced expression of genes within the DLK1-MEG3 locus and the HOX loci is associated with MEN1-like sporadic tumors, our data suggests a possible role for menin-dependent H3K4me3 at these genes in the initiation and progression of sporadic pancreatic endocrine tumors. Furthermore, our investigation also demonstrates that menin-null mESCs can be differentiated in vitro into islet-like endocrine cells, underscoring the utility of menin-null mESC-derived specialized cell types for genome-wide high-throughput studies. C1 [Agarwal, Sunita K.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Jothi, Raja] Natl Inst Environm Hlth Sci, Syst Biol Sect, Biostat Branch, NIH, Res Triangle Pk, NC USA. RP Agarwal, SK (reprint author), NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. EM SunitaA@mail.nih.gov; jothi@mail.nih.gov RI Jothi, Raja/G-3780-2015; Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [1ZIADK075035-03]; National Institute of Environmental Health Sciences [1ZIAES102625-03] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (SKA; Project number: 1ZIADK075035-03), and the National Institute of Environmental Health Sciences (RJ; Project number: 1ZIAES102625-03). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 16 Z9 16 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 30 PY 2012 VL 7 IS 5 AR e37952 DI 10.1371/journal.pone.0037952 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959YF UT WOS:000305353400061 PM 22666422 ER PT J AU Liu, XF Bera, TK Kahue, C Escobar, T Fei, ZL Raciti, GA Pastan, I AF Liu, Xiu-Fen Bera, Tapan K. Kahue, Charissa Escobar, Thelma Fei, Zhaoliang Raciti, Gregory A. Pastan, Ira TI ANKRD26 and Its Interacting Partners TRIO, GPS2, HMMR and DIPA Regulate Adipogenesis in 3T3-L1 Cells SO PLOS ONE LA English DT Article ID ADIPOCYTE DIFFERENTIATION; TYROSINE PHOSPHATASE; ANKYRIN REPEAT; SUBUNIT GPS2; PROTEIN; KINASE; RHAMM; OBESITY; GENE; FIBROBLASTS AB Partial inactivation of the Ankyrin repeat domain 26 (Ankrd26) gene causes obesity and diabetes in mice and increases spontaneous and induced adipogenesis in mouse embryonic fibroblasts. However, it is not yet known how the Ankrd26 protein carries out its biological functions. We identified by yeast two-hybrid and immunoprecipitation assays the triple functional domain protein (TRIO), the G protein pathway suppressor 2 (GPS2), the delta-interacting protein A (DIPA) and the hyaluronan-mediated motility receptor (HMMR) as ANKRD26 interacting partners. Adipogenesis of 3T3-L1 cells was increased by selective down-regulation of Ankrd26, Trio, Gps2, Hmmr and Dipa. Furthermore, GPS2 and DIPA, which are normally located in the nucleus, were translocated to the cytoplasm, when the C-terminus of ANKRD26 was introduced into these cells. These findings provide biochemical evidence that ANKRD26, TRIO, GPS2 and HMMR are novel and important regulators of adipogenisis and identify new targets for the modulation of adipogenesis. C1 [Liu, Xiu-Fen; Bera, Tapan K.; Kahue, Charissa; Escobar, Thelma; Fei, Zhaoliang; Raciti, Gregory A.; Pastan, Ira] NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Liu, XF (reprint author), NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bldg 37, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 10 Z9 10 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 30 PY 2012 VL 7 IS 5 AR e38130 DI 10.1371/journal.pone.0038130 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959YF UT WOS:000305353400085 PM 22666460 ER PT J AU Nguyen, TA Sarkar, P Veetil, JV Koushik, SV Vogel, SS AF Nguyen, Tuan A. Sarkar, Pabak Veetil, Jithesh V. Koushik, Srinagesh V. Vogel, Steven S. TI Fluorescence Polarization and Fluctuation Analysis Monitors Subunit Proximity, Stoichiometry, and Protein Complex Hydrodynamics SO PLOS ONE LA English DT Article ID CA2+/CALMODULIN-DEPENDENT KINASE-II; RESONANCE ENERGY-TRANSFER; CORRELATION SPECTROSCOPY; LIVING CELLS; FRET MICROSCOPY; CAM KINASE; LIVE CELLS; CALMODULIN; IDENTIFICATION; HOLOENZYME AB Forster resonance energy transfer (FRET) microscopy is frequently used to study protein interactions and conformational changes in living cells. The utility of FRET is limited by false positive and negative signals. To overcome these limitations we have developed Fluorescence Polarization and Fluctuation Analysis (FPFA), a hybrid single-molecule based method combining time-resolved fluorescence anisotropy (homo-FRET) and fluorescence correlation spectroscopy. Using FPFA, homo-FRET (a 1-10 nm proximity gauge), brightness (a measure of the number of fluorescent subunits in a complex), and correlation time (an attribute sensitive to the mass and shape of a protein complex) can be simultaneously measured. These measurements together rigorously constrain the interpretation of FRET signals. Venus based control-constructs were used to validate FPFA. The utility of FPFA was demonstrated by measuring in living cells the number of subunits in the alpha-isoform of Venus-tagged calcium-calmodulin dependent protein kinase-II (CaMKII alpha) holoenzyme. Brightness analysis revealed that the holoenzyme has, on average, 11.9+/-1.2 subunit, but values ranged from 10-14 in individual cells. Homo-FRET analysis simultaneously detected that catalytic domains were arranged as dimers in the dodecameric holoenzyme, and this paired organization was confirmed by quantitative hetero-FRET analysis. In freshly prepared cell homogenates FPFA detected only 10.2+/-1.3 subunits in the holoenzyme with values ranging from 9-12. Despite the reduction in subunit number, catalytic domains were still arranged as pairs in homogenates. Thus, FPFA suggests that while the absolute number of subunits in an auto-inhibited holoenzyme might vary from cell to cell, the organization of catalytic domains into pairs is preserved. C1 [Nguyen, Tuan A.; Sarkar, Pabak; Veetil, Jithesh V.; Koushik, Srinagesh V.; Vogel, Steven S.] NIAAA, Sect Cellular Biophoton, Lab Mol Physiol, Natl Inst Hlth, Rockville, MD 20852 USA. RP Nguyen, TA (reprint author), NIAAA, Sect Cellular Biophoton, Lab Mol Physiol, Natl Inst Hlth, Rockville, MD 20852 USA. EM stevevog@mail.nih.gov RI Veetil, Jithesh/G-5185-2012; OI Vogel, Steven/0000-0002-3005-2667 FU National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD FX This work was supported by the intramural program of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 17 Z9 17 U1 3 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 30 PY 2012 VL 7 IS 5 AR e38209 DI 10.1371/journal.pone.0038209 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959YF UT WOS:000305353400102 PM 22666486 ER PT J AU Wu, Y Zakharova, VM Kashemirov, BA Goodman, MF Batra, VK Wilson, SH McKenna, CE AF Wu, Yue Zakharova, Valeria M. Kashemirov, Boris A. Goodman, Myron F. Batra, Vinod K. Wilson, Samuel H. McKenna, Charles E. TI beta,gamma-CHF- and beta,gamma-CHCl-dGTP Diastereomers: Synthesis, Discrete P-31 NMR Signatures, and Absolute Configurations of New Stereochemical Probes for DNA Polymerases SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PHOSPHONIC ACID ANALOGS; RNA CAP ANALOGS; NUCLEOSIDE PHOSPHATES; REVERSE-TRANSCRIPTASE; PERCHLORYL FLUORIDE; CATALYTIC MECHANISM; BETA FIDELITY; ALPHA; TRIPHOSPHATE; 5'-TRIPHOSPHATES AB Deoxynucleoside S'-triphosphate analogues in which the beta,gamma-bridging oxygen has been replaced with a CXY group are useful chemical probes to investigate DNA polymerase catalytic and base-selection mechanisms. A limitation of such probes has been that conventional synthetic methods generate a mixture of diastereomers when the bridging carbon substitution is nonequivalent (X not equal Y). We report here a general solution to this longstanding problem with four examples of /beta,gamma-CXY dNTP diastereomers: (S)- and (R)-beta,gamma-CHCI-dGTP (12a-1/12a-2) and (S)- and (R)-beta,gamma-CHF-cIGTP (12b-1/12b-2). Central to their preparation was conversion of the prochiral parent bisphosphonic acids to the P,Cdimorpholinamide derivatives 7 of their (R)-mandelic acid monoesters, which provided access to the individual diastereomers 7a-1, 7a-2, 7b-1, and 7b-2 by preparative HPLC. Selective acidic hydrolysis of the P N bond then afforded "portal" diastereomers, which were readily coupled to morpholine-activated dGMP. Removal of the chiral auxiliary by H-2 (Pd/C) gave the four individual diastereomeric nucleotides 12, which were characterized by P-31, H-1, and F-19 NMR spectroscopy and by mass spectrometry. After treatment with Chelex-100 to remove traces of paramagnetic ions, at pH similar to 10 the diastereomer pairs 12a,b exhibit discrete P-alpha and P-beta P-31 resonances. The more upheld P-alpha and more downfield P-beta resonances (and also the more upheld F-19 NMR resonance in 12b) are assigned to the R configuration at the P-beta-CHX-P-gamma, carbons on the basis of the absolute configurations of the individual diastereomers as determined from the X-ray crystallographic structures of their ternary complexes with DNA and polyrnerase beta. C1 [Wu, Yue; Zakharova, Valeria M.; Kashemirov, Boris A.; Goodman, Myron F.; McKenna, Charles E.] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. [Goodman, Myron F.] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Batra, Vinod K.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP McKenna, CE (reprint author), Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. EM mckenna@usc.edu FU NIH [5-U19-CA105010, Z01-ES050158]; National Institutes of Health, National Institute of Environmental Health Sciences FX This research was supported by NIH Grant 5-U19-CA105010 and in part by Research Project Z01-ES050158 (S.H.W.), Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. We thank Inah Kong for assistance in preparing the manuscript. NR 52 TC 14 Z9 15 U1 0 U2 26 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 MAY 30 PY 2012 VL 134 IS 21 BP 8734 EP 8737 DI 10.1021/ja300218x PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 949IU UT WOS:000304570700002 PM 22397499 ER PT J AU Vendruscolo, LF Barbier, E Schlosburg, JE Misra, KK Whitfield, TW Logrip, ML Rivier, C Repunte-Canonigo, V Zorrilla, EP Sanna, PP Heilig, M Koob, GF AF Vendruscolo, Leandro F. Barbier, Estelle Schlosburg, Joel E. Misra, Kaushik K. Whitfield, Timothy W., Jr. Logrip, Marian L. Rivier, Catherine Repunte-Canonigo, Vez Zorrilla, Eric P. Sanna, Pietro P. Heilig, Markus Koob, George F. TI Corticosteroid-Dependent Plasticity Mediates Compulsive Alcohol Drinking in Rats SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PITUITARY-ADRENAL AXIS; CORTICOTROPIN-RELEASING HORMONE; ANXIETY-LIKE BEHAVIOR; GLUCOCORTICOID-RECEPTOR; ETHANOL-CONSUMPTION; PLASMA-CORTICOSTERONE; GENE-EXPRESSION; STRESS; BRAIN; WITHDRAWAL AB Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e. g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism. C1 [Vendruscolo, Leandro F.; Schlosburg, Joel E.; Misra, Kaushik K.; Whitfield, Timothy W., Jr.; Logrip, Marian L.; Zorrilla, Eric P.; Koob, George F.] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Repunte-Canonigo, Vez; Sanna, Pietro P.] Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA. [Barbier, Estelle; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. [Rivier, Catherine] Salk Inst Biol Studies, Clayton Fdn Labs Peptide Biol, La Jolla, CA 92037 USA. RP Vendruscolo, LF (reprint author), Scripps Res Inst, Comm Neurobiol Addict Disorders, 10550 N Torrey Pines Rd,SP30-2400, La Jolla, CA 92037 USA. EM leandro@scripps.edu RI koob, george/P-8791-2016 FU National Institutes of Health from the National Institute on Drug Abuse [DA004043]; National Institutes of Health from National Institute of General Medicine [GM085659]; National Institutes of Health from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) [AA006420, AA017371, AA012602, AA013191]; Pearson Center for Alcoholism and Addiction Research; NIAAA [T32AA007456, F32AA018914] FX This is publication number 21284 from The Scripps Research Institute. This work was financially supported by National Institutes of Health Grant DA004043 from the National Institute on Drug Abuse, Grant GM085659 from National Institute of General Medicine, Grants AA006420, AA017371, AA012602, and AA013191 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the Pearson Center for Alcoholism and Addiction Research. Training was provided for authors J.E.S. and T. W. W. by NIAAA Grant T32AA007456, and for author M. L. L. by NIAAA Grant F32AA018914. We thank Michael Arends for proofreading the manuscript, Dr. Scott Edwards for critical comments regarding the manuscript, and Ashley Juniper, Daniel Ramirez, Zach Roy, Amand Srivastara, Imran Damany, Natalie Varnay, and Alexander Le for help with the behavioral experiments. NR 76 TC 89 Z9 90 U1 2 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 30 PY 2012 VL 32 IS 22 BP 7563 EP 7571 DI 10.1523/JNEUROSCI.0069-12.2012 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 950CQ UT WOS:000304627100014 PM 22649234 ER PT J AU Guo, L Yeh, ML Carlson, VCC Johnson-Venkatesh, EM Yeh, HH AF Guo, Lan Yeh, Mason L. Carlson, Verginia C. Cuzon Johnson-Venkatesh, Erin M. Yeh, Hermes H. TI Nerve Growth Factor in the Hippocamposeptal System: Evidence for Activity-Dependent Anterograde Delivery and Modulation of Synaptic Activity SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; SEPTOHIPPOCAMPAL CHOLINERGIC NEURONS; VASOACTIVE INTESTINAL POLYPEPTIDE; RECEPTOR-MEDIATED RESPONSES; RETROGRADE AXONAL-TRANSPORT; GREEN FLUORESCENT PROTEIN; NEUROTROPHIC FACTOR BDNF; GABAERGIC CELL SUBTYPES; RAT BASAL FOREBRAIN; MESSENGER-RNA AB Neurotrophins have been implicated in regulating neuronal differentiation, promoting neuronal survival, and modulating synaptic efficacy and plasticity. The prevailing view is that, depending on the target and mode of action, most neurotrophins can be trafficked and released either anterogradely or retrogradely in an activity-dependent manner. However, the prototypic neurotrophin, nerve growth factor (NGF), is not thought to be anterogradely delivered. Here we provide the neuroanatomical substrate for an anterograde hippocamposeptal transport of NGF by demonstrating its presence in mouse hippocampal GABAergic neurons and in their hippocamposeptal axons that ramify densely and abut neurons in the medial septum/diagonal band of Broca (MS/DB). We also demonstrate an activity-dependent increase in septal NGF levels that is dependent on the pattern of intrahippocampal stimulation. In addition, we show that acute exposure to NGF, via activation of TrkA, attenuates GABAA receptor-mediated inhibitory synaptic currents and reduces sensitivity to exogenously applied GABA. These acute actions of NGF display cell type and functional selectivity insofar as (1) they were found in cholinergic, but not GABAergic, MS/DB neurons, and (2) glutamate-mediated excitatory synaptic activity as well as AMPA-activated current responses were unaffected. Our results advocate a novel anterograde, TrkA-mediated NGF signaling in the CNS. C1 [Guo, Lan; Yeh, Hermes H.] Dartmouth Hitchcock Med Ctr, Geisel Sch Med Dartmouth, Dept Physiol & Neurobiol, Lebanon, NH 03756 USA. [Yeh, Mason L.] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England. [Carlson, Verginia C. Cuzon] NIAAA, Lab Integrat Neurosci, Rockville, MD 20852 USA. [Johnson-Venkatesh, Erin M.] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. RP Yeh, HH (reprint author), Dartmouth Hitchcock Med Ctr, Geisel Sch Med Dartmouth, Dept Physiol & Neurobiol, Lebanon, NH 03756 USA. EM Hermes.Yeh@Dartmouth.edu FU United States Public Health Service [R01 NS048603, R01 MH069826] FX This work was supported in part by United States Public Health Service Grants R01 NS048603 and R01 MH069826. We thank Pamela Yeh for excellent technical assistance. Caroline Nelson contributed to some of the images included in Figure 2. Walburga Croteau participated in collecting data for the experiments involving NGF ELISA. NR 73 TC 5 Z9 7 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 30 PY 2012 VL 32 IS 22 BP 7701 EP 7710 DI 10.1523/JNEUROSCI.0028-12.2012 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 950CQ UT WOS:000304627100028 PM 22649248 ER PT J AU Tovar, A Hennessy, E Pirie, A Must, A Gute, DM Hyatt, RR Kamins, CL Hughes, SO Boulos, R Sliwa, S Galvao, H Economos, CD AF Tovar, Alison Hennessy, Erin Pirie, Alex Must, Aviva Gute, David M. Hyatt, Raymond R. Kamins, Christina Luongo Hughes, Sheryl O. Boulos, Rebecca Sliwa, Sarah Galvao, Heloisa Economos, Christina D. TI Feeding styles and child weight status among recent immigrant mother-child dyads SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Feeding styles; Children; Obesity; Immigrants ID BODY-MASS INDEX; UNITED-STATES; PHYSICAL-ACTIVITY; PARENTING STYLES; AFRICAN-AMERICAN; LOW-INCOME; OBESITY; OVERWEIGHT; FAMILIES; ACCULTURATION AB Background: Research has shown that parental feeding styles may influence children's food consumption, energy intake, and ultimately, weight status. We examine this relationship, among recent immigrants to the US. Given that immigrant parents and children are at greater risk for becoming overweight/obese with increased time in the US, identification of risk factors for weight gain is critical. Methods: Baseline data was collected on 383 mother-child dyads enrolled in Live Well, a community-based, participatory, randomized controlled lifestyle intervention to prevent weight gain in recent immigrant mothers. Socio-demographic information together with heights and weights were collected for both mother and child. Acculturation, behavioral data, and responses to the Caregiver's Feeding Styles Questionnaire (CFSQ) were also obtained from the mother. Results: The children's average age was 6.2 +/- 2.7 years, 58% male. Mothers had been in the country for an average of 6.0 +/- 3.3 years, and are Brazilian (36%), Haitian (34%) and Latino (30%). Seventy-two percent of the mothers were overweight/obese, while 43% of the children were overweight/obese. Fifteen percent of mothers reported their feeding style as being high demanding/high responsive; 32% as being high demanding/low responsive; 34% as being low demanding/high responsive and 18% as being low demanding/low responsive. In bivariate analyses, feeding styles significantly differed by child BMIz-score, ethnic group, and mother's perceived stress. In multiple linear regression, a low demanding/high responsive feeding style was found to be positively associated (beta = 0.56) with a higher child weight as compared to high demanding/high responsive, controlling for known covariates (p = 0.01). Conclusions: Most mothers report having a low demanding/high responsive feeding style, which is associated with higher child weight status in this diverse immigrant population. This finding adds to the growing literature that suggests this type of feeding style may be a risk factor for childhood obesity. Further research is needed to help understand the larger socio-cultural context and its influence on feeding dynamics among immigrant families and families of lower incomes. How parents establish a certain feeding style in their home country compared to when they move to the US "obesogenic" environment, should also be explored. C1 [Tovar, Alison; Kamins, Christina Luongo; Boulos, Rebecca; Sliwa, Sarah; Economos, Christina D.] Tufts Univ, John Hancock Res Ctr Phys Act Nutr & Obes Prevent, Gerald J & Dorothy R Friedman Sch Nutr Sci & Poli, Boston, MA 02111 USA. [Hennessy, Erin] NCI, NIH, Bethesda, MD 20892 USA. [Pirie, Alex] Somerville Community Corp, Immigrant Serv Providers Grp Hlth, Somerville, MA 02143 USA. [Must, Aviva; Hyatt, Raymond R.] Tufts Univ, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Gute, David M.] Tufts Univ, Sch Engn, Medford, MA 02155 USA. [Hughes, Sheryl O.] Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Galvao, Heloisa] Brazilian Womens Grp, Boston, MA 02134 USA. RP Tovar, A (reprint author), Tufts Univ, John Hancock Res Ctr Phys Act Nutr & Obes Prevent, Gerald J & Dorothy R Friedman Sch Nutr Sci & Poli, 150 Harrison Ave, Boston, MA 02111 USA. EM alison.tovar@tufts.edu FU National Institutes of Health, Bethesda MD [5R01HD057841]; Boston Nutrition Obesity Research Center [DK046200] FX Funding for this research was provided by grant 5R01HD057841 from the National Institutes of Health, Bethesda MD. Postdoctoral research funds for Alison Tovar were provided by a supplement from this grant.; We would also like to acknowledge support from the Boston Nutrition Obesity Research Center (DK046200). NR 47 TC 36 Z9 36 U1 4 U2 36 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD MAY 29 PY 2012 VL 9 AR 62 DI 10.1186/1479-5868-9-62 PG 8 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 989GK UT WOS:000307548100001 PM 22642962 ER PT J AU Tweedie, D Ferguson, RA Fishman, K Frankola, KA Van Praag, H Holloway, HW Luo, WM Li, YZ Caracciolo, L Russo, I Barlati, S Ray, B Lahiri, DK Bosetti, F Greig, NH Rosi, S AF Tweedie, David Ferguson, Ryan A. Fishman, Kelly Frankola, Kathryn A. Van Praag, Henriette Holloway, Harold W. Luo, Weiming Li, Yazhou Caracciolo, Luca Russo, Isabella Barlati, Sergio Ray, Balmiki Lahiri, Debomoy K. Bosetti, Francesca Greig, Nigel H. Rosi, Susanna TI Tumor necrosis factor-alpha synthesis inhibitor 3,6 '-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Neuroinflammation; Neurodegeneration; TNF-alpha; Neuroprotection; Alzheimer's disease; Mild cognitive impairment; Amyoid-beta peptide; Tau; Thalidomide; Lenalidomide ID AMYLOID PRECURSOR PROTEIN; RNA-BINDING PROTEINS; TNF-ALPHA; PARKINSONS-DISEASE; NEURODEGENERATIVE DISEASES; SYNAPTIC PLASTICITY; MESSENGER-RNA; A-BETA; PERISPINAL ETANERCEPT; COGNITIVE DEFICITS AB Background: Neuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer's disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF alpha. Elevated TNF alpha levels are commonly detected in the clinic and animal models of AD. Methods: The potential benefits of a novel TNF-alpha-lowering agent, 3,6'-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and A beta(1-42) challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6'-dithiothaliodmide. Results: 3,6'-Dithiothaliodmide lowered TNF-alpha, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-alpha production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with A beta(1-42) peptide, prior systemic 3,6'-dithiothalidomide suppressed A beta-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6'-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, A beta peptide and A beta-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment. Conclusions: Our data suggest a strong beneficial effect of 3,6'-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-alpha in disease progression and their targeting as a means of clinical management. C1 [Tweedie, David; Frankola, Kathryn A.; Van Praag, Henriette; Holloway, Harold W.; Luo, Weiming; Li, Yazhou; Greig, Nigel H.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Ferguson, Ryan A.; Fishman, Kelly; Rosi, Susanna] Univ Calif San Francisco, Brain & Spinal Injury Ctr, San Francisco, CA 94143 USA. [Caracciolo, Luca; Russo, Isabella; Bosetti, Francesca] NIA, Mol Neurosci Unit, Brain Physiol & Metab Sect, Intramural Res Program,NIH, Bethesda, MD 20892 USA. [Barlati, Sergio] Univ Brescia, Div Biol & Genet, Dept Biomed Sci & Biotechnol, I-25123 Brescia, Italy. [Barlati, Sergio] Univ Brescia, Natl Inst Neurosci, I-25123 Brescia, Italy. [Ray, Balmiki; Lahiri, Debomoy K.] Indiana Univ Sch Med, Lab Mol Neurogenet, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. [Bosetti, Francesca] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Rosi, Susanna] Univ Calif San Francisco, Dept Phys Therapy Rehabil Sci, San Francisco, CA 94143 USA. [Rosi, Susanna] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. RP Greig, NH (reprint author), NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM greign@grc.nia.nih.gov RI van Praag, Henriette/F-3939-2015; OI van Praag, Henriette/0000-0002-5727-434X; Russo, Isabella/0000-0002-6151-2451 FU NIA, NIH; Alzheimer's Association [NIRG-08-90589, IIRG-11- 202064]; National Institutes of Health [R01CA133216, R01-AG18379, R01-AG18884] FX This manuscript is dedicated to our friend, mentor and colleague, Arnold Brossi (1923-2011), a godfather of alkaloid chemistry who provided significant input into this project. This research was supported in part by the (1) Intramural Research Program of NIA, NIH, (2) the Alzheimer's Association grants NIRG-08-90589 (SR) and IIRG-11- 202064 (SR), and (3) the National Institutes of Health grants R01CA133216 (SR), R01-AG18379 (DKL) and R01-AG18884 (DKL). NR 90 TC 60 Z9 63 U1 2 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAY 29 PY 2012 VL 9 AR 106 DI 10.1186/1742-2094-9-106 PG 16 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 982AP UT WOS:000307014400001 PM 22642825 ER PT J AU Frommelt, PC Guey, LT Minich, LL Bhat, M Bradley, TJ Colan, SD Ensing, G Gorentz, J Heydarian, H John, JB Lai, WW Levine, JC Mahle, WT Miller, SG Ohye, RG Pearson, GD Shirali, GS Wong, PC Cohen, MS AF Frommelt, Peter C. Guey, Lin T. Minich, L. LuAnn Bhat, Majeed Bradley, Tim J. Colan, Steve D. Ensing, Greg Gorentz, Jessica Heydarian, Haleh John, J. Blaine Lai, Wyman W. Levine, Jami C. Mahle, William T. Miller, Stephen G. Ohye, Richard G. Pearson, Gail D. Shirali, Girish S. Wong, Pierre C. Cohen, Meryl S. CA Pediat Heart Network Investigators TI Does Initial Shunt Type for the Norwood Procedure Affect Echocardiographic Measures of Cardiac Size and Function During Infancy? The Single Ventricle Reconstruction Trial SO CIRCULATION LA English DT Article DE echocardiography; hypoplastic left heart syndrome; Norwood; single ventricle ID LEFT-HEART SYNDROME; PULMONARY-ARTERY CONDUIT; PALLIATION; CHILDREN; HEMODYNAMICS; PERFORMANCE; REPAIR; ROOT AB Background-The Pediatric Heart Network trial comparing outcomes in 549 infants with single right ventricle undergoing a Norwood procedure randomized to modified Blalock-Taussig shunt or right ventricle-pulmonary artery shunt (RVPAS) found better 1-year transplant-free survival in those who received RVPAS. We sought to compare the impact of shunt type on echocardiographic indices of cardiac size and function up to 14 months of age. Methods and Results-A core laboratory measured indices of cardiac size and function from protocol exams: early after Norwood procedure (age 22.5 +/- 13.4 days), before stage II procedure (age 4.8 +/- 1.8 months), and at 14 months (age 14.3 +/- 1.2 months). Mean right ventricular ejection fraction was <50% at all intervals for both groups and was higher in the RVPAS group after Norwood procedure (49 +/- 7% versus 44 +/- 8%; P < 0.001) but was similar by 14 months. Tricuspid and neoaortic regurgitation, diastolic function, and pulmonary artery and arch dimensions were similar in the 2 groups at all intervals. Neoaortic annulus area (4.2 +/- 1.2 versus 4.9 +/- 1.2 cm(2)/m(2)), systolic ejection times (214.0 +/- 29.4 versus 231.3 +/- 28.6 ms), neoaortic flow (6.2 +/- 2.4 versus 9.4 +/- 3.4 L/min per square meter), and peak arch velocity (1.9 +/- 0.7 versus 2.2 +/- 0.7 m/s) were lower at both interstage examinations in the RVPAS compared with the modified Blalock-Taussig shunt group (P < 0.001 for all), but all were similar at 14 months. Conclusions-Indices of cardiac size and function after the Norwood procedure are similar for modified Blalock-Taussig shunt and RVPAS by 14 months of age. Interstage differences between shunt types can likely be explained by the physiology created when the shunts are in place rather than by intrinsic differences in cardiac function. C1 [Frommelt, Peter C.; Gorentz, Jessica] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Guey, Lin T.] New England Res Inst, Watertown, MA 02172 USA. [Minich, L. LuAnn] Univ Utah, Salt Lake City, UT USA. [Bhat, Majeed] Nemours Cardiac Ctr, Wilmington, DE USA. [Bradley, Tim J.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Colan, Steve D.; Levine, Jami C.] Childrens Hosp, Boston, MA 02115 USA. [Ensing, Greg; Ohye, Richard G.] Univ Michigan, Ann Arbor, MI 48109 USA. [Heydarian, Haleh] Cincinnati Childrens Hosp, Cincinnati, OH USA. [John, J. Blaine] Pediat Cardiol Associates Pediatrix, Tampa, FL USA. [Lai, Wyman W.] Columbia Univ, New York, NY USA. [Mahle, William T.] Emory Univ, Atlanta, GA 30322 USA. [Miller, Stephen G.] Duke Univ, Durham, NC USA. [Pearson, Gail D.] NHLBI, Bethesda, MD 20892 USA. [Shirali, Girish S.] Med Univ S Carolina, Charleston, SC USA. [Wong, Pierre C.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Cohen, Meryl S.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Frommelt, PC (reprint author), Childrens Hosp Wisconsin, 9000 W Wisconsin Ave,MS 713, Milwaukee, WI 53226 USA. EM pfrommelt@chw.org FU National Heart, Lung, and Blood Institute [HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057] FX This study is supported by U01 grants from the National Heart, Lung, and Blood Institute (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057). The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute. NR 21 TC 20 Z9 22 U1 1 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 MAY 29 PY 2012 VL 125 IS 21 BP 2630 EP 2638 DI 10.1161/CIRCULATIONAHA.111.072694 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981MQ UT WOS:000306972800020 PM 22523314 ER PT J AU Pang, T Wang, J Benicky, J Sanchez-Lemus, E Saavedra, JM AF Pang, Tao Wang, Juan Benicky, Julius Sanchez-Lemus, Enrique Saavedra, Juan M. TI Telmisartan directly ameliorates the neuronal inflammatory response to IL-1 beta partly through the JNK/c-Jun and NADPH oxidase pathways SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Angiotensin II AT(1) receptor blockers; SK-N-SH neuroblasts; Cortical neurons; Neuronal inflammation; Neuroprotection; Oxidative stress; COX-2; PGE(2) release; JNK activation; IL-1 beta neurotoxicity ID ACTIVATED-RECEPTOR-GAMMA; NF-KAPPA-B; HUMAN NEUROBLASTOMA-CELLS; ANGIOTENSIN-II; PPAR-GAMMA; ALZHEIMERS-DISEASE; PROTEIN-KINASE; PARKINSONS-DISEASE; HYPERTENSIVE-RATS; OXIDATIVE STRESS AB Background: Blockade of angiotensin II type 1 (AT(1)) receptors ameliorates brain inflammation, and reduces excessive brain interleukin-1 beta (IL-1 beta) production and release from cortical microglia. The aim of this study was to determine whether, in addition, AT(1) receptor blockade directly attenuates IL-1 beta-induced inflammatory responses in neuronal cultures. Methods: SK-N-SH human neuroblasts and primary rat cortical neurons were pretreated with telmisartan followed by exposure to IL-1 beta. Gene expression was determined by reverse transcriptase (RT)-PCR, protein expression and kinase activation by western blotting, NADPH oxidase activity by the lucigenin method, prostaglandin E-2 (PGE(2)) release by enzyme immunoassay, reactive oxygen species (ROS) generation by the dichlorodihydrofluorescein diacetate fluorescent probe assay, and peroxisome proliferator-activated receptor gamma (PPAR gamma) involvement was assessed with the antagonists GW9662 and T0070907, the agonist pioglitazone and the expression of PPAR gamma target genes ABCG1 and CD36. Results: We found that SK-N-SH neuroblasts expressed AT(1) but not AT(2) receptor mRNA. Telmisartan reduced IL-1 beta-induced cyclooxygenase-2 (COX-2) expression and PGE(2) release more potently than did candesartan and losartan. Telmisartan reduced the IL-1 beta-induced increase in IL-1R1 receptor and NADPH oxidase-4 (NOX-4) mRNA expression, NADPH oxidase activity, and ROS generation, and reduced hydrogen peroxide-induced COX-2 gene expression. Telmisartan did not modify IL-1 beta-induced ERK1/2 and p38 mitogen-activated protein kinase (MAPK) phosphorylation or nuclear factor-kappa B activation but significantly decreased IL-1 beta-induced c-Jun N-terminal kinase (JNK) and c-Jun activation. The JNK inhibitor SP600125 decreased IL-1 beta-induced PGE(2) release with a potency similar to that of telmisartan. The PPAR gamma agonist pioglitazone reduced IL-1 beta-induced inflammatory reaction, whereas telmisartan did not activate PPAR gamma, as shown by its failure to enhance the expression of the PPAR gamma target genes ABCG1 and CD36, and the inability of the PPAR gamma antagonists GW9662 and T0070907 to modify the effect of telmisartan on COX-2 induction. The effect of telmisartan on IL-1 beta-stimulated COX-2 and IL-1R1 mRNA expression and ROS production was replicated in primary rat cortical neurons. Conclusions: Telmisartan directly ameliorates IL-1 beta-induced neuronal inflammatory response by inhibition of oxidative stress and the JNK/c-Jun pathway. Our results support the hypothesis that AT(1) receptor blockers are directly neuroprotective, and should be considered for the treatment of inflammatory conditions of the brain. C1 [Pang, Tao; Wang, Juan; Benicky, Julius; Sanchez-Lemus, Enrique; Saavedra, Juan M.] NIMH, Div Intramural Res Programs, NIH, Dept Hlth & Human Serv,Sect Pharmacol,DHHS, Bethesda, MD 20892 USA. RP Pang, T (reprint author), NIMH, Div Intramural Res Programs, NIH, Dept Hlth & Human Serv,Sect Pharmacol,DHHS, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM pangt@mail.nih.gov FU Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA FX This study was supported by the Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA. NR 76 TC 31 Z9 32 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAY 29 PY 2012 VL 9 AR 102 DI 10.1186/1742-2094-9-102 PG 19 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 986SD UT WOS:000307364000001 PM 22642771 ER PT J AU McShane, LM AF McShane, Lisa M. TI Statistical challenges in the development and evaluation of marker-based clinical tests SO BMC MEDICINE LA English DT Editorial Material DE Marker; biomarker; biostatistics; prognostic; predictive; treatment effect modifier; clinical test; translational research ID REPORTING RECOMMENDATIONS; AMERICAN SOCIETY; BIOMARKER; ONCOLOGY; CANCER AB Exciting new technologies for assessing markers in human specimens are now available to evaluate unprecedented types and numbers of variations in DNA, RNA, proteins, or biological structures such as chromosomes. These markers, whether viewed individually, or collectively as a 'signature', have the potential to be useful for disease risk assessment, screening, early detection, prognosis, therapy selection, and monitoring for therapy effectiveness or disease recurrence. Successful translation from basic research findings to clinically useful test requires basic, translational, and regulatory sciences and a collaborative effort among individuals with varied types of expertise including laboratory scientists, technology developers, clinicians, statisticians, and bioinformaticians. The focus of this commentary is the many statistical challenges in translational marker research, specifically in the development and validation of marker-based tests that have clinical utility for therapeutic decision-making. C1 [McShane, Lisa M.] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. [McShane, Lisa M.] NCI, Canc Diag Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP McShane, LM (reprint author), NCI, Biometr Res Branch, 6130 Execut Blvd,EPN 8126, Bethesda, MD 20892 USA. EM McShaneL@CTEP.NCI.NIH.gov NR 14 TC 6 Z9 6 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD MAY 29 PY 2012 VL 10 AR 52 DI 10.1186/1741-7015-10-52 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 963IB UT WOS:000305612500001 PM 22642713 ER PT J AU Sanchez-Martinez, S Aloia, AL Harvin, D Mirro, J Gorelick, RJ Jern, P Coffin, JM Rein, A AF Sanchez-Martinez, Silvia Aloia, Amanda L. Harvin, Demetria Mirro, Jane Gorelick, Robert J. Jern, Patric Coffin, John M. Rein, Alan TI Studies on the Restriction of Murine Leukemia Viruses by Mouse APOBEC3 SO PLOS ONE LA English DT Article ID GENOMIC RNA; IN-VIVO; INFECTION; REPLICATION; PROTEINS; GENE; GAG; VIRIONS; PATHOGENESIS; REPLACEMENT AB APOBEC3 proteins function to restrict the replication of retroviruses. One mechanism of this restriction is deamination of cytidines to uridines in (-) strand DNA, resulting in hypermutation of guanosines to adenosines in viral (+) strands. However, Moloney murine leukemia virus (MoMLV) is partially resistant to restriction by mouse APOBEC3 (mA3) and virtually completely resistant to mA3-induced hypermutation. In contrast, the sequences of MLV genomes that are in mouse DNA suggest that they were susceptible to mA3-induced deamination when they infected the mouse germline. We tested the possibility that sensitivity to mA3 restriction and to deamination resides in the viral gag gene. We generated a chimeric MLV in which the gag gene was from an endogenous MLV in the mouse germline, while the remainder of the viral genome was from MoMLV. This chimera was fully infectious but its response to mA3 was indistinguishable from that of MoMLV. Thus, the Gag protein does not seem to control the sensitivity of MLVs to mA3. We also found that MLVs inactivated by mA3 do not synthesize viral DNA upon infection; thus mA3 restriction of MLV occurs before or at reverse transcription. In contrast, HIV-1 restricted by mA3 and MLVs restricted by human APOBEC3G do synthesize DNA; these DNAs exhibit APOBEC3-induced hypermutation. C1 [Sanchez-Martinez, Silvia; Aloia, Amanda L.; Harvin, Demetria; Mirro, Jane; Rein, Alan] NCI, HIV Drug Resistance Program, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Gorelick, Robert J.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. [Jern, Patric] Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, Uppsala, Sweden. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Sanchez-Martinez, S (reprint author), NCI, HIV Drug Resistance Program, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. EM reina@mail.nih.gov OI Jern, Patric/0000-0003-3393-5825 FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Swedish Wenner-Gren foundations; Swedish research council FORMAS; American Cancer Society; F.M. Kirby Foundation FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. P.J. was supported by the Swedish Wenner-Gren foundations and the Swedish research council FORMAS. J.M.C. was supported by a Research Professorship from the American Cancer Society, with support from the F.M. Kirby Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 16 Z9 16 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 29 PY 2012 VL 7 IS 5 AR e38190 DI 10.1371/journal.pone.0038190 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959WT UT WOS:000305349600070 PM 22666481 ER PT J AU Yaniv, Y Spurgeon, HA Lyashkov, AE Yang, DM Ziman, BD Maltsev, VA Lakatta, EG AF Yaniv, Yael Spurgeon, Harold A. Lyashkov, Alexey E. Yang, Dongmei Ziman, Bruce D. Maltsev, Victor A. Lakatta, Edward G. TI Crosstalk between Mitochondrial and Sarcoplasmic Reticulum Ca2+ Cycling Modulates Cardiac Pacemaker Cell Automaticity SO PLOS ONE LA English DT Article ID SPONTANEOUS BEATING RATE; RYANODINE RECEPTOR; MYOCYTES; RABBIT; INHIBITION; CGP-37157; EXCHANGE; CHANNELS; OSCILLATIONS; CONTRACTION AB Background: Mitochondria dynamically buffer cytosolic Ca2+ in cardiac ventricular cells and this affects the Ca2+ load of the sarcoplasmic reticulum (SR). In sinoatrial-node cells (SANC) the SR generates periodic local, subsarcolemmal Ca2+ releases (LCRs) that depend upon the SR load and are involved in SANC automaticity: LCRs activate an inward Na+-Ca2+ exchange current to accelerate the diastolic depolarization, prompting the ensemble of surface membrane ion channels to generate the next action potential (AP). Objective: To determine if mitochondrial Ca2+ (Ca-m(2+)), cytosolic Ca2+ (Ca-c(2+))-SR-Ca2+ crosstalk occurs in single rabbit SANC, and how this may relate to SANC normal automaticity. Results: Inhibition of mitochondrial Ca2+ influx into (Ru360) or Ca2+ efflux from (CGP-37157) decreased [Ca2+](m) to 80 +/- 8% control or increased [Ca2+](m) to 119 +/- 7% control, respectively. Concurrent with inhibition of mitochondrial Ca2+ influx or efflux, the SR Ca2+ load, and LCR size, duration, amplitude and period (imaged via confocal linescan) significantly increased or decreased, respectively. Changes in total ensemble LCR Ca2+ signal were highly correlated with the change in the SR Ca2+ load (r(2) = 0.97). Changes in the spontaneous AP cycle length (Ru360, 111 +/- 1% control; CGP-37157, 89 +/- 2% control) in response to changes in [Ca2+](m) were predicted by concurrent changes in LCR period (r(2) = 0.84). Conclusion: A change in SANC Ca-m(2+) flux translates into a change in the AP firing rate by effecting changes in Ca (2+)(c) and SR Ca2+ loading, which affects the characteristics of spontaneous SR Ca2+ release. C1 [Yaniv, Yael; Spurgeon, Harold A.; Lyashkov, Alexey E.; Yang, Dongmei; Ziman, Bruce D.; Maltsev, Victor A.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Yaniv, Y (reprint author), NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM LakattaE@mail.nih.gov RI Yaniv, Yael/B-3311-2015 OI Yaniv, Yael/0000-0002-5183-6284 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX The work was supported entirely by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 21 Z9 21 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 29 PY 2012 VL 7 IS 5 AR e37582 DI 10.1371/journal.pone.0037582 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959WT UT WOS:000305349600023 PM 22666369 ER PT J AU Buehler, E Khan, AA Marine, S Rajaram, M Bahl, A Burchard, J Ferrer, M AF Buehler, Eugen Khan, Aly A. Marine, Shane Rajaram, Misha Bahl, Amit Burchard, Julja Ferrer, Marc TI siRNA off-target effects in genome-wide screens identify signaling pathway members SO SCIENTIFIC REPORTS LA English DT Article ID CANCER; GENES AB We introduce a method for analyzing small interfering RNA (siRNA) genetic screens based entirely on off-target effects. Using a screen for members of the Wnt pathway, we demonstrate that this method identifies known pathway components, some of which are not present in the screening library. This technique can be applied to siRNA screen results retroactively to confirm positives and identify genes missed using conventional methods for on-target gene selection. C1 [Buehler, Eugen; Ferrer, Marc] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Khan, Aly A.] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10065 USA. [Marine, Shane] Merck Res Labs, N Wales, PA 19454 USA. [Rajaram, Misha] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Bahl, Amit; Burchard, Julja] Merck & Co Inc, West Point, PA 19486 USA. RP Buehler, E (reprint author), NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM eugen.buehler@nih.gov OI Buehler, Eugen/0000-0001-7167-676X NR 25 TC 33 Z9 35 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 29 PY 2012 VL 2 AR 428 DI 10.1038/srep00428 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 952FL UT WOS:000304776400001 PM 22645644 ER PT J AU Altman, DG McShane, LM Sauerbrei, W Taube, SE AF Altman, Douglas G. McShane, Lisa M. Sauerbrei, Willi Taube, Sheila E. TI Reporting recommendations for tumor marker prognostic studies (REMARK): explanation and elaboration SO BMC MEDICINE LA English DT Article ID BREAST-CANCER PATIENTS; CELL LUNG-CANCER; GROUP RANDOMIZED-TRIALS; MULTIVARIATE DATA-ANALYSIS; EPITHELIAL OVARIAN-CANCER; ENDOTHELIAL GROWTH-FACTOR; HAZARDS REGRESSION-MODEL; DISEASE-FREE SURVIVAL; TIME-DEPENDENT BIAS; LEUKEMIA GROUP-B AB Background: The Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) checklist consists of 20 items to report for published tumor marker prognostic studies. It was developed to address widespread deficiencies in the reporting of such studies. In this paper we expand on the REMARK checklist to enhance its use and effectiveness through better understanding of the intent of each item and why the information is important to report. Methods: REMARK recommends including a transparent and full description of research goals and hypotheses, subject selection, specimen and assay considerations, marker measurement methods, statistical design and analysis, and study results. Each checklist item is explained and accompanied by published examples of good reporting, and relevant empirical evidence of the quality of reporting. We give prominence to discussion of the 'REMARK profile', a suggested tabular format for summarizing key study details. Summary: The paper provides a comprehensive overview to educate on good reporting and provide a valuable reference for the many issues to consider when designing, conducting, and analyzing tumor marker studies and prognostic studies in medicine in general. To encourage dissemination of the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): Explanation and Elaboration, this article has also been published in PLoS Medicine. C1 [Altman, Douglas G.] Univ Oxford, Ctr Stat Med, Oxford OX2 6UD, England. [McShane, Lisa M.] US Natl Canc Inst, Bethesda, MD 20892 USA. [Sauerbrei, Willi] Univ Freiburg Klinikum, Inst Med Biometrie & Med Informat, D-79104 Freiburg, Germany. [Taube, Sheila E.] ST Consulting, Bethesda, MD 20817 USA. RP Altman, DG (reprint author), Univ Oxford, Ctr Stat Med, Oxford OX2 6UD, England. EM doug.altman@csm.ox.ac.uk FU Cancer Research UK [C5529] FX No direct funding was received for this study. DGA is supported by a grant from Cancer Research UK (C5529). The other authors were personally salaried by their institutions during the period of writing (though no specific salary was set aside or given for the writing of this paper). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 212 TC 101 Z9 101 U1 0 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD MAY 29 PY 2012 VL 10 AR 51 PG 39 WC Medicine, General & Internal SC General & Internal Medicine GA 950BG UT WOS:000304623300001 PM 22642691 ER PT J AU Tang, JY Germain, RN Cui, M AF Tang, Jianyong Germain, Ronald N. Cui, Meng TI Superpenetration optical microscopy by iterative multiphoton adaptive compensation technique SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunology; neuron imaging; nonlinear imaging; lymphocyte imaging; nonlinear iterative feedback ID GREEN FLUORESCENT PROTEIN; RANDOM SCATTERING MEDIA; 2-PHOTON MICROSCOPY; ILLUMINATION MICROSCOPY; PLANE ILLUMINATION; RAMAN-SCATTERING; FOCUSING LIGHT; TURBID LAYERS; EXCITATION; DEEP AB Biological tissues are rarely transparent, presenting major challenges for deep tissue optical microscopy. The achievable imaging depth is fundamentally limited by wavefront distortions caused by aberration and random scattering. Here, we report an iterative wavefront compensation technique that takes advantage of the nonlinearity of multiphoton signals to determine and compensate for these distortions and to focus light inside deep tissues. Different from conventional adaptive optics methods, this technique can rapidly measure highly complicated wavefront distortions encountered in deep tissue imaging and provide compensations for not only aberration but random scattering. The technique is tested with a variety of highly heterogeneous biological samples including mouse brain tissue, skull, and lymph nodes. We show that high quality three-dimensional imaging can be realized at depths beyond the reach of conventional multiphoton microscopy and adaptive optics methods, albeit over restricted distances for a given correction. Moreover, the required laser excitation power can be greatly reduced in deep tissues, deviating from the power requirement of ballistic light excitation and thus significantly reducing photo damage to the biological tissue. C1 [Cui, Meng] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Tang, Jianyong; Germain, Ronald N.] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Cui, M (reprint author), Howard Hughes Med Inst, Janelia Farm Res Campus,19700 Helix Dr, Ashburn, VA 20147 USA. EM cuim@janelia.hhmi.org FU Howard Hughes Medical Institute; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors thank Charles Shank, Na Ji, Eric Betzig, Mats Gustafsson, and Karel Svoboda for helpful discussions. We also thank Wolfgang Kastenmuller and Michael Gerner for help on live mouse imaging. Jeff Zhu (National Institutes of Health) kindly provided the T-bet:GFP mice. The research is supported by Howard Hughes Medical Institute and Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 35 TC 71 Z9 72 U1 5 U2 33 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 29 PY 2012 VL 109 IS 22 BP 8434 EP 8439 DI 10.1073/pnas.1119590109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 953PD UT WOS:000304881700024 PM 22586078 ER PT J AU Daniels, BR Rikhy, R Renz, M Dobrowsky, TM Lippincott-Schwartz, J AF Daniels, Brian R. Rikhy, Richa Renz, Malte Dobrowsky, Terrence M. Lippincott-Schwartz, Jennifer TI Multiscale diffusion in the mitotic Drosophila melanogaster syncytial blastoderm SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BICOID MORPHOGEN GRADIENT; NUCLEAR; EMBRYO; DYNAMICS; EMBRYOGENESIS; STABILITY; MOBILITY; PROTEIN; MITOSIS AB Despite the fundamental importance of diffusion for embryonic morphogen gradient formation in the early Drosophila melanogaster embryo, there remains controversy regarding both the extent and the rate of diffusion of well-characterized morphogens. Furthermore, the recent observation of diffusional "compartmentalization" has suggested that diffusion may in fact be nonideal and mediated by an as-yet-unidentified mechanism. Here, we characterize the effects of the geometry of the early syncytial Drosophila embryo on the effective diffusivity of cytoplasmic proteins. Our results demonstrate that the presence of transient mitotic membrane furrows results in a multiscale diffusion effect that has a significant impact on effective diffusion rates across the embryo. Using a combination of live-cell experiments and computational modeling, we characterize these effects and relate effective bulk diffusion rates to instantaneous diffusion coefficients throughout the syncytial blastoderm nuclear cycle phase of the early embryo. This multiscale effect may be related to the effect of interphase nuclei on effective diffusion, and thus we propose that an as-yet-unidentified role of syncytial membrane furrows is to temporally regulate bulk embryonic diffusion rates to balance the multiscale effect of interphase nuclei, which ultimately stabilizes the shapes of various morphogen gradients. C1 [Daniels, Brian R.; Renz, Malte; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Rikhy, Richa] Indian Inst Sci Educ & Res, Pune 411021, Maharashtra, India. [Dobrowsky, Terrence M.] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov RI Rikhy, Richa/J-4481-2012; OI Rikhy, Richa/0000-0002-4262-0238 NR 23 TC 10 Z9 10 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 29 PY 2012 VL 109 IS 22 BP 8588 EP 8593 DI 10.1073/pnas.1204270109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 953PD UT WOS:000304881700050 PM 22592793 ER PT J AU Zhao, H Han, DD Dawid, IB Pieler, T Chen, YL AF Zhao, Hui Han, Dandan Dawid, Igor B. Pieler, Tomas Chen, Yonglong TI Homeoprotein hhex-induced conversion of intestinal to ventral pancreatic precursors results in the formation of giant pancreata in Xenopus embryos SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE endoderm regionalization; endocrine; exocrine; proliferation; apoptosis ID HOMEOBOX GENE HEX; PROGENITOR CELLS; MOUSE EMBRYO; MORPHOGENETIC MOVEMENTS; ENDODERM DEVELOPMENT; SIGNALING PATHWAYS; WNT/BETA-CATENIN; LIVER BUD; FATE MAPS; DIFFERENTIATION AB Liver and ventral pancreas develop from neighboring territories within the endoderm of gastrulae. ventral pancreatic precursor 1 (vpp1) is a marker gene that is differentially expressed in a cell population within the dorsal endoderm in a pattern partially overlapping with that of hematopoietically expressed homeobox (hhex) during gastrulation. In tail bud embryos, vpp1 expression specifically demarcates two ventral pancreatic buds, whereas hhex expression is mainly restricted to the liver diverticulum. Ectopic expression of a critical dose of hhex led to a greatly enlarged vpp1-positive domain and, subsequently, to the formation of giant ventral pancreata, putatively by conversion of intestinal to ventral pancreatic precursor cells. Conversely, antisense morpholino oligonucleotide-mediated knockdown of hhex resulted in a down-regulation of vpp1 expression and a specific loss of the ventral pancreas. Furthermore, titration of hhex with a dexamethasone-inducible hhex-VP16GR fusion construct suggested that endogenous hhex activity during gastrulation is essential for the formation of ventral pancreatic progenitor cells. These observations suggest that, beyond its role in liver development, hhex controls specification of a vpp1-positive endodermal cell population during gastrulation that is required for the formation of the ventral pancreas. C1 [Dawid, Igor B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Han, Dandan; Chen, Yonglong] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Key Lab Regenerat Biol, Guangzhou 510530, Guangdong, Peoples R China. [Zhao, Hui] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Pieler, Tomas] Univ Gottingen, Ctr Mol Biosci, Dept Dev Biochem, D-37077 Gottingen, Germany. [Han, Dandan] Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China. RP Dawid, IB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM idawid@mail.nih.gov; tpieler@gwdg.de; chen_yonglong@gibh.ac.cn RI chen, yonglong/I-8439-2012; Zhao, Hui/B-8429-2016 FU National Basic Research Program of China [2009CB941202]; Deutsche Forschungsgemeinschaft [Pi 159/9]; Research Grants Council of Hong Kong [CUHK480709]; Chinese Academy of Sciences [KSCX2-YW-R-083]; National Institute of Child Health and Human Development, National Institutes of Health FX We thank Marion Dornwell for expert technical assistance and all our colleagues for making available the molecular markers used in this study. This work was supported in part by National Basic Research Program of China Grant 2009CB941202, Deutsche Forschungsgemeinschaft Grant Pi 159/9, Research Grants Council of Hong Kong General Research Fund Grant CUHK480709, Key Project of Knowledge Innovation Program of the Chinese Academy of Sciences Grant KSCX2-YW-R-083, and the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health. NR 44 TC 4 Z9 5 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 MAY 29 PY 2012 VL 109 IS 22 BP 8594 EP 8599 DI 10.1073/pnas.1206547109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 953PD UT WOS:000304881700051 PM 22592794 ER PT J AU Dagdug, L Vazquez, MV Berezhkovskii, AM Zitserman, VY Bezrukov, SM AF Dagdug, Leonardo Vazquez, Marco-Vinicio Berezhkovskii, Alexander M. Zitserman, Vladimir Yu. Bezrukov, Sergey M. TI Diffusion in the presence of cylindrical obstacles arranged in a square lattice analyzed with generalized Fick-Jacobs equation SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID CONDUCTIVITY AB The generalized Fick-Jacobs equation is widely used to study diffusion of Brownian particles in three-dimensional tubes and quasi-two-dimensional channels of varying constraint geometry. We show how this equation can be applied to study the slowdown of unconstrained diffusion in the presence of obstacles. Specifically, we study diffusion of a point Brownian particle in the presence of identical cylindrical obstacles arranged in a square lattice. The focus is on the effective diffusion coefficient of the particle in the plane perpendicular to the cylinder axes, as a function of the cylinder radii. As radii vary from zero to one half of the lattice period, the effective diffusion coefficient decreases from its value in the obstacle free space to zero. Using different versions of the generalized Fick-Jacobs equation, we derive simple approximate formulas, which give the effective diffusion coefficient as a function of the cylinder radii, and compare their predictions with the values of the effective diffusion coefficient obtained from Brownian dynamics simulations. We find that both Reguera-Rubi and Kalinay-Percus versions of the generalized Fick-Jacobs equation lead to quite accurate predictions of the effective diffusion coefficient (with maximum relative errors below 4% and 7%, respectively) over the entire range of the cylinder radii from zero to one half of the lattice period. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4720385] C1 [Dagdug, Leonardo; Vazquez, Marco-Vinicio] Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. [Dagdug, Leonardo; Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Zitserman, Vladimir Yu.] Russian Acad Sci, Joint Inst High Temp, Moscow 125412, Russia. [Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Dagdug, L (reprint author), Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. FU NIH; Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We are grateful to Professor Juris Kalnin for helpful discussions and Super Computer Division of Universidad Autonoma Metropolitana-Iztapalapa for the use of their computational facilities. This study was supported by the Intramural Research Program of the NIH, Center for Information Technology and Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 21 TC 16 Z9 16 U1 0 U2 8 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 28 PY 2012 VL 136 IS 20 AR 204106 DI 10.1063/1.4720385 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 952UL UT WOS:000304818400007 PM 22667539 ER PT J AU Riley, WT AF Riley, William T. TI Leveraging Technology for Multiple Risk Factor Interventions SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material C1 NHLBI, Clin Applicat & Prevent Branch, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP Riley, WT (reprint author), NHLBI, Clin Applicat & Prevent Branch, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,MSC 7936, Bethesda, MD 20892 USA. EM wiriley@mail.nih.gov NR 8 TC 4 Z9 4 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAY 28 PY 2012 VL 172 IS 10 BP 796 EP 798 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 948FK UT WOS:000304488800009 PM 22636825 ER PT J AU Combs, GF Jackson, MI Watts, JC Johnson, LK Zeng, HW Idso, J Schomburg, L Hoeg, A Hoefig, CS Chiang, EC Waters, DJ Davis, CD Milner, JA AF Combs, Gerald F., Jr. Jackson, Matthew I. Watts, Jennifer C. Johnson, LuAnn K. Zeng, Huawei Idso, Joseph Schomburg, Lutz Hoeg, Antonia Hoefig, Carolin S. Chiang, Emily C. Waters, David J. Davis, Cindy D. Milner, John A. TI Differential responses to selenomethionine supplementation by sex and genotype in healthy adults SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Selenium; Biomarkers; Selenoprotein P; Glutathione peroxidase; Genotype; Supplementation ID SINGLE-NUCLEOTIDE POLYMORPHISM; GLUTATHIONE-PEROXIDASE; SELENIUM SUPPLEMENTATION; DIETARY METHIONINE; SELENOPROTEIN-P; CANCER-RISK; 3'-UNTRANSLATED REGION; PROSTATE-CANCER; IMMUNE FUNCTION; SERUM SELENIUM AB A year-long intervention trial was conducted to characterise the responses of multiple biomarkers of Se status in healthy American adults to supplemental selenomethionine (SeMet) and to identify factors affecting those responses. A total of 261 men and women were randomised to four closes of Se (0, 50, 100 or 200 mu g/d as L-SeMet) for 12 months. Responses of several biomarkers of Se status (plasma Se, serum selenoprotein P (SEPP1), plasma glutathione peroxidase activity (GPX3), buccal cell Se, urinary Se) were determined relative to genotype of four selenoproteins (GPX1, GPX3, SEPP,L, selenoprotein 15), dietary Se intake and parameters of single-carbon metabolism. Results showed that supplemental SeMet did not affect GPX3 activity or SEPP1 concentration, but produced significant, close-dependent increases in the Se contents of plasma, urine and buccal cells, each of which plateaued by 9-12 months and was linearly related to effective Se close (mu g/d per kg(0.75)). The increase in urinary Se excretion was greater for women than men, and for individuals of the GPX1 679 T/T genotype than for those of the GPX1 679 C/C genotype. It is concluded that the most responsive Se-biomarkers in this non-deficient cohort were those related to body Se pools: plasma, buccal cell and urinary Se concentrations. Changes in plasma Se resulted from increases in its non-specific component and were affected by both sex and GPX1 genotype. In a cohort of relatively high Se status, the Se intake (as SeMet) required to support plasma Se concentration at a target level (Sepl-target) is: Se-in = [(Sepl-target - Se-pl)/(18.2 ng d kg(0.75)/ml per mu g)]. C1 [Combs, Gerald F., Jr.; Jackson, Matthew I.; Watts, Jennifer C.; Johnson, LuAnn K.; Zeng, Huawei; Idso, Joseph] USDA ARS, Grand Forks Human Nutr Res Ctr, Grand Forks, ND 58202 USA. [Schomburg, Lutz; Hoeg, Antonia; Hoefig, Carolin S.] Inst Expt Endokrinol, Berlin, Germany. [Chiang, Emily C.; Waters, David J.] Gerald P Murphy Canc Fdn, W Lafayette, IN USA. [Davis, Cindy D.; Milner, John A.] NCI, Nutr Sci Res Grp, Bethesda, MD 20892 USA. RP Combs, GF (reprint author), USDA ARS, Grand Forks Human Nutr Res Ctr, 2420 2nd Ave N,Stop 9034, Grand Forks, ND 58202 USA. EM gerald.combs@ars.usda.gov FU Grand Forks Human Nutrition Research Center CRIS [5450-51000-036-00D]; NCI-ARS [07-0A-5450-330]; Deutsche Forschungsgemeinschaft DFG [Scho849/2-2, GraKo 1208]; Deutsche Krebshilfe [10-1792 Scho2] FX We appreciate the contribution of the supplements used in this trial by the Sabinsa Corporation. We gratefully acknowledge the expert contributions of the following members of the Grand Forks Human Nutrition Research Center staff: Brenda Ling for subject recruiting; Wesley Canfield, for subject health oversight; Emily Nielsen, Doreen Rolshoven, Judy Schumacher, and Ruth Christianson, for coordinating subject visits and sample collection; Sandy Botnen, Teresa Numedahl, Wendy Mayer, Pat Wilson and Kay Williams for sample preparation and clinical biochemical analyses; Bonnie Hoverson, Elvira Bell, Sue Sherette, Charlene Kuntz and Doris Zidon and Mary Jo Peltier for preparation and distribution of supplement packets; Laura Ids for sample preparation and enzyme analyses; Eric Uthus for advice on several analytical methods; and Craig Lacher and Bill Martin for Se analyses. The authors responsibilities were as follows: G. F. C., J. C. W., C. D. D. and J. A. M. designed the research; G. F. C., M. I. J., D. J. W., H. Z., J. I.. L. S., A. H., C. S. H., E. C. C. and D. J. W. conducted the research; L. K. J. analysed the data; G. F. C. and M. I. J. wrote the paper and had responsibility for its final content. None of the authors had any competing interests to declare. This research was supported by the Grand Forks Human Nutrition Research Center CRIS project no. 5450-51000-036-00D and NCI-ARS Interagency Agreement 07-0A-5450-330, and Deutsche Forschungsgemeinschaft DFG (Scho849/2-2, GraKo 1208) and Deutsche Krebshilfe (10-1792 Scho2) (to L. S.). NR 52 TC 21 Z9 21 U1 1 U2 6 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD MAY 28 PY 2012 VL 107 IS 10 BP 1514 EP 1525 DI 10.1017/S0007114511004715 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 944SA UT WOS:000304222900016 PM 21936966 ER PT J AU Chun, TW AF Chun, Tae-Wook TI Towards a cure for HIV: a long road ahead SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Chun, Tae-Wook] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD MAY 25 PY 2012 VL 9 SU 1 AR I12 DI 10.1186/1742-4690-9-S1-I12 PG 1 WC Virology SC Virology GA 015UN UT WOS:000309472000013 ER PT J AU Medeiros, SD Martins, AN Dias, CGA Tanuri, A Brindeiro, RD AF Medeiros, Sheila de Oliveira Martins, Angelica Nascimento Almeida Dias, Carlos Gabriel Tanuri, Amilcar Brindeiro, Rodrigo de Moraes TI Natural transmission of feline immunodeficiency virus from infected queen to kitten SO VIROLOGY JOURNAL LA English DT Article DE Vertical transmission; FIV; Stray cats ID PLACENTAL IMMUNOPATHOLOGY; CATS; FAILURE; FETAL; MODEL; FIV AB Background: Feline immunodeficiency virus (FIV) is a naturally occurring lentivirus that infects cats. The primary mode of transmission occurs through bite wounds, and other routes are difficult to observe in nature. Findings: The purpose of this study was to evaluate FIV transmission from queen to kitten in a colony of naturally infected stray cats. With this aim, a queen was monitored over a period of three years. A blood sample was taken to amplify and sequence gag, pol and env regions of the virus from the queen, two kittens and other cats from the colony. Conclusion: Phylogenetic analysis showed evidence of queen to kitten transmission. C1 [Medeiros, Sheila de Oliveira; Almeida Dias, Carlos Gabriel; Tanuri, Amilcar; Brindeiro, Rodrigo de Moraes] Univ Fed Rio de Janeiro, Lab Virol Mol Anim, Rio De Janeiro, Brazil. [Martins, Angelica Nascimento] NCI, HIV Drug Resistance Program, Virus Cell Interact Sect, Frederick, MD 21701 USA. RP Tanuri, A (reprint author), Univ Fed Rio de Janeiro, Lab Virol Mol Anim, Rio De Janeiro, Brazil. EM atanuri@biologia.ufrj.br NR 18 TC 1 Z9 1 U1 2 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD MAY 25 PY 2012 VL 9 AR 99 DI 10.1186/1743-422X-9-99 PG 7 WC Virology SC Virology GA 003IC UT WOS:000308603100001 ER PT J AU Gabbita, SP Srivastava, MK Eslami, P Johnson, MF Kobritz, NK Tweedie, D Greig, NH Zemlan, FP Sharma, SP Harris-White, ME AF Gabbita, S. Prasad Srivastava, Minu K. Eslami, Pirooz Johnson, Ming F. Kobritz, Naomi K. Tweedie, David Greig, Nigel H. Zemlan, Frank P. Sharma, Sherven P. Harris-White, Marni E. TI Early intervention with a small molecule inhibitor for tumor necrosis factor-alpha prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Alzheimer's disease; memory; neuroinflammation; thalidomide; thiothalidomide; tumor necrosis factor-alpha ID CENTRAL-NERVOUS-SYSTEM; BETA-AMYLOID STIMULATION; MARROW-DERIVED CELLS; BLOOD-BRAIN-BARRIER; TNF-ALPHA; NEURODEGENERATIVE DISEASES; PERISPINAL ETANERCEPT; SYNAPTIC PLASTICITY; HEMATOPOIETIC-CELLS; THERAPEUTIC TARGET AB Background: Chronic neuroinflammation is an important component of Alzheimer's disease and could contribute to neuronal dysfunction, injury and loss that lead to disease progression. Multiple clinical studies implicate tumor necrosis factor-alpha as an inflammatory mediator of neurodegeneration in patients with Alzheimer's because of elevated levels of this cytokine in the cerebrospinal fluid, hippocampus and cortex. Current Alzheimer's disease interventions are symptomatic treatments with limited efficacy that do not address etiology. Thus, a critical need exists for novel treatments directed towards modifying the pathophysiology and progression. Methods: To investigate the effect of early immune modulation on neuroinflammation and cognitive outcome, we treated triple transgenic Alzheimer's disease mice (harboring PS1(M146V), APP(Swe), and tau(P301L) transgenes) with the small molecule tumor necrosis factor-alpha inhibitors, 3,6'-dithiothalidomide and thalidomide, beginning at four months of age. At this young age, mice do not exhibit plaque or tau pathology but do show mild intraneuronal amyloid beta protein staining and a robust increase in tumor necrosis factor-alpha. After 10 weeks of treatment, cognitive performance was assessed using radial arm maze and neuroinflammation was assessed using biochemical, stereological and flow cytometric endpoints. Results: 3,6'-dithiothalidomide reduced tumor necrosis factor-alpha mRNA and protein levels in the brain and improved working memory performance and the ratio of resting to reactive microglia in the hippocampus of triple transgenic mice. In comparison to non-transgenic controls, triple transgenic Alzheimer's disease mice had increased total numbers of infiltrating peripheral monomyelocytic/granulocytic leukocytes with enhanced intracytoplasmic tumor necrosis factor-alpha, which was reduced after treatment with 3,6'-dithiothalidomide. Conclusions: These results suggest that modulation of tumor necrosis factor-alpha with small molecule inhibitors is safe and effective with potential for the long-term prevention and treatment of Alzheimer's disease. C1 [Srivastava, Minu K.; Eslami, Pirooz; Johnson, Ming F.; Kobritz, Naomi K.; Sharma, Sherven P.; Harris-White, Marni E.] Univ Calif Los Angeles, Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Srivastava, Minu K.; Eslami, Pirooz; Johnson, Ming F.; Kobritz, Naomi K.; Sharma, Sherven P.; Harris-White, Marni E.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90073 USA. [Gabbita, S. Prasad; Zemlan, Frank P.] P2D Biosci, Cincinnati, OH 45242 USA. [Tweedie, David; Greig, Nigel H.] NIA, NIH, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Harris-White, ME (reprint author), Univ Calif Los Angeles, Vet Adm Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd 151, Los Angeles, CA 90073 USA. EM marni@ucla.edu FU Veterans Administration; Michael J. Fox Foundation; Alzheimer's Drug Discovery Foundation; Intramural Research Program of NIA, NIH FX The authors would like to thank Dr. Russell Brown at Eastern Tennessee State University for assistance with the design and analysis of the Radial Arm Maze experiments, Dr. Louis Hersh at the University of Kentucky for providing breeding pairs of 3 x Tg mice and Dr. Kenneth Hensley at the University of Toledo for assistance with data interpretation and critical scientific review of the manuscript. This work was supported by Veterans Administration Merit Funding (MEHW and SPS), Michael J. Fox Foundation (SPG), Alzheimer's Drug Discovery Foundation (MEHW and SPG) and the Intramural Research Program of NIA, NIH (DT and NHG). NR 81 TC 26 Z9 27 U1 2 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAY 25 PY 2012 VL 9 AR 99 DI 10.1186/1742-2094-9-99 PG 16 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 976PV UT WOS:000306597700001 PM 22632257 ER PT J AU He, P Ng, BG Losfeld, ME Zhu, WH Freeze, HH AF He, Ping Ng, Bobby G. Losfeld, Marie-Estelle Zhu, Wenhong Freeze, Hudson H. TI Identification of Intercellular Cell Adhesion Molecule 1 (ICAM-1) as a Hypoglycosylation Marker in Congenital Disorders of Glycosylation Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; MASS-SPECTROMETRY; QUALITY-CONTROL; AMINO-ACIDS; EXPRESSION; PROTEINS; DOLICHOL; CULTURE; SURFACE; GOLGI AB Many human inherited disorders cause protein N-glycosylation defects, but there are few cellular markers to test gene complementation for such defects. Plasma membrane glycoproteins are potential biomarkers because they may be reduced or even absent in plasma membranes of glycosylation-deficient cells. We combined stable isotope labeling by amino acids in cell culture (SILAC) with linear ion trap mass spectrometry (LTQ Orbitrap (TM)) to identify and quantify membrane proteins from wild-type CHO and glycosylation-deficient CHO (Lec9) cells. We identified 165 underrepresented proteins from 1447 unique quantified proteins, including 18 N-glycosylated plasma membrane proteins. Using various methods, we found that intercellular cell adhesion molecule 1 (ICAM-1) was reduced in Lec9 cells and in fibroblasts from 31 congenital disorder of glycosylation (CDG) patients compared with normal controls. Mannose supplementation of phosphomannose isomerase-deficient CDG-Ib (MPI-CDG) cells and complementation with PMM2 in PMM2-deficient CDG-Ia (PMM2-CDG) cells partially corrected hypoglycosylation based on increased ICAM-1 presence on the plasma membrane. These data indicate that ICAM-1 could be a useful hypoglycosylation biomarker to assess gene complementation of CDG-I patient cells and to monitor improved glycosylation in response to therapeutic drugs. C1 [Zhu, Wenhong; Freeze, Hudson H.] NCI, Ctr Prote Facil, Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA. [He, Ping; Ng, Bobby G.; Losfeld, Marie-Estelle; Freeze, Hudson H.] Sanford Childrens Hlth Res Ctr, Genet Dis Program, La Jolla, CA 92037 USA. RP Freeze, HH (reprint author), NCI, Ctr Prote Facil, Sanford Burnham Med Res Inst, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM hudson@sanfordburnham.org OI Freeze, Hudson/0000-0001-6316-0501 FU National Institutes of Health [R01 DK55615]; Rocket Fund FX This work was supported, in whole or in part, by National Institutes of Health Grant R01 DK55615. This work was also supported by the Rocket Fund. NR 28 TC 12 Z9 12 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 MAY 25 PY 2012 VL 287 IS 22 BP 18210 EP 18217 DI 10.1074/jbc.M112.355677 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 974EC UT WOS:000306411600029 PM 22496445 ER PT J AU Dolezal, D Jones, CE Lai, XQ Brister, JR Mueser, TC Nossal, NG Hinton, DM AF Dolezal, Darin Jones, Charles E. Lai, Xiaoqin Brister, J. Rodney Mueser, Timothy C. Nossal, Nancy G. Hinton, Deborah M. TI Mutational Analysis of the T4 Gp59 Helicase Loader Reveals Its Sites for Interaction with Helicase, Single-stranded Binding Protein, and DNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GENE 59 PROTEIN; VIROLOGY JOURNAL SERIES; REPLICATION FORK; ASSEMBLY PROTEIN; LOADING PROTEIN; BACTERIOPHAGE-T4 REPLISOME; CRYSTAL-STRUCTURE; PURIFICATION; POLYMERASE; COMPLEX AB Efficient DNA replication involves coordinated interactions among DNA polymerase, multiple factors, and the DNA. From bacteriophage T4 to eukaryotes, these factors include a helicase to unwind the DNA ahead of the replication fork, a single-stranded binding protein (SSB) to bind to the ssDNA on the lagging strand, and a helicase loader that associates with the fork, helicase, and SSB. The previously reported structure of the helicase loader in the T4 system, gene product (gp) 59, has revealed an N-terminal domain, which shares structural homology with the high mobility group (HMG) proteins from eukaryotic organisms. Modeling of this structure with fork DNA has suggested that the HMG-like domain could bind to the duplex DNA ahead of the fork, whereas the C-terminal portion of gp59 would provide the docking sites for helicase (T4 gp41), SSB (T4 gp32), and the ssDNA fork arms. To test this model, we have used random and targeted mutagenesis to generate mutations throughout gp59. We have assayed the ability of the mutant proteins to bind to fork, primed fork, and ssDNAs, to interact with SSB, to stimulate helicase activity, and to function in leading and lagging strand DNA synthesis. Our results provide strong biochemical support for the role of the N-terminal gp59 HMG motif in fork binding and the interaction of the C-terminal portion of gp59 with helicase and SSB. Our results also suggest that processive replication may involve the switching of gp59 between its interactions with helicase and SSB. C1 [Dolezal, Darin; Jones, Charles E.; Lai, Xiaoqin; Brister, J. Rodney; Nossal, Nancy G.; Hinton, Deborah M.] NIDDK, Gene Express & Regulat Sect, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Mueser, Timothy C.] Univ Toledo, Dept Chem, Toledo, OH 43606 USA. RP Jones, CE (reprint author), Bldg 8,Rm 202, Bethesda, MD 20892 USA. EM CharlesJ@niddk.nih.gov; dhinton@helix.nih.gov FU National Institutes of Health; NIDDK; National Science Foundation [0346960] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program, a grant from the NIDDK, and National Science Foundation Career Award 0346960 (to T. C. M.). NR 36 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 25 PY 2012 VL 287 IS 22 BP 18596 EP 18607 DI 10.1074/jbc.M111.332080 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 974EC UT WOS:000306411600070 PM 22427673 ER PT J AU Byun, K Bayarsaikhan, E Kim, D Kim, CY Mook-Jung, I Paek, SH Kim, SU Yamamoto, T Won, MH Song, BJ Park, YM Lee, B AF Byun, Kyunghee Bayarsaikhan, Enkhjaigal Kim, Daesik Kim, Chae Young Mook-Jung, Inhee Paek, Sun Ha Kim, Seung U. Yamamoto, Tadashi Won, Moo-Ho Song, Byoung-Joon Park, Young Mok Lee, Bonghee TI Induction of Neuronal Death by Microglial AGE-Albumin: Implications for Alzheimer's Disease SO PLOS ONE LA English DT Article ID AMYLOID-BETA-PEPTIDE; ADVANCED GLYCATION ENDPRODUCTS; CENTRAL-NERVOUS-SYSTEM; CEREBROSPINAL-FLUID; PROGRESSION FACTOR; OXIDATIVE STRESS; APOPTOSIS; PROTEIN; CELLS; ACTIVATION AB Advanced glycation end products (AGEs) have long been considered as potent molecules promoting neuronal cell death and contributing to neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we demonstrate that AGE-albumin, the most abundant AGE product in human AD brains, is synthesized in activated microglial cells and secreted into the extracellular space. The rate of AGE-albumin synthesis in human microglial cells is markedly increased by amyloid-beta exposure and oxidative stress. Exogenous AGE-albumin upregulates the receptor protein for AGE (RAGE) and augments calcium influx, leading to apoptosis of human primary neurons. In animal experiments, soluble RAGE (sRAGE), pyridoxamine or ALT-711 prevented A beta-induced neuronal death in rat brains. Collectively, these results provide evidence for a new mechanism by which microglial cells promote death of neuronal cells through synthesis and secretion of AGE-albumin, thereby likely contributing to neurodegenerative diseases such as AD. C1 [Byun, Kyunghee; Bayarsaikhan, Enkhjaigal; Kim, Daesik; Lee, Bonghee] Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Ctr Genom & Prote, Inchon, South Korea. [Byun, Kyunghee; Lee, Bonghee] Gachon Univ Med & Sci, Dept Anat & Cell Biol, Inchon, South Korea. [Kim, Chae Young; Mook-Jung, Inhee] Seoul Natl Univ, Coll Med, Dept Biochem & Biomed Sci, Seoul, South Korea. [Paek, Sun Ha] Seoul Natl Univ, Coll Med, Dept Neurosurg, Seoul, South Korea. [Kim, Seung U.] Univ British Columbia, Dept Med, Vancouver, BC, Canada. [Yamamoto, Tadashi] Niigata Univ, Inst Nephrol, Grad Sch Med & Dent Sci, Niigata, Japan. [Won, Moo-Ho] Kangwon Natl Univ, Coll Med, Inst Neurodegenerat & Neuroregenerat, Chunchon, South Korea. [Won, Moo-Ho] Kangwon Natl Univ, Coll Med, Dept Anat & Neurobiol, Chunchon, South Korea. [Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Park, Young Mok] Korea Basic Sci Inst, Mass Spectrometer Res Ctr, Chungcheong Bukdo, South Korea. RP Byun, K (reprint author), Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Ctr Genom & Prote, Inchon, South Korea. EM ympark@kbsi.re.kr; bhlee@gachon.ac.kr RI Mook, Inhee/J-2754-2012; Paek, Sun Ha/J-2760-2012 FU National Research Foundation grant; Korean Government [SC-2110, 20110003677, 2010-0002054]; KBSI (Korea Basic Science Institute) grant [G30124] FX This work was supported by the National Research Foundation grant funded by the Korean Government (No. SC-2110, 20110003677 and 2010-0002054) and the KBSI (Korea Basic Science Institute) grant (G30124; Y.M.P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 27 Z9 28 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 25 PY 2012 VL 7 IS 5 AR e37917 DI 10.1371/journal.pone.0037917 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UY UT WOS:000305342300140 PM 22662249 ER PT J AU Fredriksson, K Fielhaber, JA Lam, JK Yao, XL Meyer, KS Keeran, KJ Zywicke, GJ Qu, X Yu, ZX Moss, J Kristof, AS Levine, SJ AF Fredriksson, Karin Fielhaber, Jill A. Lam, Jonathan K. Yao, Xianglan Meyer, Katharine S. Keeran, Karen J. Zywicke, Gayle J. Qu, Xuan Yu, Zu-Xi Moss, Joel Kristof, Arnold S. Levine, Stewart J. TI Paradoxical Effects of Rapamycin on Experimental House Dust Mite-Induced Asthma SO PLOS ONE LA English DT Article ID CHRONIC AIRWAY INFLAMMATION; MAMMALIAN TARGET; ALLERGIC INFLAMMATION; SENSITIZED RATS; DENDRITIC CELLS; IN-VITRO; MTOR; LYMPHANGIOLEIOMYOMATOSIS; EOSINOPHILS; SIROLIMUS AB The mammalian target of rapamycin (mTOR) modulates immune responses and cellular proliferation. The objective of this study was to assess whether inhibition of mTOR with rapamycin modifies disease severity in two experimental murine models of house dust mite (HDM)-induced asthma. In an induction model, rapamycin was administered to BALB/c mice coincident with nasal HDM challenges for 3 weeks. In a treatment model, nasal HDM challenges were performed for 6 weeks and rapamycin treatment was administered during weeks 4 through 6. In the induction model, rapamycin significantly attenuated airway inflammation, airway hyperreactivity (AHR) and goblet cell hyperplasia. In contrast, treatment of established HDM-induced asthma with rapamycin exacerbated AHR and airway inflammation, whereas goblet cell hyperplasia was not modified. Phosphorylation of the S6 ribosomal protein, which is downstream of mTORC1, was increased after 3 weeks, but not 6 weeks of HDM-challenge. Rapamycin reduced S6 phosphorylation in HDM-challenged mice in both the induction and treatment models. Thus, the paradoxical effects of rapamycin on asthma severity paralleled the activation of mTOR signaling. Lastly, mediastinal lymph node re-stimulation experiments showed that treatment of rapamycin-naive T cells with ex vivo rapamycin decreased antigen-specific Th2 cytokine production, whereas prior exposure to in vivo rapamycin rendered T cells refractory to the suppressive effects of ex vivo rapamycin. We conclude that rapamycin had paradoxical effects on the pathogenesis of experimental HDM-induced asthma. Thus, consistent with the context-dependent effects of rapamycin on inflammation, the timing of mTOR inhibition may be an important determinant of efficacy and toxicity in HDM-induced asthma. C1 [Fredriksson, Karin; Lam, Jonathan K.; Yao, Xianglan; Meyer, Katharine S.; Moss, Joel; Levine, Stewart J.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Keeran, Karen J.; Zywicke, Gayle J.] NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. [Qu, Xuan; Yu, Zu-Xi] NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. [Fielhaber, Jill A.; Kristof, Arnold S.] McGill Univ, Dept Med, Ctr Hlth, Crit Care Div, Montreal, PQ, Canada. [Fielhaber, Jill A.; Kristof, Arnold S.] McGill Univ, Dept Med, Ctr Hlth, Div Resp, Montreal, PQ, Canada. [Fielhaber, Jill A.; Kristof, Arnold S.] McGill Univ, Meakins Christie Labs, Dept Med, Ctr Hlth, Montreal, PQ, Canada. RP Fredriksson, K (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU Division of Intramural Research of the National Heart, Lung, and Blood Institute of the National Institutes of Health; LAM Foundation; Tuberous Sclerosis Alliance; Canadian Institutes of Health; National Institutes of Health [R01 CA125436]; National Institutes of Health (NIH) [60/528,340] FX This work was funded by the Division of Intramural Research of the National Heart, Lung, and Blood Institute of the National Institutes of Health. ASK has received research support from the LAM Foundation, the Tuberous Sclerosis Alliance, the Canadian Institutes of Health, and the National Institutes of Health (R01 CA125436). ASK also has received funding through a National Institutes of Health Intramural Research Program Contract. The funders had no role in study design, data collection and analysis, decision to publish, or presentation of the manuscript.; JM has received royalties from a patent (United States Provisional Patent Application No. 60/528,340 filed 09 Dec 2003) licensed from the National Institutes of Health (NIH) that is related to the topic of this manuscript. ASK has received research support from the LAM Foundation, the Canadian Institutes of Health, and the NIH (R01 CA125436). ASK also has received funding through a NIH Intramural Research Program Contract. ASK has a patent on a topic related to this manuscript (United States Provisional Patent Application No. 60/528,340 filed 09 Dec 2003). SJL has two patents that are unrelated to the topic of this manuscript (United States Patent 7,135,303, Filed February 28, 2001 and United States Patent 7,655,752 B2, Filed March 24, 2006). These competing interests do not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the PLoS One guide for authors. NR 43 TC 7 Z9 8 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 25 PY 2012 VL 7 IS 5 AR e33984 DI 10.1371/journal.pone.0033984 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UY UT WOS:000305342300002 PM 22685525 ER PT J AU Hassan, F Ren, DB Zhang, WH Merkel, TJ Gu, XX AF Hassan, Ferdaus Ren, Dabin Zhang, Wenhong Merkel, Tod J. Gu, Xin-Xing TI Moraxella catarrhalis Activates Murine Macrophages through Multiple Toll Like Receptors and Has Reduced Clearance in Lungs from TLR4 Mutant Mice SO PLOS ONE LA English DT Article ID NONTYPABLE HAEMOPHILUS-INFLUENZAE; ACUTE OTITIS-MEDIA; IMMUNE-RESPONSE; EPITHELIAL-CELLS; PNEUMOCOCCAL INFECTION; MOUSE MODEL; SEROTYPE-A; RECOGNITION; EXPRESSION; LIPOPOLYSACCHARIDE AB Moraxella catarrhalis is a Gram negative bacterium and a leading causative agent of otitis media (OM) in children. Several recent reports have provided strong evidence for an association between toll like receptors and OM. It has been found that both Streptococcus pneumoniae and nontypeable Haemophilus influenzae activate host protective immune responses through toll like receptors (TLRs), however, the precise mechanism by which Moraxella catarrhalis initiates the host immune response is currently unknown. In this report, using murine macrophages generated from a series of knock-out mice, we have demonstrated that M. catarrhalis lipooligosaccharide (LOS) and either heat killed or live bacteria are recognized by one or more TLRs. LOS activates the host immune response through a membrane bound CD14-TLR4 complex, while both heat killed and live M. cat require recognition by multiple toll like receptors such as TLR2, TLR4 and TLR9 without the requirement of CD14. We have also shown that M. cat stimuli are capable of triggering the host innate immune response by both MyD88- and TRIF- dependent signaling pathways. We further showed that M. cat induced activation of mitogen activated protein kinase (MAPK) is essential in order to achieve optimal secretion of pro-inflammatory cytokine TNF-alpha. We finally showed that TLR4 mutant C3H/HeJ mice produce significantly lower levels of pro-inflammatory cytokines TNF-alpha and IL-6 in vivo, An increased bacterial loads at 12 and 24 hours (P<0.001) in their lungs upon challenge with live M. cat in an aerosol chamber compared to wild-type (WT) control mice. These data suggest that TLRs are crucial for an effective innate immune response induced by M. cat. The results of these studies contribute to an increased understanding of molecular mechanism and possible novel treatment strategies for diseases caused by M. cat by specifically targeting TLRs and their signaling pathways. C1 [Hassan, Ferdaus; Ren, Dabin; Zhang, Wenhong; Gu, Xin-Xing] Natl Inst Deafness & Other Commun Disorders, Vaccine Res Sect, Rockville, MD USA. [Merkel, Tod J.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Hassan, F (reprint author), Univ Missouri, Sch Med, Shock Trauma Res Ctr, Kansas City, MO 64108 USA. EM hassanmf@umkc.edu; guxx@mail.nih.gov RI Ren, Dabin/H-6263-2013 FU Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), United States of America [NIH0010103632] FX This research was supported by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), United States of America (#NIH0010103632). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 10 Z9 10 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 25 PY 2012 VL 7 IS 5 AR e37610 DI 10.1371/journal.pone.0037610 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UY UT WOS:000305342300069 PM 22662179 ER PT J AU Moen, EL Wen, SC Anwar, T Cross-Knorr, S Brilliant, K Birnbaum, F Rahaman, S Sedivy, JM Moss, SF Chatterjee, D AF Moen, Erika L. Wen, Sicheng Anwar, Talha Cross-Knorr, Sam Brilliant, Kate Birnbaum, Faith Rahaman, Sherida Sedivy, John M. Moss, Steven F. Chatterjee, Devasis TI Regulation of RKIP Function by Helicobacter pylori in Gastric Cancer SO PLOS ONE LA English DT Article ID KINASE INHIBITOR PROTEIN; EPITHELIAL-MESENCHYMAL TRANSITION; TRANSCRIPTION FACTOR SNAIL; NF-KAPPA-B; INDUCED APOPTOSIS; GASTROINTESTINAL-TRACT; EXPRESSION; CELLS; ACTIVATION; PROSTATE AB Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium that infects more than half of the world's population and is a major cause of gastric adenocarcinoma. The mechanisms that link H. pylori infection to gastric carcinogenesis are not well understood. In the present study, we report that the Raf-kinase inhibitor protein (RKIP) has a role in the induction of apoptosis by H. pylori in gastric epithelial cells. Western blot and luciferase transcription reporter assays demonstrate that the pathogenicity island of H. pylori rapidly phosphorylates RKIP, which then localizes to the nucleus where it activates its own transcription and induces apoptosis. Forced overexpression of RKIP enhances apoptosis in H. pylori-infected cells, whereas RKIP RNA inhibition suppresses the induction of apoptosis by H. pylori infection. While inducing the phosphorylation of RKIP, H. pylori simultaneously targets non-phosphorylated RKIP for proteasome-mediated degradation. The increase in RKIP transcription and phosphorylation is abrogated by mutating RKIP serine 153 to valine, demonstrating that regulation of RKIP activity by H. pylori is dependent upon RKIP's S153 residue. In addition, H. pylori infection increases the expression of Snail, a transcriptional repressor of RKIP. Our results suggest that H. pylori utilizes a tumor suppressor protein, RKIP, to promote apoptosis in gastric cancer cells. C1 [Moen, Erika L.; Wen, Sicheng; Anwar, Talha; Cross-Knorr, Sam; Brilliant, Kate; Birnbaum, Faith; Moss, Steven F.; Chatterjee, Devasis] Rhode Isl Hosp, Dept Med, Providence, RI 02903 USA. [Moen, Erika L.; Cross-Knorr, Sam; Brilliant, Kate; Chatterjee, Devasis] Rhode Isl Hosp, Ctr Biomed Res Excellence COBRE, Providence, RI USA. [Rahaman, Sherida] Brown Univ, Dept Pathobiol, Grad Program, Providence, RI 02912 USA. [Sedivy, John M.] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA. RP Moen, EL (reprint author), Rhode Isl Hosp, Dept Med, Providence, RI 02903 USA. EM dchatter@lifespan.org OI Moen, Erika/0000-0002-9800-8742 FU National Institute of General Medical Sciences of the National Institutes of Health [P20GM103421]; National Center for Research Resources (NCRR) [P20 RR 017695, R01 CA111533, R21 CA133601] FX This work was supported by National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM103421 (DC); the previous segment of this project was supported by the National Center for Research Resources (NCRR) under P20 RR 017695 (DC), R01 CA111533 (SFM) and R21 CA133601 (JMS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 7 Z9 11 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 25 PY 2012 VL 7 IS 5 AR e37819 DI 10.1371/journal.pone.0037819 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UY UT WOS:000305342300120 PM 22662230 ER PT J AU Rockx-Brouwer, D Chong, A Wehrly, TD Child, R Crane, DD Celli, J Bosio, CM AF Rockx-Brouwer, Dedeke Chong, Audrey Wehrly, Tara D. Child, Robert Crane, Deborah D. Celli, Jean Bosio, Catharine M. TI Low Dose Vaccination with Attenuated Francisella tularensis Strain SchuS4 Mutants Protects against Tularemia Independent of the Route of Vaccination SO PLOS ONE LA English DT Article ID LIVE VACCINE; AEROSOL CHALLENGE; GUINEA PIG; INFECTION; VIRULENCE; MICE; IMMUNIZATION; S4; PULMONARY; NOVICIDA AB Tularemia, caused by the Gram-negative bacterium Francisella tularensis, is a severe, sometimes fatal disease. Interest in tularemia has increased over the last decade due to its history as a biological weapon. In particular, development of novel vaccines directed at protecting against pneumonic tularemia has been an important goal. Previous work has demonstrated that, when delivered at very high inoculums, administration of live, highly attenuated strains of virulent F. tularensis can protect against tularemia. However, lower vaccinating inoculums did not offer similar immunity. One concern of using live vaccines is that the host may develop mild tularemia in response to infection and use of high inoculums may contribute to this issue. Thus, generation of a live vaccine that can efficiently protect against tularemia when delivered in low numbers, e.g. < 100 organisms, may address this concern. Herein we describe the ability of three defined, attenuated mutants of F. tularensis SchuS4, deleted for FTT0369c, FTT1676, or FTT0369c and FTT1676, respectively, to engender protective immunity against tularemia when delivered at concentrations of approximately 50 or fewer bacteria. Attenuated strains for use as vaccines were selected by their inability to efficiently replicate in macrophages in vitro and impaired replication and dissemination in vivo. Although all strains were defective for replication in vitro within macrophages, protective efficacy of each attenuated mutant was correlated with their ability to modestly replicate and disseminate in the host. Finally, we demonstrate the parenteral vaccination with these strains offered superior protection against pneumonic tularemia than intranasal vaccination. Together our data provides proof of principle that low dose attenuated vaccines may be a viable goal in development of novel vaccines directed against tularemia. C1 [Rockx-Brouwer, Dedeke; Chong, Audrey; Wehrly, Tara D.; Child, Robert; Celli, Jean] NIAID, Tularemia Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Crane, Deborah D.; Bosio, Catharine M.] NIAID, Immun Pulm Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Rockx-Brouwer, D (reprint author), NIAID, Tularemia Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM jcelli@niaid.nih.gov; bosioc@niaid.nih.gov RI Bosio, Catharine/D-7456-2015 FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 17 Z9 17 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 25 PY 2012 VL 7 IS 5 AR e37752 DI 10.1371/journal.pone.0037752 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UY UT WOS:000305342300100 PM 22662210 ER PT J AU Roberts, SA Sterling, J Thompson, C Harris, S Mav, D Shah, R Klimczak, LJ Kryukov, GV Malc, E Mieczkowski, PA Resnick, MA Gordenin, DA AF Roberts, Steven A. Sterling, Joan Thompson, Cole Harris, Shawn Mav, Deepak Shah, Ruchir Klimczak, Leszek J. Kryukov, Gregory V. Malc, Ewa Mieczkowski, Piotr A. Resnick, Michael A. Gordenin, Dmitry A. TI Clustered Mutations in Yeast and in Human Cancers Can Arise from Damaged Long Single-Strand DNA Regions SO MOLECULAR CELL LA English DT Article ID SACCHAROMYCES-CEREVISIAE; IN-VIVO; HOMOLOGOUS RECOMBINATION; MULTIPLE MUTATIONS; SOMATIC MUTATION; POLYMERASE-ZETA; APOBEC PROTEINS; BASE SEQUENCES; BREAK REPAIR; UV LESIONS AB Mutations are typically perceived as random, independent events. We describe here nonrandom clustered mutations in yeast and in human cancers. Genome sequencing of yeast grown under chronic alkylation damage identified mutation clusters that extend up to 200 kb. A predominance of "strand-coordinated" changes of either cytosines or guanines in the same strand, mutation patterns, and genetic controls indicated that simultaneous mutations were generated by base alkylation in abnormally long single-strand DNA (ssDNA) formed at double-strand breaks (DSBs) and replication forks. Significantly, we found mutation clusters with analogous features in sequenced human cancers. Strand-coordinated clusters of mutated cytosines or guanines often resided near chromosome rearrangement breakpoints and were highly enriched with a motif targeted by APOBEC family cytosine-deaminases, which strongly prefer ssDNA. These data indicate that hypermutation via multiple simultaneous changes in randomly formed ssDNA is a general phenomenon that may be an important mechanism producing rapid genetic variation. C1 [Roberts, Steven A.; Sterling, Joan; Thompson, Cole; Resnick, Michael A.; Gordenin, Dmitry A.] NIEHS, Mol Genet Lab, NIH, DHHS, Durham, NC 27709 USA. [Harris, Shawn; Mav, Deepak; Shah, Ruchir] SRA Int Inc, Durham, NC 27709 USA. [Kryukov, Gregory V.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Kryukov, Gregory V.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Malc, Ewa; Mieczkowski, Piotr A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA. [Malc, Ewa; Mieczkowski, Piotr A.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. RP Gordenin, DA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Durham, NC 27709 USA. EM gordenin@niehs.nih.gov RI Kryukov, Gregory/A-9592-2008; OI Kryukov, Gregory/0000-0002-6131-9483; Gordenin, Dmitry/0000-0002-8399-1836 FU NIEHS (NIH, DHHS) [ES065073]; NIH [RO1 ES018091-02]; UNC University; NIEHS/NIH [GS-23F-9806H, HHSN273201000086U] FX We would like to thank Drs. Torn Kunkel, Paul Wade, Kin Chan, and Scott Lujan for advice and critical reading of the manuscript. This work was supported by the Intramural Research Program of the NIEHS (NIH, DHHS) project ES065073 to MAR., by NIH Grant RO1 ES018091-02 and UNC University Cancer Research Fund to P.A.M., and by NIEHS/NIH Contract GS-23F-9806H and order HHSN273201000086U to R.S. NR 53 TC 132 Z9 132 U1 1 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAY 25 PY 2012 VL 46 IS 4 BP 424 EP 435 DI 10.1016/j.molcel.2012.03.030 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 948QY UT WOS:000304518900007 PM 22607975 ER PT J AU Lands, B Lamoreaux, E AF Lands, Bill Lamoreaux, Etienne TI Using 3-6 differences in essential fatty acids rather than 3/6 ratios gives useful food balance scores SO NUTRITION & METABOLISM LA English DT Article DE Arachidonic cascade; Calories; Cardiovascular; Essential fatty acids; Health risk assessment; Highly unsaturated; Inflammatory; Omega-3; Omega-6; Polyunsaturated ID FISH-OIL; N-3; SUPPLEMENTATION; PREVENT; TISSUES; DISEASE; RISK AB Background: The vitamin-like omega-3 and omega-6 essential fatty acids are converted in the body to a large family of hormones which act at selective receptors that occur on nearly every cell and tissue. A relative omega-3 deficit allows overabundant actions of omega-6 hormones to develop into health disorders. People need simple, explicit information on the balance of essential fatty acids in their foods to avoid accumulating unintended imbalances in their tissue omega-3 and omega-6 fatty acids. Results: We developed an Omega 3-6 Balance Food Score that summarizes in a single value the balance among eleven omega-3 and omega-6 essential fatty acids in a food. The value allows a quantitative estimate of the impact of each food item on the proportions of omega-3 and omega-6 that will accumulate in the 20- and 22-carbon highly unsaturated fatty acids of blood, which is an important health risk assessment biomarker. Conclusions: The impact of an individual food item upon a useful health risk assessment biomarker is easily evident in a simple, explicit value for the balance among eleven essential fatty acids nutrients. Foods with more positive Omega 3-6 Balance Food Scores will increase the percent of omega-3 in the biomarker, whereas those with more negative Scores will increase the percent of omega-6 in the biomarker. C1 [Lands, Bill] ASN, College Pk, MD 20740 USA. [Lamoreaux, Etienne] NIAAA, NIH, Bethesda, MD 20892 USA. EM wemlands@att.net NR 24 TC 12 Z9 12 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-7075 J9 NUTR METAB JI Nutr. Metab. PD MAY 24 PY 2012 VL 9 AR 46 DI 10.1186/1743-7075-9-46 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 066SI UT WOS:000313240100001 PM 22624598 ER PT J AU Hassan, F Ren, DB Zhang, WH Gu, XX AF Hassan, Ferdaus Ren, Dabin Zhang, Wenhong Gu, Xin-Xing TI Role of c-Jun N-Terminal Protein Kinase 1/2 (JNK1/2) in Macrophage-Mediated MMP-9 Production in Response to Moraxella catarrhalis Lipooligosaccharide (LOS) SO PLOS ONE LA English DT Article ID ACUTE OTITIS-MEDIA; MATRIX-METALLOPROTEINASES; BRANHAMELLA-CATARRHALIS; TYMPANIC MEMBRANE; SEROTYPE-A; EXPRESSION; LIPOPOLYSACCHARIDE; RAT; INHIBITION; INJURY AB Moraxella catarrhalis is a Gram negative bacterium and a leading causative agent of otitis media (OM) in children. Recent reports have provided strong evidence for the presence of high levels of matrix metalloproteinase (MMPs) in effusion fluids from children suffering with OM, however, the precise mechanisms by which MMPs are generated are currently unknown. We hypothesized that MMPs are secreted from macrophages in the presence of M. catarrhalis lipooligosaccharide (LOS). In this report, we demonstrate that in vitro stimulation of murine macrophage RAW 264.7 cells with LOS leads to secretion of MMP-9 as determined by ELISA and zymogram assays. We have also shown that inhibition of ERK1/2 and p38 kinase completely blocked LOS induced MMP-9 production. In contrast, inhibition of JNK1/2 by the specific inhibitor SP600125 actually increased the level of expression and production of MMP-9 at both mRNA and protein levels, respectively by almost five fold. This latter result was confirmed by knocking down JNK1/2 using siRNA. Similar results have been observed in murine bone marrow derived macrophages in vitro. In contrast to and in parallel with the LOS-induced increased levels of MMP-9 in the presence of SP600125, we found a corresponding dose-dependent inhibition of TIMP-1 (tissue inhibitor of matrix metalloproteinase-1) secretion. Results of subsequent in vitro studies provided evidence that when JNK1/2 was inhibited prior to stimulation with LOS, it significantly increased both the extent of macrophage cell migration and invasion compared to control cells or cells treated with LOS alone. The results of these studies contribute to an increased understanding of the underlying pathophysiology of OM with effusion in children. C1 [Hassan, Ferdaus; Ren, Dabin; Zhang, Wenhong; Gu, Xin-Xing] Natl Inst Deafness & Other Commun Disorders, Vaccine Res Sect, Rockville, MD USA. RP Hassan, F (reprint author), Univ Missouri, Sch Med, Shock Trauma Res Ctr, Kansas City, MO 64108 USA. EM guxx@mail.nih.gov RI Ren, Dabin/H-6263-2013 FU Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), United States of America [NIH0010103632] FX This research was supported by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), United States of America (#NIH0010103632). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 6 Z9 6 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 24 PY 2012 VL 7 IS 5 AR e37912 DI 10.1371/journal.pone.0037912 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UB UT WOS:000305338900057 PM 22655080 ER PT J AU Iqbal, J Shen, YL Liu, YY Fu, K Jaffe, ES Liu, CL Liu, ZF Lachel, CM Deffenbacher, K Greiner, TC Vose, JM Bhagavathi, S Staudt, LM Rimsza, L Rosenwald, A Ott, G Delabie, J Campo, E Braziel, RM Cook, JR Tubbs, RR Gascoyne, RD Armitage, JO Weisenburger, DD McKeithan, TW Chan, WC AF Iqbal, Javeed Shen, Yulei Liu, Yanyan Fu, Kai Jaffe, Elaine S. Liu, Cuiling Liu, Zhongfeng Lachel, Cynthia M. Deffenbacher, Karen Greiner, Timothy C. Vose, Julie M. Bhagavathi, Sharathkumar Staudt, Louis M. Rimsza, Lisa Rosenwald, Andreas Ott, German Delabie, Jan Campo, Elias Braziel, Rita M. Cook, James R. Tubbs, Raymond R. Gascoyne, Randy D. Armitage, James O. Weisenburger, Dennis D. McKeithan, Timothy W. Chan, Wing C. TI Genome-wide miRNA profiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis SO BLOOD LA English DT Article ID GENE-EXPRESSION; MICRORNA EXPRESSION; TUMOR-SUPPRESSOR; COLORECTAL-CANCER; PROLIFERATION; DIFFERENTIATION; PATHWAY; SURVIVAL; METASTASIS; ACTIVATION AB miRNA deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1-positive MCL (n = 30) and cyclin D1-negative MCL (n = 7) and compared them with small lymphocytic leukemia/lymphoma (n = 12), aggressive B-cell lymphomas (n = 138), normal B-cell subsets, and stromal cells. We identified a 19-miRNA classifier that included 6 up-regulated miRNAs and 13 down regulated miRNA that was able to distinguish MCL from other aggressive lymphomas. Some of the up-regulated miRNAs are highly expressed in naive B cells. This miRNA-classifier showed consistent results in formalin-fixed paraffin-embedded tissues and was able to distinguish cyclin D1-negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from small lymphocytic leukemia/lymphoma, dominated by 23 up-regulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL patients demonstrated a cluster characterized by high expression of miRNAs from the polycistronic miR17-92 cluster and its paralogs, miR-106a-363 and miR-106b-25, and associated with high proliferation gene signature. The other clusters showed enrichment of stroma-associated miRNAs, and also had higher expression of stroma-associated genes. Our clinical outcome analysis in the present study suggested that miRNAs can serve as prognosticators. (Blood. 2012;119(21):4939-4948) C1 [Chan, Wing C.] Univ Nebraska Med Ctr, Ctr Res Lymphoma & Leukemia, Dept Pathol & Microbiol, Omaha, NE 68198 USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Vose, Julie M.; Armitage, James O.; McKeithan, Timothy W.] Univ Nebraska Med Ctr, Dept Hematol Oncol, Omaha, NE 68198 USA. [Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rimsza, Lisa] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Rosenwald, Andreas] Univ Wurzburg, Dept Pathol, D-8700 Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Delabie, Jan] Univ Oslo, Norwegian Radium Hosp, Dept Pathol, Oslo, Norway. [Campo, Elias] Univ Barcelona, Hosp Clin, Barcelona, Spain. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Dept Clin Pathol, Portland, OR 97201 USA. [Cook, James R.; Tubbs, Raymond R.] Cleveland Clin, Dept Mol Pathol & Lab Med, Cleveland, OH 44106 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. RP Chan, WC (reprint author), Univ Nebraska Med Ctr, Ctr Res Lymphoma & Leukemia, Dept Pathol & Microbiol, 983135 Nebraska Med Ctr, Omaha, NE 68198 USA. EM jchan@unmc.edu OI Delabie, Jan/0000-0001-5023-0689; McKeithan, Timothy/0000-0003-2242-3074; Jaffe, Elaine/0000-0003-4632-0301; Campo, elias/0000-0001-9850-9793 FU National Cancer Institute [5U01/CA114778] FX This work was supported in part by the National Cancer Institute (grant 5U01/CA114778). NR 48 TC 44 Z9 48 U1 1 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 24 PY 2012 VL 119 IS 21 BP 4939 EP 4948 DI 10.1182/blood-2011-07-370122 PG 10 WC Hematology SC Hematology GA 959CZ UT WOS:000305290400020 PM 22490335 ER PT J AU Fares, J Koller, R Humeniuk, R Wolff, L Bies, J AF Fares, Joanna Koller, Richard Humeniuk, Rita Wolff, Linda Bies, Juraj TI The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells SO BLOOD LA English DT Article ID MOUSE BONE-MARROW; TRANSCRIPTION FACTOR PU.1; COLONY-STIMULATING FACTOR; MYELODYSPLASTIC SYNDROMES; MYELOID-LEUKEMIA; P15(INK4B); EXPRESSION; PROGENITORS; GENE; HYPERMETHYLATION AB The tumor suppressor p15Ink4b is frequently inactivated by methylation in acute myeloid leukemia and premalignant myeloid disorders. Dendritic cells (DCs) as potent APCs play critical regulatory roles in antileukemic immune responses. In the present study, we investigated whether p15Ink4b can function as modulator of DC development. The expression of p15Ink4b is induced strongly during differentiation and activation of DCs, and its loss resulted in significant quantitative and qualitative impairments of conventional DC (cDC) development. Accordingly, ex vivo-generated BM-derived DCs from p15Ink4b-knockout mice express significantly decreased levels of the antigen-presenting (MHC II) and costimulatory (CD80 and CD86) molecules and have impaired immunostimulatory functions, such as antigen uptake and T-cell stimulation. Reexpression of p15Ink4b in progenitors restored these defects, and confirmed a positive role for p15Ink4b during cDC differentiation and maturation. Furthermore, we have shown herein that p15Ink4b expression increases phosphorylation of Erk1/Erk2 kinases, which leads to an elevated activity of the PU.1 transcription factor. In conclusion, our results establish p15Ink4b as an important modulator of cDC development and implicate a novel function for this tumor suppressor in the regulation of adaptive immune responses. (Blood. 2012;119(21):5005-5015) C1 [Fares, Joanna; Koller, Richard; Humeniuk, Rita; Wolff, Linda; Bies, Juraj] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Fares, Joanna] Georgetown Univ, Med Ctr, Dept Biochem Mol & Cellular Biol, Washington, DC 20007 USA. RP Bies, J (reprint author), NCI, Cellular Oncol Lab, NIH, Bldg 37-4124,37 Convent Dr, Bethesda, MD 20892 USA. EM biesj@mail.nih.gov FU Center for Cancer Research, NCI, NIH (Bethesda, MD) FX This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH (Bethesda, MD). NR 50 TC 4 Z9 5 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 24 PY 2012 VL 119 IS 21 BP 5005 EP 5015 DI 10.1182/blood-2011-10-387613 PG 11 WC Hematology SC Hematology GA 959CZ UT WOS:000305290400027 PM 22461492 ER PT J AU Chapurlat, RD Gensburger, D Jimenez-Andrade, JM Ghilardi, JR Kelly, M Mantyh, P AF Chapurlat, Roland D. Gensburger, Deborah Jimenez-Andrade, Juan M. Ghilardi, Joseph R. Kelly, Marilyn Mantyh, Patrick TI Pathophysiology and medical treatment of pain in fibrous dysplasia of bone SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article ID MCCUNE-ALBRIGHT-SYNDROME; NERVE GROWTH-FACTOR; QUALITY-OF-LIFE; INTRAVENOUS PAMIDRONATE; CELLS; CHILDREN; OSTEOARTHRITIS; EXPRESSION; TURNOVER; THERAPY AB One of the most common complications of fibrous dysplasia of bone (FD) is bone pain. Usual pain killers are often of inadequate efficacy to control this bone pain. The mechanism of bone pain in FD remains uncertain, but by analogy with bone tumors one may consider that ectopic sprouting and formation of neuroma-like structures by sensory and sympathetic nerve fibers also occur in the dysplastic skeleton. Bone pain has been reported in up to 81% of adults and 49% of children. It affects predominantly the lower limbs and the spine. The degree of pain is highly variable and adults reports more pain than children. Bisphosphonates have been shown to reduce bone pain in uncontrolled studies. Their influence on bone strength remains unknown. In a randomized trial testing alendronate, bone pain was not significantly improved. Another trial assessing the effect of risedronate is ongoing. Possible future therapies include tocilizumab, denosumab and drugs targeting nerve growth factor and its receptor TrkA. C1 [Chapurlat, Roland D.; Gensburger, Deborah] Univ Lyon, Hosp Civils Lyon, Hop E Herriot, INSERM UMR 1033, F-69437 Lyon, France. [Chapurlat, Roland D.; Gensburger, Deborah] Hop Edouard Herriot, Natl Reference Ctr Fibrous Dysplasia Bone, F-69437 Lyon, France. [Jimenez-Andrade, Juan M.; Mantyh, Patrick] Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA. [Ghilardi, Joseph R.; Mantyh, Patrick] Vet Adm Med Ctr, Res Serv, Minneapolis, MN 55417 USA. [Kelly, Marilyn] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Mantyh, Patrick] Univ Arizona, Arizona Canc Ctr, Tucson, AZ 85724 USA. RP Chapurlat, RD (reprint author), Univ Lyon, Hosp Civils Lyon, Hop E Herriot, INSERM UMR 1033, F-69437 Lyon, France. FU Fibrous Dysplasia Foundation; Zimmer FX This article has been published as part of Orphanet Journal of Rare Diseases Volume 7 Supplement 1, 2012: International Meeting on Fibrous Dysplasia/McCune-Albright Syndrome and Cherubism. The full contents of the supplement are available online at http://www.ojrd.com/supplements/7/S1. Publication of the proceedings was funded by the Fibrous Dysplasia Foundation and an unrestricted grant from Zimmer. NR 36 TC 16 Z9 19 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD MAY 24 PY 2012 VL 7 SU 1 AR S3 DI 10.1186/1750-1172-7-S1-S3 PG 9 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 951YJ UT WOS:000304756300003 PM 22640953 ER PT J AU Collins, MT Singer, FR Eugster, E AF Collins, Michael T. Singer, Frederick R. Eugster, Erica TI McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article ID G-ALPHA-S; GROWTH-HORMONE EXCESS; STIMULATORY G-PROTEIN; TERM-FOLLOW-UP; PRIMARY HYPERPARATHYROIDISM; SOMATOSTATIN ANALOG; ADENYLYL-CYCLASE; CUSHING SYNDROME; BONE; MUTATIONS AB Fibrous dysplasia (FD) is sometimes accompanied by extraskeletal manifestations that can include any combination of cafe-au-lait macules, hyperfunctioning endocrinopathies, such as gonadotropin-independent precocious puberty, hyperthyroidism, growth hormone excess, FGF23-mediated renal phosphate wasting, and/or Cushing syndrome, as well as other less common features. The combination of any of these findings, with or without FD, is known as McCune-Albright syndrome (MAS). The broad spectrum of involved tissues and the unpredictable combination of findings owe to the fact that molecular defect is due to dominant activating mutations in the widely expressed signaling protein, G(s)alpha, and the fact these mutations arises sporadically, often times early in development, prior to gastrulation, and can distribute across many or few tissues. The complexity can be mastered by a systematic screening of potentially involved tissues and cognizance that the pattern of involved tissues is established, to some degree, in utero. Thorough testing allows the clinician to establish, often times at presentation, the full extent of the disease, and importantly as well what tissues are unaffected. Treatment and follow-up can then be focused on affected systems and a meaningful prognosis can be offered to the patient and family. The authors outline screening and treatment strategies that allow for effective management of the extraskeletal manifestations of FD. C1 [Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Singer, Frederick R.] John Wayne Canc Inst, Director Endocrine & Bone Dis Program, Santa Monica, CA USA. [Eugster, Erica] Indiana Univ, Sch Med, Dept Pediat, Sect Pediat Endocrinol, Indianapolis, IN 46202 USA. RP Collins, MT (reprint author), Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. FU National Institute of Dental and Craniofacial Research; Office of Rare Diseases; Fibrous Dysplasia Foundation; Division of Intramural Research of the National Institute of Dental and Craniofacial Research, National Institutes of Health; Zimmer, Inc.; Zimmer; NIH FX This article was developed as part of the Proceedings of the International Meeting on Fibrous Dysplasia/McCune-Albright Syndrome and Cherubism that took place at the National Institutes of Health, Bethesda, MD, October 3-5, 2010. The meeting was supported by funding from the National Institute of Dental and Craniofacial Research and Office of Rare Diseases, NIH, and the Fibrous Dysplasia Foundation. This manuscript was supported in part by funding from the Fibrous Dysplasia Foundation and the Division of Intramural Research of the National Institute of Dental and Craniofacial Research, National Institutes of Health. The publication of this manuscript was supported by the Fibrous Dysplasia Foundation and an unrestricted grant from Zimmer, Inc.; This article has been published as part of Orphanet Journal of Rare Diseases Volume 7 Supplement 1, 2012: International Meeting on Fibrous Dysplasia/McCune-Albright Syndrome and Cherubism. The full contents of the supplement are available online at http://www.ojrd.com/supplements/7/S1. Publication of the proceedings was funded by the Fibrous Dysplasia Foundation and an unrestricted grant from Zimmer. NR 69 TC 38 Z9 42 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD MAY 24 PY 2012 VL 7 SU 1 AR S4 DI 10.1186/1750-1172-7-S1-S4 PG 14 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 951YJ UT WOS:000304756300004 PM 22640971 ER PT J AU Lee, JS FitzGibbon, EJ Chen, YR Kim, HJ Lustig, LR Akintoye, SO Collins, MT Kaban, LB AF Lee, J. S. FitzGibbon, E. J. Chen, Y. R. Kim, H. J. Lustig, L. R. Akintoye, S. O. Collins, M. T. Kaban, L. B. TI Clinical guidelines for the management of craniofacial fibrous dysplasia SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article ID MCCUNE-ALBRIGHT-SYNDROME; OPTICAL COHERENCE TOMOGRAPHY; STIMULATORY G-PROTEIN; ANTERIOR SKULL BASE; TEMPORAL BONE; PARANASAL SINUSES; PAMIDRONATE TREATMENT; MALIGNANT TRANSFORMATION; ACTIVATING MUTATIONS; FIBROOSSEOUS LESIONS AB Fibrous dysplasia (FD) is a non-malignant condition caused by post-zygotic, activating mutations of the GNAS gene that results in inhibition of the differentiation and proliferation of bone-forming stromal cells and leads to the replacement of normal bone and marrow by fibrous tissue and woven bone. The phenotype is variable and may be isolated to a single skeletal site or multiple sites and sometimes is associated with extraskeletal manifestations in the skin and/or endocrine organs (McCune-Albright syndrome). The clinical behavior and progression of FD may also vary, thereby making the management of this condition difficult with few established clinical guidelines. This paper provides a clinically-focused comprehensive description of craniofacial FD, its natural progression, the components of the diagnostic evaluation and the multi-disciplinary management, and considerations for future research. C1 [Lee, J. S.] Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. [FitzGibbon, E. J.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Chen, Y. R.] Chang Gung Univ, Chang Gung Mem Hosp, Chang Gung Craniofacial Ctr, Tao Yuan, Taiwan. [Kim, H. J.] Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, NIH, Bethesda, MD USA. [Kim, H. J.] Georgetown Univ, Med Ctr, Dept Otolaryngol Head & Neck Surg, Washington, DC 20007 USA. [Lustig, L. R.] Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, San Francisco, CA USA. [Akintoye, S. O.] Univ Penn, Sch Dent Med, Dept Oral Med, Philadelphia, PA 19104 USA. [Collins, M. T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Kaban, L. B.] Harvard Univ, Sch Dent Med, Massachusetts Gen Hosp, Walter C Guralnick Prof & Chairman Dept Oral & Ma, Boston, MA 02115 USA. RP Lee, JS (reprint author), Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. FU Fibrous Dysplasia Foundation; Zimmer FX This article has been published as part of Orphanet Journal of Rare Diseases Volume 7 Supplement 1, 2012: Proceedings of the International Meeting on McCune-Albright Syndrome and Cherubism. The full contents of the supplement are available online at http://www.ojrd.com/supplements/7/S1. Publication of the proceedings was funded by the Fibrous Dysplasia Foundation and an unrestricted grant from Zimmer. NR 100 TC 26 Z9 27 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD MAY 24 PY 2012 VL 7 SU 1 AR S2 DI 10.1186/1750-1172-7-S1-S2 PG 19 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 951YJ UT WOS:000304756300002 PM 22640797 ER PT J AU Yu, X Chung, S Chen, DY Wang, SM Dodd, SJ Walters, JR Isaac, JTR Koretsky, AP AF Yu, Xin Chung, Seungsoo Chen, Der-Yow Wang, Shumin Dodd, Stephen J. Walters, Judith R. Isaac, John T. R. Koretsky, Alan P. TI Thalamocortical Inputs Show Post-Critical-Period Plasticity SO NEURON LA English DT Article ID MANGANESE-ENHANCED MRI; EXPERIENCE-DEPENDENT PLASTICITY; LONG-TERM POTENTIATION; RAT BARREL CORTEX; FAST-SPIKING INTERNEURONS; SOMATOSENSORY CORTEX; IN-VIVO; FEEDFORWARD INHIBITION; CORTICAL PLASTICITY; BRAIN PLASTICITY AB Experience-dependent plasticity in the adult brain has clinical potential for functional rehabilitation following central and peripheral nerve injuries. Here, plasticity induced by unilateral infraorbital (IO) nerve resection in 4-week-old rats was mapped using MRI and synaptic mechanisms were elucidated by slice electrophysiology. Functional MRI demonstrates a cortical potentiation compared to thalamus 2 weeks after 10 nerve resection. Tracing thalamocortical (TC) projections with manganese-enhanced MRI revealed circuit changes in the spared layer 4 (L4) barrel cortex. Brain slice electrophysiology revealed TC input strengthening onto L4 stellate cells due to an increase in postsynaptic strength and the number of functional synapses. This work shows that the TC input is a site for robust plasticity after the end of the previously defined critical period for this input. Thus, TC inputs may represent a major site for adult plasticity in contrast to the consensus that adult plasticity mainly occurs at cortico-cortical connections. C1 [Yu, Xin; Chen, Der-Yow; Wang, Shumin; Dodd, Stephen J.; Koretsky, Alan P.] Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Chung, Seungsoo; Isaac, John T. R.] Natl Inst Neurol Disorders & Stroke, Dev Plast Sect, NIH, Bethesda, MD 20892 USA. [Walters, Judith R.] Natl Inst Neurol Disorders & Stroke, Neurophysiol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. [Chung, Seungsoo] Yonsei Univ, Coll Med, Dept Physiol, Brain Korea Project Med Sci 21, Seoul 120752, South Korea. [Wang, Shumin] Auburn Univ, Dept Elect & Comp Engn, Auburn, AL 36849 USA. RP Isaac, JTR (reprint author), Eli Lilly & Co, Windlesham GU20 6PH, Surrey, England. EM isaacjo@lilly.com; koretskya@ninds.nih.gov RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU NIH, NINDS FX This research was supported by the Intramural Research Program of the NIH, NINDS. We thank Dr. Afonso Silva for his support to provide the in vivo recording environment and the help from Mr. Colin Gerber and Ms. Marian Wahba. We thank Ms. Kathryn Sharer, Ms. Nadia Bouraoud, and Ms. Lisa Zhang for their technical support. NR 97 TC 22 Z9 22 U1 0 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAY 24 PY 2012 VL 74 IS 4 BP 731 EP 742 DI 10.1016/j.neuron.2012.04.024 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 951VD UT WOS:000304747200016 PM 22632730 ER PT J AU Curreli, F Choudhury, S Pyatkin, I Zagorodnikov, VP Bulay, AK Altieri, A Do Kwon, Y Kwong, PD Debnath, AK AF Curreli, Francesca Choudhury, Spreeha Pyatkin, Ilya Zagorodnikov, Victor P. Bulay, Anna Khulianova Altieri, Andrea Do Kwon, Young Kwong, Peter D. Debnath, Asim K. TI Design, Synthesis, and Antiviral Activity of Entry Inhibitors That Target the CD4-Binding Site of HIV-1 SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID KINASE INHIBITORS; NEUTRALIZATION EPITOPES; BIOLOGICAL EVALUATION; ACCURATE DOCKING; CD4; GP120; RECEPTOR; BINDING; INFECTION; DISCOVERY AB The CD4 binding site on HIV-1 gp120 has been validated as a drug target to prevent HIV-1 entry to cells. Previously, we identified two small molecule inhibitors consisting of a 2,2,6,6-tetramethylpiperidine ring linked by an oxalamide to a p-halide-substituted phenyl group, which target this site, specifically, a cavity termed "Phe43 cavity". Here we use synthetic chemistry, functional assessment, and structure-based analysis to explore variants of each region of these inhibitors for improved antiviral properties. Alterations of the phenyl group and of the oxalamide linker indicated that these regions were close to optimal in the original lead compounds. Design of a series of compounds, where the tetramethylpiperidine ring was replaced with new scaffolds, led to improved antiviral activity. These new scaffolds provide insight into the surface chemistry at the entrance of the cavity and offer additional opportunities by which to optimize further these potential-next-generation therapeutics and microbicides against HIV-1. C1 [Curreli, Francesca; Choudhury, Spreeha; Debnath, Asim K.] New York Blood Ctr, Lindsley F Kimball Res Inst, New York, NY 10021 USA. [Pyatkin, Ilya; Zagorodnikov, Victor P.; Bulay, Anna Khulianova; Altieri, Andrea] Asinex Ltd, Moscow 125480, Russia. [Do Kwon, Young; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Debnath, AK (reprint author), New York Blood Ctr, Lindsley F Kimball Res Inst, 310 E 67th St, New York, NY 10021 USA. EM adebnath@nybloodcenter.org RI Kwon, Young Do/A-6957-2010 FU New York Blood Center; Intramural AIDS Targeted Antiviral Program (IATAP); National Institute of Allergy and Infectious Diseases FX This study was supported by an intramural fund from the New York Blood Center (A.K.D.), the Intramural AIDS Targeted Antiviral Program (IATAP), and intramural funding from the National Institute of Allergy and Infectious Diseases. NR 27 TC 33 Z9 34 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 24 PY 2012 VL 55 IS 10 BP 4764 EP 4775 DI 10.1021/jm3002247 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 946GF UT WOS:000304338800018 PM 22524483 ER PT J AU Tosh, DK Deflorian, F Phan, K Gao, ZG Wan, TC Gizewski, E Auchampach, JA Jacobson, KA AF Tosh, Dilip K. Deflorian, Francesca Phan, Khai Gao, Zhan-Guo Wan, Tina C. Gizewski, Elizabeth Auchampach, John A. Jacobson, Kenneth A. TI Structure-Guided Design of A(3) Adenosine Receptor-Selective Nucleosides: Combination of 2-Arylethynyl and Bicyclo[3.1.0]hexane Substitutions SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; HIGHLY POTENT; HIGH-AFFINITY; (N)-METHANOCARBA NUCLEOSIDES; ISCHEMIA/REPERFUSION INJURY; CRYSTALLOGRAPHIC STRUCTURE; RHEUMATOID-ARTHRITIS; CRYSTAL-STRUCTURE; PARTIAL AGONISTS; RAT-BRAIN AB (N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)enhancing modifications, i.e., 2-(arylethynyl)adenine and N-6-methyl or N-6-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K-i similar to 0.6 nM, N-6-methyl 2-(halophenylethynyl) analogues 13 and 14). Combined 2-arylethynyl-N-6-3-chlorobenzyl substitutions preserved A(3)AR affinity/selectivity in the (N)-methanocarba series (e.g., 3,4-difluoro full agonist MRS5698 31, K-i 3 nM, human and mouse A(3)) better than that for ribosides. Polyaromatic 2-ethynyl N-6-3-chlorobenzyl analogues, such as potent linearly extended 2-p-biphenylethynyl MRS5679 34 (K-i hA(3) 3.1 nM; A(1), A(2A), inactive) and fluorescent 1-pyrene adduct MRS5704 35 (K-i hA(3) 68.3 nM), were conformationally rigid; receptor docking identified a large, mainly hydrophobic binding region. The vicinity of receptor-bound C2 groups was probed by homology modeling based on recent X-ray structure of an agonist-bound A(2A)AR, with a predicted helical rearrangement requiring an agonist-specific outward displacement of TM2 resembling opsin. Thus, the X-ray structure of related A(2A)AR is useful in guiding the design of new A(3)AR. agonists. C1 [Tosh, Dilip K.; Deflorian, Francesca; Phan, Khai; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, NIH, LBC, Bethesda, MD 20892 USA. [Wan, Tina C.; Gizewski, Elizabeth; Auchampach, John A.] Med Coll Wisconsin, Dept Pharmacol, Milwaukee, WI 53226 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, NIH, LBC, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases; NIH [R01 HL077707] FX We thank Dr. John Lloyd and Dr. Noel Whittaker (NIDDK) for mass spectral determinations. This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases, and by NIH R01 HL077707. NR 61 TC 35 Z9 35 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 24 PY 2012 VL 55 IS 10 BP 4847 EP 4860 DI 10.1021/jm300396n PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 946GF UT WOS:000304338800024 PM 22559880 ER PT J AU Nager, CW Brubaker, L Litman, HJ Zyczynski, HM Varner, RE Amundsen, C Sirls, LT Norton, PA Arisco, AM Chai, TC Zimmern, P Barber, MD Dandreo, KJ Menefee, SA Kenton, K Lowder, J Richter, HE Khandwala, S Nygaard, I Kraus, SR Johnson, HW Lemack, GE Mihova, M Albo, ME Mueller, E Sutkin, G Wilson, TS Hsu, Y Rozanski, TA Rickey, LM Rahn, D Tennstedt, S Kusek, JW Gormley, EA AF Nager, Charles W. Brubaker, Linda Litman, Heather J. Zyczynski, Halina M. Varner, R. Edward Amundsen, Cindy Sirls, Larry T. Norton, Peggy A. Arisco, Amy M. Chai, Toby C. Zimmern, Philippe Barber, Matthew D. Dandreo, Kimberly J. Menefee, Shawn A. Kenton, Kimberly Lowder, Jerry Richter, Holly E. Khandwala, Salil Nygaard, Ingrid Kraus, Stephen R. Johnson, Harry W. Lemack, Gary E. Mihova, Marina Albo, Michael E. Mueller, Elizabeth Sutkin, Gary Wilson, Tracey S. Hsu, Yvonne Rozanski, Thomas A. Rickey, Leslie M. Rahn, David Tennstedt, Sharon Kusek, John W. Gormley, E. Ann CA Urinary Incontinence Treatment Net TI A Randomized Trial of Urodynamic Testing before Stress-Incontinence Surgery SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PELVIC ORGAN PROLAPSE; URINARY-INCONTINENCE; BURCH COLPOSUSPENSION; WOMEN; VALIDATION; HEALTH; STANDARDIZATION; TERMINOLOGY; DYSFUNCTION; GUIDELINES AB BACKGROUND Urodynamic studies are commonly performed in women before surgery for stress urinary incontinence, but there is no good evidence that they improve outcomes. METHODS We performed a multicenter, randomized, noninferiority trial involving women with uncomplicated, demonstrable stress urinary incontinence to compare outcomes after preoperative office evaluation and urodynamic tests or evaluation only. The primary outcome was treatment success at 12 months, defined as a reduction in the score on the Urogenital Distress Inventory of 70% or more and a response of "much better" or "very much better" on the Patient Global Impression of Improvement. The predetermined noninferiority margin was 11 percentage points. RESULTS A total of 630 women were randomly assigned to undergo office evaluation with urodynamic tests or evaluation only ( 315 per group); the proportion in whom treatment was successful was 76.9% in the urodynamic-testing group versus 77.2% in the evaluation-only group ( difference, -0.3 percentage points; 95% confidence interval, -7.5 to 6.9), which was consistent with noninferiority. There were no significant between-group differences in secondary measures of incontinence severity, quality of life, patient satisfaction, rates of positive provocative stress tests, voiding dysfunction, or adverse events. Women who underwent urodynamic tests were significantly less likely to receive a diagnosis of overactive bladder and more likely to receive a diagnosis of voiding-phase dysfunction, but these changes did not lead to significant between-group differences in treatment selection or outcomes. CONCLUSIONS For women with uncomplicated, demonstrable stress urinary incontinence, preoperative office evaluation alone was not inferior to evaluation with urodynamic testing for outcomes at 1 year. C1 [Nager, Charles W.; Albo, Michael E.] Univ Calif San Diego, La Jolla, CA 92037 USA. [Menefee, Shawn A.] Kaiser Permanente So Calif, San Diego, CA USA. [Brubaker, Linda; Kenton, Kimberly; Mueller, Elizabeth] Loyola Univ, Chicago, IL 60611 USA. [Litman, Heather J.; Dandreo, Kimberly J.; Mihova, Marina; Tennstedt, Sharon] New England Res Inst, Watertown, MA 02172 USA. [Zyczynski, Halina M.; Lowder, Jerry; Sutkin, Gary] Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. [Varner, R. Edward; Richter, Holly E.; Wilson, Tracey S.] Univ Alabama Birmingham, Birmingham, AL USA. [Amundsen, Cindy] Duke Univ, Durham, NC USA. [Sirls, Larry T.; Khandwala, Salil] William Beaumont Hosp, Royal Oak, MI 48072 USA. [Sirls, Larry T.; Khandwala, Salil] Oakwood Hosp, Dearborn, MI USA. [Norton, Peggy A.; Nygaard, Ingrid; Hsu, Yvonne] Univ Utah, Salt Lake City, UT USA. [Arisco, Amy M.; Kraus, Stephen R.; Rozanski, Thomas A.] Univ Texas San Antonio, San Antonio, TX USA. [Chai, Toby C.; Johnson, Harry W.; Rickey, Leslie M.] Univ Maryland, Baltimore, MD 21201 USA. [Zimmern, Philippe; Lemack, Gary E.; Rahn, David] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Barber, Matthew D.] Cleveland Clin, Cleveland, OH USA. [Kusek, John W.] NIH, Bethesda, MD 20892 USA. [Gormley, E. Ann] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. RP Nager, CW (reprint author), Univ Calif San Diego, Perlman Suite 2A,Mail Code 0974,9350 Campus Pt Dr, La Jolla, CA 92037 USA. EM cnager@ucsd.edu OI Wadie, Bassem/0000-0002-6977-6849 FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK58225, U01 DK58229, U01 DK58234, U01 DK58231, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, U01DK60401]; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT00803959.; Supported by cooperative agreements (U01 DK58225, U01 DK58229, U01 DK58234, U01 DK58231, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, and U01DK60401) from the National Institute of Diabetes and Digestive and Kidney Diseases and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 26 TC 134 Z9 139 U1 1 U2 11 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 24 PY 2012 VL 366 IS 21 BP 1987 EP 1997 DI 10.1056/NEJMoa1113595 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 946LL UT WOS:000304353000009 PM 22551104 ER PT J AU Kellom, M Basselin, M Keleshian, VL Chen, M Rapoport, SI Rao, JS AF Kellom, Matthew Basselin, Mireille Keleshian, Vasken L. Chen, Mei Rapoport, Stanley I. Rao, Jagadeesh S. TI Dose-dependent changes in neuroinflammatory and arachidonic acid cascade markers with synaptic marker loss in rat lipopolysaccharide infusion model of neuroinflammation SO BMC NEUROSCIENCE LA English DT Article DE Arachidonic acid; Cytokine; Synapse; Drebrin; Lipopolysaccharide; Synaptophysin; Phospholipase A(2); Neuroinflammation; NF-kappa B ID ACTIVATED PROTEIN-KINASE; NF-KAPPA-B; NITRIC-OXIDE SYNTHASE; ALZHEIMERS-DISEASE; GENE-EXPRESSION; PHOSPHOLIPASE A(2); BINDING-PROTEIN; INTRACEREBROVENTRICULAR INFUSION; DOCOSAHEXAENOIC ACID; EXCITATORY SYNAPSES AB Background: Neuroinflammation, caused by six days of intracerebroventricular infusion of bacterial lipopolysaccharide (LPS), stimulates rat brain arachidonic acid (AA) metabolism. The molecular changes associated with increased AA metabolism are not clear. We examined effects of a six-day infusion of a low-dose (0.5 ng/h) and a high-dose (250 ng/h) of LPS on neuroinflammatory, AA cascade, and pre- and post-synaptic markers in rat brain. We used artificial cerebrospinal fluid-infused brains as controls. Results: Infusion of low- or high-dose LPS increased brain protein levels of TNF alpha, and iNOS, without significantly changing GFAP. High-dose LPS infusion upregulated brain protein and mRNA levels of AA cascade markers (cytosolic cPLA(2)-IVA, secretory sPLA(2)-V, cyclooxygenase-2 and 5-lipoxygenase), and of transcription factor NF-kappa B p50 DNA binding activity. Both LPS doses increased cPLA(2) and p38 mitogen-activated protein kinase levels, while reducing protein levels of the pre- synaptic marker, synaptophysin. Post-synaptic markers drebrin and PSD95 protein levels were decreased with high-but not low-dose LPS. Conclusions: Chronic LPS infusion has differential effects, depending on dose, on inflammatory, AA and synaptic markers in rat brain. Neuroinflammation associated with upregulated brain AA metabolism can lead to synaptic dysfunction. C1 [Kellom, Matthew; Basselin, Mireille; Keleshian, Vasken L.; Chen, Mei; Rapoport, Stanley I.; Rao, Jagadeesh S.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Rao, JS (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 9,1S-126, Bethesda, MD 20892 USA. EM jrao@mail.nih.gov FU National Institute on Aging, National Institutes of Health FX This research was supported entirely by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. We thank the NIH Fellow Editorial Board for assistance. NR 69 TC 10 Z9 13 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD MAY 23 PY 2012 VL 13 AR 50 DI 10.1186/1471-2202-13-50 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 015XS UT WOS:000309480300001 PM 22621398 ER PT J AU Workman, TE Fiszman, M Hurdle, JF AF Workman, T. Elizabeth Fiszman, Marcelo Hurdle, John F. TI Text summarization as a decision support aid SO BMC MEDICAL INFORMATICS AND DECISION MAKING LA English DT Article ID PHYSICIANS CLINICAL QUESTIONS; BIOMEDICAL TEXT; INFORMATION; CARE; POINT; KNOWLEDGE; PROGRAM; MEDLINE; SYSTEM AB Background: PubMed data potentially can provide decision support information, but PubMed was not exclusively designed to be a point-of-care tool. Natural language processing applications that summarize PubMed citations hold promise for extracting decision support information. The objective of this study was to evaluate the efficiency of a text summarization application called Semantic MEDLINE, enhanced with a novel dynamic summarization method, in identifying decision support data. Methods: We downloaded PubMed citations addressing the prevention and drug treatment of four disease topics. We then processed the citations with Semantic MEDLINE, enhanced with the dynamic summarization method. We also processed the citations with a conventional summarization method, as well as with a baseline procedure. We evaluated the results using clinician-vetted reference standards built from recommendations in a commercial decision support product, DynaMed. Results: For the drug treatment data, Semantic MEDLINE enhanced with dynamic summarization achieved average recall and precision scores of 0.848 and 0.377, while conventional summarization produced 0.583 average recall and 0.712 average precision, and the baseline method yielded average recall and precision values of 0.252 and 0.277. For the prevention data, Semantic MEDLINE enhanced with dynamic summarization achieved average recall and precision scores of 0.655 and 0.329. The baseline technique resulted in recall and precision scores of 0.269 and 0.247. No conventional Semantic MEDLINE method accommodating summarization for prevention exists. Conclusion: Semantic MEDLINE with dynamic summarization outperformed conventional summarization in terms of recall, and outperformed the baseline method in both recall and precision. This new approach to text summarization demonstrates potential in identifying decision support data for multiple needs. C1 [Workman, T. Elizabeth; Hurdle, John F.] Univ Utah, Dept Biomed Informat, Salt Lake City, UT 84112 USA. [Fiszman, Marcelo] Natl Lib Med, Bethesda, MD 20894 USA. RP Workman, TE (reprint author), Univ Utah, Dept Biomed Informat, HSEB 5775, Salt Lake City, UT 84112 USA. EM emaillizw@yahoo.com FU National Library of Medicine [T15LM007123] FX We express our gratitude to Denise Beaudoin, Bruce Bray, and Stan Huff for serving as data reviewers. We also thank Stephane Meystre for his counsel in disease topic selection, and Thomas Rindflesch for his essential work in natural language processing. We also thank the National Library of Medicine for funding this work through grant number T15LM007123. NR 40 TC 2 Z9 3 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6947 J9 BMC MED INFORM DECIS JI BMC Med. Inform. Decis. Mak. PD MAY 23 PY 2012 VL 12 AR 41 DI 10.1186/1472-6947-12-41 PG 12 WC Medical Informatics SC Medical Informatics GA 004DO UT WOS:000308660500001 PM 22621674 ER PT J AU Hara, Y Punsoni, M Yuk, F Park, CS Janssen, WGM Rapp, PR Morrison, JH AF Hara, Yuko Punsoni, Michael Yuk, Frank Park, C. Sehwan Janssen, William G. M. Rapp, Peter R. Morrison, John H. TI Synaptic Distributions of GluA2 and PKM zeta in the Monkey Dentate Gyrus and Their Relationships with Aging and Memory SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PROTEIN-KINASE-C; LONG-TERM POTENTIATION; AGED RHESUS-MONKEYS; AMPA RECEPTOR TRAFFICKING; RECOGNITION MEMORY; HIPPOCAMPAL-NEURONS; DENDRITIC SPINES; RAT HIPPOCAMPUS; ALZHEIMERS-DISEASE; NONHUMAN-PRIMATES AB Rhesus monkeys provide a valuable model for studying the neurobiological basis of cognitive aging, because they are vulnerable to age-related memory decline in a manner similar to humans. In this study, young and aged monkeys were first tested on a well characterized recognition memory test (delayed nonmatching-to-sample; DNMS). Then, electron microscopic immunocytochemistry was performed to determine the subcellular localization of two proteins in the hippocampal dentate gyrus (DG): the GluA2 subunit of the glutamate AMPA receptor and the atypical protein kinase C zeta isoform (PKM zeta). PKM zeta promotes memory storage by regulating GluA2-containing AMPA receptor trafficking. Thus, we examined whether the distribution of GluA2 and PKM zeta is altered with aging in DG axospinous synapses and whether it is coupled with memory deficits. Monkeys with faster DNMS task acquisition and more accurate recognition memory exhibited higher proportions of dendritic spines coexpressing GluA2 and PKM zeta. These double-labeled spines had larger synapses, as measured by postsynaptic density area, than single-labeled and unlabeled spines. Within this population of double-labeled spines, aged monkeys compared with young expressed a lower density of synaptic GluA2 immunogold labeling, which correlated with lower recognition accuracy. Additionally, higher density of synaptic PKM zeta labeling in double-labeled spines correlated with both faster task acquisition and better retention. Together, these findings suggest that age-related impairment in maintenance of GluA2 at the synapse in the primate hippocampus is coupled with memory deficits. C1 [Hara, Yuko; Punsoni, Michael; Yuk, Frank; Park, C. Sehwan; Janssen, William G. M.; Morrison, John H.] Mt Sinai Sch Med, Fishberg Dept Neurosci, New York, NY 10029 USA. [Hara, Yuko; Punsoni, Michael; Yuk, Frank; Park, C. Sehwan; Janssen, William G. M.; Morrison, John H.] Mt Sinai Sch Med, Kastor Neurobiol Aging Labs, New York, NY 10029 USA. [Hara, Yuko; Punsoni, Michael; Yuk, Frank; Park, C. Sehwan; Janssen, William G. M.; Morrison, John H.] Mt Sinai Sch Med, Friedman Brain Inst, New York, NY 10029 USA. [Morrison, John H.] Mt Sinai Sch Med, Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Morrison, John H.] Mt Sinai Sch Med, Computat Neurobiol & Imaging Ctr, New York, NY 10029 USA. [Rapp, Peter R.] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. RP Morrison, JH (reprint author), Mt Sinai Sch Med, Dept Neurosci, Box 1065,1 Gustave L Levy Pl, New York, NY 10029 USA. EM john.morrison@mssm.edu RI Hara, Yuko/B-9172-2012; Morrison, John/F-9229-2012 OI Hara, Yuko/0000-0001-5828-442X; FU National Institute on Aging [R37 AG06647, R01 AG010606] FX This work was supported by National Institute on Aging Grants R37 AG06647 and R01 AG010606 to J.H.M., and in part by the Intramural Research Program of the National Institute on Aging. We thank Mary Roberts, Sania Fong, Deborah Kent, Katie Hartley, Sona Santos, Heather McKay, and Anne Canfield at the California National Primate Research Center for their expert technical assistance involving the rhesus monkeys, and Dr. Donald Canfield for assistance in veterinary work. We also thank Susan Fink, Ginelle Andrews, Shannon Wadsworth, and Rishi Puri for expert technical assistance in tissue processing. NR 63 TC 30 Z9 30 U1 1 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 23 PY 2012 VL 32 IS 21 BP 7336 EP 7344 DI 10.1523/JNEUROSCI.0605-12.2012 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 947HR UT WOS:000304421000026 PM 22623679 ER PT J AU Park, JY Ikeda, H Ikenaga, T Ono, F AF Park, Jee-Young Ikeda, Hiromi Ikenaga, Takanori Ono, Fumihito TI Acetylcholine Receptors Enable the Transport of Rapsyn from the Golgi Complex to the Plasma Membrane SO JOURNAL OF NEUROSCIENCE LA English DT Article ID TETRATRICOPEPTIDE REPEAT DOMAINS; NEUROMUSCULAR-JUNCTION; IN-VIVO; FUNCTIONAL-PROPERTIES; SCAFFOLDING PROTEIN; CLUSTER FORMATION; EXOCYTIC PATHWAY; MUSCLE SYNAPSES; ZEBRAFISH; AGRIN AB The accumulation of acetylcholine receptors (AChRs) at nerve terminals is critical for signal transmission at the neuromuscular junction, and rapsyn is essential for this process. Previous studies suggest that AChRs might direct rapsyn self-clusters to the synapse. In vivo experiments with fluorescently tagged AChR or rapsyn in zebrafish larvae revealed that rapsyn self-clusters separate from AChRs did not exist before synapse formation. Examination of rapsyn in the AChR-less mutant sofa potato revealed that rapsyn in the absence of AChR was localized in the Golgi complex. Expression of muscle-type AChR in sofa potato restored synaptic clustering of rapsyn, while neuronal type AChR had no effect. To determine whether this requirement of protein interaction is reciprocal, we examined the mutant twitch once, which has a missense mutation in rapsyn. While the AChRs distributed nonsynaptically on the plasma membrane in twitch once, mutant rapsyn was retained in the Golgi complex. We conclude that AChRs enable the transport of rapsyn from the Golgi complex to the plasma membrane through a molecule-specific interaction. C1 [Park, Jee-Young; Ikeda, Hiromi; Ikenaga, Takanori; Ono, Fumihito] NIAAA, Sect Model Synapt Syst, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Ono, F (reprint author), NIAAA, Sect Model Synapt Syst, Lab Mol Physiol, NIH, MSC9411, Bethesda, MD 20892 USA. EM onof@mail.nih.gov OI Ikenaga, Takanori/0000-0002-7321-9703 FU NIH/NIAAA FX This study was supported by the intramural program of NIH/NIAAA. We thank Dr. Michael Linhoff for his technical help in the immunohistochemistry of rapsyn. We thank Drs. Yujin Won and Meghan Mott for their help in maintaining the fish facility. We thank Drs. Henry Puhl and Meghan Mott for critical reading of the manuscript. NR 50 TC 6 Z9 6 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 23 PY 2012 VL 32 IS 21 BP 7356 EP 7363 DI 10.1523/JNEUROSCI.0397-12.2012 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 947HR UT WOS:000304421000028 PM 22623681 ER PT J AU Rienstra, M McManus, DD Benjamin, EJ AF Rienstra, Michiel McManus, David D. Benjamin, Emelia J. TI Novel Risk Factors for Atrial Fibrillation Useful for Risk Prediction and Clinical Decision Making? SO CIRCULATION LA English DT Review DE atrial fibrillation; epidemiology; heart diseases; risk factors ID AMERICAN-HEART-ASSOCIATION; NATRIURETIC PEPTIDE LEVELS; EPICARDIAL ADIPOSE-TISSUE; CA2+-ACTIVATED K+ CHANNEL; BLOOD-PRESSURE; CARDIOVASCULAR HEALTH; ATHEROSCLEROSIS RISK; AFRICAN-AMERICANS; CHROMOSOME 4Q25; EUROPEAN ANCESTRY C1 [Rienstra, Michiel] Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, NL-9700 RB Groningen, Netherlands. [McManus, David D.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [McManus, David D.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Cardiac Electrophysiol Sect, Worcester, MA USA. [McManus, David D.] Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01609 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Rienstra, M (reprint author), Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, Hanzepl 1, NL-9700 RB Groningen, Netherlands. EM m.rienstra@umcg.nl OI Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU NIH [1R01HL092577, 1R01HL102214, 1RC1HL101056] FX This work was supported by grants from the NIH to Dr Benjamin (1R01HL092577; 1R01HL102214; 1RC1HL101056). NR 62 TC 31 Z9 31 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 22 PY 2012 VL 125 IS 20 BP E941 EP E946 DI 10.1161/CIRCULATIONAHA.112.112920 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981NK UT WOS:000306974900002 PM 22615425 ER PT J AU Gerena, Y Skolasky, RL Velez, JM Toro-Nieves, D Mayo, R Nath, A Wojna, V AF Gerena, Yamil Skolasky, Richard L. Velez, Joyce M. Toro-Nieves, Dianedis Mayo, Raul Nath, Avindra Wojna, Valerie TI Soluble and Cell-Associated Insulin Receptor Dysfunction Correlates with Severity of HAND in HIV-Infected Women SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; BECK DEPRESSION INVENTORY; MULTICENTER AIDS COHORT; COGNITIVE IMPAIRMENT; NEUROCOGNITIVE DISORDERS; DIABETES-MELLITUS; HIV-1-INFECTED PATIENTS; NEUROLOGIC DISEASE; GLUCOSE-METABOLISM AB Background: Blood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HIV-associated neurocognitive disorders (HAND). These abnormalities may occur as a result of chronic HIV infection, long-term use of combined antiretroviral treatment (CART), aging, genetic predisposition, or a combination of these factors, and may increase morbidity and mortality in this population. Objective: To determine if changes in soluble and cell-associated insulin receptor (IR) levels, IR substrate-1 (IRS-1) levels, and IRS-1 tyrosine phosphorylation are associated with the presence and severity of HAND in a cohort of HIV-seropositive women. Methods and Results: This is a retrospective cross-sectional study using patient database information and stored samples from 34 HIV-seropositive women and 10 controls without history of diabetes from the Hispanic-Latino Longitudinal Cohort of Women. Soluble IR subunits [sIR, ectodomain (a) and full-length or intact (ab)] were assayed in plasma and CSF samples by ELISA. Membrane IR levels, IRS-1 levels, and IRS-1 tyrosine phosphorylation were analyzed in CSF white cell pellets (WCP) using flow cytometry. HIV-seropositive women had significantly increased levels of intact or full-length sIR in plasma (p<0.001) and CSF (p<0.005) relative to controls. Stratified by HAND, increased levels of full-length sIR in plasma were associated with the presence (p<0.001) and severity (p<0.005) of HAND. A significant decrease in IRS-1 tyrosine-phosphorylation in the WCP was also associated with the presence (p<0.02) and severity (p<0.02) of HAND. Conclusions: This study provides evidence that IR secretion is increased in HIV-seropositive women, and increased IR secretion is associated with cognitive impairment in these women. Thus, IR dysfunction may have a role in the progression of HAND and could represent a biomarker for the presence and severity of HAND. C1 [Gerena, Yamil; Velez, Joyce M.; Toro-Nieves, Dianedis; Mayo, Raul; Wojna, Valerie] Univ Puerto Rico, NeuroAIDS Specialized Neurosci Res Program, San Juan, PR 00936 USA. [Gerena, Yamil] Univ Puerto Rico, Sch Pharm, San Juan, PR 00936 USA. [Skolasky, Richard L.] Johns Hopkins Univ, Dept Orthopaed Surg, Baltimore, MD USA. [Mayo, Raul] Univ Puerto Rico, Dept Phys Med, San Juan, PR 00936 USA. [Mayo, Raul] Univ Puerto Rico, Dept Rehabil, San Juan, PR 00936 USA. [Nath, Avindra] Natl Inst Neurol Disorders & Stroke, Sect Infect Nervous Syst, NIH, Bethesda, MD USA. [Wojna, Valerie] Univ Puerto Rico, Internal Med Neurol Div, San Juan, PR 00936 USA. RP Gerena, Y (reprint author), Univ Puerto Rico, NeuroAIDS Specialized Neurosci Res Program, San Juan, PR 00936 USA. EM valerie.wojna1@upr.edu OI Wojna, Valerie/0000-0002-4014-9921; Skolasky, Richard/0000-0002-2598-4427 FU National Institutes of Health (NIH) [1R21MH095524-01, 5S11NS046278-07, 5U54NS043011-11, 1U54RR026139-01A1, 5G12RR003051-25] FX This work was partially supported by the National Institutes of Health (NIH) grants: 1R21MH095524-01, 5S11NS046278-07, 5U54NS043011-11, 1U54RR026139-01A1, and 5G12RR003051-25. Its contents are solely the responsibility of authors and do not necessarily represent the official view of NCRR or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 70 TC 6 Z9 6 U1 3 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 22 PY 2012 VL 7 IS 5 AR e37358 DI 10.1371/journal.pone.0037358 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959VQ UT WOS:000305345300034 PM 22629383 ER PT J AU He, JY Votruba, S Pomeroy, J Bonfiglio, S Krakoff, J AF He, Jianying Votruba, Susanne Pomeroy, Jeremy Bonfiglio, Susan Krakoff, Jonathan TI Measurement of Ad Libitum Food Intake, Physical Activity, and Sedentary Time in Response to Overfeeding SO PLOS ONE LA English DT Article ID ENERGY-BALANCE; BODY-WEIGHT; GHRELIN CONCENTRATIONS; RESPIRATORY CHAMBER; SHORT-TERM; HUMANS; APPETITE; OBESITY; LEPTIN; FAT AB Given the wide availability of highly palatable foods, overeating is common. Energy intake and metabolic responses to overfeeding may provide insights into weight gain prevention. We hypothesized a down-regulation in subsequent food intake and sedentary time, and up-regulation in non-exercise activity and core temperature in response to overfeeding in order to maintain body weight constant. In a monitored inpatient clinical research unit using a cross over study design, we investigated ad libitum energy intake (EI, using automated vending machines), core body temperature, and physical activity (using accelerometry) following a short term (3-day) weight maintaining (WM) vs overfeeding (OF) diet in healthy volunteers (n = 21, BMI, mean +/- SD, 33.2 +/- 8.6 kg/m(2), 73.6% male). During the ad libitum periods following the WM vs. OF diets, there was no significant difference in mean 3-d EI (4061 +/- 1084 vs. 3926 +/- 1284 kcal/day, p = 0.41), and there were also no differences either in core body temperature (37.0 +/- 0.2 degrees C vs. 37.1 +/- 0.2 degrees C, p = 0.75) or sedentary time (70.9 +/- 12.9 vs. 72.0 +/- 7.4%, p = 0.88). However, during OF (but not WM), sedentary time was positively associated with weight gain (r = 0.49, p = 0.05, adjusted for age, sex, and initial weight). In conclusion, short term overfeeding did not result in a decrease in subsequent ad libitum food intake or overall change in sedentary time although in secondary analysis sedentary time was associated with weight gain during OF. Beyond possible changes in sedentary time, there is minimal attempt to restore energy balance during or following short term overfeeding. C1 [He, Jianying; Votruba, Susanne; Pomeroy, Jeremy; Bonfiglio, Susan; Krakoff, Jonathan] NIDDK, Phoenix Epidemiol & Clin Res Branch, US Dept HHS, NIH, Phoenix, AZ USA. RP He, JY (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, US Dept HHS, NIH, Phoenix, AZ USA. EM hejianying@mail.nih.gov FU Intramural Research Program of the National Institute of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This study was funded by the Intramural Research Program of the National Institute of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The study was approved by the National Institute of Diabetes and Digestive and Kidney Diseases Institutional Review Board. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 4 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 22 PY 2012 VL 7 IS 5 AR e36225 DI 10.1371/journal.pone.0036225 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959VQ UT WOS:000305345300005 PM 22629311 ER PT J AU Wu, JW Cross, AJ Baris, D Ward, MH Karagas, MR Johnson, A Schwenn, M Cherala, S Colt, JS Cantor, KP Rothman, N Silverman, DT Sinha, R AF Wu, J. W. Cross, A. J. Baris, D. Ward, M. H. Karagas, M. R. Johnson, A. Schwenn, M. Cherala, S. Colt, J. S. Cantor, K. P. Rothman, N. Silverman, D. T. Sinha, R. TI Dietary intake of meat, fruits, vegetables, and selective micronutrients and risk of bladder cancer in the New England region of the United States SO BRITISH JOURNAL OF CANCER LA English DT Article DE diet; micronutrients; bladder cancer ID N-NITROSO COMPOUNDS; FOOD-FREQUENCY QUESTIONNAIRE; PROSPECTIVE COHORT; VITAMIN-C; RED MEAT; HETEROCYCLIC AMINES; UROTHELIAL CANCER; CONSUMPTION; HEALTH; CAROTENOIDS AB BACKGROUND: Despite many studies on diet and bladder cancer, there are areas that remain unexplored including meat mutagens, specific vegetable groups, and vitamins from diet. METHODS: We conducted a population-based case-control study of bladder cancer in Maine, New Hampshire, and Vermont. A total of 1171 cases were ascertained through hospital pathology records and cancer registries from 2001 to 2004. Overall, 1418 controls were identified from the Department of Motor Vehicles (< 65 years) and Center for Medicaid and Medicare Services (65-79 years) and were frequency-matched to cases by state, sex, and age (within 5 years). Diet was assessed with a self-administered Diet History Questionnaire. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Processed meat intake was positively associated with bladder cancer (highest vs lowest quartile OR: 1.28; 95% CI: 1.00-1.65; P-trend = 0.035), with a stronger association for processed red meat (OR: 1.41; 95% CI: 1.08-1.84; P-trend = 0.024). There were no associations between intake of fruits or vegetables and bladder cancer. We did, however, observe an inverse association with vitamin B12 intake (OR: 0.77; 95% CI: 0.61-0.99; P = 0.019). CONCLUSION: Vitamin B12 from diet may be protective against bladder cancer, whereas consuming processed meat may increase risk. British Journal of Cancer (2012) 106, 1891-1898. doi:10.1038/bjc.2012.187 www.bjcancer.com Published online 8 May 2012 (C) 2012 Cancer Research UK C1 [Wu, J. W.; Cross, A. J.; Baris, D.; Ward, M. H.; Colt, J. S.; Cantor, K. P.; Rothman, N.; Silverman, D. T.; Sinha, R.] NCI, NIH, US Dept HHS, Rockville, MD 20852 USA. [Karagas, M. R.] Dartmouth Med Sch, Epidemiol & Biostat Sect, Lebanon, NH 03756 USA. [Johnson, A.] Vermont Canc Registry, Burlington, VT 05402 USA. [Schwenn, M.] Maine Canc Registry, Augusta, ME 04333 USA. [Cherala, S.] New Hampshire Dept Hlth & Human Serv, Concord, NH 03301 USA. [Cantor, K. P.] KP Cantor Environm LLC, Silver Spring, MD 20910 USA. RP Sinha, R (reprint author), NCI, NIH, US Dept HHS, 6120 Execut Blvd, Rockville, MD 20852 USA. EM sinhar@mail.nih.gov RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU Intramural Research Program FX We thank Anna McIntosh, Paul Hurwitz, Patricia Clark and Vanessa Olivo (Westat, Rockville, MD, USA) for their support in study and data management, and Anne Taylor and Mary McAdams (Information Management Services, Silver Spring, MD, USA) for their programming help. We would like to acknowledge Dr Michael Jones (Maine Medical Center), Sue Ledoux and Dawn Nicolaides (Maine Cancer Registry), Kimberley Walsh and Christina Robinson (Dartmouth Medical School), Dr Masatoshi Kida (University of Vermont), William Apao and Carolyn Greene (Vermont Cancer Registry) for their contributions during the fieldwork and data collection phases. We also thank all fieldwork staff, interviewers, and data abstractors for their dedicated work, and our study participants for agreeing to be part of this study. This research was supported by the Intramural Research Program NR 57 TC 16 Z9 17 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 22 PY 2012 VL 106 IS 11 BP 1891 EP 1898 DI 10.1038/bjc.2012.187 PG 8 WC Oncology SC Oncology GA 946LQ UT WOS:000304353500026 PM 22568968 ER PT J AU Schetter, AJ Harris, CC AF Schetter, Aaron J. Harris, Curtis C. TI Tumor suppressor p53 (TP53) at the crossroads of the exposome and the cancer genome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID SQUAMOUS-CELL CARCINOMA; MOLECULAR EPIDEMIOLOGY; MUTATIONS; GENE; ENVIRONMENT; STOOL C1 [Schetter, Aaron J.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov FU Intramural NIH HHS NR 21 TC 11 Z9 12 U1 4 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 22 PY 2012 VL 109 IS 21 BP 7955 EP 7956 DI 10.1073/pnas.1205457109 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 947QY UT WOS:000304445800018 PM 22592801 ER PT J AU Cozens, C Pinheiro, VB Vaisman, A Woodgate, R Holliger, P AF Cozens, Christopher Pinheiro, Vitor B. Vaisman, Alexandra Woodgate, Roger Holliger, Philipp TI A short adaptive path from DNA to RNA polymerases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE processivity; protein engineering; second gate ID RIBONUCLEOTIDE INCORPORATION; DIRECTED EVOLUTION; SUGAR RECOGNITION; RESIDUE; CONFORMATION; SPECIFICITY; ARCHAEON; HYBRID; BYPASS; ETA AB DNA polymerase substrate specificity is fundamental to genome integrity and to polymerase applications in biotechnology. In the current paradigm, active site geometry is the main site of specificity control. Here, we describe the discovery of a distinct specificity checkpoint located over 25 angstrom from the active site in the polymerase thumb subdomain. In Tgo, the replicative DNA polymerase from Thermococcus gorgonarius, we identify a single mutation (E664K) within this region that enables translesion synthesis across a template abasic site or a cyclobutane thymidine dimer. In conjunction with a classic "steric-gate" mutation (Y409G) in the active site, E664K transforms Tgo DNA polymerase into an RNA polymerase capable of synthesizing RNAs up to 1.7 kb long as well as fully pseudouridine-, 5-methyl-C-, 2'-fluoro-, or 2'-azido-modified RNAs primed from a wide range of primer chemistries comprising DNA, RNA, locked nucleic acid (LNA), or 2'O-methyl-DNA. We find that E664K enables RNA synthesis by selectively increasing polymerase affinity for the noncognate RNA/DNA duplex as well as lowering the K-m for ribonucleotide triphosphate incorporation. This gatekeeper mutation therefore identifies a key missing step in the adaptive path from DNA to RNA polymerases and defines a previously unknown postsynthetic determinant of polymerase substrate specificity with implications for the synthesis and replication of noncognate nucleic acid polymers. C1 [Cozens, Christopher; Pinheiro, Vitor B.; Holliger, Philipp] MRC, Mol Biol Lab, Cambridge CB2 0QH, England. [Vaisman, Alexandra; Woodgate, Roger] NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Holliger, P (reprint author), MRC, Mol Biol Lab, Cambridge CB2 0QH, England. EM ph1@mrc-lmb.cam.ac.uk RI Vaisman, Alexandra/C-3766-2013; OI Vaisman, Alexandra/0000-0002-2521-1467; Bernardes Pinheiro, Vitor/0000-0003-2491-0028 FU Medical Research Council [U105178804]; European Union [FP6-STREP029092]; National Institute of Child Health and Human Development/National Institutes of Health FX This work was supported by Medical Research Council Grant U105178804 (to C.C., V.B.P., and P.H.), European Union Grant FP6-STREP029092 NEST (to V.B.P. and P.H.), and the National Institute of Child Health and Human Development/National Institutes of Health Intramural Research Program (A.V. and R.W.). NR 36 TC 29 Z9 29 U1 3 U2 25 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 22 PY 2012 VL 109 IS 21 BP 8067 EP 8072 DI 10.1073/pnas.1120964109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 947QY UT WOS:000304445800036 PM 22566643 ER PT J AU Xue, W Kitzing, T Roessler, S Zuber, J Krasnitz, A Schultz, N Revill, K Weissmueller, S Rappaport, AR Simon, J Zhang, J Luo, WJ Hicks, J Zender, L Wang, XW Powers, S Wigler, M Lowe, SW AF Xue, Wen Kitzing, Thomas Roessler, Stephanie Zuber, Johannes Krasnitz, Alexander Schultz, Nikolaus Revill, Kate Weissmueller, Susann Rappaport, Amy R. Simon, Janelle Zhang, Jack Luo, Weijun Hicks, James Zender, Lars Wang, Xin Wei Powers, Scott Wigler, Michael Lowe, Scott W. TI A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer genomics; chromosome 8p deletion; RNAi screen ID HUMAN HEPATOCELLULAR-CARCINOMA; HIGH-RESOLUTION ANALYSIS; LIVER-CANCER; COPY-NUMBER; IN-VIVO; BREAST-CANCER; ARM 8P; IDENTIFICATION; EXPRESSION; REVEALS AB The large chromosomal deletions frequently observed in cancer genomes are often thought to arise as a "two-hit" mechanismin the process of tumor-suppressor gene (TSG) inactivation. Using a murine model system of hepatocellular carcinoma (HCC) and in vivo RNAi, we test an alternative hypothesis, that such deletions can arise from selective pressure to attenuate the activity of multiple genes. By targeting the mouse orthologs of genes frequently deleted on human 8p22 and adjacent regions, which are lost in approximately half of several other major epithelial cancers, we provide evidence suggesting that multiple genes on chromosome 8p can cooperatively inhibit tumorigenesis in mice, and that their cosuppression can synergistically promote tumor growth. In addition, in human HCC patients, the combined down-regulation of functionally validated 8p TSGs is associated with poor survival, in contrast to the down-regulation of any individual gene. Our data imply that large cancer-associated deletions can produce phenotypes distinct from those arising through loss of a single TSG, and as such should be considered and studied as distinct mutational events. C1 [Weissmueller, Susann; Wigler, Michael] Cold Spring Harbor Lab, Watson Sch Biol Sci, Cold Spring Harbor, NY 11724 USA. [Roessler, Stephanie; Wang, Xin Wei] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Schultz, Nikolaus] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Simon, Janelle; Lowe, Scott W.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA. RP Wigler, M (reprint author), Cold Spring Harbor Lab, Watson Sch Biol Sci, POB 100, Cold Spring Harbor, NY 11724 USA. EM wigler@cshl.edu; lowes@mskcc.org RI Wang, Xin/B-6162-2009; OI Wigler, Michael/0000-0003-4396-1971 FU German Research Foundation [KI1605/1-1]; American Association for Cancer Research; National Cancer Institute; Cancer Target Discovery and Development consortium; Don Monti Memorial Research Foundation; Department of the Army [W81XWH04-1-0477]; Breast Cancer Research Foundation FX We thank B. Ma, A. Shroff, and S. Muller for excellent technical assistance; Z. Xuan for help with statistics; L. Dow and M. Saborowski for critically reading the manuscript; and all members of the S.W.L. laboratory for critical discussions throughout the course of the study. T.K. is a recipient of German Research Foundation Postdoctoral Fellowship KI1605/1-1, W.X. is a recipient of an American Association for Cancer Research Centennial Predoctoral Fellowship, J. Zuber is a Seligson clinical fellow, S.W.L. is a Howard Hughes Medical Institute Investigator, and M.W. is an American Cancer Society Research Professor. This work was supported by a program project grant from the National Cancer Institute, a Cancer Target Discovery and Development consortium grant, and the Don Monti Memorial Research Foundation. M.W.'s support for this work comes from the Department of the Army (W81XWH04-1-0477) and the Breast Cancer Research Foundation. NR 40 TC 49 Z9 49 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 22 PY 2012 VL 109 IS 21 BP 8212 EP 8217 DI 10.1073/pnas.1206062109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 947QY UT WOS:000304445800061 PM 22566646 ER PT J AU O'Donnell, KA Keng, VW York, B Reineke, EL Seo, D Fan, DH Silverstein, KAT Schrum, CT Xie, WR Mularoni, L Wheelan, SJ Torbenson, MS O'Malley, BW Largaespada, DA Boeke, JD AF O'Donnell, Kathryn A. Keng, Vincent W. York, Brian Reineke, Erin L. Seo, Daekwan Fan, Danhua Silverstein, Kevin A. T. Schrum, Christina T. Xie, Wei Rose Mularoni, Loris Wheelan, Sarah J. Torbenson, Michael S. O'Malley, Bert W. Largaespada, David A. Boeke, Jef D. TI A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer gene identification; mouse models of cancer; Myc oncogene; hepatocellular carcinoma ID HUMAN HEPATOCELLULAR-CARCINOMA; CHEMICAL HEPATOCARCINOGENESIS; TRANSPOSON MUTAGENESIS; COLORECTAL-CANCER; GENE DISCOVERY; SELF-RENEWAL; ZFX CONTROLS; C-MYC; MOUSE; PROTEIN AB The Sleeping Beauty (SB) transposon mutagenesis system is a powerful tool that facilitates the discovery of mutations that accelerate tumorigenesis. In this study, we sought to identify mutations that cooperate with MYC, one of the most commonly dysregulated genes in human malignancy. We performed a forward genetic screen with a mouse model of MYC-induced liver cancer using SB-mediated mutagenesis. We sequenced insertions in 63 liver tumor nodules and identified at least 16 genes/loci that contribute to accelerated tumor development. RNAi-mediated knockdown in a liver progenitor cell line further validate three of these genes, Ncoa2/Src-2, Zfx, and Dtnb, as tumor suppressors in liver cancer. Moreover, deletion of Ncoa2/Src-2 in mice predisposes to diethylnitrosamine-induced liver tumorigenesis. These findings reveal genes and pathways that functionally restrain MYC-mediated liver tumorigenesis and therefore may provide targets for cancer therapy. C1 [O'Donnell, Kathryn A.; Schrum, Christina T.; Xie, Wei Rose; Boeke, Jef D.] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Mularoni, Loris; Wheelan, Sarah J.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Mularoni, Loris; Wheelan, Sarah J.] Johns Hopkins Univ, Sch Med, Div Biostat & Bioinformat, Baltimore, MD 21205 USA. [Torbenson, Michael S.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [O'Donnell, Kathryn A.; Schrum, Christina T.; Xie, Wei Rose; Boeke, Jef D.] Johns Hopkins Univ, Sch Med, High Throughput Biol Ctr, Baltimore, MD 21205 USA. [Keng, Vincent W.; Fan, Danhua; Silverstein, Kevin A. T.; Largaespada, David A.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Keng, Vincent W.; Largaespada, David A.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [Keng, Vincent W.; Largaespada, David A.] Univ Minnesota, Ctr Genome Engn, Minneapolis, MN 55455 USA. [York, Brian; Reineke, Erin L.; O'Malley, Bert W.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Seo, Daekwan] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP O'Donnell, KA (reprint author), Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. EM Kathryn.ODonnell@UTSouthwestern.edu; jboeke@jhmi.edu RI Largaespada, David/C-9832-2014; Mularoni, Loris/B-3777-2017; OI Mularoni, Loris/0000-0001-7053-7717; Keng, Vincent/0000-0003-3473-0653; Boeke, Jef/0000-0001-5322-4946 FU National Institutes of Health [CA16519]; National Cancer Institute [R01CA113535]; Damon Runyon Cancer Research Foundation [DRG-1918-06]; Cancer Prevention Research Institute of Texas FX We thank Dean Felsher for tet-o-MYC and LAPtTA mice; Scott Lowe for Trp53-/-; Myc liver progenitor cells; Adam Dupuy, Nancy Jenkins, and Neal Copeland for Rosa26-SB11 mice; Eric Cooper for Gag/Pol, Rev, and VSV-G helper plasmids; and J. Mendell and C. Dang for critical reading of the manuscript. The Minnesota Supercomputing Institute provided system administration support and the computational research infrastructure used to perform the analysis. This work was supported by National Institutes of Health Grant CA16519 (to J.D.B.) and National Cancer Institute Grant R01CA113535 (to D.A.L.). K.A.O. was a Damon Runyon fellow supported by the Damon Runyon Cancer Research Foundation Grant DRG-1918-06 and currently is a Cancer Prevention Research Institute of Texas Scholar in Cancer Research. NR 59 TC 27 Z9 27 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 22 PY 2012 VL 109 IS 21 BP E1377 EP E1386 DI 10.1073/pnas.1115433109 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 947QY UT WOS:000304445800011 PM 22556267 ER PT J AU Lockwood, WW Wilson, IM Coe, BP Chari, R Pikor, LA Thu, KL Solis, LM Nunez, MI Behrens, C Yee, J English, J Murray, N Tsao, MS Minna, JD Gazdar, AF Wistuba, II MacAulay, CE Lam, S Lam, WL AF Lockwood, William W. Wilson, Ian M. Coe, Bradley P. Chari, Raj Pikor, Larissa A. Thu, Kelsie L. Solis, Luisa M. Nunez, Maria I. Behrens, Carmen Yee, John English, John Murray, Nevin Tsao, Ming-Sound Minna, John D. Gazdar, Adi F. Wistuba, Ignacio I. MacAulay, Calum E. Lam, Stephen Lam, Wan L. TI Divergent Genomic and Epigenomic Landscapes of Lung Cancer Subtypes Underscore the Selection of Different Oncogenic Pathways during Tumor Development SO PLOS ONE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; DNA METHYLATION PROFILES; GENE-EXPRESSION; MOLECULAR-ORIGINS; CLINICOPATHOLOGICAL FEATURES; HISTONE MODIFICATIONS; TRANSCRIPTION FACTORS; LINEAGE DEPENDENCY; HYBRIDIZATION DATA; DOWN-REGULATION AB For therapeutic purposes, non-small cell lung cancer (NSCLC) has traditionally been regarded as a single disease. However, recent evidence suggest that the two major subtypes of NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SqCC) respond differently to both molecular targeted and new generation chemotherapies. Therefore, identifying the molecular differences between these tumor types may impact novel treatment strategy. We performed the first large-scale analysis of 261 primary NSCLC tumors (169 AC and 92 SqCC), integrating genome-wide DNA copy number, methylation and gene expression profiles to identify subtype-specific molecular alterations relevant to new agent design and choice of therapy. Comparison of AC and SqCC genomic and epigenomic landscapes revealed 778 altered genes with corresponding expression changes that are selected during tumor development in a subtype-specific manner. Analysis of >200 additional NSCLCs confirmed that these genes are responsible for driving the differential development and resulting phenotypes of AC and SqCC. Importantly, we identified key oncogenic pathways disrupted in each subtype that likely serve as the basis for their differential tumor biology and clinical outcomes. Downregulation of HNF4 alpha target genes was the most common pathway specific to AC, while SqCC demonstrated disruption of numerous histone modifying enzymes as well as the transcription factor E2F1. In silico screening of candidate therapeutic compounds using subtype-specific pathway components identified HDAC and PI3K inhibitors as potential treatments tailored to lung SqCC. Together, our findings suggest that AC and SqCC develop through distinct pathogenetic pathways that have significant implication in our approach to the clinical management of NSCLC. C1 [Lockwood, William W.; Wilson, Ian M.; Coe, Bradley P.; Chari, Raj; Pikor, Larissa A.; Thu, Kelsie L.; MacAulay, Calum E.; Lam, Stephen; Lam, Wan L.] British Columbia Canc Res Ctr, Dept Integrat Oncol, Vancouver, BC V5Z 1L3, Canada. [Solis, Luisa M.; Behrens, Carmen; Wistuba, Ignacio I.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Nunez, Maria I.; Wistuba, Ignacio I.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. [Yee, John] Vancouver Gen Hosp, Dept Surg, Vancouver, BC, Canada. [English, John] Vancouver Gen Hosp, Dept Pathol, Vancouver, BC V5Z 1M9, Canada. [Murray, Nevin] British Columbia Canc Agcy, Dept Med Oncol, Vancouver, BC V5Z 4E6, Canada. [Tsao, Ming-Sound] Univ Toronto, Ontario Canc Inst, Toronto, ON, Canada. [Tsao, Ming-Sound] Univ Toronto, Dept Pathol, Univ Hlth Network Princess Margaret Hosp, Toronto, ON, Canada. [Minna, John D.; Gazdar, Adi F.] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. RP Lockwood, WW (reprint author), NHGRI, Canc Biol & Genet Sect, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM william.lockwood@nih.gov RI Coe, Bradley/A-2878-2009; MacAulay, Calum/K-1795-2016 FU Canadian Institutes for Health Research (CIHR) [MOP-86731, MOP-77903, MOP-110949]; Canadian Cancer Society [CCS20485]; NCI Early Detection Research Network; Department of Defence [CDMRP W81XWH-10-1-0634]; CIHR; NSERC (Natural Sciences and Engineering Research Council); CIHR Jean-Francois Saint Denis Fellowship in Cancer Research; Banting Postdoctoral Fellowship; Vanier Canada Graduate Scholarships FX This work was supported by grants from the Canadian Institutes for Health Research (CIHR) (MOP-86731, MOP-77903, MOP-110949), Canadian Cancer Society (CCS20485), NCI Early Detection Research Network, and Department of Defence (CDMRP W81XWH-10-1-0634). W. W. L., I. M. W., B. P. C., R. C., K. L. T. and L. A. P. were supported by scholarships from CIHR and NSERC (Natural Sciences and Engineering Research Council), and W. W. L. by a CIHR Jean-Francois Saint Denis Fellowship in Cancer Research, R. C. by a Banting Postdoctoral Fellowship, K. L. T. and L. A. P. by Vanier Canada Graduate Scholarships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 96 TC 25 Z9 26 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 21 PY 2012 VL 7 IS 5 AR e37775 DI 10.1371/journal.pone.0037775 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959VD UT WOS:000305343100049 PM 22629454 ER PT J AU Musunuru, K Romaine, SPR Lettre, G Wilson, JG Volcik, KA Tsai, MY Taylor, HA Schreiner, PJ Rotter, JI Rich, SS Redline, S Psaty, BM Papanicolaou, GJ Ordovas, JM Liu, K Krauss, RM Glazer, NL Gabriel, SB Fornage, M Cupples, LA Buxbaum, SG Boerwinkle, E Ballantyne, CM Kathiresan, S Rader, DJ AF Musunuru, Kiran Romaine, Simon P. R. Lettre, Guillaume Wilson, James G. Volcik, Kelly A. Tsai, Michael Y. Taylor, Herman A., Jr. Schreiner, Pamela J. Rotter, Jerome I. Rich, Stephen S. Redline, Susan Psaty, Bruce M. Papanicolaou, George J. Ordovas, Jose M. Liu, Kiang Krauss, Ronald M. Glazer, Nicole L. Gabriel, Stacey B. Fornage, Myriam Cupples, L. Adrienne Buxbaum, Sarah G. Boerwinkle, Eric Ballantyne, Christie M. Kathiresan, Sekar Rader, Daniel J. TI Multi-Ethnic Analysis of Lipid-Associated Loci: The NHLBI CARe Project SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY-HEART-DISEASE; TRIGLYCERIDES; DESIGN; GENES; RISK AB Background: Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities. Methodology/Principal Findings: We tested a set of similar to 50,000 polymorphisms from similar to 2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed. Conclusions/Significance: We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans. C1 [Musunuru, Kiran; Gabriel, Stacey B.] Broad Inst, Cambridge, MA USA. [Musunuru, Kiran; Kathiresan, Sekar] Harvard Univ, Sch Med, Boston, MA USA. [Musunuru, Kiran; Kathiresan, Sekar] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Romaine, Simon P. R.] Univ Leeds, Leeds, W Yorkshire, England. [Lettre, Guillaume] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Wilson, James G.; Taylor, Herman A., Jr.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Volcik, Kelly A.; Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Schreiner, Pamela J.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Taylor, Herman A., Jr.; Buxbaum, Sarah G.] Jackson State Univ, Jackson, MS USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Rich, Stephen S.] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [Redline, Susan] Univ Hosp, Case Med Ctr, Cleveland, OH USA. [Redline, Susan] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Psaty, Bruce M.] Univ Washington, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Papanicolaou, George J.] NHLBI, NIH, Bethesda, MD 20892 USA. [Ordovas, Jose M.] Tufts Univ, Human Nutr Res Ctr Aging, JM United States Dept Agr, Boston, MA 02111 USA. [Krauss, Ronald M.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. [Glazer, Nicole L.; Cupples, L. Adrienne] Boston Univ, Boston, MA 02215 USA. [Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ballantyne, Christie M.] Baylor Coll Med, Houston, TX 77030 USA. [Rader, Daniel J.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Musunuru, K (reprint author), Broad Inst, Cambridge, MA USA. EM cmb@bcm.edu; sekar@broadinstitute.org; rader@mail.med.upenn.edu RI Buxbaum, Sarah/E-1970-2013; OI Buxbaum, Sarah/0000-0002-4886-3564; Cupples, L. Adrienne/0000-0003-0273-7965 FU T32 grant in Cell and Molecular Training for Cardiovascular Biology from the National Heart, Lung, and Blood Institute [K99-HL098364]; University of Virginia [R01-HL-071205] FX The following nine parent studies have contributed parent study data, ancillary study data, and DNA samples through the Broad Institute of Massachusetts Institute of Technology and Harvard (N01-HC-65226): Atherosclerosis Risk in Communities: University of North Carolina at Chapel Hill (N01-HC-55015, N01-HC-55018), Baylor Medical College (N01-HC-55016), University of Mississippi Medical Center (N01-HC-55021), University of Minnesota (N01-HC-55019), Johns Hopkins University (N01-HC-55020), University of Texas, Houston (N01-HC-55022); Cardiovascular Health Study: University of Washington (N01-HC-85079, N01-HC-55222, U01-HL-080295), Wake Forest University (N01-HC-85080), Johns Hopkins University (N01-HC-85081, N01-HC-15103), University of Pittsburgh (N01-HC-85082), University of California, Davis (N01-HC-85083), University of California, Irvine (N01-HC-85084), New England Medical Center (N01-HC-85085), University of Vermont (N01-HC-85086), Georgetown University (N01-HC-35129), University of Wisconsin (N01-HC-75150); Cleveland Family Study: Case Western Reserve University (R01-HL-46380, M01-RR-00080); Cooperative Study of Sickle Cell Disease: University of Illinois (N01-HB-72982, N01-HB-97062), Howard University (N01-HB-72991, N01-HB-97061), University of Miami (N01-HB-72992, N01-HB-97064), Duke University (N01-HB-72993), George Washington University (N01-HB-72994), University of Tennessee (N01-HB-72995, N01-HB-97070), Yale University (N01-HB-72996, N01-HB-97072), Children's Hospital-Philadelphia (N01-HB-72997, N01-HB-97056), University of Chicago (N01-HB-72998, N01-HB-97053), Medical College of Georgia (N01-HB-73000, N01-HB-97060), Washington University (N01-HB-73001, N01-HB-97071), Jewish Hospital and Medical Center of Brooklyn (N01-HB-73002), Trustees of Health and Hospitals of the City of Boston, Inc., (N01-HB-73003), Children's Hospital-Oakland (N01-HB-73004, N01-HB-97054), University of Mississippi (N01-HB-73005), St. Luke's Hospital-New York (N01-HB-73006), Alta Bates-Herrick Hospital (N01-HB-97051), Columbia University (N01-HB-97058), St.; Jude's Children's Research Hospital (N01-HB-97066), Research Foundation, State University of New York-Albany (N01-HB-97068, N01-HB-97069), New England Research Institute (N01-HB-97073), Interfaith Medical Center-Brooklyn (N01-HB-97085); Coronary Artery Risk in Young Adults: University of Alabama at Birmingham (N01-HC-48047, N01-HC-95095), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), Tufts-New England Medical Center (N01-HC-45204), Wake Forest University (N01-HC-45205), Harbor-University of California Los Angeles Research and Education Institute (N01-HC-05187), University of California, Irvine (N01-HC-45134, N01-HC-95100) ;Framingham Heart Study: Boston University (N01-HC-25195, R01-HL-092577, R01-HL-076784, R01-AG-028321); Jackson Heart Study: Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), Tougaloo College (N01-HC-95172); Multi-Ethnic Study of Atherosclerosis: University of Washington (N01-HC-95159), University of California, Los Angeles (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-University of California Los Angeles Research and Education Institute (N01-HC-95169), Cedars-Sinai Medical Center (R01-HL-071205), University of Virginia (subcontract to R01-HL-071205); Sleep Heart Health Study: Johns Hopkins University (U01-HL-064360), Case Western University (U01-HL-063463), University of California, Davis (U01-HL-053916), University of Arizona (U01-HL-053938, U01-HL-053934), University of Pittsburgh (U01-HL-077813), Boston University (U01-HL-053941), MedStar Research Institute (U01-HL-063429), Johns Hopkins University (U01-HL-053937). This work was also supported in part by a T32 grant in Cell and Molecular Training for Cardiovascular Biology and K99-HL098364 from the National Heart, Lung, and Blood Institute (KM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 13 Z9 13 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 21 PY 2012 VL 7 IS 5 AR e36473 DI 10.1371/journal.pone.0036473 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959VD UT WOS:000305343100005 PM 22629316 ER PT J AU Parra, GI Bok, K Taylor, R Haynes, JR Sosnovtsev, SV Richardson, C Green, KY AF Parra, Gabriel I. Bok, Karin Taylor, Ross Haynes, Joel R. Sosnovtsev, Stanislav V. Richardson, Charles Green, Kim Y. TI Immunogenicity and specificity of norovirus Consensus GII.4 virus-like particles in monovalent and bivalent vaccine formulations SO VACCINE LA English DT Article DE Noroviruses; GII.4 noroviruses; Consensus virus like-particles; Gastroenteritis ID NORWALK VIRUS; IMMUNE-RESPONSES; CAPSID PROTEIN; SUBTYPE-B; VOLUNTEERS; GASTROENTERITIS; DIVERSITY; MUCOSAL; BACULOVIRUS; EXPRESSION AB Noroviruses, a major cause of acute gastroenteritis worldwide, present antigenic diversity that must be considered for the development of an effective vaccine. In this study, we explored approaches to increase the broad reactivity of virus-like particle (VLP) norovirus vaccine candidates. The immunogenicity of a GII.4 "Consensus" VLP that was engineered from sequences of three genetically distinct naturally occurring GII.4 strains was examined for its ability to induce cross-reactive immune responses against different clusters of GII.4 noroviruses. Rabbits immunized with GII.4 Consensus VLPs developed high serum antibody titers against VLPs derived from a number of distinct wild-type GII.4 viruses, including some that had been circulating over 30 years ago. Because the sera exhibited low cross-reactivity with antigenically distinct GI norovirus strains, we investigated the serum antibody response to a bivalent vaccine formulation containing GI.1 (Norwalk virus) and GII.4 Consensus VLPs that was administered to animals under varying conditions. In these studies, the highest homologous and heterologous antibody titers to the bivalent vaccine were elicited following immunization of animals by the intramuscular route using Alhydrogel (Al(OH)(3)) as adjuvant. Our data indicate that the use of both genetically engineered norovirus VLPs that incorporate relevant epitopes from multiple strains and multivalent vaccine formulations increase the breadth of the immune response to diverse variants within a genotype and, thus, prove helpful in the rational design of VLP-based vaccines against human noroviruses. Published by Elsevier Ltd. C1 [Parra, Gabriel I.; Bok, Karin; Sosnovtsev, Stanislav V.; Green, Kim Y.] NIAID, Caliciviruses Sect, Infect Dis Lab, NIH,DHHS, Bethesda, MD 20892 USA. [Taylor, Ross; Haynes, Joel R.; Richardson, Charles] LigoCyte Pharmaceut Inc, Bozeman, MT USA. RP Green, KY (reprint author), NIAID, Caliciviruses Sect, Infect Dis Lab, NIH,DHHS, 50 South Dr,Bldg 50,Room 6318, Bethesda, MD 20892 USA. EM kim.green@nih.gov OI Parra, Gabriel/0000-0002-1102-4740 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes-of Health, U.S. Department of Health and Human Services FX The nasal vaccine incorporates Chitosan. This application of Chitosan (ChiSys (R)) has been licensed from Archimedes Development Ltd. ChiSys is a trademark of Archimedes Development Ltd., and is registered as a CTM, as a US Registered Trademark and in certain other jurisdictions. This research was supported, in part, by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes-of Health, U.S. Department of Health and Human Services. NR 42 TC 41 Z9 45 U1 1 U2 20 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAY 21 PY 2012 VL 30 IS 24 BP 3580 EP 3586 DI 10.1016/j.vaccine.2012.03.050 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 951SY UT WOS:000304741500013 PM 22469864 ER PT J AU Pretty, IA McGrady, M Zakian, C Ellwood, RP Taylor, A Sharif, MO Iafolla, T Martinez-Mier, EA Srisilapanan, P Korwanich, N Goodwin, M Dye, BA AF Pretty, Iain A. McGrady, Michael Zakian, Christian Ellwood, Roger P. Taylor, Andrew Sharif, Mohammed Owaise Iafolla, Timothy Martinez-Mier, E. Angeles Srisilapanan, Patcharawan Korwanich, Narumanas Goodwin, Michaela Dye, Bruce A. TI Quantitative Light Fluorescence (QLF) and Polarized White Light (PWL) assessments of dental fluorosis in an epidemiological setting SO BMC PUBLIC HEALTH LA English DT Article ID MAXILLARY CENTRAL INCISORS; EXAMINATION SURVEY NHANES; ORAL-HEALTH COMPONENT; PHOTOGRAPHIC ASSESSMENT; QUALITY-ASSURANCE; NATIONAL-HEALTH; FLUORIDE INTAKE; INDEX; PREVALENCE; AGREEMENT AB Background: To determine if a novel dual camera imaging system employing both polarized white light (PWL) and quantitative light induced fluorescence imaging (QLF) is appropriate for measuring enamel fluorosis in an epidemiological setting. The use of remote and objective scoring systems is of importance in fluorosis assessments due to the potential risk of examiner bias using clinical methods. Methods: Subjects were recruited from a panel previously characterized for fluorosis and caries to ensure a range of fluorosis presentation. A total of 164 children, aged 11 years (+/- 1.3) participated following consent. Each child was examined using the novel imaging system, a traditional digital SLR camera, and clinically using the Dean's and Thylstrup and Fejerskov (TF) Indices on the upper central and lateral incisors. Polarized white light and SLR images were scored for both Dean's and TF indices by raters and fluorescence images were automatically scored using software. Results: Data from 164 children were available with a good distribution of fluorosis severity. The automated software analysis of QLF images demonstrated significant correlations with the clinical examinations for both Dean's and TF index. Agreement (measured by weighted Kappa's) between examiners scoring clinically, from polarized photographs and from SLR images ranged from 0.56 to 0.92. Conclusions: The study suggests that the use of a digital imaging system to capture images for either automated software analysis, or remote assessment by raters is suitable for epidemiological work. The use of recorded images enables study archiving, assessment by multiple examiners, remote assessment and objectivity due to the blinding of subject status. C1 [Pretty, Iain A.; McGrady, Michael; Zakian, Christian; Ellwood, Roger P.; Taylor, Andrew; Goodwin, Michaela] Univ Manchester, Sch Dent, Colgate Palmol Dent Hlth Unit, Manchester M15 6SH, Lancs, England. [Sharif, Mohammed Owaise] Univ Manchester, Sch Dent, Oral Hlth Unit, Manchester M15 6SH, Lancs, England. [Dye, Bruce A.] CDC, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Iafolla, Timothy] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Martinez-Mier, E. Angeles] Indiana Univ, Sch Dent, Oral Hlth Res Inst, Indianapolis, IN 46202 USA. [Srisilapanan, Patcharawan; Korwanich, Narumanas] Chiang Mai Univ, Fac Dent, Chiang Mai 50200, Thailand. RP Pretty, IA (reprint author), Univ Manchester, Sch Dent, Colgate Palmol Dent Hlth Unit, Lloyd St N,Manchester Sci Pk, Manchester M15 6SH, Lancs, England. EM iain.pretty@manchester.ac.uk FU Colgate Palmolive; Colgate Palmolive (UK); CDC/NCHS; NIH/NIDCR FX None of the authors are aware of any competing interests in the production of this manuscript. The University of Manchester Dental Health Unit is co-funded by Colgate Palmolive.; The University of Manchester Dental Health Unit is supported by an unrestricted grant from Colgate Palmolive (UK). IAP is an NIHR (UK) Clinician Scientist. The CDC/NCHS and NIH/NIDCR supported the study under a special project award. NR 34 TC 6 Z9 6 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD MAY 20 PY 2012 VL 12 AR 366 DI 10.1186/1471-2458-12-366 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 037CR UT WOS:000311079500001 PM 22607363 ER PT J AU Kreitman, RJ Tallman, MS Robak, T Coutre, S Wilson, WH Stetler-Stevenson, M FitzGerald, DJ Lechleider, R Pastan, I AF Kreitman, Robert J. Tallman, Martin S. Robak, Tadeusz Coutre, Steven Wilson, Wyndham H. Stetler-Stevenson, Maryalice FitzGerald, David J. Lechleider, Robert Pastan, Ira TI Phase I Trial of Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox (CAT-8015 or HA22) in Patients With Hairy Cell Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TERM-FOLLOW-UP; MINIMAL RESIDUAL DISEASE; HEMATOLOGIC MALIGNANCIES; RFB4(DSFV)-PE38 BL22; COMPLETE REMISSION; SINGLE COURSE; CLADRIBINE; 2-CHLORODEOXYADENOSINE; PENTOSTATIN; ERADICATION AB Purpose To conduct a phase I dose-escalation trial assessing safety and response of recombinant immunotoxin moxetumomab pasudotox (CAT-8015, HA22) in chemotherapy-resistant hairy cell leukemia (HCL). Patients and Methods Eligible patients had relapsed/refractory HCL after >= two prior therapies and required treatment because of abnormal blood counts. Patients received moxetumomab pasudotox 5 to 50 mu g/kg every other day for three doses (QOD x3), with up to 16 cycles repeating at >= 4-week intervals if patients did not experience disease progression or develop neutralizing antibodies. Results Twenty-eight patients were enrolled, including three patients each at 5, 10, 20, and 30 mu g/kg, four patients at 40 mu g/kg, and 12 patients at 50 mu g/kg QOD x3 for one to 16 cycles each (median, four cycles). Dose-limiting toxicity was not observed. Two patients had transient laboratory abnormalities consistent with grade 2 hemolytic uremic syndrome with peak creatinine of 1.53 to 1.66 mg/dL and platelet nadir of 106,000 to 120,000/mu L. Drug-related toxicities in 25% to 64% of the 28 patients included (in decreasing frequency) grade 1 to 2 hypoalbuminemia, aminotransferase elevations, edema, headache, hypotension, nausea, and fatigue. Of 26 patients evaluable for immunogenicity, 10 patients (38%) made antibodies neutralizing more than 75% of the cytotoxicity of 1,000 ng/mL of immunotoxin, but this immunogenicity was rare (5%) after cycle 1. The overall response rate was 86%, with responses observed at all dose levels, and 13 patients (46%) achieved complete remission (CR). Only 1 CR lasted less than 1 year, with the median disease-free survival time not yet reached at 26 months. Conclusion Moxetumomab pasudotox at doses up to 50 mu g/kg QOD x3 has activity in relapsed/refractory HCL and has a safety profile that supports further clinical development for treatment of this disease. J Clin Oncol 30:1822-1828. (c) 2012 by American Society of Clinical Oncology C1 [Kreitman, Robert J.; Wilson, Wyndham H.; Stetler-Stevenson, Maryalice; FitzGerald, David J.; Pastan, Ira] NCI, NIH, Bethesda, MD 20892 USA. [Lechleider, Robert] MedImmune, Gaithersburg, MD USA. [Tallman, Martin S.] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, New York, NY USA. [Coutre, Steven] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Robak, Tadeusz] Med Univ Lodz, Lodz, Poland. RP Kreitman, RJ (reprint author), Bldg 5124B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU National Institutes of Health, National Cancer Institute; MedImmune FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and by MedImmune. NR 28 TC 116 Z9 123 U1 0 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 BP 1822 EP 1828 DI 10.1200/JCO.2011.38.1756 PG 7 WC Oncology SC Oncology GA 947JZ UT WOS:000304427600017 PM 22355053 ER PT J AU Adesunloye, B Huang, X Ning, YM Madan, RA Gulley, JL Beatson, M Kluetz, PG Adelberg, DE Arlen, PM Parnes, HL Mulquin, M Steinberg, SM Wright, JJ Trepel, JB Dawson, NA Chen, C Bassim, C Apolo, AB Figg, WD Dahut, WL AF Adesunloye, Bamidele Huang, Xuan Ning, Yangmin M. Madan, Ravi A. Gulley, James L. Beatson, Melony Kluetz, Paul Gustav Adelberg, David E. Arlen, Philip M. Parnes, Howard L. Mulquin, Marcia Steinberg, Seth M. Wright, John Joseph Trepel, Jane B. Dawson, Nancy Ann Chen, Clara Bassim, Carol Apolo, Andrea Borghese Figg, William Douglas Dahut, William L. TI Dual antiangiogenic therapy using lenalidomide and bevacizumab with docetaxel and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, US FDA, Silver Spring, MD USA. NCI, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, CCR, NIH, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. Natl Inst Dent & Craniolfacial Res, NIH, Bethesda, MD USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 4569 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802887 ER PT J AU Ahmed, SR Ball, DW Cosgrove, D Scardina, A Petito, E Downs, M Nelkin, B Chen, HX Doyle, LA Donehower, RC Carducci, MA Azad, NS AF Ahmed, Shabina Roohi Ball, Douglas Wilmot Cosgrove, David Scardina, Angela Petito, Emily Downs, Melinda Nelkin, Barry Chen, Helen X. Doyle, Laurence A. Donehower, Ross C. Carducci, Michael Anthony Azad, Nilofer Saba TI A phase I, single-institution, open-label, dose escalation trial with an expansion cohort evaluating the safety and tolerability of AZD6244 and IMC-A12 in subjects with advanced solid malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. NCI, Canc Therapy Evaluat Program, Rockville, MD USA. NIH, Rockville, MD USA. Sidney Kimmel Comprehens Canc, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3020 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802243 ER PT J AU Alter, BP Giri, N Savage, SH AF Alter, Blanche P. Giri, Neelam Savage, Sharon H. TI Head and neck cancer in Fanconi anemia and dyskeratosis congenita SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 5563 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800621 ER PT J AU Amiri-Kordestani, L Wilkerson, J Balasubramaniam, S Bates, SE Fojo, AT AF Amiri-Kordestani, Laleh Wilkerson, Julia Balasubramaniam, Sanjeeve Bates, Susan Elaine Fojo, Antonio Tito TI Difference between duration of treatment (DOT) and progression-free survival (PFS) as a marker of unbalanced censoring. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2548 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802026 ER PT J AU Apolo, AB Philips, G Ostrovnaya, I Rosenberg, JE Milowsky, MI Small, EJ Bajorin, DF Halabi, S AF Apolo, Andrea Borghese Philips, George Ostrovnaya, Irina Rosenberg, Jonathan E. Milowsky, Matthew I. Small, Eric Jay Bajorin, Dean F. Halabi, Susan TI External validation of prognostic models for overall survival (OS) in patients (pts) with advanced cancer (UC) treated with cisplatin-based chemotherapy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Washington, DC USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol,Med Sch, Boston, MA 02115 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Duke Univ, Med Ctr, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 4592 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803088 ER PT J AU Appleman, LJ Beumer, JH Jiang, YX Puhalla, S Lin, Y Owonikoko, TK Harvey, RD Stoller, R Petro, DP Tawbi, HAH Argiris, A Strychor, S Kiesel, B Chu, E Shepherd, SP Giranda, VL Chen, AP Belani, CP Ramalingam, SS AF Appleman, Leonard Joseph Beumer, Jan Hendrik Jiang, Yixing Puhalla, Shannon Lin, Yan Owonikoko, Taofeek Kunle Harvey, R. Donald Stoller, Ronald Petro, Daniel P. Tawbi, Hussein Abdul-Hassan Argiris, Athanassios Strychor, Sandra Kiesel, Brian Chu, Edward Shepherd, Stacie Peacock Giranda, Vincent L. Chen, Alice P. Belani, Chandra Prakash Ramalingam, Suresh S. TI A phase I study of veliparib (ABT-888) in combination with carboplatin and paclitaxel in advanced solid malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Penn State Hershey Canc Inst, Hershey, PA USA. Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Abbott Labs, Abbott Pk, IL 60064 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3049 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802251 ER PT J AU Arnaldez, FI Yeung, CL Smith, CJ Caplen, N Helman, LJ AF Arnaldez, Fernanda Irene Yeung, Choh L. Smith, Carly J. Caplen, Natasha Helman, Lee J. TI Identification of TNK2 as a critical kinase in rhabdomyosarcoma through a loss of function shRNA screen. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Gene Silencing Sect, Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9511 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800229 ER PT J AU Arora, NK Jensen, RE Forsythe, LP Mitchell, SA Bellizzi, KM Aziz, N Rowland, JH Hamilton, AS Potosky, AL AF Arora, Neeraj K. Jensen, Roxanne E. Forsythe, Laura Pence Mitchell, Sandra A. Bellizzi, Keith M. Aziz, Noreen Rowland, Julia Howe Hamilton, Ann S. Potosky, Arnold L. TI Cognitive symptoms in non-Hodgkin lymphoma survivors: Prevalence and discussion with doctors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Bethesda, MD 20892 USA. Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. Univ Connecticut, Storrs, CT USA. NINR, Bethesda, MD 20892 USA. Univ So Calif, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9130 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803449 ER PT J AU Ascierto, ML Idowu, MO Zhao, YD Bedognetti, D Ascierto, PA Bear, HD Wang, E Marincola, F De Maria, A Manjili, M AF Ascierto, Maria Libera Idowu, Michael O. Zhao, Yingdong Bedognetti, Davide Ascierto, Paolo Antonio Bear, Harry Douglas Wang, Ena Marincola, Franco De Maria, Andrea Manjili, Masoud TI Involvement of NK cell molecular signatures in favorable prognosis of breast cancer patients. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Richmond, VA USA. NCI, Bethesda, MD 20892 USA. Ist Nazl Tumori Fdn Pascale, Unit Med Oncol & Innovat Therapy, Naples, Italy. Virginia Commonwealth Univ, Masey Canc Ctr, Richmond, VA USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. Univ Genoa, Genoa, Italy. RI de maria, andrea/F-7116-2016 OI de maria, andrea/0000-0001-5782-333X NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 10565 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804173 ER PT J AU Balar, AV Iyer, G Apolo, AB Regazzi, AM Garcia-Grossman, IR Pendse, D Ostrovnaya, I Chou, JF Bochner, B Dalbagni, G Herr, HW Milowsky, MI Bajorin, DF AF Balar, Arjun Vasant Iyer, Gopa Apolo, Andrea Borghese Regazzi, Ashley Marie Garcia-Grossman, Ilana Rebecca Pendse, Deepa Ostrovnaya, Irina Chou, Joanne F. Bochner, Bernard Dalbagni, Guido Herr, Harry W. Milowsky, Matthew I. Bajorin, Dean F. TI Phase II trial of neoadjuvant gemcitabine (G) and cisplatin (C) with sunitinib in patients (pts) with muscle-invasive bladder cancer (MIBC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 4581 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803246 ER PT J AU Bandman, O Delcayre, A Laus, R Godfrey, WR Kantoff, PW Schlom, J Gulley, JL AF Bandman, Olga Delcayre, Alain Laus, Reiner Godfrey, Wayne Russell Kantoff, Philip W. Schlom, Jeffrey Gulley, James L. TI Prospect: A randomized, double-blind, phase III efficacy trial of PROSTVAC. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 BN ImmunoTherapeut, Mountain View, CA USA. Bavarian Nord Immunotherapeut, Mountain View, CA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS4699 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803319 ER PT J AU Bates, SE Balasubramaniam, S Parise, RA Bryla, C Bonner, W Redon, CE Nakamura, A Wright, JJ Piekarz, R Jiang, YX Eiseman, J Chu, E Belani, CP Beumer, JH Appleman, LJ AF Bates, Susan Elaine Balasubramaniam, Sanjeeve Parise, Robert A. Bryla, Christina Bonner, William Redon, Christophe E. Nakamura, Asako Wright, John Joseph Piekarz, Richard Jiang, Yixing Eiseman, Julie Chu, Edward Belani, Chandra Prakash Beumer, Jan Hendrik Appleman, Leonard Joseph TI Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of intravenous dimethane sulfonate (DMS612, NSC 281612) in advanced malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. Osaka Med Coll, Dept Anat & Cell Biololgy, Osaka, Japan. NCI, Rockville, MD USA. Penn State Hershey Canc Inst, Hershey, PA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2553 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801792 ER PT J AU Bedognetti, D Tomei, S Spivey, TL De Giorgi, V Ascierto, ML Wang, E Dudley, ME Uccellini, L Sertoli, MR Marincola, F Rosenberg, SA AF Bedognetti, Davide Tomei, Sara Spivey, Tara L. De Giorgi, Valeria Ascierto, Maria Libera Wang, Ena Dudley, Mark E. Uccellini, Lorenzo Sertoli, Mario Roberto Marincola, Francesco Rosenberg, Steven A. TI Evaluation of chemokine-ligand pathways in pretreatment tumor biopsies as predictive biomarker of response to adoptive therapy in metastatic melanoma patients. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. Univ Genoa, Genoa, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 8576 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801717 ER PT J AU Bible, KC Suman, V Menefee, ME Smallridge, RC Molina, JR Maples, WJ Karlin, NJ Traynor, AM Kumar, P Goh, BC Lim, WT Bossou, AR Isham, CR Webster, KP Kukla, AK Bieber, C Burton, JK Harris, PJ Erlichman, C AF Bible, Keith Christopher Suman, VeraJean Menefee, Michael E. Smallridge, Robert C. Molina, Julian R. Maples, William James Karlin, Nina J. Traynor, Anne M. Kumar, Priya Goh, Boon C. Lim, Wan-Teck Bossou, Ayoko R. Isham, Crescent R. Webster, Kevin P. Kukla, Andrea K. Bieber, Carolyn Burton, Jill K. Harris, Pamela Jo Erlichman, Charles TI A multi-institutional phase II trial of pazopanib monotherapy in advanced anaplastic thyroid cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Mayo Clin, Rochester, MN USA. Mayo Clin, Jacksonville, FL 32224 USA. Mayo Clin, Scottsdale, AZ USA. Univ Wisconsin, Madison, WI USA. Univ Minnesota, Minneapolis, MN USA. Natl Univ Hlth Syst, Singapore, Singapore. Natl Canc Ctr, Singapore, Singapore. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 5544 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803240 ER PT J AU Boman, BM Bandos, H Wickerham, DL Petrelli, NJ O'Connell, MJ Wolmark, N AF Boman, Bruce M. Bandos, Hanna Wickerham, D. Lawrence Petrelli, Nicholas J. O'Connell, Michael J. Wolmark, Norman TI Statin polyp prevention trial in patients with resected colon cancer: NSABP protocol P-5. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Natl Surg Adjuvant Breast & Bowel Project, Newark, DE USA. Helen F Graham Canc Ctr, Newark, DE USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, NSABP Biostat Ctr, Pittsburgh, PA 15261 USA. Allegheny Gen Hosp, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. Christiana Care Hlth Syst, Natl Surg Adjuvant Breast & Bowel Project, Newark, DE USA. Christiana Care Hlth Syst, Helen F Graham Canc Ctr, Newark, DE USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS1615 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801249 ER PT J AU Carvajal, RD Ambrosini, G Wolchok, JD Chapman, PB Dickson, MA D'Angelo, SP Bluth, MJ Paucar, D Fusco, A Bohr, D Roman, RA Montefusco, M Doyle, LA Marr, B Abramson, DH Chou, JF Panageas, K Schwartz, GK AF Carvajal, Richard D. Ambrosini, Grazia Wolchok, Jedd D. Chapman, Paul B. Dickson, Mark Andrew D'Angelo, Sandra P. Bluth, Mark J. Paucar, Daniel Fusco, Anne Bohr, David Roman, Ruth Ann Montefusco, Mary Doyle, L. Austin Marr, Brian Abramson, David H. Chou, Joanne F. Panageas, Katherine Schwartz, Gary K. TI Pharmacodynamic activity of selumetinib to predict radiographic response in advanced uveal melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 8598 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802595 ER PT J AU Chapman, JAW Costantino, JP Dong, B Margolese, RG Pritchard, KI Shepherd, LE Gelmon, KA Wolmark, N Pollak, MN AF Chapman, Judy-Anne W. Costantino, Joseph P. Dong, Bin Margolese, Richard G. Pritchard, Kathleen I. Shepherd, Lois E. Gelmon, Karen A. Wolmark, Norman Pollak, Michael N. TI Randomized trials of adjuvant tamoxifen versus tamoxifen and octreotide LAR in early-stage breast cancer: NCIC CTG MA.14 and NSABP B-29 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Queens Univ, NCIC Clin Trials Grp, Kingston, ON, Canada. Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Biostat, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. NSABP, Montreal, PQ, Canada. McGill Univ, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada. Univ Toronto, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Allegheny Gen Hosp, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 538 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800456 ER PT J AU Cherry, BM Korde, N Kwok, M Manasanch, EE Bhutani, M Yancey, MA Mulquin, M Maric, I Calvo, KR Braylan, R Stetler-Stevenson, M Yuan, C Tembhare, P Zingone, A Costello, R Roschewski, MJ Landgren, O AF Cherry, Benjamin M. Korde, Neha Kwok, Mary Manasanch, Elisabet E. Bhutani, Manisha Yancey, Mary Ann Mulquin, Marcia Maric, Irina Calvo, Katherine R. Braylan, Raul Stetler-Stevenson, Maryalice Yuan, Constance Tembhare, Prashant Zingone, Adriana Costello, Rene Roschewski, Mark J. Landgren, Ola TI A prospective clinical study evaluating current models for risk of progression from smoldering multiple myeloma (SMM) to multiple myeloma (MM). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Multiple Myeloma Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NIH, Hematol Serv, DLM, CCR, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, CCR, NIH, Bethesda, MD 20892 USA. RI Calvo, Katherine/A-8109-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 8088 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804017 ER PT J AU Cheung, WY Noone, AM Aziz, N Rowland, JH Potosky, AL Ayanian, J Virgo, KS Ganz, PA Stefanek, ME Earle, C AF Cheung, Winson Y. Noone, Anne Michelle Aziz, Noreen Rowland, Julia Howe Potosky, Arnold L. Ayanian, John Virgo, Katherine S. Ganz, Patricia A. Stefanek, Michael Edward Earle, Craig TI A comparison of primary care providers' and oncologists' preferences for different models of cancer survivorship care SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. NINR, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Amer Canc Soc, Atlanta, GA 30329 USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. Rollins Sch Publ Hlth, Atlanta, GA USA. Inst Clin Evaluat Sci, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 6006 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801253 ER PT J AU Chung, CH Wang, H Tsottles, N Gourin, CG Agrawal, N Molinolo, A Gutkind, S Forastiere, AA Marur, S AF Chung, Christine H. Wang, Hao Tsottles, Nancy Gourin, Christine Gail Agrawal, Nishant Molinolo, Alfredo Gutkind, Silvio Forastiere, Arlene A. Marur, Shanthi TI A phase I study of everolimus in combination with cetuximab and cisplatin as first-line therapy inrecurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Johns Hopkins Univ, Baltimore, MD USA. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e16061 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802097 ER PT J AU Cobleigh, MA Anderson, SJ Julian, TB Siziopikou, KP Arthur, DW Rabinovitch, R Zheng, P Mamounas, EP Luknic, AM Behrens, RJ Chu, L Leasure, NC Atkins, JN Polikoff, J Seay, TE Noyes, RD Stella, PJ McCaskill-Stevens, WJ Wolmark, N AF Cobleigh, Melody A. Anderson, Stewart J. Julian, Thomas B. Siziopikou, Kalliopi P. Arthur, Douglas W. Rabinovitch, Rachel Zheng, Ping Mamounas, Eleftherios P. Luknic, Alice Marie Behrens, Robert J. Chu, Luis Leasure, Nick C. Atkins, James Norman Polikoff, Jonathan Seay, Thomas E. Noyes, R. Dirk Stella, Philip J. McCaskill-Stevens, Worta J. Wolmark, Norman TI A phase III clinical trial to compare trastuzumab (T) given concurrently with radiation therapy (RT) to RT alone for women with HER2+DCIS resected by lumpectomy (Lx): NSABP B-43 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Rush Univ, Med Ctr, Natl Surg Adjuvant Breast & Bowel Project, Chicago, IL 60612 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Natl Surg Adjuvant Breast & Bowel Project Biostat, Pittsburgh, PA USA. Allegheny Gen Hosp, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. Northwestern Univ, Feinberg Sch Med, Natl Surg Breast & Bowel Program, Chicago, IL 60611 USA. Natl Surg Adjuvant Breast & Bowel Project, Richmond, VA USA. Virginia Commonwealth Univ, Richmond, VA USA. Univ Colorado, Natl Surg Breast & Bowel Project, Aurora, CO USA. NSABP Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Aultman Hosp, Natl Surg Breast & Bowel Project, Canton, OH USA. Exempla St Joseph Hosp, Colorado Canc Res Program, Natl Surg Breast & Bowel Project, Denver, CO USA. Iowa Oncol Res Assoc, Natl Surg Breast & Bowel Project, Des Moines, IA USA. Florida Canc Specialists, Natl Surg Breast & Bowel Project, Sarasota, FL USA. Reading Reg Canc Ctr, Natl Surg Breast & Bowel Project, W Reading, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Goldboro, NC USA. SCCC CCOP, Goldboro, NC USA. Natl Surg Breast & Bowel Project, San Diego, CA USA. Kaiser Permanente Southern Calif, San Diego, CA USA. Atlanta Reg Community Clin Oncol Program, Natl Surg Breast & Bowel Project, Atlanta, GA USA. Intermt Med Ctr, Natl Surg Adjuvant Breast & Bowel Project, Salt Lake City, UT USA. NSABP, Ann Arbor, MI USA. St Joseph Mercy Hlth Syst, Ann Arbor, MI USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS657 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800316 ER PT J AU Deming, DA Schelman, WR Lubner, SJ Mulkerin, D LoConte, NK Fioravanti, S Greten, T Eickhoff, JC Kolesar, J Compton, K Doyle, LA Wilding, G Duffy, AG Liu, G AF Deming, Dustin A. Schelman, William R. Lubner, Sam Joseph Mulkerin, Daniel LoConte, Noelle K. Fioravanti, Suzanne Greten, Tim Eickhoff, Jens C. Kolesar, Jill Compton, Kathryn Doyle, Laurence A. Wilding, George Duffy, Austin G. Liu, Glenn TI A phase I study of selumetinib (AZD6244/ARRY-142866) in combination with cetuximab (cet) in refractory solid tumors and KRAS mutant colorectal cancer (CRC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. NCI, Bethesda, MD 20892 USA. NIH, Rockville, MD USA. RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3103 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802310 ER PT J AU Desai, P Braun, E Dehghan-Paz, I Gattuso, P Canar, J Cobleigh, MA AF Desai, Palak Braun, Eduardo Dehghan-Paz, Irene Gattuso, Paolo Canar, Jeff Cobleigh, Melody A. TI Synchronous bilateral breast cancer (SBBC): Concordance of receptor status between right and left breast SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Rush Univ, Med Ctr, Chicago, IL 60612 USA. US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. Rush Univ, Natl Surg Adjuvant Breast & Bowel Project, Med Ctr, Chicago, IL 60612 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 572 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800078 ER PT J AU Diaz-Padilla, I Clarke, BA Hirte, HW Welch, S Mackay, H Biagi, JJ Reedijk, M Weberpals, JI Fleming, GF Wang, LS Li, J Strevel, EL Eisenhauer, A Ivy, SP Oza, AM AF Diaz-Padilla, Ivan Clarke, Blaise A. Hirte, Hal W. Welch, Stephen Mackay, Helen Biagi, James Joseph Reedijk, Michael Weberpals, Johanne Ingrid Fleming, Gini F. Wang, Lisa Li, Jennifer Strevel, Elizabeth Laureen Eisenhauer, Anne Ivy, S. Percy Oza, Amit M. TI A phase II study of RO4929097 (RO), a gamma-secretase inhibitor, in advanced platinum (Pt)-resistant (R) ovarian cancer (OC): A study of the PMH, Chicago, and California phase II consortia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Univ Toronto, Toronto, ON, Canada. Juravinski Canc Ctr, Hamilton, ON, Canada. London Reg Canc Program, London, ON, Canada. Princess Margaret Hosp, Univ Hlth Network, Toronto, ON M4X 1K9, Canada. Canc Ctr Southeastern Ontario, Kingston, ON, Canada. Ottawa Hosp, Ottawa, ON, Canada. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Princess Margaret Hosp, Dept Biostat, Toronto, ON M4X 1K9, Canada. Credit Valley Hosp, Mississauga, ON, Canada. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 5019 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803401 ER PT J AU Ding, Y Black, A Hsing, AW Andriole, GL AF Ding, Yan Black, Amanda Hsing, Ann W. Andriole, Gerald L. TI Polymorphisms in fragile histidine triad gene (FHIT) associated with aggressive prostate cancer and cancer specific mortality. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 City Hope Natl Med Ctr, Duarte, CA USA. NCI, Bethesda, MD 20892 USA. Canc Prevent Inst Calif, Fremont, CA USA. Washington Univ, Sch Med, Barnes Jewish Hosp, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 4646 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802801 ER PT J AU Doroshow, JH Ji, JJ Chen, A Allen, D Zhang, YP Lawrence, SM Pfister, TD Wang, LH Redon, CE Bonner, W Speranza, G Weil, MK Eiseman, J Holleran, JL Kinders, RJ Beumer, JH Parchment, RE Pommier, Y Tomaszewski, JE Kummar, S AF Doroshow, James H. Ji, Jiuping Jay Chen, Alice Allen, Deborah Zhang, Yiping Lawrence, Scott M. Pfister, Thomas D. Wang, Lihua Redon, Christophe E. Bonner, William Speranza, Giovanna Weil, Marcie K. Eiseman, Julie Holleran, Julianne L. Kinders, Robert J. Beumer, Jan Hendrik Parchment, Ralph E. Pommier, Yves Tomaszewski, Joseph E. Kummar, Shivaani TI Proof of mechanism (POM) in the first-in-human trial of two novel indenoisoquinoline, non-camptothecin topoisomerase I (TOP1) inhibitors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. SAIC Frederick, Bethesda, MD USA. NCI, Rockville, MD USA. NCI, Bethesda, MD 20892 USA. SAIC Frederick, Frederick, MD USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Div Canc Treatment & Diag, Bethesda, MD USA. NCI, Dev Therapeut Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3031 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802187 ER PT J AU Duchnowska, R Jassem, J Goswami, CP Gokmen-Polar, Y Li, L Thorat, MA Flores, N Hua, E Woditschka, S Palmieri, D Steinberg, SM Biernat, W Sosinska-Mielcarek, K Szostakiewicz, B Czartoryska-Arlukowicz, B Radecka, B Tomasevic, Z Sledge, GW Steeg, PS Badve, SS AF Duchnowska, Renata Jassem, Jacek Goswami, Chirayu Pankaj Gokmen-Polar, Yesim Li, Lang Thorat, Mangesh A. Flores, Natasha Hua, Emily Woditschka, Stephan Palmieri, Diane Steinberg, Seth M. Biernat, Wojciech Sosinska-Mielcarek, Katarzyna Szostakiewicz, Barbara Czartoryska-Arlukowicz, Bogumila Radecka, Barbara Tomasevic, Zorica Sledge, George W. Steeg, Patricia Schriver Badve, Sunil S. CA Polish Brain Metastasis Consortium TI 13-gene signature to predict rapid development of brain metastases in patients with HER2-positive advanced breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Mil Inst Med, Warsaw, Poland. Med Univ Gdansk, Gdansk, Poland. Indiana Univ Sch Med, Indianapolis, IN USA. Wolfson Inst Prevent Med, London, England. NCI, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. Bialystok Oncol Ctr, Bialystok, Poland. Opole Oncol Ctr, Opole, Poland. Inst Oncol & Radiol, Belgrade, Serbia. Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. RI Palmieri, Diane/B-4258-2015 NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 505 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800359 ER PT J AU Dueck, AC Mendoza, TR Mitchell, SA Reeve, BB Castro, KM Denicoff, A O'Mara, AM Rogak, LJ Clauser, SB Bryant, DM Gillis, TA Bearden, JD Siegel, RD Harness, JK Paul, DB Cleeland, CS Sloan, JA Schrag, D Minasian, LM Basch, EM AF Dueck, Amylou C. Mendoza, Tito R. Mitchell, Sandra A. Reeve, Bryce B. Castro, Kathleen M. Denicoff, Andrea O'Mara, Ann M. Rogak, Lauren J. Clauser, Steven B. Bryant, Donna M. Gillis, Theresa A. Bearden, James D. Siegel, Robert D. Harness, Jay K. Paul, Diane B. Cleeland, Charles S. Sloan, Jeff A. Schrag, Deborah Minasian, Lori M. Basch, Ethan M. TI Validity and reliability of the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Mayo Clin, Scottsdale, AZ USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. NCI, Rockville, MD USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Canc Program Our Lady Lake & Mary Bird Perkins, Baton Rouge, LA USA. Christiana Care Hlth Syst, Helen F Graham Canc Ctr, Newark, DE USA. Gibbs Canc Ctr, Spartanburg, SC USA. Hartford Hosp, Helen & Harry Gray Canc Ctr, Hartford, CT 06115 USA. St Joseph Hosp Orange, Ctr Canc Prevent & Treatment, Orange, CA USA. Mayo Clin, Rochester, MN USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9047 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804389 ER PT J AU Duffy, AG Zhao, F Fioraventi, S Greten, T AF Duffy, Austin G. Zhao, Fei Fioraventi, Suzanne Greten, Tim TI Comparative analysis of myeloid-derived suppressor cell (MDSC) subsets in patients with gastrointestinal (GI) malignancies. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Gastrointestinal Malignancies Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 10566 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800133 ER PT J AU Dunleavy, K Neelapu, SS Kwak, LW Grant, C Santos, CF Popa, MA White, T Miller, B Jaffe, ES Steinberg, SM Wilson, WH AF Dunleavy, Kieron Neelapu, Sattva Swarup Kwak, Larry W. Grant, Cliona Santos, Carlos F. Popa, Mihaela A. White, Therese Miller, Barry Jaffe, Elaine S. Steinberg, Seth M. Wilson, Wyndham Hopkins TI Association of idiotype vaccine-induced T-cell response with improved survival and time-to-next treatment (TTNT) in untreated mantle cell lymphoma (MCL). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. Biovest Int Inc, Tampa, FL USA. Ctr Canc Res, Bethesda, MD USA. NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, CCR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2528 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801677 ER PT J AU Fabian, CJ Kimler, BF Zalles, CM Petroff, BK Metheny, T Phillips, TA Echalier, BR Bailey, HH Cornelison, TL AF Fabian, Carol J. Kimler, Bruce F. Zalles, Carola M. Petroff, Brian K. Metheny, Trina Phillips, Teresa A. Echalier, Ben R. Bailey, Howard Harry Cornelison, Terri L. TI Reduction in Ki-67 in benign breast tissue of high-risk premenopausal women with the SERM acolbifene SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. Mercy Hosp, Miami, FL USA. Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 520 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800445 ER PT J AU Falk, R Maas, P Schairer, C Buys, SS Chatterjee, N Lee, T Ziegler, RG Isaacs, C AF Falk, Roni Maas, Paige Schairer, Catherine Buys, Saundra S. Chatterjee, Nilanjan Lee, Theresa Ziegler, Regina G. Isaacs, Claudine TI Alcohol and breast cancer risk in postmenopausal women: The PLCO experience SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. Lombardi Comprehens Canc Ctr, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 1521 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801257 ER PT J AU Farrell, BT Hamilton, BE Dosa, E Rimely, E Nasseri, M Gahramanov, S Lacy, C Frenkel, EP Doolittle, ND Jacobs, PM Neuwelt, EA AF Farrell, Brian T. Hamilton, Bronwyn E. Dosa, Edit Rimely, Endre Nasseri, Morad Gahramanov, Seymur Lacy, Cindy Frenkel, Eugene P. Doolittle, Nancy Diane Jacobs, Paula M. Neuwelt, Edward A. TI Utility of iron oxide nanoparticles in the radiographic diagnosis of CNS lymphoma and inflammatory diseases. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2077 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801450 ER PT J AU Fehrenbacher, L Jeong, JH Rastogi, P Geyer, CE Paik, S Ganz, PA Land, SR Costantino, JP Swain, SM Mamounas, EP Wolmark, N AF Fehrenbacher, Louis Jeong, Jong-Hyeon Rastogi, Priya Geyer, Charles E. Paik, Soonmyung Ganz, Patricia A. Land, Stephanie R. Costantino, Joseph P. Swain, Sandra M. Mamounas, Eleftherios P. Wolmark, Norman TI NSABP B-47: A phase III trial of adjuvant therapy comparing chemotherapy alone (six cycles of docetaxel plus cyclophosphamide or four cycles of doxorubicin plus cyclophosphamide followed by weekly paclitaxel) to chemotherapy plus trastuzumab in women with node-positive or high-risk, node-negative, HER2-low invasive breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Natl Surg Adjuvant Breast & Bowel Project, Vallejo, CA USA. Kaiser Permanente Northern Calif, Vallejo, CA USA. NSABP, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Magee Womens Canc Program, Pittsburgh, PA USA. Statewide Clin Trials Network Texas, Addison, TX USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. Washington Hosp Ctr, Washington, DC 20010 USA. Aultman Hosp, Canton, OH USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS1142 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800814 ER PT J AU Figg, WD Spencer, SD Pisle, ST Pressler, HM Troutman, SM Eisner, JR Rafferty, SW Schotzinger, RJ Moore, WR AF Figg, William Douglas Spencer, Shawn D. Pisle, Stephen T. Pressler, Heather M. Troutman, Sarah M. Eisner, Joel Robert Rafferty, Stephen W. Schotzinger, Robert J. Moore, William R. TI Activity of oral VT-464, a selective CYP17-lyase inhibitor, in the LNCaP prostate cancer xenograft SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. Natl Canc Inst Frederick, SAIC Frederick, Bethesda, MD USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. Viamet Pharmaceut Inc, Morrisville, NC USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 4671 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802622 ER PT J AU Fisch, M Zhao, FM O'Mara, AM Wang, XS Cella, D Cleeland, CS AF Fisch, Michael Zhao, Fengmin O'Mara, Ann M. Wang, Xin Shelley Cella, David Cleeland, Charles S. CA Eastern Cooperative Oncology Grp TI Determinants of fatigue improvement in outpatient oncology according to baseline categories of fatigue severity SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9112 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804287 ER PT J AU Fisch, M Zhao, FM O'Mara, AM Wang, XS Cella, D Cleeland, CS AF Fisch, Michael Zhao, Fengmin O'Mara, Ann M. Wang, Xin Shelley Cella, David Cleeland, Charles S. CA Eastern Cooperative Oncology Grp TI Determinants of fatigue improvement in outpatient oncology according to baseline categories of fatigue severity. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9112 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804085 ER PT J AU Fleming, GF Suman, V Goetz, MP Haluska, P Moynihan, TJ Nanda, R Olopade, OI Pluard, TJ Erlichman, C Chen, HX Guo, ZF Ellis, MJ Ma, CX AF Fleming, Gini F. Suman, VeraJean Goetz, Matthew P. Haluska, Paul Moynihan, Timothy Jerome Nanda, Rita Olopade, Olufunmilayo I. Pluard, Timothy J. Erlichman, Charles Chen, Helen X. Guo, Zhanfang Ellis, Matthew James Ma, Cynthia X. TI A phase I trial of the IGF-1R antibody IMC-A12 in combination with temsirolimus in patients with metastatic breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Mayo Clin, Rochester, MN USA. Univ Chicago, Chicago, IL 60637 USA. Washington Univ, Sch Med, St Louis, MO USA. NCI, CTEP, Bethesda, MD 20892 USA. Washington Univ, Med Ctr, Dept Internal Med, Div Oncol, St Louis, MO USA. Washington Univ, Med Ctr, Siteman Canc Ctr, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 534 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800446 ER PT J AU Fouladi, M Perentesis, JP Wagner, LM Ingle, AM Thomas, G Krueger, DA Houghton, P Vinks, AA Doyle, LA Weigel, B Blaney, S AF Fouladi, Maryam Perentesis, John Peter Wagner, Lars M. Ingle, Ashish M. Thomas, George Krueger, Darcy A. Houghton, Peter Vinks, A. A. Doyle, L. Austin Weigel, Brenda Blaney, Susan TI A phase I trial of IMC A12 and temsirolimus in children with refractory solid tumors: A Children's Oncology Group study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. Childrens Oncol Grp, Arcadia, CA USA. Metabol Dis Inst, Cincinnati, OH USA. Cincinnati Childrens Hosp Med Ctr, Dept Pediat & Neurol, Cincinnati, OH USA. Nationwide Childrens Hosp, Columbus, OH USA. NCI, Rockville, MD USA. Univ Minnesota, Minneapolis, MN USA. Texas Childrens Canc Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9541 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800307 ER PT J AU Fung, C Fossa, SD Milano, MT Yu, M Worman, M Travis, LB AF Fung, Chunkit Fossa, Sophie D. Milano, Michael T. Yu, Mandi Worman, Melissa Travis, Lois B. TI Second malignant neoplasms (SMN) among 18,627 testicular cancer survivors (TCS) after chemotherapy (CHEM) or surgery (SURG). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Rochester, Sch Med & Dent, James P Wilmot Canc Ctr, Rochester, NY USA. Norwegian Radium Hosp, Oslo Univ Hosp, Oslo, Norway. Univ Rochester, Sch Med & Dent, Dept Radiat Oncol, Rochester, NY USA. NCI, NIH, Rockville, MD USA. Univ Rochester, Med Ctr, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 1536 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801099 ER PT J AU Gammoh, E Rahma, OE Simon, R Khleif, S AF Gammoh, Emily Rahma, Osama E. Simon, Richard Khleif, Samir TI An alternative clinical trial design for early cancer vaccine development to phase 3+3 design. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2578 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801629 ER PT J AU Ganz, PA Lopa, SH Yothers, G Ko, CY Arora, A Atkins, JN Bahary, N Soori, GS Robertson, JM Eakle, JF Marchello, BT Wozniak, TF Wolmark, N AF Ganz, Patricia A. Lopa, Samia H. Yothers, Greg Ko, Clifford Y. Arora, Amit Atkins, James Norman Bahary, Nathan Soori, Gamini S. Robertson, John M. Eakle, Janice F. Marchello, Benjamin T. Wozniak, Timothy F. Wolmark, Norman CA NSABP TI Comparative effectiveness of sphincter-sparing surgery (SSS) versus abdomino-perineal resection (APR) in rectal cancer: Patient-reported outcomes (PROs) from NSABP R-04 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. Univ Pittsburgh, Grad Sch Publ Hlth, NSABP, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, NSABP Biostat Ctr, Pittsburgh, PA USA. NSABP Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. Kaiser Permanente Med Ctr, Hayward, CA USA. Natl Surg Adjuvant Breast & Bowel Project, Goldboro, NC USA. SCCC CCOP, Goldboro, NC USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Missouri Valley Canc Consortium CCOP, Omaha, NE USA. William Beaumont Hosp, Royal Oak, MI 48072 USA. Florida Canc Specialists, Ft Myers, FL USA. Hematol Oncol Ctr Northern Rockies, Billings, MT USA. Helen F Graham Canc Ctr, Newark, DE USA. Allegheny Gen Hosp, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3545 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804814 ER PT J AU Gerstner, ER Emblem, KE Chi, AS Eichler, AF Hochberg, F Drappatz, J Quant, EC Norden, AD Pinho, MC Polaskova, P Jennings, D Ancukiewicz, M Ivy, SP Wen, PY Jain, RK Sorensen, AG Batchelor, T AF Gerstner, Elizabeth Robins Emblem, Kyrre E. Chi, Andrew S. Eichler, April F. Hochberg, Fred Drappatz, Jan Quant, Eudocia Carmen Norden, Andrew David Pinho, Marco C. Polaskova, Pavlina Jennings, Dominique Ancukiewicz, Marek Ivy, S. Percy Wen, Patrick Y. Jain, Rakesh K. Sorensen, A. Gregory Batchelor, Tracy TI Effects of cediranib, a VEGF signaling inhibitor, in combination with chemoradiation on tumor blood flow and survival in newly diagnosed glioblastoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. AA Martinos Ctr Biomed Imaging, Boston, MA USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Univ Pittsburgh, Pittsburgh, PA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. Massachusetts Gen Hop, Martinos Ctr Biomed Imaging, Boston, MA USA. NCI, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2009 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801527 ER PT J AU Gerstner, ER Emblem, KE Chi, AS Eichler, AF Hochberg, F Drappatz, J Quant, EC Norden, AD Pinho, MC Polaskova, P Jennings, D Ancukiewicz, M Ivy, SP Wen, PY Jain, RK Sorensen, AG Batchelor, T AF Gerstner, Elizabeth Robins Emblem, Kyrre E. Chi, Andrew S. Eichler, April F. Hochberg, Fred Drappatz, Jan Quant, Eudocia Carmen Norden, Andrew David Pinho, Marco C. Polaskova, Pavlina Jennings, Dominique Ancukiewicz, Marek Ivy, S. Percy Wen, Patrick Y. Jain, Rakesh K. Sorensen, A. Gregory Batchelor, Tracy TI Effects of cediranib, a VEGF signaling inhibitor, in combination with chemoradiation on tumor blood flow and survival in newly diagnosed glioblastoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. AA Martinos Ctr Biomed Imaging, Boston, MA USA. Massachusetts Gen Hosp Canc Ctr, Boston, MA USA. Univ Pittsburgh, Pittsburgh, PA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. NCI, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2009 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801525 ER PT J AU Go, RS Zaren, H Nair, SG Lanier, KS Thompson, MA Enos, RA Zhao, JX Fleming, DL Leighton, JC Gribbin, TE Bryant, DM Carrigan, A Corpening, JC Csapo, KA Dimond, EP Ellison, C Gonzalez, MM Harr, JL Wilkinson, K Denicoff, A AF Go, Ronald S. Zaren, Howard Nair, Suresh G. Lanier, Keith S. Thompson, Michael A. Enos, Rebecca A. Zhao, Jinxiu Fleming, Deborah L. Leighton, John Charles Gribbin, Thomas Edward Bryant, Donna M. Carrigan, Angela Corpening, Jennifer C. Csapo, Kimberly A. Dimond, Eileen P. Ellison, Christie Gonzalez, Maria Magdalena Harr, Jodi L. Wilkinson, Kathy Denicoff, Andrea CA NCCCP Early-Phase Working Grp TI Early-phase (EP) clinical trials (CTs) in the community: Results from the National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) Early-Phase Working Group (EPWG) Baseline Assessment Study (BAS). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Gundersen Lutheran Hlth Syst, La Crosse, WI USA. St Josephs Candler Hlth Syst Inc, Savannah, GA USA. Lehigh Valley Hosp, Allentown, PA USA. Providence Canc Ctr, Oncol & Hematol Care Clin, Portland, OR USA. ProHlth Reg Canc Ctr, Waukesha, WI USA. EMMES Corp, Rockville, MD USA. St Josephs Candler Hosp, Savannah, GA USA. Albert Einstein Canc Ctr, Philadelphia, PA USA. St Marys Hlth Care, Lacks Canc Ctr, Grand Rapids, MI USA. Our Lady Lake & Mary Bird Perkins, Canc Program, Baton Rouge, LA USA. SAIC Frederick Inc, Frederick, MD USA. Spartanburg Reg Healthcare Syst, Spartanburg, SC USA. St Joseph Med Ctr, Inst Canc, Towson, MD USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. Sanford Canc Ctr, Sioux Falls, SD USA. St Joseph Hosp, Orange, CA USA. Penrose Canc Ctr, Penrose St Francis Hlth Serv, Colorado Springs, CO USA. Billings Clin, Billings, MT USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e16561 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804142 ER PT J AU Goncalves, PH Ruch, JM Byer, J Shields, AF Choi, M Kim, RD Zalupski, MM Philip, PA AF Goncalves, Priscila Hermont Ruch, Joshua Michael Byer, Jennifer Shields, Anthony Frank Choi, Minsig Kim, Richard D. Zalupski, Mark M. Philip, Philip Agop TI Multi-institutional experience using 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in patients with pancreatic cancer (PCA). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Karmanos Canc Inst, Detroit, MI USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ S Florida, Tampa, FL USA. Wayne State Univ, Karmanos Canc Inst, Natl Surg Adjuvant Breast & Bowel Project, Detroit, MI USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e14519 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801222 ER PT J AU Goodman, OB Chi, KN Molina, A Logothetis, C Jones, RJ Staffurth, J North, SA Vogelzang, NJ Saad, F Mainwaring, PN Harland, SJ Li, JH San Kheoh, T Haqq, CM Scher, HI Fizazi, K AF Goodman, Oscar B. Chi, Kim N. Molina, Arturo Logothetis, Christopher Jones, Robert J. Staffurth, John North, Scott A. Vogelzang, Nicholas J. Saad, Fred Mainwaring, Paul N. Harland, Stephen John Li, Jinhui San Kheoh, Thian Haqq, Christopher M. Scher, Howard I. Fizazi, Karim TI Exploratory analysis of survival benefit and prior docetaxel (D) treatment in COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Las Vegas, NV USA. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Janssen Res & Dev, Los Angeles, CA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Inst Canc Sci, Glasgow, Lanark, Scotland. Cardiff Univ, Velindre Hosp, Cardiff CF10 3AX, S Glam, Wales. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Comprehens Canc Ctr Nevada, Las Vegas, NV USA. US Oncol Res, Las Vegas, NV USA. Univ Montreal, Montreal, PQ, Canada. Haematol Clin Australasia, Brisbane, Qld, Australia. Oncol Clin Australasia, Brisbane, Qld, Australia. UCL Canc Inst, London, England. Janssen Res & Dev, Raritan, NJ USA. Genom Syst, San Francisco, CA USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Inst Gustave Roussy, Villejuif, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 4558 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802774 ER PT J AU Gounder, MM Dickson, MA Wu, N Ivy, SP Carvajal, RD D'Angelo, SP Keohan, ML Qin, LX Erinjeri, JP Takebe, N Tanner, L Morales, R Condy, MM Ustoyev, Y Maki, RG Tap, WD Schwartz, GK AF Gounder, Mrinal M. Dickson, Mark Andrew Wu, Nian Ivy, S. Percy Carvajal, Richard D. D'Angelo, Sandra P. Keohan, Mary Louise Qin, Li-Xuan Erinjeri, Joseph Patrick Takebe, Naoko Tanner, Lanier Morales, Rita Condy, Mercedes M. Ustoyev, Yelena Maki, Robert G. Tap, William D. Schwartz, Gary K. TI A first-in-human, phase Ib combination study to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a hedgehog inhibitor, GDC-0449, with a Notch inhibitor, RO4929097, in patients with advanced sarcoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Bethesda, MD 20892 USA. Canc Therapy Evaluat Program, Invest Drug Branch, Rockville, MD USA. NR 0 TC 3 Z9 3 U1 2 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 10004 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800594 ER PT J AU Grant, C Dunleavy, K Janik, JE Shovlin, M Steinberg, SM D'Amore, F Stetler-Stevenson, M Pittaluga, S Jaffe, ES Wilson, WH AF Grant, Cliona Dunleavy, Kieron Janik, John E. Shovlin, Margaret Steinberg, Seth M. D'Amore, Francesco Stetler-Stevenson, Maryalice Pittaluga, Stefania Jaffe, Elaine S. Wilson, Wyndham Hopkins TI Efficacy of alemtuzumab (ALZ) in combination with dose-adjusted EPOCH (DA-EPOCH) in untreated nodal peripheral T-cell lymphoma (PTCL). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, CCR, NIH, Bethesda, MD 20892 USA. Ctr Canc Res, Bethesda, MD USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 8051 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803817 ER PT J AU Halpern, MT Spain, P Holden, DJ Stewart, A McNamara, EJ Gay, EG Clauser, SB Das, IP AF Halpern, Michael T. Spain, Pamela Holden, Debra J. Stewart, Andrew McNamara, Erica J. Gay, E. Greer Clauser, Steven B. Das, Irene Prabhu TI Association of increases in quality of care with the NCI Community Cancer Center Program (NCCCP) pilot SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 RTI Int, Washington, DC USA. RTI Int, Res Triangle Pk, NC USA. Amer Coll Surg, Commiss Canc, Chicago, IL USA. Natl Canc Data Base, Commiss Canc, Chicago, IL USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 6046 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803457 ER PT J AU Hasegawa, Y Ando, M Kubo, A Isa, S Yamamoto, S Tsujino, K Kurata, T Ou, SHI Takada, M Koshiol, J Kawaguchi, T AF Hasegawa, Yoshikazu Ando, Masahiko Kubo, Akihito Isa, Shunichi Yamamoto, Satomi Tsujino, Kazuyuki Kurata, Takayasu Ou, Sai-Hong Ignatius Takada, Minoru Koshiol, Jill Kawaguchi, Tomoya TI Human papillomavirus in non-small cell lung cancer in never smokers in east Asia: A systematic review of the literature SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Kishiwada City Hosp, Osaka, Japan. Nagoya Univ Hosp, Nagoya, Aichi, Japan. Aichi Med Univ, Sch Med, Nagakute, Aichi, Japan. Natl Hosp Org, Kinki Chuo Chest Med Ctr, Osaka, Japan. Natl Hosp Org, Kinki Chuo Chest Med Ctr, Sakai, Osaka, Japan. Osaka Univ, Grad Sch Med, Osaka, Japan. Osaka Univ, Sch Med, Osaka, Japan. Chao Family Comprehens Canc Ctr, Orange, CA USA. Kinki Univ, Sch Med, Sakai Hosp, Dept Med Oncol, Osaka 589, Japan. NCI, Bethesda, MD 20892 USA. RI ANDO, Masahiko/F-7035-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e18128 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804372 ER PT J AU Hassan, R Jahan, TM Kindler, HL Bazhenova, L Reck, M Pastan, I Ellis, A Fatato, PM Heyburn, J Schweizer, C Parno, J Wallin, B AF Hassan, Raffit Jahan, Thierry Marie Kindler, Hedy Lee Bazhenova, Lyudmila Reck, Martin Pastan, Ira Ellis, Alison Fatato, Penny Marie Heyburn, John Schweizer, Charles Parno, Jeff Wallin, Bruce TI Amatuximab, a chimeric monoclonal antibody to mesothelin, in combination with pemetrexed and cisplatin in patients with unresectable pleural mesothelioma: Results of a multicenter phase II clinical trial. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. Hosp Grosshansdorf, Grosshansdorf, Germany. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Morphotek, Exton, PA USA. United BioSource Corp, Blue Bell, PA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 7030 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802460 ER PT J AU Heery, CR Madan, RA Bilusic, M Kim, JW Singh, NK Rauckhorst, M Chen, C Dahut, WL Stadler, WM DiPaola, RS Stein, MN Hodge, JW Schlom, J Gulley, JL AF Heery, Christopher Ryan Madan, Ravi A. Bilusic, Marijo Kim, Joseph W. Singh, Nishith K. Rauckhorst, Myrna Chen, Clara Dahut, William L. Stadler, Walter Michael DiPaola, Robert S. Stein, Mark N. Hodge, James W. Schlom, Jeffrey Gulley, James L. TI Interim analysis of a phase II randomized clinical trial of samrium-153 (Sm-153) with or without PSA-TRICOM vaccine in metastatic castration-resistant prostate cancer after docetaxel. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. Univ Chicago, Chicago, IL 60637 USA. Canc Inst New Jersey, New Brunswick, NJ USA. Ctr Canc Res, Tumor Immunol & Biol Lab, Bethesda, MD USA. RI Hodge, James/D-5518-2015; Gulley, James/K-4139-2016 OI Hodge, James/0000-0001-5282-3154; Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2526 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802130 ER PT J AU Hershman, DL Unger, JM Crew, KD Moinpour, C Minasian, LM Hansen, L Lew, D Okane, P Wade, JL Wong, SF Hortobagyi, GN Meyskens, FL Albain, KS AF Hershman, Dawn L. Unger, Joseph M. Crew, Katherine D. Moinpour, Carol Minasian, Lori M. Hansen, Lisa Lew, Danika Okane, Patricia Wade, James Lloyd Wong, Siu-Fun Hortobagyi, Gabriel N. Meyskens, Frank L. Albain, Kathy S. TI SWOG S0715: Randomized placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy during adjuvant breast cancer therapy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Columbia Univ, Med Ctr, New York, NY USA. SWOG Stat Ctr, Seattle, WA USA. Columbia Univ, New York, NY USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NCI, Bethesda, MD 20892 USA. Legacy Good Samaritan Hosp, Portland, OR USA. SW Oncol Grp, Ctr Stat, Seattle, WA USA. SWOG Operat Off, San Antonio, TX USA. Canc Care Specialists Cent Illinois, Decatur, IL USA. Loma Linda Univ, Sch Pharm, Loma Linda, CA 92350 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Chao Family Comprehens Canc Ctr, Orange, CA USA. Loyola Univ, Med Ctr, Maywood, IL 60153 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9018 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800069 ER PT J AU Huggins-Puhalla, SL Beumer, JH Appleman, LJ Tawbi, HAH Stoller, RG Lin, Y Kiesel, B Tan, AR Gibbon, D Jiang, YX Garcia, A Chew, HK Morgan, R Shepherd, SP Giranda, VL Chen, AP Belani, CP Chu, E AF Huggins-Puhalla, Shannon Leigh Beumer, Jan Hendrik Appleman, Leonard Joseph Tawbi, Hussein Abdul-Hassan Stoller, Ronald G. Lin, Yan Kiesel, Brian Tan, Antoinette R. Gibbon, Darlene Jiang, Yixing Garcia, Agustin Chew, Helen K. Morgan, Robert Shepherd, Stacie Peacock Giranda, Vincent L. Chen, Alice P. Belani, Chandra Prakash Chu, Edward TI A phase I study of chronically dosed, single-agent veliparib (ABT-888) in patients (pts) with either BRCA 1/2-mutated cancer (BRCA plus ), platinum-refractory ovarian cancer, or basal-like breast cancer (BRCA-wt). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Pittsburgh, Magee Womens Hosp, Inst Canc, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Univ Pittsburgh, Ctr Canc, Pittsburgh, PA USA. Canc Inst New Jersey, New Brunswick, NJ USA. Penn State Hershey Canc Inst, Hershey, PA USA. USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. City Hope Natl Med Ctr, Duarte, CA USA. Abbott Labs, Abbott Pk, IL 60064 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3054 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802192 ER PT J AU Jain, N Curran, E Iyengar, NM Diaz-Flores, E Kunnavakkam, R Popplewell, L Kirschbaum, MH Erba, HP Green, M Poire, X Koval, G Shannon, K Atallah, EL Dy, P Smith, SE Doyle, LA Larson, RA Stock, W Odenike, O AF Jain, Nitin Curran, Emily Iyengar, Neil M. Diaz-Flores, Ernesto Kunnavakkam, Rangesh Popplewell, Leslie Kirschbaum, Mark H. Erba, Harry Paul Green, Margaret Poire, Xavier Koval, Greg Shannon, Kevin Atallah, Ehab L. Dy, Philip Smith, Scott E. Doyle, L. Austin Larson, Richard A. Stock, Wendy Odenike, Olatoyosi CA Univ Chicago Phase II Consortium TI Phase II study of the oral MEK inhibitor selumetinib (AZD6244) in advanced acute myeloid leukemia (AML). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. City Hope Natl Med Ctr, Duarte, CA USA. Univ Michigan, Med Ctr, Ann Arbor, MI USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Decatur Mem Hosp, Decatur, IL USA. Loyola Univ, Med Ctr, Maywood, IL 60153 USA. NCI, Rockville, MD USA. Univ Chicago, Chicago, IL 60637 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 6582 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803034 ER PT J AU Janjigian, YY Tang, LH Shibata, S Kelsen, DP Segal, M Cheng, C Schwartz, GK Doyle, LA Shah, MA AF Janjigian, Yelena Yuriy Tang, Laura H. Shibata, Stephen Kelsen, David Paul Segal, Michal Cheng, Catherine Schwartz, Gary K. Doyle, L. Austin Shah, Manish A. TI A multicenter random assignment phase II study of irinotecan and flavopiridol versus irinotecan alone for patients with p53 wild-type gastric adenocarcinoma (NCI 8060) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. City Hope Natl Med Ctr, Duarte, CA USA. NCI, Rockville, MD USA. New York Presbyterian Hosp, Weill Cornell Med Coll, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e14586 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804900 ER PT J AU Jankowitz, RC Abraham, J Tan, AR Limentani, SA Adamson, LM Buyse, ME Jacobs, SA Wolmark, N AF Jankowitz, Rachel Catherine Abraham, Jame Tan, Antoinette R. Limentani, Steven A. Adamson, Laura M. Buyse, Marc E. Jacobs, Samuel A. Wolmark, Norman TI A phase I dose-escalation study evaluating weekly paclitaxel with neratinib and trastuzumab in women with metastatic HER2-positive breast cancer, NSABP FB-8. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Pittsburgh, Magee Womens Hosp, Med Ctr, Pittsburgh, PA 15213 USA. NSABP, Morgantown, WV USA. W Virginia Univ, Morgantown, WV 26506 USA. NSABP, Pittsburgh, PA USA. Canc Inst New Jersey, Pittsburgh, PA USA. NSABP, Charlotte, NC USA. Levine Canc Inst, Charlotte, NC USA. Int Inst Drug Dev, Louvain, Belgium. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 611 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800259 ER PT J AU Jawed, I Wilkerson, J Duffy, AG Fojo, AT AF Jawed, Irfan Wilkerson, Julia Duffy, Austin G. Fojo, Antonio Tito TI Two decades of therapy in metastatic colorectal cancer (mCRC): An analysis to discern the contribution and progress made by chemotherapy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Canc Care Northwest, Spokane, WA USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e14064 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802631 ER PT J AU Karzai, FH Apolo, AB Adelberg, D Madan, RA Gulley, JL Arlen, PM Parnes, HL Pierpoint, A Kohler, DR Trepel, JB Price, DK Steinberg, SM Figg, WD Dahut, WL AF Karzai, Fatima H. Apolo, Andrea Borghese Adelberg, David Madan, Ravi A. Gulley, James L. Arlen, Philip M. Parnes, Howard L. Pierpoint, Ann Kohler, David R. Trepel, Jane B. Price, Douglas K. Steinberg, Seth M. Figg, William Douglas Dahut, William L. TI A phase I study of TRC105 (Anti-CD105 [endoglin] antibody) in metastatic castration resistant prostate cancer (mCRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, CCR, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3043 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802291 ER PT J AU Keogh, LA Fisher, D Gorin, SS Schully, SD Lowery, J Ahnen, DJ Maskiell, JA Lindor, NM Hopper, JL Burnett, T Holter, S Arnold, J Gallinger, S Laurino, M Esplen, MJ Sinicrope, PS AF Keogh, Louise A. Fisher, Douglass Gorin, Sherri Sheinfeld Schully, Sheri D. Lowery, Jan Ahnen, Dennis J. Maskiell, Judith A. Lindor, Noralane M. Hopper, John L. Burnett, Terrilea Holter, Spring Arnold, Julie Gallinger, Steven Laurino, Mercy Esplen, Mary-Jane Sinicrope, Pamela S. CA Colon Canc Family Registry TI Implications of generating genetic test results for colon cancer in the international, population-based colon cancer family registry SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Melbourne, Melbourne, Vic, Australia. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Columbia Univ, New York, NY USA. NCI, Bethesda, MD 20892 USA. Univ Colorado Denver, Aurora, CO USA. Univ Colorado, Denver, CO 80202 USA. Mayo Clin, Rochester, MN USA. Univ Hawaii, Honolulu, HI 96822 USA. Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. Auckland City Hosp, Auckland, Australia. Univ Toronto, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3567 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804854 ER PT J AU Do, KT Speranza, G Chen, AP Trepel, JB Lee, MJ Lee, S Phillips, L Collins, JM Weil, MK Kinders, RJ Khin, S Allen, D Parthasarathy, R Doroshow, JH Kummar, S AF Khanh Tu Do Speranza, Giovanna Chen, Alice P. Trepel, Jane B. Lee, Min-Jung Lee, Sunmin Phillips, Larry Collins, Jerry M. Weil, Marcie K. Kinders, Robert J. Khin, Sonny Allen, Deborah Parthasarathy, Ramya Doroshow, James H. Kummar, Shivaani TI Phase I study assessing a two-consecutive-day (QD x 2) dosing schedule of the HSP90 inhibitor, AT13387, in patients with advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. SAIC Frederick, Frederick, MD USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Dev Therapeut Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3087 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802516 ER PT J AU Kim, JW Heery, CR Bilusic, M Singh, NK Madan, RA Sabzevari, H Schlom, J Gulley, JL AF Kim, Joseph W. Heery, Christopher Ryan Bilusic, Marijo Singh, Nishith K. Madan, Ravi A. Sabzevari, Helen Schlom, Jeffrey Gulley, James L. TI First-in-human phase I trial of NHS-IL12 in advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Tumor Immunol & Biol Lab, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. EMD Serono, Rockland, MA USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS2617 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801668 ER PT J AU Kim, JW Lindenberg, ML Dahut, WL Gulley, JL Madan, RA Wood, LV McKinney, Y Choyke, PL Kurdziel, KA Apolo, AB AF Kim, Joseph W. Lindenberg, Maria Liza Dahut, William L. Gulley, James L. Madan, Ravi A. Wood, Lauren V. McKinney, Yolanda Choyke, Peter L. Kurdziel, Karen A. Apolo, Andrea Borghese TI A pilot study on the clinical value of F-18-sodium fluoride PET/CT in advanced prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 10589 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800494 ER PT J AU Korde, N Zingone, A Kwok, M Manasanch, EE Bhutani, M Costello, R Yancey, MA Mulquin, M Calvo, KR Maric, I Tembhare, P Yuan, C Stetler-Stevenson, M Arthur, DC Choyke, PL Kurdziel, KA Steinberg, SM Raffeld, M Roschewski, MJ Landgren, O AF Korde, Neha Zingone, Adriana Kwok, Mary Manasanch, Elisabet E. Bhutani, Manisha Costello, Rene Yancey, Mary Ann Mulquin, Marcia Calvo, Katherine R. Maric, Irina Tembhare, Prashant Yuan, Constance Stetler-Stevenson, Maryalice Arthur, Diane Carol Choyke, Peter L. Kurdziel, Karen A. Steinberg, Seth M. Raffeld, Mark Roschewski, Mark J. Landgren, Ola TI Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone (CRd) in newly diagnosed multiple myeloma (MM) patients. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Metab Branch, NIH, Bethesda, MD 20892 USA. Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. NCI, Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Hematol Serv, DLM, CCR, Bethesda, MD 20892 USA. NCI, Pathol Lab, CCR, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, CCR, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, CCR, NIH, Bethesda, MD 20892 USA. NCI, Mol Diagnost Core Lab, CCR, NIH, Bethesda, MD 20892 USA. RI Calvo, Katherine/A-8109-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e18568 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804029 ER PT J AU Kreitman, RJ Arons, E Sapolsky, J Roth, L Zhou, H Stetler-Stevenson, M Wilson, WH Raffeld, M FitzGerald, DJP Ji, F Ibrahim, RA Pastan, I AF Kreitman, Robert J. Arons, Evgeny Sapolsky, Jeffrey Roth, Laura Zhou, Hong Stetler-Stevenson, Maryalice Wilson, Wyndham Hopkins Raffeld, Mark FitzGerald, David J. P. Ji, Fei Ibrahim, Ramy A. Pastan, Ira TI Durability of complete remission by moxetumomab pasudotox (HA22 or CAT-8015) assessed by clone-specific real-time quantitative PCR (RQ-PCR). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. MedImmune, Gaithersburg, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2503 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802013 ER PT J AU Kummar, S Oza, AM Fleming, GF Sullivan, D Gandara, DR Erlichman, C Villalona-Calero, MA Morgan, R Chen, AP Ji, JJ Allen, D Lih, CJ Steinberg, SM Williams, PM Conley, BA Doroshow, JH AF Kummar, Shivaani Oza, Amit M. Fleming, Gini F. Sullivan, Daniel Gandara, David R. Erlichman, Charles Villalona-Calero, Miguel Angel Morgan, Robert Chen, Alice P. Ji, Jiuping Jay Allen, Deborah Lih, Chih-Jian Steinberg, Seth M. Williams, P. Mickey Conley, Barbara A. Doroshow, James H. TI Randomized trial of oral cyclophosphamide (C) with or without veliparib (V), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent BRCA-positive ovarian, or primary peritoneal or high-grade serous ovarian carcinoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Dev Therapeut Clin, Bethesda, MD 20892 USA. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. Mayo Clin, Rochester, MN USA. Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. City Hope Natl Med Ctr, Duarte, CA USA. NCI, Bethesda, MD 20892 USA. SAIC Frederick, Frederick, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 5020 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803674 ER PT J AU Kwok, M Korde, N Manasanch, EE Bhutani, M Maric, I Calvo, KR Zingone, A Costello, R Cherry, BM Yancey, MA Mulquin, M Roschewski, MJ Landgren, O AF Kwok, Mary Korde, Neha Manasanch, Elisabet E. Bhutani, Manisha Maric, Irina Calvo, Katherine R. Zingone, Adriana Costello, Rene Cherry, Benjamin M. Yancey, Mary Ann Mulquin, Marcia Roschewski, Mark J. Landgren, Ola TI Role of immune-related conditions in smoldering myeloma and MGUS. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Hematol Serv, DLM, CCR, Bethesda, MD 20892 USA. NCI, Multiple Myeloma Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. RI Calvo, Katherine/A-8109-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 8104 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804055 ER PT J AU Larsen, E Raetz, EA Winick, NJ Salzer, WL Nachman, JB Devidas, M Hunger, S Carroll, WL AF Larsen, Eric Raetz, Elizabeth A. Winick, Naomi Joan Salzer, Wanda L. Nachman, James B. Devidas, Meenakshi Hunger, Stephen Carroll, William L. TI Outcome in adolescent and young adult (AYA) patients compared with younger patients treated for high-risk B-precursor acute lymphoblastic leukemia (HR-ALL): A report from the Children's Oncology Group study AALL0232 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol C1 Maine Childrens Canc Program, Scarborough, ME USA. NYU, Langone Med Ctr, New York, NY USA. UTSW, Dallas, TX USA. Childrens Med Ctr, Ctr Canc & Blood Disorders, Dallas, TX 75235 USA. NIH, Silver Spring, MD USA. Childrens Oncol Grp, Gainesville, FL USA. Univ Colorado Denver, Sch Med, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA CRA9508 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802293 ER PT J AU Lee, JM Hays, JL Noonan, AM Squires, J Annunziata, CM Wood, BJ Yu, MS Houston, ND Azad, NS Kohn, EC AF Lee, Jung-min Hays, John L. Noonan, Anne M. Squires, Jennifer Annunziata, Christina M. Wood, Bradford J. Yu, Minshu Houston, Nicole D. Azad, Nilofer Saba Kohn, Elise C. TI Feasibility and safety of sequential research-related tumor core biopsies in clinical trials with anti-angiogenic and targeted therapies. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Dept Radiol & Imaging Sci, NIH, Bethesda, MD 20892 USA. RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2545 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802139 ER PT J AU Litiere, S De Vries, E Seymour, L Sargent, DJ Shankar, L Bogaerts, J AF Litiere, Saskia De Vries, Elisabeth Seymour, Lesley Sargent, Daniel J. Shankar, Lalitha Bogaerts, Jan CA RECIST Working Grp TI The components of progression as explanatory variables for overall survival in the RECIST database SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 European Org Res Treatment Canc, Brussels, Belgium. Univ Med Ctr Groningen, Dept Med Oncol, NL-9713 AV Groningen, Netherlands. NCIC Clin Trials Grp, Kingston, ON, Canada. Mayo Clin, Rochester, MN USA. NCI, Canc Imaging Program, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 10602 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802762 ER PT J AU Lopez-Chavez, A Rajan, A Thomas, A Raffeld, M Xi, LQ Meltzer, PS Duffy, RM Pack, S Sandler, A Corless, CL Killian, K Oberholtzer, C Abdullaev, Z Giaccone, G AF Lopez-Chavez, Ariel Rajan, Arun Thomas, Anish Raffeld, Mark Xi, Liqiang Meltzer, Paul S. Duffy, Regan M. Pack, Svetlana Sandler, Alan Corless, Christopher L. Killian, Keith Oberholtzer, Carl Abdullaev, Zied Giaccone, Giuseppe TI Pilot trial of molecular profiling and targeted therapies in advanced thoracic malignancies: Non-small cell lung cancer, small cell lung cancer and thymic malignancies (CUSTOM). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Oregon Hlth & Sci Univ, Portland, OR 97201 USA. NCI, Bethesda, MD 20892 USA. NCI, Mol Diagnost Core Lab, CCR, NIH, Bethesda, MD 20892 USA. Oregon Hlth & Sci Univ, Knight Diagnost Labs, Portland, OR 97201 USA. RI Pack, Svetlana/C-2020-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS7609 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804207 ER PT J AU Luke, JJ Rubinstein, L Smith, GL Ivy, SP Harris, PJ AF Luke, Jason John Rubinstein, Larry Smith, Gary L. Ivy, S. Percy Harris, Pamela Jo TI The role of phase I clinical trials in advanced malignant melanoma: Retrospective analysis of CTEP-sponsored trials 1995-2011. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Div Canc Treatment & Diag, Bethesda, MD USA. NCI, Rockville, MD USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2606 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802153 ER PT J AU Mai, PL Sherman, ME Piedmonte, M Ioffe, OB Ronnett, BM Van Le, L Mutch, DG Cohn, DE Thigpen, JT Tewari, KS Disilvestro, P Kauff, ND Lu, KH Greene, MH AF Mai, Phuong L. Sherman, Mark E. Piedmonte, Marion Ioffe, Olga B. Ronnett, Brigitte M. Van Le, Linda Mutch, David Gardner Cohn, David E. Thigpen, J. Tate Tewari, Krishnansu Sujata Disilvestro, Paul Kauff, Noah D. Lu, Karen H. Greene, Mark H. TI Pathologic findings at risk-reducing salpingo-oophorectomy among women at increased ovarian cancer risk: Results from GOG-199. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Rockville, MD USA. Div Canc Epidemiol & Genet, Rockville, MD USA. New York State Dept Hlth, Roswell Pk Mem Inst, Gynecol Oncol Grp, Buffalo, NY 14263 USA. Univ Maryland, Baltimore, MD 21201 USA. Johns Hopkins Sch Med, Baltimore, MD USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Washington Univ, Sch Med, St Louis, MO USA. Siteman Canc Ctr, St Louis, MO USA. Ohio State Univ, Div Gynecol Oncol, Columbus, OH 43210 USA. Univ Mississippi, Sch Med, Jackson, MS 39216 USA. Univ Calif Irvine, Irvine Med Ctr, Orange, CA 92668 USA. Brown Univ, Women & Infants Hosp, Providence, RI USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 1519 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801098 ER PT J AU Mandrekar, SJ Foster, NR Qi, YW Dy, GK Jatoi, A Molina, JR Jett, JR Stella, PJ Schild, SE Adjei, AA AF Mandrekar, Sumithra J. Foster, Nathan R. Qi, Yingwei Dy, Grace K. Jatoi, Aminah Molina, Julian R. Jett, James R. Stella, Philip J. Schild, Steven E. Adjei, Alex A. CA Alliance North Cent Canc Treatment TI Impact of disease progression (DP) date determination method on post progression survival (PPS) and DP metrics in advanced lung cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Mayo Clin, Rochester, MN USA. NCCTG, Rochester, MN USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. NSABP, Ann Arbor, MI USA. St Joseph Mercy Hlth Syst, Ann Arbor, MI USA. Mayo Clin, Scottsdale, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 7605 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804346 ER PT J AU Marshall, J Hwang, JJ Pishvaian, MJ He, AR Weiner, LM Sandene, EK Gulley, JL Heery, CR Schlom, J Speyer, S Richman, J Ferraro, J Coeshott, C Cohn, A Apelian, D Rodell, TC AF Marshall, John Hwang, Jimmy J. Pishvaian, Michael J. He, Aiwu Ruth Weiner, Louis M. Sandene, Erin K. Gulley, James L. Heery, Christopher Ryan Schlom, Jeffrey Speyer, Sue Richman, Joni Ferraro, John Coeshott, Claire Cohn, Allen Apelian, David Rodell, Timothy C. TI A pilot trial of a combination of therapeutic vaccines (GI-4000 and GI-6207) as adjunctive therapy with first-line therapy with bevacizumab plus either FOLFOX or FOLFIRI in stage IV patients with newly diagnosed Ras-mutant positive or negative metastatic colorectal cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. Ctr Canc Res, Lab Tumor Immunol & Biol, Bethesda, MD USA. GlobeImmune Inc, Louisville, CO USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS3638 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804527 ER PT J AU Marshall, J Hwang, JJ Pishvaian, MJ He, AR Weiner, LM Sandene, EK Gulley, JL Heery, CR Schlom, J Speyer, S Richman, J Ferraro, J Coeshott, C Cohn, A Apelian, D Rodell, TC AF Marshall, John Hwang, Jimmy J. Pishvaian, Michael J. He, Aiwu Ruth Weiner, Louis M. Sandene, Erin K. Gulley, James L. Heery, Christopher Ryan Schlom, Jeffrey Speyer, Sue Richman, Joni Ferraro, John Coeshott, Claire Cohn, Allen Apelian, David Rodell, Timothy C. TI A pilot trial of a combination of therapeutic vaccines (GI-4000 and GI-6207) as adjunctive therapy with first-line therapy with bevacizumab plus either FOLFOX or FOLFIRI in stage IV patients with newly diagnosed Ras-mutant positive or negative metastatic colorectal cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. Ctr Canc Res, Lab Tumor Immunol & Biol, Bethesda, MD USA. GlobeImmune Inc, Louisville, CO USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS3638 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801723 ER PT J AU Massett, H Jaeckle, KA Hopkins, JR Mann, BS Denicoff, A Dilts, DM AF Massett, Holly Jaeckle, Kurt A. Hopkins, Jenny R. Mann, Bhupinder Singh Denicoff, Andrea Dilts, David M. TI Intervention to increase site activations for multicenter trials to improve accrual SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Rockville, MD USA. Mayo Clin, Jacksonville, FL 32224 USA. Westat Corp, Rockville, MD USA. NCI, NIH, Bethesda, MD 20892 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e16569 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801182 ER PT J AU Mehnert, JM Semlani, N Wen, Y Tan, AR Moss, RA Adams, S Stein, MN Ross, M Kane, MP Gibbon, D Wright, JJ Aisner, J Chen, SZ Goydos, JS AF Mehnert, Janice M. Semlani, Neha Wen, Yvonne Tan, Antoinette R. Moss, Rebecca Anne Adams, Shari Stein, Mark N. Ross, Mikel Kane, Michael P. Gibbon, Darlene Wright, John Joseph Aisner, Joseph Chen, Suzie Goydos, James S. TI A phase I trial of riluzole and sorafenib in patients with advanced solid tumors and melanoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Canc Inst New Jersey, New Brunswick, NJ USA. UMDNJ, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. Natl Canc Inst, Rockville, MD USA. Rutgers State Univ, Piscataway, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS3112 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802575 ER PT J AU Merchant, MS Baird, K Wexler, LH Rodriguez-Galindo, C Mackall, C AF Merchant, Melinda S. Baird, Kristin Wexler, Leonard H. Rodriguez-Galindo, Carlos Mackall, Crystal TI Ipilimumab: First results of a phase I trial in pediatric patients with advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9545 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801660 ER PT J AU Mileshkin, LR Narayan, K Moore, KN Rischin, D Trimble, EL Stockler, MR King, M Kolodziej, I Martyn, J Friedlander, M Quinn, M Shrivastava, SK Small, W Thomas, G Craighead, PS Gebski, V AF Mileshkin, Linda R. Narayan, Kailash Moore, Kathleen N. Rischin, Danny Trimble, Edward Lloyd Stockler, Martin R. King, Madeleine Kolodziej, Ilka Martyn, Julie Friedlander, Michael Quinn, Michael Shrivastava, Shyam K. Small, William Thomas, Gillian Craighead, Peter S. Gebski, Val CA Gynecologic Canc Intergrp TI A phase III trial of adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The OUTBACK TRIAL. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. NCI, Bethesda, MD 20892 USA. Univ Sydney, NHMRC Clin Trials Ctr, Sydney, NSW 2006, Australia. Univ Sydney, Sydney, NSW 2006, Australia. Prince Wales Hosp, Sydney, NSW, Australia. Tata Mem Hosp, Mumbai 400012, Maharashtra, India. Northwestern Univ, Chicago, IL 60611 USA. Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. Tom Baker Canc Clin, Calgary, AB, Canada. RI friedlander, michael/G-3490-2013; Stockler, Martin/N-3859-2016 OI friedlander, michael/0000-0002-6488-0604; Stockler, Martin/0000-0003-3793-8724 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS5116 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803669 ER PT J AU Mitchell, SA Lang, K Nichols, C Clauser, SB Federico, V Lalla, D Tripathy, D Hurvitz, SA Castro, KM Reeve, BB Rogak, LJ Denicoff, A Chen, A Piekarz, R Bennett, AV Atkinson, TM O'Mara, AM Minasian, LM Basch, EM AF Mitchell, Sandra A. Lang, Kathy Nichols, Christine Clauser, Steven B. Federico, Victoria Lalla, Deepa Tripathy, Debu Hurvitz, Sara A. Castro, Kathleen M. Reeve, Bryce B. Rogak, Lauren J. Denicoff, Andrea Chen, Alice Piekarz, Richard Bennett, Antonia V. Atkinson, Thomas Michael O'Mara, Ann M. Minasian, Lori M. Basch, Ethan M. TI Validation of the NCI patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in women receiving treatment for metastatic breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Bethesda, MD 20892 USA. Boston Hlth Econ Inc, Waltham, MA USA. NCI, Outcomes Res Branch, Rockville, MD USA. Genentech Inc, San Francisco, CA USA. Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Univ N Carolina, Chapel Hill, NC USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9144 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804324 ER PT J AU Mitchell, SA Lang, K Nichols, C Clauser, SB Federico, V Lalla, D Tripathy, D Hurvitz, SA Castro, KM Reeve, BB Rogak, LJ Denicoff, A Chen, A Piekarz, R Bennett, AV Atkinson, TM O'Mara, AM Minasian, LM Basch, EM AF Mitchell, Sandra A. Lang, Kathy Nichols, Christine Clauser, Steven B. Federico, Victoria Lalla, Deepa Tripathy, Debu Hurvitz, Sara A. Castro, Kathleen M. Reeve, Bryce B. Rogak, Lauren J. Denicoff, Andrea Chen, Alice Piekarz, Richard Bennett, Antonia V. Atkinson, Thomas Michael O'Mara, Ann M. Minasian, Lori M. Basch, Ethan M. TI Validation of the NCI patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in women receiving treatment for metastatic breast cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Bethesda, MD 20892 USA. Boston Hlth Econ Inc, Waltham, MA USA. NCI, Outcomes Res Branch, Rockville, MD USA. Genentech Inc, San Francisco, CA 94080 USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Univ N Carolina, Chapel Hill, NC USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9144 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804127 ER PT J AU Mohrbacher, A Kang, MH Yang, AS Groshen, SG Vergara, L Gutierrez, M Murgo, AJ Kummar, S Quick, D Reynolds, CP Newman, EM Maurer, B AF Mohrbacher, Ann Kang, Min H. Yang, Allen S. Groshen, Susan G. Vergara, Lori Gutierrez, Martin Murgo, Anthony J. Kummar, Shivaani Quick, Donald Reynolds, C. Patrick Newman, Edward M. Maurer, Barry TI Phase I trial of fenretinide (4-HPR) intravenous emulsion in hematologic malignancies: A California Cancer Consortium study (PhI-42). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. USC, Los Angeles, CA USA. NCI, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Dev Therapeut Clin, Bethesda, MD 20892 USA. Covenant Med Ctr, Lubbock, TX USA. City Hope Natl Med Ctr, Duarte, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 8073 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803782 ER PT J AU Mohrbacher, A Kang, MH Yang, AS Groshen, SG Vergara, L Gutierrez, M Murgo, AJ Kummar, S Quick, D Reynolds, CP Newman, EM Maurer, B AF Mohrbacher, Ann Kang, Min H. Yang, Allen S. Groshen, Susan G. Vergara, Lori Gutierrez, Martin Murgo, Anthony J. Kummar, Shivaani Quick, Donald Reynolds, C. Patrick Newman, Edward M. Maurer, Barry TI Phase I trial of fenretinide (4-HPR) intravenous emulsion in hematologic malignancies: A California Cancer Consortium study (PhI-42). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ So Calif Keck Sch Med, Los Angeles, CA USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Texas Tech Univ Hlth Sci Ctr, Lubbock, TX USA. USC, Los Angeles, CA USA. NCI, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Dev Therapeut Clin, Bethesda, MD 20892 USA. Covenant Med Ctr, Lubbock, TX USA. City Hope Natl Med Ctr, Duarte, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 8073 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803768 ER PT J AU Morris, JC Rossi, GR Harold, N Tennant, L Ramsey, WJ Vahanian, NN Link, CJ AF Morris, John Charles Rossi, Gabriela R. Harold, Nancy Tennant, Lucinda Ramsey, William Jay Vahanian, Nicholas N. Link, Charles J. TI Correlation of interferon-g (IFN-gamma) response with survival in a phase II hyperacute (HAL) immunotherapy trial for non-small cell lung cancer (NSCLC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Cincinnati, Cincinnati, OH USA. NewLink Genet, Ames, IA USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2571 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801847 ER PT J AU Naing, A LoRusso, P Fu, SQ Hong, DS Chen, HL Doyle, LA Phan, A Habra, MA Kurzrock, R AF Naing, Aung LoRusso, Patricia Fu, Siqing Hong, David S. Chen, Helen Doyle, L. Austin Phan, Alexandria Habra, Mouhammed Amir Kurzrock, Razelle TI Activity of insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic refractory adrenocortical carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Phase Program 1, Houston, TX 77030 USA. Karmanos Canc Inst, Detroit, MI USA. NCI, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 4639 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802607 ER PT J AU Nekhlyudov, L Aziz, N Lerro, CC Virgo, KS AF Nekhlyudov, Larissa Aziz, Noreen Lerro, Catherine C. Virgo, Katherine S. TI Oncologists' and primary care providers' awareness of late effects of cancer treatment: Implications for survivorship care. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Harvard Univ, Sch Med, Boston, MA USA. Harvard Vanguard Med Associates, Boston, MA USA. NINR, Bethesda, MD 20892 USA. Amer Canc Soc, Atlanta, GA 30329 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 6008 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801814 ER PT J AU Nichols, C Mitchell, SA Lang, K Federico, V Castro, KM Rogak, LJ Lalla, D Clauser, SB Reeve, BB Denicoff, A Chen, AP Piekarz, R Atkinson, TM Mayer, M Brammer, MG Sit, L O'Mara, AM Minasian, LM Basch, EM AF Nichols, Christine Mitchell, Sandra A. Lang, Kathy Federico, Victoria Castro, Kathleen M. Rogak, Lauren J. Lalla, Deepa Clauser, Steven B. Reeve, Bryce B. Denicoff, Andrea Chen, Alice P. Piekarz, Richard Atkinson, Thomas Michael Mayer, Musa Brammer, Melissa G. Sit, Laura O'Mara, Ann M. Minasian, Lori M. Basch, Ethan M. TI Acceptability of the NCI patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in women with metastatic breast cancer (MBC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Boston Hlth Econ Inc, Waltham, MA USA. NCI, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Genentech Inc, San Francisco, CA 94080 USA. Univ N Carolina, Chapel Hill, NC USA. NCI, Rockville, MD USA. AdvancedBC Org, New York, NY USA. Univ Chicago, Chicago, IL 60637 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e19633 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804597 ER PT J AU O'Brien, DM Bright, MA Clauser, SB Fennell, M Harness, JK Hood, DD Johnson, M Katurakes, NC McCaskill-Stevens, W Zapka, J Adjei, BA Castro, KM Dimond, EP St Germain, DC Springfield, S AF O'Brien, Donna M. Bright, Mary Anne Clauser, Steven B. Fennell, Mary Harness, Jay K. Hood, Deborah D. Johnson, Maureen Katurakes, Nora C. McCaskill-Stevens, Worta Zapka, Jane Adjei, Brenda A. Castro, Kathleen M. Dimond, Eileen P. St Germain, Diane C. Springfield, Sanya TI The NCI Community Cancer Centers Program (NCCCP): A model for reducing cancer health care disparities. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI NCCCP Program, Bethesda, MD USA. NCI, Rockville, MD USA. NCI, Outcomes Res Branch, Rockville, MD USA. Brown Univ, Providence, RI 02912 USA. St Joseph Hosp Orange, Ctr Canc Prevent & Treatment, Orange, CA USA. Catholic Hlth Initiat, Denver, CO USA. Project Officer NCCCP, NCI Off Director, Bethesda, MD USA. Christiana Care, Newark, DE USA. Community Oncol & Prevent Trials Res Grp, Rockville, MD USA. Med Univ S Carolina, Charleston, SC 29425 USA. NCI, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, Ctr Reduce Canc Hlth Dispar, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 6086 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800221 ER PT J AU O'Connell, M Lee, M Lopatin, M Yothers, G Clark-Langone, K Millward, C Paik, S Sharif, S Shak, S Wolmark, N AF O'Connell, Michael Lee, Mark Lopatin, Margarita Yothers, Greg Clark-Langone, Kim Millward, Carl Paik, Soonmyung Sharif, Saima Shak, Steven Wolmark, Norman TI Validation of the 12-gene colon cancer recurrence score (RS) in NSABP C07 as a predictor of recurrence in stage II and III colon cancer patients treated with 5FU/LV (FU) and 5FU/LV+oxaliplatin (FU plus Ox) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Genom Hlth, Redwood City, CA USA. NSABP Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3512 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804549 ER PT J AU O'Connell, M Lee, M Lopatin, M Yothers, G Clark-Langone, K Millward, C Paik, S Sharif, S Shak, S Wolmark, N AF O'Connell, Michael Lee, Mark Lopatin, Margarita Yothers, Greg Clark-Langone, Kim Millward, Carl Paik, Soonmyung Sharif, Saima Shak, Steven Wolmark, Norman TI Validation of the 12-gene colon cancer recurrence score (RS) in NSABP C07 as a predictor of recurrence in stage II and III colon cancer patients treated with 5FU/LV (FU) and 5FU/LV+oxaliplatin (FU plus Ox). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Genom Hlth, Redwood City, CA USA. NSABP Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3512 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801850 ER EF